WO2001085243A1

WO2001085243A1 - Inhalation chamber

Info

Publication number: WO2001085243A1
Application number: PCT/GB2001/001993
Authority: WO
Inventors: Philip Braithwaite
Original assignee: Innovata Biomed Ltd; ML Laboratories PLC
Current assignee: Innovata Ltd; Innovata Biomed Ltd
Priority date: 2000-05-05
Filing date: 2001-05-04
Publication date: 2001-11-15
Anticipated expiration: 2002-11-05
Also published as: AU6247901A

Abstract

There is described a chamber for use in the delivery of a particulate material which comprises means for introducing an electric charge to the chamber and/or the particulate material and means for separating coarse particles form fine particles. There is also described an inhaler system using the chamber and a method of administering a medicament to a patient using such an inhaler system.

Description

INHALATION CHAMBER

This invention relates to a novel form of chamber and to inhalers used in conjunction with such a chamber.

Delivery of medicament to the lung of a patient for the treatment of respiratory or systemic diseases relies upon introducing appropriately sized medicament particles into the patient's airways. The nature of these particles will vary depending upon, inter alia, the region of the airway/lung being targeted, the particular inhalation device used, etc. Thus, for example, a dry powder inhaler (DPI) will produce a cloud of solid medicament or medicament and excipient particles. Whereas a metered dose inhaler (MDI) will produce a cloud which comprises propellant and medicament, often the medicament being contained in a surfactant aerosol. A nebuliser will produce a mist comprising a solution or suspension of medicament particles in a solvent, usually water.

In general terms conventional inhalers act by delivery of an aerosol, whether that be particles dispersed in a propellant gas (MDI) or in air (DPI). The term "aerosol" used hereinafter shall be taken to encompass any conventionally delivered medicament particles and shall not be restricted to MDIs.

For delivery to the airways in an aerosol, it is well established that the optimum particle size range is from 1 to 10 μm.

Achieving such an aerosol is dependant on a number of factors including the processing of the medicament and/or excipient particles (often by micronisation) and suitable formulation of the product. The characteristics and performance of the delivery device are also critical in determining the extent of medicament delivery to the targeted pulmonary regions. Furthermore, optimum delivery is itself influenced by a number of variables, including, but not limited to, the static interaction between medicament particles, between medicament particles and an excipient, and between medicament particles and the surfaces of the delivery device.

One of the principle difficulties experienced with inhalers is maximising delivery of the medicament. Medicament particles will tend to agglomerate to produce particles outside the optimum range of 1 to 10 μm. Deagglomeration is usually attempted by the use of a carrier e.g. lactose. However, applying energy to a powder in order to deagglomerate it and create an aerosol of fine particles, creates electrostatic charges on the particle surfaces. These electrostatic charges cause particles to be attracted to corresponding oppositely charged particles and/or to charged (or neutral/earthed) surfaces. Thus, the electrostatic charges can cause a reduction in optimisation of the delivery of medicament due to, inter alia, agglomeration or surface depositing of the medicament. Particles can become charged (intentionally or not) in a variety of manners. The three most common methods are triboelectrification, corona charging and induction charging.

Triboelectric charging (tribocharging) is the process of charging by frictional effects only and arises from two materials being rubbed together and then subsequently separated.

Corona charging uses an electrode with a sharp point, or consisting of a fine-gauge wire, is connected directly, or via a high voltage ballast resistance, to a high voltage source. This type of electrode geometry causes significant field enhancement near the electrode, and for a high enough voltage, corona discharges are initiated, as the limiting value of the reduced electric field E/n (E is the electric field and n is the number density of the gas) is exceeded. The polarity of the discharge may be either positive or negative. For a negative polarity the electrons, which have a high mobility, are rapidly trapped by air molecules to form a low-mobility negative ion. Although these slower moving ions move away from the electrode, they accumulate into a space charge cloud before drifting into a low-field region under the action of the electric field. Thus to ensure the creation of a space charge the rate of ion creation has to exceed the rate of the ion drift. Powder particles, emanating from a nozzle, travel through the space charge, picking up ions on their flight. Thus three species of particles are produced, these being negative ions, uncharged and negatively charged powder particles.

The method of induction charging is widely used in liquid charging systems and requires the particle that is to be charged to be more conductive (p ~ 10⁸ Ωm) than most powder particles. For materials in this state, electronic conduction through the bulk of the material may be achieved relatively easily, and it will readily acquire charge of the same polarity as the electrode and will retain this charge when contact is broken. Since no free ions are produced, the system performance will be similar to that of a tribo-charged system.

There is a range of mechanical devices for the direct administration of drugs. The most common ones are described here. One factor they have in common is that they impart charge, often inadvertently, onto the drug being delivered and this charge is known to have a strong effect on drug deposition.

Drug delivery to the bronchial system can be administered either orally or directly. Oral administration has an efficiency of about 0.5%^' whereas direct administration is about 10% efficient, and is thus the method of choice. For maximum deposition in the lower airways the particle size should be in the range 2-5 μm. Above 5 μm impaction limits the progress of particles. This occurs primarily at the bifurcation of airway surfaces.

It has been shown in the use of commercial MDIs that actuation of the inhaler produces charge on the inhaled spray. The results in Table 1 illustrate that the dose becomes negatively charged (the experiment was arranged so that only particles of diameter less than 5.8 μm were transmitted through the system and subsequently measured with an electrometer).

Table 1 : Charge induced on metered dose inhalers

Furthermore, it has been shown that the surface of a new, plastic spacer has a substantial electric charge on it. This affects the aerosol particles and lead to their deposition on the spacer wall. The dose can be improved by multiple actuations of the MDI. For hygiene reasons spacers have to be washed regularly and this returns the spacer wall to its "new" condition.

Various attempts have been made to overcome these disadvantages. For example, it is known to formulate the medicament particles to reduce electrostatic charge or to provide the medicament particles with an anti-static coating. However, there is generally a desire to limit the excipients which are inhaled by a patient.

To promote the deposition of powdered medicaments in the lung, fine particles of a carrier (e.g. lactose) are added to the medicament. Tests have been carried out on lactose particles to investigate the electrostatic effect of adding fine lactose particles. The coarse lactose particle diameters were in the range 63-90 μm and those of the fine particles were <10 μm. It was found that the triboelectric charge acquired by passing the powders through a stainless steel pipe, had a negative polarity, and ranged from about 70 nC g^"1 for a powder with no fine particles to about 8 nC g^" for a powder with 30% fine particles. However, it was also noted that as the fine particle content increased then so did the degree of adhesion to the container walls. This greater degree of adhesion may enhance the effect of particle-particle interaction. Therefore other attempts to address the problems encountered with electrostatic charges have involved the use of specific anti-static inhalation devices. One such device is described in International Patent Application No WO 93/00951, Inhale Inc., which describes a device for delivering a medicament aerosol into the lungs of a patient, the aerosol is transferred to a chamber, from which the patient draws the aerosol into the lungs, this is followed by an inhalation of atmospheric air which acts to push the initial dose well into the lung of the patient.

A further alternative device is that described by Kδhler in European Patent Application No 95118325.0. In addition, antistatic spacers are known, for example, a device comprising a metal spacer is available from Astra Zeneca

We have now found a novel device which overcomes or mitigates the creation of electrostatic charges normally created during the energising of an aerosol, e.g. a powder.

Generally the device of the invention utilises an inherent/existing charge in particulate material and/or applies a charge . to such particles, by exciting and energising the particles. Thus, by applying a charge to the chamber and/or the particulate material, movement is generated in the particles by charge repulsion/attraction; and a "floating cloud" of particulate material can be produced which prevents deposition and/or agglomeration of particles.

Thus according to the invention we provide a chamber for use in the delivery of a particulate material which comprises means for introducing an electric charge to the chamber and/or the particulate material and means for separating coarse particles from fine particles.

In an embodiment of the invention the electric charge is applied to the particulate material, such a charge may be applied directly to the particles or may be applied via the charge applied to the chamber. Furthermore, charge may be applied solely to the particles or the charge may be applied to both the particles and the chamber.

In a yet further embodiment of the invention the charge is applied solely to the chamber. Alternatively charge can be applied to both the chamber and the particulate material.

According to a further feature of the invention, the means for introducing an electric charge to the chamber will comprise at least a pair of electrodes. Preferably the means will comprise a plurality of such pairs of electrodes, generally greater control and usability is achieved if the number of electrodes is increased.

Preferentially the electrodes are used to set up a substantially uniform field of charge within the space of the chamber. Furthermore, the performance of the chamber may be optimised by varying, for example, the configuration of the chamber, the applied voltage, the electrode gap spacing, the peak and/or average electric field, the atmospheric conditions, particulate composition and size, the pulse width, the number of electrodes and/or the repetition rate.

The output of the pairs of electrodes may vary from between 1 v and 50 kN, more preferably between 1 v and 10 kV, most preferably between 1 kN and 10 kV, for example 5 kN to 10 kV and especially 7 or 8 kN.

The means for separating the fine and coarse particles will generally comprise at least a pair of electrodes. Preferably, the means comprises a plurality of pairs of electrodes connected such that the power to each of the electrodes will be pulsed. The separation of coarse and fine particles may occur separately, simultaneously or sequentially with the application of the electric charge. Thus, the separation may occur separately to the application of electric charge. Alternatively it may occur simultaneously. Preferentially the separation occurs sequentially with application of the electric charge. Generally, because the charge to mass ratio is higher for smaller particles, the fine particles will be repelled away from the electrodes, e.g. to the middle portion of the chamber, whilst the coarser particles will remain closer to the electrodes, e.g. inner surface of the chamber.

Therefore, the frequency of the pulsed power may be varied, depending, inter alia, upon the size and nature of the medicament particles being delivered. However, a frequency of between 0.1 and 1000 pulses per second (pps) is desirable, preferably a frequency between 100 and 1000 pps is desirable, more preferably between 200 and 800 pps.

The chamber of the invention is especially advantageous in the delivery of medicaments and especially particulate material in the form of a powder. Thus, such powdered medicaments are especially useful as an inhalation therapy e.g. in the treatment of respiratory disorders or systemic disorders, for example, insulin dependent diabetes.

Therefore in a further embodiment of the invention we provide an inhaler system comprising an inhaler in conjunction with a chamber as hereinbefore described. The inhaler and chamber of the invention may be provided separately, together or as a kit of parts. We especially provide a dry powder inhaler as hereinbefore described.

The particle size of the medicament may be varied depending, inter alia, on the type of aerosol being formed. In the case of a dry powder medicament, the particle size of the medicament, and the carrier, if one is present, may be varied. The nature of the carrier may also be varied. Thus, the particle size of the medicament may be substantially between 1 and 20 μm, more preferably between 1 and 10 μm. That is, at least 90% w/w of the medicament should have a particle size of between 1 and 20 μm. In a dry powder formulation a variety of carriers may be used. Certain carriers may be mentioned, by way of example only, such as sugars, e.g. dextran, mannitol and lactose, for example cc-lactose monohydrate. The particle size of the carrier may be across a wide range, between 0.1 and 500μm, preferably between 1 and 200 μm, more preferably between 1 and 100 μm and especially between 1 and 20 μm. Alternatively, he carrier may itself comprise a mixture of fine and coarse particles.

In one embodiment of the invention the chamber may be substantially spherical in shape. A plurality of electrodes may be situated around the periphery of the chamber. Preferably, the chamber may comprise a plurality of segments wherein each segment comprises an electrically conductive portion and an electrically insulating portion. For example, each segment may comprise an electrically conducting inner portion with an electrically insulating outer portion. The inner portion preferably comprises a mesh arrangement and especially an electrically conducting wire mesh. The outer portion can comprise any conventionally known insulating material, such as a plastics material. Furthermore, each segment is preferably a parabolic shape to facilitate coupling a plurality of such segments to form a sphere.

It is an especially advantageous feature of the present invention that, in use, when a patient inhales, air is drawn through the apertures of the mesh, thus improving the flow of medicament from the chamber. Therefore, according to a yet further feature of the invention we provide a chamber as hereinbefore described characterised in that the chamber is adapted such that, in use, air can be drawn through the walls of the chamber upon inhalation by a patient.

Each of the parabolic shaped segments may be connected to a pulsed and phased high voltage generator. In this embodiment the generator has three phase connections A, B and C and are connected to the parabolic segments in sequence as follows: A connected to 1, 4, 7 and 10, B connected to 2, 5, 8 and 11 and C connected to 3, 6, 9 and 12. The inhaler system of the invention is therefore useful in the treatment of e.g. bronchial disorders. Therefore, any medicaments and/or excipients known to be used in such treatments may be used in the inhaler system of the invention. A variety of medicaments may be administered by using the inhaler system of the invention. Such medicaments are generally antibiotics, bronchodilators or other anti-asthma drugs. Such medicaments include, but are not limited to bronchodilators, e.g. fenoterol, formoterol, pirbuterol, reproterol, rimiterol, salbutamol, salmeterol and terbutaline; non-selective beta-stimulants such as isoprenaline; xanthine bronchodilators, e.g. theophylline, aminophylline and choline theophyllinate; anticholinergics, e.g. ipratropium bromide; mast cell stabilisers, e.g. sodium cromoglycate and ketotifen; bronchial anti-inflammatory agents, e.g. nedocromil sodium; and steroids, e.g. beclomethasone dipropionate, fluticasone, budesonide and flunisolide; and combinations thereof.

Specific combinations of medicaments which may be mentioned include combinations of steroids, such as, beclomethasone dipropionate, fluticasone, budesonide and flunisolide; and combinations of to bronchodilators, such as, formoterol and salmeterol. It is also within the scope of this invention to include combinations of one or more of the aforementioned steroids with one or more of the aforementioned bronchodilator. A specific combination which is preferred is a combination of fluticasone and salmeterol.

Further medicaments which may be mentioned include systemically active materials, such as, proteinaceous compounds and/or macromolecules, for example, hormones and mediators, such as insulin, human growth hormone, leuprolide and alpha interferon; growth factors, anticoagulants, immunomodulators, cytokines and nucleic acids.

According to a further feature of the invention we provide a method of admimstering a medicament to a patient using an inhaler system as hereinbefore described. We further provide a method of treatment of a patient suffering from a disorder which comprises the administration of a therapeutically effective amount of an appropriate medicament using an inhaler system as hereinbefore described.

Thus, we also provide a method of treatment of a patient suffering from a bronchial disorder which comprises the administration of a therapeutically effective amount of an appropriate medicament using an inhaler system as hereinbefore described.

In a yet further alternative we provide a method of treatment of a patient suffering from insulin dependant diabetes which comprises the administration of a therapeutically effective amount of insulin using an inhaler system as hereinbefore described.

More specifically the methods of the invention comprise: (i) introducing the medicament into the chamber;

(ii) applying a charge to influence the medicament particles;

(iii) permitting air to be drawn through the walls of the chamber when the patient inhales.

Any conventional lαiown power source may be used in conjunction with the device of the invention. Thus, the power source may be battery driven or mains supply driven. For example, a dc source may be from 1 to 100 v and^' an ac source from 1 to 240 v

The invention will now be described by way of example only and with reference to the accompanying drawings, in which

Figure 1 is a perspective view of a parabola shaped segment; Figure 2 is a perspective view of a chamber; Figure 3 is an end view of a chamber; Figure 4 is an end view of the chamber showing the circuitry arrangement; and Figure 5 is an end view of the chamber showing the particle distribution within the chamber.

Referring to Figure 1, a chamber segment (1) comprises a parabolic shaped wire mesh (2) held in a plastics frame (3). Each end (4 and 5) of the frame (3) is provided with a lug (6 and 7) which enables a plurality of segments (1) to be held together.

Referring to Figures 2 and 3, a plurality of parabolic segments (1) are placed together to make a sphere (8). The lugs (6 and 7) lie adjacent to each other in a circular arrangement (not shown) and a fixing ring (9 and 10) is slotted over each end (11 and 12) holding the lugs (6 and 7) together and retaining the spherical shape.

The first fixing ring (9) is apertured (not shown) also acts as an inlet and the second fixing ring (10) is apertured (13) to act as an outlet.

Referring to Figure 4 an electrical circuit is connected to the wire mesh (2) of the segments (1). All of the parabola shaped pieces are connected to a pulsed and phased high voltage generator. In this embodiment the generator has three phase connections A, B and C and are connected to the parabola pieces in sequence as follows: A connected to 1, 4, 7 and 10, B connected to 2, 5, 8 and 11 and C connected to 3, 6, 9 and 12.

The plastics frames (3) act as an insulator for each segment (1).

Referring to Figure 5, when the oscillating power is initiated the coarse particles (14) are charged and move a short distance away from the inner surface (15) of the sphere (8) whilst the fine particles (16) move a greater distance and rest substantially in the central position (17) of the sphere (8).

In operation a medicament or medicament and excipient formulation is introduced into the inside of the chamber from an inhaler through the inlet orifice (4). The pulse generator is actuated, causing the particles to be charged. Those that are negatively charged are attracted to the positively charged portions of the sphere; and those that are positively charged to are attracted to the negatively charged portions of the sphere. As the pulses are phased, the particles are rapidly, alternatively attracted and repelled, forcing them into a rotating motion within the sphere.

The patient then inhales through an outlet orifice (5), air is drawn from outside of the sphere through the fine mesh (2) entraining the powder as it passes into the patient's airways.

Example 1

Modelling of Electrode Configuration and Particle Motion

An electrostatic model of the electrospacer configurations was developed for the three operational stages, which are powder capture, confinement and expulsion. Although the expulsion stage was not carried out electrostatically, it was anticipated that residual charge, present in the powder, may have some effect upon the expulsion mechanism. Modelling enabled this effect to be determined. The modelling process provided the necessary information on electric field distribution and intensity that allows each of the three stages to be accomplished reliably. It also enables the early identification of accidental high electric field regions that lead to partial or complete insulation failure. In addition to the electrode design work, modelling of different particles was undertaken to examine the effects of particle properties on their motion in the field. This enables a degree of prediction about the powder behaviour prior to experimentation.

Example 2

Development of an Experimental System

An experimental electrospacer was instructed enabling a series of experiments to be undertaken with different types of powders. This device was flexible and versatile to enable a number of different geometries to be tested. It was also large enough to allow suitable diagnostic techniques to be incorporated. A fixed high voltage framework was developed that allows different electrode configurations to be examined. A suitable pulse generator was also developed to drive the experimental electrospacer.

Example 3

Characterisation of Particle Behaviour for Different Powders

The experimental electrospacer was used to characterise the behaviour of different ■ powders within the electric field. There are a significant number of electrical parameters that influence particle motion including electric field intensity, voltage pulse duration and pulse repetition frequency, electrode geometry and phase requirements. Each powder type requires its own set of parameter values for initial capture and stable confinement. The important powder properties that were examined during this experimental stage include density, appearance (fluffy or pellet), conductivity (water content), electrical permitivity and mass/size.

Example 4

Deterioration of Operating Parameters for a Prototype System

The results from Example 3 were considered to identify specifications for a prototype electrospacer and suitable pulse generator. The design was specific to one type of powder. The prototype design takes into account operational issues such as size, power requirements and safety.

P30202WO.1

Claims

1. A chamber for use in the delivery of a particulate material which comprises means for introducing an electric charge to the chamber and/or the particulate material and means for separating coarse particles from fine particles.

2. A chamber according to Claim 1 characterised in that the charge is applied solely to the particulate material.

3. A chamber according to Claim 1 characterised in that the charge is applied to the chamber.

4. A chamber according to Claim 1 characterised in that- the charge is applied to the chamber and the particulate material.

5. A chamber according to Claim 1 or 4 characterised in that charge is applied to the particulate material via the chamber.

6. A chamber according to Claim 1 characterised in that the means for introducing an electric charge to the chamber comprises at least a pair of electrodes.

7. A chamber according to Claim 1 characterised in that the electric charge is introduced at a point where the particulate material enters the chamber.

8. A chamber according to Claim 6 characterised in that the means for introducing an electric charge comprises a plurality of pairs of electrodes.

9. A chamber according to Claim 6 characterised in that the output of the pairs, of electrodes is between 1 v and 10 kV.

10. A chamber according to Claim 1 characterised in that the power applied to the means for introducing an electric charge to the particulate material is pulsed.

11. A chamber according to Claim 10 characterised in that the frequency of the pulsed power is between 0.1 and lOOOpps.

12. A chamber according to claim 1 characterised in that the particulate material is a powder.

13. A chamber according to claim 1 characterised in that the particulate material

/ is a medicament optionally including a pharmaceutically acceptable^' adjuvant, diluent or carrier.

14. An inhaler system comprising an inhaler in conjunction with a chamber according to claim 1.

15. An inhaler system according to Claim 14 characterised in that the inhaler is a dry powder inhaler.

16. An inhaler system according to Claim 15 comprising a medicament and characterised in that the particle size of the medicament is substantially between 1 and 20 μm.

17. An inhaler system according to Claim 15 characterised in that the particle size of the excipient is between 1 and 200μm.

18. A chamber according to Claim 1 characterised in that the chamber is substantially spherical in shape.

19. A chamber according to Claim 18 characterised in that the electrodes are situated around the periphery of the chamber.

20. A chamber according to Claim 18 characterised in that the chamber comprises a plurality of segments.

21. A chamber according to Claim 20 characterised in that each segment comprises an electrically conductive portion and an electrically insulating portion.

22. A chamber according to Claim 21 characterised in that each segment comprises an electrically conducting inner portion and an electrically insulating outer portion.

23. A chamber according to Claim 22 characterised in that the inner portion comprises a mesh arrangement.

24. A chamber according to Claim 22 characterised in that the outer portion comprises a plastics insulating material.

25. A chamber according to Claim 20 characterised in that each segment has a parabola shape to facilitate coupling a plurality of such segments to form a sphere.

26. A chamber according to Claim 25 characterised in that each of the parabola shaped pieces are connected to a pulsed and phased high voltage generator.

27. A chamber according to Claim 26 characterised in that each of the generator has three phase connections and the chamber comprises twelve segments.

28. A chamber according to Claim 26 characterised in that each of the parabolic segments is connected in sequence to the phase connections A, B, C as follows: A connected to 1, 4, 7 and 10, B connected to 2, 5, 8 and 11 and C connected to 3, 6, 9 and 12.

29. A chamber according to Claim 1 characterised in that the chamber is adapted such that, in use, air can be drawn through the walls of the chamber upon inhalation by a patient.

30. A method of administering a medicament to a patient which comprises the use of an inhaler system according to Claim 14.

31. A method of treatment of a patient suffering from a disorder which comprises the administration of a therapeutically effective amount of an appropriate medicament using an inhaler system according to Claim 14.

32. A method of treatment according to Claim 31 characterised in that the disorder is a bronchial disorder.

33. A method of treatment according to Claim 31 characterised in that the disorder is insulin dependant diabetes and the medicament is insulin.

34. A method according to Claims 30 or 31 which comprises:

(i) introducing the medicament into the chamber; (ii) applying a charge to influence the medicament particles;

35. A chamber or an inhaler system substantially as described with reference to the accompanying drawings.

P36202 O.1