FIELD OF THE INVENTION
This invention relates to pharmaceutical combinations of Mesalamine or a
pharmaceutically acceptable salt or prodrugs thereof and Rifaximin or a pharmaceutically
acceptable salt or prodrugs thereof to treat patients suffering from Inflammatory bowel
disease (IBD) and/or irritable bowel syndrome (IBS). This invention also relates to
additive and/or synergistic combinations of Mesalamine and Rifaximin. Preferable those
synergistic combinations are useful in treating subjects suffering from irritable bowel
syndrome and Inflammatory bowel disease.
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.
Several Mesalamine formulations are currently being marketed such as Asacol, Pentasa,
Lialda, Canasa. Asacol is a DR tablet (2x400mg TID, total dose 2.4 g). Pentasa is a CR
capsule (250 and 500mg, QID, total dose 4 g). Lialda is a modified release (delayed and
controlled, 2x1200mg, OD, total dose 2.4 g) tablet. Canasa is a rectal suppository
(500mg BID and 1000mg QD).
The mechanism of action of Mesalamine is not fully understood, but appears to be
topical. Mucosal production of arachidonic acid (AA) metabolites, both through the
cyclooxygenase pathways, i.e., prostanoids, and through the lipoxygenase pathways,
i.e., leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs), is increased in
patients with chronic inflammatory bowel disease, and it is possible that Mesalamine
diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin (PG)
production in the colon. Recent data also suggest that Mesalamine can inhibit the
activation of NFKB, a nuclear transcription factor that regulates the transcription of many
genes for pro-inflammatory proteins.
2

U.S. 4,632,921 further discloses a process for the production of readily soluble 5-ASA
preparations by mixing 5-ASA with physiologically and toxicologically acceptable, basic
auxiliaries and/or buffer mixtures, which in a 1% aqueous solution give pH-values in the
range from 8 to 12, and the mixture obtained is processed in known manner to form
tablets, film tablets, capsules or suppositories for use in the treatment of inflammatory
bowel disease (IBD).
U.S 4,880,794 discloses a method for the treatment of IBD comprising orally
administering an effective amount of a composition consisting essentially of a
pharmaceutically acceptable salt of free 5-ASA in admixture with a pharmaceutically
acceptable carrier which will control the release of said effective amount of said salt of 5-
ASA to the actual site of said disease.
U.S. 5,013,727 discloses a pharmaceutical composition containing as active ingredient
5-ASA or a pharmaceutically acceptable salt or ester thereof allowing the treatment of
IBD by oral administration. A particular slow-release tablet formulation and its
preparation are disclosed.
The antibiotic rifaximin was originally disclosed in Italy as IT Patent 1154655. The related
U.S. Pat. No. 4,341,785 to Marchi et al. discloses imidazo-rifamicyn derivatives having
antibacterial utility, and the related process for preparing it. The US 785 patent also
discloses a pharmaceutical antibacterial composition and a method of using it to treat
antibacterial diseases of the gastrointestinal tract.
Rifaximin is essentially a non-absorbable, non-systemic, semi-synthetic antibiotic, related
to rifamycin. The antimicrobial spectrum (in vitro) includes most gram-positive and gram-
negative bacteria; and both aerobes and anaerobes. Rifaximin is approved in certain
countries for the treatment of pathologies whose etiology is in part or totally due to
intestinal acute and chronic infections sustained by gram-positive and gram-negative
bacteria, with diarrhea syndromes, altered intestinal microbial flora, summer diarrhea-like
episodes, traveler's diarrhea and enterocolitis; pre- and post- surgery prophylaxis of the
infective complications in gastro intestinal surgery; and hyperammonaemia therapy as
coadjutant. The drug has been found to have no significant side effects.
3

Rifaximin is currently marketed as tablets at the dosage of 200 mg for traveller's diarrhea
under the brand name "Xifaxan".
Inflammatory Bowel Disease (IBD) is a chronic and debilitating illness. It is characterized
by chronic intestinal inflammation that often shows an intermittent course with acute
attacks followed by periods of remission. Clinical symptoms during acute attacks include
diarrhea, bleeding, abdominal pain, fever, joint pain, and weight loss. These symptoms
can range from mild to severe, and may gradually and subtly develop from an initial
minor discomfort, or may present themselves suddenly in full-blown form. IBD can
manifest itself in a variety of forms, the most common of which are Crohn's disease and
ulcerative colitis. Both of these diseases are similar in terms of clinical symptoms, even
though their inflammation patterns are distributed differently in the Gl tract. Crohn's
disease is a chronic transmural inflammation of the bowel, which can affect the whole
gastrointestinal tract, usually in a discontinuous pattern. The initial location of CD is most
commonly in the lower ileum. From here the inflammation typically spreads towards
proximal parts of the small intestine. However, the colon is also often involved.
Ulcerative colitis is a chronic inflammatory bowel disease affecting only the colon and
shows a continuous distribution in the gastrointestinal mucosa. In most patients the focal
point of the inflammation is in the distal part of the colon and the rectum. From this origin,
the inflammation often spreads proximally. In the most severe cases, the whole colon is
affected which is called as "pancolitis". About 30% of patients suffer from this severe
form of UC.
Ulcerative colitis and Crohn disease occur in areas of the gastrointestinal tract with the
highest concentrations of luminal bacteria. The distal ileum contains 107 to 108 primarily
anaerobic bacteria/gram of luminal contents, whereas the colon has 1011 to 1012 bacterial
colonies/gram, with Bacteroides, Clostridium, and Bifidobacterium species
predominating. Chronic intestinal inflammation is the consequence of an overly
aggressive cell-mediated immune response to commensal (normal endogenous) enteric
bacteria in a genetically susceptible host. It is thought that bloating and flatulence,
especially troublesome in patients with irritable bowel syndrome (IBS), may be caused
by bacterial overgrowth in the small intestine. 10% to 84% of patients with IBS may have
small intestinal bacterial overgrowth, as confirmed by lactulose breath tests.
4

Individual membrane-bound toll-like receptors (TLR-1 to 9) each recognize a different
bacterial product. Similarly, NOD1 and NOD2 receptors bind intracellular peptidoglycan.
Binding of bacterial adjuvants to these receptors activates nuclear factor- B (NF B), a
central signaling pathway that initiates transcription of multiple proinflammatory
molecules found in active IBD and experimental intestinal inflammation. Although
intestinal epithelial cells do not constitutively express NOD2 and have low expression of
TLR-4, these receptors are upregulated during active IBD by proinflammatory cytokines,
particularly tumor necrosis factor (TNF), through an NF B-dependent mechanism.
Although, normal commensal bacteria may provide the constant antigenic stimulus
driving cell-mediated immune responses that cause chronic intestinal inflammation, the
possibility remains that a classic pathogen could cause Crohn disease or ulcerative
colitis.
Balfour et al 1 studied the use of antibiotics in the treatment of IBD. The studies
concluded that broad-spectrum antibiotics are more effective than selective agents. Also
the antigens and adjuvant from the commensal, nonpathogenic enteric bacteria that
provides the constant immunological stimulus (there by inducing chronic cell mediated
immune response) can be attenuated by decreasing the concentration of enteric
bacterial species or by inhibiting bacterial invasion of tissue by using antibiotics.
Shafran et al has conducted an open label studies as preliminary assessment of
Rifaximin for the treatment of Crohn's disease Rifaximin 200mg was administered to the
patients having the symptoms of the Crohn's disease for 4 months after which 78% of
the patients showed improvement in the condition. So, it was proved that the rifaxine
may be useful for the treatment of Crohn's disease.
Ginoeashetti et al conducted a study in which patents suffering from the colonic
disorders were treated with 400mg twice daily of Rifaximin for 10 days and it was found
that there is a decrease in the frequency of bleeding. So, the Rifaximin shows a
promising results in the treatment in the IBS.
Irritable bowel syndrome (IBS) is a disorder characterized most commonly by cramping,
abdominal pain, bloating, constipation, and diarrhea. IBS causes a great deal of
discomfort and distress, but it does not permanently harm the intestines and does not
lead to a serious disease, such as cancer. Most people can control their symptoms with
5

diet, stress management, and prescribed medications. For some people, however, IBS
can be disabling. They may be unable to work, attend social events, or even travel short
distances.Distrutti and etal studies indicate that the IBS is linked to inflammation of GIT
their investigation on the role of the Mesalamine derivatives and assessed the pain by
abdominal withdrawal response and spinal Cfos expression.
Mesalamine and Rifaximin are two different types of drugs offering some symptomatic
relief to the IBD patients. Mesalamine treats inflammation, whereas, Rifaximin reduces
bioburden. However, in both cases, the disease is not completely cured and needs long-
term treatment and still the disease relapses. Current individual drug treatments needed
larger doses per day, such as 2.4 to 4 g of Mesalamine or 1.2 g of Rifaximin. Patient
needs to take 2 to 16 tablets or capsules of Mesalamine or up to 6 tablets of Rifaximin
per day.
It is evident from the above discussion that currently there are only the individual drug
dosage forms, which involve repeated administration of large amount of the drug for long
period of time, which may not effectively cure the condition. As the disease condition is
localized at the distal end of the GIT most of the conventional forms of the drugs release
the therapeutic agent in the upper part which precipitates the adverse action and single
drug dosage form available in the market may or may not release the drug at the site of
the inflammation or infection which indeed cause the remission of the disease or worsen
the condition and there is no patient compliance in the existing treatment. So, there is a
need to develop a combination dosage form which release the drugs only in the lower
part of the GIT for a longer period of time
OBJECTIVE OF THE INVENTION:
One objective of the invention is to prepare pharmaceutical combination comprising of 5-
ASA derivatives and its salts or prodrugs or polymorphs thereof and antiinfective drugs
and its salts or prodrugs or polymorphs thereof.
Another objective of the present invention is treatment of IBS/IBD by the administration
of Mesalamine and Rifaximin.
Another objective of the invention is to provide a Bioadhesive modified release
pharmaceutical composition consisting of Mesalamine and its salts or prodrugs or
6

polymorphs thereof and Rifaximin and its salts or prodrugs or polymorphs thereof,
optionally coated with hydrophilic or hydrophobic polymers.
Another objective is to increase residence time of the pharmaceutical composition in the
GIT by using bioadhesive polymers
Another objective of the invention is to prepare modified release pharmaceutical
composition comprising of Mesalamine and its salts or prodrugs or polymorphs thereof
and Rifaximin and its salts or prodrugs or polymorphs thereof for the treatment of IBS
and/or IBD.
Another objective of the invention is to provide a modified release pharmaceutical
composition containing both Mesalamine and Rifaximin in a single dosage form, for the
treatment of inflammation and to decrease the bioburden.
Another objective of the invention is to prepare once daily or twice daily pharmaceutical
composition containing both Mesalamine and Rifaximin
Another objective of the invention is to reduce the dose and dosing frequency of
Mesalamine and Rifaximin for the effective treatment of irritable bowel syndrome and/or
irritable bowel disease.
Another objective of the invention is to increase solubility of the pharmaceutical
formulation comprising Mesalamine and Rifaximin by the addition of solubilizers.
Yet another objective of the present invention is to provide a pharmaceutical formulation
comprising Mesalmine and Rifaximin, of which at least about 75% of drugs are released
in colon, which was achieved by the enteric coating the dosage form with one or two
polymers, which facilitate the dissolution of coating at a pH of between 5.5 and 6.5 and
above.
DETAIL DESCRIPTION OF THE INVENTION:
This invention relates to pharmaceutical combinations of Mesalamine or a
pharmaceutically acceptable salt thereof and Rifaximin releasing the drugs in lower GIT
7

with enteric coating and one or more hydrophilic or hydrophobic release controlling
agent(s) and pharmaceutical acceptable excipients, and the process of preparing it
Mesalamine can be used in the dose range of 0.8 to about 4.8 g per day and Rifaximin
can be used in the dose range of 0.2 - 1.8 g per day which can be administered once a
day or twice a day.
'Once a day' means the dosage form(s) to be taken only one time in 24 hours by which
the drug concentration is maintained for whole day in the body.
Twice a day' means th e dosage form(s) to be taken two times in 24 hours.
The active agents of the invention includes the corresponding pharmaceutically
acceptable salts, prodrugs acceptable salt, enantiomer, polymorph or metabolites thereof
which are know to the person skilled in art at the time of invention.
The term combination product includes: (1) A product comprised of two or more
regulated components, i.e., drug/device, biologic/device, drug/biologic, or
drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and
produced as a single entity;
(2) Two or more separate products packaged together in a single package or as a unit
and comprised of drug and device products, device and biological products, or biological
and drug products;
(3) A drug, device, or biological product packaged separately that according to its
investigational plan or proposed labeling is intended for use only with an approved
individually specified drug, device, or biological product where both are required to
achieve the intended use, indication, or effect and where upon approval of the proposed
product the labeling of the approved product would need to be changed, e.g., to reflect a
change in intended use, dosage form, strength, route of administration, or significant
change in dose; or
(4) Any investigational drug, device, or biological product packaged separately that
according to its proposed labeling is for use only with another individually specified
8

investigational drug, device, or biological product where both are required to achieve the
intended use, indication, or effect.
The term "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 "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 modified release includes the sustained release, controlled release,
delayed release etc.
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
9

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 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.
The term bioadhesive and mucoadhesive can be used interchangeably.
The term bioadhesive and mucoadhesive of the present invention can also include the
dosage, which retains along the length of GIT for the desired period of time. So, as to
increase the mean residence time of the dosage forms.
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
combination 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.
In one of the preffered embodiment of the present invention the combination of the
steroidal anti-inflammatory agent in combination with an anti infective agent. The
10

steroidal inflammatory agent is selected from the drugs like budesonide, Prednisone,
prednisolone.
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.
The bioadhesive or mucoadhesive 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), 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), polypheny I 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 or mucoadhesive 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
11

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 or mucoadhesive 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.
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 chemistries 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.
12

Binders include, but are not limited to, starches such as potato starch, wheat starch, corn
starch; microcrystalline cellulose such as products known under the registered trade
marks Avicel, Filtrak, Heweten or Pharmacel; 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.
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.
With membrane-modified extended-release dosage forms, a semi-permeable membrane
can surround the formulation containing the active substance of interest. Semi-
permeable membranes include those that are permeable to a greater or lesser extent to
both water and solute. This membrane can include water-insoluble and/or water-soluble
polymers, and can exhibit pH-dependent and/or pH-independent solubility
characteristics. Generally, the characteristics of the polymeric membrane, which may be
13

determined by, e.g., the composition of the membrane, will determine the nature of
release from the dosage form.
Matrix-type systems comprise an aminosalicylate active agent, 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, examples
that are described above.
Matrix formulations of the present invention can be prepared by using, for example,
direct compression or wet granulation. 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. The barrier or
sealant coat can serve the purpose of separating an active ingredient from a functional
coating, which can interact with the active ingredient, or it can prevent moisture from
contacting the active ingredient. Details of barriers and sealants are provided below.
In a matrix-based dosage form in accordance with the present invention, the drug and/or
pro-drug and optional pharmaceutically acceptable excipient(s) are 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.hdroxypropylmethylcellulose
or polyethylene glycol, and/or mixtures thereof.
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
14

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.
Matrix-based dosage form can comprise the drug or pro-drug, a filler, such as starch,
lactose, or microcrystalline cellulose ; a binder, /controlled-release polymer, such as
hydroxypropyl methylcellulose; a disintegrant,; a lubricant,; a surfactant, such as sodium
lauryl sulfate or polysorbates; and a glidant, such as colloidal silicon dioxide or talc.
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, as described below.
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
independently 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).
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. In such formulations, the less permeable
polymer Eudragit RS would generally comprise the majority of the polymeric material.
15

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 control 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 amino methacrylate copolymers of the type such as can
be obtained 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. The most preferred is Eudragit.RTM. NE
40 D
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
16

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 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 mouth or esophagus. In another example, the
additional coating remains intact until reaching the small intestine (e.g., an enteric
coating). 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. 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.
The present invention is not limited to any of the particular (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 SASP, 5-ASA, and/or 4-
17

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.
The anti infective agents are not limited to Rifaximin, ciproflaxacin and metronidazole but
also includes the antibiotics which acts on G.I micro flora.
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 controlled release polymers can be hydrophilic, hydrophobic or combination thereof.
The hydrophilic rate-controlling polymer includes but are not limited to
hydroxyethylcellulose, hydroxypropyl cellulose, Hydroxypropyl Methylcellulose, sodium
carboxymethyl cellulose, sodium alginate, carbomer (Carbopol(TM)), xanthan gum, guar
gum, locust bean gum, poly vinyl acetate, polyvinyl alcohol. Preferably the rate-
controlling polymer is hydroxypropylmethylcellulose (Low viscosity grade).
18

The hydrophobic rate controlling agent in matrix includes but are not limited to
hydrogenated vegetable oil, but other suitable agents include purified grades of
beeswax; fatty acids; long chain fatty alcohols, such as cetyl alcohol, myristyl alcohol,
and stearyl alcohol; glycerides such as glyceryl esters of fatty acids like glyceryl
monostearate, glyceryl distearate, glyceryl esters of hydrogenated castor oil and the like;
oils such as mineral oil and the like, or acetylated glycerides; ethyl cellulose.stearic acid ,
paraffin, carnauba wax, talc; and the stearate salts such as calcium, magnesium, zinc
and other materials known to one of ordinary skill in the art.
In embodiments of the present invention, a pharmaceutical composition comprises an
active agents 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.
The pharmaceutical compositions of the present invention can optionally include one or
more solubilizers, i.e., additives to increase the solubility of the pharmaceutical active
ingredient or other composition components in the solid carrier. Suitable solubilizers for
use in the compositions of the present invention include: alcohols and polyols, such as
ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol,
butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol,
dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol,
hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and
cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular
weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether
(glycofurol, available commercially from BASF under the trade name Tetraglycol) or
methoxy PEG (Union Carbide); amides, such as 2-pyrrolidone, 2-piperidone, .epsilon.-
caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-
alkylcaprolactam, dimethylacetamide, and polyvinylpyrrolidone; esters, such as ethyl
propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl
oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene
glycol diacetate, .epsilon.-caprolactone and isomers thereof, .delta.-valerolactone and
isomers thereof, .beta.-butyrolactone and isomers thereof; and other solubilizers known
in the art, such as dimethyl acetamide, dimethyl isosorbide (Arlasolve DMI (ICI)), N-
19

methyl pyrrolidones (Pharmasolve (ISP)), monooctanoin, diethylene glycol monoethyl
ether (available from Gattefosse under the trade name Transcutol), and water.
Preferred solubilizers include triacetin, triethylcitrate, ethyl oleate, ethyl caprylate,
dimethylacetamide,N-methylpyrrolidone,N-hydroxyethylpyrrolidone, polyvinylpyrrolidone,
hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol
200-600, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly
preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, SLS, polyethylene
glycols glycofurol and propylene glycol. Cyclodextrins polyoxomers, surfactants and like
Modified dosage ranges for mammals of other sizes and stages of development will be
apparent to those of ordinary skill. In the practice of the present invention, the weight
ratio of the Mesalamine and Rifaximin
EXAMPLES
Example 1 :

Composition of First layer Mg/Tab
Mesalamine 800.00
Xanthan Gum 40.00
Sodium Alginate 55.00
HPMC 70.00
MCC 50.00
PVP 75.00
Composition of Second layer Qty. (mg/tab.)
Rifaximin 200
Hypromellose 65
Poloxamer 10
Mannitol 15
Colloidal silicon dioxide 5
Enteric Coating Qty. (mg/tab.)
Methacrylic acid Copolymer, Type A.NF
(Eudragit L 100) 65
Methacrylic acid Copolymer, Type B.NF
(Eudragit S 100) 20
Triethyl Citrate USPNF 10
Manufacturing Procedure:
Mesalamine, Xanthan gum, Sodium alginate, MCC, HPMC were mixed, sieve and
granulated. The final granules were lubricated Rifaximin, Hypromellose, Poloxamer,
Mannitol were also granulated separately. Both the mixtures were compressed into
bilayered tablets.
20

Dissolution data
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 USP II apparatus contained a paddle and rotated at a speed of 50 rpm
for Mesalamine and 100 rpm for Rifaximin in 900ml dissolution media.. The tablet
formulation was placed in the apparatus and dissolution was periodically measured. The
in vitro dissolution studies of are shown below;

Time (Hrs) (% Release of
Mesalamine
pH at 7.0) (% Release of
Rifaximin
pH at 7.0)
1 NMT 10% NMT 10%
4 20 - 45% 20 - 45%
12 60 - 90% 60 - 90%
20 NLT 90% NLT 90%
Example 2:

Ingredients Mg/Tab
Mesalamine 800.00
Rifaximin 200.00
Xanthan Gum 40.00
Sodium Alginate 55.00
Hypromellose 70.00
MCC 50.00
PVP 75.00
Methacrylic acid Copolymer, Type A.NF
(EudragitUOO) 65
Methacrylic acid Copolymer, Type B.NF
(EudragitS100) 20
Triethyl Citrate USPNF 10
Manufacturing Procedure:
Mesalamine, Xanthan gum, Sodium alginate, MCC, HPMC were passed through suitable
sieve and granulated. Dried granules mixed with sifted Rifaximin and finally lubricated
and compressed into tablets and coated.
21

Example 3:

Composition of First layer Mg/Tab
Mesalamine 800.00
Xanthan Gum 40.00
Sodium Alginate 55.00
HPMC 70.00
MCC 50.00
PVP 75.00
Composition of Second layer Qty. (mg/tab.)
Rifaximin 200
Hypromellose 65
Poloxamer 10
Mannitol 15
Colloidal silicon dioxide 5
Enteric Coating Qty. (mg/tab.)
Methacrylic acid Copolymer,(Eudragit L
100) 70
Methacrylic acid Copolymer, Type B.NF
(Eudragit S 100) 10
Triethyl Citrate USPNF 10
Example 4:

Ingredients Mg/Tab
Balsalazide 800.00
Rifaximin 200.00
Xanthan Gum 40.00
Sodium Alginate 55.00
HPMCK 70.00
MCC 50.00
PVP 75.00
Methacrylic acid Copolymer,(Eudragit L
100) 65
Methacrylic acid Copolymer, (Eudragit S
100) 20
Triethyl Citrate USPNF 10
Example 5:

Ingredients Mg/Tab
Olsalazine 800.00
Rifaximin 200.00
Xanthan Gum 40.00
Sodium Alginate 55.00
HPMCK 70.00
MCC 50.00
PVP 75.00
Methacrylic acid Copolymer, Type A.NF 65.00
22

(EudragitUOO)
Methacrylic acid Copolymer, Type B.NF
(EudragitSlOO) 20.00
Triethyl Citrate USPNF 10.00
Example 6

Ingredients Mg/Tab
Cisalazine 800.00
Rifaximin 200.00
Xanthan Gum 40.00
Sodium Alginate 55.00
HPMCK 70.00
MCC 50.00
PVP 75.00
Polaxomer / SLS 45.00
Methacrylic acid Copolymer, Type A.NF
(Eudragit L 100) 65.00
Methacrylic acid Copolymer, Type B.NF
(Eudragit S 100) 20.00
Triethyl Citrate USPNF 10.00
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.
Dated this 10th day of October, 2007

23

The present invention relates to pharmaceutical combinations of mesalamine or a pharmaceutically acceptable salt or prodrugs thereof and rifaximin or a pharmaceutically acceptable salt or prodrugs thereof to treat patients suffering from inflammatory bowel disease (IBD) and/or irritable bowel syndrome (IBS). The invention also relates to additive and/or synergistic combinations of mesalamine and rifaximin.