Nasal cannula assembly with flow control passage communicating with a deformable reservoir

Abstract

The invention concerns a nasal cannula assembly (10) adapted to deliver gases to a patient comprising a first compartment (1) and a second compartment (2) separated by a separation wall (6); a pair of nasal prongs (5) in fluid communication with the first compartment (1); the first compartment (1) comprising a first inlet (11) for introducing a first gas into said first compartment (1); the second compartment (2) comprising a second inlet (2) for introducing a second gas into said second compartment (2); and the separation wall (6) comprising at least one flow restriction element (35) for controlling the passage of gas from the second compartment (2) to the first compartment (1).

Claims

1. A nasal cannula assembly (10) adapted to deliver gases to a patient, the nasal cannula assembly (10) comprising: a) a first compartment (1) and a second compartment (2) separated by a separation wall (6), b) a pair of nasal prongs (5) in fluid communication with the first compartment (1), c) the first compartment (1) comprising a first inlet (11) configured to conduct a first gas into said first compartment (1), d) the second compartment (2) comprising a second inlet (12) configured to conduct a second gas into said second compartment (2), and e) the separation wall (6) comprising at least one flow restriction channel (35) configured to permit a passage of gas from the second compartment (2) to the first compartment (1) in a reduced pressure state during an inhalation phase and prevent a majority of flow of the second gas from the second compartment (2) to the first compartment (1) in a higher pressure state, during an exhalation phase, relative to the passage of gas during a reduced pressure state, during an inhalation phase, wherein the separation wall (6) comprises at least two flow restriction channels (35), and wherein the at least two flow restriction channels (35) are arranged in the separation wall (6), directly opposite the pair of nasal prongs (5).

2. The nasal cannula assembly according to claim 1, wherein the first compartment (1) comprises the first inlet (11) forming a side gases entry in fluid communication with a gas transport conduct.

3. The nasal cannula assembly according to claim 1, wherein the nasal cannula assembly further comprises a hollow body (4) comprising an internal chamber (7) comprising at least the first compartment (1).

4. The nasal cannula assembly according to claim 1, wherein at least the first compartment (1) is part of a hollow body (4) configured to be capable of acting as a gas conduct or a gas manifold.

5. The nasal cannula assembly according to claim 1, wherein a hollow body (4) and said pair of nasal prongs (5) are integrally molded from a soft plastics material.

6. The nasal cannula assembly according to claim 1, wherein the pair of nasal prongs (5) are detachable from a hollow body (4) and selected from different sized prongs suitable for different sized patient nares.

7. The nasal cannula assembly according to claim 1, wherein the at least two flow restriction channels (35) connect the first compartment (1) and second compartment (2) and are rounded edged at an entrance from the second compartment (2) and have a reentrant aperture at an entrance from the first compartment (1).

8. The nasal cannula assembly according to claim 1, wherein the second compartment (2) comprises a deformable wall (14).

9. The nasal cannula assembly according to claim 1, wherein the second compartment (2) forms a deformable-wall reservoir comprising a fully inflated internal volume for the gas of about 0.5 to 5 ml.

10. The nasal cannula assembly according to claim 1, wherein the nasal cannula assembly does not comprise a sensor configured to detect an onset of patient inspiration.

11. The nasal cannula assembly according to claim 1, wherein the at least two flow restriction channels (35) prevent the majority of flow of the second gas from the second compartment (2) to the first compartment (1) in the higher pressure state, during an exhalation phase, relative to the passage of gas during the reduced pressure state, during an inhalation phase.

12. The nasal cannula assembly according to claim 1, wherein the at least two flow restriction channels (35) prevent >70% of flow of the second gas from the second compartment (2) to the first compartment (1) in the higher pressure state, during an exhalation phase, relative to the passage of gas during the reduced pressure state, during an inhalation phase.

13. The nasal cannula assembly according to claim 1, wherein the at least two flow restriction channels (35) prevent >90% of flow of the second gas from the second compartment (2) to the first compartment (1) in the higher pressure state, during an exhalation phase, relative to the passage of gas during a reduced pressure state, during the inhalation phase.

14. The nasal cannula assembly according to claim 8, wherein the deformable wall (14) of the second compartment (2) has a greater compliance while filling than when the second compartment (2) is full.

15. The nasal cannula assembly according to claim 1, wherein the pair of nasal prongs (5) includes an external pillow element (8) at an end.

16. The nasal cannula assembly according to claim 15, wherein said pillow element (8) is made of silicone.

17. The nasal cannula assembly according to claim 1, further comprising one or more orifices (13) in the first compartment (1) defining a fluid communication from an internal chamber (7) to an external atmosphere.

18. The nasal cannula assembly according to claim 7, wherein a diameter of each of the at least two flow restriction channels (35) is between 0.1 mm and 5 mm, and the rounded edges at an entrance to the at least two flow restriction channels (35) are designed such that the ratio between a radius of curvature of the rounded edges and the diameters of each flow restriction channel (35) is greater than 0.02.

19. A nasal cannula assembly (10) adapted to deliver gases to a patient, the nasal cannula assembly (10) comprising: a) a first compartment (1) and a second compartment (2) separated by a separation wall (6), b) a pair of nasal prongs (5) in fluid communication with the first compartment (1), c) the first compartment (1) comprising a first inlet (11) configured to conduct a first gas into said first compartment (1), d) the second compartment (2) comprising a second inlet (12) configured to conduct a second gas into said second compartment (2), and e) the separation wall (6) comprising at least one flow restriction channel (35) configured to permit a passage of gas from the second compartment (2) to the first compartment (1) in a reduced pressure state during an inhalation phase and prevent a majority of flow of the second gas from the second compartment (2) to the first compartment (1) in a higher pressure state, during an exhalation phase, relative to the passage of gas during a reduced pressure state, during an inhalation phase, wherein the second compartment (2) forms a deformable-wall reservoir comprising a fully inflated internal volume for the gas of about 0.5 to 5 ml.

Description

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

(1) The present invention will be better understood thanks to the following description and explanation made in reference to the Figures, wherein:

(2) FIG. 1 is a schematic of a first embodiment of a nasal cannula assembly according to the present invention,

(3) FIG. 2 is a schematic of a second embodiment of a nasal cannula assembly according to the present invention having nasal nare pillows (8) for securing the cannula to the nares,

(4) FIGS. 3A-D show a schematic of a second embodiment of a nasal cannula assembly according to the present invention with gas flow illustrated in the inhalation and exhalation phases with supplemental Oxygen (3A-B) and without supplemental Oxygen (3C-D), and

(5) FIG. 4 displays an estimated pattern of inhaled NO concentration that could be achieved using a nasal cannula assembly according to the present invention,

(6) FIG. 5 shows a schematic of a working model for validating restriction flow channel (35) performance under simulated breathing conditions, with elements labeled as follows: [40]Lung Simulator (ASL 5000; Ingmar Medical) [22]22 mm straight connector with sampling port [30]Gas sampling line to NO analyzer (Siemens NOA 280i; GE) [21]22 mm T piece connector [23]22 mm straight connector [24]Step-down connector, 22 mm to 4 mm [35a]4 mm flow restriction channel; internal to connector [5] [25]22 mm straight connector with injection port [90]NO injection line [27]Breathing filter (ClearGuard II; Intersurgical),

(7) FIG. 6 shows results of an exemplary experiment using the testing apparatus of FIG. 5: Flow (top) and pressure (bottom) versus time waveforms obtained from the lung simulator with no filter. The X-axis units are seconds, while the Y-axis units are L/min and cm H2O, respectively,

(8) FIG. 7 shows results of an exemplary experiment using the testing apparatus of FIG. 5: Flow (top) and pressure (bottom) versus time waveforms obtained from the lung simulator with the filter in place. The X-axis units are seconds, while the Y-axis units are L/min and cm H.sub.2O, respectively, and

(9) FIG. 8 shows results of an exemplary experiment using the testing apparatus of FIG. 5: Top row: flow versus time waveforms from the lung simulator obtained with no filter (left) and with the filter in place (right). Bottom row: NO concentration versus time waveform as sampled from the first compartment [1] with no filter (left) and with the filter in place (right).

DETAILED DESCRIPTION OF THE INVENTION

(10) A schematic of a first embodiment of the nasal cannula assembly of the present invention is shown in FIG. 1 (in cross section).

(11) The nasal cannula assembly of the present invention is a patient interface generally comprising a pair of nasal prongs 5 coupled indirectly to a deformable-wall 14 having a reservoir 2 supplied with NO contained in nitrogen (12), e.g. at 225, 450, 800 or 1000 ppm in volume.

(12) The pair of nasal prongs 5 is positioned on a hollow body 4, for example an air or oxygen conduit or manifold, comprising an internal hollow volume or chamber 7 thereby forming a first compartment 1 that receives the gases.

(13) The nasal prongs 5 are small conduits or tubes adapted for insertion into the nares of a patient and through which passes the gas mixture that is subsequently inhaled by the patient. Each prong 5 comprises an outlet orifice 15 at its end.

(14) The hollow body 4 can be made of a rigid light material, such as polymer or similar. Preferably, the hollow body 4 and the pair of nasal prong 5 are integrally molded from a soft plastics material. However, the prongs 5 can also be detachable from said hollow body 4 to allow different sized prongs to be placed on said hollow body 4 to suit different sized patients, such as adults and infants. The hollow body 4 is in turn in fluid communication via fluid transfer elements 30, such as flow restriction channel(s), with reservoir 2 formed by the deformable-wall 14 and separation wall 6. In other words, the nasal cannula assembly of the present invention is split into two main inhaled gas compartments 1 and 2 that are separated each from the other by a separation wall 6.

(15) The second compartment 2 forms a deformable reservoir 2 receiving the NO gas through an inlet 12. The deformable wall 14 of the reservoir or second compartment 2 should be made from a thin, flexible sheet of polymer material so that the reservoir readily inflates during exhalation, but collapses, at the start of inhalation. In this manner, NO-containing gas is allowed to accumulate in the reservoir while the patient exhales, and then is released as a bolus at the start of inhalation as the reservoir collapses and its contents empty through the fluid transfer elements 30, such as flow restriction channel(s), into the first compartment 1. Throughout this cycle a constant flow of NO-containing gas may be maintained through the inlet 12.

(16) The second compartment 2 fluidly communicates with the first compartment 1 through one or more fluid transfer elements 30 as shown in FIG. 1. These fluid transfer elements are arranged in the separation wall 6. Preferably, as shown in FIG. 1, two fluid transfer elements 30 are positioned along the conduit 7 forming the hollow main body 4, directly opposite the nasal prongs 5, i.e. each fluid transfer elements 30 is facing one nasal prong 5, so as to facilitate the gas circulation from the second compartment 2 to the first compartment 1 and subsequently to the nasal prongs 5.

(17) The fluid transfer elements 30 are generally one or more flow restriction channel(s) 35 connecting first compartment 1 to second compartment 2 (FIG. 1). The flow restriction channel 35 should be adapted by dimension to limit the majority of flow of NO from second compartment 2 to first compartment 1 (i.e. >50% such as 60, 70 80 or 90%) in the higher pressure state during an exhalation phase relative to the reduced pressure state during an inhalation phase. The flow rate differential between the two pressure conditions may be adjusted by selecting the appropriate flow restriction 35 dimensions (e.g. tubular size), a degree of baffling in the flow restriction channel 35, and/or any other suitable flow restriction elements (e.g. membranes, particle packing, constrictions, etc.). Independent of the specific geometric adaptation, the flow restriction element may be characterized by the equation:
P=KV.sup.2,
where P indicates the pressure drop associated with flow of a fluid with density through the flow restriction element at a velocity V representing the mean fluid velocity through the flow restriction element, as averaged, e.g., over the cross-section of the entrance to the element. The coefficient K depends on the geometry and configuration of the flow restriction element, and may thus be used to characterize the flow restriction element, where a larger value of the coefficient K is associated with a larger pressure drop through the flow restriction element for a given fluid density of a fluid traveling at a given mean velocity V. In other words, a larger value of the coefficient K is associated with a lower mean flow velocity V when a given pressure drop P is imposed across the flow restriction element. Therefore a flow restriction element with larger coefficient K will in general represent a larger barrier to flow through that element.

(18) In light of this understanding, one adaptation of the flow restriction channel 35 connecting first compartment 1 to second compartment 2 is an orifice with dimension selected to produce a coefficient K sufficiently large in value to limit flow from compartment 2 to compartment 1 through the flow restriction channel during the higher pressure state, where the higher pressure in compartment 1 is associated with a small pressure drop P imposed across the orifice, but at the same time sufficiently small in value to permit flow from compartment 2 to compartment 1 through the flow restriction channel during the reduced pressure state, where the reduced pressure in compartment 1 is associated with a larger pressure drop P imposed across the orifice. A circular orifice with diameter between around 0.1 mm and around 5 mm, and specifically between 0.5 mm and 2 mm serves as a reasonable solution for many patient breathing patterns. Orifices of different geometry (e.g. an oval, a square, or a slot) but of similar dimension are also reasonable solutions.

(19) A second adaptation of the flow restriction channel 35 connecting first compartment 1 to second compartment 2 is a constriction channel (FIGS. 3A & 2B) designed such that the constriction channel has a rounded edge at the entrance from compartment 2 for flow in the direction from compartment 2 into compartment 1. Further, the constriction channel protrudes into compartment 1 so as to create a reentrant type entrance for flow in the reverse direction from compartment 1 into compartment 2. It is known that the coefficient K defined above is considerably larger for a reentrant-type entrance than for a rounded-edged entrance, thus in the context of the flow restriction channel discussed here, use of a constriction channel as described above will provide little resistance to flow in the direction from compartment 2 into compartment 1 but will resist flow in the direction from compartment 1 to compartment 2. Accordingly, the constriction channel provides a further advantage for controlling the direction of flow between compartment 1 and compartment 2 in addition to performing the function of modulating flow from compartment 2 to compartment 1 between higher and reduced pressure states as described above for the flow restriction channel in general. The diameter of the constriction channel should generally be between around 0.1 mm and around 5 mm, and specifically between 0.5 mm and 2 mm. The rounded edges at the entrance to the constriction channel should be designed such that the ratio between the radius of curvature of the edge and the diameter of the constriction is greater than 0.02, preferably greater than 0.1; however, increasing this ratio beyond a value of about 0.15 provides little further benefit. For general guidance on restriction flow channel design, see Fox and McDonald, Introduction to Fluid Mechanics, Fifth edition, John Wiley & Sons, NY, 1998, Chapter 8, or Shaughnessy, Katz, and Schaffer, Introduction to Fluid Mechanics, Oxford University Press, NY, 2005, Chapter 13.

(20) In any case, the combination of flow restriction channel(s) 35 and deformable wall 14 of the embodiment depicted in FIG. 1 should be responsive to increases and decreases in pressure that develop during exhalation and inhalation, respectively, so as to allow the deformable reservoir 2 to inflate with NO-containing gas during exhalation, and then empty to release this gas through the flow restriction channel(s) 35 into the first compartment 1 during inhalation.

(21) Generally the deformable wall 14 needs to be of a thin, flexible material such that zero or near zero positive pressure above atmospheric develops in compartment 2 as it fills from the Nitric Oxide flow 12 during exhalation (so that flow of gas through the restriction channel(s) 35 remains minimal during exhalation while the bag fills). Reservoir 2 thus should be designed preferably to have infinite or near infinite Compliance (where Compliance=deltaVolume/deltaPressure), while fillingand then drop to zero or near zero Compliance once full.

(22) The first compartment 1 is supplied with an oxygen-containing gas through a first inlet port 11, whereas the second compartment 2 forming a NO-reservoir is supplied with a constant flow of NO-containing gas through a second inlet port 12.

(23) During patient exhalation, the second compartment or reservoir 2 fills with NO containing gas, whereas, during patient inhalation, NO-containing gas mixes with air and/or oxygen in the first compartment 1 as it is inhaled by the patient through the prongs 5.

(24) The volume of the second compartment 2 is configured and sized so as to be small compared to the patient's inhaled tidal volume, so that the second compartment 2 quickly empties during the initial period of the inhalation phase to create a bolus of elevated NO concentration at the start of the inhalation.

(25) Normally high concentrations of NO, e.g. 800 vol. ppm of NO in nitrogen, are delivered to the second compartment 2 from a source of NO/N.sub.2, such as a gas cylinder with integrated pressure regulator and flow metering apparatus.

(26) Patient safety is ensured by supplying only low flows of NO-containing gas. For example, to deliver to the patient an amount of NO equivalent to that delivered during continuous supply of gas containing 5 ppmv NO throughout the duration of a 500 ml tidal breath, about 3 ml of gas containing 800 ppmv NO should be supplied each breath.

(27) During tidal breathing, the expiratory time of a typical adult will range from approximately 2 to 5 seconds. Therefore, supply flows on the order of 1 ml/s of NO containing gas are required. In operation, the NO flow rate may be adjusted based on visual inspection of the inflation/deflation of deformable wall 14 to ensure the appropriate flow rate for a specific patient's inhalation pattern. Visual inspection of the inflation/deflation of the deformable wall 14 also provides feedback to the user to ensure proper function of the device, and may be used by a healthcare practitioner in fitting a patient with appropriately sized nasal prongs.

(28) FIG. 4 displays an estimated pattern of inhaled NO concentration that would be achieved using the present invention based on the numbers mentioned above.

(29) More precisely, one can see on FIG. 4 the estimated tidal flow, first compartment 1 pressure, and inhaled NO concentration curves during a typical adult tidal breathing pattern using a nasal cannula assembly 10 according to the present invention supplied with 1 ml/sec flow of gas containing 800 ppmv of NO in N.sub.2.

(30) The breathing pattern is shown in the upper curve, with positive flow representing inhalation, and negative flow representing exhalation. The variation of pressure within the first compartment 1 over the breathing cycle is shown in the middle curve. The estimated NO concentration contained in the gas mixture delivered to the patient through the nasal prongs 5 during the inhalation phase of the breathing cycle is shown in the bottom curve.

(31) The NO concentration spikes at the start of inhalation as NO-containing gas is released from the second compartment 2 before rapidly decreasing once the second compartment empties.

(32) Through the later stages of inhalation a low NO concentration is delivered as fresh NO-containing gas supplied through inlet 12 passes into the first chamber 1 and the nasal prongs 5.

(33) In contrast, throughout exhalation, flow of NO-containing gas from the second chamber to the first chamber is prevented or at least reduced by the flow restriction channel(s) 35.

(34) For some patients, it may be desirable to minimize gas leaks between the nasal prongs 5 and the patient's nares, e.g. to provide continuous positive airway pressure CPP, Bi-level positive airway pressure (Bi-PAP), or other positive pressure support in combination with NO therapy, or to provide additional control over the higher and reduced pressure states achieved during the breathing cycle. In such circumstances, the nasal cannula assembly 10 may comprise additional elements as shown in FIG. 2.

(35) First, each of the nasal prongs 5 includes an external pillow element 8 at its ends, which is intended to more tightly secure the prongs 5 inside the patient's nares or nostrils. Said pillow elements 8 can be made of soft resilient material, such as silicone or similar.

(36) Second, additional orifices or slots 13 are included between the first compartment 1 defining the internal chamber 7 and the room atmosphere, to allow entrainment of room air, e.g. during inhalation, and exhaust of gases to the room atmosphere, e.g. during exhalation. The number and dimensions of these orifices or slots 13 may be selected so as to achieve a desired range of higher and reduced pressure states during the breathing cycle.

WORKING EXAMPLE

(37) To demonstrate an embodiment of the restriction flow channel of the invention, a mechanical lung simulation device was used to produce a breathing pattern. The breathing pattern was set to that of an average adult human. Breathing patterns representing any patient could be used as the basis for validating a restriction flow channel design for a specific class of patients (e.g. pediatric breathing patterns). The exemplary experiment was performed using a single flow restriction channel [35a] positioned between a first compartment [1] and a second compartment [2]. A 22 mm diameter straight connector [22] including a port for gas sampling via the gas sampling line [30] was positioned between a lung simulator (ASL 5000; Ingmar Medical) [40] and T piece [21]. A second arm of the T piece [21] was connected to a 22 mm straight connector, which contained internally a 4 mm flow restriction channel [35a]. The third arm of the T piece [21] was either left open to the room atmosphere, or connected to a breathing filter (ClearGuard II; Intersurgical) [26], which in turn was open to the room atmosphere. The internal conduits of the straight connector with sampling port [22], the T piece [21], and the straight connector [23] formed the first compartment [1]. The flow restriction channel [35a] was connected through a step-down connector [24] to a 22 mm diameter straight connector [25] which included a port for NO gas injection from the NO gas injection line [90]. The opposite end of the straight connector [25] was open to the room atmosphere. The internal conduits of the straight connector with injection port [25] and the step-down connector [24] formed a second compartment [2].

(38) Flow into and out of the lung simulator and the pressure at the entrance to the lung simulator, representing the pressure throughout the first compartment [1], were recorded over time by the lung simulator. The concentration of NO in gas sampled via the gas sampling line [30] was monitored using a chemiluminescence NO analyzer (Siemens NOA 280i; GE). The lung simulator was programmed so as to deliver a 600 mL tidal volume breath at a frequency of 15 breaths/minute, with a sinusoidal inspiratory waveform and a passive, mono-exponential expiratory flow pattern, and an inspiratory time to expiratory time ratio of 2 to 3. A constant flow of 250 mL/min of 800 ppm NO in balance nitrogen gas was delivered through the NO injection line [9]. FIGS. 2 and 3 display flow and pressure versus time waveforms over several breathing cycles for experiments performed without and with the filter [27] in place, respectively. The flow waveform is not appreciably changed between the two experiments, while the pressure waveforms differ. With no filter in place, FIG. 2, the pressure in the first compartment [1] oscillates between a minimum of 0.2 cm H.sub.2O during inhalation and a maximum of 0.1 cm H.sub.2O during exhalation. With the filter [27] in place, FIG. 3, the small added resistance to air flow through the filter results in a reduced pressure state reaching 1.0 cm H.sub.2O during inhalation, and a higher pressure state reaching 1.0 cm H.sub.2O during exhalation.

(39) FIG. 4 again displays flow versus time waveforms (top row) over several breathing cycles for experiments performed without (top left) and with (top right) the filter [27] in place. The bottom row of FIG. 4 displays NO concentrations versus time in gas sampled from the first compartment [1] for experiments performed without (bottom left) and with (bottom right) the filter [27] in place. With no filter in place, that is with pressure states in the first compartment [1] varying between 0.2 cm H.sub.2O during inhalation and 0.1 cm H.sub.2O during exhalation, the NO concentration in gas sampled from the first compartment [1] reached just over 10 ppm during periods of low flow (e.g. at end-expiration), where pressure in the first compartment [1] was near zero, and during inhalation, where pressure in the first compartment [1] was negative, but fell to near zero when expiratory flow rates were appreciable and the pressure in the first compartment [1] rose. With the filter in place, such that the pressure in compartment [1] varied between a reduced pressure state reaching 1.0 cm H.sub.2O during inhalation, and a higher pressure state reaching 1.0 cm H.sub.2O during exhalation, the variation in delivered NO concentration was magnified: a bolus of gas containing NO concentration as high as 20 ppm passed through the first compartment [1] during inhalation, and the NO concentration fell to approximately 5 ppm during periods where expiratory flow was appreciable, such that the higher pressure state was achieved in the first compartment [1], before rising to 10 ppm through the remainder of the breathing cycle.

(40) While the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art in light of the foregoing description. Accordingly, it is intended to embrace all such alternatives, modifications, and variations as fall within the spirit and broad scope of the appended claims. The present invention may suitably comprise, consist or consist essentially of the elements disclosed and may be practiced in the absence of an element not disclosed. Furthermore, if there is language referring to order, such as first and second, it should be understood in an exemplary sense and not in a limiting sense. For example, it can be recognized by those skilled in the art that certain steps can be combined into a single step.

(41) The singular forms a, an and the include plural referents, unless the context clearly dictates otherwise.

(42) Comprising in a claim is an open transitional term which means the subsequently identified claim elements are a nonexclusive listing (i.e., anything else may be additionally included and remain within the scope of comprising). Comprising as used herein may be replaced by the more limited transitional terms consisting essentially of and consisting of unless otherwise indicated herein.

(43) Providing in a claim is defined to mean furnishing, supplying, making available, or preparing something. The step may be performed by any actor in the absence of express language in the claim to the contrary.

(44) Optional or optionally means that the subsequently described event or circumstances may or may not occur. The description includes instances where the event or circumstance occurs and instances where it does not occur.

(45) Ranges may be expressed herein as from about one particular value, and/or to about another particular value. When such a range is expressed, it is to be understood that another embodiment is from the one particular value and/or to the other particular value, along with all combinations within said range.

(46) All references identified herein are each hereby incorporated by reference into this application in their entireties, as well as for the specific information for which each is cited.