Abstract:
A laboratory animal pharmaceutical testing device comprising a substantially closed animal holding cell, having a dry powder generator communicating through a wall of the cell, and one or more filtered inlets for permitting exchange of fresh air into the cell.

Description:
CROSS REFERENCE TO RELATED APPLICATION 
     This application claims priority from U.S. Provisional Application Ser. No. 61/222,433, filed Jul. 1, 2009, the contents of which are incorporated herein by reference. 
    
    
     BACKGROUND OF THE INVENTION 
     This invention relates to drug development, and more particularly to improvements in tools for conducting preclinical safety and efficacy studies in animals. 
     FIELD OF THE INVENTION 
     Drug development is a time-consuming and costly activity. Procedures are tightly regulated both for safety and to ensure drugs are effective. Of the many compounds studied with the potential to become a medicine, most are eliminated during the initial research phases. Chemical trials follow extensive research using in vitro and animal studies. 
     Animal studies are a vital part of drug development. Typically, a candidate drug is initially tested in isolated cells, tissue slices or organs. Studies in living animals show whether a drug works the same way inside the body as it did in the artificial environment of the laboratory. They also indicate how the drug effects interactions between different cells and organs of the body. If a potential drug appears to be both safe and effective in animals, it then can be studied in human trials. 
     Dry powder dosing of animals both for pharmacology and pulmonary toxicology studies are required steps in the development of dry powder inhaled therapies. In order to conduct these studies, dry powder therapeutics need to be aerosolized and delivered to the animals in a controlled, measurable and reproducible manner, and with a prescribed particle size distribution to: 1) screen potential compounds for their efficacy and safety when presented to the animal in a similar manner to humans, and 2) satisfy the FDA that the therapeutic is safe to be tested in man. Current dry powder aerosolization systems, representing state of the art, are relatively rudimentary and inefficient, and as such are highly wasteful of what in many cases is precious amounts of an active pharmaceutical ingredient. Furthermore, these aerosolization systems are certainly not reflective of the ultimate and intended commercial delivery device. 
     SUMMARY OF THE INVENTION 
     The present invention provides an improved system for conducting animal tests of active pharmaceutical ingredients. Previously, we have described a unique dry powder inhaler employing a vibratory mechanism for deaggregation and aerosolization of dry powder pharmaceuticals in a dry powder inhaler for delivery of carefully controlled particle size active pharmaceutical ingredients to the lungs of a patient. These same dry powder inhalers also advantageously may be employed to create a “cloud” of active pharmaceutical ingredients in a closed environment for inhalation by animals in preclinical animal testing. Also, these same dry powder inhalers may be used by manually activating the vibratory mechanism to create aerosol clouds in a pulsatile fashion in order to achieve a desirable dose of drug administered over a pre-selected time period or the manual activation may be replaced with automated activation of the aerosolization engine through sensing of the animal&#39;s inhalation or tidal breathing maneuver. The closed environment may include, but is not limited to, an animal holding cell or chamber in which the animal is placed inside for full body dosing, or a cell or chamber wherein the animal breathes in from dosing stations on the outside of the chamber, or direct tubing to the animal through a facemask or a nose-only mask or a nasal cannula, e.g. as described in my co-pending U.S. application Ser. No. 12/828,133, based on U.S. Provisional Application Ser. No. 61/222,418, filed contemporaneously herewith, and incorporated herein by reference). 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       Further features and advantages of the instant invention will be seen from the following detailed description taken in conjunction with the accompanying drawings, wherein: 
         FIG. 1  illustrates a laboratory animal full body dosing apparatus in accordance with one embodiment of the present invention; 
         FIG. 2  illustrates a laboratory animal “nose-only” dosing apparatus in accordance with a second embodiment of the present invention; and 
         FIG. 3  illustrates yet another embodiment of the invention. 
     
    
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 
       FIG. 1  illustrates an embodiment of the present invention wherein a pharmaceutical nebulizer  10  communicates through a side wall  12  of an animal holding cell  14 . The nebulizer  10  preferably comprises a dry powder nebulizer and communicates via conduit  16  through an opening  18  in side wall  12  that forms an essentially airtight seal. In this embodiment, the opening  18  preferably is located in the upper part of animal holding cell  14  so that a cloud of powdered pharmaceutical will be injected into the upper part of cell  14  and the bulk of the powder will be inhaled by the animal or animals  26  in the cell  14  before the powder settles to the floor of the cell. In a preferred embodiment of the invention, air is recirculated from cell  14  via a conduit  20  and fan  22 . In that way, unused medication is returned rather than wasted. If desired, one or more filtered inlets  24  may be provided for permitting introduction of fresh air into the enclosure without permitting escape of any of the powdered pharmaceutical ingredients. 
     The pharmaceutical nebulizer preferably comprises a vibratory dry powder inhaler, incorporating a high frequency piezo vibratoir, available from MicroDose Therapeutx, Inc. of Monmouth Junction, N.J. See U.S. patent, including Nos. 6,026,809, 6,142,146, 6,152,130, 7,318,434, 7,334,577, 7,343,914 and Published U.S. Application Nos. 2005/0172962 and 2008/0202514, all assigned to the common assignee. 
       FIG. 2  illustrates an alternative embodiment of the present invention in which laboratory animals are restrained and medication delivered to the animals&#39; nose or mouth. The laboratory animal “nose-only” dosing apparatus includes a dosing chamber  30  including a main chamber  32  and a side chamber  34  opening to animal holding chambers  36 . The animal holding chambers  36  are sized to humanely restrain laboratory animals  38  with their mouths and noses  40  held in position in chambers  42  which essentially act as breathing masks. Alternatively, nasal cannulae  66  or mouthpieces  68  may be provided in chambers  42 . Chambers  42  (or the nasal cannulae or mouthpieces as the case may be), communicate with side chambers  34  which in turn communicate with main chamber  32 . Medication is introduced into main chamber  32  via an opening  44  and the lower end of the main chamber  32  as a cloud of powdered pharmaceutical which is carried to the animals via chambers  42 . The cloud is created by sweeping dry powder aerosolized pharmaceutical created at a dry powder aerosol generator  46 , and carried by pressurized carrier air stream from a pressurized air source  48 . Air pressure is regulated by pressure regulator  50  and an optional flow controller  52 . 
     The apparatus also preferably includes an outlet  54  located adjacent the top end of the dosing chamber  30  leading to a scrubber  56 , a dryer  58  and filter  60  and exhaust fan  62  before being vented into the air. In this manner loss of pharmaceutical is minimized, and exposure of laboratory workers to the pharmaceutical is also minimized. 
     As is shown in  FIG. 3 , the device of any of the various embodiments of the invention may further comprise a controller for controlling a nebulizer that is in communication with an animal mask, nasal cannula, mouthpiece, or animal holding cell. The controller may, for example, turn the nebulizer on and off synchronized to tidal breathing of the animal. Accordingly, the device may further comprise a sensor for sensing an inhalation and/or exhalation cycle of an animal. The device or the controller may further comprise a microprocessor. The device may also comprise a timer for controlling the nebulizer. The device may further comprise an electronic controller for controlling airflow equipment that is connected to the nebulizer or animal mask, nasal cannula, mouthpiece, or animal holding cell. 
     Completing the system is a computer  64  for controlling airflow, duration and frequency of operation of the dry powder aerosol generator, the number of timed or pulsed activations of the vibrating element, etc. The system may also include visual, audible or tactile feedbacks to the equipment operation indicating the status of the device and dosing, etc. 
     In yet another embodiment of the invention, the nebulizer also may be triggered to turn on and off by sensing tidal breathing of the laboratory animal, and operate over one or several breaths, e.g., following the teachings of our aforesaid co-pending U.S. application Ser. No. 12/828,133, which is incorporated herein by reference. By way of example, as shown in  FIGS. 6 and 7  of our aforesaid co-pending application, and in  FIG. 3  of the instant application, the inhalation and/or exhalation cycle is sensed by a sensor and the aerosol generator is turned on for a short duration, and then off, followed by an amount of chase air to carry or follow the particles into the animal. A sufficient quantity of chase air is necessary to ensure lung deposition when inhalation volumes are low and inhalation cycles are short. Any sensor or combination of sensors that can be used to measure or identify the difference in properties between an inhalation and exhalation maneuver can be used to synchronize and turn the aerosol generator on and off. Examples of sensors that may be used to detect the animals&#39; inhalation/exhalation are flow sensors, pressure sensors, temperature sensors that measure the temperature difference between the inhaled and exhaled breath, carbon dioxide or nitric oxide or other gas sensors that measure the gas component level difference between inhaled and exhaled breath, and also physical measurement systems such as chest straps to measure the expansion and contraction of the chest cavity, etc., can be employed for this purpose. The present invention provides several novel and significant advantages. A feature and advantage of the present invention is that the pharmaceutical nebulizer has an ability to provide greater accuracy, efficiency and reproducibility over current systems. Also, the invention permits delivery of carefully controlled pulmonary drug doses with a targeted and desired particle size distribution. The drug active ingredients may be delivered as a “neat” spray-dried or micronized drug, or lactose blend. Unlike existing laboratory animal testing chambers, laboratory animal testing devices in accordance with the present invention do not require in-line micronizers to maintain a target mass medium aerodynamic particle diameter. Thus, the present invention permits handling of extremely small quantities of drugs, reducing drug waste, and providing more controlled testing environment and greater consistency of dose delivery. Moreover, the systems described are directly reflective of the core system used in hand-held inhalers and dry nebulizers being developed for humans. Thus, administration of dry powder active pharmaceutical ingredients to laboratory animals using vibratory dry powder inhaler technology as described for animal testing more closely mimics delivery of the same active pharmaceutical ingredients in humans. Accordingly, by using essentially the same engine for delivering the dry powder active pharmaceutical ingredients to laboratory test animals as will be used in delivery to humans, scale of delivery through early pharmaceutical studies to toxicity in human trials is more predictable. 
     Various changes may be made in the above invention without departing from the spirit and scope thereof. For example, it is possible to control the amount of drug delivered to the nasal passages of the laboratory animal as opposed to just the lower respiratory track by controlling particle size. Still other change are possible. For example, referring to  FIG. 3 , in another embodiment, nebulized drugs may be administered to individual laboratory animal primates via tubing leading to face masks or nasal cannulae, and, if desired, dosing controlled, e.g. by sensing inhalation and exhalation, and turning the nebulizer on and off as described above relative to the other embodiments.