FIELD OF THE INVENTION
This invention relates to colon targeted modified release bioadhesive pharmaceutical
composition of 5-amino salicylic acid or a pharmaceutically acceptable salt or enantiomer
or polymorph or metabolites thereof, optionally one or more hydrophilic or hydrophobic
release controlling agent(s) and pharmaceutical acceptable excipient(s, and the process
of preparing it.
BACKGROUND OF THE INVENTION
Mesalazine, also known as Mesalamine or 5-aminosalicylic acid (5-ASA), is an anti-
inflammatory drug used to treat inflammation of the digestive tract (Crohn's disease) and
mild to moderate ulcerative colitis. Mesalazine is a bowel-specific aminosalicylate drug
that is metabolized in the gut and has its predominant actions there, thereby having fewer
systemic side effects Mesalazine is used in the treatment of Crohn's disease and
ulcerative colitis due to its antiinflammatory activity on the intestinal mucosa.
Ulcerative colitis is a chronic inflammatory disease of the colon of unknown etiology. The
disease causes inflammations of the mucosa of the colon, with extension to the
submucosa in severe cases.
The related disease, Crohn's disease, also known as regional enteritis or colitis
granulomatosa, is most frequently located in the small intestine (small bowel), especially
in the ileum, but may also affect the jejunum and any part of the colon, including the
rectum. Generally, the inflammation differs from that of ulcerative colitis by progressing to
layers deeper than the mucosa and affecting the epithelium to a lesser degree.
WO 81/02671 discloses a pharmaceutical composition for the treatment of IBD by oral
administration. The invention was based on findings that an oral administration of 5-ASA
has a useful therapeutic effect on ulcerative colitis, in particular when administered in the
form of sustained-release tablets. WO 81/02671 further discloses a method for the
preparation of sustained release tablets comprising the steps of preparing granules from
5-ASA and a solution of polyvinylpyrrolidone in isopropanol, evaporating the solvent,
coating the granules with ethyl cellulose and formulating the coated granules into tablets.
2

U.S.4,960,765 further discloses a method for the treatment of IBD comprising orally
administering an effective amount of a composition consisting essentially of an ester of
free 5-ASA in admixture with a pharmaceutically acceptable carrier so as to delay the
release of 5-ASA from said composition essentially until it reaches the colon of the patient.
Release dependent on pH in the colon is achieved by using a coating resulting in a
gradual release of 5-ASA. The particles are coated with ethyl cellulose.
WO 97/23199 discloses a modified release composition for treatment of IBD comprising
spherical granules comprising a core of 5-ASA and a spheronisation aid prepared in water
as a solvent and coated with a rate limiting barrier material. The composition results in a
minor release of 5-ASA in the stomach and the granules may be packed in sachets.
These granules are not suitable for use in tablets.
EP 0704 208 A2 describes coating agents and binders for drug coverings soluble in
intestinal juice. These comprise copolymers of 10 to 25% by weight methacrylic acid, 40
to 70% by weight methyl acrylate and 20 to 40% by weight methyl methacrylate. As well
as monolayer coatings, the description mentions multilayer coating systems. These may
be composed of a core, comprising for example a basic or a water-sensitive active
ingredient, may have an insulating layer of another coating material, such as cellulose
ethers, cellulose esters or a cationic polymethacrylate of the Eudragit.
EP 0704 207 A2 describes thermoplastic materials for drug coverings soluble in intestinal
juice. These comprise copolymers of 16 to 40% by weight acrylic or methacrylic acid, 30
to 80% by weight methyl acrylate and 0 to 40% by weight other alkyl esters of acrylic acid
and/or methacrylic acid. The minimum film-forming temperature (MFT according to DIN 53
778) is in the range between 0° and 25°C, so that processing is possible at room
temperature without adding plasticizer.
WO-A-83/00435 discloses compositions which can be administered orally and which are
coated with an anionic polymer which is insoluble below pH 7 but is soluble in the colon,
wherein capsules or tablets containing 5-aminosalicylic acid, Prednisolone or
Indomethacin and provided with a coating containing Eudragit S100 are described. The
3

disclosed drug forms are coated capsules or coated tablets, i.e. monolithic drug forms.
Release is said to take place selectively in the colon.
Mesalamine is currently marketed as tablets at the dosage of 400 mg Tablet (Asacol),
250mg & 500mg capsules (Pentasa) and 1200mg Tablet (Lialda) for the treatment of
ulcerative colitis. These marketed formulations are not recommended for pediatric use.
While preparing sustained, controlled-release dosage forms of a medicament topically
active in the gastrointestinal tract, it is important to ensure a controlled release following
administration. The preparation of a sustained, controlled, delayed or anyhow modified
release form can be carried out by use of insert matrices, hydrophilic matrices or
bioerodable matrices.
A number of formulations based on inert lipophilic matrices have been described: Drug
Dev. Ind. Pharm. 13 (6), 1001-1022, (1987) discloses a process making use of varying
amounts of colloidal silica as a pore formation element for a lipophilic inert matrix in which
the active ingredient is incorporated. WO 95/16451 discloses a composition only formed
by a hydrophilic matrix coated with a gastro-resistant film for controlling the dissolution
rate of Mesalazine.
PROBLEM AND SOLUTION :
In the treatment of diseases or ailments of the colon or rectum administration of the
pharmacologically active agent to the affected site may be required. Orally administrable
pharmaceutical compositions however have frequently been found ineffective in this
respect as a result of the absorption of the pharmacologically active agent in the digestive
tract before the colon or rectum is reached. Consequently, the delivery of
pharmacologically active agents to the colon or rectum has conventionally been achieved
by rectal administration, by the use of either suppositories or enemas. However, rectal
administration generally is less convenient and less acceptable to a patient than oral
administration. Further, said rectal administration is not suitable for treating the right side
of the colon. In particular, suppositories are only effective in the rectum and enemas
rarely reach beyond the left side of the colon.
4

5-ASA, or mesalamine, has now been established as a common treatment for IBD.
Additionally, 5-ASA exhibits an efficacy profile that is less than maximal, reflected in high
daily doses (1.5 g/day to 4 g/day), lower response and remission rates, and higher relapse
rates, related to its site and mechanism of action and efficiency of delivery to the cells of
the distal gut.
The administration of 5-ASA is hampered by some complications associated with its
delivery. For example, the compound is unstable in gastric fluids, and its extensive
absorption from the small intestine reduces its availability at distal sites in the gut, which
are the sites of the therapeutic effect and the preferred sites of delivery, thereby
necessitating high doses to be administered. Ideally, the compound should reach the
distal gut (ileum and/or colon) in unchanged form (i.e. as the parent compound).
Once the dosage form reaches the distal gut, the compound should be released and
subsequently absorbed at a rate consistent with maximal metabolism in the distal gut
enterocyte. Therefore, the distal gut enterocyte (i.e., the site of action of the drug) has
maximal exposure to the active form of the drug (i.e., the parent compound), thus
minimizing the dose required and in addition the systemic exposure to the parent
compound and its associated side effects are minimized by maximizing the pre-systemic
metabolism (i.e., in the gut enterocyte).
Various modified release forms have been developed. Both extended/sustained release
formulations and delayed release formulations have been developed, with the intent of
limiting 5-ASA release in the upper gut and concentrating its release in the distal gut.
For example, a sustained release formulation (PENTASA.) has been approved and used
for many years. PENTASA releases 5-ASA continuously, with approximately 50%
released in the small intestine and 50% available for release in the large intestine, and in
its approved label form reports 20-30% systemic absorption. This absorption reflects the
proximal release and absorption characteristics of this formulation in addition to any low
level absorption from the distal gut, as in the distal gut, 5-ASA is incompletely released
from PENTASA and poorly absorbed.
5

Significant effort has been spent on identifying ways to slow down the Gl transit of the
active. The advantages of controlled release products are well known in the
pharmaceutical field as these dosage forms are able 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.
Marketed preparation like Asacol 400 mg Tablets (Procter & Gamble Pharmaceuticals) is
a delayed release tablet coated with acrylic based resin, Eudragit S (Methacrylic acid
copolymer B, NF) that dissolves at pH 7 or more. However certain disadvantages
associated with Asacol are: it is not recommended for pediatric use, does not offer
sustained release of drug, multiple dosing per day required, inconvenient to patient,
Ulcerative Colitis patients0' who do not have Gl pH more than 7 resulting in incomplete
or no dissolution of coating. Because of it's coating, all or none of the drug gets deposited
in colon. It has been reported(2) that intact tablets in unchanged form have been excreted
by some patients. Also Asacol does not offer bioadhesion of formulation, hence some of
the drug may not get in close proximity of site of action (colonic mucosa).
1. Fallingborg J, Christensen L, Jacbsen B et al: Very low intraluminal colonic pH in
patients with active ulcerative colitis. Digestive Diseases and Sciences, 1993, 38(11),
1989-1993.
2. Watts P, Ilium L: Colonic drug delivery. Drug Development and Industrial Pharmacy.
1997, 23(9), 893-913.
3. Pentasa 250 mg & 500 mg CR Capsules (Shire Inc.) offers ethyl cellulose coated
controlled release formulation (pellets) of Mesalamine designed to release therapeutic
quantities of Mesalamine throughout gastrointestinal tract. However certain
disadvantages associated with Pentasa are: it is not recommended for pediatric use,
does not offer delayed release of drug, multiple dosing per day required, inconvenient
to patient, releases drug in upper Gl sites where it gets variably absorbed (20-30%)(3)
and less drug is available for its site of action (colon),due to this, a larger dose (4 g)
per day is required.
6

Lialda tablet, 1200 mg (Shire Inc) is a controlled-release tablet formulation containing
1200 mg of 5-amino-salicylic acid in an inner lipophilic matrix and an outer hydrophilic
matrix in which the lipophilic matrix is dispersed. The tablet is coated with a gastro-
resistant pH dependent polymer film, which breaks down at or above pH 7, normally in the
terminal ileum where mesalamine then begins to be released from the tablet core.
However certain disadvantages associated with Lialda are: : it is not recommended for
pediatric use, it has lipophilic matrix which does not offer uniform release pattern, does
not offer bioadhesion of formulation, hence some of the drug may not get in close
proximity of site of action (colonic mucosa) and some UC patients'1' do not have Gl pH
more than 7 resulting in incomplete or no dissolution of coating. Because of no dissolution
of coating, the drug may not get released in colon. Pentasa Package Insert. (Label).
We have surprisingly found that the formulation or dosage form materials with are suitable
to over come demerits of the above mentioned dosage forms bioadhesive characteristics,
bioadhesiveness being 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.
Considering the properties of the gastrointestinal tract, the following characteristics are
sought after in the system: for effective retention in the colon to suit the clinical demand;
convenient intake (dosing) to facilitate patient compliance; sufficient drug loading capacity;
sustained drug release profile for more than 12 hours ; no release of drug in upper Gl
tract, wherein coating dissolves in gastric juice, full degradation and evacuation of the
system once the drug release is over; and no other local adverse effects.
With respect to the above reasons, to maximize the therapeutic efficacy of 5-ASA its salts
and its metabolites, novel pharmaceutical formulations are provided herein and include,
for example, modified release tablets, which adheres to the colonic mucosa reducing the
chances for expulsion of the dosage form from the colon thus having increased residence
time and prolonging contact thereby improving the efficacy of locally acting agents which
improves patient compliance.
7

OBJECTIVE OF THE INVENTION:
This invention has mainly been attempted to avoid release in the stomach by application
of a coating resistant to gastric juice, or to improve the delaying of release by combining
coating materials.
The invention is therefore based on the objective of providing a pharmaceutical
composition for slow release of active ingredient in the colon, which substantially over
come the disadvantages mentioned above and which can be produced at a reasonable
cost and with high reproducibility.
Another objective of the present invention is to provide a pharmaceutical composition,
which permits slow release of active ingredient in the colon even when the active
ingredient content is high and the excipient content is only low.
This objective is achieved according to the invention by a pharmaceutical composition for
slow release of active ingredient in the gastrointestinal tract, comprising a extended
release matrix core coated with coating comprising a polymer insoluble in gastric juices.
The composition of the invention is particularly suitable for targeted active ingredient
release in the colon. However, in some cases it release of active ingredient may start
even in the stomach, which can likewise be achieved with the composition of the
invention. For example, it is desired in a few cases on treatment of Crohn's disease at a
high location with 5-aminosalicylic acid that active ingredient be released in the lower part
of the stomach in order to achieve an optimal effect in the short duodenal tract.
The composition of the invention has the advantage that the release of active ingredient
takes place very substantially in a pH-independent manner and thus effects of biological
differences between individual patients can be avoided almost completely.
The release delaying in the composition of the invention takes place due to a combination
of at least three measures, each of which contributes to delaying the release of active
ingredient, namely by mixing the active ingredient with a polymer insoluble in gastric juice,
through the small pore size, which is related to a corresponding compaction of the core
material, and by coating with a polymer insoluble in gastric juice.
8

Another object of the invention is to provide a pharmaceutical composition comprising
Mesalamine administered once daily to increase patient compliance for treatment of
Ulcerative colitis.
Yet another object of the present invention is to provide a pharmaceutical formulation
comprising 5-ASA or a pharmaceutically acceptable salt or enantiomer or polymorph or
metabolites having an in vitro dissolution profile, wherein at least about 80% of Mesalmine
is released on or after 12 hours.
Yet another object of the invention is to provide a pharmaceutical composition comprising
a therapeutically effective amount of 5-ASA or a pharmaceutically acceptable salt or
enantiomer or polymorph or metabolites thereof, pharmaceutically acceptable excipient(s),
optionally one or more controlled release agent(s), wherein the composition is formulated
to increase the residence time of 5-ASA or a pharmaceutically acceptable salt or
enantiomer or polymorph or metabolites thereof 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).
DETAIL DESCRIPTION OF THE INVENTION:
This invention relates to modified release bioadhesive pharmaceutical composition of 5-
amino salicylic acid or a pharmaceutically acceptable salt or enantiomer or polymorph or
metabolites thereof, optionally one or more hydrophilic or hydrophobic release controlling
agent(s) and pharmaceutical acceptable excipients, and the process of preparing it.
"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 without an undue burden.
"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.
9

The term " modified release" formulation or dosage form or composition includes
pharmaceutical preparations that achieve a desired release of the drug from the
formulation. A modified-release formulation can be designed to modify the manner in
which the active ingredient is exposed to the desired target. For example, a modified-
release formulation can be designed to focus the delivery of the active agent entirely in
the distal large intestine, beginning at the cecum, and continuing through the ascending,
transverse, and descending colon, and ending in the sigmoid colon. Alternatively, for
example, a modified-release composition can be designed to focus the delivery of the
drug in the proximal small intestine, beginning at the duodenum and ending at the ileum.
In still other examples, the modified-release formulations can be designed to begin
releasing active agent in the jejunum and end their release in the transverse colon. The
possibilities and combinations are numerous, and are clearly not limited to these
examples.
The term "modified-release" encompasses "extended-release" and "delayed-release"
formulations, as well as formulations having both extended-release and delayed-release
characteristics. An "extended-release" formulation can extend the period over which drug
is released or targeted to the desired site. A "delayed-release" formulation can be
designed to delay the release of the pharmaceutically active compound for a specified
period. Such formulations are referred to herein as "delayed-release" or "delayed-onset"
formulations or dosage forms. Modified-release formulations of the present invention
include those that exhibit both a delayed- and extended-release, e.g., formulations that
only begin releasing after a fixed period of time or after a physicochemical change has
occurred, for example, then continue releasing over an extended period. The modified
release may also include pulasatile release, burst release and the like
By "pharmaceutically acceptable" is meant a carrier comprised of a material that is not
biologically or otherwise undesirable.
"Bioadhesion" is defined as the ability of a material to adhere to a biological tissue for an
extended period of time. Bioadhesion over comes 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
10

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.
The term 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 and /or colon , or in the area of the gastrointestinal tract where the
drug is released from 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.
In a preferred embodiment of the present invention the increase in residence time of
Mesalamine formulation in the colonic mucosa is achieved by bioadhesion wherein
bioadhesion is achieved using polymers having affinity for colonic mucosa. Examples of
mucoadhesives for use in the embodiments disclosed herein include, but are not limited
to, natural, semisynthetic and synthetic polymers.
Natural polymers include but are not limited to proteins (e.g., hydrophilic proteins), such
as pectin, 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 but are not limited to 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),
11

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
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 but not necessarily
limited to 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 but not necessarily
limited to 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 phosponic acids, positively charged groups such as (protonated)
amines and neutral, polar groups such as amides and imines.
12

Preferably, the hydrophilic groups are selected to not to 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 chemistry available in the art to covalently attach ligand
molecules with bioadhesive properties to the surface-exposed molecules of the polymeric
microspheres.
Pharmaceutically acceptable excipients include but are not limited to binders, diluents,
lubricants, glidants and surface-active agents.
The amount of additive employed will depend upon how much active agent is to be used.
One excipient can perform more than one function.
Binders include, but are not limited to, starches such as potato starch, wheat starch, corn
starch; microcrystalline cellulose; celluloses such as hydroxypropyl cellulose, hydroxyethyl
cellulose, hydroxypropylmethyl cellulose (HPMC), ethyl cellulose, sodium carboxy methyl
cellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin,
povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone and the like and mixtures
thereof.
Fillers or diluents, which include, but are not limited to confectioner's sugar, compressible
sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose,
xylitol, sorbitol, talc, microcrystalline cellulose, calcium carbonate, calcium phosphate
dibasic ortribasic, calcium sulphate, and the like can be used.
13

Lubricants may be selected from, but are not limited to, those conventionally known in the
art such as Mg, Al or Ca or Zn stearate, polyethylene glycol, glyceryl behenate, mineral
oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil and talc.
Glidants include, but are not limited to, silicon dioxide; magnesium trisilicate, powdered
cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate,
colloidal silicon dioxide, silicon hydrogel and other materials known to one of ordinary skill
in the art.
The pharmaceutical formulation according to the present invention include but is not
limited to tablets (single layered tablets, multilayered tablets, mini tablets, bioadhesive
tablets, caplets, matrix tablets, tablet within a tablet, mucoadhesive tablets, modified
release tablets, pulsatile release tablets, timed release tablets), pellets, beads, granules,
sustained release formulations, capsules, microcapsules, tablets in capsules and
microspheres, matrix formulations, microencapsulation and powder/pellets/granules for
suspension.
Matrix-type dosage form comprises an aminosalicylate active agent its salts or
metabolites, mixed with either water-soluble, e.g., hydrophilic polymers, or water-
insoluble, e.g., hydrophobic polymers. Generally, the properties of the polymer used in a
modified-release dosage form will affect the mechanism of release. For example, the
release of the active agent from a dosage form containing a hydrophilic polymer can
proceed via both surface diffusion and/or erosion. Mechanisms of release from
pharmaceutical systems are well known to those skilled in the art. Matrix-type systems
can also be monolithic or multiunit, and can be coated with water-soluble and/or water-
insoluble polymeric membranes.
Matrix formulations of the present invention can be prepared by using, for example, direct
compression or wet granulation or any conventional method known in the prior art. A
functional coating, as noted above, can then be applied in accordance with the invention.
Additionally, a barrier or sealant coat can be applied over a matrix tablet core prior to
application of a functional coating.
In a matrix-based dosage form in accordance with the present invention, the drug and/or
pro-drug or metabolites and optionally pharmaceutically acceptable excipient(s) are
14

dispersed within a polymeric matrix, which typically comprises one or more water-soluble
polymers and/or one or more water-insoluble polymers. The drug can be released from
the dosage form by diffusion and/or erosion.
Suitable water-soluble polymers include, but are not limited to, polyvinyl alcohol,
polyvinylpyrrolidone,methylcellulose,hydroxypropylcellulose,hydroxypropylmethylcellulose,
or polyethylene glycol, and/or mixtures thereof and the like.
Suitable water-insoluble polymers also include, but are not limited to, ethylcellulose,
cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate
butyrate, cellulose acetate phthalate, cellulose triacetate, poly (methyl methacrylate), poly
(ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), and poly
(hexyl methacrylate), poly (isodecyl methacrylate), poly (lauryl methacrylate), poly (phenyl
methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate),
poly (octadecyl acrylate), poly (ethylene), poly (ethylene) low density, poly (ethylene) high
density, poly (ethylene oxide), poly (ethylene terephthalate), poly (vinyl isobutyl ether),
poly (vinyl acetate), poly (vinyl chloride) or polyurethane, and/or mixtures thereof and the
like.
The amounts and types of polymers, and the ratio of water-soluble polymers to water-
insoluble polymers in the inventive formulations are generally selected to achieve a
desired release profile of the drug or pro-drug or metabolites or its salts, as described
below.
Preferably amino methacrylate co-polymers such as Eudragit RS and Eudragit RL (Rohm
Pharma) are suitable for use in the modified-release formulations of the present invention.
These polymers are insoluble in pure water, dilute acids, buffer solutions, or digestive
fluids over the entire physiological pH range. The polymers swell in water and digestive
fluids independent of pH. In the swollen state they are then permeable to water and
dissolved actives. The permeability of the polymers depends on the ratio of ethylacrylate
(EA), methyl methacrylate (MMA), and trimethylammonioethyl methacrylate chloride
(TAMCI) groups in the polymer. Those polymers having EA:MMA:TAMCI ratios of 1:2:0.2
(Eudragit RL) are more permeable than those with ratios of 1:2:0.1 (Eudragit RS).
15

Polymers of Eudragit RL are insoluble polymers of high permeability. Polymers of Eudragit
RS are insoluble films of low permeability.
The amino methacrylate co-polymers can be combined in any desired ratio. For example,
a ratio of Eudragit RS:Eudragit RL (90:10) can be used. The ratios can furthermore be
adjusted to provide a delay in release of the drug or pro-drug. For example, the ratio of
Eudragit RS:Eudragit RL can be about 100:0 to about 80:20, about 100:0 to about 90:10,
or any ratio in between.
The amino methacrylate co-polymers can be combined with the methacrylic acid co-
polymers within the polymeric material in order to achieve the desired delay in release of
the drug or pro-drug. Ratios of ammonio methacrylate co-polymer (e.g., Eudragit RS) to
methacrylic acid co-polymer in the range of about 99:1 to about 20:80 can be used. The
two types of polymers can also be combined into the same polymeric material, or provided
as separate coats that are applied to the core.
In addition to the Eudragit polymers described above, a number of other such copolymers
can be used to delay drug release. These include methacrylate ester co-polymers (e.g.,
Eudragit NE 30D). Further information on the Eudragit polymers can be found in
"Chemistry and Application Properties of Polymethacrylate Coating Systems," in Aqueous
Polymeric Coatings for Pharmaceutical Dosage Forms (ed. James McGinity, Marcel
Dekker Inc., New York, pg 109-114).
Methyl acrylate copolymers and ammoniomethacrylate copolymers under the tradename
Eudragit.RTM. RS/RL/NE are particularly preferred. As functional groups, these polymers
have ester groups (Eudragit.RTM. NE) or ammonium groups (Eudragit.RTM. RL/RS).
Poly(ethyl acrylate, methyl methacrylate) and poly(ethyl acrylate, methyl methacrylate,
trimethylammonioethyl methacrylate chloride) are preferred. These polymers are
obtainable, for example, as poly(ethyl acrylate, methyl methacrylate) 2:1 in 40% strength
aqueous dispersion as Eudragit.RTM. NE 40 D and as poly(ethyl acrylate, methyl
methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1 in 12.5% strength
isopropanolic solution as Eudragit.RTM. RS 12.5 and in the composition 1:2:0.2 as
Eudragit.RTM. RL 12.5.
16

The formulations of the present invention are intended to include formulations that are
generic to treating all forms of IBD, and thus target their contents to both the distal small
intestine and the large intestine. Other formulations within the scope of the invention
include those that are more specifically designed for treating a specific disease. For
example, a formulation for treating ulcerative colitis can be designed to deliver its contents
entirely to the colon.
The formulations of the present invention can exist as multi-unit or single-unit
formulations. The term "multi-unit" as used herein means a plurality of discrete or
aggregated particles, beads, pellets, granules, tablets, or mixtures thereof, for example,
without regard to their size, shape, or morphology. Single-unit formulations include, for
example, tablets, caplets, and pills.
The methods and formulations of the present invention are intended to encompass all
possible combinations of components that exhibit modified-release and extended-release
properties. For example, a formulation and/or method of the invention can contain
components that exhibit extended-release and modified-release properties, or both
delayed-release and modified-release properties, or a combination of all three properties.
The modifications in the rates of release, such as to create a delay or extension in
release, can be achieved in any number of ways. Mechanisms can be dependent or
independent of local pH in the intestine, and can also rely on local enzymatic activity to
achieve the desired effect.
The present invention is not limited to any of the particular azo-bis compounds (5-ASA)
described herein. The present invention extends to the use and formulation of any azo-bis
compound that yields either 4-ASA and/or 5-ASA. Modified-release formulations of any
such azo-bis compound are specifically contemplated. Thus, as used herein in association
with the present invention, the term "drug" refers to compounds useful in treating IBD or
other diseases according to this invention, including but not limited to sulphasalazine, 5-
ASA, and/or 4-ASA; the term "pro-drug" refers to any compound that yields such drugs,
including but not limited to olsalazine, balsalazine, and/or any other azo-containing
compound that yields such drug or drugs.
17

These coating layers comprises one or more excipients selected from the group
comprising coating agents, opacifiers, taste-masking agents, fillers, polishing agents,
coloring agents, antitacking agents and the like.
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.
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 dosage form 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 pharmaceutical dosage form of the invention can optionally have one or more
coatings such as film coating, sugar coating, enteric coating, bioadhesive coating and
other coatings known in the art. These coatings help pharmaceutical formulations to
release the drug at the required site of action. In one example, the additional coating
prevents the dosage from contacting the stomach contents. In another example, the
additional coating remains intact until reaching the small intestine particularly colon
specific (e.g., an enteric coating).
In a preferred embodiment, the process of making the pharmaceutical formulation of the
invention comprises as described below:
- Granulation and Slugging of Active ingredient
- Addition of mixed excipients followed by granulation, Lubrication and Compression of
granules to form tablet core
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- Seal Coating followed by enteric coating
Compaction of the blend into coprimate may be carried out using a slugging technique or
roller compaction. The milling of the granules may be carried out according to
conventional milling methods.
DISSOLUTION
The formulations of the invention have a prolonged in vitro release rate. The in vitro test
used to measure release rate of the active agent from a formulation of the invention was
as follows. The apparatus contained a paddle and rotated at a speed of 50 rpm. The tablet
formulation was placed in the apparatus and dissolution was periodically measured. The
in vitro dissolution studies are shown below:

Time (hrs.) Cumulative % drug release
0 0.00
1 2
2 14
4 34
8 61
12 80
16 93
20 99
In a preferred embodiment of the present invention in order to improve the patient
compliance and target the formulation in colon, a bioadhesive, controlled release once
daily (600 mg) of 5-Amino salicylic acid or a pharmaceutically acceptable salt or
enantiomer or polymorph or metabolites thereof is explored.
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.
19

EXAMPLES:
Example 1:

Core Tablet
Ingredients % w/w
Mesalamine 80
Sodium Alginate 6
Xanthan Gum 5
Hypromellose 5
Calcium sulphate dihydrate 1.5
Povidone 1
Isopropyl Alcohol Qs
Colloidal silicon dioxide 0.5
Magnesium Stearate 1.0
Total Weight 100.00
Enteric Coating
Methacrylic acid Copolymer, Type A.NF (Eudragit L 100) 65
Methacrylic acid Copolymer, Type B.NF (Eudragit S 100) 20
Triethyl Citrate USPNF 10
Talc USP 5
Purified Water USP Qs
Isopropyl Alcohol USP Qs
Procedure:
Granulation of Mesalmine
Sift Mesalamine through #20 and kept aside. Granulate with a solution of Povidone
dissolved in Isopropyl alcohol. The dried granules were lubricated.
Preparation of Excipient Blend
Mix Xanthan Gum, Sodium Alginate, Hypromellose (CR premium) and Calcium sulphate
dihydrate were passed through desired sieve and kept aside.
Granulation, Lubrication and Compression:
Mix granules of Mesalamine and excipient blend and granulate with a solution. The
prepared granules were dried and compressed into tablets. The compressed tablet core
were coated with the seal coating solution and finally coated with enteric coating material.
20

Dissolution data (pH6.5 ,6.8, 7.0 and pH7.2 Phosphate Buffer)

Time (hrs.) Cumulative % drug release at different pH
Acid stage 0.1NHCL 0.1NHCL 0.1NHCL 0.1NHCL
1 0.00 1.10 0.00 0.00
2 0.00 1.80 0.00 0.00
Buffer 6.5 6.8 7.0 7.2
3 - 0.00 1.40 7.30
4 - 0.60 13.10 19.10
6 - 17.50 34.20 35.70
10 - 54.50 61.20 62.00
14 - 92.90 80.70 85.00
18 - 106.70 93.70 90.50
22 - - 99.50 -
EXAMPLE 2:

Core Tablet
Ingredients % w/w
Balsalazide 80
Sodium Alginate 6
Xanthan Gum 5
Hypromellose 5
Calcium sulphate dihydrate 1.5
Povidone 1
Isopropyl Alcohol Qs
Magnesium Stearate 1.0
Total Weiqht 100.00
Enteric Coating
Methacrylic acid Copolymer, Type A.NF (Eudragit L 100) 65
Methacrylic acid Copolymer, Type B.NF (Eudragit S 100) 20
Triethyl Citrate 10
Talc USP 5
Purified Water Qs
Isopropyl Alcohol Qs
Procedure:
Granulation of Balsalazide
Sift Balsalazide through #20 and kept aside. Granulate with a solution of Povidone
dissolved in Isopropyl alcohol. The dried granules were lubricated.
Preparation of Excipient Blend
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Mix Xanthan Gum, Sodium Alginate, Hypromellose and Calcium sulphate dihydrate were
passed through desired sieve and kept aside.
Granulation, Lubrication and Compression:
Mix granules of Balsalazide and excipient blend and granulate with granulation solution.
The prepared granules were dried and compressed into tablets. The compressed tablet
core were coated with the seal coating solution and finally coated with enteric coating
material
EXAMPLE 3:

Core Tablet
Ingredients % w/w
Olsalazine 80
Sodium Alginate 6
Xanthan Gum 5
Hypromellose 5
Povidone 1

Colloidal silicon dioxide 0.5
Magnesium Stearate 1.0
Total Weight 100.00
Enteric Coating
Methacrylic acid Copolymer, Type A.NF (Eudragit L 100) 65
Methacrylic acid Copolymer, Type B.NF (Eudragit S 100) 20
Triethyl Citrate 10
Purified Water Qs
Isopropyl Alcohol Qs
Procedure:
Granulation of Olsalazine
Sift Olsalazine through #20 and kept aside. Granulate with granulation solution of
Povidone dissolved in Isopropyl alcohol. The dried granules were lubricated and slugging
and deslugging were performed to get granules of active.
Preparation of Excipient Blend
Mix Xanthan Gum, Sodium Alginate, Hypromellose and Calcium sulphate dihydrate were
passed through desired sieve and kept aside.
Granulation, Lubrication and Compression:
22

Mix granules of Olsalazine and excipient blend and granulate with granulation solution.
The prepared granules were dried and compressed into tablets. The compressed tablet
core were coated with the seal coating solution and finally coated with enteric coating
material
EXAMPLE 4:

Core Tablet
Ingredients % w/w
Active ingredient (Balsalazide) 80
Sodium Alginate 6
Xanthan Gum 5
Hypromellose 5
Calcium sulphate dihydrate 1.5
Povidone 1
Isopropyl Alcohol Qs
Magnesium Stearate 1.0
Total Weiqht 100.00
Enteric Coating
Methacrylic acid Copolymer (Eudragit L 100) / (Eudragit S 100) 65
Triethyl Citrate 10
Talc USP 5
Purified Water Qs
Isopropyl Alcohol Qs
DETERMINATION OF BIOADHESION
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 of example 1 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., and 840 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
23

detachment force was considered as the bioadhesive force. The force required to
separate the tablet from biological substrate was recorded in mN.
Observation:
The Bioadhesion data is provided in Figure 1
Other than in the examples, or where otherwise indicated, all numbers expressing
quantities of ingredients, reaction conditions, and so forth used in the specification and
claims are to be understood as being modified in all instance by the term "about."
Accordingly, unless indicated to the contrary, the numerical parameters set forth in the
following specification and attached claims are approximations that may vary depending
upon desired properties sought to be obtained herein.
Notwithstanding that the numerical ranges and parameters setting forth the broad scope
are approximations, the numerical values set forth in the specific examples are reported
as precisely as possible.
The invention is further illustrated by reference to the following examples. It will be
apparent to those skilled in the art that many modifications, both to the materials and
methods, can be practiced without departing from the purpose and scope of the invention
Dated this 10th day of October 2007

24

The present invention relates to a colon targeted modified release bioadhesive pharmaceutical composition of 5-amino salicylic acid or a pharmaceutically acceptable salt or enantiomer or polymorph or metabolites thereof, optionally one or more hydrophilic or hydrophobic release controlling agent(s) and pharmaceutical acceptable excipient(s), and the process of preparing it.