WO2015001569A1 - A solid pharmaceutical composition of ivabradine for oral administration - Google Patents
A solid pharmaceutical composition of ivabradine for oral administration Download PDFInfo
- Publication number
- WO2015001569A1 WO2015001569A1 PCT/IN2014/000440 IN2014000440W WO2015001569A1 WO 2015001569 A1 WO2015001569 A1 WO 2015001569A1 IN 2014000440 W IN2014000440 W IN 2014000440W WO 2015001569 A1 WO2015001569 A1 WO 2015001569A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ivabradine
- tablet
- pharmaceutical composition
- pharmaceutically acceptable
- composition
- Prior art date
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- 229960003825 ivabradine Drugs 0.000 title claims abstract description 80
- 239000007787 solid Substances 0.000 title claims abstract description 29
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 40
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- 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 claims description 113
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Classifications
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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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
- 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
Landscapes
- 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)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention describes a stable solid oral pharmaceutical composition of ivabradine for oral administration and its process of preparation wherein ivabradine polymorphic form does not undergo transformation to another polymorphic form during manufacture and storage.
Description
A SOLID PHARMACEUTICAL COMPOSITION OF IVABRADINE FOR ORAL ADMINISTRATION
The present invention relates to a solid pharmaceutical composition of ivabradine or its pharmaceutically acceptable salt(s) for oral administration and the process of its preparation. BACKGROUND OF THE INVENTION
B-fS-iflySJ-a^-dimethox bicyclo ^^Jocata-l^^-trien-y-y meth lJmethylamino] propyl) -7,8- dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-one, commonly known as Ivabradine (INN name), and its pharmaceutically acceptable salts are used in the treatment of stable angina pectoris, heart failure and acute ischemia.
Ivabradine and its pharmaceutically acceptable salts are described in European Patent number 534859B1 (assigned to M/s Adir Et Compagnie).
European Patent number 1589005B1 (assigned to M/s Les Laboratories Servier) discloses the a crystalline form of ivabradine hydrochloride.
European patent number 1695965B1 (assigned to M/s Les Laboratories Servier) discloses the β crystalline form of ivabradine hydrochloride with superior photostability. Procoralan® tablets by Les Laboratoires Servier comprise the β crystalline form of hydrochloride salt of ivabradine.
European Patent numbers 1707562B1, 1695709B1 and 1695710B1 (assigned to M/s Les Laboratories Servier) claim various crystalline forms viz. the y, yd and 3d crystal forms respectively.
Published PCT application number 2008065681A2 (applicant M/s Cadila Healthcare Limited) discloses crystalline form I of ivabradine hydrochloride and the process for its preparation
Published PCT application number 2013150544A2 (applicant M/s Hetero Research Foundation) discloses amorphous solid dispersion of ivabradine hydrochloride by dissolving ivabradine hydrochloride and a pharmaceutically acceptable carrier selected from copovidone, hydroxypropyl methylcellulose, ethylcellulose, polyethylene glycol or soluplus in solvent selected from dimethylsulfoxide, dimethylacetamide, methanol, ethanol, isopropanol, n-butanol or n-
pentanol and its mixtures and removing the solvent by drying at about 60 to 100°C to obtain the amorphous solid dispersion of ivabradine hydrochloride in combination with a pharmaceutically acceptable carrier. However, the publication does not disclose the complex of ivabradine with crosslinked polymer of divinylbenzene methacrylate or its pharmaceutically acceptable salt(s) or its process of preparation nor does it disclose use of polymethacrylates to prepare solid pharmaceutical composition of ivabradine for oral administration.
We have now found a solid pharmaceutical composition of ivabradine for oral administration which -will eliminate probable problems of retention of crystalline form over a period of time. OBJECT OF THE INVENTION
The object of the present invention is to provide a solid oral pharmaceutical composition of ivabradine for oral administration and its process of preparation wherein ivabradine polymorphic form does not undergo transformation to another polymorphic form during manufacture and storage.
SUMMARY OF THE INVENTION
A stable pharmaceutical composition comprising crystalline form II of ivabradine hydrochloride and at least one pharmaceutically acceptable excipient optionally in the absence of solvent(s) & the process of its preparation.
Alternatively, a solid pharmaceutical composition of ivabradine for oral administration comprising complex of ivabradine or its pharmaceutically acceptable salt(s) with crosslinked polymer of divinylbenzene methacrylate or its pharmaceutically acceptable salt(s) and at least one pharmaceutically acceptable excipient & the process of its preparation.
Also included is a solid pharmaceutical composition of ivabradine for oral administration comprising ivabradine or its pharmaceutically acceptable salt(s), polymethacrylate(s) and at least one pharmaceutically acceptable excipient & the process of its preparation
DESCRIPTION OF THE INVENTION
Ivabradine is used to treat stable angina pectoris which causes chest pain. Procaralan is available as film coated tablets. Ivabradine exists in various crystalline forms which may not be retained over a period of time. We have surprisingly found a novel solid pharmaceutical composition of ivabradine hydrochloride which retains its crystalline form.
The present invention is on a stable solid pharmaceutical composition of ivabradine hydrochloride comprising crystalline form II or amorphous form of ivabradine hydrochloride. According to one embodiment of the present invention is a stable pharmaceutical composition comprising crystalline form II of ivabradine hydrochloride and at least one pharmaceutically acceptable excipient optionally in the absence of solvent(s).
Powder X-ray diffraction diagram of crystalline form II of ivabradine hydrochloride in the present invention exhibits characteristic peaks at 15.7, 16.4, 19.2, 22.6 and 24.5 +/- 0.2 degrees 2 theta .
The^solvent may be selected from water, ethanol, methanol, isopropyl alcohol, dichloromethane and the like. The crystalline form II of ivabradine hydrochloride used in the composition of the present invention is about 2 to 30 weight % of the total weight of the composition.
Specifically the stable pharmaceutical composition of crystalline form II of ivabradine hydrochloride is such that the crystalline form II of ivabradine hydrochloride is substantially stable under storage at about 40°C and about 75% relative humidity for at least about 3 months.
More specifically the stable pharmaceutical composition of crystalline form II of ivabradine hydrochloride of the present invention is such that more than 90 weight % of ivabradine hydrochloride is stably present as crystalline form II of ivabradine hydrochloride under storage at about 40°C and about 75% relative humidity for at least about 3 months.
The pharmaceutically acceptable excipient used in the composition of the present invention must be compatible with crystalline form II of ivabradine hydrochloride.
The pharmaceutical excipient may be selected from diluents, binders, lubricants, disintegrants, flavoring agents, coloring agents, stabilizers, solubilizers, surfactants, glidants, plasticizers, preservatives and sweeteners.
The composition may be selected from sprinkle granules or powder for reconstitution in a suspension, tablet, soluble tablet, rapidly disintegrating tablet, orally disintegrating tablet, rapidly disintegrating film, capsule, sachet, effervescent tablet, a chewable tablet, water dispersible tablet, orodispersible tablet, chewing gum and suspension.
The granules or tablets may be coated with functional or non-functional coating.
According to another embodiment of the present invention is a process for the preparation of a stable pharmaceutical composition comprising crystalline form II of ivabradine hydrochloride and at least one pharmaceutically acceptable excipient optionally in the absence of solvent.
Powder X-ray diffraction diagram of crystalline form II of ivabradine hydrochloride in the present invention exhibits characteristic peaks at 15.7, 16.4, 19.2, 22.6 and 24.5 +/- 0.2 degrees 2 theta.
The pharmaceutically acceptable excipient used in the composition of the present invention must be compatible with crystalline form II of ivabradine hydrochloride.
The pharmaceutical . excipient may be selected from diluents, binders, lubricants, disintegrants, flavoring agents, coloring agents, stabilizers, solubilizers, surfactants, glidants, plasticizers, preservatives and sweeteners.
The solvent may be selected from water, ethanol, methanol, isopropyl alcohol, dichloromethane and the like.
The composition of the present invention may be prepared using conventional techniques employed in the art for mixing/lubrication, compaction/slugging, wet and dry granulation, milling, drying, sizing, compressing, direct compression, filling in capsules, sachets and the like.
The steps in the wet granulation technique may be as follows:
(a) Weighing and mixing ingredients
(b) Adding binder solution or an adhesive /kneading
(c) Screening the damp mass into pellets or granules
(d) Drying and screening /sizing
(e) Mixing / lubricating and
(f) Tableting or filling in capsules / sachet.
In dry granulation there is no addition of binder solution, but the powdered drug mixture is compressed into large masses called slugs, sized into smaller granules, mixed, lubricated and compressed or filled in capsules / sachet.
The composition may be prepared by direct compression of the ingredients into tablets or minitablets which may be filled in capsules or by dry mixing of the ingredients which may be filled in capsules/sachets. The oral composition of the present invention was subjected to dissolution method (0.1N . hydrochloric acid 900 ml, paddle 50 rpm) wherein minimum 80% released in 30 minutes.
According to another embodiment of the present invention is a solid pharmaceutical composition of ivabradine for oral administration comprising complex of ivabradine or its pharmaceutically acceptable salt(s) with crosslinked polymer of divinylbenzene methacrylate or its pharmaceutically acceptable salt(s) and at least one pharmaceutically acceptable excipient and the process of its preparation.
The complexation between crosslinked polymer of divinylbenzene methacrylate or its pharmaceutically acceptable salt(s) and ivabradine or its pharmaceutically acceptable salt(s), hinders the release of ivabradine in the mouth. When the complex comes into contact with the
gastrointestinal fluid, such as the acid of the stomach, the drug is released from complex directly into solution and then absorbed in the usual way. The complex passes through the Gl tract without being absorbed.
The composition of ivabradine of the present invention may be in crystalline or amorphous form. Most preferably the composition of ivabradine is in amorphous form.
Ivabradine or its pharmaceutically acceptable salt(s) used in the composition of the present invention is about 1 to 30 weight % of the total weight of the composition. The pharmaceutically acceptable salt(s) of ivabradine may be selected from hydrochloride, hydrobromide, sulphate, phosphate, acetate, lactate, citrate, tartarate, succinate, maleate, fumarate; preferably hydrochloride.
Crosslinked polymer of divinylbenzene methacrylate or its pharmaceutically acceptable salt(s) may be selected from polacrilin or its potassium salt.
The weight ratio of ivabradine or its pharmaceutically acceptable salt(s) to crosslinked pdlyrner of divinylbenzene methacrylate or its pharmaceutically acceptable salt(s) used in the composition of present invention may range from 1:1 to 1:6, preferably 1:2 to 1:4.
The pharmaceutically acceptable excipient used in the composition of the present invention must be compatible with ivabradine.
The pharmaceutical excipient may be selected from diluents, binders, lubricants, disintegrants, flavoring agents, coloring agents, stabilizers, solubilizers, surfactants, glidants, plasticizers, preservatives, sweeteners and buffering agents
The composition may be selected from sprinkle granules or powder for reconstitution in a suspension, tablet, soluble tablet, rapidly disintegrating tablet, orally disintegrating tablet, rapidly disintegrating film, capsule, sachet, effervescent tablet, a chewable tablet, water dispersible tablet, orodispersible tablet, chewing gum and suspension.
The granules or tablets may be coated with functional or non-functional coating.
The solid pharmaceutical composition of ivabradine of the present invention was subjected to dissolution method (0.1N hydrochloric acid 900 ml, paddle 50 rpm) wherein minimum 75% released in 45 minutes.
The process for the preparation of a solid pharmaceutical composition of ivabradine for oral administration comprising
(a) completing ivabradine or its pharmaceutically acceptable salt(s) and crosslinked polymer of divinylbenzene methacrylate or its pharmaceutically acceptable salt(s);
(b) adding at least one pharmaceutical excipient; and
(c) optionally compressing into tablets.
The composition of ivabradine of the present invention may be in crystalline or amorphous form. Most preferably the composition of ivabradine is in amorphous form.
Ivabradine or its pharmaceutically acceptable salt(s) used in the composition of the present invention is about 1 to 30 weight % of the total weight of the composition. The pharmaceutically acceptable salt(s) of ivabradine may be selected from hydrochloride, hydrobromide, sulphate, phosphate, acetate, lactate, citrate, tartarate, succinate, maleate, fumarate; preferably hydrochloride.
Crosslinked polymer of divinylbenzene methacrylate or its pharmaceutically acceptable salt(s) may be selected from polacrilin or its potassium salt.
The weight ratio of ivabradine or its pharmaceutically acceptable salt(s) to crosslinked polymer of divinylbenzene methacrylate or its pharmaceutically acceptable salt(s) used in the composition of present invention may range from 1:1 to 1:6, preferably 1:2 to 1:4.
The pharmaceutically acceptable excipient used in the composition of the present invention must be compatible with ivabradine.
The composition of the present invention may be prepared by complexing with crosslinked polymer of divinylbenzene methacrylate or its pharmaceutically acceptable salt(s), compaction/slugging, wet and dry granulation, milling, drying, sizing, compressing, direct compression, filling in capsules, sachets and the like.
The steps in the wet granulation technique may be as follows:
(a) weighing and mixing ingredients
(b) adding binder or diluent solution or an adhesive /kneading
(c) screening the damp mass into pellets or granules
(d) drying and screening /sizing
(e) mixing / lubricating and
(f) tableting /coating or filling in capsules / sachet.
In dry granulation there is no addition of binder solution, but the powdered drug mixture is compressed into large masses called slugs, sized into smaller granules, mixed, lubricated and compressed or filled in capsules / sachet. The powered drug mixture is derived from the following steps:
(a) weighing of ingredients
(b) complexing with crosslinked polymer of divinylbenzene methacrylate or its pharmaceutically acceptable salt(s)
(c) filtering the suspension
(d) screening the damp mass into pellets or granules and
(e) drying.
The composition may be prepared by direct compression of the ingredients into tablets or minitablets which may be filled in capsules or by dry mixing of the ingredients which may be filled in capsules/sachets. Typically it may be prepared as follows
(a) weighing and complexing with crosslinked polymer of divinylbenzene methacrylate or its pharmaceutically acceptable salt
(b) filtering the suspension
(c) screening the damp mass into pellets or granules
(d) drying and screening /sizing
(e) mixing / lubricating and
(f) tabletting/coating or filling in capsules/sachet.
According to yet another embodiment of the present invention is a solid pharmaceutical composition of ivabradine for oral administration comprising ivabradine or its pharmaceutically acceptable salt(s), polymethacrylate(s) and at least one pharmaceutical excipient and the process of its preparation.
The polymethacrylates are commercially available as eudragits® such as dimethylaminoethyl methacrylate and the like. Preferably E-100 and Eudragit ® EPO. They are soluble in gastric fluid as well as in weakly acidic buffer solutions (up to about pH 5). The weight ratio of ivabradine or its pharmaceutically acceptable salt(s) to polymethacrylate(s) used in the composition of the present invention may range from 1:10 to 10:1.
The composition of ivabradine of the present invention may be in crystalline or amorphous form. Most preferably the composition of ivabradine is in amorphous form.
Ivabradine or its pharmaceutically acceptable salt(s) used in the composition of the present invention is about 1 to 30 weight % of the total weight of the composition.
The pharmaceutically acceptable salt(s) of ivabradine may be selected from hydrochloride, hydrobromide, sulphate, phosphate, acetate, lactate, citrate, tartarate, succinate, maleate, fumarate; preferably hydrochloride.
The pharmaceutically acceptable excipient used in the composition of the present invention must be compatible with ivabradine.
The pharmaceutical excipient may be selected from diluents, binders, lubricants, disintegrants, flavoring agents, coloring agents, stabilizers, solubilizers, surfactants, glidants, plasticizers, preservatives, sweeteners and buffering agents.
The composition may be selected from sprinkle granules or powder for reconstitution in a suspension, tablet, soluble tablet, rapidly disintegrating tablet, orally disintegrating tablet, rapidly disintegrating film, capsule, sachet, effervescent tablet, a chewable tablet, water dispersible tablet, orodispersible tablet, chewing gum and suspension.
The granules or tablets may be coated with functional or non-functional coating.
The process for preparing a solid pharmaceutical composition of ivabradine for oral administration comprising ivabradine or its pharmaceutically acceptable salt(s) with polymethacrylate(s) and at least one pharmaceutical excipient, comprises
(a) adsorbing/coating non-pareil seeds or inert particles with a mixture of ivabradine or its pharmaceutically acceptable salt(s) and polymethacrylate(s); or loading non-pareil seeds or inert particles with ivabradine or its pharmaceutically acceptable salt(s) followed by coating with polymethacrylate(s); or mixing ivabradine or its pharmaceutically acceptable salt(s) with polymethacrylate(s);
(b) adding at least one pharmaceutical excipient; and
(c) optionally compressing into tablets.
The non-pareil seeds or inert particles may be selected from water soluble and water insoluble non- fine particles such as directly compressible dibasic calcium phosphate, microcrystalline cellulose, directly compressible sugar such as directly compressible mannitol commercially available as PEARLITOL, starch and the like.
In all the above embodiments the pharmaceutically acceptable excipient may be selected from the below mentioned list of excipients. Diluents may be selected from calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline cellulose, microcrystalline silicified cellulose, powdered
cellulose, dextrates, dextrose, fructose, lactitol, lactose anhydrous, lactose monohydrate, lactose dihydrate, lactose trihydrate, mannitol, sorbitol, starch, pregelatinized starch, sucrose, talc, xylitol, maltose, isomalt, maltodextrin, maltitol and the like. Diluents may be in the range of 30-99 weight % of the total weight of the composition. Binders may be selected from acacia, alginic acid, carbomer, carboxymethylcellulose calcium, carbomethylcellulose sodium, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gelatin liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, maltodextrin, methylcellulose, cellulose acetate, polydextrose, polyethylene oxide, povidone, sodium alginate, starch paste, pregelatinized starch, sucrose, tragacanth, low-substituted hydroxypropyl cellulose, glucose, sorbitol. Suitable fillers are preferably selected from atleast one of starch derivatives, such as corn starch, potato starch, maize starch maize or rice starch. Polysaccharides such as dextrins, maltodextrins, dextrates, microcrystalline cellulose, powdered cellulose, mixture of microcrystalline cellulose and guar gum, coprocessed blends of microcrystalline cellulose; and polyhydric alcohols, such as xylitol, sorbitol and the like. Binders may be in the range of 1-40 weight % of the total weight of the composition.
Disintegrants may be selected from alginic acid, carbon dioxide, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, croscarmelose sodium, crospovidone, sodium docusate, gum, hydroxypropyl cellulose, methylcellulose, polacrilin potassium , poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate, sodium starch glycolate, starch, pregelatinized starch, low-substituted hydroxypropyl cellulose and the like. Disintegrants may be in the range of 5 - 25 weight % of the total weight of the composition.
Glidants may be selected from calcium silicate, powdered cellulose, starch, talc, colloidal silicon dioxide and the like. Glidants may be in the range of 0.01-2 weight % of the total weight of the composition.
Lubricants may be selected from magnesium stearate, stearic acid, sodium stearyl fumarate, magnesium lauryl sulphate, talc, polyethylene glycol, glyceryl behenate and the like. Lubricants may be in the range of 0.1-2.5 weight % of the total weight of the composition.
Suitable sweeteners may be selected from sugars such as sucrose, lactose and glucose; cyclamate and salts thereof; saccharin and salts thereof; aspartame neohesperidine DC, acesulfame potassium and the like.
Flavouring agents may be selected from natural or synthetic flavours such as strawberry flavour, wild cherry flavour, green apple flavour, spearmint flavor, peppermint flavor and the like.
Solubilizers may be selected from complex forming agents such as cyclodextrins, ion exchange resins, crown ethers and the like. Surfactants may be selected from polyoxyethylene alcohol ethers, polysorbates, polyoxypropylene polyoxyethylene copolymers such as poloxamers and the like. Buffering agent may be selected from hydrochloric acid, sodium hydroxide, adipic acid, boric acid, citric acid monohydrate, maleic acid, potassium citrate, sodium acetate, sodium citrate dihydrate, sodium lactate, sodium phosphate
The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope of the invention.
EXAMPLES Example 1:
Prestability study results
Three different formulations of Ivabradine FC were prepared using direct compression manufacturing process and kept for prestability evaluation under different packaging conditions and storage conditions.
Different packaging and storage conditions are clarified below:
- Batch LA(044)03 kept in double polyethylene bag under long term conditions (25oC & 60%
RH) and in open vial under accelerated conditions (40oC/75% RH)
Batch LA(044)08 kept in double polyethylene bag under long term conditions (25oC & 60% RH) and in open vial under accelerated conditions (40oC/75% RH)
Batch LA(044)14: kept in aluminium blisters under intermediate term conditions (30oC & 75% RH)
Batch LA(044)16: kept in aluminium blisters under intermediate term conditions (30oC & 75% RH) and in open vial under accelerated conditions (40oC/75% RH)
Batch LA(044)17: kept in double polyethylene bag under long term conditions (25oC & 60% RH)
- Batch LA(044)23: kept in double polyethylene bag under long term conditions (25oC & 60% RH) & in aluminium blisters under intermediate term conditions (30oC & 75% RH) and in open vial under accelerated conditions (40oC/75% RH)
The IR tablets were tested for in vitro dissolution profile (USP apparatus II, HCI 0.1N) in zero time and in 1 month open vial at accelerated conditions and the results are shown below:
Results indicated an immediate release profile of API, while the profile remained stable after tablet storage in open vial at accelerated conditions for 1 month.
Batches were checked for their degradation products and the table below summarizes the % known, % unknown and % of total impurities formed during storage.
All batches were checked for their polymorphic stability.
3M LT ALU Pattern is the sum of placebo pattern and ivabradine hydrochloride form II pattern. -No additional peaks were recorded.
4M LT ALU Pattern is the sum of placebo pattern and ivabradine hydrochloride form II pattern. No additional peaks were recorded.
LA(044)23-5
40d INT ALU Pattern is the sum of placebo pattern and ivabradine hydrochloride form II pattern. No additional peaks were recorded.
2M INT ALU Pattern is the sum of placebo pattern and ivabradine hydrochloride form II pattern. No additional peaks were recorded.
2M LT (PE bag) Pattern is the sum of placebo pattern and ivabradine hydrochloride form II pattern. No additional peaks were recorded.
3M LT (PE bag) Pattern is the sum of placebo pattern and ivabradine hydrochloride form II pattern. No additional peaks were recorded.
5
XRD results indicate that the crystal form II of ivabradine hydrochloride remained stable in the proposed formulations during storage in the tested conditions.
10 Example 2:
(a) Dissolve/disperse ivabradine HCI in p.water
(b) Add IRP 64 in appropriate ratio (1:1 to 1:6)
(c) Adjust pH to 4-6
(d) Stir the dispersion for appropriate time
(e) Granulate Microcrystalline cellulose using the dispersion as granulation liquid
(f) Dry the granules
(g) Size the granules
(h) Mix with extragranular excipients
(i) Lubricate with Mg Stearate
Centrifugation/filtration method
(a) Dissolve/disperse ivabradine HCI in p.water
(b) Add IRP 64 in appropriate. ratio (1:1 to 1:6)
(c) Adjust pH to 4-6
(d) Stir the dispersion for appropriate time
(e) Centrifuge/filtrate the dispersion in order to separate the resin from the filtrate
(f) Dry resin to appropriate water content
(g) Size resin to appropriate particle size
(h) Mix the dried resin with extragranular excipients
(i) Lubricate with Mg Stearate and compress/coat Example 3:
(a) Dissolve/disperse ivabradine HCI in p. water
(b) Add IRP88 in appropriate ratio (1:1 to 1:6)
(c) Adjust pH to 4-6
(d) Stir the dispersion for appropriate time
(e) Granulate Microcrystalline cellulose using the dispersion as granulation liquid
(f) Dry the granules
(g) Size the granules
(h) Mix with extragranular excipients
(i) Lubricate with Mg Stearate
Centrifugation/filtration method
(a) Dissolve/disperse ivabradine HCI in p. water
(b) Add IRP88 in appropriate ratio (1:1 to 1:6)
(c) Adjust pH to 4-6
(d) Stir the dispersion for appropriate time
(e) Centrifuge/filtrate the dispersion in order to separate the resin from the filtrate
(f) Dry resin to appropriate water content
(g) Size resin to appropriate particle size
(h) Mix the dried resin with extragranular excipients
(i) Lubricate with Mg Stearate and compress/coat
The tablets kept in aluminum blisters under accelerated (40oC/75% RH) & intermediate term conditions (30oC & 75% RH)
Dissolution results are as follows:
5 68,5
10 82,1
15 87,2
30 92,6
45 94,5
Similarity factor f2: 78
Results indicated an immediate release profile of API, while the profile remained stable after tablet storage in open vial and aluminum blister at accelerated conditions for 1 month & 3M respectively. Tablets were checked for their degradation products and the table below summarizes the % known, % unknown and % of total impurities formed during storage.
Results indicate that API remained stable in the proposed formulation during storage in the tested conditions.
Tablets were checked for their polymorphic stability and the table below summarizes the findings during storage.
XRD results indicate that the API remained amorphous in the proposed formulation during storage the tested conditions.
Claims
1. A stable pharmaceutical composition comprising crystalline form II of ivabradine hydrochloride and at least one pharmaceutically acceptable excipient optionally in the absence of solvent(s).
2. A stable pharmaceutical composition as claimed in claim 1 wherein powder X-ray diffraction diagram of crystalline form II of ivabradine hydrochloride exhibits characteristic peaks at 15.7, 16.4, 19.2, 22.6 and 24.5 degrees 2 theta.
3. A stable pharmaceutical composition as claimed in claim 1 wherein the crystalline form II of ivabradine hydrochloride is substantially stable under storage at about 40°C and about 75% relative humidity for at least about 3 months.
4. A stable pharmaceutical composition as claimed in claim 1 wherein crystalline form II of ivabradine hydrochloride is about 2 to 30 weight % of the total weight of the composition.
5. A stable pharmaceutical composition as claimed in claim 1 wherein the composition is selected from sprinkle granules or powder for reconstitution in a suspension, tablet, soluble tablet, rapidly disintegrating tablet, orally disintegrating tablet, rapidly disintegrating film, capsule, sachet, effervescent tablet, a chewable tablet, water dispersible tablet, orodispersible tablet, a chewing gum and suspension.
6. A process for the preparation of a stable pharmaceutical composition as claimed in claim 1 comprising admixing crystalline form II of ivabradine hydrochloride and atleast one pharmaceutically acceptable excipient optionally in the absence of solvent(s).
7. A process for the preparation of a stable pharmaceutical composition as claimed in claim 9 wherein powder X-ray diffraction diagram of crystalline form II of ivabradine hydrochloride exhibits characteristic peaks at 15.7, 16.4, 19.2, 22.6 and 24.5 degrees 2 theta.
8. A process for the preparation of a stable pharmaceutical composition as claimed in claim 6 wherein the composition is selected from sprinkle granules or powder for reconstitution in a suspension, tablet, soluble tablet, rapidly disintegrating tablet, orally disintegrating tablet, rapidly disintegrating film, capsule, sachet, effervescent tablet, a chewable tablet, water dispersible tablet, orodispersible tablet, a chewing gum and suspension.
9. A solid pharmaceutical composition of ivabradine for oral administration comprising
complex of ivabradine or its pharmaceutically acceptable salt{s) with crosslinked polymer of
divinylbenzene methacrylate or its pharmaceutically acceptable salt(s) and at least one pharmaceutically acceptable excipient.
10. A solid pharmaceutical composition of ivabradine for oral administration as claimed in claim 9 wherein the composition is in amorphous or crystalline form.
1 1 . A solid pharmaceutical composition of ivabradine for oral administration as claimed in claim 9 wherein ivabradine is about 1 to 30 weight % of the total weight of the composition,
12. A solid pharmaceutical composition of ivabradine for oral administration as claimed in claim 9 wherein the weight ratio of ivabradine or its pharmaceutically acceptable salt(s) to crosslinked polymer of divinylbenzene methacrylate or its pharmaceutically acceptable salt(s) is selected from 1:1 to 1:6.
13. A solid pharmaceutical composition of ivabradine for oral administration as claimed in claim
9 wherein the composition is selected from sprinkle granules or powder for reconstitution in a suspension, tablet, soluble tablet, rapidly disintegrating tablet, orally disintegrating tablet, rapidly disintegrating film, capsule, sachet, effervescent tablet, chewable tablet, water dispersible tablet, orodispersible tablet, a chewing gum and suspension.
14. A process for the preparation of a solid pharmaceutical composition of ivabradine for oral administration as claimed in claim 9 comprising
(a) complexing ivabradine or its pharmaceutically acceptable salt(s) and crosslinked polymer of divinylbenzene methacrylate or its pharmaceutically acceptable salt(s);
(b) adding at least one pharmaceutical excipient; and
(c) optionally compressing into tablets.
13. A process as claimed in claim 14 wherein the composition is in amorphous or
crystalline form.
16. A process for the preparation of a solid pharmaceutical composition of ivabradine for oral administration as claimed in claim 14 wherein the composition is selected from sprinkle granules or powder for reconstitution in a suspension, tablet, soluble tablet, rapidly disintegrating tablet, orally disintegrating tablet, rapidly disintegrating film, capsule, sachet, effervescent tablet, chewable tablet, water dispersible tablet, orodispersible tablet, a chewing gum and suspension.
17. A solid pharmaceutical composition of ivabradine for oral administration comprising
ivabradine or its pharmaceutically acceptable salt(s), po!ymethacrylate(s) and at least one pharmaceutically acceptable excipient.
18. A solid pharmaceutical composition of ivabradine as claimed in claim 17 wherein the composition is in amorphous or crystalline form.
19. A solid pharmaceutical composition of ivabradine for oral administration as claimed in claim 17 wherein ivabradine is about 1 to 30 weight % of the total weight of the composition.
20. A solid pharmaceutical composition of ivabradine for oral administration as claimed in claim 17 wherein the weight ratio of ivabradine or its pharmaceutically acceptable salt(s) to polymethacrylate(s) is selected from 1:10 to 10:1.
21 . A solid pharmaceutical composition of ivabradine for oral administration as claimed in claim 17 wherein the dosage is selected from sprinkle granules or powder for reconstitution in a suspension, tablet, soluble tablet, rapidly disintegrating tablet, orally disintegrating tablet, rapidly disintegrating film, capsule, sachet, effervescent tablet, chewable tablet, water dispersible tablet, orodispersible tablet, a chewing gum and suspension.
22. A process for the preparation of a solid pharmaceutical composition of ivabradine for oral administration as claimed in claim 17 comprising
(a) adsorbing/coating non-pareil seeds or inert particles with a mixture of ivabradine or its pharmaceutically acceptable salt(s) and polymethacrylate(s); or loading non-pareil seeds or inert particles with ivabradine or its pharmaceutically acceptable salt(s) followed by coating with polymethacrylate(s); or mixing ivabradine or its
pharmaceutically acceptable salt(s) with polymethacrylate(s);
(b) adding at least one pharmaceutical excipient; and
(c) optionally compressing into tablets.
23. A process as claimed in claim 22 wherein the composition is in amorphous or crystalline form.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN2238/MUM/2013 | 2013-07-02 | ||
| IN3678MU2013 | 2013-11-22 | ||
| IN3678/MUM/2013 | 2013-11-22 | ||
| IN2238MU2013 IN2013MU02238A (en) | 2013-07-02 | 2014-07-02 |
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| Publication Number | Publication Date |
|---|---|
| WO2015001569A1 true WO2015001569A1 (en) | 2015-01-08 |
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ID=52143206
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2014/000440 WO2015001569A1 (en) | 2013-07-02 | 2014-07-02 | A solid pharmaceutical composition of ivabradine for oral administration |
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| Country | Link |
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| WO (1) | WO2015001569A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015145234A1 (en) * | 2014-03-27 | 2015-10-01 | Laboratorio Chimico Internazionale S.P.A. | Ivabradine adsorbates |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011098582A2 (en) * | 2010-02-12 | 2011-08-18 | Krka, D.D., Novo Mesto | Novel forms of ivabradine hydrochloride |
| WO2011157720A2 (en) * | 2010-06-14 | 2011-12-22 | Ratiopharm Gmbh | Ivabradine-containing pharmaceutical composition with modified release |
| WO2013020416A1 (en) * | 2011-08-05 | 2013-02-14 | 江苏恒瑞医药股份有限公司 | Sustained-release preparation of ivabradine or pharmaceutically acceptable salts thereof |
| WO2013093753A1 (en) * | 2011-12-24 | 2013-06-27 | Alembic Pharmaceuticals Limited | Ivabradine hydrochloride premix |
| WO2013102919A1 (en) * | 2011-11-14 | 2013-07-11 | Cadila Healthcare Limited | Polymorphic forms of ivabradine hydrochloride |
-
2014
- 2014-07-02 WO PCT/IN2014/000440 patent/WO2015001569A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011098582A2 (en) * | 2010-02-12 | 2011-08-18 | Krka, D.D., Novo Mesto | Novel forms of ivabradine hydrochloride |
| WO2011157720A2 (en) * | 2010-06-14 | 2011-12-22 | Ratiopharm Gmbh | Ivabradine-containing pharmaceutical composition with modified release |
| WO2013020416A1 (en) * | 2011-08-05 | 2013-02-14 | 江苏恒瑞医药股份有限公司 | Sustained-release preparation of ivabradine or pharmaceutically acceptable salts thereof |
| WO2013102919A1 (en) * | 2011-11-14 | 2013-07-11 | Cadila Healthcare Limited | Polymorphic forms of ivabradine hydrochloride |
| WO2013093753A1 (en) * | 2011-12-24 | 2013-06-27 | Alembic Pharmaceuticals Limited | Ivabradine hydrochloride premix |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015145234A1 (en) * | 2014-03-27 | 2015-10-01 | Laboratorio Chimico Internazionale S.P.A. | Ivabradine adsorbates |
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