FIELD OF INVENTION
The invention relates to a drug delivery system of macromolecular active
ingredients, one or more force generating components matrix, absorption modifiers
The active ingredient is entrapped into the matrix of a mucoadhesive polymer matrix
optionally coated with a degradable layer. The invention is also intended for the
delivery of hydrophilic drugs in the intestinal tract.
BACKGROUND OF THE INVENTION
Therapeutics like protein, peptide and nucleotide are unstable against acidic,
alkaline and/or enzymatic degradation upon systemic uptake and additionally they
show poor intestinal absorption due to their high hydrophilicity. Therefore, these
compounds are administered by parenteral injection, which has the disadvantages of
painful application, risk of infections, low patient compliance and the need of trained
personnel.
Usually, oral route is the easiest and most preferred way of drug administration for
most high molecular weight drugs or active ingredients. In general the oral
absorption of peptide drugs like insulin is hampered by the properties of the drug
since the peptide molecule is unable to cross the lipophilic enterocyte membrane
and also due to the hostile environment of the gastro-intestinal tract (high acid
concentration in the stomach and high amount of enzymes (peptidases)) in the
lumen of the gut). Most of the published peptide delivery systems for oral application
are micro- or nanosized systems based on mucoadhesive and multifunctional
polymers which are able to adhere to the enteral mucosa for a certain period of time,
interact with the tight junctions protein to reversibly open the tight-junctions, to locally
de-activate the gut enzymes and to finally release the peptide drug. However it
turned out that such micro- or nanosized delivery platforms are only in invivo studies
able to induce substantial blood peptide drug levels in small animals like mice and
rats, but unable to result in similar blood peptide levels in bigger animals like pigs of
25 - 30 kg or humans.

The reason for this most probably is the overall presence of soluble mucins in the
lumen of the gut where the mucoadhesive drug delivery systems are released and
their mucoadhesive properties (which are the essential feature for functioning of the
delivery system) are immediately deactivated by the soluble mucins before the
micro/nanosized delivery systems have reached the absorbing membrane of the
enterocytes.
Attempts employing mucoadhesive polymers have been rather successful in vitro
and in vivo (example: H. L.Lueben et al; Pharm. Res.1995,12: 1293-1298; H.
L.Lueben et al. ; Pharm. Res. 1996,13: 1668-1672). However, the turn-over of
intestinal mucus covering the epithelium led to a rapid delocalization of the polymeric
delivery system (C.-M. Lehr et al. ; Int. J.Pharm. 1991,70: 235-240). It would thus be
desirable to have a system that is retained in the GIT such as at specific sites in the
gut, e.g. by controlled swelling and bioadhesion over a predetermined and extended
period of time. Such systems would have distinct advantages over other delivery
systems in terms of therapeutic effect, patient compliance and manufacturing
feasibility.
WO-A-98/36739 discloses a multiphase release system for implantation purposes.
More in particular, a non-compressed drug delivery system is described comprising
one or more active ingredients in a solid matrix having a three dimensional
architecture, which matrix comprises a bulk material in powder form and a binder.
The disadvantage is that the delivery system has to be implanted by painfull surgical
procedures.
EP-A-0 873 750 discloses tablets for localized drug delivery of actives. These tablets
adhere to biological material by means of a bioadhesive layer that becomes
adhesive after impregnation with water or biological fluids. After adhesion, an active
ingredient is released. The matrix system consists of polymers such as cellulose
derivatives. The drug delivery system in presence of food will not have a desired
release pattern.

US 5292518 discloses a prolonged release composition consisting of active, gel
forming dietary fiber and mineral salts which release gas up on ingestion. The
delivery system described above is not feasible for site-specific drug delivery (small
intestine).
EP0542364 discloses a device, which essentially contains an aperture through
which the drug is released. The release rate is independent of the environmental pH
and released drug even in stomach. This sort of a delivery system is a disadvantage
for the acid sensitive active agents like peptides and proteins.
Studies has been done to prepare a floating drug delivery systems of the orally
active drugs where the investigators attempted to delivery the drug from a floating
dosage form in the contents of the GIT released the drug in the stomach. The
disadvantage is that it is not a suitable site for active agents like peptides or proteins.
WO01/30322 has disclosed the use of super porous hydrogels (SPHs) or SPHs
Composites (SPHCs) the latter system also containing a super disintegrant like Ac-
Di Sol. which swells up on contact with aqueous fluid up to 200-fold of their dry
volume and contains voids filled with drug composition which are sealed and coated
mucoadhesive polymers, optionally enteric coated upon rupture of the enteric
coating swells to mechanically fixed for a certain period of time at a desired position
of the intestine, to bring the peptide delivery subunit system in direct contact with the
mucosal membrane on the entrecotes and to release the drug. Afterwards the SPHs
or SPHC carrier systems (shuttle system) is over hydrated and broken down by the
peristaltic forces of the gut and excreted as fine polymer powder. The invivo study in
pigs resulted in reproducible absolute bioavailabilities of 16± 3.3%. (F.A. Dorkoosh
et.al; J. Control. Release. 2004,99:199-206)
These SPHs and SPHCs formulations fulfill the requirements bringing the peptide
drugs in direct contact with the absorption membrane. However the synthesis and

fabrication of the delivery systems is based on SPHs or SPHCs technology, which is
difficult and not commercially feasible on production scale. Another disadvantage is
their big size (i.e. capsule size 000), which is not easy to be swallowed.
Hence the new invention aims at developing a modified formulation, which
overcomes the demerits associated with the exiting technologies disclosed in the
prior art.
OBJECTIVES OF THE INVENTION
The primary objective of the invention is to deliver primarily hydrophilic actives to the
intestinal tract and to make their absorption across the intestinal wall possible by
brining the active compounds in direct contact to the absorbing membrane of the gut
tissue using mucoadhesive polymer.
Another objective of the invention is to protect the active ingredients from the low pH
of the gastric fluid and the digestive enzymes of the Gl lumen.
Another objective of the invention is to prepare an expandable drug delivery system,
which retains for a longer period of time at the specific site of absorption and delivers
the drug at a predetermined rate through the mucus membrane.
Another objective of the invention is to use a delivery platform for the drug carrier
nanosized particles or capsules, microsized particles or capsules including
liposomes or other similar systems, micro tablets or microcapsules, quantum dots or
similar systems.
Another objective of the invention to prepare an expandable drug delivery system by
using the simple process with out involving complex procedures.

Another objective of the invention to prepare an expandable drug delivery system
comprising absorption modifiers to facilitate opening of the tight junctions of the
intestinal epithelium.
Another objective of the invention to deliver the peptide drugs (which are sensitive to
the pH and the digestive enzymes of GIT) with out exposing the drug to the GIT
contents.
Yet another objective of the invention is to release the drug at the specific site after a
lag time, which is achieved by enteric coating.
SUMMARY OF THE INVENTION
The present invention relates to the preparation of a drug delivery system
comprising of actives, swellable force generating component, absorption modifiers,
optionally coated with enteric coating polymers. The preparation may further include
pharmaceutical excipients or carriers.
The present invention also relates to preparation an expandable drug delivery
system, which delivers the drug at a specific site of the intestinal tract by adhering to
the mucous membrane using bioadhesive polymers.
The present invention also aims at the preparation of an expandable delivery system
wherein the dosage form after administration reaches the desired site of action
forms for a temporary adhesion to the mucous surface followed by imbibing the
intestinal fluids into the core, where it dissolves the absorption modifiers in the core
which generate a force to expand the dosage form and to adherers firmly to lumen.
The drug present diffuses through the polymer matrix and is absorbed by the
intestinal wall primarily by the paracellular pathway. The delivery system, which got
adhered to the walls of the intestine, slides down as the mucous membrane shuds
down and reaches the large intestine where the dosage from is degraded or
expelled as such.

The dosage form of the present invention may contain carbon dioxide releasing
agent which releases carbon dioxide, that forms a bubble layer around the dosage
form which acts as a protective layer against enzymatic degradation. The bubble
layer formed by gas generating component will remain intact in the dosage form until
it reaches the intestinal wall and adheres to the intestinal mucosa.
As the dosage form enters into the intestine the enteric coating dissolves and the
bubble layer formed due to the gas releasing agent that will prevent the hydration of
the mucoadhesive polymer which in turn prevents the dosage form to adhere to the
mucin or mucosa till it reaches the specific site.
DETAILED DESCRIPTION OF THE INVENTION
An expandable drug delivery system is a system, which consists of more the one
unit each unit acts a separate delivery system and consists of active agent in it. The
expandable drug delivery system may be a multiparticulate or non-multiparticulate
system. Multiparticulate is manufactured with any of the technique known in the prior
art or known to the person skilled in the art. Some of the examples of multiparticulate
drug delivery system but not limited to these examples nanoparticles or
nanocapsules, micro particles or microcapsules, liposomes or niosomes in
unilamellar or multilamellar structure, micro tablets or quantum dots, pellets or all
other delivery systems which are filled in the capsules or punched in to mini tablets
and filled in to capsule or compressed in to tablets. The non-multiparticulate drug
delivery system is prepared by conventional granulation technique or by hot melt
technique where in the non-multiparticulate is a monolithic tablet prepared by hot
melt technique.
The term "Absorption modifiers" is defined as the substances that influence
absorption of a drug in the gastrointestinal tract by an increase in the rate and/or the
extent of absorption of the drugs that are known or suspected of having poor

bioavailability. It is believed that such increase can rise from one or all of the
following mechanisms:
1. reducing the thickness and/or the viscosity of the mucus layer which is
present adjacent to the gastrointestinal mucosa.
2. alteration of the tight junctions between cells, thus promoting absorption
through the paracellular route.
3. inducing a change in the cell membrane structure, thus promoting
transcellular absorption.
4. increasing the hydrophobic environment within the cellular 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.
"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.
The term "Carrier or excipients" comprised of a material that is not biologically or
otherwise undesirable. The carriers or excipients may include any biologically
inactive substance known in prior art used for the preparation of any pharmaceutical
dosage form.

The formulation will, in general comprise of one or more excipients. Examples of
excipients include, but are not limited to, diluents, disintegrants, lubricant, glident,
binders, fillers, surfactant, solubilizers, and wetting agents. A combination of
excipients may also be used. Such excipients will include diluents such as mannitol,
dextrose, xylitol, sorbitol, gelatin, acacia, sucrose, microcrystalline cellulose, calcium
carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate,
lactose, starches, vinyl polymers and the likes, disintegrants referred to in the
present invention include one or more of microcrystalline cellulose, croscarmellose
sodium, crospovidone, carboxymethyl starch sodium, sodium starch glycolate and
the likes, binders referred to in the present invention include one or more celluloses
such as hydroxypropyl cellulose, hydroxy ethyl cellulose, ethyl cellulose,
hydroxypropyl methyl cellulose, methyl cellulose or mixtures thereof, acrylates,
methacrylates, povidone, sucrose, corn or maize starch, pregelatinized starch and
the like, coloring agents such as ferric oxide, FD&C dyes, lakes and the likes and
flavoring agent. Examples of glidents include but are not limited to silica,
magnesium trisilicate, powdered cellulose, talc, and starch.
The term "force-generating component" is defined as the component that is
responsible for generating force for expanding the drug delivery system and give
sufficient strength to transport the drug to the absorbing membrane for the time
period sufficient to release the drug. The force generating component comprise of
gas generating components like carbon dioxide or sulphur dioxide releasing agents
e.g. acid base mixtures, carbonates, bicarbonate and sulfites, swelling polymers,
osmogens and the like
The term "expandable drug delivery composition" is a delivery system which can
expand or swell, which is fabricated in combination of gas forming compounds,
swellable polymers and mucoadhesive polymers that adhere to the mucous
membrane and expand on hydration due to the force generating component and
adheres to the side of the lumen.

The term "multilayered dosage form" is a dosage form which is made up of one or
more layers. If it is more than on layer the layers can be laminated horizontally,
vertically or by concentric layered (where in the core has a coated layer).
The delivery system can release sub unit delivery platforms, which are driven either
by the swellable polymers or by the gas to absorbing membrane. These sub-units
delivery system can consist of nanoparticles or nanocapsules, micro particles or
microcapsules, liposomes or niosomes in unilamellar or multilamellar structure,
micro tablets or quantum dots or all other delivery systems sized from 4 mm down to
nanometer size, with or with out mucodhesive properties using mucoadhesive
polymers as described below with or with out substances which allow endocytosis or
transcytosis of the particles across the enterocyctes of the intestine (like invasions
and other similar particles across the enterocytes of the intestine (like invasions and
other similar substances), with or with out enzyme inhibitors as described below
Active agents suitable for use in the present invention include biologically active
agents (actives) and chemically active agents, including, but not limited to,
pharmacological agents, and therapeutic agents. Suitable active agents include
those that are rendered less effective, ineffective or are destroyed in the gastro-
intestinal tract by acid hydrolysis, enzymes and the like. Also included as suitable
active agents are those macromolecular agents whose physiochemical
characteristics, such as, size, structure or charge, prohibit or impede absorption
when dosed orally.
For example, biologically or chemically active agents suitable for use in the present
invention include, but are not limited to, proteins; polypeptides; peptides; hormones;
polysaccharides, and particularly mixtures of muco-polysaccharides; carbohydrates;
lipids; other organic compounds; and particularly compounds which by themselves
do not pass (or which pass only a fraction of the administered dose) through the
intestinal mucosa and/or are susceptible to chemical cleavage by acids and
enzymes in the gastro-intestinal tract; or any combination thereof.

Further examples include, but are not limited to, the following, including synthetic,
natural or recombinant sources thereof: growth hormones, including human growth
hormones (hGH), recombinant human growth hormones (rhGH), bovine growth
hormones, and porcine growth hormones; growth hormone releasing hormones;
growth hormone releasing factor, interferons, including [alpha] (e.g., interferon
alfacon-1), [beta] and [gamma]; interleukin-1; interleukin-2; glucagon; insulin,
including porcine, bovine, human, and human recombinant, optionally having
counter ions including zinc, sodium, calcium and ammonium; insulin-like growth
factor, including IGF-I; heparin, including un-fractionated heparin, heparinoids,
dermatans, chondroitins, low molecular weight heparin, very low molecular weight
heparin and ultra low molecular weight heparin; calcitonin, including salmon, eel,
porcine and human; erythropoietin; atrial naturetic factor; antigens; monoclonal
antibodies; somatostatin; protease inhibitors; adrenocorticotropin, gonadotropin
releasing hormone; oxytocin; luteinizing-hormone-releasing-hormone; follicle
stimulating hormone; glucocerebrosidase; thrombopoietin; filgrastim; prostaglandins;
cyclosporin; vasopressin; cromolyn sodium (sodium or disodium chromoglycate);
vancomycin; desferrioxamine (DFO); bisphosphonates, including alendronate,
tiludronate, etidronate, clodronate, pamidronate, olpadronate, and incadronate;
parathyroid hormone (PTH), including its fragments; anti-migraine agents such as
BIBN-4096BS and other calcitonin gene-related proteins antagonists; glucagon-like
peptide 1 (GLP-I); antimicrobials, including antibiotics, anti-bacterials and anti-fungal
agents; vitamins; analogs, fragments, mimetics or polyethylene glycol (PEG)-
modified derivatives of these compounds; or any combination thereof and the like.
Non-limiting examples of antibiotics include gram-positive acting, bacteriocidal,
lipopeptidal and cyclic peptidal antibiotics, such as daptomycin, Aliskerin and
analogs thereof.
The present invention may comprise of active agent, a carrier and at least one
swellable polymer.

A swellable polymer is a polymer that expands upon ingestion such that the
pharmaceutical composition is retained in the stomach for 30 minutes, 90 minutes, 4
hours, 6 hours, 12 hours or 24 hours or more after administration. For example, the
swellable polymer may cause the pharmaceutical composition to increase in size
10%, 15%, 50%, 100% or 200% or more as compared to its pre-ingested volume.
Generally higher molecular weights of the polymers are more desirable since they
provide a larger swollen size and stronger mechanic strength. In one embodiment of
the present invention, the swellable polymers has a molecular weight in excess of
50,000 daltons. In another embodiment, the swellable polymer has a molecular
weight in excess of 200,000 daltons. In another embodiment, the swellable polymer
has a molecular weight in excess of 7,000,000 daltons.
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.
Examples of poly (alkylene oxides) include, but are not limited to, polymers, which
contain as a unit, ethylene oxide, propylene oxide, ethylene oxide, or propylene
oxide. These polymers may consist entirely of any of the above units (as a
monomer), combinations of any of the above units, such as a copolymer. In one
embodiment, the swellable polymer is a block copolymer in which one of the
repeating units consists of ethylene oxide, propylene oxide, ethylene oxide, or
propylene oxide.
Examples of cellulose polymers include, but are not limited to, cellulose,
hydroxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxy
propyl methylcellulose (also known as hypromellose), and carboxymethyl cellulose.

Examples of polysaccharides include, but are not limited to, dextran, xanthan gum,
gellan gum, welan gum, rhamsan gum, sodium alginate, calcium alginate, chitosan,
gelatin, and maltodextrin. Examples of starch-based polymers include, but are not
limited to, hydrolyzed starch polyacrylonitrile graft copolymers, starch-acrylate-
acrylamide copolymers.
Commercially available swellable polymers include Polyox 303(TM) (Polyethylene
oxide), molecular weight 7,000,000); Polyox WSR N-12K (Polyethylene oxide),
molecular weight 1,000,000), Polyox WSR N-60K (Polyethylene oxide), molecular
weight 2,000,000), Polyox WSR 301 (Polyethylene oxide), molecular weight
4,000,000), Polyox WSR Coagulant, PolyoxWSR 303, Polyox WSR 308,
NFgrade(TM) (Polyethylene oxide) molecular weight 1,000,000).
Addition of hydro-attractants can improve the swelling properties of a dosage form
significantly, and hence can constitute a swellable polymer. Examples of hydro-
attractants which can be incorporated into pharmaceutical compositions of the
present invention include crosslinked poly(acrylic acid), crosslinked poly(vinyl
pyrrolidone), microcrystalline cellulose, crosslinked carboxymethyl cellulose, starch
granules, sodium carboxymethyl starch, alginates, low substituted hydroxypropyl
cellulose (L-HPC, 10-13% substitution by weight, Shin-Etsu Chemical Company, Ltd,
distributed by Biddle Sawyer), Croscarmellose Sodium (Primellose) (Avebe,
distributed by Generichem), Sodium Starch Glycolate (Avebe, distributed by
Generichem) sodium phosphates, such as disodium phosphate, sodium chloride,
sodium citrate, sodium acetate, succinic acid, fumaric acid, tartaric acid, tannic acid,
sugars (eg. mannitol, sucrose, lactose, fructose, sorbital) and natural amino acids.
Amino acids can also be used as permeation enhancers.
Swellable polymers can also be used as rate controlling polymers. Release
controlling polymers are often selected from the same class as swellable polymers.
Examples of release controlling polymers include, for example, poly(ethylene oxide),

poly(acrylic acid), polyvinyl alcohol, alginate, chitosan, polyvinylpyrrolidone, cellulose
polymers and polysaccharides and the like.
An orally ingested product swells and adhere to either the epithelial surface or the
mucus lining of the gastrointestinal tract. For the delivery of bioactive substances, it
can be advantageous to have a polymeric drug delivery device adhere to the
epithelium or to the mucous layer. Bioadhesion in the gastrointestinal tract proceeds
in two stages: (1) viscoelastic deformation at the point of contact of the synthetic
material into the mucus substrate, and (2) formation of bonds between the adhesive
synthetic material and the mucus or the epithelial cells. In general, adhesion of
polymers to tissues may be achieved by (i) physical or mechanical bonds, (ii)
primary or covalent chemical bonds, and/or (iii) secondary chemical bonds (i.e.,
ionic). Physical or mechanical bonds can result from deposition and inclusion of the
adhesive material in the crevices of the mucus or the folds of the mucosa.
Secondary chemical bonds, contributing to bioadhesive properties, consist of
depressive interactions (i.e., Van der Waals interactions) and stronger specific
interactions, which include hydrogen bonds. The hydrophilic functional groups
primarily responsible for forming hydrogen bonds are the hydroxyl and the carboxylic
acid groups.
Duchene et al, in Drug Dev. Ind. Pharm., 14:283-318 (1988), review the
pharmaceutical and medical aspects of bioadhesive systems for drug delivery.
Polycarbophils and acrylic acid polymers were noted as having the best adhesive
properties. Others have explored the use of bioadhesive polymers, however, the
extent of bioadhesion achieved in these studies has been limited. In addition, these
studies do not demonstrate how to prepare larger bioadhesive drug delivery devices,
such as tablets. WO 93/21906 discloses methods for fabricating bioadhesive
microspheres and for measuring bioadhesive forces between microspheres and
selected segments of the gastrointestinal tract in vitro.

Separately or in addition to the need to control the location at which a drug is
released, there is also a need to control the duration over which a drug is released
from a pharmaceutical formulation. In particular, certain drugs, especially peptide
drugs are inactivated by enzymatic degradation if those released in the stomach.
Thus, there is a need for methods for increasing the bioadhesion and thereby
absorption of pharmaceutical agents from drug delivery systems such as tablets or
multiparticulate systems through mucosal membranes.
In a preferred embodiment, the present invention is a tablet for oral delivery of a
drug, comprising a core including a drug to be delivered intestinally, and optionally a
polymeric coating, which is not bioadhesive. In a preferred embodiment, the
bioadhesive polymeric coating does not substantially swell upon hydration.
The present invention is not limited to tablets, it may contain capsules, pellets, mini-
tablets, granules, monolithic tablets spherules and the like, known to a person skilled
in the art at the time of invention. Also these dosage forms can be prepared by any
convention method known in the prior art. Another embodiment of the present
invention wherein the expandable drug delivery system is in the form of mini-tables
filled into the capsules.
The dosage form of the present invention may contain carbon dioxide releasing
agent which releases carbon dioxide, that forms a bubble layer around the dosage
form which acts as a protective layer against enzymatic degradation. The bubble
layer formed by gas generating component will remain intact in the dosage form until
it reaches the intestinal wall and adheres to the intestinal mucosa. The gas
generating component is also the transport medium bringing the drug compartment
to the absorbing mucosal surface.
As the dosage form enters into the intestine the enteric coating dissolves and the
bubble layer formed due to the gas releasing agent that will prevent the hydration of

the mucoadhesive polymer which in turn prevents the dosage form to adhere to the
mucin or mucosa till it reaches the specific site.
The present invention provides methods for improving the bioadhesive properties of
drug delivery systems such as tablets, capsules and drug-eluting devices. The
invention also provides methods for improving the adhesion of drug delivery systems
to mucosal membranes including membranes of the gastrointestinal tract. The
polymeric drug delivery systems of the invention have an improved ability to bind to
mucosal membranes, and thus can be used to deliver a wide range of drugs or
diagnostic agents in a wide variety of therapeutic applications, and/or improve
uptake of the active agent across the intestinal mucosa.
In embodiments of the present invention, the pharmaceutical composition includes a
mucoadhesive/ Bioadhesives. The mucoadhesive facilitates retention in the GIT by
binding to the mucosal surface of the GIT, or by association with the mucosal coat.
Examples of mucoadhesives include, but are not limited to, a polyacrylic acid or
polyacrylate optionally cross-linked with allyl sucrose, allyl ethers of sucrose,
allylpentaerythritol, pentaerythritol or divinyl glycol; a carboxylvinyl polymer; a
polyvinyl pyrrolidone (PVP); polyvinyl alcohol; chitosan and its quaternary derivatives
sodium carboxymethylcellulose (CMC); a dextran polymer; a copolymer of
polymethyl vinyl ether and maleic anhydride; hydroxymethylcellulose;
methylcellulose; a tragacanth; an alginic acid; gelatin; gum arabic; and a
polysaccharide optionally interrupted with a [beta]-(l-4)-linked D-glucosamine unit
and/or a N-acetyl-D-glucosamine unit, and mixtures thereof.
The preferred embodiment of the present invention involves the preparation of
expandable delivery system in which the dosage form after administration reaches
the desired site of action and will forms a temporary adhesion to the mucous surface
followed by imbibing the fluids of the Gl environment in to the core, where it
discloses the force generating material in the core which creates a force to expand

the dosage form and carries it for adhesion to luminal surface with out loosing its
mucoadhesive properties. The drug present in polymer matrix diffuses through the
intestinal wall by diffusion. The delivery system, which got adherered to the walls of
the intestine, slides down as the mucous membrane sheds down and reaches the
large intestine where the dosage from is degraded or expelled as such.
The preferred embodiment of the present invention may include other excipient like
absorption enhancers enzyme inhibitors and intestinal motility modifiers can be
integrated in the polymer matrix.
In order to increase epithelial permeability, all compounds that are used as
permeation enhancers can be integrated in the swellable polymer matrix.
Examples of such compounds are EDTA, polyacrylates (Carbomer), chitosans and
their derivatives, anionic surfactants such as sodium lauryl sulfate, nonionic
surfactants such as polyoxyethylene ethers and esters, fatty acids such as sodium
caprate, trihydroxy bile salts such as taurocholate, dihydroxy bile salts such as
taurodeoxycholate, acyl carnitines such as palmitoyl carnitine and salicylates such
as sodium salicylate, carbon dioxide and the like.
In order to reduce enzymatic activity all known classes of protease inhibitors and
other enzyme inhibiting substances can be added in the swellable polymer matrix.
Enzyme inhibitors improve the absorption of macromolecular drugs. Compounds,
which increase epithelial permeability and reduce enzymatic activity simultaneously,
can also be added. Suitable enzyme inhibitors are aprotinin, cystatin, amino acid
and its derivates, soybean trypsin inhibitor, leupeptin, bestatin and small inhibitors
based on boron compounds, such ASA- aminoboronic acid derivatives.
Another application possibility is the use of ketoconazol and levamisol as enzyme
inhibitors for cytochromes such as cytochrome P450 and especially for cytochrome
P3A4 and for other drug transporters such as P-glycoproteins within the gut wall to
overcome multidrug resistance of drugs especially anti-cancer drugs.

Further optional ingredients are compounds that can control the intestinal motility,
either decrease the motility for prolonged retention time of the dosage form at the
site of action or increase the motility for easier excretion of the dosage form. These
compounds can influence the transition of the system through specific parts of the
intestine. Examples of such compounds are loperamide.HCI, papaverine.HCI, opiate
receptor stimulators and acetylcholine antagonists.
Other Excipients
The pharmaceutical composition may also contain other conventional
pharmaceutical excipients, for example, water soluble diluents such as lactose,
dextrose, mannitol, sorbitol, and the like; water insoluble diluents such as starch,
microcrystalline cellulose, powdered cellulose, and the like; or lubricants such as
talc, stearic acid or its salt, magnesium stearate, and the like. According to the
present invention, when the pharmaceutical composition contains a water-soluble
salt of one or more polyuronic acids, the other pharmaceutical excipients preferably
should be free of calcium ions. The invention is not limited to the examples given in
the specification it may include other excipients, which are known in the field of
invention.
The delivery system was prepared by any know granulation technique with the citric
acid, Na-bicarbonate and lactose. TMC (Trimethyle chitosan), PEO, Avicel, drug and
the Na-benzoate were then added step-wise to the obtained granules and mixed.
The granules were then pressed to tablets. The variables were the percent
polyethylene oxide (PEO) as mucoadhesive polymer, percent of citric acid and Na-
bicarbonate (CO gas production), and Ac-Di-Sol as super-disintegrant. The
response was the CO gas production, tablet disintegration as well as a
mucoadhesive mass response. The variables were set as low and high values of 2.5
- 70% of the total weight for the amount of acid-base, Ac-Di-Sol and the PEO,
respectively. The prepared tables were coated with an enteric coating polymer(s).

In one of the present embodiment the use of the Co2 and the TMC had shown a
synergist effect on the permeability of the insulin across ex-vivo isolated sheep's
intestine. The apparent permeability for insulin using the expandable drug delivery
system in the presence of TMC has shown a highest value of 27 *10'7 (cm/sec) as
shown in Fig 1 which describes the effect of the GEDD system on the transport of
the insulin across the sheep's intestine.

Examples:
This example illustrates the present invention when the active ingredient is peptide
drug. Peptide drug is an example of a drug, which is absorbed, only from the upper
part of the intestine. The pharmaceutical composition is given in Table 1.



DETERMINATION OF MUCOADHESION
The mucoadhesive properties of the system were evaluated in a piece of sheep's
intestine (Jejunum). The experiment was performed according to the method
described by Smart et al. with some modifications. Briefly, a small section of fresh

sheep's intestine was removed, quickly frozen and was cut into pieces of 3 cm
lengths, opened longitudinally to expose the mucous surface and gently washed with
PBS buffer pH 6.0. A preliminary histological study indicated the absence of any
major damage to the tissue caused by the freeze-thawing process. A layer of mucus
was shown to be present on the inner surface of the intestine. The sections of
intestine were mounted on a platform and secured using a plastic cap, exposing an
11 mm diameter of the test surface. The exposed surface was equilibrated in PBS
o
buffer of pH 6.8 for 1 min at 37 C. The cap was elongated at one side to allow
sufficient distance for the tablet to be detached. Using a cyanoacrylate adhesive, the
GEDD tablets were individually attached to 1.5 g weight, lowered into PBS buffer pH
6.8 and placed in contact with the adhesive surface for 2 minutes. Subsequently, a
brass ring was placed over the 1.5 g weight. The ring was connected to the force
and position sensor of the rheometer via a pulley system (diagram 1). After 2 min the
contact platform was lowered at a rate of 2mm/min and the maximum detachment
force was calculated.

We claim:
1. An expandable drug delivery system comprising of one or more actives, force
generating components, optionally containing one or more absorption modifiers
2. An expandable drug delivery system of claim 1 where in the force generating
component is selected from the group consisting of gas generating components,
swelling polymers and osmogens
3. An expandable drug delivery system of claim 1 where in the swelling polymers
polymer is selected from the group consisting of cellulose and its derivatives, PEO,
gums, PVP, cross linked PVP, sodium starch glycolate, cross linked cellulose,
polysaccharides, cross linked polyacrylic acids, polyalkyl oxides, polyurethane
hydrogels, malic anhydrate polymers and chitosan
4. An expandable drug delivery system for oral delivery consisting of
macromolecular active, force generating component, with/with out absorption
modifiers
5. An expandable drug delivery system of claim 3 where in the macromolecular
actives selected from the group consisting of proteins; polypeptides; peptides;
hormones; polysaccharides, and particularly mixtures of muco-polysaccharides;
carbohydrates; lipids; small polar organic molecules
6. An expandable drug delivery system for oral delivery consisting of a protein or
peptide drug(s), force-generating components, with/with out absorption modifiers,
wherein the composition is formulated to increase the residence time in the GIT,
optionally coated with enteric polymers.

7. An expandable drug delivery system for oral delivery in the form of multilayered
tablets or capsules comprising protein or peptide, PEO, TMC, force-generating
component and optionally coated.
8. An expandable drug delivery system of claim 6 wherein the multilayered tablet or
capsules comprise of one or more layer.
9. An expandable drug delivery system according to any preceding claims the
increase in the gastric retention is achieved by the use of mucoadhesion or
bioadhesion
10. An expandable drug delivery system according to claim 8 the coating polymer is
a hydrophilic or hydrophobic polymers.
11.An expandable drug delivery system consisting of a peptide drug, expandable
polymer matrix, expanding force-generating component, which delivers drug after a
lag time followed by a burst release or sustained release.

An expandable drug delivery system comprising of one or more actives, force generating components, optionally containing one or more absorption modifiers