Note: Descriptions are shown in the official language in which they were submitted.
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1
Stable Drug Form for Oral Administration with Henzimidazole Derivatives as
Active Ingredient and Process for the Preparation Thereof
The present invention discloses a stable medicament for oral
administration which comprises one or more of the
benzimidazole derivatives Omeprazole, Lansoprazole or
Pantoprazole as an active ingredient as well as a method for
its production.
It is known from EP 0 005 129 that Omeprazole (5-methoxy-
2(((4-methoxy-3,5-dimethyl-2-pyridyl)methyl)-sulfinyl)-1H-
benzimidazole functions as a potent inhibitor in the secretion
of gastric acid. Omeprazole has proven itself in the therapy
of duodenal ulcer, gastric ulcer, reflux esophagitis and
Zollinger-Ellision syndrome. Parenteral and solid peroral
medicaments are employed in this connection.
The following embodiments presented for Omeprazole apply in
the same manner for Lansoprazole (2-(((3-methyl-4-(2,.2,2-
trifluoroethoxy)-2-pyridyl)methyl)-sulfinyl)-1H-benzimidazole)
and Pantoprazole (5-difluoromethoxy-2-((3,4-dimethoxy-2-
pyridyl)methyl)-sulfinyl)-1H-benzimidazole).
The administration of a medicine per os is especially
convenient because it can be carried out by patients
practically anywhere and at any time without effort and
unpleasant attendant phenomena. The oral administration
inevitably leads to the fact that the medicament reaches the
stomach at first. However, Omeprazole and its derivatives
degrade very rapidly in the acidic environment of the stomach
to ineffective compounds. For example, Omeprazole has a half-
life of less than ten minutes in aqueous solution at pH values
under 4. Therefore, solid peroral medicines (tablets,
pellets, granulates) of Omeprazole and similar active
ingredients must be completely protected against gastric
juice.
CA 02258918 1998-12-23
2
The resorption of Omeprazole occurs in the upper duodenum
whereby this active ingredient exhibits a pronounced first-
pass-effect. Therefore, an as quick and complete release as
possible of the active ingredient from the medicament after
passage of the pylorus must be ensured in order to guarantee a
sufficiently high bio-availability.
For this, Omeprazole is provided with a coating of enteric,
i.e. gastric juice-resistant materials, which is insoluble in
the acid environment of the stomach (ca. pH 1 to 3) on the one
hand, but dissolves in the weakly acidic to weakly alkaline
region of the duodenum (pH >5.5). It is known to introduce
the extremely acid sensitive active ingredient Omeprazole into
the core of a pellet formulation onto which one or more
coating layers provided.
Frequently, Eudragit~ L100 or L100-55 is used a layer
material. Eudragit~ L100 is a copolymer of methacrylic acid
and methylmethacrylate in a certain ratio and is insoluble in
an acidic environment, for example in the stomach, and
therewith forms a considerably impermeable protective layer.
Eudragit~ L100-55 is a copolymer of methacrylic acid and
ethylacrylate, whereby the ratio of the monomers is chosen in
such a manner that it is insoluble at a pH <5.5, but is
soluble at a pH above this. The reason for this essentially
lies in the fact that the carboxyl side groups of the polymer
are protonated in the acidic environment, and therewith, the
polymer is non-charged as a whole. In the weakly acidic
neutral and/or basic environment, for example in the intestine
region, the carboxyl groups deprotonate whereby the polymer
obtains negative charges. It is then water-soluble whereby
the active ingredient is released.
However, Eudragit~ cannot be applied directly onto the
Omeprazole core because the carboxyl groups in the coating
layer degrade the Omeprazole which also presents problems in
CA 02258918 1998-12-23
3
the production and storage of the medicament. Even small
amounts of degradation products already lead to unambiguous
color changes, and therewith to loss of quality, which no
longer allow administration to patients under certain
conditions. The storage problems are intensified when
moisture penetrates into the active ingredient-containing core
through hair-line cracks and other defects in the coating
layer.
Gastric juice-resistant coatings of the above-mentioned
polymers which are separated from the active ingredient-
containing core by an inert isolation layer are suitable for
the protection of solid, peroral medicaments with Omeprazole,
Lansoprazole or Pantoprazole as an active ingredient against
unfavourable storage conditions and against gastric juice in
oral ingestion. Additionally, it has also been proven to be
appropriate to stabilize the active ingredient-containing core
by addition of an alkaline reacting substance. On the other
hand, a sufficiently fast release in the intestine must be
ensured.
Bac7tground Art
DE 1 204 363 describes a medicament comprising a core with
various layers applied thereto. The first (inner most) layer
is soluble in the stomach, but insoluble in the intestine.
The second protective layer a.s water soluble (independent of
the pH value) and the third (outer most) protective layer is a
gastric juice-resistant coating. However, this formulation is
not suitable for Omeprazole because it only dissolves slowly
in the intestine. However, a fast dissolution in the
intestine is essential for the desired bio-availability.
EP 0 247 983 discloses a pharmaceutical agent for oral
administration which comprises Omeprazole as an effective
component. The core material contains Omeprazole together
with an alkaline reacting compound or an Omeprazole salt,
CA 02258918 1998-12-23
4
optionally together with an alkaline reacting adjuvant.
Intermediate layers which form a separation layer between the
alkaline reacting core and an outer layer of a gastric juice-
resistant coating comprise water-soluble tablet carrier
mediums or tablet carrier mediums quickly disintegrating in
water or polymeric, water-soluble, film-forming substance
mixtures which optionally contain buffering, alkaline
compounds and which should capture protons penetrating from
the outside. Aside from its water-solubility, the layer
material is chemically and physically inert.
However, with use of an alkaline buffering substance, such as
sodium acetate for example, this freely diffuses into the
intermediate layer and penetrates into the outer gastric
juice-resistant layer. The increase of the pH value
associated therewith can favour the penetration of moisture
through the enteric layer as a result of the increasing
solubility. This means that the danger exists with the
penetration of higher concentrations of protons that these
reach the core and destroy the Omeprazole there. This last
phenomena can easily occur especially when the outer gastric
juice-resistant layer possesses faults as a result of
imperfections which can arise in production, physical load or
through ageing manifestations in storage.
EP 0 519 144 describes Omeprazole pellets consisting of an
inert pellet core which is coded with the micronized active
ingredient and is subsequently coated with a gastric juice-
resistant layer. The following adjuvants, dispersed in water,
are employed for coating the core with Omeprazole:
hydroxymethylcellulose (HMC), water-free lactose, L-
hydroxypropylcellulose (L-HPC), sodium lauryl sulfate,
disodium hydrogen phosphate dehydrate.
Hydroxypropylmethylcellulose phthalate (HPMCP) is used as a
gastric juice-resistant coating. In this method, a possible
reaction of the Omeprazole with the polymer is not excluded
which can especially lead to a deteriorated storage stability.
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EP 0 496 437 encompasses pellet cores and/or tablets which
contain Omeprazole or an alkaline salt of Omsprazole together
with an alkaline reacting compound (buffer) arid which are
coated with a layer of water-soluble, film-forming adjuvants
which preferably react alkaline (buffer) as well as with a
gastric juice-resistant outer film.
EP 0 239 200 uses basic magnesium salts and/or basic calcium
salts for stabilizing benzimidazole derivatives with
Omeprazole as typical representative.
According to this, numerous efforts were undertaken in the
production of Omeprazole medicines which prevent the
discoloration of the active ingredient, which considerably
reduce the chemical degradation of Omeprazole, which prevent
the degradation of the active ingredient in acidic gastric
juice, but should simultaneously release the active ingredient
as quickly as possible in the environment of the small
intestine.
The present invention provides an improved
medicament as compared to the state of the art suitable far
oral administration which comprises Omeprazole, Lansoprazole
and/or Pantoprazole as an active'ingredient, optionally in
combination with further pharmaceutically effective
substances, and which possesses excellent stability in
extended storage and under chemico-physical load. In
particular, the penetration of acidic gastric juice into
faults, cracks, chips or any other imperfections of the
coating layer into the core layer should be avoided with the
medicament according to the invention and the degradation of
the acid-label active ingredient should be prevented
therewith.
The medicament according to the invention guarantees a very
high medicament security which above all should also be
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6
provided if unfavourable conditions arise in the course of the
manufacturing process of the medicament as well as in the
handling of the same and/or its packaged form by patients.
At the same time, ~t is necessary that the medicament quickly
releases the active ingredient in the small intestine after
passage through the stomach. Additionally, the degradation of
the medicament should prevent the occurrence of discoloration
of the active ingredient.
The invention in one aspect provides a
stable medicament for oral administration which
(a) comprises a core which contains an active ingredient
selected from Omeprazole, Lansoprazole and Pantoprazole
together with customary pharmaceutical adjuvants,
(b) an intermediate layer applied to the core, and
(c) a gastric juice-resistant outer layer,
characterized in that a reactive intermediate layer of gastric
juice-resistant polymer layer material partially neutralized
with'alkali with cation exchange capacity is present in (b).
Furthermore, subject-matter of the invention is a method for
the production of the above-mentioned medicament, whereby
(a) a molded article is formed hs the core which contains an
active ingredient selected from Omeprazole, Lansoprazole
and Pantoprazole, together customary pharmaceutical
adjuvants,
(b) an intermediate layer is applied to the molded article,
and
(e) the coated molded article is laminated with a gastric
juice-resistant layer,
and the method is characterized in that a reactive
intermediate layer of a gastric juice-resistant polymer coat
material partially neutralized with alkali with cation
exchange capacity is applied in (b).
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6a
The invention also provides uses of the
medicaments, compositions and capsules of the invention for
the inhibition of gastric acid secretion, or for the
prevention or treatment of duodenal ulcer, gastric ulcer,
reflux esophagitis and Zollinger-Elusion syndrome.
The invention also provides commercial packages
comprising a medicament, composition or capsule of the
invention and associated therewith instructions for the use
thereof for the inhibition of gastric acid secretion, or the
prevention or treatment of duodenal ulcer, gastric ulcer,
reflux esophagitis and Zollinger-Ellision syndrome.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a schematic layer construction
according to the invention.
FIG. 2 graphically describes the effect of pH on
charge equivalents and functional groups.
FIG. 3 shows the release of various pellet
formulas at pH 5.8.
FIG. 4 describes the release of Omeprazole pellets
exposed to a pH of 1.2 for 120 minutes and a pH of 6.8 for
60 minutes.
FIG. 5 describes the release of Omeprazole pellets
exposed to a pH of 1.2 for 120 minutes and a pH of 6.8 for
60 minutes after 12 weeks of storage at 30°C and 60% relative
humidity.
FIG. 6 describes the release of Omeprazole pellets
exposed to a pH of 1.2 for 120 minutes and a pH of 6.8 for
60 minutes after 12 weeks of storage at 30°C and 60o relative
humidity.
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6b
FIG. 7 describes the release of Omeprazole pellets
exposed to a pH of 1.2 for 120 minutes and a pH of 6.8 for
60 minutes after 12 weeks of storage at 40°C and 60o relative
humidity.
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7
The layer construction of the medicament according to the
invention is schematically given in Figure 1.
The core of the medicament according to the invention
encompasses the active ingredient Omeprazole, Lansoprazole or
Pantoprazole individually or combinations. thereof together
with customary auxiliary substances. For the stability of the
medicament according to the invention it is not necessary and
is also not preferred that the core of the active ingredient
is formulated together with an alkaline reacting compound. It
is also not necessary for an alkaline salt of the active
ingredient be employed.
As the pharmaceutical adjuvants for the core, fillers such as
mannite, hydroxypropylcellulose, microcrystalline cellulose
and water-free lactose are especially suitable. Additionally,
it has be shown that advantageous stability effects can be
obtained by using a specific combination of mannite and
hydroxypropylcellulose as a non-alkalizing adjuvant in the
core.
The core can also comprise tensides which are selected in the
suitable manner from sodium lauryl sulfate, sorbitan fatty
acid ester and polyoxyethylene sorbitan fatty acid ester.
The core of the medicament according to the invention can be
formed as a molded article. Preferred molded articles are
pellet cores, tablets microtablets or granulates.
The molded articles are coated with an intermediate layer.
This intermediate layer preferably has a layer thickness of
approximately 5 to 30 Vim. It forms a mechanical as well as
chemical barrier to the core. Thereby, it is necessary that
the intermediate layer be present in an intact film. The
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8
polymer of the intermediate layer amounts to approximately 3
to 5 ~ by weight of the core weight.
The intermediate layer comprises a gastric juice-resistant
polymer layer material which was adjusted with alkali to pH
range of 5.5 to 7.0, preferably 5.5 to 6.5. With these pH
values, not all protons of the acidic functions of the polymer
material are exchanged; the material is merely partially
neutralized. As emerges from Figure 2, less than 400 of the
carboxyl functions in the case of Eudragit~ are present at a
pH of 5_5. Despite this, a combination of Eudragit~ partially
neutralized to pH 5.5 with Omeprazole is unexpectedly stable
even under intensive storage conditions (see Example 2). At
pH 7.0, ca. 970 of the carboxyl functions of Eudragit~ are
neutralized (see Figure 2).
As alkali substances, substances are to be understood whose
solutions demonstrate alkaline reactions with water (Rompps
Chemistry Encyclopaedia, 8th Edition, 1979). In this
connection, hydroxides of alkali metals, especially sodium and
potassium, but also hydroxides of the earth alkali metals are
primarily among these. Hydroxides of the alkali metals,
especially sodium hydroxide, are preferred according to the
invention.
In the partial neutralization, protons of the acidic functions
are fixed through the polymer chains of the coat material, for
example carboxyl groups, are partially replaced by alkali
metal ions for example as counter-ions. The polymer layer
material modified in this manner is no longer physico-
chemically inert in the presence of protons, but rather, is
reactive because it now possess cation exchange capacity.
This means that when moisture and especially acidic gastric
juice penetrates into cracks, faults, chips or other
imperfections through the outer layer of the medicament
according to the invention, the penetrating protons are
captured and are exchanged by harmless alkali metal ions. A
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9
further aspect of the reactive principal of the intermediate
layer material is demonstrated by the fact the intermediate
layer is transformed at these places into a gastric juice-
resistant barrier; it possess a "self-repair-mechanism" to a
certaint degree. Practical tests have shown that with contact
of the intermediate layer with an acidic medium forms a gel-
like substance which not only captures protons but also forms
a flexible mechanical barrier which prevents the further
penetration of moisture and/or acid medium. The partial
neutralization of the polymer material for the reactive
intermediate layer to a pH range 5.5 to 6.5 is especially
preferred because a gastric juice-resistant barrier already
forms when only few protons penetrate through the outer layer;
on the other hand, the Omeprazole core is still sufficiently
stable.
Thereby, a clearly improved stability behaviour of the claimed
medicament in extended storage and under chemico-physical load
is also obtained.
Buffering and/or alkalizing additives in the intermediate
layer as proposed in EP 0 247 983 are no longer necessary and
can even be damaging because they increase solubility of the
intermediate layer and reduce its protective function. This
nearly contradicts the "self-repair-mechanism" according to
the invention; namely, the more basic equivalents that are
present in the intermediate layer, the more protons must
penetrate from the outside so that the "self-repair-mechanism"
of the reactive layer has a quick effect.
Eudragit~ L100-55, Eudragit~ L100 produced from Rohm Pharma,
Germany, as well as hydroxypropylmethylcellulose phthalate
(HPMCP) and cellulose acetate phthalate (CAP) which, as
described above, are partially neutralized with alkali before
use as an intermediate layer, i.e. before spraying of the
same, are suitable as preferred substances for the
CA 02258918 1998-12-23
intermediate layer. Particularly preferred is Eudragit~ L100-
55 obtainable world-wide as a commercial product.
The intermediate layer can contain customary additives, for
example an emollient. Preferably, triethyl citrate,
acetyltriethyl citrate, acetylated monoglycerides, propylene
glycol and polyethylene glycols are preferably suitable fore
this.
The coated molded articles, i.e. the core and the intermediate
layer, are then coated with an outer layer for the production
of the medicament according to the invention. The outer layer
represents a customary enteric, gastric juice-resistant layer..
In this connection, commercial, aqueous polymer dispersions,
such as polymethacrylates, for example Eudragit~ L100-55 (Rohm
Pharma), and coating CE 5142 (BASF) are suitable as materials.
Additionally, polymers can also be used for formation of the
gastric juice-resistant layer which are soluble in organic
solvents. For example, phthalates (cellulose acetate
phthalate, hydroxypropylmethyl cellulose phthalate) are to be
named as suitable materials. Additionally, the outer layer of
the medicament according to the invention can contain
antiblocking agents, dispersion agents, pigments and
colorants. A suitable antiblocking agent is talcum for
example.
In comparison to conventional medicinal forms with an inert
intermediate layer, it was surprisingly determined that the
inventive combination of enteric outer layer and reactive
intermediate layer shows an accelerated dissolution behaviour
in artificial intestinal fluid (pH ca. 5.8). This effect not
only allows a very quick release of the active ingredient in
the weakly acidic to weakly alkaline environment of the small
intestine, and therewith an excellent bio-availability, but
also permits improved medicament security because the enteric
outer layer can be strengthened without retarding a desired
quick release. Thereby, not only can the gastric juice-
CA 02258918 1998-12-23
11
resistance be improved, but also the medicament stability
especially under unfavourable storage conditions. Hence, the
thickness of the gastric juice-resistant outer layer of the
medicament according to the invention amounts to 20 to 60 ~m
(ca. 10 to 50% weight with respect to the core), preferably 30
to 60 Vim.
In an advantageous embodiment of the invention, the reactive
intermediate layer consists of partially neutralized Eudragit~
L100-55 at a pH value of 5.5 to 7.0, preferably 5.5 to 6.5,
and the outer layer consists of commercial Eudragit~ L100-55
(pH ca. 2 to 3). The pH transition between outer layer and
intermediate layer does not necessarily have to be
discontinuous, but rather, can also be formed as a gradient.
This can be obtained if several thin Eudragit layers are
applied from inside to outside each of which was partially
neutralized to a decreasing pH value.
The reactive intermediate layer as well as the gastric juice-
resistant outer layer can can be formed as a plurality of
single layers.
The present invention further comprises a method for the
production of a stable medicament for oral administration
which comprises Omeprazole, Lansoprazole and/or Pantoprazole
as an active ingredient.
According to the method of the invention, the active
ingredient and adjuvants, such as mannite,
hydroxypropylcellulose and sodium lauryl sulfate, are
moistened together with a suitable solvent, preferably
isopropanol, granulated and worked to the desired molded
articles (for example pellets, granulates, tablets) according
to customary methods. The molded articles are subsequently
laminated with an aqueous dispersion consisting of a gastric
juice-resistant substance partially neutralized with alkali to
a pH value of ca. 5.5 to ca.7.0, preferably Eudragit~ L100-55,
CA 02258918 1998-12-23
12
as well as antiblocking agent and/or emollient, such as talcum
and triethyl citrate, in a fluidized bed apparatus for example
under formation of the intermediate layer with cation exchange
activity. A quality product corresponding to Eudragit~ L100-
55 is also commercially obtainable as a finished suspension
under the designation Eudragit~ L30D-55. Subsequent to this,
th-a coating occurs with a gastric juice-resistant substance
(for example Eudragit~ L100-55), talcum and an emollient (such
as triethyl citrate) for formation of the enteric outer layer
of the medicament according to the invention.
The production of pellets which are filled in gelatine
capsules in an amount sufficient for the desired active
ingredient dose is preferred.
Aside from the pellets containing the mentioned benzimidazole
compounds, the capsule formulations produced in this manner
can also contain other active ingredients. Preferable is a
combination of Diclofenac- and Omeprazole-containing pellets.
The Diclofenac-containing pellets are preferably produced
according to the method of the invention, i.e. they also
contain a reactive intermediate layer. However, they can also
be produced by known methods, such as disclosed in EP 0 348
808 for example. In a further embodiment, the Diclofenac-
containing pellets are present as a mixture of gastric juice-
resistant coated pellets and retarded permeable pellets which
are first released in lower intestinal sections.
Combinations of non-steroidal inflammation inhibitors and
analgesics are known. Thus, EP 0 527 887 names the
combination of Diclofenac (0-(2,6-dichloroanilino)phenyl
acetic acid), a highly effective NSAID (Non-Steroidal Anti-
Inflammatory Drug), with Misoprostol, for example, which is
employed for the treatment of painful inflammation diseases
under the trade name Arthrotec~, Heumann Pharma GmbH, Germany.
The prostaglandin derivative Misoprostol serves in this
connection for prevention of NSAID-associated ulcer diseases.
CA 02258918 1998-12-23
13
The solid combination of Diclofenac and Omeprazole has a
number of advantageous in long-term treatment of
pain/inflammation. Thus, a combination of Diclofenac with
Omeprazole maintains a low ulcer rate in patients who have a
high risk for the development of gastrointestinal ulcers and
who require treatment with an NSAID at the same time (ulcer
prevention). Furthermore, this combination attains high ulcer
healing rates in connection with sufficient pain relief
(therapy). Patient compliance can be considerably increased as
a result of the high effectiveness and good tolerance of the
combination partners in connection with a single daily
administration,.
The capsule formulation which are suitable for direct
administration per os comprise 25 to 200 mg, preferably 75 to
150 mg, Diclofenac and 10 to 40 mg, preferably 10 or 20 mg,
Omeprazole as a unit dose in the pellets according to the
invention.
The advantages of the medicament according to the invention
with respect to Omeprazole and other benzimidazole-containing
medicines of the art particularly exist in the fact that when
any imperfections in the outer layer are present through which
moisture upon storage or acidic gastric juice after peroral
administration may penetrate into the core layer, the reactive
intermediate layer not only captures protons but is
additionally retransformed into a gastric juice-resistant
layer material. Through this "self-repair-mechanism", a gel-
like layer is formed which is able to prevent the penetration
of moisture and acid into the core of the medicament. In case
that no penetration of gastric juice occurs, the intermediate
layer remains soluble. Unexpectedly, the combination of
enteric outer layer and the active intermediate layer
additionally shows an improved dissolution behaviour in
artificial intestinal fluid which infers a correspondingly
good dissolution behaviour in the small intestine.
CA 02258918 1998-12-23
14
The invention is more closely illustrated by the following
examples without limiting the invention to said examples.
Example 1
In vitro tests for chemical/physical stability of the
medicament according to the invention: Trituration of
Omeprazole and intermediate layer material:
Storage experiments with trituration of Omeprazole and various
treated intermediate layer materials were carried out over 32
days at 40°C and 75o relative humidity (r. H). Subsequently,
thedegree to which the active ingredient Omeprazole (residual
content in % by weight) remains stable, the percentage of
degradation products arising (area-~ from purity chromatogram)
and the degree to which. discoloration occurred were examined
with HPLC. In this connection, Omeprazole with a non-pre-
treated enteric coat material used for formation of gastric
juice-resistant coatings (HPMCP, batch 1a, and Eudragit~ L100-
22, charge 1b, pH 2-3)°and Omeprazole with a pre-treated
enteric layer material (Eudragit~ L100-55) according to the
invention were triturated and stored open in Petri dishes
under the given conditions. The pre-treated Eudragit~ L100-55
was previously partially neutralized with sodium hydroxide to
pH 5.5 (batch 1c) and pH 7.0 (batch ld) .
The results are reproduced in Table 1. The given values
correspond to the average of 3 sample preparations. The
discoloration is given as a color value according to
"TaschenlexiJ~on der Farben", A. Kornerup and J.H. Wauscher,
Muster-Schmidt Publishers, Zurich, Gottingen, 3rd Edition,
1981.
CA 02258918 1998-12-23
N c ' m
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.
CA 02258918 1998-12-23
It is deduced from the column "Omeprazole content" that the
active ingredient remains considerably more stable with use of
partially neutralized, gastric juice-resistant polymer
material according to the invention that in a trituration with
a customary enteric substance which possess up to 1000 free
carboxyl groups. Thus, after 32 days storage under the named
conditions, according to the invention only 2 or 30 of the
active ingredient Omeprazole is degraded. In contrast,
Omeprazole degradation up to 15o by weight is determined when
using the customary enteric layer material HPMCP of the art in
the present trituration experiments after 32 days.
Additionally, no clear Omeprazole degradation (3o by weight)
is demonstrated with use of non-neutralized Eudragit.
Instead, clear differences result in a comparison of the
content of an Omeprazole degradation product appearing in the
HPLC-chromatogram with use of partially neutralised Eudragit
(pH 5.5 and 7.0) according to the invention with commercial
Eudragit (pH 2 to 3) (see the column "Degradation Product").
Thus, according to the invention, hardly any degradation
product is found after 32 days (0.25 area-o in both batches),
whereas ca. 0.99 area-a in the presence of commercial Eudragit
(pH 2 to 3) and even ca. 7% degradation product in the
presence of a customary layer material (HPMCP) are present.
This result is confirmed by the color comparison (see the
column "color-value"). Neither the brown product of batch la
nor the brown-orange product of batch lb are still capable of
being sold. In contrast, the treated products according to
the invention (batches lc and d) demonstrate a considerably
lesser color change.
The above experiments prove that in the presence of high
humidity and high temperature (intensified stability test) the
partially neutralized layer material in the saturated state
also functions protectively on the active ingredient
Omeprazole. In contrast, customary enteric layer material,
CA 02258918 1998-12-23
17
which has up to 1000 free COOH-groups, not only demonstrates
no such protective effect, but also causes a clear degradation
of the active ingredient.
Example 2
Stability of pellet formulations:
In a further series of experiments, the medicament according
to the invention was compared with the state of the art (EP 0
247 983). For this, various colored batches were produced
which have a three-layer construction:
~ core, with the active ingredient Omeprazole in the presence
of an alkaline buffering substance (Na2HP04, according to
the state of the art) and without alkaline buffering
substance (according to the invention).
~ intermediate layer either consisting of a enteric layer
material partially neutralized with alkali to a pH 6.0
and/or 7.0 according to the invention or inert layer
material which contains sodium acetate as a buffering
substance according to the state of the art. The reference
example contains non-neutralized enteric layer material and
sodium acetate as a buffering substance.
~ Outer layer of Eudragit L 100-55.
Additionally, a medicament was tested in the series of
experiments in which the intermediate layer was omitted.
The respective pellet batches were stored open in a Petri dish
for a week and 20 days at 40°C and 75-°s relative humidity
(r.H). Subsequently, the Omeprazole content and/or the
appearance of degradation product was determined with HPLC.
The values compiled in Table 2 represent the average of 3
sample preparations.
CA 02258918 1998-12-23
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N
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O N N U U U 4y N NM
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U
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CA 02258918 1998-12-23
In comparison with the state of the art, a clearly more stable
administration form is obtained according to the invention.
The pellets according to the invention still have 93o by
weight of the active ingredient Omeprazole in an intact form
after one week and 80o by weight of the active ingredient
Omeprazole in an intact form after 20 days under the described
intensified storage condition. Even after 4 weeks storage, an
Omeprazole content of 67o by weight was determined according
to the invention (not represented in the Table). In contrast,
the Omeprazole content in medicament not according to the
invention, i.e. those
~ with an intermediate layer of HPMC and NaOAc
~ with an intermediate layer of HPMC
~ without an intermediate layer
~ with an intermediate layer HPMCP and NaOAc
merely amount to 66, 57, 54 and 41o by weight after 20 days.
Example 3
"Self-Repair-Mechanism" of the reactive intermediate layer:
Pellets with the following construction were compared:
~ without intermediate layer (so-called pellet core)-
~ with the reactive intermediate layer according to the
invention
~ with an inert intermediate layer of HPMC (reference example)
For better judgement of the "self-repair-mechanism", the
pellets were not provided with the outer enteric coat. All
pellet- types were tested in artificial gastric juice (pH 1.2)
in a release model of the European Pharmacopoeia (basket).
The intermediate layer was partially nuetralized to pH 7.0,
the upper limit of the preferred range.
The results (pellet cores without intermediate layer: not
shown) are summarized in the following Table 3:
CA 02258918 1998-12-23
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~ ~ ~ ~ c
ccs
o ~
~
V ~ o -
N o ~
E
c~ U
L
~
U C
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N ~
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o O
O ~ O '~ T
O
O O
>1
0
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c~ U ~ Q j,
L
O
L
O Q~ ~ 0 0 0 W I7 O O O O
o
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~ ~ ~~ ~ c~n ~ ~ c~
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L L L
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0
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CA 02258918 1998-12-23
According to these results, pellets without intermediate layer
(as comparison) completely dissolve within 2 minutes. The
release medium has a strong brown coloration.
In contrast, pellets with the reactive intermediate layer
according to the invention remain intact as a function of the
layer thickness (up to 20o with respect to the core) of the
intermediate layer up to a maximum of 120 minutes. The
release medium only has a slight discoloration.
Pellets with a customary inert intermediate layer according to
the state of the art (reference example) with maximum layer
thickness of the intermediate layer also completely dissolved
within 5 minutes. The release medium has a strong brown
discoloration.
These experiments proved a measurable protective mechanism
with the intermediate layer according to the invention as
opposed to pellets with an intermediate layer according to the
state of the art. This protection mechanism brings about the
reactive transformation of the intermediate layer to a gastric
juice-resistant layer in the gastric juice acidic medium. The
closer the pH value of the partially neutralized intermediate
layer lies to 5.5, the faster this occurs.
Thus, it clearly emerges from all experiments in Examples 1 to
3 that according to the invention a medicament with
surprisingly improved stability is obtained in comparison to
those of the state of the art. The stability behaviour is
demonstrated especially at increased temperature and humidity
(trituration experiments) but also under intensified storage
conditions of 40°C and 75o r.H of pellets.
CA 02258918 1998-12-23
22
Example 4
Release behaviour of various pellet formulas:
Essential for the good bio-availability of the active
ingredient is its release as quickly as possible in the upper
small intestine region, i.e_ in a weakly acid/neutral
environment. To investigate the release behaviour pellets
with various formulas were introduced into an aqueous medium
with a pH value of 5.8 as an in vitro model for the upper
small intestine (artificial intestinal fluid) and the
Omeprazole released under stirring into the surroundings was
determined as a function of time with HPLC (analogously to the
Pharmacopia).
The'examined pellet formulas and the release results are
reproduced in Table 4:
Table 4
Batch Pellet formula Released
Omeprazole
[%]
release period 30 min 45 min 60 min
according
to the
invention
4 a Omeprazole-Core + Adjuvant72 84 89
*,
IL.: 3 % E. L 100-55 pH
7,0
gjr: 30% E. L 100-55
4 b Omeprazole-Core + Adjuvant*,40 81 88
IL.: 3 % E. L 100-55 pH
6,0
gjr: 30% E. L 100-55
comparative
examples
4 c Omeprazole-Core + Adjuvant*,3 5 8
no IL.
gjr: 30% E. L 100-55
4 d Omeprazole-Core + Adjuvant*,13 37 59
no IL
gjr: 20% E. L 100-55
*Adjuvant: Mannite, HPC, sodium lauryl sulfate
IL: Intermediate layer
E: Eudragit (percent by weight with respect to the core)
gjr: gastric juice-resistant (layer) (percent by weight with respect to the
core)
CA 02258918 1998-12-23
23
Figure 3 shows a graphic representation of the result.
The thickness of the outer enteric layer with pellet batches 4
a, b and c is each the same (30o by weight with respect to the
pellet core, corresponding to ca. 40 Vim). Despite this,
batches 4 a and 4 b provided with the reactive intermediate
layer according to the invention demonstrate a clearly quicker
dissolution in artificial intestinal fluid than when no
intermediate layer (batch 4c) is present. This is also still
the case when the enteric coating layer is more thinly formed
(batch 4b, 20o by weight with respect to the pellet core,
corresponding to ca. 30 Vim). This permits the thickness of
the outer enteric layer in the medicaments according to the
invention to be further increased which offers an improved
medicament safety in comparison to known preparations without
negatively influencing release behaviour - which was not to be
expected.
CA 02258918 1998-12-23
24
Example 5
Improved stability of the active ingredient-containing core:
Granulates of Omeprazole with various adjuvants were produced
in a mortar. After open storage over 32 days at 40°C and 750
relative humidity, the residual content of Omeprazole as well
as the appearence of degradation product were determined with
HPLC. Na2HP04 buffering in an alkaline environment, Texapon,
lactose, L-HPC, microcrystalline cellulose and mannite (batch
5b) as well as a combination of these adjuvants without
Na2HP04 (batch 5c) were employed as adjuvants. These batches
were comopared with an Omeprazole granulate which aside from
the active ingredient only contained HCP and mannite (batch
5a). The results are reproduced in Table 5.
Table 5
Batch Formula Gehalt Omeprazole Degradation product
of
Omeprazole
(Granulate) [precept by weight][area-%]
Storage conditions40C / 75 % rel.
Feuchte
Storage duration after 32 days after 32 days
production. production.
preferred
according
to
the
invention
a Omeprazole*, 100 b 100 < 0.1 b < 0.5
Mannite
HPC
Referenzbeispiel
5 b Omeprazole 100 b 100 < 0.1 b < 0.5
adjuvants
Na2HP04
5 c Omeprazole 100 b 72 < 0.1 b ca.30
adjuvants
without Na2HP04
CA 02258918 1998-12-23
As expected, the Omeprazole granulate without alkaline
reacting additive (batch 5c) demonstrated a clearly
deteriorated storage stability compared to an Omeprazole
granulate with Na2HP04 as an additive (batch 5b). Thus, the
Omeprazole content decreases to 72%;' ca. 30 area-o degradation
product arises. Surprisingly, an Omeprazole granulate with
mannite and hydroxypropylcellulose as the only adjuvants,
particularly without alkaline reacting additives (batch 5a),
also has an outstanding storage stability. Therefore, in the
preferred medicament according to the invention, it is not
necessary and is also not preferred to use alkaline reacting
adjuvants or Omeprazole salts in the core because, if
necessary, alkaline substances diffusing from the core into
the reactive intermediated layer can be hindered by the "self-
repair mechanism" as illustrated above.
Example 6
Production of medicaments according to the invention:
Formula examples
Medic~nerlt A
Core:
Omeprazole 210.00 g
Mannite 781.60 g
Hydroxypropylcellulose 3.30 g
Sodium lauryl sulfate 5.00 g
Intermediate layer:
Eudragit~ L100-55
neutralized to pH 7.0 with NaOH 50.00 g
Triethyl citrate 5.00 g
Gastric juice-resistant (outer) layer:
Eudragit~ L100-55 300.00 g
Triethyl citrate 30.00 g
CA 02258918 1998-12-23
26
Mikronized Talcum 150.00 g
Medicament B _
Core:
Omeprazole 210.00 g
Mannite 781.60 g
Hydroxypropylcellulose 3.30 g
Sodium lauryl sulfate 5.00 g
Intermediate layer:
Eudragit~ L 100-55
neutralized to pH 5.5 with NaOH 50.00 g
Triethyl citrate 5.00 g
Talcum 15.00 g
Gastric juice-resistant (outer) layer:
Eudragit~ L100-55 400.00 g
Triethyl citrate 40.00 g
Micronized talcum 200.00 g
The pre-weighed components Omeprazole, mannite and sodium
lauryl sulfate are placed in a mixer and mixed. A granulation
liquid of hydroxypropylecellulose dissolved in isopropanol is
slowly added to the pre-mixed components in the mixer under
constant stirring. If necessary, further isopropanol can be
added for better pellet formation. The mixing time amounts to
to 20 minutes until the majority of the pellets have a
desired average size of ca. 1000 ~Cm.
The moist pellets are dried in a dryer at ca. 60°C for ca. 40
min. Pellets with a diameter of < 700 ~.m or > 1200 ~.m are
sieved out_
The pellets are obtained in a fluidized state during which at
first a coating dispersion I and subsequently a coating
CA 02258918 1998-12-23
27
dispersion II is sprayed on to the pellets with a constant
rate.
For production of the coating dispersion I, purified water is
filled into a stainless steel vessel and sodium hydroxide is
dissolved in the water. The sodium hydroxide solution is
added to micronized talcum under stirring, a Eudragit~
dispersion is then slowly added to the sodium hydroxide/talcum
dispersion under stirring whereby clumps and foam formation
must be avoided. After addition of triethyl citrate to the
dispersion, stirring continued for at least 15 minutes whereby
the pH value is adjusted to pH 7.0 and/or pH 5.5 with sodium
hydroxide solution. The dispersion must be continuously
stirred during the formation of the coat.
For production of the coating dispersion II, micronized talcum
is dispersed in purified water. Subsequently, the aqueous
dispersion obtained in this manner is added to the Eudragit~
dispersion under stirring whereby the appearance of clumps or
foam must be avoided. After addition of triethyl citrate, the
dispersion is further stirred for at least 15 min. The
Omeprazole pellets are then transferred into a coating
apparatus and laminated at first-with the coating dispersion I
and then with the coating dispersion II. The finished
Omeprazole pellets are filled into hard gelatine capsules.
Example 7
In vitro experiments on chemical stability of the medicament
according to the invention:
It is known that Omeprazole loses its effectiveness with
longer storage which is traceable to a degradation of the
active ingredient_ This chemical degradation of Omeprazole
can be reduced to a minimum by applying suitable protection
layers.
CA 02258918 1998-12-23
28
It could be demonstrated in stability tests under stress
conditions (40°C/75o rel. humidity) that the medicament
according to the invention loses less than 2 percent by weight
on active ingredient (average value of each of three content
determinations) when stored in closed, brown screw-cap vials
for 4 weeks. In contrast, a commercial product (Antra 20,
VD5672-A01) lost more than 80 percent by weight on active
ingredient under identical conditions in the same time period
(see Table 6).
Table 6
Omeprazole residual content
Medicament (batch) after 12 week storage at 40C/75%
r.H. in a
closed, screw-cap vial
(percent by weight)
according to the
ivention
6 a gg.g
6 b 98.3
6 c 99.3
commercial product
6 d 16.2
In further stability tests under long-term and stress
conditions (25°C/60% r.H; 30°C/60°s r.H; 40°C/75o
r.H), it
could be demonstrated that the medicament according to the
invention loses less than 5 percent by weight on active
ingredient (average value of each of three content
determinations) when stored in the primary package for 12
weeks. The results are depicted in Table 7.
CA 02258918 1998-12-23
29
Table 7
Omeprazole
Medicament (batch)content
after 12
Weeks storage
percent by
weight
storage conditions25C/60% r.H.30C/60% 40C175% r.H.
r.H.
7 a 98.9 97.9 97.8
7 b 99.1 97.8 95.3
7 c 100.5 100.3 98.0
The results clearly demonstrate that no significant decrease
in content from the starting value was determined with the
medicament according to the invention.
Example 8
Determination of the Gastra.c-juice-resistance:
For determining the gastric-juice-resistance, samples of the
inventive medicament according to Example 6 were subjected to
an in vitro test. Thereby, each sample, which was found in a
basket at pH 1.2 and a temperature of 37°C as well as 100 rpm
of the basket, was left in the acidic medium for 120 minutes
and subsequently the sample was analysed as to the remaining
active ingredient content. The values obtained thereby are
summarized in Table 8. All values show that no significant
degradation from the starting values resulted under the
selected conditions_
CA 02258918 1998-12-23
Table 8
Omeprazole residual content
Medicament (batch)
percent by weight
according to the
ivention
8 a 98.4
8 b 98.9
8 c 96.0
Example 9
In vitro experiments on active ingredient release:
For the following experiments, an inventive medicament
according to Example 6 was also examined. The respective
sample, which was found in a basket, was exposed to a medium
(1000 ml) of pH 1.2 for 120 minutes at 37°C.
After the above-mentioned residence time in acidic medium,
this was replaced by an alkali medium (pH 6.8, phosphate
buffered) and the samples were left therein for a time period
of 5, 10, 15, 20, 30, 60 minutes respectively. After the
mentioned time intervals, analysis as to the least active
ingredient was carried out.
The determination of the in vitro active ingredient release
occurred on samples which before their storage (Figure 4) and
after 12 week storage at 25°C/60~ r.H. (Figure 5), at 30°C/60o
r.H. (Figure 6) and 40°C/75~5 r. H. (Figure 7). The
medicaments were previously filled in the designated
packaging. The obtained values are represented for the
respective batches according to the invention in Figures 4 to
7 and show that the release is stable over the storage time.
CA 02258918 1998-12-23
31
Example lp
Combination Preparation Omeprazole and Diclofenac:
Capsule fcrmulatiorb C:
A capsule contains 210 mg Diclofenac pellets corresponding to
75 mg Diclofenac-Na and 160 mg Omeprazole pellets
corresponding to 20 mg Omeprazole. The Diclofenac pellets a.s
well as the Omeprazole pellets were produced according to the
method of production according to Example 6.
Capsule form~a.l.ati.c~ D _
A capsule contains 420 mg Diclofenac pellets corresponding to
150 mg Diclofenac-Na and 160 mg Omeprazole pellets
corresponding to 20 mg Omeprazole which were produced
according to Example 6. The Diclofenac pellets were produced
according to the method given in EP 0 348 808.
