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US20070101991A1 - Optimizing release of dry medicament powder - Google Patents

Optimizing release of dry medicament powder Download PDF

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Publication number
US20070101991A1
US20070101991A1 US11/268,553 US26855305A US2007101991A1 US 20070101991 A1 US20070101991 A1 US 20070101991A1 US 26855305 A US26855305 A US 26855305A US 2007101991 A1 US2007101991 A1 US 2007101991A1
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United States
Prior art keywords
dose
substrate member
air
razor
suction tube
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/268,553
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English (en)
Inventor
Mattias Myrman
Mats Eriksson
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Mederio AG
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Mederio AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mederio AG filed Critical Mederio AG
Priority to US11/268,553 priority Critical patent/US20070101991A1/en
Priority to PCT/SE2005/001828 priority patent/WO2007055629A1/fr
Assigned to MEDERIO AG reassignment MEDERIO AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ERIKSSON, MATS, MYRMAN, MATTIAS
Publication of US20070101991A1 publication Critical patent/US20070101991A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/06—Solids
    • A61M2202/064—Powder

Definitions

  • 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.
  • MDIs metered dose inhalers
  • DPIs dry powder inhalers
  • 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 ⁇ m in aerodynamic diameter (AD). Powder particles larger than 5 ⁇ m 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.
  • 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 ⁇ m or less.
  • micronization technologies known in the art.
  • 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 ⁇ m, if pulmonary delivery is the objective.
  • FPF fine particle fraction
  • MMAD mass median aerodynamic diameter
  • Novel drugs both for local and systemic delivery, often include biological macromolecules, which put completely new demands on the formulation.
  • 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.
  • 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.
  • 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.
  • FIG. 1 illustrates the different forces acting on a stationary particle situated in a stream of air
  • FIG. 2 illustrates in a timing diagram a typical inhalation cycle showing pressure and flow
  • FIG. 3 illustrates test data from in-vitro testing of an optimized Air-razor device in an adapted DPI
  • FIG. 4 illustrates in a stylized drawing a substrate member and a concentrated dose thereon
  • FIG. 5 illustrates in a stylized drawing a substrate member and a spread-out dose thereon
  • FIG. 6 illustrates in a stylized drawing a substrate member and a dose in a spot thereon
  • FIG. 7 illustrates in perspective ( FIG. 1 a ), top ( FIG. 1 b ) and side ( FIG. 1 c ) views a particular embodiment of a sealed dose container filled with a dose of a medicament and a dose of an excipient;
  • FIG. 8 illustrates a sealed dose container after agitation filled with a dose of a medicament consisting of two deposits and a dose of an excipient consisting of three deposits where the doses have become partly mixed;
  • 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.
  • 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.
  • 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.
  • 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.
  • FPD extremely high fine particle dose
  • FPF fine particle fraction
  • 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.
  • 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 FIG. 3 , which illustrates in-vitro testing of an optimized Air-razor method and an Air-razor device applied in a dry powder inhaler device.
  • the total dose is 1 mg of a pure, micronized API.
  • the total dose in the example is equivalent to a metered dose.
  • the optimized Air-razor is quite insensitive to variations in the time period for a relative motion of substrate member and a suction tube, as illustrated (‘standard inhalation time’ signifies motion in approximately 0.7 s, ‘fast inhalation time’ signifies about 0.3 s for the motion and ‘slow inhalation time’ signifies about 1.2 s for the relative motion to be completed).
  • the Air-razor is also insensitive to the orientation of the inhaler, i.e. the Air-razor itself.
  • particle retention on the substrate member acting as carrier of the dose is also minimized by the optimization, which may optionally also include minimizing retention on the inside walls of the downstream air channels. Total retention is normally less than 10% as illustrated in FIG. 3 .
  • suitable powder formulations include those produced by jet-milling, spray-drying and super-critical crystallization. Powders of micronized, solid particles or powders of porous particles of low density can be advantageously released and aerosolized by the Air-razor method.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the dose volume and dose mass must be considered when optimizing the Air-razor performance.
  • 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.
  • FIG. 2 illustrates a timing diagram of an inhalation period ‘I’ and a suction pressure curve ‘P’ and the following airflow ‘Q’ as a result.
  • FIGS. 4, 5 and 6 illustrate top and side views of different embodiments of single deposits of doses 22 on a target area 35 of a substrate member 34 .
  • doses may be very concentrated in a spot, or spread out over most of the available area.
  • the Air-razor is preferably optimized with regard for the type of dose, including type of formulation, that is going to be loaded into an inhaler where the Air-razor is applied.
  • a so-called pod as a particular embodiment of a sealed dose container, is to be preferred in an application where the present invention is to be put to use. See our Application U.S. Ser. No. 11/154677, which is hereby included in this document by reference.
  • a pod container may, if necessary, be made as a high barrier seal container offering a very high level of moisture protection and which is in itself dry, i.e. it does not contain water. See FIG. 7 illustrating a pod carrying a sealed container in a perspective drawing.
  • FIG. 7 a shows a sealed container 33 (seal 31 ) put into a protective casing 41 adapted for insertion into a dry powder inhaler.
  • FIG. 7 b shows a top view of the carrier/container and indicates a dose of a dry powder medicament 22 and a dose of a dry powder excipient consisting of two depositions 21 inside the container 33 under a seal 31 .
  • FIG. 7 c illustrates a side view of the carrier/container shown in FIG. 1 b .
  • FIG. 8 illustrates a similar container to FIG. 7 , but the medicament dose consists of two deposits 22 and the excipient dose consists of deposit 21 after agitation of the container, whereby the deposits 21 and 22 have become partly
  • the medication powder comprises one or more pharmacologically active substances and optionally one or more excipients.
  • 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.
  • 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.
  • FIG. 1 illustrates forces acting on a particle.
  • the force caused by airflow 303 acting on a particle 101 can be divided into two parts, drag force 305 acting parallel to the airflow, and lift force 304 acting perpendicular to the airflow.
  • the condition for freeing the particle is in the static case that lift and drag forces exceed adhesion 301 and friction 302 forces.
  • 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).
  • 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.
  • 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.
  • 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 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.
  • 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.
  • the dose of a formulation of porous particles 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.
  • the Air-razor should be adapted to spreading the available airflow energy over a big volume in this case.
  • the formulation comprises fine, micronized particles from e.g.
  • 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.
  • 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.
  • individual particles require fairly high levels of supplied energy in order to be released and entrained in the airstream.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 Air-razor device comprises:
  • phrases “selected from the group consisting of;” “chosen from,” and the like include mixtures of the specified materials.

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  • Health & Medical Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
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US11/268,553 2005-11-08 2005-11-08 Optimizing release of dry medicament powder Abandoned US20070101991A1 (en)

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US11/268,553 US20070101991A1 (en) 2005-11-08 2005-11-08 Optimizing release of dry medicament powder
PCT/SE2005/001828 WO2007055629A1 (fr) 2005-11-08 2005-12-01 Optimisation de la liberation d'une poudre medicamenteuse seche

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150017602A1 (en) * 2011-06-10 2015-01-15 Max Arocha Regulated periodontal dispensing apparatus and multiple dose applicator with a semilunar valve.

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Publication number Priority date Publication date Assignee Title
US5350597A (en) * 1991-12-12 1994-09-27 Mcneil-Ppc, Inc. Method for intermittently applying particulate powder material to a fibrous substrate
US5351683A (en) * 1990-04-12 1994-10-04 Chiesi Farmaceutici S.P.A. Device for the administration of powdered medicinal substances
US5857457A (en) * 1994-05-11 1999-01-12 Orion-Yhtyma Oy Powder inhaler with remnant mover and chamber
US5983893A (en) * 1994-12-21 1999-11-16 Astra Aktiebolag Inhalation device
US6055980A (en) * 1991-05-20 2000-05-02 Dura Pharmaceuticals, Inc. Dry powder inhaler
US6142146A (en) * 1998-06-12 2000-11-07 Microdose Technologies, Inc. Inhalation device
US20030192540A1 (en) * 2002-04-12 2003-10-16 Mattias Myrman Therapeutic dry powder preparation
US6655381B2 (en) * 2000-06-23 2003-12-02 Ivax Corporation Pre-metered dose magazine for breath-actuated dry powder inhaler

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Publication number Priority date Publication date Assignee Title
SE524957C2 (sv) * 2002-04-12 2004-11-02 Microdrug Ag Förfarande för uppdelning och fördelning i luft av torrt pulvermedikament
SE525027C2 (sv) * 2002-04-12 2004-11-16 Microdrug Ag Anordning utgörande en pulverlufthyvel
SE527191C2 (sv) * 2003-06-19 2006-01-17 Microdrug Ag Inhalatoranordning samt kombinerade doser av tiotropium och fluticason
SE528121C2 (sv) * 2004-03-29 2006-09-05 Mederio Ag Preparering av torrpulver för på förhand uppmätt DPI

Patent Citations (8)

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Publication number Priority date Publication date Assignee Title
US5351683A (en) * 1990-04-12 1994-10-04 Chiesi Farmaceutici S.P.A. Device for the administration of powdered medicinal substances
US6055980A (en) * 1991-05-20 2000-05-02 Dura Pharmaceuticals, Inc. Dry powder inhaler
US5350597A (en) * 1991-12-12 1994-09-27 Mcneil-Ppc, Inc. Method for intermittently applying particulate powder material to a fibrous substrate
US5857457A (en) * 1994-05-11 1999-01-12 Orion-Yhtyma Oy Powder inhaler with remnant mover and chamber
US5983893A (en) * 1994-12-21 1999-11-16 Astra Aktiebolag Inhalation device
US6142146A (en) * 1998-06-12 2000-11-07 Microdose Technologies, Inc. Inhalation device
US6655381B2 (en) * 2000-06-23 2003-12-02 Ivax Corporation Pre-metered dose magazine for breath-actuated dry powder inhaler
US20030192540A1 (en) * 2002-04-12 2003-10-16 Mattias Myrman Therapeutic dry powder preparation

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150017602A1 (en) * 2011-06-10 2015-01-15 Max Arocha Regulated periodontal dispensing apparatus and multiple dose applicator with a semilunar valve.
US9877799B2 (en) * 2011-06-10 2018-01-30 Pharmaphd, Inc. Regulated periodontal dispensing apparatus and multiple dose applicator with a semilunar valve

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