MXPA00010159A - Pharmaceutical aerosol formulation - Google Patents

Abstract

The present invention relates to novel pharmaceutical aerosol formulations comprising:(A) a therapeutic agent in the form of particles coated by at least one coating excipient and at least one surfactant, in suspension in (B) a liquefied propellant gas for the administration of therapeutic agents particularly by the pulmonary route and to a process for preparing these formulations. It also relates to novel particles suitable for use in such formulations.

Description

PHARMACEUTICAL FORMULATION IN AEROSOL FIELD OF THE INVENTION The present invention relates to novel aerosol pharmaceutical formulations for the administration of therapeutic agents, particularly by the pulmonary route, and to a process for preparing these formulations. It also refers to novel particles suitable for use in these formulations.

BACKGROUND OF THE INVENTION The use of aerosols for the administration of medications through the peripheral airways has been known for many decades. These aerosols generally contain the therapeutic agent, one or more adjuvants such as solvents or surfactants or one or more propellants. The most commonly used propellers in the past were the C 1 or r or f or r or ca bur bur, such as CC13F Fr eon MR 11 CC12 2Fr 2 Fr eon. MR 12 or CF2C1CF2C1 Freon 114 Sin Ref. 124348 However, the recent discontinuation of these propellant gases due to their harmful effect on the ozone layer has caused aerosol spray manufacturers to use new propellant gases that protect stratospheric ozone. These gases "friendly to the ozone layer", also known as green gases, include, for example, gold, carbon dioxide containing hydrogen, hydrogen-containing fluorocarbons and per-chlorocarbons. The specific group of therapeutic agents administered by the pulmonary route are the antiasthmatics that include the bronchodilator and the steroid-type anti-inflammatory drugs, which have a local therapeutic action on the lungs and / or a therapeutic action. systemic after absorption in the blood. For these drugs, the replacement of the usual chlorine-based propellants and luorocarbons, by the novel propellants that protect the ozone layer, may be accompanied by stability problems of the suspensions.

This is because the change in the polarity of the propellant sometimes results in a partial solubility of the drug in the gas. This partial solubility can lead to an undesirable increase in the size of the particles during storage and / or to the formation of aggregates. It is then observed that the valves of the administration device are blocked and / or that the aggregates of particuleis penetrate less well into the fine lower respiratory vicis. International Patent Application No. WO 92/08446 (Glaxo Group Limited) and EP-A-0 493437 (Riker Laboratories Inc) describe the presence of surfactants in pharmaceutical aerosol formulations, however, the use of lactose or other sugars is not described. WO 94/03153 (Glaxo Gro? P Limited) discloses a beclome t asone dipropionate formulation, in suspension, but specifically excludes the presence of a t-ioac-tive agent. WO 93/11743, WO 93/11744 and WO 93/11745 (Glaxo Group Limited) also describe suspension formulations of drugs that specifically exclude the presence of the surfactant. WO 97/35562 (Danbiosyst) discloses the process of incorporating a drug into polymeric microspheres, by spray drying, however, the use of disaccharides, such as lactose, in a process is specifically excluded. like that. Furthermore, its use in formulations containing a liquefied propellant gas is not described. WO 91/16882 (Liposome Technologyi describes a process for the spray drying of an ethanol solution containing a drug / 1-ipido, but the use of surfactant in this process is not mentioned in EP-A-550031 (Hoechst) describes aerosol formulations, pre-surfaced, containing a spray-dried product, wherein the spray-dried product is obtained by spray-drying a solution of the drug, surfactant and (optionally) an auxiliary substance to provide a finely dispersed matrix The inventors of the present invention have now discovered that it is possible to improve the stability of drug suspensions in the propellant, by protecting the propellant gas drug particles, with a coating.

This protective layer prevents the partial solubilization of the drug in the propellant and the formation of aggregates. In combination with a surfactant, this coating excipient makes it possible to obtain aerosol formulations for pulmonary administration, which, protected from atmospheric humidity, are stable for months and make it possible to deliver particles of the drug having sizes that are small enough to penetrate inside the respiratory tract.

DESCRIPTION OF THE INVENTION A first issue addressed by the present invention is consequently, a pharmaceutical aerosol formulation comprising a therapeutic agent in the form of coated particles, in suspension in a propellant. A further issue addressed by the present invention is the process for preparing the particles and pharmaceutical formulations. A still further issue that is addressed here is drug particles, r ecubi ers. Additional issues will be apparent to those skilled in the art from the following description and examples. The present invention thus provides pharmaceutical aerosol formulations, which comprise (A) a therapeutic agent in the form of particles coated by at least one coating excipient and at least one surfactant, in suspension in (B) a liquefied propellant gas Therapeutic agents that can be used in these aerosol pharmaceutical formulations are all solid drugs that can be administered by the pulmonary route and that are insoluble, or very slightly soluble, in the medium that is used to coat the drug particles. A drug is considered as insoluble or very slightly soluble, if it dissolves to less than 0.1% (m / v) in the suspension medium used for the coating. These therapeutic agents include, in particular, bronchodilators and steroidal infants commonly used in the treatment of asthma, such as beclometa dipropionate, salbutamol (for example, as sulfate or free base), salmeterol (for example as the salt 1-hydroxy-2-naphthoate), fluticasone propionate or solvates thereof. Other compounds of interest include (2R, 3R, 4S, 5R) -2- [6-Amino-2- (lS-hydroxymethyl-2-phenyl-ethylamino) -purin-9-yl] -5- (2-ethyl-2H-tetrazole-5 -yl) -tetrahydro-furan-3,4-diol (for example as the maleate salt) and S- (2-oxo-t and rahydrofuran an-3-i 1) 6? Difluoro-11β-hydroxy-16oc-methyl-3-oxo-17oc-propionyloxy-androsta-1, 4-diene-17β-carbothionic acid, and S - (2 -oxo-tetrahydrofuran-3-i-1) 6x, 9o-Difluoro-11β-hydroxy-16oc, 17oc-isopropylidenedioxy-androsta-1,4-dien-17β-carbo-t-ionic acid ester. Among these, preference is given to beclomethasone dipropionate and in particular to its monohydrate. The use in relation to the xinafoate of jdte ** 1 s a lme t e r 1. Of course, the pharmaceutical formulations may also contain a combination of two or more therapeutic agents that can be administered by the pulmonary route. An example of this combination is fluticasone propionate and salmeterol xinafoate. The particles are coated, in accordance with the present invention, with one. protective layer comprising at least one coating excipient. This excipient of: coating must be physiologically acceptable when used in administration by the respiratory tract. To efficiently protect the particles of the drug, they must also be essentially insoluble in the propellant. In addition, the process for preparing the coating requires that the coating excipient be soluble in the suspension medium used to prepare the formulation, which is preferably an aqueous medium. A beneficial coating effect can be obtained with a covering layer covering the main surface of the particles. To achieve optimal protection of the drug particles, at least about 80% and more preferably at least about 90% of its surface should be covered by the coating layer. The coating excipients which satisfy all these requirements are selected from monosaccharides, disaccharides or polysaccharides, such as mannitol, lactose, trehalose, dextrose, microcrystalline cellulose. sodium carboxylate, sodium hydroxypropylcellulose or sorbitol. Among these, preference is given to one of the two diglucosides, lactose and trehalose. The drug particles are coated not only with a coating excipient described above but also with a. less a surfactant. This agent; surfactant must be physiologically acceptable; when used by inhalation. It must be insoluble (or essentially insoluble) in the gas or liquefied propellant gases, and must not have affinity with them. This surfactant agent acts essentially as a stabilizer for the liquid paste of the drug particles, in the aqueous coating medium. Examples of the active agents that can be used in accordance with the present invention are anionic surfactants such as oleic acid, nonionic surfactants such as sorbitan trioleate, sorbitan monooleate, monolaurate sorbitan, polyoxyethylene (20), sorbitan monolaurate, polyoxyethylene (20), sorbitan monooleate, natural lecithin, polyoxyethylene (2) oleyl ether, polyoxyethylene (2) stearyl ether, polyoxyethylene (4) lauryl ether, block copolymers of the ethylene and propylene oxide, synthetic lecithin, diethylene glycol dioleate, tet rahydro furan fur oleate oleate, ethyl oleate, isopropyl myristate, glyceryl monooleate, glyceryl monostearate, glyceryl antifreeze monomer, alcohol cetyl, stearyl alcohol, polyethylene glycol 400 or glyceryl monolaurate, or cationic surfactants such as ceti lpi ri dini chloride or benzalkonium Other examples of surfactants include synthetic phosphatides, for example, distearoylphosphatidylcholine. It will be used preferably lecithin. The coating of the drug particles of the present invention may optionally comprise, in addition to the surfactant agent.e and the coating excipient, a vegetable oil selected from olive oil, corn oil, cottonseed oil and seed oil. sunflower. The propellant that can be used in accordance with the present invention is any liquefiable, rigid or hydrogen-containing fiber or hydrogen-containing fuel that has a vapor pressure sufficient to enable it to act as a propellant. The propellant must be essentially a non-solvent for the coated drug particles, i.e. for the therapeutic agent, the coating excipient and the surfactant. Suitable propellants include, for example, the hydrochloro f luorocarbons of 1 to 4 carbon atoms, such as CH2C1F, CC1F2CHC1F, CF3CHCIF, CH2CC1F2, CHC1FCHF2, CF3CH2C1 and CC1F2CH3, hydrotreater of 1 to 4 carbon atoms. carbon, such as CHF2CHF2, CF3CH2F, CHF2-CH3 and CF3CHFCF3, and the per-luorocarbons such as CF3CF3 and CF3CF2CF3, or mixtures thereof. Particularly preferred propellants include CHF3, CH2F and CF3CHFCF3, and mixtures thereof. Preferably use is made of a single propellant of the hydro f luorocarbon D hydrochlorefluorocarbon type, and in particular 1,1,1,2-tetrafluoroethane (CF 3 CH 2 F) (HFA 134a). The coated drug particles, of the aerosol formulations of the present invention, must have sizes that allow them to be administered by inhalation. The particles must be small enough, on the one hand, to penetrate the pulmonary arteries without encountering obstacles and, on the other hand, they must have a size 1 (3 large enough to be deposited in the lung and not be removed by exhalation. Penetration of the drug particles as far as in the bronchioles and pulmonary alveoli is only possible for particles having an average size of less than 10 μm, preferably less than 5 μm, the size of the coated drug particles, present invention is preferably within the range of 0.5 μm to 10 μm, in particular 1 μm to 5 μm The pharmaceutical compositions according to the invention can also comprise other pharmaceutically acceptable ingredients such as solvents or surfactants. preferred of the present invention, the formulations do not contain more surfactants than that which is applied as a coating on the drug particles and does not contain cosolvents. The present invention also provides a method for preparing a pharmaceutical aerosol formulation which comprises coating drug particles with at least one coating excipient and with at least one surfactant and packaging them, together with the propellant, in a pressurized cartridge. The process for the preparation of the aerosol pharmaceutical formulation, of the present, comprises, more specifically, the steps consisting of (a) preparing a suspension containing - the therapeutic agent in the form of particles, - a suspending medium that is not a solvent for the therapeutic agent, the excipient for carrying out im- iency dissolved in the suspending medium and - the surfactant; (b) spray-drying the suspension of the therapeutic agent obtained in step (a) to obtain drug particles coated by the excipient and the surfactant; (c) suspending the coated drug particles obtained in step (b) in the liquefied propellant gas.

The particles of the therapeutic agent used in step (a) will also be of a size suitable for inhalation, for example of a size of less than 10 μm (eg, 0.5 μm to 10 μm), preferably less than 5 μm (eg. , from 1 μm to 5 μm). In one embodiment of the process of the invention, the suspension of step (a) above is prepared by dissolving the excipient and dispersing the surfactant in the suspension medium and subsequently dispersing the drug particles in the colloidal solution thus obtained. It is also possible, in accordance with the embodiment of the inventive process, to adsorb, in a first step, the surfactant agent on the uncoated drug particles, and subsequently to disperse the combination of agent / agent et ens ioact see, in the suspension medium containing, in the dissolved form, the coating excipient. The suspending medium used for the coating of the drug particles has to be essentially a non-solvent for the surfactant and a good solvent for the coating excipient. The preferred suspending medium is water. The content of therapeutic agent in the suspension prepared in step (a) may vary within wide limits. It is generally within the range of 1 to 40% (more to / vo lumen), preferably in the range of 5 to 20% (more to / volume). The ratio of the coating excipient to the therapeutic agent, in the suspension, before spray drying, is between 1 and 20% by weight, preferably between 5 and 10% by weight. The ratio of the surfactant to the therapeutic agent, in the suspension obtained in step (a), is generally between 1 and 20% by weight, preferably between 5/10% by weight. The suspension described above is subsequently subjected to spray drying, in an appropriate device. The suspension to be dried is dispersed as fine droplets in a stream of hot air, which instantly transforms them into small grains of dust. A person skilled in the art would know how to adjust the parameters of; operation, such as the flow of the suspension that reaches the drying chamber, the size of the nozzle, the inlet and outlet temperature, the atomization or spray pressure, and the atomization air flow, in accordance with the manufacturer's recommendations and as a function of the characteristics of the product you want to obtain. A suitable spray dryer that makes it possible to dry the drug particles of the present invention is the Mini Spray Dryer Büchi 191 (Büchi Company, Switzerland). The physical parameters of the atomization in that device, which make it possible to obtain the particles of the active principle, coated, from the suspension of stage (a) are the following: • Input air temperature: 110-170 ° C • Output air temperature: 70-120 ° C • Atomization air flow rate: 400-1000 liters per hour (preferably 400-800 liters per hour) • Speed of the pumps: 10-45 rpm (preferably 10-15 rpm). Typically this is equal to 2-10 liters per minute (preferably about 3 mi po .: minute).

The spray dried material obtained is composed of particles having an average size between 1 mm and 10 μm and a water content between 0.1 and 5% 15 n weight. Another suitable spray dryer which makes it possible to dry the drug particles in the present invention is the NIRO Minor Mobile Spray Dryer. The physical parameters of the atomization in that device, which make it possible to obtain the particles of the active principle, coated, from the suspension of stage (a) are the following: • Input air temperature: 100-220 ° C • Output air temperature: 60-120 ° C • Atomization air flow ratio: 50-130 m3 / h • Suspension flow ratio: 300-5000 ml / h The spray dried material obtained is composed of particles having an average size between 0.1 μm and 10 μm and a water content between 0.1 and 5% by weight. If necessary, the particles obtained by spray drying can be subjected to the reduction or any other method that is capable of reducing their average size to a value of less than 10 μm and preferably less than 5 μm. Indeed, spray drying can result in partial aggregation of the particles bound to each other by the coating layer, and this aggregation substantially increases the apparent average particle size. The main purpose of this step is to break these aggregates. It is optional and its utility depends, of course, on the presence of aggregates, in other words, the size of the particles after spray drying. The mi rtonation is carried out in devices known as my compressed air crushers or fluid jet mills. In these devices, the particles are transported by a strong current of air into a chamber designed in such a way that the particles are subjected thereto to a large number of impacts. According to the invention, in order to have drug particles, coated, having an appropriate size, these devices should be operated at a pressure between x 10"5 and 1.4 x 10 'Pa, preferably between 9 x 10 3 and 1.2 x 10 ~ 4 Pa The cartridges can be filled by any means that makes it possible to obtain a homogeneous suspension of the drug particles, coated, in the propellant.The cartridges can be filled, for example, first with the powder and then with the propellant ( "dual stage") or alternatively with a prepared suspension, of the powder in the propulsion :: ("simple stage"). This refilling will be carried out preferably in a controlled atmosphere, with a low relative humidity, to limit the hydration of the particles during e-1 re 11. Cartridges will generally be equipped with a metering valve and a metered dose inhaler (MDI) will comprise that cartridge and valve along with a channeling device. suitable for the delivery of the formulation to the lung. The cartridges are preferably, but not necessarily, stored in a package composed of a film that is impervious to atmospheric moisture. The suspensions contained in these wrapped cartridges are stable for several months at room temperature (25 ° C). Other means may also be employed to resist the ingress of moisture into the container.

E j emp the It is intended that the following examples illustrate the invention and not have a limiting nature.

Example 1 Dissolve 0.5 g of lactose and 0.5 g of lecithin in 100 ml of demineralized water, at room temperature. After obtaining a colloidal solution, 5 g of beclomethasone dipropionate monohydrate (DBP) as micronized particles are dispersed with agitation in the aqueous solution. The suspension thus obtained contains 5% BDP, 0.5% lecithin and 0.5% lactose. This suspension is then dried by spraying in a Mini Spray Dryer Büchi 191, working with the following parameters: • Inlet air temperature: 160 ° C • Outlet air temperature: 105 ° C • Compressed air pressure: 9.5 x 10"5 Pa • Atomizing air flow rate: 1000 liters per hour • Pump speed : 15 rpm (typically this equals 3 mi per minute).

The spray drying performance is between 60 and 70%. The spray-dried material obtained is micronized in a fluid jet mill (MCC 50, JET Pharma S.A.) under a pressure of 9 x 10 ~ 5 Pa. The data from the electronic chemical spectrometric analysis (ESCA) of the micronized particles showed that at least 90% of the surface of the particle was covered by the coating layer, after the micronisation. The characteristics of the particles before being placed in the cartridges are the following: average diameter: 1.5 μm (100% of the particles have a size smaller than 5 μm) water content: 0.6% The cartridges are filled manually in a room with controlled atmosphere (20 ± 2 ° C), relative humidity less than 15%) introducing successively the micronized material and then the gas. The gas used is the pressurized HFA134a gas. The cartridges are wrapped with a film that is impervious to moisture at the earliest. The finished product, thus obtained, is stable for several months at room temperature (25 ° C).

Example 2 0.5 g of trehalose and 0.5 g of lecithin are dissolved in 100 ml of demineralized water at room temperature. After obtaining a colloidal solution, 5 g of beclomethasone dipropionate monohydrate (BDP), as micronized particles, are dispersed with agitation, in the aqueous solution. The suspension thus obtained obtained 5% BDP, 0.5% lecithin and 0.5% trehalose. This suspension is dried after spraying in a Büchi 191 Mini Spray Dryer operating with the following parameters: • Inlet air temperature: 160 ° C • Exit air temperature: 105 ° C • Compressed air pressure: 9.5 x 10"5 Pa • Atomization air flow ratio: 100 liters per hour • Pump speed: 15 rpm (typically this equals 3 mi per minute).

The spray drying performance is between 60 and 70%. The spray-dried material, obtained, is micronized in a fluid jet mill (MCC 50, JET Pharma SA) under a pressure of 9 x 10"5 Pa. The particles, before being placed in the cartridges, have a size average of 1.5 μm (100% of the particles have a size smaller than 5 μm) .The cartridges are filled manually . * ^ * & amp; & amp; X in a room with controlled atmosphere (20 ± 2 ° C) relative humidity less than 15 's) introducing successively the micronized material and then the gas. The gas used is pressurized HFA134a gas. The cartridges are wrapped in a film that is impervious to moisture atmo s f ér i ca.

Example 3 g of micronized particles of dipropionate ce bec lome t a s ona monohydrate are triturated with 1 g of lecithin, in mortar, until a homogenous physical mixture is obtained. Dissolve 2 g of lactose in 100 v1 of demineralized water at room temperature. The physical mixture of BDP / lecithin is subsequently dispersed with agitation in the aqueous solution of the lactose. The suspension thus obtained contains 20% BDP, 1% lecithin and 2% lactose. This suspension is spray-dried in a Büchi 191 Mini Spray Dryer operating with the following parameters: • Inlet air temperature: 145 ° C • Outlet air temperature: 110 ° C • Compressed air pressure: 6 x 10"5 Pa • Atomization air flow ratio: 400 liters per hour • Pump speed: 15 rpm (typically this equals 3 mi per minute).

The spray drying efficiency is approximately 10%. The spray dried material, obtained, is micronized in a fluid jet mill (MCC 50, JET Pharma SA) under a pressure of 9 x 10"5 Pa. The characteristics of the particles, before being placed in the cartridges, they are like: average diameter: 1.5 μm (100% of the particles have a size smaller than 5 μ) water content: 0.9% The cartridges are filled manually in a room with controlled atmosphere (20 ± 2 ° C, relative humidity less than 15%) introducing successively the micronized material and then the gas. The gas used is ga Hf 134a pressurized. The cartridges are wrapped with a film that is impervious to moisture at the earliest.

Example 4 2 g of lactose and 2 g of lecithin are dissolved in 100 ml of cold water at room temperature. After obtaining a colloidal solution, 20 g of beclomethasone dipropionate monohydrate (BDP), as micronized particles, are dispersed with agitation in the aqueous solution. The suspension thus obtained contains 20% BDP, 2% lecithin and 2% lactose. This suspension is then dried by spraying in a Büchi 191 Mini Spray Dryer operating with the following parameters: • Inlet air temperature: 150 ° C • Exit air temperature: 100 ° C • Compressed air pressure: 6 x 10" 5 Pa • Atomization air flow ratio: 400 liters per hour • Pump speed: 15 rpm (typically this equals 3 mi per minute).

The spray drying performance is between 50 and 60%. The spray dried material is micronized in a fluid jet mill (MCC 50, JET Pharma S.A.) under a pressure of 9 x 10"5 Pa. The data, by ESCA, of the micronized particles, show that at least 90% of the surface of the particles was still covered by the coating layer, after micro-zoning. The particles, before being placed in a cartridge, have an average diameter of 1.5 μm (100% of the particles have a size smaller than 5 μm). The cartridges are filled manually in a room with controlled atmosphere (20 ± 2 ° C, relative humidity less than 15) introducing successively the micronized material and then the gas. The gas used is pressurized HFA134a gas. The cartridges are wrapped with a film that is impervious to moisture at tmo s f é r i c a.

Example 5 Dissolve 2 g of lecithin in 100 ml of demineralized water at room temperature. 20 g of mono-methyl acetate dipropionate becyl-tasone are premixed with 2 g of lactose and the mixture is dispersed with stirring in the aqueous lecithin solution. The suspension is spray-dried in a Büchi Mini Spray Dryer 191 with parameters such as those described in Example 4. The particles, before being placed in a cartridge, have an average diameter of 1.5 μm (100% of the particles). they have a size smaller than 5 μm). The cartridges are manually filled in a controlled atmosphere room (20 ± 2 ° C, relative humidity less than 15 i) by successively introducing the micronized material and then the pressurized HFA134a gas. The cartridges are wrapped with a film that is impervious to moisture at the earliest. The cartridges were prepared with composition in the analysis, as follows: For a product of 250 μg / dose (63 μl metering valve): BDP: 40 mg Lecithin: 4 mg Lactose: 4 mg HFA134a: 11,952 g For a product of 100 μg / dose 63 μl metering valve) BDP: 16 mg Lecithin 1.6 mg Lactose: 1.6 mg HFA134a: 11,981 g For a product of 50 μg / dose metering valve of 63 μl): BDP: 8 mg Lecithin 0.8 mg Lactose: 0.8 mg HFA134a: 11,990 g Example 6 Dissolve 15 g of lecithin in 1000 ml of demineralized water at room temperature (20 ° C ± 2 ° C). 150 g of bec lome-tasone dipropionate monohydrate are premixed with 15 g of lactose and the mixture is dispersed with stirring in the aqueous lecithin solution. The suspension is spray-dried in a NIRO Minor Mobile spray dryer using the following parameters • Inlet air temperature: 160 ° C • Exit air temperature: 93 ° C • Compressed air pressure (rotary atomizer): 6 x 10 ~ 5 Pa (32, 000 rpm) • Atomization air flow ratio : 100 m3 / h • Pump speed: 353 mi per hour The spray drying performance is between 50 and 90%. The water content of the powder is between 0.5 and 1% (m / m). The particles, before micronization have an average diameter d 23.6 μm. The spray-dried material is micronized in a fluid jet mill (MCC 50, JET Pharma S.A). The particles before being placed in the cartridges, have an average diameter of 1.5 μm (100% of the particles have a size smaller than 5 μm). The cartridges are automatically filled in a room with controlled atmosphere (20 ° C ± 2 ° C, relative humidity less than 15%) using a filling machine such as a Pamasol system. The micronized material is introduced successively and mixed with HFA134a and then only pressurized HFA134a gas is used to clean the cartridge valves. The cartridges are wrapped with a film that is impervious to moisture at the same time. The cartridges are wrapped and the analysis of the composition gives the following results: For a product of 2 5 0 μ g / do s i s (63 μl metering valve): BDP: 40 mg Lecithin: 4 mg Lactose: 4 mg HFA134a: 11,952 g For a product of 100 μg / dos s metering valve 63 μl): BDP: 16 mg Lecithin 1.6 mg Lactose: 1.6 mg HFAl34a: 11,981 g For a product of 50 μg / dose (63 μl metering valve): BDP: 8 mg Lecithin: 0.8 mg Lactose: 0.8 mg HFA134a: 11,990 g Example 7 22.5 g of lecithin are dissolved in 1500 ml of demineralized water at room temperature (20 ° C ± 2 ° C). 225 g of bec lome-tasone dipropionate monohydrate are premixed with 22.5 g of lactose and the mixture is dispersed with stirring in the aqueous lecithin solution. The suspension is spray dried in a NIRO Minor Mobile spray dryer using the following parameters: • Input air temperature: 160 ° C • Output air temperature: 87-90 ° C • Compressed air pressure (rotary atomizer): 6.5 x 10 ~ 5 Pa • Atomizing air flow ratio: 100 m3 / h • Pump speed: 353 mi per hour The spray drying performance is between 50 and 90%. The water content of the powder is between 0.5 and 1% (m / m). The particles, before micronization have an average diameter of 19 μm.

Example 8 22.5 of lecithin are dissolved in 1500 ml of demineralized water at room temperature (20 ° C ± 2 ° C). 225 g of beclomethasone dipropionate monohydrate are premixed with 22.5 g of lactose and the mixture is dispersed with stirring in the aqueous lecithin solution. The suspension is spray dried in a NIRO Minor Mobile spray dryer using the following parameters: • Inlet air temperature: 160 ° C • Outlet air temperature: 91-92 ° C • Compressed air pressure (rotary atomizer): 6.5 x 10 ~ 5 Pa • Atomizing air flow ratio: 100 m3 / h • Pump speed: 353 mi per hour The spray drying performance is between 50 and 90%. The water content of the powder is between 0.5 and 1 (m / m). The particles, before micronization, have an average diameter of 25.3 μm. The spray-dried material is micronized in a fluid jet mill (MCC 50, JET Pharma S.A). The particles before being placed in the cartridges, have an average diameter of 1.5 μm (100% of the particles have a size smaller than 5 μm).

Example 9 g of lecithin are dissolved in 2000 ml of demineralized water at room temperature (20 ° C ± 2 ° C). 300 g of bec 1 omega-1-dipropionate monohydrate are premixed with 30 g of lactose and the mixture is dispersed with stirring in the aqueous lecithin solution. The suspension is spray dried in a NIRO Minor Mobile spray dryer using the following parameters: • Input air temperature: 160 ° C • Output air temperature: 93-94 ° C • Compressed air pressure (rotary atomizer): 6.5 x 10"5 Pa • Atomizing air flow ratio: 100 m3 / h • Pump speed: 480 mi per hour The spray drying performance is between 50 and 90%. The water content of the powder is between 0.4 and 1% (m / m). The particles, prior to my cronicization, have an average diameter of 21.4 μm. The spray-dried material is micronized in a fluid jet mill (MCC 50, JET Pharma S.A). The particles before being placed in the cartridges, have an average diameter of 1.7 μm (100% of the particles have a size smaller than 5 μ). The cartridges are automatically filled in a room with controlled atmosphere (20 ° C ± 2 ° C, relative humidity less than 15%) using a filling machine such as a Pamasol system. The micronized material is introduced successively and mixed with HFA134a and then only pressurized HFA134a gas is used to clean the cartridge valves. The cartridges are wrapped with a film that is impervious to atmospheric moisture. The cartridges are wrapped and the analysis of the composition provides the following results: For a product of 250 μg / dose (63 μl metering valve): BDP: 40 mg Lecithin 4 mg Lactose: 4 mg HFA134a: 11,952 g For a product of 100 μg / dose (63 μl dosing valve): BDP 16 mg Lecithin: 1.6 mg Lactose: 1.6 mg HFA134a: 11.981 g For a product of 50 μg / do or 63 μl metering valve BDP: 8 mg Lecithin: 0.8 mg Lactose: 0.8 mg HFA134a: 11,990 g Example 10 g of lecithin are dissolved in 2000 ml of deminerized water at room temperature (20 ° C ± 2 ° C). 300 g of bec lomene dipropionate monohydrate are premixed with 30 g of lactose and the mixture is dispersed under stirring in aqueous lecithin solution. The suspension is spray dried in a NIRO Minor Mobile spray dryer using the following parameters: • Inlet air temperature: 160 ° C • Outlet air temperature: 88-94 ° C • Compressed air pressure (rotary atomizer): 6.5 x 10 - "5D Pa • Atomizing air flow ratio: 100 m3 / h • Pump speed: 480 mi per hour The spray drying performance is between 80 and 90%. The particles, prior to my cronicization, have an average diameter of 12.5 μm. The spray-dried and micronized material in a fluid jet mill (MCC 50, JET Pharma S.A). The particles before being placed in the cartridges, have an average diameter of 1.5 μm (100% of the particles have a size smaller than 5 μm).

Example 11 Dissolve 15 g of lecithin in 1000 ml of demineralized water at room temperature (20 ° C ± 2 ° C). 150 g of dipropionate monohydrate of 1 to 100 grams of lactose are premixed and the mixture is dispersed with stirring in the aqueous lecithin solution. The suspension is spray dried in a NIRO Minor Mobile spray dryer using the following parameters: • Inlet air temperature: 200 ° C • Outlet air temperature: 88-94 ° C • Compressed air pressure (two nozzle atomizer for fluid): 4 x 10"5 Pa • Atomization air flow ratio : 100 m3 / h • Pump speed: 480 mi per hour The spray drying performance is between 50 and 90%. The spray dried material is micronized in a fluid jet mill (MCC 50, JET Pharma S.A.).

The particles, before being placed in cartridges, have an average diameter of 1.5 μm (100% of the particles have a size smaller than 5 μm). The cartridges are manually filled in a room with controlled atmosphere (20 ° C ± 2 ° C, relative humidity less than 15%) by successively introducing the micronized material and then the pressurized HFA134a gas. The cartridges are wrapped with a film that is impervious to moisture at the earliest. The cartridges are wrapped and the analysis of the composition gave the following results: For a product of 250 μg / dose (63 μl metering valve): BDP: 40 mg Lesson: 4 mg Lactose: 4 mg HFA134a: 11,952 g Example 12 g of lecithin are dissolved in 2000 ml of demineralized water at room temperature (20 ° C ± 2 ° C). 150 g of beclomethasone dipropionate monohydrate are premixed with 30 g of lactose and the mixture dispersed with stirring in the aqueous lecithin solution. The suspension is spray dried in a NIRO Minor Mobile spray dryer using the following parameters: • Inlet air temperature: 150 ° C • Outlet air temperature: 83-90 ° C • Compressed air pressure (two nozzle atomizer for fluid): 6 x 1 O "5 Pa • Air flow ratio of atomization: 100 m3 / h • Pump speed: 1.41 kg / h The spray drying performance is between 50 and 90%.

The spray dried material is micronized in a fluid jet mill (MCC 50, JET Pharma S.A.).

The particles, before being placed in cartridges, have an average diameter of 1.5 μm (100% of the particles have a size smaller than 5 μm).

The cartridges are filled manually in a room with controlled atmosphere (20 ° C ± 2 ° C, relative humidity less than 151) by successively introducing the micronized material and then the pressurized HFA134a gas.

The cartridges are wrapped with a film that is impervious to atmospheric moisture.

The cartridges are wrapped and the analysis of the composition gave the following results: For a product of 250 μg / dose. s (63 μl metering valve): BDP: 4 O mg Lecithin: 4 mg Lactose: 4 mg HFA134a: 11,952 g Example 13 g of lecithin are dissolved in 2000 ml of demineralized water at room temperature (20 ° C ± 2 ° C). 300 g of beclomethasone dipropionate monohydrate are premixed with 30 g of lactose and the mixture is dispersed with stirring in the aqueous lecithin solution.

The suspension is spray dried in a NIRO Minor Mobile spray dryer using the following parameters: • Inlet air temperature: 170 ° C • Outlet air temperature: 83-90 ° C • Compressed air pressure (two nozzle atomizer for fluid): 6 x 10"5 Pa • Atomization airflow ratio : 100 m3 / h • Pump speed: 2.33 kg / h The spray drying performance is between 50 and 90%.

The spray dried material is micronized in a fluid jet mill (MCC 50, JET Pharma S.A.).

The particles, before being placed in cartridges, have an average diameter of 1.5 μm (100% of the particles have a size smaller than 5 μm).

The cartridges are filled manually in a room with controlled atmosphere (20 ° C ± 2 ° C, relative humidity less than 15%) successively introducing the micronized material and then the pressurized HFA134a gas.

The cartridges are wrapped with a film that is impervious to moisture at the same time. The cartridges are wrapped and the analysis of the composition gave the following results: For a product of 250 μg / dose (metering valve of 63 μl): BDP: 40 mg Leci t ina: 4 mg Lactose: 4 mg HFA134a: 11,952 g Example 14 0.2 g of lecithin can be dissolved in 200 ml of demineralized water at room temperature (20 ° C ± 2 ° C). 10 g of xinafoate; salmeterol, as micronized particles, are premixed with 2g of lactose and the mixture is e. it can be dispersed under agitation in the aqueous lecithin solution. The suspension thus obtained contains 5% salmeterol xinafoate, 1% lecithin and 1% lactose. The spray suspension can then be dried in a Mini Spray Dryer Büchi 191, with the following parameters: • Inlet air temperature: 105 ° C • Exit air temperature: 58 ° C • Compressed air pressure: 7 x 10"5 Pa • Atomizing air flow ratio: 800 Nl / h • Air flow drying: 28 m3 / h • Feed flow: 5 ml / h The spray drying performance should be around 70%. The water content of the powder should be less than 0.5% (m / m). The particles, before being micronized, should have an average diameter between 2 and 5 μm.

The spray-dried material obtained can be micronized in a fluid jet mill (MCC 50, JET Pharma S.A.). under a pressure of 8 x 10 ~ 5 Pa.

The particles, before being placed in cartridges, should have an average diameter of around 1.5 μ.

The cartridges can be filled manually by successively introducing the micronized material and then the pre-surfaced HFA 134a gas.

It is noted that in relation to this date, the best method known by the applicant to carry out the present invention is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following

Claims (39)

1. A pharmaceutical aerosol formulation, characterized in that it comprises: (A) a therapeutic agent in the form of particles coated by at least one coating excipient and at least one surfactant, in suspension in (B) a liquefied propellant gas, selected from of 1,1,1,2-tet ra f luoroe t an, 1,1,1,2,3,3,3-hept af luoropropane and mixtures thereof.

2. An aerosol pharmaceutical formulation, according to claim 1, characterized in that the drug is a therapeutic agent that can be administered by the pulmonary route and that is insoluble in the suspension medium used for the preparation of the formulation.

3. A pharmaceutical aerosol formulation, according to claim 2, characterized in that the therapeutic agent is selected from beclomethasone dipropionate, salbutamol (for example as sulfate or free base), salmeterol (for example as the salt 1-hydroxy-2-naphoate) ), fluticasone propionate or solvates thereof.

4. A pharmaceutical aerosol formulation according to claim 3, characterized in that the therapeutic agent is beclomethasone dipropionate or a solvate thereof, in particular beclomethasone dipropionate monohydrate.

5. A pharmaceutical aerosol formulation, according to claim 3, characterized in that it can contain a combination of two or more therapeutic agents.

6. A pharmaceutical aerosol formulation, according to any of claims 1 to 5, characterized in that the surfactant is a surfactant that can be administered by the pulmonary route, selected from nonionic, anionic and cationic surfactants.

7. A pharmaceutical aerosol formulation, according to claim 6, characterized in that the surfactant is selected from oleic acid, sorbitan trioleate, sorbitan monooleate, sorbitan monolaurate, polyoxyethylene (20), sorbitan monolaurate, polyoxyethylene (20), monooleate of sorbitan, natural lecithin, polyoxyethylene (2) oleyl ether, polyoxyethylene (2) eth r stearyl, polyoxyethylene (4) lauryl ether, block copolymers of ethylene oxide and propylene oxide, synthetic lecithin, diethylene glycol dioleate, oleate tetrahydrofurfuryl, ethyl oleate, myristate *, or isopropyl, glyceryl monooleate, glyceryl monostearate, glyceryl monoricinolate, cetyl alcohol, stearyl alcohol, polyethylene glycol 400 or monolaurate or glyceryl, ce tiylpiperium chloride or benzalkonium chloride .

8. A pharmaceutical formulation in aerosol, according to claim 1, characterized in that the surfactant is the lecithin.

9. A pharmaceutical aerosol formulation, according to any of claims 1 to 8, characterized in that the drug particles are additionally coated by a vegetable oil.

10. A pharmaceutical aerosol formulation, according to claim 9, characterized in that the vegetable oil is selected from olive oil, corn oil, cottonseed oil and sunflower seed oil.

11. A pharmaceutical aerosol formulation, according to any one of claims 10, characterized in that the propellant is 1, 1, 1, 2 - 1 e t ra f luoroe t ano.

12. A pharmaceutical aerosol formulation, according to any of claims 1 to 11, characterized in that the average size of the coated drug particles is within the range of 0.5 to 10 μm.

13. A pharmaceutical aerosol formulation according to claim 12, characterized in that the average size of the coated drug particles is within the range of 1 to 5 μm.

14. A pharmaceutical aerosol formulation, according to any of claims 1 to 13, characterized in that it contains, in addition to the components (A) and (B), additional ingredients such as solvents or surfactants other than those coated on the drug particles.

15. A pharmaceutical aerosol formulation, according to any of claims 1 to 13, characterized in that it does not contain ingredients other than the particles of the drug (A) and the propellant (B).

16. A process for the preparation of an aerosol pharmaceutical formulation, according to any of claims 1 to 15, characterized in that it comprises the steps consisting of: (a) preparing a suspension containing - the therapeutic agent in the form of particles, - a suspending medium that is not a solvent for the therapeutic agent - the coating excipient dissolved in the suspension medium and - the surfactant; (b) spray-drying the suspension of the therapeutic agent obtained in step (a) to obtain drug particles coated by the excipient and the surfactant; (c) suspending the coated drug particles obtained in step (b) in the liquefied propellant gas.

17. A process for the preparation of an aerosol pharmaceutical formulation, according to claim 16, characterized in that it comprises an additional step of reducing the size of the coated particles, obtained by spray drying, before suspending the propellant.

18. A process for the preparation of an aerosol pharmaceutical formulation, according to claim 16 or 17, characterized in that the average size of the coated drug particles is within the range of 0.5 to 10 μm.

19. A process for the preparation of an aerosol pharmaceutical formulation, according to claim 18, characterized in that the average size of the coated drug particles is between 1 μm and 5 μm.

20. A process for the preparation of a pharmaceutical aerosol formulation, according to any of claims 16 to 19, characterized in that the suspending medium is a medium that is not a solvent for the drug and that is a solvent for the excipient of coating.

21. A process for the preparation of an aerosol pharmaceutical formulation, according to claim 20, characterized in that the suspending medium is water.

22. A process for the preparation of a pharmaceutical aerosol formulation, according to any of claims 16 to 21, characterized in that the step of preparing the suspension (step (a)) consists in directly suspending the drug particles in a suspension medium containing the dissolved coating excipient and the surfactant.

23. A process for the preparation of a pharmaceutical aerosol formulation, of; according to any of claims 16 to 21, characterized in that the step of preparing the suspension (step (a)) comprises two successive steps consisting of (i) reabsorb the agent t ens i oac t i o on the particles of the drug, and then (ii) suspend the drug particles carrying the surfactant, in the suspension medium containing, in the dissolved form, the coating excipient.

24. A process for the preparation of an aerosol pharmaceutical formulation, according to any of claims 16 to 23, characterized in that the content of the therapeutic agent in the suspension obtained in step (a) is within the range of 1 to 40% (mass / volume).

25. A process for the preparation of an aerosol pharmaceutical formulation, according to claim 24, characterized in that the content of therapeutic agent in the suspension is within the range of 5 to 20% (more to / vo lumen).

26. A process for the preparation of a pharmaceutical aerosol formulation, in accordance with any of 1 a. s claims 16 to 25, characterized in that the agent / drug / agent ratio in the suspension of step (a) is in the range of 1 to 20% by weight.

27. A process for the preparation of an aerosol pharmaceutical formulation, according to claim 26, characterized in that the agent / drug / agent ratio is in the range of 5 to 10% by weight.

28. A process for the preparation of a pharmaceutical aerosol formulation, according to any of claims 16 to 27, characterized in that the coating excipient / drug ratio, in the suspension of step (a) is found in the range from 1 to 20% by weight.

29. A process for the preparation of an aerosol pharmaceutical formulation, according to claim 28, characterized in that the excipient / drug ratio is in the range of 5 to 10% by weight.

30. A process for the preparation of a pharmaceutical aerosol formulation, according to any of claims 16 to 29, characterized in that it comprises filling cartridges, successively, with the particles obtained after spray drying or micronization and then with the propellant. .

31. A process for the preparation of a pharmaceutical aerosol formulation, according to any of claims 16 to 30, characterized in that it comprises filling cartridges, in a single step, by introducing a suspension of the coated particles, which is obtained after spray drying or my croni zation, in the propellant.

32. A process for the preparation of a pharmaceutical aerosol formulation, according to any of claims 16 to 30, characterized in that it comprises filling cartridges, first by the introduction of coated particles, which are obtained after spray drying or micronizing. tion, and secondly by the introduction of the pr opul sor.

33. A process for the preparation of an aerosol pharmaceutical formulation, according to any of claims 30 to 32, characterized in that it comprises wrapping the refilled cartridges with a film that is impermeable to atmospheric humidity.

34. The particles of active pharmaceutical principles suitable for use, in combination with a propellant gas, in an aerosol pharmaceutical formulation according to any of claims 1 to 19, characterized in that they are composed of a therapeutic agent coated by at least one coating excipient and at least one surfactant.

35. Particles of pharmaceutical active ingredients characterized in that they can be obtained by a process comprising the steps consisting of: (a) prepare a suspension containing - the therapeutic agent in the form of particles, - a suspending medium that is not a solvent for the therapeutic agent - at least one excipient selected from lactose and trehalose dissolved in the suspension medium and - the surfactant; (b) spray-drying the suspension of the active principle obtained in step (a) to obtain drug particles coated by the excipient and by the surfactant;

36. The particles according to claim 35, characterized in that the therapeutic agent is beclomethasone dipropionate or a solvate thereof, the suspending medium is water, the coating excipient is lactose and the surfactant is lecithin.

37. A pharmaceutical aerosol formulation, characterized in that it can be obtained by a process according to any of claims 16 to 29.

38. A cartridge characterized in that it contains a pharmaceutical aerosol formulation according to any of claims 1 to 15 and 37.

39. A cartridge according to claim 38, characterized in that it is wrapped with a film that is impervious to atmospheric humidity.