U.S. patent application number 16/379709 was filed with the patent office on 2020-01-02 for gastroresistant pharmaceutical formulations containing rifaximin.
The applicant listed for this patent is ALFASIGMA S.P.A.. Invention is credited to Ernesto PALAZZINI, Maria Rosaria PANTALEO, Giuseppe Claudio VISCOMI, Villiam ZAMBONI.
Application Number | 20200000726 16/379709 |
Document ID | / |
Family ID | 36694343 |
Filed Date | 2020-01-02 |
United States Patent
Application |
20200000726 |
Kind Code |
A1 |
VISCOMI; Giuseppe Claudio ;
et al. |
January 2, 2020 |
GASTRORESISTANT PHARMACEUTICAL FORMULATIONS CONTAINING
RIFAXIMIN
Abstract
The object of the invention consists of pharmaceutical
formulations containing rifaximin in the shape of microgranules
made gastroresistant by an insoluble polymer at pH values between
1.5 and 4.0 and soluble at pH values between 5:0 and 7.5, by their
preparation and by their use in the manufacture of medicinal
preparations useful in the treatment of inflammatory bowel diseases
(IBD) and mainly Crohn's disease.
Inventors: |
VISCOMI; Giuseppe Claudio;
(BOLOGNA, IT) ; PALAZZINI; Ernesto; (BOLOGNA,
IT) ; ZAMBONI; Villiam; (BOLOGNA, IT) ;
PANTALEO; Maria Rosaria; (BOLOGNA, IT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ALFASIGMA S.P.A. |
Milano (MI) |
|
IT |
|
|
Family ID: |
36694343 |
Appl. No.: |
16/379709 |
Filed: |
April 9, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14044844 |
Oct 2, 2013 |
10285944 |
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16379709 |
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11814628 |
Jul 24, 2007 |
8568782 |
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PCT/EP2006/002022 |
Mar 6, 2006 |
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14044844 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/5026 20130101;
A61P 1/00 20180101; A61K 9/1652 20130101; A61P 29/00 20180101; A61K
31/395 20130101; A61K 9/5073 20130101; A61K 9/2054 20130101; A61P
1/14 20180101; A61K 31/437 20130101; A61K 9/0095 20130101; Y02A
50/473 20180101; A61P 31/04 20180101; A61K 31/44 20130101; A61P
1/04 20180101; A61K 9/28 20130101; A61K 9/1635 20130101; Y02A 50/30
20180101; A61K 9/2027 20130101; A61P 1/12 20180101 |
International
Class: |
A61K 9/16 20060101
A61K009/16; A61K 9/00 20060101 A61K009/00; A61K 9/20 20060101
A61K009/20; A61K 31/395 20060101 A61K031/395; A61K 31/44 20060101
A61K031/44; A61K 9/28 20060101 A61K009/28; A61K 9/50 20060101
A61K009/50; A61K 31/437 20060101 A61K031/437 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 7, 2005 |
IT |
BO2005A000123 |
Claims
1.-17. (canceled)
18. A method for preparing gastroresistant microgranule of
rifaximin, the method comprising spraying on rifaximin
microgranules an aqueous suspension containing a gastroresistant
polymer insoluble over a pH range of from 1.5 to 4.0 and soluble
over a pH range from 5.0 to 7.5 together with pharmaceutically
acceptable excipients, the spraying performed in a fluid apparatus,
in which air flows, to obtain the gastroresistant microgranule of
rifaximin directly coated with the gastroresistant polymer in which
the rifaximin is retained at pH lower than 4.0 and is released at
pH higher than 5.
19. The method of claim 18, wherein the air flow is in entrance at
a temperature between 50.degree. C. and 75.degree. C. and with an
output 450 and 650 m.sup.3 per hour under a pressure between 1.0
and 1.5 bar and a flow speed between 150 and 300 g/min through a
nozzle on the mixture of rifaximin maintained in a suspension fluid
bed apparatus.
20. The method of claim 18 wherein the product temperature during
the spraying is maintained at a value between 20.degree. C. and
40.degree. C.
21. The method according of claim 19 wherein the air temperature in
entrance is at a temperature between 60.degree. C. and 70.degree.
C.
22. The method of claim 18, wherein the gastroresistant polymer is
selected in the group consisting of cellulose acetate phthalate,
hydroxypropyl cellulose acetate phthalate, hydroxypropyl
methylcellulose phthalate, polyvinyl acetate phthalate, co-polymers
of methacrylic acid and combinations thereof.
23. The method of claim 18 wherein the gastroresistant
microgranules have a delayed release.
24. The method of claim 18, wherein the pharmaceutically acceptable
excipients are selected from the group consisting of plasticizer,
diluent, anti-sticking, anti-agglomerative, glidants, anti-foam and
colouring substances.
25. The method according to claim 24, wherein the pharmaceutically
acceptable excipients are in an amount from 1% to 50% by the weight
of the gastroresistant microgranule of rifaximin.
26. The method of claim 18, wherein the spraying provides a film
coating on the rifaximin microgranules.
27. The method of claim 18, wherein the gastroresistant polymer is
in an aqueous suspension at a concentration between 15 and 30%
(V/V).
28. The method of claim 18, wherein rifaximin is in a polymorphous
form selected from form a, form 3, form y, form 6 and form c.
29. The method of claim 18, wherein the aqueous suspension is
prepared by suspending said gastroresistant polymers in
demineralized water and homogenised before spraying on the
rifaximin powder.
30. The method of claim 18, wherein the gastroresistant polymer is
from 5% to 75% of the gastroresistant microgranule of rifaximin,
from 10% to 60%, from 20% to 55%, from 30 to 80%, or from 25% to
50% of weight of the gastroresistant microgranule of rifaximin.
31. The method of claim 24, wherein the plasticizer is selected
from the group consisting of acetylated monoglycerides, butyl
phthalyl butyl glycolate, dibutyl tartrate, diethyl phthalate,
dimethyl phthalate, ethyl phthalyl ethyl glycolate, glycerin,
ethylene glycol, propylene glycol, triacetin citrate, triacetin,
tripropinoin, diacetin, dibutyl phthalate, acetyl monoglyceride,
polyethylene glycols, castor oil, triethyl citrate, polyhydric
alcohols, acetate esters, gylcerol triacetate, acetyl triethyl
citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl
phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl
azelate, epoxidized tallate, triisoctyl trimellitate, diethylhexyl
phthalate, di-n-octyl phthalate, di-1-octyl phthalate, di-1-decyl
phthalate, di-n-undecyl phthalate, di-n-tridecyl phthalate,
tri-2-ethylhexyl trimellitate, di-2-ethylhexyl adipate,
di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl
sebacate, glyceryl monocaprylate, glyceryl monocaprate and
combinations thereof.
32. The method of claim 31, wherein the plasticizer is in an amount
from 10% to 50%, by weight, based on the weight of the dry
polymer.
33. The method of claim 18, further comprising coating the
gastroresistant microgranule of rifaximin with a semipermeable
polymer.
34. The method of claim 33, wherein the semipermeable polymer is
selected between cellulose acetate, cellulose acetate butyrate,
cellulose acetate propionate, ethyl cellulose, fatty acid and their
esters, waxes, and/or zein.
35. The method of claim 34, wherein the semipermeble polymers are
combined with hydrophilic polymers
36. The method of claim 35, wherein the hydrophilic polymer is
selected from hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methylcellulose and polyvinipyrrolidone.
37. A gastroresistant microgranule of rifaximin comprising a
rifaximin microgranule directly coated with a gastroresistant
polymer insoluble over a pH range of from 1.5 to 4 and soluble over
a pH range from 5.0 to 7.5, in which the rifaximin is retained at
pH lower than 4.0 and is released at pH higher than 5.
38. The gastroresistant microgranule of claim 37, further
comprising a protective layer over the gastroresistant polymer, the
protective layer containing a semi-permeable polymer.
39. A pharmaceutical composition comprising the gastroresistant
microgranule of claim 37, together with pharmaceutically acceptable
excipients.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 14/044,844 filed on Oct. 2, 2013, which, in turn, is a
continuation of U.S. application U.S. Ser. No. 11/814,628 filed on
Jul. 24, 2007, now U.S. Pat. No. 8,568,782 issued on Oct. 29, 2013,
which, in turn is a national phase entry under 35 USC 371 of PCT
application PCT/EP2006/002022 filed on Mar. 6, 2006, which, in
turn, claims priority to Italian patent application BO2005A000123
filed on Mar. 7, 2005, each of which are herein incorporated by
reference in their entirety. This application may also be related
to U.S. application Ser. No. 12/695,945 filed on Jan. 28, 2010.
[0002] The object of the invention consists of pharmaceutical
formulations containing rifaximin in the shape of microgranules
made gastroresistant by an insoluble polymer at pH values between
1.5 and 4.0 and soluble at pH values between 5.0 and 7.5, by their
preparation and by their use in the manufacture of medicinal
preparations useful in the treatment of inflammatory bowel diseases
(IBD) and mainly Crohn's disease.
BACKGROUND OF THE INVENTION
[0003] The intestinal apparatus is affected by many inflammatory
diseases generally capped as inflammatory bowel diseases. In
particular, Crohn's disease is a severe chronic inflammatory
disease affecting various levels of the digestive tract, from the
mouth to the anus, particularly it can be observed in the last
portion of the small intestine, either the ileum, the colon or both
and sometimes in the mucous membrane of the colon and in the anal
region as well. In the interested intestinal part, inflammation,
swelling and ulceration occur in the whole intestinal wall causing
stenosis, bleeding ulcers and pain, while the non-affected tissue
portions appear normal. Crohn's disease exhibits alternate periods
of inflammatory symptoms of variable gravity with symptoms such as:
diarrhoea, abdominal pain, weight loss often accompanied by
rhagades or peri-rectal fistulas. From two-thirds to three-quarters
of patients with Crohn's disease require surgery at some point in
their lives.
[0004] Surgery is used either to relieve symptoms that do not
respond to medical therapy or to correct complications such as
blockage, perforation, abscess, or bleeding in the intestine.
[0005] The role of the intestinal bacterial flora in the
etiopathogenesis of the intestinal inflammatory diseases and in
particular in Crohn's disease is evidenced by, for example, the
frequency of localization to areas with high bacteria
concentrations, see Jannowitz, H. D., in Inflamm. Bowel Dis., 1998,
44, 29-39; the deviation of the faecal flow determines remission of
the endoscopic damages which reappear again at restoration of the
canalisation, see Rutgeerts, P., in Lancet, 1991, 338, 771-774;
experimental models, e.g., knock-out mouse for the IL-10 gene or
others, show that spontaneous colitis does not develop if a
"germ-free" condition is maintained, see Blumberg R. S., in Curr.
Opin. Immunol., 1999, 11(6), 648-56; inflammation of intestinal
mucous membrane develops after the contact with faecal material,
see Harper P. H., in Gut 1985, 26(3), 279-84; after surgical
"curative" therapy consisting of ileocolic anastomosis, antibiotic
treatment delays the development of both endoscopic and clinic
relapses, see Cameron J. L. in Ann. Surg., 1992, 215, 546-52; and
the presence of fistulae or abscess-sacs points out further the
bacterial contribution to the disease development.
[0006] Crohn's disease has previously been treated with drugs that
are able to decrease or control the inflammation, e.g., cortisones,
salazopirine, mesalazine, immunosupressants, specific
chemotherapeutics, antibiotics and protein inhibitors of the
actions of the Tumor Necrosis Factor (TNF). During the treatment of
the acute phase of the inflammatory bowel disease, stronger
treatments are often necessary to ensure parenteral alimentation,
to reconstitute the loss of proteins, liquids and salts, to permit
the intestine to rest to facilitate the cicatrisation of ulcers.
The purpose of the therapy is to decrease the frequency of the
reappearance of symptoms and to reduce the seriousness acute
episodes when they appear. However, with current therapies, acute
episodes respond in about 50-70% of the cases, but relapses occur
in 80% of the patients.
[0007] Antibiotics are usually used to decrease the growth of the
luminal bacteria; to decrease the inflammatory state sustained as a
result of the bacterial growth; to reduce symptoms of the acute
phase of the disease, e.g., diarrhoea, intestinal pain and
meteorism; and to prevent and to cure septic complications, e.g.,
abscesses, fistulas and toxic state.
[0008] The most frequently used antibiotics are systemically
absorbed, for example, metronidazole (active against some parasites
along with many anaerobic bacteria) and ciprofloxacin (active
against such bacteria as E. Coli and aerobic enterobacteriace).
Metronidrazol has been used at a dose of 10-20 mg/kg/day for 4
months (Sunterland, L. Gut, 1991 32, 1071-5), while ciprofloxacin
has been used at a dose of 1000 mg/day for 6 weeks (Colombel J. F.
in Am. J. Gastoenterol., 1999, 94, 674-8), while Prantera in Am. J.
Gastoenterol., 1996, 91, 328-32, adopted the combination of the two
antibiotics using metronidazole at the dose of 1000 mg/day and
ciprofloxacin at the dose of 1000 mg/day for 12 weeks. The high
systemic bioavailability of these antibiotics is at the root of
their high incidence of side effects registered in long-term
therapies, which negatively impacts their use. The incidence of
side effects in the use of metronidazole ranges from 10% to 20%,
depending on the dose and the treatment duration. The most frequent
side-effects include metallic taste, gastric intolerance, nausea,
glossitis, cephalea, vertigo, ataxia, convulsion and neurotoxicity.
Peripheral neuropathy has been recorded in 50-85% of the long-term
treated patients, which may regresses only after several months of
therapeutic interruption. The percentage of side effects described
in ciprofloxacin studies is variable and depends in part on the
dosage and the duration of the treatment. The most frequent of the
side effects are of gastrointestinal origin, but an increase of the
transaminase and skin reactions have also been frequently
described. Thus, there is a need in the art for a long-term
treatment option for inflammatory diseases of the digestive tract,
e.g., gastro enteric pathologies.
SUMMARY
[0009] Described herein are gastroresistant rifaximin microgranules
and related compositions, formulations, methods and systems.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] FIG. 1A is an image of rifaximin microgranules.
[0011] FIG. 1B is a closer image of a single rifaximin
microgranule.
[0012] FIG. 2 is a line graph which shows the dissolution profiles
of gastroresistant rifaximin microgranules.
[0013] FIG. 3 is a scanning electron microscope image of
gastroresistant rifaximin microgranules that are compressed in
tablets.
DETAILED DESCRIPTION
[0014] It is advantageous for pharmaceutical preparation used for
treating inflammatory bowel diseases (e.g., gastro enteric
pathologies) that are based on antibiotics to have one or more of
the following characteristics: intestinal level activity, low
absorption, bacteria level control in the intestinal lumen, wide
spectrum of actions against the microbes (e.g., intestinal
Gram-positive, Gram-negative, aerobic and anaerobic components),
possibility of long term therapy without side effects, ease of
administration to facilitate compliance even with the potential of
high dosage necessity, e.g., long-term dosing and/or multiple
dosing per day.
[0015] An antibiotic possessing several of these characteristics is
rifaximin (INN; see The Merck Index, XIII Ed., 8304), which is
characterized by a wide spectrum of action against many
Gram-positive and Gram-negative bacteria, including aerobic and
anaerobic bacteria. Bioavailability studies in healthy volunteers
have shown that, when given orally, less than 1% of rifaximin is
absorbed and it concentrates in the intestinal lumen and in the
faecesas described herein (Descombe J. J. et al. Pharmacokinetic
study of rifaximin after oral administration in healthy volunteers.
Int J Clin Pharmacol Res, 14 (2), 51-56, (1994)). The absence of
rifaximin absorption has been confirmed in patients affected by
chronic bowel disease, (see Rizzello, Eur. J. Clin. Pharmacol.
(1998) 54, 91-93). Moreover, the low absorption profile of
rifaximin reduces the incidence of side effects and the unwanted
risk of pharmacological interactions. Thus, rifaximin may be
considered useful in the therapy of inflammatory chronic bowel
disease and particularly in Crohn's disease. The potential efficacy
of rifaximin in chronic inflammatory bowel diseases has been
confirmed, see Gionchetti, P., Dig. Dis. Sci., 1999, 44, 1220-1,
who hypothesized the use of rifaximin in patients with moderate or
severe ulcerative colitis refractory to steroid-treatment.
[0016] Rifaximin has been described in Italian Patent IT 1154655
(1980) and EP 0161534 (1985), both of which are incorporated herein
by reference in their entirety for all purposes. EP 016153
discloses a process for rifaximin production using rifamycin O as
the starting material (The Merck Index, XIII Ed., 8301).
[0017] Guidance for rifaximin crystallisation and drying are
described in Italian Patent Application No. MI2003A002144 (2003),
in European Patent Application No. EP 1557421 (2003); in U.S.
patent application Ser. No. 10/728,090 (2003) in PCT Patent
Application No WO2005/044823; all of which are incorporated herein
by reference in their entirety for all purposes. The experimental
conditions described in these patents allow yielding polymorphic
forms of rifaximin named Form a, Form 13, Form y, Form 8 and Form
E, respectively.
[0018] Rifaximin is approved in certain countries for the treatment
of pathologies whose etiology is in part or totally due to
intestinal acute and chronic infections sustained by Gram-positive
and Gram-negative bacteria, with diarrhea syndromes, altered
intestinal microbial flora, summer diarrhoea-like episodes,
traveler's diarrhoea and enterocolitis; pre- and post-surgery
prophylaxis of the infective complications in gastro intestinal
surgery; and hyperammonaemia therapy as coadjutant. Rifaximin is
currently marketed as tablets or capsules at the dosage of 100 mg
and 200 mg, in a ready to use preparation for children, or as
ointment for the treatment of topical infections.
[0019] Studies on commercially available samples, particularly 200
mg tablets, have shown a potential usefulness of rifaximin in the
prevention of the relapse of Crohn's disease after endoscopic
resection. However, the absence of a placebo group in the clinical
trial does not allow to draw confident conclusions, see Rizzello,
Gut., 2000, 47, Supp. 3, A12. However, the suggested posology the
use of the rifaximin 200 mg tablets has to be considered sub
optimal due to the need up to six tablets a day for three months,
resulting in a poor patient compliance. The 200 mg tablets of
rifaximin have also been used in the treatment of Crohn's disease
with dosages of 600 mg/day for 16 weeks as described by Shafran,
I., Am. J. Gastroenterol., 2003, 98 (Suppl.) S-250.
[0020] Thus, there is a need in-the-art for a rifaximin
pharmaceutical formulation for the treatment of infections
specifically located in the intestinal tract. Previous
formulations, after administration, are released and spread between
the stomach and the intestine. Thus, when the rifaximin finally
reaches the intestinal tract, the concentration is too low
resulting in the need for increasing dosages. To maximize the
therapeutic efficacy of rifaximin in the treatment of bowel
diseases, new pharmaceutical formulations are provided herein and
include, for example, rifaximin microgranules coated with a
gastroresistant film which dissolves releasing the antibiotic only
in the intestinal tract. This novel formulation maximizes contact
between the active ingredient and the intestinal mucous due, in
part, to the high superficial area of the microgranules. The novel
formulations also allow for ease of high and low dose
administration, for example, in pediatric use.
[0021] The novel gastroresistant rifaximin formulations takes
advantage form the pH difference between the gastric environment
(e.g., values from about 1.5 to about 4.0, depending on the state
of fast or in presence of meal) and the intestinal lumen (e.g.,
values from 5.0 to about 7.5, depending of the tracts
considered).
[0022] The novel forms also utilize the polymorphic forms of
rifaximin.
[0023] The coating of pharmaceutical microgranules with
gastroresistant film is a technique known by many years in the
pharmaceutical field. It is generally performed in two steps:
granulation and coating. Nevertheless, many active substances,
including rifaximin, are characterized by a very fine particle
size, for example, in case of rifaximin approximately 50% of the
particles has a particle diameter between 10 .mu.m and 40 .mu.m. In
such condition it is very difficult using conventional systems like
fluid bed coating or pan technology.
[0024] Very often agglomeration occurs or random blend of coated
and uncoated particles is commonly obtained.
[0025] We have found, and this is an object of the invention, that
it is possible to obtain enteric-coated microgranules of rifaximin
by applying the fluid bed technology, which surprisingly allows in
one step and at the same time to perform the wet-granulation of the
powder and the coating of the formed microgranules with a polymer
resistant to the gastric environment, commonly called enteric
coating. With this approach the chief disadvantages of the
wet-granulation and microgranule coating, which are in separate
steps involved as well as the time and labour necessary to carry
out the entire procedure, especially on the large scale, are
minimised. This result comes from a combination between the
rifaximin properties and a proper balancing the quantity of
rifaximin, of enteric polymer, of plasticiser, and process
parameters.
[0026] The efficiency of this technology in providing a complete
coating layer around rifaximin is demonstrated by SEM microscopy as
reported in FIGS. 1a (Scanning electron microscopy of rifaximin
gastroresistant microgranules) and 1b (Scanning electron microscopy
of single granule of rifaximin gastroresistant microgranules),
where it is clearly show that rifaximin is fully coated by the
enteric polymer. The particles sizes are quite homogeneous without
large clots or very fine powder. If present, one or both of these
aspects would have negative impact in any further medicinal
preparation.
[0027] As confirmation of the completeness of the coating, the
dissolution profile of the gastroresistant microgranules of
rifaximin shows that rifaximin is completely retained at low pH and
released at pH higher than 5.0, as reported in FIG. 2 (Dissolution
profiles).
[0028] In order to maximize the release of the active ingredient
near the intestinal mucous membrane it has been utilized high pH
difference between the gastric environment, values from 1.5 to 4.0,
depending on the state of fast or in presence of meal and the
intestinal lumen, values from 5.0 to 7.5 depending of the tracts
considered. For this purpose, enteric polymeric materials having
the property to solubilize at pH values between 5.0 and 7.5 have
been used, to include: methacrylic acid copolymers with an acrylic
or methacrylic ester like methacrylic acid ethylacrylate copolymer
(1:1) and methacrylic acid methylmethacrylate copolymer (1:2),
polyvinyl acetate phthalate, hydroxypropyl cellulose acetate
phthalate and cellulose acetate phthalate, products available on
the market for example with the trademarks KOLLICOAT.RTM.,
EUDRAGIT.RTM., AQUATERIC.RTM., AQOAT.RTM..
[0029] The application of these gastroresistant films to rifaximin
powder or granules is performed with conventional apparatus for
fluid-bed coating technology. The film coating, dissolved in
organic solvents or suspended in water, is applied by spraying on
powders or granules maintained in suspension with air in fluid bed
systems. The most used organic solvents are: methylene chloride,
methyl alcohol, isopropyl alcohol, acetone, tri-ethyl acetate and
ethyl alcohol. Alternatively, the polymeric gastroresistant
material can be applied suspended in water. This technique is
preferable because it doesn't need the use of solvents and so it
avoids the toxicological and safety related problems.
[0030] Other excipients with anti-agglomerative properties, like
talc; plasticizing properties, like acetilated glycerides,
diethylphthalate, propylene glycol and polyethylene glycol;
surfactants like polysorbate and polyoxyethylenate esthers,
anti-foam as well as anti-sticking agents can be added together
with the polymeric material.
[0031] The successful application of the above mentioned technology
to the coating of rifaximin powder is remarkable because it is not
in the state-of-art of fluid-bed technology to spray the enteric
polymer directly on the active ingredient without any preliminary
treatment like granulation or layering the active ingredient on
inert particles. Indeed, several drawbacks could occur without any
powder pre-treatment such as large clamp formation, large range of
particle diameter, inhomogeneous composition of microgranules, no
uniform coating layer. The occurrence of some of these drawbacks is
common with rifaximin, the powder of which is composed by a fine
particles, and is extremely hydrophobic, electrostatic, hygroscopic
and difficult to be mixed with common excipients in powder.
Moreover it has a predisposition to segregate not allowing
homogenous mixture. In presence of such unfavourable
characteristics to get coated rifaximin would require the use of
more than one step and a large quantity of excipients, which would
limit the pharmaceutical strengths of human dosage.
[0032] As further advantage of the present invention, the
gastroresistant microgranules of rifaximin prepared on the basis of
the described technology of the present invention can directly be
used to fill capsules or can be mixed with excipients and sweetener
enhancers giving the possibility of an aqueous suspension
administration.
[0033] In addition and more remarkably the gastroresistant
microgranules of rifaximin can also be directly used for tablet
preparation through direct compression technology by adding
conventional vehicles or carriers. As additional advantage, the
tablets can be scored in order to modulate the dose strength or to
be crushed to facilitate the ingestion without losing the
gastroresistant property of the microgranules.
[0034] All these opportunities confer significant value to the
technology described in the present invention to prepare
gastroresistant microgranules of rifaximin, making it suitable for
a wide modulation of dosages and pharmaceutical forms.
[0035] In conclusion, the present invention shows, with respect to
other marketed rifaximin preparations, remarkable improvements that
can be summarized on the possibility to manufacture in only one
steps gastroresistant microgranules of rifaximin, which remain
insoluble in the stomach (e.g., at a range of pH between about 1.5
and about 4.0) and soluble in the intestine (e.g., at higher pH,
for example between about 5.5 and about 7.5), to administer high
dose, targeting the maximum release of the active ingredient in the
intestine and at the same time maximizing its contact with the
intestinal mucous membrane because of the high superficial area of
the microgranules.
DESCRIPTION OF THE INVENTION
[0036] The object of the present invention consists of
pharmaceutical formulations containing microgranules of rifaximin
coated with a gastroresistant polymer which is insoluble at pH
values ranging between 1.5 and 4.0 and soluble at pH values ranging
between 5.0 and 7.5, of their preparation and their use in
intestinal inflammatory bowel diseases and in particular in Crohn's
disease.
[0037] The microgranules may be from between about 1 micron to
about 900 microns in diameter, or more preferably from between
about 10 microns to about 500 microns in diameter.
[0038] The gastroresistance can be obtained using any material
insoluble at pH values ranging between about 1 to about 4.9, from
about 1.4 to about 4.2, or from about 1.5 and about 4.0. Suitable
polymers may also be soluble at pH values ranging from between
about 5.0 to about 7.0, 5.0 to about 7.5, or 5.0 and about 7.7 and
above.
[0039] Polymeric materials utilized in the gastroresistant
rifaximin formulations solubilize, as discussed above, at pH values
consist with the intestinal lumen, for example, from between about
4.9 and about 7.7, and can be used as gastroresistant,
entero-soluble coatings for drug release in the intestine when
desired. Examples of suitable polymeric materials include, for
example, acrylic polymers, methacrylic acid copolymers with an
acrylic or methacrylic ester (e.g., methacrylic acid ethylacrylate
copolymer (1:1) and methacrylic acid methylmethacrylate copolymer
(1:2), polyvinyl acetate phthalate, hydroxypropyl cellulose acetate
phthalate and cellulose acetate phthalate), as well as cellulose
acetate phthalate, hydroxypropyl methylcellulose phthalate,
polyvinyl acetate phthalate. Commercially available products
include, for example, KOLLIKOAT.RTM., EDRAGIT.RTM. (e.g., EUDRAGIT
40), AQUATERIC.RTM., AQOAT.RTM..
[0040] The enteric materials, which are soluble at higher pH
values, are frequently used for colon-specific delivery systems and
are employable in the gastroresistant rifaximin formulations
described herein. The enteric polymers used can also be modified by
mixing with other coating products that are not pH sensitive.
Examples of such coating products include, for example, the neutral
methacrylic acid esters with a small portion of
trimethylammonioethyl methacrylate chloride, sold currently under
the trade names EUDRAGIT.RTM. and EUDRAGIT.RTM. RL; a neutral ester
dispersion without any functional groups, sold under the trade
names EUDRAGIT.RTM. NE30D and EUDRAGIT.RTM. NE30, EUDRAGIT.RTM. 40;
polysaccharides, like amylose, chitosan, chondroitin sulphate,
dextran, guar gum, inulin and pectin; and other pH independent
coating products.
[0041] The polymer is from between about 5% and about 75% of the
weight of the microgranule. In other embodiments, the polymer is
from between about 10% and about 60%, 20% and about 55%, about 20%
to about 40%,_about 30% to about 80%, or 25% and about 50% of the
weight of the micro granule.
[0042] The weight percent of the polymer to the weight of the micro
granule can depend, in part, on the polymer used, the temperature
of the polymer, the formulation (e.g., bag, pill, capsule, etc.),
and the pH at which the polymer is soluble.
[0043] The gastroresistant rifaximin microgranules may further
comprise one or more of a diluents, plasticizer,
anti-agglomerative, anti-sticking, glidants, anti-foam surfactants,
or colouring substances. These, along with other polymers and
coating (e.g., protective coatings, over-coatings, and films) are
described below.
[0044] Suitable ingredients can be incorporated into the coating
formula such as plasticizers, which include, for example, adipates,
azelates, benzoates, citrates, isoebucates, phthalates, sebacates,
stearates and glycols.
[0045] Representative plasticizers include acetylated
monoglycerides, butyl phthalyl butyl glycolate, dibutyl tartrate,
diethyl phthalate, dimethyl phthalate, ethyl phthalyl ethyl
glycolate, glycerin, ethylene glycol, propylene glycol, triacetin
citrate, triacetin, tripropinoin, diacetin, dibutyl phthalate,
acetyl monoglyceride, polyethylene glycols, castor oil, triethyl
citrate, polyhydric alcohols, acetate esters, gylcerol triacetate,
acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate,
butyl octyl phthalate, diisononyl phthalate, butyl octyl phthalate,
dioctyl azelate, epoxydised tallate, triisoctyl trimellitate,
diethylhexyl phthalate, di-n-octyl phthalate, di-1-octyl phthalate,
di-1-decyl phthalate, di-n-undecyl phthalate, di-n-tridecyl
phthalate, tri-2-ethylhexyl trimellitate, di-2-ethylhexyl adipate,
di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl
sebacate, glyceryl monocaprylate, and glyceryl monocaprate.
[0046] Other various layers, as recognized by one of skill in the
art are also envisioned. The amount of plasticizer used in the
polymeric material typically ranges from about 10% to about 50%, or
about 10% to about 25% for example, about 10, 20, 30, 40, or 50%,
based on the weight of the dry polymer.
[0047] Optional modifying components of a protective layer which
can be used over the enteric or other coatings include a water
penetration barrier layer (semi-permeable polymer) which can be
successively coated after the enteric or other coating to reduce
the water penetration rate through the enteric coating layer and
thus increase the lag time of the drug release. Coatings commonly
known to one skilled in the art can be used for this purpose by
coating techniques such as fluid bed coating using solutions of
polymers in water or suitable organic solvents or by using aqueous
polymer dispersions. For example, useful materials include
cellulose acetate, cellulose acetate butyrate, cellulose acetate
propionate, ethyl cellulose, fatty acids and their esters, waxes,
zein, and aqueous polymer dispersions such as EUDRAGIT.RTM. RS and
RL 30D, EUDRAGIT.RTM. NE 30D, EUDRAGIT.RTM. 40, AQUACOAT.RTM.,
SURELEASE.RTM., cellulose acetate latex. Combinations of the
polymers and hydrophilic polymers such as hydroxyethyl cellulose,
hydroxypropyl cellulose (KLUCEL.RTM., Hercules Corp.),
hydroxypropyl methylcellulose (METHOCEL.RTM., Dow Chemical Corp.),
polyvinylpyrrolidone may also be used.
[0048] Anti-foaming agents can also be included in the
gastroresistant rifaximin formulations. In one embodiment, the
anti-foaming agent is simethicone. The amount of anti-foaming agent
used typically comprises from 0% to 0.5% of the final formulation.
Other agents can be added to improve the processability of a
sealant or barrier layer. Such agents include, for example, talc,
colloidal silica, polyvinyl alcohol, titanium dioxide, micronized
silica, fumed silica, glycerol monostearate, magnesium trisilicate,
and magnesium stearate, or a mixture thereof.
[0049] The amount of polymer to be used in the gastroresistant
formulations is typically adjusted to achieve the desired drug
delivery properties, including the amount of drug to be delivered,
the rate and location of drug delivery, the time delay of drug
release, and the size of the multiparticulates in the formulation.
The combination of all solid components of the polymeric material,
including co-polymers, fillers, plasticizers, and optional
excipients and processing aids, typically provides about 1% to
about 50% weight of the core.
[0050] The gastroresistant rifaximin microgranules comprise
rifaximin in a polymorphous form and/or a raw form. The forms in
any microgranule may be a mixture or may be a pure form. The form
of rifaximin may depend, in part, on the form of the rifaximin that
is coated, on the composition of excipients, and on the process
used to form the microgranules. The rifaximin polymorphous forms
are selected from Form a, Form 3, Form y, Form 6, or Form e of
rifaximin, mentioned above.
[0051] The mixture containing the gastroresistant material is
prepared by suspending the components in demineralised water and
homogenizing the suspension with an high speed mixing system,
preferably an Ultra Turax homogeniser, in order to obtain a
homogeneous suspension containing between 15% and 30% of solid
particles. The homogeneous suspension containing the
gastroresistant material can be applied by means of a coating
system or a fluid bed apparatus.
[0052] In the current invention, fluid bed technology has been
used. The mixture containing the active ingredient is maintained in
suspension by a flux of warm air, at the same time the
gastroresistant suspension is sprayed by means of a jet applied in
a top part (top spray) or in a low part (bottom spray--Wurster
system) of the apparatus. For example, a fluid bed apparatus type
Glatt GPG 30 has been used with a Wurster system of 18 inch with a
1.8 mm spray jet.
[0053] Process parameters including the air entering temperature,
the product temperature and the speed of film application are
specifically controlled. The speed of film application and the air
temperature are balanced to avoid overheating of the product
resulting in a non-homogeneous gastroresistant microgranule
formation (too fast drying of the product) or, an agglomeration of
the mixture to be coated to slow drying of the product.
[0054] In formulating, for example, a 25 kg batch of
gastroresistant rifaximin, a jet spray between 150 and 300 g/min
may be used. A jet spray 150 and 250 g/min, and pressures between
1.0 and 1.5 bar may also be used. The speed and pressure may be
independently manipulated. The product temperature, during the
spraying is maintained at a constant temperature between about
20.degree. C. and about 40.degree. C. The air temperature in
entrance may also be regulated at between about 40.degree. C. and
about 75.degree. C., preferably between about 60.degree. C. and
about 70.degree. C.
[0055] The obtained gastroresistant microgranules are formulated
for medical preparations in order to obtain, after adding water, a
suspension with pleasant taste for the patients. Sweeteners agents
like: sucrose, sorbitol, mannitol, saccharine, acesulfame,
neohesperedine; suspending agents like polyvinyl pyrrolidone (PVP),
sodium carboxymethyl cellulose, pectin, xantan gum, agar and
glidants like silica gel can be added to the gastroresistant
microgranules to this end.
[0056] The gastroresistant microgranules are mixed with the above
mentioned excipients in a suitable apparatus like a biconical mixer
or V mixer for the time necessary to obtain the homogeneity of the
gastroresistant microgranules inside the mixture. The ratio between
gastroresistant microgranules and excipients is between 1:0.1 and
1:10, preferably between 1:0.5 and 1:5. The obtained mixture can be
divided in bags containing a quantity of rifaximin between 1 mg and
3000 mg, preferably between 50 mg and 800 mg.
[0057] The obtained gastroresistant microgranules of rifaximin can
be directly compressed in tablet after having mixed with
appropriate excipients such as diluents such as dicalcium
phosphate, calcium sulphate, cellulose, microcrystalline cellulose
(AVICEL.RTM.), hydroxypropyl methyl cellulose, corn starch,
lactose, kaolin, mannitol, sodium chloride, dry starch; binders
such as starch, gelatine, sugars as sucrose, glucose, dextrose,
lactose, synthetic gum, sodium alginate, carboxymethyl cellulose,
methylcellulose, polyvinylpyrrolidone, polyethylene glycol,
ethylcellulose, water, waxes, alcohol; lubricants such as talc,
magnesium stearate, calcium stearate, stearic acid, hydrogenated
vegetable, oils, polyethylenglycole; glidants such as colloidal
silicon dioxide, talc; disintegrants such as corn and potato
starch, croscarmelose, crospovidone, sodium starch glycolate,
colouring agents, sweeteners such as sucrose, sorbitol, mannitol,
saccharine, acesulfame, neohesperedine.
[0058] Conventional technology and apparatus known to expert-of-art
of tablet preparation can be applied. The gastroresistant
microgranules are mixed with the above mentioned excipients in a
suitable apparatus like a biconical mixer or V mixer for the time
necessary to obtain the homogeneity of the gastroresistant
microgranules inside the mixture.
[0059] The gastroresistant granules of rifaximin have good
properties with respect to the ability to flow freely, cohesiveness
and lubrication, therefore the ratio between gastroresistant
microgranules and excipients is between 1:0.2 and 1:0.05,
preferably between 1:0.15 and 1:0.1. The obtained mixture can be
pressed in order to obtain, using a suitable punch, tablets
containing a quantity of rifaximin between 50 mg and 600 mg,
preferably between 100 mg and 500 mg. As described above the
favorable properties of Rifaximin gastroresistant microgranules
allow achieving a suitable blend for direct compression with the
addition of minimal quantity of excipients. The possibility to
obtain tablets using a blend containing up to 93% of
gastroresistant microgranules presents a further advantage: it
allows to maintain the dose of 400 mg in a suitable size to
maintain a good compliance for the patient.
[0060] Tablets can be successively coated with a conventional
hydrophilic film to achieve taste-masking properties and improve
appearance. Suitable materials could be: hydroxyethyl cellulose,
hydroxypropyl cellulose (KLUCEL.RTM., Hercules Corp.),
hydroxypropyl methylcellulose (METHOCEL.RTM., Dow Chemical Corp.),
polyvinylpyrrolidone.
[0061] The tablet containing rifaximin gastroresistant
microgranules can be film-coated following conventional procedures
known to someone skilled in the art selecting as a polymer one or
more of cellulose and its substitutes such as hydroxypropyl
cellulose, hydroxymethyl cellulose, hydroxypropyl-methyl cellulose.
Alternatives to the cellulose ethers are certain acrylics, such as
methacrylate and methylmethacrylate copolymers. Polymers can be
employed as solutions either aqueous or organic solvent-based
system. Incorporating a plasticiser the flexibility of the coating
film is improved; by addition of plasticisers it reduced the risk
of film cracking and it is improved the adhesion of the film to the
substrate. Examples of typical plasticisers include glycerin,
propylene glycol, polyethylene glycols, triacetin, acetylated
monoglycerides, citrate esters and phthalate esters. Colorants
usually are used to improve the appearance of the product.
Water-soluble and/or organic solvent-soluble dyes can be used like
albumin lake, titanium dioxide, iron oxide. Finally, stabilisers
such as EDTA can be added to the coating.
[0062] The picture shown in FIG. 3 (Scanning electron microscopy of
rifaximin gastroresistant microgranules compressed in the tablets)
and the data of FIG. 2 show that the compression does not alter the
integrity of the gastroresistant layer of the microgranules
compressed in the tablets.
[0063] Furthermore, the obtained gastroresistant microgranules of
rifaximin have such favourable properties regarding the particle
size and the capacity of flow freely to be directly used, with the
addition of inert diluents and glidants to fill in hard gelatine
capsules. Examples of typical diluents include dicalcium phosphate,
calcium sulphate, cellulose, microcristallyne cellulose,
hydroxypropylmethylcellulose, corn starch, lactose, caolin,
mannitol, sodium chloride, dry starch, from between about 1 and to
about 225 mg. In this case the density of gastroresistant
microgranules, between 0.25 and 0.45 mg/ml allows to fill about
140-250 mg of Rifaximin in conventional 000 hard gelatine capsules
according to the content of Rifaximin in the gastroresistant
microgranules.
[0064] All the medicine preparation, namely thermo welded bags,
tablets and capsules can be usefully used in the therapy of
inflammatory bowel disease to include Crohn's disease.
[0065] The following examples have to be considered as a further
illustration of the object of the invention and not as a
limitation.
Example 1
[0066] Rifaximin Preparation in Gastroresistant Microgranules
[0067] In a fluid bed apparatus, Glatt GPC 30, with a Wurster
system of 18 inches with a 1.8 mm spray jet, 25000 g of rifaximin
powder and 125 g of Aerosil as fluidiser are loaded.
Contemporaneously in a mixer under agitation a suspension is
prepared using 48107 g of demineralised water, 9281 g of
methacrylic acid ethylacrylate copolymer marketed under the
trademark KOLLICOAT.RTM. MAE 100 P, 1392 g propylglycol, 2475 g of
talc, 557 g of titanium dioxide FU and 62 g of iron oxide E 172.
The solid components of the suspension are homogeneously mixed in
demineralised water with an high speed homogeniser (Ultra Turrax).
The prepared suspension feeds the spray system of the fluid bed
apparatus and nebulized, at a pressure between 1.0 and 1.5 bar,
trough the 1.8 mm nozzle on the mixture of rifaximin powder and
Aerosil 200 maintained in suspension in the fluid bed by a warm air
flow.
[0068] The applied conditions are described in table 1:
TABLE-US-00001 TABLE 1 Pre-warm Application of Process parameters
phase coating solution Drying Air flow in entrance 400 .+-. 100 550
.+-. 100 350 .+-. 50 (m.sup.3/hour) Air temperature in entrance 60
.+-. 2 60.degree. C. .+-. 10 50 .+-. 2 (.degree. C.) Product
temperature (.degree. C.) 32 25-27 30 .+-. 2 Jet pressure (bar)
1-1.5 .+-. 0.1 (initial phase) Jet speed (g/min) 150-200
[0069] The obtained microgranules are submitted to granulometry
analysis by Light Scattering technology using Malvern Mastersizer
2000 apparatus obtaining the following results: 100%<200 micron
[0070] 99.17%<150 micron [0071] 90.03%<100 micron [0072]
48.37%<50 micron [0073] 6.20%<10 micron
[0074] The rifaximin in the gastroresistant microgranule
preparation corresponds to 61.4% of the total particle weight.
Example 2
[0075] SEM Microscopy of Gastroresistant Microgranules of
Rifaximin
[0076] A SEM Philips 515 instrument is used for the
observations.
[0077] Rifaximin gastroresistant microgranules are sputtered with
gold by current stream of 30 mA, getting an Au-layer of about 100
nm. An accelerating voltage of 15 kV is applied.
[0078] The images are digitally recorded with a CCD camera.
[0079] An image of microgranules of rifaximin is shown in FIG. 1A,
while in FIG. 1B detail of a single microgranule is shown.
Example 3
[0080] Gastroresistant Microgranules of Rifaximin Prepared in
Thermo Welded Bags
[0081] 9.12 Kg of gastroresistant rifaximin microgranules prepared
according to the example 1, 19.58 Kg of sorbitol, 0.49 Kg of
aspartame, 0.21 Kg of anhydrous citric acid, 2.10 Kg of pectin,
2.10 Kg of mannitol, 0.21 Kg of neohesperidine DC, 1.12 Kg of
cherry flavour and 0.07 Kg of silica gel are sieved on a sieve with
mesh of 0.5 mm and then mixed for 20 minutes in a V mixer. The
resulting mixture is divided in thermo welded bags containing 5
grams of product corresponding to 800 mg of rifaximin. In the
following Table 2 the composition of the medicinal specialty,
thermo welded bag, is reported:
TABLE-US-00002 TABLE 2 Amount Components (mg) % Gastroresistant
rifaximin microgranules 1303 26.06 (corresponding to 800 mg of
rifaximin) Aspartame 70 1.40 Anhydrous citric acid 30 0.60 Pectin
300 6.00 Mannitol 300 6.00 Neohesperidin DC 30 0.60 Sorbitol 2797
55.94 Cherry-flavour 160 3.20 Silica gel 10 0.20
Example 4
[0082] Gastroresistant Microgranules of Rifaximin Prepared in
Compressed Tablets
[0083] 9.3 Kg of gastroresistant rifaximin microgranules prepared
according to the example 1, 593 g of Sodium Starch Glycolate, 100 g
of magnesium stearate are sieved on a sieve with mesh of 0.5 mm and
then mixed for 20 minutes in a V mixer. The resulting mixture is
compressed using a rotary tabletting machine (Fette 1200) equipped
with oblong, scored 19.times.9 mm punches at the final weight of
718 mg (corresponding to a content of 400 mg of rifaximin).
[0084] The tablet composition is reported in Table 3.
TABLE-US-00003 TABLE 3 Amount Tablet composition mg % Rifaximin
gastroresistant 650.00 90.53 microgranules (corresponding to 400 mg
of rifaximin) sodium 34.95 4.87 carboxymethylcellulose Avicel PH
101 24.31 3.34 Mg-stearate 8.74 1.21 718.00 100.00
[0085] The tablets are then coated, using conventional pan
equipment, with a hydroxypropylmethylcellulose film in order to
improve appearance and achieve taste mask properties. The unitary
film composition is reported in Table 4:
TABLE-US-00004 TABLE 4 Amount Coating composition (mg) HPMC 14.07
Titanium dioxide 4.10 Na-EDTA 0.05 Propylene glycol 1.37 Red Iron
Oxide E 172 0.41
Example 5
[0086] Gastroresistant Microgranules of Rifaximin Prepared in Hard
Capsule
[0087] 9.0 Kg of gastroresistant rifaximin microgranules prepared
according to the example 1, are blended and sieved on 0.5 mm with
110 g of talc and 1.1 kg of lactose. The resulting mixture is
introduced in hard gelatine capsules type 000 using a conventional
equipment like Zanasi LZ64 at a final weight of 461.00,
corresponding to a content of about 270 mg of rifaximin. The
capsule composition is reported in Table 5.
TABLE-US-00005 TABLE 5 Amount Capsule composition mg % Rifaximin
gastroresistant 406.00 88.01 granules (corresponding to 270 mg of
rifaximin) Talc 5.00 1.01 Lactose 50.00 10.8
Example 6
[0088] Dissolution Performance of Gastroresistant Microgranule of
Rifaximin Medicinal Preparations
[0089] The gastroresistence of the pharmaceutical preparation is
evaluated according to what described at page 247 of the US
Pharmacopeia (USP), 28.sup.a Ed.
[0090] The dissolution test of medicinal preparations containing
gastroresistant microgranules of rifaximin, described in examples
1, 3 and 4 and consisting of rifaximin gastroresistant
microgranules, thermo welded bags containing rifaximin
gastroresistant microgranules, and tablets containing rifaximin
gastroresistant microgranules, respectively, are evaluated by using
the following conditions:
[0091] Equipment: SOTAX AT7 Smart
[0092] Medium: HCl 0.1 N, pH 1; after 2 hours a phosphate buffer
with 2% of Sodium Lauryl Sulphate is added to bring up the pH to
6.8
[0093] Stirring speed: 100 rpm
[0094] Temperature: 37.degree. C.
[0095] Sampling time: 120, 135, 150, and 180 min.
[0096] The content of dissolved rifaximin is measured by a HPLC
method.
[0097] The results, reported in Table 6, are the average of six
measures and are expressed as percent of dissolution over the total
amount of rifaximin.
TABLE-US-00006 TABLE 6 Time Dissolution (%) Medium & pH (min)
Microgranules Tablets Bags HCl 0.1N, pH 1 120 2.41 1.07 2.57
Phosphate buffer, pH 6.8 135 93.8 67.9 90.3 Phosphate buffer, pH
6.8 150 95.4 81.6 95.1 Phosphate buffer, pH 6.8 165 97.2 88.1 96.4
Phosphate buffer, pH 6.8 180 97.4 93.1 96.2
[0098] After 12 months of storage at 25.degree. C. microgranules,
prepared as in Example 1, show a similar dissolution profile,
precisely a dissolution of 2.2% after 120 min at pH 1 in 0.1 N
hydrochloric acid and of 91.1% after 60 min in phosphate buffer at
pH 6.8.
Example 7
[0099] Treatment of Crohn's Disease
[0100] The medicinal rifaximin preparation containing
gastroresistant microgranules described in example 3 has been used
in a clinical multi-center randomised trial versus placebo in
patients affected by Crohn's disease. 55 Crohn's disease patients
in acute, mild to moderate grade, phase, having CDAI (Crohn Disease
Active Index) value between 200 and 300, have been recruited. The
primary end point was represented by the percentage of the patients
in clinic remission defined as CDAI lower than 150 points at the
end of the study. The patients, randomised in two groups: group A,
of 27 patients and group B of 28 patients, have been treated for 12
weeks according to the following therapeutic schemes:
[0101] Group A: rifaximin 800 mg, administrated 2 times a day for a
total dosage equal to 1600 mg/die;
[0102] Group B: placebo, administrated 2 times in a day in a such
quantity to correspond to the content of the dose of the active
principle.
[0103] The primary end point, the clinical remission after 12 weeks
of therapy, is achieved by 51.9% of the patients with the
gastroresistant formulation and by 32.1% of the patient treated
with placebo. Moreover only one patients of the group treated with
rifaximin has been forced early to leave the clinical trial because
of the therapeutic failure, while nine patients treated with
placebo discontinued the treatment.
[0104] The results are summarised in Table 7
TABLE-US-00007 TABLE 7 Number of clinical Number of therapeutic
Group remission failure A (rifaximin) 27 patients 14 (51.9%) 1
(3.4%) B (placebo) 28 patients 9 (32.1%) 9 (32.1%)
Example 8
[0105] Treatment of Crohn's Patients Characterized by a Protein C
Reactive Value Higher than Normal
[0106] At the beginning of the treatment, 31 patients had a protein
C reactive value, an index of inflammation in course, higher than
normal. The patients have been divided into two groups: one of 16
treated with rifaximin and the other treated with placebo, as
described in example 3.
[0107] The primary end point, the clinical remission, has been
obtained in 62.5% of the patients treated with the new formulation
of rifaximin and in 20.5% only of the patients treated with
placebo. Moreover, none of the patients of the subgroup treated
with rifaximin dropped from the study for therapeutic failure,
unlike 6 of the patients of the subgroup treated with placebo.
[0108] The Table 8 shows the obtained results.
TABLE-US-00008 TABLE 8 Number of Subgroup with protein C value
clinical Number of higher than normal values remission therapeutic
failure 16 patients treated with rifaximin 10 (62.5%) 0 (0%) 15
patients treated with placebo 3 (20%) 6 (40%)
[0109] The incidence of side effects has been similar in the two
groups confirming the excellent tolerability of the rifaximin
formulation in continuous and prolonged use.
* * * * *