CA2370853C - Compositions for aerosolization and inhalation - Google Patents
Compositions for aerosolization and inhalation Download PDFInfo
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- CA2370853C CA2370853C CA002370853A CA2370853A CA2370853C CA 2370853 C CA2370853 C CA 2370853C CA 002370853 A CA002370853 A CA 002370853A CA 2370853 A CA2370853 A CA 2370853A CA 2370853 C CA2370853 C CA 2370853C
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- aerosol
- active ingredient
- aerosol device
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/02—Inhalators with activated or ionised fluids, e.g. electrohydrodynamic [EHD] or electrostatic devices; Ozone-inhalators with radioactive tagged particles
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
- B05B5/00—Electrostatic spraying apparatus; Spraying apparatus with means for charging the spray electrically; Apparatus for spraying liquids or other fluent materials by other electric means
- B05B5/025—Discharge apparatus, e.g. electrostatic spray guns
- B05B5/0255—Discharge apparatus, e.g. electrostatic spray guns spraying and depositing by electrostatic forces only
Abstract
A composition used in combination with an electrohydrodynamic device capable of delivering an active ingredient to the aerodigestive system of the user. The composition comprises three or optionally four basic components: an active ingredient;
a carrier material in which the active ingredient may be dissolved, suspended, or emulsified; an aerosol properties adjusting material which provides the composition with the physical characteristics required to create an aerosol cloud by electrostatic or electrohydro-dynamic means; and optionally at least one excipient that further adjusts, preserves, stabilizes, or enhances the overall performance of the composition.
a carrier material in which the active ingredient may be dissolved, suspended, or emulsified; an aerosol properties adjusting material which provides the composition with the physical characteristics required to create an aerosol cloud by electrostatic or electrohydro-dynamic means; and optionally at least one excipient that further adjusts, preserves, stabilizes, or enhances the overall performance of the composition.
Description
COMPOSTTIONS FOR AEROSOLIZATION AND INHALATION
BACKGROUND OF THE INVENTION
This invention relates to compositions for aerosolization and delivery to the user's aerodigestive system by inhalation of the aerosolized composition, as well methods for making and using these compositions.
Administration of active ingredients directly to the aerodigestive system (i.e., the pulmonary system and/or digestive tract) of a patient by means of an inhaled aerosol may be preferable to other methods of drug delivery in certain ckcu*~+Qtances.
Delivery of drugs or other active ingredients directly to the patient's lungs provides numerous advantages including: providing an extensive surface area for drug absorption, direct delivery of therapeutic agents to the disease site in the case of regional drug therapy, eliminating the possibility of drug degradation in the patient's intestinal tract (a risk associated with oral administration), and eliminating the need for repeated subcutaneous injections. Furthermore, delivery of drugs to the pulmonary system by means of aerosol inhalation may be used to deliver drugs systemically, as well as for targeted local drug delivery for treatment of respiratory ailments such as lung cancer or asthma.
At the present time, inhalation therapy is a rapidly evolving technology.
Numerous active ingredients are being developed with the expectation that effective delivery of and treatment with these agents will be possible by means of inhaled aerosols.
Aerosolizing active ingredients requires a composition with certain characteristics and properties that make the composition compatible with the aerosolization process_ The process of formulating particular active ingredients, such as drugs, with the appropriate carriers, such as organic solvents, can be particularly challenging.
Therefore, there is a need for basic or general Amended page 1 compositions which are compatible with a variety of active ingredients, a range of suitable carriers, and appropriate aerosol aeneratinQ devices.
lmportant considerations in administering an aerosolized active ingredient to the lungs of a patient include the cllaractei-istics of both the composition containing the active ingredient, and the aerosol cloud that will ultimately be inhaled by the patient or user. The composition must be a suitable carrier for the active ingredient, the active ingredient nlust be stable for a period of time in the composition, the composition nlust be consistently sprayable tllrough an aerosol-generating device, and the coinposition nlust be well-tolerated by the user.
io Furthermore, the aerosol-generating device itself must effectively and consistently convert the fornlula into an aerosol cloud with certain desired properties.
For exan-iple, an aerosol-generating device should not deliver a high velocity aerosol wllicll makes it difficult for the user to inhale aerosol particles. Preferred aerosol characteristics also include an aerosol cloud composed of particles that are roughly uniform in size. An aerosol cloud composed of unifonn particles of a predetennined size provides the most efficient and effective delivery of the therapeutic conlposition to the patient ol- user because the dosage that tlle patient receives can be nlore precisely conti-olled (i.e., unifonn particle size equals more precise delivery and dosage). Therefore, for nlaximum effectiveness of both drug and aerosol devicc, collsistellt gellel'atlOil OTUIIIfOllllly sized aerosol particles nlost occur each time the composition is aei-osolized with a particulai- device.
Aerosol devices currently used in the clinical context include nletered dose inhalers, dry powder inhalers, and nebulizers. Although effective at creating aerosols, these devices typically do not pernlit the device user to control eitller the particle size of the aerosol cloud to be inhaled, or the velocity of the aerosol delivered by the device. The particle size distribution of aerosols generated with these devices is usually too broad Or too varied to effectively and consistently deliver the conlposition to the deep lungs of the user. As a consequence, pulmonary administration of a active ingredient nlay be less tllan optimal when using metered dose inhalers, dry powder inhalers, or nebulizers due to deposition of the composition in the mouth or throat of the user or due to exhalation of the composition by the user.
BACKGROUND OF THE INVENTION
This invention relates to compositions for aerosolization and delivery to the user's aerodigestive system by inhalation of the aerosolized composition, as well methods for making and using these compositions.
Administration of active ingredients directly to the aerodigestive system (i.e., the pulmonary system and/or digestive tract) of a patient by means of an inhaled aerosol may be preferable to other methods of drug delivery in certain ckcu*~+Qtances.
Delivery of drugs or other active ingredients directly to the patient's lungs provides numerous advantages including: providing an extensive surface area for drug absorption, direct delivery of therapeutic agents to the disease site in the case of regional drug therapy, eliminating the possibility of drug degradation in the patient's intestinal tract (a risk associated with oral administration), and eliminating the need for repeated subcutaneous injections. Furthermore, delivery of drugs to the pulmonary system by means of aerosol inhalation may be used to deliver drugs systemically, as well as for targeted local drug delivery for treatment of respiratory ailments such as lung cancer or asthma.
At the present time, inhalation therapy is a rapidly evolving technology.
Numerous active ingredients are being developed with the expectation that effective delivery of and treatment with these agents will be possible by means of inhaled aerosols.
Aerosolizing active ingredients requires a composition with certain characteristics and properties that make the composition compatible with the aerosolization process_ The process of formulating particular active ingredients, such as drugs, with the appropriate carriers, such as organic solvents, can be particularly challenging.
Therefore, there is a need for basic or general Amended page 1 compositions which are compatible with a variety of active ingredients, a range of suitable carriers, and appropriate aerosol aeneratinQ devices.
lmportant considerations in administering an aerosolized active ingredient to the lungs of a patient include the cllaractei-istics of both the composition containing the active ingredient, and the aerosol cloud that will ultimately be inhaled by the patient or user. The composition must be a suitable carrier for the active ingredient, the active ingredient nlust be stable for a period of time in the composition, the composition nlust be consistently sprayable tllrough an aerosol-generating device, and the coinposition nlust be well-tolerated by the user.
io Furthermore, the aerosol-generating device itself must effectively and consistently convert the fornlula into an aerosol cloud with certain desired properties.
For exan-iple, an aerosol-generating device should not deliver a high velocity aerosol wllicll makes it difficult for the user to inhale aerosol particles. Preferred aerosol characteristics also include an aerosol cloud composed of particles that are roughly uniform in size. An aerosol cloud composed of unifonn particles of a predetennined size provides the most efficient and effective delivery of the therapeutic conlposition to the patient ol- user because the dosage that tlle patient receives can be nlore precisely conti-olled (i.e., unifonn particle size equals more precise delivery and dosage). Therefore, for nlaximum effectiveness of both drug and aerosol devicc, collsistellt gellel'atlOil OTUIIIfOllllly sized aerosol particles nlost occur each time the composition is aei-osolized with a particulai- device.
Aerosol devices currently used in the clinical context include nletered dose inhalers, dry powder inhalers, and nebulizers. Although effective at creating aerosols, these devices typically do not pernlit the device user to control eitller the particle size of the aerosol cloud to be inhaled, or the velocity of the aerosol delivered by the device. The particle size distribution of aerosols generated with these devices is usually too broad Or too varied to effectively and consistently deliver the conlposition to the deep lungs of the user. As a consequence, pulmonary administration of a active ingredient nlay be less tllan optimal when using metered dose inhalers, dry powder inhalers, or nebulizers due to deposition of the composition in the mouth or throat of the user or due to exhalation of the composition by the user.
WO 00/66206 pCT/US00/11799 U.S. Patent 4,829,996 to Noakes et al., and U.S. patent 5,707,352 to Sekins et al. both disclose forrrlulations suitable for use with aerosol devices;
however, these devices and fonnulas are suboptimal when compared with the perfonnance of electollydrodynamic (EHD) aerosol systenls. EHD aerosol generators are capable of generating aerosols in wllich pal-ticle size, ael-osol velocity, and the resultant deposition pattenis can be more precisely controlled. EHD aerosol generators, therefore, are ideal devices for use with therapeutic compositions tllat are to be delivered to the patient's pulmonary systenl by inhalation. Thus, there is a need for therapeutic compositions that are conlpatible with both a variety of active ingredients as well as electrostatic and EHD aerosol generating devices.
SUMMARY OF THE INVENTION
The present invention includes general compositions capable of: being aerosolized; inhaled by the user; delivering a predetennined dosage of a active ingredient to the lungs of the user; and wllich al-e optiniized for use witll an electrohydrodynanlic aerosol generator. These compositions may contain two or more basic components which nlay be present in a variety of combinations, concentrations, and ratios to one another.
In a preferred embodiment of the present invention, the general COl11pOSltiOn CO111PriSCS FOllr basic, or fUl1da111Clltal, conlhoncnts. The fil-st component is a active ingredient; examples of which include drugs, vaccines, and protCllls. The SCColld CO111pOI1Cilt oI tI1C tI1Cr1117CL1t1C C01111)OSitlOn is a carrier ]naterial in which the active ingredient may be dissolved, suspended, or enlulsified;
exanlples of which include water or alcollol. The tlllyd co111po11Cnt oCthe therapeutic composition is an aerosol properties adjusting material, which adjusts the physical properties of the liquid composition to be within ranges desil-ed fol-aerosolization with an electrostatic or electrohydrodynamic device. In some embodiments of the invention the carrier material may act as the property adjusting material so as to bring the composition within the desired ranges of physical or chemical properties. In such cases no additional third basic component is required.
The fourth optional component of the basic composition is at least one excipient that individually or in combination with other excipients preserves, stabilizes, or enhances the overall performance of the therapeutic conlposition. Examples of suitable excipients include ionic materials, surfactants, and antimicrobial agents.
Therefore, it is an object of the present invention is to provide a general base composition that includes a suitable carrier for a variety of active ingredients, and in which the active ingT-edients will be stable for an extended period of time.
Another object of the present invention is to provide a base composition which is compatible with electrostatic or electrobydrodynamic aerosol generating devices.
A further object of the present invention is to provide a liquid composition with a commercially reasonable shelf-life.
Further objects, advantages, and novel aspects of tliis invention will become apparent from a consideration of the subsequent detailed description.
DETAILED DESCRIPTION OF THE INVENTION
Broadly, the present invention provides compositions, and niethods for making and using conipositions, which have certain preferred characteristics and properties required for generating aerosols also having particular prefei-red characteristics. In a preferred embodiment of the present invention, the compositions are aerosolized witli an electrostatic or- electrohydrodynamic (EHD) aerosol genei-ating device. A typical embodiment of tliis invention includes a liquid composition having pi-edetennined physical and chemical properties wliich facilitate aei-osolization of the composition witli an EHD aei-osol device.
This liquid composition typically includes thi-ee or four basic components whicli are (i) an active ingredient; (ii) a liquid cari-iei- for the active ingi-edient;
(iii) an aerosol properties adjusting nlaterial; and optionally (iv) at least one excipient.
The combination of these components pi-ovides a tliei-apeutic composition liaving enhanced properties for delivery to a user by means of generating an inhalable aerosol.
Electrohydrodynamic Aerosols The therapeutic compositions of this invention must be compatible with an aerosol-generating device so that an aerosol cloud with certain preferred properties WO 00/66206 CA 02370853 2001-10-31 pCT/US00/11799 and characteristics is reproduced each time the device is used. Aerosols having uniformly-sized particles and uniform distribution patterns are desirable over aerosols that do not possess these characteristics because they exhibit more desirable deposition properties within the aerodigestive tract of the user (i.e., they have a higher respirable fraction). When used with conlpatible compositions, EHD
aerosol generating devices can be adjusted to create substantially mononiodal aerosols having particles more unifonn in size than aerosols generated by other devices or metliods.
Typical EHD devices include a spray nozzle in i7uid communication with a source of liquid to be aerosolized, at least one discharge electrode, a first voltage source for maintaining the spray nozzle at a negative (or positive) potential relative to the potential of the discharge electrode, and a second voltage source for maintaining the discharge electrode at a positive (or negative) potential relative to the potential of the spray nozzle. Most EHD devices create aerosols by causing a liquid to forni droplets that entei- a region of high electi-ic field strengtli. The electric field then imparts a net electi-ic charge to tliese droplets, and tliis net electric charge tends to remain on the surface of tlie droplet. The repelling force of the charge on the surface of the droplet balances against the surface tension of the liquid in the droplet, thereby causing the droplet to form a conc-like structure known as a Taylor Cone. In the tip of this cone-like sti-ucture, the electric force exerted on the surface of the d--oplet overcomes the surface tension of the liquid, thereby generating a streanl of liquid that dispeises into a many smaller droplets of roughly the same size. These smaller droplets fonn a mist which constitutes the aerosol cloud that the user ultimately inhales.
Physical Characteristics of Liquid Coinposition Liquid compositions that are compatible with EHD aerosol generating devices must have characteristics and properties that fall within certain parameters for the aerosol cloud to have the desired properties. In a preferred enlbodiment of the present invention, the most relevant physical characteristics of the composition include surface tension, electrical resistivity, and electrical pennittivity (dielectric constant). Additionally, viscosity of the composition can also be of importance in preparing liquid therapeutic compositions for use with electrostatic or EHD
devices.
Surface tension is a property possessed by liquid sul-faces whereby these surfaces behave as if covered by a thin elastic menlbrane in a state of tension.
Surface tension is a measure of the energy needed to increase the surface area of the liquid; therefore, liquids with a lower surface tension will aerosolize more easily than liquids with higher surface tension. Surface tension is measured by the force acting nonnally across unit length in the surface. The phenomenon of surface tension is due to unbalanced molecular cohesive forces near the surface of a liquid.
In a bl-oad cnlbodinlcnt of thc prescnt invcntion, thc sin-facc tcnsion of thc composition is typically within the range of about 10 to 72 milliNewtons/meter. In anotller elnbodiment of the present invention, the sui-face tension of the conlposition is typically within the rangc of about 15 to 45 milliNewtons/nleter. In a preferred enlbodiment of the present invention, the sul-face tension of the composition is typically within the range of about 20 to 35 milliNewtons/meter.
Electrical conductivity is the ability of a solution to tl-ansport electrical charge. The inverse of electrical conductivity is electl-ical 1-esistivity.
Thus, electrical resistivity is a measure of the ability of a material to resist the transport of electrical cun-ent, and is a property of a conductor, which gives the resistance in tCIll1S of the condllctor's dllllCllslollS. L1qLnd CO111l)OSItlO11S \Vltll 1'eslstivlty valUCS Of 10 to 100,000 ohm-meters can be aerosolized using EHD aerosol devices, provided that other relevant physical properties are within optimal operating paranieters.
Thus, in a broad enlbodiment of the present invention, the electrical resistivity of the composition is typically within the range of about 10 to 100,000 ohm-meters.
In another embodiment of the present ii-ivention, the electrical resistivity of the composition is typically within the range of about 50 to 10,000 ohm-meters. In a preferred embodiment of the present invention, the electrical resistivity of the liquid composition is typically within the range of about 200 to 2000 ohm-meters.
Electrical pennittivity is a measure of the polarizibility of a liquid, and is relevant in electrostatic spraying processes as it describes the increase in electrical field strength where a fluid is pl-esent. To aerosolize solvents with high pem7ittivity (e.g., water), a higher electrical field strength (voltage) is required. The WO 00/66206 CA 02370853 2001-10-31 pCT/US00/11799 permittivity of a liquid composition is not significantly affected by the addition of a small amount (less than 5%) of non-ionic excipients or solvents. In a broad embodiment of the present invention, the electrical permittivity of the composition is typically within the range of about 5 to 500. In another embodiment of the present invention, the electrical permittivity is typically within the range of about to 150. In a preferred embodiment of the present invention, the electrical pennittivity of the composition is typically witliin the i-ange of about 15 to 50.
Electrical pennittivity is a dimensionless value denoting the ration of the electrical permittivity of a liquid or material to that of a vacuum.
10 Viscosity is the measw-e of the resistance to fluid flow; tlius solutions that flow easily generally have lower viscosity. The viscosity of a liquid composition is not affected significantly by the addition of small aniounts of drug to the composition. However, the addition of certain suspending agents or very high concentrations of drugs can increase the viscosity of the liquid composition.
Viscosity may not be a key solvent parameter in aerosolization of the present invention, but it does affcct pai-ticle size distribution. Highly viscous materials tend to forn-- aerosols with morc dispei-se oi- bimodal disti-ibutions, and with particle sizes larger than desired for respirable aerosols.
Liquid compositions having physical properties within the optimal parameters disclosed above will aerosolize when used with most EHD devices. In the present invention, controlling the voltage delivered to the system to create the region of high electric field strength also controls the particle size of the aerosol cloud generated by an EHD device. In a broad embodiment of the present invention directed toward inlialation, the size of respirable aerosol particles is typically about 0.1 to 10.0 micrometers. Aerosol particles at the lower end of this range are required for delivery of the liquid composition to the deep lung, while aerosol particles at the upper end of this range are required for delivery of the composition to the proximal respiratory tract. For deposition of the composition in the central and peripheral areas of the lung, the preferred size of the aerosol particles is about 1.0 to 6.0 micrometers.
however, these devices and fonnulas are suboptimal when compared with the perfonnance of electollydrodynamic (EHD) aerosol systenls. EHD aerosol generators are capable of generating aerosols in wllich pal-ticle size, ael-osol velocity, and the resultant deposition pattenis can be more precisely controlled. EHD aerosol generators, therefore, are ideal devices for use with therapeutic compositions tllat are to be delivered to the patient's pulmonary systenl by inhalation. Thus, there is a need for therapeutic compositions that are conlpatible with both a variety of active ingredients as well as electrostatic and EHD aerosol generating devices.
SUMMARY OF THE INVENTION
The present invention includes general compositions capable of: being aerosolized; inhaled by the user; delivering a predetennined dosage of a active ingredient to the lungs of the user; and wllich al-e optiniized for use witll an electrohydrodynanlic aerosol generator. These compositions may contain two or more basic components which nlay be present in a variety of combinations, concentrations, and ratios to one another.
In a preferred embodiment of the present invention, the general COl11pOSltiOn CO111PriSCS FOllr basic, or fUl1da111Clltal, conlhoncnts. The fil-st component is a active ingredient; examples of which include drugs, vaccines, and protCllls. The SCColld CO111pOI1Cilt oI tI1C tI1Cr1117CL1t1C C01111)OSitlOn is a carrier ]naterial in which the active ingredient may be dissolved, suspended, or enlulsified;
exanlples of which include water or alcollol. The tlllyd co111po11Cnt oCthe therapeutic composition is an aerosol properties adjusting material, which adjusts the physical properties of the liquid composition to be within ranges desil-ed fol-aerosolization with an electrostatic or electrohydrodynamic device. In some embodiments of the invention the carrier material may act as the property adjusting material so as to bring the composition within the desired ranges of physical or chemical properties. In such cases no additional third basic component is required.
The fourth optional component of the basic composition is at least one excipient that individually or in combination with other excipients preserves, stabilizes, or enhances the overall performance of the therapeutic conlposition. Examples of suitable excipients include ionic materials, surfactants, and antimicrobial agents.
Therefore, it is an object of the present invention is to provide a general base composition that includes a suitable carrier for a variety of active ingredients, and in which the active ingT-edients will be stable for an extended period of time.
Another object of the present invention is to provide a base composition which is compatible with electrostatic or electrobydrodynamic aerosol generating devices.
A further object of the present invention is to provide a liquid composition with a commercially reasonable shelf-life.
Further objects, advantages, and novel aspects of tliis invention will become apparent from a consideration of the subsequent detailed description.
DETAILED DESCRIPTION OF THE INVENTION
Broadly, the present invention provides compositions, and niethods for making and using conipositions, which have certain preferred characteristics and properties required for generating aerosols also having particular prefei-red characteristics. In a preferred embodiment of the present invention, the compositions are aerosolized witli an electrostatic or- electrohydrodynamic (EHD) aerosol genei-ating device. A typical embodiment of tliis invention includes a liquid composition having pi-edetennined physical and chemical properties wliich facilitate aei-osolization of the composition witli an EHD aei-osol device.
This liquid composition typically includes thi-ee or four basic components whicli are (i) an active ingredient; (ii) a liquid cari-iei- for the active ingi-edient;
(iii) an aerosol properties adjusting nlaterial; and optionally (iv) at least one excipient.
The combination of these components pi-ovides a tliei-apeutic composition liaving enhanced properties for delivery to a user by means of generating an inhalable aerosol.
Electrohydrodynamic Aerosols The therapeutic compositions of this invention must be compatible with an aerosol-generating device so that an aerosol cloud with certain preferred properties WO 00/66206 CA 02370853 2001-10-31 pCT/US00/11799 and characteristics is reproduced each time the device is used. Aerosols having uniformly-sized particles and uniform distribution patterns are desirable over aerosols that do not possess these characteristics because they exhibit more desirable deposition properties within the aerodigestive tract of the user (i.e., they have a higher respirable fraction). When used with conlpatible compositions, EHD
aerosol generating devices can be adjusted to create substantially mononiodal aerosols having particles more unifonn in size than aerosols generated by other devices or metliods.
Typical EHD devices include a spray nozzle in i7uid communication with a source of liquid to be aerosolized, at least one discharge electrode, a first voltage source for maintaining the spray nozzle at a negative (or positive) potential relative to the potential of the discharge electrode, and a second voltage source for maintaining the discharge electrode at a positive (or negative) potential relative to the potential of the spray nozzle. Most EHD devices create aerosols by causing a liquid to forni droplets that entei- a region of high electi-ic field strengtli. The electric field then imparts a net electi-ic charge to tliese droplets, and tliis net electric charge tends to remain on the surface of tlie droplet. The repelling force of the charge on the surface of the droplet balances against the surface tension of the liquid in the droplet, thereby causing the droplet to form a conc-like structure known as a Taylor Cone. In the tip of this cone-like sti-ucture, the electric force exerted on the surface of the d--oplet overcomes the surface tension of the liquid, thereby generating a streanl of liquid that dispeises into a many smaller droplets of roughly the same size. These smaller droplets fonn a mist which constitutes the aerosol cloud that the user ultimately inhales.
Physical Characteristics of Liquid Coinposition Liquid compositions that are compatible with EHD aerosol generating devices must have characteristics and properties that fall within certain parameters for the aerosol cloud to have the desired properties. In a preferred enlbodiment of the present invention, the most relevant physical characteristics of the composition include surface tension, electrical resistivity, and electrical pennittivity (dielectric constant). Additionally, viscosity of the composition can also be of importance in preparing liquid therapeutic compositions for use with electrostatic or EHD
devices.
Surface tension is a property possessed by liquid sul-faces whereby these surfaces behave as if covered by a thin elastic menlbrane in a state of tension.
Surface tension is a measure of the energy needed to increase the surface area of the liquid; therefore, liquids with a lower surface tension will aerosolize more easily than liquids with higher surface tension. Surface tension is measured by the force acting nonnally across unit length in the surface. The phenomenon of surface tension is due to unbalanced molecular cohesive forces near the surface of a liquid.
In a bl-oad cnlbodinlcnt of thc prescnt invcntion, thc sin-facc tcnsion of thc composition is typically within the range of about 10 to 72 milliNewtons/meter. In anotller elnbodiment of the present invention, the sui-face tension of the conlposition is typically within the rangc of about 15 to 45 milliNewtons/nleter. In a preferred enlbodiment of the present invention, the sul-face tension of the composition is typically within the range of about 20 to 35 milliNewtons/meter.
Electrical conductivity is the ability of a solution to tl-ansport electrical charge. The inverse of electrical conductivity is electl-ical 1-esistivity.
Thus, electrical resistivity is a measure of the ability of a material to resist the transport of electrical cun-ent, and is a property of a conductor, which gives the resistance in tCIll1S of the condllctor's dllllCllslollS. L1qLnd CO111l)OSItlO11S \Vltll 1'eslstivlty valUCS Of 10 to 100,000 ohm-meters can be aerosolized using EHD aerosol devices, provided that other relevant physical properties are within optimal operating paranieters.
Thus, in a broad enlbodiment of the present invention, the electrical resistivity of the composition is typically within the range of about 10 to 100,000 ohm-meters.
In another embodiment of the present ii-ivention, the electrical resistivity of the composition is typically within the range of about 50 to 10,000 ohm-meters. In a preferred embodiment of the present invention, the electrical resistivity of the liquid composition is typically within the range of about 200 to 2000 ohm-meters.
Electrical pennittivity is a measure of the polarizibility of a liquid, and is relevant in electrostatic spraying processes as it describes the increase in electrical field strength where a fluid is pl-esent. To aerosolize solvents with high pem7ittivity (e.g., water), a higher electrical field strength (voltage) is required. The WO 00/66206 CA 02370853 2001-10-31 pCT/US00/11799 permittivity of a liquid composition is not significantly affected by the addition of a small amount (less than 5%) of non-ionic excipients or solvents. In a broad embodiment of the present invention, the electrical permittivity of the composition is typically within the range of about 5 to 500. In another embodiment of the present invention, the electrical permittivity is typically within the range of about to 150. In a preferred embodiment of the present invention, the electrical pennittivity of the composition is typically witliin the i-ange of about 15 to 50.
Electrical pennittivity is a dimensionless value denoting the ration of the electrical permittivity of a liquid or material to that of a vacuum.
10 Viscosity is the measw-e of the resistance to fluid flow; tlius solutions that flow easily generally have lower viscosity. The viscosity of a liquid composition is not affected significantly by the addition of small aniounts of drug to the composition. However, the addition of certain suspending agents or very high concentrations of drugs can increase the viscosity of the liquid composition.
Viscosity may not be a key solvent parameter in aerosolization of the present invention, but it does affcct pai-ticle size distribution. Highly viscous materials tend to forn-- aerosols with morc dispei-se oi- bimodal disti-ibutions, and with particle sizes larger than desired for respirable aerosols.
Liquid compositions having physical properties within the optimal parameters disclosed above will aerosolize when used with most EHD devices. In the present invention, controlling the voltage delivered to the system to create the region of high electric field strength also controls the particle size of the aerosol cloud generated by an EHD device. In a broad embodiment of the present invention directed toward inlialation, the size of respirable aerosol particles is typically about 0.1 to 10.0 micrometers. Aerosol particles at the lower end of this range are required for delivery of the liquid composition to the deep lung, while aerosol particles at the upper end of this range are required for delivery of the composition to the proximal respiratory tract. For deposition of the composition in the central and peripheral areas of the lung, the preferred size of the aerosol particles is about 1.0 to 6.0 micrometers.
Active Ingredieitt To benefit the user, the aerosolized liquid composition of the present invention contains at least one active ingredient at a concenti-ation permitting delivery of the desired dosage to the patient. The nunlber and types of active ingredients suitable for delivery to a patient by means of an inhaled aerosol varies widely and includes numerous options. A preferred enibodiment of the present invention typically includes at least one active inQredient which may be any of the following: small molecule and syntlietic drugs sucli as sodium cromoglycate, albuterol sulfate, and triamcinolone acetonide; chemo-therapeutic or l0 cliemopreventive agents such as paclitaxel and doxorubicin; vaccines;
nucleic acids, including DNA and RNA vectoi-s and vaccines; aptamers, proteins such as insulin; gene therapy agents for treating diseases such as cystic fibrosis;
enzyines, hormones; antibodies; vitamins; peptides and polypeptides; oligonucleotides;
cells;
antigens; allergens; pulmonary surfactant and otliei- surfactants (including synthetic surfactants); anti-infectious agents including antimicrobials, antibiotics, antifungals and antivirals; and pain management drugs such as narcotics.
Preferred initial concentrations of active ingredients in the composition are determined by the required effective dosage of each active ingredient, as well as the efficiency of the pulnionat-y delivery of the inhaled aerosol. Delivery efficiency and drug efficacy is typically impacted by the selected deposition site within the user's lung.
Carrier Material In the present invention, the composition to be aerosolized also provides a carrier in which the active ingredient may be dissolved, suspended or emulsified. A
variety of solvents or emulsifying agents are suitable for this purpose. In a typical embodiment of the present invention, eithei- water or etlianol (depending on the solubility characteristics of the active ingredient) is used as the solvent in which the active ingredient may be dissolved or suspended. In a prefeiTed embodiment, the carrier (solvent) fraction of the composition may represent 5 to 95% of the total volume of the composition. In other embodiments, the fraction of the composition represented by the carrier varies depending on the solubility or insolubility of the active ingredient. For example, if a active ingredient is highly soluble in the can-ier (e.g. water), tlien the cai-rier fraction of the total composition may be as low as about 5'Yo to 10%. 1 f an active ingi-cclicnt is only moclcratc:ly solublc in watcr, a larger fraction of water may be i-equired to completely dissolve or sufficiently suspend the actlvC Ill-fcdlcllt.
The pl-1 ol'desired solvent, as .vcll as the pH of the entire composition, may impact the solubility and stability of the active ingredient. Although pH
requirements ai-e likely to differ among specific compositions depending on the active ingredient being used, pH ranges useful in the present invention for the t0 liquid carriei- niay be in the range of pH about 2 to 9. Pi-efcrably, a pH
range of about 3 to 8 is used, and most preferably a pH range of about 5 to 8 is used.
In a preferred embodinlent of the present invention, the solvents selected as carriers are chosen for use as carriers based both on compatibility with certain active ingredients and on their compatibility with EHD devices, and typically include water or ethanol. In an alternative embodiment, phospholipids or pulmonary surfactant is used as a carrier. In still another enibodiment, other alcohols such as isopropanol are employed as carriers. In otlier embodiments of the present invention, perfluoronated compounds such as perfluorooctanol and perfluorodecalin are substituted for some or all of the water or ethanol as the carrier material. Such perfluoronated compounds are useful as alternative carriers for drugs soluble in perfluoronated carriers, micro-suspended medicaments or emulsif ed mixtures of such pharmaceutical products in water.
Aerosol Properties Adjustin- Material Certain physical properties of a liquid composition are critical in enhancing the effectiveness of aerosolization of the composition with an electrostactic or EHD device. Therefore, in the present invention, an aerosol properties adjusting material that provides the desired physical characteristics to the composition represents another possible fraction of the total volume of the liquid composition.
In a broad embodiment of this invention, the physical properties of the liquid composition typically comprise: (i) a surface tension of about 10 to 72 milliNewtons/meter; (ii) an electrical resistivity of about 5 to 100,000 ohm-meters;
nucleic acids, including DNA and RNA vectoi-s and vaccines; aptamers, proteins such as insulin; gene therapy agents for treating diseases such as cystic fibrosis;
enzyines, hormones; antibodies; vitamins; peptides and polypeptides; oligonucleotides;
cells;
antigens; allergens; pulmonary surfactant and otliei- surfactants (including synthetic surfactants); anti-infectious agents including antimicrobials, antibiotics, antifungals and antivirals; and pain management drugs such as narcotics.
Preferred initial concentrations of active ingredients in the composition are determined by the required effective dosage of each active ingredient, as well as the efficiency of the pulnionat-y delivery of the inhaled aerosol. Delivery efficiency and drug efficacy is typically impacted by the selected deposition site within the user's lung.
Carrier Material In the present invention, the composition to be aerosolized also provides a carrier in which the active ingredient may be dissolved, suspended or emulsified. A
variety of solvents or emulsifying agents are suitable for this purpose. In a typical embodiment of the present invention, eithei- water or etlianol (depending on the solubility characteristics of the active ingredient) is used as the solvent in which the active ingredient may be dissolved or suspended. In a prefeiTed embodiment, the carrier (solvent) fraction of the composition may represent 5 to 95% of the total volume of the composition. In other embodiments, the fraction of the composition represented by the carrier varies depending on the solubility or insolubility of the active ingredient. For example, if a active ingredient is highly soluble in the can-ier (e.g. water), tlien the cai-rier fraction of the total composition may be as low as about 5'Yo to 10%. 1 f an active ingi-cclicnt is only moclcratc:ly solublc in watcr, a larger fraction of water may be i-equired to completely dissolve or sufficiently suspend the actlvC Ill-fcdlcllt.
The pl-1 ol'desired solvent, as .vcll as the pH of the entire composition, may impact the solubility and stability of the active ingredient. Although pH
requirements ai-e likely to differ among specific compositions depending on the active ingredient being used, pH ranges useful in the present invention for the t0 liquid carriei- niay be in the range of pH about 2 to 9. Pi-efcrably, a pH
range of about 3 to 8 is used, and most preferably a pH range of about 5 to 8 is used.
In a preferred embodinlent of the present invention, the solvents selected as carriers are chosen for use as carriers based both on compatibility with certain active ingredients and on their compatibility with EHD devices, and typically include water or ethanol. In an alternative embodiment, phospholipids or pulmonary surfactant is used as a carrier. In still another enibodiment, other alcohols such as isopropanol are employed as carriers. In otlier embodiments of the present invention, perfluoronated compounds such as perfluorooctanol and perfluorodecalin are substituted for some or all of the water or ethanol as the carrier material. Such perfluoronated compounds are useful as alternative carriers for drugs soluble in perfluoronated carriers, micro-suspended medicaments or emulsif ed mixtures of such pharmaceutical products in water.
Aerosol Properties Adjustin- Material Certain physical properties of a liquid composition are critical in enhancing the effectiveness of aerosolization of the composition with an electrostactic or EHD device. Therefore, in the present invention, an aerosol properties adjusting material that provides the desired physical characteristics to the composition represents another possible fraction of the total volume of the liquid composition.
In a broad embodiment of this invention, the physical properties of the liquid composition typically comprise: (i) a surface tension of about 10 to 72 milliNewtons/meter; (ii) an electrical resistivity of about 5 to 100,000 ohm-meters;
and (iii) and an electrical permittivity of about 5 to 500. In some embodiments, it may be possible to achieve a liquid composition with pliysical properties falling within these parameters by simply combining the active ingredient and the carrier matcl-ial. 1-lowcvc--, if tlic combination of tlic active in~rcdicnt and the cal-l-icl-material does not produce a liquid composition having physical properties falling witliin tliese parameters, the addition of tllc acrosol 1)rol)crtlcs adjusting matcrlal will bring the composition within the required parameters.
In a prefel-red embodiment of the invention, the aerosol pl-operties adjusting material is pl-escnt as about a 5 to 90% fraction of the total volume of thc composition. The volumc of thc acrosol propcl-tics adjusting material fi-action will vary depending on the volume of the carrier that is required. For example, if the carrier represents 20% of the total volume of the composition, the aerosol properties adjusting material could represent the remaining 80% of the total volume. The 20/80 volume ratio can apply even with the active ingredient present because the active ingredient is dissolved in the carrier and/or aerosol property adjusting material. In some instances, the can=ier itself may selve as the aerosol properties adjusting material.
In a preferred embodiment of the present invention, the aerosol properties adjusting material may be at least one of the following materials or their derivatives; ethanol or otlier alcohols; propylene glycol; polyethylene glycol;
glycerol; oleic acid; medium chain triglycerides; fatty acids; soybean oil;
olive oil;
phospholipids, and perfluorocarbons. Combinations of these materials is advantageous in some enlbodiments. For example, the use of ethanol alone may create an aerosol, but the particle size of the aerosol may be below the preferred range. By combining ethanol and polyethylene glycol in a predetei-mined ratio to one another, the prefei-red particle size can be achieved. In one embodiment of the present invention, the aerosol enhancing component comprises 80% ethanol and 10% polyethylene glycol for a fraction representing 90% of the total volume of the liquid composition.
Excipient As discusscd, there are acceptablc rangcs of solvent pai-ameters that permit a liquid composition to be aerosolized by the electi-ohydrodynamic process.
Due to the characteristics of certain active ingredients (e.g., ionic, solubility limits, etc.) it may be dif(icult to formulatc a drul.' at dcsircd conccntrations in an appropriate carrier solvent while remaining within the required solvent parameter values.
The addition of an excipient can alter a solvent parametei- and bring the composition back within the optimal ranges. Addition of an excipient is necessary only in embodiments of the present invention in which the combined active ingredient, lo carrier material, and aerosol properties adjusting material do not yield an aerosol with all of the desii-ed characteristics.
Various embodiment of the present invention include at least one excipient or a combination of excipients. A broad de[inition of an excipient is anything in a composition other than an active ingredient. In the more narrow context -of the present invention, an excipient is added for a variety of purposes including:
stabilization of the liquid composition; facilitating control of aerosol particle size;
increasing the solubility of the active ingredient in the composition; and lowering the surface tension of the liquid.
Once solubilized, suspended or emulsified, the active ingredient must also be stable in the carrier itself, and stable in the final composition.
Stability requires that the active ingredient not lose activity pi-ior to aerosolization (i.e.
retains a reasonable shelf-life), and that the active ingredient not lose activity or degrade significantly as a result of the process of aerosolization. Furthermore, the complete composition must itself be stable over time. In various embodiments, stability issues can be addressed by the addition of a stabilizing excipient to the composition.
In a preferred embodiment of the present invention, at least one of the following excipients is added to increase physical stability of the composition: oils, glycerides, polysorbates, celluloses lecithin, polyvinyl pyrrolidone, polyethyl glycol, saccharide gums, and alginates; while ascorbic acid, citric acid, cyclodextrin, tocopherols or other antioxidants are added to increase chemical stability. In another enibodiment of the present invention, chelating or complexing agents such as citl-ic acid, cyclodextrins, and etliylenediaminetetracetic acid may be added to stabilize drug conlpositions and to increase the solubility of the active ingredient in the composition.
In Otller C111bOd1111C11tS, a11t10x1dalltS Sllch as ascorbic acid and aSCOrb1C
acid esters, Vitaniin E, tocopherols, butylated hydroxyanisole, and butylated hydroxytoluene are added to reduce degradation of a drug composition caused by oxidation.
An excipient may also be added as a preservative to maintain the nlicrobial integrity of the therapeutic composition. In one enzbodiment of the present invention, at least one of the following excipients is added to preserve compositions against microbial contamination or attack: benzalkonium chlorides, phenol, parabens, or any other acceptable antimicrobial or antifungal agent.
By further adjusting physical properties, the addition of excipients may also enhance the overall perfo>.-mance of the composition in tenns of the quality of aerosol produced by an EHD device. In one embodiment of the present invention all IOIIIC COllll)Olllld (e.g., S.11t) SIICh aS SOdllllll ClllOrlde, Sodiulll IICCtatC, benzalkonium chloride, or lecithin, is added to further adjust electrical resistivity, thereby facilitating control of aerosol particle size.
In another embodiment of the present invention, surfactants such as lecithin, polysorbates, poloaxamers, sorbitan esters, glycerides, ethoxylated alcohols, ethoxylated phenols, and ethylene oxide-propylene oxide copolymers are added to lower the surface tension of the liquid. In a preferred embodiment, non-ionic ethoxlyated decyl alcohol (Desonic DA-4) having hydrophilic-lipophilic balance (HLB) of about 10.5 is added to higllly aqueous compositions to enhance the dispersion characteristics of the composition. The present invention contemplates the use of both pulmonary surfactant and other natural or synthetic surfactants.
In another embodiment of the present invention, suspending agents such as celluloses, polyvinyl pyrrolidone (povidone or PVP), polyvinyl alcohol (PVA), triglycerides, ethoxylated oils, polyethyl glycol, saccharide gums, and alginates may be added to facilitate suspension of particles, or creation of an emulsion, in a liquid composition.
In a prefel-red embodiment of the invention, the aerosol pl-operties adjusting material is pl-escnt as about a 5 to 90% fraction of the total volume of thc composition. The volumc of thc acrosol propcl-tics adjusting material fi-action will vary depending on the volume of the carrier that is required. For example, if the carrier represents 20% of the total volume of the composition, the aerosol properties adjusting material could represent the remaining 80% of the total volume. The 20/80 volume ratio can apply even with the active ingredient present because the active ingredient is dissolved in the carrier and/or aerosol property adjusting material. In some instances, the can=ier itself may selve as the aerosol properties adjusting material.
In a preferred embodiment of the present invention, the aerosol properties adjusting material may be at least one of the following materials or their derivatives; ethanol or otlier alcohols; propylene glycol; polyethylene glycol;
glycerol; oleic acid; medium chain triglycerides; fatty acids; soybean oil;
olive oil;
phospholipids, and perfluorocarbons. Combinations of these materials is advantageous in some enlbodiments. For example, the use of ethanol alone may create an aerosol, but the particle size of the aerosol may be below the preferred range. By combining ethanol and polyethylene glycol in a predetei-mined ratio to one another, the prefei-red particle size can be achieved. In one embodiment of the present invention, the aerosol enhancing component comprises 80% ethanol and 10% polyethylene glycol for a fraction representing 90% of the total volume of the liquid composition.
Excipient As discusscd, there are acceptablc rangcs of solvent pai-ameters that permit a liquid composition to be aerosolized by the electi-ohydrodynamic process.
Due to the characteristics of certain active ingredients (e.g., ionic, solubility limits, etc.) it may be dif(icult to formulatc a drul.' at dcsircd conccntrations in an appropriate carrier solvent while remaining within the required solvent parameter values.
The addition of an excipient can alter a solvent parametei- and bring the composition back within the optimal ranges. Addition of an excipient is necessary only in embodiments of the present invention in which the combined active ingredient, lo carrier material, and aerosol properties adjusting material do not yield an aerosol with all of the desii-ed characteristics.
Various embodiment of the present invention include at least one excipient or a combination of excipients. A broad de[inition of an excipient is anything in a composition other than an active ingredient. In the more narrow context -of the present invention, an excipient is added for a variety of purposes including:
stabilization of the liquid composition; facilitating control of aerosol particle size;
increasing the solubility of the active ingredient in the composition; and lowering the surface tension of the liquid.
Once solubilized, suspended or emulsified, the active ingredient must also be stable in the carrier itself, and stable in the final composition.
Stability requires that the active ingredient not lose activity pi-ior to aerosolization (i.e.
retains a reasonable shelf-life), and that the active ingredient not lose activity or degrade significantly as a result of the process of aerosolization. Furthermore, the complete composition must itself be stable over time. In various embodiments, stability issues can be addressed by the addition of a stabilizing excipient to the composition.
In a preferred embodiment of the present invention, at least one of the following excipients is added to increase physical stability of the composition: oils, glycerides, polysorbates, celluloses lecithin, polyvinyl pyrrolidone, polyethyl glycol, saccharide gums, and alginates; while ascorbic acid, citric acid, cyclodextrin, tocopherols or other antioxidants are added to increase chemical stability. In another enibodiment of the present invention, chelating or complexing agents such as citl-ic acid, cyclodextrins, and etliylenediaminetetracetic acid may be added to stabilize drug conlpositions and to increase the solubility of the active ingredient in the composition.
In Otller C111bOd1111C11tS, a11t10x1dalltS Sllch as ascorbic acid and aSCOrb1C
acid esters, Vitaniin E, tocopherols, butylated hydroxyanisole, and butylated hydroxytoluene are added to reduce degradation of a drug composition caused by oxidation.
An excipient may also be added as a preservative to maintain the nlicrobial integrity of the therapeutic composition. In one enzbodiment of the present invention, at least one of the following excipients is added to preserve compositions against microbial contamination or attack: benzalkonium chlorides, phenol, parabens, or any other acceptable antimicrobial or antifungal agent.
By further adjusting physical properties, the addition of excipients may also enhance the overall perfo>.-mance of the composition in tenns of the quality of aerosol produced by an EHD device. In one embodiment of the present invention all IOIIIC COllll)Olllld (e.g., S.11t) SIICh aS SOdllllll ClllOrlde, Sodiulll IICCtatC, benzalkonium chloride, or lecithin, is added to further adjust electrical resistivity, thereby facilitating control of aerosol particle size.
In another embodiment of the present invention, surfactants such as lecithin, polysorbates, poloaxamers, sorbitan esters, glycerides, ethoxylated alcohols, ethoxylated phenols, and ethylene oxide-propylene oxide copolymers are added to lower the surface tension of the liquid. In a preferred embodiment, non-ionic ethoxlyated decyl alcohol (Desonic DA-4) having hydrophilic-lipophilic balance (HLB) of about 10.5 is added to higllly aqueous compositions to enhance the dispersion characteristics of the composition. The present invention contemplates the use of both pulmonary surfactant and other natural or synthetic surfactants.
In another embodiment of the present invention, suspending agents such as celluloses, polyvinyl pyrrolidone (povidone or PVP), polyvinyl alcohol (PVA), triglycerides, ethoxylated oils, polyethyl glycol, saccharide gums, and alginates may be added to facilitate suspension of particles, or creation of an emulsion, in a liquid composition.
In still another enibodlment of the prCSent Inventlon, ad)Llvants suell as clove oil, citric acid, caffeine, vaccine adjuvants such as alLUn, polymers, macroniolecules, and oligonuclcotides arc added to provide enhanced synergistic efficacy effect between the active ingredient and the excipient.
Excipients may also be added to enhance or increase the patient's ability to receive the aerosolized composition. For example, in one embodiment of the present invention, sugars, including sucrose, trehalose, and mannitol, are added either to stabilize compositions containing proteins, or to serve as sweeteners to improve the taste of the composition. In other embodiments, flavoring agents such lo as sugars, oils, citric acid, menthol, and camphor are added to improve the flavor of a composition.
Examples The following examples of possible liquid compositions for aerosolization with an electroliydrodynaniic device are meant to be illustrative of the invention, and are not meant to limit the filll bl-eadtli of the invention disclosed herein.
Aerosol Composition 1: Paclitaxel (drug).
75 mg/ml paclitaxel in 80% ethanol; 19.8% polyethylene glycol; 0.2% citric acid.
Aerosol Composition 2: Sodium Cromoglycate (drug) 1% solution of sodium cromoglycate; 50% ethanol; 49% propylene glycol.
Aerosol Composition 3: Albuterol Sulfate (drug) 0.25% solution of albuterol sulfate; 70% ethanol; 29.75% water.
Aerosol Composition 4: Triamcinolone Acetonide (drug) 1% solution of triamcinolone acetonide; 70% ethanol; 29% glycerol.
While the above description discloses specific composition ingredients, ranges, and other specificities, these should not be construed as limitations on the scope of the invention, but ratller as exel,iplification of typical embodiments thereof. Numerous other variations are possible, and it is not intended herein to mention all of the possible equivalcnt foi-ms oi- ramifications of the invention.
Various changes may be made to the present invention without departino, from the scope of the invention.
Excipients may also be added to enhance or increase the patient's ability to receive the aerosolized composition. For example, in one embodiment of the present invention, sugars, including sucrose, trehalose, and mannitol, are added either to stabilize compositions containing proteins, or to serve as sweeteners to improve the taste of the composition. In other embodiments, flavoring agents such lo as sugars, oils, citric acid, menthol, and camphor are added to improve the flavor of a composition.
Examples The following examples of possible liquid compositions for aerosolization with an electroliydrodynaniic device are meant to be illustrative of the invention, and are not meant to limit the filll bl-eadtli of the invention disclosed herein.
Aerosol Composition 1: Paclitaxel (drug).
75 mg/ml paclitaxel in 80% ethanol; 19.8% polyethylene glycol; 0.2% citric acid.
Aerosol Composition 2: Sodium Cromoglycate (drug) 1% solution of sodium cromoglycate; 50% ethanol; 49% propylene glycol.
Aerosol Composition 3: Albuterol Sulfate (drug) 0.25% solution of albuterol sulfate; 70% ethanol; 29.75% water.
Aerosol Composition 4: Triamcinolone Acetonide (drug) 1% solution of triamcinolone acetonide; 70% ethanol; 29% glycerol.
While the above description discloses specific composition ingredients, ranges, and other specificities, these should not be construed as limitations on the scope of the invention, but ratller as exel,iplification of typical embodiments thereof. Numerous other variations are possible, and it is not intended herein to mention all of the possible equivalcnt foi-ms oi- ramifications of the invention.
Various changes may be made to the present invention without departino, from the scope of the invention.
Claims (22)
1. An aerosol device comprising:
a composition comprising (a) an active ingredient; and (b) a carrier material in which said active ingredient is dissolved, emulsified, or suspended, said solution, emulsification, or suspension being within a predetermined range of properties comprising a surface tension of about 10 to about 72 milliNewtons/meter, an electrical resistivity of about 10 to about 100,000 ohm-meters, and an electrical permittivity of about 5 to about 500; and means for generating said aerosol, wherein said means consists of an electrostatic device or an electrohydrodynamic device.
a composition comprising (a) an active ingredient; and (b) a carrier material in which said active ingredient is dissolved, emulsified, or suspended, said solution, emulsification, or suspension being within a predetermined range of properties comprising a surface tension of about 10 to about 72 milliNewtons/meter, an electrical resistivity of about 10 to about 100,000 ohm-meters, and an electrical permittivity of about 5 to about 500; and means for generating said aerosol, wherein said means consists of an electrostatic device or an electrohydrodynamic device.
2. An aerosol device comprising:
a composition comprising a combination of (a) an active ingredient; (b) a carrier material in which said active ingredient is dissolved, emulsified, or suspended;
and (c) an aerosol properties adjusting material that when added to the combination of said active ingredient and said carrier, adjusts the properties of said composition to be within a desired range, wherein said desired range of said properties comprises a surface tension of about 10 to about 72 milliNewtons/meter, an electrical resistivity of about 10 to about 100,000 ohmmeters, and an electrical permittivity of about 5 to about 500; and means for generating said aerosol, wherein said means consists of an electrostatic device or an electrohydrodynamic device.
a composition comprising a combination of (a) an active ingredient; (b) a carrier material in which said active ingredient is dissolved, emulsified, or suspended;
and (c) an aerosol properties adjusting material that when added to the combination of said active ingredient and said carrier, adjusts the properties of said composition to be within a desired range, wherein said desired range of said properties comprises a surface tension of about 10 to about 72 milliNewtons/meter, an electrical resistivity of about 10 to about 100,000 ohmmeters, and an electrical permittivity of about 5 to about 500; and means for generating said aerosol, wherein said means consists of an electrostatic device or an electrohydrodynamic device.
3. The aerosol device of claim 2 wherein the composition further comprises a ionic compound for adjusting electrical properties of said composition, wherein said ionic compound is selected from the group consisting of sodium chloride, sodium acetate, benzalkonium chloride, and lecithin.
Twice amended page15
Twice amended page15
4. The aerosol device of claim 2 wherein the composition further comprises sugar for sweetening said composition.
5. The aerosol device of claim 2 wherein the composition further comprises a chelating agent for stabilizing said dissolved, suspended, or emulsified active ingredient, wherein said chelating agent is selected from the group consisting of citric acid, cyclodextrins, and ethylenediaminetetracetic acid.
6. The aerosol device of claim 2 wherein the composition further comprises a surfactant for further adjusting said surface tension, wherein said surfactant is selected from the group consisting of lecithin, polysorbates, poloaxamers, sorbitan esters, glycerides, ethoxylated alcohols, ethoxylated phenols, ethylene oxide-propylene oxide copolymers, and pulmonary surfactant.
7. The aerosol device of claim 6 wherein said surfactant is non-ionic ethoxylated decyl alcohol having a hydrophilic-lipophilic balance of substantially 10.5.
8. The aerosol device of claim 2 wherein the composition further comprises a stabilizing agent for increasing the physical stability of said composition, wherein said stabilizing agent is selected from the group consisting of oils, glycerides, polysorbates, celluloses, lecithin, polyvinyl pyrrolidone, polyethyl glycol, saccharide gums, and alginates.
9. The aerosol device of claim 2 wherein the composition further comprises a stabilizing agent for increasing the chemical stability of said composition, wherein said stabilizing agent is selected from the group consisting of ascorbic acid, citric acid, cyclodextrin, and tocopherols.
10. The aerosol device of claim 2 wherein the composition further comprises a suspending agent for facilitating the suspension or emulsification of said active page 16 ingredient, wherein said suspending agent is selected from the group consisting of celluloses, triglycerides, ethoxylated oils, polyvinyl pyrrolidone, polyvinyl alcohol, polyethyl glycol, saccharide gums, and alginates.
11. The aerosol device of claim 2 wherein the composition further comprises a preservative to inhibit microbial growth in said composition.
12. The aerosol device of claim 2 wherein the composition further comprises an antioxidant for reducing oxidative degradation of said active ingredient in said composition, wherein said antioxidant is selected from the group consisting of ascorbic acid, tocopherols, butylated hydroxyanisole, and butylated hydroxytoluene.
13. The aerosol device of claim 2 wherein the composition further comprises an adjuvant selected from the group consisting of clove oil, citric acid, alum, caffeine, vaccine adjuvants, polymers, macromolecules, and oligonucleotides and combinations thereof.
14. The aerosol device of claim 2 wherein the composition further comprises a flavoring agent for improving the taste of said composition, wherein said flavoring agent is selected from the group consisting of sugars, oils, citric acid, menthol, and camphor.
15. The aerosol device of claim 2, wherein said surface tension of said composition is about 15 to about 45 milliNewtons/meter, said electrical resistivity of said composition is about 50 to about 10,000 ohnrmeters, and said electrical permittivity of said composition is about 10 to about 150.
16. The aerosol device of claim 2, wherein said surface tension of said composition is about 20 to about 35 milliNewtons/meter, said electrical resistivity of said Twice amended pagel7 composition is about 200 to about 2000 ohm-meters, and said electrical permittivity of said composition is about 15 to about 50.
17. The aerosol device of claim 2, wherein said aerosol created by said electrohydrodynamic means has a substantially uniform particle size of about 0.1 to about 10 m.
18. The aerosol device of claim 2, wherein said active ingredient is selected from the group consisting of drugs, chemotherapeutic ingredients, chemopreventive agents, vaccines, nucleic acids, aptamers, proteins, gene therapy agents, enzymes, hormones, antibodies, vitamins, peptides, polypeptides, oligonucleotides, antigens, allergens, natural surfactants, and synthetic surfactants.
19. The aerosol device of claim 2, wherein said carrier material is a solvent selected from the group consisting of water, alcohols, phospholipids, pulmonary surfactant, and perfluoronated compounds.
20. The aerosol device of claim 2, wherein said aerosol properties adjusting material is a solvent selected from the group consisting of ethanol, propylene glycol, polyethylene glycol, glycerol, oleic acid, medium chain triglycerides, fatty acids, soybean oil, olive oil, phospholipids, and perfluorocarbons.
21. A method of making and aerosolizing a composition, comprising:
(a) combining an active ingredient and a carrier material to form a solution, suspension, or emulsification;
(b) combining said solution, suspension, or emulsification with an aerosol properties adjusting material to create a composition with a surface tension of about 10 to about 72 milliNewtons/meter, electrical resistivity of about 5 to about 100,000 ohm-meters, and electrical permittivity of about 5 to about 500;
(c) placing said composition in an aerosol generating device; and (d) generating an aerosol by electrohydrodynamic means.
Twice amended page 18
(a) combining an active ingredient and a carrier material to form a solution, suspension, or emulsification;
(b) combining said solution, suspension, or emulsification with an aerosol properties adjusting material to create a composition with a surface tension of about 10 to about 72 milliNewtons/meter, electrical resistivity of about 5 to about 100,000 ohm-meters, and electrical permittivity of about 5 to about 500;
(c) placing said composition in an aerosol generating device; and (d) generating an aerosol by electrohydrodynamic means.
Twice amended page 18
22. An aerosol generating device, comprising:
(a) a spray nozzle maintained in fluid communication with a source of fluid to be aerosolized, (b) a fluid to be aerosolized in said source of fluid, wherein said fluid is a composition comprising a active ingredient solubilized, suspended, or emulsified in a carrier material; and an aerosol properties adjusting material for adjusting the physical properties of said composition to be within a desired range comprising a surface tension of about 10 to about 72 milliNewtons/meter, an electrical resistivity of about 5 to about 100,000 ohnuneters, and an electrical permittivity of about 5 to about 500; and (c) electrohydrodynamic means for generating said aerosol, wherein said electrohydrodynamic means comprises at least one discharge electrode located near said spray nozzle; a first voltage source maintaining said spray nozzle at a negative potential relative to the potential of said discharge electrode; and a second voltage source for maintaining said discharge electrode at a positive potential relative to the potential of said spray nozzle.
page19
(a) a spray nozzle maintained in fluid communication with a source of fluid to be aerosolized, (b) a fluid to be aerosolized in said source of fluid, wherein said fluid is a composition comprising a active ingredient solubilized, suspended, or emulsified in a carrier material; and an aerosol properties adjusting material for adjusting the physical properties of said composition to be within a desired range comprising a surface tension of about 10 to about 72 milliNewtons/meter, an electrical resistivity of about 5 to about 100,000 ohnuneters, and an electrical permittivity of about 5 to about 500; and (c) electrohydrodynamic means for generating said aerosol, wherein said electrohydrodynamic means comprises at least one discharge electrode located near said spray nozzle; a first voltage source maintaining said spray nozzle at a negative potential relative to the potential of said discharge electrode; and a second voltage source for maintaining said discharge electrode at a positive potential relative to the potential of said spray nozzle.
page19
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13221599P | 1999-05-03 | 1999-05-03 | |
| US60/132,215 | 1999-05-03 | ||
| USUNKNOWN | 1999-06-07 | ||
| PCT/US2000/011799 WO2000066206A2 (en) | 1999-05-03 | 2000-05-02 | Compositions for aerosolization and inhalation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2370853A1 CA2370853A1 (en) | 2000-11-09 |
| CA2370853C true CA2370853C (en) | 2007-07-10 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002370853A Expired - Fee Related CA2370853C (en) | 1999-05-03 | 2000-05-02 | Compositions for aerosolization and inhalation |
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| Country | Link |
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| US (1) | US6503481B1 (en) |
| EP (1) | EP1173245B1 (en) |
| JP (1) | JP2002543165A (en) |
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| AU (1) | AU4979700A (en) |
| BR (1) | BR0010262A (en) |
| CA (1) | CA2370853C (en) |
| DE (1) | DE60013425T2 (en) |
| ES (1) | ES2226843T3 (en) |
| MX (1) | MXPA01011283A (en) |
| WO (1) | WO2000066206A2 (en) |
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-
2000
- 2000-05-02 BR BR0010262-8A patent/BR0010262A/en not_active IP Right Cessation
- 2000-05-02 EP EP00932001A patent/EP1173245B1/en not_active Expired - Lifetime
- 2000-05-02 JP JP2000615088A patent/JP2002543165A/en active Pending
- 2000-05-02 CA CA002370853A patent/CA2370853C/en not_active Expired - Fee Related
- 2000-05-02 ES ES00932001T patent/ES2226843T3/en not_active Expired - Lifetime
- 2000-05-02 MX MXPA01011283A patent/MXPA01011283A/en active IP Right Grant
- 2000-05-02 AT AT00932001T patent/ATE274955T1/en not_active IP Right Cessation
- 2000-05-02 AU AU49797/00A patent/AU4979700A/en not_active Abandoned
- 2000-05-02 US US09/561,648 patent/US6503481B1/en not_active Expired - Fee Related
- 2000-05-02 DE DE60013425T patent/DE60013425T2/en not_active Expired - Lifetime
- 2000-05-02 WO PCT/US2000/011799 patent/WO2000066206A2/en active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| EP1173245B1 (en) | 2004-09-01 |
| BR0010262A (en) | 2002-01-15 |
| ES2226843T3 (en) | 2005-04-01 |
| EP1173245A2 (en) | 2002-01-23 |
| DE60013425D1 (en) | 2004-10-07 |
| CA2370853A1 (en) | 2000-11-09 |
| WO2000066206A2 (en) | 2000-11-09 |
| AU4979700A (en) | 2000-11-17 |
| WO2000066206A3 (en) | 2001-02-08 |
| MXPA01011283A (en) | 2002-11-04 |
| US6503481B1 (en) | 2003-01-07 |
| DE60013425T2 (en) | 2005-09-08 |
| ATE274955T1 (en) | 2004-09-15 |
| JP2002543165A (en) | 2002-12-17 |
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