1) The study established a Level A in vitro-in vivo correlation (IVIVC) for immediate release acyclovir tablets using the Wagner-Nelson method.
2) In vitro dissolution testing found 96% of the drug dissolved within 45 minutes for both the test and reference formulations.
3) In vivo absorption studies in 36 subjects found about 90% absorption of the drug within 1 hour for both formulations.
4) A time scaling factor of 6.66 was used to correlate the in vitro and in vivo data. The IVIVC model showed good predictability with %PE for AUC and Cmax within acceptable limits.
Dissolution : Official and Non official methods, Alternative methods of dissolution testing and transport models, Drug release testing, Invitro drug release testing
Dissolution : Official and Non official methods, Alternative methods of dissolution testing and transport models, Drug release testing, Invitro drug release testing
Regulatory requirements for drug approval - industrial pharmacy IIJafarali Masi
Regulatory requirements for drug approval - industrial pharmacy IIDrug Development Teams, Non-Clinical Drug Development, Pharmacology, Drug Metabolism and Toxicology, General considerations of Investigational New Drug (IND) Application, Investigator’s Brochure (IB) and New Drug Application (NDA), Clinical research / BE studies, Clinical Research Protocols, Biostatistics in Pharmaceutical Product Development, Data Presentation for FDA Submissions, Management of Clinical Studies.
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)”.
Introduction
Brief description of the drug and the therapeutic class to which it belongs
Chemical and pharmaceutical information
Animal Pharmacolog
Animal Toxicology
Human/Clinical Pharmacology phase I
Therapeutic exploratory trials (Phase II)
Therapeutic confirmatory trials (Phase III)
Special Studies Geriatrics, pediatrics, pregnant or nursing women
Regulatory status in other countries
Prescribing information
Samples and Testing Protocol/s
DRUG MASTER FILE
Presented by :
RUSHIKESH D MENDHE
Roll no - 511
Mpharm Ist Year
(Department of Pharmaceutics)
Content : :
INTRODUCTION
TYPES OF DMF
DMF FORMAT & ASSEMBLY
DELIVERY OF DMF TO FDA
SUBMISSION OF DMF
THE MECHANISM OF A DRUG MASTER FILE
CTD & ELECTRONIC DMFS
UPDATES TO DMF
CLOSURE OF A DRUG MASTER FILE
APPLICATION OF DMF
REFERENCE
INTRODUCTION :
A Drug Master File (DMF) is a submission to the Food and Drug Administration (FDA) that may be used to provide confidential detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs.
This guideline does not impose mandatory requirements.
Objectives :
Main Objective of the DMF is to support regulatory requirements
To prove the quality, safety and efficacy of the medicinal product
TYPES OF DMF :
DMF FORMAT & ASSEMBLY :
The DMF is submitted as Original and Duplicate jackets, collated, assembled, paginated, and jacketed, using covers obtained from the government printing office and a respecifically provided for the DMFs
Multiple volumes are numbered, and the paper must be standard paper size
Paper length should not be less than 10 inches nor more than 12 inches.
Each volume of a DMF should be not more than 2 inches thick
DELIVERY OF DMF TO FDA :
DMF should be submitted at following address :
Food and Drug Administration Center for Drug Evaluation and Research Central Document Room 5901 – B Ammendale Road Beltsville, MARYLAND 20705-1266 USA
SUBMISSION OF DMF :
The DMF must be submitted in two copies, one with a blue cover and one with a red cover.
Each page of each copy of the DMF should be dated and consecutively numbered.
Each DMF submission should contain :
• A Transmittal letter
• Administrative information about the submission
• Other specific information
A. Transmittal Letter :
i) Original Submissions :
• Identification of submission: Original, the type of DMF as classified in Section III, and its subject.
• Identification of the applications, if known, that the DMF is intended to support, including the name and address of each sponsor, applicant, or holder, and all relevant document numbers.
• Signature of the holder or the authorized representative.
• Typewritten name and title of the signer.
ii) Ammendments :
• Identification of submission: Amendment, the DMF number, type of DMF, and the subject of the amendment.
• A description of the purpose of submission, e.g., update, revised formula, or revised process.
• Signature of the holder or the authorized representative.
• Typewritten name and title of the signer.
B. Administrative information about the submission:
Protein and peptide drug delivery system (PPDDS)Sagar Savale
Protein and Peptide drug delivery system are the Novel drug Delivery
System. Proteins and peptides are the most abundant components of
biological cells. They exist functioning such as enzymes, hormones, structural element and immunoglobulin.
In this presentation I have mentioned whatever the possible relevant content/guidelines require for biowaiver application.
Citation Is done at the end of slide.
Content is up to date & true to my belief.
Thanks & Best Regards.
Anurag Pandey
B.Pharm (FACULTY OF PHARMACY, INVERTIS UNIVERSITY)
M.Pharm (INSTITUTE OF PHARMACY, NIRMA UNIVERSITY)
Email :- anurag.dmk05@gmail.com
Approval and Application Process involved in Investigational New Drug (IND)Nipun Gupta
1. Introduction
During a new drug's early preclinical development, the sponsor's primary goal is to determine if the product is reasonably safe for initial use in humans, and if the compound exhibits pharmacological activity that justifies commercial development. When a product is identified as a viable candidate for further development, the sponsor then focuses on collecting the data and information necessary to establish that the product will not expose humans to unreasonable risks when used in limited, early-stage clinical studies.
2. Drug development team
3. Investigational new drug application (INDA)
4. Format and content of IND
5. Preclinical testing
6. The development process IND
application and safety
7. Clinical research
8. New drug application
9. Abbreviated new drug application
10. Changes to an approved NDA or ANDA
11. Difference between NDA and ANDA
DATION OF EQUIPMENT ICH AND WHO GUIDELINES FOR CALIBRATION AND VALIDATION OF ...deepalisanap31
Introduction to equipment
Calibration
ICH guidelines for calibration of equipment
WHO guidelines for calibration of equipment
Example for calibration of UV
Validation
ICH guidelines for validation of equipment
WHO guidelines for validation of equipment
Example for validation of tablet compression machine
Regulatory requirements for drug approval - industrial pharmacy IIJafarali Masi
Regulatory requirements for drug approval - industrial pharmacy IIDrug Development Teams, Non-Clinical Drug Development, Pharmacology, Drug Metabolism and Toxicology, General considerations of Investigational New Drug (IND) Application, Investigator’s Brochure (IB) and New Drug Application (NDA), Clinical research / BE studies, Clinical Research Protocols, Biostatistics in Pharmaceutical Product Development, Data Presentation for FDA Submissions, Management of Clinical Studies.
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)”.
Introduction
Brief description of the drug and the therapeutic class to which it belongs
Chemical and pharmaceutical information
Animal Pharmacolog
Animal Toxicology
Human/Clinical Pharmacology phase I
Therapeutic exploratory trials (Phase II)
Therapeutic confirmatory trials (Phase III)
Special Studies Geriatrics, pediatrics, pregnant or nursing women
Regulatory status in other countries
Prescribing information
Samples and Testing Protocol/s
DRUG MASTER FILE
Presented by :
RUSHIKESH D MENDHE
Roll no - 511
Mpharm Ist Year
(Department of Pharmaceutics)
Content : :
INTRODUCTION
TYPES OF DMF
DMF FORMAT & ASSEMBLY
DELIVERY OF DMF TO FDA
SUBMISSION OF DMF
THE MECHANISM OF A DRUG MASTER FILE
CTD & ELECTRONIC DMFS
UPDATES TO DMF
CLOSURE OF A DRUG MASTER FILE
APPLICATION OF DMF
REFERENCE
INTRODUCTION :
A Drug Master File (DMF) is a submission to the Food and Drug Administration (FDA) that may be used to provide confidential detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs.
This guideline does not impose mandatory requirements.
Objectives :
Main Objective of the DMF is to support regulatory requirements
To prove the quality, safety and efficacy of the medicinal product
TYPES OF DMF :
DMF FORMAT & ASSEMBLY :
The DMF is submitted as Original and Duplicate jackets, collated, assembled, paginated, and jacketed, using covers obtained from the government printing office and a respecifically provided for the DMFs
Multiple volumes are numbered, and the paper must be standard paper size
Paper length should not be less than 10 inches nor more than 12 inches.
Each volume of a DMF should be not more than 2 inches thick
DELIVERY OF DMF TO FDA :
DMF should be submitted at following address :
Food and Drug Administration Center for Drug Evaluation and Research Central Document Room 5901 – B Ammendale Road Beltsville, MARYLAND 20705-1266 USA
SUBMISSION OF DMF :
The DMF must be submitted in two copies, one with a blue cover and one with a red cover.
Each page of each copy of the DMF should be dated and consecutively numbered.
Each DMF submission should contain :
• A Transmittal letter
• Administrative information about the submission
• Other specific information
A. Transmittal Letter :
i) Original Submissions :
• Identification of submission: Original, the type of DMF as classified in Section III, and its subject.
• Identification of the applications, if known, that the DMF is intended to support, including the name and address of each sponsor, applicant, or holder, and all relevant document numbers.
• Signature of the holder or the authorized representative.
• Typewritten name and title of the signer.
ii) Ammendments :
• Identification of submission: Amendment, the DMF number, type of DMF, and the subject of the amendment.
• A description of the purpose of submission, e.g., update, revised formula, or revised process.
• Signature of the holder or the authorized representative.
• Typewritten name and title of the signer.
B. Administrative information about the submission:
Protein and peptide drug delivery system (PPDDS)Sagar Savale
Protein and Peptide drug delivery system are the Novel drug Delivery
System. Proteins and peptides are the most abundant components of
biological cells. They exist functioning such as enzymes, hormones, structural element and immunoglobulin.
In this presentation I have mentioned whatever the possible relevant content/guidelines require for biowaiver application.
Citation Is done at the end of slide.
Content is up to date & true to my belief.
Thanks & Best Regards.
Anurag Pandey
B.Pharm (FACULTY OF PHARMACY, INVERTIS UNIVERSITY)
M.Pharm (INSTITUTE OF PHARMACY, NIRMA UNIVERSITY)
Email :- anurag.dmk05@gmail.com
Approval and Application Process involved in Investigational New Drug (IND)Nipun Gupta
1. Introduction
During a new drug's early preclinical development, the sponsor's primary goal is to determine if the product is reasonably safe for initial use in humans, and if the compound exhibits pharmacological activity that justifies commercial development. When a product is identified as a viable candidate for further development, the sponsor then focuses on collecting the data and information necessary to establish that the product will not expose humans to unreasonable risks when used in limited, early-stage clinical studies.
2. Drug development team
3. Investigational new drug application (INDA)
4. Format and content of IND
5. Preclinical testing
6. The development process IND
application and safety
7. Clinical research
8. New drug application
9. Abbreviated new drug application
10. Changes to an approved NDA or ANDA
11. Difference between NDA and ANDA
DATION OF EQUIPMENT ICH AND WHO GUIDELINES FOR CALIBRATION AND VALIDATION OF ...deepalisanap31
Introduction to equipment
Calibration
ICH guidelines for calibration of equipment
WHO guidelines for calibration of equipment
Example for calibration of UV
Validation
ICH guidelines for validation of equipment
WHO guidelines for validation of equipment
Example for validation of tablet compression machine
Bioequivalence Study of the Two Products of Efavirenz by Validated Analytical...BRNSS Publication Hub
The aim of this study was to find whether the bioavailability of a 600 mg efavirenz capsule (E.F.600 capsule, test) produced by Macneil and Argus Pharmaceutical Ltd. was equivalent to the tablet EFAVIR produced by the Cipla Ltd. (reference preparation). The pharmacokinetic parameters assessed in this study were area under the plasma –concentration time curve 0–96 h (AUCt), area under the plasma concentration time curve from time 0 to ∞ (AUCinf), the peak plasma concentration of drug (Cmax), time needed to achieve the peak plasma concentration (tmax), and the elimination half-life (t½). This was a randomized, single-blind, two-period, crossover study which included 20 healthy adult male and female subjects under fasting conditions. In each of the two study periods (separated by a washout of 1 week), single dose of test or reference drug was administered. Blood samples were taken up to 96 h past dose, the plasma was separated, and the concentrations of efavirenz were determined by high-performance liquid chromatography -UV method. Bioavailability and bioequivalence studies play a key role during the phase of drug development for both innovator drugs and generic drugs and thus have gained a great attention over the past few decades. Bioequivalence study is used to introduce generic drugs of innovator drugs at a lower cost. Hence, a thorough understanding of these bioavailability/bioequivalence studies is required.
International Journal of Pharmaceutical Science Invention (IJPSI) is an international journal intended for professionals and researchers in all fields of Pahrmaceutical Science. IJPSI publishes research articles and reviews within the whole field Pharmacy and Pharmaceutical Science, new teaching methods, assessment, validation and the impact of new technologies and it will continue to provide information on the latest trends and developments in this ever-expanding subject. The publications of papers are selected through double peer reviewed to ensure originality, relevance, and readability. The articles published in our journal can be accessed online.
Root cause Analysis (RCA) & Corrective and Preventive action (CAPA) in MRCT d...Bhaswat Chakraborty
This presentation describes Identification & differentiation of Protocol deviation & violation; Different methods of RCA & best suitable method for Multiregional Clinical Trial; CAPA management and CAPA application to other trial sites/CRO/SMO/ Country that is involved in same trial (Strategic Management and application of CAPA in MRCT)
This presentation gives effective solutions to outliers issue in bioequivalence trials. It described what would be acceptable to Regulatory agencies as well as some new approaches.
Equivalence approches for complex generics DIA 11 april 2019 Bhaswat Chakraborty
This is a workshop that i gave a few days ago on bioequivalence of complex generics like peptides, polymers, liposomes, colloids, ophthamic and topical produtcts.
Clinical trials that are needed for efficacy & safety evidence of Medical devices include feasibility (pilot) and Pivotal trials. An extended battery of preclinical trials are also needed for high risk devices.
Writing Science papers for for publication requires something more thatn creativity. Target journals, content organization, wrting style, elegance and referencing are equally important.
Multidisc review of NDAs and BLAs nipicon 2018 Dr. ChakrabortyBhaswat Chakraborty
NDAS and BLAs cannot be authoritatively reviewed these days until experts from different disciplines act together like a team. This presentation give some foundational points and an illustrative example in that regard.
Teaching by stories, anecdotes and historical facts sept 25 2018Bhaswat Chakraborty
Many difficult principles in science and humanities can be taught best by a story (of its discovery), by an anecdote or some historical facts about them.
Orientation and Adaptation for Post-Graduate Pharmacy ProgramsBhaswat Chakraborty
PG Pharmacy programs are more focused and professionally oriented than the undergraduate counterpart. Many soft skills are required along with the curricular competence for excellence at the PG level.
Scientific integrity calls for some basic originality. Plagiarism can destroy this original creativity and ideation. This presentation defines plagiarism (stealing from others' works) and some of the creative and systematic remedies.
Best Practices to Risk Based Data Integrity at Data Integrity Conference, Lon...Bhaswat Chakraborty
Data integrity can be implemented using several approaches. One of the most effective ways to implement DI is a risk based approach. The speaker elaborates this.
There are several dimensions in Pharmaceutical ethics -- Practice-, research- and community oriented. This presentation mainly deals with Clinical research oriented Ethics.
Young pharmaceutical scientists are and can get involved in all aspects of new drug discovery and development. They have to be appropriately qualified, trained and experienced though,
This presentation mainly deals with clinical development of biosimilar products. It also gives enough on non-clinical development so that the audience is well oriented.
High variability in PK can be a characteristic of certain drug products which require different from ordinary strategies and study designs for establishing bioequivalence.
High variability in PK can be a characteristic of certain drug products which require different from ordinary strategies and study designs for establishing bioequivalence.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Anti ulcer drugs and their Advance pharmacology ||
Anti-ulcer drugs are medications used to prevent and treat ulcers in the stomach and upper part of the small intestine (duodenal ulcers). These ulcers are often caused by an imbalance between stomach acid and the mucosal lining, which protects the stomach lining.
||Scope: Overview of various classes of anti-ulcer drugs, their mechanisms of action, indications, side effects, and clinical considerations.
- 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
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
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.
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.
Factory Supply Best Quality Pmk Oil CAS 28578–16–7 PMK Powder in Stockrebeccabio
Factory Supply Best Quality Pmk Oil CAS 28578–16–7 PMK Powder in Stock
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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.
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
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.
1. Sakore, et al. Int J Pharm 2012; 2(3): 598-604 ISSN 2249-1848
www.pharmascholars.com 598
Research Article CODEN: IJPNL6
IN-VITRO AND IN-VIVO CORRELATION OF IMMEDIATE RELEASE ACYCLOVIR TABLET USING
WAGNER NELSON METHOD
Somnath Sakore* and Bhaswat Chakraborthy
Cadila Pharmaceuticals Ltd. Dholka, Ahmedabad, Gujrat. India
*Corresponding author e-mail: somnath.sakore@cadilapharma.co.in
ABSTRACT
The purpose of this study was to establish In-Vitro and In-Vivo correlation of immediate release Acyclovir tablets of
800 mg. In vitro and in vivo studies are done on the test product as Acyclovir Tablet USP 800 mg (containing
Acyclovir 800 mg) of Cadila Pharmaceuticals Ltd., India versus Zovirax®
Tablet 800 mg (containing Acyclovir 800
mg) of GlaxoSmithKline, USA. In vivo studies are done in 36 healthy, adult, human subjects under fasting
condition.In vitro dissolution study was done using USP apparatus II at 50 rpm in 0.1N HCL for 45 minutes. The in
vitro–in vivo correlation of Acyclovir shows R-squared value 0.9794 in excel work sheet, which depicts a successful
correlation between in vitro and in vivo Characteristic of the drug. In addition, %PE AUC and %PE Cmax was found to
be –4.604 and -11.19 respectively for each formulation. The present study shows a good correlation between in vivo
and in vitro PK profiles of the formulation used as the test drug in the study.
Keywords: Acyclovir 800 mg tablets, In Vitro Dissolution, In Vivo absorption, IVIVC.
INTRODUCTION
In vitro in vivo correlations play a key role in the
drug development and optimization of formulation is
an integral part of manufacturing and marketing
which is certainly a time consuming and expensive
process. In vitro-in vivo correlation (IVIVC)
demonstrates the direct relationships between in
vitro dissolution / release and in vivo absorption
profiles. The in vitro property generally is the rate or
amount of drug dissolution or release, while in vivo
response is plasma drug concentration or amount of
drug absorbed. [1]
The in vitro release data of a dosage form containing
the active substance serve as characteristic in vitro
property, while the in vivo performance is generally
represented by the time course of the plasma
concentration of the active substance. These In vitro
& In vivo data are then treated scientifically to
determine correlations. For oral dosage forms, the in
vitro release is usually measured and considered as
dissolution rate. The relationship between the in vitro
and in vivo characteristics can be expressed
mathematically by a linear or nonlinear correlation.
However, the plasma concentration cannot be directly
correlated to the in vitro release rate; it has to be
converted to the in vivo release or absorption data,
either by pharmacokinetic compartment model
analysis or by linear system analysis. Different
IVIVC model are used as a tool for formulation
development and evaluation of immediate and
extended release dosage forms for setting a
dissolution specification and as a surrogate for
bioequivalence testing. Practically, the purpose of
IVIVC is to use drug dissolution results from two or
more products to predict similarity or dissimilarity of
expected plasma drug concentration (profiles).
Before one considers relating in vitro results to in
vivo, one has to establish as to how one will establish
similarity or dissimilarity of in vivo response i.e.
plasma drug concentration profiles.
As a result, considerable effort goes into their
development and the main outcome is “the ability to
predict, accurately and precisely, expected
bioavailability characteristics for an extended release
(ER) drug product from dissolution profile
characteristics. [2,3]
The methodology of establishing
similarity or dissimilarity of plasma drug
concentrations profile is known as bioequivalence
testing. There are very well established guidances
International Journal of Pharmacy
Journal Homepage: http://www.pharmascholars.com
2. Sakore, et al. Int J Pharm 2012; 2(3): 598-604 ISSN 2249-1848
www.pharmascholars.com 599
and standards available for establishing
bioequivalence between drug profiles and products [4,
5]
. There are four levels of IVIVC that have been
described in the FDA guidance, which include levels
A, B, C, and multiple C [6,7]
.
The concept of correlation level is based upon the
ability of the correlation to reflect the complete
plasma drug level-time profile which will result from
administration of the given dosage form. An IVIVC
Level A correlates the entire in vitro and in vivo
profiles has regulatory relevance. This level of
correlation is the highest category of correlation and
represents a point-to-point relationship between in
vitro dissolution rate and in vivo input rate of the
drug from the dosage form [8]
.
The objective of IVIVC evaluation is to estimate the
magnitude of the error in predicting the in vivo
bioavailability results from in vitro dissolution data.
This objective should guide the choice and
interpretation of evaluation methods. Any appropriate
approach related to this objective may be used for
evaluation of predictabilityPrediction errors are
estimated for Cmax and AUC to determine the validity
of the correlation. Various approaches of are used to
estimate the magnitude of the error in predicting the
in vivo bioavailability results from in vitro
dissolution data [8,9]
.
It can be calculated by Prediction error that is the
error in prediction of in vivo property from in vitro
property of drug product. Depending on the intended
application of an IVIVC and the therapeutic index of
the drug, evaluation of prediction error internally
and/or externally may be appropriate. [5]
Acyclovir is a synthetic purine nucleoside analogue
with in vitro and in vivo inhibitory activity against
herpes simplex virus types 1 (HSV-1), 2 (HSV-2),
and varicella-zoster virus (VZV). The inhibitory
activity of Acyclovir is highly selective due to its
affinity for the enzyme thymidine kinase (TK)
encoded by HSV and VZV. This viral enzyme
converts Acyclovir into Acyclovir monophosphate, a
nucleotide analogue. The monophosphate is further
converted into diphosphate by cellular guanylate
kinase and into triphosphate by a number of cellular
enzymes. In vitro, Acyclovir triphosphate stops
replication of herpes viral DNA. The greater antiviral
activity of Acyclovir against HSV compared to VZV
is due to its more efficient phosphorylation by the
viral TK [10]
. Acyclovir pharmacokinetics has been
extensively investigated during the various phases of
clinical development. Most of the administered drug
is eliminated from the body unchanged, via the
kidneys by glomerular filtration and tubular
secretion. After intravenous dosing of patients with
normal renal function, 8 to 14% of the dose is
recovered in the urine as the metabolite 9-
carboxymethoxymethylguanine.
After oral administration, the bioavailability of
Acyclovir was approximately 20%. The plasma
elimination half life of acyclovir is 2.5 to 3.3 hr and
protein binding is 9%-33% [11]
.
MATERIAL AND METHODS
Materials: All materials used for analysis were of
analytical grade. The test product for In Vivo study
used Acyclovir Tablet USP 800 mg of Cadila
Pharmaceuticals Ltd., India reference product used
was Zovirax®
Tablet 800 mg of GlaxoSmithKline.
In vitro Evaluation:The dissolution of Acyclovir
tablets was carried out using USP Type II Dissolution
apparatus for 45 minutes. The dissolution media used
was 900 ml 0.1 N HCL at 37ºC ± 0.5ºC and rotated
at a speed of 50 rpm. Analysis of the withdrawn
samples was carried out using UV spectrophotometer
at the maximum 254 nm against 0.1 N Hydrochloric
acid as a blank.
Dissolution procedure: Parameters of the instrument
were set as mentioned above and the medium was
degas prior to use. 900 ml of Dissolution media was
transferred into each of the six dissolution vessels
and apparatus was operated as per requirement. One
tablet was dropped into each of six different vessels
& dissolution apparatus was started immediately.
After 45 min solution was withdrawn, & fiiltered the
solution through whatmann filter paper No.1; discard
first 2-3 ml of the filtrate. One mL of the filtered
sample was diluted to 100 ml with dissolution
medium and mixed. (Use this solution as sample
preparation)
Procedure for analysis: Absorbance was measured
for the standard preparation and sample preparation
on a suitable spectrophotometer at the maximum
254nm against 0.1 N Hydrochloric acid as a blank.
Percentage of Acyclovir dissolved in 45 minutes in
individual tablets was calculated.
In vivo Absorption study: A randomized, open label,
two-treatment, two-period, two-sequence, two-way
crossover comparative bioavailability study of a
single oral dose of Acyclovir Tablet USP 800 mg
(containing Acyclovir 800 mg) of Cadila
Pharmaceuticals Ltd., India versus Zovirax®
Tablet
800 mg (containing Acyclovir 800 mg) of
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GlaxoSmithKline, USA in 36) healthy, adult, human
subjects under fasting condition.
Screen Procedure: During screening procedure
Demography data, standard physical examination
with Vital signs, Clinical laboratory tests on blood
and urine samples, Electrocardiogram (ECG) and
Chest X-ray were done.
Study Design; A randomized, open-label, two-
treatment, two-period, two-sequence, two-way
crossover, comparative bioavailability study, during
which subjects were administered a single dose of
test or reference product under fasting condition with
at least 7 days washout period between each
administration.
Sample Size: Minimum of 36 + (04 standby) healthy,
adult, subjects was enrolled to allow dosing in both
periods.
Administration: Single a single oral dose of test
(Acyclovir Tablet USP 800 mg) or reference product
( Zovirax®
Tablet 800 mg) products were
administered along with 240 mL of drinking water
after an overnight fasting of at least 10 hours in each
Period.
Bio-analysis of Plasma sample: Samples were
analyzed for the quantification of Acyclovir in
plasma using Liquid Chromatography with Mass
Spectrometry (LCMS) procedures. Data analysis was
carried out using Win-Nonlin software to get the
Cmax, AUC 0-t, AUC 0- and kel.
Statistical Analysis: Statistical analysis was
performed on the pharmacokinetic parameters data
obtain from subjects (Completing both the periods)
using the SAS Statistical Software version 9.1.3
(SAS Institute INDIA Pvt. Ltd).
RESULTS AND DISCUSSION
In Vitro dissolution: The mean percent dissolved is
calculated on the basis of time and it showed that
within the first 15 min, 91.0% of Acyclovir drug and
within the first 20 min, 89 % of Zovirax had
dissolved. It was observed that 96.0 % of acyclovir
and Zovirax dissolved within 45 min.
Percent dissolved versus in vitro dissolution time (in
min) when plotted generates a dissolution profile
curve as shown below in table 1. The amount of drug
dissolved over a period of time for test & reference
formulation is given in the figure 1.
In vivo absorption: The fraction of drug absorbed
was calculated by Wagner Nelson method using
following equation.
0
T
0
A
TA
CdtK
CdtKCT
)X(
)X(
Above equation relates the cumulative amount of
drug absorbed after a certain time to the amount of
drug absorbed. The fraction of drug absorbed
calculated using Wagner Nelson method for test &
reference formulation is summarized in the Table 2.
The following figure 2 and figure 3 summarizes the
fraction of drug absorbed of the Acyclovir molecule
Test and reference respectively at given blood
sampling time points for test drug. It shows that at 1
hr almost 90% of the drug was absorbed for both test
& reference formulation.
Determination of intensity factor : Since the in
vitro dissolution data was available only for one hour
and hence a time scaling factor (i.e., intensity factor)
was calculated using Ratio of time of 90 % absorbed
and 90 % dissolved & Ratio of time of 50 %
absorbed and 50 % dissolved.
In vivo observed data: With the help of time
scaling factor the in vitro data was compared with In
vivo data. Table 3 summarizes fraction of drug
absorbed & percent drug absorbed vs. time data of
Zovirax 800 mg tablets obtained using Wagner
Nelson Method.
Development and evaluation of Level A IVIVC
Model: The in vitro data was taken based on minutes
and the in vivo absorption based on hours. It was
apparent that these two processes occurred over
different time scale. To make the time difference
between in vitro and in vivo data, uniform, a time
scaling factor (intensity factor) was calculated. The
intensity factor, I, obtained was 6.66. Thus by using
this factor we have converted the in vitro time points
to hours in order to match with the in vivo time
points. Time scaled normalization of in vitro and in
vivo data with intensity factor is given in figure 4.
Correlation calculation: The correlation graph
(Figure 5) was plotted as % absorbed verses %
dissolved and there exists an extremely good
correlation of formulation between in vitro and in
vivo data.
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Prediction Error: IVIVC model predictability was
determined by the calculating percent Cmax and
AUC prediction errors. Prediction error as %PE,
AUC and %PE Cmax was found to be – 4.604 and -
11.19 respectively for each formulation.
An IVIVC should be evaluated to demonstrate that
predictability of in vivo performance of a drug
product from its in vitro dissolution characteristics is
maintained over a range of in vitro dissolution rates
and manufacturing process.
If in vitro dissolution is shown to be independent of
dissolution conditions such as PH, surfactants,
osmotic pressure, agitation intensity, a set of
dissolution data obtain from one formulation is
correlated with that of in vivo absorption data.
To demonstrate a correlation, fraction absorbed in
vivo should be plotted against fraction dissolved in
vitro. If this relationship becomes linear with a slope
of 1, then curves are super imposable, and there is a
1:1 relationship which is defined as point-to-point or
Level A correlation.
Regression analysis was also performed on Excel
spread sheet with the same in vitro and in vivo data.
R-squared value obtained from graph was 0.9794.
According to FDA guidelines and expertise, statistic
from Level A analysis is r, the correlation coefficient.
It’s square, i.e. R-squared, ranges from 0 to 1 and is a
measure of strength of relationship between fractions
absorbed against fraction dissolved. Often, results
with sufficient large R-squared (e.g., greater than 0.9)
yielded “a successful correlation”.
The in vitro–in vivo correlation of Acyclovir shows
R-squared value 0.9794 in excel work sheet, which
depicts a successful correlation between in vitro and
in vivo Characteristic of the drug.
In a linear correlation, in vitro dissolution and in vivo
input curves may be directly super imposable or may
be made to be super imposable by the use of
appropriate scaling factor (time corrections). Time
scaling factor should be the same for all formulations
and different time scales for each formulation
indicate absence of an IVIVC.
Percent prediction error (PE%) of 10% or less for
Cmax and AUC establishes the predictability of the
IVIVC. In addition, the PE% for each formulation
should not exceed 15%. Here %PEAUC and %PECmax
was found to be –4.604 and -11.19 respectively.
CONCLUSION
The present study shows a good correlation between
in vivo and in vitro PK profiles of the formulation
used as the test drug in the study. The in vitro–in vivo
correlation of Acyclovir shows R-squared value
0.9794 in excel work sheet, which depicts a
successful correlation between in vitro and in vivo
Characteristic of the drug. In addition, %PE AUC and
%PE Cmax was found to be –4.604 and -11.19
respectively for each formulation. The concept of
correlation level is based upon the ability of the
correlation to reflect the complete plasma drug level-
time profile which will result from administration of
the given dosage form. An IVIVC Level A correlates
the entire in vitro and in vivo profiles has regulatory
relevance. This level of correlation is the highest
category of correlation and represents a point-to-
point relationship between in vitro dissolution rate
and in vivo input rate of the drug from the dosage
form.
TABLE 1: IN VITRO DISSOLUTION DATA OF ACYCLOVIR 800 MG TABLETS (TEST) AND ZOVIRAX 800
MG TABLETS (REFERENCE)
0.1 N HCl
Time (min)
Acyclovir 800 mg (test)
Tablets
Zovirax 800mg (Reference)
tablets
0 0 0
10 86 74
15 91 81
20 94 89
30 95 94
45 96 96
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TABLE 2: FRACTION OF DRUG ABSORBED FOR TEST & REFERENCE
Fraction of Drug Absorbed
Time (hr) Test Reference
0 0 0
0.333 0.208509 0.283505
0.667 0.600566 0.809927
1 0.902686 0.99656
1.333 1.086002 1.195828
1.667 1.187093 1.321714
2 1.13907 1.327762
2.5 1.173928 1.330732
3 1.257711 1.281141
4 1.137136 1.175827
5 1.067112 1.088926
6 0.956591 0.981582
8 0.886052 0.901321
10 0.851755 0.878418
12 0.835008 0.851137
14 0.841072 0.844374
16 0.852433 0.850673
24 0.876586 0.875232
TABLE 3: Fraction of Drug Absorbed
Time (hr) Fraction drug absorbed % Drug absorbed
0 0 0
0.333 0.283505 28.3505
0.667 0.809927 80.9927
1 0.99656 99.656
1.333 1.195828 119.5828
1.667 1.321714 132.1714
2 1.327762 132.7762
FIGURE 1: FRACTION OF DRUG DISSOLVED VS TIME GRAPH FOR ACYCLOVIR 800 MG TABLETS
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% Drug absorbed vs Time Graph
0
20
40
60
80
100
0 0.5 1 1.5 2 2.5 3
Time
%Absorbed
% F
FIGURE 2: FRACTION OF DRUG ABSORBED VS TIME GRAPH FOR ACYCLOVIR 800 MG TABLETS
(TEST)
% Drug absorbed vs Time Graph
0
20
40
60
80
100
0 0.5 1 1.5 2 2.5 3
Time
%Absorbed
% F
FIGURE 3: FRACTION OF DRUG ABSORBED VS TIME GRAPH FOR ZOVIRAX 800 MG TABLETS
(REFERENCE)
Time scale normalization of IVIVC
0
20
40
60
80
100
0 0.5 1 1.5 2 2.5
Time (hr)
%DrugAbsorbedor
Dissolved
In vivo observed In vitro observed In vitro predicted
FIGURE 4: TIME SCALED NORMALIZATION OF IN VITRO AND IN VIVO DATA WITH INTENSITY
FACTOR
FIGURE 5: THE LINEAR REGRESSION PLOT OF % ABSORBED AND % DISSOLVED
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REFERENCES
1. Leeson L. J. Drug Information Journal, 1995; 29: 903-915.
2. Gaynor C, Dunne A, Davis J., International Biometric Society,
http://ibc2008abstracts.tibs.org/Other/IBC2008_Paper_ref_466.pdf
3. Modi NB, Lam A, Lindemulder E, Wang B, Gupta SK. Biopharm Drug Dispos, 2000; 21:321-326
4. Uppoor VRS. J Control Rel. 2001; 72:127-132.
5. Chilukuri DM, Sunkara G. Drug Delivery Technology, 2003; 3:4
6. Sirisuth N, Eddington ND, Int. J. Generic Drugs, 2002; Part 3:250-258.
7. Qureshi SA , The Open Drug Delivery Journal, 2010; 4: 38-47.
8. Jaber E. J. Pharm Pharmaceut Sci, 2006; 9 (2): 169-189.
9. Jayaprakasam B, Seeram NP, Nairs MG. Cancer Lett, 2003; 189 (1): 11-6.
10. www.rxlist.com
11. http://www.drugs.com/pdr/ Zovirax Tablets.html.