US20040074931A1

US20040074931A1 - Dual microliter dosage system

Info

Publication number: US20040074931A1
Application number: US10/296,487
Authority: US
Inventors: Louis Coffelt, Jr.
Original assignee: Individual
Current assignee: Individual
Priority date: 2001-05-22
Filing date: 2001-05-22
Publication date: 2004-04-22

Abstract

The invention is a dual microliter dosage system. This system includes; a dual microliter dose (12) suspended below an outlet (5). The first dose is one ball of liquid (6) or medicament. The second dose is one ball of gas (7). A typical first dose can be 3, 4, 5, 6, 7, 8 or 9 microliters, including others. The second dose is approximately 2 microliters, including others.

Description

CROSS REFERENCE TO RELATED APPLICATIONS

not applicable

STATEMENT OF FEDERALLY SPONSORED RESEARCH/DEVELOPMENT

not applicable

REFERENCE TO A MICROFICHE APPENDIX

not applicable

BACKGROUND OF THE INVENTION

There are many devices, designed to dispense microliter dosages of liquid or medicament. For example, in Laibovitz, et al., U.S. Pat. No. 5,997,518, an apparatus and method for delivery of small volumes of liquid is disclosed. This device utilizes a jet pump to dispense a dosage having the form of many droplets. In column 14, Table 1, experimental results of Laibovitz include:

experiment No. 1: Average 2.0 microliter, Standard Deviation 0.5, Max 2.9 microliter, Min 1.3 microliter.

experiment No. 2: Average 6.0 microliter, Standard Deviation 0.6, Max 7.1 microliter, Min 4.7 microliter.

In Cohen, et al, U.S. Pat. No. 5,881,956, a microdispensing ophthalmic pump is disclosed. This device dispenses a dose of approximately 5 microliters. The accuracy of the dosage for this device is unknown.

In Coffelt, Jr, U.S. Pat. No. 6,206,297, there is shown, devices and methods of manufacturing a gasdrop. These devices are typically a dual chamber device. The accuracy of the devices, for microliter dosages, is unknown.

Therefor the present invention will be greatly appreciated for delivering a microliter dose of a liquid or medicament, or a dual dose. And further, the liquid dose is accurate to within plus or minus 0.5 microliters.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING

The invention is further described by reference to the appended drawings taken in conjunction with the following description where: [0010]
FIG. 1 is a perspective sectional view of a dual microliter dosage system ([0011] 1); motive air via inlet (4) is ejecting the dual microliter dose (12).
FIG. 2 is a front view of a dispenser which includes: dosage system ([0012] 1); tube (8); bottle (10).
FIG. 3 is a front perspective sectional view of a dual microliter dose ([0013] 12) (microdose).
FIG. 4 is a sectional view of the system after beginning injection of air; the liquid having a concave surface at the upstream end of the liquid. [0014]
FIG. 5 is a front sectional view of the system after beginning injection of air; the concave surface of FIG. 2 beginning to form a bubble ([0015] 14); air injected into bubble (14) at point “B”.
FIG. 6 is a front sectional view of the system after beginning injection of air; the opening at point “B” (FIG. 3) is closed; a bubble ([0016] 14); a bubble (7); a dual microliter dose (15)(microdose) suspended below the outlet (5).
FIG. 7 is a front perspective sectional view of the dual microliter dosage system ([0017] 1) (static state).

DETAILED DESCRIPTION OF THE INVENTION

The present invention resides in a dual microliter dosage system. This system is utilized to dispense a dual microliter dose (microdose). The microdose is a spheroidal ball of liquid (first dose) enclosing a spheroidal ball of gas (second dose). [0018]
The microdose may be the first dose enclosing a plurality of the second dose. [0019]
In Coffelt, Jr., U.S. patent application Ser. No. 09/706,329, filed Nov. 4, 2000 (abandoned), an apparatus and method for manufacturing a gasdrop is disclosed. The accuracy of the devices in this Application, in the microliter range, is unknown. [0020]
The present invention includes a novel dual microliter dosage system. This system includes: [0021]
a flow channel having an inlet, and an outlet; [0022]
a first dose of a liquid disposed within the flow channel; [0023]
a second dose of a gas disposed within the liquid. [0024]
Embodiments of the present invention are hereinafter described with reference to the drawings, in which identical or corresponding parts are indicated by the same reference characters or numbers through the several views. [0025]
Referring to FIG. 7, there is shown, a left side perspective sectional view of a dual microliter dosage system ([0026] 1). The system is symmetrical, therefore, the right side view is a mirror image of FIG. 7. The system includes a conical tubular wall (2). The longitudinal axis of wall (2) is vertical. The upper end of wall (2) is integrally formed with a horizontal disk shaped wall (3). Wall (2) and wall (3) form a flow channel (33). Wall (3) is formed with a centrally located 0.25 millimeter diameter opening (4).
The inner diameter of the upstream end of the flow channel (located at wall ([0027] 3)) is 0.6 millimeters. The downstream end (5) of the flow channel is an annular arcuate surface, and the lowest extremity of this surface is a circle lying in a horizontal plane. The inner diameter of the flow channel (at 1 millimeter above said circle) is 1.4 millimeters. The volume of the flow channel is calculated to be approximately 8.9 microliters. For example, wall (2), wall (3), and opening (4) can be a standard dispensing tip from a 30 milliliter bottle of CLEAR EYES eye drops. The flow channel may have alternate configurations. For example, the flow channel may be cylindrical, 1 millimeter ID and 2 millimeter OD, including others.
A microliter dose ([0028] 6) is disposed within the flow channel as shown in FIG. 7. The lower surface of dose (6) is indicated by the arcuate line at point “A”. The upper surface of dose (6) is adjacent to wall (3). Dose (6) can be TIMOLOL 0.5%, TIMOLOL 0.3%, CLEAR EYES, VISINE, or water, including others. TIMOLOL is a product manufactured by Bausch & Lomb Pharmaceuticals, Inc. Tampa, Fla. 33637. CLEAR EYES is a product manufactured by Abbot Laboratories, Columbus, Ohio 43215. VISINE is a product manufactured by Pfizer Inc. New York, N.Y. 10017. Dose (6) is inherently in a static state (no motion). Dose (6) shown in FIG. 7 is 5 microliters.
A ball of gas (bubble) ([0029] 7) is centrally located in dose (6). Bubble (7) contains 2 microliters of a gas. The thickness of the liquid wall (between the bubble and wall (2) is inherently predetermined. Alternate volumes and quantities of bubble (7) can be empirically determined. Dose (6) and bubble (7), in FIG. 7, is inherently in a static state. A method of manufacturing system (1) (FIG. 7) includes:
(1.) With the longitudinal axis of the flow channel horizontal: inserting a syringe through the outlet; locating the tip of the needle near wall ([0030] 3); injecting dose (6). At this step, dose (6) is a unitary ball of liquid; the upper surface of the liquid is at wall (3).
(2.) Inserting a syringe though the outlet; locating the tip of the needle near the center of dose ([0031] 6); injecting a gas into dose (6) via the needle. This step injects bubble (7) into dose (6).
Obviously there are variations of the above method. For example: wall ([0032] 2) may be adapted with an inlet near wall (3), and an inlet near the center of the flow channel.
The flow channel can be any material which holds dose ([0033] 6) in a static state. For example, low density polyethylene, teflon, or vinyl. If plastic, the flow channel can be manufactured standard methods, including injection molding.
Referring to the above described dosage system ([0034] 1), the following is a method, among others, of use.
The system is fitted to a transparent vinyl tube ([0035] 8). Tube (8) is 6.3 millimeters OD, and 4.3 millimeters ID, and 15 millimeters length. Wall (3) is located at the end of tube (8). Tube (8) is co-axial with wall (2). An annular leak tight seal (9) rigidly attaches the system to tube (8). For example, seal (9) and subsequent seals can be an epoxy resin.
The upper end of tube ([0036] 8) is fitted with a 30 milliliter flexible plastic bottle (10). A 1 millimeter diameter opening (16) is bored through the bottle wall at point “S”. The objective of opening (16) is to remove a possible undesired pressure drop across opening (4) during injection of dose (6) and bubble (7). For example, bottle (10) can be a standard 30 milliliter CLEAR EYES bottle. An annular leak tight seal (11) rigidly attaches the bottle to tube (8). The longitudinal axis of the bottle is co-axial with tube (8).
Dose ([0037] 6) and bubble (7) are injected into the flow channel, as described above, and shown in FIG. 7.
The bottle is held by a thumb at point “S” and a finger at point “T”. Points “S” and “T” are opposing points on the body of the bottle. These points are the typical points used to dispense a normal (approx 29 microliter) pendant drop of liquid from the unaltered CLEAR EYES bottle. The thumb and finger apply opposing compressive force on the bottle. This compressive force closes opening ([0038] 16). Alternate methods may be utilized to close opening (16) during compression of the bottle. For all of the above listed liquids (e.g. TIMOLOL), the total displacement of the bottle walls, required to dispense the microdose, is approximately 3 millimeters. The total time required for this displacement is approximately 550 milliseconds. Alternate displacements and collapsing velocities can be empirically determined. The above volume reduction of the bottle creates a pressure drop across opening (4). Therefore, the gas disposed in the bottle is injected into the flow channel via opening (4) in the direction shown by the vertical arrow in FIG. 1. This gas flow (motive air) ejects the microdose (12) from the flow channel through the outlet, as shown in FIG. 1. While holding the dispenser above a target, the microdose will fall vertically upon the target.
The configuration of the microdose, after ejection is inherently predetermined. This configuration is observed to be identical for each trial. For dose ([0039] 6) between approximately 7 microliters to approximately 9 microliters, the configuration of the microdose may be as shown in FIGS. 4, 5 and 6. For example: an 8 microliter dose (6) may have the configuration as shown in FIG. 6.
Given the above parameters, there are 2 possible configurations as follows: [0040]
(1.) the microdose is one ball of liquid enclosing one ball of air (microdose ([0041] 12)).
(2.) the microdose is one ball of liquid enclosing at least 2 compartments; and each compartment encloses a gas (microdose ([0042] 15)).
FIG. 1, and FIG. 3 shows the configuration of a 3 microliter dose ([0043] 6). This configuration is a spheroidal ball of liquid (6) enclosing a ball of gas (7) (microdose (12)
FIG. 4, FIG. 5, and FIG. 6 show a possible sequence of events which dispense the microdose in the form of a microdose ([0044] 15). In FIG. 4, the upper surface of the dosage becomes concave. In FIG. 5, the concave surface of the liquid begins to form a bubble, having an opening at point “B”. In FIG. 6, the opening at point “B” closes, forming a bubble (14). Therefore, the combination of dose (6), bubble (14), and bubble (7) forms a microdose (15).
The following experiments A to D, were executed utilizing the above described method and dispenser. The equipment utilized in these experiments is as follows: [0045]
(1.) Prototype “P[0046] 1”. This prototype has the form of the dispenser as shown and described above in FIG. 2. The flow channel (33), and opening (4) is provided by a standard dispensing tip from CLEAR EYES eye drop bottle. The bottle (10) is a standard flexible plastic 30 milliliter CLEAR EYES eye drop bottle.
(2.) Liquid dose as noted. [0047]
(3.) Standard 1 cc syringe (for liquid), 29 gauge (12.7 mm) needle manufactured by Becton Dickinson, Franklin Lakes, N.J. 07417 US. A # 8-32 nut is rigidly attached co-axial with the plunger. A 5 centimeter diameter wheel is rigidly attached (co-axial) to a # 8-32 screw. The wheel is marked at 30 degree increments. The markings are located at the OD of the wheel. The objective of the screw is to displace the plunger. The objective of the wheel is to measure the rotation of the screw. The end of the screw is milled to a conical shape having a diameter of 0.3 millimeters at the end. A thin sheet of steel is rigidly attached to the end of the plastic plunger. Prior to attaching, a centrally located depression is formed on the sheet of steel. This depression is 0.5 millimeters diameter. The objective of the depression is to maintain the location of the screw on the plunger. The screw is placed on the nut. This syringe is used to inject dose ([0048] 6). Calculations indicate a 27 degree rotation dispenses 1 microliter
(4.) Standard 1 cc syringe (for air). This syringe is identical to the syringe described in No. 3 above. This syringe is used to inject bubble ([0049] 7).
(5.) Holding fixture “C” for the air syringe (fixed location). [0050]
(6.) Holding fixture “D” for Prototype “P[0051] 1” (moveable). These holding fixtures maintain the needle co-axial with the flow channel.
(7.) Magnifying glass, 90 millimeter diameter, approx 5 times power. [0052]
(8.) Scale, 100 divisions per inch, No. 305 R, manufactured by L. S. Starrett, Athol, Mass. US. [0053]
The procedure for experiments A to D include the following steps: [0054]
(1.) For dose ([0055] 6), insert needle (syringe is hand held) into the flow channel (via the outlet of the flow channel), locate the tip of the needle near wall (3), rotate wheel, wait 12 seconds, remove needle, record delta AL (angular rotation of the wheel for liquid). NOTE: It takes approximately 70 seconds to eject the entire quantity of liquid. And the residual liquid remaining on the needle after each trial is 0.5 microliters for delta AL between 90 degrees and 210 degrees; the residual liquid remaining on the needle is 0.2 microliters for delta AL between 30 degrees and 60 degrees.
(2.) For bubble ([0056] 7), (while holding fixture “D” only) insert needle (syringe is on fixture “C” and prototype “P1” is on fixture “D”) into the flow channel (via the outlet of the flow channel), locate the tip on the needle near the center of dose (6), rotate wheel, wait approx 5 seconds, air is injected into dose (6), a bubble (7) is located near the center of dose (6), while holding fixture “D” only: remove the needle. Record delta AA (quantity of rotation of wheel (for air) in degrees. Note: The longitudinal axis of the needle, and the longitudinal axis of the flow channel are horizontal for steps 1 and 2. For approximately 1000 trials, the location of dose (6) and bubble (7) were measured with the above described scale and magnifying glass.
(3.) While holding fixture “D” only: rotate fixture “D” such that the longitudinal axis of the flow channel is vertical. Observe configuration of dose ([0057] 6) and bubble (7).
(4.) compress bottle walls at points “S” and “T” a total distance of approximately 3 millimeters. This displacement occurs within approximately 550 milliseconds. a possible time includes approximately 900 milliseconds. [0058]
(5.) observe output, and record data. [0059]
In the following experiments: [0060]
delta AL is the quantity of rotation of the wheel (for dose ([0061] 6)), in degrees. delta AA is the quantity of rotation of the wheel (for bubble (7)), in degrees. And the dose is the actual quantity of liquid injected into the flow channel.

EXPERIMENT A

Results in Table I; dose ([0062] 6)=TIMOLOL 0.3%, delta AL=90 degrees, dose (6)=3 microliters, delta AA=60 degrees, bubble (7)=2 microliters, air temperature at # 1 is 27.0 C and at # 21 is 24.5 C, the average total time per trial is 150 seconds (this time includes the time required to record data). NOTE: 4 trials were executed (prior to experiment D) with prototype “P1” utilizing TIMOLOL 0.5%, results:
Trials 1 and 2: dose ([0063] 6)=3 microliters, bubble (7)=2 microliters, bubble (7) was located at the upstream end of liquid. Trials 1 and 2 dispensed a microdose/1.4 mm diameter.
Trial 3: dose ([0064] 6)=4 microliters, quantity 2 bubbles (7) 1 microliter each, bubbles are centrally located in the liquid. Trials 3 dispensed a microdose/1.8 mm diameter.
Trial 4: dose ([0065] 6)=4 microliters, quantity 3 bubbles (7), first bubble (7)=0.5 microliters located near upstream end, second bubble (7)=1 microliter located midstream, third bubble (7)=0.5 microliters located near downstream end. Trial 4 dispensed a microdose/2 millimeters diameter.
For these trials 1 to 4, there was excessive residue in the flow channel, and this is likely undesirable, therefore no further experiments were executed with 0.5% liquid. [0066]

EXPERIMENT B

Results in Table II; dose ([0067] 6)=CLEAR EYES, delta AL=90 degrees, dose (6)=3 microliters, delta AA=60 degrees, bubble (7)=2 microliters, air temperature at # 1 is 27.2 C, the average total time per trial is 270 seconds.

EXPERIMENT C

Results in Table III; dose ([0068] 6)=CLEAR EYES, delta AL=150 degrees, dose (6)=5 microliters, delta AA=60 degrees, bubble (7)=2 microliters, air temperature at # 1 is 26.5 C and at # 26 is 27.0 C, the average total time per trial is 122 seconds.

EXPERIMENT D

Results in Table IV; dose ([0069] 6)=SPARKLETTS distilled drinking water. SPARKLETTS is a product manufactured by Danone Waters of North America, Stamford, Conn. 06902 US, delta AL=90 degrees, dose (6)=3 microliters, delta AA=60 degrees, bubble (7)=2 microliters, the air temperature at # 1 is 27.0 C and at # 17 is 25.0 C, the average total time per trial is 133 seconds. NOTE: this experiment includes trials # 18 to 23, with a dose (6)=4 microliters, bubble (7)=2 microliters,
Results: [0070]
4 trials dispensed a microdose/1.2 mm dia. [0071]
2 trials dispensed overspray only. [0072]
Additional experiments with “P[0073] 1” and the above liquids and parameters dispensed microdoses having a dose (6) of 7, 8, and 9 microliters. The results for these 7 to 9 microliter doses are similar to the above results. Also experiments were executed with a cylindrical flow channel, 1 millimeter ID, 2 millimeter OD, 13 millimeter length, high density polyethylene. The results with this cylindrical flow channel (for dose (6) between 3 to 5 microliters) are similar to the above results.
The syringe and dispenser were flushed 20 times with SPARKLETTS distilled water, prior to experiment D. [0074]
All dimensions of the diameter of the microdose are estimates based on visual observation. For example, the configuration of the microdose appears to be identical for each trial, therefore, the diameter of each microdose appears to be identical, for each trial. The accuracy of the liquid dose is calculated to be plus or minus 0.5 microliters. The same person executed all trials. [0075]
There are variations of the above describe system, which will dispense a microdose. Several of the variations are described in experiment A. For example, there may be two or three bubbles ([0076] 7), the flow channel may be cylindrical having a 1 millimeter ID, there may be alternate collapsing velocities, alternate solutions, alternate gases, alternate mechanical methods of injecting dose (6); bubble (7). Opening (4) may have alternate diameters.

The bottle compressed by hand may be replaced by a mechanical apparatus. For example, a syringe adapted with a spring actuated piston, including others.

TABLE I


(TIMOLOL 0.3%)

		MICRODOSE
	TRIAL #	DIAMETER

	1	1.3 mm
	2	1.3 mm
	3	1.3 mm
	4	1.3 mm
	5	1.3 mm
	6	1.3 mm & overspray
	7	1.3 mm
	8	1.3 mm
	9	overspray only
	10	1.3 mm
	11	overspray only
	12	1.3 mm
	13	1.3 mm
	14	1.3 mm
	15	overspray only
	16	overspray only
	17	1.3 mm
	18	overspray only
	19	1.3 mm
	20	1.3 mm
	21	1.3 mm

TABLE II


(CLEAR EYES)

		MICRODOSE
	TRIAL #	DIAMETER

	1	1.2 mm
	2	1.2 mm
	3	1.2 mm
	4	1.2 mm
	5	1.2 mm
	6	1.2 mm
	7	1.2 mm
	8	1.2 mm
	9	1.2 mm
	10	1.2 mm
	11	1.2 mm
	12	1.2 mm
	13	1.2 mm
	14	1.2 mm
	15	1.2 mm
	16	1.2 mm
	17	1.2 mm
	18	1.2 mm

TABLE III


(CLEAR EYES)

		MICRODOSE
	TRIAL #	DIAMETER

	1	1.3 mm & overspray
	2	1.3 mm
	3	1.3 mm
	4	1.3 mm
	5	1.3 mm & overspray
	6	1.3 mm & overspray
	7	1.3 mm
	8	1.3 mm
	9	1.3 mm & overspray
	10	1.3 mm
	11	1.3 mm
	12	1.3 mm
	13	1.3 mm
	14	1.3 mm
	15	1.3 mm
	16	1.3 mm
	17	1.3 mm
	18	1.3 mm
	19	1.3 mm
	20	1.3 mm
	21	1.3 mm & overspray
	22	1.3 mm
	23	1.3 mm & overspray
	24	1.3 mm
	25	1.3 mm
	26	1.3 mm

TABLE IV


(SPARKLETTS)

		MICRODOSE
	TRIAL #	DIAMETER

	1	1.2 mm
	2	1.2 mm
	3	1.2 mm
	4	1.2 mm
	5	1.2 mm
	6	overspray only
	7	1.2 mm
	8	1.2 mm
	9	1.2 mm
	10	1.2 mm
	11	overspray only
	12	overspray only
	13	overspray only
	14	1.2 mm
	15	overspray only
	16	overspray only
	17	1.2 mm

The present Specification includes three distinct inventions as follows: [0081]
(1.) the appended claims; [0082]
(2.) A dual microliter dose consisting essentially of: [0083]
a first dose; [0084]
a second dose wherein; [0085]
said first dose is one ball of liquid; [0086]
said second dose is one ball of gas; [0087]
said first dose encloses said second dose; [0088]
(3.) A dual microliter dosage system comprising: [0089]
a flow channel having an inlet and an outlet; [0090]
a first dose disposed within said flow channel; [0091]
said first dose encloses a second dose wherein; [0092]
said first dose is one ball of liquid; [0093]
said second dose is one ball of gas. [0094]
Inherent properties of the microdose include: [0095]
(1.) exist suspended below a surface; [0096]
(2.) exist as a discrete article; [0097]
(3.) form a particular and repeatable overall size; [0098]
(4.) form one accurate and repeatable dose; [0099]
(5.) form two accurate and repeatable doses. [0100]
The present Specification includes specific doses, and these specific doses are presented for example only, and therefor, the range of the first dose, range of the second dose, particular first dose, or particular second dose, which dispense a microdose, can be empirically determined. [0101]
Obviously, many modifications and variations of the present invention, as hereinbefore set forth, may be made without departing from the spirit and scope thereof, and therefor, only such limitations should be imposed as are indicated by the appended claims. [0102]

Claims

I claim:

1. A microdose suspended below a surface comprising:

a first dose;

a second dose wherein;

said first dose is one ball of liquid;

said first dose encloses said second dose;

said second dose is one ball of gas;

said first dose is suspended below a surface.

2. The microdose suspended below a surface according to claim 1 wherein, said first dose is between approximately 3 microliters to approximately 9 microliters; said second dose is approximately 2 microliters.

3. The microdose suspended below a surface according to claim 1 wherein, said first dose encloses a plurality of said second dose.