The document provides an overview of oral controlled release drug delivery systems. It discusses the anatomy and physiology related to oral drug administration. Some key advantages of controlled release oral dosage forms are enhanced bioavailability, reduced dosing frequency, and more consistent drug levels in the body. The document also covers various mechanisms for controlled release, including osmotic pumps, floating systems, and coating technologies. It provides examples of commercially available controlled release drugs and classifications of these systems.
1.0.bioavailability, pharmacokinetics and efficacy determinationsalummkata1
Bioavailability is a measure of the rate and fraction of the initial dose of a drug that successfully reaches either; the site of action or the bodily fluid domain from which the drug’s intended targets have unimpeded access.
For majority purposes, bioavailability is defined as the fraction of the active form of a drug that reaches systemic circulation unaltered. This definition assumes 100% of the active drug that enters systemic circulation will successfully reach the target site. However, it should be appreciated that this definition is not inclusive of drugs that do not require access to systemic circulation for function (i.e., certain topical drugs). The bioavailability of these drugs is measured by different parameters discussed elsewhere.
Bioavailability and bioequivalence
Bioavailability-
Whenever a drug is given by oral route it has to go through certain pathway to reach the systemic circulation. Eg. If 100 mg drug is given orally, and if 80 mg is absorbed and 20 mg gets excreted then 80 mg absorbed drug reaches liver through portal system. In liver it gets metabolized, here if 30 mg gets metabolized by the liver 50 mg reaches the systemic circulation in the unchanged from. But Bioavailability is expressed in mg it has to be expressed in fraction. So Bioavailability is basically the fraction of unchanged from of the drug that reaches the systemic circulation following administration by any route.
As the drug given by intravenous route reaches directly into the systemic circulation. So the Bioavailability of drug given i.v is 100 %. % Bioavailability can be calculated as- Area under the curve (AUC oral)/ (AUC i.v) *100.
Bioavailability depends on both the rate and extent of absorption.
Rate of absorption depends on- site of adminstration and the drug formulation.
Extent (amount) of absorption depends on- route of drug administration
Factors affecting absorption and Bioavailability-
Pharmaceutical and pharmacological factors:
Pharmaceutical factors include- particle size, crystal from, salt form, water of hydration, Nature of excipients and adjuvants, degree of ionisation.
Pharmacological factors- gastric emptying & g.i mobility, g.i diseases, food and other substances, first-pass effect, Drug-drug interaction, pharmacogenetics, miscellaneous factors like route of administration, area of absorbing surface, state of circulation at site of absorption.
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
Bioavailability and Bioequivalence Studies (BABE) & Concept of BiowaiversJaspreet Guraya
The presentation gives an insight on BABE studies, mathematical and statistical procedures involved in designing these studies, the official guidelines regarding study design. In the later part it also discusses about biowaivers and their role.
1.0.bioavailability, pharmacokinetics and efficacy determinationsalummkata1
Bioavailability is a measure of the rate and fraction of the initial dose of a drug that successfully reaches either; the site of action or the bodily fluid domain from which the drug’s intended targets have unimpeded access.
For majority purposes, bioavailability is defined as the fraction of the active form of a drug that reaches systemic circulation unaltered. This definition assumes 100% of the active drug that enters systemic circulation will successfully reach the target site. However, it should be appreciated that this definition is not inclusive of drugs that do not require access to systemic circulation for function (i.e., certain topical drugs). The bioavailability of these drugs is measured by different parameters discussed elsewhere.
Bioavailability and bioequivalence
Bioavailability-
Whenever a drug is given by oral route it has to go through certain pathway to reach the systemic circulation. Eg. If 100 mg drug is given orally, and if 80 mg is absorbed and 20 mg gets excreted then 80 mg absorbed drug reaches liver through portal system. In liver it gets metabolized, here if 30 mg gets metabolized by the liver 50 mg reaches the systemic circulation in the unchanged from. But Bioavailability is expressed in mg it has to be expressed in fraction. So Bioavailability is basically the fraction of unchanged from of the drug that reaches the systemic circulation following administration by any route.
As the drug given by intravenous route reaches directly into the systemic circulation. So the Bioavailability of drug given i.v is 100 %. % Bioavailability can be calculated as- Area under the curve (AUC oral)/ (AUC i.v) *100.
Bioavailability depends on both the rate and extent of absorption.
Rate of absorption depends on- site of adminstration and the drug formulation.
Extent (amount) of absorption depends on- route of drug administration
Factors affecting absorption and Bioavailability-
Pharmaceutical and pharmacological factors:
Pharmaceutical factors include- particle size, crystal from, salt form, water of hydration, Nature of excipients and adjuvants, degree of ionisation.
Pharmacological factors- gastric emptying & g.i mobility, g.i diseases, food and other substances, first-pass effect, Drug-drug interaction, pharmacogenetics, miscellaneous factors like route of administration, area of absorbing surface, state of circulation at site of absorption.
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
Bioavailability and Bioequivalence Studies (BABE) & Concept of BiowaiversJaspreet Guraya
The presentation gives an insight on BABE studies, mathematical and statistical procedures involved in designing these studies, the official guidelines regarding study design. In the later part it also discusses about biowaivers and their role.
Fundamental concept of modified drug releaseAbhinayJha3
Different Terminologies used in a modified release
1. Sustained release
2. Delayed release
3. Prolonged release
4. Extended-release
5. Controlled release
6. Site-specific targeting and receptor targeting
SELECTION OF DRUG CANDIDATE FOR ORAL SUSTAINED RELEASE SYSTEMS, BIOPHARMACEUTICAL CLASSIFICATION SYSTEM.
Bioavailability and Bioequivalence studyMcpl Moshi
Bioavailability and Bioequivalence study, BCS is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability.
It is a drug development tool that allows estimation of solubility, dissolution and intestinal permeability affect that oral drug absorption.
Recent Advances in Colon Targeted Drug Delivery SystemDarshil Shah
Colon Targeted Drug delivery is the most convenient and desirable drug targeting method for the drugs which degrades in acidic environment, and also preferable for prolong or delayed release and also desease specisic to colon.
“ 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."
Biopharmaceutic considerations in Drug Product DesignRiaz Islam
Drug product Design remain one of the most challenging aspects in formulation development. But nowadays formulation strategies have been far more successful in improving the bioavailability of the compounds with poor solubility, poor dissolution rate, and poor chemical stability in acidic environment. This article begins with a brief discussion on Physical and Chemical Properties of the Drug Impacting Oral Absorption. This article also reviews the Factors Contributing to Poor Aqueous Solubility. and a brief relationship between Physicochemical Properties and Drug Delivery System.
A brief presentation on the factors affecting bioavailability of drugs along with a quick overview on what is bioequivalence, clinical equivalence, therapeutic equivalence, chemical equivalence and pharmaceutical equivalence.
This presentation involves the information about Modified-Release Drug Products, Targeted Drug Delivery Systems and Biotechnological Products in Pharmaceutics
Fundamental concept of modified drug releaseAbhinayJha3
Different Terminologies used in a modified release
1. Sustained release
2. Delayed release
3. Prolonged release
4. Extended-release
5. Controlled release
6. Site-specific targeting and receptor targeting
SELECTION OF DRUG CANDIDATE FOR ORAL SUSTAINED RELEASE SYSTEMS, BIOPHARMACEUTICAL CLASSIFICATION SYSTEM.
Bioavailability and Bioequivalence studyMcpl Moshi
Bioavailability and Bioequivalence study, BCS is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability.
It is a drug development tool that allows estimation of solubility, dissolution and intestinal permeability affect that oral drug absorption.
Recent Advances in Colon Targeted Drug Delivery SystemDarshil Shah
Colon Targeted Drug delivery is the most convenient and desirable drug targeting method for the drugs which degrades in acidic environment, and also preferable for prolong or delayed release and also desease specisic to colon.
“ 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."
Biopharmaceutic considerations in Drug Product DesignRiaz Islam
Drug product Design remain one of the most challenging aspects in formulation development. But nowadays formulation strategies have been far more successful in improving the bioavailability of the compounds with poor solubility, poor dissolution rate, and poor chemical stability in acidic environment. This article begins with a brief discussion on Physical and Chemical Properties of the Drug Impacting Oral Absorption. This article also reviews the Factors Contributing to Poor Aqueous Solubility. and a brief relationship between Physicochemical Properties and Drug Delivery System.
A brief presentation on the factors affecting bioavailability of drugs along with a quick overview on what is bioequivalence, clinical equivalence, therapeutic equivalence, chemical equivalence and pharmaceutical equivalence.
This presentation involves the information about Modified-Release Drug Products, Targeted Drug Delivery Systems and Biotechnological Products in Pharmaceutics
Oral drug delivery is one of the most preferred routes for administering medications due to its convenience, patient compliance, and non-invasiveness. Over the years, significant advancements have been made in oral drug delivery systems to enhance drug bioavailability, control release kinetics, and overcome various physiological barriers. This article provides a comprehensive review of the current state of oral drug delivery systems, including their principles, components, and recent advancements. Moreover, it highlights the challenges associated with oral drug delivery and discusses potential future directions for improving therapeutic outcomes.
ABSTRACT
The main objective of present research work is to formulate the floating tablets of Carvedilol Phosphate using 32 factorial design. Carvedilol Phosphate, non-selective α1-β1-blocking agent belongs to BCS Class-II and Indicated for treatment of Hypertension/moderate Heart Failure. The Floating tablets of Carvedilol Phosphate were prepared employing different concentrations of HPMCK100M and Sodium bicarbonate in different combinations by Direct Compression technique using 32 factorial design. The concentration of HPMCK100M and Sodium bicarbonate required to achieve desired drug release was selected as independent variables, X1 and X2 respectively whereas, time required for 10% of drug dissolution (t10%), 50% (t50%), 75% (t75%) and 90% (t90%) were selected as dependent variables. Totally nine formulations were designed and are evaluated for hardness, friability, thickness, % drug content, Floating Lag time, In-vitro drug release. From the Results concluded that all the formulation were found to be with in the Pharmacopoeial limits and the In-vitro dissolution profiles of all formulations were fitted in to different Kinetic models, the statistical parameters like intercept (a), slope (b) & regression coefficient (r) were calculated. Polynomial equations were developed for t10%, t50%, t75%, t90%. Validity of developed polynomial equations were verified by designing 2 check point formulations (C1, C2). According to SUPAC guidelines the formulation (F8) containing combination of 25% HPMCK100M and 3.75% Sodium bicarbonate, is the most similar formulation (similarity factor f2=88.801, dissimilarity factor f1= 2.250 & No significant difference, t= 0.095) to marketed product (CARDIVAS). The selected formulation (F8) follows Higuchi’s kinetics, and the mechanism
ABSTRACT
Objective: The main objective of present investigation is to formulate the controlled release tablet of Lamivudine using 3² factorial design. Lamivudine, a basic molecule and antiretroviral drug belongs to BCS Class III, having low permeability and high solubility. Methods: The controlled release tablets of lamivudine were prepared employing different concentrations of Carboplol974P and Xanthan gum in different combinations as a rate retarding agent by Direct Compression technique using 32 factorial design. The quantity/ concentration of rate retarders, Carboplol974P and Xanthan gum required to achieve the desired drug release was selected as independent variables, X1 and X2 respectively whereas, time required for 10% of drug dissolution t10%, t50%, t75%,t90% were selected as dependent variables. Results: Totally nine formulations were designed and are evaluated for hardness, friability, thickness, % drug content, in-vitro drug release. From the results it was concluded that all the formulation were found to be with in the pharmacopoeial limits and the in-vitro dissolution profiles of all formulations were fitted in to different Kinetic models, the statistical parameters like intercept (a), slope (b) & regression coefficient (r) were calculated. Polynomial equations were developed for t10%, t50%, t75%,t90%. Conclusions: According to SUPAC guidelines the formulation (F5) containing combination of 10% Carboplol974P and 10% Xanthan gum, is the most similar formulation (similarity factor f2=85.04 & No significant difference, t= 0.20046) to Innovator product (Lamivir). The selected formulation (F5) follows Higuchi’s kinetics, and the mechanism of drug release was found to be Case-II transport or typical Zero order release (Non-Fickian, n= 0.915).
The main objective of present investigation is to formulate the floating tablets of
Ranitidine.HCl using 32 factorial design. Ranitidine.HCl, H2-receptor antagonist belongs to
BCS Class-III. The Floating tablets of Ranitidine.HCl were prepared employing different
concentrations of HPMCK4M and Guar Gum in different combinations as a release rate
modifiers by Direct Compression technique using 32 factorial design. The concentration of
Polymers , HPMCK4M and Guar Gum required to achieve desired drug release was selected
as independent variables, X1 and X2 respectively whereas, time required for 10% of drug
dissolution (t10%), 50% (t50%), 75% (t75%) and 90% (t90%) were selected as dependent variables.
Totally nine formulations were designed and are evaluated for hardness, friability, thickness,
% drug content, Floating Lag time, In-vitro drug release. From the Results concluded that all
the formulation were found to be within the Pharmacopoeial limits and the In-vitro
dissolution profiles of all formulations were fitted in to different Kinetic models, the
statistical parameters like intercept (a), slope (b) & regression coefficient (r) were calculated.
Polynomial equations were developed for t10%, t50%, t75%, t90%. Validity of developed
polynomial equations were verified by designing 2 check point formulations(C1, C2).
According to SUPAC guidelines the formulation (F5) containing combination of 22.5%
HPMCK4M and 22.5% Guar Gum, is the most similar formulation (similarity factor f2=85.01,
dissimilarity factor f1= 15.358 & No significant difference, t= 0.169) to marketed product
(ZANTAC). The selected formulation (F5) follows Higuchi’s kinetics, and the mechanism of
drug release was found to be Non-Fickian Diffusion (n= 0.922).
ABSTRACT
The main objective of present investigation is to formulate the sustained release tablet of Metoprolol Succinate
using 32 factorial design. Metoprolol Succinate, is a selective β1blocker, to treat Hypertension & Heart Failure. The
SR tablets of Metoprolol Succinate were prepared employing different concentrations of HPMCK15M and
HPMCK100M in different combinations as a rate retardants by Direct Compression technique using 32 factorial
design. The quantity of rate retarders, HPMCK15M and HPMCK100M required to achieve the desired drug release
was selected as independent variables, X1 and X2 respectively whereas, time required for 10% of drug dissolution
(t10%), 50% (t50%), 75% (t75%) and 90% (t90%) were selected as dependent variables. Totally nine formulations were
designed and are evaluated for hardness, friability, thickness, % drug content, In-vitro drug release. From the
Results it was concluded that all the formulation were found to be with in the Pharmacopoeial limits and the Invitro
dissolution profiles of all formulations were fitted in to different Kinetic models, the statistical parameters like
intercept (a), slope (b) & regression coefficient (r) were calculated. Polynomial equations were developed for t10%,
t50%, t75%, t90%. Validity of developed polynomial equations were verified by designing 2 check point formulations(C1,
C2). According to SUPAC guidelines the formulation (F5) containing combination of 10% HPMCK15M and 10%
HPMCK100M, is the most similar formulation (f2=92.38 & No significant difference, t= 0.0216) to marketed
product (Metocard). The selected formulation (F5) follows Higuchi’s kinetics, the mechanism of drug release was
found to be Super case II transport (Non-Fickian, n= 0.981).
ABSTRACT
The main objective of present investigation is to formulate the sustained release tablet of Zidovudine using 32
factorial design. Zidovudine, antiretroviral drug belongs to BCS Class I. The SR tablets of Zidovudine were
prepared employing different concentrations of Carboplol974P and Xanthan gum in different combinations as a
rate retardants by Direct Compression technique using 32 factorial design. The quantity of rate retarders,
Carboplol974P and Xanthan gum required to achieve the desired drug release was selected as independent
variables, X1 and X2 respectively whereas, time required for 10% of drug dissolution (t10%), 50% (t50%), 75% (t75%)
and 90% (t90%) were selected as dependent variables. Totally nine formulations were designed and are evaluated
for hardness, friability, thickness, % drug content, In-vitro drug release. From the Results it was concluded that all
the formulation were found to be with in the Pharmacopoeial limits and the In-vitro dissolution profiles of all
formulations were fitted in to different Kinetic models, the statistical parameters like intercept (a), slope (b) &
regression coefficient (r) were calculated. Polynomial equations were developed for t10%, t50%, t75%, t90%. Validity of
developed polynomial equations were verified by designing 2 check point formulations(C1, C2). According to
SUPAC guidelines the formulation (F5) containing combination of 5% Carboplol974P and 5% Xanthan gum, is the
most similar formulation (f2=85.04 & No significant difference, t= 0.20046) to marketed product (Retrovir). The
selected formulation (F5) follows Higuchi’s kinetics, the mechanism of drug release was found to be Case-II
transport or typical Zero order release (Non-Fickian, n= 0.915).
GIT ABSORPTION FOR ORAL Administered DrugAli Mashwani
In this Lecture I have covered how the Drug is absorbed when it is administered orally, what is BCS classification system, Role of BCS and Importance of Biopharmaceutics Classification System. I have discussed how the Pharmakinetics process occur, what is Absorption, Distribution, Metabolism and Excretion.
Floating drug delivery approach uses low-density systems that have sufficient buoyancy to flow over the
gastric contents and remains buoyant in the stomach without affecting the stomachic emptying rate for a
chronic period of time. This result is increased gastric retention time and better control of the fluctuations
in plasma drug concentration with a low risk of toxicity. Drugs, which are locally active in the stomach,
drugs having narrow absorption window and unstable in the intestine, and colonic environment, are the
potential drug candidates. The approach not only improves drug absorption but also minimizes the mucosal
irritation of drugs. As the approach requires a high fluid level in the stomach to float and work efficiently,
it makes the approach limited up to some extent. Many buoyant systems have been developed based on
granules, powders, capsules, tablets, laminated films, and hollow microspheres and few formulations have
been commercialized in the market at the present time. This review gives an overview of the approach of
floating drug delivery at present with sequential demystification thus enabling a greater understanding of
their role in medicine and drug delivery
1. Oral Control Release Drug Delivery System
A Project report submitted to the Department of Pharmacy, University of Asia
Pacific, for partial fulfillment of the requirements for the degree of Master of
Science in Pharmaceutical Technology
Submitted By:
Name: Nadia Nabila Anam Arin
Registration No.: 13207005
Session: Fall-2013
Submission Date: 22 June, 2014
Department of Pharmacy
University of Asia Pacific
3. Table of contents
SL no. Topic Pages
Dedication
Summary of study
Table of contents
List of tables
List of figures
Summary 1
1 Introduction 2
2 Anatomy And Physiology For
Oral Drug
5
2.1 Anatomy of mouth 5
2.2 BASIC ANATOMICAL &
PHYSIOLOGICAL OF G.I.T
6
3 Advantages and disadvantages 9
3.1 Advantages 9
3.2 Disadvantages 10
4 List of commercially marketed
oral osmotic drug delivery
Products.
11
5 Classification controlled oral
dosage form
11
5.1 Controlled oral drug delivery
system
11
5.2 Classification of the Oral
Osmotic Drug Delivery
Systems
12
6 Differences between
conventional oral dosage from
and controlled oral dosage
from
13
6.1 Advantages 13
6.2 Limitation of conventional
oral dosage form
13
4. 7 Mechanism 13
7.1 Osmotic Controlled Release
Oral Delivery System
Technology
13
7.2 Multiparticulate System 15
7.3 Compression Coated Tablets 16
7.4 Melt-Extrusion Technology 17
7.5 Layered Tablets or
RingCap™Tablets
18
7.6 Ion Exchange Resins as Drug
Delivery Systems
19
7.7 Gel-Cap™Technology 19
7.8 In situ Forming Devices 20
7.9 Elementary Osmotic Pump
(EOP)
22
7.10 Push-Pull Osmotic Pump
(PPOP)
23
7.11 Controlled Porosity Osmotic
Pump (CPOP)
23
7.12 Sandwiched Osmotic Tablets
(SOTS)
24
7.13 Monolithic Osmotic Systems 24
7.14 Liquid Oral Osmotic System
(L-OROS)
25
7.15 Colon Targeted Oral Osmotic
System (OROS-CT)
26
7.16 Osmotic Matrix Tablet
(OSMAT)
26
8 Exceptional controlled oral
dosage
27
8 Floating Controlled Oral
Dosage Form
27
8 Mechanism 27
8.1 High density system 27
8.2 Swelling and expanding
systems
27
8.3 Incorporating delaying
excipients
28
5. 8.4 Modified systems 29
8.5 Mucoadhesive & bioadhesive
systems
29
8.6 Floating systems 30
8.7 CLASSIFICATION OF FDDS
BASED ON MECHANISM
OF BUOYANCY
30
A Single unit 30
B Multiple unit 31
C Raft forming systems 33
9 Spansule Technology 33
9.1 Classification 34
10 References 35
List of Tables
Table Number Table Description Page
1 List of commercially marketed
oral osmotic drug delivery
Products.
11
6. List of Figures
Figure Number Figure Description Page
1 Graph showing controlled oral
release dosage importance
3
2 Anatomy for oral drug 5
3 Mouth (Oral Cavity) 6
3
Anatomy of Stomach 7
4 Histology of stomach 8
5 Classification of the Oral
Osmotic Drug Delivery
Systems
12
6 Osmotic Controlled Release
Oral Delivery System
Technology
14
7 Multiparticulate System 16
8 Compression Coated Tablets 17
9 Layered Tablets or
RingCap™Tablets
18
10 Elementary Osmotic Pump 22
11 Mechanism of Drug Delivery
from a Push-Pull
Osmotic Pump (PPOP)
23
12 Controlled Porosity Osmotic
Pump (CPOP)
23
13 High density systems 24
14 Swellable tablet in stomach 25
15 Different geometric forms of
unfoldable systems
26
16 The mechanism of floating
systems
27
17 High density systems 28
18 Swellable tablet in stomach 28
19 Different geometric forms of
unfoldable systems
29
20 The mechanism of floating
systems
30
7. Summary of Study
The oral route for the delivery of various challenging drug such as small polar molecules,
vaccine, proteins and hormone are creating much interest day by day. Oral route is chosen
because it is easy to administrated .Control oral dosage form is use for the patient to avoid
frequent drug administration. Control oral dosage from release in the body time to time to
maintain the drug concentration level in the body. Many drug are design for oral control dosage
from, CiprofloxacinTsosorbide, Onoitrare, Venlafaxine, Aspirin, loratadine etc to release drug in
body time to time in control manner to maintain the drug concentration level in the body for
better efficacy. This review also sets out to discuss many factors influencing drug absorption;
bioavailability and strategies to overcome obstacle .Novel drug delivery system for oral route
and the application for controlled oral dosage from are also confirmed elaborately.
8. 1. Introduction
The creation and manufacture of dosage forms has been at the center of pharmacy practice for
the past thousand years. For American pharmacists of the nineteenth century, secundem artem, or
the acronym “S.A.” in physicians’ prescriptions, instructed them to use their special skills
“according to the art” of their profession to compound a medicine; it was out of this art, rather
than science, that almost all of today's major dosage forms arose. Tablets, capsules, injectables,
and oral solutions were all known to pharmacists and physicians a century ago. In addition, there
were scores of specialized dosage forms that attempted to meet the medical needs of patients,
even if the drugs administered in these doses were ineffective or designed to treat symptoms
rather than the underlying disease. The origins of most of these dosage forms are lost in history.
For this reason, the authors have elected to forego a contrived narrative tying together the few
facts at hand with an equally large amount of speculation about the history of dosage forms.
Rather, we have assembled a glossary of terms used in orthodox Western medicine to describe
both common and unusual modes of drug administration (Burkiet et al., 2006).
The overall action of a drug molecule is dependent onits inherent therapeutic activity and the
efficiency with which it is delivered to the site of action. An increasing appreciation of the latter
has led to the evolution and development of novel drug delivery systems (NDDS), aimed at
performance enhancement of potential drug molecules. Novel drug delivery systems (NDDS) are
the key area of pharmaceutical research and development. The reason is relatively low
development cost and time required for introducing a NDDS ($20 ñ 50 million and 3 ñ 4 years,
respectively) as compared to new chemical entity (approximately $500 million and10 ñ 12 years,
respectively). The focus on NDDS includes, design of NDDS for new drugs on one hand and on
the other NDDS for established drugs augment commercial viability (Shah et al., 2012).
Why Oral route for drug administration:
Many drugs can be administered orally as liquids, capsules, tablets, or chewable tablets. Because
the oral route is the most convenient and usually the safest and least expensive, it is the one most
often used. However, it has limitations because of the way a drug typically moves through the
9. digestive tract. For drugs administered orally, absorption may begin in the mouth and stomach.
However, most drugs are usually absorbed from the small intestine. The drug passes through the
intestinal wall and travels to the liver before it is transported via the bloodstream to its target site.
The intestinal wall and liver chemically alter (metabolize) many drugs, decreasing the amount of
drug reaching the bloodstream. Consequently, these drugs are often given in smaller doses when
injected intravenously to produce the same effect.
When a drug is taken orally, food and other drugs in the digestive tract may affect how much of
and how fast the drug is absorbed. Thus, some drugs should be taken on an empty stomach,
others should be taken with food, others should not be taken with certain other drugs, and still
others cannot be taken orally at all.
Figure 1.Graph showing controlled oral release dosage importance (Ravikumar, 2014).
Most conventional (immediate release) oral drug products, such as tablets and capsules, are
formulated to release the active drug immediately after oral administration. In the formulation of
conventional drug products, no deliberate effort is made to modify the drug release rate.
Immediate-release products generally result in relatively rapid drug absorption and onset of
accompanying pharmacodynamic effects. In the case of conventional oral products containing
prodrugs, the pharmacodynamic activity may be slow due to conversion to the active drug by
hepatic or intestinal metabolism or by chemical hydrolysis. Alternatively, conventional oral
products containing poorly soluble (lipophilic drugs), drug absorption may be gradual due to
slow dissolution in or selective absorption across the GI tract, also resulting in a delayed onset
time.
10. The pattern of drug release from modified-release (MR) dosage forms is deliberately changed
from that of a conventional (immediate-release) dosage formulation to achieve a desired
therapeutic objective or better patient compliance. Types of MR drug products include delayed
release (eg, enteric coated), extended release (ER), and orally
Disintegrating tablets (ODT).
The term modified-release drug product is used to describe products that alter the timing and/or
the rate of release of the drug substance. A modified-release dosage form is a formulation in
which the drug-release characteristics of time course and/or location are chosen to accomplish
therapeutic or convenience objectives not offered by conventional dosage forms such as
solutions, ointments, or promptly dissolving dosage forms. Several types of modified-release oral
drug products are recognized:
Extended-release drug products. A dosage form that allows at least a twofold reduction in dosage
frequency as compared to that drug presented as an immediate-release (conventional) dosage
form. Examples of extended-release dosage forms include controlled-release, sustained-release,
and long-acting drug products.
Delayed-release drug products. A dosage form that releases a discrete portion or portions of drug
at a time other than promptly after administration. An initial portion may be released promptly
after administration. Enteric-coated dosage forms are common delayed-release products (eg,
enteric-coated aspririn and other NSAID products).
Targeted-release drug products. A dosage form that releases drug at or near the intended
physiologic site of action .Targeted-release dosage forms may have either immediate- or
extended-release characteristics.
Orally disintegrating tablets (ODT). ODT have been developed to disintegrate rapidly in
the saliva after oral administration. ODT may be used without the addition of water. The drug is
dispersed in saliva and swallowed with little or no water.
11. The term controlled-release drug product was previously used to describe various types of oral
extended-release-rate dosage forms, including sustained-release, sustained-action, prolonged-
action, long-action, slow-release, and programmed drug delivery. Other terms, such as ER, SR
(Keraliya et al., 2012).
2. Anatomy and Physiology for Oral Drug
Figure 2.Anatomy for oral drug (Bureki, 2013).
2.1. Anatomy of mouth:
12. The mouth is the part of the body that has a lot of very important functions, but the two functions
that it is most used for are for eating and for speaking. It uses its many different parts for both
functions. It has a lot of parts, some of which are the teeth, lips, gums, tongue, and tonsils. Its
bigger parts that connect it to the rest of the skull are the lower and upper jaw. The lower jaw is
that which moves up and down to enable the opening and closing of the mouth, and the upper
jaw is that which connects the mouth to the rest of the skull. The following is a breakdown that
hopes to simplify the fascinating anatomy of the human mouth (American society for
gastrointestinal endoscopy, 2010).
Figure 3.Mouth Oral cavity (Willson, 2011).
2.2. BASIC ANATOMICAL & PHYSIOLOGICAL OF G.I.T.:
Stomach
Small intestine – Duodenum, jejunum, and ileum
Large intestine
The gastrointestinal tract is a long muscular tube, starting from the mouth and end at the anus,
which capture the nutrient inside the body and eliminate by different physiological processes
13. such as secretion, digestion, absorption, excretion include the basic onstruction of
gastrointestinal tract from stomach to large intestine.
Stomach
The main function of the stomach is to store food temporarily, grind it and then release it
slowly into the duodenum. The stomach is an important site of enzyme production.Due to its
small surface area very little absorption takes place from the stomach. Various factors such as
volume ingested and posture affect the exact position of the stomach. Anatomically it can be
divided mainly into three regions,
Fundus
Body
Pylorus (or Antrum.)
The main function of fundus and body is storage of food, whereas that of antrum is mixing and
grinding. The fundus adjusts to the increased volume during eating by relaxation of fundal
muscle fibers. The fundus also exerts a steady pressure on the gastric contents, pressing them
towards the distal stomach. To pass through the pyloric valve into the small intestine, particles
should be of the order of 1- 2 mm. Antrum region is responsible for the mixing and grinding of
gastric content. There are two main secretions: mucusand acid, produced by specialized cell in
stomach lining. Mucus is secreted by goblet cells and gastric acid by parietal cells (oxyntric) The
Mucus spread and cover the rest of GI tract.
14. Figure 4. Anatomy of Stomach (Jeferson et al., 2014).
Under fasting condition the stomach is a collapsed bag with a residual volume of 50 ml and
contains a small amount of gastric fluid (pH 1-3) and air.6The stomach wall is composed of the
four basic layers. Simplecolumnar epithelial cells line the entire mucosal surface of thestomach.
Epithelial cells extend down into the Lamina propria,where they form columns of secretory cells
called gastric glands.The gastric glands contain three types of exocrine gland cells that secrete
their products into the stomach lumen.
Mucous neck cells,
Chief cells and
Parietal cells.
The chief cells secrete pepsinogen and gastric lipase. Parietal cells produce hydrochloric acid and
intrinsic factor. Both mucous surface cells and mucous neck cells secrete mucus and bicarbonate.
They protect the stomach from adverse effects of hydrochloric acid. As
mucous has a lubricating effect, it allows chyme to move freely through the digestive system.
15. Figure. 5: Histology of Stomach (Borase, 2012).
Functions of stomach:
The stomach carries out three major functions. It stores food, digests food and delivers food to
the small intestine at a rate that the small the intestine can handle
Mixes saliva, food, and gastric juice to form chyme.
It acts as a reservoir for holding food before release into the
Small intestine.
Secretes gastric juice, which contains hydrochloric acid, pepsin,
Intrinsic factor and gastric lipase.
Secrete gastrin into the blood (Borase, 2012) .
3. Advantages and Disadvantages:
3.1. Advantages:
16. 1. Enhanced Bioavailability: The bioavailability of riboflavin CRGRDF is significantly
enhanced in comparison to the administration of non-GRDF CR polymeric formulations.
2. Enhanced first-pass biotransformation: The pre-systemic metabolism of the tested
compound may be considerably increased when the drug is presented to the metabolic
enzymes (cytochrome P450, in particular CYP3A4) in a Sustained manner, rather than by a bolus
input.
3. Sustained drug delivery/reduced frequency of dosing:
For drugs with relatively short biological half-life, sustained and slow input from CR-GRDF
may result in a flip-flop Pharmacokinetics and enable reduced dosing frequency. This feature is
associated with improved patient compliance, and thereby improves therapy.
4. Targeted therapy for local ailments in the upper GIT.
5. Reduced fluctuations of drug concentration.
6. Improved selectivity in receptor activation.
7. Reduced counter-activity of the body: In many cases, the pharmacological Response which
intervenes with the natural physiologic processes provokes a rebound activity of the bodythat
minimizes drug activity. Slow input of the drug into the body was shown to minimize the counter
activity leading tohigher drug efficiency.8. Extended time over critical (effective) concentration:
For certain drugs that have non-concentration dependent
pharmacodynamics, such as betalactam antibiotics, the clinical response is not associated with
peak concentration, but rather with the duration of time over a critical therapeutic concentration.
The sustained mode of administration enables extension of the time
over a critical concentration and thus enhances the pharmacological effects and improves the
clinical outcomes.
9. Minimized adverse activity at the colon: This pharmacodynamic aspect provides the
rationale for GRDF formulation for beta-lactam antibiotics that are absorbed only.
Total dose is low.
Reduce GIT side effect.
Reduce toxic effect.
Less fluctuation in plasma drug concentration.
Reduce dosing frequency.
Better patient acceptance. (Borase, 2012; Dixit et al., 2011).
17. 3.2. Disadvantages:
Decreased systemic availability in comparison to immediate release conventional dosage
forms, which may be due to incomplete release, increased first-pass metabolism, increased
instability, insufficient residence time complete release, site specific absorption, pH dependent
stability, etc.
Poor in vitro – in vivo correlation.
Retrieval of drug is difficult in case of toxicity, poisoning or hypersensitivity reactions.
Reduced potential for dose adjustment of drugs normally administered in varying strengths
(Dixit et al., 2011)
4. Table 1. List of commercially marketed oral osmotic drug delivery Products.
Product name Drug
Acutrim Phenylpropranol
Alpress LP Prazosin
Calan SR Verapamil
Cardura XL Doxazocin
18. mesylate
Concenta Methylphenidate
Covera HS Verapamil
Ditrophan XL Oxybutynin
chloride
DynaCirc CR Isradipine
Efidac 24 Pseudoephedrine
Glucotrol XL Glipizide
(Monali et al., 2013).
5. Classification controlled oral dosage form
5.1. Controlled oral drug delivery system
A. Controlled Release B. Delayedrelease
Sustain release.
Prolong release.
Extended release (Kushal et al., 2013).
5.2. Classification of the Oral Osmotic Drug Delivery Systems
20. 6 Differences between conventional oral dosage from and controlled oral dosage from
6.1. Advantages
Reduce dosing frequency
Dose reduction
Improve patient compliance
Constant level of drug concentration in blood
Reduce toxicity and over dosing
Night time dosing avoided
6.2. Limitation of conventional oral dosage form
Poor patient compliance
The unavoidable fluctuation of drug concentration may lead to under medication or over
medication
A typical peak-valley plasma concentration time profile is obtained which makes steady-state
condition impossible (Monali et al., 2013).
7. Mechanism
21. 7.1.Osmotic Controlled Release Oral Delivery System Technology
Osmotic controlled release oral delivery system (OROS) is a unique oral drug delivery
system that releases the drug at a "zero order" rate. It is a complex system, which consists
of a tablet core containing a water soluble drug and osmotic agents such as NaCl,
mannitol, sugars, PEGs, Carbopol, Polyox, etc. The tablet core is coated with a
semipermeable polymer such as cellulose acetate. This semi-permeable coating is
permeable to water but not to the drug. A laser-drilled hole, 100-250 μm in size, is created
as a drug delivery orifice. The osmotic pressure of the body fluid is 7.5 atm, whereas the
osmotic pressure in an OROS tablet is around 130-140 atm. As a result, aqueous fluid
present in the gastrointestinal (GI) tract enters into the OROS tablet through the
semipermeable membrane and pushes the drug out through a delivery orifice. The osmotic
pressure of the GI fluid remains constant throughout the GI tract, and as a result, the
OROS tablet provides controlled drug release at a constant zero order rate. However, the
drugs suitable for this delivery system should be highly water soluble (>100 mg/mL).
Poorly soluble drugs cause insufficient osmotic pressure and prevent complete drug
release. To overcome this limitation, Alza Corporation came up with "OROS Pull-Push
technology" in which, tablets are made with multiple drug layers and a push layer at the
bottom. The push layer contains a water-swellable polymer, osmotic agents and other
excipients. As water ermeates inside the tablet, the hydrophilic polymer absorbs the water
and swells. The swelled layer pushes solution from the upper drug layers out of the system
through the delivery orifice.
22. Figure7. Osmotic Controlled Release Oral Delivery System Technology
L-OROS was developed for highly insoluble drugs, polypeptides such as hormones, steroids,
etc., and for liquid drugs. L-OROS consists of a liquid filled softgel coated with multiple
layers such as osmotic push layer and a semipermeable layer. The internal osmotic layer pushes
against the drug compartment and forces the liquid drug formulation from the delivery orifice
present in the outer layers of a coated capsule. Glucotrol XL® and Procardia XL® are classical
examples of OROS tablets (Shah et al., 2012).