EP3280399A1 - Pharmaceutical composition comprising ivabradine oxalate - Google Patents
Pharmaceutical composition comprising ivabradine oxalateInfo
- Publication number
- EP3280399A1 EP3280399A1 EP16717586.8A EP16717586A EP3280399A1 EP 3280399 A1 EP3280399 A1 EP 3280399A1 EP 16717586 A EP16717586 A EP 16717586A EP 3280399 A1 EP3280399 A1 EP 3280399A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- pharmaceutical composition
- antioxidant
- tablet
- composition according
- ivabradine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
Definitions
- composition comprising Ivabradine Oxalate
- the present invention relates to an immediate-release solid pharmaceutical composition for oral administration containing ivabradine oxalate, and furthermore, to the use of an antioxidant for preventing chemical degradation of ivabradine oxalate in a solid pharmaceutical composition.
- Ivabradine is a specific heart rate lowering agent, acting by reducing the rate of pacemaker activity in the sinoatrial node.
- the drug is marketed under the tradename Procoralan* in the form of film-coated tablets, which contain 5 or 7.S mg ivabradine as hydrochloride salt
- Procoralan* is approved for the treatment of coronary heart diseases and chronic heart failure.
- the tablet core contains lactose monohydrate, magnesium stearate, maize starch, maltodextrin and highly dispersed silicon dioxide.
- the tablets are chemically stable under ICH conditions (40 °C/75 % RH for six months, 30 °C/60 % RH for twelve months and 30 °C/70 % RH for 36 months).
- Ivabradine hydrochloride shows extended polymorphism.
- US 7,176,197 discloses the crystalline form a of ivabradine hydrochloride, which is obtained by crystallization from toluene/1 -methyl-2-pyrrolidone.
- US 7,361,649 describes the synthesis of crystalline form ⁇ of ivabradine hydrochloride by crystallization from water. Form ⁇ is a tetrahydrate that can be dehydrated as described in US 7,361,652 to afford crystalline form ⁇ d.
- US 7,361,650 describes the synthesis of the ⁇ -form by precipitation from 2-ethoxyethanol; form ⁇ is a monohydrate. After drying the monohydrate as described in US 7,361,651 the dehydrated form ⁇ d is obtained.
- US 7,358,240 describes the synthesis of the 5-form of ivabradine hydrochloride by crystallization from acetonitrile. This form may be converted into the crystalline form ⁇ 5d by tempering at 85 °C, as reported in US 7,384,932.
- WO 2013/102919 discloses the crystalline forms II and III of ivabradine hydrochloride, which do not convert into another crystalline form, in particular into form ⁇ , ⁇ ⁇ ⁇ after storage for six months at 25 °C/60 % RH or 40 °C/75 % RH.
- the inventors found that the crystalline forms II and III are physically unstable (low polymorphic stability) at elevated temperatures.
- the crystalline form II converts into the crystalline form ⁇ when stored at 50 °C/75 % RH.
- ivabradine hydrochloride may be molecularly dispersed in a pharmaceutical excipient to form a solid solution as described in WO 2011/157722.
- the solid solution can be prepared by spray-drying or melt-extrusion. It was an objective of the present invention to provide an immediate-release solid pharmaceutical composition for oral administration containing ivabradine in a physically and chemically stable form. This objective is attained by the subject matter as defined in the claims.
- the immediate-release solid pharmaceutical composition for oral administration according to the present invention contains ivabradine oxalate in crystalline form.
- WO 2008/146308 describes the synthesis of a specific crystalline form of ivabradine oxalate, which is preferably used in the present invention and characterized by an XRD-pattern having peaks at 4.3, 7.2, 8.1, 8.5, 9.4, 11.0, 13.7, 14.5, 15.1, 16.1, 16.5, 17.4 and 18.4 ⁇ 0.2 °2 ⁇ , whereby the XRD is measured with Cu radiation.
- ivabradine oxalate the forms I-III
- WO 2011/157720 crystalline forms of ivabradine oxalate, the forms I-III, are described in WO 2011/157720.
- This application relates to a modified-release pharmaceutical composition that preferably contains ivabradine adipate in combination with a water- insoluble and a water-soluble excipient The water-insoluble and water-soluble excipients form a hydrophilic matrix, which releases the active substance in a modified manner.
- An immediate-release pharmaceutical formulation containing ivabradine adipate is disclosed in WO 2011/157721.
- this formulation requires the presence of an adhesion enhancer in order to reduce the separation tendency of mixtures containing ivabradine adipate and pharmaceutical excipients and to stabilize the polymorphic form of the drug in compacted or compressed form.
- the immediate-release pharmaceutical composition of the present invention does not require the presence of such an adhesion enhancer.
- no polymorphic transformation into the amorphous form or another crystalline form was observed after storage at 50 °C/75 % RH for three months.
- chemical degradation products have been detected after storage at 50 °C/75 % RH for three months.
- the chemical stability of ivabradine oxalate in the pharmaceutical composition is improved in the presence of an antioxidant
- the pharmaceutical composition according to the present invention contains an antioxidant.
- the antioxidant is selected from water-soluble antioxidants, oil-soluble antioxidants, metal chelating agents, and mixtures thereof.
- an oil-soluble antioxidant is preferred, optionally in combination with sodium metabisulfite or citric acid.
- water-soluble antioxidants include ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite and sodium sulfite;
- oil-soluble antioxidants include ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate and ⁇ -tocopherol;
- metal chelating agents include citric acid, tartaric acid and ethylenediamine tetraacetic acid (EDTA).
- the pharmaceutical composition of the present invention preferably contains BHT, BHA or propyl gallate.
- the pharmaceutical composition according to the present invention is preferably an optionally film-coated tablet.
- This tablet may be prepared using wet granulation, dry granulation or direct compression, whereby the dry granulation technique is preferred.
- the tablet or the tablet core comprises ivabradine oxalate, a diluent, a disintegrant, an antioxidant, a lubricant and optionally a glidant
- the tablet or tablet core does not contain any other pharmaceutical excipients than those mentioned above, i.e. it consists of ivabradine oxalate, a diluent, a disintegrant, an antioxidant, a lubricant and optionally a glidant.
- diluents include lactose monohydrate, anhydrous lactose and microcrystalline cellulose; examples of disintegrants include sodium starch glycolate, crospovidone and croscarmellose sodium.
- examples of lubricants include magnesium stearate, sodium stearyl fumarate and hydro genated vegetable oil, and suitable glidants are silicon dioxide and talc.
- the tablet contains ivabradine oxalate in the crystalline form disclosed in WO 2008/146308, anhydrous lactose, croscarmellose sodium, silicon dioxide, and magnesium stearate, and is optionally film-coated.
- the tablet or tablet core according to the present invention is preferably prepared using dry granulation comprising the method steps: i) subjecting a mixture containing ivabradine oxalate, a diluent, a disintegrant, an antioxidant, and optionally a glidant and/or a lubricant, to dry granulation, ii) mixing the granulate obtained in step (i) with a lubricant, iii) subjecting the mixture obtained in step (ii) to compression to obtain a tablet, and optionally, iv) subjecting the tablet obtained in (iii) to film-coating.
- direct compression is a suitable technique for preparing the tablet of the present invention.
- An immediate-release solid pharmaceutical composition according to the present invention is a product that releases not less than 80 % of the amount of ivabradine oxalate within 20 minutes, preferably within 15 minutes, in the following media: pH 1.2, pH 4.0 and pH 6.8 (cf. EMA guideline on test procedures and acceptance criteria for new veterinary drug substances and new medicinal products dated November 15, 2005).
- Thc present invention further relates to the use of an antioxidant, preferably selected from BHT, BHA and propyl gallate, for preventing chemical degradation of ivabradine oxalate in a solid pharmaceutical composition.
- the stability data was obtained from samples stored at 50 °C/75 % RH for
- the tablet was prepared by direct compression. Results: Polymorphic conversion was observed in samples stored at 50 °C/75 % RH for three months. The tablet contained the form ⁇ of ivabradine hydrochloride as contaminant.
- Example 1
- the tablet was prepared by dry granulation.
- Results The drug is physically and chemically stable in the tablet.
- the tablet was prepared by dry granulation. Results: The drug is physically stable, but chemically unstable in the tablet.
- the tablets were prepared by dry granulation.
- Results The drug is physically and chemically stable in the tablet.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to an immediate-release solid pharmaceutical composition for oral administration containing ivabradine oxalate, and furthermore, to the use of an antioxidant for preventing chemical degradation of ivabradine oxalate in a solid pharmaceutical composition.
Description
Alfred E. Tiefenbacher (GmbH & Co. KG)
Van-der-Smissen-Strasse 1, 22767 Hamburg, Germany
Hexal AG
Industriestrasse 35, 83607 Holzkirchen
Pharmaceutical Composition comprising Ivabradine Oxalate
The present invention relates to an immediate-release solid pharmaceutical composition for oral administration containing ivabradine oxalate, and furthermore, to the use of an antioxidant for preventing chemical degradation of ivabradine oxalate in a solid pharmaceutical composition. Ivabradine is a specific heart rate lowering agent, acting by reducing the rate of pacemaker activity in the sinoatrial node. The drug is marketed under the tradename Procoralan* in the form of film-coated tablets, which contain 5 or 7.S mg ivabradine as hydrochloride salt Procoralan* is approved for the treatment of coronary heart diseases and chronic heart failure. It is an immediate-release tablet prepared by wet granulation, whereby the tablet core contains lactose monohydrate, magnesium stearate, maize starch, maltodextrin and highly dispersed silicon dioxide. According to the EPAR scientific discussion concerning Procoralan® (EMEA 2005), the tablets are chemically stable under ICH conditions (40 °C/75 % RH for six months, 30 °C/60 % RH for twelve months and 30 °C/70 % RH for 36 months).
Ivabradine hydrochloride shows extended polymorphism. US 7,176,197 discloses the crystalline form a of ivabradine hydrochloride, which is obtained by crystallization from toluene/1 -methyl-2-pyrrolidone. US 7,361,649 describes the synthesis of crystalline form β of ivabradine hydrochloride by crystallization from water. Form β
is a tetrahydrate that can be dehydrated as described in US 7,361,652 to afford crystalline form βd. US 7,361,650 describes the synthesis of the γ-form by precipitation from 2-ethoxyethanol; form γ is a monohydrate. After drying the monohydrate as described in US 7,361,651 the dehydrated form γd is obtained. US 7,358,240 describes the synthesis of the 5-form of ivabradine hydrochloride by crystallization from acetonitrile. This form may be converted into the crystalline form <5d by tempering at 85 °C, as reported in US 7,384,932.
According to US 7,358,240 and US 7,384,932 the forms S and <5d are obtained by crystallization from acetonitrile, which is a potentially harmful solvent WO 2013/017582 discloses an alternative process for preparing the forms ί and <¾, in which an ivabradine hydrochloride acetonate was stored at 45 % RH and ambient temperature for 72 h in order to obtain form δ, or in which the acetonate was dried at reduced pressure and 70 °C for 14 h in order to obtain form δL
WO 2013/102919 discloses the crystalline forms II and III of ivabradine hydrochloride, which do not convert into another crystalline form, in particular into form β, δ οτ γ after storage for six months at 25 °C/60 % RH or 40 °C/75 % RH. However, the inventors found that the crystalline forms II and III are physically unstable (low polymorphic stability) at elevated temperatures. The crystalline form II converts into the crystalline form γ when stored at 50 °C/75 % RH.
In order to avoid the polymorphic stability problems of ivabradine hydrochloride, WO 2008/146308 suggests the use of amorphous ivabradine hydrochloride. Alternatively, ivabradine hydrochloride may be molecularly dispersed in a pharmaceutical excipient to form a solid solution as described in WO 2011/157722. The solid solution can be prepared by spray-drying or melt-extrusion.
It was an objective of the present invention to provide an immediate-release solid pharmaceutical composition for oral administration containing ivabradine in a physically and chemically stable form. This objective is attained by the subject matter as defined in the claims.
It has been found that ivabradine oxalate is physically stable compared to its hydrochloride salt. Preferably, the immediate-release solid pharmaceutical composition for oral administration according to the present invention contains ivabradine oxalate in crystalline form. WO 2008/146308 describes the synthesis of a specific crystalline form of ivabradine oxalate, which is preferably used in the present invention and characterized by an XRD-pattern having peaks at 4.3, 7.2, 8.1, 8.5, 9.4, 11.0, 13.7, 14.5, 15.1, 16.1, 16.5, 17.4 and 18.4 ± 0.2 °2Θ, whereby the XRD is measured with Cu radiation. Other crystalline forms of ivabradine oxalate, the forms I-III, are described in WO 2011/157720. This application relates to a modified-release pharmaceutical composition that preferably contains ivabradine adipate in combination with a water- insoluble and a water-soluble excipient The water-insoluble and water-soluble excipients form a hydrophilic matrix, which releases the active substance in a modified manner. An immediate-release pharmaceutical formulation containing ivabradine adipate is disclosed in WO 2011/157721. It is stated that this formulation requires the presence of an adhesion enhancer in order to reduce the separation tendency of mixtures containing ivabradine adipate and pharmaceutical excipients and to stabilize the polymorphic form of the drug in compacted or compressed form. The immediate-release pharmaceutical composition of the present invention does not require the presence of such an adhesion enhancer. Moreover, no polymorphic transformation into the amorphous form or another crystalline form was observed after storage at 50 °C/75 % RH for three months. However, chemical degradation products have been detected after storage at 50 °C/75 % RH for three months. The chemical stability of ivabradine oxalate in the pharmaceutical composition is
improved in the presence of an antioxidant Hence, the pharmaceutical composition according to the present invention contains an antioxidant. Preferably, the antioxidant is selected from water-soluble antioxidants, oil-soluble antioxidants, metal chelating agents, and mixtures thereof. Among these antioxidants, an oil-soluble antioxidant is preferred, optionally in combination with sodium metabisulfite or citric acid.
Examples of water-soluble antioxidants include ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite and sodium sulfite; examples of oil-soluble antioxidants include ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate and α-tocopherol; examples of metal chelating agents include citric acid, tartaric acid and ethylenediamine tetraacetic acid (EDTA). The pharmaceutical composition of the present invention preferably contains BHT, BHA or propyl gallate.
The pharmaceutical composition according to the present invention is preferably an optionally film-coated tablet. This tablet may be prepared using wet granulation, dry granulation or direct compression, whereby the dry granulation technique is preferred. The tablet or the tablet core comprises ivabradine oxalate, a diluent, a disintegrant, an antioxidant, a lubricant and optionally a glidant According to a preferred embodiment of the present invention, the tablet or tablet core does not contain any other pharmaceutical excipients than those mentioned above, i.e. it consists of ivabradine oxalate, a diluent, a disintegrant, an antioxidant, a lubricant and optionally a glidant.
Examples of diluents include lactose monohydrate, anhydrous lactose and microcrystalline cellulose; examples of disintegrants include sodium starch glycolate, crospovidone and croscarmellose sodium. Examples of lubricants include magnesium stearate, sodium stearyl fumarate and hydro genated vegetable oil, and suitable glidants are silicon dioxide and talc.
According to a preferred embodiment of the present invention, the tablet contains ivabradine oxalate in the crystalline form disclosed in WO 2008/146308, anhydrous lactose, croscarmellose sodium, silicon dioxide, and magnesium stearate, and is optionally film-coated.
The tablet or tablet core according to the present invention is preferably prepared using dry granulation comprising the method steps: i) subjecting a mixture containing ivabradine oxalate, a diluent, a disintegrant, an antioxidant, and optionally a glidant and/or a lubricant, to dry granulation, ii) mixing the granulate obtained in step (i) with a lubricant, iii) subjecting the mixture obtained in step (ii) to compression to obtain a tablet, and optionally, iv) subjecting the tablet obtained in (iii) to film-coating. In principle, direct compression is a suitable technique for preparing the tablet of the present invention. However, if the mixture intended for direct compression tends to separate, so that a uniform distribution of the drug in the mixture cannot be achieved, dry granulation may be used in order to improve content uniformity. An immediate-release solid pharmaceutical composition according to the present invention is a product that releases not less than 80 % of the amount of ivabradine oxalate within 20 minutes, preferably within 15 minutes, in the following media: pH 1.2, pH 4.0 and pH 6.8 (cf. EMA guideline on test procedures and acceptance criteria for new veterinary drug substances and new medicinal products dated November 15, 2005).
Thc present invention further relates to the use of an antioxidant, preferably selected from BHT, BHA and propyl gallate, for preventing chemical degradation of ivabradine oxalate in a solid pharmaceutical composition.
The invention is further illustrated by reference to the following examples. Examples Ivabradine oxalate in the crystalline form disclosed in WO 2008/146308 was used in the examples and comparative examples.
The stability data was obtained from samples stored at 50 °C/75 % RH for
1-3 months in pharmaceutically acceptable and commercially available aluminium- aluminium blisters.
Comparative Example 1
Process: The tablet was prepared by direct compression.
Results: Polymorphic conversion was observed in samples stored at 50 °C/75 % RH for three months. The tablet contained the form γ of ivabradine hydrochloride as contaminant. Example 1
Process: The tablet was prepared by dry granulation.
Results: The drug is physically and chemically stable in the tablet.
Comparative Example 2
Process: The tablet was prepared by dry granulation.
Results: The drug is physically stable, but chemically unstable in the tablet.
Examples 2A-M
Table 1.
Process: The tablets were prepared by dry granulation.
Results: Stability data of samples stored at 50°C/75 % RH for one month showed that the antioxidants improved the chemical stability of the ivabradine oxalate contained in the tablet. Example 3
Process: The tablets were prepared by dry granulation.
Results: The drug is physically and chemically stable in the tablet.
Claims
1. Immediate-release solid pharmaceutical composition for oral administration containing ivabradine oxalate and an antioxidant
2. The pharmaceutical composition according to claim 1, wherein the ivabradine oxalate is in crystalline form. 3. The pharmaceutical composition according to claim 2, wherein the ivabradine oxalate is characterized by an XRD pattern having peaks at 4.
3, 7.2, 8.1, 8.5, 9.4, 11.0, 13.7, 14.5, 15.1, 16.1, 16.5, 17.4 and 18.4 ± 0.2 °2Θ.
4. The pharmaceutical composition according to any one of the preceding claims, wherein the antioxidant is selected from water-soluble antioxidants, oil-soluble antioxidants, metal chelating agents, and mixtures thereof.
5. The pharmaceutical composition according to claim 4, wherein the water-soluble antioxidant is selected from ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite and sodium sulfite, wherein the oil-soluble antioxidant is selected from ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate and alpha-tocopherol, and wherein the metal chelating agent is selected from citric acid, tartaric acid and ethylenediamine tetraacetic acid (EDTA).
6. The pharmaceutical composition according to claim 5, wherein the antioxidant is selected from BHT, BHA and propyl gallate.
7. The pharmaceutical composition according to any one of the preceding claims, wherein the composition is an optionally film-coated tablet
8. The pharmaceutical composition according to claim 7, wherein the tablet or the tablet core comprises ivabradine oxalate, a diluent, a disintegrant, an antioxidant, a lubricant and optionally a glidant.
9. The pharmaceutical composition according to claim 8, wherein the tablet or the tablet core consists of ivabradine oxalate, a diluent, a disintegrant, an antioxidant, a lubricant and optionally a glidant
10. Process for preparing an optionally film-coated tablet according to claim 8 or 9, comprising the method steps: i) subjecting a mixture containing ivabradine oxalate, a diluent, a disintegrant, an antioxidant, and optionally a glidant and/or a lubricant, to dry granulation,
ii) mixing the granulate obtained in step (i) with a lubricant,
iii) subjecting the mixture obtained in step (ii) to compression to obtain a tablet, and optionally,
iv) subjecting the tablet obtained in step (iii) to film-coating.
11. Use of an antioxidant for preventing chemical degradation of ivabradine oxalate in a solid pharmaceutical composition.
12. The use according to claim 11, wherein the antioxidant is selected from BHT, BHA and propyl gallate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1006DE2015 | 2015-04-10 | ||
| PCT/EP2016/057652 WO2016162437A1 (en) | 2015-04-10 | 2016-04-07 | Pharmaceutical composition comprising ivabradine oxalate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP3280399A1 true EP3280399A1 (en) | 2018-02-14 |
Family
ID=55802344
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP16717586.8A Withdrawn EP3280399A1 (en) | 2015-04-10 | 2016-04-07 | Pharmaceutical composition comprising ivabradine oxalate |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP3280399A1 (en) |
| WO (1) | WO2016162437A1 (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011157721A2 (en) * | 2010-06-14 | 2011-12-22 | Ratiopharm Gmbh | Ivabradine-containing pharmaceutical composition |
| EP3025705B8 (en) * | 2014-11-25 | 2018-11-28 | Sanofi Ilaç Sanayi ve Ticaret Anonim Sirketi | Stable ivabradine formulations |
-
2016
- 2016-04-07 EP EP16717586.8A patent/EP3280399A1/en not_active Withdrawn
- 2016-04-07 WO PCT/EP2016/057652 patent/WO2016162437A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO2016162437A1 (en) | 2016-10-13 |
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