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Special Delivery

Rania Salama at Sydney University delves into advances and challenges in controlled release therapy for pulmonary diseases

Delivering therapeutic agents to the respiratory tract has so far been the first line of treatment for asthma, making use of bronchodilators, steroids and mast cell stabilisers. In addition, the treatment of chronic obstructive pulmonary disease (COPD), as well as respiratory infections, has also been a classic target for local inhalation therapies. The lung has limited enzymatic activity compared to the gastrointestinal tract, and a rich blood supply via the tremendously large capillary network. Confining the therapeutic agent in the airways has proven useful for both maximising its concentration in lung tissue while using small doses which decrease systemic exposure as much as possible. In addition, when formulated for the lower respiratory tract, systemic absorption is promoted, and the potential for delivery of systemic agents becomes an option.

Pressurised metered-dose inhalers (pMDIs) were the first convenient therapy introduced for bronchodilators and corticosteroids. Successful development of chlorofluorocarbon (CFC) free pMDIs resolved the environmental concerns of the original pMDI, however issues such as performance, the freon effect, chemical stability and poor coordination have given rise to the dry powder inhaler (DPI). Overcoming patient coordination difficulties and increasing the drug stability in dry powder form have led to the development of DPIs. The discovery of disodium cromoglycate in 1965 and its formulation in a DPI started an era of flourishing research and development of DPIs for local drug delivery to the lungs. So, various inhalation therapies exist for the treatment of respiratory illnesses; however, no controlled release inhalation system exists to date. DPIs are propellant free, easy to operate (as they do not require breath-actuation), portable, particularly suitable for chronic illnesses and, being in a dry powder form, constitute a more stable alternative to pMDIs or nebulisers.

CONTROLLED RELEASE PULMONARY THERAPY

Unfortunately, the short duration of action and the need to deliver drugs at least three to four times a day are significant drawbacks of current inhalation therapies. The advantages of controlling the release of drugs to the respiratory tract is well documented (1,2). For example, prolonging the presence of β2-agonists at the β2-adrenergic receptors may potentially reduce the exacerbation of asthma during sleep (as asthma is influenced by the circadian rhythm). Drug molecules that have already been investigated for their potential as a local controlled release agent in the lung include antivirals, antibacterials, antifungals, cytotoxic agents and immunosuppressives. Furthermore, recombinant human DNase for the treatment of cystic fibrosis, α-1-antitrypsin as a potential treatment of emphysema and DNA vaccines for mucosal immunity all demand a delivery system capable of achieving long-term expression of the molecule to enhance response.

Many systemic molecules which are being developed for inhalation would also benefit from a controlled-release mechanism; insulin, calcitonin, interferons, parathyroid hormone, vaccines, gene therapy, human growth hormone and leuprolide are just a few examples. Furthermore, the systemic controlled release of small painkiller molecules, such as morphine, would be extremely advantageous for postoperative or cancer patients’ pain management.

PHYSIOLOGICAL CHALLENGES

Formulating medicines for inhalation is not an easy task. A key criterion for a successful inhalation dosage form is that the therapeutic agent is consistently and reliably generated within an optimum respirable size range. Since the performance of such particulate systems is dependent on many variables, the fundamental study of the relationship between morphology, surface energy and aerosol performance is generally limited, and performance related theories are based on empirical observation, since modification of one variable (for example particle shape) inherently alters other physical variables (such as surface chemistry). Although multiple variables pose a significant problem when attempting to understand the intricacies of these systems, significant advancement in understanding has been achieved through empirical study. However, the formulation of controlled release therapies has compounding challenges specific to their function. In particular, the inhaled medicine has to have a particle size of less than 6μm to be able to penetrate the airways (3). Additionally, for controlled release formulations, a release modifier has to be included at the particle production step, which is effective in retarding the release of medicine after delivery. Both these steps are challenging, as with the reduction in size there comes a significant increase in surface area to mass ratio, and subsequently it becomes more difficult to produce a controlled release profile and incorporate effective release agents.

The physiology of the lung and its impact on resident particles need to be considered carefully. If the aerodynamic particle size of a formulation is in the range of 2.5-6.0μm (as for local therapy), then the deposited particles will be removed primarily by the mucociliary escalator towards the pharynx and ultimately deposited in the gastrointestinal tract within a day (4). Moreover, some of these particles may be absorbed through the epithelium in this region into the blood or the lymphatic system. In comparison, the particles will be deposited primarily in the alveoli if they have an aerodynamic diameter of smaller than 2.5μm, as for systemic delivery (3). Insoluble particles deposited in the alveolar sac are subjected to clearance mainly via alveolar macrophages. These exist in numbers equivalent to five to seven macrophages per alveolus and engulf and enzymatically degrade foreign particulate matter or microorganisms. This is then migrated to the mucociliary escalator or lymph tissue in a time frame of weeks to months (4,5).

A very important issue when developing controlled release formulations for inhalation is the toxic, inflammatory and accumulation effects of the release modifying agents used. Although some toxicity work has been conducted on certain release modifiers, the depth and breath of these studies vary. Furthermore, because this area of research has not yet been subjected to commercial production or authorities’ registrations, there are no specifically tailored guidelines for the assessment of their release testing or quality controls.

PRODUCTION OF CONTROLLED RELEASE FORMULATIONS FOR PULMONARY INHALABLE DRUG MOLECULES

Synthetic and Natural Solid Biodegradable Excipient-Based Matrices

Slowing down the release of the active drug molecules can be achieved by encapsulation into matrices, where, after inhalation, they ‘land’ at the air-liquid interface in the lung. These systems generally rely on the high molecular weight, poor solubility of the polymer or drug-molecule interactions to limit drug release. Subsequently, the drug passively diffuses out of the particulate to be slowly released into the systemic circulation.

Many synthetic and natural materials have been used to prepare controlled release microparticle systems. These include biocompatible synthetic polymers such as PLGA, polylactic acid (PLA), polyethylene glycol (PEG), polyvinyl alcohol (PVA) and natural polymers or proteins such as chitosan or albumin.

PLGA and PLA have been the most commonly reported polymers utilised for potential respiratory sustained release systems. Insulin-loaded nanospheres with mannitol showed significantly decreased blood glucose levels, as well as prolonged pharmacological effects due to the preferable inhalation performance and gradual release of insulin from nanospheres in the nanocomposite (6).

Large size and low density particles of both insulin and testosterone with PLGA and PLA were produced (7). The particles were inhaled deep into the lungs and compared to the conventional particles. The large porous particles showed elevated blood levels of insulin beyond four hours, with a relatively constant insulin release observed up to at least 96 hours. Similarly, for testosterone, blood levels remained above background levels for 12 to 24 hours.

While PLGA and PLA microparticles have been shown to have great potential as release modifying agents in the lung, they have also been shown to cause a significant reduction in cell viability when compared to lipid-based particles in cell-based toxicity screens. Furthermore, pulmonary administration of PLA microspheres to rabbits was associated with raised neutrophil count, inflammation at sites close to microparticle deposition and haemorrhage (8). In addition, it has been suggested that the long residence time, due to slow degradation, might lead to pulmonary accumulation of these polymers, especially with daily administration. Unfortunately, a recent comparative study of a series of potential polymers has shown that PLGA had the greatest toxicity when studied on the Calu-3 monolayers (9). This study concluded that hydroxypropyl cellulose had high delivery efficiency, sodium hyaluronate and chitosan showed low toxicity and controlled release behaviour, and ovalbumin and chitosan had improved systemic delivery of a model proteinloaded particle system prepared by spray drying.

PVA has also been studied as a potential biocompatible polymer for pulmonary delivery. Salama et al have studied the effect of PVA on the characteristics and release profiles of spray-dried disodium cromoglycate (DSCG) and bovine serum albumin microparticles for pulmonary inhalation (10-12). PVA was found to improve the aerosolisation efficiency of DSCG and prolong the release of the active drug from the microparticles. Furthermore, a preliminary A549 cell toxicity study indicated that PVA had a limited effect on cell viability after a 24-hour exposure.

The use of natural protein carriers may be one means of overcoming potential toxicity and accumulation of these polymers in the lung. Incorporation of albumin in the formulation of dry powder inhalers is expected to prolong the release of particles in the alveoli and, as a result, either increase the absorption of the active drug substance or be subjected to enzymatic degradation.

Mucoadhesive polymers such as chitosan and hydroxypropyl cellulose have the potential to prolong residence time through physical adsorption, thus avoiding mucociliary clearance. In addition, chitosan is also an absorption enhancer as it has been reported to loosen the tight junctions between the epithelial cells, facilitating absorption. Mucoadhesive surface modification PLGA nanospheres using chitosan have been reported to lead to slower elimination from the lungs as well as enhancing the absorption of the active drug rather than the unmodified PLGA nanospheres (13).

Large molecular mass polymers or proteins can also be used as a conjugate (as opposed to just forming encapsulating matrices as described above). These conjugates primarily rely on increasing the total molecular weight of the system, in turn retarding the rate of absorption of the active ingredient across the epithelium of the alveoli. However, applying this well-known approach to the respiratory tract may carry some disadvantages. For example, the conjugation of two large molecules would result in a slower metabolism and potential accumulation in the lung due to low enzymatic activity. Furthermore, attaching polymeric materials to proteins requires a thorough understanding of the position of the functional groups so as not to block the active protein site. This approach has been utilised and the influence of calcium phosphate-PEG particles on the delivery and transport of insulin was studied (14). In this study, the bioavailability and duration of action of insulin were enhanced when administered to the lungs of rats when compared to conventional subcutaneous delivery.

Liposomal-Based Systems

Since liposomes can be formulated from a variety of lipids, it is possible to produce a wide range of physicochemical properties that can accommodate a variety of entrapped drug molecules. Liposome size, surface charge, number of bilayers and method of preparation all affect drug encapsulation. The vesicles’ size range (from around 20nm to several micrometres) and the number of bilayers are the major parameters controlling the extent of drug encapsulation and its half-life. While absorption of liposomal drugs may be dependent on both the composition and size of the liposomes, sizes of 50-200nm are reported to be optimal for avoiding phagocytosis by macrophages while still being a useful size to encapsulate drugs. Furthermore, depending on the preparation conditions and chemical composition, different surface charges and bilayer fluidity can be manipulated for a desired physiological effect. For example, cationic liposomes have been used to bind negatively charged DNA and fuse to cell membranes for the treatment of cystic fibrosis. Such an approach avoids the safety issues and the immunogenic response associated with the use of viral vectors; however, their transfection efficiencies are lower. Interestingly, liposomal and phospholipidbased liquid formulations have been used for the treatment of neonatal respiratory distress syndrome and seasonal asthma, thus making these relatively safe vehicles for controlled release applications (15).

 Examples of recent research in this area include the work by Stark et al, where a vasoactive intestinal peptide was encapsulated into unilamellar liposomes. This study concluded that sterically stabilised liposomal formulations have the potential to enhance the life-span and biological activity of peptide drugs in the metabolic environment of the lung (16). Another study by Chono et al indicated that, according to pharmacokinetic/ pharmacodynamic analysis, the pulmonary administration of mannosylated ciprofloxacine-liposomes exhibited potent antibacterial effects against many tested bacteria and could be useful against intracellular parasitic infections (17).

An expansion of the liposomal-based system is agglomerated vesicle technology. Essentially, lipid-based nanoparticles can be produced with a variety of ligands at the distal ends of spacer polyethylene glycol (PEG) chains. In vivo cleavage of the agglomerated liposomes, which are used as core nanoparticles, result in controlled release of the drug (18).

Despite the continuous research into liposomal formulation, the high production cost, stability issues relating to disruption and loss of entrapped medications during storage or nebulisation, remain significant challenges. One possible alternative is to take these highly ordered structures and formulate them into a dry powder, overcoming potential physical stability issues linked to its liquid state.

Solid Lipid Particles

Although a limited number of reports are available in this field, the formation of solid lipid particles as a powder from liposomal-based systems has many advantages over their liquid counterparts. Specifically, these particles are more chemically and physically stable than liposomes, have good entrapment yields, use inexpensive carriers and avoid toxic solvent residues (when using specific solvent evaporation techniques).

Salbutamol acetonide loaded solid lipid nanoparticles of glyceryl behenate showed delayed release profiles in vitro when compared to the free drug or the physical mixtures. No significant inflammatory airway response was observed in similar systems after intratracheal administration in rats (19).

A further modification of the solid lipid microparticles approach involves coating or encapsulating drug particles in a lipid outer shield. Interestingly, uptake of PLGA microparticles by cultured macrophages was found to be significantly reduced when dipalmitoylphosphatidylcholine (DPPC) was incorporated into the formulation (20). In another study, chitosan nanoparticles containing insulin were coated with a lipid film of DPPC and dimyristoylphosphatidylcholine. These complexes were successful in controlling the release of insulin from the nanoparticles under in vitro conditions (21).

Viscous Semisolid Systems

In principle, these systems are similar to many of the solid matrix systems, as the drug is uniformly dispersed throughout the gel and passively diffuses out through the matrix into the surrounding tissue. The use of semi-solid viscous vehicles, which effectively form a gel interface for the transport of drug upon deposition in the lung, is an alternative to the use of solid matrices and molecular dispersions.

Recent work by Yamamoto et al has demonstrated that a range of polymers in a less than five per cent aqueous solution can have a significant effect on drug plasma levels in rats after intratracheal administration to the lung (22). The pulmonary absorption of 5(6)-carboxyfluorescein was regulated in the presence of five per cent gelatine, one per cent PVA, one per cent hydroxypropyl cellulose, one per cent methyl cellulose 400 or one per cent hyaluronic acid. The excipients effect on the release profile appeared to be drug specific since the release rate of fluorescein isothiocyanatelabeled dextrans was not regulated by gelatine or PVA.

In another study, iota- and kappacarrageenans were shown as potential release modifying polysaccharides gels. Yamada et al showed a modified absorption rate of theophylline and flutecasone propionate when the polymers were utilised in solutions less than five per cent weight/volume, with no evident damaging or inflammatory effect on lung tissue (23).

CONCLUSION

Although significant advances in pulmonary controlled release therapy have been made, many more are required to bring such formulations to the market. Furthermore, the evaluation of the toxicity of materials used to modify the release behaviour of the active pharmaceutical ingredients needs to be scrutinised in much greater detail. Although many challenges exist, controlled release formulations to the lung have not yet reached their full potential and are still understated.

References

  1. Zeng XM, Martin GP and Marriott C, The Controlled Delivery of Drugs to the Lung, International Journal of Pharmaceutics 124(2): pp149-164, 1995
  2. Salama R, Traini D, Chan H-K and Young PM, Recent advances in controlled release pulmonary therapy, Current Drug Delivery 6, pp404-414, 2009
  3. Pritchard JN, The influence of lung deposition on clinical response, Journal of Aerosol Medicine- Deposition Clearance and Effects in the Lung 14, S19-S26, 2001
  4. Martonen TB, Mathematical model for the selective deposition of inhaled pharmaceuticals 82(12): pp1,191-1,199, 1993
  5. Stone KC, Mercer RR, Gehr P, Stockstill B and Crapo JD, Allometric relationship of cell numbers and size in the mammalian lung, American Journal of Respiratory Cell and Molecular Biology 6, pp235-243, 1992
  6. Yamamoto H, Hoshina W, Kurashima H, Takeuchi H, Kawashima Y, Yokoyama T and Tsujimoto H, Engineering of poly(DL-lactic-co-glycolic acid) nanocomposite particles for dry powder inhalation dosage forms of insulin with the spray-fluidised bed granulating system, Advanced Powder Technology 18(2): pp215-228, 2007
  7. Edwards DA, Hanes J, Caponetti G, Hrkach J, Ben-Jebria A, Eskew ML, Mintzes J, Deaver D, Lotan N and Langer R, Large Porous Particles for Pulmonary Drug Delivery, Science 276(5320), pp1,868-1,872, 1997
  8. Armstrong DJ, Elliott PN, Ford JL, Gadsdon D, McCarthy GP, Rostron C and Worsley MD, Poly-(D,L-lactic acid) microspheres incorporating histological dyes for intra-pulmonary histopathological investigations, The Journal of Pharmacy and Pharmacology 48(3): pp258-262, 1996
  9. Sivadas N, O’Rourke D, Tobin A, Buckley V, Ramtoola Z, Kelly JG, Hickey AJ and Cryan S-A, A comparative study of a range of polymeric microspheres as potential carriers for the inhalation of proteins, International Journal of Pharmaceutics, 358(1-2): pp159-167, 2008
  10. Salama R, Hoe S, Chan HK, Traini D and Young PM, Preparation and characterisation of controlled release co-spray dried drug-polymer microparticles for inhalation 1: Influence of polymer concentration on physical and in vitro characteristics, European Journal of Pharmaceutics and Biopharmaceutics 69(2): pp486-495, 2008
  11. Salama RO, Traini D, Chan HK, Sung A, Ammit AJ and Young PM, Preparation and evaluation of controlled release microparticles for respiratory protein therapy, Journal of Pharmaceutical Sciences 98(8): pp2,709-2,717, 2009
  12. Salama RO, Traini D, Chan HK and Young PM, Preparation and characterisation of controlled release co-spray dried drug-polymer microparticles for inhalation 2: Evaluation of in vitro release profiling methodologies for controlled release respiratory aerosols, European Journal of Pharmaceutics and Biopharmaceutics 70(1): pp145-152, 2008
  13. Yamamoto H, Kuno Y, Sugimoto S, Takeuchi H and Kawashima Y, Surface-modified PLGA nanosphere with chitosan improved pulmonary delivery of calcitonin by mucoadhesion and opening of the intercellular tight junctions, Journal of Controlled Release 102(2): pp373-381, 2005
  14. Garcia-Contreras L, Morçöl T, Bell SJD and Hickey AJ, Evaluation of Novel Particles as Pulmonary Delivery Systems for Insulin in Rats, AAPS PharmSci 5(2), Article 9, 2003
  15. Labiris NR and Dolovich MB, Pulmonary drug delivery – Part II: The role of inhalant delivery devices and drug formulations in therapeutic effectiveness of aerosolised medications, British Journal of Clinical Pharmacology 56(6): pp600-612, 2003
  16. Stark B, Andreae F, Mosgoeller W, Edetsberger M, Gaubitzer E, Koehler G and Prassl R, Liposomal vasoactive intestinal peptide for lung application: Protection from proteolytic degradation, European Journal of Pharmaceutics and Biopharmaceutics 70(1): pp153-164, 2008
  17. Chono S, Tanino T, Seki T and Morimoto K, Efficient drug targeting to rat alveolar macrophages by pulmonary administration of ciprofloxacin incorporated into mannosylated liposomes for treatment of respiratory intracellular parasitic infections, Journal of Controlled Release 127(1): pp50-58, 2008
  18. Karathanasis E, Ayyagari AL, Bhavane R, Bellamkonda RV and Annapragada AV, Preparation of in vivo cleavable agglomerated liposomes suitable for modulated pulmonary drug delivery, Journal of Controlled Release 103(1): pp159-175, 2005
  19. Jaspart S, Bertholet P, Piel G, Dogné JM, Delattre L and Evrard B, Solid lipid microparticles as a sustained release system for pulmonary drug delivery, European Journal of Pharmaceutics and Biopharmaceutics 65(1): pp47-56, 2007
  20. Evora C, Soriano I, Rogers RA, Shakesheff KM, Hanes J and Langer R, Relating the phagocytosis of microparticles by alveolar macrophages to surface chemistry: the effect of 1,2-dipalmitoylphosphatidylcholine, Journal of Controlled Release 51 (2-3): pp143-152, 1998
  21. Grenha A, Remuñán-López C, Carvalho ELS and Seijo B, Microspheres containing lipid/chitosan nanoparticles complexes for pulmonary delivery of therapeutic proteins, European Journal of Pharmaceutics and Biopharmaceutics 69(1): pp83-93, 2008
  22. Yamamoto A, Yamada K, Muramatsu H, Nishinaka A, Okumura S, Okada N, Fujita T and Muranishi S, Control of pulmonary absorption of water-soluble compounds by various viscous vehicles, International Journal of Pharmaceutics 282(1-2): pp141-149, 2004
  23. Yamada K, Kamada N, Odomi M, Okada N, Nabe T, Fujita T, Kohno S and Yamamoto A, Carrageenans can regulate the pulmonary absorption of antiasthmatic drugs and their retention in the rat lung tissues without any membrane damage, International Journal of Pharmaceutics 293(1-2): pp63-72, 2005

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Rania Salama is an Associate Lecturer in Pharmaceutics at the Faculty of Pharmacy, University of Sydney, NSW, Australia. Her research expertise is in inhalation medicine, with a specific interest in controlled release formulations and in vitro/in vivo methodologies and correlations. She has experience in the development and implementation of comparative bioavailability and bioequivalence studies (in human volunteers), undertaken while working as an Assistant Lecturer at the University of Alexandria, Egypt. Rania is an early career researcher leading projects under the supervision of Associate Professor Paul Young in the Advance Drug Delivery Group. She has extensive expertise in undergraduate and postgraduate education. To date, Rania has published 20 research articles and conference proceedings, including six peer-reviewed articles since 2007.
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