‫بسم هللا الرحمن الرحيم‬

A drug delivery system (DDS)

By
Dr. Suhaib Alsafi Ahmed
BSc &Msc Pharma
MUCOSAL DRUG DELIVERY SYSTEM

• Oral delivery has so far been the most common and preferred route of administration for most of the
therapeutic agents. The popularity of the oral route has been attributed to the patient acceptance, ease of
administration, accurate dosing, cost effective manufacturing method, least sterility constraints, flexible
design of dosage forms and generally improved shelf-life of the product.
• Mucoadhesive drug delivery has been a topic of interest in the design of drug delivery systems to
lengthen the residence time of the dosage form at the site of application or absorption and to facilitate
intimate contact of the formulation with the underlying absorption surface, so as to improve and enhance
the bioavailability of drug.
• Mucoadhesive drug delivery systems are beneficial, since they give a controlled drug release over a
period of time and can also be utilized for localizing the drug to a specific site in the body.
Mucoadhesive substances could also be used as therapeutic agents in their own right, to coat and protect
and soothe the injured tissues (gastric ulcers or lesions of the oral mucosa) or as lubricants (in the oral
cavity, eye and vagina).
• Mucoadhesion may be defined as a state in which two components, of which one is
of biological source, are joined together for prolonged periods of time by the aid of
interfacial forces. 'Bioadhesion' broadly includes adhesive interactions with any
biological or biologically derived substance, whereas 'Mucoadhesion' is used when
the bond is formed with a mucosal surface, while the term cytoadhesive means
adhesion to cells. Mucoadhesive drug delivery systems are also a sub-type of
gastroretentive drug delivery systems.
• In the formulation of oral controlled release dosage forms, significant benefits may
follow from the use of mucoadhesive polymers providing brief adhesion between
the drug delivery system and the mucous or epithelial cell surface of the alimentary
canal. The bond between polymer and mucous membrane involves secondary
forces, such as hydrogen bonds or Van der Waal’s forces. Mucoadhesives may,
therefore, be regarded as a specific class of bioadhesives.
• Mucoadhesive/bioadhesive drug delivery system can be applied to the
following systems:
• • Buccal delivery system
• Oral delivery system
• Vaginal delivery system
• Rectal delivery system
• Nasal delivery system
• Ocular delivery system
• Mucous Membranes:
• Mucous membranes (mucosae) are the moist surfaces, lining the walls of various
body cavities such as the gastrointestinal and respiratory tracts. They consists of
a connective tissue layer (the lamina propria) above which is an epithelial layer,
the upper part of which is made moist usually due to the presence of a mucous
layer. The epithelia may be either single layered (e.g. the stomach, small and
large intestine and bronchi) or multilayered/stratified (e.g. in the oesophagus,
vagina and cornea).
• The primary components of all mucous gels are mucin glycoproteins, lipids,
inorganic salts and water, the latter comprising more than 95% of its weight,
making it a highly hydrated system. The mucin glycoproteins are the most
important structure forming component of the mucous gel, which provide the
mucous with its characteristic gel-like, cohesive and adhesive properties.
• Composition of Mucous Layer:
• Mucous is translucent and viscous secretion which forms a thin, continuous gel layer
sticking to the mucosal epithelial surface. Mucous glycoproteins are high molecular weight
proteins possessing attached oligosaccharide units containing, L-fructose, D-galactose,
N-acetyl-D-glucosamine, N-acetyl-D-galactosamine and Sialic acid.
• Functions of Mucous Layer:
• • Mucous layer is protective because of its hydrophobicity.
• • It influences the bioavailability of drugs as it acts as a barrier in tissue absorption of
drugs and other substrates.
• It strongly bonds with the epithelial cell surface as a continuous gel layer.
• It plays a major role in the lubrication of the mucosal membrane and maintenance of its
moisture.
• Need of Mucoadhesive:
• • For sustained release of drug.
• • To target drug delivery and also for localized drug delivery.
• • To bypass or minimize hepatic first pass metabolism so that drug
degradation can be avoided.
• • For prolonged therapeutic effect.
• • For high and rapid drug movement through the absorbing tissue.
• • To reduce in fluctuation of steady state plasma level.
• Mechanism of Mucoadhesion:
• Mucoadhesion is a complex process
involving wetting, adsorption and
interpenetration of polymer chains.
Mucoadhesion is established in the
following stages:
• • Contact stage: Intimate physical
contact between a
Bioadhesive/Mucoadhesive material and
a membrane (wetting or swelling
phenomenon).
• • Consolidation stage: Penetration of the
Bioadhesive/Mucoadhesive into
underlying the tissue or into the surface of
the mucous membrane (interpenetration).
• Mucoadhesion Theories
• Various theories exist to explain at least some of the experimental
observations made during the bioadhesion process. Unfortunately, each
theoretical model can only explain a limited number of the diverse range of
interactions that constitute the bioadhesive bond.
• However five main theories can be distinguished.
• 1. Wetting theory
• 2. Electronic theory
• 3. Fracture theory
• 4. Adsorption theory
• 5. Diffusion theory
• Wetting Theory:
• The wetting theory applies to liquid systems which presents affinity to the surface in order
to spread over it. This affinity can be found by using measuring techniques such as the
contact angle. The general rule states that the lower the contact angle then the greater
the affinity. The contact angle should be equal or close to zero to provide adequate
spreadability.
Electronic Theory:
• The electronic theory depends on the assumption that the bioadhesive material and the
target biological material have different electronic surface characteristics. Based on this,
when two surfaces come in contact with each other, electron transfer occurs in an attempt
to balance the Fermi levels, resulting in the formation of a double layer of electrical charge
at the interface of the bioadhesive and the biologic surface. The bioadhesive force is
believed to be present.
• Adsorption Theory:
• This theory states that the bioadhesive bond formed between an adhesive substrate and the tissue
is due to the weak Van der Waal's forces and hydrogen bond formation. For example, hydrogen
bonds are the prevalent interfacial forces in polymers containing carboxyl groups. Such forces have
been considered the most important in the adhesive interaction phenomenon because, although
they are individually weak, a great number of interactions can result in an intense global adhesion.
• 4. Fracture Theory:
• This theory describes the force required for the separation of two surfaces after adhesion. The
fracture strength is equivalent adhesive strength.
• Diffusion Theory:
• The concept of the interpenetration and entanglement of the bioadhesive polymer chains and
mucous polymer chains is supported by the diffusion theory. The bond strength increases with the
increase in the degree of the penetration. This penetration rate depends on the diffusion coefficient,
flexibility and nature of the mucoadhesive chains, mobility and contact time.
• Mechanical Theory
• Mechanical theory considers adhesion to be due to the filling of
the irregularities on a rough surface by a mucoadhesive liquid.
Moreover, such roughness increases the interfacial area
available to interactions thereby aiding dissipating energy and
can be considered the most important phenomenon of the
process. It is unlikely that the mucoadhesion process is the
same for all cases and therefore it cannot be described by a
single theory. In fact, all theories are relevant to identify the
important process variables.
 Advantages of Mucoadhesive Drug
Delivery System:
• Mucoadhesive delivery system offers several • • Better patient compliance.
advantages over conventional drug delivery
systems which are as follows: • Moreover, rapid cellular recovery and healing of
the local site.
• • Prolongs the residence time of the dosage form
at the site of absorption, hence increases the • • Reduces dosing frequency.
bioavailability.
• • Shorter treatment period.
• • Excellent accessibility, rapid onset of action
possible. • • Increases safety margin of high potency drugs
• • Rapid absorption because of enormous blood due to better control of plasma levels.
supply and good perfusion rates. • • Maximum utilization of drug enabling
• • An alternative to oral route, whereby the drug reduction in total amount of drug administered.
is protected from degradation in the acidic
environment of the GIT.
• Disadvantages:
• • Drugs, which irritate the oral mucosa, have a bitter or unpleasant taste, odour,
cannot be administered by this route.
• • Drugs, which are unstable at buccal pH, cannot be administered by this route.
• • Only drugs with small dose requirements can be administered.
• • Drugs may be swallowed along with the saliva and lose the advantages of
buccal route.
• • Only those drugs, which are absorbed by passive diffusion, can be administered
by this route.
• • Eating and drinking may become restricted.
• • In case of vaginal drug delivery, the drug has to be stable in the acidic vaginal
pH.
• • The vaginal formulation may interfere with sexual intercourse.
• • The vaginal formulation may leak and cause messiness.
• • The vaginal formulation may be contraindicated in case of pregnancy.
• • In case of ocular formulations, the formulation may cause uneasiness
and blurring.
• • It may get dislodged.
• • In case of nasal formulations, the presence of the formulation may
stimulate sneezing and subsequent dislodgement of the formulation.
• • The formulation may irritate the sensitive nasal mucosa.
• • Over hydration may lead to the formation of slippery surface and
structural integrity of the formulation may get disrupted by the swelling and
hydration of the bioadhesive polymers.
• Formulation
• In case of both mucosal (local) and transmucosal (systemic) administration, conventional dosages
are not able to assure therapeutic level.
• Mucosal drug delivery systems contains active drug along with the following functional agents:
• (1) Mucoadhesive polymers (2) Penetration enhancers (3) Enzyme inhibitors.
• (a) Mucoadhesive Polymers: The polymer hydration and consequently the mucous cohesive
properties that promote mucoadhesion (MA). Swelling should favour polymer chain flexibility and
interpenetration o/w polymer and mucin chains.
(b) Penetration Enhancers (PE): PE is also required when a drug has to reach the systemic
circulation to exert its action.
• Must be non-irritant and have a reversible effect.
• Recently, chitosan and its derivatives, polymers already known for MA properties help for
transportion of drug through paracellular pathway.
• List of Permeation Enhancer: Benzalkonium chloride, Dextran
sulfate, Fatty acid, Propylene glycol, Menthol, Phosphatidylcholine,
Polysorbate 80, Sodium EDTA.
• (c) Enzyme inhibitors: Drug + enzyme inhibitors —> improving the
buccal absorption of drugs, particulary peptides.
• Examples: 1. Aprotinin 2. Bestatin 3. Puromycin bile salts stabilise
protein drugs by different mechanism (effecting the activity of the
enzymes, altering the conformation of the protein. Chemical
modification of chitosan with EDTA produces polymer conjugate
chitosan EDTA that is a very potent inhibitor of metallopeptidases
(carboxypeptidase).
• Various types of polymers are used in mucoadhesive formulation. The polymers have the following
properties:
• 1. It must be loaded substantially by the active compound.
• 2. Swell in the aqueous biological environment of the delivery absorption site.
• 3. Interact with mucous or its components for adequate adhesion.
• 4. When swelled they allow, controlled release of the active compound.
• 5. It should be excreted unaltered or biologically degraded to inactive, non-toxic oligomers.
• 6. Sufficient quantities of hydrogen bonding chemical groups.
• 7. Possess high molecular weight.
• 8. Possess high chain flexibility.

• 9. Surface tension that will induce spreading into mucous layer

• Classification of Mucoadhesive Polymers
• I. Based on Specificity:
• (a) The specific bioadhesive polymers: These have the ability to adhere specific
chemical structures within the biological molecules, e.g. Lectins, fimbrin.
• (b) The non-specific bioadhesive polymers: These have the ability to bind with
both the cell surfaces and the mucosal layer, e.g. Polyacrylic acid, cyanoacrylates.
• II. Based on Origin:
• (a) Synthetic Polymers
• For example: Cellulose derivatives: Methyl cellulose, ethyl cellulose,
hydroxyethyl cellulose.
• Polyacrylic acid polymers: Polymethylacrylate, polyvinylpyrrolidone, polyvinyl
alcohol.
• (b) Natural Polymers
• For example: Tragacanth, sodium alginate, karaya gum, guar gum, xanthan
gum, lectin, soluble starch, gelatin, pectin, chitosan.
• III. According to their Charge:
• (a) Anionic polymers: carbopol, polyacrylates.
• (b) Cationic polymers: chitosan.
• (c) Neural/non-ionic polymers: eudragit analogues.
• IV. Based on Solubility:
• (a) Water soluble polymers (b) Water insoluble polymers
• Factors Affecting Mucoadhesion:
• The mucoadhesion of a drug carrier system to the mucous membrane
depends on the below mentioned factors.
• I. Polymer Based Factors:
• • Molecular weight of the polymer,
• • Concentration of polymer used of polymer chain.
• • Swelling factor
• • Stereochemistry of polymer.
• II. Physical Factors:
• • pH at polymer substrate interface
• • Applied strength,
• • Contact time.
• III. Physiological Factors
• • Mucin turnover rate
• • Diseased state.
• Applications of Mucosal Drug Delivery System
• Mucoadhesive Dosage Forms are available in various following forms summarized in
table :
• 1) Tablets: Tablets are small, flat and oval, with a diameter of approximately 5-8 mm.
Unlike the conventional tablets, mucoadhesive tablets allow for drinking and speaking
without major discomfort. They soften, adhere to the mucosa, and are retained in position
until dissolution and/or release is complete. Mucoadhesive tablets, in general, have the
potential to be used for controlled release drug delivery, but coupling of mucoadhesive
properties to tablet has additional advantages, for example, it offers efficient absorption
and enhanced bioavailability of the drugs due to a high surface to volume ratio and
facilitates a much more intimate contact with the mucous layer.
• Films: Mucoadhesive films may be preferred over adhesive tablets
in terms of flexibility and comfort. In addition, they can circumvent
the relatively short residence time of oral gels on the mucosa, which
are easily washed away and removed by saliva. Moreover, in the
case of local delivery for oral diseases, the films also help to protect
the wound surface, thus help to reduce pain, and treat the disease
more effectively. An ideal film should be flexible, elastic, and soft, yet
adequately strong to withstand breakage due to stress from mouth
movements.It must also possess good mucoadhesive strength in
order to be retained in the mouth for the desired duration of action.
Swelling of film, if it occurs, should not be too extensive in order to
prevent discomfort.
• Patches: Patches are laminates consists of an impermeable
backing layer, a drug¬ containing reservoir layer from which the
drug is released in a controlled manner, and a mucoadhesive
surface for mucosal attachment. Patch systems are similar to
those used in transdermal drug delivery. Two methods used to
prepare adhesive patches includes solvent casting and direct
milling. In the solvent casting method, the intermediate sheet
from which patches are punched is prepared by casting the
solution of the drug and polymer(s) onto a backing layer sheet,
and subsequently allowing the solvent(s) to evaporate.
• Gels and Ointments: Semisolid dosage forms, such as gels and ointments,
have the advantage of easy dispersion throughout the oral mucosa. However,
drug dosing from semisolid dosage forms may not be as accurate as from tablets,
patches, or films. Poor retention of the gels at the site of application has been
overcome by using mucoadhesive formulations.
• Certain mucoadhesive polymers, for example, sodium carboxymethylcellulose,
carbopol, hyaluronic acid and xanthan gum, undergo a phase change from liquid
to semisolid. This change enhances the viscosity, which results in sustained and
controlled release of drugs. Hydrogels are also a promising dosage form for
buccal drug delivery.
• They are formed from polymers that are hydrated in an aqueous environment and
physically entrap drug molecules for subsequent slow release by diffusion or
erosion. The application of mucoadhesive gels provides an extended retention
time in the oral cavity, adequate drug penetration, as well as high efficacy and
patient acceptability.
 ‫لالطالع‬
• Evaluation
• (1) Tensile Stress Measurement:
• (a) Wilhelmy plate technique: The Wilhelmy plate technique is traditionally used for the
measurement of dynamic contact angles. The instrument measures the bioadhesive force
between mucosal tissue and the dosage form. By using the CAHN software system,
parameters such as fracture strength, deformation to failure and work of adhesion can be
analysed.
• (b) Electromagnetic force transducer (EMFT) uses a calibrated electromagnet to
detach a magnetic loaded polymer DDS from a tissue sample.
• • It has the unique ability to record remotely and simultaneously the tensile force
information as well as high magnification video images of bioadhesive interactions at near
physiological conditions.
• • EMFT measures tissue adhesive forces by monitoring the magnetic force required to
exactly oppose the bioadhesive force.
• Shear Stress Measurement:
• The shear stress technique measures the force that causes a mucoadhesive to slide
with respect to the mucous layer in a direction parallel to their plane of contact.
• Adhesion tests based on the shear stress measurement involves two glass slides
coated with polymer and a film of mucous. Mucous forms a thin film between the
two polymer coated slides, and the test measures the force required to separate the
two surfaces.
• (3) Rheological Approach:
• The rheological properties of the mucoadhesive interface (i.e. of the hydrated gel)
are influenced by the occurrence of interpenetration step in the process of
bioadhesion. Chain interlocking, conformational changes and chemical interaction,
which occur between bioadhesive polymer and mucin chains, produce changes in
the rheological behaviour of the two macromolecular species.
• Colloidal Gold Staining Method:
• This technique employs red colloidal gold particles, which are stabilized by the adsorbed
mucin molecule by forming mucin-gold conjugates.
• • Upon interaction with mucin-gold conjugates, bioadhesive hydrogels develops a red
colour on the surface.
• • Thus, the interaction between them can easily be quantified, either by the measurement
of the intensity of the red colour on the hydrogel surface or by the measurement of the
decrease in the concentration of the conjugates from the absorbance changes at 525 nm.
• (5) Viscometeric Method:
• A simple viscometric method is used to quantify mucin-polymer bioadhesive bond
strength viscosities of 15% w/v porcine gastric mucin dispersion in 0.1 M HCI (pH 1) or
0.1 M acetate buffer (pH 5.5) are measured with a Brookefield viscometer in the absence
or presence of selected neutral, anionic, and cationic polymers. Viscosity components
and the forces of bioadhesion are calculated.
• Fluorescent Probe Method:
• Fluorescent probe method is used to study polymer interaction with a conjunctival
epithelial cell membrane. The experiment consists of adding a fluorescent lipo soluble
probe, pyrene, which localizes in the lipid bilayer of the cell membrane, to a suspension of
cultured human conjunctival epithelial cells. The cells are then mixed with various
bioadhesive polymers. The addition of a polymer, which binds to the cell membrane,
resulted in compression of the lipid bilayer, causing a change in fluorescence proportional
to polymer binding. Measurement of pyrene fluorescence provides a quantitative way to
compare the interaction of polymers with the cell membrane.
• (7) Thumb Test:
• It is a simple method which can be used to identify mucoadhesives. The adhesiveness is
quantitatively measured by the difficulty of pulling the thumb from the adhesive as a
function of the pressure and the contact time. Although the thumb test may not be
conclusive, it provides useful information on mucoadhesive potential.
• (8) Buccal Absorption Test: (Swirl and spit test)
• Buffered drug solution, of known volume and concentration, is
placed in the subject's mouth and is swirled in the mouth for a
defined length of time. The solution is then expelled and assayed.
The amount of drug absorbed is determined by the difference
between the amounts of drug introduced and recovered.
• (9) In-vivo Perfusion Studies:
• Perfusion experiments are done by attaching the perfusion
chambers to the oral mucosa of an anesthetized dog. Drug solutions
are circulated through the device and collected at different time
intervals.
• (10) GI Transit using Radio-opaque Technique:
• It involves the use of radio-opaque markers, e.g.,
barium sulfate, encapsulated in bioadhesive DDS to
determine the effects of bioadhesive polymers on GI
transit time.
• Faeces collection (using an automated faeces collection
machine) and X-ray inspection provide a non-invasive
method of monitoring total GI residence time without
affecting normal GI motility.
• Gamma Scintigraphy Technique:
• It is a valuable tool used in the development of pharmaceutical dosage
forms. With this methodology, it is possible to obtain information non-
invasively. This technique gives information in terms of:
• o oral dosage forms across the different regions of GI tract
• o the time and site of disintegration of dosage forms
• o the site of drug absorption
• o also the effect of food
• o disease
• o size of the dosage form on the in-vivo performance of the dosage forms.
GASTRORETENTIVE DRUG DELIVERY
SYSTEM
• Various drugs have their greatest therapeutic effect when released in the stomach,
particularly when the release is prolonged in a continuous, controlled manner.
Drugs delivered in this manner have a lower level of side effects and provide their
therapeutic effects without the need for repeated dosages or with a low dosage
frequency.
• • Drugs that are absorbed from the proximal part of the gastrointestinal tract
(GIT).
• • Drugs that are less soluble or are degraded by the alkaline pH they encounters at
the lower part of GIT.
• • Drugs that are absorbed due to variable gastric emptying time.
• • Local or sustained drug delivery to the stomach and proximal small intestine to
treat certain conditions.
• • Particularly useful for the treatment of peptic ulcers caused by H. Pylori
Infections.
• In general, appropriate candidates for GRDDS are molecules that have poor colonic
absorption but are characterized by better absorption properties at the upper parts of the
GIT:
• • Drugs acting locally in the stomach, e.g. Antacids and drugs for H. Pylori viz.,
Misoprostol.
• • Drugs that are primarily absorbed in the stomach, e.g. Amoxicillin. Drugs that is poorly
soluble at alkaline pH. e.g. Furosemide, Diazepam, Verapamil, etc.
• • Drugs with a narrow window of absorption e.g. Cyclosporine, Methotrexate, etc.
• • Drugs which are absorbed rapidly from the GI tract, e.g. Metonidazole, tetracycline.
• • Drugs that degrade in the colon, e.g. Ranitidine, Metformin HCI.
• • Drugs that disturb normal colonic microbes e.g. antibiotics against Helicobacter pylori.
• Factors Affecting Gastric Retention Time of the Dosage Form
• • Density: GRT is a function of dosage form buoyancy that is dependent on the density.
• • Size and Shape of dosage form: Shape and size of the dosage forms are important in
designing indigestible single unit solid dosage forms.
• • Single or multiple unit formulation: Multiple unit formulations shows a more
predictable release profile and insignificant impairing of performance due to failure of
units allow co-administration of units with different release profiles or containing
incompatible substances and permit a larger margin of safety against dosage form failure
compared with single unit dosage forms.
• • Fed or unfed state: Under fasting conditions: GI motility is characterized by periods of
strong motor activity or the migrating myoelectric complex (MMC) that occurs every 1.5
to 2 hours.
• • Nature of meal: Feeding of indigestible polymers or fatty acid salts can
change the motility pattern of the stomach to a fed state, thus decreasing the
gastric emptying rate and prolonging drug release.
• • Caloric content: GRT can be increased by 4 to 10 hours with a meal that is
high in proteins and fats.
• • Frequency of feed: The GRT can increase by over 400 minutes, when
successivemeals are given compared with a single meal due to the low
frequency of MMC.
• • Gender: Male: 3.4 ± 0.6 hr to Female: 4.6 ± 1.2 hr.
• • Age: Elderly people, especially those over 70, have a significantly longer GRT.
• • Posture: GRT can vary between supine and upright ambulatory states of the
patient.
• • Concomitant drug administration: Anticholinergic like atropine, propenthelineincrease
GRT. Metoclopramide and cisapride decrease GRT.
• • Disease state: Gastric ulcer, diabetes, hypothyroidism increase GRT. Hyperthyroidism,
duodenal ulcers decrease GRT.
• Advantages of Gastroretentive Delivery Systems:
• 1. Improvement of bioavailability and therapeutic efficacy of the drugs and
possible reduction of dose e.g. Furosemide.
• 2. Maintenance of constant therapeutic levels over a prolonged period and thus
reduction in fluctuation in therapeutic levels minimizing the risk of resistance
especially in case of antibiotics. For example: p-lactam antibiotics (penicillins and
cephalosporins).
• 3. For drugs with relatively short half life, sustained release may result in a flip-
flop pharmacokinetics and also enable reduced frequency of dosing with
improved patient compliance.
• 4. They also have an advantage over their conventional system as it can be used
to overcome the adversities of the gastric retention time (GRT) as well as the
gastric emptying time (GET). As these systems are expected to remain buoyant
on the gastric fluid without affecting the intrinsic rate of employing because their
bulk density is lower than that of the gastric fluids.
• 5. Gastro retentive drug delivery can produce prolongs and sustains release of drugs from
dosage forms which avail local therapy in the stomach and small intestine Hence, they are
useful in the treatment of disorders related to stomach and smallintestine.
• 6. The controlled, slow delivery of drug from gastro retentive dosage form provides sufficient
local action at the diseased site, thus minimizing or eliminating systemic exposure of drugs.
This site-specific drug delivery reduces undesirable effects of side effects.
• 7. Gastro retentive dosage forms minimize the fluctuation of drug concentrations and effects.
Therefore, concentration dependent adverse effects that are associated with peak
concentrations can be presented. This feature is of special importance for drug with a narrow
therapeutic index.
• 8. Gastro retentive drug delivery can minimize the counter activity of the body leading to higher
drug efficiency.
• 9. Reduction of fluctuation in drug concentration makes it possible to obtain improved
selectivity in receptor activation.
• 10. The sustained mode of drug release from Gastro retentive doses form enables extension of
the time over a critical concentration and thus enhances the pharmacological effects and
improves the chemical outcomes.
• Limitations:
• 1. Require a higher level of fluids in the stomach.
• 2. Not suitable for Drugs that...
• • Have solubility problems in gastric fluid, e.g. Phenytoin
• • Cause G.I. irritation, e.g. NSAIDS.
• • Are unstable in acidic environment.
• 3. Drugs intended for selective release in the colon e.g. 5-amino salicylic acid and corticosteroids etc.
• 4. The floating systems in patients with achlorhydria can be questionable in case of swellable system.
• 5. Retention of high density systems in the antrum part under the migrating waves of the stomach is
questionable.
• 6. The mucous on the walls of the stomach is in a state of constant renewal, resulting in unpredictable
adherence.
Approaches to Achieve Gastric Retention
• Floating - A Low Density Approach
• • Floating Drug Delivery Systems (FDDS) or hydro-dynamically balanced systems have a bulk
density lower than gastric fluids and thus remain buoyant in the stomach without affecting the
gastric emptying rate for a prolonged period of time. While the system is floating on the gastric
contents, the drug is released slowly at a desired rate from the stomach. After the release of the
drug, the residual system is emptied from the stomach. This results in an increase in the gastric
retention time and a better control of fluctuations in the plasma drug concentration in some cases.
• • The floating sustained release dosage forms present most of the characteristics of hydrophilic
matrices and are known as ‘Hydrodynamically Balanced Systems' ('HBS’) since they are able to
maintain their low apparent density, while the polymer hydrates and builds a gelled barrier at the
outer surface. The drug is released progressively from the swollen matrix, as in the case of
conventional hydrophilic matrices. These forms are expected to remain buoyant (3-4 hours) on the
gastric contents without affecting the intrinsic rate of emptying because their bulk density is lower
than that of the gastric contents.
• • The Floating Drug Delivery System (FDDS) can be divided into effervescent and noneffervescent
systems.
• A) Effervescent Systems:
• • These are matrix type of systems prepared with the help of swellable 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 gastric contents, CO2 is liberated and gets entrapped in swollen
hydrocolloids, which provides buoyancy to the dosage forms.
• (i) Volatile Liquid Containing Systems:
• • These have an inflatable chamber which contains a liquid e.g. ether, cyclopentane, that
gasifies at body temperature to cause the inflation of the chamber in the stomach.
• • These systems are osmotically controlled floating systems containing a hollow
deformable unit. There are two chambers in the system first contains the drug and the
second chamber contains the volatile liquid.
• (ii) Gas Generating Systems:
• • These buoyant systems utilised matrices prepared with swellable polymers like
methocel, polysaccharides like chitosan, effervescent components like sodium
bicarbonate, citric acid and tartaric acid or chambers containing a liquid that
gasifies at body temperature. The optimal stoichiometric ratio of citric acid and
sodium bicarbonate for gas generation is reported to be 0.76 : 1.
• • The common approach for preparing these systems involves resin beads
loaded with bicarbonate and coated with ethylcellulose. The coating, which is
insoluble but permeable, allows permeation of water. Thus, carbon dioxide is
released, causing the beads to float in the stomach.
• • Other approaches and materials that have been reported are highly swellable
hydrocolloids and light mineral oils, a mixture of sodium alginate and sodium
bicarbonate, multiple unit floating pills that generate carbon dioxide when
ingested, floating minicapsules with a core of sodium bicarbonate, lactose and
polyvinyl pyrrolidone coated with hydroxypropyl methylcellulose (HPMC) and
floating systems based on ion exchange resin technology, etc.
• (iii) Matrix Tablets:
• • Single layer matrix tablet is prepared by incorporating bicarbonates
in matrix forming hydrocolloid gelling agent like HPMC, chitosan,
alginate or other polymers and drug. Bilayer tablet can also be
prepared by gas generating matrix in one layer and second layer
with drug for its SR effect. Floating capsules also prepared by
incorporating such mixtures.
• • Triple layer tablet also prepared having first swellable floating layer,
second sustained release layer of two drugs (Metronidazole and
Tetracycline) and third rapid dissolving layer of bismuth salt. This
tablet is prepared as single dosage form for Triple Therapy of H.
Pylori.
• (B) Non-effervescent System:
• • Non-effervescent floating dosage forms use a gel forming or swellable cellulose
type of 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.
• (i) Hydrodynamically Balanced Systems:
• • Sheth and Tossounian first designated these 'hydrodynamically balanced
systems’. These systems contains drug with gel-forming hydrocolloids meant to
remain buoyant on the stomach content. These are single-unit dosage form,
containing one or more gel-forming hydrophilic polymers.
• • Hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC),
hydroxypropyl cellulose (HPC), sodium carboxymethyl cellulose (NaCMC),
polycarbophil, polyacrylate, polystyrene, agar, carrageenans or alginic acid are
commonly used excipients to develop these systems.
• • The polymer is mixed with drugs and usually administered in
hydrodynamically balanced system capsule.
• • The capsule shell dissolves in contact with water and mixture swells to form a
gelatinous barrier, which imparts buoyancy to dosage form in gastric juice for a
long period. Because, continuous erosion of the surface allows water penetration
to the inner layers maintaining surface hydration and buoyancy to dosage form.
• • Incorporation of fatty excipients gives low-density formulations reducing the
erosion. Madopar LP®, based on the system was marketed during the 1980s.
• • Effective drug deliveries depend on the balance of drug loading and the effect
of polymer on its release profile several strategies have been tried and
investigated to improve efficiencies of the floating hydrodynamically balanced
systems.
• (ii) Microballoons/Hollow Microspheres:
• • Microballoons/hollow microspheres loaded with drugs in their other polymer
shelf are prepared by simple solvent evaporation or solvent diffusion evaporation
methods (Fig. 3.29) to prolong the gastric retention time (GRT) of the dosage
form.
• • Commonly used polymers to develop these systems are polycarbonate,
cellulose acetate, calcium alginate, Eudragit S, agar and low methoxylated pectin
etc. Buoyancy and drug release from dosage form are dependent on quantity of
polymers, the plasticizer polymer ratio and the solvent used for formulation.
• • The microballoons floated continuously over the surface of an acidic dissolution
media containing surfactant for > 12 hours. At present hollow microspheres are
considered to be one of the most promising buoyant systems because they
combine the advantages of multiple-unit system and good floating.
• (iii) Alginate Beads:
• • Talukdar and Fassihi recently developed a multiple-unit floating system based on
cross-linked beads. They were made by using Ca2+ and low methoxylated pectin
(anionic polysaccharide) or Ca2+ low methoxylated pectin and sodium alginate. • In
this approach, generally sodium alginate solution is dropped into aqueous solution of
calcium chloride and causes the precipitation of calcium alginate.
• • These beads are then separated and dried by air convection and freeze drying,
leading to the formulation of a porous system, which can maintain a floating force for
over 12 hrs. These beads improve gastric retention time (GRT) more than 5.5 hrs.
• (iv) Microporous Compartment System:
• • This approach is based on the principle of the encapsulation of a drug reservoir inside
a microporous compartment with pores along its top and bottom walls.
• • The peripheral walls of the device are completely sealed to present any direct contact
of the gastric surface with the undissolved drug.
• • In the stomach the floatation chamber containing entrapped air causes the delivery
system to float in the gastric fluid.
• • Gastric fluid enters through the aperture, dissolves the drug and causes the dissolved
drug for continuous transport across the intestine for drug absorption.
Bioadhesive Systems
• • Bio/mucoadhesive systems are those which bind to the
gastric epithelial cell surface or mucin and serve as a
potential means of extending the Gastro retention of drug
delivery system (DDS) in the stomach by increasing the
intimacy and duration of contact of drug with the biological
membrane.
• • A bio or muco-adhesive substance is a natural or synthetic
polymer capable of producing an adhesive interaction
based on hydration mediated, bonding mediated or receptor
mediated adhesion with a biological membrane or mucous
lining of GI mucosa.
• Swelling System
• • These are the dosage forms, which after swallowing, swells to
an extent that prevents their exit from the pylorus.
• • As a result, the dosage form is retained in the stomach for a
longer period of time. These systems may be named as 'plug
type systems'.
• • Sustained and controlled drug release may be achieved by
selection of polymer of proper molecular weight and swelling of
the polymer retards the drug release, on coming in contact with
gastric fluid, the polymer imbibes water and swells.
• High Density Systems
• • These systems with a density of about 3 g/cm3 are retained in the antrum part of the
stomach and are capable of withstanding its peristaltic movements.
• • The only major drawbacks with such systems is that it is technically difficult to
manufacture such formulations with high amount of drug (>50%) and to achieve a density
of about 2.8 g/cm3.
• • It is necessary to use diluents like barium sulfate, zinc oxide, titanium dioxide, iron
powder etc. to manufacture such high density formulations.
• • Floating Drug Delivery Systems (FDDS) have a bulk density lower than gastric fluids and thus
remain buoyant in the stomach for a prolonged period of time, without affecting the gastric emptying
rate.
• • While the system is floating on the gastric contents, the drug is released slowly at a desired rate
from the system.
• • After the release of the drug, the residual system is emptied from the stomach. This results in an
increase in the GRT and a better control of fluctuations in the plasma drug concentrations.
• Expandable System
• • After being swallowed, these dosage forms swell to a size that prevents their
passage through the pylorus. As a result, the dosage form is retained in the
stomach for a long period of time.
• • These systems are sometimes referred to as plug type systems because they
tend to remain lodged at the pyloric sphincter.
• • These polymeric matrices remain in the gastric cavity for several hours even in
the fed state. Sustained and controlled drug release may be achieved by
selecting a polymer with the proper molecular weight and swelling properties.
• • As dosage form coming in contact with gastric fluid, the polymer imbibes water
and swells. The extensive swelling of these polymers is a result of the presence
of physical-chemical crosslinks in the hydrophilic polymer network.
• • These cross-links prevent the dissolution of the polymer and thus maintain
the physical integrity of the dosage form.
• • The expandable GRDFs are usually based on three configurations:
• • A small collapsed configuration which enables sufficient oral intake.
• • Expanded form that is achieved in the stomach and thus prevents passage
through the pyloric sphincter.
• • A smaller form that is achieved in the stomach when the retention is no
longer required i.e. after the GRDF has released its active ingredient, thereby
enabling evacuation.
• • The expansion can be achieved by
• (i) Swelling system
• (ii) Unfolding system
• Magnetic Systems
• • This system is based on a simple idea that the dosage form
contains a small internal magnet and a magnet placed on the
abdomen over the position of the stomach.It et al. used this
technique in rabbits with bioadhesives granules containing
ultrafine ferrite (g-Fe2O3). They guided them to the esophagus
with an external magnet (1700 G) for the initial 2 min. and
almost all the granules are retained in the regionafter 2 hrs.
Although these systems seem to work, the external magnet
must be positioned with a degree of precision that might
compromise patient compliance.
• Evaluation of Gastroretentive Dosage Form
• The various parameters that need to be evaluated for their effect on GRT of formulations can mainly
be categorized into the following different classes:
• 1. Galencial parameters: Diametric size (Cut-off size), flexibility and density of matrices.
• 2. Control parameters: Floating time, dissolution, specific gravity, content uniformity, hardness and
friability.
• 3. Geometric parameters: Shape.
• 4. Physiology parameters: Age, sex, posture, food and bioadhesion.
• 5. In-vitro testing: Drug release parameters.
• 6. In-vivo testing: Gastric residence time.
• 7. Pharmacodynamic and pharmacokinetics.
• In-vitro Evaluation
• (i) Floating Systems:
• Floating characteristics are as follows:
• (a) Buoyancy Lag Time:
• It is determined in order to assess the time taken by the dosage form to float on the top of the dissolution
medium, after it is placed in the medium. These parameters can be measured as a part of the dissolution
test.
• (b) Floating Time:
• Test for buoyancy is usually performed in Simulated Gastric Fluid (SGF) maintained at 37°C. The time for
which the dosage form continuously floats on the dissolution media is termed as floating time.
• (c) Specific Gravity / Density:
• Density can be determined by the displacement method using Benzene as displacement medium.
• (d) Resultant Weight
Now we know that bulk density and floating time are the main parameters for describing buoyancy. But
only single determination of density is not sufficient to describe the buoyancy because density changes
with change in resultant weight as a function of time.
• (ii) Swelling Systems: (a) Swelling Index:
• After immersion of swelling dosage form into SGF at 37°C, dosage form is
removed out at regular interval and dimensional changes are measured in
terms of increase in tablet thickness/diameter with time.
• (b) Water Uptake:
• It is an indirect measurement of swelling property of swellable matrix. Here
dosage form is removed out at regular interval and weight changes are
determined with respect to time. So it is also termed as Weight Gain.
• Water uptake = WU = (Wt- Wo) x 100/Wo
• Where, Wt = Weight of dosage form at time t Wo = Initial weight of dosage
form
COLON TARGETED DRUG DELIVERY SYSTEM
• Colonic drug delivery has gained increased importance not just for the
delivery of the drugs for the treatment of local diseases associated with the
colon like Crohn's disease, ulcerative colitis, irritable bowel syndrome and
constipation but also for the systemic delivery of proteins, therapeutic
peptides, antiasthmatic drugs, antihypertensive drugs and antidiabetic
agents. There are various methods or techniques through which colon
drug targeting can be achieved, for example, formation of prodrug, coating
with pH sensitive polymers, coating with biodegradable polymers,
designing formulations using polysaccharides, timed released systems,
pressure controlled drug delivery systems, osmotic pressure controlled
systems. Coating of the drugs with pH-sensitive polymers provides simple
approach for colon-specific drug delivery.
• Advantages of Colon Targeting Drug Delivery System:
• 1. Colon is an ideal site for the delivery of agents to cure the local diseases of the colon.
• 2. Local treatment has the advantage of requiring smaller drug quantities.
• 3. Reduces dosage frequency. Hence, lower cost of expensive drugs.
• 4. Possibly leading to a reduced incidence of side effects and drug interactions.
• 5. The colon is an attractive site where poorly absorbed drug molecules may have an improved
bioavailability.

• 6. Reduces gastric irritation caused by many drugs (e.g. NSAIDS).

• 7. Bypass initial first pass metabolism.
• 8. Extended day time or night-time activity.
• 9. Improves patient compliance.
• 10. Targeted drug delivery system.
• 11. It has a longer retention time and appears highly responsive to agents that enhance
• the absorption of poorly absorbed drugs.
• 12. It has low hostile environment, less peptidase activity so peptides, oral vaccines, insulin, growth
hormones, can be given through this route.
• Limitations of Colon Targeting Drug Delivery System:
• 1. Multiple manufacturing steps.
• 2. The resident microflora could also affect colonic performance via metabolic degradation of the
drug.
• 3. Incomplete release of drug.
• 4. Bioavailability of drug may be low due to potentially binding of drug in a non-specific way to
dietary residues, intestinal secretions, mucous or faecal matter.
• 5. Drug should be in solution form before absorption and therefore, rate limiting step for poor
soluble drugs.
• 6. An important limitation of the pH sensitive coating technique is the uncertainty of the location and
environment in which the coating may start to dissolve. Normal in patients with ulcerative colitis.
• 7. Limitations of prodrug approach is that it is not very versatile approach as its formulation depends
upon the functional group available on the drug moiety for chemical linkage.
• Need for Colon Targeted Systems
• Colon is rich in lymphoid tissue, e.g., uptake of antigen into mast cells of colonic mucosa
produces rapid local production of antibodies and this helps in efficient vaccine delivery. Region
of colon is recognized as having a somewhat less hostile environment with less diversity and
intensity of activity than stomach and small intestine. Thus, colon targeting is useful.
• • To ensure direct treatment at the disease site, lower dosing and fewer systemic side effects.
• • Colon-specific formulation could also be used to prolong the drug delivery.
• • It should be considered as beneficial in the treatment of colon diseases.
• • The colon is a site where both local or systemic drug delivery could be achieved.
• Topical treatment of inflammatory bowel disease, e.g. ulcerative colitis or Crohn’s Disease.
Such inflammatory conditions are usually treated with glucocorticoids and Sulphasalazine. A
number of others serious diseases of the colon, e.g. colorectal cancer, might also be capable
of being treated more effectively if drugs are targeted to the colon.
• • Formulations for colonic delivery are also suitable for delivery of drugs which polar nature
and/or susceptible to chemical and enzymatic degradation in the upper GI tract, highly affected
by hepatic metabolism, in particular, therapeutic proteins and peptides.
• Factors Affecting Colon Targeted Drug Delivery
• 1. Physiological factors
• 2. Pharmaceutical factors
• 1. Physiological Factors
• (a) Gastric Emptying:
• Drug delivery to the colon upon oral administration depends mainly on gastric emptying and bowel transit
time. Upon reaching the colon the transit time of dosage form depends on the size of the particles.
Smaller particles have more transit time compared to larger particles. Diarrhoea patients have shorter
transit time whereas constipation patients have longer transit times.
• (b) pH of Colon:
• The pH of GIT varies between different individuals. The food intakes, diseased state, etc. Influences the
pH of the GIT. This change in the pH in different parts of GIT is the basis for the development of colon
targeted drug delivery systems. Coating with different polymers is done to target the drug to the site.
• (c) Colonic Micro-flora and Enzymes:
• The GIT contains a variety of microorganisms that produces many enzymes need for metabolism.
Growth of this micro-flora is controlled by the GIT contents and peristaltic movements. The enzymes
released by different microorganisms E. coll, Clostridia, Lactobacilli, Eubacteria, Streptococci are
responsible for the various metabolic reactions that take place in the GIT.
• 2. Pharmaceutical Factors:
• Criteria for selection of drug for colonic drug delivery:
• (a) Drug Candidate:
• Drugs which show poor absorption from the stomach as intestine including peptide are most
suitable for CDDS. The drug used in treatment of IBD, ulcerative colitis, diarrhoea and colon
cancers are ideal candidates for local colon delivery.
• (b) Drug Carrier:
• The selection of carrier for particular drug candidate depends on the
physiochemical nature of the drug as well as the disease for which
the system is to be used. The factors such as chemical nature,
stability and partition coefficient of drug and the type of absorption
enhancers chosen influence the carrier selection.
• Moreover, the choice of drug carrier depends on the functional
groups of drug molecule. The carriers which contain additives like
polymers (may be used as matrices and hydro gels as coating
agents) may influence the release properties and efficacy of the
systems.
• Polymers Used in Colon Targeting:
• Polymer contains a large number of structural unit joined by same type linkage, form into a chain
like structure. These are nowadays used in formulating various pharmaceutical products. Naturally
found polymer, which include gummy exudates, proteins, enzymes, muscle fibre, polysaccharides.
In olden days natural polymers were widely used in pharmacy but a variety of synthetic polymer are
used nowadays for pharmaceutical and cosmetic development, using these polymers many
therapeutic systems of body namely controlled drug delivery systems, are achieved.
• Natural polymer: Guar gum, Pectin, Cyclodextrin, Dextran, Amylase, Chitosan, Chondrotin
sulphate, Locust bean gum.
• Synthetic polymer: Shellac, Ethyl cellulose, Cellulose acetate phthalate, Hydroxy propyl methyl
cellulose, Eudragit, Polyvinyl acetate phthalate.
• Approaches for Colonic Drug Delivery:
• Approaches for colon targeted drug delivery can be summarized as follows:
• 1. Primary approaches for colon targeted drug delivery:
• (a) pH sensitive polymer coated drug delivery system.
• (b) Delayed release drug delivery system.
• (c) Microbially triggered drug delivery: (i) Prodrug approach (ii) Polysaccharide based system.
• 2. New approaches for colon targeted drug delivery:
• (a) Pressure controlled drug delivery system (PCDDDS)
• (b) CODE
• (c) Osmotic controlled drug delivery system (OROS-CT)
• (d) Pulsatile: (i) Pulsincap system, (ii) Port system
• (e) Azo hydrogels
• (f) Multiparticulate system based drug delivery.
 ‫لالطالع‬
• Evaluation
• (A) In-vitro Evaluation:
• No standardized evaluation technique is available for evaluation of CDDS as an ideal in-vitro model
should possess in-vivo conditions of GIT such as pH, volume, stirring, bacteria, enzymes, enzyme activity
and components of food. These conditions are influenced by diet and physical stress. The in-vitro
evaluation of colon targeted drug delivery systems includes the in-vitro dissolution study and in-vitro
enzymatic test.
• 1. In-vitro Dissolution Test:
• The dissolution testing is done using the conventional basket method. The dissolution testing is done in
different buffers to characterize the behaviour of formulations at different pH levels. The different media
that are used for the dissolution testing of colon targeted drug delivery are pH 1.2 to simulate gastric fluid,
pH 6.8 to simulate small intestine, pH 7.4 to simulate large intestine. The colon targeted drug delivery
systems are tested for 2 hrs. in 0.1 N HCI, 3 hrs in pH 6.8 phosphate buffer and finally at pH 7.4
phosphate buffer. Buffers of the above pH are prepared to evaluate the colon targeted drug delivery
systems.
• 2. In-vitro Enzymatic Test:
• There are two tests for the in-vitro enzymatic test. The carrier drug system is incubated in fermenter containing suitable
medium for bacteria. The amount of drug released at different time intervals is determined.
• Drug release study is performed in buffer medium containing enzymes pectinase, dextranase or rat or guinea pig or
rabbit cecal contents. The amount of drug released in a particular time is directly proportional to rate of degradation of
polymer carrier.
• (B) In-vivo Evaluation:
• The in-vivo evaluation of the CDDS is done in dogs, guinea pigs, rats and pigs as they resemble the anatomic and
physiological conditions, microflora of human GIT. The distribution of various enzymes in GIT of rat and rabbit is
comparable to that in human. Different techniques are available for testing the in vivo performance of the colon drug
delivery system in human beings which are as follows:
• (a) Endoscopy:
• In this technique, the patient should have to swallow the endoscopic tube and a fibre (gastroscope) is used to monitor
the behaviour of the dosage form.
• Demerits:
• This method requires administration of a mild sedative for the swallowing of the endoscopic tube, which will alter the GI
motility.
• (b) String technique:
• In this technique, the dosage form is attached to a string piece and the subject should
swallow the dosage form leaving string hanging from mouth. At different time periods the
dosage form is withdrawn with the help of string and it is examined for disinfection.
• Demerits:
• As strip also passes through the GIT, it will alter motility and physical environment.
• (c) Roentgenography:
• In this method, a radiopaque material is included into the dosage form and the dosage
form is visualized by the use of X-rays.
• (d) Gamma scintigraphy:
• This is the most widely used non-invasive technique for studying the in-vivo behaviour of
solid oral dosage forms under normal physiological conditions. This method requires the
presence of a gamma emitting radioactive isotope in the dosage form that can be
detected in-vivo by an extended gamma camera. For example: "mTc, 111In
• Advantages:
• • Gives very little radiation exposure.
• • Gives qualitative and quantitative results.
• • Allows for in-vivo evaluation of a dosage form under normal physiological conditions.
• OPTHALMICS
• One of the problems associated with the use of ophthalmic solutions is
the rapid loss of administered drug because of the blinking of the eye
and the Bushing effect of lacrimal fluids. Up to 80% of an
administered dose may be lost through tears and the action of
nasolacrimal drainage within 5 minutes of installation. Extended
periods of therapy may be achieved by formulations that increase the
contact time between the medication and the corneal surface. This may
be accomplished by the use of agents that increase the viscosity of
solutions, by ophthalmic suspensions which the drug particles slowly
dissolve, by slowly dissipating ophthalmic ointments, or by the use of
ophthalmic inserts.
• Gels Extended Release
It is useful to note here certain preparations designed to extend drug action. The following
are but two examples of proprietary products that use viscosity-increasing agents to increase
corneal contact time. Pilocarpine (Pilopine HS Gel, Alcon) employs Carbopol 940, a
synthetic high molecular weight cross-linked polymer of acrylic acid. Timolol maleate
(Timoptic-XE, Merck) employs gellan gum (Gelrite), which forms a gel upon contact with
the precorneal tear film.
• Ophthalmic Inserts
• Lacrisert
• Lacrisert (Merck) is a rod-shaped watersoluble form of hydroxypropyl cellulose.
The insert is placed in the inferior cul-de-sac of the eye once or twice daily for the
treatment of dry eyes. The inserts soften and slowly dissolve, thickening the precorneal
tear film and prolonging the tear film breakup.
What Are Circadian Rhythms?
• Circadian rhythms are the physical, mental, and behavioral changes an organism experiences over a 24-hour
cycle. Light and dark have the biggest influence on circadian rhythms, but food intake, stress, physical
activity, social environment, and temperature also affect them.
• Most living things have circadian rhythms, including animals, plants, and microorganisms. In humans, nearly
every tissue and organ has its own circadian rhythm, and collectively they are tuned to the daily cycle of day
and night.
• Circadian rhythms influence important functions in the human body, such as:
• Sleep patterns
• Hormone release
• Appetite and digestion

• Temperature
• What Scientists Know About How
• Circadian Rhythms Are Controlled
• The system that regulates an organism’s innate sense of time and controls circadian rhythms is called a
biological clock. It’s composed of proteins encoded by thousands of genes that switch on and off in a specific
order. A master clock coordinates all the biological clocks in an organism.
• In vertebrate animals, including humans, the master clock exists in the brain. The human master clock is a
large group of nerve cells that form a structure called the suprachiasmatic nucleus (SCN). Among other
functions, the SCN controls production of the hormone melatonin based on the amount of light the eyes
receive. In the evening, a person’s master clock tells their brain to make more melatonin, causing sleepiness.
The SCN also synchronizes the circadian rhythms in different organs and tissues across the body.
Health Effects of Disrupted Circadian
Rhythms
• Circadian rhythms can fall out of sync with the outside world due to factors in the human body or
environment. For example:
• Drowsiness, poor coordination, and difficulty with learning and focus may occur when circadian rhythms fall
out of sync short term. Long-term sleep loss and continually shifting circadian rhythms can increase the risks
of obesity, diabetes, mood disorders, heart and blood pressure problems, and cancer, and can also worsen
existing health issues.
• Variants of certain genes can affect the proteins that control biological clocks.
• Neurological diseases, such as Alzheimer’s disease, can disrupt circadian rhythms, causing poor sleep quality
and changes in symptoms from day to night.
• Travel between time zones (jet lag) and shift work alters the normal sleep-wake cycle.

• Light from electronic devices at night can confuse biological clocks.