Pressurized Metered dose inhalers: -

Abstract

The phase-out of chlorofluorocarbons (CFCs) has spurred the development of alternative

pulmonary drug delivery systems to pressurized metered dose inhalers (MDIs), such as dry
powder inhalers and pocket size nebulizers. Reformulation of CFCMDIs with
hydrofluoroalkanes (HFAs) 134a and 227 is also an opportunity to improve these widely
accepted systems with respect to ease of handling, compliance, dosing, and more reliable and
efficient lung deposition. MDIs have the advantage to protect the drug substance from external
parameters such as temperature and humidity and to meter and de-agglomerate the drug
independent from patients inspiratory flow rates. Novel formulation technologies combined with
improved valves and actuators should help to overcome dose uniformity and priming problems
and will increase the percentage of fine particles capable of reaching the deeper regions of the
lungs. Spacer mouthpieces can reduce the cold freon effect and undesired oropharyngeal
deposition caused by the rapid evaporation of the propellant and plume velocity of the aerosol
cloud. More advanced delivery devices may allow the patient to inhale at predetermined flow
rates (fast/slow) to target the deposition of fine drug particles (16 m) to specific sites into the
lungs. Breath-actuated devices make these systems more effective and patient friendly. The
above features in combination with numerical counters showing the remaining number of shots,
and built-in blocking mechanisms to avoid tail-off dependent dose uniformity problems of the
last labeled shots, should help to improve both acceptance and compliance of pMDIs compared
to other inhalation devices. However, only those inhalation systems, which are accepted and
appreciated by patients and offering an ambulatory treatment at reasonable cost, will be
successful in a more and more competitive market. These issues must be considered in the
development of future devices and formulations.

AEROSOL DRUG DELIVERY: DEVELOPMENTS IN DEVICE DESIGN

AND CLINICAL USE:

Aerosolised drugs are prescribed for use in a range of inhaler devices and systems. Delivering
drugs by inhalation requires a formulation that can be successfully aerosolised and a delivery
system that produces a useful aerosol of the drug; the particles or droplets need to be of sufficient
size and mass to be carried to the distal lung or deposited on proximal airways to give rise to a
therapeutic effect. Patients and caregivers must use and maintain these aerosol drug delivery
devices correctly. In recent years, several technical innovations have led to aerosol drug delivery
devices with efficient drug delivery and with novel features that take into account factors such as
dose tracking, portability, materials of manufacture, breath actuation, the interface with the
patient, combination therapies, and systemic delivery. These changes have improved
performance in all four categories of devices: metered dose inhalers, spacers and holding
chambers, dry powder inhalers, and nebulisers. Additionally, several therapies usually given by
injection are now prescribed as aerosols for use in a range of drug delivery devices. In this
Review, we discuss recent developments in the design and clinical use of aerosol devices over
the past 1015 years with an emphasis on the treatment of respiratory disorders.

DRY POWDER INHALERS (DPIS)A REVIEW OF DEVICE

RELIABILITY AND INNOVATION:

A wide range of dry powder inhaler (DPI) devices are currently available on the market to
deliver drugs into lungs with a view to maximise drug delivery with low variability. DPIs also
face numerous clinical challenges, particularly related to variable patient factors such as age,
clinical condition and inspiratory flow. Due to the drug formulation and the design of devices,
different DPIs do not show the same performance and manufacturers are taking a variety of
device design approaches. The characteristics of an ideal DPI, recent innovations in powder
formulation and device design are not universally reliable in terms of dose variability, clinical
efficacy, user friendliness and economy. This mini review examines whether device reliability is
more important than innovation. This study enables a comparison of the relative merits of
optimising existing DPIs or seeking to develop novel devices.

Pulmonary Drug Delivery Systems: Recent Developments

and Prospects:

Targeting drug delivery into the lungs has become one of the most important aspects of systemic
or local drug delivery systems. Consequently, in the last few years, techniques and new drug
delivery devices intended to deliver drugs into the lungs have been widely developed. Currently,
the main drug targeting regimens include direct application of a drug into the lungs, mostly by
inhalation therapy using either pressurized metered dose inhalers (pMDI) or dry powder inhalers
(DPI). Intratracheal administration is commonly used as a first approach in lung drug delivery in
vivo. To convey a sufficient dose of drug to the lungs, suitable drug arriers are required. These
can be either solid, liquid, or gaseous excipients. Liposomes, nano- and microparticles,
cyclodextrins, microemulsions, micelles, suspensions, or solutions are all examples of this type
of pharmaceutical carrier that have been successfully used to target drugs into the lungs. The use
of microreservoir-type systems offers clear advantages, such as high loading capacity and the
possibility of controlling size and permeability, and thus of controlling the release kinetics of the
drugs from the carrier systems. These systems make it possible to use relatively small numbers
of vector molecules to deliver substantial amounts of a drug to the target. This review discusses
the drug carriers administered or intended to be administered into the lungs. The transition to
CFC-free inhalers and drug delivery systems formulated with new propellants are also discussed.
Finally, in addition to the various advances made in the field of pulmonary-route administration,
we describe new systems based on per. uorooctyl bromide, which guarantee oxygen delivery in
the event of respiratory distress and drug delivery into the lungs

Current Therapies and Technological Advances in

Aqueous Aerosol Drug Delivery
Recent advances in aerosolization technology have led to renewed interest in pulmonary delivery
of a variety of drugs. Pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPIs)
have experienced success in recent years; however, many limitations are presented by
formulation difficulties, inefficient delivery, and complex device designs. Simplification of the
formulation process as well as adaptability of new devices has led many in the pharmaceutical
industry to reconsider aerosolization in an aqueous carrier. In the acute care setting, breath-
enhanced air-jet nebulizers are controlling and minimizing the amount of wasted medication,
while producing a high percentage of respirable droplets. Vibrating mesh nebulizers offer
advantages in higher respirable fractions (RFs) and slower velocity aerosols when compared with
air-jet nebulizers. Vibrating mesh nebulizers incorporating formulation and patient adaptive
components provide improvements to continuous nebulization technology by generating aerosol
only when it is most likely to reach the deep lung. Novel innovations in generation of liquid
aerosols are now being adapted for propellant-free pulmonary drug delivery to achieve
unprecedented control over dose delivered and are leading the way for the adaptation of systemic
drugs for delivery via the pulmonary route. Devices designed for the metered dose delivery of
insulin, morphine, sildenafil, triptans, and various peptides are all currently under investigation
for pulmonary delivery to treat nonrespiratory diseases. Although these devices are currently still
in clinical testing (with the exception of the Respimat), metered dose liquid inhalers (MDLIs)
have already shown superior outcomes to current pulmonary and systemic delivery methods.

Dry powder inhalers for pulmonary drug delivery:

The pulmonary route is an interesting route for drug administration, both for effective local
therapy (asthma, chronic obstructive pulmonary disease or cystic fibrosis) and for the systemic
administration of drugs (e.g., peptides and proteins). Well-designed dry powder inhalers are
highly efficient systems for pulmonary drug delivery. However, they are also complicated
systems, the the performance of which relies on many aspects, including the design of the inhaler
(e.g., resistance to air flow and the used de-agglomeration principle to generate the inhalation
aerosol), the powder formulation and the air flow generated by the patient. The technical
background of these aspects, and how they may be tuned in order to obtain desired performance
profiles, is reviewed. In light of the technical background, new developments and possibilities
for further improvements are discussed.

New advances in aerosolised drug delivery:

vibrating membrane nebuliser technology

Innovative nebuliser systems bear the potential to greatly improve and expand the administration
of therapeutic aerosols for the treatment of respiratory diseases. Exploiting the technology of a
microperforated vibrating membrane offers a close control of the droplet size that is being
generated and targeted to reach the lower airways, with little oropharyngeal deposition, thereby
reducing undesired side effects. The greatly improved efficiency of such devices, as exemplified
by the eFlow nebuliser (PARI), provides further advantages for the patient. A high respirable
fraction due to the precisely defined perforations, low residual losses and the high liquid output
rate combine to produce a highly efficient and fast administration of inhaled medications.
Portability, ease of handling and noiseless operation has a positive effect on patient compliance,
control of the therapy by the physician and the therapy costs.

PULMONARY DRUG DELIVERY: FROM GENERATING AEROSOLS

TO OVERCOMING BIOLOGICAL BARRIERSTHERAPEUTIC
POSSIBILITIES AND TECHNOLOGICAL CHALLENGES:

Research in pulmonary drug delivery has focused mainly on new particle or device technologies
to improve the aerosol generation and pulmonary deposition of inhaled drugs. Although
substantial progress has been made in this respect, no significant advances have been made that
would lead pulmonary drug delivery beyond the treatment of some respiratory diseases. One
main reason for this stagnation is the still very scarce knowledge about the fate of inhaled drug
or carrier particles after deposition in the lungs. Improvement of the aerosol component alone is
no longer sufficient for therapeutic success of inhalation drugs; a paradigm shift is needed, with
an increased focus on the pulmonary barriers to drug delivery. In this Review, we discuss some
pathophysiological disorders that could benefit from better control of the processes after aerosol
deposition, and pharmaceutical approaches to achieve improved absorption across the alveolar
epithelium, prolonged pulmonary clearance, and targeted delivery to specific cells or tissues.