U.S. patent application number 12/695945 was filed with the patent office on 2010-12-30 for gastroresistant pharmaceutical formulations containing rifaximin.
This patent application is currently assigned to ALFA WASSERMANN S.P.A.. Invention is credited to Ernesto Palazzini, Maria Rosaria Pantaleo, Giuseppe Claudio Viscomi, Villiam Zamboni.
Application Number | 20100330129 12/695945 |
Document ID | / |
Family ID | 36694343 |
Filed Date | 2010-12-30 |
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United States Patent
Application |
20100330129 |
Kind Code |
A1 |
Viscomi; Giuseppe Claudio ;
et al. |
December 30, 2010 |
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) |
Correspondence
Address: |
TechLaw LLP
10755 Scripps Poway Parkway, Suite 465
San Diego
CA
92131
US
|
Assignee: |
ALFA WASSERMANN S.P.A.
Allano
IT
|
Family ID: |
36694343 |
Appl. No.: |
12/695945 |
Filed: |
January 28, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11814628 |
Jul 24, 2007 |
|
|
|
PCT/EP2006/002022 |
Mar 6, 2006 |
|
|
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12695945 |
|
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Current U.S.
Class: |
424/400 ;
514/279 |
Current CPC
Class: |
A61K 9/5026 20130101;
A61K 31/437 20130101; A61K 31/44 20130101; A61K 9/2027 20130101;
A61P 1/14 20180101; A61P 1/04 20180101; Y02A 50/30 20180101; A61K
9/28 20130101; Y02A 50/473 20180101; A61P 1/12 20180101; A61P 31/04
20180101; A61K 9/1635 20130101; A61K 9/5073 20130101; A61K 9/1652
20130101; A61K 9/2054 20130101; A61P 29/00 20180101; A61K 9/0095
20130101; A61K 31/395 20130101; A61P 1/00 20180101 |
Class at
Publication: |
424/400 ;
514/279 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 31/437 20060101 A61K031/437; A61P 1/12 20060101
A61P001/12; A61P 29/00 20060101 A61P029/00; A61P 1/14 20060101
A61P001/14; A61P 31/04 20060101 A61P031/04 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 7, 2005 |
IT |
BO 2005 A 000123 |
Claims
1. A pharmaceutical composition comprising a therapeutically
effective amount of rifaximin or polymorph thereof, one or more
release controlling agents and at least one pharmaceutically
acceptable excipient.
2. The pharmaceutical composition according to claim 1, wherein the
composition is formulated to delay release of rifaximin in the
gastrointestinal tract.
3. The pharmaceutical composition according to claim 2, wherein the
composition is formulated to delay release of rifaximin in the
intestinal tract.
4. The pharmaceutical composition according to claim 2, wherein the
composition is formulated to give binding properties in the
gastrointestinal tract.
5. The pharmaceutical composition according to claim 4, wherein the
binding properties are achieved with one or more binder compounds
selected from the group consisting of cellulose, cellulose
derivatives, starches, gums, synthetic gum, polyvinylpyrrolidone,
sodium carboxymethyl cellulose, polyethylene glycol, gelatin,
polypropylene glycol, alginic acid, alginate salts, sugars, and
combinations thereof.
6. The pharmaceutical composition according to claim 5, wherein
said sugars are selected from the group consisting of sucrose,
glucose, dextrose, and lactose.
7. The pharmaceutical composition according to claim 2, wherein
delay in release of rifaximin is achieved with excipients selected
from the group consisting of proteins carbohydrates,
polysaccharides, cellulose derivatives, acetylated glycerides,
diethylphthalate, propylene glycol, polyethylene glycol,
polysorbate, polyoxyethylenate esthers, poly vinylacetate
phthalate, polyvinyl alcohol, acrylic polymer, acrylic methacrylic
acid copolymers with an acrylic or methacrylic ester, polyvinyl
alcohols, polyvinylpyrrolidone, polymers of acrylic and methacrylic
esters, blends and copolymers or mixtures thereof, polyols,
dextrans, sodium alginate, gums, xanthan gum, guar gum, and
synthetic gum.
8. The pharmaceutical composition according to claim 7, wherein
said proteins are selected from the group consisting of pectin,
zein, and gelatin.
9. The pharmaceutical composition according to claim 7, wherein
said carbohydrates are selected from the group consisting of starch
and chitosan.
10. The pharmaceutical composition according to claim 7, wherein
said polysaccharide is cellulose.
11. The pharmaceutical composition according to claim 7, wherein
said cellulose derivatives are selected from the group consisting
of methyl cellulose, ethyl cellulose, hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, hydroxypropyl cellulose acetate
phthalate, cellulose acetate phthalate, cellulose acetate,
cellulose acetate propionate, cellulose acetate butyrate, and
sodium carboxymethyl cellulose.
12. The pharmaceutical composition according to claim 1, wherein
the release controlling agent is a hydrophilic polymer or
hydrophobic polymer or combination thereof.
13. The pharmaceutical composition according to claim 1, wherein
the release controlling agent is a hydrophilic polymer.
14. The pharmaceutical composition according to claim 13, wherein
the hydrophilic polymer is selected from the group consisting of
carbohydrate, cellulose derivatives, gum, alginates,
polyvinylacetate, polyvinylalcohol, povidone, polyvinylpyrrolidone,
acrylic and methacrylic acid copolymers and mixtures thereof.
15. The pharmaceutical composition according to claim 14, wherein
the carbohydrate is cellulose.
16. The pharmaceutical composition according to claim 14, wherein
the cellulose derivative is ethylcellulose, hydroxypropylcellulose,
or hydroxypropylmethylcellulose.
17. The pharmaceutical composition according to claim 14, wherein
the gum is xanthan gum.
18. The pharmaceutical composition according to claim 12, wherein
the hydrophobic polymer is selected from the group consisting of
waxes, fatty acids and their esters, glyceryl ester, hydrogenated
oil, castor oil, mineral oil, paraffin, stearate salts, stearic
acid, talc, and mixture thereof.
19. The pharmaceutical composition according to claim 18, wherein
the glyceryl ester is glyceryl monostearate or glyceryl
distearate.
20. The pharmaceutical composition according to claim 18, wherein
the stearate salt is magnesium stearate or calcium stearate.
21. The pharmaceutical composition according to claim 1, further
comprising one or more solubilizing agents.
22. The pharmaceutical composition according to claim 21, wherein
the solubilizing agent is selected from the group consisting of
surfactants, polysorbates, polyoxyethylene esters, dextrins, waxes,
monohydric alcohol esters, trialkyl citrates, lower alcohol fatty
acid esters, glycerol acetates, acetin, diacetin, triacetin,
glycerol fatty acid esters, monoglycerides, diglycerides,
triglycerides, acetylated mono and diglycerides, propylene glycol
esters, ethylene glycol esters, and combinations thereof.
23. The pharmaceutical composition according to claim 1, wherein
the at least one pharmaceutically acceptable excipient is selected
from the group consisting of binders, diluents, lubricants,
surfactants, plasticizers, and glidants.
24. The pharmaceutical composition according to claim 23, wherein
the diluent is selected from the group consisting of cellulose or
cellulose derivatives, polyhydric alcohol, sugar alcohols, sulphate
or phosphate salts of inorganic metals, and mixtures thereof.
25. The pharmaceutical composition according to claim 23, wherein
the lubricant is selected from the group consisting of magnesium or
calcium stearate, polyethylene glycol, stearic acid, hydrogenated
vegetable oil, glyceryl stearate, cornstarch, talc, magnesium
silicate, colloidal silicon dioxide, silicon hydrogel, and mixtures
thereof.
26. The pharmaceutical composition according to claim 23, 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, 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.
27. The pharmaceutical composition according to claim 23, wherein
the glidant is selected from the group consisting of silicon
dioxide, colloidal silica, powdered cellulose, talc, dicalcium
phosphate, and mixtures thereof.
28. A pharmaceutical composition according to claim 1, wherein the
composition is a one or multiple daily dose form comprising from 1
to 3000 mg of rifaximin in one or more polymorph forms or raw
form.
29. A pharmaceutical composition according to claim 28, comprising
50 to 800 mg of rifaximin in one or more polymorph forms or raw
form.
30. A pharmaceutical composition according to claim 28, wherein the
unit dosage is 200 mg, or 400 mg or 550 mg or 600 mg or 800 mg of
rifaximin in one or more polymorph forms or raw form.
31. A method of treating or preventing a gastrointestinal disorder
in a subject in need thereof comprising administering to said
subject the pharmaceutical composition of claim 1, wherein said
gastrointestinal indication is selected from the group consisting
of traveler's diarrhea, infectious diarrhea, an antibacterial
prophylactic prior to colon surgery, Crohn's disease, small
intestinal bacterial overgrowth, traveler's diarrhea prophylaxis,
inflammation of intestinal mucous membrane, surgical prophylaxis
and gastric dyspepsia.
32. The method according to claim 31, wherein the composition is
used for the treatment of gastrointestinal inflammatory
diseases.
33. The method according to claim 31, wherein the composition is
used for the treatment of disease caused by E. coli.
34. The method according to claim 31, wherein said composition is
further coated with a coating which includes a film coating, a
sugar coating, and/or an enteric coating.
35. The method according to claim 34, wherein the coating comprises
coating agents, plasticizers, antisticking agents, surfactants,
coloring agents, or mixtures thereof.
36. A pharmaceutical composition according to claim 1, wherein the
composition is formulated as a tablet, granule, capsule,
microcapsule, tablet in capsule, or microgranules for
suspension.
37. A pharmaceutical composition comprising a therapeutically
effective amount of rifaximin or polymorph thereof, one or more
release controlling agents and one or more pharmaceutically
acceptable excipients, wherein said release controlling agents or
excipients are selected from the group consisting of methacrylic
acid ethylacrylate copolymer (1:1), methacrylic acid
methylmethacrylate copolymer (1:2), polyvinyl acetate phthalate,
polyvinylpyrrolidone, cellulose, microcrystalline cellulose,
hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, carboxymethyl cellulose, methylcellulose,
hydroxypropyl methyl cellulose, cellulose acetate, cellulose
acetate butyrate, cellulose acetate propionate, ethyl cellulose,
hydroxypropyl methylcellulose phthalate, hydroxypropyl cellulose
acetate phthalate/cellulose acetate phthalate, cellulose acetate
phthalate, cellulose acetate latex, hydroxypropyl methylcellulose,
sodium carboxymethyl cellulose, acetylated glycerides,
diethylphthalate, ethylene glycol, propylene glycol, polyethylene
glycol, polysorbate, polyoxyethylenate esthers, amylose, chitosan,
chondroitin sulphate, dextran, guar gum, inulin, adipates,
azelates, benzoates, citrates, isoebucates, phthalates, sebacates,
stearates, glycols, acetylated monoglycerides, butyl phthalyl butyl
glycolate, dibutyl tartrate, diethyl phthalate, dimethyl phthalate,
ethyl phthalyl ethyl glycolate, glycerin, triacetin citrate,
triacetin, tripropinoin, diacetin, dibutyl phthalate, acetyl
monoglyceride, 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,
epoxydized 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, fatty
acids, fatty acid esters, waxes, zein, simethicone, polyvinyl
alcohol, titanium dioxide, micronized silica, silica gel, fumed
silica, colloidal silica, colloidal silicon dioxide, glycerol
monostearate, magnesium trisilicate, magnesium stearate, sucrose,
sorbitol, mannitol, glucose, dextrose, lactose, saccharine,
acesulfame, neohesperedine, pectin, xanthan gum, agar, dicalcium
phosphate, calcium sulphate, kaolin, sodium chloride, dry starch,
starch, corn starch, potato starch, gelatin, synthetic gum, sodium
alginate, talc, calcium stearate, stearic acid, hydrogenated
vegetable, oils, croscarmelose, crospovidone, sodium starch
glycolate, coloring agents, acetylated monoglycerides, citrate
esters, albumin lake, iron oxide, and mixtures thereof.
38. A pharmaceutical composition comprising a therapeutically
effective amount of rifaximin or polymorph thereof, one or more
release controlling agents and one or more pharmaceutically
acceptable excipients, wherein said composition is
multi-layered.
39. A pharmaceutical composition according to claim 38, wherein at
least one enteric layer is present.
40. A pharmaceutical composition according to claim 39, further
comprising a hydrophilic film.
Description
[0001] This application is a continuation under 35 U.S.C. .sctn.120
of U.S. patent application Ser. No. 11/814,628, filed Jul. 24,
2007, which is a 35 U.S.C. .sctn.371 national phase filing of PCT
Application No. PCT/EP2006/002022, filed Mar. 6, 2006, which claims
priority to Italian Application No. BO 2005 A 000123, filed Mar. 7,
2005, the contents of each of which are hereby incorporated by
reference.
[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:
diarrhea, 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. 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.
[0004] 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
canalization, 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.
[0005] 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.
[0006] 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., diarrhea, intestinal pain and
meteorism; and to prevent and to cure septic complications, e.g.,
abscesses, fistulas and toxic state.
[0007] 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 enterobacteria).
Metronidrazol has been used at a dose of 10-20 mg/kg/day for 4
months (Sunterland, L. Gut, 199132, 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.
[0008] 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 of 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.
[0009] 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
feces 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.
[0010] 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 0 as
the starting material (The Merck Index, XIII Ed., 8301).
[0011] Guidance for rifaximin crystallization 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 .alpha., Form .beta., Form .gamma.,
Form .delta. and Form .epsilon., respectively.
[0012] 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 diarrhea-like episodes,
traveler's diarrhea 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.
[0013] 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.
[0014] 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 paediatric use.
[0015] 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).
[0016] The novel forms also utilize the polymorphic forms of
rifaximin.
[0017] 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. Very often agglomeration
occurs or random blend of coated and uncoated particles is commonly
obtained.
[0018] 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 labor necessary to carry out
the entire procedure, especially on the large scale, are minimized.
This result comes from a combination between the rifaximin
properties and a proper balancing the quantity of rifaximin, of
enteric polymer, of plasticizer, and process parameters.
[0019] 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.
[0020] 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).
[0021] 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..
[0022] 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.
[0023] Other excipients with anti-agglomerative properties, like
talc; plasticizing properties, like acetylated glycerides,
diethylphthalate, propylene glycol and polyethylene glycol;
surfactants like polysorbate and polyoxyethylenate esters,
anti-foam as well as anti-sticking agents can be added together
with the polymeric material.
[0024] 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 required the use of
more than one step and a large quantity of excipients, which would
limit the pharmaceutical strengths of human dosage.
[0025] 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.
[0026] In addiction 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.
[0027] 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.
[0028] 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.
BRIEF DESCRIPTION OF DRAWINGS
[0029] FIG. 1A is an image of microgranules of rifaximin.
[0030] FIG. 1B is a closer image of a single microgranule.
[0031] FIG. 2 is a line graph which shows the dissolution profiles
of gastroresistant rifaximin.
[0032] FIG. 3 is a scanning electron microscope image of rifaximin
gastroresistant microgranules that are compressed in tablets.
DESCRIPTION OF INVENTION
[0033] 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.
[0034] 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.
[0035] 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.
[0036] 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, AQOAT.RTM..
[0037] 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. NE3OD 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.
[0038] 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 30%
to about 80%, or 25% and about 50% of the weight of the
microgranule. The weight percent of the polymer to the weight of
the microgranule 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.
[0039] The gastroresistant rifaximin microgranules may further
comprise one or more of a diluents, plasticizer,
anti-agglomerative, anti-sticking, glidants, anti-foam surfactants,
or coloring substances. These, along with other polymers and
coating (e.g., protective coatings, over-coatings, and films) are
described below.
[0040] 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. 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. 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%,
for example, about 10, 20, 30, 40, or 50%, based on the weight of
the dry polymer.
[0041] 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 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.
[0042] 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.
[0043] 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.
[0044] 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 .alpha., Form .beta., Form .gamma., Form
.delta., or Form .epsilon. of rifaximin, mentioned above.
[0045] 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.
[0046] 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.
[0047] 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.
[0048] 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.
[0049] 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, xanthan gum, agar and
glidants like silica gel can be added to the gastroresistant
microgranules to this end.
[0050] 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.
[0051] 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, gelatin, 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, polyethylenglycol; glidants such as colloidal
silicon dioxide, talc; disintegrants such as corn and potato
starch, croscarmelose, crospovidone, sodium starch glycolate,
coloring agents, sweeteners such as sucrose, sorbitol, mannitol,
saccharine, acesulfame, neohesperedine.
[0052] 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.
[0053] The gastroresistant granules of rifaximin have good
properties in respect of 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
addiction 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.
[0054] 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.
[0055] The tablet containing rifaximin gastroresistant
microgranules can be film-coated following conventional procedure
known to someone skilled in the art selecting as polymer one or
more of cellulose and its substitutes such as hydropropylcellulose
hydromethylcellulose, hydropropyl-methylcellulose. Alternatives to
the cellulose ethers are certain acrylics, such as metacrylate and
methylmetacrylate 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 is 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
glicol, polyethylene glycols, triacetin, acetylated monoglycerides,
citrate esthers and phtalate esthers. 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.
[0056] 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.
[0057] Furthermore, the obtained gastroresistant microgranules of
rifaximin have such favorable properties regarding the particle
size and the capacity of flow freely to be directly used, with the
addiction of inert diluents and glidants to fill in hard gelatin
capsules. Examples of typical diluents include dicalcium phosphate,
calcium sulphate, cellulose, microcrystalline cellulose,
hydroxypropylmethylcellulose, corn starch, lactose, kaolin,
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 gelatin capsules
according to the content of Rifaximin in the gastroresistant
microgranules.
[0058] 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.
[0059] The following examples have to be considered as a further
illustration of the object of the invention and not as a
limitation.
Example 1
Rifaximin Preparation in Gastroresistant Microgranules
[0060] 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.
[0061] 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 (gamin) 150-200
[0062] The obtained microgranules are submitted to granulometry
analysis by Light Scattering technology using Malvern Mastersizer
2000 apparatus 5 obtaining the following results: 100%<200
micron [0063] 99.17%<150 micron [0064] 90.03%<100 micron
[0065] 48.37%<50 micron [0066] 6.20%<10 micron
[0067] The rifaximin in the gastroresistant microgranule
preparation corresponds to 61.4% of the total particle weight.
Example 2
SEM Microscopy of Gastroresistant Microgranules of Rifaximin
[0068] A SEM Philips 515 instrument is used for the
observations.
[0069] 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.
[0070] The images are digitally recorded with a CCD camera.
[0071] An image of microgranules of rifaximin is shown in FIG. 1A,
while 20 in FIG. 1B a detail of a single microgranule is shown.
Example 3
[0072] Gastroresistant Microgranules of Rifaximin Prepared in
Thermo Welded Bags
[0073] 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 speciality,
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
Gastroresistant Microgranules of Rifaximin Prepared in Compressed
Tablets
[0074] 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).
[0075] 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
[0076] 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
Gastroresistant Microgranules of Rifaximin Prepared in Hard
Capsule
[0077] 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 gelatin 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
Dissolution Performance of Gastroresistant Microgranule of
Rifaximin Medicinal Preparations
[0078] The gastroresistance of the pharmaceutical preparation is
evaluated according to what described at page 247 of the US
Pharmacopeia (USP), 28.sup.a Ed.
[0079] 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:
[0080] Equipment: SOTAX AT7 Smart
[0081] 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
[0082] Stirring speed: 100 rpm
[0083] Temperature: 37.degree. C.
[0084] Sampling time: 120, 135, 150, and 180 min.
[0085] The content of dissolved rifaximin is measured by a HPLC
method.
[0086] 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 HC1 0.1 N, 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
[0087] 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
Treatment of Crohn's Disease
[0088] 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's
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:
[0089] Group A: rifaximin 800 mg, administrated 2 times a day for a
total 15 dosage equal to 1600 mg/die;
[0090] 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.
[0091] 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.
[0092] The results are summarized 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
Treatment of Crohn's Patients Characterized by a Protein C 5
Reactive Value Higher than Normal
[0093] 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.
[0094] 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.
[0095] The Table 8 shows the obtained results.
TABLE-US-00008 TABLE 8 Subgroup with protein C value Number of
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%)
[0096] 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.
* * * * *