EP3307249A1 - Composition pharmaceutique comprenant du chlorhydrate d'ivabradine et procédé pour la préparer - Google Patents

Composition pharmaceutique comprenant du chlorhydrate d'ivabradine et procédé pour la préparer

Info

Publication number
EP3307249A1
EP3307249A1 EP16733287.3A EP16733287A EP3307249A1 EP 3307249 A1 EP3307249 A1 EP 3307249A1 EP 16733287 A EP16733287 A EP 16733287A EP 3307249 A1 EP3307249 A1 EP 3307249A1
Authority
EP
European Patent Office
Prior art keywords
excipients
ivabradine
pharmaceutical composition
composition according
active ingredient
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Withdrawn
Application number
EP16733287.3A
Other languages
German (de)
English (en)
Inventor
Evangelos Karavas
Efthymios Koutris
Vasiliki SAMARA
Ioanna Koutri
Anastasia Kalaskani
Christina KIZIRIDI
Morfis Abatzis
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmathen SA
Original Assignee
Pharmathen SA
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Pharmathen SA filed Critical Pharmathen SA
Publication of EP3307249A1 publication Critical patent/EP3307249A1/fr
Withdrawn legal-status Critical Current

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
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • 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
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A61K9/2036—Silicones; Polysiloxanes
    • 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
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a stable pharmaceutical formulation for oral administration containing a therapeutically effective quantity of Ivabradine HQ polymorph IV or ⁇ and a method for the preparation thereof.
  • beta blockers and some calcium-channel antagonists reduce heart rate, but their use may be limited by adverse reactions or contraindications.
  • Ivabradine is a novel medication used for the treatment of stable angina pectoris and chronic heart failure. It acts by reducing the heart rate via specific inhibition of the funny channel, a mechanism different from beta blockers and calcium channel blockers.
  • Ivabradine acts on the If (f is for "funny” so called because it had unusual properties compared with other current systems known at the time of its discovery) ion current, which is highly expressed in the sinoatrial node. If is a mixed Na + -fC + inward current activated by hyperpolarization and modulated by the autonomic nervous system. It is one of the most important ionic currents for regulating pacemaker activity in the sinoatrial (SA) node. Ivabradine selectively inhibits the pacemaker If current in a dose-dependent manner. Blocking this channel reduces cardiac pacemaker activity, slowing the heart rate and allowing more time for blood to flow to the myocardium.
  • Ivabradine HQ is 3-(3- ⁇ [((7S)-3,4-dimethoxybicyclo[4.2.0]octa-l,3,5- trien-7-yl)methyl]methylamino ⁇ propyl)-l,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-ben2azepin- 2-one hydrochloride and its molecular formula is C 27 H 37 CIN 2 0 5 corresponding to a molecular weight of 505.05. It is a white to slightly yellow powder. It is freely soluble in water, dimethylsulfoxide, methanol and methylene chloride, soluble in ethanol and slightly soluble in acetone.
  • Ivabradine hydrochloride is optically active and corresponds to the S isomer. Ivabradine hydrochloride shows polymorphism. It may be present in a variety of crystalline forms, some of them being hydrates or solvates. The most stable form is the tetrahydrate form (form ⁇ ) and all other forms have a tendency of converting to this form under high moisture.
  • EP 1695965 B discloses the crystalline form ⁇ , a tetrahydrate form of Ivabradine HQ, characterized by PXRD and a process for its preparation.
  • EP 1775288 A discloses the crystalline form ⁇ , a hydrated form of Ivabradine HC1, characterized by PXRD and a process for its preparation.
  • WO 2013/064307 A discloses Ivabradine HC1 form IV, which is a hemihydrate.
  • EP 1474152 B discloses an orodispersible solid pharmaceutical composition
  • Ivabradine which is characterised in that it contains Ivabradine or one of the pharmaceutically acceptable salts thereof and granules consisting of co-dried lactose and starch.
  • EP-2579859 A2 discloses a pharmaceutical composition with modified release comprising Ivabradine adipate and a combination of a water-insoluble and a water-soluble excipient.
  • an object of the present invention to provide an improved stable solid dosage formulation for oral administration containing Ivabradine HQ as an active ingredient, which overcomes the deficiencies of the prior art and avoids polymorphic transformation of the active pharmaceutical ingredient. Further object of the present invention is to provide a film-coated tablet comprising Ivabradine HQ as an active ingredient, which is bioavailable and with sufficient self-life.
  • a major object of the present invention is the selection of the optimal combination of pharmaceutical acceptable excipients and method of preparation in order to achieve the appropriate dissolution profile and stability for the finished dosage form. Said dosage form affords predictable and reproducible drug release rates in order to achieve better treatment to a patient.
  • a further approach of the present invention is to provide a tablet composition for oral administration comprising Ivabradine which is manufactured through a fast, simple and cost-effective process.
  • a pharmaceutical composition for oral administration comprising Ivabradine as an active ingredient in combination with moisture protection excipients and/or low or non- hygroscopic excipients in order to avoid polymorphic transformation.
  • a process for the preparation of a stable, solid dosage form for oral administration, containing Ivabradine HQ as an active ingredient in combination with moisture protection excipients and/or low or non- hygroscopic anhydrous excipients comprises the following steps:
  • a pharmaceutical composition comprising an active ingredient is considered to be “stable” if said ingredient degrades less or more slowly than it does on its own and/or in known pharmaceutical compositions.
  • the main object of the present invention is to provide a stable pharmaceutical composition of Ivabradine HQ for oral administration that avoids polymorphic transformation of the active pharmaceutical ingredient, is simple to manufacture, bioavailable, cost effective and possesses good pharmacotechnical properties.
  • form IV which is a hemihydrate and form ⁇ with 2.8% water content.
  • the X-ray diffractogram of polymorph IV comprises characteristic peaks at the following 2 theta (+/- 0.2) angles: 8.8°, 15.6°, 17.1°, 19.9°, 24.2° and 24.5°.
  • the X-ray diffractogram of polymorph ⁇ comprises characteristic peaks at the following 2 theta (+/- 0.2) angles: 8.1°, 14.7°, 15.1° and 21.9°.
  • Ivabradine HC1 used in the compositions of the present invention is 2 to 10 weight % of the total weight of the composition. Most preferably is 7 weight % of the total weight of the composition.
  • the excipients were selected with the perspective to enhance dissolution, physicochemical properties and stability of drug substances in the finished dosage form and thus were subjected to compatibility study with the API.
  • Water can be associated with the drug or the excipients. It can be incorporated during manufacture of the dosage form or acquired from the environment during processing, packaging or storage. Excipients with affinity for moisture might be expected to mitigate moisture sensitivity. Thus, formulations with a substance having a greater affinity for water compared with the drug could mean that moisture in the product is sequestrated by the excipient.
  • Ivabradine polymorphic forms do not undergo transformation to the most stable tetrahydrate form in solid compositions comprising moisture protection excipients and/or low or non-hygroscopic anhydrous excipients.
  • Moisture protection excipients have the property of either adsorbing or repelling water in order to protect the active ingredient from moisture and prevent any conversion of Ivabradine polymorphic forms to another polymorfic form. Dimethicone, attapulgite and a specific type of colloidal silicon dioxide (Syloid® FP) were used in the present invention for moisture protection.
  • Syloid® AL-l/FP is a highly porous with the smallest particle size silica powder.
  • the high porosity of Syloid® FP silica is capable of adsorbing a considerable amount of moisture, keeping the product dry and improving the stability. It is effective in amounts up to 20% in a two- step mixing process in which in first mixing it is blended with the active ingredient protecting it from moisture and then mixing with the rest of the excipients.
  • Syloid 244/FP is also highly porous with bigger particle size and is used as glidant.
  • the higher density of Syloid FP silicas, when compared to many fumed colloidal silicas, makes it easier to handle, results in less dust for a cleaner production environment and eliminates the need for sieving prior to usage.
  • Moisture protection excipients are comprised in the compositions of the present invention in an amount of from 1 to 25 weight % of the total weight of the composition.
  • excipients do not absorb or attract moisture from the surrounding environment.
  • excipients for example maltodextrin, copovidone, mannitol spray-dried in Ivabradine solid compositions eliminates the problem of polymorphic transformation over a period of time.
  • diluents for example lactose anhydrous, mannitol, starlac, microcrystalline cellulose, dextrose and fructose were used in formulation trials in order to enhance flowability and compaction properties of the powder blend.
  • Disintegrants provide the necessary force to rapture and eventually disintegrate the tablets.
  • Common disintegrants include crospovidone, primojel, sodium starch glycolate, alginic acid, carboxymethylcellulose sodium.
  • crospovidone and primojel were used in the present invention. Due to their large swelling capacity in aqueous solution they enhance the force needed to push particles apart within tablet pores exerted by the water, resulting in rapid tablet disintegration.
  • Binders promote cohesiveness to the powders and improve their processability.
  • Common binders include carbomer, ethyl cellulose, gelatin, guar gum, hydroxyethyl cellulose, maltodextrin, copovidone.
  • maltodextrin and copovidone were used in the present invention.
  • Colloidal silicon dioxide was used as glidant in order to improve flow properties of the powder blend and magnesium stearate was used in formulations as lubricant to prevent any sticking during compression.
  • the tablets of the present invention may be optionally film-coated with an immediate release coating preparation which has no effect on the release of the active ingredient.
  • an immediate release coating preparation which has no effect on the release of the active ingredient.
  • Such coating may have no functionality such as Opadry® ⁇ or it may confer moisture protection to the composition such as Opadry® AMB.
  • wet granulation using substantial amounts of wetting agent is the method which is most commonly used in pharmaceutical industry, as it provides better prospects in terms of ease of processing and presumably less problems associated with physical characteristics of various ingredients in the formulation.
  • Direct compression is more economic over wet granulation since it requires fewer unit operations. This means less equipment, lower power consumption, less space, less time and less labor leading to reduced production cost of tablets.
  • the tablets prepared by direct compression disintegrate into API particles instead of granules that directly come into contact with dissolution fluid and exhibits comparatively faster dissolution.
  • composition 1 2 3 4 5 6 7 8
  • compositions 1 to 8 were prepared with two different polymorphic forms of Ivabradine, form IV and form ⁇ .
  • Composition 1 was prepared with dry and wet granulation using starlac as diluent which is a co-dried mixture of lactose monohydrate with starch. Also, maltodextrin and primojel were used as binder and disintegrant respectively.
  • Composition 1 was prepared through dry granulation process according to the following steps:
  • Composition 1 was also prepared through wet granulation process according to the following steps:
  • composition 1 obtained through both dry and wet granulation were not the desirable.
  • composition 2 crospovidone was used as disintegrant instead of primojel and the physical properties were tested again for both dry and wet granulation.
  • Composition 2 was prepared with the same processes as Composition 1.
  • Tablets of Composition 1 and 2 with both polymorphs were packed in several blister types like Aluminum, PVC and triplex (PVC/PE/PVDQ as well as HDPE bottles with mounted desiccant and closed under nitrogen and the stability of the active ingredient's solid state was studied under normal (25°C/ 60% RH) and accelerated conditions (40°C/ 75% RH) through XRD analysis. According to the results, when wet granulation process was applied both polymorphs were converted to some extent to the most stable form ⁇ (tetrahydrate) at zero time since water is incorporated in the manufacturing process.
  • Dry formulations were stable in all packages under normal conditions but under accelerated conditions they converted to some extent to form ⁇ after 3 months in Aluminum blister and bottle and completely convert to form ⁇ in FVC and triplex blister.
  • several compositions have been prepared using dry mixing process with anhydrous excipients that are not hygroscopic and/or have very low moisture content.
  • composition 3 starlac was replaced by lactose anhydrous which has very low moisture content and is used with moisture sensitive drug substances. Also, it has very good flow properties and can be used in direct compression processes.
  • Composition 3 was prepared according to the following manufacturing process:
  • Composition 4 was prepared with mannitol spray-dried as diluent which is non-hygroscopic and is commonly used with moisture sensitive drugs.
  • Composition 4 was prepared according to the following manufacturing process:
  • compositions 3 and 4 provided rapid dissolution profiles and good physical characteristics of the tablets. Physical and chemical stability of Compositions 3 and 4 was tested after 6 months storage under normal (25°C/60% RH) and accelerated conditions (40°C/75%RH). The X-ray diffractograms indicated that Compositions 3 and 4 with both crystal forms were stable after 6 months storage under accelerated conditions in Aluminum blister and HDPE bottle. In the other blister types (PVC and triplex) the characteristic peaks of each form were not detected thus concluding that conversion to another polymorph took place. In particular, the most characteristic peak of form IV is at 15.5° which was detected in Compositions 3 and 4 only in Aluminum blister and HDPE bottle. In form ⁇ the characteristic peaks are at 8.1°, 14.7°, 15.1° and 21.9° and were also present in Compositions 3 and 4 only in Aluminum blister and HDPE bottle.
  • compositions were prepared with moisture protection excipients that prevent any conversion of the polymorphic forms to the tetrahydrate form.
  • Composition 5 was prepared using lactose anhydrous as diluent and dimethicone as water repellent in an amount of 1%.
  • Composition 6 attapulgite was used as water adsorbent in an amount of 5% and again lactose anhydrous as diluent.
  • compositions 5 and 6 were prepared with the same process as Composition 3.
  • Composition 7 copovidone as binder instead of maltodextrin since it is less hygroscopic.
  • Composition 7 was prepared with the same process as Composition 3.
  • Composition 8 a specific type of colloidal silicon dioxide, Syloid® FP was used for moisture protection.
  • Composition 8 was prepared according to the following manufacturing process:
  • Tablets of Composition 5 to 8 have been also tested for their physical and chemical stability under normal (25°C/60%RH) and accelerated conditions (40°C/75%RH).
  • the polymorphic forms were stable in Aluminum blister and HDPE bottle. In the other blister types (PVC and triplex) the characteristic peaks of each form were not detected thus concluding that conversion to another polymorph took place.

Abstract

La présente invention concerne une formulation pharmaceutique stable de formes posologiques solides pour administration orale contenant une quantité thérapeutiquement efficace de polymorphe IV ou δ d'ivabradine HCl en combinaison avec des excipients de protection contre l'humidité et/ou des excipients anhydres faiblement ou non hygroscopiques, de manière à éviter la transformation polymorphe de l'ingrédient actif. L'invention concerne également un procédé pour préparer la formulation.
EP16733287.3A 2015-06-11 2016-06-06 Composition pharmaceutique comprenant du chlorhydrate d'ivabradine et procédé pour la préparer Withdrawn EP3307249A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GR20150100270A GR1008821B (el) 2015-06-11 2015-06-11 Φαρμακευτικο σκευασμα που περιλαμβανει υδροχλωρικη ιβαμπραδινη και μεθοδος παρασκευης αυτου
PCT/EP2016/000928 WO2016198154A1 (fr) 2015-06-11 2016-06-06 Composition pharmaceutique comprenant du chlorhydrate d'ivabradine et procédé pour la préparer

Publications (1)

Publication Number Publication Date
EP3307249A1 true EP3307249A1 (fr) 2018-04-18

Family

ID=56292652

Family Applications (1)

Application Number Title Priority Date Filing Date
EP16733287.3A Withdrawn EP3307249A1 (fr) 2015-06-11 2016-06-06 Composition pharmaceutique comprenant du chlorhydrate d'ivabradine et procédé pour la préparer

Country Status (3)

Country Link
EP (1) EP3307249A1 (fr)
GR (1) GR1008821B (fr)
WO (1) WO2016198154A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112206235B (zh) * 2019-07-12 2021-09-14 鲁南制药集团股份有限公司 一种盐酸伊伐布雷定片剂及其制备方法

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2834896B1 (fr) 2002-01-23 2004-02-27 Servier Lab Composition pharmaceutique orodispersible d'ivabradine
FR2882553B1 (fr) 2005-02-28 2007-05-04 Servier Lab Forme cristalline beta du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent
FR2891826B1 (fr) 2005-10-11 2007-12-28 Servier Lab Forme cristalline 6 du chlorhydrate de l'ivabradine, son procede de preparation et les compositions pharmaceutiques qui la contiennent
CA2800442C (fr) 2010-06-14 2018-05-22 Ratiopharm Gmbh Composition pharmaceutique contenant de l'ivabradine a liberation modifiee
EP2589594A1 (fr) 2011-11-04 2013-05-08 Urquima S.A. Forme IV d'hydrochlorure d'ivabridine
ES2717715T3 (es) * 2014-02-14 2019-06-24 Synthon Bv Composición farmacéutica que comprende polimorfo IV de clorhidrato de ivabradina

Also Published As

Publication number Publication date
WO2016198154A1 (fr) 2016-12-15
GR1008821B (el) 2016-08-01

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