Nasopulmonary drug delivery system: Introduction to Nasal and Pulmonary routes of drug delivery, Formulation of Inhalers (dry powder and metered dose), nasal sprays, nebulizers
Mucoadhesive drug delivery system interact with the mucus layer covering the mucosal epithelial surface, & mucin molecules & increase the residence time of the dosage form at the site of the absorption.
Mucoadhesive drug delivery system is a part of controlled delivery system.
Since the early 1980,the concept of Mucoadhesion has gained considerable interest in pharmaceutical technology.
combine mucoadhesive with enzyme inhibitory & penetration enhancer properties & improve the patient complaince.
MDDS have been devloped for buccal ,nasal,rectal &vaginal routes for both systemic & local effects.
Hydrophilic high mol. wt. such as peptides that cannot be administered & poor absorption ,then MDDS is best choice.
Mucoadhesiveinner layers called mucosa inner epithelial cell lining is covered with viscoelasticfluid
Composed of water and mucin.
Thickness varies from 40 μm to 300 μm
General composition of mucus
Water…………………………………..95%
Glycoproteinsand lipids……………..0.5-5%
Mineral salts……………………………1%
Free proteins…………………………..0.5-1%
The mechanism responsible in the formation of mucoadhesive bond
Step 1 : Wetting and swelling of the polymer(contact stage)
Step 2 : Interpenetration between the polymer chains and the mucosal membrane
Step 3 : Formation of bonds between the entangled chains (both known as consolidation stage)
Electronic theory
Wetting theory
Adsorption theory
Diffusion theory
Fracture theory
Advantages over other controlled oral controlled release systems by virtue of prolongation of residence of drug in GIT.
Targeting & localization of the dosage form at a specific site
-Painless administration.
-Low enzymatic activity & avoid of first pass metabolism
If MDDS are adhere too tightlgy because it is undesirable to exert too much force to remove the formulation after use,otherwise the mucosa could be injured.
-Some patient suffers unpleasent feeling.
-Unfortunately ,the lack of standardized techniques often leads to unclear results.
-costly drug delivery system
Introduction to Nasal drug delivery system,Anatomy of Nasal cavity,Advantages n limitataions of Nasal DDS,Mechanism,factors affecting Nasal DDS,Formulation,methods to enhance Nasal DDS,Dosage forms,Evalaution
Mucoadhesive drug delivery system interact with the mucus layer covering the mucosal epithelial surface, & mucin molecules & increase the residence time of the dosage form at the site of the absorption.
Mucoadhesive drug delivery system is a part of controlled delivery system.
Since the early 1980,the concept of Mucoadhesion has gained considerable interest in pharmaceutical technology.
combine mucoadhesive with enzyme inhibitory & penetration enhancer properties & improve the patient complaince.
MDDS have been devloped for buccal ,nasal,rectal &vaginal routes for both systemic & local effects.
Hydrophilic high mol. wt. such as peptides that cannot be administered & poor absorption ,then MDDS is best choice.
Mucoadhesiveinner layers called mucosa inner epithelial cell lining is covered with viscoelasticfluid
Composed of water and mucin.
Thickness varies from 40 μm to 300 μm
General composition of mucus
Water…………………………………..95%
Glycoproteinsand lipids……………..0.5-5%
Mineral salts……………………………1%
Free proteins…………………………..0.5-1%
The mechanism responsible in the formation of mucoadhesive bond
Step 1 : Wetting and swelling of the polymer(contact stage)
Step 2 : Interpenetration between the polymer chains and the mucosal membrane
Step 3 : Formation of bonds between the entangled chains (both known as consolidation stage)
Electronic theory
Wetting theory
Adsorption theory
Diffusion theory
Fracture theory
Advantages over other controlled oral controlled release systems by virtue of prolongation of residence of drug in GIT.
Targeting & localization of the dosage form at a specific site
-Painless administration.
-Low enzymatic activity & avoid of first pass metabolism
If MDDS are adhere too tightlgy because it is undesirable to exert too much force to remove the formulation after use,otherwise the mucosa could be injured.
-Some patient suffers unpleasent feeling.
-Unfortunately ,the lack of standardized techniques often leads to unclear results.
-costly drug delivery system
Introduction to Nasal drug delivery system,Anatomy of Nasal cavity,Advantages n limitataions of Nasal DDS,Mechanism,factors affecting Nasal DDS,Formulation,methods to enhance Nasal DDS,Dosage forms,Evalaution
Ophthalmic drug delivery system :Challenges and Approaches.Ashish Kumar Mishra
This presentation mainly cover all the challenges which the pharmaceuticals scientist are facing in formulation of an ocular drug delivery system and the method involved to overcomes the problems and provided an more stable and convenient ODDS with increased Bio-availability.
Among all diff. routes, oral has achieved more attention & quite successful.
This is due to fact that GI physiology provides more flexibility then other routes.
Transdermal Drug Delivery System (TDDS) is the one of the novel technology to deliver the molecules through the skin for long period of time.
Transdermal Drug Delivery System (TDDS) are defined as self contained, discrete dosage forms which are also known as “patches” 2, 3 when patches are applied to the intact skin, deliver the drug through the skin at a controlled rate to the systemic circulation
Ophthalmic drug delivery system :Challenges and Approaches.Ashish Kumar Mishra
This presentation mainly cover all the challenges which the pharmaceuticals scientist are facing in formulation of an ocular drug delivery system and the method involved to overcomes the problems and provided an more stable and convenient ODDS with increased Bio-availability.
Among all diff. routes, oral has achieved more attention & quite successful.
This is due to fact that GI physiology provides more flexibility then other routes.
Transdermal Drug Delivery System (TDDS) is the one of the novel technology to deliver the molecules through the skin for long period of time.
Transdermal Drug Delivery System (TDDS) are defined as self contained, discrete dosage forms which are also known as “patches” 2, 3 when patches are applied to the intact skin, deliver the drug through the skin at a controlled rate to the systemic circulation
In ancient time Ayurvedic system of medicine used nasal route for administration of drugs and the process is called as “Nasya”.
Nasal route has been used for local effects of decongestants but, in recent time it is being considered as a preferred route of drug delivery for systemic bioavailability.
Various proteins & peptides have shown a good bioavailability through this route.
Nasal Drug Delivery is Part of the Novel Drug Delivery System(NDDS) for effective drug delivery to the Brain, Lungs, and Local administartion. It has its own challenges and advantages.
Hard gelatin capsules: Introduction, Extraction of gelatin and production of hardgelatin capsule shells. size of capsules, Filling, finishing and special techniques of formulation of hard gelatin capsules. In process and final product quality control tests for capsules.
Soft gelatin capsules
Tablets: a.Introduction, ideal characteristics of tablets, Classification of tablets. Excipients, Formulation of tablets, granulation methods, compression and processing problems.
FLUID FLOW
A fluid is a substance that continually deforms (flows) under an applied shear stress. Fluids are a subset of the phases of matter and include liquids, gases.
“Fluid flow may be defined as the flow of substances that do not permanently resist distortion”
The subject of fluid flow can be divided into-
fluid statics
fluid dynamics
June 3, 2024 Anti-Semitism Letter Sent to MIT President Kornbluth and MIT Cor...Levi Shapiro
Letter from the Congress of the United States regarding Anti-Semitism sent June 3rd to MIT President Sally Kornbluth, MIT Corp Chair, Mark Gorenberg
Dear Dr. Kornbluth and Mr. Gorenberg,
The US House of Representatives is deeply concerned by ongoing and pervasive acts of antisemitic
harassment and intimidation at the Massachusetts Institute of Technology (MIT). Failing to act decisively to ensure a safe learning environment for all students would be a grave dereliction of your responsibilities as President of MIT and Chair of the MIT Corporation.
This Congress will not stand idly by and allow an environment hostile to Jewish students to persist. The House believes that your institution is in violation of Title VI of the Civil Rights Act, and the inability or
unwillingness to rectify this violation through action requires accountability.
Postsecondary education is a unique opportunity for students to learn and have their ideas and beliefs challenged. However, universities receiving hundreds of millions of federal funds annually have denied
students that opportunity and have been hijacked to become venues for the promotion of terrorism, antisemitic harassment and intimidation, unlawful encampments, and in some cases, assaults and riots.
The House of Representatives will not countenance the use of federal funds to indoctrinate students into hateful, antisemitic, anti-American supporters of terrorism. Investigations into campus antisemitism by the Committee on Education and the Workforce and the Committee on Ways and Means have been expanded into a Congress-wide probe across all relevant jurisdictions to address this national crisis. The undersigned Committees will conduct oversight into the use of federal funds at MIT and its learning environment under authorities granted to each Committee.
• The Committee on Education and the Workforce has been investigating your institution since December 7, 2023. The Committee has broad jurisdiction over postsecondary education, including its compliance with Title VI of the Civil Rights Act, campus safety concerns over disruptions to the learning environment, and the awarding of federal student aid under the Higher Education Act.
• The Committee on Oversight and Accountability is investigating the sources of funding and other support flowing to groups espousing pro-Hamas propaganda and engaged in antisemitic harassment and intimidation of students. The Committee on Oversight and Accountability is the principal oversight committee of the US House of Representatives and has broad authority to investigate “any matter” at “any time” under House Rule X.
• The Committee on Ways and Means has been investigating several universities since November 15, 2023, when the Committee held a hearing entitled From Ivory Towers to Dark Corners: Investigating the Nexus Between Antisemitism, Tax-Exempt Universities, and Terror Financing. The Committee followed the hearing with letters to those institutions on January 10, 202
Operation “Blue Star” is the only event in the history of Independent India where the state went into war with its own people. Even after about 40 years it is not clear if it was culmination of states anger over people of the region, a political game of power or start of dictatorial chapter in the democratic setup.
The people of Punjab felt alienated from main stream due to denial of their just demands during a long democratic struggle since independence. As it happen all over the word, it led to militant struggle with great loss of lives of military, police and civilian personnel. Killing of Indira Gandhi and massacre of innocent Sikhs in Delhi and other India cities was also associated with this movement.
Normal Labour/ Stages of Labour/ Mechanism of LabourWasim Ak
Normal labor is also termed spontaneous labor, defined as the natural physiological process through which the fetus, placenta, and membranes are expelled from the uterus through the birth canal at term (37 to 42 weeks
Francesca Gottschalk - How can education support child empowerment.pptxEduSkills OECD
Francesca Gottschalk from the OECD’s Centre for Educational Research and Innovation presents at the Ask an Expert Webinar: How can education support child empowerment?
Exploiting Artificial Intelligence for Empowering Researchers and Faculty, In...Dr. Vinod Kumar Kanvaria
Exploiting Artificial Intelligence for Empowering Researchers and Faculty,
International FDP on Fundamentals of Research in Social Sciences
at Integral University, Lucknow, 06.06.2024
By Dr. Vinod Kumar Kanvaria
Safalta Digital marketing institute in Noida, provide complete applications that encompass a huge range of virtual advertising and marketing additives, which includes search engine optimization, virtual communication advertising, pay-per-click on marketing, content material advertising, internet analytics, and greater. These university courses are designed for students who possess a comprehensive understanding of virtual marketing strategies and attributes.Safalta Digital Marketing Institute in Noida is a first choice for young individuals or students who are looking to start their careers in the field of digital advertising. The institute gives specialized courses designed and certification.
for beginners, providing thorough training in areas such as SEO, digital communication marketing, and PPC training in Noida. After finishing the program, students receive the certifications recognised by top different universitie, setting a strong foundation for a successful career in digital marketing.
This slide is special for master students (MIBS & MIFB) in UUM. Also useful for readers who are interested in the topic of contemporary Islamic banking.
A review of the growth of the Israel Genealogy Research Association Database Collection for the last 12 months. Our collection is now passed the 3 million mark and still growing. See which archives have contributed the most. See the different types of records we have, and which years have had records added. You can also see what we have for the future.
Unit 8 - Information and Communication Technology (Paper I).pdfThiyagu K
This slides describes the basic concepts of ICT, basics of Email, Emerging Technology and Digital Initiatives in Education. This presentations aligns with the UGC Paper I syllabus.
Biological screening of herbal drugs: Introduction and Need for
Phyto-Pharmacological Screening, New Strategies for evaluating
Natural Products, In vitro evaluation techniques for Antioxidants, Antimicrobial and Anticancer drugs. In vivo evaluation techniques
for Anti-inflammatory, Antiulcer, Anticancer, Wound healing, Antidiabetic, Hepatoprotective, Cardio protective, Diuretics and
Antifertility, Toxicity studies as per OECD guidelines
3. INTRODUCTION:
3
⚫ In ancient times the Indian Ayurvedic system of medicines used
nasal route for administration of drug and the process is called
as “Nasya”
⚫ Intranasal drug delivery is now recognized to be a useful and
reliable alternative to oral and parenteral routes. Undoubtedly,
the intranasal administration of medicines for the symptomatic
relief and prevention or treatment of topical nasal conditions
has been widely used for a long period of time.
⚫ However, recently, the nasal mucosa has seriously emerged as a
therapeutically viable route for the systemic drug delivery.
4. ⚫ In general, among the primary targets for intranasal
administration are pharmacologically active compounds with
poor stability in gastrointestinal fluids, poor intestinal
absorption and/or extensive hepatic first-pass elimination, such
as peptides,proteins and polar drugs. The nasal delivery seems
to be a favourable way to circumvent the obstacles for blood-
brain barrier (BBB) allowing the direct drug delivery in the
biophase of central nervous system (CNS)-active compounds. It
has also been considered to the administration of vaccines.
4
5. ADVANTAGES
⚫ Hepatic first pass metabolism avoided.
⚫ Rapid drug absorption and quick onset of action.
⚫ Bioavailability of larger drug molecules can be improved by
means of absorption enhancer.
⚫ BAfor smaller drug molecules is good.
⚫ Convenient for long term therapy, compared to parenteral
medication.
⚫ Drugs possessing poor stability G.I.T fluids given by nasal route.
⚫ Easy and convenient.
⚫ Easily administered to unconscious patients.
5
6. DISADVANTAGES
• Pathologic conditions such as cold or allergies may alter
significantly the nasal bioavailabilty.
• The histological toxicity of absorption enhancers used in
nasal drug delivery system is not yet clearly established.
• Relatively inconvenient to patients when compared to oral
delivery systems since there is a possibility of nasal irritation.
• Nasal cavity provides smaller absorption surface area when
compared to GIT.
6
8. • The nasal cavity consists three main regions:
1) Nasal vestibule
2) Respiratory region
major drug absorption.
15-20 % of the respiratory cells covered by layer of long
cilia size 2-4 μm.
3) Olfactory region
small area in the roof of the nasal cavity of about 10 cm2
drug is exposed to neurons thus facilitate it across the cerebro-
spinal fluid.
• Normal pH of the nasal secretions in adult 5.5-6.5.
• Infants and young children 5.0- 6.7.
• Nasal cavity is covered with a mucous membrane.Mucus secretion is
composed of 95%- water,2%-mucin,1%-salts,1%-of other proteins
such as albumin,lysozyme and lactoferrin and 1%-lipids.
9. MECHANISM OF DRUGABSORPTION
10
• Paracellular (intercellular)
Slow and passive
absorption of peptides and
proteins associated with
intercellular spaces and
tight junctions.
• Transcellular : Transport
of lipophilic drugs passive
diffusion/active transport.
• Transcytotic: Particle is
taken into a vesicle and
transferred to the cell.
10. Mucoadhesive Carrier
Hydration and swell of polymer
Hydrophilic Macromolecular drug
Interaction with Mucus
Drug release
Cilliary clearance Enzymatic Metabolism
InternalAbsorption
Fig:2 Scheme of Mucoadhesive Nasal Drug Delivery
11
11. 12 22-Apr-12
Theory Mechanism of bioadhesion Comments
Electronic theory Attractive electrostatic forces between
glycoprotein mucin network and the bioadhesive
material
Electron transfer occurs between the two forming
a double layer of electric charge at the interface
Adsorption theory Surface forces resulting in chemical bonding Strong primary forces: covalent bonds
Weak secondary forces: ionic bonds, hydrogen
bonds and van der Waal’s forces
Wetting theory Ability of bioadhesive polymers to spread and
develop intimate contact with the mucus
membranes
Spreading coefficients of polymers must be
positive Contact angle between polymer and cells
must be near to zero
Diffusion theory Physical entanglement of mucin strands and the
flexible polymer chains Interpenetration of
mucin strands into the porous structure of the
polymer substrate
For maximum diffusion and best bioadhesive
strength: solubility parameters (δ) of the
bioadhesive polymer and the mucus
glycoproteins must be similar
Fracture theory Analyses the maximum tensile stress developed
during detachment of the BDDS from the
mucosal surfaces
Does not require physical entanglement of
bioadhesive polymer chains and mucin strands,
hence appropriate to study the bioadhesion of
hard polymers, which lack flexible chains
THEORIES OF MUCOADHESION
13. 14
⚫ Nasal Gels
• High-viscosity thickened suspensions or
solutions
• Advantages:
• Reduction of post-nasal drip due to high viscosity
• Reduction of taste impact due to reduced swallowing
• Reduction of anterior leakage of the formulation
• Reduction of irritation by using emollient excipients.
⚫ Nasal Drops
• Nasal drops are one of the most simple and convenient
systems developed for nasal delivery. The main disadvantage
of this system is the lack of the dose precision and therefore
nasal drops may not be suitable for prescription products. It
has been reported that nasal drops deposit human serum
albumin in the nostrils more efficiently than nasal sprays.
14. 15
Nasal sprays
• Both solution and suspension formulations can be formulated into
nasal sprays.
• Due to the availability of metered dose pumps and actuators, a nasal
spray can deliver an exact dose from 25 to 200 μm.The particles size
and morphology (for suspensions)of the drug and viscosity of the
formulation determine the choice of pump and actuator assembly.
Nasal Powder
• This dosage form may be developed if solution and suspension dosage
forms cannot be developed e.g., due to lack of drug stability.
• The advantages to the nasal powder dosage form are the absence of
preservative and superior stability of the formulation. However, the
suitability of the powder formulation is dependent on the solubility,
particles size, aerodynamic properties and nasal irritancy of the active
drug and /or excipients. Local application of drug is another
advantage of this system.
15. 16
Liposomes
• Liposomal Nasal solutions can be formulated as drug alone or in
combination with pharmaceutically acceptable excipients.
• Administered to the respiratory tract as an aerosol or solution for a
nebulizer, or as a microfine powder for insufflation, alone or in
combination with an inert carrier such as lactose,the particles of the
formulation have diameters of less than 50 microns.
Microspheres
• Specialized systems becoming popular for designing nasal products,
as it provides prolonged contact with the nasal mucosa
• Microspheres (in the powder form) swell in contact with nasal
mucosa to form a gel and control the rate of clearance from the nasal
cavity.Thus increases the absorption and bioavailability by adhering
to the nasal mucosa and increase the nasal residence time of drug.
• The ideal microsphere particle size requirement for nasal delivery
should range from 10 to 50 µm as smaller particles.
16. STRATEGIES TO IMPROVE NASALABSORPTION
22-Apr-12
17
Permeation enhancers
Type of
compound
Examples Mechanisms of action
Bile salts (and
derivatives)
Sodium deoxycholate, sodium
glycocholate,
sodiumTaurodihydrofusidate
Disrupt membrane, open tight
junctions,
enzyme inhibition, mucolytic activity
Surfactancts SLS, saponin, polyoxyethylene-9-lauryl
Ether
Disrupt membranes
Chelating agents Ethylenediaminetetraacetic acid (EDTA),
Salicylates
Open tight junction
Fatty acids Sodium caprylate, sodium laurate,
Phospholipids
Disrupt membranes
Bioadhesive
materials
Powders
Carbopol, starch microspheres, chitosan Reduce nasal clearance, open tight
junctions
Liquids Chitosan, carbopol Reduce nasal clearance, open tight
junction
17. ⚫ Prodrug approach
The absorption of peptides like angiotensin II, bradykinin,
vasopressin and calcitonin are improved when prepared into
enamine derivatives.
⚫ Structural modification
Chemical modification of salmon calcitonin to ecatonin (C-N
bond replaces the S-S bond) showed better bioavailability.
⚫ Particulate drug delivery
Microspheres, nanoparticles and liposomes
Nasal enzyme inhibitors
peptidases and proteases
tripsin, aprotinin, borovaline, amastatin, bestatin and
boroleucin inhibitors.
18
18. Evaluation tests
19
For Nasal Gels
• Mucoadhesive testing
• A 1x1 cm piece of goat nasal mucosa was tied to a glass
slide using thread. Microparticles spread on the tissue
specimen and the prepared glass slide was hung on one of
the groves of a USP tablet disintegration test
apparatus.The tissue specimen was given regular up and
down movements in the beaker of the disintegration
apparatus containing phosphate buffer pH 6.4.
• Time required for complete washing of microparticles was
noted.
• In vitro drug diffusion study
• The drug diffusion from different formulation was determined
using treated cellophane membrane and Franz diffusion cell.
• Drug was placed on cellophane membrane in the donor
compartment contained phosphate buffer (pH 6.4).
• Samples were analyzed spectrophotometrically.
19. In vitro drug release studies of the gels
• 1 ml of the gel was taken into a small test tube. The open end of
the test tube was closed with the nasal membrane of the pig by
tying it with a thread. Then this was placed in a beaker containing the
media.
Measurement of Gelation Temperature (T1) and Gel Melting
Temperature (T2):
• A2ml aliquot of gel was taken in a test tube, immersed in a water bath.
• The temperature of water bath was increased slowly and left to
equilibrate for 5min at each new setting.
• The sample was then examined for gelation, the meniscus would
no longer moves upon tilting through 900. i.e GELATION temp T1.
• Furtherheating of gel causes liquefaction of gel and form viscous
liquid and it starts flowing, this temperature is noted as T2 GEL
MELTING temp.
2
20. MARKETED DRUGS Local Delivery
Drug Brand Main
Excipients
Supplier Main
Indications
Azelastine Astelin Benzalkonium
chloride,
edetate disodium,
Meda
Pharmaceutic
als
Beclometasone Beconase Microcrystalline
cellulose,
carboxymethyl
cellulose sodium,
benzalkonium
chloride
GlaxoSmithKline
Levocabastine Livostin Benzalkonium
chloride,
edetate disodium,
disodium
phosphate
Jansen-
Cilag
Management/
treatment of
symptoms of
seasonal and
perennial
rhinosinusitis
21. 22 22-Apr-12
Drug Brand Main Excipients Supplier Main
Indications
Olapatadine Patanase Benzalkonium
chloride,
dibasic sodium
phosphate,
edetate disodium
Alcon
Laboratories
Sodium
cromoglicate
Nasalcrom Benzalkonium
chloride,
edetate disodium
Sanofi-Aventis
Mupirocin Bactroban Paraffin and a
mixture of
glycerin esters
(Softisan 649)
GlaxoSmithKline Eradication of
nasal
staphylococci
Triamcinolone
acetonide
Nasacort Microcrystalline
cellulose,
CMC sodium,
polysorbate 80
SanofiAventis
22. Systemic Delivery
23 22-Apr-12
Drug Brand Main
Excipients
Supplier Main
Indications
Nicotine Nicotrol NS Disodium
phosphate,
sodium
dihydrogen
phosphate, citric
acid
Pfizer Smoking
cessation
Oxytocin Syntocinon Citric acid,
chlorobutanol,
sodium chloride
Novartis Labour induction;
lactation
stimulation
Buserelin Suprefact Sodium
hydroxide,
sodium chloride,
sodium
dihydrogen
Sanofi-Aventis Treatment of
prostate cancer
24. RECENTADV
ANCES
⚫ Currently,the majority of intranasal products on the market are targeted
toward local relief or the prevention of nasal symptoms. The trend
toward the development of intranasal products for systemic absorption
should rise considerably over the next several years. The development
of these products will be in a wide variety of therapeutic areas from
pain management to treatment for erectile dysfunction.
⚫ However, the primary focus of intranasal administration, correlated with
increasing molecular scientific knowledge and methods, will be the
development of peptides, proteins, recombinant products, and vaccines.
The nasal cavity provides an ideal administration site for these agents
because of its accessibility, avoidance of hepatic first-pass metabolism,
and large vascular supply.
⚫ Future technologies in the intranasal arena will be concentrated on
improved methods for safe, efficient delivery systems primarily for
molecular agents, but also for numerous therapeutic categories.
25. Delivery of non-peptide Pharmaceuticals
• Adrenal corticosteroids
• Sex hormones: 17ß-estradiol, progesterone, norethindrone,
and testosterone.
• Vitamins: vitamin B
• Cardiovascular drugs: hydralazine,Angiotensin II
antagonist, nitroglycerine, isosobide dinitrate, propanolol.
• CNS stimulants: cocaine, lidocaine
• Narcotics and antagonists: bupemorphine, naloxane
• Histamine and antihistamines: disodium cromoglycate,
meclizine
• Antimigrane drugs: dierogotamine, ergotamine, tartarate
• Phenicillin, cephalosporins, gentamycin
• Antivirals: Phenyl-p-guanidine benzoate, enviroxime.
26. Delivery of peptide-based pharmaceuticals
• Peptides and proteins are hydrophilic polar molecules
of high molecular weight, poorly absorbed.
• Absorption enhancers like surfactants, glycosides,
cyclodextrin and glycols increase the bioavailability.
Examples are insulin, calcitonin, pituitary hormones etc.
Delivery of diagnostic drugs
• Phenolsulfonphthalein is used to diagnose kidney
function. Secretin for Pancreatic disorders of the diabetic
patients.
Delivery of Vaccines through Nasal Routs
• Anthrax and influenza are treated by using the nasal vaccines
• prepared by using the recombinant Bacillus anthracis
protective antigen (rPA) and chitosan respectively.
• 30
27. • Delivery of Drugs to Brain through Nasal Cavity
Conditions like Parkinson’s disease,Alzheimer’s disease or pain
28. CONCLUSION
⚫ Considering the widespread interest in nasal drug delivery and
the potential benefits of intranasal administration, it is expected
that novel nasal products will continue to reach the market. They
will include not only drugs for acute and long term diseases, but
also novel nasal vaccines with better local or systemic protection
against infections.
⚫ The development of drugs for directly target the brain in order to
attain a good therapeutic effect in CNS with reduced systemic
side effects is feasible. However, it was also stated that
intranasal route presents several limitations which must be
overcome to develop a successful nasal medicine Physiological
conditions, physicochemical properties of drugs and
formulations are the most important factors determining nasal
drug absorption.
29. • The use of prodrugs, enzymatic inhibitors, absorption
enhancers, mucoadhesive drug delivery systems and new
pharmaceutical formulations are, nowadays, among the mostly
applied strategies. Each drug is one particular case and, thus,
the relationship between the drug characteristics, the strategies
considered and the permeation rate is essential.
31. INTRODUCTION
⚫ The respiratory tract is one of the oldest routes used for the
administration of drugs.Over the past decades inhalation therapy
has established itself as a valuable tool in the local therapy of
pulmonary diseases such as asthma or COPD (Chronic
Obstructive Pulmonary Disease) .
⚫ This type of drug application in the therapy of these diseases is a
clear form of targeted drug delivery.
⚫ Currently, over 25 drug substances are marketed as inhalation
aerosol products for local pulmonary effects and about the same
number of drugs are in different stages of clinical development.
22-Apr-12
32. ⚫ The drug used for asthma and COPD eg.- β2-agonists such as
salbutamol (albuterol), Terbutalin formoterol, corticosteroids such
as budesonide, Flixotide or beclomethasone and mast-cell
stabilizers such as sodium cromoglycate or nedocromi,.
⚫ The latest and probably one of the most promising applications of
pulmonary drug administration is
1) Its use to achieve systemic absorption of the
administered drug substances.
2) Particularly for those drug substances that exhibit
a poor bioavailability when administered by the
oral route, as for example peptides or proteins,
the respiratory tract might be a convenient port of
entry.
33. ADVANTAGES OF PULMONARY DRUG DELIVERY.
• It is needle free pulmonary delivery.
• It requires low and fraction of oral dose.
• Pulmonary drug delivery having very negligible side effects
since rest
• of body is not exposed to drug.
• Onset of action is very quick with pulmonary drug delivery.
• Degradation of drug by liver is avoided in pulmonary drug
delivery.
LIMITATIONS
⚫ Stability of drug in vivo.
⚫ Transport.
⚫ Targeting specificity.
⚫ Drug irritation and toxicity.
⚫ Immunogenicity of proteins
⚫ Drug retention and clearance.
35. ⚫ The human respiratory system is a complicated organ system of very
close structure–function relationships.
The system consisted of two regions:
The conducting airway
The respiratory region.
⚫ The airway is further divided into many folds: nasal cavity and the
associated sinuses, and the nasopharynx, oropharynx, larynx, trachea,
bronchi, and bronchioles.
⚫ The respiratory region consists of respiratory bronchioles, alveolar
ducts, and alveolar sacs
⚫ The human respiratory tract is a branching system of air channels with
approximately 23 bifurcations from the mouth to the alveoli.The major
task of the lungs is gas exchange, by adding oxygen to, and removing
carbon dioxide from the blood passing the pulmonary capillary bed.
35
36. FORMULATION APPROACHES
⚫ Pulmonary delivered drugs are rapidly absorbed except large
macromolecules drugs, which may yield low bioavailability due
to enzymatic degradation and/or low mucosal permeability.
⚫ Pulmonary bioavailability of drugs could be improved by
including various permeation enhancers such as surfactants,
fatty acids, and saccharides, chelating agents and enzyme
inhibitors such as protease inhibitors.
⚫ The most important issue is the protein stability in the
formulation: the dry powder formulation may need buffers to
maintain the pH, and surfactants such as Tween to reduce any
chance of protein aggregation. The stabilizers such as sucrose are
also added in the formulation to prevent denaturation during
prolonged storage.
36
37. ⚫ Pulmonary bioavailability largely depends on the physical
properties of the delivered protein and it is not the same for
all peptide and protein drugs.
⚫ Insulin liposomes are one of the recent approaches in the
controlled release aerosol preparation. Intratracheal delivery of
insulin liposomes (dipalmitoylphosphatidyl choline:cholesterol
,7:2) have significantly enhanced the desired hypoglycemic
effect.
⚫ The coating of disodium fluorescein by hydrophobic lauric acid
is also an effective way to prolong the pulmonary residence time
by increasing the dissolution half time. In another method,
pulmonary absorption properties were modified for
protein/peptide drug (rhGCSF)in conjugation with polyethylene
glycol (PEGylation) to enhance the absorption ofthe protein
drug by using intratracheal instillation delivery in rat.
37
38. AEROSOLS
38
⚫ Aerosol preparations are stable dispersions or suspensions of
solid material and liquid droplets in a gaseous medium. The
drugs, delivery by aerosols is deposited in the airways by:
gravitational sedimentation, inertial impaction, and diffusion.
Mostly larger drug particles are deposited by first two
mechanisms in the airways, while the smaller particles get their
way into the peripheral region of the lungs by following
diffusion.
⚫ There are three commonly used clinical aerosols:
1. Jet or ultrasonic nebulizers
2. Metered–dose Inhaler (MDI)
3
. D
ry-powder inhaler (DPI)
⚫ The basic function of these three completely different devices
is to generate a drug-containing aerosol cloud that contains the
highest possible fraction of particles in the desired size range.
39. DEVICES
Nebulizers
⚫ Nebulizers are widely used as aerosolize drug solutions or
suspensions for drug delivery to the respiratory tract and are
particularly useful for the treatment of hospitalized patients.
⚫ Delivered the drug in the form of mist.
⚫ There are two basic types:
1) Air jet
2) Ultrasonic nebulizer
39
42. Dry Powder Inhalers(DPI)
⚫ DPIs are bolus drug delivery devices that contain solid drug in a
dry powder mix (DPI) that is fluidized when the patient inhales.
⚫ DPIs are typically formulated as one-phase, solid particle
blends.The drug are in micronized form used.
⚫ Dry powder formulations either contain the active drug alone or
have a carrier powder (e.g. lactose) mixed with the drug to
increase flow properties of drug.
⚫ DPIs are a widely accepted inhaled delivery dosage form,
particularly in Europe, where they are currently used by
approximately 40% of asthma patients.
Advantages
Propellant-free.
Less need for patient co-ordination.
Less formulation problems.
Dry powders are at a lower energy state, which reduces the rate of
chemical degradation.
46
43. 47
Disadvantages
Dependency on patient’s inspiratory flow rate and profile.
Device resistance and other design issues.
Greater potential problems in dose uniformity.
More expensive than pressurized metered dose inhalers.
Not available worldwide
Unit-Dose Devices
⚫ Single dose powder inhalers are devices in which a powder
containing capsule is placed in a holder. The capsule is opened
within the device and the powder is inhaled.
⚫ Eg. Aerolozer, Rotahaler
Multidose Devices
⚫ This device is truly a metered-dose powder delivery system. The
drug is contained within a storage reservoir and can be dispensed
into the dosing chamber by a simple back and forth twisting
action on the base of the unit. Eg. DISKUS
45. Metered Dose Inhalers (MDI)
⚫ Used for treatment of respiratory diseases such as asthma and
COPD.
⚫ They can be given in the form of suspension or solution.
⚫ Particle size of less than 5 microns.
⚫ Used to minimize the number of administrations errors.
⚫ It can be deliver measure amount of
medicament accurately.
46. Advantages of MDI
⚫ It delivers specified amount of dose.
⚫ Small size and convenience.
⚫ Usually inexpensive as compare to dry powder inhalers and
nebulizers.
⚫ Quick to use.
⚫ Multi dose capability more than 100 doses available.
Disadvantages of MDI
⚫ Difficult to deliver high doses.
⚫ There is no information about the number of doses left in the
MDI.
⚫ Accurate co-ordination between actuation of a dose and
inhalation is essential.
51. Newer Development
Dr Reddy's launches 'Dose Counter Inhalers' in India
Dr Reddy's Laboratories (DRL) has launched an innovation in
the metered dose inhaler (MDI) space with launch of 'Dose
Counter Inhalers (DCI) for the first time in India. This the first
MDI in India that gives patients an advance indication of
when the inhaler is going to be empty. DCI is a new drug
delivery device with a single device having 120 metered doses.
There is a window in the inhaler that changes color from green
to red. Green indicates the inhaler is full and red indicates the
inhaler is empty. Half green and half red in the window indicate
it's time to change the inhaler.
66
52. REFERENCES
⚫ Chien Y.W., Su K.S.E., Chang S.F., Nasal Systemic Drug Delivery,
Ch. 1, Marcel-Dekker, New York 1-77.
⚫ Illum.L, Jorgensen.H, Bisgard.H and Rossing.N, Bioadhesive
microspheres as a potential nasal drug delivery system. Int. J.of
Pharmaceutics 189-199.
⚫ Jain S.K, Chourasia M. K and Jain. R. K, Development and
Characterization of Mucoadhesive Microspheres Bearing Salbutamol
for Nasal Delivery. Drug delivery 11:113-122
⚫ Martin.A, Bustamante. P and ChunA.H, Eds. Physical Pharmacy, 4th
Edn, B. J. waverly Pvt. Ltd.
⚫ Aulton M.E. “ Pharmaceutics – The science of dosage form design”
Churchill Livingston., 494.
⚫ Hussain A, Hamadi S, Kagoshima M, Iseki K, Dittert L. Does
increasing the lipophilicity of peptides enhance their nasal absorption.
J Pharm Sci 1180-1181.
⚫ Illum L. In: Mathiowitz E, Chickering DE, Lehr CM Ed, Bioadhesive
formulations for nasal peptide delivery: Fundamentals, Novel
Approaches and Development. Marcel Dekker. New York 507-539.
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53. 22-Apr-12
• Sharma PK, Chaudhari P
, Kolsure P
,AjabA, V
aria N. Recent trends in
nasal drug delivery system ‐ an overview. 2006; 5: vol 4.
• John J. Sciarra, Christopher J. Sciarra,Aerosols. In:Alfonso R.
Geearo, editor. Remington: Science and practice of pharmacy, second
edition.vol-1.New York: Lippincott Williams and Wilkins publication;
2001.p.963-979.
• Anthony J. Hickey, Physiology of airway. In: Anthony J. Hickey,
editor. Pharmaceutical inhalation aerosols technology, second
edition.vol-54.New York: Marcel Dekker;1992.p.1-24.
• Paul J. Atkins, Nicholas P.Barker, Donald P.Mathisen, The design and
development of inhalation drug delivery system. In : Anthony J.
Hickey, editor. Pharmaceutical inhalation aerosols technology, second
edition.vol-54.New York: Marcel Dekker;1992.p.155-181.
• Critical Reviews in Therapeutic Drug Carrier Systems 14(4): 395-453.
• International PharmaceutcialAerosol Consortium, 1997. Ensurin
patient care- the role of the HFC MDI.
• Metered dose pressurized aerosols and the ozone layer. European
6R
9 esp. J.3:495-497.
54. ⚫ Mygind N, Dahl R.Anatomy, physiology and function of the nasal
cavities in health and disease.Adv Drug Del Rev 1998; 29.
⚫ Grace, J., and Marijnissen, J., 1994. “Areview of liquid atomization
by electric means”. Journal ofAerosol Science 25, pp. 1005–1019.
⚫ Ashhurst I, MaltonA, PrimeD and Sumby B, “Latestadvances in The
Development of dry-powder inhalers”, PSTT 2000,Vol 3, No 7, pp
246-256.
• ClarkAR. Medical aerosol inhalers. Past,present and future.Aerosol
Sci Technol.1995;22:374–391.
⚫ P.Quinet, C.A.Young, F.Heritier, The use of dry powder inhaler
devices by elderly patients suffering from chronic obstructive
pulmonary disease,Annals of Physical and Rehabilitation Medicine 53
(2010) 69–76.
• http://www.pharmabiz.com
⚫ http://www.lungusa.org
⚫ http://www.ijrps.pharmascope.org
22-Apr-12
55. 1. Flammability & Combustibility
a) Flash Point
b) Flash extension & Flashback
2. Biological Testing
i) Therapeutic efficacy/activity
ii) Toxicity
3. Physicochemical characteristics
4. Performance
a) Aerosols valve discharge rate
b) Leakage
c) particle size determination
d) Foam stability
e) Net content
f) Spray pattern
g) Dosage with meter valve
5. Evaluation of Packaging components of Aerosol
I. Protection
II. Compatibility
III. Safety
56.
57. 1. FLAMMABILITY & COMBUSTIBILITY
a) Flash Point
In order to determine the flash point
of an aerosol, two basic apparatus
types are available which are an open
cup and closed cup.
Apparatus: Open Cup Tag Apparatus
Flash-point test is done by cooling the
temperature of the aerosol product to
25F.
Test liquids temp. is allowed to
increase slowly & temp. at which
vapors Ignite is called as Flash Point.
58. Closed cup tests
Closed cup tests purpose to simulate the situation of a fluid spill
in a closed environmental condition.
In closed cup tests to determine the flash point the investigated
sample is placed inside a sealed test cup and introduced to a
potential ignition source, determining the temperature at which
the sample flashes.
An open cup apparatus will constantly give a higher flash point
than a closed cup one as the open cup permits loss of internal
vapors to the atmosphere above the apparatus
59. b) Flash extension & Flashback
This type of evaluation test is also known as the flame projection
test. Product is sprayed through an open candle flame for about
4 seconds at a fixed distance of 6 inches. (15 cm), & the flame’s
extension is measured in (cm) and recording the length of the
flame projection. An aerosol product is judged flammable if its
flame extends 18 inch. (46 cm) or more through an open flame, or
if the flame flashes back to the actuator.
60. 2. BIOLOGICAL TESTING
i) Therapeutic efficacy/activity
For Inhalation Aerosols is depends on the particle size.
For Topical Aerosols is applied to test areas &
adsorption of therapeutic ingredient is determined.
ii) Toxicity
For Inhalation Aerosols:- exposing test animals to
vapor sprayed from Aerosol container.
For Topical Aerosols:- Irritation & Chilling effects are
determined
61. 3. PHYSICOCHEMICAL CHARACTERISTICS
PROPERTY METHOD
Vapour Presssure Can Puncturing Device
Pressure Gauge
Density Hydrometer
Pycnometer
Moisture content Karl Fisher method
Gas Chromatography
Propellant identification Gas Chromatography
IR Spectroscopy
62. 4. PERFORMANCE
a) Aerosols valve discharge rate
Content of the aerosol product of known weight is discharged for a specific
period of time.
By reweighting the container after the time limit, the change in the weight
per time dispensed gives the discharge rate (gram per second).
b) Leakage
It is done by measuring the Crimp’s dimension & comparing. Final testing of
valve closure is done by passing filled containers through water bath.
c) particle size determination
Particle size of aerosol product are determined by Cascade Inspector and
light scattering decay.
Cascade Inspector
Principle: Stream of particles projected through a series of nozzle and glass
slide at high velocity, larger particles are impacted first on lower velocity
stages and smaller particles are collected at Higher velocity stage.