Patent Application
20160175079
The present disclosure relates to a drug delivery system, including an insufflation apparatus and methods for delivering a consistent powder discharge to an animal's lungs during inhalation cycles. In particular, the apparatus is configured with an automated computerized system which can be used to deliver drugs by insufflation, for example, to experimental animals for local and/or systemic drug administration studies. The apparatus achieves drug delivery with consistency and reproducibly.
All references cited in this specification, and their references, are incorporated by reference herein in their entirety where appropriate for teachings of additional or alternative details, features, and/or technical background.
The pulmonary route of administration is useful for delivering medicines into the lungs for treatment of local conditions or to achieve systemic absorption. For local treatments, the medicine can be delivered directly to the site of need where the compound can exert effect. Most current drugs delivered to the lungs are designed to have an effect on the tissue of the lungs. Examples of drugs for lung delivery include, vasodilators, surfactants, chemotherapeutic agents, or vaccines for flu, or other respiratory illnesses for the treatment of diseases, including, asthma, COPD, cystic fibrosis, and pulmonary infections. Pulmonary administration enables rapid treatment of these chronic and acute conditions. Drug formulations for treating pulmonary diseases such as asthma are available by several methods, including, using nebulizers such as treatment with PULMOZYME®, using metered-dose inhalers such as SYMBICORT®, and dry powder inhalers such as ADVAIR DISKUS®, PULMICORT FLEXHALER®. Other types of treatments, including biologics such as nucleotides drugs in genetic therapy have been delivered to the lungs, for example, for gene therapy of cystic fibrosis, where retroviral vectors expressing an effective adenosine deaminase are administered to the lungs.
Currently, formulations for treating systemic disease using biologic products are available primarily through injectable compositions. Dry powder compositions for pulmonary inhalation and systemic delivery of insulin have been used, including EXUBERA®, and AFREZZA®.
In cases where systemic absorption is desired, the large surface area of the lung, its thin wall structure, and its local proximity to the systemic circulation are beneficial. Drug delivery to the lungs provides advantages over oral administration of active agents such as proteins and peptides, which are sensitive to enzymatic deactivation or degradation in the gut. In addition, absorption through the lungs into the systemic circulation is more effective in reaching target tissues, bypassing the liver, which is the site of metabolic action of most drugs delivered by injections and other routes of administration. The potential for delivering many other compounds through the lungs for systemic administration, ranging from peptides and proteins to small molecules often requires numerous studies and approaches depending on the delivery system used.
For pulmonary delivery, medicines are often formulated into a liquid or dry powder format so that they can be aerosolized and inhaled by patients. Aerosolization is achieved by delivery devices such as inhalers, atomizers, and nebulizers, which convert a payload of the liquid or dry powder formulation into a respirable dispersion. The dispersion is comprised of particles suitably small for navigating the airway and depositing in the lung. Particles that are too large carry excessive inertia, impact the back of the throat, and are swallowed. Particles that are too small can be exhaled and never deposit in the lung.
Early development work on drug formulations often requires non-clinical testing. This may involve small animals, including, mice, rats and other rodents, wherein drug delivery, exposure and the resulting effects can be studied before progressing to large animals and into human administration studies. Pharmacokinetic and pharmacodynamic effects along with adverse events can be assessed using an animal model to help progress or halt development of candidate drug formulations. It is therefore, extremely important in evaluating a potential drug that the delivery of the formulation being tested is consistent to ascertain with more accuracy the envisioned delivery in humans. For example, if the drug is intended for delivery in a single inhalation using an inhaler together with a dry powder formulation, then the small animal testing should approximate the envisioned approach in humans.
Current model methodologies used to assess delivery and efficacy of drugs for pulmonary delivery, include liquid instillation or dry powder insufflation. These methods have been developed by researchers to enable placement of candidate drug formulations directly into the lung. The methods involve syringe-like systems such as the PennCentury DP-4, wherein an elongated blunted cannula, dry powder chamber and syringe are used to disperse the contents of the chamber into the animal's lungs. To perform the insufflation, the animal is lightly anesthetized and intubated to insert the device cannula past the vocal cords and into the trachea just before the carina, the tracheal bifurcation leading into the bronchi. Oftentimes, a laryngoscope is used to help the researcher guide the cannula during the insertion step. The syringe barrel is then depressed forcing the contents, either liquid, suspension, or powder out of the chamber, down the cannula, and into the animal's lung. The air volume to discharge the powder from an insufflator is typically between 1.0 to 5.0 mL depending on the animal species. Using this equipment, a valve feature within the powder chamber prevents air flow and the subsequent aerosolization until a minimum threshold pressure is achieved. Accordingly, researchers exert significant manual force to depress the syringe plunger during activation thereby aerosolizing the contents of the chamber with minimal air volume.
Two major challenges are encountered with the aforementioned techniques. The first challenge is one of timing delivery of the drug during the breathing cycle. Discharge of powder into an animal during exhalation results in sub-optimal delivery as the contents can be blown back and are not delivered to the test subject. With powder delivery, powder blow back condition results in exhalation of drug, making it impossible to estimate the magnitude of drug delivery and confounding any measurable effects by the drug. Manual discharge of powder or liquid to avoid blow back is difficult in animals with high respiratory rates and or small lung capacity, for example, in mice having typically, 90 breaths per minute. The second challenge is repeatability and/or consistency. Current technology requires a minimum pressure to disperse a drug formulation. The devices allow for a range of pressures above that minimum which affect both the quality and consistency of the dispersion. Airflows occurring with the minimum required pressure may produce an aerosol discharge with large particle sizes that are not able to be inhaled deep into the lung. Large sizes are prevented from navigating deep into the lung because inertial forces become too large forcing the drug laden particles into the upper airway branches of the lung. Conversely, airflows occurring with higher applied pressures may produce aerosol discharges with far greater quality. Particle sizes within these emitted aerosols will likely be reduced and therefore will have a much greater likelihood of depositing deeper in the lung. The dependence of consistency on the applied syringe plunger pressure is also difficult to overcome. Instillation and/or insufflation studies typically involve multiple animals which can lead to variations in drug delivery from animal to animal if procedures are manually executed. Sources of variation in the drug delivery make assessment of drug effect more difficult to interpret.
Dosing reproducibility during experiments requires that the drug formulation be delivered to the subject with consistent and reproducible results. Therefore, the inventors have seen the need to design and manufacture an apparatus, system, and method to overcome the problems encountered with standard apparatuses and procedures currently used.
A drug delivery system is provided comprising an apparatus and a method for delivering a drug composition, including aerosolized particles to the lungs are disclosed.
The apparatus comprises devices configured for measuring and recording an animal's breathing cycles; ascertaining the intervals of the breathing cycles and delivering an aerosol at a predetermined interval relative to an animal's breathing, in particular during an inhalation. The apparatus can comprise one or more sensors selecting from a variety of sensors, including, but not limited to accelerometers, microphones, strain gauges and transducers.
In one embodiment, computer algorithms specific to the sensors can then characterize and quantitate the animal's breathing pattern and determine when to trigger the insufflation in order to synchronize delivery with a natural inhalation maneuver. In one embodiment, delivery of dose composition can also be synchronized with different portions of the breathing cycle prior to or during an inhalation. The duration of the inhalation can also be checked, and assessed to determine the extent of delivery relative to the start and end of the inhalation. In one embodiment, active monitoring of the animal's breathing also generates data on duration of inhale/exhale, regularity of breathing, and other characteristics of the breathing cycle. In this and other embodiments, the apparatus is provided with an automated driving mechanism that displaces air through the insufflation device, by adapting an electromechanical device. In one embodiment, a linear solenoid can be used to displace a driving pump's piston, which ensures repeatable driving force and results in repeatable discharge flow rates.
In one embodiment, an apparatus is provided comprising:
a first device comprising a platform comprising an area for positioning an animal and configured to hold an animal in place and comprising an adjustable strap adapted with at least one sensor which detects movement of distension of the animal's thorax and/or abdomen due to breathing; said sensor generates a signal and communicates the signal to a microprocessor for analysis; and mounting means, including a stand for securing to said platform;
a second device comprising a solenoid, a syringe pump and a powder reservoir; wherein said solenoid is actuated by an onboard relay output system to pressurize the syringe pump; said second device further comprising a computer interface comprising a programmable algorithm which detects an animal's breathing pattern and said solenoid is actuated to pressurize the syringe pump at a predetermined interval during an inhalation to release a powder plume from the powder reservoir.
In one embodiment, the first device can further comprise a second sensor, which can detect sound generated from the animal's breathing cycles. In this and other embodiments, the apparatus can also comprise one or more modules comprising a relay board for relaying an output signal, such as an automated on and off switch; and a data acquisition board. In this embodiment, a first sensor communicates a first set of input signals to a first microprocessor configured with a data acquisition board which captures the input signals from the sensors, processes and analyzes the first set of signals in the first device and continuously streams to a computer and communicates with a relay board to actuate the solenoid and pressurize the syringe to discharge a powder contained in the powder reservoir at a predetermined interval.
In one embodiment, the first device comprises an adjustable cantilevered arm on which a transducer is mounted and can be positioned in the desired position on an animal to best measure physiological changes associated with breathing, such as diaphragm distention.
In a particular embodiment, a drug delivery system is provided comprising: an air pump adapted with a solenoid; an insufflation or instillation device adaptable to said air pump and comprising a chamber for containing a drug composition and a cannula; one or more sensors which can detect signals from breathing cycles of an animal; and a data acquisition board comprising an executable algorithm analyzing and transmitting signals from said one or more sensors, wherein the executable algorithm contains instructions to actuate the solenoid at a predetermined interval of a breathing cycle of the animal. In an example embodiment, the acquisition board can process the signals from the sensors within a computer, which makes the system modular, or can be part of a microprocessor built-in with the solenoid. In one embodiment, the animal is anesthetized and the system can have at least two sensors, including an accelerometer and a microphone.
In further embodiments, a method for insufflating an animal, including for example dogs, cats, monkeys, and rodents such as a mouse or a rat is disclosed. In a particular embodiment, the method comprises: anesthesizing an animal; positioning one or more sensors on or near the animal in the insufflation apparatus; detecting and analyzing the animals breathing cycles and administering a dose of a test composition at the inhalation interval of said animal. In an alternate embodiment, the method can also be used to instill a solution, a suspension, and/or a vapor to an animal.
In a particular embodiment, detecting and analyzing the animal's breathing cycles comprises positioning one or more sensors, such as an accelerometer, a microphone, or a transducer on or near the animal, which sensor(s) can detect signals from the animal, and transmit the signals to a data acquisition board, through which signals are analyzed and evaluated using an algorithm executable by, for example, a microprocessor on board a computer, or a programmable logic controller (PLC).
In one embodiment, signals from one or multiple sensors including, but not limited to microphones, thermocouples, strain gauges, accelerometers, and the like are used to optimally position the sensor(s) relative to the animal. In this embodiment, positioning information is relayed via a computer interface in which an algorithm detects the sensor output. An algorithm determines if the position is acceptable using sensor specific criteria, for example, validity of signal to noise, peak detection, slope detection, baseline noise and the like. The positioning of the sensor can occur manually by an operator or automatically using computer controlled, including motors and pneumatics, and sensor feedback.
In one embodiment, the method comprises, positioning an animal to be tested to an accessible area, for example, strapping the animal to a platform comprising an adjustable belt comprising one or more sensor(s), including an accelerometer, a transducer and/or a microphone; positioning the one or more sensor(s) to detect one or more signals generating from the animal's breathing cycles; actuating a power source and setting the accelerometer to detect a predetermine number of input signals to characterize the breathing pattern of the animal; and delivering an aerosolized powder plume to the animal during an inhalation. In a specific embodiment, the method comprises, determining the animal's breathing rate and inhalation intervals; and delivering a dose of an aerosolized composition at an inhalation interval. In some embodiments, the animal can optionally be strapped to the platform comprising a restraining area. In some embodiments, the adjustable belt can comprise an elastic material.
In embodiments disclosed herein, there is disclosed an apparatus, a system, and a method for delivering drugs to an animal by insufflation.
In an exemplary embodiment illustrated in
In this embodiment and illustrated in
In this and other embodiments, the actuation of the air pump 16 by solenoid 17 can also be controlled to exert constant or varying force levels based on selection of hardware and software algorithm features. In one embodiment, the trigger of the automated air pump 16 is controlled by an executable algorithm and can then be actuated at any point in the breathing cycle. This will allow for triggering of the pump offset from a feature within the breathing cycle or in a manner predictive of inhale, exhale, or other marker in the breathing cycle. In this embodiment, the optimal actuation is expected to be upon start of an animal's inhalation period. In one embodiment, aerosol delivery will occur in a single or multiple short bursts and during a single, or multiple consecutive, or non-consecutive inhalations depending on the dose and the animal.
In an exemplary embodiment as disclosed in
As previously stated, the insufflation system can be used to administer liquids, suspensions and dry powders by intratracheal insufflation.
In an alternate embodiment, the insufflation apparatus comprises a platform 40 for use with animals that may not need to be strapped or restrained. In this embodiment shown in
In some embodiments, platform 40 can further include a nose cone 57 that can removably attach to the top end of the platform. Nose cone 57 can serve as a mount allowing tubing to be passed through in order to keep an animal anesthetized.
In an alternate embodiment, the sensor on the cantilevered arm can comprise an accelerometer or other types of sensing device. The sensor 54 can be placed at the distal end of the arm for monitoring breathing signals from the animal.
The preceding disclosures are illustrative embodiments. It should be appreciated by those of skill in the art that the techniques disclosed herein elucidate representative techniques that function well in the practice of the present disclosure. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.
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Sprague-Dawley rats were used in these experiments. Rats were anesthetized, intubated and monitored using the insufflation assembly shown in
The data in Table 1 shows that the breathing cycles detected by the apparatus herein are greater than 0.5 seconds. Specifically, the data shows the rats breathing cycles detected indicated that the rats were breathing at intervals between 0.68 and 1.52 seconds with inhalations lasting from about 62 to about 300 milliseconds.
The preceding disclosures are illustrative embodiments. It should be appreciated by those of skill in the art that the techniques disclosed herein elucidate representative techniques that function well in the practice of the present disclosure. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.
Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
The terms “a,” “an,” “the” and similar referents used in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.
Certain embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.
Furthermore, numerous references have been made to patents and printed publications throughout this specification. Each of the above-cited references and printed publications are individually incorporated herein by reference in their entirety.
Specific embodiments disclosed herein may be further limited in the claims using consisting of or and consisting essentially of language. When used in the claims, whether as filed or added per amendment, the transition term “consisting of” excludes any element, step, or ingredient not specified in the claims. The transition term “consisting essentially of” limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s). Embodiments of the invention so claimed are inherently or expressly described and enabled herein.
In closing, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that precisely as shown and described.
This application claims the benefit of U.S. provisional patent application No. 61/862,484, filed Aug. 5, 2013, the entire disclosure of which is incorporated herein by reference.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2014/049817 | 8/5/2014 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 61862484 | Aug 2013 | US |
