This document discusses various approaches for delivering drugs to the brain by bypassing the blood-brain barrier (BBB). It describes invasive approaches like convection-enhanced delivery which involves inserting a catheter into the brain. It also discusses pharmacological, physiological, and prodrug approaches. Various carrier systems are covered like liposomes, nanoparticles, monoclonal antibodies, and colloidal carriers. The mechanisms of transport through the BBB like endocytosis, receptor-mediated transcytosis, and adsorption are also summarized. Overall, the document provides a comprehensive overview of the challenges of brain drug delivery and different strategies researchers are exploring to enhance transport of therapeutics across the BBB.
This slides contains information about the Brain specific drug delivery.Its history and background, strategies to deliver drugs to BBB,application and examples of marketed products.
This slides contains information about the Brain specific drug delivery.Its history and background, strategies to deliver drugs to BBB,application and examples of marketed products.
Brain Targeted Drug Delivery System
Prepared by :
Surbhi
M.Pharmacy II sem
Submitted to :
Dr. Anupama Diwan
MAGIC BULLET : CONCEPT OF PAUL EHRLICH
Brain Targeting: Challenges
Blood brain barrier (BBB): Brain is tightly segregated from the circulating blood by a unique membranous barrier.
The brain and spinal cord are lined with a layer of special endothelial cells that lack fenestrations and are sealed with tight junctions that greatly restrict passage of substances from the bloodstream.
These endothelial cells, together with perivascular elements such as astrocytes and pericytes, constitute the BBB.
Rate-limiting factor in determining permeation.
The factors affecting particular substance to cross BBB
Drug related factors at the BBB
Concentration at the BBB and the size,
Flexibility,
Conformation,
Ionization (nonionized form penetrates BBB)
Lipophilicity of the drug molecule,
Cellular enzyme stability and cellular sequestration,
Affinity for efflux mechanisms (i.e. P-glycoprotein),
Hydrogen bonding potential (i.e. charge),
Affinity for carrier mechanisms, and
Effect on all of the above by the existing pathological conditions
Transport Mechanisms
Several specialized transport mechanisms of solute transfer across endothelial cells and into the brain interstitium are also present within the BBB Carrier system for monosaccharides, monocarboxylic acid, neutral amino acids, basic amino acid, acidic amino acids, amines, purine bases, nucleosides, vitamins and hormones.
The more lipophilic substances that are present in the blood can diffuse passively directly through the lipid of the cell membrane and enter the endothelial cells and brain by this means.
Strategies for Brain Targeting Mechanisms for drug targeting in the brain involve going either "through" or "behind" the BBB.
Neurosurgical or Invasive Strategies
BBB disruption :Disruption of BBB by osmotic means (Hyperosmolar solutions),
Intraventricular drug infusion
Intracerebral Implants: Biodegradable implants,
Physiologic based Strategies
Psuedo nutrients eg L-dopa
Cationic antibodies.These undergo Absorption mediated trancytosis through BBB owing to positive charge.
Chimeric peptides.
Nucleic acid based therapeutic drug delivery systemtadisriteja9
Nucleic acid based Drug delivery system is one of the trending research area, which i have taken and made as Powerpoint for easy and quick learning purpose
Myself Omkar Tipugade , M- Pharm ,Sem - II, Department of pharmaceutics , from Shree Santkrupa College Of Pharmacy , ghogaon . Today I upload presentation on Active Transport like P-gp , BCPR, Nucleoside transporters etc .
Several methods making drugs overcome blood-brain barier obstacle .Abeer Abd Elrahman
The blood-brain barrier (BBB) represents a major obstacle to the delivery of drugs to the central nervous system (CNS). and there are several methods to overcome this obstacle as Disease itself (enhanced permeability and retention EPR), Exosomes, Pro-drugs, Encapsulation into a biocompatible polymer,..etc
Brain Targeted Drug Delivery System
Prepared by :
Surbhi
M.Pharmacy II sem
Submitted to :
Dr. Anupama Diwan
MAGIC BULLET : CONCEPT OF PAUL EHRLICH
Brain Targeting: Challenges
Blood brain barrier (BBB): Brain is tightly segregated from the circulating blood by a unique membranous barrier.
The brain and spinal cord are lined with a layer of special endothelial cells that lack fenestrations and are sealed with tight junctions that greatly restrict passage of substances from the bloodstream.
These endothelial cells, together with perivascular elements such as astrocytes and pericytes, constitute the BBB.
Rate-limiting factor in determining permeation.
The factors affecting particular substance to cross BBB
Drug related factors at the BBB
Concentration at the BBB and the size,
Flexibility,
Conformation,
Ionization (nonionized form penetrates BBB)
Lipophilicity of the drug molecule,
Cellular enzyme stability and cellular sequestration,
Affinity for efflux mechanisms (i.e. P-glycoprotein),
Hydrogen bonding potential (i.e. charge),
Affinity for carrier mechanisms, and
Effect on all of the above by the existing pathological conditions
Transport Mechanisms
Several specialized transport mechanisms of solute transfer across endothelial cells and into the brain interstitium are also present within the BBB Carrier system for monosaccharides, monocarboxylic acid, neutral amino acids, basic amino acid, acidic amino acids, amines, purine bases, nucleosides, vitamins and hormones.
The more lipophilic substances that are present in the blood can diffuse passively directly through the lipid of the cell membrane and enter the endothelial cells and brain by this means.
Strategies for Brain Targeting Mechanisms for drug targeting in the brain involve going either "through" or "behind" the BBB.
Neurosurgical or Invasive Strategies
BBB disruption :Disruption of BBB by osmotic means (Hyperosmolar solutions),
Intraventricular drug infusion
Intracerebral Implants: Biodegradable implants,
Physiologic based Strategies
Psuedo nutrients eg L-dopa
Cationic antibodies.These undergo Absorption mediated trancytosis through BBB owing to positive charge.
Chimeric peptides.
Nucleic acid based therapeutic drug delivery systemtadisriteja9
Nucleic acid based Drug delivery system is one of the trending research area, which i have taken and made as Powerpoint for easy and quick learning purpose
Myself Omkar Tipugade , M- Pharm ,Sem - II, Department of pharmaceutics , from Shree Santkrupa College Of Pharmacy , ghogaon . Today I upload presentation on Active Transport like P-gp , BCPR, Nucleoside transporters etc .
Several methods making drugs overcome blood-brain barier obstacle .Abeer Abd Elrahman
The blood-brain barrier (BBB) represents a major obstacle to the delivery of drugs to the central nervous system (CNS). and there are several methods to overcome this obstacle as Disease itself (enhanced permeability and retention EPR), Exosomes, Pro-drugs, Encapsulation into a biocompatible polymer,..etc
Various approaches to Targeted Drug Delivery Systems (TDDS) in its formuation and evaluation in a pharmaceutical industry and research is outlined in this presentation.
Protein and peptide are biopolymers which yield more than two amino acids on hydrolysis.
Although the terms ‘proteins’ and ‘peptides’ are used freely, peptides are those with molecular weight below 10,000 and proteins are molecules with higher molecular weight.
Most therapeutic proteins and peptide-based drugs are administered by parenteral route and are incorporated in liposomes to prolong their action or fused with Immunoglobulins or Albumin to improve their half-life.
PEGylation is a proven technique for improving the potentials of Proteins/peptide delivery systems.
primary and secondary active transport difference,Computer aided drug design P glycoprotein transport,bcrp,nt,Abst,oATP,oct,BBB choline transporter,hpepti
Proteins are the large organic compounds made of amino acids arranged in a linear chain and joined together by peptide bonds.
Protein > 50 amino acids
PEPTIDES: These are short polymers formed from the linking, in a defined order of amino acids.
peptide < 50 amino acids
Liquid dosage forms: Advantages and disadvantages of liquid dosage forms. Excipients used in formulation of liquid dosage forms. Solubility enhancement techniques
Good Laboratory Practices: General Provisions, Organization and Personnel, Facilities, Equipment,
Testing Facilities Operation, Test and Control Articles, Protocol for Conduct of a Nonclinical Laboratory
Study, Records and Reports, Disqualification of Testing Facilities, Organization and Personnel, Facilities, Equipment,
Testing Facilities Operation, Test and Control Articles, Protocol for Conduct of a Nonclinical Laboratory
Study, Records and Reports, Disqualification of Testing Facilities
PHARMACEUTICAL QUALITY ASSURANCE SIXTH SEMSTER B PHARM
Introduction, definition and general principles of calibration, qualification
and validation, importance and scope of validation, types of validation, validation master plan. Calibration of pH meter, Qualification of UV-Visible spectrophotometer, General principles of Analytical
method Validation.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
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Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
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- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
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- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
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Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
2. AIM
To emphasize on drug delivery to brain by using various
approaches.
To study the Blood – Brain barrier.
To study different approaches to bypass the BBB and to
deliver therapeutics into the brain.
2
3. INTRODUCTION
Drug delivery to the brain is the process of passing
therapeutically active molecules across the Blood Brain Barrier
for the purpose of treating brain maladies. This is a complex
process that must take into account the complex anatomy of the
brain as well as the restrictions imposed by the special junctions
of the Blood Brain Barrier.
In response to the insufficiency in conventional delivery
mechanisms, aggressive research efforts have recently focused
on the development of new strategies to more effectively deliver
drug molecules to the CNS.
Various routes of administration as well as conjugations of
drugs, e.g. with liposomes and nanoparticles are considered.
3
4. APPROACHES
To bypass the BBB and to deliver therapeutics into the
brain, thre different approaches are currently used
4
7. Convection-enhanced delivery
The general principle of CED involves the stereotactically guided
insertion of a small-caliber catheter into the brain parenchyma.
Through this catheter, infusate is actively pumped into the brain
parenchyma and penetrates in the interstitial space.
The infusion is continued for several days and the catheters are
removed at the bedside.
CED has been shown in laboratory experiments to deliver high
molecular weight proteins 2 cm from the injection site in the brain
parenchyma after as little as 2 h of continuous infusion
Limitations: Some areas of the brain are difficult to saturate fully with
infusate, particularly — infiltrated tissues surrounding a cavity.
7
8. Pharmacological Approach
The pharmacological approach to crossing the BBB is based on the
observation that some molecules freely enter the brain, e.g. alcohol,
nicotine and benzodiazepine.
This ability to passively cross the BBB depends on the molecular size
being less than 500 D, charge (low hydrogen bonding capabilities) and
lipophilicity (the more lipophilic, the better the transport).
This approach consists of modifying, through medicinal chemistry, a
molecule that is known to be active against a CNS target to enable it to
penetrate the BBB
8
9. Modification of drugs through a reduction in the relative
number of polar groups increases the transfer of a drug
across the BBB. Lipid carriers have been used for transport,
and there are successful examples of both these
approaches.
Limitations: The modifications necessary to cross the BBB
often result in loss of the desired CNS activity. Increasing the
lipophilicity of a molecule to improve transport can also result
in making it a substrate for the efflux pump P- glycoprotein
(P-gp).
9
10. Physiological approach
Among all the approaches used for increasing brain delivery of
therapeutics, the most accepted method is the use of the
physiological approach which takes advantage of the transcytosis
capacity receptors expressed at the BBB. The of specific low
density lipoprotein receptor related protein (LRP) is the most
adapted for such use with the engineered peptide compound
(EPiC) platform incorporating the advanced withAngiopep peptide
in new the most promising data in the clinic.
Eg. Receptor-mediated transcytosis
10
12. PRODRUGS
Prodrug is lipid soluble (pharmacologically inactive compounds)
cross the BBB
metabolized within the brain
converted to the parent drug
Esterification or amidation of hydroxy-, amino-, or carboxylic acid-
containing drugs, may greatly enhance lipid solubility and,
hence, entry into the brain
12
13. WHAT TO DO AND WHY
Drug covalently linked to an inert chemical moiety.
Improve physicochemical property such as solubility and membrane
permeability.
Prodrug is cleaved by hydrolytic or enzymatic processes.
Examples levodopa, gaba, niflumic acid, valproate
Heroin, a diacyl derivative of morphine, is a notorious example that
crosses the bbb about 100 times more easily than its parent drug just
by being more lipophilic
Limitations of the prodrug
•. The increased molecular weight of the drug that follow from lipidation.
• Adverse pharmacokinetics
13
14. DRUG CONJUGATES
Lipidization of molecules generally increases the volume of distibution.
Chemical approaches include lipophilic addition and modification of
hydrophilic drugs ( e.g. Nmethylpyrimidium 2 carbaldoxime chloride)
Example:
Glycosylated analogs of various opioid compounds
Antioxidant + pyrrolopyrimidines – increase access
For Ganciclovir : to hydroxymethyl group + 1methyl 1,4
dihydronicotinate- increase transport
For small drugs: use of fatty acids like N docosahexaenoyl(DHA)
increase uptake
For Casomorphin is a heptapeptide , able to pass the BBB.
14
15. CARRIER MEDIATED
TRANSPORT
Peptide transporters: for glutathione, peptide harmones, growth factor,
enkephalins, t vasopressin , arginine
Amine transporter: for mepyramine
Nucleoside transporter(purine bases like adenine guanine) anticancer
agent, antiviral agent, 3 azidodeoxythymide
Choline transporter( for choline, thiamine)
Transport via organic acid transporter(MCT) salicyclic acid, lactate,
acetate, propionate
Drug transfered via amino acid transporter (LAT1):
Ldopa for parkinsonism
Gabapentin for epilepsy
Alpha methyl dopa for high blood pressure
Melphalan for brain cancer
15
16. RECEPTOR / VECTOR MEDIATED
Conjugation of drug to transport vector is facilitated with chemical
linkers avidin–biotin technology, polyethylene glycol linkers.
vector such as the Monoclonal antibody Mab
Portals of entry for large molecular drug attached to endogenous RMT
ligands
VECTO
R
DRUG
LINKE
R
BRAIN
SPECIFICIT
Y
HIGH
YIELD
COUPLING
CLEAVABILITY
PHARMAC
OKINETICS
RETENTION OF
AFFINITY AFTER
CLEAVAGE
INTRINSIC
RECEPTOR
16
17. CHIMERIC PEPTIDES AS
CARRIER
Conjucated proteins may be endogenous peptides, monoclonal
antibodies, modified protein, cationized albumin etc.
Chimeric peptides are transported to brain by various pathways like
peptide specific receptor.
E.g. Insulin and transferrin by transcytosis
Conjugation of drug with antibodies e.g. OX-26, 8D3 Mab
antibody to red transferrin receptor
DRUG
VECTOR
MODIFIED
PRODUCT
17
18. COLLOIDAL
The vesicular systems are highly ordered assemblies of one or several
concentric lipid bilayer formed, when certain amphiphillic building blocks
are confronted with water
Coated with surfactants like polyoxyethylene/propylene, PEG
AIM:
slowly degrade, react to stimuli and be site-specific
increase the availability of the drug at the disease site.
Prevent harmful side effects
control degradation of drug
Advantages
Delays elimination of rapidly metabolizable drugs and thus function as
sustained release systems.
Both hydrophilic and lipophilic drugs can be incorporated.
Improves the bioavailability especially of poorly soluble drugs.
Prolong the existence of the drug in systemic circulation
18
19. NANOPARTICLES
• Size 1-1000 nm
• includes both nanocapsules, with a core-shell structure (a
reservoir system) and nanospheres (a matrix system)
• Materials used: polyacetates, acrylic copolymers, poly(lactide),
poly(alkylcyanoacrylates) (PACA), poly(D,L-lactide-co-glycolide
Radiolabeled polyethylene glycol coated hexadecylcyanoacrylate
nanospheres targeted and accumulated in a rat gliosarcoma.
Polyoxyethylene sorbitan monooleate coated nanoparticles
containing drug easily cross BBB.
Polysorbate coated nanoparticles can mimic LDL to cross BBB. )
Mechanisms of transport Adhesion Fluidization of BBB endothelium
by surfactants Opening of tight junction Transcytosis /
Endocytosis Blockage of glycoprotein
19
20. Mechanisms of transport
Adhesion
Fluidization of BBB endothelium by
surfactants
Opening of tight junction
Transcytosis / Endocytosis
Blockage of glycoprotein
20
22. TARGETTING
Due to this coating the particles adsorb apolipoproteins E or A-
1 from the blood
: The coating of polyalkylcyanoacrylate or poly-lactic-co-
glycolic acid (PLGA) nanoparticles with polysorbate 80 or
poloxamer 188.
Interact with the LRP1 or with the scavenger receptor followed
by transcytosis across the blood-brain barrier into the brain.
22
23. for the treatment of glioblastomas are presently in Clinical
Phase I. Human serum albumin nanoparticles conjucated
with antibodies(OX26/R17217) against transferrin receptor
e.g. For lopera
Cell penetrating peptide(trans activating transduction protein
) modified liposome i.e. Tat-LIP having positive charge
transported via adsorptive mechanism. E.g. for caumarin
These particles loaded with doxorubicin mide, 5-florouracil(5-
FU)
Human serum albumin nanoparticles conjucated with
antibodies(29B4) against insulin receptor e.g. for targeting
loperamide
23
25. OTHER APPROACH:
Photodynamic therapy (PDT), Photofrin along with iron oxide
nanoparticles which is used to target tumor cells. In this, iron oxide is
used as contrast agent to get improved magnetic resonance imaging
(MR
Trojan horses coated with sugar layer, is another modern approach
containing magnetized, iron-containing nanoparticles
• Advantages of using nanoparticles for CNS targeted drug delivery
The use of biodegradable materials ---allows sustained drug release at
the targeted site after injection
small size --- penetrate into even small capillaries ---taken up within
cells ----drug accumulate at the targeted sites
protect drugs against chemical and enzymatic degradation.
• Limitations of using nanoparticles for CNS targeted drug delivery
small particles size and large surface area result in limited drug loading
and burst release.
small size and large surface area ----particle-particle aggregation--
physical handling of oparticles difficult in liquid and dry forms.
25
26. LIPOSOMES
lipid based vesicles are microscopic (unilamellar or multilamellar)
vesicles
Lipid soluble or lipophilic drugs get entrapped within the bilayered
membrane whereas water soluble or hydrophilic drugs get entrapped in
the central aqueous core of the vesicles
• Advantages
reduced toxicity and increased stability of entrapped drug via
encapsulation (eg.Amphotericin B, Taxol).
could encapsulate macromolecules like superoxide dismutase,
haemoglobin, erythropoietin, interleukin-2 and interferon-g.
suitable for delivery of hydrophobic, amphipathic and hydrophilic drugs
and agents.
Limitation :
Leakage and fusion of encapsulated drug / molecules
High production cost , Short half-life , Low solubility , Less stability
26
27. Mechanism: receptor/adsorptive mediated transport
liposome coated with mannose reaches brain tissue where
mannose coat assists transport
Addition of sulphatide (a sulphate ester of galactocerebroside)
to liposome increases availability
TARGETING
A non viral supercoiled plasmid DNA is
encapsulated in an interior of an 85nm liposome
Liposome surface is conjucated with 1000-
2000 strands of 2000 dalton peg to form
pegylated liposome
Tips of 1-2 % peg strands are conjucated with a
peptidomimetic Mab(HIR/TR) to form pegylated
immunoliposomeS
Transfer via RMT
27
29. MONOCYTES
Used as a Torjan Horse
Ideal endogenous carriers
Express certain receptors involved in receptor mediated
endocytosis upon interaction with suitable ligands
29
31. INTRANASAL DELIVERY
Drug delivered intranasally are transported along olfactory
sensory neurons to yield significant concentrations in the CSF
and olfactory bulb and then enter into other regions of brain by
diffusion(facilitated by perivascular pump)
DIFFICULTIES : enzymatic activity, low pH nasal epithelium,
mucosal irritation or large variability caused by nasal pathology
(common cold)
THE OLFACTORY PATHWAYS: the olfactory nerve pathway
(axonal transport) and the olfactory epithelial pathway. •
AXONAL TRANSPORT (slow route) : Agent enters the olfactory
neuron via endocytotic or pinocytotic mechanisms travels to the
olfactory bulb compounds pass paracellularly across the
olfactory epithelium into the perineural space continues to the
subarachnoid space & in direct contact with the CSF.
31
32. AXONAL TRANSPORT (slow
route)
Agent enters the olfactory neuron via
endocytotic or pinocytotic mechanisms
travels to the olfactory bulb
compounds pass paracellularly across
the olfactory epithelium into the
perineural space
continues to the subarachnoid space &
in direct contact with the CSF.
32
34. IONTOPHORETIC DELIVERY
Iontophoresis is the introduction of ionised molecules into
tissues by means of an electric current
biologically active agent is transported by means of
iontophoresis and/or phonophoresis directly to the CNS
using the olfactory pathway to the brain and thereby
circumventing the BBB and is known as transnasal
iontophoretic delivery .
34
36. CONCLUSION
The treatment of brain diseases is particularly challenging
because the delivery of drug molecules to the brain is often
precluded by a variety of physiological, metabolic and
biochemical obstacles that collectively comprise the BBB, BCB
and BTB.
Drug delivery directly to the brain interstitium has recently been
markedly enhanced through the rational design of polymer-
based drug delivery systems.
Substantial progress will only come about, however, if
continued vigorous research efforts to develop more therapeutic
and less toxic drug molecules are paralleled by the aggressive
pursuit of more effective mechanisms for delivering those drugs
to their brain targets.
36