Pulmonary Drug Delivery

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Pulmonary Drug Delivery describes various systems, devices, formulations, and methods of delivery of drugs to the lung for the treatment of diseases of the respiratory tract for systemic delivery via the lung. it offer advantages that Supply drugs into the bloodstream directly. Its allow for those molecules that currently can only be delivered by injection. Growing attention has been given to the potential of a pulmonary route as an non-invasive administration for systemic delivery of therapeutic agents (mainly peptides and proteins) due to the fact that the lungs provides an big surface area through which molecules can be absorbed and goes direct into the bloodstream. The conducting airways branch 12–23 times and their surface area measures approximately 0.8m.sq.In adults could provide a large absorptive surface area (up to 100 m2 ) but extremely thin (0.1 μm – 0.2 μm) absorptive mucosal membrane and good blood supply. However, recent advances show great promise, but pulmonary delivery of peptides and proteins is complicated by the complexity of the anatomic structure of the human respiratory system and the effect of disposition exerted by the respiration process.

The present presentation includes
> Introduction
> Route of administration
> Inhaleables
> Aerodynamic diameter
> Aerosols
> Methods of inhalation delivery
A. Pressurized metered-dose inhalers (mdis or pmdis)
B. Dry powder inhalers (dpis)
C. Nebulizers
>Approaches in pulmonary delivery
>Challenges in pulmonary delivery
>Latest developments
Key words: Dry powder inhaler, handling, preference, asthma, COPD diabetes, vaccination and cancer.

Profile page link of the author : http://www.pharmainfo.net/harsh-bansal/biography

Profile page link of the guide: http://www.pharmainfo.net/atul-gupta/biography

[swf file="pppc08/Harsh-Pulmonary-Drug-Delivery.swf"]

Comments

G N S HEMA SREE's picture

hi, your presentation is very simple and nice but i have some queries how is the drug absorbed into the blood and by which mechanisms and you have mentioned about the drug deposition in slide no 13 can you tell me for which particles it nearly suits in terms of particle size.

G.N.S.Hemasree

Harsh bansal's picture

hello, thanks for appreciation , i have again simple answer for u, hello, thanks, i hv a simple ans, for u ,, The lung presents a very attractive route for the noninvasive delivery of systemically active compounds. The large surface area coupled with the very thin epithelium and highly vascularized nature of the pulmonary region of the lung, optimized for the efficient exchange of oxygen and carbon dioxide between the circulatory system and inhalation air, can be utilized as a "portal of entry" for the delivery of medication. However, the bronchial airways, in addition to being a distribution system of inhaled air to the pulmonary region, are also a highly evolved filter for removing particles from inhaled air and clearing them from the lung. Efficient delivery to the systemic circulation requires particles small enough to bypass this filter. Reference :- Pulmonary Delivery of Drugs by Inhalation Igor Gonda and Jeff Schuster Aradigm Corporation, Hayward, California, U.S.A. if u hv any question you can ask me again, thank you

harsh bansal

G.Sailesh's picture

Can you tell me more about aerodynamic diameter? What is the difference between normal particle size or diameter and this aerodynamic diameter along with its significance in pulmonary delivery
Harsh bansal's picture

The large surface area coupled with the very thin epithelium and highly vascularized nature of the pulmonary region of the lung, optimized for the efficient exchange of oxygen and carbon dioxide between the circulatory system and inhalation air, can be utilized as a "portal of entry" for the delivery of medication.

harsh bansal

G.Sailesh's picture

What happens if the drug reaches "deep lung" and if it reaches the "peripheral" region. Is the aerodynamic diameter or the actual particle size that must be considered for targeting drug for local and systemic action?
Harsh bansal's picture

hello sailesh, i hv something for u .. Larger particles are dominated by their inertial mass and will impact in upper airways due to their inertia. This impaction is exacerbated by higher inhalation flow rates, and even at controlled inhalation flow, oropharyngeal deposition shows very high levels of inter- and intrasubject variability [4]. Smaller particles (aerodynamic diameter _ 0.5 ?m) are dominated by thermal interactions with the air molecules and will diffuse to the respiratory tract surfaces during inhalation. However, the generation of such small particles has not been possible for commercial application (of course, molecular-size gases are used as inhalational anesthetics but typical therapeutic drugs do not exist as gases or vapors at ordinary atmospheric conditions). Inspired particles larger than approximately 1 ?m will deposit by gravitational sedimentation during a modest breath-holding period of 10 s or less [5]. Thus, efficient, reproducible delivery of pharmaceutical aerosols requires administration of 1- 3.5 ?m (aerodynamic size) particles early in the breath followed by a deep inhalation at a low, controlled inhalation flow rate. This type of controlled delivery is especially important if the target is the small airways and alveoli. A short period of breath holding is usually required to enhance deposition by sedimentation and diffusion and thus to prevent exhalation of the small particles reference :- Pulmonary Delivery of Drugs by Inhalation Igor Gonda and Jeff Schuster Aradigm Corporation, Hayward, California, U.S.A.

harsh bansal

G.Sailesh's picture

So, finally can I think that those particles ranging from 1 to 3.5 (micro) meters are called as particles with aerodynamic diameter? and the term aerodynamic relates only to size? Waiting for your answer regarding deep lung and peripheral lung too. Thank you
Harsh bansal's picture

ya of course thank you its fine

harsh bansal

Harsh bansal's picture

When the drug reaches "deep lung The large surface area coupled with the very thin epithelium and highly vascularized nature of the pulmonary region of the lung, optimized for the efficient exchange of oxygen and carbon dioxide between the circulatory system and inhalation air, can be utilized as a "portal of entry" for the delivery of medication. However, the bronchial airways, in addition to being a distribution system of inhaled air to the pulmonary region, are also a highly evolved filter for removing particles from inhaled air and clearing them from the lung. And and if it reaches the "peripheral" region its use for targeting drug delivery for diseases of the respiratory tract and regions ,its depend upon the particle size of drug. Depends upon particle size of drug. e.g. if the particle size is less them 100 nm it goes to blood stream. If its between 2-10 micro meter its tapped in airway etc plz see slide no 7 for that. Reference :- Pulmonary Delivery of Drugs by Inhalation Igor Gonda and Jeff Schuster Aradigm Corporation, Hayward, California, U.S.A. Thank you

harsh bansal

Harsh bansal's picture

hello, thanks for appreciation , i have again simple answer for u, The lung presents a very attractive route for the noninvasive delivery of systemically active compounds. The large surface area coupled with the very thin epithelium and highly vascularized nature of the pulmonary region of the lung, optimized for the efficient exchange of oxygen and carbon dioxide between the circulatory system and inhalation air, can be utilized as a "portal of entry" for the delivery of medication. However, the bronchial airways, in addition to being a distribution system of inhaled air to the pulmonary region, are also a highly evolved filter for removing particles from inhaled air and clearing them from the lung. Efficient delivery to the systemic circulation requires particles small enough to bypass this filter. Reference :- Pulmonary Delivery of Drugs by Inhalation Igor Gonda and Jeff Schuster Aradigm Corporation, Hayward, California, U.S.A. if u hv any question you can ask me again, thank you

harsh bansal

Harsh bansal's picture

sorry its by mistake no comment from my side

harsh bansal

Madhu Mohan's picture

Hello Mr.Harsh bansal I wish to know what is meant by Intra-tracheal instillation. What are the drugs used by this techniques ?

Madhu Mohan Sri Venkateswara College of Pharmacy, Chittoor (A.P.) India

Harsh bansal's picture

The intratracheal instillation was to surgically expose the trachea and inject the enzymes through the tracheal wall and directly into the lung. Animals that have been successfully used for these studies include hamsters, rats and guinea pigs. More recently, the intratracheal route has been used for administration of enzyme inhibitors. Smaller animals, such as the mouse, have seldom been used for studies of this nature, partly due to the difficulty in intratracheal administration.

harsh bansal

G N S HEMA SREE's picture

hi, thanks for your answer, the latest news is to formulate large size porous particles in order to decrease the aggolomeration of particles, the main drug formulated in this way is insulin. but the aerodynamic filters are present in lungs, then 1)how is the systemic delivery acheived in the above case and 2)what is the particle size and by 3)what mechanism the drug is deposited. these are the questions that i am not getting it if you know plz elaborate it

G.N.S.Hemasree

Harsh bansal's picture

1) When insulin is inhaled, studies of a rodent type 1 diabetes model show increased insulin antibodies and decreased T-cell proliferation with increased cytokines such as IL-10 and with induction of regulatory CD8 T cells, which decrease the rate of development of diabetes from approximately 80% to 60%. 2) The particle size increases from about 2 mm, deposition in the oropharynx and large conducting airways becomes more likely; although less aerosol is exhaled, less reaches the most peripheral parts of the lungs. The ideal size for pulmonary delivery of particles into the deep lung region is between 1 and 5 mm in geometric diameter, assuming the density of the particle is 1 g/cm3 Reference:- 1) Pulmonary Delivery of Insulin Zachary T Bloomgarden, MD 2)Inhaled Insulin for Diabetes Mellitus: Factors Affecting the Pulmonary Delivery of Insulin

harsh bansal

Harsh bansal's picture

3)Insulin loaded PLGA nanospheres having weight mean diameters of 400 nm were prepared by the modified emulsion solvent diffusion method in water. The nanosphere recovery and the drug recovery in the nanospheres were 74.8%+-4.71 and 46.8%+-7.01, respectively. Eighty five percent of the drug was released from the nanospheres at the initial burst, followed by prolonged releasing of the remaining drug for a few hours in saline at 37degC. Reference:- Pulmonary delivery of insulin with nebulized -lactide/glycolide copolymer (PLGA) nanospheres to prolong hypoglycemic effect Y. Kawashima , H. Yamamoto, H. Takeuchi, S. Fujioka and T. Hin thank you

harsh bansal

Sandeep Reddy's picture

goog morning your presentation was really super 1)is this nanoparticles used in the pulmonary drug delivary system then what is the mechanism?
Harsh bansal's picture

Hello, Sandeep Thanks for appreciation, I have ans. For u, Yes nanoparicle can be use for this delivery, Nano particle-based drug delivery systems have considerable potential for treatment of tuberculosis (TB). nanocarriers administered by pulmonary route to treat and to diagnose respiratory and non respiratory diseases. nanodevices or nanosystems which are defined as particles having a size ranging from 1 nm to 1 mm. To be suitable for pulmonary drug delivery, nano carriers aim to minimize drug degradation and loss, prevent harmful side effects and increase the availability of the drug at the disease site. And Aerosol administration of the therapeutics to the pulmonary epithelium for systemic delivery represents a significant opportunity for many classes of drugs and applications, including anti-tumor therapy, gene therapy, AIDS therapy, radiotherapy, Reference :- nanocarriers as pulmonary drug delivery systems to treat and to diagnose respiratory and non respiratory diseases Malgorzata Smola,1,2 Thierry Vandamme,1 and Adam Sokolowski2

harsh bansal

Sandeep Reddy's picture

thanks for answring 1)can you write any drug-drug interactions in this system?
Harsh bansal's picture

hello sandeep, ya off course their are numbers of drugs which show drug-drug interactions with other drugs some examples are 1)warfarin is an oral anticoagulant that inhibits the synthesis of clotting factors, interact with numbers of drugs such as Aspirin, acetaminophen ,ibuprofen, cimetidine (Tagamet), oxandrolone (Oxandrin),etc. thank you

harsh bansal

Sandeep Reddy's picture

thanks and all the best
Harsh bansal's picture

thank you thanks a lot i need it

harsh bansal

Anil kumar appapurapu's picture

Abstract: Pulmonary Drug Delivery describes various systems, devices, formulations, and methods of delivery of drugs to the lung for the treatment of diseases of the respiratory tract for systemic delivery via the lung. it offer advantages that Supply drugs into the bloodstream directly "Its allow for those molecules that currently can only be delivered by injection" can u pls elaborate the meaning of quoted note?

anilkumar

Harsh bansal's picture

hello anil, very gud eve. ya off course i will try 1) Pulmonary Drug Delivery describes various systems, devices, formulations, and methods of delivery of drugs to the lung for the treatment of diseases of the respiratory tract for systemic delivery via the lung. it is the definition of pulmonary drug delivery system, ( i,e various system which use for it eg AEROSOLS Pressurized Metered-Dose Inhalers (MDIs or pMDIs)Dry Powder Inhalers (DPIs, Nebulizers and different formulations eg dry powder etc,) and 2) it offer advantages that Supply drugs into the bloodstream directly "Its allow for those molecules that currently can only be delivered by injection" e.g in case of insulin this route is noninvasive as comprehension to subcutaneous daily. i think its sufficient but if not u can ask me again thank you

harsh bansal

Anil kumar appapurapu's picture

is this delivery not allowed for other drugs apart from currently given by injection

anilkumar

Harsh bansal's picture

NO, it can be use for other drug delivery today its use for no. of treatments e.g antibiotics, antivirals, copd, narcotic analgsic you can go throw the slide no. 26th i think that sufficient for your question thankyou

harsh bansal

Sirisha Pingali's picture

hello harsh You have got good information regarding PDDS. Are CFCs free inhalers being manufactured by indian companies?? Is this system ideal only for adults??

Sirisha Pingali

http://www.pharmainfo.net/sirisha

Viswanadha Institute of Pharmaceutical Sciences.

www.vnips.edu.in

Harsh bansal's picture

Hello sirisha tanks for appreciation. i have a ans for u Yes ,off course it is safe for adults also I read it in times of India that Ranbaxy has already introduced a range of inhalers using HFA technology. pharma companies are now introducing new technology in their inhalers which is CFC-free, and hence not harmful. The new MDI (Metered Dose Inhalers) use HFA (Hydro Fluoro Alkanes) technology India, presently, has an estimated 15-20 million asthmatic patients and the estimated prevalence rate in 5-11 year old children is between 10-15% only. Reference:- CFC-free inhalers for asthma patients Rupali Mukherjee, TNN, Sep 16, 2007, 05.45am IST thankyou

harsh bansal

Pooja Chowdary's picture

Can steroids be administered by pulmonary delivery? If yes are their any side effects with such delivery ? How can the side effects be treated?

pooja

Harsh bansal's picture

2) Anti-inflammatory steroids can act systemically as well as locally. Therefore, while systemic administration of anti-inflammatory steroids will diminish airway inflammation in asthmatics, it can also cause such adverse effects as general immunosuppression and imbalances in mineral metabolism. The corticosteroids commonly used in asthma treatment have a high ratio of topical to systemic potency. That is, these corticosteroids are highly active when delivered directly to the site of inflammation but relatively inactive when passed through the systemic circulation. The portion of an inhaled dose which is swallowed and absorbed through the intestine or absorbed through the lung tissue into the circulation is subjected to metabolism by the liver and converted to less active compounds with short half-lives. These metabolites are quickly eliminated from the blood, reducing the incidence of systemic side effects. Reference:-Aqueous compositions containing corticosteroids for nasal and pulmonary delivery United States Patent 6241969

harsh bansal

Harsh bansal's picture

the most commonly used steroids are aldosterone, beclomethasone, betamethasone, budesonide, cloprednol, cortisone, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluorometholone, flurandrenolone, fluticasone, halcinonide, hydrocortisone, icomethasone, meprednisone, methylprednisolone, mometasone, paramethasone, prednisolone, prednisone, tixocortol, triamcinolone, and others, and their respective pharmaceutically acceptable derivatives, such as beclomethasone diproprionate, dexamethasone 21-isonicotinate, fluticasone propionate, icomethasone enbutate, tixocortol 21-pivalate, triamcinolone acetonide, and others. Fortunately, some of these synthetic steroids have low potentials for systemic absorption because of their unique structures and metabolism.

harsh bansal

Abhishek Rathi's picture

Dear Harsh, A very nice presentation. Just a few simple Questions. 1.Apart from the preparations available as aerosols and Inhalers,which are mostly anti-asthamatics ans insulins which is under developments....which other drugs could be designed as Pulmonary delivery systems?i just want a idea....if any other drug is/are under development... 2.Which Chelating agent,enzyme inhibitors,permeation enhancers are commonly used.....??? Because they are to be carefully selected as the they are going to be exposed directly to systemic circulation....

Abhishek Rathi

Harsh bansal's picture

The drug may be suspended or solubilized in a non-aqueous propellant, which is typically a chlorofluorocarbon or fluorinated hydrocarbon that is a liquid under pressure at room temperature. In turbo inhalers and dry powder inhalers, the drug is present in the form of a micronized powder. Most organic solvents that are currently approved for use in inhalation devices are propellants, such as chlorofluorocarbons (CFCs), which will soon be eliminated from manufacturing for environmental reasons, or the newer hydrofluorocarbons and low boiling hydrocarbons, all of which are expected to evaporate prior to penetrating the lungs. the drug is to blend cosolvents such as ethanol, propylene glycol, or polyethylene glycol with water. Classes of enhancers used for transmucosal delivery include bile salts, dihydrofusidates, cyclodextrins, surfactants, and chelating agents. Each of these agents exerts its enhancing effects by a different mechanism, and each has been associated with adverse effects. aprotinin, bacitracin, soybean trypsin inhibitor (STI) were used as protease inhibitors reference :- Pulmonary absorption enhancement of peptides by absorption enhancers and protease inhibitors Akira Yamamoto, Takuya Fujita and Shozo Muranishi

harsh bansal

Abhishek Rathi's picture

Thanks for the answer.

Abhishek Rathi

Harsh bansal's picture

welcome abhishek its my pleaser

harsh bansal

Harsh bansal's picture

hello thanks for appreciation, Yes there are no. of drugs administrated by this route For targeting as well as for systemic delivery of drugs Such drugs are antibiotic, antiviral, asthma durgs COPD, and influenze . You can go to slide no 26 for more details . with regard harsh

harsh bansal

pankuu's picture

well hi mr. harsh bansal, recently i ve gone through ur ppt really good it is, just keep it up, i must appreciate d kind of invention upeople r doing in pharma sector. best wishes from ma side. pankaj sachdeva QA chemist isll dera bassi mohali.
p@nk@j.
Harsh bansal's picture

hello sir, thanks for appreciation,

harsh bansal

pankuu's picture

well harsh thanks a ton for ur feed backs and lookin for same responce in future too, best of luck for ur carrear and just keep doing dese kind of unique and nobel causes. p@nk@j QA chemist isll mohali.
p@nk@j.
pankuu's picture

well hi harsh culd u pls clear ma 1 more quiry? wel i just wante to know that is this roa got any sort of approvel from usfda or any other regulatory agenciy? well approvel from any regulatory agency means green signal for safety point of view too. waitin for ur reply....... pAnKAj QA chemist ind-swift labs ltd. mohali.
p@nk@j.
pankuu's picture

well hi harsh, i want to ask that no doubt this route of admistration is quite novel and unique one. but may i ask that can we admisniter all the drugs thru dis ROA or its also specific, moreover from recently develpod drugs wat are the major one which doest show any sort of complication when given thru dis route.
p@nk@j.
Harsh bansal's picture

hello pankaj i try to ans. to you No, all drugs are not possible through this route only 17% of total drug categories are able through this route. but this route is best for targeting for lungs and trachea in case of asthma and other pulmonary disease . it is also good for systemic drugs but drug should be in small particle size. and should not show harmfull effect on connected regions, insulin can be administrate through this route easily. and it is non invasive route that is no induce any pain during administration and you can go to slide no 26 for more example. thank you

harsh bansal

Harsh bansal's picture

hello pankaj i try to ans. you No, all drugs are not possible through this route only 17% of total drug categories are able through this route. but this route is best for targeting for lungs and trachea in case of asthma and other pulmonary disease . it is also good for systemic drugs but drug should be in small particle size. and should not show harmfull effect on connected regions, insulin can be administrate through this route easily. and it is non invasive route that is no induce any pain during administration and you can go to slide no 26 for more example. thank you

harsh bansal

pankuu's picture

so what should be the ideal particle size for systemic drug delivery.
p@nk@j.
Harsh bansal's picture

dear pankaj the idea particle size is 1 to 3 um. but different particle size use for different regions that is for targeting as well systemic circulation, u can go to slide no 7 i think its sufficient for your query. thank you

harsh bansal

Sonam Mittal's picture

Dear Harsh, 1.For the proper dosage by pulmonary route, is the design of individual's respiratory tract should be considered, if yes, which parameters should be considered? 2.Can you please tell the diseases currently being targeted by pulmonary drug delivery? Regards, sonam

Sonam Mittal M.Pharm Head Department of Pharmaceutical Chemistry Vaish Institute of Pharmaceutical Education and Research (VIPER)

Harsh bansal's picture

hello sonam, yes, an individual's respiratory system indeed plays an important role in design of optimal dosage by pulmonary route. factors to be considered are 1) rate of inspiration and expiration, 2)lung volume and respiratory volume, 3)rate of diffusion through the lung tissue and 4) bifurcation in airways which may result in constantly changing hydrodynamic flow field. thank you

harsh bansal

Pooja Chowdary's picture

1)Pulmonary drug delivery in case of drugs like insulin though very effective possesses toxic effects such as bleeding and bronchial asthma ? 2)Can you suggest some measures to prevent or reduce these instances?

pooja

Harsh bansal's picture

hello pooja, yes you right it possesses toxic effect as you say, but The toxic effects of bleeding and bronchial asthma can be occurs some time but it is mainly due to the particle size of the inhaled formulation. So if we choose intermediate size that is neither too small nor too large for the aerodynamic window. because large particle size causes inertial deposition in the mucosa of the lungs, leading to tissue damage by natural killer cells and bleeding an bronchial asthma, So for reducing these instances use of liposomes to incorporate insulin for this route of administration, thankyou

harsh bansal

Shreesha Bhat's picture

hi harsh... just wanted to share a piece of info.. the Advanced Inhalation Research (AIR) system developed by Alkermes Inc. is a potential pulmonary delivery system of dry insulin powder under clinical development. the AIR particles have a large size but low density..hence the large particles behave aerodynamically like small particles..moreover they are easy to disperse..and have much less toxic potential... So, this can be a potential breakthrough in pulmonary drug delivery.. refer the sites below.. http://www.liebertonline.com/doi/pdf/10.1089/dia.2007.0218 http://www.ncbi.nlm.nih.gov/pubmed/17850203

Shreesha V Bhat Ramanbhai Patel College of Pharmacy, Education campus Changa, Gujarat, India. http://www.pharmainfo.net/shreeshabhat

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