Gastro-Retentive Drugs: A Novel Approach Towards Floating Therapy

Sponsored Links

Mr. S.J. Daharwal

Mr. S.J. Daharwal

Conventional
drug delivery system achieves as well as maintains the drug concentration
within the therapeutically effective range needed for treatment only when taken
several time a day.

This results in a, significant fluctuation in drug levels.
Recently, several technical advancements have led to the development of several
novel drug delivery systems (NDDS) that could revolutionize method of
medication and provide a number of therapeutic benefits.


The
most important objective of the new drug delivery systems are:

It
would be single dose, the duration of treatment, which releases the active
ingredient over an extended period of time and, it should deliver the active
entity directly to the site of action, thus minimizing or eliminating side
effects.

There
are many steps which are worked out in the process of development of a drug.
Right from the beginning, i.e., from the phase of drug discovery, development
of a proper formulation and deciding upon the proper dosage form for the drug.
A drug can be developed as a liquid, semi – solid or solid dosage form
primarily. All the dosage forms have their own merits and demerits. The choice
of these dosage forms is made to suit the properties of the drug so as to
obtain maximum therapeutic efficacy with minimum adverse effects. Or in other words
a dosage form which will produce maximum plasma levels of drug or that will
give maximum bioavailability is chosen.

Modified drug
release can be either delayed or expended release. Delayed release products are
usually enteric coated. Extended release products are designed to release their
medication at a predetermined rate, duration and location to achieve and
maintain optimum therapeutic blood levels.

Rationale for extended release
pharmaceuticals:

These are some drugs
which have long half life and hence are long lasting and they are required to
be given one a day to system adequate blood levels and the desired therapeutic
effects. There are on the other hand many drugs which are not long lasting and
require multiple daily dosing to achieve the desired therapeutic levels.

Multiple daily
dosing is after is inconvenient for the patient and can result in missed doses,
made up doses and patient non compliance with the therapeutic regimen. Another
drawback of multiple dosing is that when doses are not administered on
schedule, the resulting peaks and valleys reflect less than optimum drug
therapy and if the doses are administered too frequently minimum toxic
concentrations may be recalled with toxic side effects resulting. If doses are
missed, periods of sub therapeutic blood levels or those below the minimum
effective concentration   may result, with no patient benefit.

Advantages of extended release dosage form

Advantages of extended release dosage
form:

(1) This decreases the need for multiple dosing and hence
improves patient compliance and chances of toxicity.

(2) It provides an immediate release of drug which promptly
produces the desired therapeutic effect which then is followed by the gradual
and continual release of additional amounts of drug to maintain this effect
over a pre-determined period of time.

(3) The sustained release drug levels provided by extended
release drug products often eliminate the need for night dosing which is
beneficial for the patient and the caregiver.

(4) Reduction in drug blood level fluctuations by controlling
the rate of drug release, “Peak and Valley” of drug blood levels are
eliminated.

(5) Reduction in adverse side effects

(6) Reduction in overall health care costs. Although the
initial cost may be greater then that for conventional the overall cost of
treatment may be less due to enhanced therapeutic benefit, fewer side effects
and reduced time required of health care personnel to dispense and administer
drugs and monitor patients.

Disadvantages of extended release dosage
form:

The loss of
flexibility in adjusting the drug dose and / or dosage regimen and an increased
risk of sudden and total drug release or “dose dumping” due to failure of the
technology of the dosage unit.

Disadvantages of extended release dosage form
 

MODIFIED RELEASE 

Characteristics of a drug for being
chosen as an extended release product:

(1) They exhibit neither very slow nor very fast rates of
absorption and excretion. Drugs with very short half lives, i e, < 2 hrs are
poor candidates for extended release dosage form because of the large
quantities of drug required for such a formulation whereas those drugs with a
very slow rate of excretion also do not need to be formulated as an extended
release product.

(2) They are uniformly absorbed from the gastrointestinal
tract.

(3) They are administered in relatively small doses.

(4) They possess a good margin of safety: the most widely
used measure of the margin of a drug’s safety is its therapeutic index, i.e.,
the median toxic dose divided by the median effective dose for very potent
drugs the therapeutic index may be narrow or very small. The larger the
therapeutic index the safer the drug. Drugs which are administered in very
small doses or posses very narrow therapeutic index are poor candidates for
formulation into extended release formulations because of technological
limitations of precise control over release rate and risk of dose “dumping” due
to a product defect.

(5) They are used in the treatment of chronic rather than
acute conditions.

Techniques for producing an extended
release product:

The technology is
mainly based on

(1)
Modifying drug dissolution by
controlling access of biologic fluids to the drug through the use of barrier
coatings.

(2)
Controlling drug diffusion sets from
dosage forms.

(3)
Chemically reacting or interacting
between the drug substance or its pharmaceutical barrier and site specific
biologic fluids.

Some of extended release oral dosage
forms are available as:

-
Coated beads, Granules or Micro sphere

-
Multi tablet System

-
Microencapsulated Drug

-
Embedding drug in slowly eroding or
hydrophilic matrix system.

-
Embedding drug in inert plastic
metrics.

-
Complex formation

-
Ion exchange resins

-
Osmotic pump

- Floating tablets  


Gastroretentive System

Sustained
release through gastric retention:

During
the last decade many studies have been performed concerning the sustained
release dosage form of drugs, which have aimed at the prolongation of gastric
emptying time (GET). The GET has been reported to be from 2 to 6 hours in humans in the fed state. Accordingly orally, sufficient bio availability and
prolongation of the effective plasma level occasionally can not be obtained.

Controlled
release drug delivery systems that can be retained in stomach for a long time
are important for drug that are degraded in intestine or for drugs like
antacids or certain enzymes that should act locally in the stomach. If the
drugs are poorly soluble in intestine due to alkaline pH, gastric retention may
increase solubility before they are emptied, resulting in improved
gastrointestinal absorption of drugs with narrow absorption window as well as
for controlling release of drugs having site-specific absorption limitation.

Approaches
to gastric retention:

Over the
last three decades, various approaches have been pursued to increase the
retention of an oral dosage form in the stomach.

· Incorporation of passage delaying
food excipients, principally fatty acids, to decrease the gastric emptying
rate.

· Bio adhesive research based upon
the adhesive capacity of some polymer with glycoprotein (Mucin) closely applied
to the surface epithelium of the stomach and intestine.

· The other approach is to alter the
formulation's density by using either high or low-density pellets, so called
altered density approach.

High
density approach:

Here,
the density of the pellets must exceed that of normal stomach and should be at
least 1.40. In preparing such formulations, drug can be coated on a heavy core
or mixed with heavy, inert materials such as barium sulfate, titanium dioxide,
iron powder and oxide. The weighed pellet can then be covered with a diffusion
controlled membrane.

Low-density
approach:

While
the system is floating on the gastric contents the drug is slowly released from
the low density pellets or floating drug delivery systems (FDDS) and are also
called as hydro dynamically balanced systems (HBS). FDDS or HBS have a bulk
density lower than gastric fluid, that is, bulk density of less than one. HBS
remains buoyant in the stomach without affecting the gastric emptying rate for
a prolonged period of time and 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.

Shells
of polymer with lower density than that of the gastrointestinal fluid, (ex
polystyrene) have been used for this purpose. Swelling type dosage forms are
such that on swallowing these products swell to an extent that prevents their
exit from the stomach through the pylorus. As a result, the dosage form is
retained in the stomach for a long period of time. These systems may be
referred as 'plug type system' since they exhibit tendency to remain logged at
the pyloric sphincter. Modified shape systems are no disintegrating geometric
shapes molded from silstic elastomer or extruded from polyethylene blends which
extend the gastric retention time depending on size, shape and flexural modulus
of the drug delivery system.

Unfortunately,
most of these systems have many drawbacks. Floating system requires presence of
food to delay their gastric emptying. They do not always release the drug at
the intended sit. Bio-adhesive system adheres to the mucus. This adhesion is a
result of electrostatic and H-bond formation at the mucus-polymer boundary. The
bond formation is prevented by acidic environment and thick mucus present in
the stomach.

Factors
affecting gastric retention:

These
factors include density, size and shape of dosage form, concomitant intake of
food and drug such as anti-cholinergic agents (e.g. Atropine, propantheline),
opiates (e.g. Codeine) and prokinetic agents (e.g. Metoclopramide) and
biological factors such as gender, posture, age, body mass index and disease
state. (e.g. Diabetes).

In
order for a HBS dosage form to float in the stomach the density of the dosage
form should be less than the gastric contents. However, the floating force
kinetics of such dosage form has shown that the bulk density of a dosage form
is not the most appropriate parameters for describing its buoyancy.

These
are better represented and monitored by resultant weight measurements and
swelling experiments. This is because the magnitude of floating strength may
vary as a function of time and usually decreases after immersion of the dosage
form into fluid consequently to the evolution of its hydro-dynamical
equilibrium.

The
prolongation of gastric residence time (GRT) by food is expected to maximize
drug absorption form FDDS due to increased dissolution of drug and longer
residence at the most favorable sites of absorption. GRT of a dosage form in
the fed state can also be influenced by its size.

Technological
developments in FDDS (floating drug delivery system):

Most
of the floating systems reported in the literature are single unit systems,
such as floating tablets. These systems are unreliable and irreproducible in
prolonging residence time in the stomach when orally administered owing to
their fortuitous (all-or-nothing) emptying process. On the other hand, multiple
unit dose forms appear to be better suited since they are claimed to reduce the
inter subject variability in absorption and lower the probability of
dose-dumping.

It
also eliminates the dependence of the drug effect on gastric emptying, the mini
depots being sufficiently small to make possible their passage through pylorus
even between its actual openings. As a result, the drug will reach the site of
optimum absorption and a high local concentration will also be avoided.






Floating drug delivery system Tablet:

Broad
outline of various features of a tablet:

A solid dosage form will be
comprised of all the ingredients which are in solid state. And the final
texture of the drug will be solid and this will show the properties of solid.
They will have a definite, size shape, thickness, hardness, solubility,
density, optical density, etc.

Tablets-

Among all the
orally administered forms of drug the tablets are most convenient both from the
point of view of the patient as well as the manufacturer. The tablets are the
unit dosage forms these tablets are mainly spherical in shape but the shape can
be round, oval, oblong, etc. these are manufactured by the compression and
compaction of the granules and other additives. Tablets have the following
advantages along with all the advantages of solid dosage form.

Advantages of Tablet:

(1) Ease of Handling: The Tablet unlike
the liquid is easily maintained they do not require more space for storage.

(2)

Transportation:

The drug when
present in the Tablet can be easily transported from one place to another.

(3)

Less Prone to
Microbial Infections:

The Tablet does not offer as a platform for substantial
microbial growth unlike the liquid dosage form.

(4)

Less Probability of
Dosage Error:

These drugs have a definite dose and the accuracy is
maintained. This dose accuracy is not maintained in liquid dosage form.


(5)


Tamper Proof:

 Tablet can not be
easily tampered or they are less prone to adulteration as compared to their
liquid dosage forms.


(6)


Ease of
Manufacturing:

Manufacturing of Tablet is not as complicated and costly as
the liquid dosage form.

(7) Their cost is lowest of all the oral dosage forms.

(8) They are the lightest and most compact of all the dosage
forms.

(9) They are in general the easiest and cheapest to package
and ship of all the other dosage forms.

(10) Product identification is simplest and cheapest when employing an
embossed or monogrammed punch.

(11) They provide the case of swallowing with least tending to hang up
especially above the stomach.

(12) They lend themselves to certain special release profile products such as
enteric or delayed release products.

(13) They are later suited to large scale productions then other unit oral
forms.

(14)  Greatest dose precision and the least content variability.

Disadvantages:

(1) Some drugs resist compression into dense compacts owing
to their amorphous nature or flocculent, low density character.

(2) Drugs with poor wetting, and slow dissolution properties,
intermediate to large dosages, optimum absorption high in the gastrointestinal
tract or any combination of these features may be difficult or impossible to
formulate and manufacture as a tablet that will still associate adequate or
full drug bioavailability.

(3) Bitter tasting drugs with an objectionable odor or drugs
that are sensitive to oxygen or atmospheric moisture may require encapsulation
or entrapment

prior to
compression in such cases, the capsule may offer the best and lowest cost
approach.

(4)They do not give maximum bioavailability
in the same duration in which the liquids achieve maximum plasma levels.

(5)This type of dosage forms are
often disliked by elderly patients and young children and even can not be
administered to infants.

(6)Some solid dosage forms like
capsules are a very costly affair.

Properties of a Tablet:

(1) Tablet should be an elegant product having its own
identity which being free of defects such as chips, cracks, discoloration,
contaminant etc .

(2) Should have the strength to withstand the rigors of
mechanical shocks encountered in its production, packaging, shipping etc.

(3) Should have the chemical and physical stability to
maintain its physical attributes over time.

(4) It should be able to release the medicinal agent in a
predictable and reproducible manner.

(5) Must have a suitable chemical stability over time so as
not to allow alteration of the medicinal agents.

Types and Classes of Tablets:


The tablets can be
classified by their:

·  
Route of administration or function

·  
By the type of drug delivery system
they represent within that route

·  
By the form and method of manufacture.

Tablets Ingested Orally:  

Orally ingested tablets are designed to be swallowed
intact with the exception of chewable tablets.

(1) Compressed Tablets
or standard compressed Tablets:

This category refers
to standard uncoated tablets made by compression and employing any of the three
basic methods of manufacture are Wet granulation, double compaction or direct
compression. As the solubility of the drug decreases, especially with acidic
drug moieties that are absorbed best in the upper G.I.T.

(II) Multiple Compressed Tablets:  

There are two classes of multiple compressed tablets
layered tablets and compression coated tablets. Both types may be either two
component or 3 component system : 2 or 3 layer tablets, a tablet within a
tablet. Each tablet is first laid down with a light compression.

Purpose of Such Tablets :

To
separate physically or chemically incompatible substances, or to produce repeat
action or prolonged action products.

(III) Sugar Coated Tablets:  

Sometimes the compressed tablets can be covered with a layer of colored
or uncolored sugar layer. This coating is water soluble and is quickly
dissolved on swallowing. It provides of protective layer to the objectionable
taste or odour.

Disadvantages : As
lot of time and expertise is required in the manufacturing of sugar coated
tablets.

As also the size and
weight of the sugar coated tablets increases considerably leading to an
increase in the cost of transportation.

(IV) Film Coated Tablets:

These are compressed tablets coated with a thin layer of polymer which
forms a skin like film over the tablet.

Advantage –

(a) It is more
durable

(b) Less bulky

(c) Less time
consuming to manufacture..

These rupture and
expose the core tablet at the desired location is G.I.T.  

(V) Gelatin Coated Tablet :

Is recent introduction in tablet coating and the innovator products
called GEL CAPS, is a capsule shaped compressed tablet that allows the coated
product to be 1/3 smaller than a capsule filled with an equivalent amount of
powder

Advantage: As
gelatin coating facilitates swallowing and gelatin coated tablets are more
tamper evident.

(VI) Enteric Coated tablets:

They possess delayed release features. They are designed to pass
unchanged through the stomach with transit to the intestine where the tablets
disintegrate and allow drug dissolution and absorption. These are applied in
those cases in which the drug substance is destroyed by gastric mucosa.

(VII) Buccal or Sublingual Tablets:

Are flat, oval tablets intended to be dissolved in the
buccal pouch or beneath the tongue for absorption through the oral mucosa. They
enable the absorption of those drugs which are poorly absorbed in the G.I.T. or
are destroyed by the gastric fluid enzymes buccal tablets erode slowly but the
sublingual tablets dissolve promptly and provide a rapid effect.

(VIII) Lozenges or Troches:

Are disc shaped, solid dosage forms containing a medicinal agent and
generally a flavoring substance in a hard candy or sugar base.

(IX) Chewable Tablets:

Have a smooth, rapid disintegration when chewed or swallowed to dissolve in the
mouth, have a creamy base of specially flavored and colored mannitol.

(X) Effervescent Tablets:

Are prepaid by compressing granular effervescent salts that release gas when in
contact with water these tablets generally contain medicinal substances which
dissolve rapidly when added to water.

(XI) Molded Tablets:

Such are the tablets which are prepared by molding rather than compression.
Therefore, the resultant tablets are very soft, soluble and are designed for
rapid dissolution.

(XII) Tablet Triturates:

Are usually small, cylindrical, molded or compressed tablets containing small
amounts of parent drugs.

(XIII) Hypodermic Tablets:

The required number of tablets was dissolved in a suitable vehicle,
sterility attained and the injection performed. However, because of the
difficulty in achieving sterility have eliminated the use of these hypodermic
tablets.

(XV) Immediate Release Tablets:

Are designed to disintegrate and release their
medication absent of any rate controlling features as special coatings and
other techniques.

(XVI) Instant Disintegrating or Dissolving Tablets:

Instant release tablets characterized by disintegrating
/ dissolving in the mouth within one minute; some within  10 secs. Mainly
designed for pediatric and geriatric patients or for any patient having
difficulty in swallowing tablets. These tablets are prepared using very water
soluble excipients designed to “wick” water into the tablet for rapid
disintegration or dissolution.

(XVII) Vaginal Tablets:

Also known as vaginal inserts these are uncoated and bullet or avoid shaped
tablets which are inserted into the vagina for localized effect.

(XVIII) Modified Release Tablets:

Extended / controlled release tablets are designed to
release medication at a predetermined rate. These are the tablets which by the
virtue of special formulation and product design, have a modified Drug release
pattern.

Floating
Tablets

Floating Systems:
These systems are retained in the stomach and are useful for drugs that are
poorly soluble or unstable in intestinal fluids. The underlying principle is
very simple. One attempts to make the dosage form less dense than the gastric
fluids so that it can float on them. The density of the system can be reduced
by incorporating a number of low density fillers into the systems such as hydroxyl
cellulose, lactates or microcrystalline cellulose. However, this system is not
ideal because its performance is highly dependent on the presence of food and
fluid in the stomach. It is not reliable and is highly variable. The basic idea
behind the development of such a system was to maintain a constant level of
drug in the blood plasma inspire of the fact that the drug dose not underage
disintegration. The drug usually keeps floating in the gastric fluid and slowly
dissolves at a predetermined rate to release the drug from the dosage form and
maintain constant drug levels in the blood. The concept of floating tablets is
mainly based on the matrix type drug delivery system such that the drug remains
embedded in the matrix which after coming in contact with the gastric fluid
swells up and the slow erosion of the drug without disintegration of the tablet
takes place. Sometimes for generating a floating system we even need to add
some effervescent or gas generating agent which will also ultimately reduce the
density of the system and serve the goal of achieving a floating system for
onward drug delivery.

These systems have a
particular advantage that they can be retained in the stomach and assist in
improving the oral sustained delivery of drugs that have an absorption window
in a particular region of the G.I. tract. There systems help in continuously
releasing the drug before it reaches the absorption window, thus ensuring
optimal bioavailability.

Several approaches
are currently used to prolong the gastric retention time. These include
floating drug delivery systems also known as hydro dynamically balanced
systems, swelling and expanding systems, polymeric bio-adhesive systems,
modified shape systems, high density systems and other delayed gastric emptying
devices. The principle of buoyant preparation offers a simple and practical
approach to achieve increased gastric residence time for the dosage form and
sustained drug release.

Advantages:

(1) This type of drug delivery systems is especially very
useful in the treatment of the disorders related to the stomach. As the prime
objective of such systems is to produce a gastro retentive product. Or a
product which has an enhanced retention time in the stomach.

(2) All those molecules with considerably short half life can
be administered in this manner to get an appreciable therapeutic activity.

(3) This is a primary manner in which the bioavailability of
a therapeutic agent can be enhanced. Especially all those drugs which get metabolized
in the upper GIT.

(4) They also have an advantage over the conventional system
as it can be used to over come the adversities of gastric retention time as
well as the gastric emptying time. As these systems are expected to remain
buoyant on the gastric fluid without affecting the intrinsic rate of emptying
because their bulk density is lower than that of the gastric fluids.

(5) The duration of treatment through a single dose, which
releases the active ingredient over an extended period of time.

(6) The active
entity is delivered to the site of action, thus minimizing or eliminating the
side effects.

Based
on the mechanism of buoyancy two distinctly different technologies, i.e.
non-effervescent and effervescent systems have been utilized in the development
of FDDS.

Technologies
based on buoyancy mechanism for FDDS:

Non-effervescent
system:

Commonly used excipients,
here are gel-forming or highly swellable cellulose type hydrocolloids,
polysaccharides and matrix forming polymers such as polycarbonate, polyacrylate,
polymethacrylate and polystyrene. One of the approaches to the formulation of
such floating dosage forms involves intimate mixing of drug with a gel forming
hydrocolloid which swells in contact with gastric fluid after oral administration
and maintains a relative integrity of shape and a bulk density of less than
unity within the outer gelatinous barrier.

The
air entrapped by the swollen polymer confers buoyancy to these dosage forms.
The gel structure acts as a reservoir for sustained drug release since the drug
is slowly released for sustained drug release since the drug is slowly released
by a controlled diffusion through the gelatinous barrier.

Effervescent
system:

These Buoyant Delivery System
are Prepared with swellable polymers such as methocel or polysaccharides e.g.
chitiosan and effervescent component e.g. sodium bicarbonate citric or tartaric
acid or matrices containing chambers of liquid that gasify at body
temperature  

The
matrices are fabricated so that upon contact with gastric fluid, carbon dioxide
is liberated by the acidity of gastric contents and is entrapped in the
gelyfied hydrocolloid. This produces an upward motion of the dosage form and
maintains its buoyancy. The carbon dioxide generating components may be
intimately mixed within the tablet matrix to produce a single-layered tablet or
a bi-layered tablet may be compressed which contains the gas generating
mechanism in one hydrocolloid containing layer and the drug in the other layer
formulated for the SR effect.




The
floating dosage forms are kept in the stomach for extended periods of time the
therapeutic agents are not immediately released after ingestion. Controlled
release of such therapeutic agents from the dosage forms prevents enzyme
saturation thereby improving the bioavailability of such therapeutic agents. So
it  improves the bioavailability of by administering such therapeutic agent in
a floating dosage from.

Background
for development of FDDS:

Many
therapeutic agents ate metabolized in the upper GI tract into an active form.
This active form is then through the wall intestine. The therapeutic agents ate
metabolized by enzymes in the upper GI tract. If the therapeutic agent is
present in large quantities, saturation of these enzymes can occur with the
result that most of the therapeutic agent passes through the GI tract therefore
limits the potency of the therapeutic agent.

Conventional
controlled release dosage forms have a density greater than that of gastric
contents, thus these dosage forms sink to the bottom of the stomach once
ingested. The de novo design of oral controlled drug systems (DDS) is known in
the art to achieve more predictable bioavailability of drugs.  However, it is
well known that conventional release DDS do not Overcome adversities such as
gastric residence time (GST) and gastric empty time (GET). Gastric emptying is
the process by the fasted stomach exhibits a cyclic activity called the inter-digestive
migrating motor complex (IMMC). The purpose of this cycle is to migrate the
contents of the stomach through the pyloric sphincter although ingestion of
food interrupts the cycle.

One
approach to overcome the adversities of GRT and GET is the floating system also
known as hydrodynamically balanced systems. These systems are expected to
remain lastingly buoyant on the gastric contents without affecting the intrinsic
rate of emptying because their bulk density is lower than that of the gastric
fluids. The floating forms maintain their low density value while the polymer
hydrates and forms a gel. The drug is progressively release from the swollen
matrix in the case of conventional hydrophilic matrices. Id.

The
following is a list of drugs explored for various floating forms.

Micro- Aspirin; griseofulvin and
p-nitoaniline; spheres : terfrnadine ; tranilast. Granules: Diclofenc sodium :
Indomethacin; Prednisolone; Tablet/ Pills: Acetaminophen, acetylicylic acid;
amoxycillin thrihydrate ampicillin; atenolol ; chlorpheniramine malete;
cinnarizine; diltiazem; fluoroural; isosorbide mononitrate; isosorbide dinitrate;
p aminobenzoic acid; pirtanide; prednisolone, quinidine gluconate; riboflavin
5'- phosphate; satalol; theophyllline;

Common tablet excipients for
conventional tablet:

Diluents
:Lactose, Dextrose,
Microcrystalline cellulose, hydrolyzed starches, Sucrose, sorbitol, Mannitol.

Binders and Adhesives:  Acacia, tragacanth, Gelatin, starch, polyvinyl
pyrrolidone

Disintegrants: Starch, clays, cellulose, Alginates.

Lubricants: Stearic acid, talc, stearic acid salts, waxes,
surfactants.

Glidants: Silica derivatives, talc, etc.

Color and Flavor:  FD and C and D and C dyes and lakes as color.

Excipients for floating tablets:

(i) 
Hydrophilic Polymers: Hydroxy
propylmethylcellulose (Metolose)

(ii)
Carrier matrix: Gelucire

(iii) Gel forming hydrocolloids / Matrix Formers: Polycarbonate, Polyacrylate, Polymethacrylate and
polystyrene

(iv) Swellable polymers used in Effervescent Systems: Chitosan and sodium bicarbonate and citric acid or
tartaric acid

(v)
Matrix forming polymers: HPMC, Polyarcylates, cargeenan gum guar, gum arabic

(vi) Fillers: Lactose,
microcrystaline cellulose.

(vii) Lubricant: Magnesium
stearate purified talc

(viii)
Buoyancy Agents: Cellulose,
gums, polysaccharides, starch, gelatin.

(ix) Diluents:  Lactose,
sorbitol, mannitol, glucose, microcrystalline cellulose, gelatin, starch, di-calcium
phosphate, polyethylene glycol.

 (x) Porosity
Agents

: Lactose

Manufacturing Processes:

Tablet Compression Machines:

Tablets are made by
compressing formulation on stamping machines called presses.

About the tableting presses:

Tableting presses
are used for uniaxial pressing powdered materials into shaped tablets or
compacts. Tableting presses usually operate at high speeds. Parts can often be
pressed and sintered to dimensional tolerance levels that do not require
additional machining. For demanding applications, cold pressed and sintered
parts may require subsequent coining/.repressing, infiltration, hot pressing or
forging to reach the required density and strength.

Tableting presses
are designed in two configurations: Multistation tableting press and single
station press. Multistation tableting presses also referred to as rotary
presses, use a punch and die system with multiple stations or punches for
compacting materials into tablets, or metal powders into simple flat or
multilevel shaped parts like gears, cams, or fittings. Rotary types have a
series of stations or tool sets (dies and punches) arranged in a ring in a
rotary turret. As the turret rotates, a series of cams and press rolls control
filling, pressing and ejection. Pharmaceutical tablet and high volume metal
part production facilities often use high-speed automatic rotary presses.

Single station
presses consist of a single tool set (die and punch set) in die table. Single
action opposed ram presses use a die with both upper and lower punches. Anvil
type presses have only a die and single lower punch. Single station compacting
presses are available in several types basic types such as cam, toggle /
knuckle and eccentric/ crank presses with varying capabilities such as single
action, double action, floating die,  movable platen, opposed ram, screw,
impact, hot pressing, coining or sizing.

Uniaxial hot presses
are used to consolidate ceramic carbide and other refractory powders, as well
as diffusion bond materials. Larger powdered metal parts are typically
compacted on single station, uniaxial presses.

When working with
tableting presses, force is the appropriate measure to determine the degree to
which materials may be compacted. By contrast, pressure is the determining
factor when working with isostatic presses. The maximum operating press load or
force required to reach the desired density during part production when using a
tableting press is expressed as follows:

Press Load =
Required compaction pressure (psi) for the material x Part’s Projected Area
(sq. in.)

Additionally, the
functionality of a given tableting press is determined by three important
specifications; it’s unit rate production, the diameter or width of the die
cavity, and maximum internal length of the cavity. Unit rate production is the
number of units produced per minute or hour. The unit’s capacity maybe stated
in terms of compacts, parts, tablets, pill, strokes or cycles per unit time.
Diameter and length of the inner cavity are determinants of the maximum size of
the die that the press may accommodate. This in turn reflects the size or type
of compact the press can produce.

Tableting presses 
are used in a wide range of industrial activities including the compaction of
confections, cosmetics, detergents, electronic components, ferrite cores,
healthcare products and pharmaceuticals, food service, nuclear fuel pellets,
and precision metal parts.

Basic components of the tablet
compression machine:

(1) Hopper for holding and feeding granulation to be
compressed.

(2) Dies that define the size and shape of the tablet.

(3) Punches for compressing the granulation within the dies.

(4) Cam tracks for
guiding the movement of the punches.

(5) A feeding mechanism for moving granulation from the
hopper into the dies.

Granulation techniques:

(1) Dry Granulation

(2)  Wet Granulation

(3) Compression Granulation

Dry
Granulation:

When tablet
ingredients are sensitive to moisture or are unable to withstand elevated
temperature during drying and when the tablet ingredients have sufficient
inherent binding or cohesive properties, slugging may be used to form granules.
This method is referred to as dry granulation pre compression or double
compression. The active ingredient, diluents and a part of lubricant are
blended powdered material contains a considerable amount of air, under pressure
this air to expelled and a fairly dense piece is formed. The more time allowed
for this air to escape the better the tablet or slug. When slugging is used,
large tablets are made as slugs because fine powders flow better into large
cavities Now these compressed slugs are comminuted through the desirable mesh
screen either by hand or for large quantities through the Fitzpatrick or
similar comminuting mills after this the granulation is blended gently with
lubricants and then compressed to form tablets.

Wet Granulation

The unique portions
of wet granulation process involve the wet massing of powders, wet sizing or
milling and drying.

Methods:

Wet granulation
forms the granules by binding the powders together with an adhesive instead of
compaction. The wet granulation technique employs a solution suspension or
slurry containing a binder which is usually added to the powder mixture however
the binder may be incorporated dry into the powder mix and the liquid may be
added by itself. The method of introducing the binder depends on its solubility
and on the components of the mixture since, in general, the mass should merely
be moist rather than wet or pasty, there is a limit to the amount of so lvent
that may be employed.

There fore, when
only a small quantity is permissible, the binder is blended in with the dry
powders initially; when a large quantity is required the binder is usually
dissolved in the liquid.

Once the granulating
liquid has been added mixing continues until a uniform dispersion is attained
and all the binder has been activated. After sufficient blending now the wet
mass is made to undergo wet screening by passing through a hammer mill or
oscillating granulator equipped with screens having large perforations. Now the
wet material undergoes drying and the dried mass is said to undergo dry
screening or dry milling and the granules now obtained now undergo compression.

Direct
Granulation:

Implies direct
compression consists of compressing tablets directly from powdered material
without modifying the physical nature of the material itself. Formerly this
method was only applicable to chemicals like potassium salts (Chlorate,
Chloride, Bromide, etc) ammonium chloride and methenamine. These materials
possess cohesive and flow properties that make direct compression possible.
Increasing attention is paid to this method because of incredible economy and
efficiency offered by it.

Direct compression
vehicles or carriers must have good flow and compressible characters these
properties are imparted by predisposing these vehicles to slugging, spray
drying or crystallization. Most commonly used carriers are dicalcium phosphate
trihydrate, tricalcium phosphate, etc.

Floating dosage form available:

-
Micro – Aspirin

-
Griseofulvin and P – nitro aniline

-
Ibuprofen

-
SPHARES : terfenadine, Tranilast

-
Granules: Diclofenace sodium,.
Indomethacin

-
Tablets / Pills: Acetaminophen,

-
Acetyl salicylic acid, amoxycillin
trihydrate, ampicillin atenolol, diltiazem, etd

-
Capsules: chlordiazepoxide, Diazepam
Furosemide, Misoprostol, Cinnarizine

Depending of the pharmacokinetic data
the drugs which can be given in the form of FDDS


Name of Drug


Half Life (hrs)


Use


Peak Time (hrs)


Peak concentration

Abacavir

1.0 (0.8-13)

Anti-HIV

Tab.: 0.63

Sol: 0.5

 

Tab:
2.6            (2.3-2.9) mg/ml

Sol: 2.9          
(2.5-3.4) mg/ml

Cimetidine

2 ± 0.3

Used in Treatment
of peptic ulcers

0.5 – 1.5

0

C

2-3 mg/ml

Cephalexin

0.9± 0.18

Antibiotic

1.4 08

28±6.4 mg/ml

Diltiazem

4.4±1.3

Anti-hyper tensive

4.0 ±0.4

151± 6.4 mg/ml

Ibuprofen

2 ±0.5

NSAIDs

1.6 ±0.3

61.1+5.5 mg/ml

Isoniazid

1.1± 0.1

Anti-TB

1.1± 0.5

5.4± 2.0 mg/ml

Nifedipine

1.8± 0.4

Calcium Channel
Blocker

0.5 0.2

79 ± 44ng/m

Omeprazole

0.7± 0.5

Peptic Ulcer

-

-

Ranitidine

2.1±0.2

Peptic Ulcer

2.1± 0.31

462± 54ng/nl

Evaluation

Evaluation parameters of a tablet:

To design tablets
and later monitor tablet production quality, quantitative evaluations and
assessments of a tablet’s chemical, physical and bioavailability properties
must be made. Not only could all three property classes have a significant
stability profile, but the stability profiles may be interrelated, ie, chemical
breakdown or interactions between tablet properties greatly changing the
bioavailability of tablet system.

Hardness and friability:

Tablets require a
certain amount of strength as hardness and resistance to friability to
withstand mechanical shocks of handling in manufacture, packaging, and
shipping. There exists a direct relationship between hardness and dissolution
studies.

Hardness is defined
as the force required to break a tablet in diametric compression test. Hardness
is hence also termed as the Tablet crushing strength.

Some devices which
are used to test hardness are Monsanto tester, strong cobb tester, pfizer
tester, etc.

The laboratory
friability tester iis known as the Roche Friabilator.

This consists of a
device which subjects a number of tablets to the combined effects of abrasion
and shock by utilizing a plastic chamber that revolves at 25 rpm, dropping the
tablets a distance of six inches with each revolution. Normally, a pre weighed
tablet sample is placed in the friabilator which is then operated for 100
revolutions. Conventional compressed tablets that lose less than 0.5 to 1.0 %
of their weight are generally considered acceptable.

Most of the
effervescent tablets undergo high friability weight losses, which accounts for
the special stack packaging. That may be required for these types of tablets.

Weight variation:

With a tablet
designed to contain a specific amount of drug in a specific amount of tablet
formula, the weight of the tablet being made is routinely measured to help
ensure that a tablet contains the proper amount of drug. In practice, composite
samples of tablets (usually 10) are taken and weighed throughout the
compression process. The composite weight divided by 10, however provides an
average weight but contains a problem of averaged value. To help alleviate this
problem the USP provides limits for the permissible variations in the weights
of individual tablets expressed as a percentage of the average weight of the
sample. The USP provides the weight variation test by weighing 20 tablets
individually, calculating the average weight, and comparing the individual
tablet weights to the average the tablets meet the USP test if no more than 2
tablets are outside the percentage limit and if no tablet differs by more than
2 times the percentage limit.

Disintegration:

The USP device to 
test disintegration uses 6 glass tubes that are 3 inches long, open at the top,
and held against a 10 mesh screen at the bottom end of the basket rack
assembly. To test for disintegration time one tablet is positioned in a 1-L
beaker of water, simulated gastric fluid or simulated intestinal fluid at 37C
(35-39c) such that the tablets remain 2.5cm below the surface of the liquid on
their upward movement and descend not closer than 2.5 cm from the bottom of the
beaker . Uncoated USP tablets have disintegration time standards as low as 5
min, but majority of the tablets have a maximum disintegration time of 30 min.
Enteric coated tablets are to show no evidence of disintegration after 1 hour
in simulated gastric fluid.  Floating tablets do not disintegrate for a long
period of time.

Dissolution time:

The drug is
available for absorption only after. It is available in dissolved form. So only
comparing the disintegration time with the plasma levels is baseless because
the real parameter for the measurement of plasma levels of drug is the
dissolution time.

The method of
dissolution testing is that the drug is placed in a hemispherical cylinder
filled with 100 ml beaker and mechanical stirrer is attached with rotator at a
definite speed and the fluid is taken from the cylinder at regular interval and
assay is conducted as per the pharmacopoeial standards.






Conclusion

Floating tablets
have plenty of advantages over the conventional tablets. As these floating
tablets provide a dosage form which is stable and provides a sustained release
dosage form.

The most important
application of the floating tablets is that they provide a new possibility of
treating the stomach infected with Helicobacter pylori. The objective of this
study was to select suitable materials for the formulation of floating tablets
with sustained drug release properties. In the preformulation studies the
differences between cellulose polymer isotherms were estimated using the DVS
method and the disappearance of gas generating agent at higher relating
humidifies was observed. The correlation between wettability and the floating
lag time proves that the first contact with water is not essential for good
floating. These tablets enable a more than 8- hour long controlled drug release
from non– disintegrated matrices plays an important role in prolonging gastric
residence time.

The studies
conducted on the floating tablets indicated that the proper balance between a
release rate enhancer and a release rate retardant can produce a drug
dissolution profile similar to a theoretical dissolution profile. The criteria
which favors the development of a sustained release dosage form like floating
tablets is the short biological half life of drug. The gastro retentive drug
delivery systems can be retained in the stomach and assist in improving the
oral sustained delivery of drugs that have an absorption window in a particular
region of the GIT. These systems help in continuously releasing the drug before
it reaches the absorption window, thus ensuring optimal bioavailability.

Several approaches
are currently used to prolong gastric retention time. These include floating
drug delivery systems, also known as hydrodynamically balanced systems,
swelling and expanding systems, polymer bioadhesive systems, modified shape
systems, high density systems and other delayed gastric emptying devices

The principle of
buoyant preparation offers a simple and practical approach to achieve increased
gastric residence time for the dosage form and sustained drug release.

When a drug is
formulated with gel forming hydrocolloids such as HPMC it swells in the gastric
fluid with a bulk density of less than are It then remains buoyant and floats
in the gastric fluid, affording a prolonged gastric residence time. This
floating dosage is known as hydrodynamically balanced systems (HBS).

Methods in HBS which
increase the gastric residence time are floating, swelling, adhesion, laser
pores and film coating. KCL has been demonstrated to exhibit a zero order
release by compressing it with HPMC and entrapped air to produce floating
tablet type dosage form.

The most important criteria
which has to be looked into for the productions of a floating drug delivery
system is that the density of the dosage form should be less than that of
gastric fluid. And so, it was seen that these dosage form serve the best in the
treatment of diseases related to the GIT and for extracting a prolonged action
from a drug with a short half life. In addition to this the FDDS is still more
important because of the numerous advantages it offers over the conventional
dosage form. The popularity of FDDS is a testimony to its usefulness. Day after
day the FDDS shows more promise for a bright future.

Bibliography:

  1. Ansel
    H.C. Introduction to Dosage Forms, Lea and Febiger
  2. Lachman,
    Lieberman, Kanig. The Theory and Practice of Industrial Pharmacy 3

    rd

    Edition, Varghese Publishing House
  3. Remington.
    The Science and Practice of Pharmacy, Vol., 20

    th

    edition
  4. Critical
    Reviews in Therapeutic Drug Carrier System.
  5. Goodman
    and Gilman's the Pharmacological Basic of Therapeutics, 10 th edition
  6. Gastro
    retentive drugs: a review, by Prahlad Tayade, Pharma Pulse Express
  7. Singh
    et al. Journal of Controlled Release
  8. Stockwell
    at al. Journal of Controller Release
  9. U.S. Patent No. 3,
    087, 860
  10. U.
    S. Patent No. 4, 814, 179
  11. U.
    S. Patent No. 4, 167, 558
  12. U.S. Patent No. 5,
    169, 638
  13. http:
    // material – handling. global spaec. Com

About Authors

Pooja Koner, R. B. Saudagar and  S. J. Daharwal*

Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur. 492 010. (CG) India

* Corresponding author

Mr. S.J. Daharwal

{cb_profile=sjdaharwal} Mr. S.J. Daharwal {/cb_profile} has nearly 15 years of research and teaching experience. He did his bachelor and masters degree in pharmacy   from Dept. of Pharmaceutical sciences, Nagpur  University, Nagpur (MS) India. He also did his master in business management from IGNOU, New Delhi. He has submitted the thesis of Ph. D. at Pt. Ravishankar Shukla University, Raipur (CG) India. He has over 15 publications to his credit published in international and national journals. His research interest extends from development of new economical analytical methods of multicomponent dosage forms, Drug synthesis and computer added drug designing. Presently, he is working as a Lecturer at Institute of Pharmacy Pt. Ravishankar Shukla University, Raipur, (CG) India.

R. B. Saudagar

Mr. R. B. Saudagar has nearly 15 years of research and teaching experience. He did his bachelor degree from Pravara Rural College of Pharmacy, Pravaranagar, University of Pune (MS) India and masters degree in pharmacy   from Dept. of Pharmacy, SGSITS, Devi Ahilya University, Indore (MP) India. He has over 15 publications to his credit published in international and national journals. His research interest extends from analytical methods and Drug synthesis. Presently, he is working as a Lecturer at Institute of Pharmacy Pt. Ravishankar Shukla University, Raipur, (C.G.)

Pooja Koner

Ms. Pooja Koner , did her bachelor degree from Institute of Pharmacy Pt. Ravishankar Shukla University, Raipur, (C.G.) India and doing masters degree in pharmacy   at SLT Institute of Pharmacy Guru Ghasidas University, Bilaspur, (C.G.) India. She has excellent academic and extra curricular record.

Volumes and Issues: 
Reviews: