Note: Descriptions are shown in the official language in which they were submitted.
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CAPSULES OF ACTIVE PHARMACEUTICAL INGREDIENTS AND
'POLYUNSATURATED FATTY ACID ESTERS FOR THE TREATMENT OF
CARDIOVASCULAR DISEASES
FIELD OF THE INVENTION
This invention relates to a pharmaceutical composition in the form of a
capsule which
comprises a suspension of polymeric microcapsules suspended in an oil which
contains polyunsaturated fatty acid alkyl esters (PUFA), wherein the
microcapsules
contain at least one polymer and one active pharmaceutical ingredient, and its
use for
the treatment and/or prevention of cardiovascular diseases.
BACKGROUND OF THE INVENTION
Among the most used active pharmaceutical ingredients for the treatment of
cardiovascular diseases, in particular for the treatment of hypertension,
there are the
angiotensin-converting enzyme inhibitors (ACE inhibitors) and the angiotensin
II
receptor blockers (ARB, angiotensin II receptor antagonists). ACE inhibitors
and ARBs
act on the renin-angiotensin system. ACE inhibitors inhibit the angiotensin-
converting
enzyme, preventing the conversion of angiotensin I to angiotensin II. They are
very
effective anti-hypertensive agents which are also used for the treatment of
heart failure
and myocardial infarction. The majority of ACE inhibitors are administered
with the
carboxyl group in alpha position with regards to the secondary amino group in
the form
of diethyl ester, although its acids are the biologically active form.
The ARBs act by blocking the angiotensin II receptor in the arteries,
preventing its
action. Therefore, the ARBs are also a first-line treatment for hypertension,
particularly
in the case of patients who develop cough due to ACE inhibitors. ARBs are also
used
for the treatment of heart failure and diabetic nephropathy.
Polyunsaturated fatty acids (PUFA) also possess a known beneficial effect on
the
prevention of cardiovascular events and are often used in combination therapy
in
patients who have suffered some type of cardiovascular episode. There are
numerous
studies on anti-hypertensive, reduction of serum cholesterol, anti-
hypertriglyceridemic,
antiarrhythmic, antiplatelet and anti-inflammatory effects of PUFAs [Bucher
H.C. et al.
Am. J. Med. 112: 298-304 (2002); Benatti P. et al. J. Am. Coll. Nutr. 23: 281-
302
CONFIRMATION COPY
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(2004); Lee J.H. et al. Mayo Clin. Proc. 83: 324-332 (2008); Heinz R.
Adv.Ther. 26:
675-690 (2009)].
PUFAs are essential fatty acids and should be obtained from a person's diet.
They are
divided into omega-3 and ' omega-6 fatty acids depending on the position of
the first
unsaturation (n-3 and n-6 respectively). The principal omega-3 fatty acids are
found in
fish oils, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
PUFAs can be found in the form of triglycerides or alkyl esters. Commercial
compositions of omega-3 fatty acid alkyl esters vary in purity and content of
fatty acids
and are normally expressed in relation to the content in EPA and DHA.
PUFAs, in any of their forms, are easily oxidized and should be stored under
an inert
atmosphere and protected from light. Commercial compositions contain
antioxidants to
minimize their degradation.
The great instability of the aforementioned pharmaceutical antihypertensive
active
ingredients is also known, particularly of the ACE inhibitors. ACE inhibitors
can suffer
from three types of degradation: a) internal cyclization to form
diketopiperazines, b)
hydrolysis of the ester group of the side chain to give the diacid, and c)
oxidation that
produces unwanted colored products. Degradation occurs both in liquid and
solid state.
According to WO 2006/050533 A2, EP 0317878 B1, US 5442008 A, US 5151433 A,
WO 2004/064809 Al and EP 1429748 B1, the instability of the known formulations
of
ramipril is influenced by different factors, such as mechanical stress
(compression), the
manufacturing process, excipients, storage conditions, heat and moisture. As a
consequence, ramipril needs very controlled formulation conditions to minimize
the
decomposition and avoid the formation of the aforementioned degradation
products
(diketopiperazine and diacid). According to WO 2008/000040 Al and WO
2008/001184
A2, the choice of the different excipients can affect the stability of
ramipril and other
ACE inhibitors such as quinapril, enalapril or spirapril, accelerating their
degradation;
furthermore, a significant cause of decomposition is mechanical stress
associated with
the manufacturing process.
According to US 2007281000 Al, to improve the stability of the active
pharmaceutical
ingredients sensitive to moisture, water scavenger compounds can be
incorporated in
the formulation, such as copovidone in the case of cilazapril. Fosinopril is
unstable
since it is susceptible to hydrolytic degradation in the ester and
phosphodiester groups,
and the same occurs with the trandolapril ester group; in EP 1906931 Bl the
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compositions of these two active ingredients are stabilized with dimethicone,
so that
cyclization, hydrolysis and/or oxidation are inhibited.
There are numerous examples in the literature which confirm that different ACE
inhibitors decompose during the formulation of the active pharmaceutical
ingredient,
even during the process of preparation of the tablet. This problem is
attempted to be
solved, for example, by adding acid stabilizers [EP 0264888 B1; EP 0468929 B1;
US
4830853 A], the formation of enalapril salts [WO 01/32689], with meglumine [WO
2005/041940 Al], by mixing the ACE inhibitor with a metal dispersion in
alcohol [WO
04/071526 Al], through the use of alkali carbonates or alkaline earth metals
to inhibit
the cyclization or changes in color and a saccharide to inhibit hydrolysis [US
4743450
.A], or with magnesium oxide as a stabilizer against the cyclization and means
of
moisture control [EP 1083931 B1; WO 2008/000040 Al].
The approaches to the stabilization of pharmaceutical compositions which
contain ACE
inhibitors that do not use the addition of stabilizing excipients would be
those which use
polymer coatings, such as polymer coatings of agglomerate [US 5151433 A] or of
individual particles of ramipril in the final solid formulation [WO
2006/050533 A2], or
coating an inert nucleus with the active ingredient itself [US 2005202081 Al]
that would
avoid degradation induced both by the mechanical stress of compression and the
contact of the active ingredient with potentially incompatible excipients.
Some ARBs also show formulation problems, it being necessary to avoid the
presence
of water according to that deduced from the formulations described in the
literature for
valsartan [EP 1674080 Al].
Irbesartan, valsartan (both bulky powders) and candesartan cilexetil (sticky),
for
example, are very difficult to formulate in tablets or capsules due to the
physical
properties of the solids [EP 0747050 Bl, EP 1774967 Al, WO 2008/012372 Al].
Formulations as suspensions of the losartan potassium salt degrade in the
presence of
light, resulting in the destruction of the imidazole ring [Seburg R.A. et al.
J. Pharm.
Biomed. Anal. 42: 411-422 (2006)]. Losartan potassium salt, furthermore, is
not stable
in the amorphous form and tends to turn into the less soluble and less
bioactive
crystalline forms. This amorphous form can be stabilized by using polymers for
its
subsequent formulation into tablets WO 2004/064834 Al, US 2006160871 Al]. This
is
also the case for valsartan [US 2007166372 Al, US 2008152717 All].
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Candesartan cilexetil is stable with regards to temperature, moisture and
light when it is
isolated, but it decomposes over time when it is formulated with excipients in
tablets.
The principal product of degradation is the derivative O-desethyl. This
degradation
caused by pressure, abrasion and heat applied during the granulation or high
pressure
molding process can be reduced through the incorporation in the formulation
prior to
the compression of oily substances with a low melting point [EP 0546358 B1],
of lipids
or phospholipids [WO 2005/079751 A2], of different co-solvents [WO 2005/070398
A2],
of carbohydrates for the formation of adsorbates of the active ingredient [EP
1952806
Al], of water soluble polymers [WO 2005/084648 Al] or of methacrylate polymers
with
the amorphous active ingredient [EP 1997479 Al].
Compressive forces that promote degradation are inevitable in the preparation
of tablet
type solid oral formulations. An alternative to this type of solid oral
formulations are
gelatin capsules.
Gelatin capsules, whether they are hard or soft, allow the active
pharmaceutical
ingredients to be incorporated into their interior, but the protection of the,
active
ingredient is not satisfactory in the event that the substance is degradable
or unstable
in the presence of moisture or oxidizing agents.
Conventional gelatin capsules possess an external layer whose basic ingredient
is
gelatin, and in general this capsule can be hard or soft, the latter
containing
plasticizers. The coating of the conventional gelatin capsules consists of a
single
external layer, with a uniform thickness and composition, which covers the
inside,
which contains the active pharmaceutical ingredient mixed with the appropriate
excipients. The content of the soft gelatin capsules is normally liquid or
semi-liquid: oils,
polar liquids, microemulsions, suspensions, waxes or colloids. The content in
water of
the liquid inside cannot exceed 20% so that it does not dissolve the gelatin
layer.
The external layer of the capsule contains a certain amount of water as an
ingredient.
However, the presence of water in the coating of the conventional gelatin
capsules
constitutes a serious problem, in the case that the active pharmaceutical
ingredients or
their salts to be formulated are water soluble, degradable in the presence of
moisture
or unstable in contact with water. In fact, using the usual ingredients and
techniques to
produce the soft gelatin capsules, it is impossible to avoid the active
pharmaceutical
ingredient contained in the capsule coming into contact with the moisture of
the gelatin
mass of the outside layer, whether this is during the production process or
during the
storage process of the finished capsules, due to the partial diffusion of the
water of the
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coating towards the inside of the capsule, or due to the contact of a part of
the active
ingredient with the capsule walls. Since the outer coating of the capsule
contains, as
well as water, a notable quantity of conventional additives such as
plasticizers,
colorants, opacifiers and preservatives, it is also very difficult to
satisfactorily prevent or
5 control the possible incompatibilities between these and the active
ingredient. These
additives can facilitate the oxidation, degradation or hydrolysis processes,
causing a
loss of activity of the active ingredient formulated [EP 0769938 B1]. Another
factor to
take into account is the possible chemical interaction between the content and
gelatin
in the capsule, which may favor cross-linking and thus reduce the capsule's
solubility in
the aqueous medium (delaying its speed of disintegration).
Therefore, although soft gelatin capsules are widely used in the
pharmaceutical
industry, their use is not recommended in the case of active ingredients which
are
unstable in the presence of moderate quantities of water.
In an attempt to overcome this difficulty of formulating active ingredients
susceptible to
hydrolysis in soft gelatin capsules, in EP 0769938 131 there are described one
or more
hydrophobe polymer layers under the gelatin layer, as well as silicone resins
in the
inside of the capsule. The active ingredient, which can be an ACE inhibitor,
or an
anticholesterol agent such as omega-3 fatty acid eicosapentaenoic acid (EPA)
or
docosahexaenoic acid (DHA), among others, are found on the inside, mixed,
dissolved,
suspended or bound in the silicone resin. However, the processes and
manufacturing
equipment require significant modifications with regards to the usual ones.
It is also known that formulations based on lipids increase the
bioavailability of certain
active pharmaceutical ingredients. Examples of formulations which increase
bioavailability of the active ingredients through the use of PUFA are
described in the
literature, generally by the formation of emulsions. Therefore, in US 5447729
A a
release system is proposed which consists of an emulsion or dispersion of
particles of
an active ingredient, which can be an ACE inhibitor, among others, that
alternate
different hydrophobic and hydrophilic layers; the emulsion can be incorporated
onto
capsules or tablets, and for its formulation long chain fatty acids such as
linolenic,
linoleic or arachidonic acids are used. In WO 2006/135415 A2 the preparation
of
microemulsions formed by nanoparticles of acids such as eicosapentaenoic acid
(EPA)
are described, which contain active pharmaceutical ingredients such as ACE
inhibitors
or ARBs, among others. In all these cases the contact with water or excipients
of the
formulation would not be avoided, which is a cause of degradation for many
active
ingredients.
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As well as the examples discussed regarding formulations specifically aimed at
minimizing the degradation of ACE inhibitors and ARBs, there are other
examples in
the literature of formulations with the same objective and that can also
incorporate
PU FA.
As has been stated previously, in WO 2005/079751 A2 candesartan cilexetil is
stabilized in tablets through the addition of lipids or phospholipids to the
composition.
The lipids can be fatty acids such as linoleic and/or arachidonic acid, or
their glyceryl
esters.
In WO 2007/103557 A2 it proposed as a solution to the problems of chemical
incompatibilities in compositions with two or more active pharmaceutical
ingredients,
the physical separation of the components in a gelatin capsule, hard or soft,
which
contains a first active ingredient such as the omega-3 fatty acids, with one
or more
capsule coatings wherein at least one of them consists of a polymer combined
with
another active ingredient such as enalapril, and the coating which contains
this active
ingredient is isolated from the capsule and optionally from the outside by
additional
coatings. The manufacturing process is complex due to the fragility and
solubility in
water of the gelatin coatings and requires a rigorous control of the
temperature and
speed of deposition during coating.
In WO 2006/081518 A2, in order to achieve a modified release of multiple
active
ingredients, among them antihypertensive agents, complexes of the active
ingredients
with ion exchange resins are prepared, with or without polymeric coatings,
suspended
in a non-ionic and non-aqueous vehicle ("NINA" vehicle) such as alcohols,
polyols, oils,
triglycerides or waxes, among them omega-3. The active pharmaceutical
ingredient
must contain an acid or basic functional group in order to be able to form the
complex.
In the examples in this document, furthermore, the application of these
formulations is
solely by topical route. The use of resinates for oral administration is
controversial,
since the administration of large quantities of ion exchange resins or their
prolonged
use in chronic treatments can change the ionic force of the gastrointestinal
fluids and
cause electrolyte imbalances.
Although many of the references described represent an attempt to solve the
problems
of instability associated with the pharmaceutical compositions which contain
ACE
inhibitors and/or ARBs, the problem arising from the technique is the need to
improve
the stability of these pharmaceutical compositions, especially in the presence
of
moisture. The solution proposed by this invention is a pharmaceutical capsule
which
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incorporates alkyl esters of PUFA and microcapsules of the desired active
ingredient
which is isolated by means of a polymer.
The subject-matter of this invention is a pharmaceutical composition in the
form of a
capsule which provides a greater protection for active pharmaceutical
ingredients
against moisture, oxidizing agents and/or the possible chemical interactions
with the
additives of the exterior coating. The pharmaceutical capsule of the invention
allows
active pharmaceutical ingredients known for their instability to be
conveniently
formulated, such as the angiotensin-converting enzyme inhibitors (ACE
inhibitors)
and/or the angiotensin II receptor blockers (ARB), avoiding its degradation
through the
isolation provided by the combination of a polymer coating of the active
pharmaceutical
ingredient and its suspension in alkyl esters of PUFA.
DESCRIPTION OF THE INVENTION
Therefore, this invention relates to a new pharmaceutical composition which
avoids the
problems of degradation of active pharmaceutical ingredients such as the
angiotensin-
converting enzyme inhibitors (ACE inhibitors) and/or the angiotensin II
receptor
blockers (ARB) when they are formulated in pharmaceutical capsules for oral
administration.
In a first aspect, this invention relates to a pharmaceutical capsule which
comprises a
suspension of polymer microcapsules which comprise at least one polymer and
active
pharmaceutical ingredient selected from the group formed by the ACE inhibitors
and
the ARBs, these microcapsules are suspended in an oil which contains
polyunsaturated fatty acid alkyl esters. The polymer of the microcapsules
constitutes
their external part and provides a complete coating for the active
pharmaceutical
ingredient in the capsule.
In the pharmaceutical capsule of the invention, the active' pharmaceutical
ingredients
are found inside the polymer microcapsules in suspension in an oil which
contains alkyl
esters of PUFA. The active pharmaceutical ingredients are isolated both from
the
exterior medium and the alkyl esters of PUFA through the polymer, which
disintegrates
easily in the gastrointestinal medium. The pharmaceutical capsule of the
invention
allows, as well as the joint administration of active pharmaceutical
ingredients in a
combination therapy, the active pharmaceutical ingredient to be isolated from
moisture
and capsule coating additives, as well as moisture and oxygen from the
outside. The
polymer coating provides stability to the active pharmaceutical ingredients,
avoiding the
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formation of degradation products caused by moisture, compression and high
temperatures during the preparation process of the final composition in the
form of
pharmaceutical capsules.
Preferably, the fatty acids of the alkyl esters of PUFA belong to the omega-3
series.
Preferably, the PUFAs are selected from the group formed by the (0-cis)-
5,8,11,14,17-
eicosapentaenoic or eicosapentaenoic (EPA) or timnodonic acid or icosapent
(C20:5
n-3), the (all-cis)-4,7,10,13,16,19-docosahexaenoic or docosahexaenoic (DHA)
or
cervonic acid or doconexent (C22:6 n-3), and/or mixtures thereof, such as
Omacor ,
Lovaza or Zodin , among others. In a preferred embodiment, the EPA:DHA
relationship can range between 100:0 and 0:100, preferably between 4:1 and
1:4, and
more preferably between 1:2 and 2:1. The PUFAs can comprise just EPA or just
DHA.
Preferably, the alkyl radical of the alkyl esters of PUFA is selected from the
group
formed by short chain alkyl radicals, with from 1 to 8 carbon atoms.
Preferably, the
alkyl radical is selected from the group formed by ethyl, methyl, propyl,
butyl and/or
mixtures thereof. More preferably, the alkyl radical is an ethyl group.
Preferably, the oil containing alkyl esters of PUFA is an oil enriched in
alkyl esters of
PUFA, preferably, the oil contains more than 50% of alkyl esters of PUFA, more
preferably more than 60% of alkyl esters of PUFA and even more preferably,
more
than 85% of alkyl esters of PUFA.
In a preferred embodiment, the quantity of alkyl esters of PUFA contained in
the
pharmaceutical capsule of the invention is comprised between 0.01 and 4 g,
preferably
between 0.1 and 2 g.
In a particular embodiment, the active pharmaceutical ingredient is an
angiotensin-
converting enzyme inhibitor, selected, without restriction, from the group
formed by
captopril, enalapril, enalaprilat, ramipril, quinapril, perindopril,
lisinopril, benazepril,
fosinopril, spirapril, trandolapril, moexipril, cilazapril, imidapril,
rentiapril, temocapril,
alacepril, delapril, moveltipril, zofenopril, pentopril, libenzapril,
pivopril, ceronapril,
indolapril, teprotide, their pharmaceutically acceptable salts and their
acids.
In another particular embodiment, the active pharmaceutical ingredient is an
angiotensin II receptor blocker, selected, without restriction, from the group
formed by
candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan,
valsartan,
tasosartan, pratosartan, azilsartan, saralasin, ripisartan, elisartan,
milfasartan,
amp busartan, fonsa tai , saprisartan, zolasartan, forasartan, pomisartan,
abitesartan,
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fimasartan, N-benzyl-losartan, enoltasosartan, glycyl-losartan, opomisartan,
trityl-
losartan, sarmesin, isoteolin and their pharmaceutically acceptable salts.
The polymer of the microcapsules of the pharmaceutical capsule of this
invention is
selected, without restriction, from the group formed by proteins,
polysaccharides,
polyesters, polyacrylates, polycyanoacrylates, polyethylene glycol and/or
mixtures
thereof. Preferably, the polymer of the microcapsules is selected from the
group formed
by gelatin, albumin, alginates, carrageenans, pectins, gum arabic, chitosan,
carboxymethylcelIulose, ethylcellulose, hydroxypropyl methylcellulose (HPMC),
nitrocellulose, cellulose' acetate butyrate, cellulose acetate phthalate,
hydroxypropyl
methylcellulose phthalate, hydroxypropyl methylcellulose acetate-succinate,
polyvinyl
acetate phthalate, poly(s-ca prolactone), poly(p-dioxanone), poly(S-
valerolactone),
poly(R-hydroxybutyrate), poly((3-hydroxybutyrate) copolymers and (3-
hydroxyvale rate,
poly(P-hydroxypropionate), methacrylic acid copolymers (Eudragit L and S),
dimethylaminoethyl methacrylate copolymers (Eudragit E), trimethylammonium
ethyl
methacrylate copolymers (Eudragit RL and RS), polymers and copolymers of
lactic
and glycolic acids, polymers and copolymers of lactic and glycolic acids and
polyethylene glycol and/or mixtures thereof. More preferably, the polymer is
formed by
copolymers of methacrylic acid (Eudragit L and S), polymers and copolymers of
lactic
and glycolic acids, polymers and copolymers of lactic and glycolic acids and
polyethylene glycol, and/or mixtures thereof.
Optionally, the polymer of the microcapsules of the pharmaceutical capsule of
this
invention can comprise a plasticizer additive. The plasticizer additive is
selected,
without restriction, from the group formed by alkyl esters of the citric acid
such as
triethyl citrate, tributyl citrate, acetyl tributyl citrate and acetyl
triethyl citrate, phthalates
such as butyl phthalate and diethyl phthalate, glycerin, sorbitol, maltitol,
propylene
glycol, polyethylene glycol, glucose, sucrose, lanolin, palmitic acid, oleic
acid, stearic
acid, metal salts of fatty acids such as stearic acid or palmitic acid, sodium
stearate,
potassium stearate, propylene glycol monostearate, acetylated monoglycerides
such
as monoacetylated glycerin and glyceryl triacetate or triacetin, glyceryl
lecithin, glyceryl
monostearate, alkyl sebacates such as dibutyl sebacate or diethyl sebacate,
alkyl
fumarates, alkyl succinates, medium chain triglycerides (MCT), ricin oil,
hydrogenated
vegetable oils, wax and/or mixtures.
Optionally other technical additives of the polymer can be incorporated which
improve
or facilitate the encapsulation process such as fluidifying agents, such as
talc, colloidal
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silicon dioxide, glycerin, polyethylene glycol, glycerin monostearate and/or
metal
stearate salts.
Optionally, the pharmaceutical capsule of this invention comprises at least
one
antioxidant, such as and not restricted to, butylhydroxytoluene (BHT),
5 butylhydroxyanisole (BHA), tert-butylhydroquinone (TBHQ), gallic acid esters
such as
propyl gallate, tocopherols such as vitamin E acetate, ascorbic acid esters
such as
ascorbyl palmitate and ascorbyl acetate, carnitine and/or mixtures thereof.
Preferably,
the antioxidant is vitamin E acetate.
In a particular embodiment, the microcapsules represent between 0.001% and 80%
of
10 the total weight of the pharmaceutical capsule of this invention,
preferably between
0.01% and 60%, and more preferably between 0.1% and 50% of the total weight of
the
pharmaceutical capsule of this invention.
The amount of active pharmaceutical ingredient incorporated in these
microcapsules is
comprised between 1% and 80% in weight, preferably between 1% and 60% in
weight
with respect to the total weight of the microcapsules. The total amount of
active
pharmaceutical ingredient included in the pharmaceutical capsule of this
invention
depends on the recommended daily doses.
The pharmaceutical capsule of this invention can be a hard or soft capsule, of
gelatin
or any usual polymer in the preparation of capsules in the pharmaceutical
industry,
such as and not restricted to, hydroxypropyl methylcellulose (HPMC), pullulan,
modified starches, carrageenans and/or mixtures thereof. Preferably, it is a
gelatin
capsule. More preferably, this capsule is made of soft gelatin. Optionally,
the capsule
has an enteric coating. The capsule coating can contain other additives such
as
plasticizers, colorants, pigments, opacifiers, preservatives, moisturizers,
surfactants,
sweeteners and/or flavorings. The preparation of the capsule is carried out
through the
usual procedures in the pharmaceutical industry, and can be any form and size
known
by the person skilled in the art.
The preparation of the microcapsules can be carried out by following any of
the
procedures described in the literature. As a description and not restricted to
them, the
different procedures for obtaining microcapsules can be grouped in the
following
sections:
A) Simple coacervation procedure
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A solution of the polymer together with its possible additives is prepared in
an
appropriate solvent. In this solution of the polymer the active pharmaceutical
ingredient to be encapsulated is suspended and a solvent in which the polymer
is
not soluble is added to force the polymer deposition on the crystals of the
active
ingredient. Examples of these procedures can be found in documents such as ES
2009346 A6, EP 0052510 A2 and EP 0346879 Al.
B) Complex coacervation procedure
It is based on the interaction between two colloids with an opposite
electrical
charge to generate an insoluble complex which is deposited on the particles of
the
active pharmaceutical ingredient to be encapsulated forming a membrane which
isolates it. Examples of these procedures can be found in documents such as GB
1393805 A.
C) Double emulsion procedure
The active pharmaceutical ingredient to be encapsulated is dissolved in water
or in
a solution of another coadjuvant and is emulsified in a solution of the
polymer and
additives in an appropriate solvent such as dichloromethane. The resulting
emulsion is in turn emulsified in water or in an aqueous solution of an
emulsifier
such as polyvinyl alcohol. Once this second emulsion has been carried out the
solvent in which the polymer and the plasticizer were dissolved in is
eliminated by
evaporation or extraction. The resulting microcapsules are directly obtained
by
filtration or evaporation. Examples of these procedures can be found in
documents
such as US 4652441 A.
D) Simple emulsion procedure
The active pharmaceutical ingredient to be encapsulated, the polymer and the
additives are jointly dissolved in an appropriate organic solvent. This
solution is
emulsified in water or in a solution of an emulsifier such as polyvinyl
alcohol and
the organic solvent is eliminated by evaporation or extraction. The resulting
microcapsules are recovered by filtration or drying. Examples of these
procedures
can be found in documents such as US 5445832 A.
E) Solvent evaporation procedure
The active pharmaceutical ingredient to be encapsulated, the polymer and the
additives are jointly dissolved in an appropriate solvent. This solution is
evaporated
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and the resulting residue is micronized to obtain the suitable size, or it is
dried by
spray-drying. Examples of this procedure can be found in documents such as GB
2209937 A.
Another aspect of this invention relates to the pharmaceutical capsule of this
invention
for the treatment and/or prevention of cardiovascular diseases. Preferably,
the
cardiovascular diseases are selected from the group formed by hypertension,
heart
failure and myocardial infarction.
Another aspect of this invention relates to a method of treatment and/or
prevention of
cardiovascular diseases which comprises the administration of the
pharmaceutical
capsule of the invention. Preferably, the cardiovascular diseases are selected
from the
group formed by hypertension, heart failure and myocardial infarction.
The following specific examples provided here serve to illustrate the nature
of this
invention. These examples are included solely for illustrative purposes and
should not
be interpreted as a limitation to the invention claimed herein.
EXAMPLES
Example 1. Preparation of pharmaceutical capsules which contain ramipril
microcapsules with gelatin through simple coacervation procedures.
A 1 % solution of gelatin in water was prepared.
100 mL of this solution were taken and 1 g of ramipril powder was dispersed in
it. Then
mL of saturated sodium sulfate solution in water were added. The mixture was
stirred for 1 hour and 0.5 mL of 50% glutaraldehyde solution in water were
added.
The microcapsules formed by filtration were collected, washed with water and
dried in
a vacuum drying oven. The ramipril content of these microcapsules was 35%.
25 The resulting microcapsule powder was dispersed directly in oil containing
a minimum
of 90% of ethyl esters of PUFA, with a minimum EPA/DHA content of 85% in a
ratio of
1.2:1 (719 mg of the suspension of microcapsules obtained per 100 g of oil).
Next, 1.00
g of the dispersion of microcapsules in oil was incorporated to a soft gelatin
capsule to
obtain a dose of 2.5 mg of ramipril per capsule.
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Example 2. Preparation of pharmaceutical capsules which contain trandolapril
microcapsules with poly(lactic-co-glycolic acid) (PLGA) and vitamin E.
Preparation of the microcapsules by the simple emulsion method (oil in water).
Solution A: A 10% solution in dichloromethane (DCM) of PLGA with an intrinsic
viscosity (I.V.) of 0.17 and a lactic/glycolic ratio of 1:1 was prepared.
Solution B: 5 g of trandolapril and 1 g of vitamin E acetate were dissolved in
100 mL of
solution A.
Solution C: A 1 % solution of polyvinyl alcohol (PVA) in water was prepared.
100 mL of solution B were added slowly and under intense stirring to 1000 mL
of
solution C until a milky emulsion was obtained. During this stirring, a
nitrogen current
was passed through the previous emulsion for two hours to eliminate most of
the DCM.
Subsequently the resulting suspension was frozen and lyophilized. A powder was
obtained which was washed with a great amount of water to eliminate the excess
of
PVA and was dried under reduced pressure.
The microcapsule powder obtained contained 31% of trandolapril, and was
directly
dispersed in oil containing a minimum of 60% of ethyl esters of PUFA, with a
minimum
DHA content of 40%. Next, the dispersion of microcapsules in oil obtained was
incorporated to a soft gelatin capsule. The quantities used to prepare
capsules of
different sizes and doses of trandolapril are shown in Table 1.
Dispersion: Dose of trandolapril
microcapsules/100 g oil Weight of dispersion/capsule capsule
0.65 g 0.50 g 1 mg
0.43 0.75 1 mg
1.31g 0.50g 2mg
0.65 1.00 2 m
Table 1
Example 4. Preparation of pharmaceutical capsules which contain lisinopril
microcapsules with poly(lactic-co-glycolic acid) (PLGA) prepared by the triple
emulsion method.
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Solution A: 5 g of PLGA with an intrinsic viscosity (I.V.) of 0.4 dUg and a
lactic/glycolic
ratio of 1:1 were dissolved in 50 mL of dichloromethane (DCM).
Solution B: 1.08 g of lisinopril dihydrate were dissolved in 10 mL of water.
Solution C: A 0.5% p/v concentration solution of polyvinyl alcohol (PVA) in
water was
prepared.
The aqueous phase (solution B) was emulsified in the solution of PLGA
(solution A)
with the help of an Ultra Turrax homogenizer (W/O emulsion).
The previously prepared W/O emulsion was added to 1 L of the PVA solution
(solution
C) under intense stirring. The new emulsion formed was stirred whilst a
nitrogen
current was passed through the reactor at a flow no less than 50Uminute to
evaporate
the DCM. The microcapsules were recovered by filtration through a membrane
with a
pore diameter of 5 pm, they were washed with abundant water to eliminate the
excess
of PVA and were dried by lyophilization.
The microcapsule powder obtained contained 16%, of lisinopril, and was
directly
dispersed in oil containing a minimum of 90% of ethyl esters of PUFA, with a
minimum
EPA/DHA content of 85% in a ratio of 1.2:1 (1.59 g of the microcapsule
suspension
,obtained per 100 g of oil). Next, 1.00 g of the microcapsule dispersion in
oil was
incorporated to a soft gelatin capsule, to obtain a dose of 2.5 mg of
lisinopril per
capsule..
Example 4. Preparation of pharmaceutical capsules that contain microcapsules
of candesartan cilexetil with gelatin and carboxymethyl cellulose prepared by
a
complex coacervation procedure.
Solution A: A 1 % solution of gelatin in water was prepared and the pH was
adjusted so
it was equal or higher than 7.
Solution B: Another 1% solution of sodium carboxymethyl cellulose in water was
prepared and the pH was adjusted so it was equal or higher than 7.
250 mL of solution A and 250 mL of solution B were mixed and heated to, 40 C.
4 g of
powdered candesartan cilexetil were dispersed in the mixture. When all the
powder
was dispersed and there were no lumps the pH was adjusted to 4-4.5 by adding
acetic
acid. The mixture was stirred for 1 hour at 40 C and afterwards the solution
was cooled
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to 10 C, maintaining this temperature for another hour. 2 mL of 50%
glutaraldehyde
solution in water were added.
The resulting suspension was dried by spray-drying, to give a microcapsule
powder
which contained 40% of candesartan cilexetil.
5 This microcapsule powder was directly dispersed in oil containing a minimum
of 90% of
ethyl esters of PUFA, with a minimum EPA/DHA content of 85% in a ratio of
1.2:1.
Next, the dispersion of microcapsules in oil obtained was incorporated to a
soft gelatin
capsule. The quantities used to prepare the capsules of different size and
doses of
candesartan cilexetil are shown in Table 2.
Dispersion: Dose of candesartan
microca sules/100 oil Weight of dispersion/capsule cilexetil / capsule
2.04 g 1.00 g 8 mg
1.35 g 1.50 g 8 mg
4.17g 1.00 g 16 mg
2.74 1.50 16 m
Table 2
Example S. Preparation of pharmaceutical capsules which contain valsartan
microcapsules and a methacrylic acid copolymer.
10 g of valsartan were suspended in 100 mL of a suspension of Eudragit FS 30D
(suspension in water of 30% methacrylic acid, methyl methacrylate and methyl
acrylate
copolymers) until a fine suspension was obtained. Triethyl citrate was added
to this
suspension (polymer plasticizer) until a concentration of 5%.
The resulting suspension was dried by spray-drying, to give a microcapsule
powder
which contained 22% of valsartan.
The resulting microcapsule powder was directly dispersed in oil containing a
minimum
of 65% of ethyl esters of PUFA, with a minimum EPA/DHA content of 45% in a
ratio of
1.2:1 (25.0 g of the suspension of microcapsules obtained per 100 g of oil).
Next, 1.00
g of the microcapsule dispersion in oil was incorporated to a soft gelatin
capsule, to
obtain a dose of 40 mg of valsartan per capsule.
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Example 6. Studies of stability of the soft gelatin capsules which contain
ramipril, trandolapril, lisinopril, candesartan cilexetil and valsartan
microcapsule
suspensions in an oil which contains alkyl esters of PUFA.
Studies of accelerated stability (40 2 C, 75 5 % RH) were carried out on the
soft
gelatin capsules which contained suspensions of the active pharmaceutical
ingredients
in an oil which contained alkyl esters of PUFA, wherein:
a) The active pharmaceutical ingredient does not have a polymer coating
(control
composition).
b) The active pharmaceutical ingredient is in microcapsules prepared according
to
the previous examples (composition of the invention).
The percentages of the active pharmaceutical ingredient in the capsules were
determined through HPLC after storage in amber glass containers for 1 month, 2
months, 3 months and 4 months. The percentages of the active pharmaceutical
ingredient are shown in Table 3.
The stability of PUFAs was also studied (concentration of alkyl esters of EPA
and DHA,
as well as the EPA/DHA ratio) through gas chromatography, although no
variations
were observed in the composition.
Active Stabili (40 2 C, 75 5 % RH)
ingredient Initial 1 month 2 months 3 months 4 months
%
Ramipril exam le 1)
a 99.2 96.3 91.7 87.0 81.1
b 98.9 99.0 - 98.8 98.9
Trandolapril (example 2; dose 2 mg, capsule 1
a 99.1 97.0 93.2 88.6 84.5
b 99.2 99.0 - 99.1 99.0
Lisinopril exam le 3; dose 2.5 mg, capsule 1
a 99.0 96.2 91.3 85.6 79.2
b 99.1 98.9 - 98.9 98.8
Candesartan cilexetil (example 4; dose 16 mg, capsule 1c _
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a 98.8 97.5 94.8 91.9 87.9
b 98.7 98.8 - 98.6 98.4
Valsartan exam le 5)
a 98.4 97.1 94.5 92.1 89.4
b 98.5 98.4 - 98.2 98.1
Table 3
