CHRONOPHARMACOKINETICS AND TIME DEPENDENT PHARMACOKINETICSN Anusha
Chronopharmacokinetic studies have been demonstrating that time of administration is a possible factor of variation in the kinetics of the drug.
It entails the study of temporal changes in drug absorption, distribution, metabolism and elimination.
It investigates the variation in drug plasma levels as a function of time of day and the mechanisms responsible for time dependant variations.
The term circadian coined by Franz Halberg, comes from Latin.
“Circa” means around &“diem” means day.
This presentation includes introduction, physiology of GIT, factors affecting GRDDS, Advantages and disadvantages, approaches to GRDDS and their mechanism, some of the marketed products using GRDDS mechanism.
CHRONOPHARMACOKINETICS AND TIME DEPENDENT PHARMACOKINETICSN Anusha
Chronopharmacokinetic studies have been demonstrating that time of administration is a possible factor of variation in the kinetics of the drug.
It entails the study of temporal changes in drug absorption, distribution, metabolism and elimination.
It investigates the variation in drug plasma levels as a function of time of day and the mechanisms responsible for time dependant variations.
The term circadian coined by Franz Halberg, comes from Latin.
“Circa” means around &“diem” means day.
This presentation includes introduction, physiology of GIT, factors affecting GRDDS, Advantages and disadvantages, approaches to GRDDS and their mechanism, some of the marketed products using GRDDS mechanism.
Controlled Release Oral Drug Delivery System
Controlled drug delivery is one which delivers the drug at a predetermined rate, for locally or systemically, for a specified period of time.
Methods for Measurement of bioavailability pharmacampus
Which are the Methods for Measurement of bioavailability?- Pharmacokinetic method- Plasma level time studies, Urinary excretion studies.
Pharmacodynamic method: Acute pharmacologic response, Therapeutic response.
Gastro retentive drug delivery systems by shubham patilShubham Patil
General Discussion on Drug delivery System specially focused on Gastro-Retentive. I've covered various types and theories & understandably prepared this presentation for everyone who reads it.
Model dependent approach for drug release testing of controlled drug deliveryNehaFernandes2
A controlled drug delivery system is the one which delivers the drug at a predetermined rate, locally or systemically, for a specified period of time. Drug release is an important property of a therapeutic system, constituting a pre-requisite to absorption of the therapeutic agent and one that contributes to the rate and extent of active availability to the body. Hence while formulating such dosage forms one important factor that has to be taken into consideration is the release kinetics.
To provide particular, predetermined release profiles, it is necessary to know the exact mass transport mechanisms involved in drug release, and to predict quantitatively the resulting drug release kinetics. This is when the mathematical equations come into picture.
Mathematical equations describe the dependence of release in function of time. The use of this tool is very beneficial to predict the release kinetics before the release systems are comprehended. This analytical solution comprises of several models that have been used to design a number of simple and complex drug delivery systems and devices and to predict the overall release behavior. By achieving such a goal, the development process can be accelerated and innovative products can be introduced more rapidly than if such predictions are unavailable.
Application of a wide-range bioavailability model facilitates screening of potential drug candidates for controlled release, optimizing formulation design, and interpreting bioavailability data.
Bioavailability (BA) studies play a major role in the drug development phase for both new drug products and their generic equivalents, and thus attract considerable attention globally. There are several approaches to assess BA and each regulatory authority has its own regulations/guidance for conducting BA studies before approving generic products for marketing in their country. Therefore, a thorough understanding is required of these BA concepts and basic regulatory considerations for conducting BA studies. This article briefly reviews the BA concepts, approaches, designs, and conducting and analysis of data obtained.
INTRODUCTION
• Bioavailability means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.
• Results in 100% bioavailability as the absorption process is bypassed.
• The absolute bioavailability of a drug, when administered by an extra vascular route is usually less than one (i.e. F<100%).> Oral > Rectal > Topical.
A systematic approach to ensure bioavailability of pharmaceutical products:
BIOAVAILABILITY
It the degree to which, or the rate at which, a medication or other substance is absorbed or becomes available at the targeted place in the body. Bioavailability can be influenced by inactive ingredients (see Excipients) in the drug such as additives that prevent the medication from dissolving in the stomach. If a medication that is intended to be taken on an empty stomach is taken instead with food, this can also change the absorption rate and affect the bioavailability of the active ingredient
BIO AVAILABILITY FRACTION (F):
Bio available fraction it refers to the fraction of administered dose that enters the systemic circulation.
*100
Controlled Release Oral Drug Delivery System
Controlled drug delivery is one which delivers the drug at a predetermined rate, for locally or systemically, for a specified period of time.
Methods for Measurement of bioavailability pharmacampus
Which are the Methods for Measurement of bioavailability?- Pharmacokinetic method- Plasma level time studies, Urinary excretion studies.
Pharmacodynamic method: Acute pharmacologic response, Therapeutic response.
Gastro retentive drug delivery systems by shubham patilShubham Patil
General Discussion on Drug delivery System specially focused on Gastro-Retentive. I've covered various types and theories & understandably prepared this presentation for everyone who reads it.
Model dependent approach for drug release testing of controlled drug deliveryNehaFernandes2
A controlled drug delivery system is the one which delivers the drug at a predetermined rate, locally or systemically, for a specified period of time. Drug release is an important property of a therapeutic system, constituting a pre-requisite to absorption of the therapeutic agent and one that contributes to the rate and extent of active availability to the body. Hence while formulating such dosage forms one important factor that has to be taken into consideration is the release kinetics.
To provide particular, predetermined release profiles, it is necessary to know the exact mass transport mechanisms involved in drug release, and to predict quantitatively the resulting drug release kinetics. This is when the mathematical equations come into picture.
Mathematical equations describe the dependence of release in function of time. The use of this tool is very beneficial to predict the release kinetics before the release systems are comprehended. This analytical solution comprises of several models that have been used to design a number of simple and complex drug delivery systems and devices and to predict the overall release behavior. By achieving such a goal, the development process can be accelerated and innovative products can be introduced more rapidly than if such predictions are unavailable.
Application of a wide-range bioavailability model facilitates screening of potential drug candidates for controlled release, optimizing formulation design, and interpreting bioavailability data.
Bioavailability (BA) studies play a major role in the drug development phase for both new drug products and their generic equivalents, and thus attract considerable attention globally. There are several approaches to assess BA and each regulatory authority has its own regulations/guidance for conducting BA studies before approving generic products for marketing in their country. Therefore, a thorough understanding is required of these BA concepts and basic regulatory considerations for conducting BA studies. This article briefly reviews the BA concepts, approaches, designs, and conducting and analysis of data obtained.
INTRODUCTION
• Bioavailability means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.
• Results in 100% bioavailability as the absorption process is bypassed.
• The absolute bioavailability of a drug, when administered by an extra vascular route is usually less than one (i.e. F<100%).> Oral > Rectal > Topical.
A systematic approach to ensure bioavailability of pharmaceutical products:
BIOAVAILABILITY
It the degree to which, or the rate at which, a medication or other substance is absorbed or becomes available at the targeted place in the body. Bioavailability can be influenced by inactive ingredients (see Excipients) in the drug such as additives that prevent the medication from dissolving in the stomach. If a medication that is intended to be taken on an empty stomach is taken instead with food, this can also change the absorption rate and affect the bioavailability of the active ingredient
BIO AVAILABILITY FRACTION (F):
Bio available fraction it refers to the fraction of administered dose that enters the systemic circulation.
*100
NOVEL DRUG
1.INTRODUCTION: Novel Drug delivery system is the advance drug delivery system which improve drug potency, control drug release to give a sustained therapeutic effect, provide greater safety, finally it is to target a drug specifically to a desired tissue.
2.ADVANTAGES
3.DISADVANTAGES
4.SELECTION OF DRUG CANDIDATES FOR CONTROL RELEASE DOSAGE FORM
5.APPROACHES TO DESIGN CONTROLLED RELEASE FORMULATIONS
6.FACTORS INFLUENCING THE DESIGN AND ACT OF CONTROLLED RELEASE PRODUCTS
DELIVERY SYSTEM
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
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ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
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
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
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
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- 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
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
Title: Sense of Smell
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 primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
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.
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
2. Controlled Release Drug Delivery System
Controlled release means controlling the rate at which a
drug is released into the system unlike conventional delivery
systems that is it delivers the drug at a pre-determined rate
for a specified period of time & maintains constant drug
levels in blood or tissue.
3. Rationale of Controlled Drug Delivery System
.
The basic rationale of a controlled release drug delivery system is to optimize the
biopharmaceutic, pharmacokinetic and pharmacodynamic properties of a drug in such a way that
its utility is maximized through reduction in side effects and cure or control of condition in the
shortest possible time by using smallest quantity of drug, administered by the most suitable route.
4. Drug release can be controlled via a variety of mechanisms.
Chemical Approaches
• In the delivery through chemical reaction, the biomaterial making the delivery
vehicle degrades in the presence of water or other agent.
• Chemical approaches utilize chemical degradation, or enzymatic degradation, to
effect CR of drug molecules from a drug–polymer conjugate.
Physical Approaches
Physical approaches focus on
four main mechanisms:
• Dissolution Control
• Diffusion Control
• Osmotic Pressure Control
• Ion Exchange Control
Mechanisms of Controlling Drug Release
Controlled
Release Drug
Delivery
System
Osmotic
Pressure
Control
Dissolutio
n Control
Diffusion
Control
Ion Exchange
Control
5. 1. Dissolution Control
The drug is associated with a polymeric carrier, which slowly dissolves, thereby
liberating the drug. The polymeric carrier can be as follows:
1. A reservoir system (encapsulated dissolution system), whereby a drug core
is surrounded by a polymeric membrane. The rate of drug release is determined by
the thickness and dissolution rate
of the membrane.
2. A matrix system,
whereby the drug is distributed
through a polymeric matrix.
Dissolution of the matrix
facilitates drug release.
6. 2. Diffusion Control
• The drug must diffuse through a polymeric carrier. Again, two main types of design
system are used:
1. A reservoir system, whereby the drug is surrounded by a
polymeric membrane, known as a rate-controlling membrane (RCM).
The rate of drug release is dependent on the rate of diffusion through
the RCM.
2. A matrix system (also known as a monolithic device), whereby
the drug diffuses through a polymeric matrix.
Reservoir System Matrix System
7. 3. Osmotic Pressure Control
• Osmotic pressure induces the diffusion of water across a
semipermeable membrane, which then drives drug release through an
orifice of the DDS.
4. Ion-Exchange Control
• Ion-exchange resins are water-insoluble polymeric materials that
contain ionic groups. Charged drug molecules can associate with an
ion-exchange resin via electrostatic interaction between oppositely
charged groups. Drug release results from the exchange of bound
drug ions with ions commonly available in body fluids (such as Na+,
K+, or Cl–).
8. Factors Influencing the Design and Performance
of Controlled Drug Delivery System
BIOPHARMACEUTIC CHARACTERISTICSOFTHE DRUG
Molecular weight of the drug
Aqueous Solubility of the drug
Apparent Partition Coefficient
Drug Pka and Ionization at Physiological pH
Drug Stability
Mechanism and site of absorption
Route of administration
PHARMACOKINETIC CHARACTERISTICS OFTHE DRUG
Absorption rate
Distribution of drug
Rate of metabolism
Elimination half-life
Dosage form index
11. Biopharmaceutics
• Biopharmaceutics can be defined as the study of the physical and
chemical properties of drugs and their proper dosage as related to
the onset, duration, and intensity of drug action, or it can be defined
as the study of the effects of physicochemical properties of the drug
and the drug product, in vitro, on the bioavailability of the drug, in
vivo, to produce a desired therapeutic effect.
Biopharmaceutic Characteristics of a Drug in the Design of CRDDS
• The former depends upon the fabrication of the formulation and the
physicochemical properties of the drug while the latter element is dependent upon
pharmacokinetics of drug.
The performance of a drug presented as a controlled-release system depends upon its:
1. Release from the formulation.
2. Movement within the body during its passage to the site of action
.
12. Biopharmaceutical Considerations
For designing a controlled drug delivery system, the following
physicochemical properties of drugs must be considered:
1. The molecular weight of the drug and its Particle Size
• Drugs of lower the molecular weight, more accurately, of lower molecular
size, are absorbed faster and more completely. Through passive diffusion, about
95% of the drugs are absorbed.
Diffusivity is well-defined as the ability of a substance (drug) to diffuse through
the membrane. It is inversely related to the molecular size.
• Thus, drugs with large molecular weight rather large molecular size are not
ideally suitable for controlled release systems e.g. peptides and proteins.
13. • Smaller the particle size of the drug, greater will be the effective surface
area, more will be the intimate contact between the solid surface and aqueous
solvent that will lead to higher dissolution rate and will enhance the
absorption efficiency.
• Particle size reduction has been used to enhance the solubility and
absorption of poorly soluble drugs such as tolbutamide.
14. 2. The diffusion coefficient and molecular size
After reaching the systemic circulation, the drug needs to diffuse through:
rate-controlling polymeric membranes or matrix
different biological membranes.
The capacity of a drug to diffuse through these membranes is called
diffusibility, diffusivity or diffusion coefficient (D). Diffusibility of the drug
depends on its molecular size or molecular weight.
Usually, drugs having a molecular weight within 150 to 400 Da (Dalton)
possess diffusivity of 10–6 –10–9 cm2/sec through flexible polymers.
The drugs having molecular weight more than 500 Da have very small
diffusivity such as 10– 12cm2/sec.
High molecular weight drugs usually show very slow release kinetics in
extended release dosage form; if the mechanism of drug release is
diffusion control.
15. 3.The aqueous solubility of the drug
• For oral controlled release dosage form, the drug should have excellent
aqueous solubility and are independent of pH; such drugs are good
candidates.
• The amount of drug absorbed into systemic circulation is a function of
the amount of the drug present in an unionized form in a solution of
G.I fluid.
• Before absorption, the drug must go into a solution of GI fluid and then
partitions into the absorbing membrane.Thus, absorption of a drug is
related to its partitioning between the lipid layer and an aqueous phase,
and the rate of dissolution is related to its aqueous solubility.
16. The Noyes-Whitney equation can express the relation between the rate of
dissolution and aqueous solubility as below;
Where,
dC/dt is the rate of dissolution
kD is the dissolution rate constant
A is the total surface area of the drug particle
CS is the saturation solubility of the drug.
17. pH of the medium can influence the total solubility of a weakly acidic or weakly
basic drug having a given pKa.
According to the pH-partition hypothesis, the unionized form of a weakly acidic
drug present in the stomach (pH ≈ 1–2) will be absorbed very well.
Similarly, weakly basic drugs predominantly remain unionized in the small
intestine (pH ≈5–7) and will be excellently absorbed; but these drugs remain in
ionized form in the stomach resulting in poor absorption.
Therefore, it can be summarized
‘for better absorption in GI tract (oral route) the drug must have an adequate
aqueous solubility, must be released from the dosage form at a required rate,
and be available as unionized form at the site of its absorption’
18. 4. Apparent partition coefficient
The partition coefficient is the measure of the lipophilicity of a drug
and an indication of its ability to cross the cell membrane. It is
defined as the ratio between un-ionized drug distributed between the
organic and aqueous layers at equilibrium.
Larger the apparent partition coefficient of a drug (Ko/w), greater its
lipophilicity and hence, greater would be its rate and extent of
absorption.
• These types of drugs even cross the highly selective blood-brain barrier.
• Both permeation of a drug across the biological membrane and diffusion
through the rate controlling membrane or matrix depend on the partition
coefficient of the drug.
19. • The apparent oil/water partition coefficient of a drug is considered as a measure of its
membrane permeability.The apparent oil/water partition coefficient, K is defined as;
Where
Co represents the equilibrium concentration of all forms of the drug in an organic phase,
usually in n-octanol, and Cw represents the equilibrium concentration of all forms of the
drug in the aqueous phase.
• There should be an optimum partition coefficient for required permeability.
• When the value of partition coefficient is more than the optimum value, the aqueous
solubility of a drug is reduced, and the lipid solubility is increased; under this
circumstance once the drug enters into lipid membrane cannot diffuse out of the lipid
membrane.
• Usually, the optimum value of K is 1000 when measured using the n-octanol/water
system.
• Drugs having partition coefficient value more than or less than the optimum values are
not suitable candidates for making controlled release formulations.
20. 5. Drug pKa and ionization at Physiological pH
pKa is a number that describes the acidity of a particular molecule. It
measures the strength of an acid by how tightly a proton is held by a Bronsted
acid.
• Drug molecules are therapeutically active only in their unionized form and in this
form the drug can easily penetrate the lipoidal membrane.
• The amount of drug that remains in unionized form is a function of its
dissociation constant and pH of the fluid at the site of absorption.
21. Henderson-Hasselbalch equation.
For a weak acid:
• pH = pKa + log(A-/HA), where A- is the ionized drug and HA the unionized
drug.
For a weak base:
• pH = pKa + log(B/HB+), where B is the unionized drug and HB+ is the ionized
drug.
• Thus, when the local pH is equal to the pKa of the drug, the drug will be 50% ionized and
50% unionized (log 1 = 0).
• When the pH of the environment is less than the pKa of the compound, the environment
is considered acidic and the compound will exist predominantly in its protonated form.
• When the pH of the environment is greater than the pKa of the compound, the
environment is considered basic and the compound will exist predominately in its
deprotonated form.
• Thus, the drug which remains in ionized form at its absorption site is not suitable for
SR/CR dosage form. Drugs, such as hexamethonium, exist largely in ionized forms are
poor candidates for controlled delivery systems
22. 6. Drug Stability
• Once the drug is administered, biological fluids that are in direct contact with a drug
molecule may influence the stability of drug.
• Drugs may be susceptible to both chemical and enzymatic degradation, which results in
the loss of drug activity.
• Drugs with poor acidic stability, when coated with enteric coating materials will bypass
the acidic stomach and release the drug at lower portion of the GI tract.
• Drugs unstable in gastric pH, e.g. propantheline can be designed for sustained delivery in
intestine with limited or no delivery in stomach.
• On the other hand, a drug unstable in intestine, e.g. probanthine, can be formulated as
gastro retentive dosage form.
23. 7. Route of Drug Administration
• Oral and Parenteral (I.M) routes are the most suitable for the administration of
controlled release dosage forms followed by the transdermal routes.The features
for the drug given by particular route are:
1. Oral Route
The drug should have the following properties to be a successful candidate
• It must get absorbed through the entire length of GIT.
• The transit time can be extended for 12-24 hours.
• Dose as high as 1000mg can be given through this route.
• A drug with pH dependent absorption, prone to be destabilized by GI
fluids/enzymes, undergoes extensive pre-systemic metabolism (nitroglycerin),
absorbed actively e.g. (riboflavin) is a poor candidate for oral CRDDS.
24. 2. Intramuscular/subcutaneous route
This route is preferred because
• The action is to be prolonged for 24 hours to 12 months. E.g. ER intramuscular
naltrexone that provide SR for 28 days period
• Small amount of drug can be administered by these routes.
The drug release by such route is influenced by factors such as:
• solubility of the drug in surrounding tissue
• molecular weight
• partition coefficient
• pKa of the drug and
• contact surface between drug and the surrounding tissues.
25. 3.Transdermal route
This route is selected for drugs which show extensive first-pass metabolism upon
oral administration or drugs with a low dose.
Low dose drugs like nitroglycerine can be administered by this route
Important factors to be considered are:
•The partition coefficient of drug
• Contact area
• Skin condition, permeability & skin perfusion rate etc.
In short the main determinants in selecting the route of drug administration for CR
products are physicochemical properties of the drug, dose size, absorption
efficiency and desired duration of action of drug.
26. Marketed formulations of drugs with the technology used
8. Mechanism of Absorption:
Drugs which are absorbed by carrier mediated transport procedure or
through a window are not entirely suitable candidates for the development of
controlled release systems, such as Vitamin B
28. Pharmacokinetic Properties of drugs
Pharmacodynamic Properties of the drug
PHARMACOKINETIC CHARACTERIZATION OF
DRUG FOR DESIGN OF CRDDS
Compartment Model
29. To achieve a sustained or extended action, the concentration of the drug is to be maintained within the
therapeutic window for a long period. For this, it is essential to provide a therapeutic concentration
immediately after administration; so that the absorption pool of drug is maintained. Using a
conventional or immediate release dosage form this can be done. This can be illustrated schematically
as follows;
Dosage Form Kr Absorption pool Ka Site Of Action Ke
Drug Release Absorption Elimination
Where, kr, ka, and ke are release rate constant, absorption rate constant, and overall elimination rate
constant respectively.
30. When the drug is released immediately as in case of the conventional dosage form, i.e.
kr>>> ka.
The absorption of the drug becomes the rate-limiting step for the drug to reach its site of
action .
On the other hand, for a dosage form which does not release the drug immediately, i.e.
kr<<< ka
Release of drug at the site of absorption become the rate-limiting step for the drug to reach
its site of action
Rate-Limiting Step
31. The three-step process is reduced to the two-step process. This indicates that once the drug is released from
the dosage it is immediately absorbed, and it reaches its site of action.
Thus, to design or develop a sustained/extended release dosage form attention should be paid towards
altering the rate of release (alteration of the kr).
For designing or developing an SR/CR dosage form, the plasma concentration of the drug should
remain at a constant level.
The concentration of the drug should remain within the therapeutic window throughout the period. Thus,
the drug should be administered at a constant rate over a period without considering the amount of drug
remaining in the dosage form. Thus, the drug would be released from the dosage form following zero-
order kinetics.
32. .
The purpose of SR/CR dosage form is to provide an immediate effect and to extend this effect for a
more extended period. Hence, there are two parts of SR/CR dosage form – immediate or initial dose (Di)
and sustaining or maintenance dose (Dm). The sum of these doses makes the total dose, W.
W = Di + Dm
When the maintenance dose releases the drug by zero order process for a definite period, the total dose
may be calculated as;
W = Di + KrTd
Where, Tୢ is the total time required for the extended release of drug from one dose. If the maintenance
dose starts releasing the drug along with the initial dose (when t = 0), the total amount of drug released
shall be more than the amount released from the initial dose.
33. In such case, a correction is necessary to account for the extra amount (amount
released from maintenance dose, and the equation is rewritten as;
W=Di+KrTd-KrTp
◦ Where, Tp is the time required for attaining peak drug level, Cmax.
◦ In fact, the maintenance dose starts releasing the drug after the time, Tp.
◦ This is an ideal situation; making the maintenance in such a way that it releases the drug,
following zero-order kinetics is the simplest way to achieve this.
34. A constant drug level can be maintained by formulating the initial dose and
maintenance dose which releases the drug by first order process.
Total dose for such a system can be calculated as;
W = Di + (KeCd) Vd
(Kr)
35. Types Of Release System
Some of the types of release systems are ;
Continued Release system
Dissolution Controlled system
Diffusion controlled system
Delayed Transit And Continous Release system
Mucoadhesive Formulation
Floated formulation
Delayed Release System
Colon Specific delivery
37. Absorption rate
A drug is which is fabricated into a
controlled release system should be absorbed
efficiently.
Absorption window
For the formulation of a controlled/extended
release dosage form, the rate, extent, and
uniformity of absorption of drug are essential
factors. Thus, absorption window is one more
limiting factor for bioavailability of orally
administered drugs.
Distribution
The distribution characteristic of a drug is expressed using its apparent volume of distribution
and ratio of drug in tissues to the drug in plasma (T/ P )
Pharmacokinetic Parameters
38. Drugs selected for CR formulations should be completely metabolized, but the rate of metabolism should not
be too rapid.
There are two situations related to metabolism which affect the design of SR/CR dosage form significantly.
A drug will be considered a Poor Candidate for SR/CR formulation if it:
Induces or inhibits synthesis of the enzyme when it is administered for an extended period.
Drugs which induce enzymes are primidone, phenytoin, griseofulvin, rifampicin, barbiturates,
meprobamate, cyclophosphamide, etc.
Drugs which inhibit enzymes are erythromycin, Fluconazole, ketoconazole, isoniazid, cimetidine,
Amiodarone, MAO-inhibitors, 4-aminosalicylic acid, allopurinol, coumarins, etc
39. 2. A drug will be considered a Poor Candidate for SR/CR formulation;
◦ if there is a varying concentration of it in the blood either due to tissue/intestinal metabolism or due to
hepatic metabolism (first pass effect).
◦ Drugs which are metabolized in the intestine are chlorpromazine, clonazepam, hydralazine, levodopa,
salicylamide, isoproterenol, etc.
40. In the case of an ideal CRDD System, the rate of drug absorption should be equal to
the rate of drug elimination.
◦ Drugs having t1/2 in the range of 1 to 8 hours are ideal candidates for controlled
release system.
◦ If the biological half-life(t1/2) of a drug is small (less than 1 hours), then more amount
of drug would be present in a single dose of the controlled release dosage form.
◦ Drugs with long half-life should not be formulated into controlled release dosage form.
41. TOTAL Clearance (CL)
The CL is a measure of the volume of distribution
cleared of drug per unit of time. It is the key
parameter in estimating the required dose rate for
CRDDS , and for predicting the steady state
concentration .
Drug-Protein Binding
The elimination half-life of drugs usually
increases when the percent of the bound drug to
plasma increases. Such drugs should not be
formulated as sustained/controlled release
formulations.
42. Dosage form index
Dosage form index is defined as the ratio of
Css.max to Css.min. Its value must be nearer to
unity.
Therapeutic Concentration
(Css)
The therapeutic concentrations are the desired or
target steady state peak concentration (Css.max ) ,
the desired or target minimum steady state
concentration (Css.min ), and the mean steady state
concentration ( Css.av )
The difference between Css.max and Css.min is
the fluctuation. The smaller the desired fluctuation
the greater must be the precision of the dosage
form performance.
43. .
Pharmacokinetic Properties Desired Value
Absolute bioavailability > 75%
Intrinsic rate of absorption Greater than the release rate
Elimination half-life 0.5 to 8 hr
Elimination rate constant As necessary for the design
The apparent Volume of
Distribution (Vd)
Should not be large
Minimum Effective
Concentration (MEC)
Should not be high; if both MEC and Vd are
less, the dose
size of SR/CR dosage form will be small
Toxic concentration Should be large; i.e., wider therapeutic window
can provide safety of the dosage form
44. (a) Therapeutic range:
For controlled release drug delivery system, a drug should have its therapeutic range wide enough so that any variation in the
release rate do not produce its concentration beyond this level.
(b) Therapeutic index:
It is the most widely used parameter to measure the margin of safety of a drug. Therapeutic index = TD50 /ED50.The longer the
value of the therapeutic index, the safer is the drug. A drug is considered to be safe, if its therapeutic index value is greater than
10. Drugs with a very small value of therapeutic index are not suitable candidates for the formulation of sustained release
products.
(c) Plasma concentration-response relationship:
Drugs such as reserpine whose pharmacological activity is independent of its concentration are poor candidates for the
controlled-release system.
45. The general absorbability must be established.
Ideally the liberation or drug release rate (therefore the term: controlled-release delivery system) is the
rate-limiting step for the absorption process.
CRDDS are multiple dose systems designed to result in steady state concentrations, Css.
The magnitude of Css depends on the dose rate, D/T, (amount drug per unit of time), and the total
clearance, CL tot, ( loss of drug from the volume of distribution per unit of time ) of the drug.
To understand the design and evaluation of CRDDS, some basic principles are discussed here.
46. Assuming first-order elimination, which is the case for
most drugs, and plotting the concentration-time data
semilogarithmically, the terminal slope is the elimination
phase, characterized by a straight line. One can now back-
extrapolate this terminal phase to the ordinate. We will
find three possibilities as in figure.
1. If the drug is rapidly absorbed and rapidly distributed
between systemic circulation and those tissues to which
the drug eventually goes, the peak will be below the
back-extrapolated, terminal line (A in fig).
47. If the drug is rapidly absorbed but slowly distributed
between systemic circulation (central compartment) and
those tissues to which the drug eventually goes
(peripheral compartment), the peak will be above the
back-extrapolated, terminal line (B in fig)
If the drug is absorbed but rapidly distributed between
central and peripheral compartment, the peak will be
below the back-extrapolated, terminal line (C in Fig).
The insets on the right hand side in Fig. symbolize the
compartment models. A in Fig is a one-compartment
model, B and C are two-compartment models.
48. The distribution phase in two
Compartment models may vary between a few
minutes to a few hours.
Since in controlled drug delivery systems the
drug liberation is usually over a longer period of
time than the distribution phase, we can
“collapse’’ the two compartment model into a
one compartment model.