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).
