Note: Descriptions are shown in the official language in which they were submitted.
CA 02304516 2000-03-28
WO 99/16436 PCT/GB98/02933
1 -
This invention relates to use of a nitric oxide
donor for the treatment of inflammatory bowel disease
(IBD) and irritable bowel syndrome (IBS) and to post-
gastrically delayed release oral (DRO) and rectally
administrable compositions containing a nitric oxide or a
nitric oxide donor.
IBS is a functional bowel disorder of abdominal pain
and altered bowel habit. Pain is characteristically
relieved by defecation and may be associated with
increase or decrease in stool frequency, alterations in
stool consistency, straining or urgency, a sensation of
incomplete evacuation, passage of mucus, or abdominal
distension. The pathophysiology is poorly understood
despite the fact that about a quarter of the population
in the UK may exhibit the symptoms.
IBD covers chronic non-specific inflammatory
conditions of the gastro-intestinal tract, of which the
two major forms are Crohn's disease and ulcerative
colitis including protococolitis, ileocolitis, protitis
and pouchitis. The aetiology of these diseases is
uncertain. Many inflammatory mediators have been
proposed including prostanoids, leukotrienes, platelet
activating factor, cytokines, and free oxygen radicals.
Although specific inhibitors of most of these have been
tried in experimental models, the most effective drugs
currently available for these diseases have a broad
activity against inflammatory processes.
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WO 99/16436 2 PCT/GB98/02933
Crohn':~ disease is characterised by thickened areas
of the gastro-intestinal wall, with inflammation
extending through all layers, deep ulceration and
fissuring of: the mucosa, and the presence of granulomas.
Affected areas may occur in any part of the gastro-
intestinal tract, although the terminal ileum is
frequently involved, and they may be interspersed with
areas of relatively normal tissue. Symptoms depend on
the site of disease but may include abdominal pain,
diarrhoea, fever, weight loss and rectal bleeding.
In ulcerative colitis, the disease is limited to the
colon and rectum. Inflammation is superficial but
continuous aver the affected area and granulomas are
rare. In mild disease, the rectum alone may be affected
(proctitis). In severe disease ulceration is extensive
and much of the mucosa may be lost, with an increased
risk of toxic dilatation of the colon, a potentially
life-threatening complication.
Numerous compounds have been examined in the last
twenty years to find effective measures for the treatment
of IBD. Such compounds include azathioprine, arsenicals,
disodium cromoglycate, metronidazole, lignocaine, 5-
aminosalicyclic acid (5-ASA), fish oils, thalidomide and
cyclosporin. The wide diversity of treatments is an
indication of the complexity and intransigence of this
condition.
There have been a number of different theories of
how Crohn's disease is initiated. Surgically resected
CA 02304516 2000-03-28
WO 99/16436 3 PCT/GB98/02933
specimens from patients with Crohn's disease when
perfused with resin, show substantial damage to the
normal blood supply - particularly in the areas which are
macroscopically abnormal (Lancet 1989, ii:1057-1062).
This was coined ~multifocal gastrointestinal infarction'.
Similar pathological changes are seen in animal models
when the blood supply is obstructed (Gastroenterology
1992; 102(51:1591-1596). Granulomas, the patholoqical
hallmark of Crohn's, appear to form mainly within the
walls of blood vessels (Gastroenterology 1991;
100(5):1279-1287). Vascular damage with rupture of
capillaries occurs early on in the damage process, even
before the wall is infiltrated by inflammatory cells (Gut
1993; 34:375-381) .
Glycer~,rl trinitrate and other organic nitrates have
been the mainstays of therapy in cardiovascular disease
for many years. In recent years, it has been found that
these compounds are actually prodrugs for nitric oxide.
This in turn has been found to have two main roles: as a
vasodilator and as an antiplatelet agent (The American
Journal of Cardiology Volume 70, Sept. 24, 1992: A
Symposium Nitroglycerin Therapy). Glyceryl trinitrate
and other nitric oxide donors were also found to be
useful in tile treatment of anal fissures (WO-A-9532715).
In Nature Medicine, Jan. 1997; (3)1: 30-31, it is
reported that nitric oxide levels in the intestines were
more than 11)0 times higher in ulcerative colitis patients
and 30 time:3 higher in patients with Crohn's as compared
to normal patients. In Pharmacol. Rev. 1991; 43:109-142
CA 02304516 2000-03-28
P~005P~:T IPE 08/99
nitric oxide wa~> suggested as an inhibitory nonadrenergic
noncholinergic (~IANC) neurotransmitter which cc~~ld play an
important role i.n the autonomic innervation of smoc=:~
muscle, in the gastrointestinal tract, the pelvic viscera
and the airways. In US-A-5574068, use of S-nit=osc_hiols
(nitric oxide donors) were proposed for disorders which
involve non-vascular smooth muscle such as respiratory
disorders, gastrointestinal disorders, urological
dysfunctions, impotence, uterine dysfunction and premature
labour.
DE-A-4420523 disr_loses the treatment and prophylaxis
of systemic inflammatory response syndrome (SIRS) by
administration of a nitric oxide donor. Specified
conditions which can result in SIRS include ulcerative
colitis and Crohn's disease and specified nitric oxide
donors include nitroglycerin (i.e. glyceryl trinitrate) and
isosorbide dinit:rate. Reference is made to both oral and
rectal administration but there is no reference to delayed
or sustained release ar any indication that the donors
would be useful to treat ulcerative colitis or Crohn's
disease by topical administration to the disease site.
EP-A-03047..0 discloses the treatment of colic pain by
a combination of: an N-alkylscopolaminium salt and
nitroglycerin
EP-A-066109:5 discloses a hydrogel-type sustained-
release preparat:ion far releasing a drug in the lower
digestive tract. Exemplified drugs include isosorbide
dinitrate and nitroglycerin (as cardiocirculatory system
drugs ) .
JP-A-06227969 discloses improving the enteric
properties of sparingly water-soluble drugs by suspending
crystals of the drugs in air, treating the suspended
AMENDED SHEET
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o7p~5P~T :?E 03/99 5
crystals with solutions or suspensions of an enteric
polymer and subsequently drying the treated particles.
Specified drugs include isosorbide nitrate.
US-A-4428925 disr_loses as oral sustained release
dosage form of qlyceryl trinitrate. Reference is made to
the treatment of: angina pectoris and other cardiac related
conditions.
US 5632981 discloses a nitric oxide-releasing
composition containing a protein or other biopolymer to
which NzOz- functional groups are bound. A number of nitric
oxide-releasing compounds are acknowledged in the
introduction including glyceryl trinitrate and sodium
nitroprusside used as nitrovasodilators and S-nitroso-N-
acetylpenicillamine for inhibiting DNA synthesis. ---
Discussion of the users of the biopolymer-bound compositions
include a reference to nitric oxide being implicated in
gastric motility.
WO-A-9003776 discloses an excipient for use in the
buccal administration of drugs. Exemplified drugs include
nitroglycerin.
WO-A-93120Ei8 discloses the use of S-nitrosothiols to
relax r_on-vascular smooth muscle. Exemplified conditions
to be treated include "gastrointestinal disorders" as
exemplified by <~chalasia, diarrhoea, dumping syndrome and
irritable bowel. Reference is made to the use of
sublingual nitroglycerin to alleviate gastrointestinal
muscle spasm. :Ct is :reported that nitroglycerin is not
used clinically because of its systemic side effects and
also that it is significantly less effective as a smooth
muscle relaxant than S-nitrosothiols. Routes of
administration for the S-nitrosothiols include oral and
rectal.
AMENDED SHEET
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P7005Pr:T IPE 09/99 ja - .. . ..' ..
WO-A-9505172 discloses the use of vasodilators to
modulate sexual response. Specified vasodilators include
nitroglycerin and amyl nitrate. Routes of administration
of the vasodilators include rectal administration but oral
administration i.s staged to be contraindicated by
presystemic elimination.
WO-A-9725979 discloses localized drug release in the
gastrointestinal. tract by use of a liquid-adsorbing coating
on a drug-containing core. The coating comprises a water-
soluble hydrophilic particulate material embedded in a
water-insoluble carrier. The particulate matter adsorbs
liquid to form channels providing access to the core.
Exemplified carriers include Eudragit E, NE, RL and RS.
Reference is made to the treatment of IBD and IBS.
Specified drugs include isosorbide dinitrate, isosorbide ---
mononitrate and nitroglycerin but the only activity
specified for these compounds is as anti-hypertensives.
Vidal 1993 includes the product Langoran LPT'~ (Marion
Merrel Dow) which contains isosorbide dinitrate in the form
of gelatin capsules containing microgranules of isosorbide
dinitrate. The capsules have a delayed release of 1 hour
and a sustained release of 8 to 12 hours depending on the
isosorbide dinit:rate strength. It is apparent from the
stated formulations that the capsules are intended to
provide a systemic effect and do not provide sustained
release of isosorbide dinitrate in the lower intestinal
tract. They are: not intended to treat IBD or IBS and would
not be suitable for that purpose.
Rote Liste 1997 includes the product Turimonit RetardT'~
(Jenapharm) which a contains isosorbide mononitrate in the
form of delayed and/or sustained release tablets. It is
~~r~E~!~7Et7 SHEET
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P7UOSPr:T iPE u9/94 5b ~.. ,.' ..'
apparent from the stated formulations that the tablets are
intended to provide a systemic effect and do not provide
sustained release of isosorbide mononitrate i~ the lower
intestinal tract. They are ::ot intended to treat IBD or
IBS and would not be suitable for that purpose.
Rote Liste 1997 also includes the product Nitro Mack
RetardT'" which contains glycerol trinitrate in the form of
delayed release capsules. It is apparent from the stated
formulations that the capsules are intended to provide a
systemic effect and do not provide sustained release of
glycerol trinit:rate in the lower intestinal tract. They
are not intended to treat IBD or IBS and would not be
suitable for that purpose.
The inventors have now discovered that nitric oxide
and physiological derivatives thereof can be used topically
to treat both I:BD and IBS at the disease site. The nitric
oxide is delivered in vivo classically by a nitric oxide
donor such as is used to treat angina pectoris. However
nitric oxide could also be introGUCed directly to the
intestine, such as in the form o. a gas or dissolved gas.
In a first aspect of the invention, there is provided
a post-gastric delayed release oral (DRO) pharmaceutical
composition for the treatment or prophylaxis of IBD or IBS,
said composition comprising an active compound selected
from nitric oxide, nitric oxide donors and
pharmacologically acceptable der=vatives thereof and a
pharmaceutically acceptable carrier or vehicle providing
sustained release of the active compound in the lower
intestinal tract.
AMENDED SHEET
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P7005P~:': LPE 09/99 jC ~ ~ .. ..
In a 'second aspect of the invention, there is pro=vided
use of ni_ric oxide or a nitri: oxide donor or
phar~nacological:.,i acceptable deri native th=r?o', in th=
preparation of a medicament for the treatment c.
S prophylaxis of :CBD or IBS by topical action at the disease
site.
A further aspect of the invention is a method for the
treatment of IBD or IBS comprising topically administering
to the disease site in the patient a nitric oxide or a
nitric oxide donor or physiologically acceptable derivative
thereof.
The nitric oxide donor can be selected from the group
of compounds known as nitrovasodilators and is preferably
an organic nitrate or nitrite such as glyceryl trinitrate,
amyl nitrate, o~~tyl nitrate, propatylnitrate, sorbide
nitrate, trolnitrate (phosphate), ethylene glycol
dinitrate, glyc~~ryl 1,2-dinitrate, glyceryl 1,3-dinitrate,
glyceryl 1-mononitrate, butane 1,2,4-triol nitrate,
mannitol hexanitrate, pentaerythrityl tetranitrate,
pentaerythrityl trinitrate, isosorbide dinitrate,
isosorbide mononitrate, erythrityl tetranitrate, or other
organic esters of nitric acid of the formula R-[C-0-NOZ];~,
where R is an alkyl, cycloalkyl, or alkenyl group having
from 1 to 18 carbon atoms or an aromatic group having from
6 to 18 carbon atoms and where x is an integer of from 1 to
5, or a combination of two or more of the foregoing. Other
preferred nitric oxide donors are the S-nitrosothiols such
as S-nitroso-N-acetylpenicillamine (SNAP), S-
nitrosoglutathione (C-~SNO) (described in more detail in
Analytical Biochemistry 249, 1-9 (1997)), S-nitroso-N-
acetylcysteine, S-nit.rosocysteine, S-nitroso-homocysteine,
S-nitrosopantathoeine~ derivatives and S-nitraso-captopril.
AhACNDE~ c~~~r-~
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WO 99/16436 6 PCT/GB98/02933
It is not known how the nitric oxide or its
derivatives improve the disease state, but the
inflammation is decreased.
5 Although it is thought that nitric oxide acts either
directly o:r indirectly to help resolve the disease, a
derivative of nitric oxide such as the S-nitrosothiols
may be involved in the mechanistic pathway. Therefore
physiological derivatives of nitric oxide which are
10 metabolised from or as a result of nitric oxide are also
within the scope of the invention. The term nitric oxide
donor also encompasses pharmaceutically acceptable salts
thereof .
15 The nitric oxide donor is preferably delivered to
the small or large intestine, rectally or via a post-
gastric DR(~ composition. In this way the active agent
can be delivered to the disease site and is believed to
exhibit a beneficial topical action against both IBD and
20 irritable bowel system. Furthermore since systemic
absorption from the intestine of glyceryl trinitrate and
other nitric oxide donors is limited by a high first pass
hepatic metabolism, the side effects such as headaches
and nausea classically present with nitric oxide is
25 minimised. Thus high doses of nitric oxide donor can be
delivered t:o treat the disease without the normal
concomitant: side effects. In this respect glyceryl
trinitrate is particularly preferred.
30 A preferred form of the invention provides a delayed
and sustained-release pharmaceutical composition for oral
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WO 99/16436 ~ PCT/GB98/02933
administration. By delayed release we mean that release
is substantially post-gastric, and by sustained release
we mean that the total release of the nitric oxide donor
is slow and sustained over a period of time, as opposed
to being released as a bolus. The sustained release of
the nitric oxide donor will preferably be over a 2 to 12
hour period, preferably a 4 to 8 hour period, such as a 4
to 6 hour period.
According to one embodiment of the present
invention, the pharmaceutical composition takes the form
of an enema formulation such as a liquid or foam enema
which is rectally administered to the lower colon.
Useful enema formulations comprise an effective amount of
nitric oxide donor dissolved or dispersed in a suitable
flowable carrier vehicle, such as deionised and/or
distilled water. The formulation can be thickened with
one or more thickeners, such as xanthan gum or carbomer,
can contain a buffer, and can also comprise an effective
amount of a lubricant such as a natural or synthetic fat
or oil, e.g. a tris-fatty acid glycerate or lectithin.
Non-toxic non-ionic surfactants can also be included as
wetting agents and dispersants. Unit doses of enema
formulations can be administered from pre-filled bags or
syringes. In the case of a pressurised enema formulation
the carrier vehicle may also comprise an effective amount
of a foaming agent such as n-butane, propane or i-butane.
Such formulations can be delivered from a preloaded
syringe or ;pressurised container, so that the vehicle is
delivered to the colon as a foam, which inhibits its
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WO 99/16436 8 PCT/GB98/02933
escape from the target site. Enema foams may also
comprise expanding agents and foam-stabilisers.
The viscosity of the enema is preferably 3 to 5
milliNewton metres (mNm) as measured using a RheomatT'" 108
rotary viscometer' (50 to 85 Pa.s) and the pH is
preferably 3.5 to 5.5.
The DRO composition of the invention are ideally
coated so as to release the unit dosage form in the lower
intestinal tract, e.g. in the mid to distal small bowel
and/or in the colon of the patient. Enteric coatings
such as acrylic or methacrylic acid resins remain intact
in the stomach, but dissolve and release the contents of
the dosage form once it reaches the region of the
intestine where the pH is optimal for dissolution for the
coating used.
The majority of the release will be targeted to the
part of the small intestine or colon where the active
disease is prevalent and this varies for Crohn's disease
and ulcerative colitis. Thus typically for an enteric
coated capsule, the enteric coating should dissolve in
the pH of the jejunum, ileum or colon. Thereafter
preferably sustained release, of the nitric oxide donor
will take place.
The dosage of nitric oxide donor such as glyceryl
trinitrate in a rectally administrable composition
typically an enema or foam enema would be 1 to 50 mg,
preferably 1 to 15 mg.
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WO 99/16436 9 PCT/GB98/02933
Aqueous film-coating technology is advantageously
employed for the enteric coating of pharmaceutical dosage
forms. A useful enteric coating is one that remains
intact in the low pH of the stomach, but readily
dissolves when the optimum dissolution pH of the
particular coating is reached. This can vary between pH
3 to 7.5 depending on the chemical composition of the
enteric coating. The thickness of the coating will
depend on the solubility characteristics of the coating
material and the site to be treated.
Preferably the unit dosage of nitric oxide donor,
such as isosorbide dinitrate or glyceryl trinitrate, in a
rectally ac3ministrable (e.g. enema) or DRO composition is
1 to 50 mg, more preferably 1 to 30 mg, more preferably
still 1 to 15 mg. The inventors are presently using 3
mg glycery:l trinitrate in their trial. The total daily
dose for a 70 kg patient for any composition would be
from 3 to :100 mg, preferably up to 30 mg.
In one embodiment of the invention, a delayed
release oral formulation is provided in which an enteric
coated capsule containing a nitric oxide donor of the
invention :has a coating, thickness of coating and
dissolution profile as described in EP-A-0097651 (the
contents of which are incorporated herein by reference).
A delayed-release formulation can also be achieved by
coating a ;powder or microgranular formulation of a nitric
oxide donor of the invention with, for example,
ethylcellulose or an acrylic resin based on acrylic and
methacrylic acid esters containing a low content of
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WO 99/16436 1 ~ PCT/GB98/02933
quaternary ammonium groups at a predetermined molar
ratio. Suitable resins include EUDRAGITTM L, S, RL and
RS. The coated microgranules or material may then be
compressed into tablets or packed into hard gelatin
capsules suitable for oral administration. Suitable
coatings are: thicknesses to achieve this sustained
release are disclosed in EP-A-0572486 (incorporated
herein by reference) .
A sustained release of the nitric oxide donor can
also be ach~.eved by incorporating it into a saturated
polyglycoli::ed glyceride excipient comprising a mono-,
di- and tric~lycerides and o~ mono- di-fatty acid esters
of polyethy7.ene glycol (PEG) hydrophobic matrix. The
polyglycoli.:ed glyceride can be adapted to have a
different melting point and hypophilic-lipophilic balance
(HLB) depending on the type and proportion of
triglyceride: and fatty acid esters of PEG used. For
example, foz- a more lipophilic nitric oxide donor the
melting point/HLB could suitably be 42/12, 44/14 or
50/13. On t:he other hand, for more hydrophilic nitric
oxide donor such as various water soluble salts, the
melting point/HLB could suitably be 46/07, 48/09, 53/10
or 50/13. A particularly preferred melting point/HLB,
particularly for use with isosorbide dinitrate and
glyceryl trinitrate is a mixture of 42/12 and 50/13, or
50/13 alone. An example of a commercially available
polyglycolired excipient for use with the invention is
GelucireTM (available from Gattefosse, France) .
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P7005PCT IPE 08/99 1 1
' _ A polyacrylic acid deri~~ative can also be used to
achieve sustained release of the nitric oxide donor by,
for example, forming a nitric oxide donor - pclyacrylate
complex. A preferred polyacrylate is a carbomer, such as
Carbopol (avai.lable from B.F. Goodrich). Carbomers are
synthetic, high molecular weight, non-linear, polymers of
acrylic acid, cross-linked with polyalkenyl polyether. A
sustained release nicotine-carbomer complex in an enteric
coated capsule: is described in WO-A-9728801 (incorporated
herein by refe:rencej and the same technology would be
applicable to the present invention.
As acidic: material for the coating of oral
compositions of the invention for delayed-release,
anionic polymers, particularly anionic acrylate polymers
and especially anionic polymers synthesised from
methacrylic acid and methyl methacrylate, may be used.
Carboxyl groups in such polymers render the material
capable of foi:ming ;salts in alkaline environments in
which they are' sparingly soluble while in the acid to
neutral pH range the coatings are substantially insoluble
and substantially impermeable thus protecting the active
ingredient contained within from gastric acids.
The coatings may be applied conventionally,
typically as a lacquer or solution containing the acidic
material from which the solvent or carrier is then
evaporated.
A particularly suitable acidic material for coating
the compositions of the invention for lower bowel
~.i'.~:LJ~i:.J ~.;;JC~T
CA 02304516 2000-03-28
WO 99/1643b 12 PCT/GB98/02933
treatment is the anionic methacrylate polymer sold under
the registered Trade Mark EUDRAGIT S by Rohm Pharma GmbH
of Darmstadt, Germany. Capsules coated with EUDRAGITT"'
S100 disintegrate in the ascending colon of the patients.
EUDRAGITTM :~ is a copolymer of methacrylic acid and methyl
methacrylate in which the ratio of free carboxyl groups
to ester groups is approximately 1:2 and having a mean
molecular weight of 135,000. Coatings of acidic
materials, such as that sold as EUDRAGIT L (composition
as EUDRAGIT S but having a carboxyl/ester ratio of 1:1),
may be used in the coating of tablets or capsules to
release active agents in the small intestine, although
they may be applied in much greater thicknesses than was
hitherto conventional thereby delaying release of the
active agent until the tablet or capsule reaches the
large intestine. It will be apparent to the skilled
person that mixtures of substances, such as EUDRAGITTM S
and EUDRAGI'T L, may be used as coating materials.
In general coating thicknesses of 25 to 200 ~.m, and
especially '75 to 150 um, are preferred using 3 to 25 mg,
preferably ~3 to 15 mg, of acidic coating material per cm2
of tablet o:r capsule surface. The precise coating
thickness wall however depend upon the solubility
characteristics of the acidic material used and site to
be treated.
Together with the acidic material, the coating
material may contain additives such as colouring agents,
plasticiser;~, opaque film coatings, gloss producers and
auxiliary materials (e. g. talc).
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WO 99/16436 13 PCTlGB98/02933
The provision of the coating to the compositions of
the invention may be achieved in conventional manner,
e.g. by the use of spraying, fluidized bed, immersion
tube and immersion blade techniques. (See for example D.
Dreher "Film coatings on acrylic resin basis for dosage
forms with controlled drug release" Pharma International
1/2 (1975) 3 }. Preferably, the coating is applied from
aqueous suspension.
The coating can, and usually will, contain
plasticises and possibly other coating additives such as
colouring agents, gloss producers, talc and/or magnesium
stearate as well known in the coating art. In
particular, anionic carboxylic acrylic polymers usually
contain 10 to 25% by weight of a plasticises especially
diethyl phthalate, although the presence of such a
plasticises may not be necessary when using an aqueous
suspension for coating.
Usually, the capsule into which the coated material
is loaded will be a soft or, preferably, hard gelatin
capsule although other capsules which will dissolve in
the small intestine can be used. The capsule is coated
with an enteric coating which will protect it during
passage through the stomach. Any conventional enteric
coating material which is soluble in the small intestine
can be used, e.g. cellulose acetate phthalate, hydroxy
propylmethyl cellulose phthalate or initially ethyl
cellulose followed by polyvinyl acetate phthalate, but it
is preferred to use an anionic polymer having an
appropriate dissolution profile. The presently preferred
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WO 99/16436 14 PCT/GB98/02933
polymers are anionic carboxylic polymers, e.g. EUDRAGITT'"
L.
In addition to the nitric oxide donor ingredient,
5 the tablet or capsule cores (e.g. in the form of
microgranules) for the compositions of the present
invention may also contain additives such as fillers
(e. g. lactose or dicalcium phosphate), binders (e. g.
starch or polyvinylpyrrolidone), lubricants (e. g.
10 magnesium s~tearate, stearic acid or talc) and
disintegrants (e. g. alginic acid or sodium starch
glycolate). The tablet or capsule cores may be prepared
in a conventional manner.
15 It is preferable to include a suitable disintegrant,
such as ExplotabTM (a brand of sodium starch glycollate
made by K&R: Greef ) , or Primoj elTM ( from AVEBE,
Netherlands) in the orally administered compositions
according to the invention.
In a particularly preferred DRO form of the
invention, a capsule containing a nitric oxide donor,
such as glyceryl trinitrate, in a polyglycolized
excipient .;uch as GelucireTM, is enteric coated, such as
25 by Eudragit:TM L (dissolving at pH6.8) or EudragitT"' S for
release in the mid to distal small bowel and/or colon.
The invention will now be described by way of
example on7.y in which the attached figure is a graph of
the release: profiles of isosorbide dinitrate from various
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WO 99/16436 15 PCT/GB98/02933
capsules containing GelucireTM of different melting
points/HLB.
2% w/w isosorbide dinitrate in lactose powder (120 mg =
30 mg isosorbide dinitrate) was incorporated into the
melted Gelucire'" and dispersed into size 1 opaque hard
gelatin capsules. Initially six formulations were
prepared using Gelucire"" (G) 42/12, 44/14, 53/10, 53/13,
46/07 and 48/09 so that each capsule contained 120 mg of
the isosorbide pawder dispersed in 440 mg of Gelucire'"".
Subsequently additional formulations were prepared
using mixtures of two Gelucires'". These were 642/12 1
part plus 650/13 2 parts (33%), 642/12 1 part plus 650/13
6 parts (15%), and 642/12 1 part plus 650/13 9 parts
(10%) .
The dissolution profile of these capsules were
tested using a ErwekaTM Tablet dissolution tester model
DT80.
Peak investigation was determined from which the
amount (in mg) of isosorbide dinitrate present in the
sample was calculated. The results are shown in the
attached figure. A good release pattern over a 4-6 hour
time period., (and released 30 mg of isosorbide dinitrate
from the Gelucire'~) was achieved by the mixture of
GelucireT'" 42/12 plus Gelucire'" 50/13, 10% and 15%. These
are indicated on the attached figure as 642/50 (10%) and
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WO 99/i6436 16 PCT/GB98/02933
642/50 (15%~). The capsule containing Geluc~.reTM 50/13
also gave a. good sustained release of isosorbide
dinitrate.
ale Z
Gelatin capsules containing 30 mg isosorbide dinitrite
and Gelucire'" 42/12 plus Gelucire'" 50/13 (10% and 15%)
were prepared as outlined above and coated using
EudragitTM-:L.
Example 2 was repeated, but using 3 mg glyceryl
trinitrite in place of the 30 mg isosorbide dinitrate.
A pre7_iminary clinical trial was conducted to assess
the effect of oral glycerol trinitrate (GTN) in active
Crohn's disease. 14 patients were treated for 6 weeks
with 2 capsules of Example 3 (6 mg GTN) twice daily and
the CDAI assessed at commencement of the trial and after
3 and 6 weeks. The treatment was withdrawn over the
25 subsequent 4 weeks to enable the patients to assess the
effect upon their symptoms. Five of the patients had
ileal Crohn's disease, two patients had large bowel
Crohn's dis3ease and seven patients had Crohn's disease at
both sites. The CDAI was greater thanel 50 in only 7 of
the patieni:s at commencement of the trial. Nine of the
patients were receiving steroids. There was some change
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WO 99/16436 1 ~ PCT/GB98/02933
in the steroid dase in three of them during the course of
the trial (one was on a reducing dose before entry; two
had an increase in steroids during the trial). One
patient had intra-articular steroids for an arthritis and
two patients discontinued their steroids on commencement
of the trial. These variations in treatment about the
time of and during the trial made it a little difficult
to draw firm conclusions.
The GTN was very well tolerated. One patient had
vague headaches for a couple of days, and a second
patient had a fainting episode but both were able to
continue with the treatment. The CDAI was lower at 6
weeks than on commencement in ten patients and the
reduction in CDAI appeared clinically significant in 6 of
these patients, About half of the patients had a
reduction in stool frequency but there was little effect
on the pain score.
Five patients requested to continue with the
treatment at the end of the trial. All were women with
ileal Crohn's disease; two also had small bowel
involvement proximal to the terminal ileum; two had'
recurrent ileal Crohn's disease after surgical
resection; and two had colonic involvement. Four of
these 5 patients increased the daily dose to 6 capsules
(18 mg GTN) without side effects. All 5 patients
reported that their symptoms had improved whilst taking
GTN over this period and noticed a reduction in episodes
3 0 of pain .
