A liquid aerosol formulation comprising at least one thermally stable active ingredient selected from the group consisting of butalbital, lorazepam, ipratropium, baclofen, morphine, scopolamine, pharmaceutically acceptable salts and esters thereof and derivatives thereof. The liquid formulation can include an organic solvent such as propylene glycol and one or more optional excipients. The active ingredient can be present in an amount of 0.01 to 5 weight percent and the formulation can be heated to provide a vapor which forms an aerosol having a mass median aerodynamic diameter of less than 3 .mu.m.

Description of the Invention

FIELD OF THE INVENTION

The invention relates generally to an liquid aerosol formulation. More specifically, the invention relates to a liquid aerosol formulation comprising at least one thermally stable active ingredient selected from the group consisting of butalbital, lorazepam, ipratropium, baclofen, morphine, scopolamine, pharmaceutically acceptable salts and esters thereof and derivatives thereof. The invention further relates to aerosol generating devices and methods for generating aerosols.

BACKGROUND

Aerosols are gaseous suspensions of fine solid or liquid particles. Aerosols are useful in a wide variety of applications. For example, medicated liquids may be administered in aerosol form. Medicated aerosols include materials that are useful in the treatment of respiratory ailments. In such applications, the aerosols may be produced by an aerosol generator and inhaled into a patient's lungs.

Aerosol generators are known that include a heated tube for vaporizing liquid. For example, commonly assigned U.S. Pat. No. 5,743,251, which is incorporated herein by reference in its entirety, discloses an aerosol generator including a tube and a heater operable to heat the tube to a sufficient temperature to volatilize liquid in the tube. It is disclosed that the volatilized material expands out of an end of the tube and admixes with ambient air, thereby forming an aerosol.

Other aerosol generators including a heated tube for vaporizing liquids to produce an aerosol are described in commonly-assigned U.S. Pat. Nos. 6,234,167 and 6,568,390 and U.S. patent application Ser. No. 10/003,437 filed Dec. 6, 2001 and U.S. Provisional Application No. 60/408,894, filed Sep. 6, 2002, each being incorporated herein by reference in its entirety.

SUMMARY

One embodiment provides a liquid aerosol formulation comprising at least one thermally stable active ingredient selected from the group consisting of butalbital, lorazepam, ipratropium, baclofen, morphine, scopolamine, pharmaceutically acceptable salts and esters thereof and derivatives thereof. The formulation may contain any desired amount of the active ingredient. In a preferred embodiment, the formulation may contain 0.01 to 5% by weight of the thermally stable active ingredient.

The liquid aerosol formulation may further comprise an organic solvent. The organic solvent may be, but is not limited to, a short chain (C.sub.1-C.sub.6) alcohol. The short chain (C.sub.1-C.sub.6) alcohol may be, but is not limited to, glycerin, ethylene glycol, diethylene glycol, propylene glycol, n-propyl alcohol, isopropyl alcohol, butanol, ethanol, sorbitol, dipropylene glycol, tripropylene glycol, and hexylene glycol. Preferably, the organic solvent is propylene glycol or dipropylene glycol.

The liquid aerosol formulation may further comprise at least one pharmaceutically acceptable excipient. The excipient may be, but is not limited to, antioxidants, stabilizing agents, flavoring agents, solubilizers, cosolvents, preservatives and combinations thereof. Preferably, the cosolvent is ethanol, water, glycerol and/or diethyl ether. Preferably, the solubilizer is ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives, and/or mixtures thereof.

In a preferred embodiment, the thermally stable active ingredient comprises butalbital and the organic solvent is propylene glycol.

In a preferred embodiment, the thermally stable active ingredient comprises lorazepam and the organic solvent is propylene glycol.

In a preferred embodiment, the thermally stable active ingredient comprises ipratropium and the organic solvent is propylene glycol.

In a preferred embodiment, the thermally stable active ingredient comprises baclofen and the organic solvent is propylene glycol.

In a preferred embodiment, the thermally stable active ingredient comprises morphine and the organic solvent is propylene glycol.

In a preferred embodiment, the thermally stable active ingredient comprises scopolamine and the organic solvent is propylene glycol.

According to one embodiment, a method of generating an aerosol comprises supplying a liquid aerosol formulation to a flow passage, heating the liquid aerosol formulation in the flow passage so as to volatilize a liquid component thereof and form a vapor which exits from an outlet of the flow passage, and contacting the vapor with a gaseous medium so as to form an aerosol, wherein the liquid aerosol formulation includes at least one thermally stable active ingredient selected from the group consisting of butalbital, lorazepam, ipratropium, baclofen, morphine, scopolamine, pharmaceutically acceptable salts and esters thereof. For drug delivery, the liquid aerosol formulation preferably comprises particles of propylene glycol having a mass median aerodynamic diameter (MMAD) of less than 3 .mu.m. The liquid aerosol formulation may further include at least one thermally stable active ingredient and the aerosol comprises particles of the thermally stable active ingredient having an MMAD of less than 3 .mu.m.

In a preferred embodiment, the thermally stable active ingredient comprises butalbital and the aerosol comprises butalbital particles having an MMAD of less than 3 .mu.m.

In a preferred embodiment, the thermally stable active ingredient comprises lorazepam and the aerosol comprises lorazepam particles having an MMAD of less than 3 .mu.m.

In a preferred embodiment, the thermally stable active ingredient comprises ipratropium and the aerosol comprises ipratropium particles having an MMAD of less than 3 .mu.m.

In a preferred embodiment, the thermally stable active ingredient comprises baclofen and the aerosol comprises baclofen particles having an MMAD of less than 3 .mu.m.

In a preferred embodiment, the thermally stable active ingredient comprises morphine and the aerosol comprises morphine particles having an MMAD of less than 3 .mu.m.

In a preferred embodiment, the thermally stable active ingredient comprises scopolamine and the aerosol comprises scopolamine particles having an MMAD of less than 3 .mu.m.

In a preferred embodiment, the flow passage is a capillary sized flow passage and the aerosol is formed in a mouthpiece of a handheld inhaler. The aerosol may include particles of the thermally stable active ingredient having an MMAD of 0.1 to 2.5 .mu.m and the aerosol preferably has a recovery rate of at least 90% during generation of the aerosol. Preferably, the flow passage is heated by a resistance heater located in a handheld inhaler, the inhaler including a power supply and control electronics which controls supply of electrical power to the heater as a function of a resistance target in a range of 0.5 to 1 ohm.

According to one embodiment, an aerosol generator comprises a flow passage adapted to receive a liquid aerosol formulation from a liquid supply, the liquid aerosol formulation comprising at least one thermally stable active ingredient selected from the group consisting of butalbital, lorazepam, ipratropium, baclofen, morphine, scopolamine, pharmaceutically acceptable salts and esters thereof and derivatives thereof, and a heater operable to heat the liquid formulation in at least a portion of the flow passage sufficiently to vaporize the liquid formulation and generate an aerosol containing the active ingredient. The aerosol generator may comprise a hand-held inhaler having a mouthpiece, the flow passage comprising a capillary sized flow passage having an outlet in fluid communication with an interior of the mouthpiece. In a preferred embodiment, the heater is a resistance heater comprising a section of a metal capillary tube and the flow passage comprises the interior of the metal capillary tube. The aerosol generator may comprise a hand-held inhaler having a power supply and control electronics which controls supply of electrical power to the heater as a function of a control parameter selected to achieve boiling of the liquid formulation in the flow passage. The liquid supply may comprise a reservoir containing the liquid formulation under a pressure of no greater than about atmospheric pressure.

4. DETAILED DESCRIPTION

Liquid aerosol formulations, aerosol generating devices and methods for generating aerosols are provided.

The liquid aerosol formulations can provide aerosols having selected compositions and controlled particle sizes. The liquid aerosol formulations are suitable for different applications including systemic delivery of medicaments. For example, for drug delivery applications via inhalation, the formulations comprise aerosols having a desirable mass median aerodynamic diameter (MMAD) for targeted delivery. For pulmonary delivery, particles of smaller size are desired than for tracheobronchial delivery or delivery to the oropharynx or mouth. In preferred embodiments, the aerosols have a controlled particle size that is effective to achieve pulmonary delivery of drug formulations.

The liquid aerosol formulation preferably includes an organic solvent and at least one thermally stable active ingredient. The thermally stable active ingredients may be selected from the group consisting of butalbital, lorazepam, ipratropium, baclofen, morphine, scopolamine, pharmaceutically acceptable salts and esters thereof and derivatives thereof. The thermally stable active ingredients can be somewhat or completely soluble in the liquid aerosol formulation. In addition, the liquid aerosol formulation is preferably propellant free.

Butalbital, lorazepam, ipratropium, baclofen, morphine, scopolamine, pharmaceutically acceptable salts and esters thereof and derivatives thereof are sufficiently soluble in an organic solvent to form solutions at ambient conditions. The concentration of butalbital, lorazepam, ipratropium, baclofen, morphine, scopolamine, pharmaceutically acceptable salts and esters in the solution can be varied to control the amount of the active ingredient in such aerosols.

The liquid aerosol formulation may further comprise additional active ingredients, in combination with butalbital, lorazepam, ipratropium, baclofen, morphine, scopolamine, pharmaceutically acceptable salts and esters thereof and/or derivatives thereof.

The liquid aerosol formulation may further comprise an organic solvent. Examples of organic solvents include, but are not limited to, short chain (C.sub.1-C.sub.6) alcohols, such as n-propyl alcohol, isopropyl alcohol, butanol, ethanol, glycerin, ethylene glycol, diethylene glycol, propylene glycol, sorbitol, dipropylene glycol, tripropylene glycol, and hexylene glycol. Preferred short chain alcohols are propylene glycol and dipropylene glycol. Propylene glycol (PG) is especially preferred.

The liquid aerosol formulation may also include any pharmaceutically acceptable excipient. Such excipients may include, but are not limited to, antioxidants, stabilizing agents, flavoring agents, solubilizers, cosolvents, preservatives and combinations thereof.

Preferably, the cosolvent is ethanol, water, glycerol and diethyl ether. Preferably, the solubilizer is ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives or mixtures thereof.

In a preferred embodiment, the liquid aerosol formulation is flowed through a capillary sized flow passage in which the liquid is heated to a sufficiently high temperature to vaporize the liquid. The vapor exits the flow passage and admixes with gas, preferably ambient air, to produce an aerosol which is inhaled by a user. The size of the aerosol particles thus produced can be controlled for delivery to the lung.

The capillary passage can have different transverse cross-sectional shapes, such as round, oval, triangular, square, rectangular, other polygonal shapes, or the like, as well as other non-geometric shapes. Different portions of the capillary passage can have different cross-sectional shapes. As described below, the size of the capillary passage can be defined by its transverse cross-sectional area. For a capillary passage having a round cross-section, the size of the flow passage may be defined by its diameter. Alternatively, the capillary passage may be non-circular in cross section and the size of the capillary passage may be defined by its width. For example, the capillary passage can have a maximum width of 0.01 to 10 mm, preferably 0.05 to 1 mm, and more preferably 0.1 to 0.5 mm. Alternatively, the capillary passage can be defined by its transverse cross sectional area, which can be 8.times.10.sup.-5 to 80 mm.sup.2, preferably 2.times.10.sup.-3 to 8.times.10.sup.-1 mm.sup.2, and more preferably 8.times.10.sup.-3 to 2.times.10.sup.-1 mm.sup.2.

Details of an aerosol generator which can be used to aerosolize the liquid formulation are described in commonly assigned U.S. Pat. Nos. 5,743,251; 6,234,167; 6,516,796; and 6,568,390, the entire disclosures of which are hereby incorporated by reference. Other suitable aerosol generators are described in commonly assigned U.S. patent application Ser. No. 10/341,521 filed Jan. 14, 2003, the entire disclosure of which is hereby incorporated by reference. Control schemes for heating the flow passage are described in commonly assigned U.S. Pat. No. 6,501,052, the entire disclosure of which is hereby incorporated by reference, and in commonly assigned U.S. patent application Ser. No. 10/206,320 filed Jul. 29, 2002, the entire disclosure of which is hereby incorporated by reference.

As described in commonly-assigned U.S. Provisional Patent Application No. 60/408,295, filed Sep. 6, 2002, which is incorporated herein by reference in its entirety, embodiments of the capillary passage can comprise an outlet section, which controls the velocity of vapor exiting the outlet end of the capillary passage, i.e, the exit velocity of the vapor, so as to control the particle size of aerosol generated by the aerosol generating device.

The material forming the capillary passage can be any suitable material, including metals, plastics, polymers, ceramics, glasses, or combinations of these materials. Preferably, the material is a heat-resistant material capable of withstanding the temperatures and pressures generated in the capillary passage, and also resisting the repeated heating cycles utilized to generate multiple doses of aerosols. In addition, the material forming the capillary passage preferably is non-reactive with the liquid that is aerosolized.

In another alternative embodiment, the capillary passage can be formed in a polymer, glass, metal and/or ceramic monolithic or multilayer (laminated) structure (not shown). Suitable ceramic materials for forming the capillary passage include, but are not limited to, alumina, zirconia, silica, aluminum silicate, titania, yttria-stabilized zirconia, or mixtures thereof. A capillary passage can be formed in the monolithic or multilayer body by any suitable technique, including, for example, machining, molding, extrusion, or the like.

In embodiments, the capillary passage can have a length from 0.5 to 10 cm, and preferably from 1 to 4 cm.

The liquid aerosol formulation supplied from a liquid source is heated in the capillary passage to form a vapor during operation of the aerosol generating device. In a preferred embodiment, the capillary comprises metal tubing heated by passing an electrical current along a length of the capillary tubing via a first electrode and a second electrode. However, as described above, the capillary passage can have other alternative constructions, such as a monolithic or multi-layer construction, which include a heater such as a resistance heating material positioned to heat the fluid in the capillary passage. For example, the resistance heating material can be disposed inside of, or exterior to, the capillary passage.

The capillary passage may comprise an electrically conductive tube provided with a downstream electrode and an upstream electrode. In this embodiment, the capillary is a controlled temperature profile (CTP) construction, such as disclosed in copending and commonly assigned U.S. application Ser. No. 09/957,026, filed Sep. 21, 2001, which is incorporated herein by reference in its entirety. In the controlled temperature profile capillary, the downstream electrode has an electrical resistance sufficient to cause it to be heated during operation of the aerosol generating device, thereby minimizing heat loss at the outlet end of the capillary tube.

The tube forming the capillary passage can be made entirely of stainless steel or any other suitable electrically conductive materials. Alternatively, the tube can be made of a non-conductive or semi-conductive material incorporating a heater made from an electrically conductive material, such as platinum. Electrodes connected at spaced positions along the length of the tube or heater define a heated region between the electrodes. A voltage applied between the two electrodes generates heat in the heated region of the capillary passage based on the resistivity of the material(s) making up the tube or heater, and other parameters such as the cross-sectional area and length of the heated region section. As the fluid flows through the capillary passage into the heated region between the first and second electrodes, the fluid is heated and converted to a vapor. The vapor passes from the heated region of the capillary passage and exits from the outlet end. In some preferred embodiments, the volatilized fluid is entrained in ambient air as the volatilized fluid exits from the outlet, causing the volatilized fluid to condense into small droplets and form a condensation aerosol. In a preferred embodiment, the MMAD of the droplet size is 0.1 to 2.5 .mu.m.

The temperature of the liquid in the capillary passage can be calculated based on the measured or calculated resistance of the heating element. For example, the heating element can be a portion of a metal tube, or alternatively a strip or coil of resistance heating material. Control electronics can be used to regulate the temperature of the capillary passage by monitoring the resistance of the heater. For example, the control electronics can control the temperature profile of the capillary passage during operation of the aerosol generating device. The control electronics can also control the output of the display. The display is preferably a liquid crystal display (LCD). The display can depict selected information pertaining to the condition or operation of the aerosol generating device. The control electronics can also control the operation of one or more valves during operation of the aerosol generating device; monitor the initial pressure drop caused by inhalation and sensed by the pressure sensor; and monitor the condition of the battery unit that provides electrical power to components of the aerosol generating device.

Preferably, the aerosol particles have a MMAD between about 0.1 .mu.m and about 2.5 .mu.m. As described above, the aerosol generating device can provide aerosols having a controlled particle size, including aerosols sized for the targeted delivery of drugs to the lung. These aerosols offer a number of advantages for delivering drugs to the deep lung. For example, mouth and throat deposition are minimized, while deposition in the deep lung is maximized, especially when combined with a breath hold. Moreover, when using a suitable hydrophilic carrier, deposition may be further enhanced by hygroscopic growth.

The aerosol generating device preferably generates aerosols in which 95% of the aerosol particles (aerosol droplets) have a size in the range between about 0.1 .mu.m to about 2.5 .mu.m. The aerosol generating device preferably incorporates a processor chip for controlling the generation process. The processor, with suitable sensors, also triggers the aerosol generation at any desired time during an inhalation. The drug to be aerosolized is provided with a carrier. By the choice of suitable hydrophilic carriers, the aerosol generating device can take advantage of hygroscopic growth in the respiratory system.

Operation of the preferred aerosol generating device for delivering aerosolized thermally stable active ingredients is as follows. First, a liquid aerosol formulation including at least one thermally stable active ingredient is delivered to the heated capillary passage. The liquid vaporizes in the capillary passage and exits as a vapor jet from the open end of the capillary passage. The vapor jet entrains and mixes with ambient air, and forms a highly concentrated, fine aerosol. As described above, application of heat to vaporize the liquid is typically achieved by resistive heating from passing an electric current through the heater. The applied power is adjusted to maximize the conversion of the fluid into a vapor.

As will be appreciated, the aerosol generating device is capable of controlled vaporization and aerosol formation of drug formulations. The aerosol generating device can provide immediate delivery of aerosol to a patient, thereby not wasting lung capacity, which may be limited due to the health of the patient. Also, the aerosol generating device can provide consistent delivery of controlled amounts of drug formulation to a patient. In addition, in preferred embodiments, the aerosol generated by the aerosol generating device including a capillary passage is only slightly affected by relative humidity and temperature.
 

Claim 1 of 11 Claims

1. A method of generating an aerosol comprising: supplying a liquid aerosol formulation to a capillary-sized flow passage, heating the liquid aerosol formulation in the capillary-sized flow passage so as to volatilize a liquid component thereof and form a vapor which exits from an outlet of the capillary-sized flow passage, and contacting the vapor with a gaseous medium so as to form an aerosol, wherein the liquid aerosol formulation includes at least one thermally stable active ingredient selected from the group consisting of scopolamine, pharmaceutically acceptable salts and esters thereof.

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