recent trends in applications of pulmonary drug delivery: a review

Publication Ref No.: IJPRD/2011/PUB/ARTI/VOV-2/ISSUE-12/FEB/018

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RECENT TRENDS IN APPLICATIONS OF PULMONARY DRUG DELIVERY: A REVIEW Siraj Shaikh*1 Syed Nazim1, Afsar Shaikh1 , Tarique Khan1, Md.Zameeruddin1, Quazi Majaz1, Shailesh Chalikwar 2 1

Siraj Shaikh

Ali-Allana college of pharmacy Akkalkuwa Dist, Nandurbar, Maharashtra, India. 2 R.C.Patel college of pharmacy,Shirpur Dist Dhule, Maharashtra, India. Email:[email protected]

ABSTRACT Pulmonary drug delivery system is a needle free technique. The origin of inhaled therapies seen in 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. Now a day’s pulmonary drug delivery remains the preferred route for administration of various drugs. It is an important research area which impacts the treatment of illnesses including asthma, chronic obstructive pulmonary disease and various diseases. Drug is delivered directly to the conducting zone of the lungs. In this article, we summarize recent advances in applications of pulmonary drug delivery system. previously pulmonary drug delivery is used for management of Asthma and COPD only but due advancement in application nowadays Pulmonary drug delivery is useful to treat Diabetes, angina pectoris, cancer , bone disorders ,migraine,tuberculosis,acute lung injury and others. .

Key Words: Asthma, pulmonary route, application, bone disorders, inhalation therapy. INTRODUCTION The development of an inhalation therapy that is effective and safe depends not only on a pharmacologically active molecule, but also on a delivery system and its applications. The respiratory tract is exposed to a relatively large number of biological and non biological particulates. These are contained in the 20,000

L of air that must be inhaled daily to accomplish gas exchange. It is a characteristic of the effectiveness of lung defense mechanisms that in healthy people’s lungs are sterile below the larynx. 1 By pulmonary route drug goes gives direct to a target organ. In the treatment of obstructive respiratory diseases, pulmonary delivery can

International Journal of Pharma Research and Development – Online

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minimize systemic side effects, provide rapid response and minimize the required dose since the pulmonary route is better alternative to other routes because if we compare it with parental route injection is associated with pain. Seconadly, chronic injection is an unpleasant prospect with a host of hygiene issues and potential side effects. At worst, it can create a barrier to patient compliance with the particular drug regimen required to most effectively treat a given disease, since some patients choose irregular treatment or no treatment at all when faced with frequent injections. 2 While injecteble route is another option has served as the primary means of delivering drug but it is invasive in nature so, many noninvasive routes have been explored as alternatives. Oral route remains the most common method of delivery for most small molecule drugs. However, oral delivery most often does not work for macromolecules because proteins are digested before they have an opportunity to reach the bloodstream. As compare to pulmonary route more dose is required to show action by oral route. 3,4 Drug delivery by Nasal route is inefficient in terms of the amount of drug actually delivered to the body and to improve its efficiency penetration enhancers must be added that may cause local irritation. But in case of pulmonary route research has shown that many molecules are absorbed through the deep lung into the bloodstream naturally with relatively high bioavailability and without the need for enhancers used by other noninvasive routes. Intradermal route offers an even less naturally permeable boundary to macromolecules than the gastrointestinal tract. The devices, which inject proteins like insulin, have been available for years, however they have not very well accepted by doctors as well as patients due to the discomfort and the potential for ‘‘splash back’’ to transmit blood borne diseases associated with it .Thus pulmonary route is better route as compare to other routes,5,6,7,

ADVANTAGES DELIVERY.

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OF

PULMONARY

DRUG

1) It is needle free pulmonary delivery. 2) It requires low and fraction of oral dose. 3) Pulmonary drug delivery having very negligible side effects since rest of body is not exposed to drug. 4) Onset of action is very quick with pulmonary drug delivery. 5) Degradation of drug by liver is avoided in pulmonary drug delivery.8,9,10 CURRENT APPLICATIONS OF PULMONARY DRUG DELIVERY 1) Application of pulmonary drug delivery in Asthma and COPD.11,12 Asthma is a chronic long term lung disease that is characterized by inflammation and narrowing of airways. Asthma causes recurring periods of wheezing, chest tightness, shortness of breath, and coughing. The coughing often occurs at night or early in the morning. Asthma affects people of all ages, but it most often starts in childhood. In the United States, more than 22 million people are known to have asthma. Nearly 6 million of these people are children. Aerosol systems that deliver bronchodilators to relax airways and corticosteroids to control inflammation in asthma and COPD are widely used today and carry a proven track record. Today’s inhaled drug delivery market is dominated by the three main classes of drug such as bronchodilators, corticosteroids, and anticholinergic. Nowadays all above three classes of drugs given by pulmonary route. For managment of asthma advances done in drugs such levosalbutamol inhalers which having superior efficacy as compare to salbutamol.COPD means chronic obstructive pulmonary diseases. COPD is linked to smoking, comprises chronic bronchitis and emphysema and causes one million deaths


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annually.Titropium inhalers market to teat COPD.

are

2) Recent role pulmonary patients on ventilators

present

in

delivery

in

Aerosols to patients on ventilators have received much accepted by doctors as well as patient in 1990. Some studies of early delivery techniques documented low (2.2%) deposition in the lung with half retained in the nebulizer, and considerable intersubject variability. Recently to improve inhalation coordination of patient devices like Baby mask are mostly used.This mask is attached to spacer for small tidal volumes and low inspiratory flow rates infant and young Childers..By using baby mask we can easily give medication to child up to 2 years this is recent advancements in applications of pulmonary drug delivery. 3) Pulmonary delivery in cystic fibrosis Nowadays cystic fibrosis is very common disease .Pulmonary delivery played an important role in the management of CF for decades. The main aim of aerosol system is to deliver drugs to infants and chidrens. Recentallly following drugs are given by pulmonary route for cystic fibrosis. I) N-Acetylcysteine N-acetylcysteine (NAC) is Mucolytic agents have been used by pulmonary route to help in sputum clearance. It will help to liquefy tenacious secretions and make their clearance easier. Recently newer mucolytic agent, nacystelyn, has been developed for delivery via a dry powder inhaler. II) Recombinant human deoxyribonuclease aerosol Rerecentallly deoxyribonuclease is given by pulmonary route .Recombinant human deoxyribonuclease aerosol mainy used to

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liquefy secretions in CF patient. III). Tobramycin-spray dried. Tobramycin powders containing Nanoparticles for pulmonary delivery.Tobramycin is widely used to treat patients with CF. Overall, evidence suggests improved lung function and probably reduced hospitalization when tobramycin is part of maintenance therapy in CF .13 4) New use of pulmonary delivery in diabetes Diabetes is a syndrome of disordered metabolism and inappropriate hyperglycemia resulting from a deficiency of insulin secretion or resistance. Diabetes can cause a heart attack, stroke, blindness, kidney disease, nerve damage and other serious health problems. The most common form of this therapy is twice-daily subcutaneous injections of insulin. This type of treatment is painful and as a result encourages noncompliance by up to half of the diabetics. Peptides and/or proteins are becoming more important in medication. When taken orally, peptides and/or proteins are degraded by the proteolytic enzymes in the gastrointestinal tract, and might be impermeable to the intestinal mucosa due to their hydrophilicity and large molecular size. As a result, systemic delivery of these macromolecular drugs and other therapeutic and diagnostic agents has been limited to the parenteral route. Repeated injections are required due to the short half-lives of peptide/protein drugs.14 The first attempts at intrapulmonary delivery were made in the 1920s . However, almost 50 years feasibility of arolosied insiulinwas demonstrated Initial observations were soon confirmed by others revealing a more rapid absorption and clearance compared to subcutaneous administered insulin. Several companies are working on insulin inhalers than any other insulin delivery option. Insulin inhalers would work much like asthma inhalers.


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The products fall into two main groups the dry powder formulations and solution, which are delivered through different patented inhaler systems. E.g. Novel pMDI formulations for pulmonary delivery of proteins.15, 16,17,18.19,20. (Refer Table No. 01) 5) In migraine Ergotamine is drug of choice for migraine. Many years ago, ergotamine via metered dose inhaler was used successfully to treat migraine headache.13 6) Angina pectoris Angina pectoris is not a disease itself it is symptoms of myocardial ischemia it is arises as a result of imbalance between oxygen supply and demand of myocardium.Nitroglycerine. is drug of choice for angina pectoris has been given generally by sublingual route .It is well known as is a known coronary vasodilator, the rapid relief of angina is probably caused by a reduced demand on the heart and the consequent reduced cardiac work. An aerosol form has been tested in Europe and has been found comparable to sublingual nitroglycerine. In particular, its efficacy has been found better than nitroglycerine tablets in patients with dry mouth. Isosorbide aerosol has also been reported useful in hypertensive crisis. In United States inhalation therapy for angina pectoris is very well accepted.13 7) Role of pulmonary delivery in vaccination 21

While there was moderate interest in aerosol vaccination 15–20 years ago, progress toward application has been modest seen.Nearly 100 vaccines are approved in the U. S. About half of these prevent respiratory infections, yet all are currently injected. As compare to injectable they remove needle fears, especially in children, but they could also generate more potent local immune responses than when they are injected into muscles.

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Measles infects 30 to 40 million children in underdeveloped nations. Recently inhaled measles vaccine given by nebulizer. As far back as the 1960s, influenza experts tested aerosol flu vaccines. 8) In emphysema Emphysema is most popular respiratory disorder due to deficiency of Alpha 1 antitrypsin uncontrolled neutrophil elastase deficiency formed which leads to lung destruction and the formation of emphysema. Nowadays recombinant AAT (rAAT) given intravenously (IV) is very well accepted treatment. Early evaluation of aerosolized AAT documented adequate alveolar fluid AAT and penetration into the lung interstitum. Neutrophil elastics’ inhibitor, secretory leukocyte protease inhibitor, has also been considered for protection against elastase in CF and patients with AAT deficiency. 9) Recent use of pulmonary drug delivery in transplantation Inhalation route play a role very important role in transplantation. Legion is problems of transplanted organs and lung transplantation is one of the most difficult transplants to maintain. During lung transplantation, pulmonary vascular pressure and an intrapulmonary shunt have been shown to respond to inhaled nitric oxide and inhaled aerosolized prostacyclin .prostacyclin which is given by pulmonary route has also been described as an alternative to nitric oxide in the management of reperfusion injury after lung transplantation. Acute and chronic rejections are major problems compromising transplant and patient survival. Aerosolized cyclosporine a is useful for reducing the risk of acute rejection. 13 10) In Pulmonary arterial hypertension22 This is new use of pulmonary route in 2004, the FDA approved Ventavis (iloprost), an


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inhaled treatment for pulmonary arterial hypertension, made by CoTherix (South San Francisco, CA, U. S. A.). In pulmonary arterial hypertension, severe restriction of blood vessels results in early death. 11) In acute lung injury13 Drug given by pulmonary route plays very important role in acute lung injury. Major complication of acute lung injury is Hypoxemia and it is often difficult to manage. Mediators such as nitric oxide and prostacyclin can improve oxygenation by increasing blood flow through ventilated areas. Prostaglandin E1 (PGE1) by continuous aerosol via a ventilator has also been shown to improve oxygenation. 12) Application of pulmonary drug delivery as a surfactant aerosol In respiratory distress of premature infants and neonatal surfactant plays important role. In adults loss of surfactant is probably a contributing factor in pathogenesis of acute respiratory distress syndrome. A recent study showed no difference in outcome for spontaneously breathing newborns who inhaled either surfactant or placebo via a CPAP mask. There continues to be great appeal for the use of surfactant in adults because of the apparent success in neonates, but its use should not become practice until well controlled trials document clinically meaningful efficacy. 13) Gene therapy via pulmonary route23 This is new research in application of pulmonary drug delivery .Main aim Gene therapy given by pulmonary route is treatment of cystic fibrosis. Cationic-lipid-mediated CFTR gene transfer can significantly influence the underlying chloride defect in the lungs of patients with CFC. There are many problems to be overcome before clinical applications are practical. Some of these are safety, successful transfer of sufficient genetic material to appropriate tissue, adequate gene expression,

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maintenance of expression over time, and efficacy of expression. 14) Application of pulmonary drug delivery in cancer chemotherapy Cancer is one of major disease which takes death of people. Lung cancer is the leading cause of cancer deaths globally, and inhaled chemotherapy seems a logical approach to treat lung cancer. A multicenter Phase I clinical trial is evaluating doxorubicin HCI inhalation solution in lung cancer patients. As many as 400 000 lung cancer patients could benefit from inhaled chemotherapy; a study is going on aerosolized paclitaxel solution to mice with lung tumors. The treatment significantly reduced lung tumors and prolonged survival. Aerosol delivery of the anticancer agent’s difluoro methylornithine and 5fluorouracil reduced lung tumors in mice 50 % and 60 %, respectively. Interleukin-2 stimulates immune function in cancer patients, but injections cause fever, malaise, and local swelling. 24 15) Delivery of pentamidine by pulmonary route25 protozoan Pneumocystis carinii(PCP) is major cause of Pneumonia in Patients with acquired immunodeficiency syndrome . Aerosol pentamidine is not only useful in treating mild PCP and, but also for prophylaxis against PCP. Pentamidine aerosol is delivered to the alveolar space, where the P. carinii organisms are found. The deposition fraction of pentamidine is relatively low, around 2–3% of total dose in the nebulizer but as a fraction of total lung capacity, it is greater in children, and so there is need to reduce the dose in children. 16) Delivery of Amphotericin by pulmonary route26 Now days Amphotericin aerosol has been successfully used to treat various infections.


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Such use should not become clinical practice without good randomized controlled trials. Ribavirin aerosol has also been used for treatment or prophylaxis following bone marrow transplantation but controlled trials are needed to better clarify efficacy. 17) Delivery of route

Gentamycin

by pulmonary

For chronic Pseudomonas aeruginosa (PA) infections in CF gentamycin given by pulmonary route plyas important role.It was observed daily inhalations of gentamicin delays the acquisition of chronic PA infections and decreases disease progression in children with zanamivir, made by GSK, was the first inhaled anti-viral medication approved by the FDA in 1999. For treatment of flue dose of dry powder inhalers is twice daily for 5 days. 27 8) Diagnostic application pulmonary drug delivery 27 Pulmonary drug delivery is not only useful for therapeutic purpose but also for diagnosis purpose. Several diagnostic tests utilizing specific-size nonradioactive aerosols and also radioactive aerosols with standard nuclear medicine technology are practiced in respiratory medicine. For example, inhalation of aerosols of methacholine and histamine is widely used to assess nonspecific bronchial responsiveness in asthma. 19) Nicotine aerosol for smoking cessation As we know that smoking is injurious to health .It is very difficult to cess such habit. From ancient times people smokes cigarette and get addicted with smoking. Primary reason for cigarette smoking is Nicotine addiction, and nicotine replacement is appealing as a means of reducing cigarette use to ultimately achieve

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cessation. Nicotine for inhalation and for nasal delivery is available, and studies indicate some improvement in the success of cessation efforts beyond placebo. Inhaled nicotine substitution for cigarettes has much potential because it most mimics delivery by smoking, giving a rapid rise in blood nicotine level. 20) Inhaled drug delivery for tuberculosis therapy28 Tuberculosis is most infectious diseases because One third of the world population is infected with tuberculosis and new infections occur at a rate of one per second. The urgency to treat TB may be addressed with approaches consisting of newer drugs and delivery systems The recent increase in the emergence of drugresistant strains of Mycobacterium tuberculosis and the dearth of anti-TB drugs is threatening the future containment of TB. Administering drugs by the pulmonary route to the lungs allows higher drug concentrations in the vicinity of these lesions. Supplementing conventional therapy with inhaled antiTB therapy may allow therapeutic concentrations of drug to penetrate effectively into lung lesions and treat the resident mycobacterium. Drugs Used Experimentally to Treat TB by the Pulmonary Route is as rifampicin, ionized and pyrazinamide. As we know that drug resistance is major hurdle in treatment of tuberculosis if drugs given by pulmonary route for management of TB reduces chances of drug resistance TB.Various drug delivery systems such as micro particles, nanoparticles and Liposomes can be delivered to the periphery of the lungs for instantaneous and targeted or controlled release. This may lead to therapeutically effective drug concentrations in regions of the lungs containing large burdens of bacteria. Aerosol delivery to the lungs as an adjunct to conventional therapy has the potential to decrease the dosing frequency and the duration


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of therapy. This may ultimately lead to less severe side effects, improved patient compliance and reduced emergence of drug resistant strains of TB. 21) Pulmonary delivery of lower molecular weight Heparin29 Now days , low molecular weight heparins is better as an alternative to unfractionated heparin because of improved pharmacokinetic profiles and reduced cost of therapy in the treatment of deep vein thrombosis and pulmonary embolism . Low molecular weight heparins are given by subcutaneous and intravenous routes. Administration of an anticoagulant drug directly to the pulmonary circulation would be ideal for the treatment of pulmonary embolism. A pulmonary formulation of LMWH will allow direct administration of the drug into the lungs, and consequently this formulation is likely to reduce the mortality from an attack of pulmonary embolism. This pulmonary therapy is non invasive because it is needle free. 22) Controlled delivery of drugs to lungs by pulmonary route Recent application of pulmonary drug delivery is controlled delivery by lungs. Most Drugs in inhalation required to be take 3-4 times in day because of its short duration action so sustained release of drugs in lungs prolong action in lung for that Liposomes, microsphere Nanoparticles carriers are used Sustained release from a therapeutic aerosol can prolong the residence of an administered drug in the airways or alveolar region, minimize the risk of adverse effects by decreasing its systemic absorption rate, and increase patient compliance by reducing dosing frequency. E.g. ribavirin aerosol, novel sustained released microspheres for pulmonary drug delivery, studies showed that plasma glucose level was effectively reduced when liposomal insulin was

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delivered by inhalation route of using aerosolized insulin encapsulated liposomes. Liposomes, as a pulmonary drug delivery vehicle, have been studied for years and used as a means of delivering phospholipids to the alveolar surface for treatment of neonatal respiratory distress syndrome. More recently, they have been investigated as a vehicle for sustained-release therapy in the treatment of lung disease, gene therapy and as a method of delivering therapeutic agents to the alveolar surface for the treatment of systemic diseases. Liposomes can be produced from a variety of phospholipids from natural sources, that are endogenous to the lungs and that carry either no charge or net negative or positive charges.30,31,32. 33 23) Recent use of pulmonary delivery for bone disorders34 Disease such as osteoporosis and Paget’s disease of bones can be treated by pulmonary delivery. The predicted increase in the number of patients with osteoporosis and the lack of ideal therapies dictates the need for better treatments. Clinical evidence from a variety of other peptides and proteins indicates that pulmonary delivery is safe, efficient, well tolerated and preferred by patients so pulmonary route is better option to treat bone disorders. Following are drugs used to treat osteoporosis are the naturally occurring peptides calcitonin and parathyroid hormone, which regulate bone metabolism. For the peptides to become viable therapies, formulations must be developed that bypass the need for injection. Pulmonary delivery of calcitonin and parathyroid hormone appears likely in the near future. The recent introduction of a nasal formulation of calcitonin points to the feasibility of lung delivery. A pulmonary formulation inhaled through the mouth that delivers


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calcitonin or PTH into the deep lung should improve the bioavailability and efficacy of the drugs. 24) Current use of pulmonary delivery of opioids as pain therapeutics35 For pain management painful inject able are given. To avoid pain associated with inject able pain killer Pulmonary opioid delivery is better alternative. Early clinical studies involving inhaled opioids were focused on treatment of dyspnoea and not pain management, but they showed that inhalation of various opioid compounds is safe, even in severely ill patients. The advent of specialized and efficient pulmonary drug delivery systems has facilitated the evaluation of inhaled opioids, such as morphine and fentanyl, for management of severe pain associated with surgery or malignant disease. In the past, the few studies evaluating pulmonary delivery of opioids for the management of severe pain has with limited success. Earlier attempts at systemic delivery of opioids through the lungs utilized standard jet nebulizer/compressor systems which have minimal efficiency for deep lung delivery. Studies are going on to introduce new molecules for management of pain trough pulmonary route Studies with efficient pulmonary delivery systems, designed for systemic drug applications, conclusively show that inhaled opioids are rapidly, completely and reproducibly absorbed into the bloodstream. Thus, the pulmonary route has excellent potential for treating non-invasively severe pain in the postoperative setting and in malignant disease. So by giving pain killer via pulmonary route we can give parental efficacy with oral convenience to patients. So by pulmonary drug delivery it easy to manage pain. CONCLUSION The lung has served as a route of drug administration for thousands of years. Now a

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day’s pulmonary drug delivery remains the preferred route for administration of various drugs. Pulmonary drug delivery is an important research area which impacts the treatment of illnesses including asthma, chronic obstructive pulmonary disease and various diseases. Inhalation gives the most direct access to drug target. In the treatment of obstructive respiratory diseases, pulmonary delivery can minimize systemic side effects, provide rapid response and minimize the required dose since the drug is delivered directly to the conducting zone of the lungs .It is a needle free several techniques have been developed in the recent past, to improve the Quality of pulmonary drug delivery system without affecting their integrity. Because of advancement in applications of pulmonary drug delivery it is useful for multiple diseases. So pulmonary drug delivery is best route of administration as compare to other routes. REFERENCES 1. Clark AR. Medical aerosol inhalers. Past, present and future. Aerosol Sci Technol. 1995;22:374–391. 2. Grossman J. The evolution of inhaler technology. J Asthma. 1994;31:55–6 3. Newman SP, Clarke SW. Inhalation devices and techniques. In: Clark TJH, Godfrey S, Lee TH, editors. Asthma. 3. London: Chapman & Hall; 1992. pp. 469–505. 4. Pedersen S. Inhalers and nebulizers: which to choose and why. Resp Med. 1996;90:69–77. 5. Ganderton D. Targeted delivery of inhaled drugs: current challenges and future goals. J Aerosol Med. 1999;12(1):s3–s8. 6. Dolovich M. New propellant-free technologies under investigation. J Aerosol Med. 1999;12(1):s9–s17. 7) Michael T. Newhouse, “Encyclopedia of Pharmaceutical Technology”, Informa Healthcare USA, Page no.1279-1285.


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8) Derek Ivan Daniher, Jesse Zhu, Review on “dry powder platform for pulmonary drug delivery”,www.sciencedirect.com,Particuology(2 008)225– Henderik W. Frijlink, Anne H. de Boer, “Trends in the technologydrivenDevelopment of new inhalation devices”, drug discovery today.technology,elesevier vol.2.no.1 2005. 9) David A. Edwards, Abdelaziz Ben-Jebria, and Robert Lange “Recent advances in pulmonary drug delivery using large, porous inhaled particles,” J Appl Physiology 85: 1998, Vol. 85, Issue 2, page no.379-385, . 10) www.cipladoc.com 11) Harrison Principles of Internal medicine, mc ,Grew,Hill medical publication,17 Edition volume, 1 Page No- 1596-1636 12) John S. Patton, “Market Trends in Pulmonary Therapies,” www.inspiration 2006. 13) ) Kathryn Senior, “New technology fo22) Gabrielle Pilcer a, Francis Vanderbist b, Karim Amighi, “Preparation and characterization of spray-dried tobramycin powders containing Nanoparticles for pulmonary delivery”, International Journal of Pharmaceutics, International Journal of Pharmaceutics 365 (2009) page no.162–169. 14) Yi-You Huang , Ching-Hua Wang, Pulmonary delivery of insulin by liposomal carriers, Journal of Controlled Release 113 (2006) 9–14. 15) David A. Edwards, Andre´ X. Valente, Jonathan Man, and Nicolas Tsapis Harvard University, Cambridge, Massachusetts, U.S., “Recent Advances Related to the Systemic Delivery of Therapeutic Molecules by Inhalation”, modern pharmaceutics marcelDekker 2004 page no.1-10 , 16) David R. Owens Geremia B. Bolli and , Bernard Zinman “Future options for insulin therapy, current science”, vol. 83, no. 12, 25 december 2002,page no.1548-1554.

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17) K Gowthamarajan and Giriraj T Kulkarni, Oral Insulin – Fact or Fiction? resonece may-2003,page no.38-40. 18) MM Al-Tabakha, AI Arida “challenges in insulin drug delivery system”, Indian journal of pharmaceutical,science,2008,pageno.278-284. 19) R.Naryani, “oral delivery of insulin making needless”, trends biometer.artifs.organ, vol. 15910, 2001 Page no. 12-16. 20) Jaleh Varshosaz, “Insulin Delivery Systems for Controlling Diabetes”, Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2007, 1, page no. 25-40. 21) Derek T. O’Hagan and Rino Rappuoli “Novel Approaches to Vaccine Delivery”, Pharmaceutical Research, vol.21, NO.9 September 2004. Page no.1519-1520. 22)Robyn J. Barst, MD, “Recent Advances in the Treatment of Pulmonary Artery Hypertension”, Acc Current Journal Review November/December 1998Published by Elsevier Science Inc page no.61-63. 23) Justin Hanes, Michelle Dawson, Yah-el Harel, Junghae Suh, and Jennifer Fiegel Johns Hopkins ,University, Baltimore, Maryland, U.S.A.,” Gene Delivery to the Lung,” ,modern pharmaceutics marcelDekker 2004 page no.151. 24)John S. Patton, “Market Trends in Pulmonary Therapies”, inspiration2006.doc page no.1-10 25) 34) A. Bruce Montgomery, “Aerosolized Pentamidine for Treatment and Prophylaxis of pneumocystis carinii Pneumonia in Patients with Acquired Immunodeficiency Syndrome”, modern pharmaceutics Marcel Dekker 2004 page no.1-14. 26) Brain e. “pulmonary delivery of antitiritroviral drugs”, dept. of microbiology, immunology, and seminar in paed infectious disese, volume 7 no.2 April 1996 page no.148-154. 27) Practical Aspects of Imaging Techniques Employed to Study Aerosol deposition and Clearance”,, modern pharmaceutics Marcel


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Dekker 2004 page no.38-43. 28). Pavan Muttil,1 Chenchen Wang,1 and Anthony J. Hickey, “Inhaled Drug Delivery for Tuberculosis Therapy”, Pharmaceutical Research, Vol. 26, No. 11, November 2009. 29) Tianzhi Yang, 1 Fatima Mustafa,1 Shuhua Bai, “Pulmonary Delivery of Low Molecular Weight Heparins”, Pharmaceutical Research, Vol. 21, No. 11, November 2004 ,page no.2009 -2014. . 30)Schreier H, Gonzalez-Rothi RJ, Stecenko AA. Pulmonary delivery of liposomes. J Controlled Release. 1993;24:209–223. 31). Schreier H, Sawyer SM. Liposomal DNA vectors for cystic fibrosis gene therapy. Current applications, limitations

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32) Xian ming zeng, “controllerd delivery of drugs to lungs”, International Journal of Pharmaceutics 12(1995) 149-164. 33)Robert O. Cooka,T, Rupi K. Pannub, “Novel sustained release microspheres for pulmonary drug delivery”, Journal of Controlled Release 104 (2005) page no.79-90 34) John S. Patton, “Pulmonary delivery of drugs for bone disorders”, Advanced Drug Delivery Reviews 42 (2000) 239–248. 35) Stephen J. Farr , Babatunde A. Otulan, “Pulmonary delivery of opioids as pain therapeutics”, Advanced Drug Delivery Reviews 58 (2006) , Page no.1076–1088.

TABLES Table no.1. Characteristics of devices for intrapulmonary delivery of insulin. Name of Device Formulation Requirement Dose organization of Insulin of adjustment breath activation Alkemes/Eli AIR Dry Yes coarse Lilly powders Aerogun/Becton Aero Dose Liquid Yes Fine Dickinson Elmsford Med Tone Dry No coarse powders, Pfizer/Aventis Inhance/Exubera Dry No coarse powders, Aradigm/Novo AERX idms Liquid Yes Fine Nordisk

Battery size

No

Small

Yes

Small

No

small

No

Large

Yes

Large

…End…


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