Dhanya. K et al. / Journal of Pharmacy Research 2012,5(12),5069-5073
Review Article ISSN: 0974-6943
Available online through www.jpronline.info
Pulmonary Drug Delivery Systems – Past and Present Approaches : A Review 1 a.
Dhanya. K*1, Dr. C.Vijaya Raghavan2, Vijesh Varghese3 Devaki Amma Memorial College of Pharmacy, Chelembra,Kerala,India. b. Karpagam University, Coimbatore, Tamil Nadu,India. 2 PSG College of Pharmacy, Coimbatore,Tamil Nadu,India. 3 MES College for Advanced Studies, Edathala,Kerala,India.
Received on:12-06-2012; Revised on: 17-07-2012; Accepted on:26-08-2012 ABSTRACT The past 15 years have been marked by intensive research efforts on pulmonary drug delivery not only for local treatment of respiratory diseases but also for systemic therapy as well as diagnostic purposes due to the several advantages offered by the pulmonary route over other routes of drug administration. Development of novel drug deliver devices leads to the use of lungs for systemic delivery of proteins and peptides, analgesics and vaccines. The physiology of lungs makes it possible to target them via two different routes, i.e. through the circulation (parenteral) and through the respiratory tract (inhalation). The inhalational technology employs Nebulizers, Pressurized metered dose inhalers and Dry powder inhalers. Currently particulate drug carriers like liposomes, large porous particles, microparticles and nanoparticles are developed to overcome the challenges encountered by scientists. This review tries to summarize the past and present approaches to pulmonary drug delivery. Key words: Pulmonary Drug delivery, Respiratory deposition, Lung targeting, Aerosol
INTRODUCTION The lung has served as a route of drug administration for thousands of years. The origin of inhaled therapies can be traced back 4000 years ago to India, where people smoked the leaves of the Atropa belladonna plant to suppress cough. In the 19th and early 20th centuries, asthmatics smoked asthma cigarettes that contained stramonium powder mixed with tobacco to treat the symptoms of their disease [1].The past 15 years have been marked by intensive research efforts on pulmonary drug delivery not only for local treatment of respiratory diseases but also for systemic therapy as well as diagnostic purposes due to the several advantages offered by the pulmonary route over other routes of drug administration. Drugs that undergo extensive first-pass metabolism or gastrointestinal degradation (such as proteins and peptides) are ideal candidates for pulmonary delivery.
enormous surface area, very thin diffusion layer, slow surface clearance and antiprotease defence system [4].
The aim of the review is to give an outline about the historic approaches to lung delivery and also to overview the most recent developments in this field. Physiological aspects of lungs The respiratory system works with the circulatory system to deliver oxygen from the lungs to the cells and remove carbon dioxide, and return it to the lungs to be exhaled. Healthy lungs take in about 1 pint of air about 12–15 times each minute. All of the blood in the body is passed through the lungs every minute [2]. The respiratory tract is divided into two main parts: the upper respiratory tract, consisting of the nose, nasal cavity and the pharynx. The lower respiratory tract consisting of the larynx, trachea, bronchi and the lungs. The trachea, which begins at the edge of the larynx, divides into two bronchi and continues into the lungs. The trachea allows air to pass from the larynx to the bronchi and then to the lungs. The bronchi divide into smaller bronchioles which branch in the lungs forming passageways for air. The terminal parts of the bronchi are the alveoli. The alveoli are the functional units of the lungs and they form the site of gaseous exchange. The high bioavailability of macromolecules deposited in the lung (10–200 times greater than nasal and gastrointestinal values) may be due to its
*Corresponding author. Dhanya. K Devaki Amma Memorial College of Pharmacy,Chelembra, Kerala,India.
Figure 1: Human respiratory system[ 3].
The physiology of lungs makes it possible to target them via two different routes, i.e through the circulation (parenteral) and through the respiratory tract (Inhalation) [5]. Mechanisms of respiratory deposition in lungs When particles are inhaled into the lung, a certain fraction is caught in the respiratory system through contact with the wet airspace surfaces. This phenomenon is generally referred to as particle deposition and is the basis of inhalation therapy [6]. Impaction Impaction of particles in the respiratory system is due to inertia of particles. The probability of particle deposition by impaction is related to the mass
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Dhanya. K et al. / Journal of Pharmacy Research 2012,5(12),5069-5073 of the individual particle i.e. size and density and on the particle’s travelling velocity, which is determined by the respiratory flow velocity prevailing in the airways [6]. Impaction is the dominant deposition mechanisms for particles >1µm in the upper tracheobronchial regions. Each time the airflow changes due to a bifurcation in the airways, the suspended particles tend to travel along their original path due to inertia and may impact on an airway surface. This mechanism is highly dependent on aerodynamic diameter [7]. Sedimentation Sedimentation is the settling out of particles in the smaller airways of the bronchioles and alveoli, where the air flow is low and airway dimensions are small. Sedimentation is due to gravitational forces and the rate of sedimentation is dependent on the terminal settling velocity of the particles. So sedimentation plays a greater role in the deposition of particles with larger aerodynamic diameters. It becomes negligible for particles < 0.5 µm. Hygroscopic particles may grow in size as they pass through the warm, humid air passages, thus increasing the probability of deposition by sedimentation [2]. Interception Interception occurs when a particle contacts an airway surface due to its physical size or shape. Unlike impaction, particles are deposited by interception do not deviate from their air streamlines. Interception is most likely to occur in small airways in small airways or when air streamline is close to an airway wall [2]. Diffusion Diffusion is the primary mechanism of deposition for particles less than 0.5 microns in diameter and is governed by geometric rather than aerodynamic size. Hence, the highest probability of particle deposition due to diffusional displacement occurs for very small particles inhaled into the lung periphery with its small airway dimensions [6]. Diffusional deposition occurs mostly when the particles have just entered the nasopharynx, and is also most likely to occur in the smaller airways.
Figure 2: Descriptions of particle deposition mechanisms at an airway branching site.
As consequence of these physical forces acting on the aerosol particle, its deposition in the lung is highly dependent on diameter .Generally particles larger than 10 ?m will impact in the upper airways and are rapidly removed by coughing, swallowing and mucociliary processes. An 8 ?m particle inhaled at 30 Lmin-1 has approximately a 50% chance of impacting on the throat. Submicron particles may not be deposited since some will be removed from the lung on the exhaled airstream before sedimentation can occur. The “respirable fraction” of a therapeutic aerosol particle is less than 5 ?m in size. Lung targting through IV route The capillaries of filter organ acts as mechanical filters that entrap microparticles. After IV administration, microparicles larger than the capillaries become entrapped in the pulmonary circulation. The studies shows that particles <4µm pass through lung and become entrapped in the
RES where as paricles with size >10 µm become entrapped in lung. This passive targeting offers the opportunity to treat lung disease and to overcome the draw backs of inhalation therapy. Aerosol for pulmonary delivery Aerosol is developed to deliver drugs to the lungs in inhalation therapy. An aerosol can be considered as a colloidal, relatively stable two-phase system, consisting of finely divided condensed matter in a gaseous continuum. The dispersed phase may be liquid, solid or a combination of the two. Atomization is the process by which an aerosol is produced and can be electrically, pneumatically or mechanically powered. Currently there are three principal categories of aerosol generator employed which include Nebulizers, Pressurized metered dose inhalers and Dry powder inhalers. Nebulizer Nebulizers are devices for converting aqueous solutions or micronized suspensions of drug in to an aerosol for inhalation. Water insoluble drugs can be formulated either by micellar solubilization, or by forming a micronized suspension. Nebulizer solutions are often presented as concentrated solutions from which aliquots are withdrawn for dilution before administration. Such solutions require the addition of preservation. The current tendency is to use small unit dose solution that are isotonic and free from preservative and antioxidants. There are two basic types of nebulizer, jet and ultrasonic nebulizers. The jet nebulizer functions by the Bernoulli principle by which compressed gas (air or oxygen) passes through a narrow orifice creating an area of low pressure at the outlet of the adjacent liquid feed tube. This results in drug solution being drawn up from the fluid reservoir and shattered into droplets in the gas stream. The ultrasonic nebulizer uses a piezoelectric crystal vibrating at a high frequency (usually 1–3 MHz) to generate a fountain of liquid in the nebulizer chamber; the higher the frequency, the smaller the droplets produced. Constant output jet nebulizers can aerosolize most drug solutions and provide large doses with very little patient co-ordination or skill. Treatments using these nebulizers can be time-consuming but are also inefficient, with large amounts of drug wastage. Most of the prescribed drug never reaches the lung with nebulization. The majority of the drug is either retained within the nebulizer or released into the environment during expiration. On average, only 10% of the dose placed in the nebulizer is actually deposited in the lungs. To overcome these problems novel nebulizers are developed which ensure less drug wastage and more delivery efficiency. Adaptive aerosol delivery monitors a patient’s breathing pattern in the first three breaths and then targets the aerosol delivery into the first 50% of each inhalation. This ensures that the aerosol is delivered to the patient during inspiration only, thereby eliminating drug loss during expiration that occurs with continuous output nebulizers [1]. Metered-dose inhalers MDIs are introduced in1950s and have remained the most popular means for achieving domiciliary inhalation therapy. The MDI was a revolutionary invention that overcame the problems of nebulizer, as the first portable outpatient inhalation device and is the most widely used aerosol delivery device today.
Figure 3: Diagram of a metered–dose inhaler.
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Dhanya. K et al. / Journal of Pharmacy Research 2012,5(12),5069-5073 A typical MDI unit comprises the following container, metering valve, an elastomer seal and actuator. The MDI contains a therapeutic material, and a propellent as well as a surfactant and other excipients that avoid drugaerosol coagulation and lubricate moving parts of the metering valve. Traditionally propellants have consisted of chlorofluorocarbon (CFC) blends which have ensured low pulmonary toxicity, high chemical stability and compatibility with packaging materials. The three most widely used CFCs are Trichlorofluromethane (CFC11), Dichloroflurametane (CFC12), 1, 2-di chlorotetrafluromethane (CFC114). Although CFC substances are being phased out worldwide because released chlorine atom deplets Earth’s ozone layer hydrofluoroalkanes (HFAs), specifically HFA-134a and HFA-227, have been identified as suitable substitutes for CFC propellants. The HFA– drug solutions can produce aerosols with a superior fine particle fraction and can achieve much greater deposition into the periphery of the lung. MDIs deliver only a small fraction of the drug dose to the lung. Typically, only 10–20% of the emitted dose is deposited in the lung. The high velocity and large particle size of the spray causes approximately 50–80% of the drug aerosol to impact in the oropharyngeal region. The delivery efficiency of an MDI depends on a patient’s breathing pattern, inspiratory flow rate (IFR) and hand–mouth co-ordination [1]. When aerosols are inhaled slowly, deposition by gravitational sedimentation in peripheral regions of the lung is enhanced. Breath-actuated MDIs have also been developed to eliminate co-ordination difficulties by firing in response to the patient’s inspiratory effect. In patients with poor MDI technique, the breath-actuated pressurized inhaler, Autohaler™ (3M Pharmaceuticals, Minnesota, USA), increased lung deposition from 7.2% (with a conventional MDI) to 20.8% of the dose. However, breath-actuated MDIs do not help patients who stop inhaling at the moment of actuation, nor do they improve lung deposition in those patients with good MDI technique. In addition, the oropharyngeal dose remains the same as for the MDI device. Patients preferred using the Autohaler™ to the MDI even though clinical outcomes were the same. Dry powder inhalers DPI delivers the drug to the airways as a dry powder aerosol. These were designed to eliminate the co-ordination difficulties associated with the MDI. All currently available DPIs are breath –actuated, thus the reparable cloud is produced in response to the patient’s effort. The first single-dose dry powder inhaler, the Spinhaler™ (formerly Fisons, Loughborough, UK), appeared on the market 30 years ago. The spinhaler contains pins for perforating the capsule, the cap of which fits into an impeller which rotates as the patient inhales through the device. Particles are are thus dispersed into the airstreams. During the next 20 years, devices that were easier to manipulate, such as the Rotahaler™ (GlaxoWellcome,Ware, UK), were introduced, and devices incorporating four and eight doses such as the Diskhaler™ (GlaxoWellcome) appeared. The Rotahaler has a blade which cuts in the capsule in two: the body containing the powder falls into the inhaler while the cap is retained in the capsule loading port. The powder mass empties from the capsule body by the forces imparted by the inhale airstream and the drug particles subsequently enter the airways of the lung. The first true multidose device, the Turbohaler™ (AstraZeneca, Lund, Sweden) was introduced in 1988. This inhaler incorporates up to 200 doses in a reservoir of drug powder; the doses being dispensed at the point of inhalation by the patient twisting the base of the device. The Diskus™/Accuhaler™ (GlaxoWellcome) was first launched in the mid1990s with the alternative design criterion of factory-metered doses in a blister strip. This strip consists of a double foil strip of blisters each containing a unit dose of powder formulation [8]. Advantages of DPI over MDI includes Propellant-free, Less need for patient coordination, Less potential for formulation problems and Less
Figure 4: The Essential components of a Turbuhaler.
potential for extractables from device components.Lung deposition varies among the different DPIs. Approximately 12–40% of the emitted dose is delivered to the lungs with 20–25% of the drug being retained within the device. Inefficient deaggregation of the fine drug particles from coarser carrier lactose particles or drug pellets are the reason behind poor drug deposition. With DPIs, the drug aerosol is created by directing air through loose powder. Most particles from DPIs are too large to penetrate into the lungs due to large powder agglomerates or the presence of large carrier particles (e.g. lactose). Thus, dispersion of the powder into respirable particles depends on the creation of turbulent air flow in the powder container. The turbulent airstream causes the aggregates to break up into particles small enough to be carried into the lower airways and also to separate carrier from drug [1]. Recent developments in DPI technology have focused on eliminating these problems. Active DPIs are being investigated that reduce the importance of a patient’s inspiratory effort. By adding either a battery-driven propeller that aids in the dispersion of the powder (Spiros; Dura Pharmaceuticals, San Diego, CA, USA) or using compressed air to aerosolize the powder and converting it into a standing cloud in a holding chamber, the generation of a respirable aerosol becomes independent of a patient’s inspiratory effort (Inhance Pulmonary Delivery System, Inhale Therapeutic Systems, San Carlos, CA, USA). Particulate systems for drug delivery To further exploit the other advantages of lungs as well as to overcome some challenges encountered scientists developed particulate drug delivery systems for pulmonary administration. Particulate drug carriers include liposomes, large porous particles, microparticles and nanoparticles. Liposomes Liposomes are phopholipid vesicles composed of lipid bilayers enclosing one or more aqueous compartments.based on number of lipid bilayers, they are known unilamellar multilamellar vesicle. The liposomal drug formulations for aerosol delivery has many advantages like sustained pulmonary release to maintain therapeutic drug levels and facilitated intra-cellular delivery particularly to alveolar macrophages. Furthermore, drug-liposomes may prevent local irritation and reduce toxicity both locally and systematically. Increased potency with reduced toxicity is characteristic of many drugliposomal formulations [4]. Liposomal aerosols have proven to be non-toxic in acute human and animal studies. Liposomes, as a pulmonary drug delivery vehicle, have been studied for years. Recently they have been investigated as a vehicle for sustainedrelease therapy in the treatment of lung disease, gene therapy and as a method of delivering therapeutic agents to the alveolar surface for the
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Dhanya. K et al. / Journal of Pharmacy Research 2012,5(12),5069-5073 treatment of systemic diseases. Liposomes after reaching alveoli are cleared by macrophages. This opsonization can be used to treat intracellular respiratory infections. Recognition and uptake of the immune system and to prolongation of its residence can be achieved by the development of liposomes with a hydrophilic polymer surface coating, such as polyethylene glycol (PEG). These formulations are known as sterically stabilized liposomes or Stealth™ liposomes (Sequus Pharmaceuticals, Menlo Park, CA, USA) [1]. Liposomal formulations containing antibiotics to treat pulmonary diseases appear promising. Preparations containg antiasthma drugs like salbutamol, sodium cromoglycate, terbutaline and corticosteroids have been studied. Aliasgar Shahiwala and Ambikanandan Misra prepare Levonogestrel encapsulated liposomes compared bioavailabilities with the plain drug suspension and the physical mixture. These studies demonstrated the superiority of pulmonary drug delivery with regards to maintenance of effective therapeutic concentration of the Levonorgestrel in the plasma over a period of 6 to 60 hours and on the other hand to reduce frequency of dosing and systemic side effects associated with oral administration of Levonorgestrel [9]. Sumio Chono et al were examined the pulmonary insulin delivery characteristics of aerosolized liposomes. The liposomes containing insulin were administered into rat lungs and the enhancing effect on insulin delivery was evaluated by changes of plasma glucose levels. Liposomes with dipalmitoyl phosphatidylcholine (DPPC) enhanced pulmonary insulin delivery in rats, however, liposomes with dilauroyl, dimyristoyl, distearoyl or dioleoyl phosphatidylcholine did not [10]. Antibody targeting of Doxorubicin-loaded Liposomes to suppress the Growth and metastatic spread of established Human Lung Tumor Xenografts in Severe Combined Immunodeficient Mice were studied by Masahiko Sugano et al [11]. liposomes are versatile drug carrier and they may play a prominent role in pulmonary delivery. Large porous particles A new type of aerosol formulation is the large porous hollow particles, called Pulmospheres™. They have low particle densities, excellent dispersibility and can be used in both MDI and DPI delivery systems. These particles can be prepared using polymeric or nonpolymeric excipients, by solvent evaporation and spray-drying techniques. Pulmospheres™ are made of phosphatidylcholine, the primary component of human lung surfactant [1]. Pulmospheres™ are lighter and larger than the typical dry powder particles. with a mass density of approximately 0.4 g cm?3 and geometric diameter of >5 µm. By virtue of their hollow and porous characteristics, Pulmospheres™ give rise to smaller aerodynamic diameters than their geometric diameter. Because of their large size and low mass density, the particles can aerosolize more efficiently (less aggregation) than smaller nonporous particles, resulting in higher respirable fractions of the formulation. Edwards and colleagues have also demonstrated an increase in systemic bioavailability of insulin and testosterone using this technology, making Pulmospheres™ attractive for systemic inhalation therapies, as well as for sustained-release therapies, with dosing every 1–2 days while avoiding local side-effects [12]. Micro particles Microparticles include the microspheres (uniform sphere constituted of a polymeric matrix) and the microcapsules (container constituted of an oily
core surrounded by a thin polymeric membrane). Biodegradable microspheres, designed from natural or synthetic polymers, have been largely used as drug targeting systems via different routes. Hydrophilic and lipophilic molecules can be encapsulated or incorporated into microspheres. Compared to liposomes, microspheres have an in vivo and in vitro more stable physicochemical behaviour and should allow a slower release and a longer pharmacological activity of the encapsulated drugs [2].Pulmonary administration of aerosolized microspheres allows a sustained and prolonged release of drugs for respiratory or non respiratory diseases Studies relative to pulmonary targeted dosage forms using encapsulated drugs into microspheres have been developed recently. Lung-targeting albumin loaded ofloxacin microspheres were prepared by water in oil emulsion method by Sree Harsha et al [13]. The microspheres were found to release the drug to a maximum extent in the target tissue, lungs .Malika Skiba et al formulated cyclodextrin microspheres for pulmonary drug delivery containing Amikacin Sulfate [14]. Mokhtar M et al developed poly( -lactic acid) (PLA) microspheres containing nedocromil sodium and beclomethasone dipropionate (BDP) for aerosolisation to the respiratory tract [15]. Solomon et al developed paclitaxel loaded PLGA microspheres and found that microspheres were effectively prevent growth of tumor cells in culture through the induction of apoptosis [16]. Nanoparticles Nanoparticles consists of polymers or lipids and drugs are bound either at the surface of the particles or encapsulated in it. Nanoparticles with their special characteristics such as small particle size and large surface area have numerous advantages compared with other delivery systems. Drug targeting studies using these by pulmonary route have been essentially conducted by encapsulating insulin. Microencapsulated chitosan nanoparticle for lung protein delivery was developed by Ana Grenha et al. these nanoparticles were able to release75-80% insulin within 15 minues[17]. Poly-lactic-glycolic acid nanoparticles were investigated for sustained drug release in lungs by Yao Liu et al. Lorraine M. Nolan et al developed nanoporous microparticles of budesonide for pulmonary delivery and characterised these particles. Budesonide was spray dried with and without ammonium carbonate from ethanol/water or methanol/water solutions [18] . Zahoor et al developed Inhalable alginate nanoparticles containg isoniazid, rifampicin and pyrazinamide. The relative bioavailabilities of all drugs in nanoparticles were significantly higher compared with oral free drugs [19]. Solid lipid nanoparticles (SLN) have been developed in order to design alternative colloidal drug targeting particles to liposomes and polymeric nanoparticles. Indeed, SLN combine the advantages of the biocompatibility of lipids and the possibility of industrial scale up of nanoparticles Already, drugs like prednisolone, diazepam and camptotecin have been incorporated into SLN for pulmonary applications In vitro release studies have showed that an encapsulated drug into solid lipid nanoparticles can diffuse during a period of time ranging from 5 to 7 weeks. Also, dispersions of solid lipid nanoparticles can be spray dried without significant change of the sizes of the particles. Qing-yu-Xiang et al developed a novel solid lipid nanoparticle (SLN) for the lung-targeting delivery of dexamethasone acetate. The in vitro drug release study showed that dexamethasone from solid lipid nanoparticle 68% at first two hours, the remaining drug is released gradually over the following 48 hours. This result indicates SLN may be promising lung targeting drug carrier for lipophilic drugs [20].
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Dhanya. K et al. / Journal of Pharmacy Research 2012,5(12),5069-5073 CONCLUSION Availability of efficient pulmonary delivery devices and newer formulations makes the choice of a wide variety of device and formulation combinations that will target specific cells or regions of the lung, avoid the lung’s clearance mechanisms and be retained within the lung for longer periods. The more efficient, user-friendly delivery devices may allow for smaller total deliverable doses, decrease unwanted side-effects and increase clinical effectiveness and patient compliance. Targeted delivery of drug to lungs will bring a sharp improvement in existing approaches to diagnosis and treatment of various diseases. REFERENCES 1. Labiris NR , Dolovich MB, Pulmonary drug delivery. Part II: The role of inhalant delivery devices and drug formulations in therapeutic effectiveness of aerosolized medications, Br J Clin Pharmacol 2003, 56(6), 600–612. 2. Malgorzata Smola,Thierry Vandamme, Adam Sokolowski, Nanocarriers as pulmonary drug delivery systems to treat and to diagnose respiratory and non respiratory diseases, Int J Nanomedicine,2008, 3(1), 1–19. 3. Kleinstreuer C, Zhang Z, Donohue JF, Targeted Drug-Aerosol Delivery in the Human Respiratory System, Annu. Rev. Biomed. Eng, 2008, 10, 195-220. 4. Labiris NR, Dolovich MB, Pulmonary drug delivery. Part I: Physiological factors affecting therapeutic effectiveness of aerosolized medications, Br J Clin Pharmacol, 2003, 56(6), 588–599. 5. Vladimir.P. Torchilin, Drug targeting, European journal of Pharm sciences, 11,2, 2000, S81-91. 6. Holger Schulz: Mechanisms and factors affecting intrapulmonary particle deposition: implications for efficient inhalation therapies. PSTT , 1998, 8,336-344. 7. Glyn Taylor, Ian Kellaway, pulmonary drug delivery system, Gutenberg press, Malta ,275-297. 8. Ian Ashurst, Ann Malton, David Prime, and Barry Sumby, Latest advances in the development of dry powder inhalers. Reviews PSTT 2000; 3(7): 246-256. 9. Aliasgar Shahiwala, Ambikanandan Misra: Pulmonary Absorption of Liposomal Levonorgestrel. AAPS PharmSciTech 2004; 5 (1).1-5. 10. Sumio Chono, Rie Fukuchi, Toshinobu Seki, Kazuhiro Morimoto: Aerosolized liposomes with dipalmitoyl phosphatidylcholine enhance pulmonary insulin delivery. Journal of Controlled Release 2009; 137. 104–109.
11. Masahiko Sugano, Nejat K. Egilmez, Sandra J. Yokota, Fang-An Chen, Jennifer Harding, Shi Kun Huang and Richard B. Bankert: Antibody Targeting of Doxorubicin-loaded Liposomes Suppresses the Growth and Metastatic Spread of Established Human Lung Tumor Xenografts in Severe Combined Immunodeficient Mice. Cancer Research 2000;60. 6942-6949. 12. David A. Edwards,Justin Hanes, Giovanni Caponetti, Jeffrey Hrkach, Abdelaziz Ben-Jebria, Mary Lou Eskew, Jeffrey Mintzes, Daniel Deaver, Noah Lotan, Robert Langer: Large Porous Particles for Pulmonary Drug Delivery. Science 1997; 276. 18681871. www.sciencemag.org. 13. Sree Harshaa, Chandramouli Rb, Shobha Rani: Ofloxacin targeting to lungs by way of microspheres. International Journal of Pharmaceutics2009; 380. 127–132. 14. Malika Skiba, Frédéric Bounoure, Cécile Barbot, Philippe Arnaud, Mohamed Skiba : Development of cyclodextrin microspheres for pulmonary drug delivery. J Pharm Pharmaceut Sci 2005; 8(3):409418. www.cspscanada.org 15. Mokhtar M. El-Baseir and Ian W. Kellaway : Poly( -lactic acid) microspheres for pulmonary drug delivery: release kinetics and aerosolization studies. International Journal of Pharmaceutics1998; 175(2).135-145. 16. Solomon.M.A, Joseph.Walpole BS, Sepideh Amirifeli MD, Kendra NT, Mark WG, Yolonda LC, Prevention of local tumour growth with Paclitaxel loaded Microsheres. The journal of Thoracic and Cardiovascular surgery, 135(5), 2008, 1014-1021. 17. Ana Grenha, Begona Seijo, Carmen Remunan-Lopez: Microencapsulated chitosan nanoparticles for lung protein delivery. European Journal of Pharmaceutical Sciences 2005; 25. 427–437. 18. Lorraine M. Nolan, Lidia Tajber, Bernard F. McDonald, Ahmad S. Barham: Excipient-free nanoporous microparticles of budesonide for pulmonary delivery.European Journal of Pharmaceutical Sciences 2009; 37. 593–602. 19. A. Zahoor, Sadhana Sharma, G, K. Kuller:Inhalable alginate nanoparticles as antitubercular drug carriers against experimental Tuberculosis. International journal if antimicrobial agents 2005; 26. 298-303. 20. Qing-yu Xiang , Min-ting Wang , Fu Chen, Tao Gong, Yan-lin Jian, Zhi-rong Zhang, and Yuan Huang: Lung-Targeting Delivery of Dexamethasone Acetate Loaded Solid Lipid Nanoparticles. Arch Pharm Res Vol 30, No 4, 519-525, 2007.
Source of support: Nil, Conflict of interest: None Declared
Journal of Pharmacy Research Vol.5 Issue 10.October 2012
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