Note: Descriptions are shown in the official language in which they were submitted.
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TREATMENT OF CHRONIC INFLAMMATORY DISORDERS
OF THE GASTROINTESTINAL TRACT
Joel Bolonick
Alan Stewart
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to a composition and
method for treatment of chronic inflammatory disorders of
the gastrointestinal tract in mammals.
Prior Art
Chronic inflammatory disorders of the
gastrointestinal tract are generally grouped under the
heading of inflammatory bowel disease, although the
disease can affect any part of the gastrointestinal tract
from the esophagus to the large intestine. Inflammatory
bowel disease is of unknown etiology, although
psychological, immunologic, and genetic sources have been
discussed as possible etiologic factors. The
gastrointestinal inflammation associated with inflammatory
bowel disease causes a range of symptoms of increasing
severity and with a variety of intestinal and
extraintestinal manifestations.
The manifestations of chronic inflammatory bowel
disease range from mild to very severe, the more severe
including colitis, characterized by an inflammatory
reaction involving primarily the colonic mucosa, and
Crohn's disease, characterized by inflammation Gh~oughout
the gastrointestinal tract. The clinical features o.f
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ulcerative colitis and Crohn~s disease can be similar.
Characteristic symptoms include abdominal pain, straining,
diarrhea with or without blood, fatigue, fever, and weight
loss. Even the mildest of these conditions can carry
obvious emotional and psychological burdens. The quality
of life of an affected individual can be significantly
reduced.
Methods of treatment of inflammatory bowel disease
generally involve drug therapy directed towards the
suppression of gastrointestinal inflammation. Of the
anti-inflammatory drugs, adrenal corticosteroids such as
prednisone and prednisolone have been found to be the most
efficacious treatment of Crohn~s disease and ulcerative
colitis. However, the effectiveness of corticosteroids in
relieving the symptoms of gastrointestinal inflammation is
often accompanied by unfortunate steroid side effects,
including hair loss, increased water and food intake,
weight gain, and immunosuppression. These systemic side
effects can develop after even short-term treatment.
Thus, a treatment that is effective in controlling tie
symptoms of gastrointestinal inflammation but with minimal
systemic effects has been sought.
Recent investigations have studied the efficacy of
budesonide, a corticosteroid analogue with low systemic
bioavailability, as a treatment for inflammatory bowel
disease. Budesonide has been found to be efficacious when
used as an enema to treat colitis. (Lofberg et al.,
Alimentary Pharmacology and Therapeutics, 8(6):623-629
(1994).] The drug has also been used in clinical trials
as a treatment for Crohn~s disease. Administered in place
of a corticosteroid such as prednisone or prednisolone,
budesonide minimizes systemic side effects associated with
corticosteroid treatment.
A recent clinical trial [Rutgeerts et al., The New
England Journal of Medicine, 331(13):842-845 (1994)]
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compared the efficacies and safeties of prednisolone and
budesonide in treating Crohn's disease. Granular
budesonide Was administered in a controlled-release
capsule directed for ileal release in a dosage of 9 mg per
day for eight weeks and then 6 mg per day for two weeks.
The subjects treated with budesonide demonstrated fewer
systemic side effects and less adrenal-suppression than
those treated with prednisolone. However, budesonide was
found to be less efficacious than prednisolone in reducing
the symptoms of Crohn's disease.
In another clinical trial investigating the
safety and efficacy of budesonide in treating Crohn's
disease (Greenberg et al., The New England Journal of
Medicine 331(13):836-841 (1994)), groups of subjects
received two daily dosages totalling 3, 9, or 15 mg
of budesonide per day. The dosage was administered in
a formulation of microgranules of budesonide contained
in a controlled-ileal-release gelatin capsule.
Greenberg et al. found 9 mg to be the lowest effective
dose for induction of remission of Crohn's disease.
Greenberg et al. additionally found that at such a dose
steroid-related side effects, though less severe than
those associated with prednisone, were present in a
significant proportion of the subjects.
A treatment effective both in treating
gastrointestinal inflammation and in reducing the systemic
side effects associated with corticosteroid treatment is
still being sought.
SUNQ~IAR.Y OF THE INVENTION
3fl The present invention provides an oral formulation
for treating gastrointestinal inflammation that includes
an effective amount of budesonide suspended in an edible
oil, typically a vegetable oil such as avocado oil. In an
embodiment of the invention, the suspension of budesonide
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is encapsulated in a controlled-release coating for
release in a specific portion of the gastrointestinal
tract.
A method for treating gastrointestinal inflammation
in mammals is also provided. The method includes orally
administering a composition of this invention to the
mammal. In one embodiment, an initial dosage is
administered daily for.about two to four weeks and the
dosage is subsequently tapered, generally at about two
week intervals, in response to a reduction in symptoms.
The reduction in dosage can be from about 1/3 to about 1/2
of the initial dosage until a minimum dose that controls
symptoms is determined.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an oral formulation of
budesonide for treatment of gastrointestinal inflammation.
The formulation effectively controls the symptoms of
inflammatory bowel disease.at a lower dosage than the
prior art formulations, thus minimizing the side effects
associated with corticosteroid treatment. A method of
treatment is also provided.
An oral formulation of this invention for treating
gastrointestinal inflammation includes an effective amount
of budesonide suspended in an. edible oil. The terms
"gastrointestinal inflammation", "inflammatory bowel
disease", and "inflammation of the gastrointestinal tract"
are used interchangeably herein to mean inflammation of
any portion of the gastrointestinal tract, from the
esophagus to the sigmoid flexure or the termination of the
colon in the rectum. The inflammation can be acute, but,
generally, the composition of this invention is used to
treat chronic conditions.
Budesonide is a corticosteroid manufactured by Astra
Draco (Lund, Sweden). Budesonide is commercially
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available as a granular powder that can be suspended in an
oil without further processing. However, additional
processing to ensure that all particles are of a suitably
small size for preparation of a suspension can be
performed. Such processing can include sieving of the
granules to obtain those of the desired size or further
powdering or milling to minimize the presence of larger
granules.
The budesonide is suspended in an edible oil. Any
edible oil is suitable for use in the formulation. In
general, the oil is liquid at room temperature and
somewhat below room temperature. Conveniently, the oil is
a vegetable oil. However, fish oils and other edible
animal oils also can be used. Suitable edible oils
include those vegetable oils that are recommended for
dietary uses such as corn, safflower, olive, and avocado
oils, and mixtures of such oils. The oil can be selected
to comport with any specific dietary guidelines.
Polyunsaturated oils are preferred. When the suspension
is administered to the animal to be treated by placing the
suspension on the food or in a food dish, an oil that is
palatable to the animal, such as avocado oil, is
conveniently used. The palatability of the oil is not of
concern when the suspension is administered in an
encapsulated form.
Budesonide is present in the formulation in an
effective amount. The amount needed for effective
treatment varies depending on numerous well known factors
such as the severity and chronicity of the disease, the
species, histopathologic type, and weight of the treated
animal, the,length and course of treatment, the region of
the gastrointestinal tract to be treated, and the
responsiveness of the treated animal. Determination of an
effective dose is described in detail hereinafter.
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Conveniently, budesonide is suspended in the oil at a
concentration of about 1 mg/ml to about 2 mg/ml. Such
concentrations are suitable for administration of typical
dosages required for treatment of humans and domestic
animals, such as dogs and cats. The suspension is
relatively viscous at concentrations much above 2 mg/ml.
Therefore, concentrations at 2 mg/ml or less are more
suitable for ease of administration. This is less of a
concern when the formulation is encapsulated. At
concentrations much below 1 mg/ml, larger volumes of~the
suspension need to be administered to achieve the
effective dose for larger animals, such as large dogs or
humans. Therefore, concentrations of about 1 mg/ml to
about 2 mg/ml are convenient for administration and
formulation of an effective dose.
In addition, such concentrations of budesonide also
are capable of being formulated as stable colloidal
suspensions. In particular, colloidal suspensions of
budesonide at 1 mg/ml in various vegetable oils were
stable at room temperature for at least four months in
that no precipitation of budesonide was observed.
The suspension can be encapsulated in a controlled-
release coating, conveniently for release in the affected
organ when the inflammation is localized to a particular
region of the gastrointestinal tract. A controlled=
release formulation directed for release in a specific
portion of the gastrointestinal tract permits localized
exposure to budesonide and reduces unnecessary exposure of
other portions of the gastrointestinal tract to the drug,
further minimizing side effects. Even when the target
organ is the stomach, use of an enteric coating is
beneficial in eliminating exposure of the mouth and
esophagus to the drug and thus minimizing side effects.
The controlled-release capsules can conveniently be
formulated to contain total amounts of budesonide for ease
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of administration to the intended mammal. For example,
capsules convenient for use in treatment of humans can
contain dosages of 3 mg, 6 mg, or 9 mg of budesonide.
The method of treatment of the present invention
includes oral administration of a suspension of budesonide
in edible oil to a mammal. As represented in the present
application, the mammal can be a human, dog, or cat. In
addition, the method is also suitable for treatment of
commercially valuable mammals, including domestic animals
such as horses, pigs, cattle, and sheep, and rare and
exotic mammals such as those in zoos.
The proper dosage and an appropriate dosage regimen
varies depending on numerous well known factors such as
the severity and chronicity of the disease, the species,
histopathologic type, and weight of the treated animal,
the length and course of treatment, the region of the
gastrointestinal tract to be treated, and the sensitivity
of the treated animal to corticosteroid treatment. For
example, in cats, gastrointestinal disorders often include
stomach and duodenal involvement. In dogs,
gastrointestinal disorders mostly effect the small and
large intestine, while in humans ileal and bowel
involvement is most common. Since the sensitivity of
humans to corticosteroids is similar to that of dogs,
appropriate dosage ratios for_treatment of
gastrointestinal inflammation in humans can be
extrapolated from the dosages suitable for treatment of
gastrointestinal inflammation in dogs.
Cats are as responsive to treatment with
corticosteroids as dogs, but experience fewer side
effects. In general, the initial dose for cats is about
four times that for dogs. More specifically, cats were
started on an initial dose of 0.2 mg/kg twice a day and
tapered to a usual maintenance~dose of 0.1 mg/kg
administered every other day. Dogs were started on an
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initial dose of 0.05 mg/kg twice a day and tapered
according to response to be drug free or maintained at a
dose of 0.05 mg/kg administered every other day. Although
the daily dosage was conveniently administered in two
portions, a single dose of twice the amount can also be
used. The dose in humans is similar to that in dogs.
To determine starting doses for other mammals, a
comparison of the relative doses of other corticosteriods
can be used. In particular, the potency of budesonide is
about 10-20 times that of prednisolone. A typical dosage
of budesonide in oil should thus generally be about 1/10
to 1/20 that of the dosage of prednisone or prednisolone
expected to be suitable for the particular animal.
Determination of initial and maintenance doses is
described more fully below.
As is well known in treating gastrointestinal
inflammation, in general, a relatively large initial dose
is given, usually for a period of two to four weeks or
longer depending on the severity of the disease. In
particular, a portion of the initial dose of drug fails to
be absorbed due to uncontrolled diarrhea. As the symptoms
of the disease are. alleviated by the portion of the drug
that is absorbed, the full effect of the drug becomes
apparent. Then the dose is generally reduced, usually to
about one-half of the initial_dose for a period of an
additional two weeks to four weeks.
However, smaller reductions, such as by one-third,
can also be used, particularly after one or more
reductions in dose have been instituted. If the reduced
dose does not lead to the return of symptoms, the dose can
be further reduced. If the symptoms return, the earlier
dose can be~repeated, then reduced by a smaller fraction.
If the reduced dose is effective for two to four weeks, a
further reduction in dosage can be attempted. As is well
known, each.dose must be administered for a period~of a
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week or more because a high dose can control symptoms for
days after the drug is withdrawn. Preferably, each dose
following the initial dose is given fox at least about two
weeks.
To determine the efficacy of a dose of the drug
clinically, the intestines are palpated to determine if
they are thickened or if the palpation causes or
aggravates discomfort.. The two keys to determining that
symptoms are effectively controlled that can be asked of a
IO patient or readily determined by the owner of an animal
are the presence of a firm stool and the absence of
vomiting or discomfort.
The treatment of gastrointestinal inflammation is
idiosyncratic and adjustment of dosages of corticosteroids
1~5 is well within the level.of skill. However, usually the
disease comes in cycles having periods of elevated
symptoms at the early stages. Often, the disease is..
aggravated by periods of stress at any stage of the
disease. In the early stages, symptoms are often
20 intermittent, and administering an effective form of
therapy may be difficult. Later, the cycles tend to
cease, and the symptoms are present consistently. Often a
maintenance dose must be administered daily in the later
stages of the disease.
25 The formulation of this.invention is prepared~by well
known methods. In particular, budesonide is suspended in
an edible oiI by adding the amount of budesonide necessary
for the desired concentration to the selected oil and
shaking or otherwise admixing the preparation until a
30 suspension is achieved. Usually, the suspension is a
stable colloidal suspension. In particular, a colloidal
suspension can be prepared by hand or mechanical shaking
of the drug in oil for a period of two minutes for a
concentration of 1 mg/ml without any initial processing o_f
35 budesonide as obtained from the manufacturer. The
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suspension appears stable once it is prepared and requires
no special storage.
Once the suspension is prepared, it can be
encapsulated by standard techniques. Techniques for
encapsulation are well known and are described in
Rernington's Pharmaceutical Sciences [Gennaro et al., eds.,
Rentington's Pharmaceutical Sciences, 18th ed., 1658-1664
(1990)]. In addition,.formulations for enteric release of
budesonide are described in Greenberg et al., The New
England Journal of Medicine 331(13) :836-8a1 (1994);
Rutgeerts et al., The New England Journal of
Medicine, 331(13):842-845 (1994); and Reynolds et al.,
Digestive Diseases, 11:334-342 (1993) .
It is understood that the application of the
teachings of the present. invention to a specific problem
or situation will be within the capabilities of one having
ordinary skill in the art in light of the teachings
contained herein. Examples of the products of the present
invention and representative processes for their
isolation, use, and manufacture appear below, but should
not be construed to limit the invention. Examples set
forth in the past tense have been actually reduced to
practice. Examples set forth in the present tense are
constructively reduced to practice.
EXAMPLE 1
A clinical trial of the formulation of this invention
for treatment of gastrointestinal inflammation was
performed at a veterinary hospital. The study was
conducted on dogs and cats with inflammations of the
_,
gastrointestinal tract which were diagnosed as forms of
inflammatory bowel disease using endoscopy and biopsy.
The: study was performed as described below.
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gormulation
The formulation was powdered budesonide (Sigma
Chemical Company; St. Louis, MO; Catalog No. B-7777)
suspended in either avocado oil or safflower oil at a
concentration of 1 mg/ml. The avocado oil was chosen
originally because of its palatability to cats. However,
one cat developed a sensitivity to avocado oil and
safflower oil was substituted. The drug was weighed out
in small quantities (approximately 40 mg), added to a
centrifuge tube, and sufficient oil ffor 40 m1 total
volume) was added to make the desired concentration of 1
mg/ml.
The tube was then vigorously shaken until all the
material was completely suspended. On standing, a small
percentage of the total material may have settled out and
required additional shaking to resuspend. This was
attributed to the variation in size of particles in the
original powder, with the heavier particles not entering a
truly colloidal phase. In general, not more than about 5%
of the powdered budesonide settled out after the initial
suspension was prepared.
Deliverv
Cats were started on an initial dose of 0.2 mg/kg
twice a day. The dose was tapered according to the
response, usually being maintained at 0.1 mg/kg every
other day. The dosages were tapered after two to four
weeks. Dogs were started at 0.05 mg/kg twice a day. The
dose was also tapered according to response, the animals
ultimately being maintained drug free or on a dose of 0.05
mg/kg every.other day. The suspension was administered to
animals either directly into the mouth via a syringe or by
simply allowing the animal to eat a measured amount of the
drug alone or with food.
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Clinical Data
The clinical trial of the formulation was begun with
a single cat having severe inflammatory gastric and
intestinal disease. By about seven months later, a total
of 2 dogs and 8 cats had been enrolled in the study. All
animals had previously been medicated with prednisone or
prednisolone. The average starting dose for prednisone or
prednisolone was 1 mg/kg orally twice a day, which was
tapered depending on the animal's response.
The animals were chosen for the.budesonide oil
suspension study based on one or more of the following
reasons: insufficient control of symptoms by prednisolone;
side effects of prednisolone; and concurrent diseases
making the use of systemic steroids undesirable, including
diabetes, immunosuppression, viral infections, and
pancreatitis.
Once begun on the budesonide oil suspension
formulation, all animals remained under observation for at
least six months, except for a single cat which was
euthanized for unrelated reasons by another veterinary
clinic. The shortest period of treatment was 2 months
and the longest was 6 months. A questionnaire was sent
to the owners of all animals on the drug, following
about 4 months in the study. The questionnaire requested
information regarding the treatment. The questionnaire
included both objective criteria (frequency of vomiting,
and quality of stool), and more subjective criteria (ease
of administration, appetite, energy level, and overall
comfort). The pets' owners were asked to rate the
budesonide in oil suspension treatment in comparison to
prior treatment with prednisolone and in comparison to no
treatment and to rate use of prednisolone in comparison to
no treatment,~rating the treatment from much worse to much
improved. More specifically, the treatment was rated as
much worse (scored as -3); moderately worse (scored
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as -2); slightly worse (scored as -1); no change (scored
as 0); slightly improved (scored as 1); moderately
improved (scored as 2); and much improved (scored as 3).
The average scores for each category were tabulated.
The results are illustrated below in Table 1.
TABLE 1
prednisolone budesonide budesonide
vs vs vs
no drug no drug prednisolone
Category
ease of NA~ NA~ 2.0
administration
overall comfort 0.0 2.2 2.1
frequency of 1.2 1.9 1.2
vomiting
quality of 0.6 1.8 ~ 1.7
stool
energy level -0.1 1.6 1.9
appetite 0.0 1.5 1.6
~NA: Not applicable (information was not requested)
Based on the scores, it is apparent that the
budesonide formulation was a significant improvement over
prednisone and prednisolone for the treatment of
inflammatory bowel disease in dogs and cats. This
improvement'was attributed to both greater potency of the
formulation and fewer associated side effects.
The study determined that the formulation of a
suspension of budesonide in an edible oil provides'not
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only noticeably diminished side-effects over prednisolone
but also superior efficacy for the control of the disease
over both prednisolone and budesonide when formulated as
other than an oil suspension.
EXAMPLE 2
Alternate formulations were tried on one cat and one
dog with much poorer results than the vegetable oil
formulation. One formulation was budesonide (also
at 1 mg/ml) suspended in 4Q% glycerol, 60% water. Another
vehicle was 10% polyethylene glycol (molecular weight 800)
and 90% water with budesonide suspended at 1 mg/ml. In
both cases the budesonide appeared to be evenly suspended,
creating a milky white suspension. However, both
formulations were so inferior in efficacy to the vegetable
oil formulation that it was judged improper to continue
and the animals were treated as described in Example 1.
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