NZ616907B2 - Oral complex composition comprising omega-3 fatty acid ester and hmg-coa reductase inhibitor - Google Patents
Oral complex composition comprising omega-3 fatty acid ester and hmg-coa reductase inhibitor Download PDFInfo
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- NZ616907B2 NZ616907B2 NZ616907A NZ61690712A NZ616907B2 NZ 616907 B2 NZ616907 B2 NZ 616907B2 NZ 616907 A NZ616907 A NZ 616907A NZ 61690712 A NZ61690712 A NZ 61690712A NZ 616907 B2 NZ616907 B2 NZ 616907B2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4891—Coated capsules; Multilayered drug free capsule shells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
The disclosure relates to an oral complex composition comprising omega-3 fatty acid esters and HMG-CoA reductase inhibitor, which can effectively raise serum HDL level while reducing serum LDL and TG levels and can be used to treat hyperlipidemia owing to its good drug dissolution rate and storage stability with showing no delayed release behavior even after 6 months of accelerated storage. The oral complex composition comprises: (a) a soft capsule core comprising omega-3 fatty acid esters; (b) a first coating layer which encases the soft capsule core and comprises a hydrophobic coating material selected from the group consisting of cellulose acetate, polyvinyl acetate, ethyl cellulose, (meth)acrylic acid copolymers and a mixture thereof; and (c) a second coating layer deposited on the first coating layer, which comprises: (i) rosuvastatin or a pharmaceutically acceptable salt thereof, and (ii) polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer or a mixture thereof. tability with showing no delayed release behavior even after 6 months of accelerated storage. The oral complex composition comprises: (a) a soft capsule core comprising omega-3 fatty acid esters; (b) a first coating layer which encases the soft capsule core and comprises a hydrophobic coating material selected from the group consisting of cellulose acetate, polyvinyl acetate, ethyl cellulose, (meth)acrylic acid copolymers and a mixture thereof; and (c) a second coating layer deposited on the first coating layer, which comprises: (i) rosuvastatin or a pharmaceutically acceptable salt thereof, and (ii) polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer or a mixture thereof.
Description
ORAL COMPLEX COMPOSITION COMPRISING OMEGA-3 FATTY
ACID ESTER AND HMG-COA REDUCTASE INHIBITOR
FIELD OF THE INVENTION
The present invention relates to an oral complex composition comprising
omega-3 fatty acid esters and a HMG-CoA reductase inhibitor.
BACKGROUND OF THE INVENTION
Marine oils, also commonly referred to as fish oils, are the main sources of
omega-3 fatty acids, i.e. eicosapentaenoic acid (EPA) and docosahexaenoic acid
(DHA), which modulate lipid metabolism. Omega-3 fatty acids can, with no
adverse side effects, increase serum high-density lipoprotein (HDL) cholesterol
while reducing serum triglycerides (TG), systolic and diastolic blood pressure, the
heart rate, and the activation of blood coagulation factor VII-phospholipids complex.
Currently available omega-3 fatty acids drugs are omega-3 fatty acid ethyl
esters (hereinafter, referred as "omega-3 fatty acid esters"), an ethyl-esterified
concentration of omega-3 fatty acids, i.e. polyunsaturated fatty acids from DHA and
EPA-containing fish oils, and is sold under the trademark OMACOR . Such
omega-3 fatty acid esters are generally formulated into a capsule form such as
gelatin capsules, as disclosed in U.S. Patent Nos. 5,502,077, 5,656,667 and
,698,594.
Besides natural fermentation products, mevastatin and lovastatin
(MEVACOR ; see U.S. Patent No. 4,231,938), different types of synthesized and
semisynthesized HMG-CoA reductase inhibitors are exist including simvastatin
(ZOCOR ; see U.S. Patent No. 4,444,784), pravastatin sodium salt
(PRAVACHOL ; see U.S. Patent No. 4,346,227), fluvastatin sodium salt
(LESCOL ; see U.S. Patent No. 5,354,772), atorvastatin calcium salt (LIPITOR ;
see U.S. Patent No. 5,273,995), cerivastatin sodium salt (also known as rivastatin;
see U.S. Patent No. 5,177,080), rosuvastatin calcium salt (CRESTOR ; see KR.
Patent No. 105431) and pitavastatin calcium salt (LIVARO ; see KR Patent No.
101149). Such HMG-CoA reductase inhibitors contain 3-hydroxy lactones or
corresponding ring opened dihydroxy acids, and are often referred to as "statins."
Statins were typically used for treatment to maintain cholesterol levels within the
normal range. Statins can inhibit HMG-CoA reductase which regulates cholesterol
synthesis thereby slowing down the production of cholesterol, or can reduce serum
low-density lipoprotein (LDL) cholesterol by upregulating LDL receptors in the
liver. Thus, the main function of the statins is diminishing LDL cholesterol.
Statins are known to reduce the risk of coronary heart disease (CHD) by one third,
yet have limited effects on TG and serum HDL.
Patients with hypercholesterolemia and mixed dyslipidemia show high
levels of LDL and TG. It is advantageous to use a pharmaceutical combination of
omega-3 fatty acid esters and statins because it is applicable to treat high levels of
both LDL and TG.
Therefore, development of a pharmaceutical combination of omega-3 fatty
acid esters and statins may be useful for treating hyperlipidemia by raising serum
HDL while reducing LDL and TG levels. Hence, there has been much research on
combined formulation of omega-3 fatty acid esters. For example, U.S. Patent
Publication No. 2007/0212411 disclosed combined formulations of OMACOR by
conducting, in sequence, polymer barrier coating, drug coating and top coating.
Examples of active pharmaceutical ingredients which can be used for the coatings
include simvastatin, fenofibrate, pravastatin, propranolol, enalapril and
prioglitazone.
Korean Patent Publication Nos. 2007-0038553, 2007-0108945 and 2009-
0086078 disclose pharmaceutical compositions of directly mixing omega-3 fatty
acid esters with statins, however their drug stability cannot be guaranteed when
directly mixed. Also, Korean Patent Publication Nos. 2007-0108945 and 2007-
0083715 relate to pharmaceutical compositions comprising statins or microcapsules
thereif. The compositions are formulated into a soft capsule form, mixed with
omega-3 fatty acid oils which cause a delayed release of statin, so the dissolution
rate of statin is much slower than that of commercially available statin drugs.
Currently, there is no complex composition drug comprising omega-3 fatty
acid esters and HMG-CoA reductase inhibitor available having the same dissolution
rate of statin as the commercial statin drugs. Therefore, there has been a need to
develop a complex composition comprising omega-3 fatty acid esters and HMG-
CoA reductase inhibitors which is pharmaceutically stable; having the same
dissolution rate and efficacy as commercial statin drugs; and does not show a
delayed release behavior even after long-term storage.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide an oral
complex composition comprising omega-3 fatty acid esters and rosuvastatin or a
pharmaceutically acceptable salt thereof, which exhibits an improved rosuvastatin
releasing rate and does not show a delayed release behavior even after long-term
storage, and/or to provide a method for preparing the oral complex composition,
and/or to provide the public with a useful choice.
In accordance with one aspect of the present invention, there is provided an
oral complex composition, which comprises: (a) a soft capsule core comprising
omega-3 fatty acid esters; (b) a first coating layer which encases the soft capsule
core and comprises a hydrophobic coating material; and (c) a second coating layer
deposited on the first coating layer, which comprises (i) rosuvastatin or a
pharmaceutically acceptable salt thereof, and (ii) polyvinyl alcohol (PVA),
polyvinyl alcohol-polyethylene glycol (PVA-PEG) graft copolymer, or a mixture
thereof, wherein the hydrophobic coating material is selected from the group
consisting of cellulose acetate, polyvinyl acetate, ethyl cellulose, (meth)acrylic acid
copolymers and a mixture thereof.
In accordance with another aspect of the present invention, there is provided
a method for preparing the oral complex composition, which comprises the steps of:
(1) preparing a soft capsule core comprising omega-3 fatty acid esters; (2) forming a
first coating layer which encases the soft capsule core and comprises a hydrophobic
coating material; and (3) forming a second coating layer on the first coating layer,
which comprises (i) rosuvastatin or a pharmaceutically acceptable salt thereof, and
(ii) PVA, PVA-PEG graft copolymer, or a mixture thereof, wherein the hydrophobic
coating material is selected from the group consisting of cellulose acetate, polyvinyl
acetate, ethyl cellulose, (meth)acrylic acid copolymers and a mixture thereof.
The term 'comprising' as used in this specification and claims means
'consisting at least in part of'. When interpreting statements in this specification
and claims which include the term 'comprising', other features besides the features
prefaced by this term in each statement can also be present. Related terms such as
'comprise' and 'comprised' are to be interpreted in similar manner.
In this specification where reference has been made to patent specifications,
other external documents, or other sources of information, this is generally for the
purpose of providing a context for discussing the features of the invention. Unless
specifically stated otherwise, reference to such external documents is not to be
construed as an admission that such documents, or such sources of information, in
any jurisdiction, are prior art, or form part of the common general knowledge in the
art.
In the description in this specification reference may be made to subject
matter that is not within the scope of the claims of the current application. That
subject matter should be readily identifiable by a person skilled in the art and may
assist in putting into practice the invention as defined in the claims of this
application.
BRIEF DESCRIPTION OF THE DRAWINGS
The above and other objects and features of the present invention will become
apparent from the following description of the invention, when taken in conjunction
with the accompanying drawings, which respectively show:
Fig. 1: the disintegration times of the capsules obtained in Comparative
Examples 1, 3 and Examples 1 to 7;
Fig. 2 : the disintegration times depending on the amount of ethyl cellulose
in the capsules obtained in Comparative Example 3 and Examples 1 to 7;
Fig. 3 : the changes in water content of the capsules obtained in
Comparative Examples 1, 3 and Examples 1 to 7; and
Fig. 4 : the changes in dissolution rates of rosuvastatin in the capsules
obtained in Comparative Examples 2, 4, 5 and Examples 8 to 12.
DETAILED DESCRIPTION OF THE INVENTION
The inventive oral complex composition is characterized by comprising: (a)
a soft capsule core comprising omega-3 fatty acid esters; (b) a first coating layer
which encases the soft capsule core and comprises a hydrophobic coating material;
and (c) a second coating layer deposited on the first coating layer, which comprises
the ingredients of (i) rosuvastatin or a pharmaceutically acceptable salt thereof, and
(ii) PVA, PVA-PEG graft copolymer, or a mixture thereof, wherein the hydrophobic
coating material is selected from the group consisting of cellulose acetate, polyvinyl
acetate, ethyl cellulose, (meth)acrylic acid copolymers and a mixture thereof.
Hereinafter, the components contained in the oral complex composition of
the present invention are described in detail.
(a) Soft capsule core
The soft capsule core of the complex composition according to the present
invention comprises omega-3 fatty acid esters as the first active pharmaceutical
ingredient.
In one embodiment of the present invention, the omega-3 fatty acid esters
may comprise ethyl esters of EPA and DHA in an amount of 80% by weight or more,
preferably at least 40% by weight of EPA ethyl ester of and at least 34% by weight
of DHA ethyl ester. Preferably, the omega-3 fatty acid esters may comprise ethyl
ester of omega-3 fatty acid in an amount of 90% by weight or more.
The amount of the omega-3 fatty acid esters present in the soft capsule core
may be 100 mg to 2,000 mg.
In a preferred embodiment of the present invention, the amount of the
omega-3 fatty acid esters may be 70% to 95% by weight, based on the total weight
of the soft capsule core, but not limited thereto.
Also, the soft capsule core can be prepared in a conventional manner for
manufacturing soft capsules by using typical materials for soft capsules, e.g.
gelatins.
(b) First coating layer
In the oral complex composition of the present invention, the first coating
layer comprises a hydrophobic coating material which encapsulates the soft capsule
core in order to prevent a change in water content inside the soft capsule core from
affecting the dissolution rate of rosuvastatin-containing second coating layer and
increase of related materials. When rosuvastatin is coated directly on the soft
capsule core containing omega-3 fatty acid ester, then the water content of the
capsule can affect the content of the rosuvastatin, reduce its dissolution rate and
increase its related materials. In the present invention, however, the first coating
layer comprising a hydrophobic coating material is employed in between the
omega-3 fatty acid ester-containing soft capsule core and the rosuvastatin-
containing second coating layer, minimizing the effect of water content as well as
other potential risks.
The hydrophobic coating material is selected from the group consisting of
cellulose acetate, polyvinyl acetate, ethyl cellulose, and (meth)acrylic acid
copolymers, i.e. Eudragit , preferably ethyl cellulose. The amount of the
hydrophobic coating material used may be, based on the total amount of the first
coating layer, 15% to 75% by weight, preferably 16% to 75% by weight, more
preferably 16% to 72% by weight. If the amount of the hydrophobic coating
material used is less than 15% by weight, the change in water content becomes
greater, causing deterioration of storage stability by reducing rosuvastatin content
and dissolution rate as well as increasing related materials.
The first coating layer may further comprise conventional coating materials
such as hydroxypropyl methyl cellulose (HPMC) and hydroxylpropyl cellulose
(HPC), which are generally used in the pharmaceutical field. In addition, the first
coating layer may further comprise other pharmaceutically acceptable additives
such as disintegrants, diluents, stabilizers, binders, and slip modifiers to the extent
they do not adversely affect the disintegration rate of the capsule.
The first coating layer may be prepared by dissolving or dispersing the
hydrophobic coating material in water, ethanol, or a mixture thereof, preferably in
the mixed solvent, to obtain a coating solution and then applying the solution onto
the surface of the soft capsule core.
The first coating layer may be coated on the soft capsule core in an amount of
2 parts by weight or more, preferably 4 to 10 parts by weight, based on 100 parts by
weight of the soft capsule core.
(c) Second coating layer
In the oral complex composition of the present invention, the second coating
layer comprises the ingredients of: (i) rosuvastatin or a pharmaceutically acceptable
salt thereof, as the second active pharmaceutical ingredient, and (ii) PVA, PVA-PEG
graft copolymer or a mixture thereof, as a coating material, which permits rapid
release of rosuvastatin when dissolved and also prevents delayed release of
rosuvastatin after being stored.
The second coating layer may be prepared by dissolving or dispersing said
ingredients (i) and (ii) in water, ethanol or a mixture thereof, preferably in the mixed
solvent, to obtain a coating solution, followed by applying the solution onto the
surface of the first coating layer.
The amount of the ingredient (i) employed in the second coating layer may be
1 mg to 50 mg, and the amount of the ingredient (ii) employed may be 25% to 85% by
weight, preferably 25% to 80% by weight, based on the total amount of the second
coating layer.
The second coating layer may further comprise HPMC, polyvinylpyrrolidone
(PVP), or a mixture thereof, and may also comprise other pharmaceutically acceptable
additives such as alkaline stabilizers, if necessary.
The second coating layer may be coated on the first coating layer in an amount
of 3 to 30 parts by weight, preferably 5 to 20 parts by weight, based on 100 parts by
weight of the soft capsule core.
The present invention also provides a method for preparing the oral complex
composition of the present invention, which comprises the steps of: (1) preparing a
soft capsule core comprising omega-3 fatty acid esters; (2) forming a first coating
layer which encases the soft capsule core and comprises a hydrophobic coating
material; and (3) forming a second coating layer on the first coating layer, which
comprises the ingredients of (i) rosuvastatin or a pharmaceutically acceptable salt
thereof, and (ii) PVA, PVA-PEG graft copolymer, or a mixture thereof, wherein the
hydrophobic coating material is selected from the group consisting of cellulose
acetate, polyvinyl acetate, ethyl cellulose, (meth)acrylic acid copolymers and a
mixture thereof.
Specifically, the method for preparing the oral complex composition of the
present invention may comprise the following steps of: (1) preparing a soft capsule
core containing omega-3 fatty acid esters in a conventional manner for
manufacturing soft capsules; (2) forming a first coating layer encasing the soft
capsule core by dissolving a hydrophobic coating material in a suitable solvent for
barrier coating, e.g. in a mixture of ethanol and water, applying the coating solution
onto the soft capsule core, and then drying the solution; and (3) forming a second
coating layer on the first coating layer by dissolving the ingredients (i) and (ii) with
alkaline stabilizers and/or other pharmaceutically acceptable additives in a suitable
solvent, e.g. in a mixture of ethanol and water, applying the coating solution onto
the surface of the first coating layer, and then drying the solution.
The complex composition of the present invention can be formulated into a
capsule form, and can be administered orally.
The oral complex composition of the present invention can show a
rosuvastatin or its pharmaceutically acceptable salt releasing rate of 80% or more in
0.05M citrate buffer within 30 min, preferably within 10 min; and no delayed release
after storage duration of 6 months at 40 C under 75% relative humidity (RH). The
above test results indicate good dissolution rate and storage stability and hence, it is
possible to use in composite forms.
The oral complex composition of the present invention contains both omega-3
fatty acid esters and rosuvastatin, as active pharmaceutical ingredients, which can
raise serum HDL level while reducing both LDL and TG levels. Thus, it can be used
for effectively preventing or treating hypertriglyceridemia, hypercholesteremia,
coronary arterial heart diseases (CAHD), dyslipidemia, and increased serum LDL
cholesterol levels, and it can be used for preventing or treating cardiovascular diseases
as well.
EXAMPLES
The following Examples are provided to illustrate preferred embodiments of
the present invention, and are not intended to limit the scope of the present invention.
Preparation of soft capsule core
Comparative Example 1: Soft capsule comprising omega-3 fatty acid ester
A soft capsule was prepared with 1,000 mg of omega-3 fatty acid ester oils by
using a conventional method for manufacturing soft gelatin capsule.
Comparative Example 2: Soft capsule comprising omega-3 fatty acid esters and
rosuvastatin
A soft capsule was prepared by repeating the procedures of Comparative
Example 1, except for employing a homogeneous mixture of 1,000 mg of omega-3
fatty acid ester oils and 10 mg of rosuvastatin.
First coating
Comparative Example 3: Omega-3 fatty acid ester soft capsule with
conventional barrier coating
In accordance with the ingredients described in Table 1, hydroxypropyl methyl
cellulose (HPMC 2910, Shinetsu Co. Ltd., Japan), polyethylene glycol (PEG 6000,
Sanyo Chemical Industries, Ltd., Japan) and polyvinylpyrrolidone (PVP K-30, BASF
SE, Germany) were added to a mixture of ethanol and water, and then mixed to obtain
a coating solution.
The coating solution was coated onto the surface of the soft capsule core
prepared in Comparative Example 1 by using a coater (SFC-30, SEJONG Co., Ltd.),
wherein the supply air temperature was 45 C and the product temperature was
adjusted to 30 C. The product was dried for 30 minutes to remove residual solvent
so that a soft capsule with a barrier coating was obtained.
Examples 1 to 7: Omega-3 fatty acid ester soft capsule with hydrophobic
barrier coating
In accordance with the ingredients described in Table 1, a soft capsule with a
hydrophobic barrier coating was prepared by repeating the procedures of Comparative
Example 3, except for adding ethyl cellulose (Dow Chemical Company, US) as a
hydrophobic coating material.
The compositions of soft capsules and barrier coatings are summarized in
Table 1.
Table 1
Comp.
Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7
Ex. 3
Comp. Comp. Comp. Comp. Comp. Comp. Comp. Comp.
Soft capsule core
Ex. 1 Ex. 1 Ex. 1 Ex. 1 Ex. 1 Ex. 1 Ex. 1 Ex. 1
HPMC 2910
80 72 64 48 32 16 8 0
(% by weight)
PEG 6000
10 10 10 10 10 10 10
(% by weight)
PVP K-30
10 10 10 10 10 10 10
(% by weight)
Ethyl cellulose
0 8 16 32 48 64 72 80
(% by weight)
Ethanol
(1040) (1040) (1040) (1040) (1040) (1040) (1040) (1040)
(mg)
Distilled water
(440) (440) (440) (440) (440) (440) (440) (440)
(mg)
Total amount
of first coating layer 100 100 100 100 100 100 100 100
(% by weight)
EC content
in first coating layer 0 8.0 16.0 32.0 48.0 64.0 72.0 80.0
(% by weight)
Second coating
Comparative Examples 4 to 6: Omega-3 fatty acid ester soft capsule with
rosuvastatin coating
Rosuvastatin calcium salt, hydroxypropyl methylcellulose (HPMC 2910,
Shinetsu Co., Ltd., Japan), polyethylene glycol (PEG 6000, Sanyo Chemical
Industries, Ltd., Japan) and PVA (Kurary Co., Ltd., Japan) were added to a mixture of
ethanol and water, and then mixed to obtain a coating solution.
The coating solution was coated onto the surface of the omega-3 fatty acid
ester soft capsules obtained in Comparative Examples 1, 3 and Example 5,
respectively, by using a coater (SFC-3, SEJONG Co., Ltd.), wherein the supply air
temperature was 45 C and the product temperature was adjusted to 30 C. The
products were dried for 30 minutes to remove residual solvent so that complex
compositions were obtained.
Examples 8 to 12: Omega-3 fatty acid ester soft capsule with rosuvastatin
coating
Rosuvastatin calcium, hydroxypropyl methylcellulose (HPMC 2910, Shinetsu
Co., Ltd., Japan), and polyethylene glycol (PEG 6000, Sanyo Chemical Industries,
Ltd., Japan) were added to a mixture of ethanol and water. Further, PVA (Kurary Co.,
Ltd., Japan) or PVA-PEG graft copolymer (Kollicoat IR, BASF SE, Germany) was
added thereto and then mixed to obtain a coating solution.
The coating solution was coated onto the surface of the omega-3 fatty acid
ester soft capsule obtained in Example 5 by using a coater (SFC-3, SEJONG Co.,
Ltd.), wherein the supply air temperature was 45 C and the product temperature was
adjusted to 30 C. The products were dried for 30 minutes to remove residual solvent
so that complex compositions were obtained.
The compositions of second coating layers are summarized in Table 2.
Table 2
Comp. Comp. Comp.
Ex. 8 Ex. 9 Ex. 10 Ex. 11 Ex. 12
Ex.4 Ex. 5 Ex.6
Comp. Comp.
Soft capsule core
Ex. 5 Ex. 5 Ex. 5 Ex. 5 Ex. 5 Ex. 5
(with first coating) Ex. 1 Ex. 3
Rosuvastatin calcium
.4 10.4 10.4 10.4 10.4 10.4 10.4 10.4
(mg)
HPMC 2910(P645)
10 54 36 26 10 0 0
(mg)
PEG 6000
.6 5.6 5.6 5.6 5.6 5.6 5.6 5.6
(mg)
44 44 0 18 28 44 54 0
(mg)
Kollicoat IR
0 0 0 0 0 0 0 54
(mg)
Ethanol
(644) (644) (644) (644) (644) (644) (460) (460)
(mg)
Distilled water
(276) (276) (276) (276) (276) (276) (460) (460)
(mg)
Total weight of
70 70 70 70 70 70 70 70
second coating layer (mg)
PVA or Kollicoat content
in second coating layer 62.9 62.9 0.0 25.7 40.0 62.9 77.1 77.1
(% by weight)
PVA/(HPMC+PVA)
81.5 81.5 0.0 33.3 51.9 81.5 100.0 100.0
(% by weight)
EVALUATION
Test 1: Disintegration test of soft capsules with barrier coating
A disintegration test was performed on the soft capsule prepared in
Comparative Example 1, the soft capsule with barrier coating prepared in
Comparative Example 3 and the soft capsules with hydrophobic coating prepared in
Examples 1 to 7, according to the method described in the general test method of the
Korean Pharmacopoeia. The results are shown in Figs. 1 and 2.
As shown in Figs. 1 and 2, the soft capsule prepared in Comparative Examples
1 and 3 showed satisfying results in disintegration time of less than 20 minutes
according to the standards of the Korean Pharmacopoeia.
Satisfactory results were also obtained from the soft capsules prepared in
Examples 1 to 7. The soft capsule prepared in Example 7, however, showed a delay
in disintegration time due to added hydrophobic excipient, i.e. ethyl cellulose, in an
amount exceeded 75% by weigh for preventing a change in water content.
Therefore, it can be found that the preferable amount of the hydrophobic
coating material in the first coating layer is 75% by weight or less, more preferably
72% by weight or less, based on the weight of the first coating layer, in order to satisfy
the standards of the disintegration test.
Test 2: Water absorption rate of soft capsules with barrier coating
The capsules prepared in Comparative Examples 1 and 3, and Examples 1 to 7
were dried for 6 days at 30% RH, and the water content of gelatin capsule coating was
measured. The water content change was observed by measuring weight loss on
drying according to the method as described in the general test method of the Korean
Pharmacopoeia, wherein the measurement was taken at 90 C in an equilibrium state,
where weight of the sample no longer changes, and then the results were recorded as
the initial water contents.
The samples were also tested for water penetration prevention effect by
repeating the measuring method after 24 hrs exposure at 25 C/60% RH and the results
were recorded as the final water content, which are shown in Fig. 3.
As shown in Fig. 3, the soft capsules with no coating and conventional barrier
coating as prepared in Comparative Example 1 and 3, respectively, showed a relatively
great change in water content, i.e., 6% or more, as compared with the initial water
content.
However, the soft capsules with hydrophobic coating containing ethyl
cellulose prepared in Examples 1 to 7 resulted a slight change in water content. In
particular, the soft capsules with hydrophobic coating containing ethyl cellulose in an
amount of 16% or more, resulted only 3% change or less in water content, which
shows the employment of ethyl cellulose significantly improves stability of the
composition by reducing the water absorption by 50% or greater in comparison to
coatings without ethyl cellulose. Further, it can be found that the preferable amount
of the hydrophobic coating material used in the first coating layer is 15% to 75% by
weight, more preferably 16% to 75% by weight, most preferably 16% to 72% by
weight, based on the weight of the first coating layer.
Test 3: Dissolution rate of rosuvastatin
A dissolution test of rosuvastatin was performed on Crestor (AstraZeneca plc,
UK) as a control drug, and the complex compositions prepared in Comparative
Examples 2, 4 to 6, and Examples 8 to 12.
The test was conducted, based on paddle method in the Korean Pharmacopoeia,
at 50 rpm by using dissolution medium of 900 mL of 0.05 M citric acid buffer and the
mediums were collected after 10 minutes, then their initial dissolution rates were
measured. Also, the samples were stored in sealed HDPE bottles for six months
under accelerated storage condition (40 C/75% RH) and their dissolution rates were
measured. The results are shown in Fig. 4.
As shown in Fig. 4, the complex composition prepared in Comparative
Example 2 had poor dissolution rate of rosuvastatin from the initial measurement.
The complex compositions prepared in Comparative Examples 4 and 5 had decent
initial dissolution rates of 80% or greater, but the rates deteriorated after six months of
accelerated storage. Also, the complex composition prepared in Comparative
Example 6, which did not contain any PVA or PVA-PEG graft copolymer, had poor
dissolution rate in comparison to the complex compositions of Examples 8 to 12.
On the other hand, the complex compositions prepared in Examples 8 to 12,
wherein the first coating layer contains hydrophobic coating material, i.e., ethyl
cellulose, in an amount of 16% to 72% by weight and the second coating layer
contains PVA or PVA-PEG graft copolymer with rosuvastatin, had initial dissolution
rates of 80% or greater. Also, the complex compositions exhibited little or no
delayed release even after 6 months of accelerated storage, showing pharmaceutically
stable dissolution rates. Accordingly, it can be found from the results that the
complex composition of the present invention has in vivo efficacy.
While the invention has been described with respect to the above specific
embodiments, it should be recognized that various modifications and changes may be
made to the invention by those skilled in the art which also fall within the scope of the
invention as defined by the appended claims.
Claims (10)
1. An oral complex composition, which comprises: (a) a soft capsule core comprising omega-3 fatty acid esters; (b) a first coating layer which encases the soft capsule core and comprises a hydrophobic coating material; and (c) a second coating layer deposited on the first coating layer, which comprises: (i) rosuvastatin or a pharmaceutically acceptable salt thereof, and (ii) polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer or a mixture thereof, wherein the hydrophobic coating material is selected from the group consisting of cellulose acetate, polyvinyl acetate, ethyl cellulose, (meth)acrylic acid copolymers and a mixture thereof.
2. The oral complex composition of claim 1, wherein the omega-3 fatty acid esters comprise ethyl esters of eicosapentaenoic acid and docosahexaenoic acid in an amount of 80% by weight or more.
3. The oral complex composition of claim 1 or claim 2, wherein the omega-3 fatty acid esters are present in an amount ranging from 100 mg to 2,000 mg.
4. The oral complex composition of any one of claims 1-3, wherein the hydrophobic coating material is present in an amount ranging from 15% to 75% by weight based on the total amount of the first coating layer.
5. The oral complex composition of any one of claims 1-4, wherein rosuvastatin or the pharmaceutically acceptable salt thereof is present in an amount ranging from 1 mg to 50 mg.
6. The oral complex composition of any one of claims 1-5, wherein polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer or the mixture thereof is present in an amount ranging from 25% to 85% by weight based on the total amount of the second coating layer.
7. The oral complex composition of any one of claims 1-6, which shows a rosuvastatin or its pharmaceutically acceptable salt releasing rate of 80% or more in 0.05 M citrate buffer within 10 min.
8. A method for preparing the oral complex composition of claim 1, which comprises the steps of: (1) preparing a soft capsule core comprising omega-3 fatty acid esters; (2) forming a first coating layer which encases the soft capsule core and comprises a hydrophobic coating material; and (3) forming a second coating layer on the first coating layer, which comprises: (i) rosuvastatin or a pharmaceutically acceptable salt thereof, and (ii) polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer or a mixture thereof. the hydrophobic coating material is selected from the group consisting of cellulose acetate, polyvinyl acetate, ethyl cellulose, (meth)acrylic acid copolymers and a mixture thereof.
9. An oral complex composition of claim 1, substantially as herein described with reference to any example thereof.
10. A method of claim 9, substantially as herein described with reference to any example thereof. 25.0 20.0 15.0 10.0 Comp. Comp. Ex.1 Ex.2 Ex.3 Ex.4 Ex.5 Ex.6 Ex.7 Ex.1 Ex.3 25.0 20.0 15.0 10.0 0.0% 20.0% 40.0% 60.0% 80.0% Content of ethyl cellulose Disintegration time (min) Disintegration time (min) 16.0 Initial After 24 hrs exposure 12.0 Comp. Comp. Ex.1 Ex.2 Ex.3 Ex.4 Ex.5 Ex.6 Ex.7 Ex.1 Ex.3 Initial After 6 months of accelerated storage 100.0 80.0 60.0 40.0 Comp. Comp. Comp.Comp. Crestor Ex.8 Ex.9 Ex.10 Ex.11 Ex.12 Ex.2 Ex.4 Ex.5 Ex.6 Dissolution rate (%) Water content (%)
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR20110025940 | 2011-03-23 | ||
KR10-2011-0025940 | 2011-03-23 | ||
KR10-2011-0041168 | 2011-04-29 | ||
KR1020110041168A KR101310710B1 (en) | 2011-03-23 | 2011-04-29 | Oral complex composition comprising omega-3 fatty acid ester and hmg-coa reductase inhibitor |
PCT/KR2012/002134 WO2012128587A2 (en) | 2011-03-23 | 2012-03-23 | Oral complex composition comprising omega-3 fatty acid ester and hmg-coa reductase inhibitor |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ616907A NZ616907A (en) | 2016-02-26 |
NZ616907B2 true NZ616907B2 (en) | 2016-05-27 |
Family
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