U.S. patent application number 16/585330 was filed with the patent office on 2020-08-27 for solid composition for the oral administration of dyes and diagnostic use thereof.
This patent application is currently assigned to COSMO TECHNOLOGIES LTD.. The applicant listed for this patent is COSMO TECHNOLOGIES LTD.. Invention is credited to Mauro Severino AJANI, Giuseppe CELASCO, Luigi MORO, Alessandro REPICI, Roberto VILA.
Application Number | 20200268909 16/585330 |
Document ID | / |
Family ID | 1000004814716 |
Filed Date | 2020-08-27 |
United States Patent
Application |
20200268909 |
Kind Code |
A1 |
MORO; Luigi ; et
al. |
August 27, 2020 |
SOLID COMPOSITION FOR THE ORAL ADMINISTRATION OF DYES AND
DIAGNOSTIC USE THEREOF
Abstract
The present application discloses solid compositions for the
oral administration of dyes, and diagnostic use thereof.
Preferably, such diagnostic use is aimed at the diagnostic
evaluation of the gastrointestinal tract.
Inventors: |
MORO; Luigi; (Cairate,
IT) ; AJANI; Mauro Severino; (Milano, IT) ;
VILA; Roberto; (Lecco, IT) ; CELASCO; Giuseppe;
(Genova, IT) ; REPICI; Alessandro; (Torino,
IT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
COSMO TECHNOLOGIES LTD. |
Dublin |
|
IE |
|
|
Assignee: |
COSMO TECHNOLOGIES LTD.
Dublin
IE
|
Family ID: |
1000004814716 |
Appl. No.: |
16/585330 |
Filed: |
September 27, 2019 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
15877591 |
Jan 23, 2018 |
|
|
|
16585330 |
|
|
|
|
15061232 |
Mar 4, 2016 |
10265420 |
|
|
15877591 |
|
|
|
|
13932321 |
Jul 1, 2013 |
9402922 |
|
|
15061232 |
|
|
|
|
13602875 |
Sep 4, 2012 |
8545811 |
|
|
13932321 |
|
|
|
|
PCT/IB2011/050881 |
Mar 2, 2011 |
|
|
|
13602875 |
|
|
|
|
61327557 |
Apr 23, 2010 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 5/0084 20130101;
A61K 49/0089 20130101; A61K 9/2054 20130101; A61B 1/31 20130101;
A61B 1/041 20130101; A61K 9/2059 20130101; A61K 9/2846 20130101;
A61K 49/0073 20130101; A61K 49/003 20130101; A61B 1/273 20130101;
A61M 31/005 20130101; A61K 49/006 20130101 |
International
Class: |
A61K 49/00 20060101
A61K049/00; A61K 9/20 20060101 A61K009/20; A61K 9/28 20060101
A61K009/28; A61B 1/31 20060101 A61B001/31; A61B 5/00 20060101
A61B005/00; A61M 31/00 20060101 A61M031/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 4, 2010 |
IT |
MI2010A000345 |
Claims
1. A method of detecting a pathology in a subject undergoing
colonoscopy, comprising the subject swallowing one or more doses of
an extended release tablet prior to the colonoscopy, the tablets
comprising: (a) methylene blue; (b) at least one lipophilic
compound; and (c) at least one hydrophilic compound; and wherein
the tablet is coated with a composition comprising at least one
gastro-resistant substance.
2. The method according to claim 1, wherein the pathology is
selected from inflammatory, ulcerative, dysplastic, pre-neoplastic
and neoplastic pathologies.
3. The method according to claim 2, wherein the pathology is a
pre-neoplastic pathology or a neoplastic pathology.
4. The method according to claim 3, wherein the pathology is
selected from cancerous forms, pre-cancerous forms, polyps and
pseudopolyps.
5. The method according to claim 1, wherein the extended release
tablet comprises 25 mg of methylene blue.
6. The method according to claim 1, wherein the at least one
lipophilic compound is selected from saturated, unsaturated or
hydrogenated long chain alcohols, saturated, unsaturated or
hydrogenated fatty acids, salts thereof, esters or amides, mono-,
di- or triglycerides of fatty acids, polyethoxylated derivatives
thereof, waxes, ceramides, cholesterol, and cholesterol
derivatives.
7. (canceled)
8. (canceled)
9. (canceled)
10. The method according to claim 1, wherein the at least one
hydrophilic compound is selected from polymers or copolymers of the
acrylic or methacrylic acid, alkyl vinyl polymers, alkyl
celluloses, hydroxyalkyl celluloses, carboxyalkyl celluloses,
modified celluloses, plurisubstituted celluloses, polysaccharides,
dextrins, pectins, starches, complex starches, starch derivatives,
alginic acid, synthetic rubber, natural rubber, and
polyalcohol.
11. The method according to claim 10, wherein the at least one
hydrophilic compound is selected from alkyl celluloses,
hydroxyalkyl celluloses, carboxyalkyl celluloses, modified
celluloses, plurisubstituted celluloses, polysaccharides, dextrins,
pectins, and starches.
12. The method according to claim 11, wherein the at least one
hydrophilic compound is selected from alkyl celluloses,
hydroxyalkyl celluloses, carboxyalkyl celluloses, and starches.
13. (canceled)
14. (canceled)
15. A method for delivering methylene blue to the colon of a
subject, comprising administering to the subject an extended
release tablet comprising: (a) methylene blue; (b) at least one
lipophilic compound; and (c) at least one hydrophilic compound; and
wherein the tablet is coated with a composition comprising at least
one gastro-resistant substance.
16. The method according to claim 15, wherein the extended release
tablet comprises 25 mg of methylene blue.
17. The method according to claim 15, wherein the at least one
lipophilic compound is selected from saturated, unsaturated or
hydrogenated long chain alcohols, saturated, unsaturated or
hydrogenated fatty acids, salts thereof, esters or amides, mono-,
di- or triglycerides of fatty acids, polyethoxylated derivatives
thereof, waxes, ceramides, cholesterol, and cholesterol
derivatives.
18. (canceled)
19. (canceled)
20. (canceled)
21. The method according to claim 15, wherein the at least one
hydrophilic compound is selected from polymers or copolymers of the
acrylic or methacrylic acid, alkyl vinyl polymers, alkyl
celluloses, hydroxyalkyl celluloses, carboxyalkyl celluloses,
modified celluloses, plurisubstituted celluloses, polysaccharides,
dextrins, pectins, starches, complex starches, starch derivatives,
alginic acid, synthetic rubber, natural rubber, and
polyalcohol.
22. The method according to claim 21, wherein the at least one
hydrophilic compound is selected from alkyl celluloses,
hydroxyalkyl celluloses, carboxyalkyl celluloses, modified
celluloses, plurisubstituted celluloses, polysaccharides, dextrins,
pectins, and starches.
23. The method according to claim 22, wherein the at least one
hydrophilic compound is selected from alkyl celluloses,
hydroxyalkyl celluloses, carboxyalkyl celluloses, and starches.
24. The method according to claim 23, wherein the at least one
hydrophilic compound is selected from hydroxyalkyl celluloses.
25. (canceled)
26. (canceled)
27. The method according to claim 15, wherein the at least one
gastro-resistant substance is soluble at a pH of between about 5
and about 7.
28. The method according to claim 27, wherein the at least one
gastro-resistant substance is selected from of polymers of acrylic
acid, polymers of methacrylic acid, copolymers of acrylic acid,
copolymers of methacrylic acid, cellulose derivatives,
hydroxybutyrate-based polymers, and shellac.
29. The method according to claim 28, wherein the at least one
gastro-resistant substance is selected from polymers of acrylic
acid, polymers of methacrylic acid, copolymers of acrylic acid, and
copolymers of methacrylic acid.
30. The method according to claim 15, wherein the at least one
gastro-resistant substance is selected from methacrylic acid
copolymer type A and methacrylic acid copolymer type B.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation of U.S. patent
application Ser. No. 15/877,591 filed on Jan. 23, 2018, which in
turn is a continuation of U.S. patent application Ser. No.
15/061,232 filed on Mar. 4, 2016, now U.S. Pat. No. 10,265,420,
which in turn is a continuation of U.S. patent application Ser. No.
13/932,321 filed on Jul. 1, 2013, now U.S. Pat. No. 9,402,922,
which in turn is a continuation of U.S. patent application Ser. No.
13/602,875 filed on Sep. 4, 2012, now U.S. Pat. No. 8,545,811,
which in turn is a continuation-in-part of International Patent
Application No. PCT/IB2011/050881 filed on Mar. 2, 2011, which in
turn claims priority to U.S. Provisional Patent Application Ser.
No. 61/327,557 filed on Apr. 23, 2010 and to Italian Patent
Application No. MI2010A000345 filed on Mar. 4, 2010. Each of these
applications is incorporated herein in its entirety.
PRIOR ART
[0002] The endoscopy is an exceptionally important diagnostic
technique for the diagnosis of inflammatory, ulcerative and
neoplastic pathologies of the gastrointestinal tract.
[0003] Actually, the endoscopy allows observing--from inside the
lumen--the state of preservation and development of the mucosa that
covers the gastrointestinal cavity, as well as the surface spraying
thereof, the presence of deformations and/or ulcerations.
[0004] More and more powerful and sophisticated endoscope probes
have enabled to improve this technique considerably; the progress
of the used materials also allowed improving performance in terms
of illumination and resolution power.
[0005] More recently there has been an improvement of the
conventional diagnostic-therapeutic aspects due to the use of image
magnification and vital dyes, useful for locally developing a
contrasting colour capable of amplifying the resolution diagnostic
power of the conventional technique. The use of dyes in endoscopy
lead to coining the term "chromoendoscopy" for describing this
diagnostic procedure, particularly useful for identifying
suspicious areas for degenerative characteristics.
[0006] The use of colouring is generally adopted after completing
the endoscopic analysis during the step of withdrawing the
endoscopic probe, and after accurately cleaning the mucosa tract to
be examined; currently, the dye is applied to the mucosa by
spraying a small volume of a solution averagely concentrated with
dye, using a catheter or capillary pipe directly inserted into the
cavity of the endoscopic probe.
[0007] The diffusion of the dye and absorption thereof by the vital
cells markedly differentiates the cells with normal vitality from
those in the advanced replication stage, for example characteristic
of neoplastic cells.
[0008] The dyes usually used are mainly, but not exclusively, the
following: methylene blue, congo red, carmine indigo, and/or
toluidine blue.
[0009] Methylene blue and toluidine blue are uniformly absorbed by
the whole intestinal mucosa, while, in case of an inflammatory
process, absorption thereof by the mucosal cells tends to reduce as
the phlogosis worsens. Due to this characteristic, the two dyes are
also useful in the step of remission of the inflammatory processes
and in the differential diagnosis between pseudopolyps and true
polyps. Also carmine indigo has a similar action, finding
application in the long duration inflammatory forms and with the
aim of highlighting carpet lesions, which can contain tumoral
forms, which are difficult to detect with the conventional
endoscopy in absence of contrasting colour.
[0010] Within the procedure for applying the dye, it should be
observed that use thereof reveals several practical problems that
are difficult to resolve due to the considerable application
difficulty. First and foremost the pharmacy of the institute where
the endoscopy is performed should be capable of preparing solutions
with concentrations generally comprised between 0.1% and 1% of the
dye; then, the endoscopic probe should be provided with a channel
for inserting the capillary catheter which carries the solution up
to the point of application; then the dye should be dispensed
uniformly so as to cover the mucosal surface subject of the
evaluation. The need for the simultaneous presence of these precise
conditions contributes to the difficulty of executing the
chromoendoscopy procedure, which is exclusively carried out by the
best diagnostic centres up to date, with extensive defections by
hospitals and nursing homes specialized in gastroenterology.
[0011] Furthermore, it should be taken into account that the use of
a solution to be locally sprayed on the mucosal wall does not
entirely solve the problem regarding forms still latent, in that
too small to be detected, as well as the degenerative processes of
the digestive system.
[0012] Thus, there arises the need of providing a simple and safe
use of a dye in diagnostic endoscopies, through a suitable means of
administration also capable of guaranteeing a homogeneous and
complete distribution for an ideal effect of the dye in the area in
question.
[0013] Now, it has been surprisingly discovered that a solid
composition for oral administration allows formulating one, or
more, dyes which can thus reach the desired site providing the
contrasting image required for endoscopic diagnostic
evaluation.
BRIEF DESCRIPTION OF THE FIGURES
[0014] The patent or application file contains at least one drawing
executed in color. Copies of this patent or patent application
publication with color drawing(s) will be provided by the Office
upon request and payment of the necessary fee. As the color
drawings are being filed electronically via EFS-Web, only one set
of the drawings is submitted.
[0015] FIG. 1 shows a colon endoscopic image, obtained during the
endoscopy of a patient who has taken the composition of the
invention within the 24 hours preceding the endoscopy. This figure
shows a non-pathologic, non-coloured endoscopic view.
[0016] FIG. 2 shows a colon endoscopic image, obtained during the
endoscopy of a patient who has taken the composition of the
invention within the 24 hours preceding the endoscopy. The
endoscopic view is characterized by an excellent visualization of
the details of the mucosa and in particular of the pattern of
crypts, which are thus clear due to the enhancement and
reinforcement action of the dye which, deposited homogeneously,
markedly highlights the details of the mucosa that would not be
noticeable to the naked eye.
[0017] FIG. 3 shows a colon endoscopic image, obtained during the
endoscopy of a patient who has taken the composition of the
invention within the 24 hours preceding the endoscopy. This view
shows that the action of the homogeneously distributed dye allows a
clear distinction between the pathologic areas (red) and the
non-pathologic areas (lighter). Such distinction would be less
marked and clear without the colouring contrast whose action shows
an accurate definition of the details of the mucosa and thus an
accurate distinction between pathologic and non-pathologic areas in
a clearer manner with respect to the endoscopic vision without the
dye.
[0018] FIG. 4 shows a colon endoscopic image, obtained during the
endoscopy of a patient who has taken the composition of the
invention within the 24 hours preceding the endoscopy. This view
shows that the action of the homogeneously distributed dye allows a
clear distinction between the pathologic areas (red) and the
non-pathologic areas (lighter). Such distinction would be less
marked and clear without the colouring contrast whose action shows
an accurate definition of the details of the mucosa and thus an
accurate distinction between pathologic and non-pathologic areas in
a clearer manner with respect to the endoscopic vision without the
dye.
[0019] FIG. 5 shows that the tablet absorption profile (circles) is
markedly different from that of the vial (squares) and it can be
classified as a typical absorption profile of a controlled release
formulation.
[0020] FIG. 6 shows that the tablet absorption profile for the 400
mg tablet (circles) is very similar to the profile obtained with
the 200 mg tablet (dots) and, once again, it can be classified as a
typical absorption profile of a controlled release formulation,
also as outlined by the chart B below, where the chart with the dot
refers to the 200 mg dose while the one with the triangle refers to
the 400 mg one.
DESCRIPTION
[0021] Thus, the present invention is aimed at providing a solid
composition for oral administration containing at least one dye
suitable for the preparation and evaluation of the endoscopic
diagnostic analysis, and at least one physiologically acceptable
excipient.
[0022] Physiologically acceptable excipients according to the
invention are preferably excipients useful for reaching a mass
identifiable uniquely, in terms of quality and quantity, and which
can be easily administered through the oral cavity.
[0023] In particular, the composition of the invention is intended
for oral uptake, before being subjected to the endoscopic
diagnostic analysis, during or at the end of the procedure for
preparing such analysis.
[0024] Thus, an object of the present invention is represented by a
solid composition, for oral administration, containing at least one
dye in association with at least one physiologically acceptable
excipient, intended for allowing early local identification of
pathologic forms at the gastrointestinal mucosa level, preferably
precancerous forms or mucosal areas with high inflammation
rate.
[0025] The composition of the present invention can be
instant-release or controlled-release type, preferably of the
controlled release type capable of selectively carrying the dye in
the regions subject of the analysis, thus preventing dispersion
thereof into areas not subject of the analysis.
[0026] The expression "instant-release" is used to indicate a
composition capable of disintegrating quickly and dissolving in the
gastric cavity, simultaneously releasing the entire dye contained
therein.
[0027] The instant-release composition of the invention preferably
comprises at least one dye in association with physiologically
acceptable excipients, technologically indispensable to guarantee
the quick disintegration and dissolution of the form in the gastric
cavity; more preferably, are used the so-called super
disintegrants, i.e. polymeric substances capable of swelling on
contact with aqueous fluids and triggering a hydrodynamic tension
within the pharmaceutical form which leads to the breakage thereof
into fragments with the ensuing considerable increase of the
surface/volume ratio and, thus, to a more rapid dissolution of the
dye/s contained in the administration form.
[0028] Suitable super disintegrants are preferably selected from
among modified starches, modified celluloses, polymers or
cross-linked copolymers (such as, for example, cross-linked
polyvinylpyrrolidone) or mixtures thereof.
[0029] The instant-release composition of the invention may also
comprise an outer coating, preferably selected from among polymers
and copolymers of the acrylic or methacrylic acid, alkyl or
hydroxyalkyl cellulose derivatives or mixtures thereof.
[0030] The possible presence of such an outer coating is useful for
avoiding the coloration of the mucosa of the mouth and/or of the
throat during the uptake and swallowing by the patient.
[0031] The expression "controlled release" of the invention is used
to indicate a composition capable of releasing the dye in a
selective site-time manner, i.e. progressive in the areas of
interest. Thus, such expression comprises the "rapid, delayed or
modified" release definition.
[0032] The technology suitable for the formulation of controlled
release composition of the invention can be selected from among the
matrix technologies and the reservoir diffusion technologies known
in the sector.
[0033] Preferably the controlled release solid oral composition of
the invention is formulated according to the multimatrix technology
commercially known under the trade name MMX.RTM., described in the
international patent applications WO00/76481 and WO00/76478,
incorporated herein by reference.
[0034] According to a preferred embodiment of the invention, the
controlled release solid oral composition comprises at least one
dye and a multimatrix structure containing:
[0035] a) a matrix which consists of lipophilic compounds with
melting point below 90.degree. C., and optionally amphiphilic
compounds, in which at least one dye is at least partly
incorporated;
[0036] b) an outer hydrophilic matrix in which the lipophilic
matrix, and optionally the amphiphilic matrix are dispersed;
[0037] c) optionally other physiologically acceptable
excipients;
[0038] d) optional gastro-resistant coating.
[0039] According to a further embodiment, the composition
containing at least one dye comprises:
[0040] a) a matrix which consists of lipophilic compounds with
melting point below 90.degree. C. and amphiphilic compounds in
which said at least one dye is at least partly incorporated;
[0041] b) an outer hydrophilic matrix in which the
lipophilic/amphiphilic matrix is dispersed;
[0042] c) optionally other physiologically acceptable
excipients;
[0043] d) optional gastro-resistant coating.
[0044] According to another embodiment, the composition containing
at least one dye comprises:
[0045] a) a matrix which consists of lipophilic compounds with
melting point below 90.degree. C., in which said at least one dye
is at least partly incorporated;
[0046] b) an outer matrix which consists of hydrophilic compounds
and optionally amphiphilic compounds, in which the lipophilic
matrix, is dispersed;
[0047] c) optionally other physiologically acceptable
excipients;
[0048] d) optionally a gastro-resistant coating.
[0049] Suitable lipophilic compounds in the present invention are
preferably selected from among saturated, unsaturated or
hydrogenated long chain alcohols, saturated or unsaturated or
hydrogenated fatty acids, salts thereof, esters or amides, mono-,
di- or triglycerides of fatty acids, polyethoxylated derivatives
thereof, waxes, ceramides, cholesterol, cholesterol derivatives or
mixtures thereof.
[0050] Suitable amphiphilic compounds in the present invention are
then preferably selected from among polar lipids of type I or II
(lecithin, phosphatidylcholine, phosphatidylethanolamine or a
mixture thereof), ceramides, glycol alkyl ethers (such as for
example, diethylene glycol monomethyl ether), alkyl sulfate or
sulfosuccinate salts or mixtures thereof.
[0051] Suitable hydrophilic compounds in the present invention are
preferably compounds forming hydrogel (i.e. compounds which form
hydrogel on contact with aqueous solvents), more preferably
selected from among polymers or copolymers of the acrylic or
methacrylic acid, alkyl vinylpolymers, alkyl celluloses,
hydroxyalkyl celluloses, carboxyalkyl cellulose, modified or
plurisubstituted celluloses, polysaccharides, dextrins, pectins,
starches, complex starches and starch derivatives, alginic acid,
synthetic rubber, natural rubber, polyalcohols or mixtures
thereof.
[0052] Suitable gastro-resistant coating according to the invention
is preferably selected from among polymers of the acrylic or
methacrylic acid, copolymers of the acrylic or methacrylic acid,
cellulose derivatives (such as for example cellulose acetate
phthalate) hydroxybutyrate-based polymers, shellac or mixtures
thereof. Such gastro-resistant coatings of the invention can also
be combined with plasticisers, opacifiers, dyes or mixtures
thereof.
[0053] While the oral administration of instant-release solid
pharmaceutical forms allows obtaining a coloration of the first
portion of the digestive tract, such as oesophagus or stomach, the
administration of controlled release compositions of the invention
actually allows releasing the dye contained in the composition
precisely starting from the gastrointestinal segment intended to be
subjected to endoscopic evaluation.
[0054] Preferably the composition of the present invention is
formulated in form of tablet, capsules, granules, microgranules or
pellets. The capsule form according to the invention may in turn
contain granules, microgranules or pellets.
[0055] More preferably, the composition of the invention may be
formulated in form of gastro-resistant tablet or in form of a
capsule containing granules, microgranules or gastro-resistant
pellets.
[0056] Furthermore, the composition of the invention may be
formulated in a double layer form, preferably a double layer
tablet.
[0057] More precisely, instant-release compositions to be
administered a few minutes before carrying out the endoscopy
analysis using a glass of aqueous liquid are preferable for
gastroscopy.
[0058] The aqueous liquid is used for facilitating the dissolution
of the composition, thus forming--in loco--a coloured solution that
allows the dye to homogeneously reach the mucosa which covers the
digestive cavity, and to be absorbed or not by the cells of the
mucosa covering the stomach.
[0059] In case of gastroscopic analysis, the composition of the
invention is thus preferably in form of instant-release tablet or
capsule.
[0060] The same target may be attained in the small or large
intestine, due to the use of forms of controlled or targeted
release oral administration of the dye; in particular, a
composition coated with a thin film of controlled release
gastro-resistant polymers is preferred for an environmental pH of
about 5 for the small intestine.
[0061] In case of endoscopic analysis on the small intestine, the
composition of the invention is thus preferably in form of
controlled release capsule or tablet, with the presence of a
gastro-resistant coating more preferably selected from among
mixtures of acrylic and methacrylic copolymers of type A (Eudragit
L, or RL, for example).
[0062] Even in case of colon endoscopy, it is preferable to use
forms of oral administration in solid oral form, coated with
gastro-resistant substances, preferably tablet or capsule.
[0063] Such gastro-resistant substances are preferably selected
from among acrylic and methacrylic copolymers of type A, type B
(such as for example those commercially known under the trade name
Eudragit S or RS), and/or mixtures based on cellulose acetate
phthalate, insoluble in an acid environment which become soluble
when the pH is neutralized and acquires a value of about 7. A
similar event also occurs when the intestinal transit leads the cud
to pass through terminal ileum or through the ileocecal valve.
Obviously, in the latter case, considering the fact that the cud
takes at least 3-5 hours to complete the transit in the small
intestine and an undetermined period of time, ranging from a few
minutes to a few hours, for the gastric emptying, the
administration of the dye composition should be carried out
suitably in advance with respect to the endoscopic analysis,
generally for a period comprised between 4-24 hours, so as to allow
the dissolution of the dye in situ, the formation of a concentrated
solution within the colon lumen due to the intestinal fluid present
therein, and the diffusion of the dye on the mucosa for a period of
time in which the endoscopic probe is introduced into the
intestinal cavity.
[0064] In order to allow a homogeneous coloration of the luminal
membrane of all colon regions, from the ileocecal area to the
ascending, transverse, descending, sigmoid and rectal colon, the
release of the dye should not be instantaneous but progressive and
in line with the advancement of the composition.
[0065] Given that the transit time of the colon tract is once again
very variable, but estimated at least 8-16 hours, it is clear that
a controlled release composition with the dye being released in
vitro in about 6-8 hours constitutes the best system to allow a
homogeneous coloration of the entire membrane to be analysed
endoscopically and, thus, to obtain the best result in terms of
diagnostic evaluation.
[0066] Useful dyes according to the present invention are
preferably selected from among congo red, carmine indigo, methylene
blue, toluidine blue or mixtures thereof. However, according to the
invention also other biocompatible dye substances can be used, as
long as they are provided with a toxicity profile that does not
represent an obstacle to oral systemic administration thereof.
[0067] Therefore, the amount of dye that can be used for maximising
the structural contrast of the mucosal cells depends: [0068] on the
inherent capacity of the dye to induce the coloration of the vital
cells, [0069] on the period of time that this coloration should be
kept in contact with the cells and [0070] on the massive presence
of the liquid for washing the mucosa swallowed during the step of
preparing the colonoscopy.
[0071] Actually, such parameters may vary the amount of dye from a
few milligrams to a few grams of substance, divided into one or
more solid oral compositions to be swallowed before or during the
step of preparing the endoscopic procedure, or at the end of the
procedure.
[0072] Preferably, the solid oral composition of the invention
comprises at least one dye in an amount comprised between 10 mg
(0.01 g) and 1500 mg (1.5 g), per single composition, more
preferably between 50 mg (0.05 g) and 1200 mg (1.2 g) per single
composition.
[0073] Said at least one dye according to the invention may also be
comprised in an amount between 2 mg (0.002 g) and 1000 mg (1 g),
more preferably between 10 mg (0.01 g) and 500 mg (0.5 g) per
single composition.
[0074] Said at least one dye according to the invention may also be
comprised in an amount between 20 mg (0.02 g) and 500 mg (0.5 g),
even more preferably between 25 mg (0.025 g) and 400 mg (0.4 g),
per single composition.
[0075] According to a preferred embodiment said at least one dye is
contained in the solid composition of the invention in an amount
equivalent to about 25 mg (0.025 g).
[0076] According to a further embodiment said at least one dye is
contained in the solid composition of the invention in an amount
equivalent to about 50 mg (0.05 g).
[0077] According to another embodiment said at least one dye is
contained in the solid composition of the invention in an amount
equivalent to about 200 mg (0.2 g).
[0078] According to a preferred embodiment of the present invention
in case of gastroscopy the administration is provided for about 30
minutes before the execution of one or more compositions of the
invention, preferably instant-release tablet or capsule.
[0079] According to a further embodiment of the present invention,
in case of endoscopy of the small intestine there is provided for
the administration of one or more compositions of the invention,
preferably a controlled release tablet protected by a
gastro-resistant coating to prevent early dispersion of the dye in
the gastric area not intended to be subjected to the endoscopic
evaluation.
[0080] According to a further preferred embodiment of the present
invention, in case of colonoscopy there is provided for the
administration of one or more compositions of the invention,
preferably a controlled release tablet so as to prevent the dye
from being dispersed into areas of the digestive tract not intended
to be subjected to colonoscopy, such as for example the stomach,
duodena and jejunum.
[0081] For the preparation of controlled release compositions, one
or more dyes are preferably formulated alongside substances capable
of imparting progressive or massive or controlled or prolonged
dissolution properties to the formulation; in addition, the
formulation is coated with substances capable of dissolving solely
upon reaching a specific pH, generally comprised between 5 and 7,
typical of the section subject of the intestinal endoscopic
evaluation.
[0082] Upon reaching the intestinal section of interest,
characterised by a specific pH value at which the gastro-protective
coating starts dissolving, it is important that the dissolution of
the dye be controlled in terms of speed so as to ensure that it
occurs within the time indispensable to the intestinal transit,
generally comprised between 4 and 24 hours. Various formulation
technologies can be used according to the invention for such
purpose.
[0083] As mentioned previously, the main and known technologies for
obtaining a colon release, such as the use of reservoir systems or
diffusion or hydrophilic matrix structures, can be applied for
preparing the controlled release composition of the invention; the
multi-matrix technology which exploits a sequence of hydrophilic,
lipophilic and amphiphilic matrices for obtaining a result as
described above is used in a preferable application of the
invention. In a typical application of this multimatrix technology,
the dye/s is/are first mixed or granulated with the material
capable of forming a lipophilic matrix, in the presence of one or
more amphiphilic substances with surfactant properties, and lastly
this matrix of powders, at any degree of aggregation, is inserted
into a dominant structure formed by polymers or copolymers of the
hydrophilic type, also known as hydrogels, in the anhydrous state
or with low residue moisture value.
[0084] Alternatively, still according to a typical application of
this technology, the dye/s should be first mixed or granulated with
the material capable of forming a lipophilic matrix, and after
granulation this matrix structure, at any degree of aggregation, is
inserted into a dominant structure formed by polymers or copolymers
of hydrophilic type in anhydrous state or with low level of residue
humidity in the presence of one or more amphiphilic substances with
surfactant properties and subsequently the final mixture is
subjected to compression.
[0085] A gastro-protective coating film, capable of preventing the
dissolution of the tablet in a strongly acid environment, is lastly
applied to the surface of the compositions.
[0086] Upon swallowing, such a multimatrix coated composition is
protected from contact with gastric and intestinal acids up to
reaching an environment with suitable pH, preferably greater than 5
or 7, where the gastro-protective coating is solubilised and where
the dissolution programme--which will lead it to progressively
distribute the dye inserted in the formulation simultaneously with
the advancement within the digestive cavity--starts.
[0087] Furthermore, an object of the present invention is the
abovementioned solid composition for oral administration for
diagnostic purpose, preferably in the endoscopic diagnostic
evaluation of inflammatory, ulcerative dysplastic, pre-neoplastic
and neoplastic pathologies of the gastrointestinal tract, more
preferably cancerous or precancerous forms, polyps, pseudopolyps or
different inflammatory pathologies of the gastrointestinal
tract.
[0088] The composition of the present invention is generally
applied for oral administration during the preparatory stage for
the gastro-intestinal endoscopic analysis in a single solution or
in two or more periods of administration. A typical applied
administration pattern provides that the administration of the
composition, preferably tablet, occurs at the end of the
preparatory or cleaning stage of the intestinal mucosa, generally
carried out through the uptake of purgatives or polyglycolic
laxative substances, or during the preparation procedure, which
usually lasts a few hours.
[0089] A further administration pattern provides that the
administration of the composition of the invention, preferably a
tablet, occurs before the previously mentioned preparatory or
cleaning stage or that said administration partly occurs before and
partly during such preparatory or cleaning step.
[0090] Lastly, an object of the present invention is a method for
performing endoscopic evaluations of the gastrointestinal tract,
comprising the administration, possibly repeated, of the
abovementioned composition to be preferably carried out within the
day prior to the endoscopy (i.e. within the preceding 24 hours:
preparatory stage), such evaluation being aimed at the diagnosis of
inflammatory, ulcerative pre-neoplastic, dysplastic or neoplastic
pathologies of the gastrointestinal tract, more preferably
cancerous or precancerous forms, polyps, pseudopolyps or different
inflammatory pathologies of the gastrointestinal tract.
[0091] According to a preferred embodiment, the administration of
the solid composition of the invention occurs, once or repeated
over time, before, simultaneously and/or after the uptake of the
preparation/cleaning composition preceding the endoscopic analysis
(for example, but not exclusively, using the drug available in the
market by the name Moviprep.RTM.).
[0092] The expression cleaning composition mentioned above is used
to indicate the previously mentioned saline, polyglycolic or
laxative solution which is commonly used for cleaning and washing
the intestinal mucosa before the endoscopic analysis, during the
preparatory stage within the preceding 24 hours.
[0093] According to a more preferred embodiment of the invention,
the solid composition is taken by the subject intending to carry
out the endoscopic evaluation of the colon in two administrations
where one dose is taken before the washing composition as described
above and the subsequent dose is taken after or during the uptake
of the washing composition as described previously. According to
such embodiment each dose can be constituted by one, or more, solid
compositions of the invention, preferably one or more tablets with
unitary content corresponding to a fraction of the entire dose to
be administered.
[0094] The examples below are meant for clarifying the invention,
without entailing any restrictions whatsoever with respect
thereto.
EXAMPLES
Example 1: Instant-Release Coated Tablet for Endoscopy
TABLE-US-00001 [0095] Description UOM Amt. per tablet Components
Methylene blue mg 50.0 Lecithin mg 3.0 Stearic acid mg 6.0 Mannitol
mg 120.0 Microcrystalline cellulose mg 50.0 Hydroxypropyl cellulose
mg 13.0 Sodium starch glycolate mg 4.0 Colloidal hydrated silica mg
2.0 Magnesium stearate mg 2.0 Coating Methacrylic acid copolymer
type A (Eudragit L) mg 12.0 Triethyl citrate mg 1.2 talc mg 5.8
Titanium dioxide mg 3.0
[0096] The production process provides for mixing the dye,
lecithin, stearic acid and mannitol up to obtaining a homogeneous
mixture. Then microcrystalline cellulose, hydroxypropyl cellulose,
sodium starch glycolate, colloidal silica are added to the mixture
and mixed once again. After adding magnesium stearate, the mixture
is compressed up to obtaining 250 mg tablets. The tablets are then
arranged in a tablet mixer and coated with a methacrylate-based
gastro-resistant film and containing triethyl citrate as
plasticiser in addition to the titanium dioxide dye and talc, an
anti-stick substance. The tablets thus obtained are subjected to a
dissolution test in an acid environment for two hours, where they
reveal to be resistant to the dyeing substance. The tablets yield
to the dye within a few minutes upon introduction into a neutral pH
environment.
Example 2: Instant-Release Coated Tablet for Endoscopy
TABLE-US-00002 [0097] Description UOM Amt. per tablet Components
Methylene blue mg 600.0 Lecithin mg 5.0 Stearic acid mg 10.0
Mannitol mg 340.0 Microcrystalline cellulose mg 123.0 Sodium starch
glycolate mg 30.0 Colloidal hydrated silica mg 20.0 Magnesium
stearate mg 12.0 Coating Methacrylic acid copolymer type A
(Eudragit L) mg 30.0 Triethyl citrate mg 3.0 talc mg 15.0 Titanium
dioxide mg 7.0
[0098] The tablet was obtained through the same process indicated
in example 1.
[0099] The dissolution test applied to the tablet of example 2
allowed establishing the substantial non-dissolution of the tablets
in an acid environment with pH at 1 and the subsequent dissolution
in vitro of the dye when moved to a 6.8 pH.
Example 3: Instant-Release Coated Tablet for Endoscopy
TABLE-US-00003 [0100] Description UOM Amt. per tablet Components
Methylene blue mg 1200.0 Lecithin mg 10.0 Stearic acid mg 20.0
Mannitol mg 200.0 Hydroxypropyl cellulose Mg 50.0 Microcrystalline
cellulose mg 20.0 Sodium starch glycolate mg 50.0 Colloidal
hydrated silica mg 30.0 Magnesium stearate mg 20.0 Coating
Methacrylic acid copolymer type A (Eudragit L) mg 40.0 Triethyl
citrate mg 4.0 talc mg 20.0 Titanium dioxide mg 9.0
[0101] The tablet was obtained through the same process indicated
in example 1.
[0102] Even in this case, the dissolution test applied to the
tablets allowed establishing the substantial non-dissolution of the
tablets in an acid environment with pH at 1 and the subsequent
dissolution in vitro of the dye when moved to a 6.8 pH, mimetic
value of the intestinal pH.
Example 4: Intestinal Release Coated Tablet for Endoscopy
TABLE-US-00004 [0103] Description UOM Amt. per tablet Components
Carmine indigo mg 50.0 Lecithin mg 3.0 Stearic acid mg 6.0 Mannitol
mg 120.0 Microcrystalline cellulose mg 40.0 Hydroxypropyl cellulose
mg 23.0 Sodium starch glycolate mg 4.0 Colloidal hydrated silica mg
2.0 Magnesium stearate mg 2.0 Coating Methacrylic acid copolymer
type A (Eudragit L) mg 6.0 Methacrylic acid copolymer type B
(Eudragit S) mg 6.0 Triethyl citrate mg 1.2 talc mg 5.8 Titanium
dioxide mg 3.0
[0104] The applied process provides for mixing the dye with the
lecithin surfactant, stearic acid, mannitol and half of the
required amount of magnesium stearate. After compacting the mixture
followed by granulation, cellulose, sodium starch glycolate,
colloidal silica and the remaining magnesium stearate are added and
then, after further mixing, the final compression is carried out up
to obtaining 250 mg tablets. The tablet is then coated with a
mixture of methacrylic copolymers of type A and B, so as to extend
the resistance to the dissolution in vitro up to a pH.gtoreq.7,
characteristic of the ileocecal and colon environment.
Example 5: Intestinal Release Coated Tablet for Endoscopy
TABLE-US-00005 [0105] Description UOM Amt. per tablet Components
Carmine indigo mg 500.0 Lecithin mg 3.0 Stearic acid mg 6.0
Mannitol mg 120.0 Microcrystalline cellulose mg 50.0
Hydroxyethylcellulose mg 13.0 Sodium starch glycolate mg 4.0
Colloidal hydrated silica mg 2.0 Magnesium stearate mg 2.0 Coating
Methacrylic acid copolymer type A (Eudragit L) mg 15.0 Methacrylic
acid copolymer type B (Eudragit S) mg 15.0 Triethyl citrate mg 3.0
talc mg 15.0 Titanium dioxide mg 7.0
[0106] The applied process provides for mixing the dye with the
lecithin surfactant, stearic acid and mannitol. After homogeneously
dispersing the dye in the mixture, cellulose, sodium starch
glycolate, colloidal silica and the lubricant magnesium stearate
are added and then, after further mixing, the final compression is
carried out up to obtaining 700 mg tablets. The nuclei are then
subjected to coating using a mixture of methacrylic copolymers of
type A and B alongside other auxiliary substances: the tablets
resist to the dissolution in vitro in an acid environment and they
dissolve at a pH.gtoreq.7, characteristic of the ileocecal and
colon environment.
Example 6: Intestinal Release Coated Tablet for Endoscopy
TABLE-US-00006 [0107] Description UOM Amt. per tablet Components
Methylene blue mg 50.0 Lecithin mg 3.0 Stearic acid mg 6.0 Mannitol
mg 120.0 Microcrystalline cellulose mg 35.0 Hydroxypropyl
methylcellulose Mg 28.0 Sodium starch glycolate mg 4.0 Colloidal
hydrated silica mg 2.0 Magnesium stearate mg 2.0 Coating
Methacrylic acid copolymer type A (Eudragit L) mg 6.0 Methacrylic
acid copolymer type B (Eudragit S) mg 6.0 Triethyl citrate mg 1.2
talc mg 5.8 Titanium dioxide mg 3.0
[0108] The preparation process provides for mixing the dye with
lecithin, stearic acid and microcrystalline cellulose, compaction
thereof into wafers followed by dry granulation, mixing with the
remaining components of the nucleus and the final compression to
the weight of 250 mg/tab. The coating uses methacrylic derivatives
as base and an alcohol solvent as application phase.
[0109] The tablets thus obtained were subjected to dissolution test
in vitro, revealing a good resistance to the acid environment and a
progressive transfer of the dye in the neutral environment with pH
at 7.2.
Example 7: A Colon Controlled Release Tablet
TABLE-US-00007 [0110] Description UOM Amt. per tablet Components
Methylene blue mg 200.0 Lecithin mg 5.0 Stearic acid mg 14.0
Methylhydroxypropyl cellulose mg 180.0 Mannitol mg 140.0
Microcrystalline cellulose mg 140.0 talc mg 10.0 Colloidal hydrated
silica mg 5.0 Magnesium stearate mg 6.0 Coating Methacrylic acid
copolymer type A (Eudragit L) mg 16.0 Methacrylic acid copolymer
type B (Eudragit S) mg 16.0 Triethyl citrate mg 6.4 talc mg 15.6
Titanium dioxide mg 6.0
[0111] The composition is obtained through advance mixing and
granulation of the dye, the lecithin as amphiphilic component, the
stearic acid as component of the lipophilic matrix, mannitol and
part of the magnesium stearate; after screening the granules
obtained preliminarily, the remaining components and in particular
cellulose, capable of producing the hydrophilic matrix structure
are added. The final pharmaceutical form, obtained by compressing
the mixture of powders and granules, weighing about 700 mg, is
subjected to coating with a mixture of copolymers of methacrylic
derivatives of type A and B, supported by a plasticiser, triethyl
citrate, by a dye pigment, titanium dioxide, and by an anti-stick
agent, such as talc, using ethylic alcohol as solvent.
[0112] The tablet thus obtained revealed in vitro a substantial
non-dissolution at acid pH for 2 hours and a progressive
dissolution for about 6 hours in a simulated intestinal medium with
7.2 pH.
Example 8: Colon Endoscope Experimental Test
[0113] The same tablet of example 7 was used for carrying out some
colon endoscopies in a human being with extremely positive results.
A single tablet was administered to a subject about 12 hours before
carrying out the endoscopy, during the intestinal preparation step,
followed by the uptake of about further 500 ml of water. The time
that elapsed between the uptake of the tablet and the execution of
the endoscopy, about 12 hours, was useful to allow the tablet to
reach the intestinal colon region and start the progressive and
slow transfer of the dye which, due to the solubilisation in the
liquid present therein, allowed the homogeneous, intense and
persistent coloration of the intestinal mucosa. Actually, after the
administration the colon environment revealed noticeable areas of
coloration, allowing a considerable contrast between the pathologic
areas and the normal mucosa which covers the ascending, transverse,
descending, sigmoid and rectal colon regions.
[0114] FIGS. 1-4 show four (4) colon endoscopic images, obtained
during the endoscopy of a patient who has taken the composition of
the invention within the 24 hours preceding the endoscopy. The
images clearly show how only some zones of the colon area of the
patient are coloured, while the others are normal. This shows how
after the uptake of the composition of the invention, the dye
highlights solely the pathologic zones of the examined colon area
(see FIGS. 2, 3-4), and not the zones to be considered
non-pathologic (see FIG. 1).
[0115] Thus, this shows the efficiency of the indicated composition
when determining the elective coloration of the pathologic
intestinal areas and, by contrast, a non-pathologic area which,
consequently, is free of coloration.
Example 8-Bis: Bioavailability Study
[0116] The same tablet was used for a bioavailability and
pharmacokinetic study in which the profile of blood absorption and
urinary elimination of the dye administered to healthy volunteers
during a clinical study of Phase I was determined; the
pharmacokinetic parameters were compared with those obtained after
intravenous administration of a 100 mg dose of dye and they were as
follows:
TABLE-US-00008 T max C.sub.max AUC.sub.(o-t) 100 mg i.v. vial 0.10
hrs 2066 ng/ml 11858 ng/ml*h 200 mg tablets 16 hrs 1662 ng/ml 32941
ng/ml*h.
[0117] The tablets absorption profile is markedly different from
that of the vial and it can be classified as a typical absorption
profile of a controlled release formulation, also as shown in FIG.
5.
Example 9: Colon Endoscope Experimental Test
[0118] Using the tablet of example 7, there was carried out an
endoscopy test of the colon by administering two tablets to a
subject awaiting colonoscopy, according to the specified uptake
method, i.e. by taking the first dye tablet at the end of the
preparatory stage and the second tablet about 6 hours before
carrying out the endoscopy evaluation. The tablets were
administered with abundant water, so as to efficiently support the
in situ dissolution of the tablets.
[0119] Also in this case, the coloration was homogeneous and well
marked, allowing carrying out the test in optimal conditions for
diagnostic purposes.
Example 9-Bis: Bioavailability Study
[0120] The same tablet was used for a bioavailability and
pharmacokinetic study in which the profile of blood absorption and
urinary elimination of the dye administered to healthy volunteers
during a clinical of Phase I was determined; the pharmacokinetic
parameters measured after the administration of two 200 mg tablets
are the following:
TABLE-US-00009 T max C.sub.max AUC.sub.(0-t) 16 hrs 1636 ng/ml
38080 ng/ml*h.
[0121] The tablets absorption profile is very similar to the
profile obtained with the 200 mg tablet and, once again, it can be
classified as a typical absorption profile of a controlled release
formulation, also as shown in FIG. 6, where the chart with the dot
refers to the 200 mg dose while the one with the triangle refers to
the 400 mg one.
Example 10: Colon Release Coated Tablet
TABLE-US-00010 [0122] Description UOM Amt. per tablet Components
Toluidine blue mg 400.0 Carmine indigo mg 100.0 Lecithin mg 5.0
Stearic acid mg 10.0 Mannitol mg 30.0 Methylhydroxypropyl cellulose
mg 95.0 Microcrystalline cellulose mg 10.0 Sodium starch glycolate
mg 25.0 Colloidal hydrated silica mg 15.0 Magnesium stearate mg
10.0 Coating Methacrylic acid copolymer type A (Eudragit L) mg 20.0
Methacrylic acid copolymer type B (Eudragit S) mg 20.0 Triethyl
citrate mg 4.0 talc mg 20.0 Titanium dioxide mg 9.0
[0123] The preparation process provides for the formation of a
granulate containing toluidine blue, lecithin, stearic acid,
mannitol and part of the magnesium stearate; after compaction and
reduction into granules through screening, the second Carmine
indigo dye, cellulose, sodium starch glycolate, colloidal silica
and the remaining magnesium stearate lubricant are added. After
homogenization, the mixture is compressed to 700 mg and
subsequently subjected to coating as described in example 7, using
the two copolymers of the methacrylic acid and the other functional
excipients.
[0124] The tablet thus obtained resists to dissolution in vitro in
buffers with pH<2 and allows a progressive release of the dye
substances in buffers with pH>7.
Example 11: Gastric Immediate Release Coated Tablet
TABLE-US-00011 [0125] Description UOM Amt. per tablet Components
Congo red mg 50.0 Lecithin mg 3.0 Stearic acid mg 6.0 Mannitol mg
120.0 Microcrystalline cellulose mg 63.0 Sodium starch glycolate mg
4.0 Colloidal hydrated silica mg 2.0 Magnesium stearate mg 2.0
Coating Methyl hydroxypropyl cellulose mg 12.0 Polyethylene glycol
6000 mg 1.2 talc mg 6.0 Titanium dioxide mg 3.8
[0126] Obtained through the direct compression method, followed by
coating in an aqueous solvent. The tablet dissolves rapidly in
vitro within a few minutes, according to the specifications
required by the regulatory authorities for immediate release
tablets.
[0127] The tablet thus obtained can be used for endoscopic
evaluations of the gastroduodenal sector for highlighting local
pathologic growths which can be related to dysplastic or neoplastic
processes still at the initial stage.
Example 12: Double Layer Tablet
TABLE-US-00012 [0128] Description UOM Amt. per tablet Layer 1 Congo
red mg 100.0 Dioctyl sulfosuccinate mg 5.0 Stearic acid mg 10.0
Mannitol mg 100.0 Microcrystalline cellulose mg 100.0 Sodium starch
glycolate mg 20.0 Colloidal hydrated silica mg 10.0 Magnesium
stearate mg 5.0 Layer 2 Methylene blue mg 100.0 Lecithin mg 7.0
Stearic acid mg 10.0 Methylhydroxypropyl cellulose mg 100.0
Mannitol mg 80.0 Microcrystalline cellulose mg 40.0 talc mg 50.0
Colloidal hydrated silica mg 7.0 Magnesium stearate mg 6.0 Coating
Methyl hydroxypropyl cellulose mg 12.0 Polyethylene glycol 6000 mg
1.2 talc mg 6.0 Titanium dioxide mg 3.8
[0129] The process provides for mixing the components of layer 1
and compression thereof, followed by the compression of a mixture
of powders and granules obtained from a previous compaction of some
components of the layer 2, precisely the dye, lecithin, stearic
acid, the microcrystalline cellulose and mannitol with half of the
magnesium stearate, with the remaining co-formulants.
[0130] The tablet, weighing about 850 mg, has two differently
coloured distinct layers formulated for differentially releasing
the dye both in the gastric sector and in the subsequent intestinal
sector.
Example 13: A Colon Controlled Release Tablet
TABLE-US-00013 [0131] Description UOM Amt. per tablet Methylene
blue mg 25.0 Lecithin mg 3.0 Stearic acid mg 10.0
Methylhydroxypropyl cellulose mg 90.0 Mannitol mg 121.0
Microcrystalline cellulose mg 140.0 talc mg 3.0 Colloidal hydrated
silica mg 5.0 Magnesium stearate mg 3.0 Coating Methacrylic acid
copolymer type A (Eudragit L) mg 8.0 Methacrylic acid copolymer
type B (Eudragit S) mg 8.0 Triethyl citrate mg 3.2 talc mg 7.8
Titanium dioxide mg 3.0
[0132] The composition is obtained through advance mixing of the
dye, the lecithin as amphiphilic component, the stearic acid as
component of the lipophilic matrix, a thirds of the quantity of
mannitol; then the remaining components were added and in
particular the celluloses, capable of producing the hydrophilic
matrix structure up to completion of the formula. The final
pharmaceutical form, obtained by compressing the mixture of powders
and granules, unitary weighing of about 320 mg, is subjected to
coating with a mixture of copolymers of methacrylic derivatives of
type A and B, supported by a plasticiser, triethyl citrate, by a
dye pigment, titanium dioxide, by a small quantity of the dye,
methylene blue, and by an anti-stick agent, such as talc, using
ethylic alcohol as solvent.
[0133] The tablet thus obtained revealed in vitro a substantial
non-dissolution at acid pH for 2 hours and a progressive
dissolution in a simulated intestinal medium with 7.2 pH with a
release of about 45% within the first 4 hours and a release part
more than 80% at the eighth hour.
* * * * *