JP2006516545A - Perfluorocarbon and hydrofluorocarbon preparations and their production and use - Google Patents

Abstract

The liquid aerosol generating formulation comprises a drug and at least one liquid perfluorocarbon and / or hydrofluorocarbon. The formulation can include at least one surfactant that stabilizes the drug. An aerosol of drug particles can be formed by heating the formulation in the flow path such that the liquid perfluorocarbon and / or hydrofluorocarbon evaporates and expands from the outlet of the flow path. The flow path can be a heated capillary sized flow path in a hand-held inhaler. Liquid perfluorocarbons and / or hydrofluorocarbons can deliver drugs with low solubility and / or low potency to patients as soft mist aerosols that require minimal patient coordination.

Description

  The present invention relates generally to aerosol generation. In particular, the present invention relates to an aerosol formulation comprising at least one liquid perfluorocarbon and / or hydrofluorocarbon, an aerosol generator, a method of making an aerosol formulation, and a method of generating an aerosol.

  Aerosols are gaseous suspensions of fine solids or liquid particles. Aerosols are useful in a wide range of applications. For example, a drug-added liquid can be administered in the form of an aerosol. Drug-added aerosols contain substances that are useful in the treatment of respiratory diseases. In such applications, the aerosol can be generated by an aerosol generator and inhaled into the patient's lungs. Aerosols are also used in non-pharmaceutical applications including, for example, industrial purposes.

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

  Other aerosol generators, including heated tubes for evaporating liquids to produce aerosols, are commonly assigned US Pat. Nos. 6,234,167, 2001.9.21, and US patent application Ser. Nos. 09/959666 and 2001. .12.6 Application No. 10/003437, each of which is hereby incorporated by reference in its entirety.

  According to one embodiment, the present invention provides a propellant-free liquid aerosol generating formulation comprising at least one liquid perfluorocarbon and / or hydrofluorocarbon, at least one agent, and at least one surfactant. The liquid perfluorocarbon and / or hydrofluorocarbon are in a liquid state under ambient conditions. The formulation can optionally include additional ingredients such as additives and / or other liquids. Liquid aerosol generating formulations preferably include solutions, suspensions or emulsions.

According to a preferred embodiment, the liquid perfluorocarbon comprises a linear perfluoroalkane, a cyclic perfluoroalkane, an oxygen-containing perfluoroalkane, a nitrogen-containing perfluoroalkane, or a derivative thereof, and the liquid hydrofluorocarbon is a liquid hydrofluoroalkane, Includes hydrofluoroalkenes, hydrofluoroethers or their derivatives. The surfactant preferably stabilizes the drug in the formulation and includes at least one of one or more of fluoroalcohol, fluoroolefin, fluoroalkyl acrylate, fluoroalkyl stearate, fluoroalkanoic acid, and fluoroalkyl citrate. Can include one partially or fully fluorinated surfactant and / or the surfactant is at least one non-fluorinated such as phospholipid, polyalcohol, polyolefin, sorbitan ester, or mixtures thereof A surfactant can be included. According to a preferred embodiment, the liquid perfluorocarbon and / or hydrofluorocarbon has a boiling point of at least about 40 ° C., a density of less than about 2 g / cm ³ and / or a vapor pressure of about 20 torr to about 200 torr.

  The medicament preferably comprises solid or liquid particles having a particle size of about 0.05 to about 10 μm. For example, the drug can be incorporated into a polymer matrix that is ground to the desired particle size. The concentration of the drug in the formulation can be selected to provide a therapeutically effective amount of the pharmaceutically active drug when the formulation is aerosolized. For example, the formulation passes a metered amount of the formulation through a capillary sized flow passage that is heated sufficiently to evaporate liquid perfluorocarbon and / or hydrofluorocarbon and form an aerosol containing drug particles. Can be aerosolized. Suitable formulations may comprise up to about 20% by weight drug and at least 5%, more preferably at least 50%, most preferably at least 80% by volume liquid perfluorocarbon and / or hydrofluorocarbon.

  According to one embodiment, the present invention provides a method of generating an aerosol, which supplies a liquid aerosol generating formulation comprising a drug and at least one liquid perfluorocarbon and / or hydrofluorocarbon to a flow path, the liquid perfluorocarbon and Heating the formulation in the flow path to evaporate the hydrofluorocarbon and form an aerosol containing the drug. For drug delivery, the aerosol preferably comprises drug particles having a MMAD of about 0.05 to about 10 μm.

  In a preferred embodiment, the flow passage is a capillary sized flow passage and the aerosol is formed in the mouthpiece of a hand-held inhaler. The flow path is preferably heated by a resistance heater provided in the hand-held inhaler, the inhaler being selected to achieve a power supply and boiling of the liquid perfluorocarbon and / or hydrofluorocarbon in the flow path Includes control electronics that control the power supply to the heater as a function of parameters.

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

  This liquid aerosol generating formulation can produce an aerosol with a selected composition and controlled particle size. This liquid formulation is suitable for various applications. For example, for drug delivery applications via inhalation, the liquid formulation can be used to produce an aerosol with the desired mass median aerodynamic particle size (MMAD) for targeted delivery. . For pulmonary delivery, a smaller particle size is more desirable for bronchial delivery or delivery to the oropharynx or mouth. In a preferred embodiment, the liquid formulation can be used to produce an aerosol with a controlled particle size that is effective to achieve pulmonary delivery of the drug formulation.

The liquid aerosol generating formulation comprises at least one liquid perfluorocarbon and / or hydrofluorocarbon and at least one drug. Liquid perfluorocarbons and hydrofluorocarbons are in a liquid state under ambient pressure and temperature conditions. According to a preferred embodiment, the liquid formulation does not comprise a propellant and the liquid perfluorocarbon comprises a linear perfluoroalkane, a cyclic perfluoroalkane, an oxygen-containing perfluoroalkane, a nitrogen-containing perfluoroalkane, or a derivative thereof, Liquid hydrofluorocarbons include liquid hydrofluoroalkanes, hydrofluoroalkenes, hydrofluoroethers or their derivatives. The liquid aerosol generating formulation preferably comprises at least 5% by volume, more preferably at least 50%, and most preferably at least 80% liquid perfluorocarbon and / or hydrofluorocarbon. According to a preferred embodiment, the liquid perfluorocarbon and / or hydrofluorocarbon has a boiling point of at least about 40 ° C. or at least about 50 ° C., a density of less than about 2 g / cm ³ and / or a vapor pressure of about 20 Torr to about 200 Torr. Have.

  The surfactant stabilizes the drug in the formulation and at least one partial or complete such as a fluoroalcohol, fluoroolefin, fluoroalkyl acrylate, fluoroalkyl stearate, fluoroalkanoic acid, and / or fluoroalkyl citrate. May contain a fluorinated surfactant. For example, in a partially fluorinated surfactant, some of the H atoms are replaced by F atoms, and in a fully fluorinated surfactant, most or all of the H atoms are replaced by F atoms. The surfactant may alternatively or additionally comprise at least one non-fluorinated surfactant such as phospholipids, polyalcohols, polyolefins, sorbitan esters, or mixtures thereof.

  Depending on the desired application, various substances can be used as drugs in liquid formulations. The drug can be present in the formulation as a solid or liquid. For example, the formulation can be a suspension comprising solid drug particles suspended in a liquid. Alternatively, the formulation can be an emulsion, where the drug is present as a liquid phase dispersed in different liquid phases. The drug can also include a solution where the drug is dissolved in the liquid.

  In the case of a suspension or emulsion, the drug preferably comprises solid and / or liquid particles having a particle size of about 0.05 to about 10 μm. The drug can be incorporated into a polymer matrix that is ground to the desired particle size. The concentration of the drug in the formulation can be selected to provide a therapeutically effective amount of the pharmaceutically active drug when the formulation is aerosolized. For example, the formulation may be aerosolized by passing a metered amount of the formulation through a capillary sized flow passage that is heated sufficiently to evaporate liquid perfluorocarbon and / or hydrofluorocarbon and form an aerosol containing the drug. Can be Suitable formulations can contain up to about 20% by weight of the drug.

  The medicament can include a variety of substances that can be incorporated into a liquid aerosol generating formulation. For example, drugs are analgesics, angina preparations, antiallergic drugs, antibiotics, antihistamines, antitussives, antiemetics, insulin, bronchodilators, diuretics, anticholinergics, hormones, antiinflammatory drugs, and Including mixtures thereof.

  The formulation is up to 20% by volume of at least one solvent or co-solvent, such as water, ethyl alcohol (ethanol), n-propyl alcohol, isopropyl alcohol, butanol, glycerin, ethylene glycol, diethylene glycol, propylene glycol, sorbitol, dipropylene glycol Optionally, organic liquids such as short chain (C1-C6) alcohols such as tripropylene glycol, and hexylene glycol. Preferred short chain diols and polyols are propylene glycol and dipropylene glycol. Propylene glycol is particularly preferred. The formulation optionally has one or more other pharmaceutically acceptable excipients (such as ethanol and / or water), fragrances, preservatives, additives, antioxidants, stabilizers, and / or Alternatively, other ingredients suitable for inclusion in a pharmaceutical formulation that is administered via inhalation therapy can be included.

  In a preferred embodiment, the liquid formulation is flowed through a capillary sized flow passage where the liquid perfluorocarbon and / or hydrofluorocarbon is heated to a temperature high enough to evaporate the liquid perfluorocarbon and / or hydrofluorocarbon. The vapor exits the flow path and mixes with the gas, preferably ambient air, to produce an aerosol that is inhaled by the user. The size of the aerosol particles thus produced can be controlled for delivery to the lung.

The capillary passage can have various cross-sectional shapes such as round, oval, triangular, square, rectangular, other polygonal shapes, etc., as well as other non-geometric shapes. Different portions of the capillary passage can have different cross-sectional shapes. As will be described below, the size of the capillary passage can be defined by its cross-sectional area. For a capillary passage having a round cross section, the size of the flow passage can be defined by its diameter. Alternatively, the capillary passage can be non-circular in cross section, and the size of the capillary passage can 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, more preferably 0.1 to 0.5 mm. Alternatively, the capillary passage can be defined by its cross-sectional area, which is 8 × 10 ⁻⁵ to 80 mm ² , preferably 2 × 10 ⁻³ to 8 × 10 ⁻¹ mm ² , more preferably 8 × can from ^{10 -3} is 2 × ¹⁰ -1 mm ^2.

  Details of aerosol generators that can be used to aerosolize liquid formulations are set forth in commonly assigned US Pat. Nos. 5,743,251, 6234167, and 6516796, the entire disclosures of which are hereby incorporated by reference. Incorporated. Other suitable aerosol generators are described in commonly assigned US Patent Application No. 10 / 341,521, filed 2003.1.14, the entire disclosure of which is hereby incorporated by reference. A control strategy for heating the flow path is set forth in commonly assigned US Pat. No. 6,501,052, the entire disclosure of which is incorporated herein by reference and the common assignee's 2002.2.79 application. No. 10/206320, the entire disclosure of which is hereby incorporated by reference.

  As described in commonly assigned US Provisional Patent Application No. 60 / 408,295, which is hereby incorporated by reference in its entirety, embodiments of capillary passages are generated by an aerosol generator. An outlet may be included to control the velocity of the vapor exiting the outlet end of the capillary passage, i.e., the vapor outlet velocity, so as to control the particle size of the generated aerosol.

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

  In another alternative embodiment, the capillary passage may be formed of a monolithic or multilayer (laminated) structure (not shown) of polymer, glass, metal and / or ceramic. 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. The capillary passage can be formed in one piece or in multiple layers by any suitable technique including, for example, machining, molding, extrusion, and the like.

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

  The fluid supplied from the liquid source is heated in the capillary passage and forms a vapor when the aerosol generator is activated. In a preferred embodiment, the capillary comprises a metal tube heated by passing an electric current along the length of the capillary through the first electrode and the second electrode. However, as mentioned above, the capillary passage can have other alternative structures, such as a monolithic or multi-layer structure, which are heaters such as resistive heating materials arranged to heat the fluid in the capillary passage including. For example, the resistance heating material can be placed inside the capillary passage or external to it.

  The capillary passage can include an electrically conductive tube with a downstream electrode and an upstream electrode. In this embodiment, the capillary is a controlled temperature distribution (CTP) structure as disclosed in co-pending and common assignee 2001.9.21 US patent application Ser. No. 09/957070. Is hereby incorporated by reference in its entirety. In a controlled temperature distribution capillary, the downstream electrode has sufficient electrical resistance to allow it to be heated during operation of the aerosol generator, 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 other suitable electrically conductive material. Alternatively, the tube can be made from a non-conductive or semi-conductive material that incorporates a heater made from an electrically conductive material such as platinum. Electrodes connected at spaced locations along the length of the tube or heater constitute a heating region between the electrodes. The voltage applied between the two electrodes is based on the resistivity of the material or materials that make up the tube or heater, and other parameters such as the cross-sectional area and length of the heated region, within the heated region of the capillary passage. Generates heat. 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 vapor. Steam passes from the heating area of the capillary passage and exits from the outlet end. The volatilized fluid is preferably entrained in the ambient air as the volatilized fluid exits the outlet, causing the drug particles to form an aerosol. In a preferred embodiment, the aerosol MMAD is from about 0.05 to about 10 μm.

  The temperature of the liquid in the capillary passage can be calculated based on parameters such as the measured or calculated resistance of the heating element. For example, the heating element can be part of a metal tube or alternatively a strip or coil of resistive heating material. Control electronics can be used to adjust the temperature of the capillary passage by monitoring the resistance of the heater. In demonstrating the operation of the aerosol generator, the target temperature for the capillary passage can be about 50 ° C. for the purpose of evaporating liquid perfluorocarbon and / or hydrofluorocarbon (PFC and HFC).

  The control electronics can perform various selected functions within the aerosol generator. For example, the control electronics can control the temperature distribution in the capillary passage during operation of the aerosol generator. The control electronics can also control the output of the display. The display is preferably a liquid crystal display (LCD). The display can show selected information regarding the status or operation of the aerosol generator. The control electronics also controls the operation of the fluid supply to the capillary passage during operation of the aerosol generator; monitors the initial pressure drop in the mouthpiece caused by inhalation and sensed by the pressure sensor; and the aerosol generator The state of the battery device that supplies power to the elements can be monitored.

  Preferably, the aerosol particles have a MMAD between about 0.05 μm and about 10 μm. As described above, the aerosol generator can provide an aerosol with a controlled particle size that includes an aerosol of a size for targeted delivery of the drug to the lungs. These aerosols offer a number of advantages for delivery of drugs to the deep lung. For example, mouth and throat adhesion is minimized while adhesion in the deep lung, especially when combined with breath holding, is maximized. Furthermore, by using liquid perfluorocarbon and / or hydrofluorocarbon, drugs with low solubility and / or low efficacy can be aerosolized by evaporation of liquid perfluorocarbon and / or hydrofluorocarbon.

  The operation of a preferred aerosol generator for delivering aerosolized medicament is as follows. First, a liquid formulation comprising liquid perfluorocarbon and / or hydrofluorocarbon and a drug is delivered to the heated capillary passage. The liquid evaporates in the capillary passage and exits from the outlet of the capillary passage as a vapor jet. The vapor jet carries the drug with it and forms a high concentration soft mist aerosol. As noted above, the application of heat to evaporate the liquid is typically accomplished by resistance heating from passing current through the heater. The applied power is adjusted to maximize the conversion of fluid to vapor.

  As will be appreciated, the aerosol generator is capable of controlled evaporation and aerosol formation of the drug formulation. The aerosol generator can provide immediate delivery of the aerosol to the patient, thereby avoiding a reduction in vital capacity that may be limited for the patient's health. The aerosol generator can also provide consistent delivery of controlled doses of the drug formulation to the patient. In addition, the aerosol generated by the aerosol generator is relatively unaffected by relative humidity and ambient temperature.

  The above-described exemplary schemes for implementing the invention are not intended to be limiting. It will be apparent to those skilled in the art that modifications thereto can be made without departing from the spirit and scope of the invention as set forth in the appended claims. For example, although a heated capillary tube has been described as a preferred structure for a capillary passage, the capillary passage is one or more passages in a laminate with a heater disposed along the passage (s), multiple Capillary tube arrangements, passages with heaters provided inside the passages, coaxial arrangements including annular passages for fluid flow, and the like can be included.

Claims (27)

  A propellant-free liquid aerosol generating formulation comprising at least one liquid perfluorocarbon and / or hydrofluorocarbon, at least one drug, and any at least one surfactant, the liquid perfluorocarbon and / or An aerosol generating formulation, wherein the hydrofluorocarbon is in a liquid state under ambient conditions.   Liquid perfluorocarbons include linear perfluoroalkanes, cyclic perfluoroalkanes, oxygen-containing perfluoroalkanes, nitrogen-containing perfluoroalkanes, or derivatives thereof, and liquid hydrofluorocarbons are liquid hydrofluoroalkanes, hydrofluoroalkenes, hydrofluoroethers The aerosol-generating preparation according to claim 1, further comprising a derivative thereof.   The surfactant stabilizes the drug in the formulation and includes at least one partly or completely comprising fluoroalcohol, fluoroolefin, fluoroalkyl acrylate, fluoroalkyl stearate, fluoroalkanoic acid, and / or fluoroalkyl citrate Characterized in that it comprises a fluorinated surfactant and / or the surfactant comprises at least one non-fluorinated surfactant such as phospholipids, polyalcohols, polyolefins, sorbitan esters, or mixtures thereof. The aerosol-generating preparation according to claim 1.   2. The aerosol generating formulation according to claim 1, wherein the liquid aerosol generating formulation comprises a solution, suspension or emulsion.   2. An aerosol generating formulation according to claim 1, wherein the suspension comprises up to about 20% by weight of drug and at least 80% by volume of liquid perfluorocarbon and / or hydrofluorocarbon.   The drug according to claim 1, wherein the drug comprises solid or liquid particles having a particle size of about 0.05 to about 10 μm, and the drug is optionally incorporated into a polymer matrix that is ground into the drug particles. Aerosol generating formulation. 7. The liquid perfluorocarbon and / or hydrofluorocarbon has a boiling point of at least about 40 ° C., a density of less than about 2 g / cm ³ and / or a vapor pressure of about 20 Torr to about 200 Torr. Aerosol-generating formulation.   The solution further comprises an organic solvent in an amount up to 20% by weight, wherein the organic solvent is ethanol, n-propyl alcohol, isopropyl alcohol, butanol, glycerin, ethylene glycol, diethylene glycol, propylene glycol, sorbitol, dipropylene glycol, tripropylene glycol, 2. The aerosol generating formulation according to claim 1, wherein the formulation is selected from short chain (C1-C6) alcohols containing hexylene glycol.   The aerosol-generating formulation according to claim 1, wherein the solution further comprises water in an amount up to 20% by weight.   A method for generating an aerosol, wherein a liquid aerosol generating formulation comprising at least one drug and at least one liquid perfluorocarbon and / or hydrofluorocarbon, wherein the liquid perfluorocarbon and / or hydrofluorocarbon is in a liquid state under ambient conditions Supplying to the flow path and heating the formulation in the flow path sufficient to evaporate the liquid perfluorocarbon and / or hydrofluorocarbon and form an aerosol containing the drug.   11. The method of claim 10, wherein the vaporized liquid perfluorocarbon and / or hydrofluorocarbon expands from the outlet of the flow path and the aerosol comprises drug particles having a MMAD of less than about 10 [mu] m.   11. The method of claim 10, wherein the formulation is free of propellant and further comprises at least one surfactant.   Liquid perfluorocarbons include linear perfluoroalkanes, cyclic perfluoroalkanes, oxygen-containing perfluoroalkanes, nitrogen-containing perfluoroalkanes, or derivatives thereof, and liquid hydrofluorocarbons are liquid hydrofluoroalkanes, hydrofluoroalkenes, hydrofluoroethers The method according to claim 10, further comprising a derivative thereof.   A surfactant stabilizes the drug in the formulation and at least one partially or fully fluorinated comprising fluoroalcohol, fluoroolefin, fluoroalkyl acrylate, fluoroalkyl stearate, fluoroalkanoic acid, and fluoroalkyl sylate And / or the surfactant comprises at least one non-fluorinated surfactant such as phospholipids, polyalcohols, polyolefins, sorbitan esters, or mixtures thereof. The method of claim 12.   11. The method of claim 10, wherein the liquid aerosol generating formulation comprises a solution, suspension or emulsion.   12. The method of claim 10, wherein the formulation comprises up to about 20% by weight drug and at least 80% by volume liquid perfluorocarbon and / or hydrofluorocarbon.   11. The drug of claim 10, wherein the drug comprises solid or liquid drug particles having a particle size of about 0.05 to about 10 μm, and the drug is optionally incorporated into a polymer matrix that is ground into the drug particles. The method described. 18. The liquid perfluorocarbon and / or hydrofluorocarbon has a boiling point of at least about 40 ° C., a density of less than about 2 g / cm ³ and / or a vapor pressure of about 20 torr to about 200 torr. Method.   11. The method of claim 10, wherein the flow passage is a capillary sized flow passage and the aerosol is formed in a mouthpiece of a hand-held inhaler.   The method for preparing an aerosol generating formulation according to claim 1, wherein a drug is mixed in the polymer matrix, and the drug matrix is formed by crushing the polymer matrix having the drug mixed therein, Forming the formulation as a liquid suspension by mixing with at least one liquid perfluorocarbon and / or hydrofluorocarbon. Aerosol generator:
A flow path adapted to receive a liquid aerosol generating formulation from a liquid source, wherein the liquid aerosol generating formulation comprises at least one liquid perfluorocarbon and / or hydrofluorocarbon and at least one drug;
A heater operable to heat the liquid formulation in at least a portion of the flow path sufficient to evaporate at least one liquid perfluorocarbon and / or hydrofluorocarbon to generate an aerosol containing the drug;
An aerosol generator comprising:   The aerosol generator of claim 21, wherein the aerosol generator includes a hand-held inhaler having a mouthpiece, and the flow path includes a capillary-sized flow path having an outlet in fluid communication with the interior of the mouthpiece.   The aerosol generator according to claim 21, wherein the heater is a resistance heater including a part of a metal capillary tube, and the flow path includes an inside of the metal capillary tube.   The aerosol generator has a power supply and handheld inhalation with control electronics that control the power supply to the heater as a function of the control parameters chosen to achieve boiling of the liquid perfluorocarbon and / or hydrofluorocarbon in the flow path The aerosol generator according to claim 21, further comprising a vessel.   The aerosol generator according to claim 21, wherein the liquid supply source includes a liquid reservoir containing a liquid preparation under a pressure of about atmospheric pressure or less.   The liquid formulation is a propellant-free solution, suspension or emulsion containing less than 20% by weight drug, more than 20% by volume liquid perfluorocarbon and / or hydrofluorocarbon, and up to 20% by weight surfactant. The aerosol generator according to claim 21.   The aerosol generator according to claim 21, wherein the aerosol generator is a hand-held inhaler having a valve mechanism for delivering a metered amount of liquid preparation to the flow path.