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 ArinRegistration No.: 13207005

Session: Fall-2013Submission Date: 22 June, 2014

Department of PharmacyUniversity of Asia Pacific

Dedicated to

My loving and respected parents and my big brother

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

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

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 Page1 List of commercially marketed

oral osmotic drug delivery Products.

11

List of Figures

Figure Number Figure Description Page1 Graph showing controlled oral

release dosage importance3

2 Anatomy for oral drug 53 Mouth (Oral Cavity) 6

3Anatomy 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 168 Compression Coated Tablets 179 Layered Tablets or

RingCap™Tablets18

10 Elementary Osmotic Pump 2211 Mechanism of Drug Delivery

from a Push-PullOsmotic Pump (PPOP)

23

12 Controlled Porosity Osmotic Pump (CPOP)

23

13 High density systems 2414 Swellable tablet in stomach 2515 Different geometric forms of

unfoldable systems26

16 The mechanism of floating systems

27

17 High density systems 2818 Swellable tablet in stomach 2819 Different geometric forms of

unfoldable systems29

20 The mechanism of floating systems

30

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.

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

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.

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.

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:

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

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.

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.

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:

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).

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

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. Delayed release

Sustain release.

Prolong release.

Extended release (Kushal et al., 2013).

5.2. Classification of the Oral Osmotic Drug Delivery Systems

Figure 6. Classification of the Oral Osmotic Drug Delivery Systems (Shah et al., 2012).

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

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.

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).