Patent Application
20100297030
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 (M:MAS, 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. Two and three milligram sublingual tablets of apomorphine hydrochloride are currently available in Europe for the treatment of male erectile dysfunction under the name UPRIMA™ (see, e.g., European Public Assessment Report (EPAR) 1945).
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 embodiment of the present invention, a method for treating sexual dysfunction via inhalation is provided which comprises inhaling a dose of from about 100 to about 1600 micrograms of apomorphine or pharmaceutically acceptable salt(s) or ester(s) thereof (based on the weight of the hydrochloride salt). Preferably, the dose comprises from about 200 micrograms to about 1600 micrograms of said apomorphine, more preferably, about 300 micrograms to about 1200 micrograms of said apomorphine, more preferably about 400 to about 1200 micrograms of said apomorphine. Most preferably, doses are provided in increments between 400 and 1200 micrograms, based upon the requirements and tolerance of the individual patients. For examples, doses may be provided of about 400, about 500, about 600, about 700, about 800, about 900, about 1000, about 1100, and/or about 1200 micrograms of said apomorphine.
In accordance with another embodiment of the present invention, a method for treating sexual dysfunction is provided which comprises inhaling a dose including apomorphine or a pharmaceutically acceptable salt or ester thereof, said dose being sufficient to provide a therapeutic effect in about 10 minutes or less.
Preferably, the dose of the above-referenced embodiments is a powder composition inhaled via a dry powder inhaler (“DPI”). However in other embodiments, the dose may be a solution or suspension formulation inhaled via a pressurized metered dose inhaler (“pMDI”).
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 salt(s) or ester(s) 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 3200 micrograms of apomorphine or pharmaceutically acceptable salt(s) or ester(s) thereof (based on the weight of the hydrochloride salt). Preferably, the dose comprises from about 100 micrograms to about 1600 micrograms of said apomorphine, more preferably, about 200 micrograms to about 1600 micrograms of said apomorphine, more preferably, about 300 micrograms to about 1200 micrograms of said apomorphine, more preferably about 400 to about 1200 micrograms of said apomorphine. Most preferably, doses are provided in increments between 400 and 1200 micrograms, based upon the requirements and tolerance of the individual patients. For examples, doses may be provided of about 400, about 500, about 600, about 700, about 800, about 900, about 1000, about 100, and/or about 1200 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 into the lungs of a patient, the dose of the powder composition delivering, in vitro, a fine particle dose of from about 100 micrograms to about 1600 micrograms of apomorphine or pharmaceutically acceptable salt(s) or ester(s) thereof (based on the weight of the hydrochloride salt), when measured by a Multistage Liquid Impinger, United States Pharmacopeia 26, Chapter 601 Apparatus 4 (2003). Preferably, the dose delivers, in vitro, a fine particle dose from about 200 micrograms to about 1000 micrograms of said apomorphine, more preferably, about 200 micrograms to about 800 micrograms of said apomorphine, more preferably, about 200 micrograms to about 600 micrograms of said apomorphine, and most preferably about 200 to about 400 micrograms of said apomorphine when measured by a Multistage Liquid Impinger, United States Pharmacopeia 26, Chapter 601 Apparatus 4 (2003).
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 salt(s) or ester(s) 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 3200 micrograms of apomorphine or a pharmaceutically acceptable salt or ester thereof (based on the weight of the hydrochloride salt). Preferably, the dose comprises from about 100 micrograms to about 1600 micrograms of said apomorphine, more preferably, about 200 micrograms to about 1600 micrograms of said apomorphine, more preferably, about 300 micrograms to about 1200 micrograms of said apomorphine, more preferably about 400 to about 1200 micrograms of said apomorphine. Most preferably, doses are provided in increments between 400 and 1200 micrograms, based upon the requirements and tolerance of the individual patients. For examples, doses may be provided of about 400, about 500, about 600, about 700, about 800, about 900, about 1000, about 100, and/or about 1200 micrograms of said apomorphine.
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 or ester 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 3200 micrograms of apomorphine or a pharmaceutically acceptable salt or ester thereof (based on the weight of the hydrochloride salt), the cavity having an opening which is sealed by a rupturable covering. Preferably, the powder composition comprises from about 100 micrograms to about 1600 micrograms of said apomorphine, more preferably, about 200 micrograms to about 1600 micrograms of said apomorphine, more preferably, about 300 micrograms to about 1200 micrograms of said apomorphine, more preferably about 400 to about 1200 micrograms of said apomorphine. Most preferably, doses are provided in increments between 400 and 1200 micrograms, based upon the requirements and tolerance of the individual patients. For examples, doses may be provided of about 400, about 500, about 600, about 700, about 800, about 900, about 1000, about 100, and/or about 1200 micrograms of said apomorphine.
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 or ester 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 15% 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 3200 micrograms of apomorphine or a pharmaceutically acceptable salt or ester thereof (based on the weight of the hydrochloride salt) and a carrier material. Preferably, the powder composition comprises from about 100 micrograms to about 1600 micrograms of said apomorphine, more preferably, about 200 micrograms to about 1600 micrograms of said apomorphine, more preferably, about 300 micrograms to about 1200 micrograms of said apomorphine, more preferably about 400 to about 1200 micrograms of said apomorphine. Most preferably, doses are provided in increments between 400 and 1200 micrograms, based upon the requirements and tolerance of the individual patients. For examples, doses may be provided of about 400, about 500, about 600, about 700, about 800, about 900, about 1000, about 100, and/or about 1200 micrograms of said apomorphine.
In other variants of this embodiment, the powder composition may include a carrier material and apomorphine or a pharmaceutically acceptable salt or ester 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 aerosolize 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 3200 micrograms of apomorphine or a pharmaceutically acceptable salt or ester thereof (based on the weight of the hydrochloride salt) and a carrier material. Preferably, the agglomerated particles comprise from about 100 micrograms to about 1600 micrograms of said apomorphine, more preferably, about 200 micrograms to about 1600 micrograms of said apomorphine, more preferably, about 300 micrograms to about 1200 micrograms of said apomorphine, more preferably about 400 to about 1200 micrograms of said apomorphine. Most preferably, doses are provided in increments between 400 and 1200 micrograms, based upon the requirements and tolerance of the individual patients. For examples, doses may be provided of about 400, about 500, about 600, about 700, about 800, about 900, about 1000, about 100, and/or about 1200 micrograms of said apomorphine.
In other variants of this embodiment, the agglomerated particles include a carrier material and apomorphine or a pharmaceutically acceptable salt or ester 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 3200 micrograms apomorphine or a pharmaceutically acceptable salt or ester thereof (based on the weight of the hydrochloride salt). Preferably, the agglomerated particles comprise a dose of from about 100 micrograms to about 1600 micrograms of said apomorphine, more preferably, about 200 micrograms to about 1600 micrograms of said apomorphine, more preferably, about 300 micrograms to about 1200 micrograms of said apomorphine, more preferably about 400 to about 1200 micrograms of said apomorphine. Most preferably, doses are provided in increments between 400 and 1200 micrograms, based upon the requirements and tolerance of the individual patients. For examples, doses may be provided of about 400, about 500, about 600, about 700, about 800, about 900, about 1000, about 100, and/or about 1200 micrograms of said apomorphine. 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 3200 micrograms of apomorphine or a pharmaceutically acceptable salt or ester thereof (based on the weight of the hydrochloride salt) and a carrier material. Preferably, the agglomerated particles comprise a dose of from about 100 micrograms to about 1600 micrograms of said apomorphine, more preferably, about 200 micrograms to about 1600 micrograms of said apomorphine, more preferably, about 300 micrograms to about 1200 micrograms of said apomorphine, more preferably about 400 to about 1200 micrograms of said apomorphine. Most preferably, doses are provided in increments between 400 and 1200 micrograms, based upon the requirements and tolerance of the individual patients. For examples, doses may be provided of about 400, about 500, about 600, about 700, about 800, about 900, about 1000, about 100, and/or about 1200 micrograms of said apomorphine. In other variants of this embodiment, the composition includes a carrier material and apomorphine or a pharmaceutically acceptable salt or ester 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 accordance with another embodiment of the present invention, a method of treating sexual dysfunction is provided, comprising inhaling a dose of a powder composition, the powder composition comprising agglomerated particles which include from about 100 to about 3200 micrograms of apomorphine or a pharmaceutically acceptable salt or ester thereof (based on the weight of the hydrochloride salt) and a carrier material. Preferably, the agglomerated particles comprise a dose of from about 100 micrograms to about 1600 micrograms of said apomorphine, more preferably, about 200 micrograms to about 1600 micrograms of said apomorphine, more preferably, about 300 micrograms to about 1200 micrograms of said apomorphine, more preferably about 400 to about 1200 micrograms of said apomorphine. Most preferably, doses are provided in increments between 400 and 1200 micrograms, based upon the requirements and tolerance of the individual patients. For examples, doses may be provided of about 400, about 500, about 600, about 700, about 800, about 900, about 1000, about 100, and/or about 1200 micrograms of said apomorphine. The step of inhaling includes entraining the agglomerated particles in a gas flow upstream from an inlet port of a vortex chamber, 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 to provide an ultrafine particle fraction, when measured by an Andersen Cascade Impactor, United States Pharmacopeia 26, Chapter 601 Apparatus 3 (2003), of at least about 70%.
In accordance with another embodiment of the present invention, a method of treating sexual dysfunction is provided, comprising inhaling a dose of a powder composition, the powder composition comprising from about 100 to about 3200 micrograms of apomorphine or a pharmaceutically acceptable salt or ester thereof (based on the weight of the hydrochloride salt). Preferably, the powder composition also includes a carrier. Preferably, the dose comprises from about 100 micrograms to about 1600 micrograms of said apomorphine, more preferably, about 200 micrograms to about 1600 micrograms of said apomorphine, more preferably, about 300 micrograms to about 1200 micrograms of said apomorphine, more preferably about 400 to about 1200 micrograms of said apomorphine. Most preferably, doses are provided in increments between 400 and 1200 micrograms, based upon the requirements and tolerance of the individual patients. For examples, doses may be provided of about 400, about 500, about 600, about 700, about 800, about 900, about 1000, about 100, and/or about 1200 micrograms of said apomorphine. In one variant of this embodiment, the step of inhaling comprises inhaling a dose having an ultrafine particle fraction, when measured by an Andersen Cascade Impactor, United States Pharmacopeia 26, Chapter 601 Apparatus 3 (2003), of at least about 70%. In another variant of this embodiment, the step of inhaling comprises inhaling a dose having a fine particle fraction, when measured by an Andersen Cascade Impactor, United States Pharmacopeia 26, Chapter Apparatus 3 (2003), of at least about 80%.
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 aerosolizing 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 or ester 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 3200 micrograms of apomorphine or a pharmaceutically acceptable salt or ester thereof (based on the weight of the hydrochloride salt), as described above. In other variants, each blister contains a powder composition including a carrier material and apomorphine or a pharmaceutically acceptable salt or ester 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, as described above.
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.
In accordance with additional aspects of the above-referenced embodiments, a dose includes from about 400 to about 800 micrograms of apomorphine hydrochloride, and the dose provides, in vivo, a mean Cmax of from about 0.7 ng/ml to about 2 ng/ml. Preferably, the dose provides, in vivo, a mean plasma level of said apomorphine at seventy minutes after administration of from about 0.2 ng/ml to about 0.6 ng/ml.
With regard to the aerosolizing device, in certain variants of this embodiment, the aerosolizing 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 aerosolizing 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 aerosolizing 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 aerosolizing 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 aerosolizing 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 aerosolizing 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 aerosolizing 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 aerosolizing 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 aerosolizing 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
The embodiments of the present invention are directed to inhalable formulations of apomorphine or its pharmaceutically acceptable salts or esters and methods for preparing the same, methods for treatment of sexual dysfunction using said formulations, inhalers including said formulations, and methods for using said inhalers.
The inhalable formulations in accordance with the present invention are preferably administered via a dry powder inhaler (DPI) formulations, but can also be administered via pressurized metered dose inhaler (pMDI) formulations, or even via a nebulized system.
In the context of the present invention, the dose (e.g., in micrograms) of apomorphine or its pharmaceutically acceptable salts or esters will be described based upon the weight of the hydrochloride salt (apomorphine hydrochloride). As such, a dose of 100 micrograms of “apomorphine or its pharmaceutically acceptable salts or esters” means 100 micrograms of apomorphine hydrochloride, or an equivalent amount of another salt, an ester, or of the base.
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 or alternative energy source 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 or ester thereof (thereinafter collectively “apomorphine”), in combination with a carrier material. An example of a suitable apomorphine ester is diisobutyryl apomorphine. Preferably, the apomorphine comprises apomorphine hydrochloride. In any event, the apomorphine is provided in an amount from about 100 micrograms to about 3200 micrograms per unit dose. Preferably, the apomorphine is provided in from about 100 micrograms to about 1600 micrograms per dose, more preferably, about 200 micrograms to about 1600 micrograms per dose, more preferably, about 300 micrograms to about 1200 micrograms per dose, more preferably about 400 to about 1200 micrograms of said apomorphine. Most preferably, doses are provided in increments between 400 and 1200 micrograms, based upon the requirements and tolerance of the individual patients. For examples, doses may be provided of about 400, about 500, about 600, about 700, about 800, about 900, about 1000, about 100, and/or about 1200 micrograms of said apomorphine.
These powder compositions, when inhaled, preferably exhibit a time to therapeutic effect of less than 15 minutes, preferably less than about 10 minutes, and most preferably less than about 9 minutes. It is further believed that these powder formulations, when inhaled, will have a therapeutic duration of about 1 to 1½ hours. Such a relatively short time period from administration through termination of therapeutic effect (about 1 hour to about 1¾ hours) is advantageous because apomorphine hydrochloride is known to have side effects such as drowsiness which may impair the patient from performing certain tasks, such as operating a motor vehicle or heavy equipment.
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%, more preferably at least 70%, and most preferably at least 80%.
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 or ester 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%, even more preferably at least 60%, even more preferably at least 70%, and most preferably at least 80%.
The term “fine particle dose” (FPD) is used herein to mean the total amount (e.g., in micrograms) of active material (in this case apomorphine or its pharmaceutically acceptable salts or esters) delivered by a device which has a diameter of not more than 5 μm. The term “ultrafine particle dose” (UFPD) is used herein to mean the total amount (e.g., in micrograms) of active material delivered by a device which has a diameter of not more than 3 μm. The total amount of active material delivered by a device (the delivered dose) is in general less than the amount of the active material that is metered in the device (the metered dose) or is present in a pre-metered dose within the device (the total dose). The term “fine particle fraction” (FPF) is used herein to mean that percentage of the total amount of active material delivered by a device which has a diameter of not more than 5 μm (i.e., FPF=100*FPD/delivered dose). The term “ultrafine particle fraction” is used herein to mean that percentage of the total amount of active material delivered by a device which has a diameter of not more than 3 μm. The term percent fine particle dose (% FPD) is used herein to mean the percentage of the total dose which is delivered with a diameter of not more than 5 μm (i.e., % FPD=100*FPD/total dose). The term percent ultrafine particle dose (% UFPD) is used herein to mean the percentage of the total dose which is delivered with a diameter of not more than 3 μm (i.e., % UFPD=100*UFPD/total dose).
Fine particle fractions, Ultrafine particle fractions, and Fine particles doses referred to herein in relation to powders can be 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%, even more preferably at least 60%, even more preferably at least 70%, and most preferably at least 80%, 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%, even more preferably at least 60%, even more preferably at least 70%, and most preferably at least 80% is generated on actuation of the inhaler device.
In accordance with another embodiment of the present invention, the dose of apomorphine or a pharmaceutically acceptable salt or ester thereof is defined in terms of the fine particle dose of the administered dose. The percentage of the apomorphine in the dose which will reach the lung (the % FPD) is dependent on the formulation used and on the inhaler used. As such, a 2000 microgram dose of apomorphine hydrochloride will deliver 700 micrograms of apomorphine to the lung of a patient if an % FPD of 35% is achieved, but deliver 1200 micrograms of apomorphine to the lung of a patient if an % FPD of 60% is achieved. As such, it is appropriate to define the dose of apomorphine in terms of the FPD of the formulation and inhaler used, as measured by a Multistage Liquid Impinger or an Anderson Cascade Impactor.
As such, 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 into the lungs of a patient, the dose of the powder composition delivering, in vitro, a fine particle dose of from about 100 micrograms to about 1600 micrograms of apomorphine or pharmaceutically acceptable salt(s) or ester(s) thereof (based on the weight of the hydrochloride salt), when measured by a Multistage Liquid Impinger, United States Pharmacopeia 26, Chapter 601 Apparatus 4 (2003). Preferably, the dose delivers, in vitro, a fine particle dose from about 200 micrograms to about 1000 micrograms of said apomorphine, more preferably, about 200 micrograms to about 800 micrograms of said apomorphine, more preferably, about 200 micrograms to about 600 micrograms of said apomorphine, and most preferably about 200 to about 400 micrograms of said apomorphine when measured by a Multistage Liquid Impinger, United States Pharmacopeia 26, Chapter 601 Apparatus 4 (2003). The dose, defined in the manner above in connection with the Multistage Liquid Impinger, can similarly be used in connection with the blisters, inhalers, and compositions described herein.
In addition to the fine particle fraction, another parameter of interest is the ultrafine particle fraction defined above. Although particles having a diameter of less than 5 microns (corresponding to the FPF) are suitable for local delivery to the lungs, it is believed that for systemic delivery, even finer particles are needed, because the drug must reach the alveoli to be absorbed into the bloodstream. As such, it is particularly preferred that the formulations and devices in accordance with the present invention be sufficient to provide an ultrafine particle fraction of at least about 50%, more preferably at least about 60% and most preferably at least about 70%.
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 and Diskhaler 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 60 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 properties of the powder. Large carrier particles are known, and include lactose particles having a mass medium aerodynamic diameter of greater than 90 microns. Alternatively, 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. An example of a suitable polysaccharide is xanthan gum. Preferred hydrophobic materials include solid state fatty acids such as oleic acid, lauric acid, palmitic acid, stearic acid, erucic acid, behenic acid, or derivatives (such as esters and salts) thereof. Specific examples of such materials include phosphatidylcholines, phosphatidylglycerols and other examples of natural and synthetic lung surfactants. Particularly preferred materials include metal stearates, in particular magnesium stearate, which has been approved for delivery via the lung.
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, single dose capsules or blisters, 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 addition to the carrier and the apomorphine. The FCAs may be provided 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%. In the context of the present invention, FCAs include, but are not limited to, anti-adherent materials. 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, the FCA comprises from about 3% to about 7%, preferably about 5%, 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 fumarate 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.
In certain embodiments of the present invention, the apomorphine formulation is a “carrier free” formulation, which includes only the apomorphine or its pharmaceutically acceptable salts or esters and one or more anti-adherents. Such carrier free formulations are described in WO 97/03649, the entire disclosure of which is hereby incorporated by reference. In accordance with these embodiments, the powder formulation includes apomorphine or a pharmaceutically acceptable salt or ester thereof and an additive material which includes an anti-adherent material. The powder includes at least 60% by weight of the apomorphine or a pharmaceutically acceptable salt or ester thereof based on the weight of the powder. Advantageously, the powder comprises at least 70%, more preferably at least 80% by weight of apomorphine or a pharmaceutically acceptable salt or ester thereof based on the weight of the powder. Most advantageously, the powder comprises at least 90%, more preferably at least 95%, more preferably at least 97%, by weight of apomorphine or a pharmaceutically acceptable salt or ester thereof based on the weight of the powder. It is believed that there are physiological benefits in introducing as little powder as possible to the lungs, in particular material other than the active ingredient to be administered to the patient. Therefore, the quantities in which the additive material is added are preferably as small as possible. The most preferred powder, therefore, would comprise more than 99% by weight of apomorphine or a pharmaceutically acceptable salt or ester thereof.
In the context of the present invention, the term anti-adherent material refers to those additive materials which will decrease the cohesion between the particles of the powder. Those materials will include those usually thought of as anti-adherent materials, for example leucine, as well as others, for example, lecithin, which are not generally thought of as being anti-adherent but may nonetheless have the effect of decreasing the cohesion between the particles of the powder. Other materials commonly added to powders for use in inhalers, for example lactose and various other carrier particle materials, are not anti-adherent materials per se but might be added to a powder in addition to a suitable anti-adherent material, for example leucine as indicated above.
Advantageously, in these “carrier free” formulations, at least 90% by weight of the particles of the powder have a particle size less than 63 microns, preferably less than 30 microns and more preferably less than 10 microns. As indicated above, the size of the apomorphine (or it pharmaceutically acceptable salts) particles of the powder should be within the range of about from 0.1 micron to 5 microns for effective delivery to the lower lung. Where the anti-adherent material is in the form of particles of material it may be advantageous for particles of the anti-adherent material to have a size outside the preferred range for delivery to the lower lung.
It is particularly advantageous for the anti-adherent material to comprise an amino acid. Amino acids have been found to give, when present as anti-adherent material, high respirable fraction of the active material and also good flow properties of the powder. A preferred amino acid is leucine, in particular L-leucine. Although the L-form of the amino acids is preferred, the D- and DL-forms may also be used. The anti-adherent material may comprise one or more of any of the following amino acids: leucine, isoleucine, lysine, valine, methionine, cysteine, phenylalanine. Advantageously, the powder includes at least 80%, preferably at least 90% by weight of apomorphine (or it pharmaceutically acceptable salts) based on the weight of the powder. Advantageously, the powder includes not more than 8%, more advantageously not more than 5% by weight of additive material based on the weight of the powder. As indicated above, in some cases it will be advantageous for the powder to contain about 1% by weight of additive material. The anti-adherent material may also (or alternatively) include magnesium stearate or colloidal silicon dioxide.
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 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
Pressurized metered dose inhalers (pMDI) typically have two components: a canister component in which the drug particles (in this case apomorphine or its pharmaceutically acceptable salts or esters) are stored under pressure in a suspension or solution form and a receptacle component used to hold and actuate the canister. Typically, a canister will contain multiple doses of the formulation, although it is possible to have single dose canisters as well. The canister component typically includes a valved outlet from which the contents of the canister can be discharged. Aerosol medication is dispensed from the pMDI by applying a force on the canister component to push it into the receptacle component thereby opening the valved outlet and causing the medication particles to be conveyed from the valved outlet through the receptacle component and discharged from an outlet of the receptacle component. Upon discharge from the canister, the medication particles are “atomized” forming an aerosol. It is intended that the patient coordinate the discharge of aerosolized medication with his or her inhalation so that the medication particles are entrained in the patient's inspiratory flow and conveyed to the lungs. Typically, pMDIs use propellants to pressurize the contents of the canister and to propel the medication particles out of the outlet of the receptacle component. In pMDI inhalers, the formulation is provided in liquid form, and resides within the container along with the propellant. The propellant can take a variety of forms. For example, the propellant can comprise a compressed gas or a liquified gas. Suitable propellants include CFC (chlorofluorocarbon) propellants such as CFC 11 and CFC 12, as well as HFA (Hydrofluoroalkane) propellants such as HFA 134a and HFA 227. One or more propellants may be used in a given formulation.
In order to better coordinate actuation of the inhaler with inhalation, a breath actuated valve system may be used. Such systems are available, for example, from Baker Norton and 3M. To use such a device, the patient “primes” the device, and then the dose is automatically fired when the patient inhales.
In accordance with certain embodiments of the present invention, a pMDI formulation is used to deliver the apomorphine or its pharmaceutically acceptable salts or esters (thereinafter collectively “apomorphine”) to the lungs of the patient. The apomorphine is provided in an amount from about 100 micrograms to about 3200 micrograms per unit dose. Preferably, the dose comprises from about 100 micrograms to about 1600 micrograms of said apomorphine, more preferably, about 200 micrograms to about 1600 micrograms of said apomorphine, more preferably, about 300 micrograms to about 1200 micrograms of said apomorphine, more preferably about 400 to about 1200 micrograms of said apomorphine. Most preferably, doses are provided in increments between 400 and 1200 micrograms, based upon the requirements and tolerance of the individual patients. For examples, doses may be provided of about 400, about 500, about 600, about 700, about 800, about 900, about 1000, about 100, and/or about 1200 micrograms of said apomorphine.
In certain embodiments, the pMDI formulation is either a “suspension” type formulation or a “solution” type formulation, each using a liquified gas as the propellant. It is believed that the in vivo affect of pMDI formulations will be similar to those of the DPI formulations described above, in terms of time to therapeutic effect, and duration of therapeutic effect.
Of pMDI technologies, solution pMDIs are believed to be the most appropriate for systemic lung delivery as they offer the finest mist, and can be more easily optimized through modifications to the device. Recently developed valves (e.g. available from Bespak) also offer payload increases over current systems, meaning that larger systemic doses can potentially be delivered in solution pMDIs than in suspension type pMDIs.
Solution pMDI techniques can be used to prepare formulations for delivery of apomorphine esters (for example, diisobutyryl apomorphine) with HFA propellants.
However, conventional solution pMDI techniques are not believed to be appropriate for the delivery of apomorphine or its pharmaceutically acceptable salts with HFA propellants. Specifically, apomorphine base is too unstable to be formulated using current approaches and apomorphine salts are too polar to be formulated as solutions in HFA propellants. For example, apomorphine HCl requires at least 50% ethanol for suitable or acceptable solubility in these systems, and such systems would neither be technologically acceptable or likely to be accepted by patients. Even with such a system, a solution concentration of <25 μg/dose is achieved, which is well below the effective doses described above in connection with Dry Powder Inhalers.
In the past, formulators sought to minimize the amount of water present in a pMDI solution because water was known to reduce the fine particle fraction of the formulation (e.g. as reported in WO 02/030499 to Chiesi) and/or to reduce the stability of the formulation (e.g., as reported in WO 01/89616 to Glaxo).
In accordance with an embodiment of the present invention, a pMDI solution including apomorphine or its pharmaceutically acceptable salts is surprisingly provided through the deliberate addition of water to the system. Specifically, it is believed that a suitable pMDI solution can be obtained by adding the apomorphine or its pharmaceutically acceptable salts to a propellant solution which includes from about 50% to about 98% w/w HFA134a (1,1,1,2-tetrafluoroethane) (and/or HFA 227 (1,1,1,2,3,3,3-heptafluoropropane)), from about 2% to about 10% w/w water, and from about 0% to about 47% w/w ethanol. Preferably, the water is provided in an amount from greater than 5% to about 10% w/w. With regard to ethanol, it is preferably provided in an amount from about 12% to about 40% w/w. Preferably, a 12ml solution would include about 170 milligrams of apomorphine hydrochloride in addition to the HFA134a, water and/or ethanol. A 3M coated (DUPONT 3200 200) canister can be used as the canister for the inhaler.
Suspension pMDIs can also be used to deliver apomorphine or its pharmaceutically acceptable salts to the lungs. However, suspension pMDIs have a number of disadvantages. For example, suspension pMDIs generally deliver lower doses than solution pMDIs and are prone to other issues related to suspensions e.g. dose inconsistencies, valve blockage, and suspension instabilities (e.g. settling). For these reasons, and others, suspension pMDIs tend to be much more complex to formulate and manufacture than solution pMDI's.
In accordance with one embodiment of the present invention, a suspension pMDI for apomorphine or its pharmaceutically acceptable salts is provided. Preferably, the propellant of the suspension pMDI is a blend of two commercially available HFA propellants, most preferably about 60% HFA227 (1,1,1,2,3,3,3-heptafluoropropane) and about 40% HFA134a (1,1,1,2-tetrafluoroethane). This approach showed initial physical stability (due to density matching) without addition of further excipients. This is suggestive that such systems are readily manufacturable, although other excipients may be added at low levels to improve pharmaceutical elegance. For example, blends of about 60% HFA227 and about 40% HFA134a were prepared with apomorphine hydrochloride in a 3M coated (Dupont 3200 200) canister with a Bespak BK630 series 0.22 mm actuator. The results of these experiments are discussed below in connection with Example 16.
Another possible method of administration is via a nebulized system. Such systems include conventional ultrasonic nebulized systems and jet nebulized systems, as well as recently introduced handheld devices such as the Respimat (available from Boehringer Ingelheim) or the AERx (available from Aradigm). In such a system, the apomorphine or a pharmaceutically acceptable salt or ester thereof could be stabilized in a sterile aqueous solution, for example, with antioxidants such as sodium metabisulfite The doses would be similar to those described above, adjusted to take into consideration the lower percentage of apomorphine that will reach the lung in a nebulized system. Although these systems can be used, they are clearly inferior to the DPI systems described above, both in terms of efficiency and convenience of use.
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 Macfarlan 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 Filler. 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 Leucine 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 this study, 35 patients were treated with 4 random doses of either placebo, 200 μg of apomorphine hydrochloride, 400 μg of apomorphine hydrochloride, or 800 μg of apomorphine hydrochloride. The doses were administered either with the blister of Example 3 (200 micrograms of apomorphine hydrochloride in a 3 mg blister) or in a placebo blister (200 micrograms of placebo in the 3 mg blister of Example 3). During each treatment, a patient took the given dose and was left alone to watch an hour of visual sexual stimulation (VSS). At 50-55 minutes after administration, the patients were warned that the study would end at 60 minutes. After 60 minutes, the patient's were asked to rate the quality and duration of their response to VSS. In this regard, the quality of response is defined as one of four grades: 0: no effect; 1: some tumescence, no rigidity; 2: some tumescence, some rigidity, but not suitable for penetration; 3: rigidity and tumescence that would enable penetration but is not complete erection; 4: complete erection. This study was conducted in a double blind fashion, where both the healthcare professional administering the treatment and the patient were not informed as to the actual dose being administered. The patients who participated in this study were randomized. During each treatment, each of the 35 patients received 4 blisters regardless of the dose i.e., a patient receiving a 400 μg HCl dose would receive 2 (two) of the apomorphine HCl blisters and 2 (two) of the placebo blisters and a patient receiving only placebo took 4 (four) of the placebo blisters. The study showed that the groups treated with 400 μg and 800 μg of apomorphine HCl experienced the quickest onset of effect, longest duration and most complete erections as compared to the groups treated with either Placebo or 200 μg apomorphine HCl dose. For example, the group treated with 800 μg apomorphine HCl exhibited a median onset of effect in about 8 or less minutes after administration of apomorphine HCl as compared to about 11 or less minutes for the 200 μg apomorphine HCl group, based upon grade 3 and 4 responders. Grade 3 or 4 responses were achieved as quickly as 4 minutes for the 400 and 800 μg groups. It is believed that if this treatment were to be repeated with single dosing as opposed to 4 doses at a time (i.e. one 800 μg blister dose), the response to treatment would exhibit an even faster onset, thereby, providing even more effective treatment.
In the study, patients treated with placebo (4 blisters, each consisting of placebo) showed a 31.4% average response rate. The 200 μg group (4 blisters, 1 containing 200 μg apomorphine HCl and the remaining 3 blisters each containing placebo) showed a 22.9% average response rate, the 400 μg group (4 blisters, 2 containing 200 μg apomorphine HCl and the remaining 2 containing placebo) showed a 48.5% average response rate, and the 800 μg group (4 blisters, each containing 200 μg apomorphine HCl) showed a 58.8% average response rate. As the patients treated with 400 μg and 800 μg displayed significantly higher response rates as compared to those patients treated with either placebo or 200 μg, the 400 μg and 800 μg doses are considered to be effective. (See table 4 below).
1The confidence interval (CI) is a one sided 95% CI. It extends from the limit shown to 100%.
The primary measure of efficacy, as defined in the protocol, was the proportion of subjects reporting a grade 3 or 4 erection, using the criteria defined in the International Index of Erectile Function (IIEF). Grade 3 and 4 erections are regarded as “sufficient for successful intercourse”. Using these criteria, the 400 μg and 800 μg doses of apomorphine HCL were deemed effective. As illustrated in
With respect to efficacy, table 5 below illustrates that the 200 μg apomorphine HCl dose group exhibited a median onset of effect of 11 minutes after administration (with a standard of deviation of 4.2), and the placebo group exhibited a median onset of effect of 10 minutes after administration (with a standard of deviation of 7.8). In contrast, the 400 μg and 800 μg apomorphine HCl dose groups exhibited the quickest median onset of effect (8 (SD 7.5) and 8 (SD 5.0) respectively). The 400 μg and 800 μg apomorphine HCl dose groups also exhibited the most complete erections, longest duration and highest response rate percentages as compared to the groups treated with either 200 μg apomorphine HCl or placebo.
A more detailed illustration of the onset and duration of effect for each individual group is provided in
Adverse events were monitored during each dosing period. The proportion of patients experiencing one or more adverse events was similar in all four treatment groups. No serious adverse events were observed and no adverse event led to the premature discontinuation of any subject. All adverse events were mild or moderate in severity and occurred in a small percentage of the groups treated. Table 6 is a summary of all adverse events. Table 7 is a summary of all treatment related adverse events, and Table 8 breaks treatment related adverse events down by body system. Referring to Table 6, only 6% of the 800 μg apomorphine HCl group experienced adverse events, which is the same percentage of those who experienced adverse events in both the placebo and 200 μg apomorphine HCl group. Referring to Table 8, adverse events were most frequently observed in the Respiratory, thoracic and mediastinal disorders body systems.
For each patient, blood samples were taken 70 minutes after inhalation. The blood samples were analyzed, and the blood levels for 400 and 800 microgram doses of apomorphine for each of the 34 patients that completed the test are set forth in table 9:
The mean plasma levels at 70 minutes after dosing (T70) at 400 μg and 800 μg were 0.22 and 0.61 ng/mL respectively. These T70 levels are below those known to be efficacious (See EPAR 1945).
It should be noted that it was not feasible to take plasma samples at earlier time points because of the need to protect the privacy and dignity of the volunteers during the period that efficacy was evaluated. Moreover, it is believed that the process of drawing blood samples during the VSS period of the test would have affected to the ability of the patients to maintain an erection. It is therefore necessary to back-calculate the plasma concentration to the time when concentration was a maximum (Cmax), as therapeutic (pharmacological) effects usually depend upon the value of Cmax. Back-calculation procedures are well known in the art, and use a model based on the half-life of the drug in plasma. Inhalation absorption is known to be rapid and complete because of the large surface area and profuse blood supply of the lung. As this pattern of absorption is similar to that of intravenous dosing, it is reasonable to take the time immediately after dosing (T0) as the approximate timepoint associated with Cmax, and to use the half-life known for intravenous administration of apomorphine (41 minutes as cited by van der Geeste, R Clin. Neuropharmacol. 21 (3) (1998)).
Using this information, the correction factor based on the half-life of apomorphine is 3.26 (270/41). Applying this to the mean T70 values of Table 9 yields estimated mean plasma levels at T0 of 0.72 ng/ml for the 400 μs dose and 1.99 ng/mL for the 800 μg dose. These levels were expected to be efficacious based upon the above-referenced EPAR 1945, which is consistent with the clinical data of Table 4 above.
In addition to the clinical data described above in connection with Tables 6-8, the blood level data of Table 9 further supports the conclusion that the inhaled apomorphine in accordance with the embodiments of the present invention minimizes the risk of side effects.
First, therapeutic (pharmacological) effects are usually dependent upon the value of Cmax. However, side-effects are often dependent upon the systemic exposure to the drug. Systemic exposure can be measured as the integral of the plasma level from time of administration until it returns to zero (i.e. the area under the curve AUC0 to ∝). The measured values of Table 9 demonstrate that plasma levels fall rather rapidly to low values after dosing via inhalation in accordance with the invention. In contrast, absorption is much less rapid and complete by most other routes of administration. For example, EPAR 1945 reports that the elimination half-life for Uprima is 2.7 hours for a 2 mg sublingual dose, 4.2 hours for a 4 mg sublingual dose, 3.9 hours for a 5 mg sublingual dose, and 4.0 hours for a 6 mg sublingual dose. (EPAR 1945, “Scientific Discussion”, p. 12).
A second but equally important beneficial effect of the short half-life associated with the inhaled formulation is that the period in which therapeutic and any side-effects is short due to the short half-life of the formulation. Consequently, side-effects, if they occur, will be short lived, allowing the patient to resume normal activities such as driving.
The data of Table 9 and
The data also indicates that doses can be readily matched to an individual subject. Referring to
A pMDI fomulation was prepared with the ingredients listed in the following table. The formulation can be placed in a 3M coated (Dupont 3200 200) canister with a Bespak BK630 series 0.22 mm actuator for subsequent delivery to the lungs of a patient as described above:
It is expected that this formulation can provide a Fine Particle Fraction of between 10% and 30%.
Suspension pMDIs were prepared with HFA227, HFA134a, and apomorphine hydrochloride in a 3M coated (Dupont 3200 200) canister with a Bespak BK630 series 0.22 mm actuator. Specifically, the following formulations were prepared:
Formulation B was tested with an Anderson Cascade Impactor over 10 discharges. The results were as follows, each value being an average of the 10 discharges:
wherein a fine particle is defined as a particle having a diameter of less than or equal to 5 microns.
Five 400 μg apomorphine hydrochloride capsules were prepared and tested in a Cyclohaler inhaler (available from Miat) in an ACI (U.S.P. 26, Chapter 601, Apparatus 3) configured for operation at 100 l·min-1. Each capsule had a fill weight of 25 mg, and included the following components:
In this regard, Pharmatose 150M, available from DMV Pharma, comprises lactose with the following particle size distribution (according to DMV Pharma literature): 100% less than 315 microns, at least 85% less than 150 microns, at least 70% less than 100 microns, and at least 50% less than 45 microns. Sorbolac 400, available from Meggle Pharma comprises lactose with the following particle size distribution (according to Meggle Pharma literature): 100% less than 100 microns, at least 99% less than 63 microns, and at least 96% less than 32 microns.
The Pharmatose, Sorbolac and Leucine were layered in the mixing bowl so that the leucine was sandwiched between the Sorbolac, which in turn was sandwiched between the Pharmatose. The powders were blended for 60 seconds at 2000 rpm using the Retsch Grindomix High Shear Mixer described above. The pre-blend was rested for 1 hour before further use.
The apomorphine hydrochloride was sandwiched between the pre-blend in the mixing bowl. Blending was carried out for 10 minutes at 2000 rpm using the Grindomix mixer. The blend was then passed through a 212 μm sieve.
Thereafter, the final blend was placed in capsules, each capsule having a fill weight of 25 mg. The capsules were then placed in a cyclohaler and tested in an ACI (U.S.P. 26, Chapter 601, Apparatus 3), with the data analyzed via the CITDAS described above, providing the following results:
Five 400 μg apomorphine hydrochloride blisters were prepared and tested in the inhaler of example 5 in an ACI (USP 26, Chapter 601, Apparatus 3) configured for operation at 60 l·min−1. Each blister had a fill weight of 2 mg, and included the following components:
The Apomorphine hydrochloride was sandwiched between the Respitose in the mixing bowl as generally described in Examples 2(a) and 2(b). The powders were blended for 5 mins at 2000 rpm using the Grindomix mixer. The blend was then passed through a 212 μm sieve. Thereafter, the blend was placed in blister, each blister having a fill weight of 2 mg. The blisters were then placed in the inhaler of Example 5 and tested in an ACI (U.S.P. 26, Chapter 601, Apparatus 3), with the data analyzed via the CITDAS described above, providing the following results:
It should be noted that the MMAD of 1.70 microns generated from the ACI data is remarkably fine, and very close to the median diameter determined by laser light diffraction, for this batch of apomorphine hydrochloride (1.453 microns as reported
When compared with the formulation and inhaler of Example 17, the formulation and inhaler of Example 18 also provided a superior delivered dose (89.2% vs 81%), fine particle fraction (81% vs 67%), % fine particle dose (72% vs 55%) and % ultrafine particle dose (67% vs 44%).
It is also apparent from the above data that the formulation and inhaler of Example 18 produces an ultra-fine particle fraction (≦3 μm) of more than 70%. While a fine particle fraction (≦5 microns) can be considered acceptable for local delivery, it is believed that for systemic delivery, even finer particles are needed, because the drug must reach the alveoli to be absorbed into the bloodstream. As such an ultrafine particle fraction in excess of 70% is particularly advantageous.
The above referenced data indicates that the preferred inhaler in accordance with the present invention, is particularly efficient when combined with the preferred formulation in accordance with the present invention.
It should also be noted that both the formulation of Example 17 (with the cyclohaler) and the formulation of Example 18 (with the preferred inhaler), provide significantly better performance than the suspension pMDI of Example 15, which had an MMAD of 3.47, an FPF of 66.7, and a % Fine Particle Dose of 52.4%.
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.
This application is a continuation-in-part of U.S. patent application Ser. No. 10/413,022, filed Apr. 14, 2003, entitled “Composition, Device, And Method For Treating Sexual Dysfunction Via Inhalation”, the entire disclosure of which is hereby incorporated by reference.
| Number | Date | Country | |
|---|---|---|---|
| Parent | 10621964 | Jul 2003 | US |
| Child | 12653179 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 10413022 | Apr 2003 | US |
| Child | 10621964 | US |
