Crystalline spherical inhalation particles incorporating a combination of two or more different active ingredients and a process for the preparation thereof. The particles have a narrow particle size distribution, rough surfaces and improved stability. The inhalation particles of the invention are particularly useful in the administration of a combination medicament, e.g. a combination of an anti-inflammatory agent and a bronchodilator, by inhalation in the treatment of asthma and other respiratory disorders.

SUMMARY OF THE INVENTION

It has now been found that, by using an aerosol flow reactor method, it is possible to prepare uncharged, spherical and crystalline inhalation particles incorporating, in an individual particle, a combination of two or more drugs in a predetermined and constant ratio. The particles provide more controlled delivery of combination medicaments by inhalation, since it is now possible to keep the ratio of the drugs in each dose constant The particles exhibit improved dispersibility and good stability as a result of their crystalline nature. The particles have a narrow aerodynamic particle size distribution, typically between about 1-5 .mu.m, which is especially suitable for the preparation of compositions for dry powder inhalers. Moreover, particle surfaces are spherical and generally rough, which reduces the force required to break-up the aggregates of the particles or detach the particle from a coarse carrier. Furthermore, the method of the invention provides a high purity product since the product purity only depends on the purity of solution precursors. Moreover, the method is simple and can be easily scaled-up to higher production rates.

In one aspect the present invention provides inhalation particles incorporating a combination of two or more different active ingredients, wherein said particles are spherical and at least one of the active ingredients is in crystalline form The mean mass aerodynamic diameter of the particles is typically between about 0.5-10 .mu.m, more typically between about 1-5 .mu.m The aerodynamic particle size distribution of said particles is typically between about 0.5-10 .mu.m, more typically between 1-5 .mu.m.

In another aspect the present invention provides an inhalation composition comprising particles incorporating a combination of two or more different active ingredients, wherein said particles are spherical and at least one of the active ingredients is in crystalline form. The particles may be formulated into an inhalation composition together with one or more pharmaceutically acceptable additives, diluents or carriers. Preferably, the composition is provided in the form of dry inhalation powder.

In still another aspect, the present invention provides a method for preparing particles incorporating a combination of two or more different active ingredients, comprising the steps of:

providing liquid feed stock comprising two or more different active ingredients in a predetermined ratio;

atomising said liquid feed stock to create droplets;

suspending said droplets in a carrier gas;

passing said carrier gas and droplets suspended therein through a heated tube flow reactor under predetermined residence time and temperature history; and

collecting the particles produced.

The present invention is particularly useful in the preparation of combination medicaments, e.g. for the treatment of asthma and other respiratory disorders. Especially preferred drug combination is a combination of an anti-inflammatory agent and a bronchodilator, for example a combination of a glucocorticosteroid and a .beta..sub.2-agonist.

DETAILED DESCRIPTION OF THE INVENTION

The particles of the invention can be used to deliver locally or systemically to a patient a variety of drug combinations. Particularly suitable are drug combinations which are typically used in the pulmonary delivery by inhalation, such as combinations used in the treatment of asthma and other respiratory diseases. These include, but are not limited to, a combination of an anti-inflammatory agent and a bronchodi-lator, e.g. a combination of a glucocorticosteroid and a .beta..sub.2-agonist. Examples of anti-inflammatory glucocorticosteroids include beclomethasone, budesonide, fluticasone, mometasone, betamethasone, triamcinolone, flunisonide and the like and their salts and hydrates. Examples of .beta..sub.2-agonists include salbutamol, formoterol, fenoterol, procaterol, salmeterol, clenbuterol and the like and their salts and hydrates. Typical combinations include beclomethasone dipropionate and formoterol fumarate, beclomethasone dipropionate and salbutamol, budesonide and formoterol fumarate, fluticasone propionate and salmeterol, beclomethasone dipropionate and salmeterol. Finding suitable ratio of the active ingredients in a given combination is considered to be a routine for one skilled in the art

Any inhalable pharmaceutically active compound which can be formulated into a powder is suitable for use in the present invention. Examples of other inhalable drugs include drugs for the treatment of respiratory disorders such as anticholinergic bronchodilators such as ipratropium bromide and the like, anti-allergic drugs such as nedocromil sodium, expectorants, mucolytics, antihistarnines, cyclooxygenase inhibitors, leukotriene synthesis inhibitors, leukotriene antagonists, PLA2 inhibitors, PAF antagonists and prophylactics of asthma and combinations thereof. Alternatively, the pharmaceutically active agent can be any of several types of inhalable, systemically active drugs including antiarrhythmnic drugs, tranquilizers, cardiac glycosides, hormones, antihypertensive drugs, antidiabetic drugs, anticancer drugs, sedatives, analgesic drugs, antibiotics, antirheumatic drugs, imrnunothera-peutics, antifungal drugs, vaccines, antiviral drugs, proteins, peptides, vitamins and combinations thereof. A combination of an anti-inflammatory agent and a broncho-dilator is particularly preferred.

The particles of the present invention are preferably prepared using an aerosol flow reactor method (aerosol synthesis method). It is a one-step continuous process, which can directly produce desirable particle size range. The method has been used to produce various materials, e.g. ceramic powder (U.S. Pat. No. 5,061,682) or zirconia powder (U.S. Pat. No. 4,999,182), at high operation temperatures. However, the method has not been used to produce pharmaceutical materials, which requires a significantly lower-temperature operation (less than 300.degree. C.).

The aerosol flow reactor method comprises generally the following steps; (a) providing liquid feed stock comprising two or more different active ingredients in a predetermined ratio, (b) atomising said liquid feed stock to create droplets, (c) suspending said droplets in a carrier gas, (d) passing said carrier gas and droplets suspended therein through a heated tube flow reactor under predetermined residence time and temperature history, and (e) collecting the particles produced.

The above method differs significantly from the conventional spray-drying process. In spray-drying, hot gas is used as a source of heat to evaporate the solvent. The spray-drying chamber is only used as a place for the heat transfer to occur, the chamber itself is not heated. The temperature of the gas is changing across the chamber as heat transfer occurs between the cold feed and the hot gas. Furthermore, the evaporation is so rapid that it is not easy to properly control the temperature history and the residence time of each droplet and product particle. The crystallization can not be easily controlled either, and therefore the particles formed are commonly amorphous.

In the present method, the droplets are already suspended in the carrier gas before they are fed into the tubular flow reactor, which is placed in an oven set at a constant temperature. The carrier gas flows evenly in the tubular reactor with a constant rate, uniform temperature field and non-circulating flow. Therefore, the temperature history and the residence time of each droplet and product particle can be properly controlled and excellent uniformity of the particles can be ensured. Accordingly, the method provides better control of the droplet size distribution, and thus the particle size distribution such that particles with optimal aerodynamic particle size distribution typically between about 1-5 .mu.m can be obtained. Furthermore, in contrast to spray drying, the method allows essentially complete crystallization of the particles. Thus, the method is able to produce consistent and controlled particle properties, including particle size and size distribution, shape, crystallinity, polymorphic phase, surface roughness and chemical purity.

The liquid feed stock of step (a) may be prepared by mixing each active ingredient with a suitable liquid solution, e.g. solvent. The two or more liquid feed stocks are then mixed to form a solution, suspension, dispersion, gel, emulsion, slurry or the like, and is preferably homogenous to ensure uniform distribution of the components in the mixture. It is also possible to mix all active ingredients directly in one liquid feed stock. The liquid feed stock in the form of a solution is preferred.

Various solvents may be employed in the preparation of the liquid feed stock, including but not limited to, water, hydrocarbons, halogenated hydrocarbons, alchohols, ketones and the like. Examples of suitable solvents include water, hexane, perfluorohexane, ethanol, methanol, acetone, chloroform, methylene chloride and combinations thereof.

In case the liquid feed stock is a solution, the active ingredients should be sufficiently soluble in the solvent of the solution so as to obtain, from the atomized droplets of the liquid feed stock, uniform particles with the desired particle size, size distribution and drug ratio. The total solids dissolved may be present in wide range of concentrations, typically from about 0.1% to about 10% by weight, for example from about 1% to about 5% by weight A liquid feed stock containing relatively low concentration of solids results in particles having relatively small diameter. The finding of suitable liquid feed stock concentrations for each active agents/solvent combinations is considered to be a routine to one skilled in the art. Usually, the liquid feed stock concentration is firstly chosen at its maximum solubility so as to obtain the largest particle size with the atomizer and atomizer conditions used. From the results, the liquid feed stock concentration required to obtain the desired particle size range with the atomizer and the atomizer conditions used can be approximated.

The liquid feed stock is atomized to create droplets in a suitable atomizer, which are well known in the art, such as a spray nozzle (e.g. a two fluid nozzle), an ultrasonic or air assisted nebuliser or a spinning disc, an ultrasonic nebulizer being preferred Examples of the devices used in this process include ultrasonic generators sold under trademarks Omron NE-U12 and RBI Pyrosol 7901. While there are no special restrictions placed on the atomisers used in the process, it is recommended to use an atomiser, which can produce uniform droplets of constant composition and in a specific size range. Such devices are suitable to produce dry powders of controlled composition and with particle size range suitable for dry powder inhalation.

The droplets of the liquid feed stock are suspended in a carrier gas before passing through a heated tube flow reactor. The carrier gas must be inert with respect to the drug molecules and the solvent. It is recommended to use nitrogen gas or other inert gases. The temperature of the carrier gas is typically ambient. To maintain a uniform solution concentration in the droplets in the suspending phase, it is preferred to bubble the carrier gas through a bottle containing the same solvent as the liquid feed stock before entering the atomizer.

Because the droplets are already suspended in the carrier gas when fed into the reactor (i.e. the droplet generation and flow reactor are separated), the temperature history and residence time of each droplet and product particle can be better controlled than in the conventional spraying method. Therefore, excellent uniformity of the resulted particles and narrow particle size distribution can be ensured.

The droplets suspended in the carrier gas are passed through a tubular flow reactor, which is maintained at a constant temperature. The temperature and the flow rate of the carrier gas are adjusted to evaporate the solvent and to allow the crystallization process to complete. The particles formed are then collected using an electrostatic precipitator, a cyclone, a planar filter (e.g. nylon) or other particle collecting devices.

The particle size may be controlled to any expected particle size ranges by selection of the atomizer and concentration of the liquid feed stock. It is also possible to employ a droplet size modification apparatus (e.g. impactor or virtual impactor, or using size selective collection of particles, e.g. a cyclone) upstream and/or downstream of the flow reactor.

For the tubular flow reactor, while there are no particular restrictions, it is recommended to use a vertical, rather than horizontal configuration in order to minimise buoyancy effects and related losses due to recirculating flow. A laminar flow is preferred. To ensure uniform temperature and flow fields in the hot zone of the reactor, CFD (Computational Fluid Dynamics) calculations have shown that it is preferable that the aerosol flows against gravity. Flow in any other direction tends to produce undesirable reactor conditions. The reactor tube is preferably placed inside an oven to maintain a uniform reactor wall temperature during the process. The oven can be of any kind, which has sufficient temperature control (i.e. .+-.1.degree. C. or less) at low temperatures (less than 300.degree. C.). The temperature of the oven is set such that the materials being processed do not decompose. Typically the selected oven temperature is within the range of about 30 to 300.degree. C., more typically between about 70 to 200.degree. C. For the combination of beclomethasone dipropionate and formoterol fumarate, for example, since the melting point of beclomethasone dipropionate is about 210.degree. C. and the melting point of formoterol fumarate is about 138.degree. C., the range of oven temperature used for the combination particle production may vary between 30 to 110.degree. C., preferably between 70 to 100.degree. C.

While there are no particular restrictions placed on the particle collection, it is recommended to use a system, which can be heated to prevent the re-condensation process. Electrostatic precipitators, cyclones and/or filters can be used for this purpose. Accordingly, the particle collection system and the line from the flow reactor outlet to the particle collection system are preferably heated to a temperature above the boiling point of the solution to prevent the recondensation process to occur. However, the temperature should not be too high so as to cause material degradation. For example, for the combination of beclomethasone dipropionate and formoterol fumarate dissolved in ethanol, the temperature of the collection system and the line may be kept constant at a temperature between 80 to 100.degree. C., preferably between 80 and 90.degree. C. To further prevent the recondensation process to occur, dry carrier gas may be flown to the particle collection system. The carrier gas is preferably heated at a temperature between 80 to 90.degree. C.

It is preferred that the aerosol flow reactor conditions are selected such that crystalline spherical particles of homogeneous constituents having a narrow particle size distribution and rough surfaces are formed. The particle size of the resulting powder is such that the mean mass aerodynamic diameter of said particles is between about 0.5-10 .mu.m, more typically between about 1 -5 .mu.m. Particularly it is preferred that more than 98% of the mass is in particles having a diameter of 5 .mu.m or less, and less than about 5% of the mass being in particles having a diameter of 0.5 .mu.m or less. It is particularly preferred that the aerodynamic particle size distribution of said particles is between about 0.5-10 .mu.m, more preferably between about 1 -5 .mu.m.

The particles obtained incorporate, in an individual particle, a combination of two or more drugs. An individual particle means here an unagglomerated particle which have the typical spherical form.

In the particle of the invention, at least one of the active ingredients is in a crystalline form, i.e. has a relative degree of crystallinity preferably 90% or higher, more preferably 95% or higher, most preferably 99% or higher. Preferably the aerosol flow reactor conditions are selected such that all active ingredients in-the particle are in a crystalline form The relative degree of crystallinity can be determined based on the x-ray powder diffraction patterns. The value of the relative degree of crystallinity can be estimated by a known method of broadening of the diffraction maxima (FWHM-values).

The particles of the invention are essentially spherical, i.e. the spherical form is consistent and apparent when examined under a scanning electron microscope. The spherical form reduces the contact areas between particles and thereby improves aerosolization and deagglomeration of the particles upon inhalation.

Generally, the surface of the spherical particles is rough, i.e. the roughness is consistent over the entire surface of the particle, apparent when examined under the scanning electron microscope, and the ratio of the maximum and minimum diameter of the particle is between 1.001-1.5, preferably between 1.002-1.2, more preferably between 1.01-1.1. Rough surface is advantageous since it increases the effective separation distance of the particles, and thus improves aerosolization and deagglomeration properties of the particles.

If desired, various additives known in the art may be additionally incorporated in the particles together with the active ingredients. Such additives include e.g. diluents such as lactose, carriers and stabilizers and the like. In such case the additives are included in the liquid feed stock of the process together with the active ingredients. Also such additives incorporated in the particle are preferably in crystalline form. It is particularly preferred that at least about 90 w-% of the total weight of the particle is in crystalline form.

However, in order to reduce the amount of material other than the active ingredients potentially reaching the lungs, it is preferred that the active ingredients constitute at least 90 w-%, preferably at least 95 w-%, more preferably at least 99 w-%, of the total weight of particles. Most preferably the particles are free from other material than the active ingredients.

The particles of the invention may be formulated into an inhalation composition together with one or more pharmaceutically acceptable additives, diluents or carriers. Examples of suitable solid diluents or carriers comprise lactose, dextran, mannitol and glucose, lactose being preferred. Examples of aerosol carriers include non-chlorofluorocarbon-based carriers such as HFA (hydrofluoroacane). The use of aqueous carriers is also possible. Typical additives include solubilizers, stabilizers, flavouring agents, colorizing agents and preserving agents.

The particles of the invention are preferably administered in the form of a dry powder composition. The particles obtained are generally in the form of individual (unagglomerated) particles which are well suited for pulmonary drug delivery by inhalation as such, e.g. they can be filled directly into capsules, cartridges, blister packs or reservoirs of dry powder inhalers. However, if desired the particles may be adapted to form loose agglomerates of several individual particles, said agglomerates breaking into individual particles upon dispersion in the inhaled air stream. The particles may also be combined with pharmaceutically acceptable carrier materials or excipients typically used in dry inhalation powders. Such carriers may be used simply as bulking agents or to improve the dispersibility of the powder. For example, the particles may be used in admixture with carrier particles, e.g. lactose, having larger particle size than the active ingredients, typically in the range of 5 to 100 .mu.m. If the composition contains a carrier, the total amount of the active ingredients is typically about 0.1-50% (w/w), preferably about 1-10% (w/w), based on total weight of the composition. Such compositions can be prepared by methods known in the art.

The particles of the invention can be also administered in the form of pressurized metered dose inhalation suspension, where the particles are suspended in pressurized aerosol carrier and delivered using pressurized metered dose inhaler (pMDI).
 

Claim 1 of 20 Claims

1. Inhalation particles incorporating, in an unagglomerated individual particle, a combination of two or more different active ingredients, wherein the active ingredients are an anti-inflammatory drug and a bronchodilator wherein said particles are spherical and at least one of the active ingredients is in crystalline form.

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