assembling and actuating a disposable dosator for dry powder drug delivery

Customizable Disposable Dosators to Deliver Dry Powder Aerosol Drugs to Mice

The use of dry powder inhalers (DPIs) for pulmonary drug delivery has garnered significant interest over the past three decades due to the global phase-out of chlorofluorocarbon propellants1,2. DPIs offer numerous benefits over other pulmonary delivery systems, such as metered dose inhalers and nebulizers, including formulation stability, portability, ease of use, and propellant-free dispersal mechanisms2. However, before moving DPI products toward clinical translation, several preclinical studies must be conducted, many of which are initially completed using a murine model. Nevertheless, technologies available to deliver dry powders accurately and reproducibly to small animals are limited.
Common methods to deliver dry powders to small animals, such as mice, include passive inhalation3,4,5,6,7 and direct administration8,9,10,11,12,13. Passive inhalation typically requires a custom chamber that utilizes large doses of spray-dried powder to prepare a sufficient aerosol cloud. As mice are obligate nose breathers14, delivery by passive inhalation requires the powder to travel through the nose and throat to reach the lungs, necessitating the maintenance of an aerosol cloud with sufficient particle aerodynamic properties7,8. While a useful technique that is more physiologically relevant than direct delivery due to inhalation as a result of normal breathing14, it may not be suitable for initial studies where powder mass is limited.
Alternatively, a number of intratracheal delivery devices for direct dry powder delivery have been reported8,9,10,11,12,13. Intratracheal devices bypass the nose and throat, delivering the powder directly to the lungs and allowing for finer control over the delivered dose14. Additionally, some devices, especially those prepared using a tamping loading procedure9, can be prepared with smaller quantities, which is an important consideration for initial proof-of-concept studies. The lack of universally available intratracheal delivery devices has hindered their potential for use, limiting availability and leading to interlaboratory differences14. In this study, we propose a simple, inexpensive, disposable dosator for intratracheal delivery that can be utilized for proof-of-concept murine studies in the development of dry powder aerosols.

Author Spotlight: Developing a Disposable Dosator for Preclinical Testing of Dry Powder Inhalers in Small Animal Models 

Disposable Dosators Intended for Dry Powder Delivery to Mice

Watch this Scientific Journal Video about Assembling and Actuating a Disposable Dosator for Dry Powder Drug Delivery at JoVE.com

Assembling and Actuating a Disposable Dosator for Dry Powder Drug Delivery  

To prepare the disposable dosator and its filling components, take a 2.5 centimeter or 1 inch blunt stainless steel needle of 21 to 25 gauge. Utilizing a precision sectioning saw or a belt sander, trim the plastic lure part of the needle, leaving about 2 to 3 millimeters of the plastic lure attached to the needle. Next, cut off approximately 1 to 1.5 centimeters from the tip of a 0.6 milliliter conical centrifuge tube.After that, fill this cut tip with 30 to 35 milligrams of the powder of interest. For storing or transporting the powder, place the cutoff tube cap onto the cut tip containing the powder. Use paraffin film to wrap the cover, minimizing the powder's exposure to ambient moisture.To load the dosator, tamp the trimmed stainless steel needle into the powder bed in the cut tip as many times as required to achieve the desired dose. Using a low lint wiper, gently wipe the sides of the needle to remove any excess powder. Then take a 3.81 centimeter or 1.5 inch polypropylene needle of 16 to 20 gauge and cautiously insert the loaded stainless steel needle into it, making sure not to dislodge any powder.Alternatively, use a 5.08 centimeter or 2 inch PTFE needle for the same. To actuate the dosator, first draw back a disposable syringe to the desired volume based on the application. Then attach the syringe to the lure lock on the polypropylene or PTFE needle before inserting the needle end of the dosator into the desired target.To analyze powder content and reproducibility, insert the dosator needle through a perforated rubber septum or paraffin film into a vial with a small quantity of liquid. Forcefully depress the syringe plunger, expelling the powder from the device into the collection vial. Finally, analyze the powder solution in the vial using UV's visible spectra photometry to monitor the dose of the powder released from the dosator.Four different spray dried powders visualized using scanning electron microscopy were considered for delivery using the demonstrated dosator. The delivered dose as a function of the number of Tamps in the powder bed, was obtained from UV visible spectra photometry of the powder solutions. Notably, all spray dried powders demonstrated a linear dose response from 1 to 4 Tamps.The first Tamp always incurred a larger dose of powder than subsequent Tamps. When compared to the demonstrated 21 gauge stainless steel with a 16 gauge polypropylene dosator, a slight increase in achievable dose was observed using a 21 gauge stainless steel with a 20 gauge PTFE dosator for powder SD 1. As expected, the achievable dose of SD 1 decreased for a 22 gauge stainless steel with an 18 gauge polypropylene dosator, having a smaller inner needle diameter.A 25 gauge stainless steel with a 20 gauge polypropylene dosator further decreased the initial and subsequent Tamp doses. This is a comparison of the four dosator systems that were evaluated, highlighting that the dosators can be customized to meet different dosage needs.

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JoVE Journal

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116 ビュー.  RTI International. 使い捨て投与剤とその充填成分を準備するには、21〜25ゲージの2.5センチメートルまたは1インチの鈍いステンレス鋼針を取ります。精密切片のこぎりまたはベルトサンダーを使用して、針のプラスチックルアー部分をトリミングし、針に取り付けられたプラスチックルアーの約2〜3ミリメートルを残します。次に、0.6ミリリットルの円錐形遠心チューブの先端から約1〜1.5...

ビデオ: Assembling and Actuating a Disposable Dosator for Dry Powder Drug Delivery  

Dry powder inhalers offer numerous advantages for delivering drugs to the lungs, including stable solid-state drug formulations, device portability, bolus metering and dosing, and a propellant-free dispersal mechanism. To develop pharmaceutical dry powder aerosol products, robust in vivo testing is essential. Typically, initial studies involve using a murine model for preliminary evaluation before conducting formal studies in larger animal species. However, a significant limitation in this approach is the lack of suitable device technology to accurately and reproducibly deliver dry powders to small animals, hindering such models&#39; utility. To address these challenges, disposable syringe dosators were developed specifically for intrapulmonary delivery of dry powders in doses appropriate for mice. These dosators load and deliver a predetermined amount of powder obtained from a uniform bulk density powder bed. This discrete control is achieved by inserting a blunt needle to a fixed depth (tamping) into the powder bed, removing a fixed quantity each time. Notably, this dosing pattern has proven effective for a range of spray-dried powders. In experiments involving four different model spray-dried powders, the dosators demonstrated the ability to achieve doses within the range of 30 to 1100 &#181;g. The achieved dose was influenced by factors such as the number of tamps, the size of the dosator needle, and the specific formulation used. One of the key benefits of these dosators is their ease of manufacturing, making them accessible and cost-effective for delivering dry powders to mice during initial proof-of-concept studies. The disposable nature of the dosators facilitates use in animal procedure rooms, where cleaning and refilling reusable systems and weighing materials is inconvenient. Thus, developing disposable syringe dosators has addressed a significant hurdle in murine dry powder delivery for proof-of-concept studies, enabling researchers to conduct more accurate and reproducible preliminary studies in small animal models for pulmonary drug delivery.

Pharmaceutical dry powder development necessitates reliable in vivo testing, often using a murine model. Device technology for accurately and reproducibly delivering dry powder aerosols to mice is restricted. This study presents disposable dosators for pulmonary drug delivery at mouse-relevant doses, aiding initial proof-of-concept research.

Dry powder inhalers offer numerous advantages for delivering drugs to the lungs, including stable solid-state drug formulations, device portability, bolus ...