Pharmaceutical Technology-II 05-Mar-2022

PD442 Pharmaceutical Technology-II

ASSIGNMENT# 1:
Recent advances in the gastro-retentive drug delivery
system

Submitted To:
Sir. Kamran Hidayat

Group Members :
1. ARSLAN MANZOOR 1600
2. DAWOOD AKHTAR 1964
3. MUHAMMAD HUZAIFAH PARWEZ 1986
4. ABDUL BASIT RAJA 2025
5. ALI AWAN
Pharmaceutical Technology-II 05-Mar-2022

Contents

 Introduction:............................................................................................................................................ 1
 Recent Advances and Approaches......................................................................................................2
 1. Bio/Muco-adhesive System:.............................................................................................................2
 2. Raft System:......................................................................................................................................... 4
 3. Low density Approach (Floating Drug Delivery):......................................................................6
 4. Plug Systems OR Expandable systems..........................................................................................9
 5. High Density Approach:....................................................................................................................9
 6. Magnetic system:.............................................................................................................................. 10
 7. Polymeric Nanofibers: Targeted Gastro-Retentive Drug Delivery Systems:.....................10
 References:.............................................................................................................................................. 11
Pharmaceutical Technology-II 05-Mar-2022

Recent Advances Gastro-retentive drug delivery system (GRDDS)

Introduction:
 Gastro-retentive drug delivery system (GRDDS) is one of the site specific delivery of the drugs at
stomach. It is obtained by retaining dosage form into stomach and drug is being released at sustained
manner to specific site either in stomach or intestine.
 Drug absorption from the gastrointestinal tract is a complex procedure and is subject to many variables.
The extent of gastrointestinal tract drug absorption is related to contact time with the small intestinal
mucosa. Small intestinal transit time is an important parameter for drugs that are incompletely absorbed.
 Gastro retentive systems can remain in the gastric region for several hours and hence significantly
prolong the gastric residence time of drugs. Prolonged gastric retention improves bioavailability, reduces
drug waste, and improves solubility for drugs that are less soluble in a high pH environment.
 The controlled gastric retention of solid dosage forms may be achieved by the mechanisms of
mucoadhesion, flotation, sedimentation, expansion, modified shape systems, or by the simultaneous
administration of pharmacological agents that delay gastric emptying.

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Pharmaceutical Technology-II 05-Mar-2022
Recent Advances and Approaches

1. Bio/Muco-adhesive System:

 Here, the drug is incorporated with bio/Muco-adhesive agents, enabling the device to adhere to the
stomach walls, thus resisting gastric emptying. However, the mucus on the walls of the Stomach is in a
state of constant renewal, Resulting in unpredictable adherence.
 The term bioadhesive describes materials that bind to biological substrates, such as mucosal membranes
and in bioadhesive drug delivery systems, the term bioadhesion is used to describe the bonding or
adhesion between a synthetic or natural polymer and soft tissues such as epithelial cells. The GI tract
and the nasal cavity have also been extensively examined as a site for bioadhesive drug delivery.
 The term mucoadhesion is the subgroup of bioadhesion and in the mucoadhesion formulation attaches
with the mucus membrane. The mucoadhesion can be defined as the adhesion between the two materials
in which one is biological material and other one is polymeric materials with the help of interfacial
forces to increase the residence time.
 Mucoadhesion is a useful strategy for drug delivery systems, such as tablets, patches, gels, liposomes,
micro/nanoparticles, nanosuspensions, microemulsions and colloidal dispersions. The mucoadhesion
bypasses the first pass metabolism and used for localized delivery of biomolecules such as peptides,
proteins and oligonucleotides. Mucoadhesion drug delivery system engages much attention due to their
benefits such as prolong retention time, fast uptake and increased bioavailability of active substance.
 Application of dosage forms to mucosal surfaces may be of benefit to drug molecules not amenable to
the oral route, such as those that undergo acid degradation or extensive first-pass metabolism. Dosage
forms designed for mucoadhesive drug delivery should be small and flexible enough to be acceptable for
patients and should not cause irritation. Other desired characteristics of a mucoadhesive dosage form
include high drug loading capacity, controlled drug release (preferably unidirectional release), good
mucoadhesive properties, smooth surface, tastelessness, and convenient application. Erodible
formulations can be beneficial because they do not require system retrieval at the end of desired dosing
interval.
 A number of relevant mucoadhesive dosage forms have been developed for a variety of drugs. Several
peptides, including thyrotropin-releasing hormone (TRH), insulin, octreotide, leuprolide, and oxytocin,
have been delivered via the mucosal route, albeit with relatively low bioavailability (0.1–5%), owing to
their hydrophilicity and large molecular weight, as well as the inherent permeation and enzymatic
barriers of the mucosa.

Dosage form can stick to mucosal surface by following mechanisms:

 The electron theory
 The wetting theory
 The diffusion theory
 The absorption theory
 The mechanical theory
 The fracture theory
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Advantages of mucoadhesive drug delivery system:

Mucoadhesive delivery systems offer several advantages over other oral controlled release systems by virtue of
prolongation of residence time of drug in gastrointestinal tract (GIT).
 Targeting and localization of the dosage form at a specific site.
 Also, the mucoadhesive systems are known to provide intimate contact between dosage form and the
absorptive mucosa, resulting in high drug flux at the absorbing tissue.

Factors Affecting Mucoadhesion:

 Molecular weight
 Flexibility
 Cross-linking density
 Hydrogen bonding capacity
 Hydration

Sites for Mucoadhesive Drug Delivery Systems:

The common sites of application where mucoadhesive polymers have the ability to deliver pharmacologically
active agents include oral cavity, eye conjunctiva, vagina, nasal cavity and GIT.
The buccal cavity has a very limited surface area of around 50 cm2 but the easy access to the site makes it a
preferred location for delivering active agents. The site provides an opportunity to deliver pharmacologically
active agents systemically by avoiding hepatic first-pass metabolism in addition to the local treatment of the
oral lesions.

Mucoadhesive Dosage Forms

These include Tablets, Films, Patches and Ointments.

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2. Raft System:
Raft forming system, is a type of floating drug delivery system, remains and helps drugs that are poorly soluble
in stomach. Floating drug delivery system will have high density than stomach fluids, so remain same for a
longer period of time without affecting the gastric emptying rate. The drug will slowly be released, at the
required rate while system floats on the gastric contents. The residue is emptied from stomach after the release
of the drug, which results in proper control of fluctuation in plasma concentration and increased gastric
residence time.
Some of the potential situations or candidates for gastroretentive drug delivery systems are, Drugs that are
degradable in colon like Metformin HCL, Drugs that are poorly soluble in Alkaline like Diazepam, Drugs
acting locally in the stomach, Drugs that are absorbed in stomach like Amoxicillin.
More than half of the total percentage of available drug delivery systems are administered through mouth, as
this is the promising drug delivery system route and based on factors like emptying process and time its
effective than others.
The mechanism involved in this system includes the formation of a viscous cohesive gel in contact with Raft
gastric fluids, wherein each portion of the liquid swells, forming a continuous layer called a raft. This raft floats
on gastric fluids because of low bulk density created by the formation of CO2.

Float Rafting System Design:

There are several factors to be considered to formulate a raft forming system and they are like drug molecule
and its physicochemical properties, and one who is diseased and condition of he/she, preference of marketing
and population of the patients etc., When we consider physicochemical properties they are like molecular
charge, molecular weight, lipophilicity.
The factors for formulation need to be considered are osmolarity, temperature, viscosity and spread ability. For
the dosage form, to achieve gastric retention of, it needs to be able to satisfy below criteria:
 The release of drug should be slow from the system
 Compliance of patient should be good
 Specific gravity should be maintained lower than gastric contents
 For the force exerted by peristaltic waves in the stomach and griding, churning moments, and
contraction, the dosage form needs to be able to withstand the force.
 The device should easily exit out of the system, after the drug is released.

Advantages:
 Therapeutic efficacy will improve.
 Floating of dosage forms faster than others.

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 Administration into the patient is easy.
 It is proved more effective because on gastric contents it forms low density viscous layer.
 Plasma level fluctuation will reduce.
 In the small intestinal region, the absorption of the drug is narrow like delivery of drugs.

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3. Low density Approach (Floating Drug Delivery):

Retained in stomach Useful for poorly water soluble OR unstable in intestinal Fluid Bulk density; Less than
gastric fluid (<1 g/cm3), so remain buoyant in the stomach without affecting gastric emptying rate for
prolonged period of time So drug release slowly at the desired rate from system.

Floating drug delivery systems are classified depending on the use of 2 formulation variables;
a) Effervescent Floating Dosage Forms:
These are matrix types of systems prepared with the help of swell-able polymers such as methylcellulose and
chitosan and various effervescent compounds, e.g., sodium bicarbonate, tartaric acid, and citric acid.
They are formulated in such a way that when in contact with the acidic gastric contents, CO2 is liberated and
gets entrapped in swollen hydrocolloids, which provides buoyancy to the dosage forms. They include:
Gas Generating Systems:
Gas bubble generation helps to achieve floatability. The swell-able polymers like methylcellulose and chitosan
and various effervescent compounds, e.g. sodium bicarbonate, tartaric acid and citric acid, help in creating
matrix type of such systems.
They are created in a manner that upon contact with gastric contents CO2 is released finally entrapping in
swollen hydrocolloids, that makes dosage forms buoyant.

 Single-Unit Dosage Forms

 Multiple-Unit Dosage Forms
 Floating System with ion exchange resins

Volatile Liquid Containing System:

This system comprises of dual chambers having an impermeable, pressure responsive, movable bladder
separation. The former chamber has drugs and the latter has volatile liquid. To sustain the GRT of a drug
delivery system an inflatable chamber has to be incorporated, that carries a liquid e.g. ether, cyclopentane. It
turns to gaseous form at body temperature causing inflatation of the chamber in the stomach.
It may contain a biodegradable plug, made of polyvinyl alcohol, polyethylene, etc. This plug gradually
dissolves making the chamber release gas and to collapse after a specific duration to allow spontaneous release
of the inflatable systems from the stomach.
These systems are further classified as below:
 Intra-gastric floating gastrointestinal drug system.
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 Inflatable gastrointestinal delivery system
 Intra-gastric-osmotically controlled drug delivery system

b) Non-Effervescent Floating Dosage Forms

Non-effervescent floating dosage forms use a gel forming or swellable cellulose type hydrocolloids,
polysaccharides, and matrix-forming polymers like polycarbonate, polyacrylate, polymethacrylate, and
polystyrene.
The formulation method includes a simple approach of thoroughly mixing the drug and the gel-forming
hydrocolloid. After oral administration this dosage form swells in contact with gastric fluids and attains a bulk
density of < 1. The air entrapped within the swollen matrix imparts buoyancy to the dosage form. The so
formed swollen gel-like structure acts as a reservoir and allows sustained release of drug through the gelatinous
mass.
These systems are further classified as below:
 Hydrodynamically balanced systems
 Microballoons/hollow microspheres
 Alginate beads
 Layered tablets
 Single layered floating tablets
 Double layered floating tablets

Applications of Floating Drug Delivery Systems:

 Floating drug delivery offers several applications for drugs having poor bioavailability because of the
narrow absorption window in the upper part of the gastrointestinal tract.
 It retains the dosage form at the site of absorption and thus enhances the bioavailability. These are
summarized as follows.
 Sustained Drug Delivery
 Site-Specific Drug Delivery
 Absorption Enhancement
 These systems are particularly advantageous for drugs that are specifically absorbed from stomach or the
proximal part of the small intestine, e.g., riboflavin and furosemide.

Limitations:
Drugs that irritate the mucosa, those that have multiple absorption sites in the gastrointestinal tract, and those
that are not stable at gastric pH are not suitable candidates to be formulated as floating dosage forms.
The use of large single-unit dosage forms sometimes poses a problem of permanent retention of rigid large-
sized single-unit forms especially in patients with bowel obstruction, intestinal adhesion, gastropathy, or a
narrow pyloric opening.
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Floating dosage form should not be given to a patient just before going to bed as the gastric emptying of such a
dosage form occurs randomly when the subject is in supine posture.

Marketed Preparations of Floating Drug Delivery Systems

 Madopar (Levodopa)
 Valrelease (Diazepam)
 Topalkan (Aluminum Magnesium Antacid)
 Almagate flatcoat (Antacid)
 Liquid gavison (Alginic Acid & Sodium Bicarbonate)

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4. Plug Systems OR Expandable systems

Expandable gastric retentive delivery systems are easily swallowed and reach a significantly larger size in the
stomach due to swelling or unfolding processes that prolong their gastric retention time.11 After drug release,
their dimensions are minimized with subsequent evacuation from the stomach. Gastro-retentivity is enhanced by
the combination of substantial dimensions with high rigidity of the dosage form to withstand the peristalsis and
mechanical contractility of the stomach. Narrow absorption window drugs compounded in such systems have
improved in vivo absorption properties.

Mechanism:
Expansion mechanism of this system is swelling to an extent that prevents their exit from the pylorus. As a
result, the dosage form is retained in the stomach for a long period of time. These systems may be named as
“plug type system”, since they exhibit the tendency to remain logged at the pyloric sphincter if that exceed a
diameter of approximately 12-18 mm in their expanded state.
The formulation is designed for gastric retention and controlled delivery of the drug into the gastric cavity. Such
polymeric matrices remain in the gastric cavity for several hours even in the fed state. A balance between the
extent and duration of swelling is maintained by the degree of cross-linking between the polymeric chains. A
high degree of cross-linking retards the swelling ability of the system maintaining its physical integrity for
prolonged period.
A dosage form in the stomach will withstand gastric transit if it is bigger than the pyloric sphincter However,
the dosage form must be small enough to be swallowed, and 13mm diameter must not cause gastric obstruction
Expansion by swelling or unfolding to a large size. either singly or by accumulation.

5. High Density Approach:

Sedimentation has been employed as a retention mechanism for pellets that are small enough to be retained in
the folds of the stomach body near the pyloric region, which is the part of the organ with the lowest position in
an upright posture.
20 Dense pellets (approx. 3g/cm3) trapped in rugae also tend to withstand the peristaltic movements of the
stomach wall. With pellets, the GI transit time can be extended from an average of 5.8–25 hours. Commonly
used excipients are barium sulphate, zinc oxide, titanium dioxide and iron powder, etc. These materials increase
density by up to 1.5–2.4g/cm3.

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6. Magnetic system:
In this system, by using a powerful magnetic field of strong magnet onto the body surface, the movement of
gastroretentive formulation with a small internal magnet is controlled.
Several reports tell about the positive result of this system, but the success of this system depends upon a
selection of the magnet position with very high precision.
Groning and Berntgen developed peroral acyclovir depot tablets with an internal magnet. An extracorporeal
magnet was used to prolong the gastric residence time of the dosage form and to influence the duration of
absorption of acyclovir.

7. Polymeric Nanofibers: Targeted Gastro-Retentive Drug Delivery Systems:

Nanofiber system provides stomach-specific drug release for longer duration; moreover, increased local action
of the drug due to prolonged contact time with the gastric mucosa. Thus, the nanofiber system promises to be
the potential approach for gastric retention drug delivery system.

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References:

https://www.jpsr.pharmainfo.in/Documents/Volumes/vol11issue12/jpsr11121913.pdf
https://www.semanticscholar.org/paper/ADVANCES-IN-GRDDS%3A-RAFT-FORMING-SYSTEM-
A-REVIEW-Mahendrakumar-Surendran/009d5ece057cc5c61522166c3517dfef80b19c37
http://jddtonline.info/index.php/jddt/article/view/3708#:~:text=The%20term%20bioadhesive
%20describes%20materials,tissues%20such%20as%20epithelial%20cells.
https://www.sciencedirect.com/science/article/pii/S1818087616300320
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523542/

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