Note: Descriptions are shown in the official language in which they were submitted.
CA 02456410 2004-O1-29
la
~ Office Van Malderen
Bxl (MT) - January 26, 2004
P.FRAN.01/CA
NSAID
STABILISED PHARMACEUTICAL COMPOSITION COMPRISING AN
EXTENDED RELEASE NON-STEROIDAL ANTI-INFLAMMATORY AGENT AND
AN IMMEDIATE RELEASE PROSTAGLANDIN
Field of the invention
[0001] The present invention is related to a
pharmaceutical composition based upon a dual release dosage
form comprising an adequate pharmaceutical carrier, an
extended release non-steroidal anti-inflammatory drug
(NSAID) and an immediate release stabilized prostaglandin.
The present invention is also related to the use of said
pharmaceutical composition for the treatment of
inflammatory conditions or diseases, like osteoarthritis
and rheumatoid arthritis.
Background of the invention and state of the art
[0002] Non-steroidal anti-inflammatory drugs
(NSAIDs) have demonstrated high therapeutic value,
especially for the treatment of inflammatory conditions or
diseases, like osteoarthritis and rheumatoid arthritis.
[0003] A great variety of NSAIDs dosage forms is
available on the market.
[0004] Usually, the NSAIDs have to be taken several
times a day, which can generate an important compliance
issue, particularly with patients population like the
elderly.
[0005] As understood in the prior art, enteric or
delay release coatings are not an efficient method for the
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delivery of NSAIDs due to the inability of such
formulations to provide or achieve a sustained therapeutic
effect due to the lack of prolonged release of the
pharmaceutical agent. Also the concurrent administration of
enteric coated or delayed release NSAIDs with food or the
presence of food in the stomach may lead to dose dumping
and unwanted secondary effects.
[0006] Optimizing the release of one or several
drugs from a dosage form is an important way of guiding
their pharmacological action and of great benefit for
patient treatment. Extended release (identified by the
abbreviations ER or XR) is the most current and official
terminology to define a controlled availability of the drug
alongside the gastrointestinal tract. Other expressions
used in the scientific literature to define the same
profile are: sustained, controlled, prolonged, retard or
similar.
[0007] Modified releases have been debated between
Experts in the Pharmaceutical Technology and are frequently
defined in scientific and official documents.
[0008) In the NSAIDS therapeutic class, the United
States Pharmacopeia, 25 edition, pages 554-555, describes
the Diclofenac Sodium Delayed-Release Tablets in an
Official Monograph.
[0009] Interestingly, a proposal of a Diclofenac
Sodium Extended-Release Tablets monograph has been recently
published on the USP Pharmacopeial Forum (Vol. 2003 pp.
319-320).
[0010] More details on Diclofenac Sodium, i.e.,
about Pharmacokinetics data, can be found in the
Prescribing Information document made by Novartis, the
Company which commercialised the drug initially.
[0011] The NSAIDS exert most of their anti-
inflammatory, analgesic and antipyretic activity and
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inhibit hormone-induced uterine contractions and certain
types of cancer growth trough inhibition of prostaglandin
G/H synthase, also known as cyclooxygenase (COX).
Inhibition of COX-1 causes a number of side effects
including inhibition of platelet aggregation associated
with disorders of coagulation, and gastrointestinal side
effects. The gastrointestinal side effects are due to a
decrease in the biosynthesis of prostaglandins which are
cytoprotective of the gastric mucosa. The prevalence of
gastrointestinal side effects is similar among "acute" and
"chronic" NSAID users and affects especially the elderly.
[0012] A high incidence of side effects has
historically been associated with the use of classic
cyclooxygenase inhibitors, all of which are about
equipotent for COX-1 or COX-2, or which are COX-1.
[0013] In view of the still very large therapeutic
use of classic NSAIDs, several approaches have been
undertaken to minimise the drugs' adverse effects.
[0014] For many years, neutralization of gastric
acid with antiacids was the only relief from the
gastrointestinal pain induced by ulcers. More recently
agents called "proton pomp inhibitors" have been
recommended and used. They provide a more specific class of
inhibitors of gastric secretion in mammals, including
humans, by blocking the final step of acid production.
[0015] The documents US-6,365,184, US-6,544,556 and
US-6,613,354 describe an oral pharmaceutical dosage form
comprising a "proton pomp inhibitor" and one or more
NSAID(s) in a fixed formulation, and their use in the
treatment of gastrointestinal side-effects associated with
NSAID treatment.
[0016] The use of prostaglandins is an improved way
to minimize the gastrointestinal ulcerations induced by the
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oral administration of NSAIDs, such PGE1, PGE2, misoprostol
and derivatives thereof.
[0017] Co-administering exogenous prostaglandins,
particularly misoprostol, in association with NSAIDS is a
"natural" way of preventing NSAID-associated ulcers and
ulcer complications as described in Silverstein F.E.,
Digestive Diseases and Sciences 1998; 43: 447-458.
[0018] Moreover, dosage forms based on misoprostol
or anti-ulcerogenic prostaglandins are cheaper than the
commercially available "proton pump inhibitors". This
results in "fixed dose combination products" priced lower,
which is an important parameter in the today Social
Security resources.
[0019] More details on Misoprostol, i.e., about
Pharmacokinetics document data, can be found in the
Prescribing Information document made by Searle, the
Company which commercialised the drug initially.
[0020] Interestingly, the European Pharmacopeia
Commission has, in June 2003, proposed a monograph for the
Misoprostol active ingredient. The document is Monograph
N°: 1731 with additional reference PA/PH/Exp.lOB/T (02)140
ANP and is currently submitted for comment to the relevant
authorities.
[0021] However, prostaglandins are unstable
compounds and have been shown degrading readily in the
presence of NSAIDs.
[0022] The documents US-5,601,843, US-6,193,779, US-
6,537,582 and W099/65496 describe different ways of
combining sodium diclofenac Enteric- or Delayed-Coated
Releases with a prostaglandin. However, these approaches
have the drawbacks of the enteric or delay releases dosage
forms highlighted here above.
(0023] Therefore, there is a need in the art to
provide a composition for administering an NSAID sustained
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release dosage form wherein the undesirable
gastrointestinal side effects of the drug are minimised.
Aims of the Invention
5 [0024] The present invention aims to provide a
pharmaceutical composition which does not present the
drawbacks of the state of the art and which finds an
adequate solution for the above-mentioned problem.
[0025] A particular aim of the present invention is
to provide such a composition that allows an extended
release delivery of non-steroidal anti-inflammatory agents
and allows an immediate release of the prostaglandin.
Summary of the Invention
[0026] The present invention is related to a solid
pharmaceutical composition comprising at least two separate
regions (or portions), wherein a first region (or portion)
comprises at least one non-steroidal anti-inflammatory drug
(NSAID) associated with an adequate pharmaceutical carrier
containing a retardant material for said non-steroidal
anti-inflammatory drug (NSAID), and a second region (or
portion) comprises a prostaglandin, preferably a stabilized
prostaglandin, and an adequate pharmaceutical carrier with
an immediate release.
[0027] According to the invention, "a solid
pharmaceutical composition" means a dosage form which is
adequate for oral administration.
[0028] In said composition, the retardant material
and the immediate release carrier are two elements selected
in order to allow respectively an extended (or sustained)
release delivery of the non-steroidal anti-inflammatory
agent and to provide the prostaglandin immediately
available for absorption.
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[0029] Furthermore, the composition comprises an
element such as an adequate pharmaceutical carrier which
allows a stabilization of the prostaglandin.
[0030] Advantageously, the pharmaceutical
composition according to the invention comprises a first
and a second regions that are separated by a third region,
which is a protective intermediate region that does not
comprise any therapeutically active compound.
[0031] The first region of the pharmaceutical
composition of the invention comprises extended release
formulations of the NSAID which eliminate the issue of
compliance as designed to be dosed once or twice a day,
providing therapeutically effective plasma levels over a
long period of time.
[0032] Pharmaceutical technology uses several
approaches to design dosage forms with an extended release
delivery.
[0033] The retardant material included in the first
region is in dosage forms to create an extended delivery of
the NSAID compounds) for at least up to 24 hours in human
patients and can include one or more pharmaceutically
acceptable hydrophilic materials and/or hydrophobic
materials which are capable of imparting controlled release
of the active agent in accordance with the present
invention.
[0034] The said retardant material is preferably
selected from the group consisting of acrylic and
methacrylic acid polymers and copolymers, alkylcelluloses,
gums, protein derived materials or a mixture thereof. Are
also suitable lipidic materials like waxes, glycerides or
aliphatic alcohols. Ther retardant materials can be used
alone or in mixture.
[0035] In a preferred embodiment of the present
invention, the above-mentioned hydrophobic material of the
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first region is an acrylic polymer selected from the group
consisting of acrylic acid and methacrylic acid copolymers,
methylacrylate polymers, methyl methylacrylate copolymers,
ethoxyethyl methacrylate polymers, cyanoethylmethacrylate
polymers, aminoalkyl methacrylate copolymers, poly(acetylic
acid), poly(methacrylic acid), methacrylic acid alkylamine
copolymers, poly(methyl methacrylate) polymers,
poly(methacrylic acid) (anhydride), polymethacrylate
polymers, polyacrylamide, poly(methacrylic acid anhydride),
glycidyl methacrylate copolymers or a mixture thereof.
(0036] According to another preferred embodiment of
the present invention, the said retardant material is an
alkylcellulose selected from the group consisting of
hydroxypropylmethylcelluloses (HPMC),
hydroxyethylcelluloses (HEC), hydroxypropylethylcelluloses
(HPEC), hydroxypropylcelluloses (HPC), methylcelluloses
(MC), ethylcelluloses (EC) or sodium
carboxymethylcelluloses (NaCMC) (possibly said celluloses
modified by addition of functional groups) or a mixture
thereof.
[0037] Preferred examples of suitable retardant
materials included in the pharmaceutical composition of the
invention are lipidic materials, methacrylic acid
copolymers or cellulose-based polymers.
[0038] It is to be noted that said listing is not
meant to be exclusive, and that any pharmaceutically
acceptable hydrophobic material and/or hydrophilic material
which is capable of imparting extended release of the
active agents) may be used in accordance with the present
invention.
[0039] The percentage of these retardant molecules
in the pharmaceutical composition according to the
invention can also be adapted by the person skilled in the
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art according to the amount and/or the type of the active
agents present in said composition.
[0040] Furthermore, organic or inorganic ingredients
can be introduced in the different regions (or portions) of
the composition to modulate the release of the NSAID(s)
from the first region (or portion). For example, a
phosphate buffer can be introduced to create a pH of about
4.5 or a suitable quantity of an organic acid to create
lower pH conditions.
[0041] In addition to the above ingredients,
suitable quantities of other elements, e.g. diluents,
lubricants, binders, granulating aids, colorants,
flavorants and glidants that are conventional in the
pharmaceutical art can be present in the first region (the
region containing NSAID) of the pharmaceutical composition
according to the invention. The quantities of these
additional elements will be sufficient to provide the
desired effect to the desired (solid) formulation.
[0042) The second region (the (preferably stabilized
gastroprotective) prostaglandin-containing region)
comprises an adequate pharmaceutical carrier for improving
the immediate release of said (stabilized gastroprotective)
prostaglandin.
[0043] Said pharmaceutical carrier is an immediate
release formulation that offers a fast disintegration,
resulting in a short dissolution period, followed by a
quick absorption of the stabilized prostaglandin
derivative.
[0044] Therefore, following the administration of
the pharmaceutical composition according to the invention,
the quick appearance of the prostaglandin in the blood is
advantageous as it can start to work immediately against
the deleterious side effects of the NSAID.
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[0045] However, the prostaglandins chemical class of
compounds is known to include drugs which are very potent,
but also very unstable and can degrade rapidly in presence
of NSAIDs.
[0046] To stabilize advantageously the
prostaglandins used as anti-ulcerogenic drugs, it is
possible to use (preferably under the form of a dispersion)
stabilizing (gastroprotective) agents such as
hydroxypropylmethylcellulose (HPMC), or
polyvinylpyrrolidone (PVP).
[0047] Other stabilizing agents include, but are not
limited to: cellulosic polymers such as hydroxypropyl
cellulose (HPC), hydroxyethyl cellulose (HEC), methyl
cellulose (MC), ethyl cellulose (EC), cellulose acetate,
cellulose acetate phthalate, cellulose acetate
trimellitate, hydroxypropyl methylcellulose phthalate,
microcrystalline cellulose and sodium
carboxymethylcellulose (NaCMC); and vinyl polymers and
copolymers such as polyvinylacetate phthalate, vinylacetate
crotonic acid copolymers, and ethylene-vinyl acetate
copolymers or a mixture thereof. The prostaglandin
stabilizing agent is present in an amount effective to
provide the desired stabilizing effect; generally, this
means that the ratio of prostaglandin / stabilizing agent
is at least about 1:500 w/w, more preferably about 1:99
w/w.
[0048] The prostaglandin-containing second region
contains various excipients that do not exhibit a
destabilizing effect and include, for example, binders,
bulking agents, diluents, disintegrants, lubricants,
fillers, carriers, and the like.
[0049] In the present invention, the non-steroidal
anti-inflammatory agents present in the first region are
preferably selected from the group consisting of:
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aceclofenac, diclofenac, diflunisal, fenbufen, flufenamic
acid, ibuprofen, indomethacin, ketoprofen, meclofenamate
sodium, meloxicam, mefenamic acid, nabumetone, naproxen,
piroxicam, suprofen, tiaprofenic acid, acetylsalicylic
5 acid, flurbiprofen, ketorolac, oxaprozin, sulindac,
tenoxicam, tiaprofenic acid and suitable salts, esters,
amides, prodrugs or analogues thereof,
[0050] The pharmaceutical composition according to
the invention could also comprise pharmaceutical acceptable
10 analogues or derivatives of these non-steroidal anti
inflammatory agents.
[0051] In the pharmaceutical composition according
to the invention, the prostaglandins present in the second
region are preferably selected from the group consisting of
the "E-series" prostaglandins, such as PGE1, PGE2,
misoprostol, enoprostol, enisoprost, rosaprostol or
miraprostol and pharmaceutical acceptable analogues or
derivatives thereof. The preferred prostaglandins are
"anti-ulcerogenic" prostaglandins.
[0052] The pharmaceutical composition according to
the invention is suitable for the treatment of inflammatory
conditions, such as exhibited inflammatory diseases, like
osteoarthritis and rheumatoid arthritis.
[0053] The present invention is also related to a
packaging preferably designed to minimize the oxygen
permeation and to contain the pharmaceutical composition
according to the invention and one or more gastric
antisecretory prostaglandin analogue medicament(s).
[0054] The present invention will be described in
detail in the following description which is presented as a
non-limiting illustration of the various aspects of the
present invention.
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Short description of the drawings
[0055] Fig. 1 represents the influence of polymer's
concentration on diclofenac sodium release when HPMC
(Hypromellose), grades 4000 and 100, is used as a retardant
material in the first region. The influence of lactose or
dibasic calcium phosphate as a diluent is also shown.
[0056] Fig. 2 represents an example of diclofenac
release from bi-layered tablets, core tablets and mini-
tablets formulations containing 75 mg diclofenac sodium and
200 ~g misoprostol. The release of Voltaren retard 75 is
shown for comparison.
Detailed Description of the Invention
[0057] The invention, as noted above, is in one
embodiment a stabilised pharmaceutical composition for
administration of an NSAID and a prostaglandin, wherein the
NSAID is in a form that allows an extended release and the
prostaglandin is in a form which allows an immediate
release. The solid composition is comprised of at least two
discrete regions (or portions).
[0058] The regions can contain different active or
inactive ingredients, can have different roles in the
composition, can influence the release of the active
ingredients, can facilitate the separation of the active
ingredients to improve compatibility and stability and can
be made of a single or of multiple units comprising (or
not) the active compounds.
[0059] Preferably, the composition comprises a first
region (or portion) wherein the extended release NSAID is
present and a second region (or portion) wherein the
immediate release prostaglandin is present.
[0060] A further region (or portion) can serve to
separate the different layers or regions comprising the
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active ingredients or to facilitate the design of the
dosage form.
(0061] Furthermore, dosage forms with two discrete
regions (or portions) are suitable to design very different
release characteristics for the active ingredients
contained in the different regions (or portions), allowing
the dual release of the pharmaceutical composition of the
invention. Secondarily, they offer the possibility of
imparting a repeat-action effect of one or each of the two
active ingredients.
[0062] The invention is not limited with respect to
the selected mentioned NSAID; the dual and stabilised
compositions of the invention can contain any NSAID, NSAID
derivative, or combination of NSAIDs. Typical NSAIDs
include, but are not limited to, aceclofenac,
acetylsalicylic acid, diclofenac, diflunisal, fenbufen,
flufenamic acid, flurbiprofen, ibuprofen, indomethacin,
ketorolac, meloxicam, mefenamic acid, naproxen, oxaprozin,
piroxicam, sulindac, tenoxicam, diflunisal and tiaprofenic
acid. Pharmaceutically acceptable analogues of such NSAIDs
are suitable as well; particularly analogues of
aceclofenac, diclofenac, ketoprofen, piroxicam, meloxicam,
naproxen, tenoxicam and their salts are preferred.
[0063] The NSAID is present in the composition in a
therapeutically effective amount; preferably, the solid
composition is unit dosage form. The amount of NSAID
administered will depend on the age, weight, and general
condition of the subject, the severity of the condition
being treated, and the judgement of the prescribing
physician. Suitable therapeutic amounts will be known to
those skilled in the art and/or are described in the
pertinent reference texts and literature. For aceclofenac a
therapeutic dose is typically about 50 mg to about 200 mg
per dosage form. For diclofenac, acid or sodium or
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potassium salts for example, a therapeutic dose is
typically about 50 to about 150 mg per dosage form,
optimally about 75 mg or about 100 mg per dosage form. For
ketoprofen, the therapeutic dose is typically 100 mg to 300
mg. The therapeutic dosing range for a dosage containing
meloxicam, piroxicam or tenoxicam is about 5 mg to about 40
mg per dosage form, optimally about 10 mg or about 20 mg
per dosage form, while the therapeutic dosing range for a
tablet containing naproxen is about 250 mg to about 1000 mg
per dosage form.
[0064] The NSAID-containing region (or portion) can
also contain various excipients, as is well known in the
pharmaceutical art, provided such excipients do not exhibit
a destabilising effect on any components in the dual
release dosage form composition.
[0065] The second region (or portion) in the dual-
release dosage form contains a prostaglandin to reduce or
eliminate the undesirable side effects of the NSAID
following oral administration. Preferred prostaglandins are
those, which are effective in this regard, i.e. are
typically "anti-ulcerogenic". The prostaglandin is
preferably selected from the "E-series" prostaglandins such
PGEl, PGE2, misoprostol, enoprostol, enisoprost,
rosaprostol or miraprostol and pharmaceutical acceptable
analogues or derivatives thereof. The most preferred
prostaglandin is misoprostol, present in an amount of about
50 to about 500 micrograms per dosage form, more preferably
about 100 to about 300 micrograms per dosage form.
Misoprostol leaves rapidly the immediate release region, is
rapidly absorbed and produces quickly its anti-secretory
effect, reducing or eliminating the ulcerogenicity of the
NSAID.
[0066] A cellulose-based polymer, preferably
Hypromellose, also called HPMC, is used to stabilise the
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prostaglandin. The stabilising agent is present in an
amount effective to provide the desired stabilising effect;
generally, this means that the ratio of prostaglandin to
the prostaglandin stabilising agent is at least about 1:500
w/w, more preferably about 1:99 w/w.
[0067] The active ingredients in the present
composition, i.e., both the NSAID and the prostaglandin,
may be administered in the form of a pharmacologically
acceptable acid, salt, ester, amide, prodrug or analogue or
as a combination thereof.
[0068] A third region can be present in the dual
release dosage form depending on its design or the need to
better separate the different active ingredients. If
existing, the third region will contain no NSAID or
prostaglandin but various excipients that do not exhibit a
destabilising effect on any components in the dual release
dosage form.
[0069] Coating can be present in one or several
regions of the invention. It can be used as a part of the
first region (or portion) to act as a retardant material in
the release of the NSAID. It can also be used to facilitate
the segregation (physical and chemical separation) between
the active ingredients. A number of coating agents are
commercially available and pharmaceutically acceptable, in
particular methacrylic and/or acrylic acid copolymers or
cellulose based polymers.
[0070] Details on suitable coating agents are well
known by the person skilled in the pharmaceutical art.
[0071] The dosage form of the pharmaceutical
composition according to the invention can be formulated as
any suitable tablet, core tablet, layered or multi-layered
tablet, or multiple unit tablets or as any suitable
capsule, or a combination of said formulations obtained by
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known machines able to produce the dosage forms of the
invention in conditions imposed by the pharmaceutical laws.
Description of Preferred Embodiments of the Invention
5 Core tablet
[0072] The core is the first region (or portion)
containing the NSAID when a core tablet is designed as a
dosage form of the invention. A coating may surround the
core to prevent direct contact between the NSAID and the
10 prostaglandin and to avoid non-beneficial interaction such
as degradation of the prostaglandin. The dimensions of the
core are suitable to allow mantle dry coating with the
immediate release prostaglandin containing second region
while finishing with a palatable dosage form.
15 [0073] Upon ingestion, the mantle disintegrates
quickly, which liberates the two regions of the dosage form
and allows the dual release.
[0074] A retardant material, in particular selected
among the group consisting of lipidic materials,
methacrylic and/or acrylic acid copolymers or cellulose
based polymers, is used to create the extended release of
the NSAID in the first region.
[0075] The second region will be designed as a
mantle made by direct compression to minimize the
degradation of the prostaglandin and to provide fast
disintegration and dissolution.
[0076] Details on other suitable materials and their
quantities are well known by them skilled in the
pharmaceutical art as are the available technologies to
manufacture and control the core tablets.
Layered or multi-layered tablets
[0077] In layered tablets, the NSAID drug and the
suitable excipients may be compressed in the lower half of
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the tablet to become the first region (or portion) of the
dosage form. The prostaglandin together with the suitable
excipients can be superposed and pressed onto it and be the
second region (or portion) of the dosage form. A third
region (or portion) containing no drug can provide a
barrier between the two active ingredient containing layers
and prevent any non-beneficial interaction such a
degradation of the prostaglandin.
[0078] Upon ingestion, the layers separate quickly,
which liberates the regions (or portions) of the dosage
form and allows the dual release.
[0079] The retardant materials) used to create the
extended release of the NSAID in the first region (or
portion) can be selected from the group described in the
summary, in particular lipidic materials, methacrylic
and/or acrylic acid copolymers or cellulose based polymers.
[0080] The second region (or portion) will be
designed as a layer made by direct compression to minimize
the degradation of the prostaglandin and to provide fast
disintegration and dissolution.
[0081] When present the third region (or portion) is
made of inert excipients suitable for direct compression
and separates the 2 other regions.
[0082] Details on other suitable materials and their
quantities are well known by them skilled in the
pharmaceutical art as are the available technologies to
manufacture and control the core tablets.
Multiple unit tablets
[0083] The first region (or portion) can be made of
granulates, beads, pellets, mini-tablets or similar units
or a mixture of them, formulated to allow the sustained
delivery of the NSAID. The multiple units can be coated
with a retardant material or to prevent direct contact
CA 02456410 2004-O1-29
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between the 2 regions. The multiple units should be soft
enough to deform only slightly under compression to avoid
agglomeration with the second region (or portion) and
modification of the release of one or of the two active
ingredients.
[0084] A retardant material, in particular selected
among the group consisting of lipidic materials,
methacrylic and/or acrylic acid copolymers or cellulose
based polymers, is used to create the extended release of
the NSAID in the first region (or portion).
[0085] The second region (or portion) can be made of
one or several units or of a powder, both directly
compressible, to minimize the degradation of the
prostaglandin and to provide fast disintegration and
dissolution.
[0086] Details on other suitable materials and their
quantities are well known by them skilled in the
pharmaceutical art as are available technologies to
manufacture and control the multiple unit tablets.
Capsules
[0087] Hard gelatine capsules (capsules) can also be
very useful to design suitable dosage forms for dual
release as they may contain multiple units corresponding to
the different regions (or portions).
[0088] Capsules are made from different polymers as
gelatine or starch for example. Interestingly, capsules
made of the cellulose derivative
hydroxypropylmethylcellulose (HPMC) are particularly
advantageous for the present invention. They are more
suited than the gelatine based capsules for example because
they offer the advantage of a low humidity content. The
classical hard gelatine capsules are using moisture as a
plasticizer and their high water content has been proven
CA 02456410 2004-O1-29
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harmful for sensitive drugs like the prostaglandins.
Interestingly, the water content of the HPMC hard gelatine
capsules is limited to maximum 6~ and it can even been
lowered by drying before use.
[0089] The first region (or portion) of the HPMC
capsule is made of granulates, beads, pellets or mini-
tablets or similar multiple units or of a mixture of them
and contains the NSAID drug formulated with an extended
release.
[0090] A retardant material, in particular selected
among the group consisting of lipidic materials,
methacrylic and/or acrylic acid copolymers or cellulose
based polymers, is used to create the extended release of
the NSAID in the first region (or portion).
[0091] The second region (or portion) of the HPMC
capsule will be made of a powder or of one or several
units.
[0092] Units of the first and/or second region (or
portion) can be coated to prevent direct contact between
the NSAID and the prostaglandin and to avoid non-beneficial
interaction such as degradation of the prostaglandin.
[0093] Upon ingestion, the HPMC capsule dissolves,
which liberates the two regions (or portions) of the dosage
form and allows the dual release.
[0094] Details on other suitable materials and their
quantities are well known by them skilled in the
pharmaceutical art as are available technologies to
manufacture and control capsules containing multiple units.
Examples
[0095] The examples are described for the purposes
of illustration and are not intended to limit the scope of
the invention.
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[0096] Methods referred to but not explicitly
described in this disclosure and examples are reported in
the literature and are well known to those skilled in the
art.
Example 1: Region 1 for layered tablets
L0097] Different grades and concentrations of
hypromellose have been tested in the design of the first
region of layered tablets. Tablets of 9 mm diameter and
weighing 225 mg have been chosen. The influence on the
diclofenac sodium extended release of the concentration and
grades of the Hypromellose 4000 mPa.s is shown in Figure 1
as is the use of dibasic calcium phosphate. The influence
of the addition of loo Hypromellose 100, 10% lactose or of
10% Dibasic Calcium phosphate is also shown.
30~ Hypromellose 4000
Diclofenac sodium 75.0 mg
Hypromellose 4000 mPa.s 70.0 mg
Microcristalline cellulose 30.0 mg
Lactose 44.6 mg
Colloidal silicondio_xide 0.4 mg
Magnesium stearate 5.0 mg
40~ Hypromellose 4000
Diclofenac sodium 75.0 mg
Hypromellose 4000 mPa.s 90.0 mg
Lactose 54.6 mg
Colloidal silicon dioxide 0.4 mg
Magnesium stearate 5.0 mg
30$ Hypromellose 4000 + 10~ Hypromellose 100
Diclofenac sodium 75.0 mg
Hypromellose 4000 mPa.s 70.0 mg
Hypromellose 100 mPa.s 20.0 mg
Lactose 54.6 mg
Colloidal silicon dioxide 0.4 mg
Magnesium Stearate 5.0 mg
CA 02456410 2004-O1-29
50~ Hypromellose 4000
Diclofenac sodium 75.0 mg
Hypromellose 4000 mPa.s 115.0 mg
Microcristalline cellulose 29.6 mg
Colloidal _silicondioxide 0 . 4 mg
Magnesium Stearate 5.0 mg
30~ H~romellose 4000: Dibasic calcium phosphate
Diclofenac sodium 75.0 mg
Hypromellose 4000 mPa.s 70.0 mg
Dibasic calcium phosphate 74.6 mg
Colloidal _si_lico_n dioxide 0.4 mg
Magnesium Stearate 5.0 mg
5 Example 2: Bi-layered tablets
(0098] Tablets dosed at 75 mg of diclofenac sodium
and 200 ~.g misoprostol (9 mm diameter, total weight:
325 mg) have been prepared using this formulation.
10099] Diclofenac sodium extended release is shown
ZO and compared to a marketed product in figure 2.
[0100] Misoprostol immediate release is not shown
but is similar to the one obtained with a commercially
available product.
15 Diclofenac sodium ER region (225 mq)
Diclofenac sodium 75.0 mg
Hypromellose 4000 mPa.s 70.0 mg
Hypromellose 100 mPa.s 20.0 mg
Lactose 34.6 mg
Dibasic calcium phosphate 20.0 mg
Colloidal silicon dioxide 0.4 mg
Magnesium stearate 5.0 mg
Stabilized Mis~rostol IR region ( 100 mg)
Misoprostol 1 ~ dispersion HPMC 20.0 mg
Microcristalline cellulose 25.0 mg
Lactose 48,8 mg
Crospovidone 5.0 mg
Colloidal silicon dioxide 0.2 mg
Glycerol behenate 1.0 mg
CA 02456410 2004-O1-29
21
Exa ~~le 3: Bi-layered tablets
[0101] A formulation of the first region of tablets
dosed at 100 mg of diclofenac sodium is described. The
second region is dosed at 200 ~g of misoprostol and is the
same than the one in example 2. The bi-layered tablet is of
9 mm diameter and weights 330 mg.
Diclofenac sodium ER region (230 mg)
Diclofenac sodium 100.0 mg
Hypromellose 4000 mPa.s 70.0 mg
Hypromellose 100 mPa.s 20.0 mg
Lactose 24.6 mg
Dibasic calcium phosphate 10.0 mg
Colloidal silicon dioxide 0.4 mg
Magnesium stearate 5.0 mg
l0 Exam~.~le 4: Tri-layered tablets
[0102] Tablets dosed at 75 mg of diclofenac sodium
and 200 ug of misoprostol (9 mm diameter, total weight:
425 mg) are defined.
[0103] The first and the second region are the same
than the ones described in example 2.
[0104] A third intermediate region is used in this
formulation. Details on the composition of the third region
are provided.
Protective intermediate region (100 mg)
Hypromellose 5 mPa.s 20.0 mg
Microcristalline cellulose 25.0 mg
Lactose 48.8 mg
Crospovidone 5.0 mg
Colloidal silicon dioxide 0.2 mg
Glycerol behenate 1.0 mg
Example 5: Tri-layered tablets
[0105] Tablets dosed at 100 mg of diclofenac sodium
and 200 ~g of misoprostol (9 mm diameter, total weight:
428 mg) are defined.
CA 02456410 2004-O1-29
22
[0106] The formulation of the first region dosed at
100 mg of diclofenac sodium is described.
[OI07] The second region dosed at 200 ug of
misoprostol is the same than the one described in example 2
and the third region is formulated as in example 4.
Diclofenac sodium ER region (228 mg)
Diclofenac sodium 100.0 mg
Hydroxyethylcellulose 80.0 mg
Lactose 30.0 mg
Colloidal silicon dioxide 1 0 mg
Povidone 9.0 mg
Talc 3.O mg
Magnesium stearate ~ 5.0 mg~
Example 6: Core tablets
[0108] Tablets dosed at 75 mg of diclofenac sodium
and 200 ~,g misoprostol (11 mm diameter biconvex, total
weight: 495 mg) have been prepared using this formulation.
[0109] Diclofenac sodium extended release from the
first region is shown and compared to a marketed product in
figure 2. A protective coating is part of the first region.
[01101 Misoprostol immediate release from the second
region is not shown but is similar to the one obtained with
a commercially available product.
Diclofenac sodium ER region (150 mg)
Diclofenac sodium 75.0 mg
Hypromellose 4000 mPa.s 50.0 mg
Hypromellose 100 mPa.s 10.0 mg
Lactose 11.8 mg
Colloidal silicon dioxide 0.2 mg
~Magnesiurn stearate 3.0 mg
CA 02456410 2004-O1-29
23
Protective coating (5 mg)
Hypromellose 5 mPa.s 4.5 mg
Macrogol 6000 0.5 mg
Purified water*
*Removed during the process
Stabilized Misoprostol IR region (340 mg)
Misoprostol . HPMC 1% dispersion _20_.0 mg
Microcristalline cellulose 299_.5 mg
Crospovidone 15.0 mg
Colloidal silicon dioxide 0.5 mg
Glycerol behenate 5.0 mg
Example 7: Core tablets
[0111] Tablets dosed at 100 mg of diclofenac sodium
and 200 ~g misoprostol (11 mm diameter biconvex, total
weight: 505 mg) are defined.
Diclofenac sodium .ER region (160 mg)
Diclofenac sodium 100.0 mg
Hypromellose 4000 mPa.s 45.0 mg
Hypromellose 100 mPa.s 10.0 mg
Dibasic calcium phosphate 1.8 mg
Colloidal silicon dioxide 0.2 mg
Magnesium stearate 3.0 mg
Protective core coating (5 mg)
Hypromellose 5 mPa.s 4.5 mg
Macrogol 6000 0.5 mg
Purified water*
*Removed during the process
Stabilized Misoprostol IR region (340 mg)
Misoprostol HPMC 1% dispersion 20.0 mg
Microcristalline cellulose 299.5 mg
Crospovidone 15.0 mg
Colloidal silicon dioxide 0.5 mg
Glycerol behenate 5.0 mg
CA 02456410 2004-O1-29
24
Example 8: HPMC Capsules containing mini-tablets
(0112] HPMC based, 0 size HPMC capsules dosed at
75 mg of diclofenac sodium and 200 ug misoprostol have been
prepared.
L0113] The region 1 is made of 6 extended release
film coated mini-tablets (4 mm diameter, 41 mg) and the
region 2 of one immediate release mini-tablet (4 mm
diameter, 45 mg).
[0114] The 2 regions are prepared separately and
introduced in the empty HPMC capsules using a suitable
capsule filling machine.
[0115) Diclofenac sodium extended release is shown
and compared to a marketed product in figure 2.
(0116) Misoprostol immediate release is not shown
but is similar to the one obtained with commercially
available products.
10117] The total net weight of the HPMC capsule is
291 mg.
Diclofenac sodium ER mini-tablets (40 mg)
Diclofenac sodium 12.5 mg
Ethylcellu lose 10 20.0 mg
Monobasic sodium phosphate 6.7 mg
Colloidal silicon dioxide 0.05 mg
- .
_
g , stearate ~ 0.75 mg~
~Ma neslum
Protective core coati~(1 mg)
Hypromellose 5 mPa.s 0.9 mg
Macrogol6000 0.1 mg
- _ _ _-_-
I ,
(Purified water*
*Removed during the process
CA 02456410 2004-O1-29
Misoprostol IR mini-tablet (45 mg)
Misoprostol H_PM_C 1% dispersion 20.0 mg
Microcrista_lline cellulose 13.0 mg
Lactose 9.4 mg
Crospovidone 2.0 mg
Colloidal silicon dioxide 0.1 mg
Hydrogenated castor oil 0.5 mg
Example 9: HPMC Capsules containing mini-tablets
[0118] HPMC based, elongated 0 size
capsules dosed
5 at 100 sodium and 200 misoprostol are
mg of diclofenac ug
defined, using the mini-t ablets described n example 8.
i
[0119] The region 1 is made of 8 extended release
film coated and the region of one immediate
mini-tablets 2
release mini-tablets.
10 [0120] The total net HPMC capsule is
weight of the
373 mg.
Example 10: HPMC Capsules containing film coated pellets
and a powder
15 [0121] HPMC based, 0 size capsules dosed at 75 mg of
diclofenac sodium and 200 ~g misoprostol are defined.
[0122] The region 1 contains film coated extended
release pellets. Uncoated pellets are made via an aqueous
granulation process, coated with a suitable retardant
20 aqueous formulation and overcoated with a protective coat.
[0123] The region 2 is made of an immediate release
powder.
[0124] Preparation of the 2 regions occurs
separately and they are introduced in the empty 0 size HPMC
25 capsules using a suitable capsule filling machine.
[0125] The total net weight of the HPMC capsule is
420 mg.
CA 02456410 2004-O1-29
26
Diclofenac sodium uncoated pellets (130 mg)
Diclofenac sodium 75.0 mg
Microcristalline cellulose 15.0 mg
Lactose 26.0 mg
Povidone K30 7.5 mg
Sucrose stearate 6.5 mg
Purified water*
*Removed during the process
Extended release coating of pellets (7.6 mg)
Methacrylate esters copolymer 4.7 mg
Talc 2.4 mg
Hypromellose 5 mPa.s 0.5 mg
Simeticone emulsion
Purified water*
*Removed during the process
Protective coating of ER_pellets (3.7
Hypromellose 5 mPa.s 3.4 mg
Macrogol 6000 0.3 mg
Purified water*
*Removed during the process
Misoprostol IR powder mixture (278.7 mg)
Misoprostol HPMC 1$ dispersion 20.0 mg
Microcristalline cellulose 100.0 mg
Lactose 141.0 mg
Crospovidone 15.0 mg
Colloidal silicon dioxide 0.2 mg
Hydrogenated castor oil 2.5 mg
Example 11: HPMC Capsules containing film coated pellets
and a mini-tablet
[0126] HPMC based, 0 size elongated capsules dosed
at 200 mg ketoprofen and 200 ~g misoprostol are defined.
[0127] The region 1 contains film coated extended
release pellets and the region 2 is made of a mini-tablet
as in example 8.
[0128] The total net weight of the HPMC capsule is
395 mg.
CA 02456410 2004-O1-29
27
Retoprofen ER film coated pellets (350 mg)
Ketoprofen 200.0 mg
Amylum 50.0 mg
Saccharosum 59.0 mg
Shellac gum 18.5 mg
Ethylcellulosum 18.5 mg
Talc 3.0 mg
Colloidal silicon dioxide 1.0 mg
Example 12: HPMC Capsules containing film coated pellets
and a powder.
[0129] HPMC based, 00 size capsules dosed at
412.5 mg of naproxen sodium and 200 ~.g of misoprostol are
def fined .
[0130] The region 1 contains the NSAID, partly as
immediate release pellets, partly as extended release
pellets. The naproxen sodium pellets are coated to avoid
direct contact with the second region. The region 2 is made
of a free flowing immediate release.
[0131] The total net weight of the HPMC capsule is
660 mg.
Naproxen sodium IR and ER re,c~ion (560 mg)
Naproxen sodique 412.5 mg
Microcrystalline cellulose 55.0 mg
Povidone 30.0 mg
Citric acid 6.0 mg
Magnesium stearate 12.0 mg
Talc 6.5 mg
PEG 6000 7.2 mg
Ammonium methacrylic ester copolymer type 10.0 mg
A
Ammonium methacrylic ester copolymer type 10.0 mg
B
Hypromellose 5mPas 10.8 mg
CA 02456410 2004-O1-29
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Stabilized Miso~rostol IR region (100 mg)
Misoprostol 1% dispersion HPMC 20.0 mg
Microcristalline cellulose 25.0 mg
Lactose 48.8 mg
Crospovidone 5.0 mg
Colloidal silicon dioxide 0.2 mg
Glycerol behenate 1.0 mg
Example 13: HPMC Capsules containing film coated pellets
and a powder
[0132] HPMC based, 0 size capsules dosed at 100 mg
of diclofenac sodium and 200 ~g of misoprostol are defined.
[0133] The region 1 contains film coated extended
release pellets. Uncoated pellets are made via a aqueous
granulation process, coated with a suitable retardant
aqueous formulation and overcoated with a protective coat.
[0134] The region 2 is made of a free flowing
immediate release powder.
[0135] Preparation of the 2 regions occurs
separately and they are introduced in the empty 0 size HPMC
capsules (total net weight: 420 mg) using a suitable
capsule filling machine.
Diclofenac sodium uncoated pellets (180.0 mg)
Diclofenac sodium 100.0 mg
Microcristalline cellulose 20.0 mg
Lactose 41.2 mg
Povidone K30 10.0 mg
Sucrose stearate 8.8 mg
Purified water*
*Removed during the process
Extended release coating of pellets (10.1 mg)
Methacrylate esters copolymer 6.3 mg
Talc 3.1 mg
Hypromellose 5 mPa.s 0.7 mg
Simeticone emulsion
Purified water*
*Removed during the process
CA 02456410 2004-O1-29
29
Protective coating of ER pellets (4.9 mg)
Hypromellose 5 mPa.s 4.5 mg
Macrogol 6000 0.4 mg
Purified water*
*Removed during the process
Misoprostol IR powder mixture (225 mg)
Misoprosto1 . HPMC 1% dispersion 20.0 mg
Microcristalline cellulose 82.0 mg
Lactose 108.8 mg
Crospovidone 12.0 mg
Colloidal silicon dioxide 0.2 mg
Hydrogenated castor oil 2.0 mg
Example 14: Multiple-unit tablets
[0136] Tablets dosed at 75 mg of diclofenac sodium
and 200 ~g misoprostol are defined (10 mm diameter
biconvex, total weight: 450 mg).
[0137] The region 1 contains film coated extended
release pellets. Uncoated pellets are made via a aqueous
granulation process, coated with a suitable retardant
aqueous formulation and overcoated with a protective coat.
[0138] The region 2 is made of a free flowing a
immediate release powder.
[0139] Preparation of the 2 regions occurs
separately and after mixture they are compressed using a
suitable tabletting machine.
Diclofenac sodium uncoated pellets (130 mg)
Diclofenac sodium 75.0 mg
Microcristalline cellulose 15.0 mg
Lactose 26.0 mg
Povidone K30 7.5 mg
Sucrose stearate 6.5 mg
Purified water*
*Removed during the process
CA 02456410 2004-O1-29
Extended release coating of pellets (7.6 mg)
Methacrylate esters copolymer 4.7 mg
Talc 2.4 mg
Hypromellose 5 mPa.s 0.5 mg
Simeticone emulsion
Purified water* _ __ _ ~_
*Removed during the process
Protective coating of ER pellets (3.7 mg)
Hypromellose 5 mPa.s 3.4 mg
Macrogol 6000 0.3 mg
- - _
Purified water* r
5 *Removed during the process
Misoprostol IR ~wder mixture (308.7 mg)
Misoprostol: HPMC 1% dispersion 20.0 mg
Microcristalline cellulose 120.0 mg
Lactose 150.4 mg
Crospovidone 15.0 mg
Colloidal silicon dioxide 0.3 mg
Hydrogenated castor oil ~ 3.0 mgl
Example 15: Multiple-unit tablets
10 [0140] Tablets dosed at 100 mg of diclofenac sodium
and 200 ~.g misoprostol are defined {10 mm diameter
biconvex, total weight: 450 mgt.
[0141] The region 1 contains film coated extended
release pellets. Uncoated pellets are made via a aqueous
15 granulation process, coated with a suitable retardant
aqueous formulation and overcoated with a protective coat.
[0142] The region 2 is made of an immediate release
compressed powder.
[0143] Preparation of the 2 regions occurs
20 separately and after mixture they are compressed using a
suitable tabletting machine.
CA 02456410 2004-O1-29
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Diclofenac sodium uncoated pellets (173.4 mg)
Diclofenac sodium 100.0 mg
Microcristalline cellulose 20.0 mg
Lactose 35.0 mg
Povidone K30 10.0 mg
Sucrose stearate 8.4 mg
Purified water*
*Removed during the process
Extended release coating of pellets (10.2 mg)
Methacrylate esters copolymer 6.3 mg
Talc 3.2 mg
Hypromellose 5 mPa.s 0.7 mg
Simeticone emulsion
Purified water*
*Removed during the process
Protective coating of ER pellets (4.9 mg)
Hypromellose 5 mPa.s 4.5 mg
Macrogol 6000 0.4 mg
Purified water*
*Removed during the process
Misoprostol IR powder mixture (261.5 mg)
Misoprostol . HPMC 1% dispersion 20.0 mg
Microcristalline cellulose 105.0 mg
Lactose 120.7 mg
Crospovidone 13.0 mg
Colloidal silicon dioxide 0.3 mg
Hydrogenated castor oil 2.5 mg
Examples of ingredients used for the development of the
different formulations
Ingredients Suppliers Function Comments
Diclofenac Amoli Organics Active Extended
sodium (Mumbai, India) ingredient release
Cambrex Profarmaco
(Landen, Belgium)
Misoprostol Cascade Biochem (Cork,Active Stabilized
.
.
HPMC (1:100) Ireland ingredient Dispersion,
IR.
Methocel K4M, Colorcon (West Point, HydrophilicRetardant,
K100 and E5 USA) polymer stabilizing
CA 02456410 2004-O1-29
32
(Hypromellose) and film
coating agent
Ethocel 10 mPa.sDow (Midland, USA) Inert Retardant
(Ethylcellulose) polymer
Kollidon K25 BASF (Ludwigshafen, Binder Wet
Germany) granulation
Pharmatose 200 DMV (Veghel, Diluent Wet
mesh and DCL11 Netherlands) granulation,
dry
compression
Emcompress Penwest Diluent
(dibasic calciumPharmaceuticals Co
phosphate (Patterson, USA)
Avicel PH101 FMC (Philadelphia, Binder Dry
et
102 USA) compression,
Microcristalline pelletisation
cellulose
NaH2PO4.1Hz0 Merck (Belgium) Buffering pH regulator
agent
Citric acid Fedora (Brussel, Acidifying pH regulator
monohydrate Belgium) agent
Compritol 888AT0Gattefoss~ (Saint Lubricant Glycerol
Priest, France) behenate
Magnesium UCB (Brussel, Belgium)Lubricant
stearate
Aerosil 200 Degussa AG (Frankfurt,Glidant
Germany)
Polyplasdone ISP ( NJ, USA) Disintegrant
XL
Cutina HR Hydrogenated
castor oil
Natrosol 250HMX Hercules Hydrophilic Retardant
(Hydroxyethyl Ltd (Aqualon) Salford,polymer
Cellulose) UK
Eudragit NE30D Rohm GmbH Barrier
(Methacrylate Darmstadt Germany coating
esters agent
copolymer)
Macrogol 6000 Merck Plasticizer
Miinchen, Germany
Talc Rldrich Anti-
Steinheim, Germany adherent
agent
Sucrose emulsionCroda Lubricant
Yorkshire, UK
Simeicon Dow Corning Anti-foaming
emulsion Midland Michigan USA agent
HPMC Capsules Shionogi Qualicaps Container Low moisture
Alcobendas Madrid content
Spain
