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Walter Zielinski is the senior scientist, program development at Mystic Pharmaceuticals, Inc.
Irach Taraporewala, PhD, is the vice president of regulatory affairs and clinical research at Mystic Pharmaceuticals, Inc.
Timothy Sullivan is the president and CEO at Mystic Pharmaceuticals, Inc.
Needle-free vaccine delivery platforms can solve the problems of stockpiling, cold-chain management, and pandemic preparedness.
Innovative delivery technologies for the needle-free delivery of vaccines by the intranasal route offer advantages to traditional parenteral needle-based delivery systems developed and produced by the vaccine industry. Dry powder intranasal vaccine technologies have recently been developed. In addition, a rapid manufacturing technology platform is described that offers distinct advantages for delivery of liquid vaccines, with future development for a breakthrough in situ aseptic reconstitution technology for freeze-dried or spray-dried vaccine powders. This latter advance offers the potential for eliminating or markedly reducing the need for cold-chain management of vaccines during transport and storage. These new technologies have wide-ranging applications and advantages for the reliable and effective administration of vaccine products.
Successful large-scale immunization of populations around the globe with vaccines calls for a convenient mode of drug delivery with accurate dosing, preferably with limited need for specialized training of health workers. As interest grows in immunizing large segments of the global population with vaccines for widespread diseases such as pandemic influenza, malaria, tuberculosis, and rotavirus infections, comes the pressing need for innovative technologies that can facilitate a more responsive and cost-effective process, and also can circumvent the drawbacks of conventional modes of syringe-based vaccine delivery.
(MYSTIC PHARMACEUTICALS, INC.)
Vaccines for potential bio-threat agents such as anthrax, plague, or Ebola virus infections also necessitate technologies compatible with ease of delivery, stockpiling ability, a rapid manufacturing paradigm, rapid deployment, and under certain high risk conditions, the capability to self-administer. In particular, needle-free methods of vaccine administration are appealing alternatives to injected vaccines in these scenarios.
Needle-based vaccine injections require highly trained health workers and an optimally performing system for effective mass vaccination campaigns. The universal fear of needle sticks is an indicator of the need of convenient and viable alternative modes of delivery. Cold-chain management of vaccines is also often necessary, and lyophilized vaccines necessitate reconstitution in diluents at the time of use under sterile conditions, often in adverse field situations. Oral vaccines or transcutaneous vaccine patches have been used but also have drawbacks such as inconsistent absorption, gastrointestinal degradation, or high cost.
Intranasal delivery of drugs and biologics is a rapidly growing means of medicinal prophylaxis and therapy, and offers compelling advantages as a needle-free approach for testing and demonstrating the efficacy of existing and new drugs and vaccines.1 The nasal mucosa provides a convenient surface for vaccine deposition and for induction of systemic and local mucosal immunity. Recent advances in the development of delivery platforms are in response to the demand for innovative approaches to intranasal vaccine delivery that are safer, can be rapidly manufactured cost effectively, and assure compatibility with a wide range of vaccines and biopharmaceuticals. A key benefit of an intranasal vaccine is its potential to induce both mucosal and humoral immunity.
A distinct advantage of intranasal drug delivery is that drug uptake into the blood circulatory system by absorption through the nasal mucosa can be quite rapid.2,3 Moreover, clinical studies have demonstrated that a rapid local immune response can be achieved within 24–48 hours using intranasal delivery, providing rapid protection against airborne pathogens that enter the body through the respiratory tract. Clinical evidence has also demonstrated that complete systemic immunity can be achieved in significantly less time (days versus weeks) through the intranasal route.
An optimal intranasal drug delivery platform must be designed to provide accurate and precise delivery through optimized device design, such that the amount of drug or vaccine for each dose must be consistent. Advantages of intranasal vaccine delivery versus administration by oral or injection routes include a more rapid circulatory uptake at a lower dose than by parenteral or oral drug delivery, lower cost, avoidance of needles, avoidance of losses caused by intestinal passage for oral drugs and first pass liver metabolism, and greater user compliance. These and other differences can translate to a capability for lower effective doses, more rapid physiological response, and fewer complications caused by a vaccine's adverse effects.
Intranasal delivery of an inactivated influenza vaccine has been reported to have an elevated risk for Bell's palsy.4 However, Centers for Disease Control and Prevention studies of 10 years of clinical data concluded that elevated Bell's palsy risk was also observed for parenteral injection delivery of inactivated flu vaccines, demonstrating that intranasal delivery of vaccines was not associated with any Bell's palsy risk.5
Advances in dry powder formulation and nanotechnology-based processes have made it possible for new intranasal delivery systems for vaccines to be developed. Dry powder formulations can afford better stability characteristics for a vaccine and potentially reduce the requirements for cold-chain management or the addition of preservatives. In some instances, a dry powder intranasal form of a vaccine may prove to be superior to its injected counterpart. A dry powder anthrax vaccine has been developed that afforded better protection against anthrax spore challenge than an intramuscular injection.6
The GelVac technology developed by DelSite Biotechnologies (Irving, TX) consists of dry powder formulations of a vaccine with a natural plant-derived acidic polysaccharide material which is administered into the nasal cavity. On contact with the nasal mucosa, the formulation generates a muco-adhesive gel, entrapping the vaccine antigen, and providing a mechanism for the prolonged exposure of the antigen to the nasal mucosal tissue to enhance the immune response. This method of vaccine delivery is potentially adaptable to inactivated antigens, live attenuated viruses, and DNA vaccines.
The Becton Dickinson (BD, Franklin Lakes, NJ) T107 Dry Powder Inhaler, developed primarily for inhalation, may also be adapted to intranasal vaccine delivery. In this innovation, air from a syringe barrel ruptures the membrane of a capsule containing the vaccine, which can be propelled into the nasal passages. This method of delivery is being adopted for influenza and anthrax vaccines. The related BD Accuspray syringe-based system is being evaluated for use with the NASVAC HBsAg +HBcAg hepatitis vaccine.
Optinose, Ltd. (Wiltshire, UK), developed an exhalation-actuated device that delivers intranasal drugs to the nasal cavity without lung deposition of the aerosol known as the Optimist for bidirectional intranasal drug and vaccine delivery. A process for the production of stable, respirable powder vaccines has been developed by Aktiv-Dry LLC, (Boulder, CO) based on innovations from the laboratory of Bob Sievers at the University of Colorado. This technology is based on carbon dioxide assisted nebulization with a bubble dryer that rapidly and efficiently converts a liquid vaccine product into a dry powder formulation. This has been used in the production of a novel stabilized measles virus inhalation vaccine; the methodology could be readily adaptable for intranasal vaccine delivery as well.
An intranasal delivery system has been developed by Mystic Pharmaceuticals for human applications (Figure 1) that is novel, simple, disposable, and capable of precise aseptic delivery of formulations in the form of an optimized plume for maximum deposition to, and rapid systemic uptake by, the nasal mucosa.
Figure 1. VersiDoser intranasal delivery devices developed by Mystic Pharmaceuticals. Left: actuation of the device; Right: multilayer laminate unit dose blister containing both the vaccine formulation and Vjet nozzle.
The technology platform for intranasal delivery developed by Mystic Pharmaceuticals is called the VersiDoser (Figure 1).7 The capability to self-administer reduces the need for extensive field training by healthcare operators, and eliminates the "sharps" needle disposal problem and biohazards associated with used contaminated syringes. The VersiDoser delivery platform includes an aseptic unit-dose packaging production capability for fill, fit, and finish production of up to 300,000 doses per day, per line. Such a rapid production capability can significantly reduce the need to establish and maintain large cold-chain managed stockpiles of prefilled syringes while enabling a rapid response capability to produce vaccine when combined with rapid vaccine or drug production capabilities.
To ensure the sterility of a vaccine formulation (without a requirement for an added preservative), Mystic has developed a unit-dose blister that contains a single dose of the vaccine formulation (Figure 2).
Figure 2. Mystic Pharmaceuticals' Versidoser unit-dose blister with Vjet nozzle
The VersiDoser delivery platform uses a proprietary aseptic form-fill-seal (FFS) unit-dose manufacturing process and technology to produce and fill blisters with a liquid vaccine or drug formulation. The blisters are USP Class VI or ISO10993 compliant multilayer laminates comprising foil and plastic resin layers. The laminate is matched with a specific vaccine formulation to assure chemical compatibility and product stability. In each blister is a VJet nozzle to ensure the intranasal delivery of optimum aerosol plume geometry for the formulation.
The Vjet is a precision-matched specially engineered piercer nozzle that is optimized to the physical properties and dose volumes of the vaccine or drug formulation being delivered and is injection molded from USP Class VI resins. Computational fluid dynamics modeling is combined with analytical testing to provide a customized solution for each product formulation. The VersiDoser unit-dose blisters can deliver dose volumes ranging from 15 to 500 μL.
The FFS drug filling, packaging, and sealing operations are conducted in an automated production system enclosed in a barrier isolator to ensure aseptic technique and minimize defect opportunities. The production system can be configured for the manufacture and packaging of live or killed virus vaccines, bacterial vaccines, or recombinant protein or DNA vaccines. After they are filled with the vaccine formulation, the blisters are packaged into drug delivery devices such as those shown in Figure 1. The illustrated disposable delivery system is compact, and cost effective for use in global-scale quantities. For bioterrorism or pandemic preparedness, numerous units could be stockpiled for distribution to the target location where they can be distributed for self-administration. After use, the delivery device locks to avoid reuse and can be discarded.
The VersiDoser intranasal delivery platform includes disposable delivery systems for mono-dose, bi-dose, dual-dose, and reloadable vaccine delivery. The dual-dose system can deliver a vaccine or drug formulation into both nostrils simultaneously, which would be applicable for a therapeutic requiring high dose volume in health emergencies or rescue situations. Alternative delivery systems under development include a reloadable vaccine dispenser for mass vaccination campaigns requiring administration of thousands of individual doses (Figure 3).
Figure 3. Multiple dose intranasal delivery system with reloadable vaccine blister tips
Vaccine formulations typically require cold-chain storage and transport to ensure their continued stability. However, a cold-chain requirement is difficult to impractical in applications involving large populations situated in geographic regions or nations that lack an established healthcare infrastructure, in clinical settings where refrigeration of vaccine doses may not always be accessible or reliable, and in crisis situations. Lyophilized or spray-dried vaccine powders are used to reduce the need for cold-chain management because they can ultimately be reconstituted to their original formulations by the addition of a diluent at point of use.
Development of a lyophilized or spray-dried intranasal vaccine powder that could be easily reconstituted in situ with a liquid diluent in a sterile environment in a delivery device could represent an ideal solution. Such a capability would also eliminate the current use of sterile vials for mixing and the associated risk for vaccine contamination during dissolution reconstitution.
The VRx2 intranasal delivery platform under development by Mystic Pharmaceuticals has the potential to reduce the risks and costs currently encountered with vaccine or drugs that require reconstitution. Reconstitution just before intranasal administration eliminates the need for cold-chain storage and distribution. VRx2 delivery systems provide an auto-reconstitution capability in each delivery device. Each VRx2 blister contains the sterile freeze-dried vaccine and the sterile diluent solution in separate reservoirs. On activation at the point of use, the vaccine powder is mixed with the diluent to accomplish in situ reconstitution in the delivery system, followed by intranasal delivery. Intranasal delivery enables self-administration and reduces the dependency on a trained healthcare provider.
Dry powder vaccine technology, the VersiDoser, and VRx2 delivery platforms provide convenient and easy dispensing approaches to needle-free administration of a wide range of vaccine products. The delivery devices based on these technologies are modular, compact, disposable after use, and can be used for self-administration. The production methods are very amenable to scale-up and to rapid production and distribution in the event of a significant disease outbreak.
The VRx2 reconstitution technology platform further eases the storage space and cold-chain requirements for maintaining vaccine stockpiles by federal and local governments and their respective agencies. It is suggested that these technologies may prove useful to applications in the development of global vaccine products, to assist a transition to noninvasive needle-free inoculations in pandemic planning and response, and potentially to reduce present cold-chain management requirements.
TIMOTHY SULLIVAN is the president and CEO, IRACH TARAPOREWALA, PhD, is the vice president of regulatory affairs and clinical research, and WALTER ZIELINSKI, PhD is senior scientist, program development, all at Mystic Pharmaceuticals, Inc., Austin, TX, 512.918.2900, firstname.lastname@example.org
1. Zielinski WL, Sullivan TR, Berens KL. Transnasal drug delivery—an expanding technology. In: Drug Delivery 2007. Touch Briefings, Cardinal Tower, London, England, pp. 41–43.
2. Swift DL. Aerosol deposition and clearance in the human upper airways. Annals Biomed Eng. 1981;9:593–604.
3. Suman JD. Nasal drug delivery. Exp Opin Biolog Therapy. 2003;3(3):519–23(5).
4. Mutsch M, Zhou W, Rhodes P, et al. Use of the inactivated intranasal influenza vaccine and the risk of Bell's palsy in Switzerland. N England J Med. 2004;350:896–903.
5. Zhou W, Pool V, DeStefano F, et al., A potential signal of Bell's palsy after parenteral inactivated influenza vaccines: reports to the Vaccine Adverse Event Reporting System (VAERS)—United States, 1991–2001. Pharmacoepidemiol. Drug Safety. 2004;13:505–10.
6. Huang J, et al. Intranasal administration of dry powder anthrax vaccine provides protection against lethal aerosol spore challenge. Hum Vaccines. 2007;3:90–3.
7. Shaw M, Sullivan T, Zielinski W. Unit-dose aseptic packaging of nasal drugs. Inhalat. 2008;2:8–11.