WO2001039892A1 - Appareil et procede permettant de delivrer des petites quantites de liquide - Google Patents

Appareil et procede permettant de delivrer des petites quantites de liquide Download PDF

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Publication number
WO2001039892A1
WO2001039892A1 PCT/US1999/028852 US9928852W WO0139892A1 WO 2001039892 A1 WO2001039892 A1 WO 2001039892A1 US 9928852 W US9928852 W US 9928852W WO 0139892 A1 WO0139892 A1 WO 0139892A1
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Prior art keywords
gas
reservoir
liquid
pressure
powder
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Application number
PCT/US1999/028852
Other languages
English (en)
Inventor
Robert A. Laibovitz
Robert L. Rogers
Original Assignee
Laibovitz Robert A
Rogers Robert L
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Laibovitz Robert A, Rogers Robert L filed Critical Laibovitz Robert A
Priority to AU18424/00A priority Critical patent/AU1842400A/en
Priority to PCT/US1999/028852 priority patent/WO2001039892A1/fr
Publication of WO2001039892A1 publication Critical patent/WO2001039892A1/fr

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B7/00—Spraying apparatus for discharge of liquids or other fluent materials from two or more sources, e.g. of liquid and air, of powder and gas
    • B05B7/14—Spraying apparatus for discharge of liquids or other fluent materials from two or more sources, e.g. of liquid and air, of powder and gas designed for spraying particulate materials
    • B05B7/1404—Arrangements for supplying particulate material
    • B05B7/1413—Apparatus to be carried on or by a person, e.g. by hand; Apparatus comprising a container fixed to the discharge device
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/0008—Introducing ophthalmic products into the ocular cavity or retaining products therein
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B7/00—Spraying apparatus for discharge of liquids or other fluent materials from two or more sources, e.g. of liquid and air, of powder and gas
    • B05B7/02—Spray pistols; Apparatus for discharge
    • B05B7/04—Spray pistols; Apparatus for discharge with arrangements for mixing liquids or other fluent materials before discharge
    • B05B7/0416—Spray pistols; Apparatus for discharge with arrangements for mixing liquids or other fluent materials before discharge with arrangements for mixing one gas and one liquid
    • B05B7/0433—Spray pistols; Apparatus for discharge with arrangements for mixing liquids or other fluent materials before discharge with arrangements for mixing one gas and one liquid with one inner conduit of gas surrounded by an external conduit of liquid upstream the mixing chamber
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B7/00—Spraying apparatus for discharge of liquids or other fluent materials from two or more sources, e.g. of liquid and air, of powder and gas
    • B05B7/24—Spraying apparatus for discharge of liquids or other fluent materials from two or more sources, e.g. of liquid and air, of powder and gas with means, e.g. a container, for supplying liquid or other fluent material to a discharge device
    • B05B7/2402—Apparatus to be carried on or by a person, e.g. by hand; Apparatus comprising containers fixed to the discharge device
    • B05B7/2405—Apparatus to be carried on or by a person, e.g. by hand; Apparatus comprising containers fixed to the discharge device using an atomising fluid as carrying fluid for feeding, e.g. by suction or pressure, a carried liquid from the container to the nozzle
    • B05B7/2416—Apparatus to be carried on or by a person, e.g. by hand; Apparatus comprising containers fixed to the discharge device using an atomising fluid as carrying fluid for feeding, e.g. by suction or pressure, a carried liquid from the container to the nozzle characterised by the means for producing or supplying the atomising fluid, e.g. air hoses, air pumps, gas containers, compressors, fans, ventilators, their drives
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B7/00—Spraying apparatus for discharge of liquids or other fluent materials from two or more sources, e.g. of liquid and air, of powder and gas
    • B05B7/24—Spraying apparatus for discharge of liquids or other fluent materials from two or more sources, e.g. of liquid and air, of powder and gas with means, e.g. a container, for supplying liquid or other fluent material to a discharge device
    • B05B7/2402—Apparatus to be carried on or by a person, e.g. by hand; Apparatus comprising containers fixed to the discharge device
    • B05B7/2405—Apparatus to be carried on or by a person, e.g. by hand; Apparatus comprising containers fixed to the discharge device using an atomising fluid as carrying fluid for feeding, e.g. by suction or pressure, a carried liquid from the container to the nozzle
    • B05B7/2416—Apparatus to be carried on or by a person, e.g. by hand; Apparatus comprising containers fixed to the discharge device using an atomising fluid as carrying fluid for feeding, e.g. by suction or pressure, a carried liquid from the container to the nozzle characterised by the means for producing or supplying the atomising fluid, e.g. air hoses, air pumps, gas containers, compressors, fans, ventilators, their drives
    • B05B7/2421—Gas containers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B7/00—Spraying apparatus for discharge of liquids or other fluent materials from two or more sources, e.g. of liquid and air, of powder and gas
    • B05B7/24—Spraying apparatus for discharge of liquids or other fluent materials from two or more sources, e.g. of liquid and air, of powder and gas with means, e.g. a container, for supplying liquid or other fluent material to a discharge device
    • B05B7/2402—Apparatus to be carried on or by a person, e.g. by hand; Apparatus comprising containers fixed to the discharge device
    • B05B7/2405—Apparatus to be carried on or by a person, e.g. by hand; Apparatus comprising containers fixed to the discharge device using an atomising fluid as carrying fluid for feeding, e.g. by suction or pressure, a carried liquid from the container to the nozzle
    • B05B7/2435—Apparatus to be carried on or by a person, e.g. by hand; Apparatus comprising containers fixed to the discharge device using an atomising fluid as carrying fluid for feeding, e.g. by suction or pressure, a carried liquid from the container to the nozzle the carried liquid and the main stream of atomising fluid being brought together by parallel conduits placed one inside the other
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B7/00—Spraying apparatus for discharge of liquids or other fluent materials from two or more sources, e.g. of liquid and air, of powder and gas
    • B05B7/24—Spraying apparatus for discharge of liquids or other fluent materials from two or more sources, e.g. of liquid and air, of powder and gas with means, e.g. a container, for supplying liquid or other fluent material to a discharge device
    • B05B7/2402—Apparatus to be carried on or by a person, e.g. by hand; Apparatus comprising containers fixed to the discharge device
    • B05B7/2467—Apparatus to be carried on or by a person, e.g. by hand; Apparatus comprising containers fixed to the discharge device a liquid being fed by a pressure generated in the container, which is not produced by a carrying fluid

Definitions

  • This invention comprises a process and apparatus (device) and the use thereof for delivering to a location of choice relatively precise, preselected quantities 5 of a material , most preferably initially in the form of a mixture of a relatively larger quantity of gas and a relatively smaller quantity of liquid in the form of microdrops, submicrodrops or a single micrdrop to a location of choice.
  • the liquid is preferably a drug and most preferably an ophthalmic drug.
  • the mixture can be one of powder in such gas.
  • the fluid initially 5 prior to delivery exists as microdroplets of liquid in conveying gas, which microdroplets are conveyed as one form of microdroplet or another over a relatively small distance in the atmosphere. It has also been discovered as part of this invention that the viscosity of the liquid to be conveyed affects the physical form of the delivered liquid. Usually, the more viscous the fluid, the fewer the number of microdrops. Moreover the apparatus of this invention can be modified into a host of different embodiments so that any chosen embodiment according to the principles of the inventive concepts described herein will deliver liquid in the form desired to a target of choice..
  • inventions In addition to the inventive process several apparatus embodiments have been developed as part of this overall invention. These embodiments are also sometimes referred to herein as devices and are novel and unobvious in themselves. In general, the devices employ novel and unobvious pump means. These are unobvious inventive modifications of eductor pumps or venturi configurations adapted to perform as a pump.
  • the pump embodiments of this invention comprise physical entrainment means, as means for delivering a preselected quantity of liquid of choice to a preselected quantity of gas in a conduit moving with a preselected velocity to be delivered to a target, as for example as a microdrop or as microdroplets. 5.
  • the present invention in its most preferred aspect concerns a system (process and apparatuses) for delivery of exceptionally small predetermined volumes (i.e. microvolumes or submicrovolumes) in the form of microdrops or a microdrop of liquid materials to the eye, nose or other parts of the animal, preferably the mammalian body, particularly the human species thereof under circumstances wherein the total amount received is preferably 1 to 10 microliters of liquid.
  • exceptionally small predetermined volumes i.e. microvolumes or submicrovolumes
  • the preferred apparatus of the invention has particular utility in patient self-treating of his or her eye(s) with predetermined microvolumes if liquids that may incorporate micro quantities of drugs (total volume is preferably from 1 to 10 microliters) in a reproducible and reliable manner without uncomfortable eye impact and irrespective of patient blinking.
  • the inventive apparatus can also be small enough to be easily handled by a patient.
  • the invention also has utility in other environments, where delivery of predetermined micro or submicro quantities, sch as microvolume drops or droplets is desired. Examples would include delivery of various components for microchip manufacture and other nonmedical applications. It can also be used in vetinarinary applications.
  • the invention can be used under very high temperatures. Moreover, it is suitable for delivery of drugs and other materials in powder form.
  • the impact power of the apparatus can be used to power various weapons and to propel liquid directly into an environment such as the skin. It can be successfully utilized where exceptionally small quantities of materials must be delivered on a site specific manner. 8.
  • the Apparatus of the Invention Meets all the Criteria of Generally Accepted as Necessary for Patient-Friendliness By the Ophthalmic Discipline
  • An especially preferred application of the process and apparatus of this invention is the delivery of micro or submicro quantities of drugs in a patient-friendly mode to the eye.
  • some very important medical criteria can be met by the invention. These criteria have been known to the art, but have not been achievable by any practical technique of the art. These criteria include: 1) delivery of the drug to the eye in total quantities of less than 30ul 2. delivery of the drug to the eye in droplets of less than 20 ul and as small as (1) one nanoliter
  • drugs for delivery are in a container that will deliver drug dosage accurately to the eye 8. There is little variability of the quantity of material that is delivered in subsequent sequences.
  • drug includes fluids, such as liquids, powders, gels and combinations thereof
  • the invention overcomes the problem of delivery of excessive amounts of drug to the eye
  • Micropipettes are known to deliver less than 30ul quantities in single droplet form.
  • Spray atomizers are known to deliver microliter droplets but in greater total liquid quantity than desired.
  • spray atomizers using either eductor pumps or direct liquid pressure are designed to deliver a gross and variable amount of spray in empirically determined and highly variable amounts, with no knowledge that there is a determinable correlation between the amount of fluid delivered and the amount of gas to entrain and transmit the fluid. They are also inherently flawed because of the high variability in the quantity of material delivered. It is very important that the same amount of drug be delivered on each sequential drug delivery step in the case of ophthalmic and other medical uses.
  • microvolumes of medicaments accurately to parts of the human body and by implication to other mammals. This is especially the case in the field of human ophthalmology.
  • the eye contains a preocular tear film to which medication may be applied.
  • the current state of the art is such that the smallest single drop (20 to 50 ul) of ophthalmic preparations self-administered by a patient in a device of the present art delivers far more volume than such preocular tear film can hold. ( An exception to this might appear to be the laboratory micropipette, but it is totally unsuitable for individual patient self-treatment, especially on a chronic basis.)
  • the normal preocular tear volume is 6.8 to 7.9 or about 7.5 ul. Under highly controlled laboratory conditions permitting normal blinking, the preocular tear volume can be transiently expanded by another 10 ul without overflow (Chrai et al., 1973). Additionally, induced reflex blinking increases the rate of drug loss as the instilled volume increases. Larger volumes of liquid result in a greater rate of preocular drug loss. Increased instilled drug volume results in both increased drainage of drug via responses from reflex tearing, thus further diluting the drug with stimulated tears. This means the rate of drug loss actually increases as the volume of drug instilled increases (Chrai et al., 1974). Fractional ocular absorption also increases with decreasing instilled volume which is an inherent advantage of the instant invention.
  • Pilocarpine a cholinergic parasympathomimetic agent that is used in the treatment of glaucoma, has ocular effects including constriction of the pupil and lowering of the intraocular pressure (IOP). Unwanted systemic effects of this drug may include intestinal spasm, broncho constriction, hypotension, and decreased heart rate.
  • Smaller ocular volumes allow maintenance of the desired ocular therapeutic effects while decreasing or eliminating undesired systemic and local side effects. These smaller volumes have been administered using calibrated micropipettes as delivery devices.
  • an antihypertensive agent Petursson et al., (1984) determined that instilling small volumes of 15 ul to the eye results in separation of the desired ocular hypotensive effects from the undesired systemic hypotensive effects and equivalent decreases in intraocular pressures as compared with larger volumes.
  • Reduced retention time caused by the activation of reflux tearing and blinking may cause the drug to be washed out and drained from the ocular surface, thus reducing preocular residence time and ocular availability.
  • Blinking that can accompany the instillation of a 30-50ul drop in the eye enhances liquid entry into the nasolacrimal drainage system, thereby increasing the rate of drug loss from the preocular tear film and its availability for subsequent systemic absorption.
  • ophthalmic drugs For ophthalmic drugs to be effective, they must be delivered with reasonable reliability to the eye. With current ocular drug delivery systems, it is possible for a patient to miss the eye completely, for example by depositing the drug on the eyelid, and to assume that the drug has been properly delivered. Thus, lack of efficacy may also be related to the shortcomings of the delivery system.
  • the instillation of too large a volume of liquid, 30ul or more, to the eye may result in a number of phenomena such as described above that reduce the efficiency of drug pharmacokinetics.
  • reflex tearing results in dilution of the delivered volume, and enhances drainage into the nasolacrimal drainage system.
  • Reflex blinking as a result of macrodrop delivery accentuates the reduction in preocular residence time, and enhances drainage through the nasolacrimal drainage system and increases the opportunity for undesired systemic absorption.
  • Use of macrodrops may further cause discomfort, such as burning and stinging, to the user.
  • the ability to consistently and reliably deliver volumes of liquid medicaments as small as 1 microliter, preferably 1 to 5 microliters or smaller is a desirable goal, that is achievable by the present invention..
  • the present invention overcomes the drawbacks and disadvantages inherent in the described prior art by providing in a preferred embodiment in a patient-friendly manner a predetermined micro or submicro volume quantity of a drug to an eye in a reliable and reproducible manner. This has the extremely beneficial effect of maximizing desired local therapeutic effects and minimizes undesirable local and systemic effects from excessive drug being delivered to the body, such as through the nasolacrimal drainage system of the eye.
  • the invention utilizes a gas stream under pressure to entrain a predetermined quantity of a liquid or powder and to deliver either or both in micro or submicro volume quantities to a desired site, such as an eye (human or animal).
  • a particular advantage of the invention is to effectuate delivery of such liquids or powder in extremely small quantities (i.e. droplets of less than lOul). These delivered droplets are much smaller than the drops from a conventional eye dropper.
  • the volume or three dimensional size of the droplets of the invention is generally from 0.1 up to but less than 30 ul, but it is preferably 1 to less than 10 ul and most preferably 0.1 to 5 ul.
  • Bottle dropper systems are used by patients and are designed to deliver a single macrodrops (30-50ul) to the open eye.
  • micropipettes ordinarily usable only for laboratory experiments and not practical for individual patient use
  • Bottle dropper drops (30 to 50ul) because of the delivery and impact effect of such size, cause soft trauma (reflex stimulation of tearing, blinking and wiping, etc. ) to the eye due to the impact of the single large droplet. It is expected that the action of the very low quantity of drugs capable of being accurately delivered by the present invention may result in more rapid and complete mixing of a drug so delivered with the ocular tear film
  • the direct ejection technique requires the use of gas which is pressurized in order to propel the ejected liquid (but in undesirable large quantities) with sufficient velocity to reach the eye.
  • the direct ejection technique causes ejection of at least some of the liquid before the gas which propels this liquid has reached a velocity sufficient to propel this liquid a sufficient distance to reach the ocular surface of the eye.
  • the direct ejection technique causes an audible pop or snap as the liquid is ejected, resulting in a reflex blinking and the potential for consequent misdirection of the liquid.
  • One method of calculating the mass of a typical drop (not desirably small) delivered from a device such as an eyedropper is to equate the gravitational forces on the drop with the surface tension of the fluid around the perimeter of the nozzle using Tate's law:
  • m is the mass of the eye drop
  • d is the diameter of the delivery tube
  • ⁇ is the surface tension of the fluid in question
  • g is the acceleration due to gravity (Brown et al., 1985). This equation suggests that reducing d, the diameter of the dropper tip, will consistently reduce the mass of the drop delivered.
  • Equation (1) is assumed to define a break-point at which the drop separates from the tip of the dropper under the influence of gravity.
  • p is the mass density of the fluid
  • ⁇ is the surface tension of the fluid
  • g is the acceleration due to gravity.
  • the units of a are length, and, if the characteristic length dimension (such as the diameter of a spherical drop) of the unit of fluid in question is small compared with a, then the surface tension forces dominate the gravitational forces in the determination of the shape of the unit of fluid.
  • ⁇ is about 0.072N/m at 20 degrees C in contact with air.
  • the corresponding capillary constant for water in air is 0.39cm.
  • the capillary constant for the typical ophthalmic preparation is about 0.29cm.
  • the diameter of a 30ul spherical drop is 0.39cm, i.e., the same as the capillary constant for water.
  • a 12ul spherical drop of water is about 0.29cm in diameter and a lul drop is about 0.12cm in diameter.
  • the separation process of the drop from the tip of a conventional dropper is actually a fluid-fluid separation and not the fluid separating from the tip material of the dropper.
  • the large drop forms a narrow "waist" in the fluid just distal to the tip of the dropper, and the waist becomes progressively narrower until the fluid below the waist separates. This creates an instability which can only be reliably induced when the characteristic dimension of the fluid volume to be delivered becomes greater than the capillary constant of the fluid, and at this point, the fluid separates from the rest of the fluid and becomes a separated drop.
  • the remaining fluid on the tip spreads out as a thin layer over the tip of the dropper.
  • the first method is a single step induction or entrainment method specifically modified in an unobvious way .
  • the single step method uses a motive gas for metering and delivering a small predetermined quantity of fluid to the eye or other target of choice.
  • the volume of liquid delivered to the eye and any other target for that matter is controlled by the volume and pressure and thus velocity of the motive gas.
  • the second method is a two step induction method.
  • the desired volume of fluid is pre-metered into a passage or compartment by either capillary action or by a mechanical action that pushes the fluid into the compartment.
  • the motive or propulsive gas is forced through the compartment to mix and eject the fluid through a nozzle to the eye.
  • a capillary tube can be used to effectuate the capillary embodiment.
  • the especially preferred embodiments shown use a piston and spring for the creation of a transient high pressure air pulse of a predetermined quantity of a material such as a liquid or powder.
  • a material such as a liquid or powder.
  • repeated pulses with concomitant repeated volumes of fluid of relative consistency will be delivered
  • the air pulse may be generated in a variety of ways, and that other gas sources such as pre-pressurized cartridges or canisters of CO 2 , N 2 or other non-toxic, preferably non-flammable gases in medical applications may be used in conjunction with appropriate valving schemes.
  • FIG. 1 An inventive single step induction (entrainment)system is illustrated in FIG. 1.
  • This system employs a measured amount of gas delivered at a given pressure to induce a measured volume of fluid to be pulled into the mixing stream of the inventive pump that becomes mixed with a propulsive gas, preferably an air stream, and then is ejected from an exit nozzle.
  • a propulsive gas preferably an air stream
  • FIG. 1, FIG. 2, FIG. 3, and FIG. 4 show the principal components of one inventive gas induction delivery system using either a eductor pump or a pump resulting from the modification of a venturi configuration as well as a r paddle wheel include examples of those embodiments included within the scope of the invention.
  • a main body or housing which houses a spring ,piston, release mechanism and cocking mechanism for compressing a plunger-driving-spring, and air and material reservoirs
  • a suitable pump means including an inventive eductor and a venturi modified to be a pump.
  • the body 10 in one preferred embodiment is typically about 3/4" to 1" in diameter and about 1" to 3" long.
  • the present invention will deliver exceptionally small dosage drug volumes i.e. submicrovolumes or preferably microvolumes totaling from 1 to lOul total dosage to the open eye with no soft trauma effects and without the necessity for consideration of the influence of spontaneous or reflex blinking of the eye.
  • drug microvolume total dosage is often comprised of a multitude of much smaller ultramicro drops in the form of a spray wherein said ultramicro drops are in the range of 1 to 100 microns in diameter.
  • the micro or submicro quantity delivered will often be a substantially unitary droplet comprised of no more than about five fragments.
  • the present invention seeks to address and overcome the many drawbacks inherent in the prior art by providing an ideal small quantity of drug delivery to the eye in order to maximize desired local therapeutic effects and minimize local systemic undesirable side effects.
  • the system employs a gas stream to entrain (induce) a controlled volume of a liquid into the gas stream and to deliver the liquid preferably in the form of a small drop of from 1 nanoliter to 5 ul) or alternatively in the form of even a greater quantity exceptionally small droplets to a desired site such as an eye.
  • the size of a given drop may be generally the size such as is found in an aerosol or mist which may be in the micron range, e.g., 1-5 microns, 10 microns or larger, up to 100 microns, preferably in the range of 10 microns.
  • the present invention provides a system/apparatus, which is patient-friendly, for delivering commonly-used ophthalmic fluids in quantities smaller than amounts delivered through conventional means excluding micropipettes).
  • the smaller quantities are especially designed to remain within the capacity of the eye to hold such quantities.
  • Exemplary uses that would benefit from administration by the disclosed system include cholinergic agonists, alpha-adrenergic agonists, beta-adrenergic receptor antagonists, mydriatic, cycloplegics, corticosteroids, and prostaglandins.
  • Cholinergic agonists such as pilocarpine, affect the autonomic effector cells innervated by parasympathetic nerves.
  • Pilocarpine' s clinical use is restricted in ophthalmic application to induce miosis (pupillary constriction) and decrease the intraocular pressure (IOP).
  • Systemic side effects of pilocarpine may include increased tone and motility of the smooth muscle of the intestine, stimulation of the bronchial smooth muscle resulting in asthmatic attacks, and a marked fall in blood pressure and heart rate.
  • Beta-blockers such as timolol, block the beta adrenergic receptors in the sympathetic effector system. Timolol is used ophthalmologically to decrease IOP in patients with glaucoma.
  • Clonidine is an alpha-adrenergic agonist that is used as a topical ophthalmic hypotensive agent. Potential side effects of this class of drugs include hypotension, sedation, fatigue bardycardia, and dry nose and/or mouth.
  • the present invention employs gas entrainment (induction) in an unobvious inventive manner to deliver small and accurate volumes of liquid in a reproducible and reliable manner.
  • the system does not rely on gravity to separate or propel the liquid for delivery. It relies instead on a preselected volume and pressure of gas to both separate and deliver a preselected quantity of a material such as a liquid.
  • the ratio of motive gas used to liquid delivered is preset as is the pressure of the gas.
  • the invention eliminates the problems encountered in droppers which involve adhesion forces including surface tension at the tip diameter, difficulties in use, lack of control of quantities (very small), and contamination.
  • the present invention employs a specially adapted embodiment of the gas eduction principle to deliver predetermined quantities of liquids as micro or submicro size drops to a selected target.
  • a specially adapted embodiment of the gas eduction principle to deliver predetermined quantities of liquids as micro or submicro size drops to a selected target.
  • the invention does not rely on gravity for delivery of a material to a target, such as an eye. Moreover, the invention delivers very much smaller quantities of liquid to such a target than is possible with a conventional eye dropper.
  • the technique of the invention relies on utilizing a preselected volume of gas to entrain a preselected micro or submicro volume or quantity of a liquid and deliver such liquid to a target, such as an eye.
  • this invention presents the advantage of eliminating the problems encountered in conventional gravity driven eye droppers, which must overcome the effects of large unwanted adhesion forces from such factors as surface tension attractions at the tip, too large a tip diameter, difficulties in use, lack of control of quantities, clogging and contamination.
  • the mixture initially exists as micro or submicro droplets of liquid in gas, which micro or submicro droplets are conveyed over a relatively small distance say up to three inches in the atmosphere.
  • the volume and velocity of the delivering gas is dependent on the pressure head on the gas at the moment it, in a preferred embodiment, is compressed and then commences its transposition through the apparatus of the invention. In such conveyance the pressure gradually diminishes.
  • the invention requires that at the exit orifice of the apparatus sufficient pressure remains to provide velocity for extraction of the liquid from the reservoir, which has been removed therefrom and will be expelled from the apparatus of the invention.
  • the pressure needed in preferred embodiments is approximately 7 to 1000 pounds per square inch for the eductor embodiment of this invention.
  • the modified venturi embodiment of this invention can use lower pressures say from 1 to 100 pounds per square inch. Virtually none of this pressure is transmitted to the eye nor perceived by it. This accounts for the high utility of this invention in the environment ocular administration.
  • an amount of gas and the velocity of delivery provided by a certain pressure head is chosen in accordance with the principles of this invention that will permit that amount of fluid and the form of the droplets containing said fluid to be so delivered.
  • This relationship between chosen amount of delivery fluid has been defined in mathematical relationships in novel and nonobvious mathematical expressions that have been developed by the inventors and form a part of the invention as described herein. These formulas provide a quantitative control aspect to this invention not previously available.
  • the liquid Once the liquid is entrained in the delivery gas, it mixes to a greater or lesser extent (depending on whether the inventive eductor modification or inventive venturi modification is employed) with such gas depending on viscosities and velocities and the like of the working gas.
  • An especially preferred application of the process and apparatus of this invention is the delivery of materials such as drugs to the eye.
  • materials such as drugs to the eye.
  • some very important medical criteria can be met by the invention. These criteria have been known to the art, but have not been achievable by any practical technique of the art and have been desired for a long time.
  • Micropipettes are known to deliver less than 30ul as low as 1.5 ul quantities in single droplet form but they are not useable for self-administration of drugs.
  • Spray atomizers are known to deliver droplets to the eye, but in far greater quantities or amounts than desired.
  • Perfume spray atomizers of the art are designed to deliver a gross and highly variable and thus unreliable amounts of spray in empirically determined gross amounts far exceeding microliter quantities with no knowledge by the manufacturer that there is a determinable correlation between the amount of fluid delivered, the amount of gas to entrain and transmit the fluid and the pressure of the gas. Indeed, empirical measurements were made by the inventors of commercially available perfume atomizers utilizing conduits of size comparable to the especially preferred conduits utilized by Applicants invention.
  • the pressures of the gas generated by the bulbs of such atomizers range from about 1 to about 5 pounds maximum of pressure per square foot of air above atmospheric pressure. This amount of pressure is greatly variable and depends on the way the bulb is squeezed with the fingers. Five pounds per square foot pressure is rarely achieved and generally requires a prodigious squeeze. Thus, the capriciousness in the delivery amounts alone makes the spray atomizers unusable for a drug delivery system.
  • the preferred eductor embodiment of this invention utilizes a pressure range of seven(7) to one thousand (1000) pounds per square inch.
  • 1000 the pressure differences in the devices of the art and that of the current invention are quite profound.
  • the preferred pressures will be more than 5 and preferably 7 or more pounds per square inch.
  • the bulb which must be squeezed to deliver droplets of perfume or the like with atomizers contains a considerably greater volume of gas than used in the preferred apparatus of the invention.
  • Such large quantities of gas result in sprays with relatively huge quantities of sprayed liquid in very large spray patterns.
  • the spray pattern of a perfume atomizer is generally greater than about two (2) inches in diameter and is therefore unsuitable for the preferred prime uses of the apparatuses of the invention which are for controlled application of extremely small quantities of drugs to the eye in less than two inch diameter patterns.
  • the present invention employs various pump means embodiments and features, which can be utilized as subcombination elements, all of which operate in response to the flow of a gas.
  • Static forces generally hold the liquid in place and no liquid is ejected until a threshold velocity of the gas is reached. Once the threshold velocity is reached, liquid is entrained into the gas stream and ejected as a drop or droplets at sufficient velocity to reach the eye or other body part. The velocity is kept below that which might be harmful or cause discomfort or reflex tearing or blinking.
  • Liquid entrainment by gas to deliver micro or submicro liter quantities is superior to direct propulsion or direct ejection of a liquid in two very important ways.
  • the apparatus of the present invention using gas induction or gas entrainment is often less complicated than many direct propulsion devices.
  • the gas entrainment subelement involves no small moving parts and the delivery and metering of gas may be performed with a piston and requires no complicated valving.
  • a cylinder of gas under pressure may also be used as a gas propulsion source.
  • the liquid is not ejected until the gas flow reaches a certain predetermined velocity as set by various criteria determined by processes which constitute one aspect of the invention.
  • the inventive device can bring the gas ejected up to appropriate velocity before liquid will be ejected with no abrupt audible pop, snap or other noise. This is extremely important in ophthalmic applications, since experience shows that a sharp audible noise such as a pop or snap will cause the user to blink and impede the delivery of the liquid to the eye.
  • the invention resides in a delivery apparatus, which produces a gas stream of a consistent predetermined volume and a consistent predetermined velocity under a preselected pressure; a liquid container as a reservoir , a gas container as a reservoir; a discharge conduit to deliver a gas stream from the apparatus, which includes a section to manage the gas stream and reduce its static pressure; and a liquid entrainment means that is pump means, such as a modified induction pump or other suitable liquid entraiment means, to draw a predetermined amount of liquid from the liquid container into the reduced pressure section for mixing with and delivery by the gas stream containing liquid through the discharge orifice or conduit to an eye or other chosen target.
  • pump means such as a modified induction pump or other suitable liquid entraiment means
  • the gas container is an important feature in that it provides a repeatable pressure and therefore a repeatable volume of gas under such repeatable pressure.
  • the gas container also includes a releasable gas pressurization device and a mechanism for activating release of the pressurizing device.
  • the gas container comprises a cylinder closed at the top and fitted with a piston capable of compressing gas upon moving toward such top.
  • the piston may have a one-way valve, so that gas is not drawn through the pump as the piston is drawn into the cocked position where the spring is compressed the desired amount. (It has been found for the preferred embodiment that the spring is preferably not compressed to its maximum nor is it released to its maximum.)
  • the piston is connected at its lower end to a cocking member, which allows the piston to be fixed at its lower travel movement location and then released .
  • the spring is partially compressed when the piston is at the top of its travel, and when the piston is drawn into the cocked position, it does not compress the spring to its full extent. This is because the force of the spring changes as the spring is compressed. Therefore, the fractional change in the force of the spring is less if the spring is moved from one partially compressed displacement to another partially compressed displacement, than it would if the spring were uncompressed when the piston was at the top of the cylinder, and fully compressed when it was at the bottom of the cylinder.
  • the cocking member takes the form of at least one spring-loaded lug or other catches which are attached at their inner ends indirectly to the piston and spring outwardly at their other ends to engage suitable recesses in the cylinder wall or other suitable hold members.
  • the piston is capable of being moved by means of a spring interposed between the piston and a fixed position in the bottom of the apparatus.
  • a stop pin inserted in the piston and engaged by a twist ring is used to hold the piston in the cocked position.
  • the piston may be moved downwardly within the cylinder, thereby compressing the spring until the piston reaches its cocked position.
  • a mechanism is actuated to release the pin, when desired, thereby allowing the spring to drive the piston upward and compress gas above the piston.
  • a pump is positioned above the cylinder, and receives compressed gas from the cylinder through a suitable gas passageway.
  • the pump is also connected by a suitable conduit to a reservoir of a liquid drug or other medicament, such that gas passing through the pump draws the liquid from the reservoir by creating a reduced pressure zone, mixes with it, and discharges the liquid as micro or submicro droplets.
  • a selected pressure through a suitable first conduit means can be applied to the liquid reservoir to facilitate the removal of liquid therefrom by means of a second conduit means. This greatly enhances the flexibility of operations.
  • the apparatus of the invention delivers low micro or submicro volumes of both liquid and gas with the very desirable characteristic of low variability.
  • the apparatus is capable of delivering small volumes of liquid on the order of 1 nanoliter to 25ul consistently. Previous devices, such as eye droppers have failed to deliver such small volumes accurately and consistently; they have delivered volumes on the order of 30 ul or more
  • the present device in contrast, is able to deliver quantities (consistent with selected gas velocities) of far less than 30 ul, say 1 nanoliter to lOul.
  • a preselected quantity of liquid to be entrained or inducted may be pre-metered into a chamber.
  • the chamber containing the preselected quantity of such liquid may be connected by a conduit to the gas stream in a pump means.
  • the preselected volume may be inducted and delivered by the gas stream when it has reached the preselected velocity.
  • a capillary tube holding a fixed amount of liquid for each delivery cycle can be employed as a form of chamber.
  • a unit dose is defined as a volume of a liquid contained in a disposable container. Said container is typically sealed and contains liquid without preservatives added.
  • the apparatus of the invention may be modified in many respects.
  • the pump may take the form of a eductor a modified venturi, or a paddle wheel.
  • the gas compression source may also take the form of a small cylinder of compressed gas available commercially such as a CO 2 cartridge connected through a suitable quick discharge valve to the pump.
  • a preferred embodiment of the invention is one that is small enough to be held in one hand and carried on one's person.
  • the overall shape may be cylindrical, rectangular, square or molded to fit the hand and may be about 1 to about 6, preferably 3 inches long and about 0.5 to about 2, preferably 1.5 inches in diameter. It may weigh about 1 to about 16 preferably about 12 ounces.
  • the specially preferred apparatus feature of this invention which embodies the process of the invention is a remarkable device for the ophthalmic field.
  • the inventors have provided for the first time a device that can simultaneously provide in a cost effective and practical manner all of the features deemed desirable for a patient-friendly delivery device for conveying drugs to an eye. (Concomitantly the principles of the invention are clearly adaptable for utilization in a multitude of other fields both medical and nonmedical)
  • the core of the inventive process is the development of a device which permits extremely small quantities of materials to be delivered (as low as 1 nanoliter to less than 10 microliters of liquid and more if desired).
  • the invention permits ophthalomogical drugs to be delivered to the human eye in a patient-friendly manner.
  • the inventive process requires making a series of selections from a variety of physical parameters. These factors selected are all interrelated with and interact with each other as follows:
  • the first selection is the quantity of material such as a liquid (drug) desired to be delivered to a target such as the human eye.
  • the second selection is the quantity i.e. volume of gas necessary to entrain and convey such material, i.e. liquid to a selected target, (ordinary air and other gases even more inert can be used).
  • the third selection is the pressure under which such gas needs to be placed in order to achieve the desired velocity necessary for both conveying such gas past a reservoir containing liquid to be delivered and also having sufficient velocity after entraining (inducing) the desired quantity of liquid to convey such liquid to the selected target,
  • the fourth selection is the gas/liquid entrainment (induction) mode by which the proper quantity of liquid is placed in the gas stream.
  • the two modes that have been found to be most effective are the eductor pump mode and an inventive modification of a venturi called a modified venturi to result in a pump. Both modifications have been invented by the inventors hereof and form important features of this invention.
  • the fifth selection is the dimensions of the device within which the patient-friendly process of the invention can be achieved.
  • the device must be relatively small, say occupying from .20 to 20, most preferably 3 to 10 cubic inches. It can be any shape but it is preferred that it be cylindrical.
  • the sixth selection is the means for gas propulsion. It can be a spring powered piston for compressing the gas and forcing it through a conduit . It can be an exterior source of gas under pressure such as from a CO 2 cartridge
  • the seventh selection is the cross-sectional size of the conduits that are used to convey the propelling gas through a pump system, where it entrains a desired preselected amount of liquid and then to the outside of the device.
  • the eighth selection is the cross-sectional diameter and length of the conduits that are needed to convey a preselected amount of liquid to the conveying gas.
  • the ninth selection is the location and design of a reservoir for material (liquid or powder) within or without the device for the material source.
  • the tenth selection is the location and design of a reservoir for the gas propulsion source either within or without the main body of the device.
  • the eleventh selection is the location and configuration of the conduits referred to above within the main body of the container
  • the twelfth selection is the release mode that initiates the sequence of events commencing with the pressurized gas flowing through a conduit on the way to one of the pumping means mentioned above.
  • the thirteenth selection is optional. It involves providing in the modified venturi mode valving means for reducing pressure on the liquid reservoir at an appropriate point in the inventive sequence thereby permitting both means for achieving the predetermined liquid to be entrained as well as allowing gas free of liquid to exit from the container to purge the exit orifice of any residual liquid so as to avoid residual material such as liquid for the next delivery cycle.
  • the fourteenth selection is that which involves the type of mixing of material in the pump means with respect to the formation of a about a single drop to formation of many even smaller droplets.
  • the fifteenth selection is the ratio of gas to liquid the mixing ratio which must be predetermined in accordance with the amount of material desired to be delivered. It is in the range of the ratio of 3000 to
  • the relative size of the conduits relates to the determination to the amount of gas to be used to achieve delivery of a given quantity of liquid .
  • the sixteenth selection is the pitch of the helix of the twist ring.
  • the pitch must be sufficient that the spring can be compressed the desired amount without an unreasonable amount of turning. Furthermore, the pitch must not be so great that the twist ring is hard to turn.
  • the use of V ⁇ to 1 full turn to fully compress the spring provides a typical range for the twist ring.
  • the vertical displacement of the piston from this twist is typically 0.1" to 0.3".
  • the seventeenth selection is that the material reservoir size must be selected relative to the total amount of conveyed air used. The reservoir size must not be so large that the reservoir cannot be sufficiently pressurized by the action of the piston to provide reasonably accurate delivery. In some cases, some empty space above the reservoir material is desirable to prevent the change in volume from the evacuation of the material from the reservoir from changing the delivery of the material. For 1ml of total air displacement, the reservoir volume should be in the range of 1 to 5 ml.
  • the eighteenth selection is to choose the length of the feeder tube for the pump. If a fixed amount of fluid is desired, with a very low variability, then a longer feeder tube is desired. If it is important that the average mixing ratio remain constant over a wide range of selected volumes to be delivered, then the feeder tube should be short.
  • a long feeder tube can be 2 or more inches long, while a short feeder tube may be 3/4" or less in length.
  • the nineteenth selection is the overall size of the device.
  • the device must typically fit in the palm of one hand. It must also be light enough that it can be easily manipulated so that the device can be aimed accurately and the material can be delivered to the desired area.
  • the gas container or reservoir is an important feature in that it pressurizes a repeatable volume of gas to a repeatable pressure and volume.
  • the gas container also includes a releasable gas pressurization device and a mechanism for activating release of the pressurizing device.
  • FIG. 1 is a schematic, longitudinal, cutaway view of one embodiment of the invention revealing internal components of the embodiment.
  • FIG. 2A is a schematic cutaway front view of the housing shown in FIG. 1.
  • FIG. 2B is a bottom view of the housing
  • FIG. 2C is a side view of the portion of the housing extending downward from the lines C-C in FIG. 2 A.
  • FIG. 3A is a schematic view of the piston and latch assembly of FIG. 1.
  • HG. 3B is a schematic, enlarged side view of a latch shown in FIG. 3 A.
  • FIG. 4A is a schematic, expanded view of one-side of the inner wall surface of the twist ring or sleeve with a latch pin shown in FIG. 1.
  • FIG. 4B is a schematic, bottom view of the twist ring or sleeve shown in FIG.
  • FIG. 4C are schematic, top and side views of a device to release the piston shown in FIG. 1.
  • FIG. 5 is a schematic, side section view of an eductor pump shown in FIG. 1.
  • FIGS. 6 A, 6B, and 6C show schematically a variation of the eductor pump of
  • FIG. 7. is a schematic diagram of a venturi inventively modified to be a pump and feeder tube portion of an embodiment of the invention otherwise similar to that in FIG. 1.
  • FIG. 8 is a schematic, side view of a form of pump which is an inventively modified venturi.
  • FIG. 9A is a schematic, cutaway, longitudinal view of an embodiment of the invention employing a metering wheel or paddle wheel to feed a liquid for induction (entrainment) into a gas stream.
  • FIG. 9B is a front view of the metering wheel in FIG. 9A.
  • FIG. 10 is a schematic, cutaway front view of another embodiment of the invention employing an eductor pump mechanism for inducing and metering a liquid into an air stream.
  • FIG. 11 is a schematic view of the device of FIG. 10 showing a venturi modified as a pump in place of the eductor (jet) pump of FIG. 10.
  • FIG. 12 is a schematic view of a pump, reservoir and feeding tube for use in embodiments of the invention enabling use of the device in a horizontal or vertical position.
  • Figure 13 is the device body (ID 150) without rings and caps
  • Figure 14 is the device body (ID 150) with rings and caps
  • the direct ejection technique requires the use of gas which is pressurized in order to propel the ejected liquid with sufficient velocity to reach the eye.
  • the direct ejection technique causes ejection of at least some of the liquid before the gas has reached a velocity sufficient to propel the liquid to the surface of the eye.
  • the direct ejection technique causes an audible pop or snap as the liquid is ejected, resulting in blinking and the potential for consequent misplacement of the liquid.
  • This invention employs a gas such as air, N 2 , CO 2 , or any other gas which is inert and safe for medical applications, to induce the delivery of a measured amount of fluid, often aqueous, to the eye.
  • a gas such as air, N 2 , CO 2 , or any other gas which is inert and safe for medical applications, to induce the delivery of a measured amount of fluid, often aqueous, to the eye.
  • the first method is a single step induction method.
  • the single step method uses the motive gas for metering and delivering a material to the eye.
  • the volume of material delivered to the eye is controlled by the volume and pressure of the motive gas.
  • the second method is a two step induction method. In this method the desired volume of material is pre-metered into a passage or compartment.
  • the motive gas is forced through the compartment to mix with and eject the preselected amount of material through a nozzle to the eye.
  • Several apparatus embodiments are described which are multiple dose devices, although they are also capable of operating as unit dose devices. These embodiments implement the overall process of the use of gas induction — i.e., the movement of a measured volume of gas to separate and deliver small preselected volumes of fluid to the eye or other sites.
  • the embodiments shown use a piston and spring for the creation of a momentary predetermined high pressure air pulse of a predetermined volume.
  • the air pulse may be generated in a variety of ways, and that other gas sources such as pre-pressured cartridges or canisters of CO 2 , N 2 or other non-toxic, non-flammable gases (such as Noble gases) may be used in conjunction with appropriate valving schemes.
  • gas sources such as pre-pressured cartridges or canisters of CO 2 , N 2 or other non-toxic, non-flammable gases (such as Noble gases) may be used in conjunction with appropriate valving schemes.
  • FIG. 1 A single step induction system is illustrated in FIG. 1. This system employs a measured amount of gas delivered at a given pressure to induce a measured volume of fluid to be pulled into the mixing stream of the pump, become mixed with the air stream, and then ejected from a nozzle.
  • FIG. 1, FIG. 2, FIG. 3, and FIG. 4 show the principal components of a gas entrainment delivery system using an eductor pump (sometimes referred to as a jet pump).
  • a venturi or paddle wheel may be substituted for the eductor pump without departing from the spirit of the invention.
  • the principal components are:
  • a main body or housing 10 which houses a spring 12, piston 14, release mechanism and cocking mechanism 16, and material reservoir 18, and serves as the base for a eductor pump 19 (or a venturi).
  • the body 10 in one preferred embodiment is typically about 3/4" to 1" in diameter and about 1" to
  • the cocking mechanism 16 enables the piston 14 to be pulled back a predetermined distance, and the spring 12 to be compressed.
  • the cocking mechanism employs a rotating sleeve 22 which enables the piston to be cocked by twisting the sleeve.
  • the sleeve has a slanted groove shown in
  • FIG. 4A which engages a catch mechanism 20 on the bottom of the piston.
  • the sleeve is typically about 1/8" to 1/4" larger in diameter than the main body and about 1/2" high.
  • the catch mechanism shown in FIG. 3 comprises two catches 24 spring loaded by metallic spurs 26 attached to a centralizing disk
  • the reservoir 18 is preferably close to the eductor pump 19, and contains a liquid.
  • the reservoir 18 has a feeder tube 32 extending through the top of the reservoir down to the bottom to enable the liquid to be pulled up into the eductor pump for delivery.
  • the reservoir 18 is doughnut shaped to permit a passage 34 to allow air to flow through the middle from above piston 14 to drive the eductor pump 19 affixed to the top of housing 10.
  • the outer diameter of the reservoir 18 is the diameter of the main housing 10, and there is an inner diameter to allow the air tube 34 to pass through the middle.
  • the eductor pump 19 converts pressurized gas from passageway 34 into suction, and pulls liquid from the reservoir 18 up the feeder tube 32 into the pump, and then ejects it onto the eye.
  • the eductor pump here comprises an inner nozzle 36 and an outer nozzle 38.
  • the inner nozzle 36 is called the jet
  • the outer nozzle 38 is called the diffuser.
  • the diameter of the diffuser is preferably larger than the diameter of the jet.
  • the operation of the eductor pump for this system is explained in more detail below.
  • the eductor pump may be cylindrical in shape.
  • the piston 14 is a free-sliding piston which is sealed against the housing 10, and connected to a shaft 11 and disk 28 for guiding the piston.
  • the guiding mechanism is connected to the cocking mechanism 16.
  • the spring 12 is positioned between the piston 14 and one or more spring stops 13.
  • the spring is also centered around the shaft 11.
  • the spring is compressed by action of the cocking mechanism as it is drawn with piston 14 by the cocking mechanism.
  • the cocking mechanism includes a sleeve 22 which has two opposed, inclined grooves or tracks 44.
  • the sleeve typically may be larger than the housing. It also includes a pair of spring loaded latches or catches 24 which snap into the grooves when the piston 14 moves downward against the spring 12.
  • the catches 24 are biased outward by spring members attached to the disk 28. Rotation of the sleeve causes the catches 24 to ride down along the grooves, until the catches enter deeper recesses or holes in the sleeve 22.
  • the release mechanism 46 may comprise elongated buttons or rods 48 which are positioned on the sleeve 22 opposite the catches 24 when in their cocked position. Simply pushing or pressing the buttons or rods 48 inward displaces the catches 24 inward and out of the grooves 44, thereby freeing the spring to thrust the piston upward. Upward movement of the piston compresses and drives a selected volume of gas through the passageway 34 and thence the eductor pump. This, in turn, draws a selected volume of liquid from the reservoir 18 through the feeder tube 32 and into the gas stream. The liquid mixes with the gas and jets through the outer nozzle 38.
  • FIG. 2A A drawing of the housing with the piston and twist ring removed is shown for clarity in FIG. 2A.
  • the piston and the locking and release mechanisms are shown in HG. 3 A and FIG. 3B.
  • the twist ring is shown in FIG. 4 with a slanted slot cut on the inner surface of the ring. There are two slots on the twist ring, one on each side of the twist ring.
  • H normalized head pressure and is a constant (meters 2 /sec 2 )
  • P pressure in pascals (Pa)
  • p mass density of the fluid
  • V the fluid velocity in meters/second (Fox and McDonald, 1992).
  • the constant, H, on the right hand side of the equation will be referred to as the head or stagnation pressure normalized to the density of the gas or fluid.
  • the stagnation pressure is a normalized quantity composed of the static pressure P and the dynamic pressure pV 2 /2. These quantities are normalized to the fluid density for simplicity. This equation is consistent for a consistent set of units, such as MKS units.
  • Vi can be considered to be zero before the fluid enters the nozzle.
  • the following equation relates the nozzle velocity to the normalized head pressure, hi.
  • Equations 5 and 5 A establish the relationship between the velocities at the nozzle and in the diffuser, and the motive, suction, and exit pressures, P ⁇ P s , and P 2 , respectively. These equations may be combined and provide an expression for the relative ability of the eductor pump to eject the suction fluid. This relative pumping ability is expressed as the head ratio, R H , expressed in terms of the pressures at the ports of the pump:
  • the density of the fluid gas mixture is difficult to determine a priori. This mixture, or average density, depends strongly on the properties of the material to be delivered, and the details of the pump. One factor, for example that changes the relative fraction of liquid or material from the reservoir induced into the eductor pump is the length of the feeder tube.
  • the mixing ratio, r may be defined as the average volume of ejected suction fluid, v SU ct_on > to the average volume of motive gas initially displaced by the piston, v gas :
  • the average mass density of the ejected mixture may be computed by finding the total mass of the ejected mixture and dividing by the total volume of the ejected mixture (at the exit or atmospheric pressure). This may be expressed in terms of the motive gas density, the suction fluid (material to be delivered) density, and the mixing ratio as:
  • Empirical measurements show that for moderate displacements of air (i.e., 2-5ml), a suction fluid of water, and a short feeder tube, the relative volume of material ejected to the volume of motive gas displaced is approximately 1.4 to 1.8 ul/ml. If the average value of these ratios as determined in the example herin is used, the inventors have 1.6ul/ml, and an average density for p 2 of 2.8kg/m 3 .
  • a predetermined amount of suction fluid may be delivered by setting the pressure and the amount of motive gas to be displaced. This may be calculated by knowing the relative velocities of the motive fluid to the mixed fluid stream and may be calculated from R H as follows:
  • V M is the velocity of the mixed fluids that are ejected, and by using conservation of momentum the inventors can write the total mass of suction fluid transferred in terms of the total mass of the motive gas:
  • Equation (11) shows that the volume of the suction fluid, v suctlon transferred is controlled through the mixing ratio, r, by the total volume and density of the motive fluid, and the head ratio, R H at which it is delivered.
  • the total volume of fluid, v suction , ejected can be controlled by controlling the amount of gas, v gas _ at a known density and pressure that is forced through the nozzle. Mixing and turbulence losses have been included by adding an empirically determined efficiency, ⁇ (19).
  • equation 11 appears to be an expression for r in terms of other variables, R H depends on r through the term p 2 .
  • the first positive real root of equation (12) will give the mixing ratio if the motive, suction, and discharge pressures, the density of the motive and suction fluids, and the empirical efficiency coefficient are known.
  • the mixing ratio can then be determined.
  • This equation is limited in its predictive ability because it cannot be used until ⁇ is determined.
  • it is useful because it gives the mixing ratio, r, as a function of all of the other parameters of the eductor pump.
  • This equation is essential for determining how the mixing ratio changes when other variables such as motive gas pressure or density are changed. Although velocity does not appear explicitly in equation 12, it is clear that the pump action is caused by the flow of gas through the inner and outer nozzles of the eductor pump.
  • FIG. 36 can deliver reliably a 5ul volume to a pre-determined target, such as the eye, with a 20% standard deviation from the average.
  • the data are shown in following Table 1.
  • the feeder tube was about 2" long and the fluid level in the reservoir was about 3/4" below the eductor pump. Thus, the total hydrostatic head against which the pump had to work was about 3/4".
  • the volume of fluid delivered was determined using a petri dish containing a small wad of dry cotton on a precision scale. The nozzle was placed in close proximity to the cotton and then discharged into the cotton. The difference in the weight of the petri dish was measured before and after the discharge.
  • the suction fluid in this case was tap water which has a known density of 103 kg/m3.
  • the temperature of the water was approximately room temperature, estimated to be about 23°C.
  • the scale was a Mettler-Toledo Model AG245 with a 10 ug accuracy.
  • a change in weight of lOOOug (lmg) corresponded to a lul delivery to the cotton.
  • the piston used was that in a standard lOcc polyethylene syringe, and the pressure was applied by the thumb. Different volumes of air (2.5, 5.0 and 7.0 ml) were displaced from the syringe by its piston. The delivery was accomplished by a quick, sharp push to the syringe piston. The same operator was used for all of the test data shown here. Since the motive piston was pushed by hand, variability was probably introduced into these results; a spring or other mechanical means as described in the preferred and especially preferred embodiments of the invention provides more repeatable motive pressure.
  • Table 1 shows the volumes of suction fluid that were delivered by the above device by ejecting different quantities of air from the syringe.
  • the data in the first or left hand column show the quantities of suction fluid (tap water) that were delivered by 2.5 ml of air displaced by the syringe in 21 different trials.
  • the second and third columns show similar results, when the syringe delivered 5.0 ml and 7.5 ml volumes of air, respectively.
  • the data in Table 1 below show that as little as 2ul average volume of suction fluid may be delivered, with a standard deviation of about 22% of the mean.
  • the maximum volume was 2.9ul, while the minimum as 1.3ul.
  • the ratio of maximum to minimum volume delivered was about 2, and it was fairly consistent for all of the test data taken so far.
  • a further important feature of this data is that the mixing ratio of total suction fluid volume to motive gas volume changes noticeably from the 2.5ml of motive gas, to the 7.5ml of motive gas used.
  • the mixing ratio changes from 0.8ul/ml for 2.5ml of motive gas to 1.45ul/ml for 7.5ml of motive gas, respectively. This is about a 45% change in the mixing ratio from the minimum volume of gas used to the maximum volume used, which corresponds to about a 3-to-l change in the volume of motive gas.
  • evaporation of the liquid from the target on the scale was potentially a significant factor in the measurements.
  • the evaporation rate was proportional to the amount of liquid delivered to the cotton; smaller delivery volumes had a smaller rate of evaporation.
  • the readings were taken as quickly as possible after the delivery to the cotton, 10 to 20 sec, and efforts were made to keep the time between delivery and the measurement of the weight change constant.
  • the determining factor on the measurement time was the time for the scale to stabilize. The cotton target was changed after 5 to 10 deliveries.
  • the evaporation of the liquid from the target ranged from less than about 0.5mg per min for a fresh target to about 3 mg/min for the larger volume deliveries after about 10 deliveries.
  • the large evaporation rates were only observed with multiple deliveries of water to the cotton at relatively high volume (i.e., lOul). Overall, the evaporation rates were not considered to be significant for the measurements made.
  • Table 2 below shows data taken with a similar early prototypic eductor pump and motive piston. The important differences were that the feeder tube was shortened to about 3/4", and the liquid was about 1/4" below the eductor pump. The experimental design was otherwise the same as that for the data in Table 1. In these trials different volumes of motive air (1.0, 2.0, 2.5 and 4.0 ml) were used to deliver tap water as the delivery liquid. It may be seen that the standard deviations for this data are all very close to about 20% of the average volume delivered, except for the 4ml of air delivery which had a standard deviation of about 15% of the average value. More importantly, the mixing ratio computed using the average ranged from a minimum of 1.4ul/ml to 1.8ul/ml. This is a change of only 14% over the entire range of volumes delivered. The ratio of the change of motive gas volumes is 4 ⁇ l/lml or a range of 4-to-l.
  • Another feature of the mixing ratio of the long feeder tube is that for large gas displacements, it asymptotes to a value that approaches the mixing ratio for the short tube. This is due to the need to overcome the inertia of the liquid in the feeder tube. The shorter the feeder tube, the less the inertia that needs to be overcome. When a larger volume of motive gas is used, the liquid approaches a more constant steady flow, resulting in a more consistent mixing ratio.
  • dV ⁇ Ps P S uc, i o s8Z + V s K + P slal + F (13) dt
  • g the pull of gravity
  • z the height of the pump above the fluid level
  • Pstat the pressure corresponding to static force such as surface tension
  • Vs the velocity of the fluid in the tube leading from the reservoir to the eductor pump
  • K is a constant computed from the absolute viscosity of the fluid at the typical temperatures that are expected and the dimensions of the feeder tube
  • F the function F of the time derivative of the suction fluid velocity in the feeder tube.
  • the viscosity term for aqueous fluids with properties similar to water is negligibly small (0.5Pa) even for small diameter feeder tubes, in this case 0.05" diameter.
  • the flow for aqueous solutions is laminar, again because of the low volume flow of the suction fluid.
  • the gravity pressure is 120Pa for 1/2" of total lift (1/2" feeder tube).
  • the static pressure term was estimated from the amount of fluid that remained in the feed tube when the tube was held free in the air vertically and was about 3/8" which corresponds to a value of about 90Pa. Thus, the value of 210 Pa was used as an estimate for the overall suction head.
  • the measured mixing ratio, and estimating the relative head ratio R H corrected for the mass densities of the mixture and motive gas one can estimate the relative efficiency, ⁇ , of the eductor pump.
  • which is the pressure in excess of atmospheric pressure, in the piston is estimated at between 60kPa to 80kPa (i.e., 60-80% of one atmosphere).
  • the suction pressure, Ps is estimated to be about 210Pa.
  • Corresponding R H is between 285 and 380, which gives an efficiency, ⁇ , in the range of 0.07 to 0.09 using equation 12. Higher head pressures will tend to have lower values of e, but the reproducibility is better. Higher head pressures result in lower standard deviations of delivery.
  • the pump is an operational element of this invention, and may comprise an eductor pump, a venturi or a paddle wheel.
  • FIG 6 shows a simple design of an eductor pump. This pump only has three parts to assemble, including the feeder tube for the suction fluid.
  • One aspect of this pump design is that the housing for the motive jet, the pressure inlet, and the exit nozzle are all molded from the same piece. The small holes may either be molded or drilled quite easily.
  • This pump may be made from plastic, such as polyolefin, polystyrene, polyvinyl chloride, metal, or any rigid, castable, or moldable (epoxy, silicone rubber, polyurethane) material that is impervious to fluids such as water.
  • the outer shape is shown as rectangular here, the outer shape does not have any effect on the performance of the pump, therefore the most convenient outer shape may be made. There are no complicated moldings or assemblies required for this unit, and is therefore low cost.
  • the dimensions shown in FIG. 6 are representative of typical dimensions for a hand-held unit for self administration and may be varied to suit the application.
  • the assembly described also is of very low cost in both materials and construction.
  • FIG. 7 shows an example of how this may be implemented.
  • the passageway 50 that provides the head for the motive air is also connected to the reservoir 52 containing the material to be delivered.
  • the piston and the locking mechanisms are essentially the same as in the previous embodiment.
  • the housing shown in FIG. 7 now has an additional passage (component 54 in FIG. 7) from the pressurized gas tube 50 into the reservoir 52 to provide the static pressure which pushes against the moving stream in the venturi 56.
  • a very small feeder tube 60 connects from the reservoir to the venturi 56, and the reduced static pressure in the venturi 56 causes a pressure differential which forces the suction fluid to flow from the reservoir to the gas passage at a rate set by the driving pressure of the piston, the known fluid properties of the material to be delivered, and the diameter of the feeder tube 60 and the gas tube.
  • the material to be delivered is moved by the difference in pressure created when the flow velocity is increased above zero. Since the reservoir that contains the material to be delivered is at the pressure induced by the piston, that is the stagnation pressure, and the velocity is zero in this chamber, there will be a pressure difference that drives the material to be delivered up and through the tube 60 into the air flow. P s at the venturi 56 will be smaller than P 0 in the reservoir. If the gas velocity in 6 (FIG. 7) is not negligibly small, the reservoir will be pressurized to a pressure ⁇ Po but > Ps . The result will be that higher gas velocity will be required before the fluid is entrained.
  • FIG. 8 shows how to analyze the modified venturi and feeder tube portion of this system using a control volume.
  • the analysis proceeds by enforcing conservation of mass and momentum flow in and out of a well defined volume in space, specifically the venturi and feeder tubes.
  • the continuity of mass flow is: ⁇ A t + sV.A ⁇ PzVzAz (14) where A], A 2 , and A 3 are the cross sectional areas of the three passages, and pi, p 2 , and p s are the average densities of the motive gas, the composite mixture of gas and material, and the suction material respectively.
  • the difference in pressure on the fluid in the feeder tube may be expressed as:
  • Equation 15 Equation 15 and 16 may be combined and solved for the mixing ratio, r, in a manner similar to that used to derive equation 12.
  • the expression for the mixing ratio, r is:
  • This equation gives the mixing ratio in terms of the motive pressure, the ambient pressure, and the suction pressure, P 0 , P atm , and Ps, respectively.
  • the positive root of this equation corresponds to the physically meaningful solution. This expression is valid for R H greater than 1. That is, where the difference between the pressure P 0 and P atm is greater than the suction pressure required to move the material from the reservoir by the pump.
  • the venturi tube is the same diameter before and after the suction fluid tap, then motive gas must compress slightly to allow for the presence of the suction fluid.
  • the suction fluid is typically of high density and small volume compared to the motive gas. Therefore, entrainment of small amounts of suction fluid, or material, will not change the volume of the motive gas significantly. This means that neglecting the compression will not result in significant error.
  • the motive pressure difference is equal to the square of the velocity multiplied by one half of the density of the motive gas. This pressure difference only exists if the motive gas is in motion.
  • the discharge of the fluid into the air passage way has the effect of reducing the flow velocity, and hence the difference in pressure. The process is self-regulating, and the flow may be determined.
  • a mixing ratio of about 39ul/ml is calculated for this method. Losses due to turbulence and mixing reduce this number similarly to the eductor pump.
  • the mixture of gas and reservoir material is ejected as a series of one or more small droplets from the end of the nozzle, and hence onto the eye.
  • the controlled volume of gas from the driving piston, and the known pressure applied to the piston determine the amount of fluid to be delivered. Other factors such as the viscosity and surface tension of the liquid control the droplet size.
  • the limiting forces determining the delivery are the pressure in the container, the viscosity, gravity, and surface tension forces in the feeder tube, and reduced static pressure in the venturi due to the increase in the flow velocity. It may also be desirable for very high viscosity solutions to restrict the flow of gas into the material reservoir; this will reduce the rate of pressure rise in the reservoir, and reduce the relative flow of fluid into the chamber.
  • the most preferred embodiment uses a two diameter stream tube shown in Figures 21, 23, and 34.
  • the purpose of the two diameter tube is to provide a control of the reservoir pressure so that the relationship between the pressure in the stream tube where the mixing occurs and the reservoir pressure can be changed to obtain the desired mixing ratio.
  • a the head pressure needs to be high enough to assure that the ophthalmic fluid is delivered to the eye.
  • the head pressure to achieve this may cause the mixing ratio to be larger than is convenient.
  • the use of the two diameter stream tube allows the exit velocity and the mixing ratio to be controlled independently.
  • the two diameter stream tube allows the modulation of the reservoir pressure so that the equation for the mixing ratios for the two-diameter stream tube is:
  • a piston it is important that the piston diameter be large enough so that the rate of rise of pressure is rapid enough to generate the stream tube velocities needed to meter and eject the liquid or powder.
  • the gas is allowed to escape continuously throughout the travel of the piston. If the piston diameter is too small, then the travel velocity must be very rapid in order to generate the pressure rapidly. For an exit orifice of 0.18 mils diameter (diameter of final diameter where mixing with the ophthalmic fluid takes place) in the most preferred embodiment, it was found that 0.15" diameter piston would not satisfactorily generate the rapid pressure rise needed, while a piston sizes larger than 0.5" in diameter and up to 0.75 "in diameter were generally satisfactory.
  • the travel velocity of the 0.15" diameter piston needed to be too large to be practical for inexpensive components such as syringe pistons.
  • the piston diameter must not be too large, since, for a given force on the piston, the maximum pressure that can be generated is inversely proportional to the area of the piston.
  • These methods disclosed here are capable of delivering small quantities of material in a preselected amount of from about 1 nanogram to 1000 micrograms for powder or from 1 nanoliter to 100 microliters of liquid, or a combination of liquid and powder. Furthermore, the mixing ratios range weight, and 0.1 to 20,000 parts of gas per every part of powder by weight.
  • the most preferred Inventive Device ID 150 of this Application comprises a hollow, cylindrical, Main Body 151 shown in Figures 13, 14, and 21 consisting of : (1) Piston Housing 151 A (with a Hollow Cylindrical Interior 151E shown in Figure 20), hollow cylindrical First Spring Housing 151B (piston guide) and hollow cylindrical Second Spring Housing 151C .(That is each Housing has a slightly decreasing cross-sectional area from the preceding one, (although Hollow Cylindrical Interior 15 IE is the same cross- sectional diameter for all said Housings, except for Housing 151 A also shown in Figure 20, which has an upward, outward internal taper.)
  • each of the B and C Housings are step-downs from the preceding Housing and all have the same interior cross-sectional diameter (the reasons for this configuration are fully set forth below) and (2) Ejector Head 152 (all as shown in Figure 13), which is 1.07" in length.
  • ID 150 The major individual components of ID 150 were fabricated by using standard lathing, drilling and machine techniques on the PVC, Acrylic and Polyethylene pieces. (For instance the step-downs described for the said Housings above were accomplished by lathing the bottom portion of Housing 151 A into smaller concentric step-downs.) PVC was chosen as the construction material for Housing 151A, First Spring Housing 151B, Second Spring Housing 151C, and Ejector Head 152( 0.76" in diameter and 1.07" in length) comprising all major elements of ID 150 (3.34" in length and 0.9"in diameter at its widest cross-sectional location at Housing 151 A) of this preferred apparatus. This is because PVC was readily available, relatively inexpensive, easily machined and was easily bonded with adhesives to itself and to other components to result in the necessary water-tight and air-tight constructions.
  • inventive apparatuses within the scope of the invention can also be fabricated from other widely available plastics, such as thermoplastic materials such as polyethylene, polypropylene and polystyrene by injection molding in a suitably designed mold. And machining can be done on other plastics such as polycarbonates.
  • plastics such as thermoplastic materials such as polyethylene, polypropylene and polystyrene
  • Reservoir 171 as Liquid reservoir 171. It should be understood that although liquid is specifically referred to, powder could also be used. Thus, Reservoir 171 could also contain a powder for delivery. This also applies to reservoir 171 A, 179 A, 179B, 1613, and 1614, and any other similar material reservoirs discussed herein.
  • the Spring 153 for ID 150 is a stainless spring steel about
  • Piston 154 consisted of a PVC shaft 0.5" in diameter and about 1.5" in length and was machined from an ordinary, purchased PVC rod.
  • Piston 154 is movingly installed in Housing 151 A, Hollow Cylindrical First Spring Housing 15 IB and Hollow Cylindrical Second Spring Housing 15 IC.
  • the lower portion of Piston 154 consists of Shaft 157 and the Bottom Surface 157A of Shaft 157 is on top of Spring 153, with Latching Means Assembly 155 associated therewith as shown in Figure 16 including Slot 154A, Small Latch Spring 156 and Latching Pin 156A all within Spring Housings 151B and 151C.
  • Spring Housing 15 IB extends concentrically from the bottom end of Housing 151 A after being lathed to reduce its outer diameter from the starting rod of PVC thereby forming 151 A to have about a 1/4" less outer diameter than the outer diameter of Housing 15 IB.
  • This starting rod was about 3.5" long and was hollowed out (151E) so the same inner cylinder dimensions prevail throughout said Housings except for Housing 151 A and being sufficiently sized to contain the Spring 153 and Piston 154.
  • Spring Housing 15 IC was made in a similar manner to Spring Housing 15 IB.
  • Spring Housing 151C also extends concentrically from Spring Housing 15 IB and has the same inner hollow cylindrical dimension.
  • Spring Housing 15 IC is closed off at its bottom end by sealing with Housing Cap 15 ID ( Figure 14).
  • Cap 15 ID also serves the additional functions of supporting Spring 153 as well as certain Ring configurations for actuating release of Spring 153, as will be detailed below.
  • the Cap 151D can be made so that the spring Housings are effectively longer by making such Cap 15 ID deeper. This imparts great flexibility to spring selection
  • the net effect of this assemblage is a continuous Hollow Cylindrical
  • a vertical open slot 154A about 1/2" in length and 1/4" wide was cut in the longitudinal direction extending upwardly from the bottom of Spring Housing 15 IB and downwardly from the top of Spring Housing 15 IC .
  • This Slot accommodates both the up and down movement of Latching Pin 156A and the in and out horizontal movement of Latch Pin 156A.
  • Piston 154 is designated as Shaft 157 in which Horizontal Notch 155B is drilled with a less than about 0.25" cross- section.
  • This Notch 155B contains Latching Pin 156A, which compresses Small Spring 156, which Spring 156 rests against the interior end of said Notch 155B.
  • the total Latching Assembly Means 155 comprises Horizontal Latching Pin 156A (approximately 0.2" in diameter and 0.35" long), Small
  • the axis 156C of Latch Spring 156 or the center of Notch 155B was located about 0.15" from the Bottom 157A of the Shaft 157 of Piston 154. Such Bottom 157 A is in direct contact with the top of Spring 153 and is the part of
  • Piston 154 has a Top Portion 158 provided with Air Sealing means 159 made from a Latex Cap 160 attached to a Polyethylene Tip 156B. Both Tip 156B and Latex Cap 160 were obtained by removing them from a commercially available glue syringe obtained from a hobby store. Tip 156B was fixedly glued to the top of Shaft 157. Latex Cap 160 was snug fitted in an airtight fashion within the Continuous Hollow 15 IE. Tip 156B and Latex Cap 160 form Top 158 of the piston.
  • Latex Cap 160 was chosen to be about 0.635" in diameter. This choice was a result of a trade-off between being small enough to fit within a 0.9" inner diameter cylinder to move Latex Cap 160, and being large enough to provide a desired 1 to 2 milliliters(ml) of air with minimal travel of Piston 154.
  • the volume or amount of gas, preferably air chosen for processing in the apparatus ID 150 is central to the delivery of the preselected amount of fluid. It has been determined and is a feature of this invention that the pressure head and quantity of propulsion gas for each action of Piston 154 should be matched to the diameter of the Stream Tube 161 shown in Figures 21, 23 and 27 in order to flow through the ID 150 apparatus in about 0.5 to 1 second (short times are essential) in response to the movement of the Piston 154 when the pressure on Spring 153 is released.
  • a piston substantially larger than the one chosen will provide insufficient maximum high pressure head required for the need required by the ID 150 apparatus. If the piston is substantially smaller than the one chosen, the rate of gas pressure rise is too slow for proper operation of the apparatus.
  • Gas Reservoir 162 is chosen so that it is not small compared with the Fluid Reservoir 171.
  • TWIST RING AND RELEASE RING - Latch Pin 156A is under Twist Ring 163 and Release Ring 165 which in the cocked or loaded position(Shown in Figures 14,15,16,17,18, and 20).
  • Piston 154 is pulled downward by Twist Ring 163 as Twist Ring Camming Surface 166B pushes Latching Pin 156 A downward into Holding Notch 177 A of Release Ring 165.
  • ID 150 is cocked by action of Twist Ring 163, Latching Pin 156 A is held both in Notch 166 of the Twist Ring, and simultaneously in Holding Notch 177 A.
  • Notch 177 A is part of Camming Surface 168 on the inner surface of Release Ring 165 and covers Latching Pin 156A when Piston 154 is held in its restraining position by Notch 166 of Twist Ring 163.
  • the force on Twist Ring 163 is communicated to the Main Body 151 through the upper surface 163 A of Twist Ring 163.
  • Surface 163 A contacts shoulder 170A of the main body and holds Twist Ring 163 in place.
  • Twist Ring 163 is engaged in place by Release Ring 165, which is held in place by Cap 15 ID.
  • Horizontal Lug 169 is a small horizontally projecting lug configuration which is fitted on Housing 15 IC and engages Ring Limiting Cut 167 in Release Ring 165.
  • Horizontal lug 169 prevents Release Ring 165 from excessive horizontal rotational movement.
  • the outer diameters of Twist Ring 163 is about 1.03," that of Release Ring 165 is about .965" and that of Housing 151 A is 0.9.”
  • Twist Ring 163 must not only withstand the force of Spring 153 transmitted through Latch Pin 156A, Twist Ring Camming Surface 166B, and Twist Ring Notch 166 as it is compressed and cocked to drive Piston 154, but it still must be able to rotate on Housing 15 IB with little resistance. Accordingly, some friction reducing means is optionally but preferably employed.
  • a strip of Teflon Tape 170 is inserted appropriately in the Shoulder 170A between Housing 151 A and Housing 15 IB so that the top of Twist Ring 163 ( Figures 13 and 21) in contact therewith under pressure is still able to accomplish the purpose of easy horizontal movement when in contact with such Shoulder 170A.
  • Release Ring 165 is 0.56" in height. It is rotatably mounted on Housing 151C just below Twist Ring 163.
  • Figure 15 shows a cross-sectional horizontal cut of Release Ring 165 in which Radial Camming Surface 168 and Rotation Limiting Groove 167 are illustrated.
  • Rotation Limiting Groove 167 is provided on the inner surface of Release Ring 165 to engage Horizontal Lug 169 ( Figure 13, 20) located from 130 to 180 degrees of rotation from Slot 154A so that only about 90 degrees of rotation are allowed, which thereby restricts the vertical movement of Release Ring 165.
  • Pin 156A When Release Ring 165 is twisted, Pin 156A is released from Notch 166. When Pin 156A is released there is no restraint to hold Piston 154 in place and Spring 153 expands rapidly driving Piston 154 which compresses a predetermined amount of gas for delivery under pressure to Stream Tube 161. When released, Pin 156A rides up in Slot 154A against the inside of Twist Ring 163. It is to be noted that as one inventive feature, an oversize Spring 153 was selected. This was done deliberately as a result of an inventive selection, so that the entire expansion capacity of the spring is not utilized in the apparatus. Only a portion thereof is used. Thus, after the total volume of gas has been delivered Spring 153 still has unused compression capacity. By the same token Spring 153 is not compressed to the ultimate degree possible prior to its release to drive Piston 154.
  • Liquid Reservoir 171 was formed from specially constructed 4-Way Lug 164 made from a solid PVC cylinder by creating a Nipple 164 A with upper threaded Hollowed outer Portion 172 therein, having an outer diameter of about 0.25 " at its narrowest and 0.9" at the widest part of Lug 164 and an inner diameter of approximately 0.09" after being hollowed out to form inner passage 176.
  • the diameter of the Upper Threaded Portion 172 of the small upper dimension was about 0.3."
  • the 4-way Lug 164 was rigidly glued to the Top 173 of housing 151A and also served as Piston Closure Cap 174, as well as providing the threaded portion 172 for attaching into Threaded Portion 180A of Air Feed Conduit 175 in Ejector Head 152.
  • Air Feed Conduit 175 consists of Threaded Portion 180A, and Upper Portion 175A which connects to L-shaped Conduit 198.
  • Threaded Portion 180A shown in Figure 27 has mating threads for Threaded Upper Portion 172 of Nipple 164 A.
  • the upper concentric outer lap portion 164C of 4-way lug 164 also serves as the base of Liquid Reservoir 171.
  • the bottom portion of 4-way lug 164 is hollowed and shaped to house the upper portion of Latex Cap 160, which has been fitted to the top of Piston 154 by means of polyethylene tip 156B.
  • Air Feed Conduit 175 was drilled into Ejector Head 152 to connect with Gas Reservoir 162 so that an air or gas passage was created through the length of Ejector Head 152, so that gas or air could pass through Ejector Head 152, which is attached onto the Upper Threaded Portion 172 of Nipple 164 A by Threaded Portion 180A of Conduit 175.
  • Reservoir wall 179 has Top 180 which contains Taper 181. This permits the outer diameter 182 of Bottom 183 of Ejector Head 152 to seal with Top 180 as shown in Figure 27.
  • Figure 27 shows a cutway, front view of the Ejector Head 152 with the cutaway plane through the middle of Ejector Head 152.
  • Ejector Head 152 has reciprocal or matching l/4"-20 threads in Threaded Portion 180A that permit attachment of Ejector head 152 to Nipple 164A, which also connects Air Feed Conduit 175 to Conduit 176. Conduit 175 communicates through Air Feed Conduit 176 with Gas Reservoir 162. When Ejector Head 152 is tightly screwed onto the Threaded upper portion 172 of Nipple 164 A, the result is a necessary air-tight seal.
  • Teflon Tape 184 is wrapped around Bottom 183 of Ejector Head 152 to assist in making an air-tight seal against the Tapered Inner Wall 181 of Reservoir Wall 179.
  • Ejector Head 152 contains Confluence Orifice 190 (about 1/4" in diameter) suitable for housing Stream Tube 161 (0.5" long), which Tube 161 ( Figure 23) serves the function of mixing and ejecting liquid from Liquid Reservoir 171 and air(gas) from Gas Reservoir 162.
  • Stream Tube 161 has Axial Conduit 185 connecting each of its ends.
  • First Chamber 186 (20 to 40 thousandths of an inch in diameter and Second Chamber 187 (10 to 15 thousandths of an inch in diameter) each are components of this Axial Conduit 185 with its connecting bottom pointing orifices, which are designated as First Tap 188 and Second Tap 189.
  • First Tap 188 is provided to pressure the Liquid Reservoir 171 ( Figure 21) in a preselected pressure mode. Such pressurization of the internal portion of Reservoir 171 ( Figure 21) aids the removal of liquid from Reservoir 171 by helping or assisting in the overcoming of the liquid-surface and liquid-liquid adhesion forces that tend to make most liquids have initial resistance to removal from their reservoirs or from tubes connecting to such reservoirs. Second Tap 189 conveys a preselected amount of liquid from
  • Reservoir 171 to be entrained within air passing within Chamber 187 and then ejected therefrom to a target.
  • the degree of mixing within Chamber 187 is dependent on many factors, including the viscosity and density of the entrained liquid, the velocity of the air flow and the air pressure at the time of entrainment and the cross-sectional diameters of Chambers 187 and 186.
  • This connection between gas amounts and liquid amounts can be used to select the desired amount of liquid to be entrained and emitted from ED 150 through Exit Orifice 200 with the given quantity of gas selected.
  • Whatever mixing ratio is desired within the operating limits of a given apparatus of this invention, it is controlled by a novel and unobvious combination of several interactive factors including the propulsive force provided by Spring 153 on Piston 154 generating a propulsion gas which in turn is regulated by the size as determined for the diameters of First Chamber 186 and Second Chamber 187.
  • the properties of the conveyed material, such as a fluid will also influence these interactive factors.
  • Propulsive gas can also be supplied by exterior sources, such as pressurized gas canisters, a CO 2 cartridge being one example.
  • Stream Tube 161 ( Figures 13, 14, 21, 23, and 27) is a subcombination element, which can exist as a separate article on its own before incorporation into Ejector Head 152 or be directly drilled or molded into Ejector Head 152.
  • a particular configuration for Stream Tube 161 is described immediately following. It is to be understood that various modifications of stream tubes can be effected, as taught herein, to obtain a range of selected quantities of emitted liquids of varying viscosities. By the same token the amount of mixing in Second Chamber 187 can be controlled by a knowledge of these interdependent factors.
  • Stream Tube 161 is approximately 1/2" in length.
  • Axial Conduit 185 is for conveying fluid and gas. It comprises First Chamber 186 (relatively large) and Second Chamber 187 (relatively small). It is drilled through the center axis of Stream Tube 161.
  • First Tap 188 was drilled perpendicular to First Chamber 186 and Second Tap 189 along the same line was drilled perpendicular to Chamber 187.
  • First Tap 188 and Second Tap 189 have diameters of approximately 0.018" and provide connects from Chambers 186 and 187 respectively to Liquid Reservoir 171.
  • First Chamber 186 has a diameter of about 0.03"
  • Second Chamber 187 has a diameter of about 0.014"
  • Second Chamber 187 In the most preferable mode, the entry point of Second Chamber 187 is flared out about 2 times its diameter in a funnel-like cross sectional portion.
  • the same flare configuration can be utilized for First Chamber 186 and it is flared about 4 times the diameter of the First Chamber 186.
  • First Tap 188 is connected to larger First Chamber 186, which in turn is connected to the air space above the liquid level in Liquid Reservoir 171.
  • Tap 189 is connected to smaller Second Chamber 187 and its other end is ultimately connected to a conduit extending below the surface of the liquid level of Liquid Reservoir 171.
  • Confluence Orifice 190 or if more loosely fitted therein it can be glued to stabilize it.
  • Stream Tube 161 occupies about 2/3 of the length of Confluence Orifice 190 at one end thereof.
  • appropriate Sealing Means 192 (Ordinary glue) was used to seal all orifices obtained by drilling passageways through Ejector Head 152.
  • other sealants such as hot melts could be used. Sealants are provided so that Confluence Orifice 190 is no longer open at the end away from Stream Tube 161.
  • Orifices 194 and 195 are configured to join with and connect to Taps 188 and 189.
  • Confluence Orifice 190 connects with various orifices and various taps and conduits between Steam Tube 161, Liquid Reservoir 171 and Gas Reservoir 162.
  • Orifice One 193 provides access to provide for driving air or gas at the sealed end of Confluence Orifice 190.
  • Orifice 193 is connected to an air pressure source, that is Gas Reservoir 162 (in this embodiment) by First L-Shaped Conduit 198, which in effect is an offset connection from the outer location of Confluence Orifice 190 to the center 176 of 4-way lug 164 where entry to Gas Reservoir 162 is located.
  • Conduit 198 is obtained by drilling two intersecting passageways through Ejector Head 152 and then gluing the entryways from the entering drill bit side with Sealing Means 192 to provide airtight seals with.
  • Figure 24 shows a useful modification which could be incorporated into ID 150.
  • Figures 24A and 24B show Pistons 204 and 205 with One-Way Valves 204A and 205A included in them. These one-way valves can serve at least two important functions. First, they allow air to flow in through the head of the piston into Gas Reservoir 162 or a similar gas reservoir when Pistons 204 or 205 are pulled downward to prepare for delivery of fluid or material.
  • One-Way Valve 204A is a flexible flap that will open and allow air to flow through the piston when the gas reservoir pressure is lower than the ambient pressure. During the upward stroke of Piston 204, the pressure closes valve 204A and prevents backwards air flow.
  • One-Way Valve 205A shown in Figure 24B in Piston 205 is a small plug which seals against Air Passage 205B during the upward stroke of Piston 205. When the Piston 205 is pulled downward to compress a spring such as
  • Passage 205B as shown in Figure 30B.
  • Figure 24B further shows that One Way Valve 205 A will unseat and allow the free flow of air through Passage 205B when it is inverted. In this configuration, it will allow air to flow freely through passage 205B whether piston Piston 205 is moving upward or downward. This will prevent the ejection of any material when the device is inverted, thus preventing possible excess material or fluid from being ejected. It will also prevent suction of material in an undesirable manner, or the accidental evacuation of Feeder Conduit 196 or similar conduits if the operation of the device is attempted when the device is inverted, thus enhancing safety and usefulness of the apparatus.
  • Button Ring Assembly 203 is composed of Ring 203A, which contains notch 203B that slides over Horizontal Lug 169.
  • Button Ring 203A holds horizontal pivot 203D on which the Pivot Button 203C is mounted.
  • Horizontal Pivot 203D and Pivot Button 203C are located in Holding Notch 203E.
  • Pivot Button 203C can pivot on 203D inside Holding Notch 203E, and this allow the button to be pulled back so that Latching Pin 156A can be cammed downwardly by Twist Ring 163.
  • Rotation Limiting Notch 203B in conjunction with Horizontal Lug 169 prevents the Button Ring Assembly 203 from rotating, and holds the Pivot Button 203C aligned with Slot 154A.
  • Piston 154 is pulled downward by Twist Ring 163 as the Twist Ring Camming Surface 166B pushes Latching Pin 156 A downward into Holding Notch 203E.
  • ID 150 When Spring 153 of ID 150 is cocked, Latching Pin 156 A is held in Notch 166 of Twist Ring 163, and simultaneously in Holding Notch 203E.
  • the inward displacement of Pivot Button 203C pushes Latching Pin 156A inward past the inner diameter of Notch 166 as previously described.
  • the Piston 154 is released and spring 153 pushes Piston 154 upward as before.
  • the advantage of the Button Release 203 over the Release Ring 165 is that in some cases, it is easier to aim and deliver the material from the device with one hand that it is using Release Ring 165.
  • the button can be depressed with a single finger while the other fingers of the same hand hold the device.
  • a small spring can be added to assist in pushing Pivot Button 203C outward after it is depressed.
  • ID 150 it is possible for the inventive device, ID 150, to be modified to carry more than one type of fluid in separate reservoirs to be delivered with two separate stream tubes. This has the advantage that compounds which are in compatible in storage, but synergistic in their combined effects, can be stored in separate reservoirs and delivered with one concerted action.
  • Figure 26 shows one such embodiment.
  • the two Reservoirs 179 A and 179B can contain different fluids separated by Wall 202.
  • the Ejector Head 207 has two Stream Tubes, 206A and 206B which are connected to the same Gas Reservoir 162A, by Conduit 172A.
  • Conduit 172A splits into two separate conduits having each nominally half of the cross sectional area of Conduit 172 A.
  • the stream tubes may be similar to Stream Tube 161 previously described, or they may be of any of the types shown in Figure 33 or otherwise designed according to the principles of this invention.
  • Each of the stream tubes, 206A and 206B connects with feeder tubes 208A and 208B respectively.
  • the reservoir pressure may optionally be supplied by Taps 209A and 209B connected with Stream Tubes 206A and 206B respectively.
  • the latching and cocking mechanisms may be similar to those used in ED 150, and are not shown in Figure 26.
  • the distance between Stream Tubes 206A and 206B may be adjusted to suit the requirements of the particular use contemplated.
  • the centerline axes of the stream tubes can be nominally parallel as shown in Figure 26, or they can be angled inwardly so that they deliver their respective materials to the same location at some distance from the Dual Ejector Head 207.
  • embodiments with three or more reservoirs and stream tubes can be employed from the principles of what is described here.
  • the role of pressure head is very significant in the operation of the embodiments of the instant invention.
  • the gas (air as described in the preferred embodiment of the invention) pressure provides the driving force (velocity) necessary to accomplish several simultaneous and sequential functions vital to achieve the several important objects of the invention. It provides the dynamic gaseous medium into which the microvolume or submicrovolume liquid portion or microgram or submicrogram powder portion from the liquid reservoir is entrained. It also provides the driving force to mix such liquid or powder (material) to a greater or lesser extent as it is entrained within such driving gas and passes through the conduit from which it is delived to an ultimate target of choice.
  • That force provides not only a driving factor to propel such powder or microvolume or submicrovolume of liquid, but it is also the force necessary to overcome the natural adhesive attraction of the molecules of such liquid to each other or powder particle to each other in the reservoir and in the conduit as well as the additional attraction of such molecules to the inside surface of the conduit leading from the reservoir from which it is removed. But those forces are not to be overcome to the extent that the quantity of liquid or powder moved from the reservoir exceeds the microgram quantities or microvolumes expressly sought by the object of the invention. It should be noted that these same adhesive forces exerted by and upon powder particles and liquid molecules in a conduit prevent micro quantities of liquid (less than lOul) from being dispensed effectively by ordinary gravity driven droppers in the form of single controllable droplets. This is because at such small droplet sizes these natural adhesive or attractive forces are not exceeded by gravitational forces.
  • the driving gas must also simultaneously provide that reservoir pressure without concomitant diminishment of force so that it cannot accomplish the objects described above. Even a remarkably small increase of reservoir pressure greatly facilitates partially or completely overcoming the adhesive and attractive forces described above. Flexible bag reservoirs within an enclosed rigid structure can also be the recipient of such additional reservoir pressure.
  • the reservoir pressure supplied is going to be higher than the static pressure in Second Chamber 187 of Stream Tube 161 where Second Tap 189 connects.
  • the pressure difference between the pressure in Reservoir 171 and the static pressure in Second Chamber 187 is the amount that is essentially the pressure required to push the reservoir material through Feeder Conduit 196, through Second Tap 189 into Second Chamber 187 which is typically the suction pressure P s .
  • the difference between the reservoir pressure and the static portion of the pressure in the stream tube where the mixing occurs is essentially the suction pressure.
  • the various embodiments of the invention using the non-educting and educting stream tubes can select the dynamics of this process so that a selected material from the reservoir is entrained notwithstanding a constant motive head (driving) pressure. It is important to note as a design factor that this pressure difference can be time varying, especially when inertial forces of the suction fluid or material are significant. This effect can be adjusted by varying the length and the cross-sectional areas of the feeder tube.
  • reservoir pressure can be surprising low and still be effective.
  • a pressure as low as about zero , but slightly exceeding zero applied to the material reservoir is operable.
  • a reservoir pressure of 0.1 to 20 pounds per square inch above atmospheric pressure is preferred, and just above zero to 1000 (one thousand), preferably just above zero to 30 pounds per square inch above atmospheric pressure is operable.
  • the term "reservoir pressure” or “reservoir pressurization” refer to pressure applied to the material reservior, such as Reservoir 171 in the most preferred embodiment.
  • the pressure head of gas in a preferred apparatus of the invention at the peak of the plunger's compression stroke is at least 7.5 pounds per square inch for the eductor facet of this invention with reservoir pressurization and as high as 1000 pounds per square inch, preferably 10 to 60 pounds per square inch and most preferably 0 to 30 pounds per square inch. These pressure numbers are all above atmospheric.
  • all of the preferred apparatuses of the invention were operated effectively at about 15 pounds per square inch of pressure atmospheric.
  • the lower end of the useful pressure range is about one (1) pound per square inch above atmospheric pressure with reservoir pressurization.
  • This embodiment requires reservoir pressurization to be operable with the stream tube embodiments shown in Figure 33 A and 33B.
  • perfume atomizers with finger-squeezed compressible bulbs that utilize an eductor configuration (as opposed to the inventively operated eductors of the invention) utilize about 1 to 5 pounds per square inch of air to deliver much higher quantities of liquid (much more than the less than lOul preferred by the invention) and in a much wider pattern (and is unacceptable for ophthalmic uses) than that of liquid delivered by the preferred apparatus of the invention.
  • Figures 28 and 29 show Stream Tube 161E with 4 chambers of 4 different cross-sectional areas such that A ⁇ >A 2 >A 3 >A .
  • Figures 28 shows the use of Stream Tube 16 IE dual reservoirs for processing different materials by the process and apparatus of the invention.
  • the First Chamber 161 A and Second Chamber 16 IB provide pressurization for two different reservoirs.
  • Chamber 161C and Chamber 161D extract fluid or powder from two separated reservoirs.
  • the tube cross- sectional areas Ai and A 2 for Chambers 161 A and 16 IB respectively are chosen in relation to A 3 and A 4 for Chambers 161C and 16 ID respectively to provide the desired mixing ratios for the materials from the two reservoirs. More than two such reservoirs can be used.
  • Figure 28 shows an ejector head and reservoir with Series Stream Tube 161E and dual reservoirs.
  • 152 A is the ejector head body
  • 1612 is the conduit for introducing pressurized gas into the tube
  • 1613 is the first reservoir containing fluid or powder
  • 1614 is the second reservoir containing fluid or powder
  • 1615 is the pressurizing tap feeding into reservoir 1613 which may or may not have a one-way valve on the orifice entering into the reservoir
  • 1616 is the pressurizing tap feeding into reservoir 1614 which may or may not have a one-way valve on the orifice entering into the reservoir,
  • 1617 is the feed tube from reservoir 1613
  • 1618 is the feed tube from reservoir 1614.
  • the mixing process occurs in the last two chambers (Chamber 161C and 161D) of Stream Tube 161E.
  • FIG 25 shows a version of an apparatus with a pressurized reservoir and a non-educting stream-tube.
  • the reservoir pressure is modulated in time and magnitude to provide a clean-out sequence in the induction of an ophthalmic fluid.
  • Conduit 154C is used to pressurize the Reservoir 171 A. It is connected to the piston by a Flush Opening 154B providing entry to Reservoir 171 A through Conduit 154C in the side wall of the Housing 1151, that is a small distance, typically about 1/4 of the total travel length of the piston below the top of the cylinder. The pressure is then conducted to the reservoir by Conduit 154C through Orifice 154F.
  • Piston 1154 which may have dimensions similar to Piston 154 described above, but is a distinctly separate piston.
  • the method of operation is as follows: Piston 1154 is cocked by the twist ring as in previously described embodiments. When Piston 1154 is released and begins to be pushed upward by the spring, Reservoir 171 A is pressurized as in the previously described modified venturi mode of operation, and the material such as fluid or powder in the reservoir is entrained into the gas stream and then ejected out of the Stream Tube 154E. When the piston has traveled about 3/4 of its total distance, the orifice for pressurizing Reservoir 171 A is now below the seal of the piston, and hence is no longer pressurized.
  • powder can be used in the apparatuses of the invention either by itself or in conjunction with a liquid delivery.
  • the quantities of materials delivered can be substantially lower than 1 micro liter in volume or one microgram in mass. Indeed quantities as low as one nanoliter in volume or one nanogram in mass can also be delivered with the apparatus of this invention.
  • FIG 33 three different examples of stream tubes useable in this invention are shown.
  • the horizontal components of the stream tubes convey the motive gas and any gas-material mixture.
  • the vertical tube intersecting the various stream tubes conveys a portion of material from the reservoir containing such material.
  • the stream tube shown in Figure 33A is fundamental and is analogous in function and placement to second chamber 187 and tap 189 in the embodiment described above in Figure 23C and is shown here for completeness of this discussion.
  • the entry and exit cross- sectional areas Aj n and A out are the same, and this type of stream tube requires reservoir pressure (source not shown) as provided in the most preferred embodiment described above.
  • a in and A out differ in their respective diameter where A in > A out and the mixing ratio for this is as described previously in equation 19.
  • This type of stream tube allows the control of the mixing ratio as well as the provision of a back pressure when the reservoir pressure is removed as in the examples shown in Figures 25 and 30.
  • This stream tube only requires one tap into the reservoir which is an improvement in simplicity over the two tap stream tube. Because of this, the mixing ratio can be controlled by the ratio of the two cross sectional areas and any reservoir pressure will be applied directly from the piston and controlled by the piston position. Thus techniques to remove remaining reservior material from the stream tube junction after delivery such as shown in Figures 25 and 30 can be applied with this type of stream tube.
  • the embodiments shown in Figure 25 and 30 could be used with the types of stream tubes shown in Figures 33A and 33C.
  • the feeder tube is preferably placed close to the neckdown of cross-sectional area from A in to A out .
  • the length of the section of cross sectional area A out should preferably be at least 2 times the characteristic length of the cross section dimension.
  • the tap should preferably be placed at or as close as possible to the transition between A in and A out -
  • the teaching of the invention contemplates a variety of adjustments from selection of tube sizes and combinations thereof coupled with appropriate location of feeder taps.
  • Figure 35 shows Stream Tube 226 with the suction material feed to the stream tube by an Annular Slot 229 around the perimeter of the Stream Tube 226.
  • the motive gas is fed into Conduit, 226A, having an initial cross-sectional area Aj n .
  • the suction fluid is pulled up into an Annular Slot 229 by the pressure difference between the gas in Conduit 226A in Stream Tube 226 and the reservoir.
  • the suction fluid or powder enters the stream tube where the annular slot connects to the stream tube and is finally ejected out of Mixing Section 227.
  • the cross-sectional area of 227 is A out , and may be smaller than or equal to A in .
  • Mixing Section 227 after the annular slot shorter than would be for a simple tap into one side of the tube and still achieve the same degree of mixing.
  • Figure 36 shows an embodiment similar to that used to create the test data shown in Tables 1 and 2.
  • a lOcc Syringe, 223, was used to provide measured motive air connected through Fitting Conduit 225 for Ejector Head 221, in which a number of pump and pressure configurations were tested.
  • the Reservoir 222 contained the suction fluid, which was pulled up into Ejector Head 221 operating in an eductor configuration and ejected to a preselected target through Exit Orifice 224.
  • the mode of operation follows: The volume of air is selected by pulling the Syringe Piston 220 back a predetermined distance. The volume of air determines the volume of suction fluid delivered by the mixing ratio described above.
  • the Exit Orifice 224 is held 1-3 inches from the area selected for delivery, and the Syringe 223 is quickly pushed with the thumb. The air is pushed through the Ejector Head 221 and the correct amount of fluid is delivered to the selected target area.
  • the embodiment in Figure 36 can be used with any of the stream tubes that are described above herein. It was tested both with and without reservior pressurization. It was found that this embodiment was particularly useful when medicaments were administered in varying controlled quantities.
  • FIG. 9 An embodiment of the invention which employs a metering wheel is shown in FIG. 9.
  • the metering wheel 63 serves to separate and meter the flow of the liquid to be delivered into an air passage for induction ejection to the eye.
  • This embodiment performs a method which is basically related to the methods of the previous embodiments. It is envisioned that this embodiment will be preferable for delivery of fluids with higher viscosities.
  • the metering wheel embodiment includes a housing 60, piston 62, reservoir 64, bellows 66, air passageway 68, nozzle 70, shaft 72, centralizer 74, spring 76, extension tube 78 and level controller 80 and piston 82.
  • This embodiment also includes a cocking mechanism and release mechanism similar to that shown in FIG. 1.
  • the cocking mechanism includes a twist sleeve or ring 84 and one or more catches spring loaded by spring struts 86.
  • the sleeve 84 has an inclined groove or track in its interior surface for each catch and along with the catches moves when being cocked.
  • the release mechanism includes a manually operated sliding button or post 86 which releases the catches, thereby enabling the spring 76 to drive the piston 62 upward.
  • the piston displaces gas against the bellows 66 and flows through passageway 60 and nozzle 70.
  • the bellows 66 acts against the piston 82 which cooperates with the level controller 80 to maintain a desired level of fluid in the reservoir.
  • the fluid level is such as to immerse teeth or paddles 61 when at the bottom of the wheel 63.
  • Gas exiting the nozzle 70 turns the wheel 63 and induces a fluid material on the exterior surface of the wheel to mix with the gas stream. The mixture then ejects from the gas passageway to impinge on an eye or other desired body part.
  • the level controller 80 in FIG. 9 includes a floating ring 84, a bar ratchet 86, and a locking pawl or tooth 88.
  • the lower end of the ratchet 86 contacts the piston 82 and is free to move within the ring 84 and the extension tube 78.
  • the pawl or tooth 88 is pivotally mounted on the ring 86 and has a cam surface on one end and a tooth on the other. It is dimensioned such that when the cam surface contacts the top end of the reservoir 64, the tooth end engages and locks movement of the ratchet 86.
  • the locking action is selected to occur in a preferred embodiment when the fluid level immerses the teeth 61 of the wheel 63.
  • the locking action also fixes the position of the piston 82 until the level of fluid diminishes.
  • the pawl 88 may alternately be pivotally attached to the top of the reservoir 64 and still be actuated by a float such as the ring 84 to lock the ratchet 86.
  • the diameter of float 84 should be greater than the diameter of the extension tube 78.
  • Extension tube 78 allows the ratchet 86 to extend up past the top of the reservoir 64 to prevent spillage of the material .
  • the ratchet extends further up into the tube as the material is used.
  • the inner diameter is large enough to allow the ratchet 86 to freely slide in and out without impediment.
  • the ratchet extension 86 effectively connects the sliding piston 82 with the float 84 and engages the locking tooth 88 to prevent the piston 82 from moving any further upward when the fluid in the reservoir reaches an intended or predetermined level.
  • the ratchet extension is approximately 1/2" to 3/4" long, and is cylindrical in shape with one side consisting of serrated teeth. This side is also flattened slightly to help prevent the float from rotating with respect to the extension.
  • the spring strut 86 is attached to the lower part of the piston 62 — i.e., the disk 74 — and also has a catch or engaging member for the twist ring 84. This catch is pressed backward when the release button 86 is pushed, and enables the air piston 62 to move upward.
  • FIG. 10 is a schematic layout of an embodiment of the invention which involves a two-step gas entrainment procedure using a pump to eject fluid.
  • the apparatus in this embodiment includes three principal components — a source of metered compressed gas or air 100, a source of a metered fluid material 102, and a pump 104, in this case, an eductor pump.
  • the source of metered gas or air 100 is very similar in principle and components to the gas or air source of FIG. 9A, and its major components are only mentioned here. They include a housing 106, a spring 108, a piston 110, an gas or air passageway 112, a twist sleeve 114 and a cocking and releasing assembly 116.
  • the source of metered fluid 102 includes a fluid reservoir 118 with an external thread 120, an internally threaded cap 122 and piston 124 assembly, and a metering tube 126. Threading of the cap 122 onto the housing forces the piston 124 upward in the fluid material reservoir 118 and the tube 126.
  • the tube 126 is preferably calibrated and clear so that a known amount of a fluid material is ready for ejection. Actuating the spring 108 forces a known or metered amount of air through the passage 112 and the eductor pump 104, thereby inducing a fixed quantity of the fluid material to be ejected.
  • the volume to be delivered is determined precisely by the dimensions of the chamber. In FIG.
  • the clear tube 126 dimensions are typically such that when the tube is full a selected volume (e.g. lOul of material will be delivered). When the chamber is half full, only 5ul of material will be delivered. The user can see the material to be delivered in the tube and judge when it is full without having to possibly waste any material .
  • the advantage of this method over the single step method is that the device is not required to be held in an upright position to operate.
  • a further advantage of this method over the single step method is that the metering can be very precise with additional safety provided from accidental overdose.
  • Example 3 Illustration of The Use of The Novel Delivery System
  • Example 1 Described in Example 1.
  • each volunteer received 5ul of 0.25% timolol hemihydrate (Betimol) to the right eye (OD) and no treatment to the left eye (OS).
  • Timolol is a beta-blocker with ocular effects of decreasing the intraocular pressure and potential systemic side effects of bronchoconstriction, decreasing blood pressure and decreasing heart rate.
  • the device of the invention used to deliver the dose was a prototype that was calibrated so that the volume of material given was known from the volume of air displaced.
  • the device was a one-step gas induction delivery device that used an eductor pump to deliver the medicine. The person giving the dose was not involved in the evaluation of the volunteer. Two hours later intraocular pressure, blood pressure and pulse rate was again measured.
  • the blood pressure included both systolic and diastolic readings.
  • the percent reduction at Hour 2 using the left eye's intraocular pressure at Hour 2 as the control ranged from 13% to 25%.
  • Two subjects had a decrease in pulse rate at Hour 2.
  • One of these subjects had a pulse rate hange from 69 at baseline to 68 at Hour 2.
  • the other three subjects demonstrated a substantial increased in pulse rate ranging from 6 to 22 beats per min.
  • Ear Optic
  • Nose Nesal
  • Throat Dental Ora 1
  • Dermatologic Wound Healing
  • Cardiovascular Oncology
  • Chemotherapy Endocrine
  • Central Nervous System neurosurgical, neurologic, Urologic, Genital, Gynecologic, Obstetrical, Colorectal, General Surgical, Gastrointestinal, Pulmonary Orthopedic, Pediatric, Rheumatologic, and Pediatric.
  • Beta Adrenergic Antagonists/Blockers 1. Timolol Maleate

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  • Health & Medical Sciences (AREA)
  • Ophthalmology & Optometry (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un appareil et un procédé permettant de délivrer des quantités (exceptionnellement faibles) de liquides et de poudres de l'ordre du microgramme/microlitre ou à l'échelle du submicron, dans des configurations et des quantités spécialement appropriées à l'auto-administration de médicaments en ophtalmologie, sensiblement sans excès de dosage, ce qui est très avantageux pour de nombreuses applications topiques de médicaments avec lesquels on doit éviter les surdoses. L'oeil est particulièrement visé, car les surdoses peuvent alors avoir bien des conséquences médicales graves. On peut donc administrer des doses ophtalmologiques exceptionnellement faibles et répéter l'opération car les volumes de substances considérés s'y prêtent. Pour les médicaments, en particulier ophtalmologiques, on peut donc effectuer de multiples administrations répétées de la même quantité de médicament/vecteur en conservant une dose uniforme reproductible. Les variations d'une dose à l'autre restent très acceptables. En mode de réalisation préféré, l'appareil fait appel à une configuration venturi (19) modifiée avec gaz sous pression pour pomper les quantités exceptionnellement faibles depuis un réservoir (18) aux fins de distribution. De préférence encore, le réservoir est pressurisé par au moins une quantité de gaz dont la pression est quelque peu supérieure à la pression atmosphérique avant d'extraire par pompage les substances à administrer.
PCT/US1999/028852 1999-12-06 1999-12-06 Appareil et procede permettant de delivrer des petites quantites de liquide WO2001039892A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU18424/00A AU1842400A (en) 1999-12-06 1999-12-06 Apparatus and method for delivery of small volumes of liquid
PCT/US1999/028852 WO2001039892A1 (fr) 1999-12-06 1999-12-06 Appareil et procede permettant de delivrer des petites quantites de liquide

Applications Claiming Priority (1)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005102538A1 (fr) * 2004-04-22 2005-11-03 Robert Bosch Gmbh Dispositif pour pulvériser des fluides de pulvérisation
EP1654071B1 (fr) * 2003-08-13 2016-01-13 Unilever PLC Dispositif de pulverisation a usage domestique
TWI559386B (zh) * 2014-07-17 2016-11-21 Ｌｓ Ｔｅｃ股份有限公司 晶舟加載台用噴嘴組件及具備其的晶舟加載台
EP3043848A4 (fr) * 2013-09-11 2017-03-08 Bixa Research and Health Inc. Pulvérisateur intranasal jetable
EP3380176A4 (fr) * 2015-11-26 2019-07-24 Goumeniouk, Alexander Philip Dispositif, procédé et système d'administration déclenchée de médicament quantique ("tqd3")

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR731062A (fr) * 1932-02-05 1932-08-29 Appareil pour la projection de matières pulvérulentes sèches ou de matières semi-liquides
US3934585A (en) 1970-08-13 1976-01-27 Maurice David M Method and apparatus for application of eye drops
WO1996000050A1 (fr) 1994-06-23 1996-01-04 R.P. Scherer Corporation Dispositif de traitement oculaire
WO1996006581A1 (fr) 1994-08-30 1996-03-07 R.P. Scherer Limited Dispositif de traitement oculaire
WO1997023177A1 (fr) 1995-12-21 1997-07-03 Pharmacia & Upjohn Ab Traitement ophtalmique
WO1999043441A1 (fr) * 1998-02-26 1999-09-02 Abplanalp Robert H Pulverisateur de liquides et ajutage rapporte

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR731062A (fr) * 1932-02-05 1932-08-29 Appareil pour la projection de matières pulvérulentes sèches ou de matières semi-liquides
US3934585A (en) 1970-08-13 1976-01-27 Maurice David M Method and apparatus for application of eye drops
WO1996000050A1 (fr) 1994-06-23 1996-01-04 R.P. Scherer Corporation Dispositif de traitement oculaire
WO1996006581A1 (fr) 1994-08-30 1996-03-07 R.P. Scherer Limited Dispositif de traitement oculaire
WO1997023177A1 (fr) 1995-12-21 1997-07-03 Pharmacia & Upjohn Ab Traitement ophtalmique
WO1999043441A1 (fr) * 1998-02-26 1999-09-02 Abplanalp Robert H Pulverisateur de liquides et ajutage rapporte

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1654071B1 (fr) * 2003-08-13 2016-01-13 Unilever PLC Dispositif de pulverisation a usage domestique
WO2005102538A1 (fr) * 2004-04-22 2005-11-03 Robert Bosch Gmbh Dispositif pour pulvériser des fluides de pulvérisation
EP3043848A4 (fr) * 2013-09-11 2017-03-08 Bixa Research and Health Inc. Pulvérisateur intranasal jetable
TWI559386B (zh) * 2014-07-17 2016-11-21 Ｌｓ Ｔｅｃ股份有限公司 晶舟加載台用噴嘴組件及具備其的晶舟加載台
EP3380176A4 (fr) * 2015-11-26 2019-07-24 Goumeniouk, Alexander Philip Dispositif, procédé et système d'administration déclenchée de médicament quantique ("tqd3")

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