Bioavailability means the rate and extent to which the active ingredient is absorbed from a drug product and becomes available at the site of action.
When the drug is given orally, only part of the administered dose appears in the plasma.
By plotting plasma concentrations of the drug versus time, one can measure the area under the curve (AUC).
This curve reflects the extent of absorption of the drug.
BIOPHARMACEUTIC CONSIDERATIONS IN DRUG PRODUCT DESIGNN Anusha
BIOPHARMACEUTICS studies the in vitro impact of physicochemical properties of drugs and drug products on delivery to body under normal or pathologic conditions.
Biopharmaceutics links the physical and chemical properties of drug and drug product to their performance, in vivo.
The aim of biopharmaceutics is to adjust the delivery of drug from drug products in such a manner as to provide: optimal therapeutic activity and safety for the patient.
It includes Introductory part about what is Dissolution...then Mechanism of Dissolution is elaborated...Theories of Dissolution also given..It also includes Factors affecting Dissolution profile..Along with References given below for easily searching..
BIOPHARMACEUTIC CONSIDERATIONS IN DRUG PRODUCT DESIGNN Anusha
BIOPHARMACEUTICS studies the in vitro impact of physicochemical properties of drugs and drug products on delivery to body under normal or pathologic conditions.
Biopharmaceutics links the physical and chemical properties of drug and drug product to their performance, in vivo.
The aim of biopharmaceutics is to adjust the delivery of drug from drug products in such a manner as to provide: optimal therapeutic activity and safety for the patient.
It includes Introductory part about what is Dissolution...then Mechanism of Dissolution is elaborated...Theories of Dissolution also given..It also includes Factors affecting Dissolution profile..Along with References given below for easily searching..
Clinical pharmacokinetic studies are performed to examine the absorption, distribution, metabolism, and excretion of a drug under investigation in healthy volunteers and/or patients
United State Pharmacopoeia (USP)The establishment of a rational relationship between a biological property, or a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage form.
Food and Drug Administration (FDA) definitionIVIVC is a predictive mathematical model describing the relationship between an in vitro property of a dosage form and a relevant in vivo response. Generally, the in vitro property is the rate or extent of drug dissolution or release while the in vivo response is the plasma drug concentration or amount of drug absorbed.
Methods For Assesment Of Bioavailability Anindya Jana
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.
Bioavailability studies are important in the Primary stages of development of a suitable dosage form for a new drug entity, determination of influence of excipients, patient related factors & possible interaction with other drugs on the efficiency of absorption, development of new formulations of the existing drugs, control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors, storage & stability on drug absorption
Biopharmaceutic considerations in drug product design and In Vitro Drug Produ...PRAJAKTASAWANT33
Introduction, biopharmaceutic factors affecting drug bioavailability, rate–limiting steps in drug absorption, physicochemical nature of the drug formulation factors affecting drug product performance
It is defined as “the predictive mathematical model that describes the relationship between in vitro property (such as rate & extent of dissolution) of a dosage form and in vivo response (such as plasma drug concentration or amount of drug absorbed)”.
1. Measurement of Bioavailability:
Direct and indirect methods may be used to assess drug bioavailability. The in-vivo bioavailability of a drug product is demonstrated by the rate and extent of drug absorption, as determined by comparison of measured parameters, e.g., concentration of the active drug ingredient in the blood, cumulative urinary excretion rates, or pharmacological effects.
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.
The design of the bioavailability study depends on the objectives of the study, the ability to analyze the drug (and metabolites) in biological fluids, the pharmacodynamics of the drug substance, the route of drug administration, and the nature of the drug product.
Pharmacokinetic and/or pharmacodynamic parameters as well as clinical observations and in-vitro studies may be used to determine drug bioavailability from a drug product.
1.1. Pharmacokinetic methods:
These are very widely used and based upon the assumption that the pharmacokinetic profile reflects the therapeutic effectiveness of a drug. Thus these are indirect methods. The two major pharmacokinetic methods are:
The major pharmacokinetic methods are:
Plasma / blood level time profile.
o Time for peak plasma (blood) concentration (t max)
o Peak plasma drug concentration (Cmax)
o Area under the plasma drug concentration–time curve (AUC)
Urinary excretion studies.
o Cumulative amount of drug excreted in the urine (Du)
o Rate of drug excretion in the urine (dDu/dt)
o Time for maximum urinary excretion (t)
C. Other biological fluids
1.2. Pharmacodynamic methods:
IT involves direct measurement of drug effect on a (patho) physiological process as a function of time. Disadvantages of it may be high variability, difficult to measure, limited choices, less reliable, more subjective, drug response influenced by several physiological & environmental factors.
They involve determination of bioavailability from:
Acute pharmacological response.
Therapeutic response.
1.3. In-vitro dissolution studies
Closed compartment apparatus
Open compartment apparatus
Dialysis systems.
1.4. Clinical observations
Well-controlled clinical trials
An in-vitro in-vivo correlation (IVIVC) has been defined by the U.S. Food and Drug Administration (FDA) as "a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response".
Dissolution, factors affecting drug dissolution, methods to evaluate dissolution, advantages and disadvantages, recent approaches--these are the topics covered in this presentation.
WHAT IS COMPRESSION ?
Compression means reduction of bulk volume of material as a result of the removal of gaseous phase (air) by applied pressure
WHAT IS CONSOLIDATION?
Consolidation is an increase in mechanical strength of material resulting from particle - particle interactions.
Clinical pharmacokinetic studies are performed to examine the absorption, distribution, metabolism, and excretion of a drug under investigation in healthy volunteers and/or patients
United State Pharmacopoeia (USP)The establishment of a rational relationship between a biological property, or a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage form.
Food and Drug Administration (FDA) definitionIVIVC is a predictive mathematical model describing the relationship between an in vitro property of a dosage form and a relevant in vivo response. Generally, the in vitro property is the rate or extent of drug dissolution or release while the in vivo response is the plasma drug concentration or amount of drug absorbed.
Methods For Assesment Of Bioavailability Anindya Jana
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.
Bioavailability studies are important in the Primary stages of development of a suitable dosage form for a new drug entity, determination of influence of excipients, patient related factors & possible interaction with other drugs on the efficiency of absorption, development of new formulations of the existing drugs, control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors, storage & stability on drug absorption
Biopharmaceutic considerations in drug product design and In Vitro Drug Produ...PRAJAKTASAWANT33
Introduction, biopharmaceutic factors affecting drug bioavailability, rate–limiting steps in drug absorption, physicochemical nature of the drug formulation factors affecting drug product performance
It is defined as “the predictive mathematical model that describes the relationship between in vitro property (such as rate & extent of dissolution) of a dosage form and in vivo response (such as plasma drug concentration or amount of drug absorbed)”.
1. Measurement of Bioavailability:
Direct and indirect methods may be used to assess drug bioavailability. The in-vivo bioavailability of a drug product is demonstrated by the rate and extent of drug absorption, as determined by comparison of measured parameters, e.g., concentration of the active drug ingredient in the blood, cumulative urinary excretion rates, or pharmacological effects.
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.
The design of the bioavailability study depends on the objectives of the study, the ability to analyze the drug (and metabolites) in biological fluids, the pharmacodynamics of the drug substance, the route of drug administration, and the nature of the drug product.
Pharmacokinetic and/or pharmacodynamic parameters as well as clinical observations and in-vitro studies may be used to determine drug bioavailability from a drug product.
1.1. Pharmacokinetic methods:
These are very widely used and based upon the assumption that the pharmacokinetic profile reflects the therapeutic effectiveness of a drug. Thus these are indirect methods. The two major pharmacokinetic methods are:
The major pharmacokinetic methods are:
Plasma / blood level time profile.
o Time for peak plasma (blood) concentration (t max)
o Peak plasma drug concentration (Cmax)
o Area under the plasma drug concentration–time curve (AUC)
Urinary excretion studies.
o Cumulative amount of drug excreted in the urine (Du)
o Rate of drug excretion in the urine (dDu/dt)
o Time for maximum urinary excretion (t)
C. Other biological fluids
1.2. Pharmacodynamic methods:
IT involves direct measurement of drug effect on a (patho) physiological process as a function of time. Disadvantages of it may be high variability, difficult to measure, limited choices, less reliable, more subjective, drug response influenced by several physiological & environmental factors.
They involve determination of bioavailability from:
Acute pharmacological response.
Therapeutic response.
1.3. In-vitro dissolution studies
Closed compartment apparatus
Open compartment apparatus
Dialysis systems.
1.4. Clinical observations
Well-controlled clinical trials
An in-vitro in-vivo correlation (IVIVC) has been defined by the U.S. Food and Drug Administration (FDA) as "a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response".
Dissolution, factors affecting drug dissolution, methods to evaluate dissolution, advantages and disadvantages, recent approaches--these are the topics covered in this presentation.
WHAT IS COMPRESSION ?
Compression means reduction of bulk volume of material as a result of the removal of gaseous phase (air) by applied pressure
WHAT IS CONSOLIDATION?
Consolidation is an increase in mechanical strength of material resulting from particle - particle interactions.
Rate limiting steps in drug absorption [autosaved]Nagaraju Ravouru
Rate limiting steps in drug absorption 1.Disintegration time
2.Dissolution and solubility
3.Physical and chemical nature of active drug substance
4.Nature of excipients
5.Method of granulation
6.Dissolution test conditions
7.Gastric emptying
University Institute of Pharmaceutical Sciences is a flag bearer of excellence in Pharmaceutical education and research in the country. Here is another initiative to make study material available to everyone worldwide. Based on the new PCI guidelines and syllabus here we have a presentation dealing with the tablets and its excipients and Ideal properties of tablet and the methods and equipment for there for manufacturing.
Thank you for reading.
Hope it was of help to you.
UIPS,PU team
This PPT includes what role does Dosage form impart on absorption. Why it is important in absorption. what should be its nature and type of dosage form.
Suspension is made of two phase system, consisting of a finely divided solid particles (Dispersed phase) distributed in a particular manner throughout another medium (Continuous phase).
ABSTRACT
The aim of the present research work was to enhance the solubility of
Carvedilol by solid dispersion method and to formulate a mouth
dissolving tablet. Drugs are more frequently taken by oral
administration. The solubility of Carvedilol enhanced with different
ratios of PVP by the solvent evaporation method .In-vitro release
profile of solid dispersion obtained in SGF without enzymes and Ph
6.8 phosphate buffer indicate that 100% drug release found within 20
min. These solid dispersion were directly compressed into tablets using
Crospovidone, sodium starch glycol ate, croscarmellose sodium and
polyacrylic potassium in different concentrations as a super
disintegrants. The prepared tablets containing the solid dispersion of
Carvedilol having sufficient strength of 2.5-4 kg/cm2. The
disintegrated in the oral cavity with in 21 sec. contain Crospovidone
(5%) as super disintegrant.
KEYWORDS: Carvedilol, PVP, Super Disintegrants, Mouth Dissolving Tablet.
Similar to FORMULATION FACTORS EFFECTING BIOAVAILABILITY OF DRUGS (20)
The brain is a delicate organ with many vital functions and many formidable mechanisms, isolate and protect it from the outside world. Unfortunately, the same mechanisms that prevent environmental chemicals accessing the brain also prevent the access of therapeutic chemicals. The brain is segregated from the circulating blood by a unique membranous barrier i.e the blood brain barrier.
DRUG INTERACTIONS (MECHANISMS OF DRUG-DRUG INTERACTIONS)N Anusha
A Drug interaction is an interaction between a drug and some other substance, such as another drug or a certain type of food, which leads to interaction that could manifest as an increase or decrease in the effectiveness or an adverse reaction or a totally new side effect that is not seen with either drug alone that can be severe enough to alter the clinical outcome.
Every time a drug is administered with any other prescription medicine, OTC products, herbs or even food we expose ourselves to the risk of a potentially dangerous interaction.
EFFECT OF PHYSICOCHEMICAL NATURE OF DRUG ON DISSOLUTIONN Anusha
pH - PARTITION THEORY, LIPID SOLUBILITY OF DRUGS, DRUG DISSOLUTION AND PH, SALTS, CRYSTAL FORM, DRUG STABILITY AND HYDROLYSIS IN GIT, COMPLEXATION, ADSORPTION
PHYSIOLOGIC FACTORS RELATED TO DRUG ABSORPTIONN Anusha
ROUTES OF DRUG ADMINISTRATION
The route of administration (ROA) that is chosen has a large impact on how fast the drug is taken up and how much of it arrives at its destination in an active form.
MEMBRANE PHYSIOLOGY
The cell membrane also known as the plasma membrane or cytoplasmic membrane is a biological membrane that separates the interior of all cells from the outside environment.
GSTERO-INTESTINAL PHYSIOLOGY
AGE
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease causing microorganism and is often made from weakened or killed forms of the microbe, its toxins or one of its surface proteins. The agent stimulates the body's immune system to recognize foreign agents, destroy it, and keep a record of it, so that the immune system can more easily recognize and destroy any of these microorganisms that it later encounters.
TRANSDERMAL THERAPEUTIC DRUG DELIVERY SYSTEMS N Anusha
Transdermal drug delivery systems (TDDS) can be defined as self-contained discrete dosage forms which, when applied to the intact skin, delivers the drug(s) through the skin at a controlled rate to the systemic circulation.
For transdermal drug delivery, it is considered ideal if the drug penetrates through the skin to the underlying blood supply without drug buildup in the dermal layers.
They provide extended therapy with a single application, thereby improving patient compliance over other dosage forms requiring more frequent dose administration.
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein produced mainly by plasma cells that is used by the immune system to neutralize pathogens such as pathogenic bacteria and viruses.
Monoclonal antibodies are important reagents used in biomedical research, in diagnosis of diseases, and in treatment of such diseases as infections and cancer.
These antibodies are produced by cell lines or clones obtained from animals that have been immunized with the substance that is the subject of study.
IMPURITY PROFILING (SOURCES OF IMPURITIES)N Anusha
The description, characterization and quantitation of identified and unidentified impurities present in the drug substances is known as impurity profile.
IMPURITIES in pharmaceuticals are unwanted chemicals, that even in small amounts may influence the efficacy and safety of the pharmaceutical products.
2 Aspects of compatibility tests are:
Identification of compatible excipients for a formulation.
Identification of stable storage conditions
2 Types:
Solid state reactions: much slower and difficult to interpret.
Liquid state reactions: easier to detect
According to Stability Guidelines by FDA following conditions should be evaluated for solutions or suspensions
1. Acidic or alkaline pH.
2. Presence of added substances
3. High oxygen and nitrogen atmospheres.
4. Effect of stress testing conditions.
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.
Asthma is a chronic inflammatory disorder of the airways that is characterized by increased responsiveness of the tracheobranchial tree to a variety of stimuli resulting in widespread spasmodic narrowing of the air passages which may be relieved spontaneously or by therapy.
Cough is a protective reflex, its purpose being expulsion of respiratory secretions or foreign particles from air passages.
It occurs due to stimulation of mechano or chemoreceptors in throat,
respiratory passages or stretch receptors in the lungs.
Act peripherally in the respiratory tract to reduce tussal impulses.
They aim to control rather than eliminate cough.
Many H-1 anti histamines have been conventionally added to antitussive /expectorant formulations.
Antihistamines afford relief in cough due to their sedative and Anticholinergic actions but lack selectivity for cough centre.
Analeptics stimulate respiration and can have resuscitative value in
Coma or fainting.
They stimulate respiration in sub convulsive doses,
but margin of safety is narrow.
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New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
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
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
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.
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
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
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
2. CONTENTS
FORMULATION FACTORS AFFECTING ORALABSORPTION
1. DISINTEGRATION TIME
2. MANUFACTURING VARIABLES
A. METHOD OF GRANULATION
B. COMPRESSION FORCE
3. NATURE & TYPE OF DOSAGE FORM
A. SOLUTIONS
B. SUSPENSIONS
C. CAPSULES
D. TABLETS
E. IN VITRO CORRELATION OF DRUG ABSORPTION
4. PHARMACEUTICAL INGREDIENTS
5. PRODUCT AGE & STORAGE CONDITIONS
ANUSHA NADIKATLA
3. INTRODUCTION
Bioavailability means the rate and extent to which the active
ingredient is absorbed from a drug product and becomes available at
the site of action.
When the drug is given orally, only part of the administered dose
appears in the plasma.
By plotting plasma concentrations of the drug versus time, one can
measure the area under the curve (AUC).
This curve reflects the extent of absorption of the drug.
ANUSHA NADIKATLA
4. Bioavailability of a drug administered orally is the ratio of the area
calculated for oral administration compared with the area calculated
for IV injection.
The bioavailability of a drug can be influenced by factors associated
with the formulation and production of the dosage form.
For a given drug, a 2 to 5 fold difference could be observed in the oral
bioavailability of a drug depending upon the nature and type of the
dosage form.
This difference is due to the relative rate at which a particular dosage
form releases the drug to the biological fluids because a number of
possible intervening steps occur between administration and
appearance of dissolved drug in the systemic circulation.
ANUSHA NADIKATLA
5. COURSE OF EVENTS THAT OCCUR
FOLLOWING ORALADMINISTRATION OF
VARIOUS DOSAGE FORMS
ANUSHA NADIKATLA
6. FORMULATION FACTORS AFFECTING ORAL
ABSORPTION
1. DISINTEGRATION TIME
2. MANUFACTURING VARIABLES
A. Method of granulation
B. Compression force
3. NATURE & TYPE OF DOSAGE FORM
4. PHARMACEUTICAL INGREDIENTS
5. PRODUCT AGE & STORAGE CONDITIONS
ANUSHA NADIKATLA
7. DISINTEGRATION TIME
Rapid disintegration is important to have a rapid absorption, so lower
disintegration time is required.
Now disintegration time of tablet is directly proportional to amount of
binder & Compression force.
And one thing should be remembered that in vitro disintegration test
gives no means of a guarantee of drugs bioavailability because if
disintegrated drug particles do not dissolve then absorption is not
possible.
ANUSHA NADIKATLA
8. MANUFACTURING VARIABLES
a) Method of granulation
Wet granulation yields a tablet that dissolves faster than those made
by other granulating methods.
But wet granulation has several limitations like formation of crystal
bridge or chemical degradation.
Other superior recent method named APOC (agglomerative phase of
communition) that involves grinding of drug till spontaneous
agglomeration and granules are prepared with higher surface area.
So tablet made up of this granules have higher dissolution rate.
ANUSHA NADIKATLA
9. b) Compression force
Higher compression force yields a tablet with greater hardness and
reduced wettability and hence tablet will have long disintegration
time.
But on other hand higher compression force cause crushing of drug
particles into smaller ones with higher effective surface area which
causes decrease in disintegration time.
So effect of compression force should be thoroughly studied on each
formulation.
ANUSHA NADIKATLA
10. NATURE AND TYPE OF DOSAGE FORM
A. SOLUTIONS
B. SUSPENSIONS
C. CAPSULES
D. TABLETS
E. IN VITRO CORRELATION OF DRUG ABSORPTION
I. DISINTEGRATION TESTING
II. DISSOLUTION TESTING
ANUSHA NADIKATLA
11. The role of the drug formulation in the delivery of drug to the site of
action should not be ignored.
With any drug it is possible to alter its bioavailability considerably by
formulation modification.
With some drugs an even larger variation between a good formulation
and a bad formulation has been observed.
Since a drug must be in solution to be absorbed efficiently from the
GIT, you may expect the bioavailability of a drug to decrease in the
order solution > suspension > capsule > tablet > coated tablet.
This order may not always be followed but it is a useful guide.
One example is the results for pentobarbital. Here the order was found
to be aqueous solution > aqueous suspension = capsule > tablet of
free acid form.
ANUSHA NADIKATLA
12. SOLUTION DOSAGE FORMS
Drugs are commonly given as solution in cough/cold remedies and in
medication for the young and elderly.
In most cases absorption from an oral solution is rapid and complete,
compared with administration in any other oral dosage form.
The rate limiting step is often the rate of gastric emptying. Since
absorption will generally be more rapid in the intestine.
When an acidic drug is given in the form of a salt, it may precipitate
in the stomach.
However, this precipitate is usually finely divided and is readily
redissolved and thus causes no special absorption problems.
There is the possibility with a poorly water soluble drug such as
phenytoin that a well formulation suspension, of finely divided
powder, may have a better bioavailability.
ANUSHA NADIKATLA
13. Some drugs which are poorly soluble in water may be dissolved in
mixed water/alcohol or glycerol solvents.
This is particularly useful for compounds with tight crystal structure
and higher melting points that are not ionic.
The crystal structure is broken by solution in the mixed solvent.
An oily emulsion or soft gelatin capsules have been used for some
compounds with lower aqueous solubility to produce improved
bioavailability.
SOLID SOLUTIONS
The solid solution is a formulation in which drug is trapped as a solid
solution or monomolecular dispersion in a water-soluble matrix.
Although the solid solution is an attractive approach to increase drug
absorption, only one drug, griseofulvin, is currently marketed in this
form
ANUSHA NADIKATLA
14. FORMULATION FACTORS AFFECTING
BIOAVAILABILITY OF SOLUTIONS
In most cases absorption of drugs from solution dosage forms is rapid
and complete, where the drug will be available in soluble form ready for
direct absorption.
FACTORS:
The chemical stability exhibited by the drug in aqueous solution and
in the gastro-intestinal fluids.
Chemical nature of the drug.
Effect of viscosity of the solution.
Solubilization.
Complexation.
ANUSHA NADIKATLA
15. SUSPENSION DOSAGE FORMS
A well formulated suspension is second only to a solution in terms of
superior bioavailability.
Absorption may be dissolution limited, however a suspension of a
finely divided powder will maximize the potential for rapid
dissolution. A good correlation can be seen for particle size and
absorption rate.
With very fine particle sizes the dispersibility of the powder becomes
important. The addition of a surface active agent will improve
dispersion of a suspension and may improve the absorption of very
fine particle size suspensions otherwise caking may be a problem.
As a suspension ages there is potential for increased particle size with
an accompanying decrease in dissolution rate. Smaller particles have
higher solubility and will tend to disappear with the drug coming out
of solution on larger particles. ANUSHA NADIKATLA
16. FORMULATION FACTORS AFFECTING
BIOAVAILABILITY OF SUSPENSIONS
This dosage form is useful in administering an insoluble or poorly
water soluble drug.
The absorption of drug from this dosage form is dissolution rate
limited.
Suspensions provide a larger surface area to the drug particles thus
enhancing the dissolution rate and absorption.
FACTORS:
Particle size of suspension
Suspension stability
Viscosity of suspension
Addition of wetting agents
Complexation ANUSHA NADIKATLA
17. FORMULATION FACTORS AFFECTING
BIOAVAILABILITY OF EMULSIONS
These dosage forms are superior to suspensions in administering
poorly aqueous soluble lipophilic drugs.
Eg: Indoxole (NSAID) when it is dissolved in a vegetable oil and
emulsified in water, absorption increases 3-fold over its aqueous
suspension.
FACTORS:
Particle size of the drug.
Addition of emulsifying agents.
Solubility of drug in oily vehicle.
ANUSHA NADIKATLA
18. CAPSULE DOSAGE FORMS
In theory a capsule dosage form should be quite efficient.
The hard gelatin shell should disrupt rapidly and allow the contents to
be mixed with the GIT contents.
The capsule contents should not be subjected to high compression
forces which would tend to reduce the effective surface area, thus a
capsule should perform better than a tablet.
This is not always the case, if a drug is hydrophobic a dispersing agent
should be added to the capsule formulation.
These diluents will work to disperse the powder, minimize
aggregation and maximize the surface area of the powder.
Tightly packed capsules may have reduced dissolution and
bioavailability.
ANUSHA NADIKATLA
20. FORMULATION FACTORS AFFECTING
BIOAVAILABILITY OF HARD GELATIN CAPSULES
Generally the bioavailability of a drug from a hard gelatin capsules will
be better than or equal to that from the same drug in a compacted tablet
FACTORS:
Dissolution rate of gelatin shell.
The rate of penetration of GI fluids into encapsulated mass.
The rate at which the mass disaggregates in the GI fluid.
The rate of dissolution of dispersed drug particles.
Packing density of the capsule contents.
Inclusion of excipients in the capsule formulation.
Effect of excipients.
ANUSHA NADIKATLA
21. SOFT GELATIN CAPSULE
Soft gelatin capsule has a gelatin shell thicker than hard gelatin
capsules, but shell is plasticized by adding glycerin, sorbitol.
Soft gelatin capsules may be used to contain non aqueous solution or
liquid or semi solid.
Soft gelatin capsules have a better bioavailability than powder filled
hard gelatin capsules and are equivalent to emulsions.
Ex: Quinine derivative was better absorbed from soft gelatin capsules
containing drug base compared with hard gelatin capsules containing
HCl salts.
Grieseoflavin exhibited 88% absorption from soft gelatin capsules
compared to hard gelatin capsules (30%)
ANUSHA NADIKATLA
22. FORMULATION FACTORS AFFECTING
BIOAVAILABILITY OF SOFT GELATIN CAPSULES
Drugs encapsulated in liquid filled capsules are dissolved or dispersed in
non-toxic, non-aqueous vehicles.
Factors:
Solubility of drug in vehicle.
Dissolution and splitting of flexible shell.
Nature of the vehicle.
Inclusion of a surfactant as a wetting or emulsifying agent.
Particle size, density, crystal form of the drug, selection of diluents
etc., influence bioavailability of soft gelatin capsules.
ANUSHA NADIKATLA
23. For hydrophobic drugs with a fine particle size in capsule results in
decrease in porosity of the powdered drug and thus decreased
penetrability by the solvent which results clumping of particle.
Soft elastic capsule dissolve faster than hard gelatin capsule & tablets,
which shows better bioavailability from oily solutions, emulsions, or
suspensions.
The problem with SGC is high water content of shell, moisture
migrate in to the shell causes crystallization of the drug which results
in altered dissolution characteristics
ANUSHA NADIKATLA
24. TABLET DOSAGE FORMS
The tablet is the most commonly used oral dosage form. It is also quite
complex in nature. The biggest problem is overcoming the reduction in
effective surface area produced during the compression process. One
may start with the drug in a very fine powder, but then proceeds to
compress it into a single dosage unit.
INGREDIENTS
Tablet ingredients include materials to break up the tablet formulation.
Drug : may be poorly soluble, hydrophobic.
Lubricant : usually quite hydrophobic.
Granulating agent : tends to stick the ingredients together.
Filler: may interact with the drug, etc., should be water soluble.
Wetting agent : helps the penetration of water into the tablet.
Disintegration agent: helps to break the tablet apart.
ANUSHA NADIKATLA
25. SUSTAINED RELEASE TABLET
BENEFITS
For short half-life drugs, sustained release can mean less frequent
dosing and thus better compliance.
Reduce variations in plasma/blood levels for more consistent result.
PROBLEMS
More complicated formulation, may produce more erratic results.
A sustained release product may contain a larger dose, i.e. the dose for
two or three (or more) 'normal' dosing intervals.
A failure of the controlled release mechanism may result in release of
a large potentially toxic dose.
More expensive technology.
ANUSHA NADIKATLA
26. TYPES OF PRODUCTS
Erosion tablets
Waxy matrix: Matrix erodes or drug leaches from matrix.
Coated pellets: Different pellets (colors) have different release
properties.
Coated ion exchange
Osmotic pump: Insoluble coat with small hole. Osmotic pressure
pushes the drug out at a controlled rate.
ANUSHA NADIKATLA
27. Disintegration time is the time required for the tablet to break down
into particles which can pass through a sieve while agitated in a
specified fluid.
This Indicates the time to break down into small particles not
necessarily solution.
In the process of tablet manufacturing the drug is often formulated
into a granular state (that is small but not fine) particles.
This is done as the granule often has better flow properties than a fine
powder and there is less de-mixing leading to better uniformity. The
granules are then compressed to produce the tablet.
The disintegration test may lead to an end point of tablet to granule
only, although the granules may be larger than the sieve opening.
ANUSHA NADIKATLA
28. FORMULATION FACTORS AFFECTING
BIOAVAILABILITY OF TABLETS
REDUCTION IN EFFECTIVE SURFACE AREA
This is due to granulation and subsequent compression into tablet.
This factor is especially important for tablets containing drugs that
should disintegrate rapidly and completely in the gastro intestinal
fluids if rapid release, dissolution and absorption are required.
PHYSICOCHEMICAL PROPERTIES OF THE DRUG
Nature and quantity of excipient.
Size of the granules and their method of manufacture.
The compaction pressure and speed of compaction used in tableting.
Drug-excipient interactions.
ANUSHA NADIKATLA
29. COATED TABLETS
Coat is generally used to mask unpleasant taste, odor and to protect
the ingredients from decomposition during storage or to improve the
tablets appearance.
This coating acts as barrier between the solid drug and drug in
solution.
This barrier must break down quickly or it may hinder a drug's
bioavailability.
ANUSHA NADIKATLA
30. SUGAR & FILM COATINGS
Presence of water impermeable sealing coat can potentially retard
drug release from sugar coated tablets.
Ex: studies with quinine tablets coated with cellulose acetate pthalate
showed a decrease in both rate and extent of absorption with increase
in thickness of coating.
Sugar coating will take more time than film coating.
Care should be taken while selecting the coating material. Ex: methyl
cellulose which retards the dissolution.
ANUSHA NADIKATLA
31. ENTERIC COATED TABLETS
It is a special film coated design to restrict the gastric fluids & to
dissolve in small intestine.
It protects the drug from the degradation in the stomach. Ex:
erythromycin.
Minimizes the gastric distress caused by some drugs. Ex: aspirin.
These tablets must empty the stomach before the drug absorption can
begin.
The polymers with pKa values ranging from 4-7 have been found to
use.
Thickness of coating will affect the bioavailability in these
formulations.
ANUSHA NADIKATLA
32. IN VITRO CORRELATION OF DRUG ABSORPTION
DISINTEGRATION
It is provided to determine the compliance with the limit on
disintegration stated in the individual monograph.
Formulations tested are un coated, plain coated, enteric coated, buccal,
sublingual tablets and hard gelatin capsules.
For un-coated tablets and capsules the disintegration time is 30 mins,
whereas for coated tablets it is 2 hrs.
Disintegration can be aided by incorporating disintegrants in suitable
amount during formulation. ANUSHA NADIKATLA
33. DISSOLUTION
The time taken for the drug to dissolve from the dosage form is a
measure of drug dissolution. Numerous factors affect dissolution.
Thus the dissolution medium, agitation and temperature are carefully
controlled.
The dissolution mediums might be water, simulated gastric juice, or
0.1M HCl. The temperature is usually 37°C.
The apparatus and specifications may be found in the U.S.P.
ANUSHA NADIKATLA
34. The U.S.P. methods are official however there is a wide variety of
methods based on other apparatus.
These are used because they may be faster, cheaper, easier, sensitive
to a particular problem for a particular drug, or developed by a
particular investigator.
Dissolution tests are used as quality control to measure variability
between batches which maybe reflected by in vivo performance.
Thus the in vitro test may be a quick method of ensuring in vivo
performance.
Thus there has been considerable work aimed at defining the in
vitro/in vivo correlation. ANUSHA NADIKATLA
35. EFFECT OF PHARMACEUTICAL INGREDIENTS OR
EXCIPIENTS ON BIOAVAILABILITY OF DRUGS
More the number of excipients in dosage form, more complex it is &
greater the potential for absorption and bioavailability problems.
Excipients are added to ensure the acceptability, physiochemical
stability, bioavailability and functionability of the drug product.
Excipients are added to a formulation to provide certain functional
properties to the drug and dosage form.
ANUSHA NADIKATLA
36. Excipients are used to improve the compressibility of the active drug,
stabilize the drug against degradation, decrease gastric irritation,
control the rate of drug absorption from the absorption site, increase
drug bioavailability.
Excipients in the drug product may also affect the dissolution kinetics
of the drug, either by altering the medium in which the drug is
dissolving or by reacting with the drug itself.
Excipients may increase the retention time of the drug in the
gastrointestinal tract and therefore increase the total amount of drug
absorbed.
ANUSHA NADIKATLA
37. EXAMPLES
Changing an excipient from calcium sulfate to lactose and increasing
the proportion of magnesium silicate, increases the activity of oral
phenytoin.
Systemic availability of thiamine and riboflavin is reduced by the
presence of Fuller’s earth.
Absorption of tetracycline from capsules is reduced by calcium
phosphate due to complexation.
Tablet lubricants such as magnesium stearate may repel water and
reduce dissolution when used in large quantities.
Coatings particularly shellac, will crosslink upon aging and decrease
the dissolution rate.
ANUSHA NADIKATLA
38. Low concentrations of surfactants decrease the surface tension and
increase the rate of drug dissolution; whereas higher surfactant
concentrations tend to form micelle with the drug and decrease the
dissolution rate.
Some excipients such as sodium bicarbonate may change the pH of
the medium surrounding the active drug substance. Aspirin a weak
acid when formulated with sodium bicarbonate will form water
soluble salt in an alkaline medium, in which the drug rapidly
dissolves.
Most of these types of interactions were reported some time ago and
are unlikely to occur in the current environment of rigorous testing of
new dosage forms and formulations.
ANUSHA NADIKATLA
40. VEHICLES
Bioavailability of a drug from vehicles depends on its miscibility with
biological fluid.
Aqueous soluble vehicles are miscible with the body fluids and drugs
from them are rapidly absorbed. Ex: propylene glycol.
In case of water immiscible vehicles the rate of drug absorption
depends upon its partitioning from oil phase to aqueous body fluids.
Viscosity of the vehicles is another factor in the absorption of drugs.
ANUSHA NADIKATLA
41. DILUENTS
Hydrophilic diluents form a coat around hydrophobic drug particles
and thus promotes dissolution and absorption of poorly water soluble
hydrophobic drugs.
Change of diluent from one to another can cause bioavailability
problems.
Ex: In phenytoin formulation calcium phosphate was replaced by
lactose in which dissolution was so fast that phenytoin levels in
plasma rise to toxic levels, due to sudden increase in bioavailability.
ANUSHA NADIKATLA
42. BINDERS AND GRANULATING AGENTS
Hydrophilic binders impart hydrophilic properties to granule surface
and show better dissolution profile with poorly wettable drugs.
Eg: phenacetin, starch, gelatin, PVP.
Large amount of binders increase hardness and decrease disintegration
and dissolution of tablets.
Eg:PEG6000 was found to be a deleterious binder as it forms a poorly
soluble complex with the drug.
ANUSHA NADIKATLA
43. DISINTEGRANTS
Mostly hydrophilic in nature.
These are required to break up capsules, tablets and granules into
primary powder particles in order to increase the surface area of the
drug exposed to the biological fluids.
A decrease in the amount of disintegrant can significantly lower the
bioavailability.
ANUSHA NADIKATLA
44. LUBRICANTS
Both tablets and capsules require lubricants in their formulation to
reduce friction between the powder and metal surfaces during their
manufacture.
The commonly used lubricants are hydrophobic in nature, thus inhibit
penetration of water into tablet and affect their dissolution and
disintegration.
Some lubricants like sodium lauryl sulphate and carbowaxes promote
drug dissolution.
ANUSHA NADIKATLA
45. SUSPENDING AGENTS/VISCOSITYAGENTS
Stabilize the solid drug particles by reducing their rate of settling
through an increase in the viscosity of medium and thus affect drug
absorption.
Viscosity imparters act as a mechanical barrier to diffusion of drug
from its dosage form and retard GI transit of drug.
Macromolecular gum forms unabsorbable complex with drug e.g. Na
CMC.
ANUSHA NADIKATLA
46. COLORANTS
Even a low concentration of water soluble dye can have an inhibitory
effect on dissolution rate of several crystalline drugs.
The dye molecules get absorbed onto the crystal faces and inhibit the
drug dissolution.
For example: Brilliant blue retards dissolution of sulfathiazole.
ANUSHA NADIKATLA
47. SURFACTANTS
These may enhance or retard drug absorption either by interacting
with the drug or the membrane or both.
Surfactants have been considered as absorption enhancers, again
mostly in animals.
Polyoxyethylene ethers have been shown to enhance gastric or rectal
absorption of lincomycin,penicillin, cephalosporins, and fosfomycin
in rats and rabbits.
However, in humans, oral polyoxyethylene-20-oleyl ether resulted in
poor and variable insulin absorption.
ANUSHA NADIKATLA
48. They enhance absorption by promotion of wetting. Eg:polysorbate 80
with phenacetin.
Surfactants also have inhibitory action on drug absorption due to
unabsorbable drug-micelle complex above critical micelle
concentration.
In general, unionic surfactants have little effect on membrane structure
but cationic surfactants have been associated with reversible cell loss
and loss of goblet cells.
Physiologic surfactants – bile salts – promotes absorption – e.g.
Griseofulvin, steroids.
It may decrease absorption when it forms the unabsorbable complex
with drug above CMC.
ANUSHA NADIKATLA
49. BILE SALTS
Bile contains conjugates of cholic acid and chenodeoxycholic acid,
which emulsify dietary fat, facilitate lipolysis, and transport lipid
molecules through the unstirred layer of the intestinal mucosa by
micellar solubilization.
The ability of bile salts to promote lipid absorption has prompted their
investigation as absorption enhancers for drugs, with modest success.
Absorption of insulin can be increased by bile salts, both in
experimental animals and in humans.
ANUSHA NADIKATLA
50. COMPLEXING AGENTS
Complex formation has been used to alter the physicochemical and
biopharmaceutical properties of the drug.
Complexation has been used to enhance drug bioavailability.
Eg: Dissolution of Ergotamine increases through formation of soluble
Ergotamine tartarate-caffeine complex.
Complexation can be deleterious to absorption of some drugs due to
formation of poorly soluble complex.
Eg:Complexation of tetracycline with divalent and trivalent cations
like calcium and iron etc..
ANUSHA NADIKATLA
52. PRODUCT AGE AND STORAGE CONDITIONS
A number of changes, especially in the physiochemical properties of a
drug in a dosage from, can result due to aging and alteration in storage
conditions which can adversely affect bioavailability.
Ex: precipitation of drug in solution, particle size of suspension and
hardening of tablet leads to decrease rate of change in drug dissolution
& absorption.
ANUSHA NADIKATLA
53. REFERENCES
1. Brahmankar D.M., Jaiswal S.B., First edition, “Absorption of
Drugs” Biopharmaceutics and Pharmacokinetics – A treatise,
Vallabh Prakashan, Delhi 1995, Page No. 5-75.
2. Shargel L., Andrew B.C., Fourth edition “Physiologic factors
related to drug absorption” Applied Biopharmaceutics and
Pharmacokinetics, Prentice Hall International, INC., Stanford
1999. Page No. 99-128.
3. Pharmaceutics , the Science of Dosage form Design By M.E.
Aulton.
4. Swarbrick J., Boylan J.C., “Absorption” Encyclopedia of
Pharmaceutical Technology, Marcel Dekker, INC., New York
1988:1:1-32.
ANUSHA NADIKATLA