GB2434098A

GB2434098A - Process for the preparation of an inhalable dry powder formulation

Info

Publication number: GB2434098A
Application number: GB0526446A
Authority: GB
Inventors: Marcus Eber; Thomas Kieckbusch; Sebastian Kaerger
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 2005-12-23
Filing date: 2005-12-23
Publication date: 2007-07-18
Also published as: GB0526446D0

Abstract

A process for preparing dry powder formulations for inhalation. The process comprises mixing one or more active pharmaceutical ingredients with one or more ternary agents and then admixing carrier particles.

Description

Case PRI4-34779P1/HO 161 2434098

ORGANIC COMPOUNDS

This invention relates to organic compounds and their use as pharmaceuticals, in particular a process for preparing inhalable dry powder formulations containing one or more active pharmaceutical ingredients.

Dry powder formulations for inhalation in the treatment of respiratory diseases are generally formulated by mixing a micronised active pharmaceutical ingredient with coarse carrier particles to give to an ordered mixture. The carrier particles, which are most commonly lactose, make the micronised active pharmaceutical ingredient less cohesive and improve its flowability. This makes the powder easier to handle during the manufacturing process. The micronised active particles tend to adhere to the surface of the carrier particles whilst stored in a dry powder inhaler device but are dispersed from the surfaces of the carrier particles on inhalation into the respiratory tract to give a fine suspension. The larger carrier particles are mostly deposited in the oropharyngeal cavity.

In recent years ternary agents such as magnesium stearate are often included in dry powder formulations for inhalation. For example, Unites States patent US 6645466 discloses the use of magnesium stearate in dry powder formulations for inhalation to improve moisture resistance and storage stability, and United States patent US 6,528,096 discloses the use of a lubricant such as magnesium stearate in dry powder formulations for inhalation to provide ordered stable mixtures without segregation of the active particles during handling and before use. Such dry powder formulations for inhalation are commonly prepared by mixing carrier particles and magnesium stearate to give a preliminary mixture or blend of magnesium stearate coated carrier particles, then admixing active particles to give the desired formulation.

It has now been found, surprisingly, that it is advantageous to mix active particles with a ternary agent such as magnesium stearate to give a preliminary mixture or blend, then admix carrier particles to give the desired formulation.

Accordingly in broad terms the present invention provides a process for preparing dry powder formulations for inhalation that comprises mixing one or more active pharmaceutical ingredients with one or more ternary agents, then admixing carrier particles.

Case PRJ4-34779P1/HO 161 The or each active pharmaceutical ingredient may be an active pharmaceutical ingredient or drug substance that is suitable for administration by inhalation, for example for the treatment of a respiratory disease. Suitable active pharmaceutical ingredients include anti-inflammatory, bronchodilatory, antihistamine, decongestant or anti-tussive drug substances. Preferred active pharmaceutical ingredients include beta-2 adrenoceptor agonists, antimuscarinic agents, steroids and PDE4 inhibitors. Suitable beta-2 adrenoceptor agonists include albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol, indacaterol, procaterol, formoterol, carmoterol, TA-2005, GSK 159797 and pharmaceutically acceptable salts thereof.

Suitable antimuscarinic agents include ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi). Suitable steroids include budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide and mometasone furoate. Suitable PDE4 inhibitors include cilomilast (Ariflo GlaxoSmithKline), Roflumilast (Byk Gulden),V- 1 1294A (Napp), BAY1 9-8004 (Bayer), SCH-35 1591 (Schering-Plough), Arofylline (Almirall), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID(TM) CC-10004 (Celgene), VMSS4/UMS6S (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo) and GRC 3886 (Oglemilast, Glenmark).

The or each active pharmaceutical ingredient active ingredient suitably has an average particle diameter of up to about 10 Jim, for example 0.1 to S p.m, preferably 1 to 5 pm. The particle size of the or each active pharmaceutical ingredient can be reduced to the desired level by conventional methods, for example by grinding in an air-jet mill, ball mill or vibrator mill, sieving, microprecipitation, spray-drying, lyophilisation or controlled crystallisation from conventional solvents or from supercritical media.

The or each ternary agent is preferably a surface active material, in particular a material that is surface active in the solid state, which may be water soluble, for example lecithin, in particular soya lecithin, or substantially water insoluble, for example solid state fatty acids such as lauric acid, palmitic acid, stearic acid, erucic acid, behenic acid, or derivatives (such as esters and salts) thereof. Specific examples of such materials include magnesium stearate; calcium stearate; sodium stearyl fumarate; sodium stearyl lactylate; phospatidylcholines, phosphatidylglycerols and other examples of natural and synthetic lung surfactants; Liposomal formulations; lauric acid and its salts, for example, sodium lauryl sulphate, magnesium lauryl sulphate; triglycerides such as Dynsan 118 and Cutina HR; and sugar esters in general. Preferably the ternary agent is magnesium stearate or calcium stearate, especially magnesium stearate.

Case PRJ4-34779P1/HO 161 Magnesium stearate is highly surface active and should therefore be added in particularly small amounts, for example 0.1 to 2% by weight or more preferably 0.25 to 1% by weight, based on the total formulation, of magnesium stearate.

The use of magnesium stearate leads to a general improvement in the inhalable fine particle fraction, and also stabilizes the carrier materials and active compounds by suppressing or slowing down undesirable morphological phase transitions. Magnesium stearate enhances the dosing efficiency of dry powder formulations administered by pulmonary inhalation by improvement of powder flowability.

The ternary agent is preferably in particulate form but it may be added in liquid or solid form and for some materials, especially where it may not be easy to form particles of the material and/or where those particles should be especially small, it may be preferred to add the material in a liquid, for example as a suspension or a solution.

The carrier particles may be composed of any pharmacologically inert material or combination of materials which is acceptable for inhalation. They are suitably composed of one or more crystalline sugars including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starches, dextran, mannitol or sorbitol. An especially preferred carrier is lactose, for example lactose monohydrate or anhydrous lactose.

Preferably substantially all (by weight) of the carrier particles have a diameter of 20 to 1000 jim, more preferably SO to 500 jim, but especially 20 to 250 jim. The diameter of substantially all (by weight) of the carrier particles is suitably less than 355 jim. This provides good flow and entrainment characteristics and improved release of the active particles in the airways to increase deposition of the active particles in the lower lung. It will be understood that, throughout, the diameter of the particles referred to is the aerodynamic diameter of the particles.

The active pharmaceutical ingredient(s) may be mixed with the ternary agent(s) using any suitable method, for example a high or low shear mixing method. The active pharmaceutical ingredient(s) and/or the ternary agent(s) may be sieved prior to mixing.

Pre-mixing the ternary agent with the active pharmaceutical ingredient in this way serves to maximize the extent to which the surface of the active particles are covered by the ternary Case PR/4-34779P11H0 161 agent. It enhances the interaction between the active particles and the ternary agent significantly. Particles of the ternary agent form a layer on the active particles that reinforce the desired effects of the ternary agent, e.g. by minimizing the negative effects of moisture on the chemical stability of the active particles.

In a preferred low shear mixing method an active pharmaceutical ingredient and a ternary agent are mixed in a low shear mixer such as a Turbula powder blender for 1 to 60 minutes at 1 to 60 revolutions per minutes. In a preferred high-shear mixing method an active pharmaceutical ingredient and a ternary agent are mixed in a high shear mixer such as a MiPro powder blender for 1 to 60 minutes at 100-4000 rpm.

The carrier particles may be mixed with the pre-mixed active pharmaceutical ingredient(s) and ternary agent(s) using any suitable method, for example a high or low shear mixing method as described above.

Where necessary or useful, the mixture of active pharmaceutical ingredient(s), ternary agent(s) and carrier particles is subjected to a final size reduction or blending step so that the dry powder formulation meets desired physical properties.

The dry powder may be contained as unit doses in capsules of, for example, gelatin or plastic, or in blisters (e.g. of aluminium or plastic), for use in a dry powder inhalation device, which may be a single dose or multiple dose device. Preferably the total weight of powder per capsule is from S mg to SO mg. Alternatively, the dry powder may be contained in a reservoir in a multi-dose dry powder inhalation (MDDPI) device adapted to deliver, for example, 3-25 mg of dry powder per actuation. A suitable device for delivery of dry powder in encapsulated form is described in US 3991761, while suitable MDDPI devices include those described in WO 97/20589 and WO 97/30743.

The invention is illustrated by the following Examples.

EXAMPLES

The following formulations are prepared to deliver 200 tg doses of indacaterol maleate in the multi-dose dry powder inhalation dry powder inhaler device described in WO 97/20589.

Case PRJ4-34779P111-JO 161

S

Example 1

Indacaterol maleate and magnesium stearate are mixed in a high shearing MiPro powder blender for 20 minutes at 250 rpm to form a pre-blend. Lactose is added to the pre-blend then mixed for 20 minutes at 250 rpm. FPF(DD) = 29.7%, where FPF means fine particle fraction and DD means delivered dose, and BU = 94.0%

Example 2

Indacaterol maleate and magnesium stearate are mixed in a high shearing MiPro powder blender for 5 minutes at 500 rpm to form a pre-blend. Lactose is added to the pre-blend then mixed (at low-shear) for 10 minutes at 220 rpm. FPF(DD) = 16.7%, BU = 99.3%

Example 3

Indacaterol maleate and calcium stearate are mixed in a low shearing a Turbula powder blender for 30 minutes at 44 rpm to form a pre-blend. Lactose is added to the pre-blend then mixed in a high shearing MiPro powder blender for 10 minutes at 22 rpm. FPF(DD) = 24.9%, BU = 95.1%

Example 4

Indacaterol maleate and magnesium stearate are mixed in a low shearing a Turbula powder blender for 10 minutes at 22 rpm to form a pre-blend. Lactose is added to the pre-blend then mixed for 10 minutes at 22 rpm. FPF(DD) 18.3%, BU = 99.5% In these Examples, indacaterol maleate, (R)-S-[2-(S,6-diethyl-indan-2-ylamino)1-hydroxy ethyll -8 -hydroxy-1 H-quinolin-2-one maleate, is prepared by reacting (R)-8-benzyloxy-5-oxiranyl-ca rbostyril with 5,6-diethyl-indan-2-ylamine to give 8 -benzyloxy-5-[(R)-2-(5,6-diethyl-indan-2-ylamino) -1 -hydroxy-ethyl] -IH-quinolin-2-one, subjecting the latter to a deprotecting reaction to replace the benzyl group by hydrogen, and recovering the resultant compound as a maleate salt. Such a process is described in detail in WO 2004/76422, the contents of which is incorporated herein by reference. (R)-8-benzyloxy-5-oxiranylcarbostyril may he prepared as described in WO 1995/25104. S,6-Diethyl-indan-2ylamine may be prepared as described in WO 2003/76387.

Claims

Case PRI4-34779P11H0 161

CLAIMS

1. A process for preparing dry powder formulations for inhalation that comprises mixing one or more active pharmaceutical ingredients with one or more ternary agents, then admixing carrier particles.

2. A process according to claim I wherein the ternary agent is a water-soluble surface-active agent.

3. A process according to claim 2 wherein the ternary agent is magnesium stearate or calcium stearate.

4. A process according to claim 1 in which the or each active pharmaceutical ingredient is selected from the group consisting of anti-inflammatory, bronchodilatory, antihistamine, decongestant or anti-tussive drug substances.

S. A process according to claim 1 in which the or each active pharmaceutical ingredient is selected from the group consisting of beta-2 adrenoceptor agonists, antimuscarinic agents, steroids or PDE4 inhibitors.

6 A process according to claim S in which the formulation'contains indacaterol maleate.

7. A process according to claim 1 wherein the carrier particles are crystalline sugars.

8. A process according to claim 7 wherein the carrier particles are lactose monohydrate or anhydrous lactose.

9. A process for preparing dry powder formulations for inhalation substantially as herein defined with reference to any one or more of the Examples.