GASTRO RETENTIVE DRUG
DELIVERY SYSTEMS
Presented by
KARTHIKA N,
M.Pharmacy I Sem
Department of Pharmaceutics,
College of Pharmacy, Madras Medical College, Chennai
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CONTENTS
GRDDS- INTRODUCTION
ADVANTAGES
DISADVANTAGES
APPROACHES FOR GRDDS
FLOATING
HIGH DENSITY SYSTEMS
INFLATABLE
GASTRO ADHESIVE SYSTEMS
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GASTRO RETENTIVE DRUG DELIVERY SYSTEMS:
INTRODUCTION:
Gastro retentive drug delivery systems are the systems which are retained in the stomach for a
longer period of time and there by improve the bioavailability of drugs.
PRINCIPLE:
▪ Gastro retentive can remain in the gastric region for several hours and hence significantly
prolong the gastric residence time of drugs.
▪ Prolonged gastric retention improves bioavailability reduce drug waste and improves the
solubility of drugs that are less soluble in a high pH environment.
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CONT’D
▪ Gastric retention helps to provide better bioavailability of new products with new therapeutic
possibilities and substantial benefits for patients.
▪ The controlled gastric retention of solid dosage forms may be achieved by the mechanisms of
mucoadhesion, floating, sedimentation, expansion modified shape system or by the simultaneous
administration of pharmacological agents that delay gastric emptying.
DEFINITION:
➢ Dosage forms that can be retained in the stomach for prolonged and predictable period of time
are called gastroretentive drug delivery systems [ GRDDS].
➢ GRDDS- prolong the presence of DDS in the stomach or upper gi tract until the entire drug is
released.
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STOMACH ANATOMY:
➢ Stomach is recognized as a depot for gastroretentive drug delivery systems both in human
and veterinary applications.
➢ “J” shaped
➢ Divided into five parts
-gastroesophageal junction [2-3 cm]
-Fundus[ corpus/ body of the stomach and fundus act as reservoir of undigested
material]
-Antrum
-pyloric antrum [narrow 1-2 cm/long, channel connecting the stomach to the
duodenum, acts as pump for gastric emptying]
-Duodenum
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PHYSIOLOGY:
Factors such as PH , nature and volume of gastric secretions and gastric mucosa playa major role
in drug release an absorption
Stomach – Digestion of food – 1-3.5
Duodenum – Neutralization of acids – 4-6.5
Jejunum – Absorption of nutrients – 5-7
Ileum – Absorption of nutrients – 6-8
Volume – Resting fluid volume of the stomach is about 25-50 ml
Gastric mucosa – Protect the stomach from digestion of pepsin and from adverse effects of
hydrochloric acid[Hcl]
Gastric acid secretion- Normal adults[60ml]
Potent stimulators-Harmone gastrin, peptides, amino acids and distention of
sMtoyPmharmaacGhuid es.Ctoimmulate Hcl release
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DIGESTION IN STOMACH:
1. MECHANICAL DIGESTION:
▪ When the bolus reaches the stomach is converted into chyme, a liquefied substance
prepared by adequate mixing of the bolus with the gastric secretions.
▪ Such mixing is caused due to the periodic (every 15-25 secs) and gentle peristaltic
movements of muscles of the stomach.
▪ Fundus portion of the stomach mainly functions to store the last part of the meal
consumed, which may have to wait for an hour before undergoing digestion.
2. CHEMICAL DIGESTION:
▪ Chemical digestion of food in the stomach is done by gastric juice.
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CONT’D
▪ The basic components of the gastric juice include gastric acid , enzymes and mucus.
▪ Gastrin stimulates the secretion of gastric juice.
▪ The total daily production of gastric juice varies in between 2-3 liters with the production
peaking after an hour of meal and undergoing drastic reduction in its levels after about 4 hrs.
a) GASTRIC ACID:
Presence of gastric acid makes the environment in the stomach acidic, a condition suitable for
the activation of proteolytic enzyme, pepsin.
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I) Termination of action of salivary amylase.
ii) Activation of pepsin from its inactive form, pepsinogen.
iii)Partial denaturation of the ingested proteins.
iv) Exertion of bacterial effects.
v) Stimulation of release of harmones which in turn induces the release of bile and pancreatic juices.
b)GASTRIC ENZYMES:
I) Pepsin:
-It is produced in stomach in its inactive form pepsinogen.This inactive form gets converted
into actual proteolytic enzyme only when it comes in contact with either HCL or other activated pepsin
molecules.
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II)RENNIN:
-Rennin is also a proteolytic enzyme, its chief substrate is milk.
-Milk rennin caseinogen.
-Only found in infants.
III)GASTRIC LIPASE:
-Lipolytic enzyme.
-Triglycerides gastric lipase monoglycerides + fatty acids
GASTRIC EMPTYING TIME:
-After thorough mixing and absorption has been done the next step is the periodic
propulsion of chyme from the stomach into the duodenum via the pyloric sphincter by a process
known as gastric emptying time.
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CONT’D
▪ The gastric emptying is dependent upon the type of meal consumed.
▪ Meal is well balanced then normally takes about 4 hrs for complete gastric emptying.
▪ Protein –requires longer time, fatty meals-longest time.
DRUG ABSORPTION WINDOW:
▪ The drug absorption of GRDDS is better in comparison with conventional oral dosage forms.
▪ Conventional drugs are administered orally, the adsorption windows in large intestine.
▪ To increase the residence time of drug dosage forms at or above absorption window
gastroretentive dosage forms like floating system, bioadhesive system, swelling system and sediment
sedimentation system.
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CONT’D
▪ GRDDS enables the extended absorption phase of drugs exhibiting narrow absorption
window.
▪ These systems after administration, retain in stomach in sustained or controlled way so that
the drug can be supplied continuously to the absorption sites in upper git.
FACTORS CONTROLLING GASTRIC RESIDENCE TIME (GRT) OF DOSAGE FORMS:
1) PARTICLE SIZE:
Particle size range between 1-2 mm so that the drug can pass through pyloric
valves into small intestine.
2)DENSITY:
Density of dosage form determines location of system in the stomach and also
effects the gastric emptying rate.
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CONT’D
▪ Dosage form with lesser density than gastric fluid can exhibit
floating behaviour as well as increased GRT.
▪ The density of gastric fluid is 1.004g/ml so the dosage form with density
lesser than 1g/ml can float in gastric fluid.
▪
3)SIZE:
▪ Size of the dosage form determines the duration for which a dosage
form can be retained in stomach.
▪ The smaller one usually gets emptied during digestion phase, whereas
the larger one gets emptied during housekeeping waves.
▪ GRT increases with increase in size of dosage form.
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4)SHAPE:
▪ The ring shaped/tetrahedron shaped dosage forms posses greater GRT.
▪ These shaped dosage forms with flexural modules of 225-48
ksi(ketopound/inch2 ) exhibits GRT upto 90-100%
5)INTAKE AND NATURE OF FOOD:
▪ GRT of dosage form increase in the presence of food.
▪ Indigestible polymers, fatty acids, salts, increased calorie, fat and
protein increases the GRT.
▪ The drugs gets emptied rapidly in fasted state compared to post
prandial state.
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6)EFFECT OF GENDER, POSTURE AND AGE:
▪ In females the GRT is greater than females, since the gastric emptying the in
females is slower than males.
▪ The GRT of dosage form also varies for individuals depending upon their
posture(left side-pyloric intrum and right opposite direction)
▪ People of age over 70 yrs shows longer GRT.
7)SIMULTANEOUS ADMINISTRATION OF DRUGS:
The drugs such as anticholinergic agents, opiates and prokinetic agents lower the
gastric emptying to increase the GRT.
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CONT’D
GASTRIC MOTILITY:
▪ Stomach produces coordinated movements the gastric contents due to three layers of smooth
muscles.
▪ Gastric emptying- occurs both in fasting and fed state
▪ Fasting state-Interdigestive series of electrical events take place.
▪ IMMC-Interdigestive Myoelectric Motor
▪ MMC- Migrating Myoelectric Motor
▪ MMC is organized into alternating cycles of activity and quiescence and can be subdivided
into
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PHASE I – BASAL
PHASE II -PREBURST
PHASE III -BURST
PHASE IV –TRANSIENT PHASE BETWEEN I&II
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CONT’D
PHASE I -30-60 min
PHASE II -20-40 min[intermittent contraction]
PHASE III -10-20 mins[housekeeper wave-intense contraction]
PHASE IV -lasts for 0-5 min which occurs between burst phase and basal phase of two consecutive
cycles.
Fed conditions-one phase is present, it contains regular & frequent contractions.
IMMC is delayed resulting in slow down of gastric emptying.[Post prandial motility]
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ADVANTAGES OF GRDDS:
• Reduced frequency of dosing with improved patient compliance for drugs with relatively
short half life
Eg: Furosemide
• There is increase in bioavailability drugs that metabolized in the upper GIT by this
gastroretentive drug delivery approach in comparison to the administration of other drug delivery.
• They also have an advantage over their conventional system as it can be used to overcome
the adversities of the gastric retention time as well as the gastric emptying time
• Gastroretentive dosage form minimize the fluctuation of drug concentrations and effects.
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CONT’D
▪ By using this drug delivery we can prolong and sustain release of drugs from dosage.
Eg: Beta lactum
▪ This site specific drug delivery we reduce undesirable effects of side effets.
▪ This drug delivery do reduction of fluctuation in drug concentration makes it possible to obtain
improved selectivity in receptor activation.
▪ Gastroretentive drug delivery can minimize the counter activity of the body leading to higher drug
efficiency.
▪ Avoids gastric irritation.
▪ Better therapeutic effect of short half life drugs can be achieved.
▪ Minimizing mucosal irritation by releasing drugs slowly at a controlled rate.
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DISADVANTAGES OF GRDDS:
▪ Drugs that have very limit drugs that absorb ed acid solubility.
Eg: Phenytoin etc.
▪ Drugs that suffer instability in the gastric environment.
Eg: Erythromycin etc.
▪ Drugs intended for selective release in the colon.
Eg: Amino salicylic acid & Corticosteroids etc.
▪ Drugs that irritates or causes gastric lesions on slow release.
Eg: Aspirin & NSAID’S
▪ Drugs that absorbs equally well through GIT
Eg: Isosorbide dinitrate, Nifedipine.
▪ Floating drug delivery systems require high fluid level in stomach to float and work effectively.
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DRUGS SELECTION CRITERIA FOR GRDDS:
▪ Drugs with narrow absorption window in GIT
Eg: Riboflavin and levodopa
▪ Drugs should get absorbed from stomach and upper part of GIT.
Eg: Chlordiazepoxide.
▪ Drugs should disturb normal colonic bacteria.
Eg: Amoxicillin trihydrate.
▪ Drugs should be locally active in the stomach.
Eg: Antacids and Misoprostol.
▪ Drugs should get degraded in colon.
Eg: Ranitidine Hcl and Metronidazole.
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LIMITATION OF GRDDS:
▪ GRDDS require high levels of fluid in stomach, so that the dosage form can float and work
easily to release the drugs.
▪ GRDDS is not well suited for drug solubility and stability problems in GIT.
▪ In the formulation of GRDDS certain drugs that undergo first pass metabolism, drugs that
cause irritation to gastric mucosa and drugs that are unstable in acidic atmosphere of stomach are
not suitable for formulation.
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APPROACHES TO EXTEND GI TRANSIT:
PHARMACOLOGICAL APPROACH:
This includes the co-administration of drug that delays gastrointestinal emptying.
Eg: Antimu scarinics (eg: propantheline)
PHYSIOLOGICAL APPROACH:
Natural minerals or fat derivatives like triethanolamine myristate that stimulate duodenal or
jejunal receptors in order to delay gastric emptying are employed.
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PHARMACEUTICAL APPROACH:
GRDDS
DENSITY CONTROLLED INFLATABLE (SWELLING) BIOADHESIVE/
SYSTEMS SYSTEMS MUCOADHESIVE SYSTEM
LOW DENSITY HIGH DENSITY
(FLOATING)SYSTEM (NON-FLOATING)SYSTEM
EFFERVESCENT NON-EFFERVESCENT
SYSTEMS SYSTEM
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DENSITY CONTROLLED SYSTEM:
A)LOW DENSITY/FLOATING SYSTEM:
▪ These drug delivery systems float over the gastric contents due to their
density being lower than the gastric contents.
▪ On contacting with gastric fluids these systems immediately float for a
prolonged period of time and release the drug at the desired rate.
▪ Low density can be attained by use of hollow chambers or by incorporation
of low density materials like fatty material, oil or foam powder.
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CONT’D
CLASSIFICATION OF FLOATING SYSTEM:
i) Single unit floating systems
ii) Multiple unit floating system
BASED ON MECHANISM
i) Effervescent floating systems
ii) Non-effervescent floating systems
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I) SINGLE UNIT FLOATING SYSTEM:
▪ This system of dosage form consist of drug surrounded by colloidal gel barriers.
▪ Preparation- mixing of matrix polymer by incorporating drug filler and propylene foam
powder.
ADVANTAGES:
▪ Good floating
▪ Controlled drug release pattern is achieved.
DISADVANTAGES:
Single units may clump together resulting in ineffective drug release and may cause
construction in gastrointestinal area.
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II) MULTIPLE UNIT FLOATING SYSTEM:
▪ Multiple unit dosage forms involves emulsion solvent diffusion method as well as emulsion
gelatin method.
▪ Former method-air compartment multiple-unit systems or hollow microspheres are prepared
whereas the micro particles based on low density foam powder and beads are prepared by the latter
method.
ADVANTAGES:
▪ DOSE DUMPING is avoided.
▪ Due to slow release, maximum therapeutic activity is retained for a longer period of time.
▪ The system gets widely distributed throughout the gastrointestinal area.
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I) EFFERVESCENT FLOATING SYSTEM:
A)GAS GENERATING EFFERVESCENT SYSTEMS:
Mechanism:
▪ Release of CO2 due to reaction of bicarbonates with coflormulated citric or tartaric
acid.
▪ Gastric matrices like gel hydrocolloid matrix with swellable polymers like chitosan and
carbomer capsules having bicarbonate with lactose and pvp may also be preparationed.
▪ Ion exchange based resins which are prepared to prolong gastric emptying time using
beads of drug resin complexed with bicarbonate ions coated with hydrophobic polymer.
▪ Multilayer systems in which permeability of co2 can be regulated through different
layers.
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Cont’d
B) VOLATILE LIQUID SYSTEMS:
▪ Volatile liquids like ether or cyclopentane that volatize at body temperature are incorporated in
order to create an inflatable layer.
▪ The device may consist of a bioerodible plug made of polyvinyl alcohol or polyethylene to create
an inflatable chamber.
▪ It may be either intragastric floating gastrointestinal drug delivery system or inflatable
gastrointestinal drug delivery system.
▪ Former system- floating chamber made to float using vacuum of inert gas is used, the drug is
encapsulated inside a microporous compartment.
▪ Later –liquids that volatize at body temperature are used to inflate the chamber.
▪ Inflatable chamber is loaded with drug and then encapsulated to form a gelatin capsule.
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II) NON EFFERVESCENT FLOATING SYSTEM:
▪ Mechanism of swelling of polymer or bioadhesion to mucosal layer in GIT.
▪ High swelling and gel forming capacity of polymers that swell upon contact with gastric fluids
forming a gel layer with entrapped air around the system core which causes floating.
▪ Other – floating is by using a microporous compartment with gas filled chamber.
POLYMERS INCLUDES:
1) SODIUM ALGINATE:
▪ Mechanism – formation of stable gel like matrices due to cross linking of sodium alginate with
polyvalent cations.
▪ They are hydrophilic and biodegradable and offer advantages of biocompatibility and non-
toxicity.
▪ Eg: sodium alginates, calcium alginate and ammonium alginates.
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CONT’D
2) CARBOPOL:
▪ It is PH dependent polymer that swells upon contacting with gastric fluid, thereby prolonging
gastric retention time.
▪ Used in mucoadhesive forms of atenolol.
▪ Eg: Carbopol 934 NF, 940 NF, 971 NF, 5984 EP.
3)HPMC:
▪ Water soluble polymer that is available in different molecular weights.
4)POLYMETHACRYLATE:
▪ Polymers are used as release retardants.
▪ Eg: Eudragit E, Eudragit RS, Eudragit RL, Eudragit S
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TYPES OF NON-EFFERVESCENT SYSTEMS:
1.SINGLE LAYER OR HYDRODYNAMICALLY BALANCED SYSTEM:
▪ The floating of system is due to drug gel forming hydrocolloid single units.
▪ Buoyancy is due to erosion of surface layers promoting penetration of water to the inside
layers.
▪ Polymers like HPMC, are mixed with drug in capsule which dissolves in water forming a
gelatinous barrier.
Eg: HPMC + ethyl cellulose— Metformin(6 hrs)
▪ Multiple/bilayer systems- immediate release(release of initial dose)
▪ Sustained release(release of maintenance dose)
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2. MICROPOROUS COMPARTMENT SYSTEM:
▪ Microporous compartments have pores that allow the passage of gastric fluids within the
compartment, thereby promoting the dissolution of drugs and affecting their release from it.
▪ Eg: slavonic acid formulated in controlled porosity osmotic pump tablets have around 12hrs
retention time.
3.ALGINATE BEADS SYSTEM:
▪ This multiple unit porous floating systems of cross linked beads is prepared using ca2+ and low
methoxylated pectin or ca2+ with low methoxylated pectin along with sodium alginate.
▪ The preparation of calcium alginate beads involves addition of aqueous solution of cacl2 to sodium
alginate that results in the precipitation of calcium alginate.
▪ The precipitate are then air dried or freeze dried. They can float around 12hrs.
▪ Treatment of peptic ulcer – famotidine & quercetin
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4. HOLLOW MICROSPHERES SYSTEMS:
▪ A hollow microsphere is prepared by solvent evaporation or solvent diffusion methods.
▪ The rate of drug release is determined by polymer quantity and plasticizer-polymer ratio and
solvent.
▪ Polymers: Poly carbonate, chitosan, Eudragit S, PVA.
APPLICATION OF FLOATING SYSTEMS:
1.Drug reservoir for sustained release:
▪ Drugs having low biological half-life and short gastric residence time may require
frequent doses.
▪ In these cases formulation of sustained release floating systems offer advantage
since gastric retention is prolonged due to floating capacity and large size.
Eg: MICARD capsules-gastric retention of 16 hrs over 8 hrs in normal oral dosage
forms.
Metformin-increased (7 hrs) gastric retention over 3 hrs for oral dosage forms.
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2. Drugs having low bioavailability:
▪ Drugs having poor bioavailability like riboflavin and levodopa that have a narrow absorption
window are formulated as floating systems to enhance drug absorption.
▪ Eg: Theophylline and famotidine that are limit by solubility are also prepared in this manner.
3.Site specific drug delivery:
▪ Drugs that show limitation by absorption in upper gastrointestinal drug, this method offers several
applications.
▪ Eg: Furosemide formulations that are absorbed better in duodenum, have 1.8 times increased
bioavailability then normal dosage forms.
▪ A combination of famotidine and quercetin is used as it has greater bioavalibility.
▪ Reduced adverse effects due to retention of drug in stomach, reduced therapeutic loss due
fluctuation of concentration and less resistance to drug due to slow release offers advantages to be
selected for drug formulations.
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B)HIGH DENSITY/NON-FLOATING SYSTEM:
▪ Also called as sinking systems.
▪ These drug delivery systems are designed such that their high density is used as
retention mechanism.
▪ When the density of dosage form is greater than that of the gastric contents,
then the dosage form settle down in the lower part of the stomach (antrum)
▪ In order to sink density 2.5-3g/cm3 which is greater than gastric contents
1.004g/cm3.
▪ Formulation-prepared by coating the drug on a heavy inert material like barium
sulphate, zitanium oxide, zinc oxide, iron powder etc.
▪ These coated drug systems sink to the bottom of the stomach where they get
entrapped within the rugae(folds) of the stomach wall and withstand the peristaltic
movements.
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CONT’D
DRAWBACK
The difficulty in preparation and ineffectiveness in human subjects was observed because of
which these systems are not preferred.
APPLICATION OF HIGH DENSITY SYSTEMS:
Owing to technical difficulty in manufacture of such formulations with high amount of drug
maintaining a density of 2.8g/cm3 and its ineffectiveness in humans, this system has no current
marketed products.
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INFLATABLE SYSTEMS:
▪ On swallowing they swell beyond the size of the pylorus, there by preventing their exit
from pylorus.
▪ Also called as plug type systems.
▪ Swelling of the dosage form is actually due to osmotic absorption of water within gastric
fluid.
▪ These systems withstand peristaltic contractions of the stomach.
▪ Prepared by hydrophilic biodegradable polymers which have strong physical-chemical
crosslinks which prevent dissolution and hence maintain physical stability even after the units
swell upto 3-6 times, thus increasing gastric retention time.
▪ Controlled sustained release may be achieved by appropriate polymer selection.
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Cont’d
The product must have,
✓ A small size for oral intake.
✓ Expandable gastroretentive form.
✓ Easy clearance after drug release.
DISADVANTAGES:
▪ Temporary obstruction caused by large empty drug skeleton.
▪ Swelling in esophagus may occur due to non-site specific expansion.
▪ Non cost effective and difficult to manufacture.
▪ Problematic storage of easily hydrolysable, biodegradable.
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APPLICATIONS OF INFLATABLE SYSTEMS:
▪ Swelling system: controlled/sustained release formulations like antihypertensive a
gastroretentive swellable controlled release formulation was developed.
Eg: Sustained release formulation of riboflavin in the form of freeze dried sponges that swell
in a very short duration in the stomach on contacting with gastric fluid was developed.
▪ The size of foldable systems makes it easy to administer drug orally. On reaching the gastric
fluid they unfold and swell to increase gastric retention and increase bioavailability.
Eg: Antihypertensive has better bioavailability as a swelling system that an immediate
release product.
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GASTROADHESIVE/MUCOADHESIVE DRUG DELIVERY SYSTEM:
▪ In this system drugs bind to the gastric epithelium cell surface or mucin and extend the GRT
by increasing the intimacy and duration of contact between the dosage form and the biological
membrane.
▪ Concept is based on the self protecting mechanism of the GIT.
▪ The mucus not only protect the surface mucosa cells from acid and peptidase but also act as
a lubricant for the passage of solids and as a barrier to antigens, bacteria and viruses.
▪ A bio/mucoadhesive substance is a natural or synthetic polymer capable of adhering to a
biological membrane of the mucus lining of the git.
▪ The epithelial adhesive properties of mucin are well known and have been applied to the
development of GRDDS through the use of bio/mucoadhesive polymers.
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CONT’D
The adherence of the delivery system to the gastric wall increases residence
time at a particular site thereby improving bioavailability.
i)Hydration mediated adhesion:
▪ This is achieved by using hydrophilic polymers which imbibe large amount
of water and become sticky, thereby achieving mucoadhesive properties.
▪ The prolonged gastro retention of the bio/mucoadhesive drug delivery
system is further controlled by the dissolution rate of the polymer.
ii)Bonding- mediated adhesion:
The adhesion of polymers to a mucus or epithelial cell surface involves
various bonding mechanisms including physical – mechanical bonds can result from
the crevices or folds of mucosa.
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iii)Receptor mediated adhesion:
▪ Polymers can bind to specific receptor site on the surface of cells thereby
enhancing the gastric retention of dosage form.
▪ Certain plant lectins such as tomato lectins interact specifically with the
sugar groups present in mucus or on the glycocalyx.
▪ Polymers used in gastroretentive mucoadhesive drug delivery system.
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EVALUATION
• A) IN-VITRO EVALUATION
I) FLOATING SYSTEMS
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.
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B) FLOATING TIME
• Test for buoyancy is usually performed in sgf-simulated gastric fluid maintained at 370C. 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.
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II) SWELLING SYSTEMS
A) SWELLING INDEX
• After immersion of swelling dosage form into SGF at 370C, 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.
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• TABLET
WATER UPTAKE = WU = (WT –WO) * 100 / WO
WHERE, WT= WEIGHT OF DOSAGE FORM AT TIME T
WO= INITIAL WEIGHT OF DOSAGE FORM
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• B) IN-VITRO DISSOLUTION TESTS
A. In vitro dissolution test is generally done by using USP apparatus with paddle and GRDDS is
placed normally as for other conventional tablets. But sometimes as the vessel is large and paddles are at
bottom, there is much lesser paddle force acts on floating dosage form which generally floats on surface.
As floating dosage form not rotates may not give proper result also not reproducible results. Similar
problem occur with swellable dosage form, as they are hydrogel may stick to surface of vessel or paddle
and gives irreproducible results.
In order to prevent such problems, various types of modification in dissolution assembly
made are as follows
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B. To prevent sticking at vessel or paddle and to improve movement of dosage form, method suggested is
to keep paddle at surface and not too deep inside dissolution medium.
C. Floating unit can be made fully submerged, by attaching some small, loose, non-reacting material ,
such as few turns of wire helix, around dosage form. However this method can inhibit three dimensional
swelling of some dosage form and also affects drug released.
D. Other modification is to make floating unit fully submerged under ring or mesh assembly and paddle
is just over ring that gives better force for movement of unit
E. Other method suggests placing dosage form between 2 ring/meshes.
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F. In previous methods unit have very small area, which can inhibit 3D swelling of swellable units,
another method suggest the change in dissolution vessel that is indented at some above place from
bottom and mesh is place on indented protrusions, this gives more area for dosage form.
G. Inspite of the various modifications done to get the reproducible results, none of them showed
co-relation with the in-vivo conditions. So a novel dissolution test apparatus with modification of
Rossett-rice test apparatus was Proposed.
H. Rossett-rice test is used for predicting in-vitro evaluation of directly acting antacid (action by
chemical neutralization of acid), where Hcl is added to mimic the secretion rate of acid from the
stomach.
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• In this modified apparatus as shown in figure, it has side arm from bottom of beaker such that it
maintains volume of 70ml in beaker and fresh SGF is added from burette at 2 ml/min rate. Thus
sink condition is maintained along with easy sampling. Stirring is done by magnetic stirrer at 70-
75 RPM. Thus this apparatus mimics in-vivo condition for GRDDS.
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BUCCAL DRUG DELIVERY
SYSTEM
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CONTENTS
• INTRODUCTION- ADVANTAGES & DISADVANTAGES
• FACTORS AFFECTING BDDS
• MECHANISM OF ADHESION
• THEORIES OF ADHESION
• FORMULATION OF BDDS
• FORMULATION
• EVALUATION
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WHAT IS BDDS?
• Delivery of drug through buccal mucosa of oral cavity is called BDDS. Buccal
mucosa lines the inner region of cheeks.
• In biological term, the product is placed between upper gingiva (gums) & cheek
to treat local & systemic conditions.
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ADVANTAGES
• Avoids 1st pass metabolism
• Avoids acid/enzyme metabolism
• Permeation is faster with respect to skin & TDDS (4-4000)
• Large surface area with respect to sub-lingual mucosa
• Good patient compliance with respect to parental
• Easy administration & removal in case of toxicity.
• For unconscious or comatose patients
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DISADVANTAGES
• Drugs with bitter taste or irritant to mucosa or having noxious
smell
• Not for children
• Eating & drinking difficulty
• Salivary erosion & it may enter GIT & choke esophagus
• Less surface area than skin
• Drugs unstable at buccal PH(6.5 to 7)
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ANATOMY/PHYSIOLOGY OF BUCCAL
CAVITY
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BUCCAL ENVIRONMENT
• It has four parts & is 500-800mm thick & 150cm^2 approx
• Epithelium: 40-50 cell thick & is major barrier for lipophilic
drug. It has initially square shaped cells which further grows in
the elliptical cells which are permeable for hydrophilic drugs. It
may be keratinized (having high MW) or non-keratinized (low
MW).
• Mostly, non-keratinized epithelium is permeable to drug very
easily due to absence of acylceramides & only small amounts
of ceramides. Also they contain small amounts of neutral but
polar lipids (cholesterol sulfate& glucosyl ceramides). Hence
more permeable to formulation
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CONT…
• Lamina propria: barrier for hydrophilic drug
• Hence highly hydrophilic & highly lipophilic drug are
not suitable for BDDS.
Salivary secretions: it is secreted by parotid, sub-maxillary
& sub-lingual Glands
1% Solute
{Na, K, Ca, Mg,
Mucin, Albumin,
99 % Aq liquid
Enzymes(Amylase,
lipase) }
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MUCIN BIOCHEMISTRY
• The PH of saliva is due to mucin (6.2-7.4).
• Mucins are synthesized by the goblet cells and special exocrine glands &
secreted by sialic cells & mucus cells
• It is gylcorylated glycoprotein having large peptide backbone & oligosaccharides
side chains & 14 side chains made up of oligosaccharide.
• End part of side chains has negative charge due to sialic acid, sulphonic grp &
fructoic grp which attract cationic polymers.
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FACTORS AFFECTING…
FACTORS…
Polymer related factors MW of polymer
Flexibility
H-bond capacity
Cross-linking density
Charge
Concentration
Drug related factors Mw of Drug,
Lipophilicity
Patient Related factors Salivary secretion rate
pH of Buccal Cavity
Eating/Drinking habit
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POLYMER RELATED FACTORS
MW of polymer MW increases, chain & ultimately adhesion
increases Eg PEG4000
Flexibility Should be high
H-bond Capacity HPMC, Carbopol, PVA, PMA
Cross-linking density Should be low as possible
Charge Charged molecule will be highly adhere
Concentration 0.5-2 % optimum, because it will directly
increase the cross linking & hence binding
decreases
DRUG RELATED FACTORS
MW of Drug Mw of drug increases, the Absorption
decreases
Lipophilicity Should be high
PATIENT RELATED FACTORS
Salivary secretion rate
pH of Buccal Cavity
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Eating/Drinking habit
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MECHANISM OF ADHESION
• The term bioadhesion is commonly defined as adhesion
between two materials where at least one of the material is of
biological origin.
• When adhesion is restricted to mucus layer lining of the
mucosal surface, then it is known as mucoadhesion.
• Generally such adhesion occurs in four different steps…
➢Wetting & swelling
➢Interpenetration of polymer chains in mucin chains
➢Formation of chemical bonds between entangled chains
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1. Wetting and swelling of polymer to permit intimate contact with biological
tissue.
2. Inter-penetration of bioadhesive polymer(BP) chains and entanglement of polymer and
mucin chains.
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3. Formation of chemical bonds between entangled chains.
Chemical bonds may be primary(covalent) or secondary(ionic,
van der vaals, H-bonds)
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THEORIES OF ADHESION
Adsorption theory: Polymer/groups form covalent/non-covalent
bonds which will bind very strongly (also H-bonds, vanderwaal’s
bonds).
Wetting theory: Polymer with positive spreading co-efficient will
have good binding.
Diffusion theory: Permeability is good in mucin due to chain
flexibility.
Fracture Theory: Irregular surface of polymer & mucin give good
physical entanglement.
Electronic theory: Electric bilayer between polymer & mucin is
responsible.
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FORMULATION OF BDDS
• Tablets • Gels • Sprays
• Patches/films • Ointments
• Wafers
• Lozenges
• Powders
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Solid Dosage forms
Semi-Solid Dosage forms
Liquid Dosage forms
BASIC FORMULATION COMPONENTS
Muco-adhesive Polymers Permeation enhancers
Preferred Drug
Candidate
Diluents Plasticizer
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SELECTION OF DRUG FOR BDDS
I. MW should be less than 1000da
II. It should be having both nature i.e. Hydro-lipophilic type
III. Should be potent {low dose so that formulation is not bulky}
IV. Non-irritant to mucosa
V. Drugs that degrades in GIT.
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LIST OF API’S DELIVERED VIA BUCCAL
ROUTE
API
Acyclovir Metronidazole
Buprenorpine Metoprolol tartrate
Carbamazepine Morphine sulphate
Chlorpheniramine maleate Nifedipine
Danazol Omeprazole
Diclofenac sodium Pentazocine
Diltiazem Pindolol
Flurbiprofen Piroxicam
Hydrocortisone acetate Rh EFG
Insulin Testosterone
Lignocaine Terbutaline sulphate
LHRH Theophyline
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Zinc sulphate Triamcinolone acetate
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MUCOADHESIVE POLYMERS
• These are the main component for adhesion.
• They attract water from the biological surrounding, get swells
& adhere to the membrane.
• Normally they should be having hydrophilicity, numerous h-
bonding groups, flexibility, interpenetration with mucus &
tissues
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IDEAL FEATURES…
• Non-toxic, Non-irritant & Pure.
• Good spreadability, wetting, swelling, solubility &
biodegradable .
• Adhesion should be quick & with sufficient mechanical
strength.
• Should have peel, tensile, shear strength.
• Should easily incorporate drug in formulation & it should not
be obstacle in drug release.
• Cost effective.
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Examples
Hydrogels:
Polyacrylates, Carbopol, Polycarbophils
PVA, Ethylene vinyl alcohol, Cellulose derivatives, Alginates
thiolated polymers
Hydrophilic macromolecules exhibiting free thiol groups on
the polymeric backbone.
Eg: Thiomers of chitosan and polyacrylic acid etc
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PERMEATION ENHANCERS
• Permeation is very limiting factor in BDDS.
• Substances that facilates permeation through buccal mucosa are
called pe.
• Epithelium & lamina propria are very effective barrier to
absorption.
• They should be used with very care & in optimum
concentration(<1%), above this concentration toxicity due to
membrane damage may occur & histopathological study should
be done.
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MECHANISMS OF PE’S
• Increasing fluidity & integrity of cell membrane.
• Extracting inter/intra cellular lipids.
• Altering cellular proteins.
• Altering mucus rheology.
• Acting at the tight junctions.
• Increasing thermodynamic activity of drugs.
• Surface tension decreasing.
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Permeation Enhancers
Types Examples
Chelators EDTA, Citric acid, Sodium salicylate,
methoxy salicylates
Surfactants SLS, Polyoxyethylene,
Benzalkonium chloride,
Cetylpyridinium chloride,
Cetyltrimethyl ammonium bromide.
Bile salts sodium glycocholate,
sodium deoxycholate,
sodium taurocholate,
sodium glycodeoxycholate,
sodium taurodeoxycholate
Fatty acids Oleic acid, Capric acid, Lauric acid,
PG, methyloleate,
Phosphatidylcholine.
Non-surfactants Unsaturated cyclic ureas.
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Inclusion complexes: Cyclodextrins
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FORMULATION
NON ATTACHED DRUG
DELIVERY SYSTEM:
The local physiological environment greatly
affects the non attached drug delivery system.
Eg: The presence of saliva, the intake of foods
and liquids.
BIO-ADHSIVE DRUG
DELIVERY SYSTEM:
These are the formulations that are
designed in such a manner so as to adhere to the
mucosa of the oral cavity they are likely to get
affected by local physiological factors as, –
presence of saliva
– Intake of foods and liquids but not
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BUCCAL ADHESIVE SYSTEM
IDEAL BUCCAL ADHESIVE
ADHESIVE TABLETS: SYSTEM:
• Hydrophilic and hydrophobic matrices have been • Maintain its position in mouth.
used.
• Release the drug in controlled
• Sodium carboxy methyl manners
cellulose(SCMC),Hydroxyl Propyl Methyl
Cellulose(HPMC),sodium alginate and guar-gum • Provide drug release in uni-
as mucoadhesive polymers. direction.
• The carbopol-934 is used as a primary polymer • Ex: mucoadhesive buccal tablet of
because of its excellent mucoadhesive property diltiazem Hcl,Verapamil buccal
and secondary polymers like HPMC,SCMC. tablets,Sumatriptan succinate
• Ex. A polymeric matrix system contain pectin, buccal tablets.
HPMC, diltiazem HCL prepared by direct
compression. Further 2 external layer are
applied.(Geo-matrix tri layer tablets)
• 2 external layer control rate of dehydration of
core, by restricting are available for diffusion.
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BUCCAL TABLETS
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BUCCAL TABLETS
• It is small, flat and oval in shape with a diameter of aprox.5-8 • Multi-layered tablets may be prepared by
mm. sequentially adding and compressing the
• The direct compression technique is most widely used for ingredients layer by layer.
preparation of buccal tablets, techniques like wet granulation can
• The two buccal bioadhesive tablets
also be employed.
commercially available buccoadhesive tablets
• Unlike conventional tablets, buccal mucoadhesive tablets allow in UK are “Buccastem” (nitro-glycerine) and “
for drinking and speaking without major discomfort Suscard buccal” (prochloroperazine)
• They are soften, adhere to the mucosa and are retained in
• Example:
position until dissolution and /or release is complete these
tablets can be applied to different sites in the oral cavity A) Nitro-glycerine bioadhesive tablets for
including the palate, the mucosa lining the cheeks, as well as the treatment of angina pectoris.
between the lip and the gum.
B) Sumatriptan succinate buccal adhesive
• Tablets have been most commonly investigated dosage form for
buccal drug delivery. Several bioadhesive buccal tablet tablet which is effective in the acute treatment
formulations have been developed by direct compression of migraine.
method in recent years either for local or systemic drug delivery.
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DRUGS GIVEN AS
DIFFERENT
BUCCAL TABLETS
MARKETED BUCCAL
• Propranalol
TABLETS
• Fentanyl Buccal Tablet • Metoprolol
• Miconazole Buccal • Metoclopromide
Tablet(oravig) • Insulin
• Glycerl Trinitrate • Nitroglycerine
Buccal Tablet(suscord)
• Prochlorperazine
Maleate Tablet
(Buccastem RM )
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METHOD OF PREPARATION:
1. DIRECT COMPRESSION
2. WET GRANULATION TECHNIQUE
• For delivery of drug via buccal route the tablets which are inserted into the
buccal pouch may dissolve or erode therefore they must be formulated and
compressed with sufficient pressure only to give a hard tablet.
• Bilayered and multilayered tablets are already formulated using bioadhesive
polymers and excipients.
• If necessary, the drug may be formulated in certain physical states such as
microspheres , prior to direct compression in order to achieve some desirable
properties,
• Example: enhanced activities and prolonged drug release.
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▪ MICROPARTICLES:
The local irritation caused by microsphere or microcapsules or
microparticles at the site of adhesion is less and are comfortable with
sensation of a foreign object within the oral cavity.They are more palatable
as compared to buccal tablets. Bioadhesive micro or nano particles offer the
same advantage as tablets but their physical properties enable them to make
intimate contact with a mucosal surface area
• Particulates have the advantage
of being relatively small and
more likely to be acceptable by
the patients.
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LOZENGES:
WAFERS: A slow release bioadhesive lozenge offers the potential
for prolonged drug release with improved patient
• A conceptually novel periodontal drug delivery
compliance thus avoiding multiple daily dose.
system.
Used for the delivery of drugs that act topically within
• Intended for the treatment of microbial infections the mouth including:
associated with periodonitis.
1. Antimicrobials
• The drug delivery system is a composite wafer with
2. Corticosteroids
surface layers possessing adhesive properties, while
the bulk layer consists of antimicrobial agents, 3. Local anaesthetics
biodegradable polymers and matrix polymers. 4. Antibiotics
5. Antifungals
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POWDERS:
• These are a mixture of
bioadhesive polymers and the
drug and are sprayed onto the
buccal mucosa the reduction in
diastolic B.P after the
administration of buccal tablet
and buccal film of nifedipine.
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VISCOUS LIQUID:
• Liquids used to coat
buccal surface are viscous
and serve as either
protective agents or as
drug vehicle for delivery of
drug on to the mucosal
surface.Lubrication can be
provided by treating dry
mouth with artificial saliva
solutions and to retain the
drug on mucosa surfaces
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HYDROGELS
• Consists of finally powdered natural or synthetic
polymer dispersed in a polyethylene or in aqueous
solution. Ex:arabase.
• It includes crosslinked polyacrylic acid that has been
used to adhere to mucosal surfaces for extended periods
of time and provide controlled release of drug.
• These are hydrophilic matrices that are capable of
swelling when placed in aqueous media.
• Hydrogels,which release the drug by swelling and there
by allowing drug transport through the spaces in the
polymer network are being widely studied for their use in
bio adhesive gels ex. Chitosan glutamate buccal hydrogel
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OINTMENTS: BUCCAL SPRAYS:
• Semisolid dosage forms have the • It delivers a mist of fine droplets
onto mucosal membrane probably
advantages of easy dispersion
onto mucin layer.
throughout the oral mucosa.
• The drug substance that in solvent
• Has been overcome by using and not immediately absorbed is
bioadhesive formulations deposited as a thin film onto mucin
layer.
• Certain bioadhesive polymers
undergo a phase change from a • Example: estradiol spray.
liquid to a semisolid ;this change
enhances the viscosity which
results in sustained and
controlled release of drugs.
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MOUTH FRESHNERS AND SPRAYS
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PATCHES
• Flexible adhesive patches are designed to • It have unique characteristics, includes rapid onset of drug delivery ,
overcome lamination of other dosage
sustained drug release and rapid decline in serum drug concentration
form. It is released in controlled manner when patch is removed these are modified release dosage form that
from the drug containing reservoir layer have potential to provide controlled drug delivery from 1-24 hours.
& bioadhesive surface for mucosal They adhere to buccal mucosa for extended period of time.It may be ,
attachment.
• Unidirctionally
• Two methods used to prepare adhesive
• Bidirectionally
patches include
• Multidirectionally
1. Solvent casting
• Consists of two poly laminates or multi layered thin film round or oval
2. Direct milling as consisting of basically of bio adhesive polymeric layer and
impermeable backing layer to provide unidirectional flow of drug
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BUCCAL FILMS:
• Films are formulated by incorporating the • It is most recently developed dosage form which
drug in alcohol solution of bio adhesive meant for buccal administration.
polymer. • It have more flexibility and comfort when
compared with adhesive tablets.
• Flexible films may be used to deliver drugs
directly to a mucosal membrane • An ideal film should be soft, elastic, flexible and
posses adequate strength to withstand breakage
• Provide measured dose of drug to the site. due to stress from mouth movements.
• Unidirectional drug delivery into the • Example: buccal film of salbutamol sulphate and
systemic circulation. terbutalin sulphate for the treatment of asthma.
• Films adheres strongly to the wet mucosal
surface.
• Drug released over minutes to hours for as
long the film is attached to the buccal tissue
via hydrogen bonding.
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Ideal drug candidates:
• Organic nitrites(glyceryl tri LIST OF DRUG DELIVERED VIA
nitrites) BUCCAL ROUTE
1. Acyclovir
• NSAIDS(diclofenac sodium)
2. Carbamazapine
• Local anaesthetics
3. Buprenorpine
• Bronchodilators(salbutamol)
4. Chlorpromazine
• Antibiotics 5. Danazol
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MANUFACTURING OF BDDS
• The main manufacturing processes involved in mucoadhesive buccal
films are,
1.Solvent casting
2.Hot melt extrusion
3.Direct milling
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SOLVENT CASTING METHOD:
API and other
excipients are
dissolved in
appropriate
solvent to
form a clear • The drug and excipients is dissolved in
viscous
solution appropriate solvent and water soluble polymers
are dissolved in water and these solutions are
stirred and at last casted into the petri plate and
The formed
solutions are dried.
mixed
• The solvent is evaporated by casting the solution
of the drug and polymer onto a backing layer
Solution is cast sheet and the patches were punched in
as a film and intermediate sheet.
allowed to dry
Film is coated
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DIRECT MILLING METHOD: Dry milling:
• Here drug and excipients are mixed mechanically by
• Drug and excipients are mixed by kneading,
milling and kneading
usually without the presence of any liquids.
• After mixing the resultant material is rolled on the release
liner till desired thickness is achieved • After the mixing process, material is rolled
on a release liner until the desired thickness
• Backing material is laminated to control the direction of
is achieved.
drug release, prevent drug loss, and minimize deformation
and disintegration of the device during the application • The backing material is then laminated.
period. API AND EXCIPIENTS are
blended by direct milling
• Examples are,
1. Isosorbide dinitrate in the form of unidirectional erodible
buccal film are developed and characterized for improving Blended mixture is rolled
bioavailability with the help of roller
2. Buccal film of salbutamol sulphate and terbutalin sulphate
for the treatment of asthma
Material is laminated and
3. Buccoadhesive film of clindamycin used for pyorrhoea film collected
treatment.
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• HOT MELT EXTRUSION: In this method blend of
pharmaceutical ingredients is molten. Blend is then
forced through an orifice to yield more homogenous
material in different shapes such as granules , tablets or
films extrude via heating melts the mixture extrude
In dry state
drug is mixed
with carriers
Extrude via
heating melts
the mixture
The mass is
cast in the films
by the die.
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DRUG DELIVERY PATHWAYS
There are two routes of
drug transport :
✓ Paracellular route
✓ Transcellular route
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PARACELLULAR ROUTE: TRANSCELLULAR ROUTE:
• The paracellular pathway is • The transcellular route
an aqueous extracellular involves crossing the skin by
route across endothelia and directly passing through
epithelia that is followed by both the lipid structures of
substances according to their the intermellar region.
size and charge. • Route for lipophilic
• Primary route for compounds lipophilic drugs
hydrophilic drugs passes through lipid rich
intercellular spaces is the plasma membranes of the
preferred route. epithelial cells.
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METHODS TO INCREASE
BUCCAL DRUG DELIVERY
The buccal drug delivery can be increased by various ways, this
include:
• Permeation enhancer:
Eg: Bilesalts, fatty acid, chelates, cyclodextrins, sodium lauryl
sulfate.
• Patch design
• Enzyme inhibitors: :protease inhibitors as aprotinin, bestatin.
• Prodrug
• Vehicle/cosolvents: propylene glycol
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EVALUATION OF BUCCAL TABLETS
THICKNESS
▪ The thickness of buccal tablets can be
determined using DIGITAL micrometer.
▪ Ten individual tablets from each batch
were used and the results averaged.
HARDNESS
▪ Hardness test can be conducted for 3
Tablets from each batch using Monsanto
hardness Tester and average values were
calculated.
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ASSAY
▪ Ten tablets were weighed and grounded
In a MORTAR and PESTLE to get fine powder.
▪ Powder equivalent to the mass of one
Tablet was dissolved in methanol by sonication
For 30min and filtered through filter paper.
▪ The drug content was analyzed spectrophotometrically at
274nm using an UV spectrophotometer.
WEIGHT VARIATION
▪ Weight variation was performed for 20 tablets from each batch
using an ELECTRONIC BALANCE and average values were
calculated.
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DISINTEGRATION TEST
▪ Test is performed for buccal tablets which are not having
backing. Six tablets were taken randomly from each batch
and placed in USP Disintegration apparatus(Basket type).
▪ Apparatus was run for 4hr and the basket was lift from the
fluid, observe whether all of the tablets have disintegrate.
FOURIER TRANSFORM
INFRARED SPECTROSCOPY
▪ The samples were crushed with kbr to make pellets under
hydraulic pressure of 10tons, and then the FTIR SPECTRA
were recorded between 400 and 4000cm-1.
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▪ To investigate the possibility of any chemical
interaction between drug and polymers used in
the Preparation.
DSC
▪ In differential scanning calorimetric analysis, the samples were heated
from 0-300 degrees at a heating rate of 10 degrees per meters under
argon temperature using a micro calorimeter and then thermograms
were obtained.
MODIFIED BALANCE METHOD
(MUCO/BIOADHESIVE METHOD)
▪ The MODIFIED PHYSICAL BALANCE METHOD was
used for determining the ex-vivo bioadhesive strength.
▪ Fresh porcine buccal mucosa obtained from a local
slaughter house was stored in ph 6.6 phosphate buffer at 4
dMeygPharremaeGsuid ec.Ceomlsius upon collection. The experiment was
performed within 3 hours of procurement of the mucosa.
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▪ The porcine buccal mucosa was fixed to the stainless
steel piece with cyanoacrylate adhesive and placed in a
beaker, then ph 6.6 phosphate buffer was added into the
beaker up to the upper surface of the porcine buccal
mucosa to maintain buccal mucosal viability during the
experiment.
▪ Then the tablet was attached to the upper clamp of the
apparatus and the beaker was raised slowly to establish
contact between porcine buccal mucosa and the tablet.
▪ A preload of 50gm was placed on the clamp for 5mins
to establish adhesive bond between the tablet and
porcine buccal mucosa.
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▪ After completion of preload time, preload was removed from
the clamp and water was added into the beaker from burette
at a constant rate.
▪ The weight of water required to detach the tablet from
porcine buccal mucosa was noted as mucoadhesive strength
and experiment was repeated with fresh mucosa in an
identical manner.
SURFACE PH STUDY
▪ The buccal tablets were placed in glass tubes and allowed to
swell in contact with PH 7.4 phosphate buffers (12ml).
▪ Thereafter, surface PH was measured by using PH PAPER
placed on the surface of the swollen tablets.
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▪ The mean of three readings was recorded.
PALATABILITY STUDY
▪ It is conducted on the basis of TASTE, after
BITTERNESS and the
Physical appearance.
▪ All the batches are rated a, b and c Grades, as per
the criteria.
▪ When the formulation scores atleast One A grade,
formulation is considered as average.
▪ Scores two a grade then considered as good and the
one with all three a grade considered good buccal
formulation.
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SWELLING INDEX
▪ THE EXTENT OF SWELLING CAN BE
MEASURED IN TERMS OF % WEIGHT
GAIN BY THE DOSAGE FORM.
▪ THE SWELLING INDEX IS
CALCULATED USING FOLLOWING
FORMULA,
S.I = WT – WO
WO
WHERE,
➢ S.I = SWELLING INDEX.
➢ WT = WEIGHT OF TABLET AT TIME
T.
➢ WO = WEIGHT OF TABLET
BEFORE PLACING IN THE BEAKER.
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STABILITY OF BUCCAL TABLETS
▪ Stability studies of buccal
TABLETS were performed for optimized
Formulation in normal human saliva.
▪ The human saliva was collected from
Humans and filtered through filter paper,
Buccal tablets were placed in separate
Petri dishes containing 5ml of human
Saliva and placed in a temperature
Controlled oven for 8hrs at 37℃ ± 0.2℃.
▪ At regular time intervals (0, 2, 4, 6 &
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8hrs), the buccal tablets were examined for change in color, surface area and integrity.
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▪ The experiments were replaced in triplicate (n = 3) in a similar
Manner.
RESIDENCE TIME
▪ According to RESIDENCE
TIME; take a slide, stick a mucosa
on it with gum.
▪ Place our dosage form on it with
few droplets of PBS with ph (6.8),
allow it to stick on it.
▪ Now make it inclined & at
Ccnstant rate add pbs 6.8 drop
Wise on it without moving the slide.
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▪ Note the time till dosage form detaches from mucosa.
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EVALUATION OF BUCCAL
FILMS/PATCHES
FILM WEIGHT
▪ The weight of each prepared film was measured using a DIGITAL
BALANCE among the three films of every formulation and the average
Weight was calculated.
Folding endurance
▪ FOLDING ENDURANCE of the films
was premeditated by repeatedly folding
one film at the same place till it broke
Or folded up to 300 times manually.
▪ The number of times the film could be
Folded at the same place until it breaks
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Gives you value of folding endurance.
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THICKNESS
▪ The thickness of each film was
Measured using a MICROMETER
SCREW GAUGE at different points
Of the film and the average was
Calculated.
SURFACE PH
▪ SURFACE PH On the surface of the swollen tablets of the
films can be determined by allowing three films of each
formulation to swell for two hours on an agar plate surface.
▪ Ph was measured by means of PH Paper positioned on the
surface of the Swollen film and a mean was calculated.
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MOISTURE CONTENT
▪ The prepared films are weight individually and kept in a
DESICCATOR containing calcium chloride at room
temperature for 24hrs.
▪ After a specified interval, the films are to be weighted again
until they show an unvarying weight.
▪ The % moisture content was calculated
By using the following formula,
% MOISTURE CONTENT
= INITIAL WEIGHT – FINAL WEIGHT
INITIAL WEIGHT X 100
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VISCOSITY
▪ The viscosity of the solution used for
Buccal films were determined using the
Brookfield viscometer.
SHEAR FORCE (FOR VARIOUS
POLYMERS)
▪ The SHEAR TEST measures the force required
To separate two polymer–coated glass slides
Joined by a thin film of natural or synthetic mucus.
▪ The results of this technique often correlate well
With in vivo test results.
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TEXTURE ANALYZER
(FOR BIOADHESION TEST)
▪ Here the TEXTURE
ANALYZER force required to
Remove the formulation from a
Model membrane is measured,
Which can be a disc composed of
Mucin, a piece of animal mucous.
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EVALUATION OF BUCCAL SEMI-
SOLID DOSAGE FORM
DETERMINATION OF PH
▪ THE PH OF THE GEL/OINTMENT WAS
DETERMINED USING A CALIBRATED PH METER.
▪ THE READINGS WERE TAKEN FOR AVERAGE
OF 3.
GELLING CAPACITY
▪ The gelling capacity of the formed
Gel was determined using VISUAL
INSPECTION and the different grades
Were allotted as per the gel integrity,
Weight and rate of formation of gel
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With respect to time.
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VISCOSITY STUDIES
▪ The rheological studies were carried out using BROOKFIELD
programmable DVIII + model pro II type (USA).
▪ The viscosity of in situ gels were determined at different
angular.
▪ Calculate the viscosity.
▪ Evaluation was conducted in triplicate.
SPREADABILITY
▪ For the determination of spreadability, excess o sample was
applied in between two glass slides and was compressed to
uniform thickness by placing 1000g weight for 5min.
▪ The time in which the upper glass slide moves over to the lower
plate was taken as measure of spreadability (s).
▪ Weight (50g) was added to the upper glass slide.
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▪ S = ML / T
▪ Where, M = weight tide to upper slide.
L = length moved on the glass slide.
T = time taken.
MEASUREMENT OF GEL STRENGTH
▪ A sample of 50g gel was placed in a 100ml graduated cylinder and gelled in a
thermostat at 37 degree celcius.
▪ The apparatus for measuring gel strength was allowed to penetrate in buccal gel.
▪ The gels strength, which means the viscosity of the gels at physiological
temperature, was determined by the time (sec), the apparatus took to sink 5cm
down through the prepared gel.
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APPLICATION:
They may be used for both local and systemic drug activity as they are better absorbed
by the intestinal microvilli and prolong the contact at the site of absorption.
ADVANTAGES:
Increased gastric retention time due to adhesion with mucus and mucus lining,
increasing the bioavailability, sustained release property.
1.For drugs having low bioavailability:
Drugs having low bioavailability like insulin, octreolide, leuprolide, oxytocin,
testosterone, calcitonin, amoxicillin are prepared as mucoadhesive formulations due to
modulation of transit time and absorption of drug.
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CONT’D
2.Reduced frequency of dosing:
▪ For drugs with short bioavailability, sustained and slow input from controlled release mucoadhesive
pattern produces drug concentration with narrow range that is useful for drugs with narrow therapeutic index.
▪ It also offers advantage of counter activity by avoiding sudden drug release leading to higher drug
efficiency.
▪ Delayed controlled release is achieved by polymers like carbopol, isapgol.
Example:
▪ Sustained release – captopril (galactomannans + sodium alginate are prepared)
▪ Antibiotics like rifampicin that are degraded in acidic medium of stomach can be
prepared by this drug delivery system in order to extend the critical concentration time
enhancing pharmacological activity.
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CONT’D
For local ailments of GI tract: by this method the upper stomach and lower small intestine are
targeted that aids in reducing systemic circulation associated toxic effects.
Eg: antibiotics formulated as mucoadhesive forms prevent the development of
resistance in microbes.
These formulation might be available as,
▪ Multilayered tablets which have acrylic polymers or cellulose to promoted mucoadhesive in
GIT.
▪ Gelatin based capsules having bioadhesive polymers like carbopol.
▪ Large surface area, sustained release, immobilization of particles on mucosal surface are the
advantages, of micro/nano particles.
Disadvantages:
▪ Bioadhesion/mucoadhesion is prevented by the acidic gastric environment and high rate of
mMuyPchaormuaGsu idpe.rCoomduction.
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REFERENCE
1. ADVANCES IN DRUG DELIVERY by “Y.Madhusudan Rao, A.V.Jithan” VOLUME-1
2. NOVEL DRUG DELIVERY SYSTEMS FOR MODULATION OF GASTROINTESTINAL
TRANSIT TIME, “Yousef Javadzader and Sanaz Hamedeyazdan”
3. AN REVIEW: GASTRORETENTIVE DRUG DELIVERY SYSTEM by “Amit Kumar Nayak.
Rama Maji Biswarup Das”
4. OVERVIEW ON BUCCAL DRUG DELIVERY SYSTEM by “N.G.Raghavendra Rao.
B.Shravani, Mettu Srikanth Reddy”.
5. MUCOADHESIVE DRUG DELIVERY SYSTEMS BY “Fiavir Chiva Carvalho” Marcos
Luciano Bruschi Raul Cesar Evangelista” BAZILLIAN JOURNAL OF PHARMACEUTICAL
SCIENCE.
6. NOVEL DRUG DELIVERY SYSTEMS BY “Chien.Yie W”.
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REFERENCE
• A REVIEW ARTICLE ON MUCOADHESIVE BUCCAL DRUG DELIVERY SYSTEM by
Jasvir singh and Pawan deep – International journal of pharmaceutical science and research.
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