Patent Application
20070101991
The present invention relates to a method for releasing and dispersing into a stream of air a metered dose of dry medication powder from a substrate member, and more specifically to a method of optimizing release of a metered dry powder dose from a substrate member and entraining the powder into an inhalation airflow.
Different types of inhalers are available on the market today, such as metered dose inhalers (MDIs), nebulizers and dry powder inhalers (DPIs). MDIs use medicaments in liquid form and may use a pressurized drive gas to release a dose. Nebulizers are fairly big, non-portable devices. Dry powder inhalers have become more and more accepted in the medical service, because they deliver an effective dose in a single inhalation, they are reliable, often quite small in size and easy to operate for a user. Two types are common, multi-dose dry powder inhalers and single dose dry powder inhalers. Multi-dose devices have the advantage that a quantity of medicament powder, enough for a large number of doses, is stored inside the inhaler and a dose is metered from the store shortly before it is supposed to be inhaled. Single dose inhalers either require reloading after each administration or they may be loaded with a limited number of individually packaged doses, where each package is opened shortly before inhalation of the enclosed dose is supposed to take place. Single dose dry powder inhalers capable of pulmonary delivery of pre-metered, systemically acting and sensitive medicaments are attracting much interest today, especially when such devices provide protection for formulations against varying ambient conditions, in particular humidity.
The active substance in dry powder form, suitable for inhalation needs to be finely divided so that the majority by mass of particles in the powder is between 1 and 5 μm in aerodynamic diameter (AD). Powder particles larger than 5 μm in AD tend not to deposit in the lung when inhaled but to stick in the mouth and upper airways, where they are medicinally wasted and may even cause adverse side effects. However, finely divided powders, suitable for inhalation, are rarely free flowing but tend to stick to all surfaces they come in contact with and the small particles tend to aggregate into lumps. This is due to van der Waal forces generally being stronger than the force of gravity acting on small particles having diameters of 10 μm or less. There are several micronization technologies known in the art. Two major categories dominate in prior art: breaking of large particles using milling process such as jet milling, pearl-ball milling or high-pressure homogenization and the production of small particles using controlled production processes such as spray drying, lyophilization, precipitation from supercritical fluid and controlled crystallization. The former category produces predominantly crystalline, homogenous particles, the latter more amorphous, ‘light’, porous particles. See e.g. “Micron-Size Drug Particles: Common and Novel Micronization techniques” by Lee Siang Hua. In this document the term ‘finely divided powder’ refers to inhalable particles in general and does not limit or preclude any method of producing such particles.
Because most active drugs are very potent, only a fraction of a milligram is needed in a dose in many cases. Before filling it is generally necessary to dilute the drug using a suitable, physiologically inert excipient, e.g. lactose. Today, nominal inhalation doses of less than I mg and even less than 0.5 mg are not unusual. Such small doses are very difficult to meter and fill using prior art methods. See for instance the publication U.S. Pat. No. 5,865,012 and WO 03/026965 A1. The problem of bad flowability in the powder is often addressed by selecting an excipient as carrier, which comprises bigger particles than the drug, i.e. aerodynamic particle diameters for the excipient larger than 10 μm. A common practice in the pharmaceutical industry is to dilute the active substance further, in order to increase the nominal dose mass to a level, which the filling method of choice can handle. Typically, volumetric doses in prior art have masses in a range from 5 to 50 mg.
Turning to the drug formulation, there are a number of well-known techniques, as mentioned above, to obtain an appropriate primary particle size distribution to ensure correct lung deposition for a high percentage of the dose. There are also a number of well-known techniques for modifying the forces between the particles and thereby obtaining a powder with e.g. small adhesive forces. Such methods include modification of the shape and surface properties of the particles, e.g. porous particles and controlled forming of powder pellets, as well as addition of an inert carrier with a larger average particle size (so called ordered mixture). Naturally, independent of which method of making the formulation is preferred, a narrow particle size distribution providing a high fine particle fraction (FPF) of the active pharmaceutical ingredient (API) formulation is an advantage, where the mass median aerodynamic diameter (MMAD) preferably is in a range between 0.5 and 3 μm, if pulmonary delivery is the objective.
Novel drugs, both for local and systemic delivery, often include biological macromolecules, which put completely new demands on the formulation. In our publication WO 02/11803 (U.S. Pat. No. 6,696,090) a method and a process is disclosed of preparing a so called electro-powder, suitable for forming doses by an electro-dynamic method. The disclosure stresses the importance of controlling the electrical properties of a medication powder and points to the problem of moisture in the powder and the need of low relative humidity in the atmosphere during dose forming.
A successful delivery to the deep lung also assumes that the inspiration takes place in a calm manner to decrease air speed in the airways and thereby reduce deposition by impaction in the upper respiratory tracts. The advantages of using the inhalation power of the user to full potential in a prolonged, continuous dose delivery interval within the inhalation cycle is disclosed in our U.S. Pat. No. 6,622,723 (WO 01/34233 A1), which is incorporated herein by reference. The patent presents several devices for efficient distribution of pharmaceutical compositions in fine powder form in the inspiration air, without needing other sources of energy than the power of the airstream resulting from the user's inhalation.
A method and device, for aerosolizing and, if necessary, de-aggregating powders for inhalation, based on a relative motion between a powder dose and a suction nozzle are disclosed in our U.S. Pat. Nos. 6,892,727 and 6,840,239, which are incorporated herein by reference. The disclosures teach that adopting an Air-razor method and device, when applied in a dry powder inhaler device, advantageously aerosolize dry, fine powder doses, but give only little information about what formulations may be used. The preferred embodiments of the disclosures were based primarily on an electro-dynamic method of producing pre-metered doses of finely divided APIs with or without excipients present in a mixture. Most of the doses were porous, which is easily obtained in the electro-dynamic forming method, and needed to be extended, thereby occupying a much larger surface area of the available substrate member than would be necessary for a similar dose metered and filled using conventional filling methods, such as volumetric filling. Having knowledge of the above mentioned documents, it would not be obvious to a person of ordinary skill in the art to assume that the Air-razor method could successfully be applied to any dry powder formulation. Furthermore, it would not be obvious to a skilled person to apply the Air-razor method to new formulations and fill doses thereof using standard industry filling methods.
The present invention is directed to improving the Air-razor method and to disclose some preferred embodiments of a device performing the improved method.
A method for releasing and dispersing into flowing air a dose of dry medication powder and more specifically a method of optimizing emission of the dose from a dry powder inhaler comprising an Air-razor device for releasing powder. In contrast to prior art, the present invention does not require other sources of energy besides the power of the inhalation effort by the receiver to produce a very high degree of dose release from a substrate member and efficient dispersal of the dose into streaming air.
The invention, together with further objects and advantages thereof, may best be understood by referring to the following detailed description taken together with the accompanying drawings, in which:
The present invention makes the Air-razor method and device applicable to all types of dry powder formulations of inhalable medication powders. Furthermore, standard filling methods and equipment may be used to meter and fill doses of a chosen formulation. The doses can then be applied to an adapted DPI, comprising an Air-razor device optimized for the formulation, where the emitted doses and the fine particle doses (FPD) delivered by the DPI present excellent results in terms of quantity and quality compared to the original, metered doses of said chosen formulation. Naturally, the emitted dose and the FPD cannot exceed what is in the metered dose before it is sucked up.
As used herein, the term “Air-razor method” refers to a method where the difference in external forces acting on two particles in a dose overcomes the adhesion and friction forces holding them together. As used herein, the term “Air-razor device” refers to a device capable of providing, via energy imput by a user via inhalation and movement of a dose and/or suction tube, a difference in external forces acting on two particles that overcomes the adhesion and friction forces holding them together. The external forces referred to ensue from the induced flow of air developing from a suction effort provided by a user and applied to an adapted DPI comprising an Air-razor device.
The present invention discloses an improved Air-razor method of releasing a dose of dry medication powder from a substrate member and dispersing the powder particles into an airstream. The invention teaches that a dose of dry medication powder may be emitted from a dry powder inhaler comprising an Air-razor device, whereby the dose is delivered to a receiver with an extremely high fine particle dose (FPD) of the emitted dose coming very close to the original fine particle fraction (FPF) of the original powder formulation. In a further aspect, the invention teaches that the Air-razor method may be optimized and the method implemented in an Air-razor device design, which offers very low retention of particles both on the substrate member, including associated surfaces, and downstream flow channels, which are in contact with the powder before and during dose emission.
Interestingly enough, we have been able to optimize the Air-razor method and device and to implement this in an adapted DPI. Test data show excellent results in emitted dose relative metered dose and in delivered fine particle dose relative emitted dose, when the Air-razor is optimized for a particular powder formulation. See
It has been possible to improve the Air-razor method to work satisfactorily regardless of what metering and filling method is preferred, including gravimetric, volumetric, electrostatic and electro-dynamic methods and combinations thereof. The most important parameters to control are suction tube inlet aperture size, which shall preferably have a slightly larger diameter at right angles to the direction of the motion than the width of the dose deposit(s), a gap between the inlet aperture and the substrate member of preferably not more than two millimetres and a speed of the relative motion between substrate member and suction tube, or vice versa, preferably not exceeding 100 mm/s. Preferably, time for the relative motion, within the time for a suction effort, e.g. an inhalation cycle, is in a range of approximately 0.2 s to 2 s from beginning to end for optimal results.
An important element of the Air-razor method is a relative motion between a suction tube, comprising an inlet nozzle, and a powder dose. In this document the term “relative motion” refers to the non-airborne powder, which constitutes a dose that is gradually moved, relatively speaking, by the motion into close proximity to the inlet aperture of said suction tube. Thus, it is irrelevant for the efficacy of the Air-razor method how the relative motion is arranged, i.e. if a suction tube is brought in motion or if it is the dose or, indeed, a combination of motions. A motion of the dose is preferably brought about by moving a substrate onto which the dose is deposited, but other means e.g. vibrating or shock devices may also be used. An airstream, induced by suction, going at speed into the suction tube inlet aperture brings about the release of individual powder particles and dispersal of particles into the airstream, optionally also providing de-aggregation of aggregated particles. Said term does not refer to airborne powder particles already entrained in air. Therefore, the mentioning of “motion” or “moving” in relation to “powder” or “powder dose” or “dose” refers to the dose, preferably loaded on a substrate member, before the powder particles are released and dispersed into air. Thus, the dose comprises at least one powder deposit, e.g. in a single, concentrated spot or in a series of such spots, or a deposit or deposits spread out onto an area of the substrate member. The pattern of how a dose is arranged onto the substrate member depends mainly on the selected method of dose filling, e.g. gravimetric, volumetric, electrostatic and electro-dynamic methods may be used, including combinations thereof.
The relative motion between powder dose and suction tube preferably begins, either automatically by breath-actuation or by manual control, when a pre-defined, minimum airflow has already been established through the suction tube. The minimum airflow develops when a pre-defined, minimum suction power is applied to the suction tube, said suction power selected to secure enough Air-razor power to release the powder of the dose. The timing of the motion must be adapted to the style and size of the substrate member and the volume and mass of the dose. We have found that an optimum time for the motion to be completed is between 0.2 and 2 seconds, but the performance of the Air-razor device is not necessarily less at shorter motion intervals than 0.2 seconds or longer intervals than 2 seconds. In any particular application the formulation of the drug powder, the dose volume and dose mass must be considered when optimizing the Air-razor performance. For instance, we have surprisingly found that compact, volumetrically metered doses in a range from below 1 mg to more than 10 mg may be very efficiently released by the Air-razor device in approximately 1 second. Such doses may be concentrated to a particular spot on a substrate or the powder may be distributed, e.g. by shaking, over the whole substrate area without any difference in Air-razor performance. So, within the indicated time frame of 0.2 to 2 seconds almost any dose is released and delivered to a user with excellent results in emitted dose and FPD.
A satisfactory Air-razor effect is normally generated by a suction between 2 and 4 kPa, which gives rise to an airflow in a range from 20 l/min to 60 l/min, depending on chosen size, distance to substrate member etc. for the suction tube inlet aperture and also other parameters play a part in the optimizing exercise. See
The medication powder comprises one or more pharmacologically active substances and optionally one or more excipients. As used herein the terms “powder” or “medication powder” are used to signify the substance in the form of dry powder, which is the subject of release from a substrate member and dispersal into an airstream by the disclosed invention and intended for deposition at a selected target area of a receiver's airways.
Short Background on the Concept of the Powder Air-Razor Method
Adhesion of Particles
Particles adjacent to other particles or to a substrate member will adhere to each other. Many different types of adhesive forces will play roles in the total adhesive force between a particle and the environment, whether that is another particle, an aggregate of particles, a substrate member or a combination thereof. The types of adhesive forces acting on a particle can be van der Waal forces, capillary forces, electrical forces, electrostatic forces, etc. The relative strengths and ranges of these forces vary with e.g. material, environment, size and shape of the particle. The sum of all these forces acting on a particle is hereinafter referred to as an adhesive force.
Release and Entrainment of Particles
In order to release particles from a substrate and/or from other particles it is not sufficient to let a force act on the particles with enough strength for release and entrainment. If a strong force acts on a cluster of particles, such that more or less the same force acts on all particles, the cluster will be entrained into the airflow without particles separating. The condition for release may thus be stated as: The difference in external forces acting on two particles must overcome the adhesion and friction forces holding them together. Attaining a difference in force from airflow may be done efficiently by creating shear forces, and hence the Air-razor method makes use of high shear forces in the area of the powder deposited onto a substrate member.
The efficiency of the Air-razor method may be optimized by careful design of the geometry of involved flow elements with the aim to reach as high a velocity as possible in the releasing area around the suction tube inlet aperture, i.e. where the dose is to be found, but at the same time a smooth transportation of air in other areas. This will minimise the dissipative losses where not wanted and so preserve energy for use in the area adjacent to and into the powder deposit(s). When suction is applied to the suction tube outlet, a low-pressure develops that accelerates the air through the suction tube inlet aperture during a short period before a steady state condition is reached. Initially, during the start-up period as the air picks up inertia, the velocity is not high enough to generate the necessary shear forces. Preferably, during this initial period the air flow is allowed to build up before the powder dose is brought adjacent to the suction tube. This ensures that the conditions for an efficient release of the powder exist before the dose deposit(s) is (are) attacked by the air stream. The Air-razor invention makes use of the concentrated flow close to the inside wall of the suction tube inlet nozzle as well as the surfaces of the substrate member, and especially the small gap between the aperture wall on the suction tube inlet and the substrate member.
Air-Razor Movement
The importance of shear forces for an efficient release of particles and the theoretical background as to why has been discussed in the foregoing. The relative motion introduced between the suction tube and the load of powder, i.e. the substrate member normally serving as carrier, is instrumental in attaining and maintaining the desired conditions stated for releasing all of a powder dose and not just part of it.
The main advantages given by the motion are:
The low-pressure created by the suction through the suction tube drives air to flow in the direction of the low-pressure. Building up inertia means accelerating the mass in a system, i.e. the mass of the air itself, hence giving the desired high velocity air flow after the acceleration period. The velocity of the flow increases to a point where the flow resistance makes further increase impossible, unless the level of low-pressure is decreased, i.e. the pressure drop is increased, or the flow resistance is decreased.
Optimizing Shear Force Spreading
The area exhibiting the highest shear forces is concentrated close to the wall of the inlet aperture of the suction tube nozzle. This concentrated area must be adapted to the powder deposit or deposits making up the dose and which occupy a small or large percentage of the available dose target area of a substrate member. Different powder formulations may behave very differently when filled as at least one deposit on the substrate member. For instance, formulations comprising very porous particles may have very low bulk density and may also present quite small adhesive forces. They often flow quite easily, even if the average particle size is small, and these powders are therefore easy to use in conventional filling systems. Because of the small adhesive forces between particles and between particles and substrate the deposited powder dose is easily broken up after filling, e.g. volumetrically, and the dose may spread itself over a large part of the available substrate area. The total volume of the dose is also rather big, since the powder bulk density is low, compared to the same dose mass of non-porous particles of the same substance. The dose of a formulation of porous particles, as the example shows, needs an Air-razor device, which is capable of spreading the shear forces over a big volume, but which must not necessarily present very high shear forces, since the individual particles are comparatively easy to release from each other and from the substrate. In short, the Air-razor should be adapted to spreading the available airflow energy over a big volume in this case. On the other hand, if the formulation comprises fine, micronized particles from e.g. a jet-mill process, the powder typically presents high adhesive forces, it does not flow easily, porosity is low, bulk density is high and filling is difficult using prior art methods. In this example the dose deposit or deposits hold together well on the substrate member after filling and the substrate area occupied by the dose is small, perhaps not more than a single deposit in the form of a dot, on a fraction of the available dose target area. In such case individual particles require fairly high levels of supplied energy in order to be released and entrained in the airstream. Here, the requirements on the Air-razor are quite different from the previous example. Shear forces need to be high and more concentrated to ensure that all particles of the dose are subjected to a sufficiently high force to be released and de-aggregated from the cluster of particles they may be part of. In this example it is still most important that the shear forces are applied gradually to the dose, even though the deposit or deposits are small in size. A third example is a formulation comprising a majority of large particles, preferably of an excipient substance, in a mixture with small particles, some of which constituting the API to be delivered to the deep lung, for instance. This formulation is called an ordered mixture where the large particles act as carriers of the small particles. When a dose of the mixture is enhaled the small particles separate from the big ones and are transported by the inspiration air into the lungs of the user, while the big particles impact in the mouth or upper airways, where they have no effect. Typical properties of an ordered mixture are high flowability, ease of filling, e.g. volumetrically, high dose mass often necessary, fairly easy to release dose, moderate adhesive forces. The dose deposit or deposits hold together well on the substrate member after filling, but take up much more space than the dose of micronized particles in the preceding example. The deposits are not difficult to break up in random clusters of particles by providing energy e.g. vibration. In the example, the Air-razor needs to cover the available dose target area and at the same time providing fairly high shear forces over a rather big volume in order to release all particles of the mixture.
Optimizing the Air-razor for a dose of a particular powder formulation involves a set of Air-razor parameters, including suction tube inlet aperture size, shape, aperture distance and angle to the substrate, duration of suction and speed and time of relative motion. The relative motion between the suction tube and the dose will let the relatively small and concentrated area of high shear stress traverse over the area occupied by the dose. The velocity of the airflow will not be affected by the motion of the suction tube in relation to the powder dose, because the speed of the relative motion is very much lower than the velocity of the air flow going into the suction tube inlet. However, the motion of the suction tube forcibly shifts the position of the driving low-pressure relative the contour of the dose in the direction of the motion. Thus, the area of high shear forces moves along a path, controlled by the relative motion of the suction tube, such that the high shear forces gradually disperse powder particles into air. Preferably, the path begins just outside a point of contact between the high shear force area of flowing air and the deposit(s) of the powder dose and passes the dose deposits, if more than one, from the beginning until the end on the substrate member. Thus, the gradual releasing and dispersal of a medication powder is an inherent essential characteristic of an Air-razor method.
For example, in a preferred embodiment of the optimized Air-razor method and device, the dose is deposited by a gravimetric, volumetric or electric method onto a substrate member of a pod container. At least a pre-defined, minimum suction is applied to an outlet of a suction tube also comprising a dose-adapted inlet aperture, thereby starting up at least a minimum airflow into the suction tube inlet e.g. from ambient air. The pod and thereby the dose therein are then moved past the inlet aperture at close proximity in an interval of preferably 0.2 to 2 seconds. The dose is hereby gradually released and entrained into the airflow going through the suction tube.
In another preferred embodiment of the optimized Air-razor method and device, similar to the above, the suction tube inlet aperture is moved at close range past the dose in the pod container, thus releasing the dose by using the Air-razor effect in analogy with the above example.
In yet another but similar embodiment to the ones described above, the suction tube inlet aperture and the dose both move to make the airflow into the inlet aperture release the dose gradually by using the Air-razor effect in analogy with the above examples.
The above written description of the invention provides a manner and process of making and using it such that any person skilled in this art is enabled to make and use the same, this enablement being provided in particular for the subject matter of the appended claims, which make up a part of the original description and including an improved method of releasing and dispersing into an airstream a dose of dry powder, releasably retained onto a substrate member, comprising:
Similarly fully enabled is a method of optimizing emission of a dose of dry powder, releasably retained on a substrate member by use of an Air-razor method, comprising
Similarly fully enabled is an Air-razor device optimized according to claim 13 for releasing a dry powder medication dose from a substrate member and disperse the dose into an airflow, wherein
the Air-razor device comprises:
As used above, the phrases “selected from the group consisting of;” “chosen from,” and the like include mixtures of the specified materials.
All references, patents, applications, tests, standards, documents, publications, brochures, texts, articles, etc. mentioned herein are incorporated herein by reference. Where a numerical limit or range is stated, the endpoints are included. Also, all values and subranges within a numerical limit or range are specifically included as if explicitly written out. Terms such as “contain(s)” and the like as used herein are open terms meaning ‘including at least’ unless otherwise specifically noted.
The above description is presented to enable a person skilled in the art to make and use the invention, and is provided in the context of a particular application and its requirements. Various modifications to the preferred embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments and applications without departing from the spirit and scope of the invention. Thus, this invention is not intended to be limited to the embodiments shown, but is to be accorded the widest scope consistent with the principles and features disclosed herein.
