Field of the Invention
The present invention relates to the various delayed release formulations of Chloride
Channel activator. The delayed release formulations reduce the incidence of nausea
associated with the administration of these agents.
The most preferred Chloride channel activator is lubiprostone which is used for the
treatment of chronic constipation,
The invention also provides the method of manufacture of delayed release
formulation of Chloride channel activator.
Background of the Invention
Chloride channels are pore-forming proteins that allow the transport of chloride ions,
the predominant anion in the extra cellular fluid, across cell membranes. Chloride
ions (CI-) not only manage transportation of water/electrolyte, secretion and
regulation of cell volume but also play an important role as a factor affecting the
response of cells. Found in virtually all cell types, they play a vital role in the function
of epithelial, muscle, and nerve cells. Chloride secretion is the major determinant of
mucosal hydration throughout the gastrointestinal tract and chloride transport is also
pivotal in the regulation of fluid secretion by organs that drain into the intestine.
It has been reported that various kinds of chloride channels are present in the cell
membrane of nerve, muscle and epithelium, and they are involved with various
physiological functions and cytophylaxis mechanisms.
Chloride channels are implicated in a variety of diseases including epilepsy,
dystrophia myotonica, Bartter syndrome, osteoporosis, and chronic pancreatitis.
Other diseases known to be caused by an abnormality in the balance of chloride ions
include diseases showing hypercalciuria such as calculus renum, anxiety, insomnia,
cystic fibrosis, epilepsia, anesthesia, asthma, bronchitis and neuropathy.
One of the most important chloride channels in the Gl tract is the cystic fibrosis trans
membrane conductance regulator (CFTR). This cyclic AMP-regulated channel is
located on the apical membrane, is normally activated by protein kinase A, and is
defective in patients with cystic fibrosis. The variation of genes, which is the cause of
this disease, occurs in CFTR genes due to the reduced permeability of chloride ions
2

caused by the deficiency in functions of CFTR in the epithelial cells of air duct,
pancreas, bowel, perspiratory gland, alimentary tract, etc.
A chloride channel is an ion-transport membrane protein for transporting chloride
ions. Further, a chloride channel cloned by cramp fish's electric organ and named
CIC-0 was later found to form a large family (CIC family). Examples of CIC family are:
CIC-1 present in the skeletal muscle of mammals; CIC-2 present in the epithelium of
various organs; CIC-3 and CIC-4 distributed in hippocampus, cerebellum, etc.; CIC-5
present in lung, kidney, etc.; CIC-6 and CIC-7 present in brain, testis, skeletal
muscle, kidney, etc.; and CICK-1 and CICK-2 specifically shown only in kidney. It is
known that the abnormality in CIC-1 causes congenital myotonia and the abnormality
in CIC-5 causes hereditary nephrolithiasis.
The transition of chloride ions into or out of cells concurrently accompanies the
transport of water and electrolyte, which results in the regulation of cell volume.
Therefore, it is suggested that chloride ions play an important role in the growth and
division of cells and the programmed cell death that accompany an abrupt change in
the cell volume. In the brain, it is known that inhibitory regulation works in the central
nervous system by maintaining chloride ions in the nerve cells at a low level. It is also
known that chloride ions play an important role in inhibiting anxiety and spasm, and
regulating sleep, memory and circadian rhythm.
In the bowel, it is known that chloride ions are deeply involved with such pathology as
diarrhea and constipation, and when opioid such as morphine is administered to
bring abnormal secretions of electrolyte such as chloride ions and fluid, it will cause
intractable constipation. Accordingly, a compound which can open chloride channels
and promotes chloride ion transportation are considered to affect on various cell
functions and cytophylaxis mechanisms, and also considered to be useful for the
treatment of pathology occurring because of abnormal chloride ion balance within or
outside the cells due to the reduced permeability of chloride ions by some cause.
Lubiprostone is a bicyclic fatty acid prostaglandin E 1 derivative that is a locally
acting chloride channel activator that enhances a chloride-rich intestinal fluid
secretion without altering sodium and potassium concentrations in the serum.
Lubiprostone acts by specifically activating CIC-2, which is a normal constituent of
the apical membrane of the human intestine, in a protein kinase A-independent
fashion. By increasing intestinal fluid secretion, lubiprostone increases motility in the
3

intestine, thereby increasing the passage of stool and alleviating symptoms
associated with chronic idiopathic constipation. The use of lubiprostone in chronic
idiopathic constipation has been disclosed in US 5,317,032.
Chronic idiopathic constipation is generally defined by infrequent or difficult passage
of stool. The signs and symptoms associated with chronic idiopathic constipation
(i.e., abdominal pain or discomfort, bloating, straining, and hard or lumpy stools) may
be the result of abnormal colonic motility that can delay the transit of intestinal
contents and impede the evacuation of rectal contents. It is estimated that 4-5 million
Americans (about 2% of the population) are affected, making it one of the most
common disorders. It is one of the most common gastrointestinal complaints with
prevalence estimates falling in the range of 12-19% and increasing in population over
65 years of age. Despite this high prevalence, treatment for constipation remains
unsatisfactory, possibly due to poor understanding of its etiology and the relative lack
of conventional therapeutic approaches for the treatment of constipation include
dietary and lifestyle modifications and exercise, and if all else fails, administration of
laxatives.
One approach to the treatment of chronic idiopathic constipation is the secretion of
fluid into the abdominal lumen through the activation of chloride channel.
Lubiprostone has emerged as a novel agent with considerable promise as a
treatment for constipation.
Lubiprostone activates CIC-2 channels on the apical membrane of intestinal epithelial
cells. Although the complete mechanism explaining lubiprostone's efficacy is not
completely understood at this time, the primary action is mediated via these
channels. When activated, there is an efflux of chloride through the channels into the
lumen of the intestinal tract. To maintain electrical neutrality, sodium ions follow
through a paracellular pathway. Water then follows, also along the paracellular
pathway, to maintain isotonic equilibrium. Opening chloride channels thus causes a
net efflux of chloride into the lumen of the intestinal tract, which promotes intestinal
fluid secretion. Secretion of fluids into the gastrointestinal tract adds fluid to stool and
promotes increased transit, likely through stimulation of local receptors sensitive to
stretch and distention. Although the small intestine and colon are able to avidly
absorb secreted fluid, the activation of CIC-2 channels throughout both the small
intestine and colon likely leads to its net stimulatory effects. Lubiprostone is specific
for CIC-2 channels and does not activate other chloride channels such as CFTR.
4

Further the activation of CIC-2 channels by lubiprostone is independent of protein
kinase A.
All of the adverse events associated with lubiprostone consist of Gl symptoms
including vomiting, nausea, and abdominal cramping. It has been observed that the
percentage of patients experiencing nausea is about 17% for 24 meg once daily dose
and 29% at a dose of 24 meg twice daily compared to 3% in placebo.
The mechanism of lubiprostone-associated nausea is not known. However, it is
possible that fluid secretion could transiently distend the lumen of the upper
gastrointestinal tract, thereby, leading to nausea. As expected, subjects receiving
lubiprostone experience more diarrhea than those on placebo. The effect did not
seem to be dose dependent as no more diarrhea was observed at the higher doses
of lubiprostone.
Thus the object of the present invention is to provide a novel formulation of
lubiprostone or any other chloride channel activators, which are devoid of nausea.
The formulation of the present invention releases lubiprostone in the lower
gastrointestinal tract thereby avoiding distention of upper gastrointestinal tract.
Objects of the Invention
The object of the present invention is to provide novel delayed release formulations
chloride channel activators.
Another object of the present invention is to provide novel delayed release
formulations of lubiprostone or its metabolites.
Another object of the present invention is to provide method of manufacturing the
delayed release formulation of lubiprostone or its metabolites.
Another object of the present invention is to provide formulation, which release the
active agent, lubiprostone in the upper gastrointestinal tract.
Detailed Description of Invention
The present invention is directed towards novel delayed release formulations of
chloride channel activators. The most preferred chloride channel activator is
lubiprostone.
5

Thus the present invention is directed towards novel delayed release formulations of
lubiprostone. It has now been found that delivering lubiprostone or its
pharmaceutically acceptable salts or metabolites or tautomers to the lower
gastrointestinal tract would avoid or reduce the nausea associated with the
administration of lubiprostone. Lubiprostone acts by activating the chloride channels,
which causes transportation of chloride ions, sodium ions and water in the
gastrointestinal tract. Secretion of fluids in the Gl tract adds fluid to stool and as a
result shows anti-constipating effect.
The object of the present invention is to delay the release of lubiprostone, so that the
dosage form releases lubiprostone in the lower gastrointestinal tract avoiding
opening of chloride channels in the stomach or upper gastrointestinal tract, which
would further avoid the transportation of chloride ions, sodium ions and water that
would in turn avoid distension of stomach. This is likely to minimize the nausea
associated with lubiprostone therapy.
Thus, according to present invention there is provided a pharmaceutical dosage form
adapted for administration to the gastrointestinal tract of the patient, comprising
lubiprostone or pharmaceutical acceptable salts or metabolites there of and a
pharmaceutically acceptable adjuvant, characterized in that the dosage form is
adapted to release lubiprostone to the lower gastrointestinal tract of the patient.
The dosage form of the invention may be of the delayed release type.
According to one of the embodiments, the formulation of present invention releases
lubiprostone in the colon.
For the present invention active agent would include lubiprostone or pharmaceutically
acceptable salts or its metabolites or tautomers or isomers thereof.
Delayed release dosage form means a dosage form, which provide a time-delay
before significant plasma levels of active agent is achieved.
Lower gastrointestinal tract" means the portion of the gastrointestinal tract between
the regions of duodenum to rectum inclusive.
By "pharmaceutically acceptable" is meant a carrier comprised of a material that is
not biologically or otherwise undesirable.
6

The formulation of the present invention may include
(a) Those in which the lubiprostone, is in a capsule coated with coating which
delays the release
(b) Those in which the lubiprostone is embedded in a matrix from which it is
released by diffusion or erosion;
(c) Those in which the lubiprostone is present in a multiparticulate core;
(d) Those in which there is an impermeable coating provided with an aperture
through which the lubiprostone is released;
(e) Those in which there is a coating of low aqueous solubility;
(f) Those in which there is a semipermeable coating;
(g) Those in which the lubiprostone is present as an ion exchange resin complex;
and
(h) Pulsatile devices from which the lubiprostone is released at specific points in
the gastrointestinal tract.
The above formulations are prepared to release the drug in the lower gastrointestinal
tract.
Other formulations, which, releases the active agent in the lower gastrointestinal tract
are also included within the scope of this invention.
Pharmaceutical^ acceptable excipients include but are not limited to binders,
diluents, lubricants, glidants, surface-active agents, stabilizer, and antioxidant.
The dosage form according to present invention may be tablet, capsules including
soft gelatin capsule, pellet, bead, spheroids, microcapsules, mini tablet, powder,
granules, drug loaded particles, liquids which may include suspension or emulsions
and others. The dosage form may also be a capsule, in which case the active agent-
containing composition may be encapsulated in the form of a liquid or solid (including
particulates such as granules, beads, powders, or pellets). Suitable capsules may be
either hard or soft, and are preferably made up of gelatin, starch, or a cellulosic
material. Two-piece hard gelatin capsules are preferably sealed, such as with gelatin
bands or the like.
The formulation of the present invention may further comprise of stabilizer. It is
known that in the absence of water, the tautomeric compound, lubiprostone, exist
predominantly in the form of the bi-cyclic compound. In aqueous media, it is believed
7

that hydrogen bonding occurs between the water molecule and, for example, the keto
group at the hydrocarbon chain of the lubiprostone, thereby hindering bi-cyclic ring
formation.
Stabilizer such as cyclodextrin, for example,, alpha.,, beta.- or .gamma.-cyclodextrin;
etherified cyclodextrin such as dimethyl-.alpha.-, dimethyl-.beta.-, trimethyl-.beta.- or
hydroxypropyl-.beta.-cyclodextrin; branched cyclodextrin such as glucosyl-, maltosyl-
cyclodextrin; formylated cyclodextrin, cyclodextrin containing sulfur; phospholipid,
triglycerides, non-polar solvents and the like. When the above cyclodextrins are
used, inclusion compound with cyclodextrins may be sometimes formed to enhance
stability.
Alternatively, phospolipid may be sometimes used to form liposome, resulting in
enhanced stability.
The present invention may also comprise medium chain fatty acid triglyceride as
stabilizer. They can be used to increase the bi-cyclic/mono-cyclic ratio. The
triglyceride may be a saturated or unsaturated fatty acid that may have a branched
chain. A preferred fatty acid is a straight chain saturated fatty acid, for example,
caproic acid, caprylic acid, capric acid, lauric acid and myristic acid. Two or more
medium chain fatty acid triglycerides may be used as a mixture.
The composition of the present invention may be dissolved or admixed in the
medium chain fatty acid triglyceride. The amount of the medium chain fatty acid
triglyceride is not limited. Preferred fatty acid is a straight chain saturated fatty acid
for example caproic acid (C6), caprylic acid (C8), capric acid (C10), lauric acid (C12)
and myristic acid (C14). In addition, 2 or more medium chain fatty acid triglycerides
may be used. Even more non-polar solvents, such as commercially available Miglyol
can be employed to increase the bi-cyclic/mono-cyclic ratio.
Any other agent may which can stabilize bicyclic tautomer may also be used as
stabilizer.
The formulation of the present invention may further include other excipients such as
binders, diluents, lubricants, disintegrating agents, glidants, stabilzers, and surface-
active agents. The amount of excipients employed will depend upon how much active
agent is to be used. One excipient can perform more than one function.
8

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,
poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth,
combinations there of and other materials known to one of ordinary skill in the art 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 or tribasic, calcium sulphate, and the like can be used.
Disintegrating agents, which may be used, includes crospovidone, croscarmellose,
sodium starch glycolate and the likes.
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 present formulations may optionally contain a surface-active agent. The
preferred agent is poloaxmer. However, other agents may also be employed such as
dioctyl sodium sulfosuccinate (DSS), triethanolamine, sodium lauryl sulphate (SLS),
polyoxyethylene sorbitan and poloxalkol derivatives, quaternary ammonium salts or
other pharmaceutical^ acceptable surface-active agents known to one ordinary
skilled in the art.
The formulation of the present invention may further comprise of hydrophilic
substance or/and hydrophobic substance.
Hydrophilic substance which may be used in the present invention includes
hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, vinyl
acetate copolymers, polysaccharides as alginates, xanthan gum, Chitosan,
9

carrageenan, dextran and the like, polyalkylene oxides as polyethylene oxide and the
likes, methaacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers,
carbomer (Carbopol(TM)), guar gum, locust bean gum, poly vinyl acetate, polyvinyl
alcohol and the like.
Hydrophobic substance includes acrylates, cellulose derivatives as ethylcellulose,
cellulose acetate and the likes, methaacrylates, high molecular weight polyvinyl
alcohols, waxes, hydrogenated vegetable oil, 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; 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.
A liquid composition for oral administration may contain pharmaceutically acceptable
emulsion, solution, suspension, syrup, elixir as well as generally used inactive
diluent. Such composition may contain, in addition to the inactive diluent, adjuvants
such as suspending agents, sweetening agents, flavoring agents, preservatives,
solubilizer, anti-oxidants, stabilizer and the like. The details of the additives may be
selected from those described in any general textbooks in the pharmaceutical field.
Such liquid compositions may be directly enclosed in soft capsules. However, the
selection of a diluent other than those mentioned above, which the bi-cyclic/mono-
cyclic compound may be dissolved or admixed in, must carefully be selected so as
not to affect the bi-cyclic/mono-cyclic ratio. The liquid formulation may also be
formulation in such a way that the active agent is released in the lower
gastrointestinal tract.
Further in accordance with the present invention the formulation releases the drug in
the lower GIT. Those agents, which may delay the release of the active agent, can
be used. The most preferred method is by coating. Preferred coating materials are
those, which does not dissolves in stomach. The coatings therefore only begin to
dissolve when they leave the stomach and enter the lower gastrointestinal tract. A
thickness of the coating depends upon the time of delay. For example a thick layer of
coating is provided which will dissolve in about 3-4 hours thereby allowing the
capsule underneath to breakup only when it has reached the terminal ileum or the
colon.
10

Delayed release formulation may comprise a core, and a coating. The core may
include lubiprostone, and excipients, notably a lubricant, and a binder and/or filler,
optionally glidants, optionally stabilizer as well as other excipients. The coating may
be, for example, a semi-permeable coating to achieve delayed release of
lubiprostone. The coating may comprise of a water-insoluble film-forming polymer,
together with a plasticizer and a water-soluble polymer. The water-insoluble film-
forming polymer can be a cellulose ether, such as ethylcellulose, a cellulose ester,
such as cellulose acetate, polyvinylalcohol, sodium alginate, acetate trimellitate
(CAT), hydroxypropylmethyl cellulose phthalate (HPMCP), polyvinyl acetate
phthalate (PVAP), cellulose acetate phthalate (CAP), shellac, polyacrylates etc. A
suitable film-forming polymer is ethylcellulose (available from Dow Chemical under
the trade name ETHOCEL).
In one of the embodiments the coating material is methacrylic acid copolymers. The
anionic EUDRAGIT® methacrylic acid copolymers can be used to avoid release of
lubiprostone in the stomach and release in upper gastrointestinal tract. The
EUDRAGIT® methacrylic acid copolymers of grades L, S and FS contain carboxylic
groups and are thus anionic in character. Enteric coatings with these EUDRAGIT®
grades release the active ingredient between pH 5.5 and >pH 7, allowing Gl targeting
from the small intestine to the colon. The release of active ingredients also depends
on the thickness of the film coatings and the solubility characteristics of the active
ingredient under physiological conditions.
The release of lubiprostone in the lower gastrointestinal tract can be achieved by
using different grades of methacrylic acid copolymers.
For release in the duodenum: EUDRAGIT® L 100-55 or the aqueous dispersion
EUDRAGIT® L 30 D-55 dissolve at pH values above 5.5.
For release in the jejunum to ileum:
EUDRAGIT® L dissolves at pH values above 6.0. Mixtures of EUDRAGIT® L and
EUDRAGIT® S dissolve in a pH range from 6.0 to 7.0.
For Colonic delivery:
EUDRAGIT® S and EUDRAGIT® FS 30 D dissolve at pH 7.0.
All polymer types can be mixed with each other in different ratios to some extent,
thus making it possible to achieve drug release at intermediate values.
11

The coating composition may include other excipients such as plasticizer, anti
tacking agents etc.
The pharmaceutical composition of the invention can be manufactured by various
methods known in the art such as by dry granulation, wet granulation, melt
granulation, direct compression, double compression, extrusion spheronization,
layering and the like.
According to one of the embodiments the formulation of the present invention may be
prepared by filling lubiprostone and other excipients in capsule and then coating the
capsule with delayed release coating. The capsule may be hard gelatin or soft gelatin
capsule.
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.
It is to be understood that while the invention has been described in conjunction with
the preferred specific embodiments thereof, that the foregoing description as well as
the examples that follow are intended to illustrate and not limit the scope of the
invention. Other aspects, advantages, and modifications within the scope of the
invention will be apparent to those skilled in the art to which the invention pertains. 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 20th day of February 2008

12