FIELD OF THE INVENTION
The present invention relates to pharmaceutical formulations of active principles for
gastrointestinal drug delivery that comprises an mucoadhesion site-controlling layer for
attaching the formulation to the selected site in the digestive tract.
BACKGROUND OF THE INVENTION
Conventional means for delivering drugs are often limited by biological, chemical, and
physical barriers. These barriers are of particular significance in the design of oral
delivery systems.
Oral drug administration is by far the most preferable route for taking medications but
oral delivery of many drugs often requires greater amounts of drug to be administered
than when administered via different route. Moreover, the therapeutic window of many
drugs is limited by their short circulating half-life, absorption and site of action in a
defined segment of the gastrointestinal tract. (Gl tract) The passage of dosage form
through this area is generally complete within three to five hours, regardless of particle
size, dosage form (e.g. liquid, microencapsulated) or presence of food. A particular
problem is that it is difficult to maintain prolonged drug availability in the stomach or
upper intestine since the unit or units are expelled from the stomach with food or fluid,
often quite quickly after swallowing. This transit time may provide a window of
opportunity that is too short to facilitate the absorption of therapeutic quantities of active
agent. Such limitations lead in many cases to frequent dosing of these medications to
achieve the required therapeutic effect. This results in "pill burden" and consequently,
decreased patient compliance. The phenomenon of absorption via a limited part of the
Gl tract has been termed the "narrow absorption window"; once the dosage form passes
the absorption window, or the site of action the drug will be neither bioavailable nor
effective. Further on oral administration, normal or pathological stomach voiding and
intestinal peristaltic movements may reduce the time for which a drug-releasing dosage
form remains in the gastrointestinal tract or at the required site of action. Specifically,
during pathological conditions such as diarrhea, peristaltic movement of the Gl Tract is
increased. Therefore, Gl transit time of dosage forms is lesser than normal. Hence
conventional dosage forms have shorter residence time at the site of absorption or at
required site of action. A rational approach to solve this problem and to enhance
bioavailability and improve pharmacokinetic and pharmacodynamic profiles is to retain
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the drug reservoir above its absorption area or the site of action, and to release the drug
in a controlled manner, for a prolonged period of time. Thus, there is always a need to
develop a novel pharmaceutical formulation of active principles that have increased
residence time in the Gl tract for the treatment of infections specifically locally in the Gl
tract.
Preferred group of drugs that could benefit from retained and controlled or immediate
release in the gastrointestinal tract are those meant for the treatment of pathologies
located in the stomach, the duodenum or the small intestine or colon.
Significant effort has been spent on identifying ways to slow down the Gl transit of the
therapeutic such as prolonged release dosage forms. The advantages of controlled
release products are well known in the pharmaceutical field and include the ability to
maintain the medicament at the required site of action over a comparatively longer
period of time while increasing patient compliance by reducing the number of
administrations necessary to achieve the same. Its difficult to formulate controlled
release formulations because if the release is too slow then the unit will be discharged
from the chosen location, or even from the body, before full release of the active
ingredient. If release is too fast it is necessary to administer another dosage form soon
after the previous dose, in order to maintain prolonged availability of the active ingredient
in the chosen environment. Moreover, residence time of a unit in the stomach varies
according to whether the patient is in the fed or fasted state. For instance there is a
tendency for a controlled release dosage form to pass through the stomach very much
faster if the patient is fasting than if the formulation is administered after food. This effect
can therefore completely overwhelm the controlled release effect that is desired.
Ideal solution of this problem can be obtained by prolonging the presence of dosage
forms at or near the locus within the host where their active ingredients are normally
absorbed. Drugs like (i) carbamazepine (an antiepileptic), furosemide (a diuretic),
metoprolol (a beta blocker) and acyclovir (an antiviral) benefit from prolonged presence
at or near the locus of absorption in terms of their bioavailability characteristics including
drugs which are absorbed most efficiently within the intestine or colon (e.g. peptides or
proteins such as insulin, interferon, calcitonin, endorphins, human growth hormone, and
various hormone growth factors). Also included are drugs that act specifically or locally
3

on the gastrointestinal tract (e.g. 5-aminosalicylic acid). Prolonging the presence of
dosage forms, at or near the locus within the host can be achieved by formulation or
dosage form materials with bioadhesive characteristics. Bioadhesiveness is defined as
the ability of a material (synthetic or biologic) to adhere to biologic tissues for a
prolonged period of time. The purpose of the bioadhesive dosage form is to keep a
pharmaceutical dosage form in the required site of action for an extended period of time,
ensuring release of effective amounts of the active ingredient throughout the
bioadhesion period. Although the length of this time cannot be given in terms of a
numerical range that would apply to all drugs and all routes of administration, it is fair to
describe such prolonged time period as a period of time (i) during which a drug is
present at or near the locus of its absorption (ii) which is longer than the standard
residence time for such drug.
Various bioadhesive agents are known which are believed to bind to the mucus layers
coating the stomach and other regions of the gastrointestinal tract. It is believed that
using such agents in combination with an active agent will result in the active agent also
being bound to the mucus layer, leading either to slow release into the gastrointestinal
tract or direct delivery to the gastrointestinal mucosa.
Known bioadhesive solid dosage forms are described, for example, in GB-2,042,888
(Teijin). A slow release pharmaceutical preparation to be used adhering to the mucosa
of the oral cavity (buccal) or nasal cavity comprising an active ingredient, 50 to 95% of a
cellulose ether and 50 to 5% of a high molecular weight crosslinked polyacrylic acid
(carboxyvinyl polymer, carbomer, carbopol).
US 6,303,147 (Janssen) describes a bioadhesive pharmaceutical composition
comprising a pharmaceutically effective amount of an active ingredient, from 80% to
98.8% (w/w/) pre-gelatinized starch, and from 1% to 10% (w/w) of a hydrophilic matrix
forming polymer, characterized in that the composition further comprises from 0.2% to
5% (w/w) alkaliC 16-22 alkyl fumarate as a lubricant.
US 6,306,789 (Reckitt Benckiser Healthcare) describes bioadhesive granules of
carbomer and in particular to such granules containing pharmaceutical active agents
4

suitable for sustained release into the gastrointestinal tract or for targeted delivery to the
gastrointestinal mucosa.
US 5,900,247 (Adir et compagnie) describes the bioadhesive films or patches
characterized by the use: of a polymer (A) composed of one or a number of vinyl
acetate/polyvinylpyrrolidone copolymers.
US 5,472,704 (Recordati S.A.) describe composition characterized by plurality of small-
size units capable of ensuring a gradual release of the active ingredient they contain the
units being coated with a bioadhesive polymer layer. The composition makes it possible
to keep the release controlling function separate from the function providing
bioadhesion.
WO 2006/031420 (Spherics) describes bioadhesive formulation includes a multilayered
core enveloped by a bioadhesive coating.
Considering the properties of the gastrointestinal tract, the following characteristics are
sought after in a gastrointestinal retention system: for effective retention in the
gastrointestinal tract to suit the clinical demand; convenient intake to facilitate patient
compliance; sufficient drug loading capacity; control over the drug release profile; full
degradation and evacuation of the system once the drug release is over; no effect on
gastric motility including emptying pattern, and no other local adverse effects.
With respect to the above reasons, to maximize the therapeutic efficacy of active
principles in the treatment, novel pharmaceutical formulations are provided herein and
include, for example, immediate or modified release dosage forms, which adheres to the
gastrointestinal mucosa reducing the chances for expulsion of the dosage form from the
gastrointestinal tract thus having increased residence time and prolonging contact
thereby improving the efficacy of active principles specifically locally acting agents.
The bioadhesive and/or mucoadhesive systems of the invention for the local or systemic
and sustained delivery of therapeutic agents allow for more efficient targeting of drugs to
the required sites on the luminal surface of the gastrointestinal tract with the reduction of
dosage level and/or dosing frequencies, several potential problems relating to
5

antimicrobial agents or other drugs may be reduced or avoided altogether, such as
gastrointestinal irritation in some patients. Reduction of dosage level and/or dosing
frequencies can also reduce or avoid disturbances of the normal enteric flora, which are
caused by certain drugs that may lead to drug-resistant bacterial enteritis or bacterial
super-infection. The potential reduction in side effects and the overall ease of
administration should greatly increase patient compliance, is expected to further improve
the therapeutic outcome.
OBJECTS OF THE INVENTION
An object o the invention is to provide a novel pharmaceutical composition, which
comprises a therapeutically effective amount of active principle(s) or a pharmaceutically
acceptable salt or enantiomer or polymorph thereof, optionally one or more controlled
release agent(s) and pharmaceutical acceptable excipient(s) thereof, wherein the
composition is formulated to increase the residence time of the said pharmaceutical
composition and/or active principle(s) in the gastrointestinal tract.
Another object of the invention is to provide a novel pharmaceutical composition
comprising: at least two entities wherein one entity is an immediate release or fast
release and the other is controlled release wherein the composition is formulated to
increase the residence time of active principle(s) in the gastrointestinal tract
Another object of the invention is to provide a novel pharmaceutical composition
comprising: at least two entities wherein one entity is an immediate release or fast
release and the other is bioadhesive wherein the composition is formulated to increase
the residence time of active principle(s) in the gastrointestinal tract.
Another object of the invention is to provide a novel pharmaceutical composition
comprising: at least two entities wherein one entity is controlled release and the other is
bioadhesive wherein the composition is formulated to increase the residence time of
active principle(s) in the gastrointestinal tract.
Another object of the invention is to provide a novel pharmaceutical composition in the
form of a multilayer tablet comprising, a) at least one layer which comprises, a
therapeutically effective amount of active principle(s) or a pharmaceutically acceptable
6

salt or enantiomer or polymorph thereof, pharmaceutically acceptable excipient(s);
wherein the said layer provides a immediate or fast release of active principle(s); and b)
at least another layer which provides increased residence time of the dosage form in the
gastrointestinal tract.
Another object of the invention is to provide a novel pharmaceutical composition in the
form of a multilayer tablet comprising, a) at least one layer which comprises, a
therapeutically effective amount of active phnciple(s) or a pharmaceutically acceptable
salt or enantiomer or polymorph thereof, pharmaceutically acceptable excipient(s);
wherein the said layer provides a controlled release of active principle(s); and b) at least
another layer which provides increased residence time of the dosage form in the
gastrointestinal tract.
Another object of the invention is to provide a novel pharmaceutical composition in the
form of a multilayer tablet comprising, a) at least one layer which comprises, a
therapeutically effective amount of active principle(s) or a pharmaceutically acceptable
salt or enantiomer or polymorph thereof, pharmaceutically acceptable excipient(s); and
b) at least one layer comprising another or same active principle(s) wherein layer (b)
provides increased residence time of the dosage form in the gastrointestinal tract.
Another object of the invention is to provide a novel pharmaceutical composition in the
form of a multilayer tablet comprising, a) at least one layer which comprises, a
therapeutically effective amount of active principle(s) or a pharmaceutically acceptable
salt or enantiomer or polymorph thereof, pharmaceutically acceptable excipient(s);
wherein the said layer provides a immediate or fast release of active principle(s); and b)
at least one layer comprising another or same active principle(s) wherein layer (b)
provides residence time of the dosage form in the gastrointestinal tract.
Another object of the invention is to provide a novel pharmaceutical composition in the
form of a multilayer tablet comprising, a) at least one layer which comprises, a
therapeutically effective amount of active principle(s) or a pharmaceutically acceptable
salt or enantiomer or polymorph thereof, pharmaceutically acceptable excipient(s);
wherein the said layer provides controlled release of active principle(s); and b) at least
7

one layer comprising another or same active principle(s) wherein layer (b) provides
increased residence time of the dosage form in the gastrointestinal tract.
Another object of the invention is to provide a novel pharmaceutical composition in the
form of a multilayer tablet comprising, a) at least one layer which comprises, a
therapeutically effective amount of active principle(s) or a pharmaceutically acceptable
salt or enantiomer or polymorph thereof, pharmaceutically acceptable excipient(s);
wherein the said layer provides a immediate or fast release of active principle(s); and b)
at least one layer comprising another or same active principle(s) wherein layer (b)
provides controlled and/or increased residence time of the dosage form in the
gastrointestinal tract.
Yet another object of the invention is to provide a novel pharmaceutical composition
comprising a therapeutically effective amount of active principle(s) or a pharmaceutically
acceptable salt or enantiomer or polymorph thereof, optionally one or more release
controlling agent(s) and pharmaceutical acceptable excipient(s) thereof, wherein the
composition is formulated to increase the residence time of the said pharmaceutical
composition and/or active principle(s) in the gastrointestinal tract, having an adhesive
strength, measured as a force of detachment, of atleast 100mN when measured using
advanced force gauge equipment (manufactured by Mecmesin, West Sussex, England).
DETAILED DESCRIPTION
The present invention relates to a novel pharmaceutical composition, which comprises a
therapeutically effective amount of active principle(s) or a pharmaceutically acceptable
salt or enantiomer or polymorph thereof, optionally one or more controlled release
agent(s) and pharmaceutical acceptable excipient(s) thereof, wherein the composition is
formulated to increase the residence time of the said pharmaceutical composition and/or
active principle(s) in the gastrointestinal tract. The pharmaceutical composition
according to the invention can remain attached for desired period of time to the epithelial
surface or to the mucosal membrane of the gastrointestinal tract. Since many drug
compounds are absorbed exclusively in the small intestine or in a limited segment of the
Gl tract, it would therefore be beneficial to develop dosage forms such as sustained
release dosage forms, which remains in the stomach and/ or in the proximal and/or in
the distal portion of the intestine for an extended period of time. The compositions of the
8

present invention are preferably administered as once-a day. It can be administered
twice a day or once a week.
Several approaches have been tried to prolong gastrointestinal residence such as by
using oral mucoadhesive formulation and/or by reducing gastrointestinal motility or a
combination of one or more techniques. In an embodiment, the gastroretentivity of the
dosage form composition might also be achieved by delaying the gastric emptying time
such as by administration of food.
The terms "active principle," "drug" "active agent" "active" and "pharmacologically active
agent" are used interchangeably herein to refer to a chemical material or compound
which, when administered to an organism (human or animal, generally human) induces
a desired pharmacologic effect. In the context of the present invention the active
principles are selected from the group consisting of anti-infectives, penicillins,
cephalosporins, cyclines, beta-lactamase inhibitors, aminosides, quinolones,
nitroimidazoles, sulfamides, antihistaminics, antiallergics, anesthetics, steroidal or non-
steroidal anti-inflammatories, analgesics with local or systemic effect, antispasmodics,
anticancers, diuretics, beta-blockers, antihypertensives, antianginals, antiarrhythmics,
vasodilators, bradycardic agents, calcium inhibitors, sedatives, cardiotonics, antifungals,
antiulceratives, vasotonics, vasoprotectants, anti-ischemics, antiemetics, anticoagulants,
antithrombotics, immunosuppressants, immunomodulators, antivirals, antiretrovirals,
antidiabetics, hypolipidemics, agents for combating obesity, anticonvulsants, hypnotics,
antiparkinsonians, antimigraines, neuroleptics, anxiolytics, antidepressants,
psychostimulants, agents for promoting memory, bronchodilators, antitussives, agents
for combating osteoporosis, peptides, hormones, steroids, enzymes, enzyme inhibitors,
proteins and melatonergic agonists or antagonists or combinations thereof. The
pharmaceutical composition of the present invention comprises from about 0.01% to
90% of the active agent.
"Therapeutically effective amount" means that the amount of active agent, which halts or
reduces the progress of the condition being treated or which otherwise completely or
partly cures or acts palliatively on the condition. A person skilled in the art can easily
determine such an amount by routine experimentation and with an undue burden.
9

"Controlled release," means drug delivery system releasing the drug at a predetermined
rate, locally or systemically, for a specified period of time. Controlled release can be
used interchangeably with prolonged release, programmed release, timed release,
extended release, sustained release and other such dosage forms.
"Optional" or "optionally" means that the subsequently described circumstance may or
may not occur, so that the description includes instances where the circumstance occurs
and instances where it does not.
By "pharmaceutically acceptable" is meant a carrier comprised of a material that is not
biologically or otherwise undesirable.
"Entities" or "Entity" can be interchangeably used with granules, pellets, beads,
minitablets and the like.
The term "mucoadhesive" used herein means a natural or synthetic component,
including macromolecules, polymers, and oligomers, or mixtures thereof, that can
adhere to a subject's mucous membrane.
"Bioadhesion" is defined as the ability of a material to adhere to a biological tissue for an
extended period of time. Bioadhesion is one solution to the problem of inadequate
residence time resulting from stomach emptying and intestinal peristalsis, and from
displacement by ciliary movement. For sufficient bioadhesion to occur, an intimate
contact must exist between the bioadhesive and the receptor tissue, the bioadhesive
must penetrate into the crevice of the tissue surface and/or mucus, and mechanical,
electrostatic, or chemical bonds must form. Bioadhesive properties of polymers are
affected by both the nature of the polymer and by the nature of the surrounding media.
Bioadhesive and mucoadhesive can be used interchangeably.
For purposes of this invention, residence time is the time required for a pharmaceutical
dosage form to transit through the stomach to the rectum i.e. the pharmaceutical dosage
forms of the invention may have an increased retention time in the stomach and/or small
and/or large intestine, or in the area of the gastrointestinal tract that absorbs the drug
10

contained in the pharmaceutical dosage form. For example, pharmaceutical dosage
forms of the invention can be retained in the small intestine (or one or two portions
thereof, selected from the duodenum, the jejunum and the ileum). These pharmaceutical
dosage forms as a whole, may include a bioadhesive polymeric coating that is applied to
at least one surface of the dosage form.
Examples of mucoadhesives for use in the embodiments disclosed herein include, but
are not limited to, natural, semisynthetic and synthetic polymers.
Natural polymers include proteins (e.g., hydrophilic proteins), such as pectine, zein,
modified zein, casein, gelatin, gluten, serum albumin, or collagen, chitosan,
oligosaccharides and polysaccharides such as cellulose, dextrans, tamarind seed
polysaccharide, gellan, carrageenan, xanthan gum, gum Arabic; hyaluronic acid,
polyhyaluronic acid, alginic acid, sodium alginate.
When the bioadhesive polymer is a synthetic polymer, the synthetic polymer is typically
selected from polyamides, polycarbonates, polyalkylenes, polyalkylene glycols,
polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers,
polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes,
polyurethanes, polystyrene, polymers of acrylic and methacrylic esters, polylactides,
poly(butyric acid), poly(valeric acid), poly(lactide-co-glycolide), polyanhydrides,
polyorthoesters, poly(fumaric acid), poly(maleic acid), and blends and copolymers or
mixtures thereof.
Other polymers suitable for use in the invention include, but are not limited to, methyl
cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
hydroxybutylmethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate
butyrate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate,
cellulose sulfate sodium salt, poly(methyl methacrylate), poly(ethyl methacrylate),
poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate),
poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate),
poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl
acrylate) polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly
(ethylene terephthalate), polyvinyl acetate), polyvinyl chloride, polystyrene, polyvinyl
11

pyrrolidone, and polyvinylphenol. Polylactides, polyglycolides and copolymers thereof,
poly(ethylene terephthalate), poly(butyric acid), poly(valeric acid), poly(lactide-co-
caprolactone), poly[lactide-co- glycolide], polyanhydrides (e.g., poly(adipic anhydride)),
polyorthoesters, blends and copolymers thereof.
Another group of polymers suitable for use as bioadhesive polymers are polymers
having a hydrophobic backbone with at least one hydrophobic group pendant from the
backbone. Suitable hydrophobic groups are groups that are generally non-polar.
Examples of such hydrophobic groups include alkyl, alkenyl and alkynyl groups.
Preferably, the hydrophobic groups are selected to not interfere and instead to enhance
the bioadhesiveness of the polymers.
A further group of polymers suitable for use as bioadhesive polymers are polymers
having a hydrophobic backbone with at least one hydrophilic group pendant from the
backbone. Suitable hydrophilic groups include groups that are capable of hydrogen
bonding or electrostatically bonding to another functional group. Example of such
hydrophilic groups include negatively charged groups such as carboxylic acids, sulfonic
acids and phosphonic acids, positively charged groups such as (protonated) amines and
neutral, polar groups such as amides and imines.
Preferably, the hydrophilic groups are selected to not interfere and instead to enhance
the bioadhesiveness of the polymers. In embodiments of the present invention, a
pharmaceutical composition comprises an active agent and atleast one swellable
polymer.
Swellable polymers include, but are not limited to, a crosslinked poly(acrylic acid), a
poly(alkylene oxide), a polyvinyl alcohol), a polyvinyl pyrrolidone); a polyurethane
hydrogel, a maleic anhydride polymer, such as a maleic anhydride copolymer, a
cellulose polymer, a polysaccharide, starch, and starch based polymers.
Polymers can be modified by increasing the number of carboxylic groups accessible
during biodegradation, or on the polymer surface. The polymers can also be modified by
binding amino groups to the polymer. The polymers can be modified using any of a
number of different coupling chemistries available in the art to covalently attach ligand
12

molecules with bioadhesive properties to the surface-exposed molecules of the
polymeric microspheres.
Lectins can be covalently attached to polymers to render them target specific to the
mucin and mucosal cell layer. The attachment of any positively charged ligand, such as
polyethyleneimine or polylysine, to a polymer may improve bioadhesion due to the
electrostatic attraction of the cationic groups coating the beads to the net negative
charge of the mucus. The mucopolysaccharides and mucoproteins of the mucin layer,
especially the sialic acid residues, are responsible for the negative charge coating. Any
ligand with a high binding affinity for mucin could also be covalently linked to most
polymers with the appropriate chemistry, such as with carbodiimidazole (CDI), and be
expected to influence the binding to the gut. For example, polyclonal antibodies raised
against components of mucin or else intact mucin, when covalently coupled to a
polymer, would provide for increased bioadhesion. Similarly, antibodies directed against
specific cell surface receptors exposed on the lumenal surface of the intestinal tract
would increase the residence time when coupled to polymers using the appropriate
chemistry. The ligand affinity need not be based only on electrostatic charge, but other
useful physical parameters such as solubility in mucin or specific affinity to carbohydrate
groups.
The covalent attachment of any of the natural components of mucin in either pure or
partially purified form to the polymers generally increases the solubility of the polymer in
the mucin layer. The list of useful ligands include but are not limited to the following:
sialic acid, neuraminic acid, n-acetyl-neuraminic acid, n- glycolylneuraminic acid, 4-
acetyl-n-acetylneuraminic acid, diacetyl-n- acetylneuraminic acid, glucuronic acid,
iduronic acid, galactose, glucose, mannose, fucose, any of the partially purified fractions
prepared by chemical treatment of naturally occurring mucin, e.g., mucoproteins,
mucopolysaccharides and mucopolysaccharide-protein complexes, and antibodies
immunoreactive against proteins or sugar structure on the mucosal surface.
The attachment of polyamino acids containing extra pendant carboxylic acid side
groups, such as polyaspartic acid and polyglutamic acid, may also increase
bioadhesiveness. The polyamino chains would increase bioadhesion by means of chain
entanglement in mucin strands as well as by increased carboxylic charge.
13

A bioadhesive controlled release pharmaceutical dosage form of the invention can have
one or more coatings such as enteric coating, controlled release coating, film coating,
sugar coating, bioadhesive coating. In one example, the additional coating prevents the
bioadhesive dosage form from contacting the mouth or esophagus. In another example,
the coating remains intact until reaching the small intestine (e.g., an enteric coating).
Examples of coatings include methylmethacrylates, zein, cellulose acetate, cellulose
phthalate, HMPC, sugars, enteric polymers, gelatin and shellac. Premature exposure of
a bioadhesive layer or dissolution of a pharmaceutical dosage form in the mouth can be
prevented with a layer or coating of hydrophilic polymers such as HPMC or gelatin.
Coating agents which are useful in the coating process, include, but are not limited to,
polysaccharides such as maltodextrin, alkyl celluloses such as methyl or ethyl cellulose,
hydroxyalkylcelluloses (e.g. hydroxypropylcellulose or hydroxypropylmethylcelluloses);
polyvinylpyrrolidone, acacia, corn, sucrose, gelatin.shellac, cellulose acetate pthalate,
lipids, synthetic resins,acrylic polymers,opadry, polyvinyl alcohol, copolymers of
vinylpyrrolidone and vinyl acetate (e.g. marketed under the brand name of Plasdone)
and polymers based on methacrylic acid such as those marketed under the brand name
of Eudragit. These may be applied from aqueous or non-aqueous systems or
combinations of aqueous and non-aqueous systems as appropriate.
The bioadhesive polymers discussed above can be mixed with one or more plasticizers
or thermoplastic polymers. Such agents typically increase the strength and/or reduce the
brittleness of polymeric coatings. The plasticizers include dibutyl sebacate, polyethylene
glycol, triethyl citrate, dibutyl adipate, dibutyl fumarate, diethyl phthalate, ethylene oxide-
propylene oxide block copolymers and di(sec-butyl) fumarate, thermoplastic polymers
include polyesters, poly(caprolactone), polylactide, poly(lactide-co-glycolide), methyl
methacrylate, cellulose and derivatives thereof such as ethyl cellulose, cellulose acetate
and hydroxypropyl methyl cellulose and large molecular weight polyanhydrides.
Antitacking agents such as talc, stearic acid, magnesium stearate and colloidal silicon
dioxide and the like. Surfactants such as polysorbates and sodium lauryl sulphate and
opacifying agents such as titanium dioxide and the like. All these excipients can be used
at levels well known to the persons skilled in the art.
14

A pharmaceutical dosage form can have one or more coatings in addition to the
bioadhesive polymeric coating, e.g., covering the surface of the bioadhesive coating.
These coatings and their thickness can, for example, be used to control where in the
gastrointestinal tract the bioadhesive coating becomes exposed.
Pharmaceutical dosage forms of the invention can be coated by a wide variety of
methods. Suitable methods include compression coating, coating in a fluidized bed or a
pan and hot melt (extrusion) coating. Such methods are well known to those skilled in
the art.
Also suitable are rupturable coating systems, e.g., Pulsincap, that use osmotic forces of
swelling from hydrophilic polymers to rupture enteric membranes to reveal underlying
bioadhesive dosage form.
Alternately, non-permeable coatings of insoluble polymers, e.g., cellulose acetate,
ethylcellulose, can be used as enteric coatings for delayed/modified release (DR/MR) by
inclusion of soluble pore formers in the coating, e.g., PEG, PVA, sugars, salts,
detergents, triethyl citrate, triacetin, etc.
Also, coatings of polymers that are susceptible to enzymatic cleavage by colonic
bacteria are another means of ensuring release to distal ileum and ascending colon.
Materials such as calcium pectinate can be applied as coatings to tablets and
multiparticulates and disintegrate in the lower gastrointestinal tract, due to bacterial
action. Calcium pectinate capsules for encapsulation of bioadhesive multiparticulates are
also available.
The pharmaceutically acceptable excipients, are selected from the group comprising
binders, diluents, lubricants, surfactants and glidants.
Binder is one or more selected from the group comprising carbohydrates like celluloses
their derivatives; starches; gums; polyvinylpyrrolidone, povidone, syrup, polyethylene
oxide, polyacryl amide, poly-N-vinyl amide, sodium carboxymethyl cellulose,
polyethylene glycol, gelatin, polyethylene oxide, poly propylene glycol, tragacanth,
alginic acid, combinations thereof.
15

Diluent is one or more selected from the group comprising carbohydrates, derivatives of
carbohydrates, polyols, sugar alcohols, carbonate, sulphate or phosphate salts of
inorganic metals or mixtures thereof.
Lubricants is one or more selected from the group comprising Magnesium, Aluminium,
Zinc or Calcium stearate, polyethylene glycol, mineral oil, sodium stearyl fumarate,
stearic acid, hydrogenated vegetable oil, glyceryl behenate, glyceryl palmitostearate,
glyceryl stearate, cornstarch, talc, calcium silicate, magnesium silicate, colloidal silicon
dioxide, silicon hydrogel, and mixtures thereof.
Surfactant can be selected from ionic or non-ionic or zwitterionic surfactants.
Glidant is one or more selected from the group comprising silicon dioxide, colloidal silica,
powdered cellulose, talc, tribasic calcium phosphate and mixtures thereof.
The novel pharmaceutical composition of the present invention can further have
solubilizing agents. Solubilizing agents include but are not limited to surfactants,
cyclodextrin and its derivatives, lipophilic substances or any combination thereof.
Unlimiting examples of surfactants include water-soluble or water dispersible nonionic,
semi-polar nonionic, anionic, cationic, amphoteric, or zwitterionic surface-active agents;
or any combination thereof.
Other solubilizing agents include vitamin E and its derivatives; monohydric alcohol esters
such as trialkyl citrates, lactones and lower alcohol fatty acid esters; nitrogen-containing
solvents; phospholipids; glycerol acetates such as acetin, diacetin and triacetin; glycerol
fatty acid esters such as mono-, di- and triglycerides and acetylated mono- and
diglycerides; propylene glycol esters; ethylene glycol esters; and combinations thereof.
In another embodiment of the novel pharmaceutical composition of the present invention
can further have stabilizing agents. Stabilizing agents include but are not limited to
catalysts, antioxidants, adsorbents, absorbents, buffers, chelating and sequestering
16

agents, carbonate salt of said amino acid is present as either the group I or II alkali or
alkali earth metal salt and combinations thereof.
Pharmaceutical compositions of the invention is but not limited to powders, pellets,
beads, granules, tablets, compacts, sustained release formulations, capsules,
microcapsules, tablets in capsules, tablets in tablets, microspheres, shear form particles,
floss, and flakes or mixtures thereof. Tablets include single layered tablets, multilayered
tablets, mini tablets, bioadhesive tablets, caplets, matrix tablets, tablet within a tablet,
mucoadhesive tablets. Sustained release is formulation include but are not limited to
matrix type controlled release, membrane diffusion controlled release, site targeted,
osmotically controlled release, pH dependent delayed release, timed release, pulsatile
release, hydrodynamic balanced system; powders, pellets, beads, granules for
suspension.
Multi-layer tablets comprises a first, a second or/and a third layer, where each layer
includes one or more excipients and optionally one or more drug.
At least one layer of the tablet includes a hydrophobic excipient or hydrophilic excipient
or combinations thereof.
Exemplary hydrophobic excipients include celluloses, particularly cellulose acetate and
ethyl cellulose, stearic acid, magnesium stearate, glycerol monostearate, fatty acids and
salts thereof, monoglycerides, diglycerides, triglycerides, oil, colloidal silicon dioxide and
talc.
Such tablets include one excipient present in an amount sufficient to be at least partially
rate-controlling with respect to release of the drug from the tablet.
For tablets containing two or more drugs, the drugs can both be present in one or more
layers or the different drugs are present in separate layers.
For drugs requiring absorption in the stomach and upper small intestine and/or topical
delivery to these sites, particularly drugs with narrow absorption windows, bioadhesive,
gastroretentive drug delivery systems are the option of choice. Drugs requiring
17

absorption or topical delivery only in the small intestine, enteric-coated, bioadhesive drug
delivery systems are preferred. For drugs requiring absorption or topical delivery only in
the lower small intestine and colon enteric-coated, bioadhesive drug delivery systems
are preferred.
Multi-layer or gradient tablets can be assembled in several different ways.
In one embodiment, the tablet comprises at least one controlled release layer and one
bioadhesive layer, where in controlled release layer comprises one or more
pharmaceutical polymers and/or pharmaceutical excipients, one or more drugs.
In one embodiment, the tablet comprises at least one controlled release layer and one
bioadhesive layer, each comprising one or more pharmaceutical polymers and/or
pharmaceutical excipients, optionally one or more drugs. Such tablets can also be used
to commence release of different drugs at different times, by inclusion of different drugs
in separate layers.
In one embodiment, the tablet comprises at least one solid inner layer and two solid
outer layers, each comprising one or more pharmaceutical polymers and/or
pharmaceutical excipients. The inner layer comprises one or more active ingredient and
rate-controlling polymer. The two solid outer layers are bioadhesive.
In one embodiment, the tablet comprises at least one solid inner layer and two solid
outer layers, each comprising one or more drugs and one or more pharmaceutical
polymers and/or pharmaceutical excipients. Such tablets can also be used to commence
release of different drugs at different times, by inclusion of different drugs in separate
layers.
In another embodiment, the multi-layer tablet consists of a solid inner layer and two solid
outer layers, each comprising a drug and one or more pharmaceutical polymers or
pharmaceutical excipients, wherein at least one polymer or excipient is hydrophobic.
In an embodiment, the composition of the present invention comprises at least two
fractions wherein one fraction is an immediate release or fast release fraction providing
18

an immediate release of the active agent and the other fraction is an extended release
fraction that releases the active agent over extended periods of time.
One or more layers of the tablet can contain permeation enhancers to provide
permeability enhancement of drugs through mucosal lining of the gastrointestinal tract
(GIT). An absorption enhancer facilitates the uptake of a drug across the gastrointestinal
epithelium. Absorption enhancers include compounds that improve the ability of a drug
to be solubilized in the aqueous environment in which it is originally released and/or in
the lipophilic environment of the mucous layer lining of the intestinal walls.
In still another embodiment, the multi-layer tablet is enteric coated. Optionally Eudragit
FS 30D or other suitable polymer may be incorporated in coating composition to retard
the release of the drug to ensure drug release in the colon.
It is also an object of the invention to provide the a pharmaceutical composition, wherein
the said composition is formulated by compressing or compacting powder, granules,
pellets, beads, shear form particles, floss, or the like, or combinations thereof. The said
composition of the present invention may be filled into capsule or made into a capsule,
wherein the said capsule is in the form of a hard gelatin capsule or soft gelatin capsule.
It is also an object of the present invention to provide pharmaceutical composition
wherein the composition is in the form of a compressed or compacted multiparticulate
composition comprising a blend of one or more types of particles, granules, pellets,
beads, compacts, minitablets, shear form particles, floss, or the like, or combinations
thereof, having different release characteristics or a multiparticulate composition made
into a capsule or filled into a capsule.
It is also an object of the present invention to provide a pharmaceutical composition of
active primciple(s), wherein the composition is in the sustained release form, timed
release form, pulsatile release form, prolonged release form, extended release form or
delayed release form, or a combination thereof. The composition can also additionally
comprise an immediate release composition.
The compositions can be prepared in an easy and cost effective manner.
19

The foregoing examples are illustrative embodiments of the invention and are merely
exemplary. A person skilled in the art may make variations and modifications without
deviating from the spirit and scope of the invention. All such modifications and variations
are intended to be included within the scope of the invention.
EXAMPLES
Example-1

Ingredients %w/w
Active 20
Sodium Alginate 40
Water QS
Calcium chloride 15
Polyethylene oxide (PEO) 10
Sodium Carboxymethyl Cellulose (NaCMC) 11
Colloidal silicon dioxide 2
Magnesium stearate 2
Procedure
i) Sodium alginate is suspended in water and active was suspended in this colloidal
solution.
ii) Calcium Chloride is dissolved in water and kept aside.
iii) Add step (i) into step (ii) dropwise to make beads under stirring, further filter the
solution to separate the beads and dry the beads.
iv) Mix the dried beads with xanthan gum and sodium alginate.
v) Lubricate the beads of step (iv) with magnesium stearate and fill into capsules or
sachets or filled in bottles with sweetening and flavouring agents as a powder for
suspension .
Example- 2

Ingredients %w/w
Active 25
Diluents (e.g., Mannitol or DCP or MCC) 40
PEO 20
Polyvinyl Pyrolidone (PVP) 10
Isopropyl Alcohol (I PA) QS
Magnesium Stearate 2
Colloidal silicon dioxide 2
DCP: Dicalcium Phosphate
20

MCC: Microcrystalline Cellulose
Procedure:
i) Sift Active, Diluent, PVP and PEO through a suitable seive .
ii)Granulate blend of step (i) with I PA.
iii)Dry the granules of step (ii) and sift through a suitable seive.
iv)Lubricate the granules of step (iii) with magnesium stearate.
v)The bioadhesive granules of step (iv) can be further compressed into tablets using
suitable diluents and lubricants or filled into capsules or sachets or filled into bottle with
sweetening and flavouring agents as a powder for suspension.
Example- 3

Ingredients %w/w
Active 20
Diluent (MCC/DCP) 40
Sodium Alginate 10
Xanthan gum 10
NaCMC 15
Sodium bicarbonate 4
Sodium Lauryl Sulphate (SLS) 1
Water QS
Procedure:
Spheronization
i)Mix all the ingredients except sodium bicarbonate in a blender.
ii)Dissolve sodium bicarbonate in water.
iii)Granulate (ii) with (i)
iv)Wet mass of step (ii) is passed through Extruder and further spheronized to get the
round pellets
The pellets can be filled into capsules, sachets or filled in bottles with sweetening and
flavouring agents as a powder for suspension or compressed into tablets .
Example 4

Ingredients %w/w
Active 30
Dliuents (e.g.,Mannitol or DCP or MCC) 30
HPMC 10
Poloxamer 10
PEO 10
Colloidal silicon dioxide 5
Maqnesium stearate 5
Procedure:
21

i) Sift Active, Diluent,HPMC, Poloxamer and PEO through a suitable seive
ii)dry blend (i) in a blender.
iii)sift colloidal silicon dioxide and magnesium stearate through a suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
v)The blend is then compressed into tablets
Example 5

Ingredients %W/W
Active 30
Diluents (e.g. Mannitol or DCP or MCC) 30
HPMC 10
Poloxamer 10
Sodium Alginate 10
Colloidal silicon dioxide 5
Magnesium Stearate 5
Procedure:
i)Active, Diluents, HPMC, Poloxamer and sodium alginate are sifted through a suitable
seive.
ii) Step (i) is dry blended in a blender.
iii)Lubricants are sifted through a suitable seive and mixed with step (ii).
iv)Blend of step (iii) is then compressed into mini tablets.
v)These mini tablets can be filled into capsules
Example 6
B) First and Third Layer

Ingredients %W/W
Active 5
HPMC 35
PEO 40
Polycarbophil 15
Collodial Silicon Dioxide 3
Magnesium Stearate 2
Procedure:
i) Sift active, HPMC, PEO and Polycarbophil through a suitable seive.
ii)dry blend (i) in a blender.
iii)sift colloidal silicon dioxide and magnesium stearate through a suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
22

v)Divide (iv) into equal portions for first and third layer.
A) Middle layer
Ingredients %W/W
Active 70
Diluents (E.g., Mannitol or DCP or MCC) 16
HPMC 10
Colloidal silicon dioxide 2
Magnesium Stearate 2
Procedure
i) Sift active, diluent and HPMC through a suitable seive
ii)dry blend (i) in an blender/granulation can be done using IPA or water.
iii)sift colloidal silicon dioxide and magnesium stearate through a suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
Blends of A and B are compressed into trilayer tablets
Example 7

Ingredients %W/W
Active 20
Diluents (e.g. Mannitol or DCP or MCC) 25
HPMC 10
PEO 15
Vitamin E TPGS* 20
Colloidal silicon dioxide 3
Magnesium Stearate 2
*D-alpha-tocopheryl polyethylene glycol 1000 succinate
Procedure
i) Mix active with Vitamin E TGPS at 70°C, cool to room temperature.
ii) Pulverize (i) using a suitable sieve
iii) Mix (ii) with all other excipients except the lubricants in a blender.
iv) Mix (iii) with magnesium stearate and colloidal silicon dioxide in a blender.
v) The blend is then compressed into tablets.
Example 8
B) First and Third Layer
23

Ingredients %W/W
Active 5
Hydroxypropylmethyl cellulose (HPMC) 30
PEO 40
Polyvinyl alcohol (PVA) 10
SLS 10
Collodial Silicon Dioxide 3
Magnesium Stearate 2
Procedure:
i) Sift active, HPMC, PEO, PVA and SLS through a suitable seive.
ii)dry blend (i) in a blender.
iii)sift colloidal silicon dioxide and magnesium stearate through a suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
v)Divide (iv) into equal portions for first and third layer.
A) Middle layer

Ingredients %W/W
Active 70
Diluents (E.g., Mannitol or DCP or MCC) 15
HPMC 10
Colloidal silicon dioxide 3
Magnesium Stearate 2
procedure
i) Sift active, diluent and HPMC through a suitable seive
ii)dry blend (i) in a blender/granulation can be done using IPA or water.
iii)sift colloidal silicon dioxide and magnesium stearate through a suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
Blends of A and B are compressed into trilayer tablets
Example 9

Ingredients %w/w
Active 30
Dliuents (e.g..Mannitol or DCP or MCC) 30
HPMC 15
PEO 25
Colloidal silicon dioxide 3
Magnesium stearate 2
Methylene chloride QS
IPA QS
Procedure:
24

i) Sift Active, Diluent,HPMC and PEO through a suitable seive.
ii)dry blend (i) in a blender.
iii)Granulate (ii) with IPA:Methylene chloride .
iv) Dry (iii) in fluid bed dryer.
v)Granules obtained in (iv) are sifted through a suitable seive.
vi)Sift Colloidal silicon dioxide and magnesium stearate through suitable seive
vii)Lubricate (v) with (vi) in a blender.
v)The blend is then compressed into tablets
Example 10

Ingredients %w/w
Active 40
Dliuents (e.g.,Mannitol or DCP or MCC) 10
HPMC 20
PEO 20
NaCMC 5
Colloidal silicon dioxide 3
Magnesium stearate 2
Procedure
i)Sift Active, Diluent, HPMC, NaCMC and PEO through a suitable seive
ii)dry blend (i) in a blender.
iii) Sift Colloidal silicon dioxide and magnesium stearate through a suiatble seive
iv)Add half quantity of (iii) to (ii) and mix in a blender.
v)Compact blend of (iv) using a roller compactor at a pressure.
vi) sift (v) through suitable seive to obtain granules
vii) Mix remaining quantity of (iii) and (vi) in a blender.
viii) Blend of (vii) is compressed into tablets.
Example 11

Ingredients %w/w
Active 50
Dliuents (e.g.,Mannitol or DCP or MCC) 15
HPMC 10
PEO 15
Guar gum 5
Colloidal silicon dioxide 3
Magnesium stearate 2
Water QS
Procedure:
25

i)Sift active, diluent, HPMC, guargum and PEO through a suitable seive
ii)dry blend (i) in a blender.
iii)Granulate (ii) with water and dry the wet mass in fluid bed dryer.
iv)Granules obtained in (iii) are sifted through a suitable seive.
v)Sift Colloidal silicon dioxide and magnesium stearate through a suitable seive.
vi) Lubricate (iv) with (v).
vii) Blend of step (vi) is then compressed into tablets.
Example 12
A) First Laver

Ingredients %w/w
Active 40
Dliuents (e.g.,Mannitol or DCP or MCC) 25
HPMC 30
Colloidal silicon dioxide 3
Magnesium stearate 2
I PA QS
Methylene chloride QS
i) Sift active, diluent and HPMC through a suitable sieve and mix in a blender.
iii) Granulate (i) with IPA:methylene chloride, and dry the wet mass in a fluid bed dryer.
iii) Granules of (iii) passed through a suitable sieve.
iv) Sift colloidal silicon dioxide and magnesium stearate through a suitable seive
v) Lubricate (iv) with (v).
B) Second layer

Ingredients %w/w
HPMC 30
PEO 35
Dliuents (e.g.,Mannitol or 25
DCP or MCC)
Colloidal silicon dioxide 5
Maqnesium stearate 5
i) Sift HPMC, diluent and PEO through a suitable seive.
ii)dry blend (i) in a blender.
iii)sift colloidal silicon dioxide and magnesium stearate through a suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
Compress both A and B to form bilayer tablet.
Example 13
26

B) First and Third Layer

Ingredients %W/W
HPMC 40
Xanthan gum 20
Polycarbophil 25
Colloidal silicon dioxide 5
Magnesium stearate 5
Procedure:
i) Sift HPMC, Xanthan gum and Polycarbophil through a suitable seive.
ii)dry blend (i) in a blender.
iii)sift colloidal silicon dioxide and magnesium stearate through a suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
A) Middle layer

Ingredients %W/W
Active 50
Diluents (e.g.,Mannitol or DCP or MCC) 15
HPMC 10
Colloidal silicon dioxide 7
Magnesium stearate 3
Water QS
i) Sift active, diluent, and HPMC through a suitable seive
ii)dry blend (i) in a blender.
iii)Granulate (i) with (ii) and dry the wet mass in fluid bed dryer
iv)Granules obtained in (iii) are sifted through a suitable seive.
v)Sift Colloidal silicon dioxide and magnesium stearate through a suitable seive.
vi) Lubricate (iv) with (v).
vii) Blend of A and B is then compressed into trilayered tablet.
Example 14
B) First and Third Layer

Ingredients %W/W
HPMC 40
Xanthan gum 20
PEO 30
Colloidal silicon dioxide 5
Magnesium stearate 5
Procedure:
27

i) Sift HPMC, Xanthan gum and PEO through a suiatble seive
ii)dry blend (i) in a blender.
iii)sift colloidal silicon dioxide and magnesium stearate through a suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
A) Middle layer

Ingredients %W/W
Active 40
Diluents (e.g.,Mannitol or DCP or MCC) 10
HPMC 15
Colloidal silicon dioxide 3
Magnesium stearate 2
IPA QS
Methylene chloride QS

Procedure:
i) Sift active, diluent, and HPMC through a suitable seive.
ii)dry blend (i) in a blender.
iii)Granulate (ii) with IPA:methylene chloride and dry the wet mass in fluid bed dryer.
iv)Granules obtained in (iii) are sifted through a suitable seive.
v)Sift Colloidal silicon dioxide and magnesium stearate through a suitable seive.
vi) Lubricate (iv) with (v).
viii) Blend A and B are then compressed into trilayer tablet.
Example 15
Ingredients %w/w
Active 35
HPMC 15
PEO 20
Dliuents (e.g.,Mannitol or 25
DCP or MCC)
Colloidal silicon dioxide 2
Magnesium stearate 3
Water QS
A) First Layer
Procedure
i) Sift active, diluent, HPMC and PEO through a suitable sieve and mix in a blender,
ii) granulate (i) with water and dry the wet mass in a fluid bed dryer.
28

iii) granules of (ii) passed through a suitable sieve.
iv) sift colloidal silicon dioxide and magnesium stearate through a suitable seive
v) lubricate (iv) with (v).
B) Second Layer

Ingredients %w/w
HPMC 40
Polyethylene Oxide (PEO) 35
Carbomer 15
Colloidal silicon dioxide 5
Magnesium stearate 5
i) Sift HPMC, carbomer and PEO through a suitable seive
ii)dry blend (i) in a blender.
iii)sift colloidal silicon dioxide and magnesium stearate through a suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
Blends of A and B are then compressed into bilayer tablets .
Example 16
A) First Layer

Ingredients %w/w
Active 30
HPMC 30
Xanthan gum 10
Dliuents (e.g.,Mannitol or 25
DCP or MCC)
Colloidal silicon dioxide 3
Magnesium stearate 2
i) Sift active, diluent, HPMC and xanthan gum through a suitable seive
ii)dry blend (i) in a blender.
iii)sift colloidal silicon dioxide and magnesium stearate through a suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
B) Second Layer

Ingredients %w/w
HPMC 35
Polyethylene Oxide (PEO) 35
Dliuents (e.g.,Mannitol or DCP or MCC) 20
Colloidal silicon dioxide 5
Magnesium stearate 5
29

i) Sift HPMC, diluent and PEO through a suitable seive
ii)dry blend (i) in a blender.
iii)sift colloidal silicon dioxide and magnesium stearate through a suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
Blends of A and B are then compressed into bilayer tablets .
Example 17
B) First and Third Layer

Ingredients %W/W
HPMC 40
Xanthan gum 20
Polycarbophil 25
Colloidal silicon dioxide 5
Magnesium stearate 5
Procedure:
i) Sift HPMC, Xanthan gum and Polycarbophil through a suitable seive
ii)dry blend (i) in a blender.
iii)sift colloidal silicon dioxide and magnesium stearate through a suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
A) Middle layer

Ingredients %W/W
Active 40
Diluents (e.g.,Mannitol or DCP or MCC) 20
HPMC 15
PEO 15
Colloidal silicon dioxide 7
Magnesium stearate 3
Water QS
i) Sift active, diluent, HPMC and PEO through a suitable seive.
ii)dry blend (i) in a blender.
iii)Granulate (ii) with water and dry the wet mass in fluid bed dryer.
iv)Granules obtained in (iii) are sifted through a suitable seive.
v)Sift Colloidal silicon dioxide and magnesium stearate through a suitable seive.
vi) Lubricate (iv) with (v).
vii) Blend of A and B is then compressed into trilayered tablets.
Example 18
A) First Layer

Ingredients %w/w
Active 70
30

HPMC 5
Dliuents (e.g.,Mannitol or 21
DCP or MCC)
Colloidal silicon dioxide 2
Magnesium stearate 2
procedure:
i) Sift active, diluent, HPMC and diluent through a suitable seive.
ii)dry blend (i) in a blender.
iii)sift colloidal silicon dioxide and magnesium stearate through a suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
B) Second Layer

Ingredients %w/w
Active 40
HPMC 35
Dliuents (e.g.,Mannitol or 20
DCP or MCC)
Colloidal silicon dioxide 3
Magnesium stearate 2
i) Sift active, diluent, HPMC and diluent through a suitable seive.
ii)dry blend (i) in a blender.
iii)sift colloidal silicon dioxide and magnesium stearate through a suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
C) Third Layer

Ingredients %w/w
HPMC 40
Xanthan gum 20
PEO 30
Colloidal silicon dioxide 5
Magnesium stearate 5
i) Sift xanthan gum, PEO and HPMC through a suitable seive.
ii)dry blend (i) in a blender.
iii)sift colloidal silicon dioxide and magnesium stearate through a suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
Blend of A, B and C is then compressed into trilayered tablets.
Example 19
A) First Layer

Ingredients %w/w
Active 50
Hydroxypropylmethyl cellulose) HPMC 20
Carbomer 10
31

Dliuents (e.g.,Mannitol or DCP or MCC) 15
Colloidal silicon dioxide 2
Maanesium stearate 3
Procedure:
i) Sift active, HPMC, carbomer and diluents through a suitable seive
ii)dry blend (i) in a blender.
iii)sift colloidal silicon dioxide and magnesium stearate through a suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
B) Second Layer

Ingredients %w/w
HPMC 30
Polyethylene Oxide (PEO) 40
Xanthan gum 20
Colloidal silicon dioxide 2
Magnesium stearate 3
i) Sift HPMC, xanthan gum and PEO through a suitable seive
ii)dry blend (i) in a blender.
iii)sift colloidal silicon dioxide and magnesium stearate through a suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
Blends of A and B are then compressed into bilayer tablets .
Example 20

Ingredients %W/W
Active 2
Diluents (e.g. Mannitol or DCP or MCC) 15
HPMC 30
PEO 45
Stabilizing agent 5
Colloidal silicon dioxide 2
Magnesium Stearate 1
Procedure:
i)Active, Diluents, HPMC, stabilizing agent and PEO are sifted through a suitable seive.
ii) Step (i) is dry blended in a blender.
iii)Lubricants are sifted through a suitable seive and mixed with step (ii).
iv)Blend of step (iii) is then compressed into tablets.
32

DETERMINATION OF BIOADHESION
33
Bioadhesion was determined by tensiometric method. For the determination, an
advanced force gauge equipment (mfg. by Mecmesin, West Sussex, England) was
used. Freshly excised Sheep intestinal tissue was taken and stored in a Tyrode solution
at 4°C until used for the experiment. The tissue was cut into pieces (3x4 cm) and
mounted on the glass slide and tightened with a thread. 0.5ml Phosphate buffered saline
(PBS) was placed on the tissue. The bioadhesive tablet was placed on this tissue and
another 0.5 ml PBS was placed on the tablet. A glass slide with a 10 g weight was
placed on the tablet and it was allowed to hydrate for 10min., 30 min., 60 min., 840 and
960 min. At the specific time interval, the hydrated tablet along with slide was mounted
on the stage of the bioadhesion apparatus. Probe was then lowered at fixed speed of 0.2
mm/sec, and upper slide was attached to the hook of the probe by means of a thread.
The peak detachment force was considered as the bioadhesive force and is expressed
by means of graph as provided in Figure 1. The force required to separate the tablet
from biological substrate was recorded in mN.



34

We Claim:
1. A novel pharmaceutical composition, which comprises a therapeutically effective
amount of active principle(s) or a pharmaceutically acceptable salt or enantiomer
or polymorph thereof, optionally one or more release controlling agent(s) and
pharmaceutical acceptable excipient(s) thereof, wherein the composition is
formulated to increase the residence time of the said pharmaceutical composition
and/or active principle(s) in the gastrointestinal tract.
2. A novel pharmaceutical composition as in claim 1, wherein the release controlling
agent is selected from a group comprising cellulose and cellulose derivatives,
waxes, carbomers, polyalkylene polyols, polycarbophils, methacrylic acid
derivatives, gelatins, gums, polyethylene oxides, and polyvinyl pyrrolidone, or
mixtures thereof.
3. A novel pharmaceutical composition as in claim 1, wherein the active principles
are selected from the group consisting of anti-infectives, penicillins,
cephalosporins, cyclines, beta-lactamase inhibitors, aminosides, quinolones,
nitroimidazoles, sulfamides, antihistaminics, antiallergics, anesthetics, steroidal
or non-steroidal anti-inflammatories, analgesics with local or systemic effect,
antispasmodics, anticancers, diuretics, beta-blockers, antihypertensives,
antianginals, antiarrhythmics, vasodilators, bradycardic agents, calcium
inhibitors, sedatives, cardiotonics, antifungals, antiulceratives, vasotonics,
vasoprotectants, anti-ischemics, antiemetics, anticoagulants, antithrombotics,
immunosuppressants, immunomodulators, antivirals, antiretroviral, antidiabetics,
hypolipidemics, agents for combating obesity, anticonvulsants, hypnotics,
antiparkinsonians, antimigraines, neuroleptics, anxiolytics, antidepressants,
psychostimulants, agents for promoting memory, bronchodilators, antitussives,
agents for combating osteoporosis, peptides, hormones, steroids, enzymes,
enzyme inhibitors, and melatonergic agonists or antagonists or combinations
thereof.
4. A novel pharmaceutical composition as in claim 1, further comprises solubilizing
agent(s).
5. A novel pharmaceutical composition as in claim 4, wherein solubilizing agent(s)
include but are not limited to surfactant(s) such as water-soluble or water
dispersible nonionic, semi-polar nonionic, anionic, cationic, amphoteric, or
35

zwitterionic surface-active agents; cyclodextrin and its derivatives; lipophilic
substances; vitamin E and its derivatives; monohydric alcohol esters such as
trialkyl citrates, lactones and lower alcohol fatty acid esters; nitrogen-containing
solvents; phospholipids; glycerol acetates such as acetin, diacetin and triacetin;
glycerol fatty acid esters such as mono-, di- and triglycerides and acetylated
mono- and diglycerides; propylene glycol esters; ethylene glycol esters or any
combination thereof.
6. A novel pharmaceutical composition as in claim 1, wherein pharmaceutically
acceptable excipients, are selected from the group comprising binders, diluents,
lubricants, surfactants and glidants.
7. A novel pharmaceutical composition as in claim 6, wherein the binder is one or
more selected from the group comprising carbohydrates like celluloses their
derivatives; starches; gums; polyvinylpyrrolidone, povidone, syrup, polyethylene
oxide, polyacryl amide, poly-N-vinyl amide, sodium carboxymethyl cellulose,
polyethylene glycol, gelatin, polyethylene oxide, poly propylene glycol,
tragacanth, alginic acid, combinations thereof.
8. A novel pharmaceutical composition as in claim 6, wherein diluent is one or more
selected from the group comprising carbohydrates, derivatives of carbohydrates,
polyols, sugar alcohols, carbonate, sulphate or phosphate salts of inorganic
metals or mixtures thereof.
9. A novel pharmaceutical composition as in claim 6, wherein lubricant is one or
more selected from the group comprising Magnesium, Aluminium, Zinc or
Calcium stearate, polyethylene glycol, mineral oil, sodium stearyl fumarate,
stearic acid, hydrogenated vegetable oil, glyceryl behenate, glyceryl
palmitostearate, glyceryl stearate, cornstarch, talc, calcium silicate, magnesium
silicate, colloidal silicon dioxide, silicon hydrogel, and mixtures thereof.
10. A novel pharmaceutical composition as in claim 6, wherein surfactant can be
selected from ionic or non-ionic or zwitterionic surfactants.
11. A novel pharmaceutical composition as in claim 6, wherein the glidant is one or
more selected from the group comprising silicon dioxide, colloidal silica,
powdered cellulose, talc, tribasic calcium phosphate and mixtures thereof.
12. A novel pharmaceutical composition as in claim 1, wherein increase in residence
time in gastrointestinal tract is achieved by bioadhesion. and/or by delaying
expulsion from gastrointestinal tract.
36

13. A novel pharmaceutical composition as in claim 12, wherein bioadhesion is
achieved with polymers having affinity for gastrointestinal mucosa selected from
a group comprising polycarbophils, carbomers, lectins, pectine, zein, modified
zein, casein, gelatin, gluten, serum albumin, collagen, chitosan, oligosaccharides
and polysaccharides such as cellulose their derivatives such as methyl cellulose,
ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
hydroxybutylmethyl cellulose, cellulose acetate, cellulose propionate, cellulose
acetate butyrate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose
triacetate, cellulose sulfate sodium salt, dextrans, tamarind seed polysaccharide,
gellan, carrageenan; hyaluronic acid, polyhyaluronic acid, alginic acid, sodium
alginate; gums like xanthan gum, guar gum, gum Arabic locust bean gum; poly
vinylacetatae, polyvinylalcohol, povidone/polyethylene oxide, acrylic and
methacrylic acid their copolymers, polyamides, polycarbonates, polyalkylenes,
polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl
alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone,
polyglycolides, polysiloxanes, polyurethanes, polystyrene, polymers of acrylic
and methacrylic esters, polylactides, poly(butyric acid), poly(valeric acid),
poly(lactide-co-glycolide), polyanhydrides, polyorthoesters, poly(fumaric acid),
poly(maleic acid), polymers having a hydrophobic backbone with at least one
hydrophilic group pendant from the backbone, polymers having a hydrophobic
backbone with at least one hydrophobic group pendant from the backbone, and
blends and copolymers or mixtures thereof.
14. A novel pharmaceutical composition as in claim 12, wherein bioadhesion is
provided for a period greater than 0.5hours.
15. A novel pharmaceutical composition as in claim 1 is formulated as a compressed
or compacted dosage form.
16. A novel pharmaceutical composition as in claim 1 is but not limited to powders,
pellets, beads, granules, tablets, compacts, sustained release formulations,
capsules, microcapsules, tablets in capsules, tablets in tablets, microspheres,
shear form particles, floss, and flakes or mixtures thereof.
17. A novel pharmaceutical composition as in claim 16, wherein tablets include
single layered tablets, multilayered tablets, mini tablets, bioadhesive tablets,
caplets, matrix tablets, tablet within a tablet, mucoadhesive tablets.
37

18. A novel pharmaceutical composition as in claim 16, where in sustained release
formulation include but are not limited to matrix type controlled release,
membrane diffusion controlled release, site targeted, osmotically controlled
release, pH dependent delayed release, timed release, pulsatile release and
hydrodynamic balanced system.
19. A novel pharmaceutical composition comprising: at least two entities wherein one
entity is an immediate release or fast release and the other is controlled release
wherein the composition is formulated to increase the residence time of active
principle(s) in the gastrointestinal tract
20. A novel pharmaceutical composition comprising: at least two entities wherein one
entity is an immediate release or fast release and the other is bioadhesive
wherein the composition is formulated to increase the residence time of active
principle(s) in the gastrointestinal tract.
21. A novel pharmaceutical composition comprising: at least two entities wherein one
entity is controlled release and the other is bioadhesive wherein the composition
is formulated to increase the residence time of active principle(s) in the
gastrointestinal tract.
22. A novel pharmaceutical composition as in claim 1 is optionally coated.
23. A novel pharmaceutical composition as in claim 22, wherein coating includes
film coating, sugar coating, enteric coating, bioadhesive coating, controlled
release coating.
24. A novel pharmaceutical composition as in claim 1 is a once-daily dosage form.
25. A novel pharmaceutical composition as in claim 1 is twice-daily dosage form.
26. A novel pharmaceutical composition as in claim 1, further comprises stabilizing
agent(s).
27. A novel pharmaceutical composition in the form of a multilayer tablet comprising,
a) at least one layer which comprises, a therapeutically effective amount of active
principle(s) or a pharmaceutically acceptable salt or enantiomer or polymorph
thereof, pharmaceutically acceptable excipient(s); wherein the said layer
provides a immediate or fast release of active principle(s); and b) at least one
layer which provides increased residence time of the dosage form in the
gastrointestinal tract.
28. A novel pharmaceutical composition in the form of a multilayer tablet comprising,
a) at least one layer which comprises, a therapeutically effective amount of active
38

principle(s) or a pharmaceutically acceptable salt or enantiomer or polymorph
thereof, pharmaceutically acceptable excipient(s); wherein the said layer
provides a controlled release of active principle(s); and b) at least one layer
which provides increased residence time of the dosage form in the
gastrointestinal tract.
29. A novel pharmaceutical composition in the form of a multilayer tablet comprising,
a) at least one layer which comprises, a therapeutically effective amount of active
principle(s) or a pharmaceutically acceptable salt or enantiomer or polymorph
thereof, pharmaceutically acceptable excipient(s); and b) at least one layer
comprising another or same active principle(s) wherein layer (b) provides
increased residence time of the dosage form in the gastrointestinal tract.
30. A novel pharmaceutical composition in the form of a multilayer tablet comprising,
a) at least one layer which comprises, a therapeutically effective amount of active
principle(s) or a pharmaceutically acceptable salt or enantiomer or polymorph
thereof, pharmaceutically acceptable excipient(s); wherein the said layer
provides a immediate or fast release of active principle(s); and b) at least one
layer comprising another or same active principle(s) wherein layer (b) provides
residence time of the dosage form in the gastrointestinal tract.
31. A novel pharmaceutical composition in the form of a multilayer tablet comprising,
a) at least one layer which comprises, a therapeutically effective amount of active
principle(s) or a pharmaceutically acceptable salt or enantiomer or polymorph
thereof, pharmaceutically acceptable excipient(s); wherein the said layer
provides controlled release of active principle(s); and b) at least one layer
comprising another or same active principle(s) wherein layer (b) provides
increased residence time of the dosage form in the gastrointestinal tract.
32. A novel pharmaceutical composition in the form of a multilayer tablet comprising,
a) at least one layer which comprises, a therapeutically effective amount of active
principle(s) or a pharmaceutically acceptable salt or enantiomer or polymorph
thereof, pharmaceutically acceptable excipient(s); wherein the said layer
provides a immediate or fast release of active principle(s); and b) at least one
layer comprising another or same active principle(s) wherein layer (b) provides
controlled and/or increased residence time of the dosage form in the
gastrointestinal tract.
39

40
33. A novel pharmaceutical composition comprising a therapeutically effective
amount of active principle(s) or a pharmaceutically acceptable salt or enantiomer
or polymorph thereof, optionally one or more release controlling agent(s) and
pharmaceutical acceptable excipient(s) thereof, wherein the composition is
formulated to increase the residence time of the said pharmaceutical composition
and/or active principle(s) in the gastrointestinal tract, having an adhesive
strength, measured as a force of detachment, of atleast 100mN when measured
using advanced force gauge equipment (manufactured by Mecmesin, West
Sussex, England).

A pharmaceutical formulation of active principles for gastrointestinal drug delivery
that comprises an mucoadhesion site-controlling layer for attaching the formulation to
the selected site in the digestive tract. The pharmaceutical composition, comprises a
therapeutically effective amount of active principle(s) or a pharmaceutically
acceptable salt or enantiomer or polymorph thereof, optionally one or more release
controlling agent(s) and pharmaceutical acceptable excipient(s) thereof, wherein the
composition is formulated to increase the residence time of the said pharmaceutical
composition and/or active principle(s) in the gastrointestinal tract.