U.S. patent application number 14/471509 was filed with the patent office on 2014-12-18 for oral antimicrobial pharmaceutical compositions.
This patent application is currently assigned to COSMO TECHNOLOGIES LIMITED. The applicant listed for this patent is COSMO TECHNOLOGIES LIMITED. Invention is credited to Mauro AJANI, Roberta BOZZELLA, Giuseppe CELASCO, Roberto VILLA.
Application Number | 20140370093 14/471509 |
Document ID | / |
Family ID | 34968899 |
Filed Date | 2014-12-18 |
United States Patent
Application |
20140370093 |
Kind Code |
A1 |
AJANI; Mauro ; et
al. |
December 18, 2014 |
ORAL ANTIMICROBIAL PHARMACEUTICAL COMPOSITIONS
Abstract
The present invention relates to oral pharmaceutical
compositions with controlled and/or programmed release containing
at least one active ingredient having antimicrobial and/or
anti-infectious activity for the treatment of infections of the
large intestine, in particular the colon.
Inventors: |
AJANI; Mauro; (Milano,
IT) ; BOZZELLA; Roberta; (Milano, IT) ;
CELASCO; Giuseppe; (Genova, IT) ; VILLA; Roberto;
(Lecco, IT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
COSMO TECHNOLOGIES LIMITED |
Dublin 1 |
|
IE |
|
|
Assignee: |
COSMO TECHNOLOGIES LIMITED
Dublin 1
IE
|
Family ID: |
34968899 |
Appl. No.: |
14/471509 |
Filed: |
August 28, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13592097 |
Aug 22, 2012 |
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14471509 |
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13451111 |
Apr 19, 2012 |
8263120 |
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13592097 |
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11571044 |
Feb 5, 2007 |
8486446 |
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PCT/EP2005/052025 |
May 3, 2005 |
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13451111 |
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Current U.S.
Class: |
424/480 ;
424/474; 424/482; 514/450 |
Current CPC
Class: |
A61K 9/282 20130101;
A61K 9/2013 20130101; A61K 9/2054 20130101; Y02A 50/30 20180101;
A61P 1/00 20180101; A61P 1/12 20180101; A61P 31/00 20180101; A61K
31/4164 20130101; A61K 9/2846 20130101; A61P 39/02 20180101; A61K
9/2826 20130101; A61P 31/04 20180101; A61P 3/12 20180101; A61K
31/395 20130101; A61P 1/16 20180101; A61P 1/04 20180101; Y02A
50/475 20180101; A61K 9/2018 20130101 |
Class at
Publication: |
424/480 ;
424/474; 424/482; 514/450 |
International
Class: |
A61K 9/28 20060101
A61K009/28; A61K 31/395 20060101 A61K031/395 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 25, 2004 |
IT |
MI2004 A 001295 |
Claims
1. A tablet comprising granules and at least one hydrophilic
compound, wherein the granules comprise: (a) rifamycin SV; (b) at
least one amphiphilic compound; and (c) at least one lipophilic
compound.
2. The tablet according to claim 1, wherein the at least one
hydrophilic compound is selected from the group consisting of a
hydroxyalkyl cellulose, an alkyl cellulose, a carboxyalkyl
cellulose, a polyvinyl alcohol, a carboxyvinyl polymer, a
carboxyvinyl copolymer, a polysaccharide derivative, a hyaluronic
acid, a glucuronic acid, a glucosamine and a pectin.
3. The tablet according to claim 1, wherein the at least one
hydrophilic compound is a hydroxyalkyl cellulose or a carboxyalkyl
cellulose.
4. The tablet according to claim 1, wherein the at least one
hydrophilic compound is a hydrophilic copolymeric substance.
5. The tablet according to claim 1, wherein the at least one
hydrophilic compound is a hydrogel.
6. The tablet according to claim 1, wherein the at least one
amphiphilic compound is selected from the group consisting of
lecithin, a sphingomyelin, a phospholipid, a ceramide, an alkyl
block copolymer, a salt of a sulphated alkyl acid, a
polyoxyethylenated alkyl and a sorbitan derivative.
7. The tablet according to claim 1, wherein the at least one
amphiphilic compound is lecithin.
8. The tablet according to claim 1, wherein the at least one
lipophilic compound is selected from the group consisting a wax,
stearic acid and stearin.
9. The tablet according to claim 1, wherein the at least one
lipophilic compound is stearic acid.
10. The tablet according to claim 1, further comprising a
gastro-resistant film coating.
11. The tablet according to claim 10, wherein the gastro-resistant
film coating comprises acrylic and/or methacrylic acid polymers, or
copolymers, or cellulose phthalate derivatives.
12. The tablet according to claim 10, wherein the gastro-resistant
film coating comprises acrylic and methacrylic acid copolymers.
13. A tablet coated with a gastro-resistant film, wherein the
gastro-resistant film comprises methacrylic acid polymers and/or
copolymers, and the tablet comprises: (i) a hydrophilic copolymeric
substance; and (ii) granules in the hydrophilic copolymeric
substance, wherein the granules comprise: (a) rifamycin SV; (b)
lecithin; and (c) stearic acid.
14. A tablet comprising rifamycin SV, at least one amphiphilic
compound, at least one lipophilic compound and at least one
hydrophilic compound prepared by a process comprising the steps:
(a) mixing rifamycin SV, at least one amphiphilic compound and at
least one lipophilic compound to form a first mixture; (b)
granulating the first mixture to form granules; (c) mixing the
granules with at least one hydrophilic compound to form a second
mixture; and (d) tableting the second mixture to form a tablet.
15. The tablet according to claim 14, wherein the at least one
hydrophilic compound is selected from the group consisting of a
hydroxyalkyl cellulose, an alkyl cellulose, a carboxyalkyl
cellulose, a polyvinyl alcohol, a carboxyvinyl polymer, a
carboxyvinyl copolymer, a polysaccharide derivative, a hyaluronic
acid, a glucuronic acid, a glucosamine and a pectin.
16. The tablet according to claim 14, wherein the at least one
hydrophilic compound is a hydroxyalkyl cellulose or a carboxyalkyl
cellulose.
17. The tablet according to claim 14 wherein the at least one
hydrophilic compound is a hydrophilic copolymeric substance.
18. The tablet according to claim 14, wherein the at least one
hydrophilic compound is a hydrogel.
19. The tablet according to claim 14, wherein the at least one
amphiphilic compound is selected from the group consisting of
lecithin, a sphingomyelin, a phospholipid, a ceramide, an alkyl
block copolymer, a salt of a sulphated alkyl acid, a
polyoxyethylenated alkyl and a sorbitan derivative.
20. The tablet according to claim 14, wherein the at least one
amphiphilic compound is lecithin.
21. The tablet according to claim 14, wherein the at least one
lipophilic compound is selected from the group consisting a wax,
stearic acid and stearin.
22. The tablet according to claim 14, wherein the at least one
lipophilic compound is stearic acid.
23. The tablet according to claim 14, wherein the tablet further
comprises a gastro-resistant film coating prepared by (e) coating
the tablet of step (d).
24. The tablet according to claim 23, wherein the gastro-resistant
film coating comprises acrylic and/or methacrylic acid polymers, or
copolymers, or cellulose phthalate derivatives.
25. The tablet according to claim 23, wherein the gastro-resistant
film coating comprises acrylic and methacrylic acid copolymers.
26. A tablet comprising rifamycin SV, at least one amphiphilic
compound, at least one lipophilic compound and at least one
hydrophilic compound prepared by a process comprising the steps:
(a) mixing rifamycin SV and at least one amphiphilic compound to
form a first mixture; (b) mixing the first mixture with the at
least one lipophilic compound to form a second mixture; (c) mixing
the second mixture with the at least one hydrophilic compound to
form a third mixture; and (d) tableting the third mixture to form a
tablet.
27. The tablet according to claim 26, wherein the at least one
hydrophilic compound is selected from the group consisting of a
hydroxyalkyl cellulose, an alkyl cellulose, a carboxyalkyl
cellulose, a polyvinyl alcohol, a carboxyvinyl polymer, a
carboxyvinyl copolymer, a polysaccharide derivative, a hyaluronic
acid, a glucuronic acid, a glucosamine and a pectin.
28. The tablet according to claim 26, wherein the at least one
hydrophilic compound is a hydroxyalkyl cellulose or a carboxyalkyl
cellulose.
29. The tablet according to claim 26 wherein the at least one
hydrophilic compound is a hydrophilic copolymeric substance.
30. The tablet according to claim 26, wherein the at least one
hydrophilic compound is a hydrogel.
31. The tablet according to claim 26, wherein the at least one
amphiphilic compound is selected from the group consisting of
lecithin, a sphingomyelin, a phospholipid, a ceramide, an alkyl
block copolymer, a salt of a sulphated alkyl acid, a
polyoxyethylenated alkyl and a sorbitan derivative.
32. The tablet according to claim 26, wherein the at least one
amphiphilic compound is lecithin.
33. The tablet according to claim 26, wherein the at least one
lipophilic compound is selected from the group consisting a wax,
stearic acid and stearin.
34. The tablet according to claim 26, wherein the at least one
lipophilic compound is stearic acid.
35. The tablet according to claim 26, wherein the tablet further
comprises a gastro-resistant film coating prepared by (e) coating
the tablet of step (d).
36. The tablet according to claim 35, wherein the gastro-resistant
film coating comprises acrylic and/or methacrylic acid polymers, or
copolymers, or cellulose phthalate derivatives.
37. The tablet according to claim 35, wherein the gastro-resistant
film coating comprises acrylic and methacrylic acid copolymers.
38. A method of treating a pathological condition of the colon
comprising administering to a patient in need thereof the
controlled release oral pharmaceutical composition according to
claim 1, wherein the pathological condition is infectious colitis,
bacillary dysentery, pseudomembranous colitis, travellers'
diarrhoea, diverticular disease and/or diverticulitis.
39. A method of treating a pathological condition of the colon
comprising administering to a patient in need thereof the
controlled release oral pharmaceutical composition according to
claim 1, wherein the pathological condition is travellers'
diarrhoea.
40. A method of treating a pathological condition of the colon
comprising administering to a patient in need thereof the
controlled release oral pharmaceutical composition according to
claim 1, wherein the pathological condition is diverticular disease
and/or diverticulitis.
41. A method of treating a pathological condition of the colon
comprising administering to a patient in need thereof the
controlled release oral pharmaceutical composition according to
claim 13, wherein the pathological condition is infectious colitis,
bacillary dysentery, pseudomembranous colitis, travellers'
diarrhoea, diverticular disease and/or diverticulitis.
42. A method of treating a pathological condition of the colon
comprising administering to a patient in need thereof the
controlled release oral pharmaceutical composition according to
claim 13, wherein the pathological condition is travellers'
diarrhoea.
43. A method of treating a pathological condition of the colon
comprising administering to a patient in need thereof the
controlled release oral pharmaceutical composition according to
claim 13, wherein the pathological condition is diverticular
disease and/or diverticulitis.
44. A method of treating a pathological condition of the colon
comprising administering to a patient in need thereof the
controlled release oral pharmaceutical composition according to
claim 14, wherein the pathological condition is infectious colitis,
bacillary dysentery, pseudomembranous colitis, travellers'
diarrhoea, diverticular disease and/or diverticulitis.
45. A method of treating a pathological condition of the colon
comprising administering to a patient in need thereof the
controlled release oral pharmaceutical composition according to
claim 14, wherein the pathological condition is travellers'
diarrhoea.
46. A method of treating a pathological condition of the colon
comprising administering to a patient in need thereof the
controlled release oral pharmaceutical composition according to
claim 14, wherein the pathological condition is diverticular
disease and/or diverticulitis.
47. A method of treating a pathological condition of the colon
comprising administering to a patient in need thereof the
controlled release oral pharmaceutical composition according to
claim 26, wherein the pathological condition is infectious colitis,
bacillary dysentery, pseudomembranous colitis, travellers'
diarrhoea, diverticular disease and/or diverticulitis.
48. A method of treating a pathological condition of the colon
comprising administering to a patient in need thereof the
controlled release oral pharmaceutical composition according to
claim 26, wherein the pathological condition is travellers'
diarrhoea.
49. A method of treating a pathological condition of the colon
comprising administering to a patient in need thereof the
controlled release oral pharmaceutical composition according to
claim 26, wherein the pathological condition is diverticular
disease and/or diverticulitis.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/592,097, filed on Aug. 22, 2012, which is a
continuation of U.S. patent application Ser. No. 13/451,111, filed
Apr. 19, 2012, now U.S. Pat. No. 8,263,120, which is a continuation
of U.S. patent application Ser. No. 11/571,044, filed Feb. 5, 2007,
now U.S. Pat. No. 8,486,446, which is a U.S. National Phase under
35 U.S.C. .sctn.371 of International Application No.
PCT/EP2005/052025, filed May 3, 2005, which claims the benefit of
Italian Patent Application MI2004 A 001295 filed on Jun. 25, 2004,
all of which are incorporated by reference herein in their
entirety.
DESCRIPTION
[0002] Intestinal infections are common diseases caused by the
colonization of the intestine by foreign pathogenic agents of
various origins, or caused by intestinal microorganisms that are
normally present becoming virulent.
[0003] It is known that the intestine is divided into two distinct
portions: the proximal portion, called the "small intestine", which
is formed, in the craniocaudal direction, by the duodenum, the
jejunum and the ileum, and the distal portion, called the "large
intestine", which is formed by the colon and the recto-anus (Faller
A, Scevola G. Anatomia e Fisiologia del Corpo Umano (Anatomy and
Physiology of the Human Body). Vol I. Edizioni Minerva Medica,
Turin, 1973, pp. 235-254).
[0004] The two portions, the small intestine and the large
intestine, are completely separated anatomically by the ileocaecal
valve which permits the passage of the intestinal contents from the
small intestine to the large intestine but not vice versa. Besides
from the anatomical-structural point of view, the large intestine
is quite different from the small intestine also, and above all,
from the functional point of view (Braga P C. Enteric microflora
and its regulation. In Drugs in Gastroenterology. Raven Press, New
York, 1991, pp. 501-508).
[0005] While the small intestine is assigned to the digestion of
the majority of the food, to the absorption thereof, to the
production of B-complex vitamins and vitamin K, to the metabolism
of biliary acids and various other organic substances and to the
rapid transfer of the alimentary bolus to the sections further
downstream, the large intestine provides for the absorption of
water, for the digestion of vegetable fibres and for the completion
of some digestive processes initiated in the small intestine. In
addition, the large intestine differs from the small intestine by
the presence of an extremely rich bacterial flora, the balance of
which is of fundamental importance in regulating the ambient pH,
motility, the production of gas and ammonia, the formation of
faeces, and the production of metabolites essential for maintaining
the good functioning of the large intestine.
[0006] These many differences between the small intestine and the
large intestine explain the distinctive nature of some pathologies
which occur at the expense of the large intestine and in particular
the colon.
[0007] The colon is the portion of the large intestine that is host
to the majority of the bacterial strains and that offers conditions
of pH, anaerobiosis, humidity and slowness of transit that are
particularly suitable for the permanent flora potentially becoming
virulent or for the proliferation of and colonization by pathogenic
bacteria. For those reasons, the colon is the sector of the
intestine most susceptible to infection; in fact, infections
located in the colon (infectious colites, bacillary dysentery,
diarrhoea, pseudomembranous colitis, diverticulitis, etc.)
constitute an important and autonomous chapter in the
gastroenterological monograph (Sorice F., Vullo V. Intossicazioni
alimentari e infezioni del tubo digerente. (Food Poisoning and
Infections of the Alimentary Canal). In: Medicina Clinica (Clinical
Medicine).Edizioni Medico Scientifiche, Turin, 2002).
[0008] In addition, the increased endoluminal pressure, linked with
the production of gas and associated with predisposing local
factors, can promote the occurrence of diverticula which are
susceptible to infection and inflammation and which are located
exclusively in the colon (Jackson B T. Diverticular disease. In:
Inflammatory Bowel Diseases Churchill Livingston, N.Y., 1997, pp.
443-447).
[0009] Currently, the oral therapy of intestinal infections, and in
particular colon infections, uses substances having antibacterial
activity which must have specific characteristics such as: broad
spectrum of activity on Gram+ and Gram- bacteria, resistance to
strongly acidic environments, such as the gastric environment,
anti-infectious activity independent of the presence of the
intestinal biomass, residence inside the intestine for an
appropriate period of time, good penetrability into the infecting
host cell and good tolerability (Braga P C. Interaction of
antibiotics on enteric microflora. In: Drugs in Gastroenterology.
Raven Press, New York, 1991, pp. 509-517).
[0010] Therapy with antibacterial agents administered in the oral
preparations employed today has at least two limitations. In the
first place, the antibacterial agents, if not suitably protected,
may lose their efficacy owing to the enzymatic or degradative
inactivation which occurs during their passage through the stomach
or through the small intestine.
[0011] In addition, the pharmaceutical forms nowadays used,
although they permit the administration of the active ingredient in
discrete doses, release it too rapidly in relation to the time
taken to pass through the digestive tract, so that the active
ingredient performs its anti-infectious activity in an
indiscriminate manner along the entire gastro-intestinal tract.
[0012] This leads to the disappearance of the non-pathogenic
bacterial flora living in the small intestine (duodenum, jejunum
and the ileum), which flora, since it is not normally the seat of
infection, should be protected and not subjected to the sterilizing
action characteristic of the formulations used today.
[0013] For it is known that this bacterial flora is important in
fundamental biological processes, such as, for example, the
digestion and absorption of alimentary nutritive components, the
production and absorption of vitamins (vitamin K and B-complex
vitamins), the metabolism of biliary acids and of steroid hormones,
the activation and inactivation of various substances, the
protection of the organism from xenobiotics, (Braga PC.
Ibidem).
[0014] In particular, the usual oral antibacterial therapies for
the treatment of pathologies located in the colon have often given
a contradictory result, probably owing to the excessive dilution of
the active ingredients in the intestinal lumen; this dilution is
caused by the premature release of the antimicrobial agent from the
pharmaceutical form containing it, which takes place as early as in
the stomach and in the immediate vicinity of the patient's pyloric
valve.
[0015] In addition, although the antimicrobial agents used for the
disinfection of the digestive tract often do not have a high rate
of metabolism, in order to maintain unaltered the therapeutic
possibility connected with the administration of a traditional form
containing antimicrobial agents, no phenomenon of metabolic
degradation should occur, in order to avoid any weakening of the
therapeutic efficacy associated with the presence of the
antimicrobial agent.
[0016] Therefore, in such cases, in order to ensure the real
efficacy of the anti-infectious therapy, it is felt that there is a
need for the possibility of a controlled and site-specific form of
administration.
[0017] For the release of the antimicrobial/anti-infectious active
ingredient in the immediate vicinity of the region where a
diverticulum or a generic infection becomes established, leads to
the formation of a much higher concentration gradient than in the
case of a conventional form of oral administration, with the
consequent greater possibility that the antimicrobial agent will
succeed in penetrating to the inside of the diverticulum.
[0018] In that situation, particular importance is attached to the
possibility of the remission also of infectious pathologies which
are not widespread but which are of considerable
socio-epidemiological importance, such as bacillary dysentery and
pseudomembranous colitis, and also of infectious complications in
surgical operations at the expense of the large intestine and in
particular the colon.
[0019] Rifamycin SV, which has been known since the 1960s, is a
semi-synthetic active ingredient which is derived from rifamycin S
and which has a strong antimicrobial and/or anti-infectious
activity both locally and parenterally. Its activity has also been
evaluated in vitro at minimum concentrations (mcg/ml) on Gram+
bacteria, such as Staphylococcus aureus or Enterococcus faecalis,
as well as at higher concentrations on Gram- bacteria, such as
Escherichia coli, Salmonella, Enterobacter aerogenes, Enterobacter
cloacae or Pseudomonas aeruginosa.
[0020] Rifamycin SV, in the form of its sodium salt, is currently
marketed under the name Rifocin.RTM. both for external topical use
and for injection. In particular, the topical use, indicated for
the local treatment of infectious processes, is limited to external
use by means of a solution of the active ingredient which is to be
diluted at the time of use.
[0021] Patent application WO01/11077, which is incorporated herein
by reference, describes the use of antimicrobial agents, including
the generic rifamycin, for the preparation of pharmaceutical
compositions that can be used in the treatment of pathologies
caused by anomalous bacterial growth (Small Intestine
Overgrowth--SIBO) at the expense of the small intestine. Those
compositions are formulated in such a manner as to release the
active ingredient rapidly in the proximal portion of the intestine,
that is to say, solely in the small intestine (duodenum, jejunum
and ileum).
[0022] Metronidazole is a nitroimidazole chemotherapeutic agent
having powerful antimicrobial activity and a broad spectrum of
action both on Gram+ bacteria and Gram- bacteria. In addition,
metronidazole is known to have a proven antiprotozoan activity
(Tracy J. W. et al., Metronidazole, in: Goodmen & Gilman's, The
Pharmacological Bases of Therapeutics, IX Ed., 1996, pp 995-998).
Current therapy with metronidazole is supported with tablets
(Flagyl.RTM.) that contain 250 mg of active ingredient and that are
formulated for immediate release.
[0023] It has now surprisingly been found that the efficacy of
antimicrobial/anti-infectious active ingredients, such as rifamycin
SV and/or metronidazole, in the treatment of infections of the
large intestine, and in particular of the colon, can be
substantially potentiated thanks to the elimination of the
undesired effects described above (avitaminosis, destruction of
non-pathogenic bacterial flora, etc.) which are caused by the
premature release of the active ingredients in the first portions
of the digestive canal, such as the stomach, the duodenum and the
jejunum, and thanks to the protection from the metabolic-enzymatic
inactivation of the active ingredients which is brought about
before the ingredients can reach the site of infection.
[0024] In particular, the efficacy of rifamycin SV was verified by
means of an evaluation of the MIC (Minimum Inhibiting
Concentration) on specific pathogenic bacterial strains, such as,
for example, Escherichia coli, Enterobacter faecalis, Proteus
vulgaris, Pseudomonas aeruginosa, Salmonella typhi and Enterobacter
cloacae as shown in the following Table A.
TABLE-US-00001 TABLE A Bacterial species MIC (mcg/ml) Escherichia
coli (ATCC 30218) 400 Enterobacter faecalis (ATCC 29212) 25 Proteus
vulgaris (ATCC 13315) 400 Pseudomonas aeruginosa (ATCC 27853)
>400 Salmonella typhi (ATCC 13331) >400 Enterobacter cloacae
(ATCC 17446431) >400 Staphylococcus aureus (ATCC 25213)
<0.4
[0025] The present invention therefore relates to oral
pharmaceutical compositions containing an active ingredient having
antimicrobial/anti-infectious activity, such as rifamycin SV and/or
metronidazole, characterized in that they are formulated in such a
manner as to release the active substances substantially in the
portion of the large intestine where their specific sterilizing
action is required, but leaving unaltered the non-pathogenic
bacterial flora present in the portions of the small intestine
which are not affected by the infection.
[0026] In particular, the formulations according to the present
invention are capable of releasing the active ingredient solely in
the colon, thus ensuring localized and restricted anti-infectious
efficacy.
[0027] Consequently, the advantage of the formulations of the
invention is the particular site-specificity in the large
intestine, and in particular in the colon, which permits a greater
concentration of the active substance in the infected distal
intestinal region with complete preservation of the healthy
proximal regions.
[0028] This advantage is displayed mainly during the treatment of
specific pathological situations in the colon region, such as
infectious colites, bacillary dysentery, diverticular disease and
diverticulitis where the site-specificity and the tolerability of
the formulations play a key role in the resolution of the
pathology.
[0029] A further advantageous application of the formulations of
the invention is their use during preparation for surgical
operations on the large intestine, in ileocolic anastomoses, and in
the sterilization of the ammonia-producing colonic flora in order
to prevent and/or treat hyperammonaemias. In these last-mentioned
cases, the site-specificity of treatment and the consequent
concentration of the activity of the active ingredient may lead to
a significant resolution of cases which would otherwise involve
substantial complications.
[0030] In the formulations of the invention, the substances having
antimicrobial/anti-infectious activity are contained in an amount
of from 10 to 90% by weight; in particular rifamycin SV is
contained in an amount of from 20% to 60% by weight, while
metronidazole is contained in an amount of from 25% to 70% by
weight. The oral formulations of the invention are selected from
tablets, capsules, granules and/or microgranules.
[0031] A preferred embodiment of the present invention comprises a
system for controlled release which is characterized by the
presence of a first, amphiphilic matrix in which the active
ingredient is incorporated and which is in turn dispersed in a
second lipophilic, matrix. The form so obtained is again in turn
dispersed in a third, hydrophilic matrix before producing the final
oral pharmaceutical form.
[0032] The lipophilic matrix of the present invention is
represented by substances having a melting point lower than
90.degree. C., such as, for example, beeswax, carnauba wax, stearic
acid, stearin and the like; the amphiphilic matrix is represented
by substances selected, for example, from phospholipids, ceramides,
sphingomyelins, lecithins, alkyl block copolymers, salts of
sulphated alkyl acids, polyoxyethylenated alkyl, derivatives of
sorbitan and the like, while the hydrophilic matrix is represented
by generally cross-linked or linear polymeric or copolymeric
substances, which are known as hydrogels, that is to say,
substances capable of increasing their mass and their weight, owing
to the polar groups present in the main or side polymer chains,
when they come into contact with molecules of water.
[0033] In particular, the hydrophilic matrix corresponds to
substances selected, for example, from cellulose derivatives, such
as hydroxyalkylcelluloses, alkylcelluloses, carboxyalkylcelluloses
and their salts or derivatives, polyvinyl alcohols, carboxyvinyl
derivatives, polysaccharide derivatives of anionic or cationic
nature, such as, for example, hyduronic acid, glucuronic acid, or
glucosamines, pectins and/or their derivatives.
[0034] In this preferred embodiment, the matrices are dispersed in
one another in succession together with the active ingredient, thus
bringing about the formation of a homogeneous structure responsible
for the site-specificity of release.
[0035] In a further embodiment of the present invention, the
tablets obtained are finally subjected to a coating process using
gastroresistant substances, such as, for example, polymers of
acrylic and methacrylic acids (Eudragit) and/or derivatives of
cellulose phthalate.
[0036] Systems of controlled and/or programmed release suitable for
the present invention are described in EP 1183014, GB 2245492 and
EP572942, which are also incorporated herein by reference.
[0037] The following Examples describe the invention in detail
without limiting the content thereof in any way.
EXAMPLE 1
[0038] 200 g of rifamycin SV are mixed with 5 g of stearic acid, 7
g of carnauba wax, 8 g of sodium dioctyl sulphosuccinate, 100 g of
lactose and 10 g of sodium edetate and granulated with a solution
containing 25 g of low-viscosity polyvinylpyrrolidone in 0.2 litre
of purified water. When the granulate has been dried, it is mixed
with 100 g of sodium carboxymethylcellulose, 25 g of silica, 5 g of
glycerol palmitostearate and 10 mg of talcum before being subjected
to compression to the unit weight of 495 mg/tablet. The cores so
obtained are then film-coated with a hydroalcoholic dispersion of
acrylic and methacrylic acid esters, titanium dioxide, talcum and
triethyl citrate, which confers on the product resistance to
disintegration in a strongly acidic environment, simulating the
environment of the stomach and the small intestine. The dissolution
of the tablets is practically zero in pH conditions of less than 7
and is progressive in an enteric buffer at pH 7.2 with the
following percentage quotas: [0039] less than 20% after 1 hour's
residence, [0040] less than 50% after 3 hours' residence, [0041]
more than 70% after 8 hours' residence.
EXAMPLE 2
[0042] 500 g of rifamycin SV are mixed with 10 g of stearic acid,
10 g of beeswax, 10 g of sodium lauryl sulphate, 200 g of mannitol
and 10 g of sodium edetate and granulated with a solution
containing 50 g of hydroxypropylcellulose in 0.5 litre of water.
When the granulate has been dried, it is mixed with 150 g of sodium
hydroxypropylmethylcellulose, 25 g of silica, 5 g of glycerol
palmitostearate and 10 mg of talcum before being subjected to
compression to the unit weight of 490 mg/tablet. The cores so
obtained are then film-coated with an aqueous dispersion of acrylic
and methacrylic acid esters, iron oxide, talcum and triethyl
citrate, with confers on the product resistance to disintegration
in an acidic environment, simulating the environment of the stomach
and the small intestine. The dissolution of the tablets is
practically zero in pH conditions of less than 7 and is progressive
in an enteric buffer at pH 7.2 with the following percentage
quotas: [0043] less than 30% after 1 hour's residence, [0044] less
than 60% after 3 hours' residence, [0045] more than 80% after 8
hours' residence.
EXAMPLE 3
[0046] 2.5 kg of metronidazole are mixed with 70 g of stearic acid,
70 g of beeswax, 400 g of saccharose, 140 g of
hydroxypropylmethylcellulose and 20 g of polysorbate and
wet-granulated by the addition of purified water to a suitable
consistency. The granulate is then dried and standardized in terms
of dimensions before the addition of a further 200 g of
hydroxymethylpropylcellulose, 600 g of microcrystalline cellulose,
30 g of glycerol palmitostearate and 70 g of silicon dioxide. After
mixing, the powder is sent for compression to the unit weight of
450 mg/tablet.
[0047] The cores so obtained are then subjected to film-coating
with a hydroalcoholic dispersion of acrylic and methacrylic acid
esters, iron oxide, talcum and triethyl citrate, which confers on
the product resistance to disintegration in an acidic environment.
The dissolution of the tablets is practically zero in pH conditions
of less than 7 and is progressive in an enteric buffer at pH 7.2
with the following percentage quotas: [0048] less than 25% within
the first hour of residence, [0049] more than 25% and less than 70%
within the third hour of residence, [0050] more than 80% after 8
hours' residence.
EXAMPLE 4
[0051] 500 g of metronidazole are mixed with the components of the
lipophilic/amphiphilic matrix, 5 g of stearic acid and 5 g of soya
lecithin, some of the hydrophilic polymer, 100 g of
hydroxypropylcellulose, and diluents, 150 g of mannitol.
[0052] The mixture is then made into a paste with a solution of
low-viscosity hydroxypropylcellulose in purified water until a
consistent granulate is obtained. After drying, the granulate
obtained is mixed with a further 100 g of hydroxypropylcellulose,
to which are added flow agents and lubricants, 5 g of silica, 5 g
of talcum and 5 g of magnesium stearate, then compressed to a final
weight of 925 mg/tablet. The tablets are finally coated with an
alcohol-based suspension of acrylic and methacrylic copolymers
capable of imparting to the tablets efficacious
gastroresistance.
[0053] The rate of dissolution of those tablets is progressive and
controlled, with approximately 20% of the active ingredient being
released after the first hour of residence in enteric juice at pH
7.2, 50% after 2 hours and more than 80% after 4 hours, these
figures being understood as quotas that are clearly subsequent to 2
hours' exposure at pH 1 and 1 hour's exposure at pH 6.4, reflecting
the environment of the stomach and of the small intestine,
respectively.
* * * * *