This invention relates to powders for use in dry powder inhalers.
Inhalers are well known devices for administering pharmaceutical products to the respiratory tract by inhalation. Inhalers are widely used particularly in the treatment of diseases of the respiratory tract.
There are a number of types of inhaler currently available. The most widely used type is a pressurised metered dose inhaler (MDI) which uses a propellant to expel droplets containing the pharmaceutical product to the respiratory tract. Those devices are disadvantageous on environmental grounds as they often use CFC propellants, and on clinical grounds related to the inhalation characteristics of the devices.
An alternative device to the MDI is the dry powder inhaler. The delivery of dry powder particles of pharmaceutical products to the respiratory tract presents certain problems. The inhaler should deliver the maximum possible proportion of the active particles expelled to the lungs, including a significant proportion to the lower lung, preferably at the low inhalation capabilities to which some patients, especially asthmatics, are limited. It has been found, however, that, when currently available dry powder inhaler devices are used, in many cases only about 10% of the active particles that leave the device on inhalation are deposited in the lower lung. More efficient dry powder inhalers would give clinical benefits.
The type of dry powder inhaler used is of significant importance to the efficiency of delivery over a range of airflow conditions of the active particles to the respiratory tract. Also, the physical properties of the powder used affect both the efficiency and reproducibility of delivery of the active particles and the site of deposition in the respiratory tract.
On exit from the inhaler device, the active particles should form a physically and chemically stable aerocolloid which remains in suspension until it reaches a conducting bronchiole or smaller branching of the pulmonary tree or other absorption site preferably in the lower lung. Once at the absorption site, the active particle should be capable of efficient collection by the pulmonary mucosa with no active particles being exhaled from the absorption site.
The size of the active particles is particularly important. For effective delivery of active particles deep into the lungs, the active particles should be small, with an equivalent aerodynamic diameter substantially in the range of 0.1 to 5 μm, approximately spherical and monodispersed in the respiratory tract. Small particles are, however, thermodynamically unstable due to their high surface area to volume ratio, which provides significant excess surface free energy and encourages particles to agglomerate. In the inhaler, agglomeration of small particles and adherence of particles to the walls of the inhaler are problems that result in the active particles leaving the inhaler as large stable agglomerates or being unable to leave the inhaler and remaining adhered to the interior of the inhaler.
The uncertainty as to the extent of formation of stable agglomerates of the particles between each actuation of the inhaler and also between different inhalers and different batches of particles, leads to poor dose reproducibility.
In an attempt to improve that situation, dry powder for use in dry powder inhalers often include coarse carrier particles mixed with fine particles of active material. The active particles adhere to the surfaces of the carrier particles whilst in the inhaler device, and are dispersed on inhalation into the respiratory tract to give a fine suspension. The carrier particles are often large particles greater than 90 μm in diameter to give good flow properties because small particles with a diameter of less than 10 μm may become coated on the wall of the delivery device and have poor flow and entrainment properties leading to poor dose uniformity.
There are, however, problems associated with the addition of carrier particles to the active particles in the dry powder, for example problems related to the efficient release of the active particles from the surfaces of the carrier particles on inhalation. Furthermore, in some cases it is preferred for no carrier particles to be present in the powder administered.
In known dry powder inhaler devices, doses of powder containing only active particles are dispensed. The powder contains no carrier particles or other additives and the amount of powder in each dose is small, usually less than 1 mg. The volume of the dose may be, for example, approximately 6.5 μl.
Problems involved in dispensing a powder containing only particles of active material include
(i) formation of stable agglomerates of the small particles which often are not broken down into individual particles in the airstream when the particles are inhaled and are, therefore, less likely to reach the lower lung on inhalation of the powder than the fine individual active particles;
(ii) variations in the amount of powder metered from a reservoir of the inhalation device due to poor flow properties of the powder and inconsistent agglomeration, leading to inconsistency in the size of dose, which may vary as much as ±50% compared with the nominal dose for the device;
(iii) incomplete removal of the dose from the device due to adherence of the particles to the walls of the device, leading to poor dose reproducibility.
An object of the present invention is to provide a dry powder for use in dry powder inhalers which overcomes or mitigates at least one of the above disadvantages.
According to the invention, there is provided a powder for use in a dry powder inhaler, the powder comprising active material and additive material, the additive material comprising an anti-adherent material and the powder including at least 60% by weight of active material based on the weight of the powder.
A purpose of the additive material is to hinder the formation of stable agglomerates of the active material in the powder. As indicated above, stable agglomeration of the active particles with the known powders may lead to decreased deposition of the active material in the lower lung, together with poor dose uniformity. That is because, when the small active particles agglomerate, the agglomerates which are formed may have a diameter of 100 μm or more. If those agglomerates do not break up when the powder is inhaled, they are unlikely to reach the lower lung due to their size.
The addition of the anti-adherent material decreases the cohesion between the particles of the powder containing the active material. It is thought that the additive material interferes with the weak bonding forces, such as Van der Waal's and Coulomb forces, between the small particles, helping to keep the particles separated and may be thought of as weak links or “chain breakers” between the particles. Adhesion of the particles to the walls of the device is also reduced. Where agglomerates of particles are formed, the addition of the additive material decreases the stability of those agglomerates so that they are more likely to break up in the turbulent airstream created on inhalation to form small individual particles which are likely to reach the lower lung.
The reduced tendency of the particles to bond strongly either to each other or to the device itself, reduces powder cohesion and adhesion and promotes better flow characteristics which leads to improvements in the dose reproducibility by reducing the variation in the amount of powder metered out for each dose and improving the release of the powder from the device as well as increasing the likelihood that the active material which does leave the device will reach the lower lung of the patient.
It is thought that it is favourable for unstable agglomerates of particles to be present in the powder when it is in the inhaler device. As indicated above, for a powder to leave an inhaler device efficiently and reproducibly, the particles of such a powder should be large, preferably larger than 45 μm. Such a powder may be in the form of either individual particles having a size of 45 μm or larger and/or agglomerates of finer particles, the agglomerates having a size of 45 μm or larger. The agglomerates formed can have a size of as much as 100 μm and, with the addition of the additive material, those agglomerates are more likely to be broken down efficiently in the turbulent airstream created on inhalation. Therefore the formation of unstable agglomerates of particles in the powder may be favoured compared with a powder in which there is substantially no agglomeration.
The reduction in the cohesion and adhesion between the active particles could lead to equivalent performance with reduced agglomerate size, or even with individual particles.
Where reference is made to anti-adherent materials, the reference is to include those materials which will decrease the cohesion between the particles of the powder. Those materials will include those usually thought of as anti-adherent materials, for example leucine, as well as others, for example, lecithin, which are not generally thought of as being anti-adherent but may nonetheless have the effect of decreasing the cohesion between the particles of the powder. Other materials commonly added to powders for use in inhalers, for example lactose and various other carrier particle materials, are not anti-adherent materials per se but might be added to a powder in addition to a suitable anti-adherent material, for example leucine as indicated below.
Furthermore, many materials are not suitable anti-adherent materials because they are “sticky” and tend to increase cohesion between particles. For example, fatty acids, increase stickiness in powders and are thought to be unsuitable as the additive material. Also, other materials such as sorbitan esters (for example SPAN 85) and cyclo dextrins are not suitable anti-adherent materials.
It is possible that materials which are anti-adherent for one type of active material, will not be anti-adherent for a different type. A suitable test to determine whether or not an additive material is anti-adherent is as follows.
The “Aeroflow” apparatus of Amherst Process Instruments Incorporated of Mountain Farms Technology Park, Hadley, Mass. 01035-9547 U.S.A., is used to assess whether a material is anti-adherent.
The Aeroflow apparatus is used to measure the flow properties of powders. A sample of powder is placed in a perspex cylinder which is rotated at a speed of about 5 rpm about a horizontal axis. As the cylinder rotates, the powder will tend to form a pile of powder which extends around the inner surface of the cylinder as powder material is carried round by the rotating cylinder. When the height of the pile reaches a certain level, powder material from the top of the pile avalanches down towards the bottom of the pile. Thus as he cylinder rotates, the powder will avalanche at a frequency dependent on the properties of the powder. For a freely flowing powder material, the time between avalanches will be low whereas for a cohesive material, the time between avalanches will be great.
The general procedure for the test is as follows:
(a) A powder for testing is made by mixing together active material and additive material as described in (i) or (ii) below to form a powder containing the concentration by weight of additive material of the powder to be tested. The particles of the powder are agglomerated by mixing the particles for 10 minutes at a relative humidity of 55% in a tumbling blender, preferably a Turbula mixer.
(i) Where the additive material is in the form of particles, blend the active and additive materials together,
(ii) where the additive material is to form a coating on the surfaces of the active particles as described below, the additive material is added to the active particles from suspension or from solution and the resulting powder is dried and divided.
(b) A 200 g sample of the powder obtained in (a) above is put into the Aeroflow apparatus and the mean time between avalanches is measured as the cylinder is rotated.
(c) (b) above is repeated for a sample of active material which has been prepared as in (a) above except that no additive material is added.
For a material which is to be taken as an anti-adherent material for the purposes of this invention, the mean time between avalanches will be lower for the material containing the additive material, indicating improved flow properties and less cohesion.
For additive materials comprising a fatty acid, the time between avalanches is greater when the fatty acid has been added to the material. Thus fatty acids are unsuitable for use as the anti-adherent material.
Where it is indicated that a material is not anti-adherent, that material might be added to the active material, for example as a diluent, provided that a suitable anti-adherent additive material is also added such that the resulting effect of the additive material and the diluent is anti-adherent. Where further components other than the active material and the anti-adherent material are included in the powder, advantageously the complete powder also “passes” the above test in that the combined effect of all of the components added to the active material is that of an anti-adherent material.
Advantageously, the powder comprises at least 70%, more preferably at least 80% by weight of active material based on the weight of the powder. Most advantageously, the powder comprises at least 90%, more preferably at least 95%, more preferably at least 97%, by weight of active material based on the weight of the powder. It is believed that there are physiological benefits in introducing as little powder as possible to the lungs, in particular material other than the active ingredient to be administered to the patient. Therefore, the quantities in which the additive material is added are preferably as small as possible. The most preferred powder, therefore, would comprise more than 99% by weight of active material.
Advantageously, at least 90% by weight of the particles of the powder have a particle size less than 63 μm, preferably less than 30 μm and more preferably less than 10 μm. As indicated above, the size of the particles of the powder should be within the range of about from 0.1 μm to 5 μm for effective delivery to the lower lung. Where the additive material is in the form of particles of material, as is described below, it may be advantageous for particles of the additive material to have a size outside the preferred range for delivery to the lower lung.
As indicated above, in some cases it will be preferred for the particles to be in the form of agglomerates in the powder. In such cases, the particle sizes indicated above are those of the individual particles making up the agglomerates.
It will be appreciated that the chemical composition of the additive material is of particular importance.
Advantageously, the additive material comprises physiologically acceptable material. Clearly, it is highly preferable for the additive material to be a material which may be safely inhaled into the lower lung, where it would usually be absorbed into the blood stream. The additive material should therefore be one which is safe to administer by inhalation. The additive material may include a combination of one or more materials.
Advantageously, the additive material includes one or more compounds selected from amino acids and derivatives thereof, and peptides and polypeptides having a molecular weight of between about 0.25 to 1000 kDa, and derivatives thereof. Amino acids, peptides and polypeptides and their derivatives are physiologically acceptable and act as anti-adherent materials when added to the active material. It is particularly advantageous for the additive material to comprise an amino acid. Amino acids have been found to give, when present as additive material, high respirable fraction of the active material and also good flow properties of the powder. A preferred amino acid is leucine, in particular L-leucine. Whilst the L-form of the amino acids is preferred in the Examples, the D- and DL- forms may also be used. The additive material may comprise one or more of any of the following amino acids: leucine, isoleucine, lysine, valine, methionine, cysteine, phenylalanine.
As indicated above, the additive material may include derivatives of amino acids or peptides. For example the additive material may be a salt or an ester, for example aspartame, or may be N acetyl-L cysteine. The additive material may comprise salts such as acesulfame K or other sweeteners, for example saccharin sodium or a cyclamate.
The additive material may include one or more water soluble compounds. Those compounds, if they penetrate into the deep lung may therefore be absorbed into the blood stream, which is advantageous.
The additive material may include one or more surface active materials which may be water soluble, for example, lecithin, in particular soya lecithin. Lecithin is not an especially preferred additive material because it is thought that at least in some cases it could give increased cohesion in the powder material.
The additive material may include dipolar ions which may be zwitterions.
Advantageously, the additive material includes a glidant material. A glidant material is one that will decrease the resistance to sliding of the particles. The addition of a glidant material, therefore, will lead to improved release of the powder from the inhaler device and therefore better dose uniformity. The glidant materials which have this effect will include those usually thought of as glidants as well as those not usually thought of as glidants but which have a glidant effect when added to the active material. Many of the anti-adherent materials described above are also glidants. The glidant material may, therefore, be the same compound as that of the anti-adherent material, or may be a different compound or a mixture of compounds.
The active material referred to throughout the specification will be material comprising one or a mixture of pharmaceutical products. It will be understood that the term “active material” includes material which is biologically active, in the sense that it is able to decrease or increase the rate of a process in a biological environment. The pharmaceutical products include those products which are usually administered orally by inhalation for the treatment of disease such as respiratory disease e.g. β-agonists, salbutamol and its salts or salmeterol and its salts. Other pharmaceutical products which could be administered using a dry powder inhaler include peptides and polypeptides, such as DNase, leucotrienes and insulin.
The active material may include a β2-agonist, which may include salbutamol, a salt of salbutamol or a combination thereof. Salbutamol and its salts are widely used in the treatment of respiratory disease. The active material may be salbutamol sulphate. The active material may be terbutaline, a salt of terbutaline, for example terbutaline sulphate, or a combination thereof. Terbutaline sulphate is of particular importance. The active material may be ipatropium bromide.
The active material may include a steroid, which may be beclomethasone dipropionate or may be fluticasone. The active material may include a cromone which may be sodium cromoglycate or nedocromil or its salts. The active material may include a leukotriene receptor antagonist.
The active material may include a carbohydrate, for example heparin.
Advantageously, the powder comprises particles of active material and particles of additive material. Where particles of additive material are used, by choosing a particular size of the additive particles, as described below,,the amount of additive material entering the lower lung may be minimised. Also, it may be preferable for the additive to be present in the powder as particles rather than, for example, a coating around the particles of active material which may hinder the absorption of the active material into the blood stream.
Advantageously, at least 90% by weight of the additive particles have a particle size less than 63 μm, preferably, less than 30 μm, and more preferably less than 10 μm. The additive particles will usually have a particle size slightly larger than the particle size of the active particles to encourage deposition of the additive particles in the upper airways. To restrict the amount of the additive material penetrating to the deep lung on inhalation, it is advantageous to include additive particles having a size greater than 5 μm. The size of the particles may be calculated by laser diffraction or other method by which the aerodynamic diameter of the particles can be determined.
The additive particles may be non-spherical in shape. The additive particles may be plate-like particles, for example leucine particles. Alternatively the additive particles may be angular, for example prisms, or dendritic in shape, for example aspartame particles. Plate-like particles may give improved surface interaction and glidant action between the surfaces of the active particles thereby decreasing bonding between the active particles and reducing stable agglomeration.
Alternatively, for example where the nature of the additive material is such that small particles are not easily formed, or for clinical reasons, the additive material may form at least a partial coating on the surfaces of particles of the active material. It is found that even when a large amount of the additive material is added to the active material, there is no “coating” of the active particles in the sense in which that word would normally be used in the art, namely to refer to a continuous envelope around the active particle. Instead, a discontinuous covering is formed on the active particle. It is believed that the presence of such a discontinuous covering, as opposed to a “coating” is an important and advantageous feature of the present invention.
Additive material may be present in the powder both in the form of small particles and in the form of a coating on the surfaces of the particles of active material.
Where the additive material is to form a coating on the surfaces of the particles of active material, the additive material may be added to the active material from a suspension or from solution. The additive material may be added to the active material by co-crystallisation, co-spray drying, co-granulation or other similar method.
Where the additive is in the form of particles, the powder may be produced by, for example, blending together micronised active material and micronised additive material. Alternatively, the components of the powder may be micronised together to form the powder material.
The ratio in which the additive material and the active material are present in the powder will depend on the type of inhaler device used, the type of active material used and the required dose. Usually, the powder comprises at least 0.1% by weight of additive material based on the weight of the powder. The powder preferably comprises between about 0.1% and 40%, more preferably between about 0.25% and 5% by weight of additive material based on the weight of the active material.
It has been found that the addition of more additive material does not necessarily give a greater improvement in the properties of the resulting powder. For example, in the case where the additive material is leucine as in Example 8 below, the addition of 1% by weight of leucine gives good results, but the addition of 5% or 10% by weight of leucine does not give better results, indeed the respirable fraction is seen to decrease with increased addition of leucine.
Furthermore, because the additive material will in many cases be inhaled into the lung, it is preferable for only a small amount of additive material to be added.
The optimum amount of additive material in the powder will depend on the active material and additive material used. Advantageously, the powder comprises not more than 8% by weight, preferably not more than 5% by weight, of additive material. In some cases it will be advantageous for the powder to contain about 1% by weight of additive material.
Advantageously, at least 95% by weight of the active particles have a particle size less than 10 μm. Preferably, at least 95% by weight of the active particles have a particle size between about 0.1 μm and 10 μm, more preferably between about 0.1 μm and 5 μm. The particles will therefore give a good suspension on release from the inhaler device and delivery of the active particles deep into the respiratory tract. The size of the particles may be calculated as described above in respect of the additive particles.
The powder may also contain, for example, flavourings and colourant materials and may also contain diluents. Advantageously the powder includes less than 20% preferably less than 10%, more preferably less than 1%, by weight of constituents other than the active material and the anti-adherent material.
According to the invention, there is also provided a powder for use in a dry powder inhaler the powder comprising active particles and additive material, at least 90% by weight of the powder particles having a particle size of less than 63 μm, the powder including at least 60% by weight of active particles based on the weight of the powder.
Advantageously, at least 90% by weight of the powder particles have a particle size of less than 30 μm, preferably less than about 10 μm. Advantageously, the powder includes at least 80%, preferably at least 90% by weight of active particles based on the weight of the powder.
Advantageously, the powder includes not more than 8%, more advantageously not more than 5% by weight of additive material based on the weight of the powder. As indicated above, in some cases it will be advantageous for the powder to contain about 1% by weight of additive material.
As indicated above, the additive material may be in the form of particles.
The invention also provides, a powder for use in a dry powder inhaler, the powder comprising active particles and additive material, the additive material forming at least a partial coating on the surfaces of the particles of active material, the powder including at least 60% by weight of active material based on the weight of the powder, at least 90% by weight of the particles of the powder having a particle size less than 63 μm.
Advantageously, the powder includes at least 80%, preferably at least 90% by weight of active material based on the weight of the powder.
According to the invention, there is also provided a dry powder inhaler including a powder as described above.
Advantageously, the inhaler may be activated to dispense a dose of less than 10 mg of the powder, preferably not more than 5 mg, more preferably not more than 1 mg. Obviously, the size of the dose will depend on the active material to be delivered and the inhaler device used.
The invention also provides a dose of powder, the dose containing not more than 5 mg of powder described above, more preferably not more than 1 mg of the powder.
The invention also provides the use of an anti-adherent additive material in a powder for use in a dry powder inhaler, for improving the flow characteristics of the powder, the powder comprising at least 60% by weight of active material based on the weight of the powder. The test to assess whether a material is an anti-adherent material is indicated above.
Unless it is clear from the context otherwise, where reference is made to a range of sizes of particles, and to the size of particles, it is to mean that the majority of the relevant particles are within that range or are of that size. Preferably at least about 90% by weight of the relevant particles will be in that range or be of that size, more preferably at least 95% by weight.
The size of particles may, where appropriate be selected and/or measured using a sieving method. Otherwise, the size of the particles may be determined using laser light diffraction, or other method in which the aerodynamic diameter of the particles may be determined, for example microscopic image analysis.
One of the objects of the invention is to hinder the formation of stable agglomerates of particles, especially active particles, in the powder. However, as described above, it may be desirable for unstable agglomerates to be formed in the powder, and the size of those agglomerates may be as large as 100 μm or more. The size of particles in the powder, when considering the agglomerates, is to be taken as the size of the individual particles making up the agglomerate. The sizes of the individual particles may be determined using microscopic image analysis.