EP3082772A1 - Pharmaceutical composition comprising amorphous ivabradine - Google Patents
Pharmaceutical composition comprising amorphous ivabradineInfo
- Publication number
- EP3082772A1 EP3082772A1 EP14815382.8A EP14815382A EP3082772A1 EP 3082772 A1 EP3082772 A1 EP 3082772A1 EP 14815382 A EP14815382 A EP 14815382A EP 3082772 A1 EP3082772 A1 EP 3082772A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- pharmaceutically acceptable
- ivabradine
- acceptable salt
- solid composite
- polymer
- 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- Withdrawn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
- 229960003825 ivabradine Drugs 0.000 title claims abstract description 38
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 19
- ACRHBAYQBXXRTO-OAQYLSRUSA-N ivabradine Chemical compound C1CC2=CC(OC)=C(OC)C=C2CC(=O)N1CCCN(C)C[C@H]1CC2=C1C=C(OC)C(OC)=C2 ACRHBAYQBXXRTO-OAQYLSRUSA-N 0.000 title claims abstract 8
- 239000002131 composite material Substances 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 239000007787 solid Substances 0.000 claims abstract description 26
- 239000000203 mixture Substances 0.000 claims abstract description 23
- 229920001577 copolymer Polymers 0.000 claims abstract description 19
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 16
- 206010002383 Angina Pectoris Diseases 0.000 claims abstract description 5
- 206010007558 Cardiac failure chronic Diseases 0.000 claims abstract description 5
- 208000007718 Stable Angina Diseases 0.000 claims abstract description 5
- 239000003814 drug Substances 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 claims description 4
- SOGAXMICEFXMKE-UHFFFAOYSA-N Butylmethacrylate Chemical compound CCCCOC(=O)C(C)=C SOGAXMICEFXMKE-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 238000007906 compression Methods 0.000 claims description 4
- 230000006835 compression Effects 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000011877 solvent mixture Substances 0.000 claims description 4
- 229920003118 cationic copolymer Polymers 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- 230000008020 evaporation Effects 0.000 claims description 3
- JKNCOURZONDCGV-UHFFFAOYSA-N 2-(dimethylamino)ethyl 2-methylprop-2-enoate Chemical compound CN(C)CCOC(=O)C(C)=C JKNCOURZONDCGV-UHFFFAOYSA-N 0.000 claims description 2
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 239000007884 disintegrant Substances 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- -1 glidants Substances 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 239000000314 lubricant Substances 0.000 claims description 2
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 2
- 239000003002 pH adjusting agent Substances 0.000 claims description 2
- 239000003381 stabilizer Substances 0.000 claims description 2
- 239000004094 surface-active agent Substances 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims 1
- HLUKNZUABFFNQS-ZMBIFBSDSA-N ivabradine hydrochloride Chemical compound Cl.C1CC2=CC(OC)=C(OC)C=C2CC(=O)N1CCCN(C)C[C@H]1CC2=C1C=C(OC)C(OC)=C2 HLUKNZUABFFNQS-ZMBIFBSDSA-N 0.000 description 55
- 229960000504 ivabradine hydrochloride Drugs 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 229920001429 chelating resin Polymers 0.000 description 8
- 238000000634 powder X-ray diffraction Methods 0.000 description 8
- 229920003119 EUDRAGIT E PO Polymers 0.000 description 7
- 239000008187 granular material Substances 0.000 description 7
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 239000003495 polar organic solvent Substances 0.000 description 5
- 229920005989 resin Polymers 0.000 description 5
- 239000011347 resin Substances 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 229960001681 croscarmellose sodium Drugs 0.000 description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 229960001021 lactose monohydrate Drugs 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 229960005455 polacrilin Drugs 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 229910002016 Aerosil® 200 Inorganic materials 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 2
- 239000002050 international nonproprietary name Substances 0.000 description 2
- NFBAXHOPROOJAW-UHFFFAOYSA-N phenindione Chemical compound O=C1C2=CC=CC=C2C(=O)C1C1=CC=CC=C1 NFBAXHOPROOJAW-UHFFFAOYSA-N 0.000 description 2
- 229960000280 phenindione Drugs 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 229920003149 Eudragit® E 100 Polymers 0.000 description 1
- 229920003150 Eudragit® E 12,5 Polymers 0.000 description 1
- 101100370100 Mus musculus Tor3a gene Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- UHZZMRAGKVHANO-UHFFFAOYSA-M chlormequat chloride Chemical compound [Cl-].C[N+](C)(C)CCCl UHZZMRAGKVHANO-UHFFFAOYSA-M 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
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
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
Definitions
- the compound is a pharmaceutically active compound used for the treatment of stable angina pectoris and chronic heart failure.
- the compound was discovered by Adir and is disclosed in EP534859.
- the compound may form acid addition salts, for instance Ivabradine
- hydrochloride which is the active ingredient in the medicinal product sold under the brand name Corlentor® and Procoralan® by Laboratoires Servier.
- Ivabradine hydrochloride exhibits polymorphism.
- WO2006092493 discloses polymorph ⁇ of ivabradine hydrochloride, its process of preparation and compositions comprising this polymorph. Polymorph ⁇ is the most stable form and is present in the marketed product.
- Other polymorphic forms of ivabradine hydrochloride are disclosed in WO2005110993, WO2006092491, WO2006092492, WO2006092494, WO2007042656, WO2007042657 and WO2013064307. The prior art thus teaches that ivabradine
- hydrochloride crystallizes very easily. Moreover, it was experienced in our laboratory that polymorphic transitions of ivabradine hydrochloride take place rather easily, especially in pharmaceutical composition. Amorphous ivabradine hydrochloride and methods for its preparation are disclosed in WO2008146308, CN101597261 and CN101463008. We observed in our laboratory that amorphous ivabradine hydrochloride is very hygroscopic and is therefore not suitable for use on pharmaceutical production scale.
- compositions comprising ivabradine, or a pharmaceutically acceptable salt thereof, which are stable and suitable for use on a commercial scale.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a solid composite of ivabradine, or a pharmaceutically acceptable salt thereof, and an acrylate (co-) polymer and one or more pharmaceutically acceptable excipients, wherein ivabradine, or a pharmaceutically acceptable salt thereof, is in an amorphous form.
- the invention provides a process for preparing said pharmaceutical composition comprising mixing or granulating said solid composite with one or more excipients, followed by compression into tablets.
- Said pharmaceutical composition may be used as a medicament, particularly in the treatment of stable angina pectoris and chronic heart failure.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a solid composite of ivabradine, or a pharmaceutically acceptable salt thereof, and an acrylate (co)polymer and one or more pharmaceutically acceptable excipients, wherein ivabradine, or a pharmaceutically acceptable salt thereof, is in an amorphous form.
- ivabradine, or a pharmaceutically acceptable salt thereof, and the acrylate (co)polymer are preferably intimately associated, meaning that there is attractive interaction between the active pharmaceutical ingredient and the (co)polymer.
- the weight ratio of ivabradine, or a pharmaceutically acceptable salt thereof, to (co)polymer in the solid composite typically ranges from 1: 1 to 1:8, preferably from 1: 1 to 1:3.
- the acrylate (co)polymer is a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate with a ratio of 2: 1 : 1.
- Typical examples of such a commercially available cationic copolymer are Eudragit® E PO, Eudragit® E 100 and Eudragit® E 12,5.
- the acrylate (co)polymer is a copolymer of methacrylic acid and divinylbenzene, and is known under the international nonproprietary name (INN) polacrilex or polacrilin resin.
- INN international nonproprietary name
- the carboxylic acid groups of the polacrilex resin are in the H+ form, while the polacrilin resin is supplied as the potassium salt.
- Typical examples of commercially available polacrilex resins include
- Amberlite® IRP64 and Indion® 214 examples of commercially available polacrilin resins include Amberlite® IRP88 and Indion® 294.
- At least a major portion of ivabradine, or a pharmaceutically acceptable salt thereof, in the solid composite is amorphous.
- the term "a major portion" of ivabradine, or a pharmaceutically acceptable salt thereof, in the solid composite is amorphous.
- ivabradine, or a pharmaceutically acceptable salt thereof means that at least 60% of the drug is in amorphous form, rather than a crystalline form.
- ivabradine, or a pharmaceutically acceptable salt thereof, in the solid composite is substantially amorphous.
- substantially amorphous means that the amount of ivabradine, or a pharmaceutically acceptable salt thereof, in amorphous form is at least 80%.
- ivabradine, or a pharmaceutically acceptable salt thereof, in the solid composite is "almost completely amorphous” meaning that the amount of ivabradine, or a pharmaceutically acceptable salt thereof, in the amorphous form is at least 90% as measured by powder X-ray diffraction or any other standard quantitative measurement.
- ivabradine, or a pharmaceutically acceptable salt thereof means that at least 60% of the drug is in amorphous form, rather than a crystalline form.
- ivabradine, or a pharmaceutically acceptable salt thereof, in the solid composite is substantially amorphous.
- the solid composite in accordance with the present invention advantageously is in the form of a free-flowing powder, with excellent handling properties and stable morphology.
- the solid composite is very suitable to be used for the preparation of pharmaceutical compositions.
- compositions of the present invention comprise the solid composite of ivabradine, or a pharmaceutically acceptable salt thereof, and an acrylate (co)polymer and one or more pharmaceutically acceptable excipients.
- the excipients to be used in accordance with the present invention are well-known and are those excipients which are conventionally used by the person skilled in the art.
- the dosage form chosen for the pharmaceutical composition the person skilled in the art will be able to select suitable pharmaceutically acceptable excipients.
- the dosage form is an immediate-release tablet and the pharmaceutically acceptable excipients are chosen from one or more binders, diluents, disintegrants, glidants, lubricants, stabilizers, surface active agents or pH-adjusting agents.
- compositions of the present invention display dissolution behavior typical for immediate-release formulations.
- compositions of the present invention, ivabradine, or a pharmaceutically acceptable salt thereof remains in the amorphous form.
- the present invention further provides a process to prepare a solid composite of ivabradine, or a pharmaceutically acceptable salt thereof, and an acrylate (co)polymer, comprising combining the (co)polymer with ivabradine, or a pharmaceutically acceptable salt thereof, in a suitable solvent or solvent mixture, followed by evaporation of the solvent(s), using equipment and methods well-known in the art.
- isolation of the solid composite may also be established by filtration.
- the solvent or solvent mixture is water, a polar organic solvent or a mixture of water and a polar organic solvent.
- ivabradine, or a pharmaceutically acceptable salt thereof is dissolved in a polar organic solvent, water or a mixture of water and a polar organic solvent and the acrylate (co)polymer is added to this solution.
- Preferred polar organic solvents are alcohols, particularly ethanol or methanol, ethers, particularly tetrahydrofuran, ketones, particularly acetone and acetonitrile.
- an alcohol, water or a mixture of an alcohol and water is used.
- the present invention still further provides a process to prepare pharmaceutical compositions comprising a solid composite of ivabradine, or a pharmaceutically acceptable salt thereof, and an acrylate (co)polymer and one or more pharmaceutically acceptable excipients.
- the process comprises mixing or granulating the solid composite with one or more pharmaceutically acceptable excipients, followed by compression into tablets, using equipment and methods well-known to the skilled artisan.
- the composite, in solution was spray-dried onto one of the main excipients, e.g. the diluent, and the resulting granulate/blend was mixed with one or more pharmaceutically acceptable excipients, followed by compression into tablets.
- the pharmaceutical composition in accordance with the present invention may be used as a medicament.
- the pharmaceutical composition typically may be used in the treatment of stable angina pectoris and chronic heart failure.
- the present invention is illustrated by the following Examples.
- Example 1 ivabradine hydrochloride: Eudragit® E PO (weight ratio 1:1)
- ivabradine hydrochloride was dissolved in 41.50 g of ethanol (96%). 5.16 g of Eudragit® E PO was added. The solution was spray-dried on 134.43 g of microcrystalline cellulose. The resulting granulate/blend was sieved and 4.50 g of croscarmellose sodium was added by mixing, followed by the addition of 0.75 g magnesium stearate. The powder blend was compacted into tablets. Tablets with a total weight of 240 mg, containing 7.5 mg of ivabradine (referring to the amount of free base) were obtained.
- the XRPD patterns of the tablets do not show any reflections in accordance with crystalline ivabradine hydrochloride.
- XRPD analysis performed 1 week after subjecting the tablets in open dish to 55°C/90% RH and 1 month to 40°C /75% RH showed that the tablets still do not show any reflections in accordance with crystalline ivabradine hydrochloride.
- Tablets showed a fast dissolution at pH 1.2, 4.5 and 6.8.
- Example 2 ivabradine hydrochloride: Eudragit® E PO (weight ratio 1:2)
- ivabradine hydrochloride was dissolved in 75.00 g of ethanol (96%). 10.33 g of Eudragit® E PO was added. The solution was spray-dried on 129.26 g of microcrystalline cellulose. The resulting granulate/blend was sieved and 4.50 g of croscarmellose sodium was added by mixing, followed by the addition of 0.75 g magnesium stearate. The powder blend was compacted into tablets. Tablets with a total weight of 240 mg, containing 7.5 mg of ivabradine (referring to the amount of free base) were obtained.
- the XRPD patterns of the tablets do not show any reflections in accordance with crystalline ivabradine hydrochloride.
- XRPD analysis performed 1 week after subjecting the tablets in open dish to 55°C/90 RH and 1 month in alu/alu packaging to 40°C /75 RH showed that the tablets still do not show any reflections in accordance with crystalline ivabradine hydrochloride.
- ivabradine hydrochloride was dissolved in 185.00 g of ethanol (96%). 25.80 g of Eudragit® E PO was added. The solution was spray-dried on 113.81 g of microcrystalline cellulose. The resulting granulate/blend was sieved and 4.50 g of croscarmellose sodium was added by mixing, followed by the addition of 0.75 g magnesium stearate. The powder blend was compacted into tablets. Tablets with a total weight of 240 mg, containing 7.5 mg of ivabradine (referring to the amount of free base) were obtained.
- the XRPD patterns of the tablets do not show any reflections in accordance with crystalline ivabradine hydrochloride.
- XRPD analysis performed 1 week after subjecting the tablets in open dish to 55°C/90% RH and 1 month to 40°C /75% RH showed that the tablets still do not show any reflections in accordance with crystalline ivabradine hydrochloride.
- Tablets showed a fast dissolution at pH 4.5 and 6.8.
- the composites were prepared by making a slurry of ivabradine hydrochloride and Amberlite® in water. The pH of the slurry was adjusted with either 0.1 M aqueous sodium hydroxide or 2.0 M aqueous hydrochloride to either 4-5 or 6-8 (see table 1). The slurries were stirred at ambient temperature over night. The composite was isolated by filtration, washed with water and dried at air.
- Example 4 ivabradine hydrochloride: Amberlite® IRP64 (weight ratio 1:3)
- Tablets were prepared with the ivabradine hydrochloride:Amberlite® IRP64 (weight ratio 1:3) solid composite, obtained as described in example 3. The composition of the tablets is shown in table 2.
- Ivabradine hydrochloride Amberlite® IRP64 (weight ratio 1:3) 15.0
- Lactose monohydrate granulate (Supertab 30 GR) 64.0
- the solid composite of ivabradine hydrochloride Amberlite® IRP64 (weight ratio 1:3) was mixed with Aerosil 200 VV and part of the lactose monohydrate granulate (Supertab 30 GR) for 10 minutes in a Turbula mixer at 22 rpm. The pre-mix was sieved over a 0.5 mm sieve. Pregelatinized starch (Starch 1500) and the rest of the lactose monohydrate granulate (Supertab 30 GR) were added and mixing was continued for 10 minutes. Magnesium stearate was sieved over a 0.6 mm sieve, added and mixed for 3 minutes at 22 rpm. Tablets were compressed.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a pharmaceutical composition comprising a solid composite of ivabradine, or a pharmaceutically acceptable salt thereof, and an acrylate (co)polymer and one or more pharmaceutically acceptable excipients, wherein ivabradine, or a pharmaceutically acceptable salt thereof, is in an amorphous form. The invention further relates to the use of said composition as a medicament, particularly in the treatment of stable angina pectoris and chronic heart failure.
Description
PHARMACEUTICAL COMPOSITION COMPRISING AMORPHOUS
IVABRADINE
BACKGROUND OF THE PRESENT INVENTION
Ivabradine, chemically 3-(3-{ [((7S)-3,4-dimethoxybicyclo[4.2.0]octa- l,3,5-trien-7- yl)methyl]methylamino }propyl)-7,8-dimethoxy- l,3,4,5-tetrahydro-2H-3-benzazepin-2-one formula (I),
(I)
is a pharmaceutically active compound used for the treatment of stable angina pectoris and chronic heart failure. The compound was discovered by Adir and is disclosed in EP534859. The compound may form acid addition salts, for instance Ivabradine
hydrochloride, which is the active ingredient in the medicinal product sold under the brand name Corlentor® and Procoralan® by Laboratoires Servier.
Ivabradine hydrochloride exhibits polymorphism. WO2006092493 discloses polymorph β of ivabradine hydrochloride, its process of preparation and compositions comprising this polymorph. Polymorph β is the most stable form and is present in the marketed product. Other polymorphic forms of ivabradine hydrochloride are disclosed in WO2005110993, WO2006092491, WO2006092492, WO2006092494, WO2007042656, WO2007042657 and WO2013064307. The prior art thus teaches that ivabradine
hydrochloride crystallizes very easily. Moreover, it was experienced in our laboratory that polymorphic transitions of ivabradine hydrochloride take place rather easily, especially in pharmaceutical composition.
Amorphous ivabradine hydrochloride and methods for its preparation are disclosed in WO2008146308, CN101597261 and CN101463008. We observed in our laboratory that amorphous ivabradine hydrochloride is very hygroscopic and is therefore not suitable for use on pharmaceutical production scale.
Thus in view of the prior art cited above, there is still a need for pharmaceutical compositions comprising ivabradine, or a pharmaceutically acceptable salt thereof, which are stable and suitable for use on a commercial scale.
BRIEF DESCRIPTION OF THE PRESENT INVENTION
The present invention provides a pharmaceutical composition comprising a solid composite of ivabradine, or a pharmaceutically acceptable salt thereof, and an acrylate (co-) polymer and one or more pharmaceutically acceptable excipients, wherein ivabradine, or a pharmaceutically acceptable salt thereof, is in an amorphous form.
It also provides a process for preparing said solid composite by combining ivabradine, or a pharmaceutically acceptable salt thereof, with an acrylate (co)polymer in a suitable solvent or solvent mixture, followed by evaporation of the solvent(s).
Additionally, the invention provides a process for preparing said pharmaceutical composition comprising mixing or granulating said solid composite with one or more excipients, followed by compression into tablets.
Said pharmaceutical composition may be used as a medicament, particularly in the treatment of stable angina pectoris and chronic heart failure.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
The present invention relates to a pharmaceutical composition comprising a solid composite of ivabradine, or a pharmaceutically acceptable salt thereof, and an acrylate
(co)polymer and one or more pharmaceutically acceptable excipients, wherein ivabradine, or a pharmaceutically acceptable salt thereof, is in an amorphous form.
In the solid composite, ivabradine, or a pharmaceutically acceptable salt thereof, and the acrylate (co)polymer are preferably intimately associated, meaning that there is attractive interaction between the active pharmaceutical ingredient and the (co)polymer. The weight ratio of ivabradine, or a pharmaceutically acceptable salt thereof, to (co)polymer in the solid composite typically ranges from 1: 1 to 1:8, preferably from 1: 1 to 1:3.
In a preferred embodiment of the invention, the acrylate (co)polymer is a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate with a ratio of 2: 1 : 1. Typical examples of such a commercially available cationic copolymer are Eudragit® E PO, Eudragit® E 100 and Eudragit® E 12,5.
In another preferred embodiment of the invention, the acrylate (co)polymer is a copolymer of methacrylic acid and divinylbenzene, and is known under the international nonproprietary name (INN) polacrilex or polacrilin resin. Typically, the carboxylic acid groups of the polacrilex resin are in the H+ form, while the polacrilin resin is supplied as the potassium salt. Typical examples of commercially available polacrilex resins include
Amberlite® IRP64 and Indion® 214. Examples of commercially available polacrilin resins include Amberlite® IRP88 and Indion® 294.
At least a major portion of ivabradine, or a pharmaceutically acceptable salt thereof, in the solid composite is amorphous. The term "a major portion" of ivabradine, or a
pharmaceutically acceptable salt thereof, means that at least 60% of the drug is in amorphous form, rather than a crystalline form. Preferably, ivabradine, or a pharmaceutically acceptable salt thereof, in the solid composite is substantially amorphous. As used herein, "substantially amorphous" means that the amount of ivabradine, or a pharmaceutically acceptable salt thereof, in amorphous form is at least 80%. More preferably, ivabradine, or a
pharmaceutically acceptable salt thereof, in the solid composite is "almost completely amorphous" meaning that the amount of ivabradine, or a pharmaceutically acceptable salt thereof, in the amorphous form is at least 90% as measured by powder X-ray diffraction or any other standard quantitative measurement. Most preferably, ivabradine, or a
pharmaceutically acceptable salt thereof, in the solid composite is in a completely amorphous form within the detection limits of the techniques used for characterization.
The solid composite in accordance with the present invention advantageously is in the form of a free-flowing powder, with excellent handling properties and stable morphology. The solid composite is very suitable to be used for the preparation of pharmaceutical compositions.
The pharmaceutical compositions of the present invention comprise the solid composite of ivabradine, or a pharmaceutically acceptable salt thereof, and an acrylate (co)polymer and one or more pharmaceutically acceptable excipients. The excipients to be used in accordance with the present invention are well-known and are those excipients which are conventionally used by the person skilled in the art. Depending on the dosage form chosen for the pharmaceutical composition, the person skilled in the art will be able to select suitable pharmaceutically acceptable excipients. Preferably, the dosage form is an immediate-release tablet and the pharmaceutically acceptable excipients are chosen from one or more binders, diluents, disintegrants, glidants, lubricants, stabilizers, surface active agents or pH-adjusting agents.
The pharmaceutical compositions of the present invention display dissolution behavior typical for immediate-release formulations. During preparation and storage of the
pharmaceutical compositions of the present invention, ivabradine, or a pharmaceutically acceptable salt thereof, remains in the amorphous form.
The present invention further provides a process to prepare a solid composite of ivabradine, or a pharmaceutically acceptable salt thereof, and an acrylate (co)polymer, comprising combining the (co)polymer with ivabradine, or a pharmaceutically acceptable salt thereof, in a suitable solvent or solvent mixture, followed by evaporation of the solvent(s), using equipment and methods well-known in the art. Alternatively, isolation of the solid composite may also be established by filtration.
Preferably, the solvent or solvent mixture is water, a polar organic solvent or a mixture of water and a polar organic solvent. In an advantageous variant of the process of the present invention, ivabradine, or a pharmaceutically acceptable salt thereof, is dissolved in a polar organic solvent, water or a mixture of water and a polar organic solvent and the acrylate (co)polymer is added to this solution. Preferred polar organic solvents are alcohols, particularly ethanol or methanol, ethers, particularly tetrahydrofuran, ketones, particularly acetone and acetonitrile. Preferably, an alcohol, water or a mixture of an alcohol and water is used.
The present invention still further provides a process to prepare pharmaceutical compositions comprising a solid composite of ivabradine, or a pharmaceutically acceptable salt thereof, and an acrylate (co)polymer and one or more pharmaceutically acceptable excipients. The process comprises mixing or granulating the solid composite with one or more pharmaceutically acceptable excipients, followed by compression into tablets, using equipment and methods well-known to the skilled artisan. In an advantageous variant of the process of the present invention, the composite, in solution, was spray-dried onto one of the main excipients, e.g. the diluent, and the resulting granulate/blend was mixed with one or more pharmaceutically acceptable excipients, followed by compression into tablets.
The pharmaceutical composition in accordance with the present invention may be used as a medicament. The pharmaceutical composition typically may be used in the treatment of stable angina pectoris and chronic heart failure.
The present invention is illustrated by the following Examples.
EXAMPLES
Example 1, ivabradine hydrochloride: Eudragit® E PO (weight ratio 1:1)
5.16 g of ivabradine hydrochloride was dissolved in 41.50 g of ethanol (96%). 5.16 g of Eudragit® E PO was added. The solution was spray-dried on 134.43 g of microcrystalline cellulose. The resulting granulate/blend was sieved and 4.50 g of croscarmellose sodium was added by mixing, followed by the addition of 0.75 g magnesium stearate. The powder blend was compacted into tablets. Tablets with a total weight of 240 mg, containing 7.5 mg of ivabradine (referring to the amount of free base) were obtained.
The XRPD patterns of the tablets do not show any reflections in accordance with crystalline ivabradine hydrochloride. XRPD analysis performed 1 week after subjecting the tablets in open dish to 55°C/90% RH and 1 month to 40°C /75% RH showed that the tablets still do not show any reflections in accordance with crystalline ivabradine hydrochloride.
Tablets showed a fast dissolution at pH 1.2, 4.5 and 6.8.
Example 2, ivabradine hydrochloride: Eudragit® E PO (weight ratio 1:2)
5.16 g of ivabradine hydrochloride was dissolved in 75.00 g of ethanol (96%). 10.33 g of Eudragit® E PO was added. The solution was spray-dried on 129.26 g of microcrystalline cellulose. The resulting granulate/blend was sieved and 4.50 g of croscarmellose sodium was added by mixing, followed by the addition of 0.75 g magnesium stearate. The powder blend
was compacted into tablets. Tablets with a total weight of 240 mg, containing 7.5 mg of ivabradine (referring to the amount of free base) were obtained.
The XRPD patterns of the tablets do not show any reflections in accordance with crystalline ivabradine hydrochloride. XRPD analysis performed 1 week after subjecting the tablets in open dish to 55°C/90 RH and 1 month in alu/alu packaging to 40°C /75 RH showed that the tablets still do not show any reflections in accordance with crystalline ivabradine hydrochloride.
Tablets showed a fast dissolution at pH 1.2, 4.5 and 6.8. Example 3, ivabradine hydrochloride: Eudragit® E PO (weight ratio 1:5)
5.16 g of ivabradine hydrochloride was dissolved in 185.00 g of ethanol (96%). 25.80 g of Eudragit® E PO was added. The solution was spray-dried on 113.81 g of microcrystalline cellulose. The resulting granulate/blend was sieved and 4.50 g of croscarmellose sodium was added by mixing, followed by the addition of 0.75 g magnesium stearate. The powder blend was compacted into tablets. Tablets with a total weight of 240 mg, containing 7.5 mg of ivabradine (referring to the amount of free base) were obtained.
The XRPD patterns of the tablets do not show any reflections in accordance with crystalline ivabradine hydrochloride. XRPD analysis performed 1 week after subjecting the tablets in open dish to 55°C/90% RH and 1 month to 40°C /75% RH showed that the tablets still do not show any reflections in accordance with crystalline ivabradine hydrochloride.
Tablets showed a fast dissolution at pH 4.5 and 6.8.
Example 4, ivabradine hydrochloride:Amberlite® composites
Several solid composites comprising ivabradine hydrochloride were prepared using different types of Amberlite® as depicted in table 1.
Table 1
The composites were prepared by making a slurry of ivabradine hydrochloride and Amberlite® in water. The pH of the slurry was adjusted with either 0.1 M aqueous sodium hydroxide or 2.0 M aqueous hydrochloride to either 4-5 or 6-8 (see table 1). The slurries were stirred at ambient temperature over night. The composite was isolated by filtration, washed with water and dried at air.
XRPD data showed that the isolated composites are fully amorphous. Example 4, ivabradine hydrochloride: Amberlite® IRP64 (weight ratio 1:3)
Tablets were prepared with the ivabradine hydrochloride:Amberlite® IRP64 (weight ratio 1:3) solid composite, obtained as described in example 3. The composition of the tablets is shown in table 2.
Table 2
Ingredient %
Ivabradine hydrochloride: Amberlite® IRP64 (weight ratio 1:3) 15.0
Lactose monohydrate granulate (Supertab 30 GR) 64.0
Pregelatinized starch (Starch 1500) 20.0
Aerosil 200 VV 0.5
Magnesium stearate 0.5
Total 100.0
The solid composite of ivabradine hydrochloride: Amberlite® IRP64 (weight ratio 1:3) was mixed with Aerosil 200 VV and part of the lactose monohydrate granulate (Supertab 30 GR) for 10 minutes in a Turbula mixer at 22 rpm. The pre-mix was sieved over a 0.5 mm sieve. Pregelatinized starch (Starch 1500) and the rest of the lactose monohydrate granulate (Supertab 30 GR) were added and mixing was continued for 10 minutes. Magnesium stearate was sieved over a 0.6 mm sieve, added and mixed for 3 minutes at 22 rpm. Tablets were compressed.
Claims
1. A pharmaceutical composition comprising a solid composite of ivabradine, or a
pharmaceutically acceptable salt thereof, and an acrylate (co)polymer and one or more pharmaceutically acceptable excipients.
2. The composition according to claim 1, wherein the acrylate (co)polymer is a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate with a ratio of 2: 1 : 1.
3. The composition according to claim 1, wherein the acrylate (co)polymer is a copolymer of methacrylic acid and divinylbenzene.
4. The composition according to any one of claims 1 to 3, wherein the weight ratio of ivabradine, or a pharmaceutically acceptable salt thereof, to the acrylate (co)polymer ranges from 1: 1 to 1:8.
5. The composition according to any one of claims 1 to 4 comprising the hydrochloric acid salt of ivabradine.
6. The composition according to any one of claims 1 to 5, wherein ivabradine, or a
pharmaceutically acceptable salt thereof, is in an amorphous form.
7. The composition according to any one of claims 1 to 6, wherein the pharmaceutical composition is a tablet and the pharmaceutically acceptable excipients are one or more binders, diluents, disintegrants, glidants, lubricants, stabilizers, surface active agents or pH-adjusting agents.
8. The solid composite according to any one of claims 1 to 7.
9. A process for preparing the solid composite according to any one of claims 1 to 7
comprising combining ivabradine, or a pharmaceutically acceptable salt thereof, with an acrylate (co)polymer in a suitable solvent or solvent mixture, followed by evaporation of the solvent(s).
10. The process according to claim 9, wherein the solvent is a polar solvent selected from the group consisting of alcohols, ethers, ketones, acetonitrile and water or a mixture thereof.
11. The solid composite according to any of claim 1 to 7 obtained by a process according to claim 10 or 11.
12. The process according to claim 10 or 11 further comprising mixing or granulating the solid composite with one or more pharmaceutically acceptable excipients, followed by compression into tablets.
13. The composition according to any one of claims 1 to 8, for use as a medicament.
14. The composition according to claim 14 for use in the treatment of stable angina pectoris and chronic heart failure.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP14815382.8A EP3082772A1 (en) | 2013-12-20 | 2014-12-19 | Pharmaceutical composition comprising amorphous ivabradine |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP13199129 | 2013-12-20 | ||
| EP14815382.8A EP3082772A1 (en) | 2013-12-20 | 2014-12-19 | Pharmaceutical composition comprising amorphous ivabradine |
| PCT/EP2014/078819 WO2015091992A1 (en) | 2013-12-20 | 2014-12-19 | Pharmaceutical composition comprising amorphous ivabradine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP3082772A1 true EP3082772A1 (en) | 2016-10-26 |
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| Application Number | Title | Priority Date | Filing Date |
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| EP14815382.8A Withdrawn EP3082772A1 (en) | 2013-12-20 | 2014-12-19 | Pharmaceutical composition comprising amorphous ivabradine |
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| EP (1) | EP3082772A1 (en) |
| WO (1) | WO2015091992A1 (en) |
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| US20170100408A1 (en) * | 2014-03-27 | 2017-04-13 | Laboratorio Chimico Internazionale S.P.A. | Ivabradine adsorbates |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2818552B1 (en) * | 2000-12-26 | 2003-02-07 | Servier Lab | SOLID THERMOFORMABLE PHARMACEUTICAL COMPOSITIONS FOR THE CONTROLLED RELEASE OF IVABRADINE |
| WO2010128525A2 (en) * | 2009-05-04 | 2010-11-11 | Dinesh Shantilal Patel | A formulation of ivabradine for treating the cardiovascular disease |
| EP2534135A2 (en) * | 2010-02-12 | 2012-12-19 | KRKA, D.D., Novo Mesto | Novel forms of ivabradine hydrochloride |
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2014
- 2014-12-19 WO PCT/EP2014/078819 patent/WO2015091992A1/en not_active Ceased
- 2014-12-19 EP EP14815382.8A patent/EP3082772A1/en not_active Withdrawn
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| WO2015091992A1 (en) | 2015-06-25 |
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