ES2370236T3 - PROCEDURE OF MANUFACTURE OF PARTICLES FOR USE IN A PHARMACEUTICAL COMPOSITION. - Google Patents

Abstract

A process for the manufacture of active particles composed for use in a pharmaceutical composition for pulmonary administration, the process comprising a grinding stage in which particles of active material are ground in the presence of particles of an additive material so as to ensure a sufficient breakage of the agglomerates of both the active material and the additive material, a homogeneous dispersion and distribution of the additive material on the active material, and so that the particles of additive material fuse with the surface of the particles of active material, being the appropriate additive material for the promotion of the dispersion of the active compound particles after the performance of an inhaler, involving the grinding stage: (a) passing a mixture of particles of additive material and particles of active material into a liquid, through a narrowing under pressure; (b) use a high pressure homogenizer in which a fluid containing the particles is forced to pass through a high pressure valve that produces high shear and turbulence conditions; (c) compressing a mixture of the active particles and the additive particles in a predetermined width space; (d) grind with balls; or (e) air-grinding particles of additive material with particles of active material, in which, when the grinding stage is (e), air-grinding, the additive material includes one or more of: an amino acid or derivative thereof; a peptide or derivative thereof; a phospholipid or derivative thereof; a metallic stearate or derivative thereof; sodium benzoate, hydrogenated oils that are solid at room temperature, talc, titanium dioxide, aluminum dioxide, silicon dioxide, starch; a surfactant material that includes a material that is surfactant in the solid state that can be soluble or insoluble in water, lecithin that includes soy lecithin; a solid state fatty acid that includes oleic acid, lauric acid, palmitic acid, stearic acid, erucic acid, behenic acid or derivatives (including esters and salts) thereof such as glyceryl behenate, phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols, lauric acid and its salts that include sodium lauryl sulfate, magnesium lauryl sulfate; triglycerides that include Dynsan 118 and Cutina HR; and sugar esters.

Description

Particle manufacturing process for use in a pharmaceutical composition

The present invention relates to particles and particle manufacturing processes. In particular, the invention relates to manufacturing processes of compound active particles comprising a pharmaceutically active material for inhalation.

Administration to patients of drugs in the form of fine particles (active particles) is known. For example, in pulmonary administration a particulate medication composition is inhaled by the patient. Pulmonary administration is particularly suitable for medications that seek to cure or relieve respiratory conditions such as asthma and for medications that are not suitable for oral ingestion such as certain biological macromolecules. Known devices for administering drugs to the respiratory system include pressurized metered dose inhalers (pMDI) and dry powder inhalers (DPI).

The size of the active particles of is of great importance in determining the absorption site. In order for the particles to be deeply transported to the lungs, the particles must be very thin, for example, having a median mass aerodynamic diameter of less than 10 µm. It is likely that particles that have aerodynamic diameters greater than 10 µm impact the throat walls and generally do not reach the lung. Particles that have aerodynamic diameters in the range of 5 µm to 0.5 µm will generally be deposited in the respiratory bronchioles, while smaller particles that have aerodynamic diameters in the range of 2 to 0.05 µm are likely to be deposited in the alveoli.

However, such small particles are thermodynamically unstable due to their high surface area to volume ratio that provides a significant excess of surface free energy and encourages the particles to agglomerate. In the inhaler, the agglomeration of small particles and the adhesion of the particles to the walls of the inhaler are problems that cause the active particles to leave the inhaler as large agglomerates or that cannot leave the inhaler and remain attached to the interior of the inhaler.

In an attempt to improve that situation, dry powders for use in dry powder inhalers frequently include particles of an excipient material mixed with fine particles of active materials. Such particles of excipient material may be thick, for example, having mediums of the mass aerodynamic diameter greater than 90 µ (such thick particles are hereinafter referred to as vehicle particles) or they may be thin.

The step of dispersing the active particles of other active particles and of particles of excipient material, if present, to form an aerosol of fine active particles for inhalation is significant in determining the proportion of the dose of active material that reaches the Desired absorption site in the lungs. In order to improve the efficiency of this dispersion it is known to include additive materials in the composition. It is believed that such additive materials reduce the forces of attraction between the particles, thus promoting their dispersion. Compositions comprising fine active particles and additive materials are disclosed in WO 97/03649.

Fine particles of active material suitable for pulmonary administration have been frequently prepared by milling, for example, jet milling. However, once the particles reach a minimum size hereinafter referred to as the critical size, they recombine at the same rate that they fracture, or do not fracture effectively and, therefore, the size is not further reduced.

Therefore, the manufacture of fine particles by grinding may require a lot of effort and there are factors that, therefore, place limits on the minimum particle size of active material that can be achieved in practice by such milling processes.

WO / 27363 discloses pressurized and non-pressurized milling operations that can be used to form drug particles having a surface modifier on their surface.

U.S. Pat. No. 5,506,203 discloses dry powder compositions containing insulin and an enhancer compound. The powder can be prepared by micronizing the active compounds, for example, by jet milling, but the compounds should be micronized separately when they have different physical properties such as hardness.

The present invention provides in a first aspect a process for the preparation of active particles composed for use in a pharmaceutical composition for pulmonary administration, the method comprising a milling stage in which the particles of active material are milled in the presence of particles of an additive material so as to ensure sufficient breakage of the agglomerates of both active material and additive material, a homogeneous dispersion and distribution of the additive material on the active material, and so that the particles of additive material fuse with the surface of The particles of active material, the additive material being suitable for the promotion of the dispersion of the active particles composed after the discharge of an inhaler, involving the grinding stage:

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(to)

to pass a mixture of particles of additive material and particles of active material, in a liquid, through a narrowing under pressure;

(b)

using a high pressure homogenizer in which a fluid containing the particles is forced to pass through a high pressure valve that produces high shear and turbulence conditions;

(C)

compress a mixture of the active particles and the additive particles in a predetermined width space;

(d)

grind with balls; or

(and)

grind particles of additive material with particles of active material,

wherein, when the grinding stage is (e), grinding with air jet, the additive material includes one or more of: an amino acid or derivative thereof; a peptide or derivative thereof; a phospholipid or derivative thereof; a metallic stearate or derivative thereof; sodium benzoate, hydrogenated oils that are solid at room temperature, talc, titanium dioxide, aluminum dioxide, silicon dioxide, starch; a surfactant material that includes a material that is surfactant in the solid state that can be soluble or insoluble in water, lecithin that includes soy lecithin; a solid state fatty acid that includes oleic acid, lauric acid, palmitic acid, stearic acid, erucic acid, behenic acid or derivatives (including esters and salts) thereof such as glyceryl behenate, phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols, lauric acid and its salts that include sodium lauryl sulfate, magnesium lauryl sulfate; triglycerides that include Dynsan 118 and Cutina HR; and sugar esters.

Composite active particles are very fine particles of active material that have a quantity of additive material on their surfaces. The additive material is preferably in the form of a coating on the surfaces of the active material particles. The coating may be a discontinuous coating. The additive material may be in the form of particles that adhere to the surfaces of the active material particles. As explained below, at least some of the active compound particles may be in the form of agglomerates.

When the compound active particles are included in a pharmaceutical composition, the additive material promotes the dispersion of the compound active particles after administration of that composition to a patient by discharge from an inhaler ("Discharge from an inhaler" refers to the procedure during which one dose of powder is removed from its resting position in the inhaler. This stage takes place after the powder has been loaded into the inhaler ready for use.) It has been found that the effectiveness of that dispersion promotion is enhanced compared to a composition prepared by simply mixing particles of similar size of active material with additive material.

The presence of the additive material on the surfaces of the active material particles may confer controlled or delayed release properties and may provide a moisture barrier.

It has also been found that grinding the particles of active material in the presence of an additive material produces significantly smaller particles and / or requires less time and less energy than the equivalent procedure carried out in the absence of the additive material. Using the method of the invention it has been possible to produce compound active particles having a median mass aerodynamic diameter (MMAD) or a volumetric mean diameter (VMD) of less than 1 µm. Frequently it is not possible to prepare such small particles by other grinding processes.

It is known that a grinding process will tend to generate and increase the level of amorphous material on the surfaces of the ground particles making them more cohesive. In contrast, the compound active particles of the invention will often be less cohesive after grinding treatment.

The word "grinding" as used herein refers to any mechanical procedure that applies sufficient force to particles of active material that can break up coarse particles (for example, particles of mass average aerodynamic diameter greater than 100 µm) to particles. Thin median of the mass aerodynamic diameter not exceeding 50 µm or applying a relatively controlled compressive force as described below in relation to the Mecano-Fusion and mixed cycle procedures. It has been found that processes such as mixing that do not apply a high degree of force are not effective in the process of the invention. It is believed that it is because a high degree of force is required to separate the individual particles from the active material and to break tightly bonded agglomerates of the active particles so that effective mixing and effective application of the additive material to the surfaces is achieved. of those particles. It is believed that an especially desirable aspect of the milling process is that the additive material can deform in the milling and is smeared with or fused with the surfaces of the active particles. However, it should be understood that in the case where the particles of active material are already fine, for example, having a median mass aerodynamic diameter of less than 20 µ before the grinding stage, the size of those particles cannot significantly reduced What is important is that the grinding process applies a sufficiently high degree of force or energy to the particles.

The process of the invention generally involves placing the additive particles in close contact with the surfaces of the active particles. In order to achieve coated particles a degree of mixing is required

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intensive to ensure sufficient breakage of agglomerates of both constituents, dispersion and homogeneous distribution of additive on the active host particles.

If the additive particles are very small (usually <1 micrometer), less work is generally required, first since it does not require breaking or deforming, but only deagglomerating, distributing and incorporating the additive particles on the active particle and in secondly due to the naturally high surface energies of such small additive particles. It is known that when two powder components are mixed and the two components differ in size there is a tendency for small particles to adhere to large particles (to form the so-called 'ordered mixtures'). Small-range van der Waals interactions for such very fine components may be sufficient to ensure adhesion. However, when both the additive and active particles are very fine (for example, less than 5 micrometers), a substantial degree of mixing will be required to ensure sufficient breakage of agglomerates of both constituents, homogeneous dispersion and distribution of additive particles on the active particles as noted above. In some cases, simple contact adhesion may be insufficient and stronger incorporation or fusion of additive particles onto active particles is required to prevent segregation, or to enhance the structure and functionality of the coating.

If the additive particles are not so small as to adhere sufficiently by van der Waals forces alone, or when there are advantages to distort and / or incorporate the additive particles substantially on the host active particle, a greater degree of energy from grinding In this case, the additive particles should experience sufficient strength to soften and / or break, to distort and flatten them. These procedures are enhanced by the presence of relatively harder active particles acting as grinding media, in addition to a deagglomerating medium for such procedures. As a consequence of this procedure, the additive particles can be wrapped around the active core particle to form a coating. These procedures are also enhanced by the application of a compressive force as mentioned above.

As a consequence of the grinding stage, complete or partial, continuous or discontinuous, porous or non-porous coatings can be formed. The coatings originate from a combination of active particles and additive. They are not coatings such as those formed by wet processes that require the dissolution of one or both components. In general, such wet coating processes are likely to be more expensive and require more time than the grinding process of the invention and also suffer the disadvantage that it is less easy to control the location and structure of the coating.

A wide range of devices and grinding conditions are suitable for use in the process of the invention. Grinding conditions, for example, intensity and duration of grinding, should be selected to provide the required degree of force. Ball milling is a preferred procedure. Centrifugal and planetary ball milling are especially preferred procedures. Alternatively, a high pressure homogenizer can be used in which a fluid containing the particles is forced to pass through a high pressure valve that produces high shear and turbulence conditions. The shear forces on the particles, the impacts between the particles and the surfaces of the machines or other particles and the cavitation due to the acceleration of the fluid can all contribute to the fracture of the particles and can also provide a compressive force. Such homogenizers may be more suitable than ball mills for use in large-scale preparations of the compound active particles. Suitable homogenizers include EmulsiFlex high pressure homogenizers that are capable of pressures up to 4000 bar (400 MPa), Niro Soavi high pressure homogenizers (which are capable of pressures up to 2000 bar (200 MPa)) and Microfluidics microfluidizers (maximum pressure 2750 bar (275 MPa)). The grinding stage may alternatively involve a high energy media mill or a stirring pearl mill, for example, the Netzch high energy media mill, or the DYNO mill (Willy A. Bachofen AG, Switzerland). Alternatively, the grinding can be a high energy dry coating process such as a Mecano-Fusion system (Hosokawa Micron Ltd) or a Hybridizer (Nara). Other possible milling devices include air jet mills, barbed mills, hammer mills, knife mills, ultracentrifugal mills and pistil and mortar mills.

Especially preferred procedures are those involving the Mecano-Fusion, Hybridiser and Mixed cycle instruments.

Preferably, the milling step involves the compression of the mixture of active particles and additive into a space (or groove) of fixed predetermined width (for example, as described later in the procedures with Mechano-Fusion and Mixed Cycle).

Some preferred milling procedures will now be described in greater detail.

Mecano-Fusion:

As the name suggests, this dry coating process is designed to mechanically fuse a first material over a second material. The first material is generally smaller and / or softer than

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the second. The working principles of Mecano-Fusión and Mixed Cycle are different from alternative grinding techniques in that they have a particular interaction between the internal element and the vessel wall and are based on providing energy by a controlled and substantial compressive force.

The fine active particles and the additive particles are fed to the Mecano-Fusion-operated vessel in which they are subjected to a centrifugal force and pressed against the inner wall of the container. The powder is compressed between the fixed space of the drum wall and a curved internal element with high relative velocity between the drum and the element. The inner wall and the curved element together form a space or groove in which the particles are pressed together. As a result, the particles experience very high shear forces and very strong compressive stresses as they are trapped between the inner wall of the drum and the inner element (which has a greater curvature than the inner wall of the drum). The particles collide violently with each other with sufficient energy to heat and soften locally, break, distort, flatten and wrap the additive particles around the core particle to form a coating. The energy is generally sufficient to break agglomerates and some degree of size reduction of both components can occur. The incorporation and fusion of additive particles on the active particles can occur, and can be facilitated, by the relative differences in the hardness (and optionally size) of the two components. Both the outer container and the inner element can rotate to provide relative movement. The space between these surfaces is relatively small, and is usually less than 10 mm and is preferably less than 5 mm, more preferably less than 3 mm. This space is fixed and, consequently, leads to a better control of the compressive energy that is provided in some other forms of the mill such as ball and media mills. Therefore, in general, the impact of grinding media surfaces is not present, so that wear and, therefore, contamination are minimized. The rotation speed can be in the range of 200 to 10,000 rpm. A scraper can also be present to break any formation of hardened material on the surface of the container. This is particularly advantageous if fine cohesive starting materials are used. The local temperature can be controlled using a heating / cooling jacket assembled on the walls of the drum container. Dust can be recirculated through the container.

Mixed cycle procedure (Hosokawa Micron):

The mixed cycle comprises a stationary conical vessel with a rapidly rotating shaft with vanes that move close to the wall. Due to the high rotational speed of the vanes, the powder is driven to the wall, and as a result the mixture experiences shear forces and very high compressive stresses between the wall and the vane. Such effects are similar to Mechano-Fusion as described above and may be sufficient to heat and soften locally, to break, distort, flatten and wrap the additive particles around the active particles to form a coating. The energy is sufficient to break agglomerates and some degree of size reduction of both components can also occur depending on the conditions and the size and nature of the particles.

Hybridiser procedure:

This is a dry process that can be described as a product incorporation or film formation of one powder over another. The fine active particles and the fine or ultrafine additive particles are fed to a conventional high shear mixer premix system to form an ordered mixture. Then, this powder is fed to the Hybridiser. The powder is subjected to impact at ultra-high speed, compression and shear as it is impacted by the blades in a high-speed rotor inside a stator vessel, and is recirculated into the vessel. The active and additive particles collide with each other. Typical rotation speeds are in the range of 5,000 to 20,000 rpm. The relatively soft fine additive particles undergo sufficient impact force to soften, break, distort, flatten and wrap around the active particle to form a coating. There may also be some degree of incorporation into the surface of the active particles.

Other preferred methods include ball mills and high energy media that can also provide the desired high shear force and compressive stresses between surfaces, although since the space is not controlled, the coating process may be less well controlled than for milling. with Mecano-Fusion and some problems may occur such as an unwanted degree of agglomeration. These media mills can be rotational, vibratory, agitation, centrifugal or planetary in nature.

It has been observed in some cases that when the active particles with additive material are ground with balls, a fine powder is not produced. Instead, the powder was compacted on the walls of the mill by the action of the mill. This has inhibited the grinding action and prevented the preparation of the active compound particles. That problem occurred particularly when certain additive materials were used, in cases where the additive material was present in small proportions (usually <2%), in cases where the grinding balls were relatively small (usually <3 mm) , in cases where the grinding speed was too slow and when the starting particles were too thin. To prevent this from occurring, it is advantageous to grind with balls in a liquid medium. The liquid medium reduces the tendency to compaction, helps in the dispersion of the additive material and improves any grinding action.

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It has been found that it is preferable to use a large number of fine grinding balls instead of less heavy balls. The finest balls perform a more efficient comolienda action. Preferably, the balls have a diameter of less than 5 mm, advantageously less than 2 mm. Liquid media that do not dissolve the active material and that evaporate rapidly and completely, for example, non-aqueous liquids such as diethyl ether, acetone, cyclohexane, ethanol, isopropanol or dichloromethane are preferred. Liquid media that are nonflammable are preferred, for example, dichloromethane and fluorinated hydrocarbons, especially fluorinated hydrocarbons that are suitable for use as propellants in inhalers.

Pestle and mortar mills are other mills that also provide very high shear force and compressive stresses between surfaces.

Mecan-Micros and Micros mills manufactured by Nara can also be used (in which the particles are compressed by rotating crushing rings). Mills called impact mixers, wear mills, barbed mills and disc mills can also be used.

The median of the mass aerodynamic diameter of the active material particles can be substantially reduced during the grinding stage, especially when the active material is in the form of coarse particles before the grinding stage. The median mass aerodynamic diameter (MMAD) of the active material particles can be reduced by at least 10%, at least 50% or at least 70% during the grinding stage depending on the grinding conditions and the MMAD of the active particles before the grinding stage.

Advantageously, after the milling step, the MMAD of the active particles is less than 9 µm, preferably less than 4 µm and more preferably less than 2 µm.

Similarly, when the additive material is in the form of coarse particles before the grinding stage, its MMAD will be substantially reduced during the grinding stage. The MMAD of the particles of additive material can be reduced by at least 10%, at least 50% or at least 70% during the grinding stage, depending on the grinding conditions and the MMAD of the particles of additive material before of the grinding stage. The size of the additive particles after the milling step is preferably significantly smaller than the size of the active particles to allow the additive materials to more effectively coat the surfaces of the active particles. In practice, this difference in size between the active particles and the additive particles is likely to be achieved as a result of grinding because the additive material will normally fracture or deform more easily than the active material and thus break up into more particles. smaller than the active material. As noted above, the particles of additive material fuse with the surfaces of the particles of active material, thus forming a coating that can be substantially continuous or discontinuous. If the coating is discontinuous, it preferably covers, on average, at least 50% (ie, at least 50% of the total surface area of the active particles will be covered by the additive material), more advantageously at least 70% and most preferably at least 90% of the surfaces of the active particles. The coating is preferably on average less than 1 µm, more preferably less than 0.5 µm and most preferably less than 200 nm thick.

The milling step can be carried out in a closed container, for example, in a ball mill or a Mechano-Fusion device. The use of a closed container prevents the loss of ultrafine particles or vapor of the additive material that has been found to occur in jet milling or other open procedures.

The milling can be wet milling, that is, the milling stage can be carried out in the presence of a liquid. This liquid medium can have high or low volatility and of any solid content as long as it does not dissolve the active particles to any significant degree and its viscosity is not so high that it prevents effective grinding. The liquid medium is preferably non-aqueous. The liquid is preferably one in which the additive material is substantially insoluble, but some degree of solubility may be acceptable provided there is sufficient additive material present such that particles of undissolved additive material remain. The presence of a liquid medium helps prevent the compaction of the particles of active material in the walls of the container and can also allow more uniform extension of the additive material on the surface of the particles of active material with respect to dry grinding.

It has been found that the Mecan-Fusion and Mixed Cycle techniques cited above frequently provide the compound active particles as individual compound active particles, that is, un agglomerated. This is unlike less controlled procedures such as ball milling, which has been found to frequently produce compound active particles in the form of agglomerated compound active particles.

The median of the mass aerodynamic diameter of the compound active particles is preferably no more than 10 µm, and advantageously no more than 5 µm, more preferably no more than 3 µm and most preferably no more than 1 µm. Accordingly, advantageously at least 90% by weight of the compound active particles have a diameter of no more than 10 µm, advantageously no more than 5 µm, preferably no more than 3 µm and more preferably no more than 1 µm . Advantageously, after the grinding stage, the active particles will be of a size suitable for inhalation to the desired part of the lung, for example, having an MMAD in

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the range of 3 to 0.1 µm for absorption in the deep lung, 5 to 0.5 µm for absorption in the respiratory bronchioles, 10 to 2 µm for administration to the upper respiratory system and 2 to 0.05 µm for administration to the alveoli. Accordingly, advantageously, the diameter of at least 90% by weight of the compound active particles has an aerodynamic diameter in the range of 3 to 0.1 µm, preferably 5 to 0.5 µm, advantageously 10 to 2 µm , and especially advantageously from 2 to 0.05 µm. The MMAD of the active particles will not normally be less than 0.01 µm.

As mentioned above, the compound active particles produced after the grinding stage can be of a size suitable for administration to the desired part of the respiratory system.

However, the compound active particles may be smaller than the appropriate size or at least some of the compound active particles may be, after the grinding stage, in the form of agglomerates that are larger than the appropriate size. Therefore, the process also comprises, after the grinding stage, a processing stage in which the degree of agglomeration of the active compound particles is changed. The processing stage may be an agglomeration stage in which the particles of active material agglomerate to form agglomerated composite active particles. In this way, agglomerates of a size adapted to the requirement can be produced. Although any agglomeration process can be used, for example, granulation, preferably, the compound active particles agglomerate in a drying step (as described below) to form agglomerated compound active particles. Preferably, the agglomeration stage is a spray drying stage. Spray drying conditions can be selected to produce droplets having a desired size in the range of 1000 µm to 0.5 µm. The size of the agglomerates produced will depend largely on the concentration of the active particles composed in the feed of the spray and the size of droplets. Other materials may be included in the spray feed, for example, binders. If the milling stage involves wet milling, the suspension can be spray dried directly after the milling stage. The agglomeration can also be performed in a fluidized bed dryer or granulator.

If, after the grinding stage, at least some of the active compound particles are in the form of agglomerates and it is desired to break those agglomerates or reduce their size, the processing stage may be a deagglomeration stage. The deagglomeration step may involve mechanical breakage of unwanted agglomerates, for example, by passing them through a sieve or subjecting them to a treatment in a dry fluidized bed, a jet mill, a ball mill or other form of grinding device. The intensity and / or duration of that treatment stage will, in general, be less than the grinding stage. The deagglomeration stage can also be a spray drying stage because, although spray drying as a drying stage is particularly useful in the preparation of agglomerated compound active particles, by proper control of the conditions it is possible to produce the particles active compounds largely as individual particles rather than as agglomerates.

The term "agglomerated compound active particles" refers to particles consisting of more than one compound active particle, those compound active particles adhering to each other. If the agglomerated particles are for inhalation they will preferably have an MMAD that makes them suitable for deposition in the desired part of the lung.

Preferably, the process comprises, after the grinding stage, a drying stage in which a mixture of the compound active particles and a liquid is dried to remove the liquid. The mixture may be in the form of a suspension. During the drying stage, especially when spray drying is used, the degree of agglomeration of the compound active particles may change, in which case the drying stage is the same stage as the processing stage mentioned above. However, the drying step may be included for other reasons, for example, when the milling is wet milling and it is desired to produce active active particles such as a dry powder.

The drying step may involve filtration followed by drying, or evaporation of the liquid. Preferably, the drying stage is a spray drying stage. Alternatively, the liquid may evaporate slowly or the drying stage may be a lyophilization stage.

The grinding is preferably dry, that is, there is no liquid present during grinding and the mixture to be milled is in the form of a dry particle. In that case, liquid may be added after the grinding stage, usually in order to use a drying step to form agglomerated compound active particles, as described above.

Advantageously, the milling step is carried out at a reduced temperature, for example, below 10 ° C and preferably below 0 ° C. Such low temperature conditions can increase the efficiency of the grinding stage and / or reduce the decomposition of the active material.

The optimum amount of additive material will depend on the chemical composition and other properties of the additive material and the nature of the active material and / or excipient material. In general, the amount of additive material in the composite particles shall not exceed 60% by weight, based on the weight of the active material and / or material of

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excipient However, it is believed that for most additive materials the amount of additive material should be in the range of 40% to 0.25%, preferably 30% to 0.5%, more preferably 20% to 2% , based on the total weight of the additive material and the active material that is ground. In general, the amount of additive material is at least 0.01% by weight based on the weight of the active material.

The terms "additive particles" and "particles of additive material" are used interchangeably herein. The additive particles comprise one or more additive materials. Preferably, the additive particles consist essentially of the additive material.

Advantageously, the additive material is a non-stick material and will tend to decrease cohesion between the compound active particles and between the compound active particles and any other particles present in the pharmaceutical composition.

Advantageously, the additive material is an antifriction (sliding) agent and will give a better fluidity of the pharmaceutical composition in, for example, a dry powder inhaler that will lead to a better reproducibility of the dose.

When reference is made to a non-stick material, or to an antifriction agent, the reference is to include those materials that can decrease cohesion between the particles, or that will tend to improve the fluidity of the powder in an inhaler, even if they cannot normally be referred to as The following non-stick material or anti-friction agent. For example, leucine is a non-stick material as defined herein and is generally believed to be a non-stick material, but lecithin is also a non-stick material as defined herein, even though it is generally not believed to be a non-stick, because it will tend to decrease cohesion between the compound active particles and between the compound active particles and any other particles present in the pharmaceutical composition.

The additive material may include a combination of one or more materials.

It will be appreciated that the chemical composition of the additive material is of particular importance. Preferably, the additive material is an animal or plant substance that occurs naturally.

Advantageously, the additive material includes one or more compounds selected from amino acids and derivatives thereof and peptides and derivatives thereof. Amino acids, peptides and peptide derivatives are physiologically acceptable and give acceptable release of active particles with inhalation.

It is particularly advantageous for the additive material to comprise amino acids. The additive material may comprise one or more of any of the following amino acids: leucine, isoleucine, lysine, valine, methionine, phenylalanine. The additive may be a salt or a derivative of an amino acid, for example, aspartame or acesulfame K. Preferably, the additive particles consist substantially of an amino acid, more preferably leucine, advantageously L-leucine. Forms D and DL can also be used. As indicated above, leucine has been found to give a particularly efficient dispersion of the active particles with inhalation.

The additive material may include one or more water soluble substances. This helps in the absorption of the substance by the body if the additive reaches the lower lung. The additive material may include dipole ions, which may be dipole ions.

Alternatively, the additive material may comprise a phospholipid or a derivative thereof. It has been found that lecithin is a good material for the additive material.

Preferably, the additive material comprises a metal stearate or a derivative thereof, for example, sodium stearyl fumarate or sodium stearyl lactylate. Advantageously, the additive material comprises a metallic stearate. For example, zinc stearate, magnesium stearate, calcium stearate, sodium stearate or lithium stearate. Preferably, the additive material comprises magnesium stearate.

The additive material may include or consist of one or more surfactant materials, in particular materials that are solid state surfactants that can be water soluble, for example, lecithin, in particular soy lecithin, or substantially water insoluble, for example , solid state fatty acids such as oleic acid, lauric acid, palmitic acid, stearic acid, erucic acid, behenic acid or derivatives (such as esters and salts) thereof such as glyceryl behenate. Specific examples of such materials are: phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols and other examples of natural and synthetic lung surfactants; lauric acid and its salts, for example, sodium lauryl sulfate, magnesium lauryl sulfate; triglycerides such as Dynsan 118 and Cutina HR; and sugar esters in general.

Other possible additive materials include sodium benzoate, hydrogenated oils that are solid at room temperature, talc, titanium dioxide, aluminum dioxide, silicon dioxide and starch.

The additive material preferably comprises one or more materials selected from the group consisting of amino acids, lecithins, phospholipids, sodium stearyl fumarate, glyceryl behenate and metal stearates (especially magnesium stearate).

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The terms "active particles" and "particles of active material" are used interchangeably herein. The active particles mentioned throughout the specification will comprise one or more pharmacologically active agents. The active particles advantageously consist essentially of one or more pharmacologically active agents. Suitable pharmacologically active agents may be materials for therapeutic and / or prophylactic use. Active agents that may be included in the formulation include those products that are normally administered orally by inhalation for the treatment of disease such as respiratory disease, for example, β-agonists.

The active particles may comprise at least one β2-agonist, for example, one or more compounds selected from terbutaline, salbutamol, salmeterol and formetorol. If desired, the active particles may comprise more than one of those active agents, provided that they are compatible with each other under storage and use conditions. Preferably, the active particles are salbutamol sulfate particles. It should be understood that references herein to any active agent include any physiologically acceptable derivative. In the case of the ß2-agonists mentioned above, the physiologically acceptable derivatives especially include salts, which include sulfates.

The active particles may be ipatropium bromide particles.

The active particles may include a steroid, which may be beclomethasone dipropionate or may be fluticasone. The active substance can include a chromone that can be sodium cromoglycate or nedocromil. The active substance may include a leukotriene receptor antagonist.

The active particles may include a carbohydrate, for example, heparin.

The active particles may advantageously comprise a pharmacologically active agent for systemic use and can advantageously be absorbed into the circulatory system by the lungs. For example, the active particles may comprise peptides or polypeptides such as DNase, leukotrienes or insulin. The pharmaceutical compositions of the invention may have particular application in the administration of insulin to diabetic patients, preferably avoiding normally invasive administration techniques used for that agent. The compound active particles could also be used for the local administration of other agents, for example, for pain relief (for example, analgesics such as tentanil or dihydroergotamine which is used for the treatment of migraine), anticancer activity, antivirals, antibiotics or local administration of vaccines to the respiratory tract.

Although it will often be desired to obtain the active compounds composed in dry form as described above, when the pharmaceutical composition is one comprising a liquid, for example, as a propellant, it may be preferable that the active particles are ground in the presence of that liquid and omit the drying step, simply using the suspension of the active particles composed in the liquid as a component in the pharmaceutical composition. Therefore, for example, if the pharmaceutical composition is for use in a pMDI, the active particles and the additive material can be milled in the presence of liquid propellant (under pressure or below room temperature if necessary). The resulting suspension can be used directly in a pMDI or additional materials may be added, for example, more propellant, surfactants or co-solvents.

Accordingly, the invention also provides in one embodiment a method of preparing compound active particles for use in a pharmaceutical composition, the process comprising a milling step in which particles of active material are ground in the presence of a liquid and a material additive that is suitable for the promotion of the dispersion of active compound particles after the discharge of a delivery device.

Preferably, the liquid comprises a propellant suitable for use in a pMDI. Suitable propellants include CFC-12, HFA-134a, HFA-227, HCFC-22 (difluorochloromethane), HCFC-123 (dichlorotrifluoroethane), HCFC124 (chlorotetrafluoroethane), dimethyl ether, propane, n-butane, isobutane, HFA-125 (pentafluoroethane ) and HFA-152 (difluoroethane).

However, if it is desired to isolate the dry compound active particles (or agglomerates thereof), the process may also include a drying stage, preferably a spray drying stage. Accordingly, in another embodiment, the invention provides a method of preparing compound active particles for use in a pharmaceutical composition, the process comprising

a wet grinding stage in which the particles of active material are milled in the presence of a liquid and an additive material that is suitable for promoting the dispersion of the active particles composed after the discharge of an administration device; and a drying stage in which the liquid is removed.

As explained above, the conditions of the drying stage, which is preferably a spray drying stage, can be chosen both to provide agglomerated composite active particles of a desired size and to provide substantially un agglomerated particles, that is, active particles. individual compounds.

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In some cases it may be preferable to perform the grinding stage in the absence of liquid (dry grinding). The compound active particles can then be agglomerated by mixing with a liquid and dried to give agglomerated compound active particles. Accordingly, in another embodiment, the invention provides a method of preparing agglomerated compound active particles for use in a pharmaceutical composition, the process comprising:

a dry grinding stage in which particles of active material are milled in the presence of an additive material that is suitable for promoting the dispersion of the active particles composed after the discharge of an administration device; and an agglomeration stage in which the compound active particles are mixed with a liquid and the mixture is dried to remove the liquid.

The invention also provides active particles composed for use in a pharmaceutical composition, preferably a pharmaceutical composition for inhalation, more preferably a powder for a dry powder inhaler.

The invention also provides composite active particles for use in a pharmaceutical composition, each active particle comprising a particle of active material and additive material comprising on the surface of that particle of active material, the active particles composed having a median of the mass aerodynamic diameter not greater than 2 µm, the additive material being suitable for the promotion of the dispersion of active compound particles after the discharge of an administration device. Preferably, the compound active particles have an MMAD not exceeding 1 µm, especially advantageously not exceeding 0.5 µm. As noted above, the composite particles may be in the form of agglomerated composite particles.

MMAD can be determined using an impactor, for example, a multi-stage liquid impactor. The mean volumetric diameters and measurements of the proportion of particles having a diameter less than a certain value can be determined by the Malvern laser light scattering procedure.

Advantageously, the compound active particles do not comprise significant amounts (more than 10% by weight) of a polymer of a type that would cause the particles to become tacky. Such polymers include polymers of an alpha-hydroxycarboxylic acid, for example, polylactic acid, lactic acid copolymers and block copolymers such as ethylene oxide / propylene oxide block copolymers or poloxamines.

The invention further provides a pharmaceutical composition comprising active compound particles. Preferably, the pharmaceutical composition is a dry powder and is suitable for use in a dry powder inhaler. Such pharmaceutical compositions may comprise essentially only the compound active particles.

or they may comprise additional components such as carrier particles and flavorings. The vehicle particles may be of any acceptable excipient material or combination of materials. For example, the carrier particles may be composed of one or more materials selected from sugar alcohols, polyols and crystalline sugars. Other suitable carriers include inorganic salts such as sodium chloride and calcium carbonate, organic salts such as sodium lactate and other organic compounds such as polysaccharides and oligosaccharides. Advantageously, the vehicle particles are of a polyol. In particular, the carrier particles may be crystalline sugar particles, for example, mannitol, dextrose or lactose. Preferably, the carrier particles are lactose.

Advantageously, substantially all vehicle particles (by weight) have a diameter that is between 20 µm and 1000 µm, more preferably 50 µm and 1000 µm. Preferably, the diameter of substantially all vehicle particles (by weight) is less than 355 µm and is between 20 µm and 250 µm. Preferably, at least 90% by weight of the vehicle particles have a diameter between 60 µm and 180 µm. The relatively large diameter of the vehicle particles improves the opportunity for other smaller particles to bond to the surfaces of the vehicle particles and provide good fluidity and drag characteristics and improved release of the active particles in the airways to Increase the deposition of active particles in the lower lung.

The ratio to which the vehicle particles (if present) and the compound active particles are mixed will, of course, depend on the type of inhaler device used, the type of active particle used and the dose required. The vehicle particles may be present in an amount of at least 50%, more preferably 70%, advantageously 90% and most preferably 95% based on the combined weight of the compound active particles and the vehicle particles.

If the carrier particles are included in the pharmaceutical composition, that composition also preferably includes small excipient particles having, for example, a particle size between 5 and 20 µm. Preferably, the small excipient particles are present in an amount of 1% to 40%, more preferably 5% to 20% based on the weight of the vehicle particles.

Compositions for use in a dry powder inhaler that include carrier particles will preferably include at least 2%, more preferably at least 5% and most preferably at least 10%

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by weight of the active compound particles based on the total mass of the composition. The compound active particles are especially suitable for dry powder compositions that do not include significant amounts of vehicle particles and in such compositions the compound active particles will preferably be present in a proportion of at least 60%, more preferably at least 80%. by weight based on the total weight of the composition.

The pharmaceutical composition may comprise a propellant and be suitable for use in a pressurized metered dose inhaler.

The invention also provides the use of an additive material as a grinding aid in the grinding of particles of active material. The term grinding aid should be understood to refer to a substance that reduces the amount of energy required to grind the particles of active material and / or excipient material.

Embodiments of the invention will now be described for purposes of illustration only with reference to the figures in which:

Figures 1 and 2 are scanning electron micrographs of the active particles composed of the Example one; Figure 3 is a scanning electron micrograph of the active particles composed of Example 1a; Figure 4 is a scanning electron micrograph of the composite particles of Example 2; Figure 5 is a scanning electron micrograph of the same sample of particles shown in the Figure 4 but at a greater increase; Figure 6 is a scanning electron micrograph of the composite particles of Example 3; Figure 7 is a scanning electron micrograph of the same sample of particles shown in the Figure 6 but at a greater increase; Figure 8 is a schematic drawing of part of a Mechano-Fusion machine; Y Figures 9 and 10 are electromicrographs of active particles composed according to the invention which they comprise salbutamol sulfate and magnesium stearate in a 19: 1 ratio (Example 4).

All percentages are by weight, unless stated otherwise.

Example 1

5 g of micronized salbutamol sulfate (particle size distribution: 1 to 5 µm) and 0.5 g of magnesium stearate were added to a 50 cm 3 stainless steel grinding vessel along with 20 cm 3 of

dichloromethane and 124 g of 3 mm stainless steel balls. The mixture was ground at 550 rpm in a Retsch S100 centrifuge mill for 5 hours. The powder was recovered by drying and sieving to remove the mill molas. An electron micrograph of the powder is shown in Figure 1. This was repeated 3 times using leucine instead of magnesium stearate and an electron micrograph of the powder is shown in Figure 2. The powders shown in Figures 1 and 2 appear to have particles in the size range of 0.1 to 0.5 µm.

Example 1a

Micronized salbutamol sulfate and magnesium stearate were combined as particles in a suspension in the 10: 1 ratio in propanol. This suspension was processed in an Emulsiflex C50 high pressure homogenizer for 5 sequential passes through the system at 25,000 psi (172.4 MPa). Then, this dry material was recovered by evaporating the propanol. The particles are shown in Figure 3.

Example 2

It was found that, on drying, the powder prepared in Example 1 that included magnesium stearate as an additive material formed assemblies of primary particles that were difficult to deagglomerate. A sample of this powder was again dispersed by ball milling for 90 minutes at 550 rpm in a mixture of ethanol, polyvinyl pyrrolidone (PVPK30) and HFA227 liquid propellant to give the following composition:

0.6% weight / weight Particles composed of salbutamol sulfate / magnesium stearate

0.2% weight / weight PVPK30

5.0% weight / weight Ethanol

94.2% weight / weight HFA 227

(PVP was included to stabilize the suspension of composite particles in ethanol / HFA227).

The suspension could be used directly as in a pMDI. However, in this example, the composition was sprayed from a pressurized can through a hole of ,40.4 mm in diameter to produce dry active particles composed of salbutamol sulfate and magnesium stearate with PVP. Those particles (shown in Figures 4 and 5) were collected and examined and found to be in the aerodynamic size range.

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from 0.1 to 4µm.

Example 3

The procedure of Example 2 was repeated, except that the composition was as follows:

3% weight / weight Particles composed of salbutamol sulfate / magnesium stearate

1% weight / weight PVPK30

3% weight / weight Ethanol

93% weight / weight HFA 227 The particles produced are shown in Figures 6 and 7. Example 4 Mixtures of salbutamol sulfate / magnesium stearate a) Homogenized magnesium stearate 240 g of magnesium stearate were suspended (Haen Riedel, size of particle by Malvern laser diffraction: d50 = 9.7 µm) in 2150 g of dichloroethane. Then, that suspension was mixed for 5 minutes in a Silverson high shear mixer. Then, the suspension was processed in an Emulsiflex C50 high pressure homogenizer equipped with a heat exchanger at 10,000 psi (68.9 MPa) for 20 minutes in circulation mode (300 cm3 / min) for 20 minutes. Then, the suspension was circulated at atmospheric pressure for 20 minutes allowing it to cool. The next day, the suspension was processed in circulation mode (260 cm3 / min) at 20,000 psi (137.9 MPa) for 30 minutes. Dichloroethane was removed by rotary evaporation followed by drying in a vacuum oven at 37 ° C overnight. The resulting cake of material was broken by grinding with balls for 1 minute. The homogenized magnesium stearate had a particle size of less than 2 µm.

b) A 9: 1 by weight mixture of salbutamol sulfate and homogenized magnesium stearate having a particle size of less than 2 µm was prepared by mixing the two materials with a spatula. An electron micrograph of the mixed material showed that the majority of the mixture was in the form of agglomerated particles, the agglomerates having diameters of 50 µm and greater. Then, the mixture was processed in a Mecano-Fusion mill

(Hosokawa) as follows:

Machine data:

Hosokawa Mecano-Fusion: AMS-Mini

Drive:

2.2 kW

Case:

Stainless steel

Rotor:

Stainless steel

Scraper:

None

Refrigeration:

Water

Purge with gas:

Any

The Mechano-Fusion device (see Figure 8) comprises a cylindrical drum 1 having an internal wall 2. In use, the drum rotates at high speed. The powder 3 of the active and additive particles is thrown by the centrifugal force against the inner wall 2 of the drum 1. A fixed arm 4 protrudes from the inside of the drum in a radial direction. At the end of the arm closest to the wall 2 the arm is provided with a member 5 having an arcuate surface 6, with a radius of curvature less than that of the inner wall 2, towards that inner wall. As the drum 1 rotates, it brings the powder 3 to the space between the arched surface 6 and the inner wall 2 in order to compress the powder. The space is of a fixed predetermined width. You can provide a scraper (not shown in Figure 8) to scratch the compressed dust from the drum wall.

All samples were premixed for 5 minutes running the machine at 1000 rpm. Then, the machine speed was increased to 5050 rpm for 30 minutes. The procedure was repeated for salbutamol sulfate / magnesium stearate in the following weight ratios: 19: 1, 3: 1, 1: 1.

The electron micrographs of the material processed at 19: 1 are shown in Figures 9 and 10 and indicate that the material was mainly in the form of small single particles with a diameter of less than 5 µm or in very loose agglomerates of such particles with only one agglomerate being visible. of the original type.

Then, the 3: 1 and 19: 1 mixtures were each loaded in a 20 mg capsule and calcined from a two-phase impactor. An unprocessed salbutamol sulfate sample was also calcined from the TSI to provide a comparison.

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Then the fine particle fractions were calculated and are given in Table 1. Table 1: Results of the fine particle fraction for mixtures of salbutamol sulfate

Composition

Fraction of fine particles in%

Salbutamol Sulfate

28

Salbutamol Sulfate / Magnesium Stearate 19: 1

66

Salbutamol Sulfate / Magnesium Stearate 3: 1

66

Example 5:

5 Micronized glycopyrrolate and homogenized magnesium stearate (as described in Example 4) were combined in a weight ratio of 75:25. Then, this mixture (~ 20 g) was ground in the AMS-Mini Mecan-Fusion system as follows. The powder was premixed for 5 minutes at ~ 900 rpm. Then, the machine speed was increased to -4,800 rpm for 30 minutes. During the milling treatment, the Mecano-Fusion machine operated with a space of 3 mm between the element and the vessel wall and water cooling was applied. So he

10 compound active particle powder was recovered from the drum container.

The experiment was repeated using the same procedure, but the active particle and homogenized magnesium stearate were combined in the 95: 5 ratio and ground for 60 minutes at 4,800 rpm.

This previous procedure was repeated using the same procedure with a sample of sodium salicylate as a model drug and homogenized magnesium stearate in the 90:10 ratio, in which sodium salicylate

15 had been produced as spheres of approximately micrometric size by spray drying from a Buchi 191 spray dryer.

It was realized that the spherical shape of these particles could be advantageous in the coating process. The grinding was for 30 minutes at 4,800 rpm.

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Claims (18)

1. A process for the manufacture of active particles composed for use in a pharmaceutical composition for pulmonary administration, the process comprising a grinding stage in which particles of active material are ground in the presence of particles of an additive material so that guarantees sufficient breakage of the agglomerates of both the active material and the additive material, a homogeneous dispersion and distribution of the additive material over the active material, and so that the particles of additive material are fused with the surface of the particles of active material , the additive material being suitable for the promotion of the dispersion of active compound particles after the performance of an inhaler, involving the grinding stage:

(to)

to pass a mixture of particles of additive material and particles of active material, in a liquid, through a narrowing under pressure;

(b)

using a high pressure homogenizer in which a fluid containing the particles is forced to pass through a high pressure valve that produces high shear and turbulence conditions;

(C)

compress a mixture of the active particles and the additive particles in a predetermined width space;

(d)

grind with balls; or

(and)

grinding air particles of additive material with particles of active material, in which, when the grinding stage is (e), grinding with air jet, the additive material includes one or more of: an amino acid or derivative thereof ; a peptide or derivative thereof; a phospholipid or derivative thereof; a metallic stearate or derivative thereof; sodium benzoate, hydrogenated oils that are solid at room temperature, talc, titanium dioxide, aluminum dioxide, silicon dioxide, starch; a surfactant material that includes a material that is surfactant in the solid state that can be soluble

or insoluble in water, lecithin that includes soy lecithin; a solid state fatty acid that includes oleic acid, lauric acid, palmitic acid, stearic acid, erucic acid, behenic acid or derivatives (including esters and salts) thereof such as glyceryl behenate, phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols, lauric acid and its salts that include sodium lauryl sulfate, magnesium lauryl sulfate; triglycerides that include Dynsan 118 and Cutina HR; and sugar esters.

2.

A method according to claim 1, wherein the space is not more than 10 mm wide.

3.

A method according to claim 1 or claim 2, wherein the milling step involves Mecan-Fusion or Mixed Cycle.

Four.

A method according to claim 1, wherein the milling step involves hybridization.

5.

A method according to claims 1 to 4, wherein the median of the mass aerodynamic diameter (MMAD) of the particles of active material and / or of the particles of additive material is substantially reduced during the milling step.

6.

A method according to any one of claims 1 to 5, wherein after the grinding step the median of the mass aerodynamic diameter of the active compound particles is not more than 10 µm.

7.

A process according to any one of claims 1 to 6 which also comprises, after the milling stage, a processing stage in which the degree of aggregation of the active active particles is changed.

8.

A method according to claim 7, wherein the processing stage is an agglomeration stage or an agglomeration stage.

9.

A process according to any preceding claim, wherein after the grinding stage liquid is added, followed by a drying stage in which the mixture of the active compound particles and the liquid is dried to remove the liquid.

10.

A process according to claim 9 during which, in the drying step, the compound active particles agglomerate to form agglomerated compound active particles.

eleven.

A method according to claim 9 or claim 10, wherein the drying stage is a spray drying stage or a lyophilization stage.

12.

A process according to claim 9 or claim 10, wherein in the drying stage the liquid evaporates slowly.

13.

A process according to any one of the preceding claims, wherein the additive material comprises an amino acid, a phospholipid or a metal stearate.

14.

A process according to claim 13, wherein the metallic stearate is zinc stearate, magnesium stearate, calcium stearate, sodium stearate or lithium stearate.

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fifteen.

Active particles composed for use in a pharmaceutical composition obtainable by a method according to any one of claims 1 to 14.

16.

Composite active particles according to claim 15 which are in the form of agglomerated compound active particles.

17. Compound active particles according to claim 15 or claim 16, wherein the additive particles form a coating on the surfaces of the particles of active material, preferably wherein the coating is a discontinuous coating and / or in the that the coating is not more than 1 µm thick. 18. A pharmaceutical composition comprising active compound particles as manufactured by a process according to any one of claims 1 to 14 or active compound particles according to any 10 of claims 15 to 17. 19. A pharmaceutical composition according to claim 18 which is a dry powder and is suitable for use in a dry powder inhaler, or comprising a propellant and is suitable for use in a pressurized metered dose inhaler. 10-21-2011 E01998328 10-21-2011 E01998328 10-21-2011 E01998328 10-21-2011 E01998328 10-21-2011 E01998328 10-21-2011