Patent Application
20100018523
The term “erectile dysfunction” has been defined by the National Institutes of Health as the inability of the male to attain and maintain erection of the penis sufficient to permit satisfactory sexual intercourse. See J. Am. Med. Assoc., 270(1):83-90 (1993). Because adequate arterial blood supply is critical for erection, any disorder that impairs blood flow may be implicated in the etiology of erectile failure. Erectile dysfunction affects millions of men and, although generally regarded as a benign disorder, has a profound impact on their quality of life. It is recognized, however, that in many men psychological desire, orgasmic capacity, and ejaculatory capacity are intact even in the presence of erectile dysfunction.
Etiological factors for erectile disorders have been categorized as psychogenic or organic in origin. Organic factors include those of a neurogenic origin and those of a vasculogenic origin. Neurogenic factors include, for example, lesions of the somatic nervous pathways which may impair reflexogenic erections and interrupt tactile sensations needed to maintain erections, and spinal cord lesions which, depending upon their location and severity, may produce varying degrees of erectile failure.
Psychogenic factors for erectile dysfunction include such processes as depression, anxiety, and relationship problems which can impair erectile functioning by reducing erotic focus or otherwise reducing awareness of sensory experience. This may lead to an inability to initiate or maintain an erection.
Vasculogenic risk factors include factors which affect blood flow and include cigarette smoking, diabetes mellitus, hypertension, alcohol, vascular disease, high levels of serum cholesterol, low levels of high-density lipoprotein (HDL), and other chronic disease conditions such as arthritis. The Massachusetts Male Aging Study (MMAS, as reported by H. A. Feldman, et al., J. Urol., 151: 54-61 (1994) found, for example, that the age-adjusted probability of complete erectile dysfunction was three times greater in subjects reporting treated diabetes than in those without diabetes. While there is some disagreement as to which of the many aspects of diabetes is the direct cause of erectile dysfunction, vascular disease is most frequently cited.
The MMAS also found a significant correlation between erectile dysfunction and heart disease with two of its associated risk factors, hypertension and low serum high density lipoprotein (HDL). It has been reported that 8-10% of all untreated hypertensive patients are impotent at the time they are diagnosed with hypertension. The association of erectile dysfunction with vascular disease in the literature is strong, with impairments in the hemodynamics of erection demonstrated in patients with myocardial infarction, coronary bypass surgery, cerebrovascular accidents, and peripheral vascular disease. It also found cigarette smoking to be an independent risk factor for vasculogenic erectile dysfunction, with cigarette smoking found to exacerbate the risk of erectile dysfunction associated with cardiovascular diseases.
As described in U.S. Pat. Nos. 5,770,606 and 6,291,471, it is known to treat both psychogenic and organic erectile dysfunction in males with the opioid apomorphine. Apomorphine is a derivative of morphine, and was first evaluated for use as a pharmacologic agent as an emetic in 1869. In the first half of the 20th century, apomorphine was used as a sedative for psychiatric disturbances and as a behavior-altering agent for alcoholics and addicts. By 1967, the dopaminergic effects of apomorphine were realized, and the compound underwent intensive evaluation for the treatment of Parkinsonism. Since that time, apomorphine has been classified as a selective dopamine receptor agonist that stimulates the central nervous system producing an arousal response manifested by yawning and penile erection in animals and man.
WO 01/74358 purports to describe a method for treatment of male erectile dysfunction using an inhaled apomophine formulation. The formulations exemplified therein comprise a solution of apomorphine and sodium metabisulfite in water, which are said to have been introduced directly into the lungs of a dog via the trachea.
U.S. Pat. No. 6,193,992 purports to describe a method of ameliorating sexual dysfunction in a human female which comprises administering to said human female apomorphine in an amount sufficient to increase intraclitoral blood flow and vaginal wall blood flow on stimulation of said female but less than the amount that induces substantial nausea
In one aspect, the present invention is directed to methods for treating sexual dysfunction via inhalation therapy.
In accordance with one such embodiment of the present invention, a method for treating sexual dysfunction via inhalation is provided which comprises inhaling a dose of a powder composition, the powder composition comprising apomorphine or pharmaceutically acceptable salts thereof. Preferably, the powder composition further includes a carrier material, the carrier material has an average particle size of from about 40 to about 70 microns, and at least 90 percent of said apomorphine has a particle size of 5 microns or less.
In accordance with another embodiment of the present invention, a method for treating sexual dysfunction via inhalation is provided which comprises inhaling a dose of a powder composition, the dose of the powder composition comprising from about 100 micrograms to about 2000 micrograms of apomorphine or pharmaceutically acceptable salts thereof. Preferably, the dose comprises from about 100 micrograms to about 1600 micrograms of said apomorphine, more preferably, about 100 micrograms to about 1000 micrograms of said apomorphine, and most preferably, about 100 micrograms to about 800 micrograms of said apomorphine.
In accordance with another embodiment of the present invention, a method for treating sexual dysfunction via inhalation is provided which comprises inhaling a dose of a powder composition, the powder composition comprising apomorphine or pharmaceutically acceptable salts thereof and a carrier material, the carrier material having an average particle size of from about 40 to about 70 microns, at least 90 percent of said apomorphine having a particle size of 5 microns or less.
In another aspect, the present invention is directed to unit doses of apomorphine.
In accordance with one such embodiment of the present invention, a dose is provided which comprises a powder composition including a carrier material and from about 100 micrograms to about 800 micrograms of apomorphine or a pharmaceutically acceptable salt thereof.
In accordance with another embodiment of the present invention, a dose is provided which comprises a powder composition including a carrier material and apomorphine or a pharmaceutically acceptable salt thereof, the carrier material having an average particle size of from about 40 to about 70 microns, at least 90 percent of said apomorphine having a particle size of 5 microns or less.
In accordance with another embodiment of the present invention, a drug loaded blister is provided which comprises a base having a cavity formed therein, the cavity containing a powder composition including a carrier material and from about 100 micrograms to about 800 micrograms of apomorphine or a pharmaceutically acceptable salt thereof, the cavity having an opening which is sealed by a rupturable covering.
In accordance with another embodiment of the present invention, a drug loaded blister is provided which comprises a base having a cavity formed therein, the cavity containing a powder composition including a carrier material and apomorphine or a pharmaceutically acceptable salt thereof, the carrier material having an average particle size of from about 40 to about 70 microns, at least 90 percent of said apomorphine having a particle size of 5 microns or less, the enclosure having an open end, the cavity having an opening which is sealed by a rupturable covering.
In the above referenced embodiments, the doses and/or drug loaded blisters preferably include from 1 to 5 milligrams of powder composition, wherein apomorphine or its pharmaceutically acceptable salts comprise from about 3% to about 80%, preferably from about 5% to about 50%, and most preferably from about 5% to about 30% of the powder composition.
In another aspect, the present invention is directed to methods for producing an inhalable aerosol of a powdered apomorphine composition.
In accordance with one such embodiment, the method comprises entraining a powdered composition in a gas flow upstream from an inlet port of a vortex chamber having a substantially circular cross-section. In this regard, in certain variants of this embodiment, the powder composition may include from about 100 micrograms to about 800 micrograms of apomorphine or a pharmaceutically acceptable salt thereof and a carrier material. In other variants of this embodiment, the powder composition may include a carrier material and apomorphine or a pharmaceutically acceptable salt thereof, the carrier material has an average particle size of from about 40 to about 70 microns, and at least 90 percent of said apomorphine has a particle size of 5 microns or less. In any event, the method further comprises directing the gas flow through the inlet port into the vortex chamber in a tangential direction; directing the gas flow through the vortex chamber so as to aerosolise the powder composition; and directing the gas flow with the powder composition out of the vortex chamber in an axial direction through an exit port, wherein a velocity of the gas flow at a distance of 300 mm outside of the exit port is less than a velocity of the gas flow at the inlet port.
In accordance with another embodiment of the present invention, the method comprises entraining a powdered composition including agglomerated particles in a gas flow upstream from an inlet port of a vortex chamber. In certain variants of this embodiment, the agglomerated particles include from about 100 micrograms to about 800 micrograms of apomorphine or a pharmaceutically acceptable salt thereof and a carrier material. In other variants of this embodiment, the agglomerated particles include a carrier material and apomorphine or a pharmaceutically acceptable salt thereof, the carrier material has an average particle size of from about 40 to about 70 microns, and at least 90 percent of said apomorphine has a particle size of 5 microns or less. In either case, the method further comprises directing the gas flow through the inlet port into the vortex chamber; depositing the agglomerated particles onto one or more walls of the vortex chamber; applying, via the gas flow through the vortex chamber, a shear to the deposited agglomerated particles to deagglomerate said particles, and directing the gas flow, including the deagglomerated particles, out of the vortex chamber, wherein a velocity of the gas flow at a distance of 300 mm outside of the exit port is less than a velocity of the gas flow at the inlet port.
In accordance with another embodiment of the present invention, the method comprises entraining agglomerated particles in a gas flow. The agglomerated particles include a carrier material having an average particle size of from about 40 microns to about 70 microns and from about 100 to about 800 micrograms apomorphine or a pharmaceutically acceptable salt thereof. Preferably, at least 90% of said apomorphine has a particle size of 5 microns or less. The method further comprises depositing the agglomerated particles onto one or more surfaces; and applying, via the gas flow, a shear to the deposited agglomerated particles to deagglomerate said particles.
In accordance with another embodiment of the present invention, the method comprises generating an air flow through an inlet port of a chamber, the air flow having entrained therein a composition. In certain variants of this embodiment, the composition comprises from about 100 micrograms to about 800 micrograms of apomorphine or a pharmaceutically acceptable salt thereof and a carrier material. In other variants of this embodiment, the composition includes a carrier material and apomorphine or a pharmaceutically acceptable salt thereof, the carrier material has an average particle size of from about 40 to about 70 microns, and at least 90 percent of said apomorphine has a particle size of 5 microns or less. The method further comprises directing the air flow through the chamber. The chamber has an axis and a wall curved about the axis and the air flow rotates about the axis. The method further directs the air flow through an exit port of the chamber, wherein a direction of the air flow through the inlet port is tangential to the wall, and a direction of the air flow through the exit port is parallel to the axis, and wherein a cross-sectional area of the air flow through the chamber is in a plane normal to the air flow and decreases with increasing distance from the inlet port.
In other aspects, the present invention is directed to inhalers for producing an inhalable aerosol of a powdered apomorphine composition.
In accordance with these embodiments, an inhaler for producing an inhalable aerosol of a powdered apomorphine composition comprises: an aerosolising device including a substantially tangential inlet port and a substantially axial exit port, one or more sealed blisters containing apomorphine or a pharmaceutically acceptable salt thereof, and an input for removably receiving one of the blisters. The inhaler, upon actuation, couples the tangential inlet port with the powder composition in the received blister.
In certain variants of this embodiment, each blister contains a powder composition including a carrier material and from about 100 micrograms to about 800 micrograms of apomorphine or a pharmaceutically acceptable salt thereof. In other variants, each blister contains a powder composition including a carrier material and apomorphine or a pharmaceutically acceptable salt thereof, the carrier material has an average particle size of from about 40 to about 70 microns, and at least 90 percent of said apomorphine has a particle size of 5 microns or less.
Although certain of the compositions, methods or treatment, inhalers, blisters, methods for inhaling, and doses have been described above as including a carrier material having a preferred average particle size of from about 40 microns to about 70 microns, it should be appreciated that in accordance with other embodiments, the carrier material in these compositions, methods or treatment, inhalers, blisters, methods for inhaling, and doses can have other average particle size ranges, for example, from about 10 microns to about 1000 microns, from about 10 microns to about 70 microns, or from about 20 microns to about 120 microns.
With regard to the aerosolising device, in certain variants of this embodiment, the aerosolising device is in the form a vortex chamber of substantially circular cross-section having a substantially tangential inlet port and a substantially axial exit port, wherein the ratio of the diameter of the vortex chamber to the diameter of the exit port is between 4 and 12.
In other variants, the aerosolising device is in the form of a vortex chamber of substantially circular cross-section having a substantially tangential inlet port, wherein the inlet port has an outer wall which defines the maximum extent of the inlet port in the radially outward direction of the vortex chamber. The extent of the outer wall in the axial direction of the vortex chamber is substantially equal to the maximum extent of the inlet port in the axial direction of the vortex chamber, and the outer wall is substantially parallel with a wall of the vortex chamber.
In other variants, the aerosolising device is in the form of a vortex chamber of substantially circular cross-section having a substantially tangential inlet port. An exit port is spaced from the inlet port in an axial direction. A bottom surface defines the furthest extent of the vortex chamber from the exit port in the axial direction, and the bottom surface further defines the furthest axial extent of the inlet port from the exit port.
In other variants, the aerosolising device is in the form of a vortex chamber of substantially circular cross-section having a substantially tangential inlet port and an inlet conduit arranged to supply a powdered composition entrained in a gas flow to the inlet port, in use, wherein the cross-sectional area of the inlet conduit decreases towards the vortex chamber. The inlet conduit is, upon actuation of the inhaler, coupled to the powder composition in the received blister.
In other variants, the aerosolising device is in the form of a vortex chamber of substantially circular cross-section having a substantially tangential inlet port and an arcuate inlet conduit arranged to supply a powdered composition entrained in a gas flow to the inlet port, in use. The inlet conduit is, upon actuation of the inhaler, coupled to the powder composition in the received blister.
In other variants, the aerosolising device is in the form of a vortex chamber having an axis and being defined, at least in part, by a wall which forms a curve about the axis. The vortex chamber has a cross-sectional area in a plane bounded by the axis, and the plane extends in one direction radially from the axis at a given angular position (θ) about the axis. The vortex chamber has a substantially tangential inlet port and a substantially axial exit port, and said cross-sectional area of the vortex chamber decreases with increasing angular position (θ) in the direction, in use, of gas flow between the inlet port and the exit port.
In other variants, the aerosolising device is in the form of a vortex chamber having an axis and being defined, at least in part, by a wall which forms a curve about the axis. The vortex chamber has a substantially tangential inlet port and a substantially axial exit port. The vortex chamber is further defined by a base, and the distance (d) between the base and a plane which is normal to the axis and is located on the opposite side of the base to the exit port increases with radial position (r) relative to the axis.
In other variants, the aerosolising device includes a chamber defined by a top wall, a bottom wall, and a lateral wall, the lateral wall being curved about an axis which intersects the top wall and the bottom wall. The chamber encloses a cross-sectional area defined by the axis, the top wall, the bottom wall and the lateral wall, and the chamber has an inlet port and an outlet port. The inlet port is tangent to the lateral wall, the outlet port is co-axial with the axis, and the cross-sectional area decreases with increasing angular position from the inlet port in a direction of a gas flow through the inlet port.
In still other variants, the aerosolising device a chamber including a wall, a base, an inlet port and an exit port. The chamber has an axis that is co-axial with the exit port and intersects the base. The wall is curved about the base, the inlet port is tangential to the wall, and a height between the base and a plane normal to the axis at the exit port decreases as a radial position from the axis to the inlet port increases.
a) is a side view of a vortex chamber with a round inlet port.
b) is a sectional view along line D-D of the vortex chamber of
a) is a side view of a vortex chamber with a rectangular inlet port.
b) is a sectional view along line E-E of the vortex chamber of
In a dry powder inhaler, the dose to be administered is stored in the form of a non-pressurized dry powder and, on actuation of the inhaler, the particles of the powder are inhaled by the patient. Dry powder inhalers can be “passive” devices in which the patient's breath is the only source of gas which provides a motive force in the device, or “active” devices in which a source of compressed gas is used. Examples of “passive” dry powder inhaler devices include the Rotahaler and Diskhaler (Glaxo-Wellcome) and the Turbohaler (Astra-Draco). Particularly preferred “active” dry powder inhalers will be described in more detail below in connection with
“Actuation of the inhaler” refers to the process during which a dose of the powder is removed from its rest position in the inhaler (e.g., a blister, reservoir, or other container) usually by a patient inhaling. That step takes place after the powder (or container or blister containing the powder) has been loaded into the inhaler ready for use.
While it is clearly desirable for as large a proportion as possible of the particles of active material to be delivered to the deep lung, it is usually preferable for as little as possible of the other components to penetrate the deep lung. Therefore, powders generally include particles of an active material, and carrier particles for carrying the particles of active material.
As described in WO 01/82906, published Nov. 8, 2001, an additive material may also be provided in a dose which indicates to the patient that the dose has been administered. The additive material, referred to below as indicator material, may be present in the powder as formulated for the dry powder inhaler, or be present in a separate form, such as in a separate location within the inhaler such that the additive becomes entrained in the airflow generated on inhalation simultaneously or sequentially with the powder containing the active material.
In accordance with an embodiment of the present invention, an inhalable powder composition is provided which includes apomorphine or a pharmaceutically acceptable salt thereof (thereinafter collectively “apomorphine”), in combination with a carrier material. The apomorphine is provided in an amount from 100 micrograms to 1600 micrograms per unit dose, and is preferably provided in an amount from 100 micrograms to 800 micrograms per dose. Most preferably, the apomorphine is provided in an amount from 100 micrograms to 600 micrograms per dose.
In certain embodiments of the present invention, each dose is stored in a “blister” of a blister pack. In this regard, apomorphine is susceptible to oxidation, and, as such, it is important to prevent (or substantially limit) oxidation of the apomorphine prior to administration. In accordance with the embodiments of the present invention which utilize blisters, exposure of the formulation to air prior to administration (and unacceptable oxidation of the apomorphine) is prevented by storing each dose in a sealed blister. Most preferably, oxidation is further prevented (or limited) by placing a plurality of blisters into a further sealed container, such as a sealed bag made, for example of a foil such as aluminum foil. The use of the sealed blisters (and optional sealed bags) eliminates any need to include anti-oxidants in the formulation.
For the effective administration by a dry powder inhaler of the particles of apomorphine material to the lung where they can be absorbed, the particle size characteristics of the powder are particularly important.
In particular, for the effective delivery of active material deep into the lung, the active particles should be small and well dispersed on actuation of the inhaler.
It is preferred for the powder to be such that a fine particle fraction of at least 35% is generated on actuation of the inhaler device. It is particularly preferred that the fine particle fraction be greater than or equal to 60%.
Thus, in certain embodiments of the present invention also provide a powder for use in an inhaler device, the powder comprising apomorphine or a pharmaceutically acceptable salt thereof in combination with a carrier material, the powder being such that it generates a fine particle fraction of at least 35%, preferably at least 45%, more preferably at least 50% and most preferably at least 60%, on actuation of the inhaler device.
The term “fine particle fraction” is used herein to mean that fraction of the total amount of active material (in this case apomorphine or its pharmaceutically acceptable salts) delivered by a device which has a diameter of not more than 5 μm. The total amount of active material delivered by a device is in general less than the amount of the active material that is metered in the device or is present in a pre-metered dose within the device.
Fine particle fractions referred to herein in relation to powders are as measured using a sample of the powder fired from a dry powder inhaler into a Multi Stage Liquid Impinger (MSLI) (United States Pharmacopeia (U.S.P) 26, chapter 601, Apparatus 4, (2003) Apparatus C, European Pharmacopoeia, Method 5.2.9.18, Supplement 2000) or Anderson Cascade Impactor (ACI) (U.S.P. 26, chapter 601, Apparatus 3 (2003)). The powder is preferably such that a fine particle fraction of at least 35%, preferably at least 45%, more preferably at least about 50%, and most preferably at least about 60%, is generated on actuation of the inhaler device.
Most preferably, the inhaler device is a high turbulence inhaler device, the arrangement being such that a fine particle fraction of at least 35%, preferably at least 50%, and most preferably at least 60%, is generated on actuation of the inhaler device.
A “high turbulence inhaler device” is to be understood as meaning an inhaler device which is configured to generate relatively high turbulence within the device and/or a relatively high incidence of impaction of powder upon internal surfaces and/or obstructions within the device, whereby efficient de-agglomeration of agglomerated powder particles occurs in use of the device.
As noted above, in addition to the active material (and an indicator material if present), the powder preferably includes carrier material in the form of particles for carrying the particles of active material. The carrier particles may be composed of any pharmacologically inert material or combination of materials which is acceptable for inhalation.
Advantageously, the carrier particles are composed of one or more crystalline sugars; the carrier particles may be composed of one or more sugar alcohols or polyols. Preferably, the carrier particles are particles of dextrose or lactose, especially lactose.
Preferably, at least 90% by weight of the active material has a particle size of not more than 10 μm, most preferably not more than 5 μm. The particles therefore give a good suspension on actuation of the inhaler.
In embodiments of the present invention which utilize conventional inhalers, such as the Rotohaler, Diskhaler, and Turbohaler described above, the particle size of the carrier particles may range from about 10 microns to about 1000 microns. In certain of these embodiments, the particle size of the carrier particles may range from about 20 microns to about 120 microns. In certain other ones of these embodiments, the size of at least 90% by weight of the carrier particles is less than 1000 μm and preferably lies between 601 μm and 1000 μm. The relatively large size of these carrier particles gives good flow and entrainment characteristics.
In these embodiments, the powder may also contain fine particles of an excipient material, which may for example be a material such as one of those mentioned above as being suitable for use as a carrier material, especially a crystalline sugar such as dextrose or lactose. The fine excipient material may be of the same or a different material from the carrier particles, where both are present. The particle size of the fine excipient material will generally not exceed 30 μm, and preferably does not exceed 20 μm. In some circumstances, for example, where any carrier particles and/or any fine excipient material present is of a material itself capable of inducing a sensation in the oropharyngeal region, the carrier particles and/or the fine excipient material can constitute the indicator material. For example, the carrier particles and/or any fine particle excipient may comprise mannitol.
The powders may also be formulated with additional excipients to aid delivery and release. For example, powder may be formulated with relatively large carrier particles which aid the flow from the dry powder inhaler into the lung. Large carrier particles are known, and include lactose particles having a mass medium aerodynamic diameter of greater than 90 microns. Alternatively, the hydrophobic microparticles may be dispersed within a carrier material. For example, the hydrophobic microparticles may be dispersed within a polysaccharide matrix, with the overall composition formulated as microparticles for direct delivery to the lung. The polysaccharide acts as a further barrier to the immediate release of the active agent. This may further aid the controlled release process. Suitable carrier materials will be apparent to the skilled person and include any pharmaceutically acceptable insoluble or soluble material, including polysaccharicles. An example of a suitable polysaccharide is xantham gum.
In some circumstances, the powder for inhalation may be prepared by mixing the components of the powder together. For example, the powder may be prepared by mixing together particles of active material and lactose.
The dry powder inhaler devices in which the powder compositions of the present invention will commonly be used include “single dose” devices, for example the Rotahaler, the Spinhaler and the Diskhaler in which individual doses of the powder composition are introduced into the device in, for example, a capsule, or a blister and also multiple dose devices, for example the Turbohaler in which, on actuation of the inhaler, one dose of the powder is removed from a reservoir of the powder material contained in the device.
As already mentioned, in the case of certain powders, a form of device that promotes high turbulence offers advantages in that a higher fine particle fraction will be obtainable than in the use of other forms of device. Such devices include, for example, the Turbohaler™ or Novolizer™, and may be devices of the kind in which generation of an aerosolized cloud of powder is driven by inhalation of the patient or of the kind having a dispersal device for generating or assisting in generation of the aerosolized cloud of powder for inhalation.
Where present, the amount of carrier particles will generally be up to 95%, for example, up to 90%, advantageously up to 80% and preferably up to 50% by weight based on the total weight of the powder. The amount of any fine excipient material, if present, may be up to 50% and advantageously up to 30%, especially up to 20%, by weight, based on the total weight of the powder.
In contrast to the particle sizes described above, in embodiments of the present invention which utilize an inhaler of the type described below in connection with
The formulations described herein may also include one or more force control additives (FCAs), in an amount from about 0.1% to about 10% by weight, and preferably from about 0.15% to 5%, most preferably from about 0.5% to about 2%. FCAs may include, for example, magnesium stearate, leucine, lecithin, and sodium stearyl fumarate, and are described more fully in U.S. Pat. No. 6,153,224, which is hereby incorporated by reference.
When the FCA is micronized leucine or lecithin, it is preferably provided in an amount from about 0.1% to about 10% by weight, preferably about 0.5% to about 5%, preferably about 2%, of micronized leucine. Preferably, at least 95% by weight of the micronized leucine has a particle diameter of less than 150 microns, preferably less than 100 microns, and most preferably less than 50 microns. Preferably, the mass median diameter of the micronized leucine is less than 10 microns.
If magnesium stearate or sodium stearyl fumate is used as the FCA, it is preferably provided in an amount from about 0.05% to about 5%, preferably from about 0.15% to about 2%, most preferably from about 0.25 to about 0.5%.
Where reference is made to particle size of particles of the powder, it is to be understood, unless indicated to the contrary, that the particle size is the volume weighted particle size. The particle size may be calculated by a laser diffraction method. Where the particle also includes an indicator material on the surface of the particle, advantageously the particle size of the coated particles is also within the preferred size ranges indicated for the uncoated particles.
Referring to
The powder formulation is stored in a blister 60 defined by a support 70 and a pierceable foil lid 75. As shown, the support 70 has a cavity formed therein for holding the powder formulation. The open end of the cavity is sealed by the lid 75. An air inlet conduit 7 of the the vortex chamber 1 terminates in a piercing head (or rod) 50 which pierces the pierceable foil lid 75. A reservoir 80 is connected to the blister 60 via a passage 78. A regulated air supply 90 charges the reservoir 80 with a gas (e.g., air, in this example) to a predetermined pressure (e.g. 1.5 bar). Preferably, the blister contains from 1 to 5 mg of powder formulation, preferably 1, 2 or 3 mg of powder formulation.
In certain embodiments, the support 70 is also made of foil. Such blisters are commonly referred to in the art as double-foil blisters. In other embodiments of the present invention, the support 70 is made of a polymer. It is believed that the foil support 70 provides greater protection against moisture and oxidation than the polymer support 70.
When the user inhales, a valve 40 is opened by a breath-actuated mechanism 30, forcing air from the pressurized air reservoir through the blister 60 where the powdered formulation is entrained in the air flow. The air flow transports the powder formulation to the vortex chamber 1, where a rotating vortex of powder formulation and air is created between the inlet port 3 and the outlet port 2. Rather than passing through the vortex chamber in a continuous manner, the powdered formulation entrained in the airflow enters the vortex chamber in a very short time (typically less than 0.3 seconds and preferably less than 20 milliseconds) and, in the case of a pure drug formulation (i.e., no carrier), a portion of the powder formulation sticks to the walls of the vortex chamber. This powder is subsequently aerosolised by the high shear forces present in the boundary layer adjacent to the powder. The action of the vortex deagglomerates the particles of powder formulation, or in the case of a formulation comprising a drug and a carrier, strips the drug from the carrier, so that an aerosol of powdered formulation exits the vortex chamber 1 via the exit port 2. The aerosol is inhaled by the user through the mouthpiece 10.
The vortex chamber 1 can be considered to perform two functions: deagglomeration, the breaking up of clusters of particles into individual, respirable particles; and filtration, preferentially allowing particles below a certain size to escape more easily from the exit port 2. Deagglomeration breaks up cohesive clusters of powdered formulation into respirable particles, and filtration increases the residence time of the clusters in the vortex chamber 1 to allow more time for them to be deagglomerated. Deagglomeration can be achieved by creating high shear forces due to velocity gradients in the airflow in the vortex chamber 1. The velocity gradients are highest in the boundary layer close to the walls of the vortex chamber.
As shown in more detail in
The ratio of the diameter of the vortex chamber to the diameter of the exit port can be significant in maximising the fine particle fraction of the medicament aerosol which is expelled from the exit port. Thus, the ratio of the diameter of the vortex chamber to the diameter of the exit port may be between 4 and 12. It has been found that when the ratio is between 4 and 12 the proportion of particles of the powdered medicament with an effective diameter in the range 1 to 3 microns is maximised. For an enhanced fine particle fraction, the ratio is preferably greater than 5, most preferably greater than 6 and preferably less than 9, most preferably less than 8. In the preferred arrangement, the ratio is 7.1.
In certain embodiments of the invention, the diameter of the vortex chamber is between 2 and 12 mm. The diameter of the vortex chamber is preferably greater than 4 mm, most preferably at least 5 mm and preferably less than 8 mm, most preferably less than 6 mm. In the preferred embodiment, the diameter of the vortex chamber is 5 mm. In these embodiments, the height of the vortex chamber is generally between 1 and 8 mm. The height of the vortex chamber is preferably less than 4 mm, most preferably less than 2 mm. In the preferred embodiment, the height of the vortex chamber is 1.6 mm. In general, the vortex chamber is substantially cylindrical. However, the vortex chamber may take other forms. For example, the vortex chamber may be frustoconical. Where the diameter of the vortex chamber or the exit port is not constant along its length, the ratio of the largest diameter of the vortex chamber to the smallest diameter of the exit port should be within the range specified above. The aerosolising device comprises an exit port, for example as described above. The diameter of the exit port is generally between 0.5 and 2.5 mm. The diameter of the exit port is preferably greater than 0.6 mm and preferably less than 1.2 mm, most preferably less than 1.0 mm. In the preferred embodiment, the diameter of the exit port is 0.7 mm.
As shown in Table 2, the proportion of the particles of medicament emitted in the aerosol having an effective particle diameter of less than 6.8 microns generated by the vortex chamber (the 6.8 micron particle fraction) depends on the ratio of the diameters of the chamber D and the exit port De. The normalised average 6.8 micron particle fraction is the emitted 6.8 micron particle fraction divided by the 6.8 micron particle fraction of the powdered medicament loaded into the inhaler. The medicament used was pure Intal™ sodium cromoglycate (Fisons UK).
It will be seen from the above table that where the ratio of the diameters of the chamber and the exit port is 4 or more, the normalised 6.8 micron particle fraction is over 85%. Thus, the deagglomeration efficiency of the vortex chamber is significantly improved where the ratio is in this range. With the preferred ratio of 7.1, a normalised 6.8 micron particle fraction of 94.3% has been achieved.
a and 5b show a vortex chamber 1 in which the inlet port 3 has a circular cross-section. As represented by the solid arrow in
However, as represented by the dashed arrow in
a and 6b show a vortex chamber 1 in which the inlet port 3 has a rectangular cross-section. The rectangular cross-section maximises the length of the perimeter of the inlet port that is coincident with the wall 12 of the vortex chamber 1, such that the maximum air flow is introduced into the boundary layer of the vortex. Similarly, the rectangular cross-section maximises the width of the perimeter of the inlet port 3 that is coincident with the bottom surface 13 of the vortex chamber 1. In this way, deposition of powder in the vortex chamber 1 is prevented, because the vortex occupies the entire chamber 1.
In addition to having a rectangular cross-section, the inlet port 3 of
Furthermore, the decreasing cross-sectional area of the inlet conduit 7 causes the flow of velocity to increase, thereby reducing deposition of powder on the way to the vortex chamber 1.
As indicated by the arrows in
A further improvement can also be achieved if the upper surface 16 of the vortex chamber 1 is flat, as shown in
In
In
The inhaler in accordance with embodiments of the invention is able to generate a relatively slow moving aerosol with a high fine particle fraction. The inhaler is capable of providing complete and repeatable aerosolisation of a measured dose of powdered drug and of delivering the aerosolised dose into the patient's inspiratory flow at a velocity less than or equal to the velocity of the inspiratory flow, thereby reducing deposition by impaction in the patient's mouth. Furthermore, the efficient aerosolising system allows for a simple, small and low cost device, because the energy used to create the aerosol is small. The fluid energy required to create the aerosol can be defined as the integral over time of the pressure multiplied by the flow rate. This is typically less than 5 joules and can be as low as 3 joules.
Initially, it should be noted that the difference between these embodiments and the embodiments described above with regard to
In the embodiment shown in
Between the inlet port 3 and the exit port 2 a vortex is created in which shear forces are generated to deagglomerate the particles of the powdered formulation. As discussed above, the length of the exit port 2 is preferably as short as possible to reduce the possibility of deposition of the drug on the walls of the exit port 2. In the embodiment shown, the vortex chamber 1 is machined from PEEK, acrylic, or brass, although a wide range of alternative materials is possible. For manufacturing ease, the radius of the vortex chamber 1 may decrease in steps rather than smoothly.
The 6.8 micron particle fraction of the aerosol generated by the vortex chamber 1 according to
Various options for the cross-section of the ramp 20 are shown in
Preferably, as shown in
As shown in
The vertical face (normal to the base) of the ramp 20 where the ramp meets the inlet 3 is likely to attract deposition because of the abrupt change in height. However, by arranging the profile of the face (looking axially) to form a smooth entry, as shown in
In one arrangement the profile is a straight line at 40° (angle φ in
In a preferred embodiment the profile is a curve moving radially inward as shown in
A sieved fraction of Respitose SV003 (DMV International Pharma, The Netherlands) lactose is manufactured by passing bulk material through a 63 μm sieve. This material is then sieved through a 45 μm screen and the retained material is collected.
Apomorphine hydrochloride was obtained from Macfrarian Smith Ltd, and was micronized according to the following product specification: >=99.9% by mass<10 microns, based upon a laser diffraction analysis. Actual typical results of the laser fraction analysis were as follows: d10<1 micron, d50: 1-3 microns; d90<6 microns, wherein d10 d50 d90 refer to the diameter of 10%, 50%, and 90% of the analyzed apomorphine hydrochloride. The apomorphine hydrochloride was micronized with nitrogen, (rather than the commonly employed air) to prevent oxidative degradation.
70 grams of the lactose of Example 1 was placed into a metal mixing vessel of a suitable mixer. 10 grams of the micronized apomorphine hydrochloride were then added. An additional 70 grams of the lactose of Example 1 was then added to the mixing vessel, and the resultant mixture was tumbled for 15 minutes. The resultant blend was then passed through a 150 μm screen. The screened blend (i.e. the portion of the blend that passed through the screen) was then reblended for 15 minutes.
The particle size distribution of the apomorphine-lactose powder, as determined by an Andersen Cascade Impactor (U.S.P. 26, chapter 601, Apparatus 3 (2003)), showed that the drug particles were well dispersed. In particular, the particle size distribution for a 200 μg dose was as follows:
72.5 grams of the lactose of Example 1 was placed into a metal mixing vessel of a suitable mixer. 5 grams of the micronized apomorphine hydrochloride were then added. An additional 72.5 grams of the lactose of Example 1 was then added to the mixing vessel, and the resultant mixture was tumbled for 15 minutes. The resultant blend was then passed through a 150 μm screen. The screened blend (i.e. the portion of the blend that passed through the screen) was then reblended for 15 minutes.
As described below with reference to
The formulations of Example 2(a) and 2(b) were each incorporated into blisters in the following manner. Three milligrams of the apomorphine-lactose formulation were placed in each blister. As described above in connection with
The above-referenced blisters containing the apomorphine-lactose formulations of Example 2(a) were placed into aluminum bags to replicate patient packs, and stored for one month at 25 C and 60% relative humidity, and for one month at 40 C and 75% relative humidity (accelerated storage conditions). The formulation was then removed from the blisters and tested using High Performance Liquid Chromatography (HPLC). The results are shown in
The above referenced blisters containing the 100 and 200 microgram apomorphine-lactose formulations were subjected to testing using the prototype inhaler shown in
In use, the user places a foil blister (not shown) onto the blister loader 2010 and inserts the blister loader into the device in the position shown in
When the user inhales via the mouthpiece, breath actuation vane 2025 moves, opening the exit valve 2020 and releasing the compressed air in the reservoir. The air flows through the blister, entraining the dose of powder and carrying it to the vortex nozzle 3000. In the nozzle the powder experiences high centrifugal and shear forces which deagglomerate the dose before delivering it to the user via the mouthpiece 10 as a finely dispersed aerosol.
Referring to
The inlet conduit 3 tapers in section from a 1.22 mm diameter where it joins the inlet tube 7 to its narrowest point where the inlet conduit 3 joins the vortex chamber 1 and has a height of 1.1 mm high and a width of 0.5 mm. As such, the inlet conduit 3 does not extend to the full height of the vortex chamber, which is 1.6 mm. The outlet port 2 diameter is 0.7 mm and the thickness of the outlet port 2 is 0.35 mm.
Referring to
The breath actuation vane 2040 is rotatably mounted on a vane pivot 2045. The vane 2040 includes a vane roller 2046 which is rotatably mounted on the vane 2045 and is free to rotate, and a vane return spring (not shown) which biases the vane 2040 to the closed position as shown in
When a user inhales through the mouthpiece 10, air flows into the airway via the inspiratory air inlet 2035. This flow and the pressure drop it generates across the breath actuation vane 2040 cause the vane 2040 to rotate about its pivot 2045. The vane roller 2046 rolls against the end of the valve arm 2022 and then becomes clear of the valve arm 2022 as the vane 2040 rotates further. This allows the valve arm 2022 to rotate under the influence of the valve spring 2030, which removes the valve seal 2023 from the output port 2 (i.e., opening the valve) to release the dose from the nozzle as shown in
The breath actuated mechanism can be reset for the next dose by rotating the valve reset lever 2050 through 90 degrees and then returning it to its original position. The reset lever 2050 acts on the valve arm 2022 to close the valve (by causing the valve seal 2023 to cover output port 2) and allow the breath actuation vane 2040 to return to its closed position under the influence of the vane return spring (not shown).
In order to obtain the inhalation data described below, the inhaler of
The DUSA is used to measure the total amount of drug which leaves the inhaler. With data from this device, the metered and delivered dose is obtained. The delivered dose is defined as the amount of drug that leaves the inhaler. This includes the amount of drug in the throat of the DUSA device, in the measuring section of the DUSA device and the subsequent filters of the DUSA device. It does not include drug left in the blister or other areas of the inhaler of
The MSLI is a device for estimating deep lung delivery of a dry powder formulation. The MSLI includes a five stage cascade impactor which can be used for determining the particle size (aerodynamic size distribution) of Dry Powder Inhalers (DPIs) in accordance with USP 26, Chapter 601 Apparatus 4 (2003) and in accordance with the European Pharmacopoeia., Method 5.2.9.18, Apparatus C, Supplement 2000.
The ACI is another device for estimating deep lung delivery of a dry powder formulation. The ACI is multi-stage cascade impactor which can be used for determining the particle size (aerodynamic size distribution) of Dry Powder Inhalers (DPI) in accordance with USP 26, Chapter 601 Apparatus 3 (2003).
As described below, the MSLI and the ACI testing devices can be used to determine, inter alia, the fine particle dose, or FPD (the amount of drug, e.g., in micrograms, that is measured in the sections of the testing device which correlates with deep lung delivery) and the fine particle fraction, or FPF, (the percentage of the metered dose which is measured in the sections of the testing device which correlates with deep lung delivery).
Referring to
In section 6000 of
In section 7000 of
b) is similar to
As illustrated in
A 400 microgram formulation can be manufactured in the manner set forth above with regard to Example 2, with the components provided in the following amounts:
A 600 microgram formulation can be manufactured in the manner set forth above with regard to Example 2, with the components provided in the following amounts:
Although the above referenced examples utilize a blister “fill weight” of 3 mg, it should be appreciated that larger or smaller fill weights may also be used. For example, in Examples 8-12 below, fill weights of 1 mg or 2 mg are provided. Although a variety of techniques for filling blisters to such fill weights may be used, it is believed that commercial production of blisters with 1 mg and 2 mg fill weights can be achieved with a Harro-Hoefliger Omnidose Drum Filter. Lower fill weights, and in particular fill weights on the order of 1 mg, are believed to provide superior fine particle fractions as compared to higher fill weights. For example, in experiments performed using an ACI with a single “shot”, a 200 microgram apomorphine hydrochloride formulation as described above provided a fine particle fraction of 73% with a 3 mg fill weight, 71% with a 2 mg fill weight, and 83% with a 1 mg fill weight.
An 800 microgram formulation can be manufactured in the manner set forth above with regard to Example 2, with the components provided in the following amounts:
A 200 microgram formulation with Magnesium Stearate with the components provided in the following amounts:
This formulation is prepared in the manner set forth above with regard to Example 2, except that Magnesium Stearate is added to the mixture along with the apomorphine hydrochloride.
A 400 microgram formulation with Magnesium Stearate With the components provided in the following amounts:
This formulation is prepared in the manner set forth above with regard to Example 2, except that micronized leucine is added to the mixture along with the apomorphine hydrochloride.
A 200 microgram formulation can be manufactured in the manner set forth above with regard to Example 2, with the components provided in the following amounts:
A 200 microgram formulation can be manufactured in the manner set forth above with regard to Example 2, with the components provided in the following amounts:
A 400 microgram formulation can be manufactured in the manner set forth above with regard to Example 2, with the components provided in the following amounts:
In the preceding specification, the invention has been described with reference to specific exemplary embodiments and examples thereof. It will, however, be evident that various modifications and changes may be made thereto without departing from the broader spirit and scope of the invention as set forth in the claims that follow. The specification and drawings are accordingly to be regarded in an illustrative manner rather than a restrictive sense.
| Number | Date | Country | |
|---|---|---|---|
| Parent | 10413022 | Apr 2003 | US |
| Child | 12459686 | US |
