U.S. patent application number 10/995595 was filed with the patent office on 2005-07-14 for use of ribofuranose derivatives against inflammatory bowel diseases.
This patent application is currently assigned to ICN Pharmaceuticals Switzerland Ltd.. Invention is credited to Brantl, Victor.
Application Number | 20050153907 10/995595 |
Document ID | / |
Family ID | 33565073 |
Filed Date | 2005-07-14 |
United States Patent
Application |
20050153907 |
Kind Code |
A1 |
Brantl, Victor |
July 14, 2005 |
Use of ribofuranose derivatives against inflammatory bowel
diseases
Abstract
A method for the prophylaxis or treatment of an inflammatory
bowel disease is provided, comprising administering to a patient
having or at risk of developing an inflammatory bowel disease a
therapeutically or preventatively effective amount of one or more
ribofuranose derivatives having the Formula (I): 1 wherein R is a
group selected from a carboxamide, an amidine, and pharmaceutically
acceptable acid addition salts thereof, and the configuration at
the C.sub.2 carbon of the ribofuranose moiety is D or L. The one or
more ribofuranose derivatives (I) may be used in combination with
further active agents such as antivirals or agents effective
against inflammatory bowel disease.
Inventors: |
Brantl, Victor; (Schliengen,
DE) |
Correspondence
Address: |
HOGAN & HARTSON L.L.P.
500 S. GRAND AVENUE
SUITE 1900
LOS ANGELES
CA
90071-2611
US
|
Assignee: |
ICN Pharmaceuticals Switzerland
Ltd.
|
Family ID: |
33565073 |
Appl. No.: |
10/995595 |
Filed: |
November 22, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10995595 |
Nov 22, 2004 |
|
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10618148 |
Jul 10, 2003 |
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Current U.S.
Class: |
514/43 |
Current CPC
Class: |
A61K 31/7056 20130101;
A61P 1/00 20180101 |
Class at
Publication: |
514/043 |
International
Class: |
A61K 031/7056 |
Claims
1. A method of treatment of an inflammatory bowel disease in a
subject in need of said treatment, said method comprising:
providing one or more ribofuranose derivatives having the Formula
(I): 4wherein R is a group selected from the group consisting of a
carboxamide, an amidine and pharmaceutically acceptable acid
addition salts thereof and the configuration at the C.sub.2 carbon
of the ribofuranose moiety is D; and administering said one or more
ribofuranose derivatives to said subject in an amount effective to
treat said inflammatory bowel disease.
2. The method of claim 1, wherein the ribofuranose derivative
having the Formula (I) comprises at least one derivative selected
from the group consisting of
1-.beta.-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide,
1-.beta.-D-ribofuranosyl-1H-1,2,4-triazole-3-amidine,
pharmaceutically acceptable acid addition salts thereof.
3. The method of claim 2, wherein the ribofuranose derivative
having Formula (I) is
1-.beta.-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide.
4. (canceled)
5. The method of claim 2, wherein the ribofuranose derivative
having Formula (I) is
1-.beta.-D-ribofuranosyl-1H-1,2,4-triazole-3-amidine.
6. (canceled)
7. The method of claim 2, wherein the ribofuranose derivative is
the hydrochloric acid addition salt of
1-.beta.-D-ribofuranosyl-1H-1,2,4-tria- zole-3-amidine.
8. (canceled)
9. The method of claim 1, wherein the ribofuranose derivative
having Formula (I) is
1-.beta.-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide and the
inflammatory bowel disease is Crohn's disease.
10. The method of claim 9, wherein said Crohn's disease is selected
from the group consisting of active Crohn's disease, refractory
Crohn's disease, and fistulizing Crohn's disease.
11. The method of claim 1, wherein the ribofuranose derivative
having Formula (I) is provided in combination with an antiviral,
wherein the ribofuranose derivative having Formula (I) and the
antiviral are administered to said subject simultaneously as an
admixture, separately and simultaneously, or separately in any
order.
12. The method of claim 11, wherein said antiviral agent is
selected from the group consisting of abacavir, acyclovir,
acyclovir sodium, acyclovir potassium, adefovir, amantadine,
amprenavir, atazanavir, brivudine, capravirine, cidofovir,
delavirdine, didanosine, efavirenz, emivirin, emtricitabine,
enfurvirtide, famciclovir, fosamprenavir, foscarnet, ganciclovir,
idoxuridine, indinavir, lamivudine, lopinavir, memantine,
mozenavir, nelfinavir, nevirapine, oseltamivir, penciclovir,
rimantidine, pentafuside, ritonavir, saquinavir, stavudine,
tenofovir, tipranavir, trifluridine, valaciclovir, valganciclovir,
zalcitabine, zanamivir, zidovudin, and the pharmaceutically
acceptable salts thereof and mixtures thereof.
13. The method of claim 11, wherein the ribofuranose derivative is
1-.beta.-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide and the
antiviral is acyclovir.
14. The method of claim 1 or 11 further comprising providing one or
more further agents effective against an inflammatory bowel disease
for simultaneous or successive administration with said derivative
having Formula (I), wherein said further active agent is selected
from the group consisting of anti-inflammatories,
immunosuppressants, antibodies, antibody fragments, humanized
monoclonal antibody against TNF-.alpha., flavonoids, monoclonal
antibodies against IL-12, monoclonal antibodies against IL-6,
monoclonal antibodies against the .alpha.4.beta.7 integrin
receptor, keratinocyte growth factor, protein inhibitors of
TNF-.alpha., glucocorticoids, peptide analogues of glucagon-like
peptide-2, glutathione peroxidase mimics, anti-sense TNF
inhibitors, anti-sense ICAM-1 inhibitor, nitric oxide-releasing
steroid derivatives, analogues of GLP-2, neurokinin-1 antagonists,
NF-kappa-B inhibitors, orally-active phosphodiesterase IV
inhibitors; thiazole derivatives, 5-lipoxygenase inhibitors,
L-selectin antagonists, enzyme inhibitors, tryptase inhibitors,
immunosuppressive macrolides, monoclonal antibodies against the
.alpha.4.beta.7 integrin receptor, glutathione peroxidase mimics,
interferon, omega-3 fatty acids, inhibitors of cytokine synthesis,
bactericidal/permeability agents, guanyl-hydrozone compounds,
apoptotic antineoplastic drugs, thalidomide, recombinant
interleukin-11 and mixtures thereof.
15. The method of claim 1, 11 or 14 further comprising providing
inflixamab, wherein the ribofuranose derivative having Formula (I)
and infliximab are administered to said subject as an admixture,
separately and simultaneously, or separately in any order.
16. The method of claim 1, wherein said administration comprises
parenteral administration, oral administration, inhalation, topical
administration, transdermal administration, rectal administration,
continuous infusion, or administration with an osmotic pump or a
sustained release implant.
17. The method of claim 1, wherein said step of administering
comprises orally administering the compound having Formula (I) in a
dose between 100 mg and 1.5 g per day for one to four weeks.
18. The method of claim 17, wherein the ribofuranose derivative
having Formula (I) is
1-.beta.-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide and the
inflammatory bowel disease is Crohn's disease.
19. The method of claim 1, wherein the step of administering
comprises: (a) intravenously administering the compound having
Formula (I) in a dose of about 10 to 40 mg/kg of body weight of the
patient for about 20 to 45 minutes; (b) intravenously administering
the compound having Formula (I) in a dose of about 5 to 25 mg/kg of
body weight of the patient every six hours for four days; and (c)
intravenously administering the compound having Formula (I) in a
dose of about 2 to 15 mg/kg of body weight of the patient every six
to eight hours for three days.
20. The method of claim 19, wherein the ribofuranose derivative
having Formula (I) is
1-.beta.-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide and the
inflammatory bowel disease is Crohn's disease.
21. The method of claim 19, wherein the step of administering
comprises: (a) intravenously administering the compound having
Formula (I) in a dose of 33 mg/kg of body weight of the patient for
30 minutes; (b) intravenously administering the compound having
Formula (I) in a dose of 16 mg/kg of body weight of the patient
every six hours for four days; and (c) intravenously administering
the compound having Formula (I) in a dose of 8 mg/kg of body weight
of the patient every eight hours for three days.
22. The method of claim 21, wherein the ribofuranose derivative
having Formula (I) is
1-.beta.-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide and the
inflammatory bowel disease is Crohn's disease.
23. The method of claim 1, wherein the disease is selected from the
group consisting of pseudomembranous colitis, hemorrhagic colitis,
hemolytic-uremic syndrome colitis, collagenous colitis, ischemic
colitis, radiation colitis, drug and chemically induced colitis,
diversion colitis, ulcerative colitis, irritable bowel syndrome,
irritable colon syndrome and Crohn's disease.
24. The method of claim 1, wherein the subject is a human.
25. The method of claim 10, wherein the agent is administered in an
amount that is from about half the dosage to the same dosage which
is, when administered alone, effective to treat said inflammatory
bowel disease.
26-63. (canceled)
Description
BACKGROUND OF INVENTION
[0001] 1. Field of the Invention
[0002] This invention relates to a method for treatment and
prevention of inflammatory bowel disease which comprises
administering an effective amount of a ribofuranose derivative or a
pharmaceutically acceptable salt thereof to a mammal. This
invention further relates to the use of such compounds in the
preparation of a medicament for the treatment and prevention of
inflammatory bowel disease.
BACKGROUND OF THE INVENTION
[0003] Inflammatory bowel disease (IBD) is a term used in the art
to generically encompass diseases of the intestine such as
ulcerative colitis (UC), irritable bowel syndrome, irritable colon
syndrome and Crohn's disease (CD). For many of these diseases, in
particular CD, the origin of the disease (bacterial, viral or
autoimmune) is unknown. There is sufficient overlap in the
diagnostic criteria for UC and CD that it is sometimes impossible
to say which a given patient has; however, the type of lesion
typically seen is different, as is the localization. UC mostly
appears in the colon, proximal to the rectum, and the
characteristic lesion is a superficial ulcer of the mucosa;
[0004] CD can appear anywhere in the bowel, with occasional
involvement of stomach, esophagus and duodenum, and the lesions are
usually described as extensive linear fissures. IBD is rather
common, with a prevalence that is claimed to be in the range of
70-170 in a population of 100,000.
[0005] Crohn's disease is currently neither medically nor
surgically curable, requiring approaches to treatment that
maintains symptomatic control, quality of life, and minimizes
short- and long-term toxicity of therapy. The current therapy of
IBD usually involves the administration of anti-inflammatory or
immunosuppressive agents, such as sulfasalazine, corticosteroids,
6-mercaptopurine/azathioprine, or cyclosporine, which usually bring
only partial results. For example, IBD's such as Crohn's disease or
ulcerative colitis have been treated in the past with salicylic
acid derivatives (such as 5-aminosalicylic acid, also known as
5-ASA or mesalazine; and prodrugs thereof, such as sulfasalazine).
Possible side effects of 5-ASA preparations include nausea,
vomiting, heartburn, diarrhea and headaches. Other treatments have
been based on corticosteroids such as cortisone, however prolonged
use of steroids has been known to result in side effects such as
weight gain, shrinking of the adrenal glands, gray cataract,
glaucoma, osteoporosis and diabetes mellitus. The use of immune
modifying drugs such as 6-mercaptopurine and its prodrug
azathioprine against Crohn's disease has increased in recent years,
but these drugs are slow acting and clinical activity cannot be
expected until several weeks or even months of treatment has
elapsed. In recent years the use of immunomodulating monoclonal
antibodies that neutralize TNF-.alpha. has been contemplated, the
only example of such an antibody that obtained marketing approval
for use against Crohn's disease currently being infliximab. A
drawback of this therapy is the high risk of severe infections when
administered by injection and the risk of lymphoproliferative
disease. A reported side effect of the treatment with infliximab is
bilateral anterior toxic optic neuropathy.
[0006] If anti-inflammatory and/or immunosuppressive therapies
fail, colectomies are the last line of defense. About 30% of CD
patients will need surgery within the first year after diagnosis.
In subsequent years, the rate is about 5% per year. Unfortunately,
CD is characterized by a high rate of recurrence; about 5% of
patients need a second surgery each year after initial surgery. In
UC, a further reason for resorting to surgery is that the patients
are known to be at much increased risk for developing colorectal
cancer, starting 10-15 years after the diagnosis of ulcerative
colitis. Presumably this is due to the recurrent cycles of injury
to the epithelium, followed by regrowth, increasing the risk of
transformation. Accordingly, colostomy is used as prophylaxis
against the development of cancer in UC patients.
[0007] From the above it is evident that there still exists the
need of drugs and therapies that are effective against inflammatory
bowel diseases and that avoid the disadvantages of the prior art
drugs and treatment.
SUMMARY OF THE INVENTION
[0008] One aspect of the present invention provides a method for
the prophylaxis or treatment of inflammatory bowel disease (IBD)
comprising administering to a patient having or at risk of
developing an inflammatory bowel disease a therapeutically or
preventatively effective amount of one or more ribofuranose
derivatives having the Formula (I): 2
[0009] wherein R is a group selected from a carboxamide, an
amidine, and pharmaceutically acceptable acid addition salts
thereof and the configuration at the C.sub.2 carbon of the
ribofuranose moiety is D or L.
[0010] The method may further comprise administering a compound
having Formula (I) in combination with one or more additional
agents effective against inflammatory bowel disease including, but
not limited to, steroids, corticosteroids, salicylates,
immunosuppressants, antibodies and/or antivirals, wherein said
compound having Formula (I) and said additional active agent are
administered simultaneously in admixture, separately and
concomitantly, or successively.
[0011] This invention further provides the use of one or more
compounds of the Formula (I) alone or in combination with one or
more additional active agents effective against inflammatory bowel
disease and/or antivirals effective against inflammatory bowel
disease in the preparation of a medicament against an inflammatory
bowel disease.
[0012] This invention further provides a medicament containing one
or more ribofuranose derivatives having Formula (I), or a
medicament containing one or more ribofuranose derivatives having
Formula (I) and at least one compound selected from the group
consisting of an antiviral and a further agent effective against
inflammatory bowel disease, as a combination for the simultaneous,
separate or successive administration against inflammatory bowel
disease.
[0013] Additional advantages and novel features of this invention
shall be set forth in part in the description that follows, and in
part will become apparent to those skilled in the art upon
examination of the following specification or may be learned by the
practice of the invention. The advantages of the invention may be
realized and attained by means of the instrumentalities,
combinations, compositions, and methods particularly pointed out in
the appended claims.
DETAILED DESCRIPTION OF THE INVENTION
[0014] One aspect of the present invention provides a method for
the treatment or prophylaxis of an inflammatory bowel disease,
comprising administering to a patient in need thereof one or more
compounds generally described by the Formula (I): 3
[0015] in a dose range effective to treat or prevent said disease,
wherein R is a group selected from a carboxamide, an amidine, and
pharmaceutically acceptable acid addition salts thereof and the
configuration at the C.sub.2 carbon of the ribofuranose moiety is D
or L. It is to be understood that any derivatives of Formula (I)
that perform the same function as the compounds of Formula (I) are
considered the equivalents of the Formula (I).
[0016] The numbering of the carbon atoms in the ribofuranose moiety
in Formula (I) is such that the carbon bearing the triazole group
is 1 (the first carbon atom), and the carbon atom bearing the
hydroxymethyl group is 4 (the fourth carbon atom). The
configurations at the third and fourth carbon atoms in the
ribofuranose moiety are as in ribavirin. The configuration of the
C.sub.2 carbon atom can be D or L. The configuration of the first
carbon atom is not critical to the invention.
[0017] Another aspect of this invention is the use of a compound
having Formula (I) for the preparation of a medicament against
inflammatory bowel disease.
[0018] The term "inflammatory bowel disease" as used herein
includes all forms of inflammatory processes in the
gastrointestinal tissue, including but not limited to,
pseudomembranous colitis, hemorrhagic colitis, hemolytic-uremic
syndrome colitis, collagenous colitis, ischemic colitis, radiation
colitis, drug and chemically induced colitis, diversion colitis,
ulcerative colitis, irritable bowel syndrome, irritable colon
syndrome and Crohn's disease; and within Crohn's disease all the
subtypes including active, refractory, and fistulizing and Crohn's
disease.
[0019] The term "against inflammatory bowel disease" as used herein
refers to a therapeutic treatment or prophylaxis for inflammatory
bowel disease, and an active agent "effective against inflammatory
bowel disease" refers to an agent serves in the treatment or
prophylaxis of inflammatory bowel disease. An "effective amount" is
intended to mean that amount of compound that, when administered to
a mammal in need of treatment or prophylaxis, is sufficient to
effect treatment or prevention, respectively, of inflammatory bowel
disease. The term "treating" is intended to mean at least the
mitigation of inflammatory bowel disease in a mammal, such as a
human, that is affected, at least in part, by the disease, and
includes, but is not limited to, modulating and/or inhibiting the
disease condition; and/or alleviating the disease condition. The
term "prophylaxis" is intended to mean at least preventing the
disease condition from occurring in a mammal, particularly when the
mammal is found to be predisposed to having the disease condition
but has not yet been diagnosed as having it.
[0020] The terms "patient" and "subject" as used herein include any
animal, including mammals and humans.
[0021] The term "medicament" as used herein includes any type of
medicament for oral, nasal, topical, transdermal, rectal and
parenteral administration (e.g., administration by injection),
whereby the medicament can be a single dosage containing one or
more ribofuranose derivatives having Formula (I) alone or in
admixture with at least on additional agent effective against
inflammatory bowel disease, or one or more ribofuranose derivatives
having Formula (I) and at least on additional agent effective
against inflammatory bowel disease in separate dosage forms.
Additionally, the term "medicament" includes a kit with one or more
dosage forms containing one or more ribofuranose derivatives having
Formula (I) and separately at least one dosage form containing at
least one additional agent effective against inflammatory bowel
disease, or a kit with one or more dosage forms containing one or
more ribofuranose derivatives having Formula (I) alone or in
admixture with one or more additional agents effective against
inflammatory bowel disease and one or more separate dosage forms
containing either the ribofuranose derivative having Formula (I) or
an additional agent effective against inflammatory bowel
disease.
[0022] Examples of ribofuranose derivatives having Formula (I) used
in the compositions, medicaments, and methods according to the
invention include:
[0023] (1) Ribavirin
(1-.beta.-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxa- mide), which
is the compound having Formula (I) where R is (C.dbd.O)NH.sub.2),
or a pharmaceutically acceptable acid addition salt thereof;
[0024] (2) Levovirin.TM.
(1-.beta.-L-ribofuranosyl-1H-1,2,4-triazole-3-car- boxamide), which
is the compound having Formula (I) where R is (C.dbd.O)NH.sub.2),
or a pharmaceutically acceptable acid addition salt thereof. This
is the L-form of Ribavirin and its synthesis is disclosed in U.S.
Pat. No. 6,130,326, which is specifically incorporated herein by
reference;
[0025] (3) 1-.beta.-D-ribofuranosyl-1H-1,2,4-triazole-3-amidine,
which is the compound having Formula (I) where R is
(C.dbd.NH)NH.sub.2), or a pharmaceutically acceptable acid addition
salt thereof;
[0026] (4) 1-.beta.-L-ribofuranosyl-1H-1,2,4-triazole-3-amidine,
which is the compound having Formula (I) where R is
(C.dbd.NH)NH.sub.2, or a pharmaceutically acceptable acid addition
salt thereof; and
[0027] (5) any mixture of compounds (1)-(4).
[0028] Preferred ribofuranose derivatives having Formula (I)
include 1-.beta.-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide,
1-.beta.-L-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, the
hydrochloric acid addition salt of
1-.beta.-D-ribofuranosyl-1H-1,2,4-tria- zole-3-amidine
(D-Viramidine.RTM.), and the hydrochloride salt of
1-.beta.-L-ribofuranosyl-1H-1,2,4-triazole-3-amidine
(L-Viramidine.RTM.). D- and L-Viramidine.RTM. are prodrugs of
Ribavirin and are disclosed in U.S. Pat. No. RE029835, which is
specifically incorporated herein by reference.
[0029] The term "pharmaceutically acceptable acid addition salt"
refers to a compound obtained upon treatment of a compound having
Formula (I) with any pharmaceutically acceptable acid, including,
but not limited to, hydrochloric, hydrobromic, acetic, propionic,
p-toluenesulfonic, sulfuric, nitric or lactic acid. Methods of
preparing acid addition salts of such compounds are well known to
those skilled in the art. One example of such a method is described
in U.S. Pat. No. 6,455,408 B1, which is incorporated herein by
reference.
[0030] When an acid addition salt of the compound having Formula
(I) is intended for administration by injection, the amount of acid
added to the compound having Formula (I) in the preparation of the
salt may be restricted by the pH of the aqueous solution of the
resulting acid addition salt, which should be within
physiologically tolerable ranges. In certain cases, where the
composition or medicament contains one or more further agents
and/or antivirals active against inflammatory bowel disease that
contain an acidic hydrogen, a "pharmaceutically acceptable salt" of
the additional agents and/or antivirals may be formed by
deprotonation of the acidic hydrogen. Such deprotonation salts
include, for example, the sodium or potassium salts of acyclovir
and valacylovir, obtained by deprotonation of the 1-imino hydrogen.
Other methods for preparing salts of agents containing an acidic
hydrogen are well known in the art.
[0031] One embodiment of this invention comprises a method of
treating or preventing inflammatory bowel disease in a patient,
comprising administering a therapeutically effective or
preventatively effective amount of one or more ribofuranose
derivatives having Formula (I) or the acid addition salts thereof
to a patient in need thereof. The amount of ribofuranose derivative
having Formula (I) that is effective for the treatment or
prevention of an inflammatory bowel disease will vary depending on
the compound used and on other factors such as the body weight of
the subject and may be determined by clinical studies on laboratory
animals or on human volunteers. An indication that a
therapeutically effective in vivo amount was used is the induction
of a clinical remission of the inflammatory bowel disease in
question. It is well within the ordinary skill of the art to modify
the route of administration and dosage regimen in order to manage
the pharmacokinetics of the present compounds for maximum
beneficial effect in patients.
[0032] An exemplary dosage regime for a ribofuranose derivative
having Formula (I) may be, when administered orally for the
treatment or prophylaxis of inflammatory bowed disease, in the
range of 100 mg to 4 g per day over a period of 1 to 4 weeks.
[0033] This dosing regime is especially suitable for the
administration of Ribavirin, and in particular for the
administration of Ribavirin for the treatment or prophylaxis of
Crohn's disease. With the lower doses within the range of 100 mg to
1.5 g per day the treatment may be extended to up to six months, in
particular for prophylactic treatment. An exemplary dosage regime
for a ribofuranose derivatives having Formula (I), when
administered as injectable intravenous solution for treatment of
acute or subacute inflammatory bowel disease, is:
[0034] a) initial administration of a loading dose of about 10 to
about 40 mg/kg body weight of the patient, over a period of about
20 to about 45 minutes;
[0035] b) administration of subsequent doses of about 5 to about 25
mg/kg body weight, in intervals of about 4 to about 6 hours, for
the first 4 days, starting one such interval after the end of
administering the loading dose of step a); and
[0036] c) administration of subsequent doses of about 2 mg to about
15 mg/kg body weight, in intervals of about 6 hours to about 10
hours, for the next 3 days, starting one such latter interval after
the end of the regime of step b). This dosing regime is especially
suitable for the administration of Ribavirin, and in particular for
the administration of Ribavirin for the treatment or prophylaxis of
Crohn's disease.
[0037] An exemplary dosing regime for the intravenous
administration of Ribavirin according to this invention for the
treatment or prophylaxis of an inflammatory bowel disease is
provided in Table 1.
1 TABLE 1 Time (hours) Day 0 18 6 12 1 Loading dose 16 mg/kg 16
mg/kg 16 mg/kg (33 mg/kg) 2 16 mg/kg 16 mg/kg 16 mg/kg 16 mg/kg 3
16 mg/kg 16 mg/kg 16 mg/kg 16 mg/kg 4 16 mg/kg 16 mg/kg 16 mg/kg 16
mg/kg 8 16 5 8 mg/kg 8 mg/kg 8 mg/kg 6 8 mg/kg 8 mg/kg 8 mg/kg 7 8
mg/kg 8 mg/kg
[0038] In one embodiment, the compound having Formula (I) is
Ribavirin. Since Ribavirin has been on the market for several
years, many dosage forms and routes of administration are known,
and all appropriate dosage forms and routes of administration may
be utilized. For example, in addition to oral administration,
ribavirin may given intravenously, intramuscularly,
intraperitoneally, topically, and the like, all of which are
known.
[0039] A compound having Formula (I), whether alone or in the
combination therapies or preventions as discussed herein, may be
administered in any appropriate pharmaceutical formulation, and
under any appropriate protocol. Thus, administration may take place
by various routes including oral (for example as tablets, lozenges,
hard or soft capsules, aqueous or oily suspensions, emulsions,
dispersible powders or granules, syrups or elixirs), parenteral
(including subcutaneous injections, intravenous, intramuscular, by
intrastemal injection or infusion techniques), transdermal (for
example as a patch which may include a penetration enhancement
agent), by inhalation spray (such as in the form of a finely
divided powder with an appropriate powdery diluent or a liquid
aerosol, to form an ordered mixture that can be inhaled with a dry
powder inhaler; or as an aerosolizable solution, to be inhaled e.g.
with a metered dose inhaler, for administration by insufflation
(for example as a finely divided powder), for topical use (for
example as creams, ointments, gels, or aqueous or oily solutions or
suspensions), buccal and suppository administration, and other
routes of administration, and in dosage unit formulations
containing conventional non-toxic pharmaceutically acceptable
carriers, adjuvants, and vehicles. Suitable
pharmaceutically-acceptable excipients for a tablet formulation
include, for example, inert diluents such as lactose, sodium
carbonate, calcium phosphate or calcium carbonate, granulating and
disintegrating agents such as corn starch or algenic acid; binding
agents such as starch; lubricating agents such as magnesium
stearate, stearic acid or talc; preservative agents such as ethyl
or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic
acid. Tablet formulations may be uncoated or coated either to
modify their disintegration and the subsequent absorption of the
active ingredient within the gastrointestinal tract, or to improve
their stability and/or appearance, in either case, using
conventional coating agents and procedures well known in the art.
Compositions for oral use may be in the form of hard gelatin
capsules in which the active ingredient is mixed with an inert
solid diluent, for example, calcium carbonate, calcium phosphate or
kaolin, or as soft gelatin capsules in which the active ingredient
is mixed with water or an oil such as peanut oil, liquid paraffin,
or olive oil.
[0040] Aqueous suspensions generally contain the active ingredient
in finely powdered form together with one or more suspending
agents, such as sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellul- ose, sodium alginate,
polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents such as lecithin or condensation products of an
alkylene oxide with fatty acids (for example polyoxethylene
stearate), or condensation products of ethylene oxide with long
chain aliphatic alcohols, for example heptadecaethyleneoxycetanol,
or condensation products of ethylene oxide with partial esters
derived from fatty acids and a hexitol such as polyoxyethylene
sorbitol monooleate, or condensation products of ethylene oxide
with partial esters derived from fatty acids and hexitol
anhydrides, for example polyethylene sorbitan monooleate. The
aqueous suspensions may also contain one or more preservatives
(such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as
ascorbic acid), coloring agents, flavoring agents, and/or
sweetening agents (such as sucrose, saccharine or aspartame).
[0041] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil (such as arachis oil, olive oil,
sesame oil or coconut oil) or in a mineral oil (such as liquid
paraffin). The oily suspensions may also contain a thickening agent
such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set out above, and flavoring agents may be added to
provide a palatable oral preparation.
[0042] These compositions may be preserved by the addition of an
anti-oxidant such as ascorbic acid.
[0043] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water generally contain
the active ingredient together with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients such as sweetening,
flavoring and coloring agents, may also be present.
[0044] The pharmaceutical compositions of the invention may also be
in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, such as olive oil or arachis oil, or a mineral oil,
such as for example liquid paraffin or a mixture of any of these.
Suitable emulsifying agents may be, for example,
naturally-occurring gums such as gum acacia or gum tragacanth,
naturally-occurring phosphatides such as soya bean, lecithin, an
esters or partial esters derived from fatty acids and hexitol
anhydrides (for example sorbitan monooleate) and condensation
products of the said partial esters with ethylene oxide such as
polyoxyethylene sorbitan monooleate. The emulsions may also contain
sweetening, flavoring and preservative agents.
[0045] Syrups and elixirs may be formulated with sweetening agents
such as glycerol, propylene glycol, sorbitol, aspartame or sucrose,
and may also contain a demulcent, preservative, flavoring and/or
coloring agent.
[0046] The pharmaceutical compositions may also be in the form of a
sterile injectable aqueous or oily suspension, which may be
formulated according to known procedures using one or more of the
appropriate dispersing or wetting agents and suspending agents,
which have been mentioned above. A sterile injectable preparation
may also be a sterile injectable solution or suspension in a
non-toxic parenterally-acceptable diluent or solvent, for example a
solution in 1,3-butanediol.
[0047] Suppository formulations may be prepared by mixing the
active ingredient with a suitable non-irritating excipient which is
solid at ordinary temperatures but liquid at the rectal temperature
and will therefore melt in the rectum to release the drug. Suitable
excipients include, for example, cocoa butter and polyethylene
glycols.
[0048] Topical formulations, such as creams, ointments, gels and
aqueous or oily solutions or suspensions, may generally be obtained
by formulating an active ingredient with a conventional, topically
acceptable, vehicle or diluent using conventional procedures well
known in the art.
[0049] Compositions for administration by insufflation may be in
the form of a finely divided powder containing particles of average
diameter of, for example, 30 .mu.m or much less, the powder itself
comprising either active ingredient alone or diluted with one or
more physiologically acceptable carriers such as lactose. The
powder for insufflation is then conveniently retained in a capsule
containing, for example, 1 to 50 mg of active ingredient for use
with a turbo-inhaler device, such as is used for insufflation of
the known agent sodium cromoglycate.
[0050] Compositions for administration by inhalation may be in the
form of a conventional pressurized aerosol arranged to dispense the
active ingredient either as an aerosol containing finely divided
solid or liquid droplets. Conventional aerosol propellants such as
volatile fluorinated hydrocarbons or hydrocarbons may be used and
the aerosol device is conveniently arranged to dispense a metered
quantity of active ingredient.
[0051] Another formulation employed in the methods of the present
invention employs transdermal delivery devices, patches, bandages,
and the like. Such transdermal patches may be used to provide
continuous or discontinuous infusion of the compounds of the
present invention in controlled amounts. The construction and use
of transdermal patches for the delivery of pharmaceutical agents is
well known in the art. See, for example, U.S. Pat. No. 5,023,252,
the disclosure of which is herein incorporated by reference. Such
patches may be constructed for continuous, pulsatile, or on demand
delivery of pharmaceutical. For example, a dose of a ribofuranose
derivative having Formula (I) may be combined with skin penetration
enhancers, such as propylene glycol, polyethylene glycol,
isopropanol, oleyl alcohol, ethoxydiglycol, sodium xylene
sulfonate, ethanol, oleic acid, N-methylpyrrolidone, laurocapram,
alkanecarboxylic acids, dimethylsulfoxide, polar lipids, and
N-methyl-2-pyrrolidone, and the like, which increase the
permeability of the skin to the dose of ribofuranose derivative
having Formula (I) and permit the dose of ribofuranose derivative
having Formula (I)to penetrate through the skin and into the
bloodstream. A patch comprising a ribofuranose derivative having
Formula (I) may further comprise one or more agents such as
moisturizers, humectants, oils, emulsifiers, thickeners, thinners,
surface active agents, fragrances, preservatives, antioxidants,
vitamins, or minerals. The ribofuranose derivative having Formula
(I) may also be further combined with a polymeric substance, such
as ethylcellulose, hydroxypropyl cellulose, ethylene/vinylacetate,
polyvinyl pyrrolidone, and the like, to provide the composition in
gel form, which may be dissolved in solvent such as methylene
chloride, evaporated to the desired viscosity, and then applied to
backing material to provide a patch. The backing can be any of the
conventional materials such as polyethylene, ethyl-vinyl acetate
copolymer, polyurethane and the like.
[0052] For further information on formulations, see Chapter 25.2 in
Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch;
Chairman of Editorial Board), Pergamon Press 1990, which is
specifically incorporated herein by reference.
[0053] The administration of a compound having Formula (I), alone
or in combination with another active ingredient as described
herein, need not be restricted to a single daily injection, but may
include alternative frequencies and routes. For example, where
relatively high amounts of a compound having Formula (I) need to be
delivered, two to four or more daily injections are contemplated.
Similarly, where high plasma concentrations of a compound having
Formula (I) are desired over an extended period, a permanent
delivery is contemplated. For example, a more permanent delivery
may include the use of a continuous infusion, an osmotic pump, or a
sustained release implant.
[0054] With respect to dosage of a compound having Formula (I),
whether alone or in combination with one or more additional agents
against inflammatory bowel disease, one of ordinary skill in the
art will recognize that a therapeutically effective amount will
vary with the infection or condition to be treated, its severity,
the treatment regimen to be employed, the pharmacokinetics of the
agent used, as well as the patient (animal or human) treated. It is
further contemplated that while treatment success may be achieved
at relatively low plasma concentrations of the compounds having
Formula (I), other conditions may require relatively high
dosages.
[0055] In embodiments wherein the compound having Formula (I) is
administered together in admixture, separate and simultaneously or
successively with one or more additional active agents and/or
antivirals effective against inflammatory disease, it is well
within the skill of those of ordinary skill in the art to decide,
depending on the type of ribofuranose derivative having Formula (I)
and the type of further active agent and/or antiviral to be
co-administered, what type of administration route to choose for
each compound. It is further within the skill of one of ordinary
skill in the art to determine whether the compound having Formula
(I) and the one or more additional active agents and/or antivirals
a can be co-formulated into one single composition or whether, for
example due to some incompatibility, they should be formulated into
separate dosage forms to then be used as a kit, or administered
independently but concomitantly or successively according to the
respective dosing regimes. Likewise the proper choice of excipients
and/or diluents is within the knowledge of the skilled person,
particularly as the ribofuranose derivatives having Formula (I) and
the further active agents per se are known compounds that have been
previously used in other therapies and indications.
[0056] Because the ribofuranose derivatives having Formula (I) are
water soluble, they can be administered in the form of an
injectable, especially intravenous solution in a pharmaceutically
acceptable solvent, such as water for injection (WFI) or
physiological saline solution, preferredly buffered to a pH of
about 5.0 to bout 7.5, and optionally by using suited
pharmaceutically acceptable cosolvents such as ethanol or DMSO.
Conventional buffers such as phosphates, bicarbonates or citrates
can be used for buffering. These solutions may be prepared
immediately prior to use.
[0057] In a further embodiment, this invention provides a method of
treatment or prophylaxis of inflammatory bowel disease in a patient
comprising administering at least one derivative having Formula (I)
in combination with one or more agents effective against
inflammatory bowel disease. Combination therapies according to the
present invention comprise the administration of at least of
compound having Formula (I) or an acid addition salt thereof and at
least one other pharmaceutically active ingredient. In this method,
a compound having Formula (I) may be administered in admixture or
separately with another active agent against inflammatory bowel
disease, and when administered separately this may occur
simultaneously or separately in any order. The amounts of the
active agent(s) and the compound having Formula (I) and the
relative timings of administration will be selected in order to
achieve the desired combined therapeutic effect.
[0058] As stated, one embodiment of this invention for the
treatment or prophylaxis of inflammatory bowel disease comprises
administering one or more derivatives having Formula (I) in an
amount effective to treat or prevent the disease. Alternatively,
the ribofuranose derivative having Formula (I) can be
co-administered and/or co-formulated with further active agents
effective against inflammatory bowel disease including, but not
limited to:
[0059] (a) conventional agents used in the field of treatment of
inflammatory bowel diseases including, but not limited to,
anti-inflammatories (e.g. steroids and corticosteroids such as
cortisone and hydrocortisone, salicylates such as mesalazine and
sulfasalazine, and cytokines), immunosuppressants such as
mercaptopurine, azathioprine, metothrexate, cyclosporine and
tacrolimus, and antibodies including active fragments thereof, such
as the immunomodulating monoclonal antibody against TNF-.alpha.
known as infliximab; and/or
[0060] (b) further antivirals different from the ribofuranose
derivative having Formula (I) including, but not limited to,
abacavir, acyclovir, acyclovir sodium, acyclovir potassium,
adefovir, amantadine, amprenavir, atazanavir, brivudine,
capravirine, cidofovir, delavirdine, didanosine, efavirenz,
emivirin, emtricitabine, enfurvirtide, famciclovir, fosamprenavir,
foscarnet, ganciclovir, idoxuridine; indinavir, lamivudine,
lopinavir, memantine, mozenavir, nelfinavir, nevirapine,
oseltamivir, penciclovir, rimantidine, pentafuside, ritonavir,
saquinavir, stavudine, tenofovir, tipranavir, trifluridine,
valaciclovir, valganciclovir, zalcitabine, zanamivir, zidovudin,
and the pharmaceutically acceptable salts thereof and mixtures
thereof; and/or
[0061] (c) additional agents for the treatment of inflammatory
bowel disease including, but not limited to, humanized monoclonal
antibody against TNF-.alpha., flavonoids, monoclonal antibodies
against IL-12 or IL-6, monoclonal antibodies against the a4.beta.7
integrin receptor, keratinocyte growth factor, protein inhibitors
of TNF-a, glucocorticoids, peptide analogues of glucagon-like
peptide-2, glutathione peroxidase mimics, anti-sense TNF
inhibitors, anti-sense ICAM-1 inhibitor, nitric oxide-releasing
steroid derivatives, analogues of GLP-2, neurokinin-1 antagonists,
NF-kappa-B inhibitors, orally-active phosphodiesterase IV
inhibitors, thiazole derivatives, 5-lipoxygenase inhibitors,
L-selectin antagonists, enzyme inhibitors (e.g., tryptase
inhibitors), immunosuppressive macrolides, glutathione peroxidase
mimics, interferon, omega-3 fatty acids, inhibitors of cytokine
synthesis, bactericidal/permeability-increasing (BPI) agents,
guanyl-hydrozone compounds, apoptotic anti-neoplastic drugs,
thalidomide, and recombinant interleukin-11. Non-limiting examples
of such compounds are listed in Table 2.
2TABLE 2* Company Product Name Product Type/Comments AstraZeneca
Budesonide Synthetic steroid Ferring Mesalazine Microsphere
formulation of 5- Pharmaceuticals aminosalicylate Provalis
Mesalazine pH-sensitive coated form of 5- Procter & Gamble
aminosalicylate Pharmacia Olsalazine Salicylate Shire
Pharmaceuticals Balsalazide Salicylate Pharmacia Methotrexate
Immunosuppressive agent Wyeth GlaxoSmithKline Azathioprine
Immunoactive and immunosuppressive 6-mercaptopurine agents Novartis
Cyclosporin Immunosuppressive agent Schering Plough Infliximab
Humanized monoclonal antibody against TNF-.alpha. Dong-A DA-6034
Flavonoid Abgenix ABX-IL8 Monoclonal antibody against IL-12 Chugai
MRA (anti-IL-6) Humanized monoclonal antibody against IL- 6 for IBD
Nobex Apaza Orally-active drug targeting the lower GI tract which
combines anti-inflammatory and immunomodulatory properties Tripep
TNF-Alpha inhibitor Protein polymerization inhibitor that inhibits
TNF-.alpha. GlaxoSmithKline SB-281832 p38 kinase inhibitor (for
IBD) SB-683698 Anti-inflammatory inhibitor of .alpha.4 integrin
(for IBD) Repifermin Keratinocyte growth factor (for IBD) IVAX
Etiprednol dicloacetate Orally-active glucocorticoid, rapidly
(EPDC) converted to its inactive form after absorption. NPS
Pharmaceuticals ALX-0600 33-amino-acid peptide analogue of
glucagon-like peptide-2 (GLP-2). OXIS Pharmaceuticals BXT-51702 A
small molecule glutathione peroxidase mimic. Accelerates metabolism
of peroxides, is a potent inhibitor of NF-.kappa.B, prevents
oxidative damage and downregulates the inflammatory response. ISIS
Pharmaceuticals ISIS 104838 Anti-sense TNF inhibitor ISIS 2302
Anti-sense ICAM-1 inhibitor (for IBD) NiCox SA NiCox 456
NO-releasing mesalazine (for IBD) NiCox 1015 NO-releasing
prednisolone derivative (for IBD) Protherics CytoAb Protein
inhibitor of TNF Pfizer C 96348 Antagonist of neurokinin-1 (NK-1)
Phytopharm plc P54 NF-kappa-B inhibitor (for IBD) Tanox Inc TNX-100
Monoclonal antibody inhibitor of CD40 Celgene CDC-801 Lead compound
from a series of small, orally-active phosphodiesterase IV
inhibitors (SelCID; Selective Cytokine Inhibitory Drugs).
Thalidomide TNF inhibitor Otsuka OPC-6535 Lead compound in a series
of non-peptidic, thiazole derivatives, acting as an inhibitor of
superoxide production by human neutrophils SangStat Corporation
RDP-58 Orally-active peptide inhibitor of TNF.alpha. mRNA
translation. It prevents translation of the TNF protein rather than
binding to the protein to inhibit function. Cantabria AM-24
5-lipoxygenase inhibitor and L-selectin antagonist Abbott (joint
D2E7 Human monoclonal antibody against TNF.alpha. development with
J695 Human monoclonal antibody against IL-12 Cambridge Antibody
Technology plc) Axys Pharmaceuticals APC-2059 Enzyme (tryptase)
inhibitor (for IBD) Fujisawa FK506 (tacrolimus) Immunosuppressive
macrolide Millenium MLN-02 Humanized monoclonal antibody to the
a4.beta.7 integrin receptor (for IBD) Oxis Pharmaceuticals GPx
Glutathione peroxidase mimic (in UC) Serono IFN-beta-1a Interferon
(cytokine) for IBD rTBP-1 Protein inhibitor of TNF Astra Zeneca
Rofleponide Oral steroid with topical action (for IBD) Celltech CDP
870 3.sup.rd generation PEG humanized anti-TNF.alpha. antibody
fragment CDP 571 Fully humanized monoclonal antibody against
TNF.alpha. Alizyme ATL-2502 Steroid derivative in special colonic
delivery formulation Elan Corporation Natalizumab Humanized
monoclonal antibody against .alpha.4 integrin Inkine
Pharmaceuticals CBO-1011 Steroidal molecule Schering Plough Tenovil
(IL-10) Anti-inflammatory cytokine Tillotts Pharma EPA Enteric
coated form of purified fish oil DHA containing free fatty acid
forms of eicosapentaenoic acid (EPA) and docosahexaenoic-omega-3
acid DHA Xoma rBPI21 (Neuprex .TM.) A recombinant
bactericidal/permeability- increasing (BPI) protein. Kills gram-
negative bacteria and neutralizes the bacterial endotoxin Cytokine
Pharma CNI-1493 A synthetic guanylhydrazone compound, Sciences
Inhibits the synthesis of inflammatory cytokines such as
TNF-.alpha. and IL-1 Cell Pathways CP-461 A Selective Apoptotic
Antineoplastic Drug (SAAND). Induces apoptosis in neoplastic cells
by inhibiting cyclic guanosine monophosphate phosphodiesterase
(cGMP PDE) Wyeth-Ayerst Research rhIL-11 A recombinant human
interleukin-11. Affects class II antigen processing and colonic
epithelial cell proliferation and metabolism *Sources:
Pharmaprojects, PJB Publications Ltd., status: April 2003; Target
Crohn's and Colitis, Information Booklet published by the
Association of the British Pharmaceutical Industry, status:
February 2002); FDA at www.clinicaltrials.gov, status: April
2003).
[0062] In any of the medicaments described herein, a compound
having Formula (I) may further be co-used with infliximab, wherein
the compound having Formula (I) and infliximab can be administered
together or separately.
[0063] Non-limiting examples of combinations of the ribofuranose
derivative having Formula (I) with other active agents against
inflammatory bowel disease according to this invention include the
following:
[0064] (i) one or more derivatives having Formula (I) with one or
more compounds of list (a) and/or with one or more antivirals such
as those selected from list (b) and/or with one or more compounds
of list (c); and
[0065] (ii) a combination as described in (i), additionally with
infliximab.
[0066] Preferably, the medicaments against inflammatory bowel
disease according to this invention may contain a combination of a
ribofuranose derivative of Formula (I) and one or more further
active agents selected from any of the above lists (a), (b) and
(c). In this embodiment, the ribofuranose derivative of Formula (I)
and the one or more further active agents are intended for
simultaneous, separate or successive administration.
[0067] The medicaments of this invention can be formulated of any
type of administration to a subject, including, but not limited to,
intravenous, parenteral, oral, inhalation, topical, transdermal, or
rectal administration, continuous infusion, or administration with
an osmotic pump or a sustained release implant.
[0068] In one preferred embodiment of a medicament of this
invention, the ribofuranose derivative having Formula (I) comprises
at least one ribofuranose derivative selected from the group
consisting of
1-.beta.-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide,
1-.beta.-L-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide,
1-.beta.-D-ribofuranosyl-1H-1,2,4-triazole-3-amidine,
1-.beta.-L-ribofuranosyl-1H-1,2,4-triazole-3-amidine, and
pharmaceutically acceptable acid addition salts thereof such as the
hydrochloric acid addition salt of
1-.beta.-D-ribofuranosyl-1H-1,2,4-tria- zole-3-amidine and the
hydrochloric acid addition salt of
1-.beta.-L-ribofuranosyl-1H-1,2,4-triazole-3-amidine. The
medicaments of this invention are suitable for treating or
preventing inflammatory diseases including, but not limited to,
pseudomembranous colitis, hemorrhagic colitis, hemolytic-uremic
syndrome colitis, collagenous colitis, ischemic colitis, radiation
colitis, drug and chemically induced colitis, diversion colitis,
ulcerative colitis, irritable bowel syndrome, irritable colon
syndrome and Crohn's disease. A preferred medicament for the
treatment of Crohn's disease comprises
1-.beta.-D-ribofuranosyl-1H-1,- 2,4-triazole-3-carboxamide, wherein
the Crohn's disease includes active Crohn's disease, refractory
Crohn's disease, and fistulizing Crohn's disease.
[0069] One exemplary medicament of this invention comprises a
ribofuranose derivative having Formula (I) in an amount between
about 100 mg and 1.5 grams.
[0070] Other preferred combinations and medicaments include
1-.beta.-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide in
admixture with acyclovir and
1-.beta.-L-ribofuranosyl-1H-1,2,4-triazole-3-carboxami- de in
admixture with acyclovir.
[0071] In the embodiment wherein one or more agents used in the
field of treatment of inflammatory bowel diseases such as those of
list (a) are co-used with one or more derivatives having Formula
(I), they may be administered in therapy and/or co-formulated in an
amount or dosage from about the same to about half the dosage that
would, when used without the ribofuranose derivative having Formula
(I), be effective to bring about a reduction in the expression of
proinflammatory cytokines (such as TNF-.alpha., TNF-.beta.,
INF-.gamma., IL-2, IL-12) in the serum or in a tissue sample of the
intestine mucosa of the subject to be treated. In the embodiment
wherein one or more antivirals such as those of list (b) are
co-used with one or more derivatives having Formula (I), they may
be administered in therapy or prevention and/or co-formulated in an
amount or dosage which is from about the same to about half the
dosage that would, when used without a compound having Formula (I),
be effective, in case an ordinary viral infection, to promote an
observable (e.g. by RT-PCR) reduction in virus load and/or
propagation.
[0072] In the embodiment wherein one or more active agents against
inflammatory bowel disease such as those of list (c) are co-used
with one or more derivatives having Formula (I), they may be
administered in therapy and/or be co-formulated in an amount or
dosage which is from about the same to about half the dosage that
would, when used without ribofuranose derivative having Formula
(I), be effective in promoting its respective functional effect,
which effect and corresponding assaying technique is described in
the respective compound's medicament information and/or drug master
file.
[0073] To prepare the pharmaceutical compositions according to the
present invention, a therapeutically effective or prophylactically
effective amount of one or more derivatives having Formula (I) (as
well as a compound provided in list (a), (b), or (c) if co-used
with the compound having Formula (I)) is preferably intimately
admixed with a pharmaceutically acceptable carrier according to
conventional pharmaceutical compounding techniques to produce a
dose. A carrier may take a wide variety of forms depending on the
form of preparation desired for administration, e.g., oral or
parenteral. Examples include excipients such as stabilizers (to
promote long term storage), emulsifiers, binding agents, thickening
agents, salts, preservatives, solvents, dispersion media, coatings,
antibacterial and antifungal agents, isotonic and absorption
delaying agents and the like. The use of such media and agents for
pharmaceutical active substances is well known in the art. Except
insofar as any conventional media or agent is incompatible with the
ribavirin, its use in the therapeutic compositions and preparations
is contemplated. Supplementary active ingredients can also be
incorporated into the compositions and preparations as described
herein.
[0074] In preparing pharmaceutical compositions in oral dosage
form, any of the usual pharmaceutical media may be used. Thus, for
liquid oral preparations such as suspensions, elixirs and
solutions, suitable carriers and additives including water,
glycols, oils, alcohols, flavoring agents, preservatives, coloring
agents and the like may be used. For solid oral preparations such
as powders, tablets, capsules, and for solid preparations such as
suppositories, suitable carriers and additives including starches,
sugar carrier, such as dextrose, mannitol, lactose and related
carriers, diluents, granulating agents, lubricants, binders,
disintegrating agents and the like may be used. If desired, the
tablets or capsules may be enteric-coated or sustained release by
standard techniques.
[0075] For parenteral formulations, the carrier will usually
comprise sterile water or aqueous sodium chloride solution, though
other ingredients including those that aid dispersion may be
included. Of course, where sterile water is to be used and
maintained as sterile, the compositions and carriers must also be
sterilized. Injectable suspensions may also be prepared, in which
case appropriate liquid carriers, suspending agents and the like
may be employed.
[0076] In the case of the combination therapies the ribofuranose
derivative having Formula (I) and an additional active agent
against inflammatory bowel disease such as those of lists (a), (b),
and (c), the compound having Formula (I) and the additional active
agent may be formulated in admixture into one single dosage.
Alternatively they may be formulated in separate dosage forms for
the simultaneous, separate or sequential use of the two -types of
dosage forms and/or to be provided as a medication kit with
appropriate directions of use.
[0077] The invention will now be illustrated in further detail by
the following non-limiting examples.
EXAMPLE 1
[0078]
3 Formulation of an injectable solution Content Ingredient (per ml
solution) Function ribavirin 100 mg agent effective against
inflammatory bowel Na.sub.2HPO.sub.4 anhydr. Ph. 0.369 mg disease
buffer Eur. KH.sub.2PO.sub.4 8.718 mg buffer 0.1 M HCl or 0.1 M
q.s. adjust pH of solution NaOH to 5.4-5.6 WFI ad 1 ml solvent Ph.
Eur.
EXAMPLE 2
Ribavirin Assay in a DNBS (2,4 Dinitrobenzenesulfonic Acid) Induced
Distal Colitis in Wistar Rats as a Model for Inflammatory Bowel
Disease in Humans
[0079] Animals
[0080] Wistar derived female rats were provided by MDS Pharma
Services Taiwan Ltd. and housed in APECR cages. All animals were
maintained in a controlled temperature (22.degree. C. -24.degree.
C.) and humidity (60-80%) environment with 12 hours light dark
cycles for at least one week in the laboratory prior to use. Free
access to standard lab chow (LabDiet, Rodent Diet, PMI Nutrition
International, USA) and tap water was granted.
[0081] All aspects of the work including housing, experimentation
and disposal of animals were performed in general accordance with
the International Guiding Principles for Biomedical Research
Involving Animals (CIOMSI Publication No. ISBN 9290360194,
1985).
[0082] Chemicals
[0083] DNBE (TCI, Japan), absolute ethanol (Merck, Germany), sodium
chloride (Wako, Japan), sulfasalazine (Sigma, USA) and Tween 80
(Wako, Japan).
[0084] Assay
[0085] Groups of 3 Wistar derived female rats weighing 180.+-.20
grams and fasted for 24 hours were used. Distal colitis was induced
by intra-colonic instillation of 2,4-ninitrobenzene sulfonic acid
(DNBS; 30 mg in 0.5 mL ethanol 30%), which was followed by
injection of air (2 mL) through a cannula to ensure that the
solution remained in the colon. Test substances (ribavirin 100
mg/kg or sulfalazine 300 mg/kg) plus vehicle (2% Tween 80 in water)
were administered p.o. 24 and 2 hours before DNBS instillation and
then daily for 5 days. Two control groups were similarly treated
with vehicle alone while challenged with either DNBS
(vehicle-control) or 0.9% NaCl solution (blank-control). The
animals were sacrificed 24 hours after the final dosing of test
compound and each colon was removed and weighed. During the
experiment, the presence of diarrhea was recorded daily.
Furthermore, when the abdominal cavity was opened, adhesions
between the colon and other organs were first noted; presence of
colonic ulceration was evaluated after removal and weighing of each
colon. The colon-to-body weight (BW) ratio was then calculated for
each animal according to the formula: Colon [(g)/BW(g)].times.100%.
The "Net" increase in the ratio of vehicle-control +DNBS group
relative to vehicle-control group was used as a base for comparison
with test substance treated groups and expressed as percent
decrease. A 30% or more (.gtoreq.30%) reduction in colon-to-body
weight ratio, relative to the vehicle-treated control group, is
considered significant. The numerical data and results of the assay
are given in Table 3. The data presented in Table 3 demonstrate
that Ribavirin is effective in this IBD model.
4 TABLE 3 B.W. Colon weight (g) Colon per Net % Treatment Dose N
Day 1 Day 8 (g) 100 g B.W. Increase Decrease Blank-Control 10 mL/kg
.times. 7 1 170 190 0.49 0.258 (2% Tween 80) 2 170 190 0.56 0.295 3
170 190 0.51 0.268 Avg 170 190 0.52 0.274 Vehicle- 10 mL/kg .times.
7 1 170 145 1.38 0.952 Control 2 180 155 1.09 0.703 (2% Tween 80) 3
180 145 1.27 0.876 Avg 177 148 1.25 0.844 0.570 Ribavirin 100 mg/kg
.times. 7 1 180 150 1.17 0.780 2 190 155 0.96 0.619 3 180 155 1.24
0.800 Avg 183 153 1.12 0.733 0.459 19 Sulfasalazine 300 mg/kg
.times. 7 1 185 160 1.01 0.631 2 180 155 0.85 0.548 3 185 155 1.08
0.697 Avg 183 157 0.98 0.625 0.351 38
[0086]
5 Intravenous infusion solution Content (per 100 ml Ingredient
infusion solution) Function Solution 1: ribavirin 100 mg agent
effective against inflammatory bowel disease WFI ad 100 ml solvent
Ph. Eur. Solution 2: acyclovir sodium 109.8 mg Further agent
effective against inflammatory bowel disease WFI ad 100 ml solvent
Ph. Eur. Final infusion solution: Solution 1 100 ml Solution 2 100
ml Solution 1 and 2 are mixed immediately prior to use.
[0087] The foregoing description is considered as illustrative only
of the principles of the invention. Further, since numerous
modifications and changes will be readily apparent to those skilled
in the art, it is not desired to limit the invention to the exact
construction and process shown as described above. Accordingly, all
suitable modifications and equivalents may be resorted to falling
within the scope of the invention as defined by the claims that
follow.
[0088] The words "comprise," "comprising," "include," "including,"
and "includes" when used in this specification and in the following
claims are intended to specify the presence of stated features,
integers, components, or steps, but they do not preclude the
presence or addition of one or more other features, integers,
components, steps, or groups thereof.
* * * * *
References