U.S. patent application number 13/456411 was filed with the patent office on 2012-09-27 for stable benzimidazole formulation.
Invention is credited to VALERIE AZOULAY, ERICA LAHAV, RAFFAEL LAHAV.
Application Number | 20120244219 13/456411 |
Document ID | / |
Family ID | 11072951 |
Filed Date | 2012-09-27 |
United States Patent
Application |
20120244219 |
Kind Code |
A1 |
LAHAV; RAFFAEL ; et
al. |
September 27, 2012 |
STABLE BENZIMIDAZOLE FORMULATION
Abstract
A stable composition with a benzimidazole derivative, such as
Omeprazole, which does not contain a separating layer between the
active compound and an enteric coating layer. Instead, the enteric
coating layer is applied as a solution with a pH value of at least
6.5, and more preferably in a range of from about 7 to about 10,
directly to the benzimidazole derivative substrate. This solution,
with the optional addition of a plasticizer, can be directly coated
onto the substrate without any necessity for an intermediate layer.
Furthermore, in this pH range, the enteric coating is optionally
applicable in an aqueous solution, thereby obviating the need for
organic solvents for dissolving the enteric coating material. The
resultant formulation maintains the stability of the benzimidazole
derivative during storage and at the same time protects the product
during passage through the acidic environment of the stomach.
Inventors: |
LAHAV; RAFFAEL; (Qiriat
Bialik, IL) ; LAHAV; ERICA; (Qiriat Bialik, IL)
; AZOULAY; VALERIE; (Pardes Hannah, IL) |
Family ID: |
11072951 |
Appl. No.: |
13/456411 |
Filed: |
April 26, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11785300 |
Apr 17, 2007 |
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13456411 |
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10018992 |
Feb 19, 2003 |
7255878 |
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11785300 |
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PCT/IL00/00364 |
Jun 21, 2000 |
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10018992 |
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Current U.S.
Class: |
424/474 ;
424/400; 424/490; 427/2.14; 514/338 |
Current CPC
Class: |
A61P 1/04 20180101; A61K
9/5078 20130101; A61K 31/4184 20130101; A61K 31/4439 20130101; A61K
9/284 20130101; A61K 9/2031 20130101; A61K 9/2866 20130101; A61K
9/0053 20130101 |
Class at
Publication: |
424/474 ;
424/400; 514/338; 424/490; 427/2.14 |
International
Class: |
A61K 9/00 20060101
A61K009/00; B05D 7/00 20060101 B05D007/00; A61K 9/14 20060101
A61K009/14; A61P 1/04 20060101 A61P001/04; A61K 31/4439 20060101
A61K031/4439; A61K 9/28 20060101 A61K009/28 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 22, 1999 |
IL |
130602 |
Claims
1-17. (canceled)
18. A stable composition for a benzimidazole derivative, the
composition comprising: (a) a substrate, said substrate featuring
the benzimidazole derivative; and (b) an enteric coating material
layered directly over said substrate, said enteric coating material
having a pH value of at least about 6.5, thereby obviating the need
for an intermediate layer between said substrate and said enteric
coating, with the proviso that said enteric coating material does
not include HPMCP (hydroxypropyl methylcellulose phthalate).
19. The composition of claim 18, wherein said substrate is an
active core for containing the benzimidazole derivative.
20. The composition of claim 19, wherein said active core is
selected from the group consisting of a pellet, a bead and a
tablet.
21. The composition of claim 20, wherein said active core is a
tablet formed by compression.
22. The composition of claim 19, wherein said substrate features:
(i) a neutral core; and (ii) an active coating containing the
benzimidazole derivative, said active coating being layered over
said neutral core such that the composition is in a form of a
pellet
23. The composition of claim 18, wherein said substrate features a
core containing the benzimidazole derivative with a suitable
binding agent, said core being prepared by spheronisation and
pelletization; such that the composition is in a form of a
pellet.
24. The composition of claim 18, wherein said enteric coating
material includes at least one enteric material selected from the
group consisting of hydroxypropyl methylcellulose acetate
succinate, polyvinyl acetate phthalate, cellulose acetate
phthalate, cellulose acetate trimellitate, hydroxypropyl
methylcellulose phthalate, polymethacrylic acid methyl methacrylate
and polymethacrylic acid ethyl methacrylate.
25. The composition of claim 24, wherein said enteric coating
material further comprises an alkaline compound, such that said pH
value is adjusted by adding said alkaline compound to said enteric
material.
26. The composition of claim 25, wherein said alkaline compound is
an inorganic alkaline compound.
27. The composition of claim 26, wherein said alkaline compound is
selected from the group consisting of basic sodium, potassium and
ammonium hydroxide.
28. The composition of claim 27, wherein said enteric coating
material is at least about 60% neutralized by adding said alkaline
compound.
29. The composition of claim 28, wherein said enteric coating
material is at least about 80% neutralized by adding said alkaline
compound.
30. The composition of claim 28, wherein said enteric coating
material is at least about 95% neutralized by adding said alkaline
compound.
31. The composition of claim 25, wherein said pH value is in a
range of from about 7 to about 10.
32. The composition of claim 25, wherein said enteric coating
material further comprises a plasticizer.
33. The composition of claim 32, wherein said plasticizer is
selected from the group consisting of a citric acid ester and a
phthalic acid ester.
34. The composition of claim 33, wherein the benzimidazole
derivative is selected from the group consisting of Omeprazole,
Pantoprazole, Lansoprazole, Leminoprazole, Perprazole, Rabeprazole,
and pharmaceutically acceptable salts thereof.
35. A stable composition for a benzimidazole derivative, the
composition consisting essentially of: (a) a substrate, said
substrate featuring the benzimidazole derivative; and (b) an
enteric coating material layered over said substrate, said enteric
coating material having a pH value of at least about 6.5 by an
alkaline compound, such that said pH value is adjusted by adding
said alkaline compound to said enteric material.
36. The composition of claim 35, wherein said substrate is an
active core for containing the benzimidazole derivative.
37. The composition of claim 36, wherein said active core is
selected from the group consisting of a pellet, a bead and a
tablet, said active core being formed by embedding the
benzimidazole derivative in poloxamer.
38. The composition of claim 36, wherein said active core is a
tablet formed by compression.
39. The composition of claim 35, wherein said substrate features:
(i) a neutral core; and (ii) an active coating containing the
benzimidazole derivative, said active coating being layered over
said neutral core.
40. The composition of claim 35, wherein said enteric coating
material includes at least one enteric material selected from the
group consisting of hydroxypropyl methylcellulose phthalate,
hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate
phthalate, cellulose acetate phthalate, cellulose acetate
trimellitate, polymethacrylic acid methyl methacrylate and
polymethacrylic acid ethyl methacrylate.
41. The composition of claim 40, wherein said alkaline compound is
an inorganic alkaline salt compound.
42. The composition of claim 41, wherein said alkaline compound is
selected from the group consisting of basic sodium, potassium or
ammonium hydroxide.
43. The composition of claim 42, wherein said enteric coating
material is at least about 60% neutralized by adding said alkaline
compound.
44. The composition of claim 43, wherein said enteric coating
material is at least about 80% neutralized by adding said alkaline
compound.
45. The composition of claim 44, wherein said enteric coating
material is at least about 95% neutralized by adding said alkaline
compound.
46. The composition of claim 41, wherein said pH value is in a
range of from about 7 to about 10.
47. The composition of claim 41, wherein said enteric coating
material further comprises a plasticizer.
48. The composition of claim 47, wherein said plasticizer is
selected from the group consisting of a citric acid ester and a
phthalic acid ester.
49. The composition of claim 35, wherein the benzimidazole
derivative is selected from the group consisting of Omeprazole,
Pantoprazole, Lansoprazole, Leminoprazole, Perprazole, Rabeprazole,
and pharmaceutically acceptable salts thereof.
50. A method for producing a stable composition for a benzimidazole
derivative, the method comprising the steps of: (a) forming a
substrate with the benzimidazole derivative; (b) preparing an
enteric coating material having a pH value of at least about 6.5;
and (c) layering said enteric coating material directly over said
substrate, with the proviso that said enteric coating material does
not include HPMCP (hydroxypropyl methylcellulose phthalate).
51. The method of claim 50, wherein said substrate is formed by
melting poloxamer and by mixing the benzimidazole derivative into
said poloxamer.
52. The method of claim 50, wherein said substrate is formed by
direct compression.
53. The method of claim 50, wherein said substrate is formed by wet
granulation.
54. The method of claim 50, wherein said substrate is formed by
coating on an inert core.
55. The method of claim 50, wherein said enteric coating material
is prepared by the steps of (i) mixing an enteric material with
water to form a mixture; and (ii) adding an alkaline compound to
said mixture to form an aqueous solution having a pH value of from
about 7 to about 10.
56. The method of claim 50, wherein said enteric coating material
is prepared by the steps of (i) mixing an enteric material with
water and alcohol to form a mixture; and (ii) adding an alkaline
compound to said mixture to form an aqueous solution having a pH
value of from about 7 to about 10.
57. The composition of claim 1, wherein the composition is in a
form of a tablet, wherein said substrate consists essentially of a
core and wherein said enteric coating material consists essentially
of a single enteric coating.
58. The composition of claim 1, wherein the composition is in a
form of a pellet, wherein said substrate consists essentially of a
core and wherein said enteric coating material consists essentially
of a single enteric coating, such that a combination of said single
enteric coating and said core forms said pellet, the composition
further comprising a tablet for containing a plurality of said
pellets, wherein said plurality of pellets is not compressed.
59. A method for producing a stable tablet composition for a
benzimidazole derivative, the method comprising the steps of: (a)
forming a single core with the benzimidazole derivative; (b)
preparing neutralized enteric coating material having a pH value of
at least about 6.5; and (c) layering a single layer of said enteric
coating material directly over said single core to form the tablet
by directly coating said single core, such that each tablet only
has said single core.
Description
[0001] This application is a Divisional application of
Continuation-in-Part application Ser. No. 10/018,992 filed on Feb.
19, 2003, which is a Continuation-in-Part Application of PCT
Application No. PCT/IL00/00364 filed on Jun. 21, 2000, and also
claims priority from Israeli Patent Application No. 130602 filed on
Jun. 22, 1999, all of which are hereby incorporated by reference as
if fully set forth herein.
FIELD AND BACKGROUND OF THE INVENTION
[0002] The present invention relates to a novel stable formulation
for an acid labile benzimidazole, and methods of preparation and
administration thereof, and in particular, for a stable formulation
of a benzimidazole which is suitable for oral administration.
[0003] Omeprazole, Pantoprazole, Lansoprazole and other derivatives
of benzimidazole, which are active proton pump inhibitors and used
conventionally for decreasing gastric secretion are known to be
susceptible to degradation and transformation in acid media.
Omeprazole,
5-methoxy-2(((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)sulfinyl)-1H-benz-
imidazole, is disclosed and described in European Patent No. 5129
and European Patent No. 124495, as well as in numerous other
patents and published patent applications.
[0004] The susceptibility of these active proton pump inhibitor
substances to degradation and transformation in acid media
increases the difficulty of preparing a pharmaceutical form
designed for oral administration. If the active substance comes
into contact with the stomach content, which is a highly acidic
medium, these chemical substances become degraded. Thus, these
benzimidazole derivatives should be protected both during storage
and during their passage through the acidic environment of the
stomach.
[0005] The stability of Omeprazole has been extensively studied
(see for example A. Pilbrant and C. Cederberg, Scan. J.
Gastroenterol., 20: 113-120, 1985). Omeprazole degrades with a
half-life of less than 10 minutes in an environment with pH values
below 4.0. At pH 6.5, the half life of Omeprazole is 18 hours and
at pH 11 about 300 days. Therefore, the environment of Omeprazole
should be kept at a sufficiently high pH value in order to maintain
the stability of the compound, in a formulation which is suitable
as a product for oral administration, for example by locating
Omeprazole within a core which also contains alkaline constituents.
This leads to an alkaline reaction aimed at improving stability of
the active substance during manufacture thereof and during storage
of the pharmaceutical formulation.
[0006] In addition, such a formulation must protect Omeprazole from
the acidic environment of the stomach, since if Omeprazole is given
orally without any protective coating, it will degrade in the acid
environment of the stomach. European Patent No. 237,200 discloses
one solution, which is to directly coat the solid core containing
Omeprazole, or another benzimidazole derivative, with an enteric
coating layer.
[0007] However, this apparent solution to the instability of
Omeprazole caused further complications, in that the alkaline core
containing Omeprazole was found to react with the enteric coating,
thereby causing the enteric coating to degrade. A solution to these
further complications is disclosed in United Kingdom Patent
Application No. 2,189,698, in which Omeprazole is contained within
a solid active core, which is coated first with a subcoating layer
and then with an enteric coating layer. The enteric coating layer
protects the Omeprazole during the passage through the stomach,
while the subcoating layer protects the enteric coating layer from
reacting negatively with the alkaline core containing
Omeprazole.
[0008] The background art describes other attempts to provide
formulations which are suitable for oral administration of
acid-labile substances. For example, PCT Application No. WO
97/12581 discloses a composition adapted for oral administration
containing Omeprazole which specifically does not include
alkaline-reacting compounds. Instead, the composition features a
core composed of a nuclei and Omeprazole compressed together, an
intermediate layer and an enteric layer.
[0009] European Patent Application No. 519,144 discloses a
formulation for Omeprazole, which features a neutral (sugar) core.
Omeprazole is sprayed onto the sugar core, after which an
intermediate coating layer and an enteric coating layer are sprayed
onto the core.
[0010] PCT Application No. WO 98/00114 discloses a modification to
other background art formulations for Omeprazole, in which the
intermediate subcoating layer is partially neutralized with an
alkaline compound. However, this modified formulation still
features the subcoating layer, which is a disadvantage in that it
complicates the manufacturing process and increases the expense and
difficulty of manufacture. Thus, the formulation disclosed in PCT
Application No. WO 98/00114, like those disclosed in European
Patent Application No. 519,144 and other background art references,
has the disadvantage of requiring the intermediate layer.
[0011] PCT Application No. WO 83/00435 discloses a solid dosage
form, such as a capsule or tablet, containing a pharmacologically
active agent coated with an anionic polymer, which is insoluble in
gastric juice and in intestinal juice below pH 7. The preferred
anionic polymer is a partly methyl esterified methacrylic acid
polymer in which the ratio of free carboxylic groups to ester
groups is about 1:2. In contrast to the present invention,
Omeprazole is not disclosed as one of the active agents.
[0012] French Application No. 2,692,146 discloses stable
compositions of microgranules of gastro-protected Omeprazole. The
composition features a center of Omeprazole diluted in mannitol.
This center is coated with an intermediate layer featuring
mannitol. An enteric coating is then added over this intermediate
layer. PCT Application No. WO 97/12581 discloses a formulation in
which an intermediate layer between the core and an enteric coating
contains silicium dioxide.
[0013] PCT Application No. WO 96/37195 discloses a formulation
which lacks a subcoating layer, but which features a core
containing titanium dioxide. Both the core containing Omeprazole
and the enteric coating layer placed on top of the core include
titanium dioxide as an ingredient. Unfortunately, titanium dioxide
is only able to mask the discoloration caused by the reaction
between Omeprazole and the enteric coating layer, but cannot
prevent such an undesirable reaction. Thus, the disclosed
formulation does not prevent the undesirable reaction between the
benzimidazole derivative and the enteric coating, which is known in
the art.
[0014] German Patent Application No. 196 26 045 A1 discloses a
method for stabilising Omeprazole by coating small tablets or
pellets, containing large amounts of mannitol, with a subcoating of
Eudragit L. The subcoating of Eudragit L is neutralized, after
which a final enteric coat of non-neutralized Eudragit L is
applied.
[0015] A formulation of a benzimidazole derivative, such as
Omeprazole, which lacks an intermediate coating layer and yet which
is stable both during storage and during the passage through the
stomach, would be highly desirable. Such a formulation would be
simpler to manufacture and would expose the sensitive benzimidazole
derivative to fewer production steps, thereby decreasing the
possibility that the active compound would degrade during
production. Unfortunately, such a stable benzimidazole formulation,
which lacks an intermediate layer, is not currently available.
[0016] There is thus a unmet need for, and it would be useful to
have, a stable benzimidazole formulation, particularly for
Omeprazole which lacks an intermediate layer and yet which is
stable both during storage and during the passage through the
stomach.
SUMMARY OF THE INVENTION
[0017] The formulation of the present invention contains a
benzimidazole derivative, such as Omeprazole, and is able to
maintain the stability of this active ingredient without a
separating layer. Instead, the enteric coating layer is applied as
a solution with a pH value of at least 6.5, and more preferably in
a range of from about 7 to about 10, directly to the benzimidazole
derivative substrate. This solution, with the optional addition of
a plasticizer, can be directly coated onto the substrate without
any necessity for an intermediate layer. Furthermore, in this pH
range, the enteric coating is optionally applicable in an aqueous
solution, thereby obviating the need for organic solvents for
dissolving the enteric coating material.
[0018] The resultant formulation maintains the stability of the
benzimidazole derivative during storage and at the same time
protects the product during passage through the acidic environment
of the stomach, where the acidic environment of the stomach causes
a partial ionic exchange to occur within the material of the
coating. This partial ionic exchange renders the coating
impermeable to the acidic liquids of the stomach. On the other
hand, during storage the problem of interaction between the enteric
coat and the alkaline core is thus completely eliminated as the
"enteric coat" is no longer acidic during the storage period.
[0019] Preferably, the benzimidazole derivative is selected from
the group consisting of Omeprazole, Pantoprazole, Lansoprazole,
Leminoprazole, Perprazole, Rabeprazole, and pharmaceutically
acceptable salts thereof, as well as any other derivatives of
benzimidazole which are proton pump inhibitors and which are
conventionally used to decrease gastric secretion.
[0020] According to the present invention, there is provided a
stable composition for a benzimidazole derivative, the composition
comprising: (a) a substrate, the substrate featuring the
benzimidazole derivative; and (b) an enteric coating material
layered over the substrate, the enteric coating material having a
pH value of at least about 6.5.
[0021] The substrate can optionally have several different
structures. For example, the substrate is optionally an active core
containing the benzimidazole derivative, in which the core is a
pellet, bead or tablet for example. The active core can be prepared
by any conventional method known in the art, including but not
limited to, pellets prepared by spheronisation, pellets prepared by
coating an inert non pareil seed with Omeprazole, tablets prepared
by granulation and compression, as well as any other methods.
[0022] The enteric coating material optionally and preferably
includes an enteric material selected from the group consisting of
hydroxypropyl methylcellulose phthalate, hydroxypropyl
methylcellulose acetate succinate, polyvinyl acetate phthalate,
cellulose acetate phthalate, cellulose acetate trimellitate,
polymethacrylic acid methyl methacrylate and polymethacrylic acid
ethyl methacrylate.
[0023] More preferably, the enteric coating material further
comprises an alkaline compound, such that the pH value is adjusted
by adding the alkaline compound to the enteric material. Most
preferably, the alkaline compound is an inorganic or organic
alkaline salt compound. Even more preferably, the alkaline compound
is selected from the group consisting of basic sodium, potassium or
ammonium hydroxide. Also most preferably, the pH value is in a
range of from about 7 to about 10.
[0024] The enteric coating material of the composition could
optionally include a plasticizer. Preferably, the plasticizer is
selected from the group consisting of a citric acid ester and a
phthalic acid ester.
[0025] According to another embodiment of the present invention,
there is provided a stable composition for a benzimidazole
derivative, the composition consisting essentially of: (a) a
substrate, the substrate featuring the benzimidazole derivative;
and (b) an enteric coating material layered over the substrate, the
enteric coating material having a pH value of at least about
6.5.
[0026] According to still another embodiment of the present
invention, there is provided a method for producing a stable
composition for a benzimidazole derivative, the method comprising
the steps of: (a) forming a substrate with the benzimidazole
derivative; (b) preparing an enteric coating material having a pH
value of at least about 6.5; and (c) layering the enteric coating
material over the substrate.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0027] The formulation of the present invention contains a
benzimidazole derivative, such as Omeprazole, and is able to
maintain the stability of this active ingredient without a
separating layer between the active compound and an enteric coating
layer. Instead, the enteric coating layer is applied as a solution
with a pH value of at least 6.5, and more preferably in a range of
from about 7 to about 10, directly to the benzimidazole derivative
substrate. This solution, with the addition of a plasticizer, can
be directly coated onto the substrate without any necessity for an
intermediate layer. Furthermore, in this pH range, the enteric
coating is optionally applicable in an aqueous solution, thereby
obviating the need for organic solvents for dissolving the enteric
coating material.
[0028] The resultant formulation maintains the stability of the
benzimidazole derivative during storage and at the same time
protects the product during passage through the acidic environment
of the stomach. The problem of interaction between the enteric coat
and the alkaline core is thus completely eliminated as the enteric
coat at this stage is no longer acidic.
[0029] Without wishing to be limited to a single mechanism, it is
hypothesized that as the formulation passes through an acidic
environment, such as the acidic environment of the stomach, the
outer layer of the enteric coat is converted to an acidic form.
This acidic form of the enteric coating material is insoluble in
the acidic environment of the stomach. If the formulation is then
placed in an environment with a more alkaline pH value, for example
by moving into the small intestine, the enteric coat dissolves and
releases the active substance.
[0030] The use of an enteric coating which includes HPMCP
(hydroxypropylmethylcellulose phthalate) neutralized with a basic
salt is disclosed in U.S. Pat. No. 5,225,202 and in two scientific
articles, "Enteric Film Coating Using Completely Aqueous Dissolved
Hydroxypropyl Methyl Cellulose Phthalate Spray Solutions" (J. W.
Stafford et al., Drug Development and Industrial Pharmacy,
8:513-530, 1982) and "The In Vitro and In Vivo Performance of
Aqueous Based Enteric Coats of to Neutralized Hydroxypropyl Methyl
Cellulose Phthalate" (J. R. Bloor et al., Drug Development and
Industrial Pharmacy, 15:2227-2243, 1989). However, the disclosed
enteric coating is not taught or suggested in any of these
references as a suitable direct enteric coating for substrates
which contain Omeprazole. As noted previously, Omeprazole and the
related benzimidazole derivatives are unusually sensitive
molecules, and as such must be carefully protected. Furthermore,
U.S. Pat. No. 5,225,202 teaches the necessity for a subcoat between
the drug-containing substrate and the enteric coating for drugs
which are not compatible with the enteric coating. By contrast, the
present invention has been shown to be highly effective without
such a subcoat, which is particularly surprising since the
background art teaches that formulations containing Omeprazole or
another benzimidazole derivative must also feature a subcoat.
Neither scientific article even considers the problems associated
with acid-sensitive drugs, and as such cannot teach or suggest the
formulation of the present invention.
[0031] As shown by both the in vitro and in vivo data given below,
the formulation of the present invention has been shown to be
particularly effective for the oral administration of Omeprazole as
the exemplary benzimidazole derivative, a result which could not
have been predicted from these references. Indeed, the article by
J. R. Bloor et al. teaches away from the use of such a neutralized
enteric coating for any formulation, as this article disclosed good
in vitro performance of the formulation but poor in vivo
performance. By contrast, as described in greater detail below with
regard to Example 7, the formulation of the present invention shows
good performance in vivo. Thus, the background art neither teaches
nor suggests the direct coating of a substrate containing
Omeprazole or another benzimidazole derivative with an enteric
coating material having a pH value of at least about 6.5, and in
fact teaches away from such a formulation.
[0032] The preparation of the benzimidazole-containing compositions
of the present invention is described first with reference to the
following general description and then with reference to the
following non-limiting examples of the preparation and application
of the compositions of the present invention.
[0033] As noted previously, the formulation of the present
invention includes a substrate which features the benzimidazole
derivative. A solution is prepared with the enteric coating
material, which has a pH value of at least 6.5 and more preferably
of from about 7 to about 10. Preferably, a pH value in the desired
range is obtained by adding an alkaline compound to an enteric
coating material. More preferably, the alkaline compound is
selected from the group consisting of sodium, potassium or ammonium
hydroxide. This enteric coating solution is then layered directly
over the substrate to form the composition of the present
invention.
[0034] The term "substrate" refers to substantially any structure
which features the benzimidazole derivative, such as Omeprazole.
For example, this structure could be an active core containing the
benzimidazole derivative. This active core could be prepared in a
number of different ways which are known in the art. For example,
the active core could be formed by compressing the benzimidazole
derivative with an alkaline substance. As another example, the
active core could be prepared by mixing the benzimidazole
derivative with an alkaline substance, spheronizing the mixture and
then forming cores through pelletisation. As yet another example,
the active core is optionally and preferably prepared by embedding
the active ingredient in a poloxamer and compressing the embedded
material into tablets. The active core is also optionally formed by
granulating the active ingredient with an alkaline substance and
compressing the granulation into tablets.
[0035] Alternatively and optionally, the structure could include a
neutral core, such as a sugar bead which does not contain the
benzimidazole derivative, over which the benzimidazole derivative
is coated. The coating includes Omeprazole or other benzimidazole
derivative with a suitable adhesive polymer.
[0036] The substrate optionally and preferably includes a basic
stabilizing material, which is more preferably at least one of
sodium stereate and arginine, particularly for the active coating.
Magnesium carbonate and/or sodium hydrogen carbonate may also
optionally be used as basic stabilizing materials, in addition to,
or alternatively in place of, these materials.
[0037] Substantially any type of neutralized suitable enteric
coating material could be used in order to coat the benzimidazole
substrate, including but not limited to, cellulose acetate
phthalate (CAP); hydroxypropyl methylcellulose phthalate (HPMCP);
polyvinyl acetate phthalate; cellulose acetate trimellitate;
polymethacrylic acid methyl methacrylate or ethyl methacrylate,
such as the various types of Eudragit; and hydroxypropyl
methylcellulose acetate succinate (HPMCAS). However, preferably the
enteric coating material is prepared with the proviso that this
material does not contain HPMCP alone, but only in combination with
at least one of these other listed enteric coating materials. More
preferably, HPMCP is not present in the enteric coating material.
The particularly preferred enteric coating material is HPMCAS.
[0038] As used herein, the term "neutralized enteric coating
material" refers to enteric coating material which has been at
least partially neutralized by reaction with an alkaline compound,
which is optionally a basic inorganic salt. Preferably, the enteric
coating material is at least about 60% neutralized, more preferably
the enteric coating material is at least about 80% neutralized, and
most preferably the enteric coating material is at least about 95%
neutralized.
[0039] The enteric coating optionally contains a plasticizer, such
as a citric acid ester, a phthalic acid ester, or any suitable
plasticizer.
[0040] The method for applying the enteric coating material to the
substrate can vary. Substantially any coating method can be used,
such as pan coating or fluidized bed coating, with the solution of
the enteric coat chosen. As noted previously, preferably this
solution is an aqueous solution. The enteric coating materials
described previously can be applied to the substrate in an aqueous
solution if the pH value of the solution is adjusted to at least
6.5, and more preferably to an alkaline value, most preferably a pH
value from about 7 to about 10.
[0041] The following specific examples illustrate various aspects
of the compositions of the present invention, and are not intended
to be limiting in any way. Specific reference is made to Omeprazole
for the purposes of description only and without intending to be
limiting.
Example 1
[0042] This example of the composition of the present invention was
prepared as follows. The substrate was in the form of an active
core, which was prepared by embedding Omeprazole in poloxamer
(Pluronic PE 6800), granulating the resulting mass, adding the
necessary auxiliary substances to the mass, and compressing the
resultant material into tablets. The substrate was then coated with
alkaline polyvinyl acetate phthalate as the enteric coating
layer.
TABLE-US-00001 Substrate (Active Embedded Core) Ingredients
Quantity per tablet Omeprazole 20 mg Poloxamer (Pluronic PE 6800)
200 mg Colloidal silicon dioxide 7 mg Magnesium carbonate 10 mg
Sodium starch glycolate 12 mg Titanium dioxide 100 mg Ludipress
.RTM. 226 mg Sodium stearyl fumarate 25 mg
TABLE-US-00002 Enteric coating layer Polyvinyl acetate phthalate 75
mg Antifoam emulsion 0.25 mg Sodium hydroxide 12 mg
[0043] For the preparation of the substrate, the poloxamer was
melted at a temperature of 80.degree. C. Omeprazole, together with
2 mg colloidal silicon dioxide, 8 mg of magnesium carbonate,
titanium dioxide and 6 mg of sodium starch glycolate were added and
mixed thoroughly. Mixing was continued until the melt solidified.
The melt was granulated and the rest of the ingredients added to
the granulate. The granulate was then compressed into tablets which
contained 20 mg Omeprazole. These tablets, which formed the
substrate of the composition, were then transferred into a
conventional coating pan and coated with the enteric coating layer,
prepared in the following manner. First, the antifoam emulsion was
dissolved in water to form an aqueous solution. Polyvinyl acetate
phthalate was then stirred into this solution for a final
concentration of about 10% weight per volume before sodium
hydroxide was added. Sodium hydroxide (1 M solution) was then added
to adjust the pH value of the solution to about 8, thereby
obtaining a basic solution of the enteric coating material. This
solution was then sprayed onto the tablets with an incoming air
temperature of 40.degree. C.
Example 2
[0044] This example of the composition of the present invention was
prepared as follows. The substrate was prepared by embedding
Omeprazole in poloxamer (Pluronic PE 6800) to form tablets, as for
Example 1. However, in this Example, the tablets were then coated
with hydroxypropyl methylcellulose acetate succinate (HPMCAS) as
the enteric coating layer.
TABLE-US-00003 Substrate Ingredients Quantity per tablet Omeprazole
20 mg Poloxamer (Pluronic PE 6800) 200 mg Colloidal silicon dioxide
7 mg Sodium starch glycolate 20 mg Ludipress .RTM. 228 mg Sodium
stearyl fumarate 25 mg
TABLE-US-00004 Enteric coating layer Hydroxypropyl Methylcellulose
Acetate 43 mg Succinate (HPMCAS) Triethyl citrate 12 mg Sodium
lauryl sulfate 1.3 mg Talc 21.4 mg Sodium hydroxide 2.3 mg
[0045] The tablets were prepared as for Example 1, except that
titanium dioxide was omitted. The tablets were then coated in a
conventional coating pan with the enteric coating solution, which
was prepared as follows. First, triethyl citrate was dissolved in
water to form an aqueous solution. Sodium lauryl sulfate was then
added to this aqueous solution. The HPMCAS and talc were dispersed
in this solution, such that the concentration of HPMCAS was about
10% weight per volume. Sodium hydroxide (1M solution) was then
added to adjust the pH value of the solution to a value from about
7 to to about 10. The enteric coating was layered over the
substrate by spraying the solution with an incoming air temperature
of 40.degree. C.
Example 3
[0046] This example of the composition of the present invention was
prepared as for Example 1, except that the enteric coating
contained alkaline HPMCP (hydroxypropylmethylcellulose phthalate)
rather than HPMCAS.
TABLE-US-00005 Substrate Ingredients Quantity per tablet Omeprazole
20 mg Poloxamer (Pluronic PE 6800) 200 mg Colloidal silicon dioxide
7 mg Sodium starch glycolate 10 mg Titanium dioxide 83 mg Ludipress
.RTM. 145 mg Sodium stearyl fumarate 25 mg
TABLE-US-00006 Enteric coating layer HPMC Phthalate (HP-55) 56.2 mg
Triethyl citrate 22.5 mg Sodium hydroxide 9 mg
[0047] The substrate was prepared as described in Example 1, and
was then coated in a conventional coating pan with the enteric
coating solution by spraying the solution at an incoming air
temperature of 40.degree. C. The enteric coating solution was
prepared as follows. The HPMC phthalate was suspended in the water
to a concentration of about 10% weight per volume (before sodium
hydroxide was added). Sodium hydroxide (1M solution) was then added
to this aqueous suspension until the HPMCP dissolved. The resultant
solution has a pH value in a range of from about 8 to about 10. The
triethyl citrate was then added to the resultant solution in order
to form the enteric coating solution, which was then layered over
the substrate as previously described.
Example 4
[0048] In this example of the composition of the present invention,
the substrate has two parts: a neutral core; and a coating layer
containing the active ingredient, which was layered over the
neutral core. The substrate was then coated with the enteric
coating solution. Hard gelatin capsules were then filled with the
resultant pellets.
Substrate
TABLE-US-00007 [0049] Neutral core Quantity per capsule Sugar
spheres 20/25 (700-850 microns) 161.63 mg
TABLE-US-00008 Active coating Ingredients Quantity per capsule
Omeprazole 20.00 mg Hydroxypropyl methylcellulose 2910 5.33 mg
Hydroxypropyl cellulose 6.00 mg Lactose 8.00 mg Disodium phosphate
anhydrous 0.64 mg Sodium lauryl sulfate 0.50 mg
TABLE-US-00009 Enteric coating layer HPMCAS 21.00 mg Triethyl
citrate 6.00 mg Sodium lauryl sulfate 0.66 mg Talc 11.00 mg Sodium
hydroxide 1.12 mg
[0050] The composition of the present invention was prepared
according to this Example as follows. First, sugar spheres were
placed in a fluid bed coating chamber, equipped with a Wurster
bottom spraying device. A suspension of the ingredients in water
was then prepared so that the concentration was approximately 20%
of total solids in water. This active coating suspension was
sprayed onto the sugar spheres. A suspension of the enteric coating
was prepared according to Example 2. This enteric coating was then
sprayed onto the substrate in order to form the finished pellets.
The pellets were then placed in capsules.
Example 5
[0051] This example of the composition of the present invention was
prepared with a compressed tablet as the substrate. The tablet was
then coated with alkaline HPMCAS (Hydroxypropyl Methylcellulose
Acetate Succinate) as the enteric coating layer, preferably having
a pH in a range of from about 7 to about 10.
TABLE-US-00010 Substrate (Active Compressed Tablet Core)
Ingredients Quantity per tablet Omeprazole 20 mg Lactose 192.5 mg
Magnesium carbonate 10 mg Sodium starch glycolate 10 mg Povidone 10
mg Sodium stearyl fumarate 7.5 mg
TABLE-US-00011 Enteric coating layer HPMCAS 16.1 mg Triethyl
citrate 4.5 mg Sodium lauryl sulfate 0.5 mg Talc 8.04 Sodium
hydroxide 0.86 mg
[0052] For the preparation of the substrate, Omeprazole, together
with lactose, magnesium carbonate, sodium starch glycolate, and
povidone were mixed thoroughly. The mixture was then granulated
with a sufficient quantity of water, and dried. Sodium stearyl
fumarate was then added to the mixture, which was then compressed
into tablets weighing 250 mg each.
[0053] These tablets, which formed the substrate of the
composition, were then transferred into a conventional coating pan
and coated with the enteric coating layer, prepared as described in
Example 4.
Example 6
[0054] Stability tests were performed with formulations prepared
according to Examples 2 and 3. For the first test, both coated and
uncoated tablets prepared according to either Example 2 or Example
3 were placed into a box which was open to the environment. The
open box was then stored at 40.degree. C. and 75% relative
humidity, which are very stringent conditions. The coated and
uncoated tablets were examined initially, after a week and after a
month to determine stability. The results are shown in the tables
below.
Tablets Prepared According to Example 2
TABLE-US-00012 [0055] Appearance of Sample Sampled Material Initial
After One Week After One Month coated tablet off white deeper off
white deeper off white uncoated tablet white white white
Tablets Prepared According to Example 3
TABLE-US-00013 [0056] Appearance of Sample Sampled Material Initial
After One Week After One Month coated tablet off white off white
deeper off white uncoated tablet white white white
[0057] The term "deeper off white" refers to a more intense off
white color which was observed for some samples, as described in
greater detail above. These results show that coated tablets
prepared according to either Example 2 or Example 3 showed good
stability, even after one month of storage under particularly
stringent conditions.
[0058] In a second stability test, coated tablets were prepared
according to Example 2. These coated tablets were then packed into
an Alu/Alu (Aluminum/Aluminum) blister, which is a well known
technique in the art for packing certain oral dosage forms. The
blister was then stored under accelerated conditions of 30.degree.
C. and 60% relative humidity; or 40.degree. C. and 75% relative
humidity. Samples of the tablets were examined initially, and after
one month of storage under one of these conditions. In addition,
samples were assayed to determine the amount of Omeprazole present
in the coated tablet, as listed under "Assay" as milligrams of
Omeprazole per tablet. A dissolution test was performed, using the
accepted USP method. The coated tablets were placed in 0.1 N HCl
for 2 hours, followed by a solution at pH 6.8 with stirring with a
paddle at 100 rpm for 15 minutes, 30 minutes or 45 minutes. Gastric
resistance was also examined by placing the coated tablets in a
simulated gastric fluid for 2 hours (pH of approximately 1), as is
well known in the art. The results are shown in the table
below.
TABLE-US-00014 Time (min) Initial 30.degree. 60% RH 40.degree. 75%
RH Description NA Off white Off white Off white Assay NA 20.4 mg
19.39 mg 19.66 mg Dissolution 120 0% 0% 0% 135 52% 42% 39% 150 96%
85% 90% 165 105% 99% 104% Gastric NA 101% 98% 96% Resistance
[0059] These results show that the coated tablets, prepared
according to Example 2, show good stability and gastric resistance,
yet are also able to dissolve in an appropriate time-dependent
manner.
Example 7
[0060] A one-way pharmacokinetic pilot study was performed in vivo
for testing the pharmacokinetic profile of the coated tablets,
which were prepared according to Example 2. The study was performed
with ten healthy male volunteers, who received a single dosage of
the coated tablets, containing 20 mg of Omeprazole. The results
showed that Omeprazole administered in the coated tablets of the
present invention had a similar lag time to absorption in
comparison to a previous study performed with the reference
product, which is the 20 mg Omeprazole dosage form of the
formulation of Astra (Aktiebolaget Hassle), and also as described
in the literature (see for example Duvauchelle, T. et al.,
"Comparative Bioavailability Study of Two Oral Omeprazole
Formulations After Single and Repeated Administrations in Healthy
Volunteers", Pharmacokinetics, 16: 141-149, 1998). The lag time to
absorption is defined as the time between the administration of the
formulation and the first detection of the active ingredient in the
samples taken from the subject, according to the sampling method
employed.
[0061] In addition, comparable bioavailability was achieved with
the coated tablets of the present invention, both to values
obtained in the previous study with the reference product and to
values which were described in the literature (see for example the
previously referenced article in Pharmacokinetics). Furthermore,
the values obtained for Cmax and Tmax concerning the rate of
absorption were comparable to results obtained in the previous
study performed with the reference product, and as described in the
literature (see for example the previously referenced article in
Pharmacokinetics). Thus, the coated tablets of the present
invention clearly show good performance both in vitro, as described
in Example 6, and in vivo.
Example 8
[0062] Coated pellets were prepared according to the process
previously described above in Example 4. However, the pellets were
coated with the following suspension:
TABLE-US-00015 Enteric coating (quantities per capsule) HPMCAS
21.00 mg Triethyl Citrate 6.00 mg Sodium lauryl sulfate 0.66 mg
Colloidal silicon dioxide 2.10 mg Sodium hydroxide 1.12 mg
Example 9
[0063] Although the previous Examples used aqueous solutions for
providing an optimal coating, the possibility of increasing the
concentration of the enteric coating polymer by using an
alcohol-based solution was studied in this Example.
[0064] Coated pellets were prepared according to the process of
Example 4, except that these pellets were coated with the following
solution, to obtain the required protection in an acidic
environment.
TABLE-US-00016 Enteric coating Solution prepared Quantities per
capsule Alcohol 95% 1.900 kg N/A Water 0.830 kg N/A HPMCAS 0.476 kg
21.00 mg Triethyl citrate 0.136 kg 6.00 mg Sodium lauryl sulfate
0.015 kg 0.66 mg Colloidal silicon dioxide 0.047 kg 2.1 mg Sodium
hydroxide 0.025 kg 1.12 mg
Example 10
TABLE-US-00017 [0065] Substrate (Active Compressed Tablet Core)
Ingredients Quantity per tablet Omeprazole 20 mg Lactose 203 mg
Magnesium carbonate 10 mg Sodium starch glycolate 10 mg Sodium
stearyl fumarate 7 mg
TABLE-US-00018 Enteric coating layer Ingredients Quantity per
tablet HPMCAS 16 mg Triethyl citrate 4.5 mg Sodium lauryl sulfate
0.5 mg Talc 8.14 mg Sodium hydroxide 0.86 mg Sepisperse .TM. (pink
pigment) 10.8 mg
For the preparation of the substrate, Omeprazole was mixed together
thoroughly with lactose, sodium starch glycolate, magnesium
carbonate and sodium stearyl fumarate. The mixture was then
compressed into tablets weighing 250 mg each. These tablets were
then transferred into a conventional coating pan and coated with
the enteric coating layer, prepared as described in Example 4, with
the addition of a pigment to the enteric coating material.
Example 11
[0066] Stability tests were performed with the formulation prepared
according to Example 10. For the tests, the tablets were packed
into alu-alu blister. The blister was then stored under room
temperature or under accelerated conditions of 30.degree. C. and
60% relative humidity (RH), or 40.degree. C. and 75% relative
humidity. Samples of the tablets were examined initially and after
6 months of storage under one of these conditions. In addition
samples were assayed. A dissolution test was performed, and gastric
resistance was also examined. The tablet gave good stability
results even after storage at 40.degree. C. The results are shown
in the table below.
TABLE-US-00019 30.degree. C./ 40.degree. C./ Test 25.degree. C. 60%
RH 75% RH performed Initial 6 month 6 month 6 month Visual conform
conform conform conform Description Assay 19.76 mg 20.19 mg 19.97
mg 19.28 mg per tablet per tablet per tablet per tablet Dissolution
96% 96% 96% 96% Gastric 96% 96% 95% 94% Resistance
Example 12
[0067] A two-way pharmacokinetic study was performed in vivo for
testing the bioequivalence of the coated tablets which were
prepared according to Example 10, as compared to the reference
product which is the 20 mg Omeprazole dosage form of the
formulation of Astra (Sweden), called Losec.TM.. The study was
performed on 39 volunteers. As shown in the table below, the
results of the study showed that the two products exhibited very
similar pharmacokinetic profiles, such that the two formulations
can be considered to be bioequivalent.
TABLE-US-00020 AUC Cmax Tmax Formulation (ng .times. hour/ml)
(ng/ml) (hours) Formulation of the 426 .+-. 256 217 .+-. 109 1.08
.+-. 0.64 present invention (Example 10) Losec .TM. (Astra) 434
.+-. 226 246 .+-. 113 1.56 .+-. 0.79
Example 13
TABLE-US-00021 [0068] Substrate (Active Compressed Tablet Core)
Ingredients Quantity per tablet Omeprazole 20 mg Lactose 203 mg
Sodium hydrogen carbonate 10 mg Sodium starch glycolate 10 mg
Sodium stearyl fumarate 7 mg
TABLE-US-00022 Enteric coating layer Ingredients Quantity per
tablet HPMCAS 16 mg Triethyl citrate 4.5 mg Sodium lauryl sulfate
0.5 mg Talc 8.14 mg Sodium hydroxide 0.86 mg Sepisperse .TM. 10.8
mg
[0069] For the preparation of the substrate, Omeprazole was
thoroughly mixed together with lactose, sodium starch glycolate,
sodium hydrogen carbonate and sodium stearyl fumarate. The mixture
was then compressed into tablets weighing 250 mg each. These
tablets were then transferred into a conventional coating pan and
coated with the enteric coating layer, prepared as described in
Example 4.
Example 14
TABLE-US-00023 [0070] Substrate (Active Compressed Tablet Core)
Ingredients Quantity per tablet Omeprazole 20 mg Lactose 203 mg
Trisodium citrate 10 mg Sodium starch glycolate 10 mg Sodium
stearyl fumarate 7 mg
TABLE-US-00024 Enteric coating layer Ingredients Quantity per
tablet HPMCAS 16 mg Triethyl citrate 4.5 mg Sodium lauryl sulfate
0.5 mg Talc 8.14 mg Sodium hydroxide 0.86 mg Sepisperse .TM. 10.8
mg
[0071] For the preparation of the substrate, Omeprazole was mixed
thoroughly together with lactose, sodium starch glycolate,
trisodium citrate and sodium stearyl fumarate. The mixture was then
compressed into tablets weighing 250 mg each. These tablets were
then transferred into a conventional coating pan and coated with
the enteric coating layer, prepared as described in Example 4.
Example 15
[0072] Stability tests were performed with the formulations
prepared according to Examples 10, 13 and 14. Both coated and
non-coated tablets were placed into an open box and stored at
40.degree. C. and 75% relative humidity, which are very stringent
conditions. The coated and uncoated tablets were examined initially
after 1 week and again after 2 weeks to determine stability. The
results are shown in the tables below.
Tablets Prepared According to Example 10
TABLE-US-00025 [0073] Appearance of sample Sampled material Initial
After 1 week After 2 weeks Coated Pink Pink Pink Uncoated White
White White
Tablets Prepared According to Example 13
TABLE-US-00026 [0074] Appearance of sample Sampled material Initial
After 1 week After 2 weeks Coated Pink Pink Pink Uncoated White
White White
Tablets Prepared According to Example 14
TABLE-US-00027 [0075] Appearance of sample Sampled material Initial
After 1 week After 2 weeks Coated Pink Pink Pink Uncoated White
White White
Example 16
[0076] In this example of the composition of the present invention,
the substrate has two parts: a neutral core; and a coating layer
containing the active ingredient, which was layered over the
neutral core. The substrate was then coated with the enteric
coating solution. Hard gelatin capsules were then filled with the
resultant pellets.
Substrate
TABLE-US-00028 [0077] Neutral core Quantity per capsule Sugar
spheres 20/25 (700-850 microns) 110 mg
TABLE-US-00029 Active coating Ingredients Quantity per capsule
Omeprazole 20.00 mg Hydroxypropyl methylcellulose 2910 5.00 mg
Hydroxypropyl cellulose 6.00 mg Sodium stearate 0.13 mg Sodium
lauryl sulfate 0.50 mg
TABLE-US-00030 Enteric coating layer HPMCAS 21.00 mg Triethyl
citrate 6.00 mg Sodium lauryl sulfate 0.66 mg colloidal silicon
dioxide 2.1 mg Arginine 3.15 mg
[0078] The composition of the present invention was prepared
according to this Example as follows. First, sugar spheres were
placed in a fluid bed coating chamber, equipped with a Wurster
bottom spraying device. A suspension of the ingredients in water
was then prepared so that the concentration was approximately 20%
of the total solids in water. This active coating suspension was
sprayed onto the neutral sugar spheres.
[0079] A suspension of the enteric coating was prepared as follows.
First, triethyl citrate was dissolved in water to form an aqueous
solution. Sodium lauryl sulfate was then added to this aqueous
solution. HPMCAS and colloidal silicon dioxide were dispersed in
this solution, such that the concentration of HPMCAS was about 10%
weight per volume. Arginine (3% weight per volume solution) was
added to adjust the pH value of the solution to a pH value in a
range of from about pH 7 to about pH 9. The enteric coating was
layered over the substrate in order to form the finished pellets.
The pellets were then placed in capsules.
Example 17
[0080] In this example of the composition of the present invention,
the substrate has two parts: a neutral core; and a coating layer
containing the active ingredient, which was layered over the
neutral core. The substrate was then coated with the enteric
coating solution. Hard gelatin capsules were then filled with the
resultant pellets.
TABLE-US-00031 Substrate Neutral core Quantity per capsule Sugar
spheres 20/25 (700-850 microns) 110 mg
TABLE-US-00032 Active coating Ingredients Quantity per capsule
Omeprazole 20.00 mg Hydroxypropyl methylcellulose 2910 5.00 mg
Hydroxypropyl cellulose 6.00 mg Arginine 0.13 mg Sodium lauryl
sulfate 0.50 mg
TABLE-US-00033 Enteric coating layer HPMCAS 21.00 mg Triethyl
citrate 6.00 mg Sodium lauryl sulfate 0.66 mg colloidal silicon
dioxide 2.1 mg Sodium hydroxide 1.12 mg
[0081] The composition of the present invention was prepared
according to this Example as follows. First, sugar spheres were
placed in a fluid bed coating chamber, equipped with a Wurster
bottom spraying device. A suspension of the ingredients in water
was then prepared so that the concentration was approximately 20%
of the total solids in water. This active coating suspension was
sprayed onto the sugar spheres.
[0082] A suspension of the enteric coating was prepared according
to Example 8. The enteric coating was layered over the substrate in
order to form to form the finished pellets. The pellets were then
placed in capsules.
Example 18
[0083] In this example of the composition of the present invention,
the substrate has two parts: a neutral core; and a coating layer
containing the active ingredient, which was layered over the
neutral core. The substrate was then coated with the enteric
coating solution. Hard gelatin capsules were then filled with the
resultant pellets.
TABLE-US-00034 Substrate Neutral core Quantity per capsule Sugar
spheres 20/25 (700-850 microns) 110 mg
TABLE-US-00035 Active coating Ingredients Quantity per capsule
Omeprazole 20.00 mg Hydroxypropyl methylcellulose 2910 5.00 mg
Hydroxypropyl cellulose 6.00 mg Arginine 0.13 mg Sodium lauryl
sulfate 0.50 mg
TABLE-US-00036 Enteric coating layer HPMCAS 21.00 mg Triethyl
citrate 6.00 mg Sodium lauryl sulfate 0.66 mg colloidal silicon
dioxide 2.1 mg Arginine 3.15 mg
[0084] The composition of the present invention was prepared
according to this Example as follows. First, sugar spheres were
placed in a fluid bed coating chamber, equipped with a Wurster
bottom spraying device. A suspension of the ingredients in water
was then prepared so that the concentration was approximately 20%
of the total solids in water. This active coating suspension was
sprayed onto the sugar spheres to form the substrate.
[0085] A suspension of the enteric coating was prepared according
to Example 16. The enteric coating was layered over the substrate
in order to form to form the finished pellets. The pellets were
then placed in capsules.
Example 19
[0086] In this example of the composition of the present invention,
the substrate has two parts: a neutral core; and a coating layer
containing the active ingredient, which was layered over the
neutral core. The substrate was then coated with the enteric
coating solution to form pellets. Hard gelatin capsules were then
filled with the resultant pellets.
Substrate
TABLE-US-00037 [0087] Neutral core Ingredients Quantity per capsule
Sugar spheres 20/25 (700-800 microns) 110 mg
TABLE-US-00038 Active coating Ingredients Quantity per capsule
Omeprazole 20 mg Hydroxypropyl methylcellulose 2910 5 mg
Hydroxypropyl cellulose 6 mg Sodium lauryl sulfate 0.5 mg Arginine
0.1 mg
TABLE-US-00039 Enteric coating layer Ingredients Quantity per
capsule Triethyl citrate 35 mg Sodium lauryl sulfate 3.8 mg HPMCAS
126 mg Colloidal silicon dioxide 19 mg Talc 17 mg Ammonia (in a 25%
solution) 3 mg
[0088] The composition of the present invention was prepared
according to this example as follows. First, sugar spheres were
placed in a fluid bed-coating chamber, equipped with a Wurster
bottom-spraying device. Next, a suspension of the ingredients in
water was then prepared for a final concentration of the total
solids of approximately 15% in water, to form the active coating.
This active coating suspension was sprayed onto the sugar spheres,
thereby forming the substrate.
[0089] A suspension of the enteric coating was then prepared as
follows. First, triethyl citrate was dissolved in water to form an
aqueous solution. Sodium lauryl sulfate was then added to this
aqueous solution. HPMCAS, colloidal silicon dioxide and talc were
dispersed in this solution, such that the concentration of HPMCAS
was about 7% weight per volume. Ammonia in a 25% solution was added
to adjust the pH value in a range of from about 7 to about 9. The
enteric coating was layered over the substrate in order to form the
finished pellets. The pellets were then placed in capsules.
Example 20
TABLE-US-00040 [0090] Substrate (active compressed tablet core)
Ingredients Quantity per capsule Omeprazole 20 mg lactose 203 mg
Magnesium carbonate 10 mg Sodium starch glycollate 10 mg Sodium
stearyl fumarate 7 mg
TABLE-US-00041 Enteric coating layer Ingredients Quantity per
capsule Triethyl citrate 4.5 mg Sodium lauryl sulfate 0.5 mg HPMCAS
16 mg Talc 8.14 mg Ammonia (in a 25% solution) 0.14 mg Sepisperse
.RTM. (pink pigment) 10.8 mg Isopropyl alcohol N/A Alcohol N/A
[0091] The substrate of the prevent invention was prepared as
described in Example 10. A suspension of the enteric coating was
then prepared as follows. First, triethyl citrate was dissolved in
a mixture of isopropyl alcohol and alcohol. Sodium lauryl sulfate
was then added to this solution. HPMCAS and talc were dispersed in
this solution, such that the concentration of HPMCAS was about 6%
weight per volume. Ammonia in a 25% solution was added to adjust
the pH value in a range of from about pH 7 to about pH 9. The
pigment was then added to the enteric coating dispersion. The
tablet cores were then transferred into a conventional coating pan
and coated with the enteric coating layer.
Example 21
TABLE-US-00042 [0092] Substrate (active compressed tablet core)
Ingredients Quantity per capsule Omeprazole 10 mg lactose 101.5 mg
Sodium stearate 5 mg Sodium starch glycollate 5 mg Sodium stearyl
fumarate 3.5 mg
TABLE-US-00043 Enteric coating layer Ingredients Quantity per
capsule Triethyl citrate 2.25 mg Sodium lauryl sulfate 0.25 mg
HPMCAS 8 mg Talc 4.7 mg Sodium hydroxide 0.43 mg Sepisperse .RTM.
(pink pigment) 5.4 mg
[0093] For the preparation of the substrate, Omeprazole was mixed
together thoroughly with lactose, sodium starch glycollate, sodium
stearate and sodium stearyl fumarate. The mixture was then
compressed into tablets weighing 125 mg each. These tablet were
then transferred into a conventional coating pan and coated with
the enteric coating layer, prepared as described in Example 10.
Example 22
[0094] Stability tests were performed with the formulation prepared
according to Example 21. For the tests, the tablets were packed
into alu-alu blister. The blister was then stored under room
temperature or under accelerated conditions of 30.degree. C. and
60% relative humidity (RH), or 40.degree. C. and 75% relative
humidity. Samples of these tablets were examined initially and
after 6 months of storage under one of these conditions. In
addition samples were assayed and purity test was performed. A
dissolution test was performed, and gastric resistance was also
examined. The tablet gave good stability results even after storage
at 40.degree. C. The results are shown in the table below.
TABLE-US-00044 30.degree. C./ 40.degree. C./ 25.degree. C. 60% RH
75% RH Test performed Initial 6 months 6 months 6 months
Description conform conform conform conform Assay 98.4% 96.7%.sup.
96.9%.sup. 96.3% Dissolution .sup. 95% 97% 95% .sup. 95% gastric
.sup. 96% 95% 97% .sup. 96% resistance individual 0.04% not not
0.23% impurity detectable detectable total impurity 0.04% not not
0.29% detectable detectable
[0095] While the invention has been described with respect to a
limited number of embodiments, it will be appreciated that many
variations, modifications and other applications of the invention
may be made.
* * * * *