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WO2018163199A1 - Compositions de ranolazine à libération prolongée - Google Patents

Compositions de ranolazine à libération prolongée Download PDF

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Publication number
WO2018163199A1
WO2018163199A1 PCT/IN2018/050113 IN2018050113W WO2018163199A1 WO 2018163199 A1 WO2018163199 A1 WO 2018163199A1 IN 2018050113 W IN2018050113 W IN 2018050113W WO 2018163199 A1 WO2018163199 A1 WO 2018163199A1
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WO
WIPO (PCT)
Prior art keywords
acid
ranolazine
sustained release
dosage form
release pharmaceutical
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.)
Ceased
Application number
PCT/IN2018/050113
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English (en)
Inventor
Venkata Nookaraju Sreedharala
Valluri GALIB SAHEB
Ravi Kumar P
Sridhar SADHULA
Varma Srinivasa Rajasekara RUDRARAJU
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.)
AIZANT DRUG RESEARCH SOLUTIONS PRIVATE Ltd
Original Assignee
AIZANT DRUG RESEARCH SOLUTIONS PRIVATE Ltd
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 AIZANT DRUG RESEARCH SOLUTIONS PRIVATE Ltd filed Critical AIZANT DRUG RESEARCH SOLUTIONS PRIVATE Ltd
Publication of WO2018163199A1 publication Critical patent/WO2018163199A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating

Definitions

  • the present invention relates to pharmaceutical compositions of Ranolazine or pharmaceutically acceptable salts, polymorphs, solvates, hydrates, enantiomers thereof.
  • the present invention relates to sustained release dosage forms of Ranolazine comprising a combination of pH-independent binders and acids, and optionally one or more pharmaceutically acceptable excipients.
  • IV intravenous formulations of dihydrochloride Ranolazine further comprising propylene glycol, polyethylene glycol 400, Tween 80 and 0.9% saline.
  • U.S. Pat. No. 5,506,229 which is incorporated herein by reference in its entirety, discloses the use of Ranolazine and its pharmaceutically acceptable salts and esters for the treatment of tissues experiencing a physical or chemical insult, including cardioplegia, hypoxic or reperfusion injury to cardiac or skeletal muscle or brain tissue, and for use in transplants. Oral and parenteral formulations are disclosed, including controlled release formulations.
  • U.S. Pat. No. 5,506,229 describes a controlled release formulation in capsule form comprising microspheres of Ranolazine and microcrystalline cellulose coated with release controlling polymers.
  • This patent also discloses IV Ranolazine formulations which at the low end comprise 5 mg Ranolazine per milliliter of an IV solution containing about 5% by weight dextrose. And at the high end, there is disclosed an IV solution containing 200 mg Ranolazine per milliliter of an IV solution containing about 4% by weight dextrose.
  • a typical oral dosage form is a compressed tablet, a hard gelatin capsule filled with a powder mix or granulate, or a soft gelatin capsule (softgel) filled with a solution or suspension.
  • a typical oral dosage form is a compressed tablet, a hard gelatin capsule filled with a powder mix or granulate, or a soft gelatin capsule (softgel) filled with a solution or suspension.
  • U.S. Pat. No. 5,472,707 discloses a high-dose oral formulation employing supercooled liquid Ranolazine as a fill solution for a hard gelatin capsule or softgel.
  • U.S. Pat. No. 6,303,607 discloses a sustained release pharmaceutical dosage form including at least 50% by weight Ranolazine and an admixture of at least one pH-dependent binder and at least one pH-independent binder, and wherein the peak to trough plasma Ranolazine level does not exceed 3 : 1 over a 24 hour period.
  • US Pat No.20060177502Al discloses a sustained release pharmaceutical formulation comprising: less than 50% Ranolazine; a pH dependent binder; a pH independent binder; and one or more pharmaceutically acceptable excipients.
  • US Pat No. 20120177729 discloses a sustained release dosage form of Ranolazine comprising a combination of at least two pH-dependent binders and optionally one or more pharmaceutically acceptable excipient(s).
  • sustained release dosage form of Ranolazine free of pH-dependent binders
  • sustained release dosage forms of Ranolazine can be prepared using combination of pH-independent binders and acids, that are bioequivalent to the marketed formulation and provide the appropriate plasma levels of Ranolazine that are necessary for the treatment of angina and other cardiovascular diseases.
  • An object of the present invention is to provide stable sustained release pharmaceutical dosage forms comprising a therapeutically effective amount of Ranolazine.
  • Another object of the present invention is to provide sustained release pharmaceutical dosage forms, comprising a therapeutically effective amount of Ranolazine,free of pH-dependent polymers.
  • Yet another object of the invention is to provide sustained release pharmaceutical dosage forms comprising a therapeutically effective amount of Ranolazine, one or more of pH-independent binders, one or more acids, and optionally one or more pharmaceutically acceptable excipients.
  • Another object of the invention is to provide sustained release pharmaceutical dosage forms comprising a therapeutically effective amount of Ranolazine, one or more of pH-independent binders, one or more acids, and optionally one or more pharmaceutically acceptable excipients, characterized in that the sustained release pharmaceutical composition of invention is bioequivalent to marketed formulation.
  • another object of the invention is to provide sustained release pharmaceutical dosage forms comprising a therapeutically effective amount of Ranolazine, one or more of pH- independent binders, one or more acids, and optionally one or more pharmaceutically acceptable excipients, wherein about 20% to about 40% of said Ranolazine is released after 2 hours; from about 45% to about 65% of said Ranolazine is released after 8 hours; not less than about 70% of said Ranolazine is released after 24 hours.
  • Yet another object of the invention is to provide simple and cost-effective method for preparation of asustained release pharmaceutical dosage forms comprising a therapeutically effective amount of Ranolazine.
  • Figure- 1 is the comparative dissolution data for Example-3
  • Figure-2 is the comparative dissolution data for Example-4
  • Figure-3 is the comparative dissolution data for Example-5
  • Figure-4 is the comparative dissolution data for Example-6
  • Figure-5 is the comparative dissolution data for Example-7
  • Figure-6 is the comparative dissolution data for Example-8
  • An present invention providesstable sustained release pharmaceutical dosage forms comprising a therapeutically effective amount of Ranolazine.
  • Ranolazine is (+-)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy) propyl]-l- piperazine-acetamide, or its enantiomers (R)-(+)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2- methoxypheno-xy)-propyl]- -1-piperazineacetamide, and (S)-(-)-N-(2,6-dimethylphenyl)-4-[2- hydroxy-3-(2 -methoxyphenoxy)-propyl]-l-piperazineacetamide and their pharmaceutically acceptable salts, polymorphs, solvates, hydrates, enantiomers and mixtures thereof.
  • pharmaceutically acceptable salts refer to derivatives of the Ranolazine wherein Ranolazine is modified by reacting it with an acid or base as needed to form an ionically bound pair.
  • pharmaceutically acceptable salts include conventional non-toxic salts or the quaternary ammonium salt of the parent compound formed, for example, from non-toxic inorganic or organic acids. Suitable non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and others known to those of ordinary skill in the art.
  • the salts prepared from organic acids such as amino acids, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenyl acetic, benzoic, salicylic, sulfanilic, fumaric, oxalic, isethionic, and others known to those of ordinarily skilled in the art.
  • the amount of Ranolazine present in the dosage form according to the present invention is in the range of 30 to 80%, more preferably 40 to 70%.
  • stable refers to physical stability and/or chemical stability of the active agent in a topical composition, wherein changes in the drug assay values and/or impurities content are less than about 10%, during stability study storage of the composition at 25° C. and 60% relative humidity (RH), or 30° C. and 65% RH, or 40° C. and 75% RH, for durations such as 3, 6, 12, 18, or 24 months.
  • sustained release as used herein in relation to the dosage form means which is not immediate release and is taken to encompass controlled release, prolonged release, timed release, retarded release, extended release and delayed release. Sustained release can be used interchangeably with prolonged release, programmed release, timed release, extended release, controlled release and other such dosage forms.
  • the "dosage form” according to the present invention include but is not limited to tablets, pellets, beads, granules, capsules, microcapsules and tablets in capsules.
  • “Therapeutically effective amount” means that the amount of active agent, which halts or reduces the progress of the condition being treated or which otherwise completely or partly cures or acts palliatively on the condition. A person skilled in the art can easily determine such an amount by routine experimentation and with an undue burden.
  • pharmaceutically acceptable is meant a carrier comprised of a material that is not biologically or otherwise undesirable.
  • An embodiment of the present invention provides sustained release pharmaceutical dosage forms, comprising a therapeutically effective amount of Ranolazine, free of pH-dependent polymers.
  • sustained release pharmaceutical dosage forms comprising a therapeutically effective amount of Ranolazine, one or more of pH- independent binders, one or more acids, and optionally one or more pharmaceutically acceptable excipients.
  • Ranolazine is relatively insoluble in aqueous solutions having a pH above about 6.5, while the solubility begins to increase dramatically below about pH 6, therefore it is very difficult to prepare a sustained release dosage form of Ranolazine wherein the drug is released throughout the gastrointestinal tract (GIT).
  • GIT gastrointestinal tract
  • a combination of one or more pH-independent binders and one or more acids are chosen, to control the dissolution rate of the Ranolazine so that the dosage form releases Ranolazine slowly and continuously as it passes through the stomach and gastrointestinal tract.
  • Proper selection and combination of pH-independent binder(s) and acid(s) in the dosage form helps in sustaining the release of Ranolazine throughout the GIT.
  • Incorporating acids into the matrix system of the pH-independent binders partially neutralizes the acidic pH of the GIT, thereby enhancing the release profile of the drug.
  • binders suitable for use in this invention are materials which include but not limited to hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, ethylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, neutral poly(meth)acrylate esters, and the like.
  • the pH-independent binders are present in the formulation of this invention in an amount ranging from about 5 to about 25 wt. %.
  • acids suitable for use in this invention include but not limited to propionic acid, isobutyric acid, butyric acid, isovaleric acid, valeric acid, caproic acid, oxalic acid, lactic acid, malic acid, maleic acid, malonic acid, tartaric acid, succinic acid, fumaric acid, acetic acid, citric acid, 4-hydroxy benzoic acid, 2,5-dihydroxy benzoic acid, adipic acid, glycolic acid, decanoic acid, un-decanoic acid, cholic acid, dexo-cholic acid, mandelic acid, d-camphonic acid, benzoic acid, methansulphonic acid, ethanesulphonic acid, benzesulphonic acid, p-toluenesulphonic acid or combinations thereof.
  • the acids are present in the formulation of this invention in an amount ranging from about 5 to about 25 wt. %.
  • "Optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • “optionally pharmaceutical excipients” indicates that a formulation so described may or may not include pharmaceutical excipients other than those specifically stated to be present, and that the formulation so described includes instances in which the optional excipients are present and instances in which they are not.
  • the pharmaceutical dosage forms of the present invention comprise additional pharmaceutically acceptable excipients selected from the group consisting diluents, lubricants, disintegrants, glidants, surface-active agents, antioxidants, thickeners, suspending agents, flavoring agents, sweeteners, and colorants.
  • additional pharmaceutically acceptable excipients selected from the group consisting diluents, lubricants, disintegrants, glidants, surface-active agents, antioxidants, thickeners, suspending agents, flavoring agents, sweeteners, and colorants.
  • the amount of excipient employed will depend upon how much active agent is to be used. One excipient can perform more than one function.
  • Fillers or diluents which include, but are not limited to confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose, xylitol, sorbitol, talc, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic or tribasic, calcium sulphate, and the like can be used.
  • Lubricants may be selected from, but are not limited to, those conventionally known in the art such as Mg, Al or Ca or Zn stearate, polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil and talc.
  • Glidants include, but are not limited to, silicon dioxide; magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel and other materials known to one of ordinary skill in the art.
  • compositions may optionally contain disintegrants which include but are not limited to starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone or crospovidone, e.g., POLYPLASDONE XL, cross-linked sodium carboxymethylcellulose or croscarmellose sodium, e.g., AC-DI-SOL from FMC; and cross-linked calcium carboxymethylcellulose; and guar gum.
  • disintegrants include but are not limited to starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone or crospovidone, e.g., POLYPLASDONE XL, cross-linked sodium carboxymethylcellulose or croscarmellose sodium, e.g., AC-DI-SOL from FMC; and cross-linked calcium carboxymethylcellulose; and gu
  • compositions may optionally contain a surface-active agent.
  • the preferred agent is copolymers composed of a central hydrophobic chain of polyoxypropylene (poly (propylene oxide)) and polyoxyethylene (poly (ethylene oxide)) that is well known as poloxamer.
  • other agents may also be employed such as dioctyl sodium sulfosuccinate (DSS), triethanolamine, sodium lauryl sulphate (SLS), polyoxyethylene sorbitan and poloxalkol derivatives, quaternary ammonium salts or other pharmaceutically acceptable surface- active agents known to one ordinary skilled in the art.
  • the sustained release pharmaceutical dosage forms comprising a therapeutically effective amount of Ranolazine, one or more of pH-independent binders, one or more acids, and optionally one or more pharmaceutically acceptable excipients, such that when the composition tested in-vitro by USP Apparatus II (Paddle) method of U.S. Pharmacopoeia at 100 rpm, at 37 °C in 900 ml of phosphate buffer, pH 6.8, about 20% to about 40% of said Ranolazine is released after 2 hours; from about 45% to about 65% of said Ranolazine is released after 8 hours; not less than about 70% of said Ranolazine is released after 24 hours.
  • Another object of the invention is to provide sustained release pharmaceutical dosage forms comprising a therapeutically effective amount of Ranolazine, one or more of pH-independent binders, one or more acids, and optionally one or more pharmaceutically acceptable excipients, characterized in that the sustained release pharmaceutical composition of invention is bioequivalent to marketed formulation.
  • the sustained release pharmaceutical dosage forms comprising a therapeutically effective amount of Ranolazine, one or more of pH-independent binders, one or more acids, and optionally one or more pharmaceutically acceptable excipients, such that Maximum Plasma Concentration (C max ) and Area Under Curve (AUC) values of the compositions are within the limit of 80 % to 125 % of C max and AUC of the marketed composition of Ranolazine modified release tablets (Ranexa ) respectively.
  • C max Maximum Plasma Concentration
  • AUC Area Under Curve
  • Another embodiment of the present invention provides a simple and cost-effective method for preparation of a sustained release pharmaceutical dosage form comprising a therapeutically effective amount of Ranolazine.
  • the pharmaceutical composition of the invention can be formed by various methods known in the art such as by dry granulation, wet granulation, melt granulation, direct compression, double compression, extrusion spheronization, layering and the like.
  • Sustained release pharmaceutical dosage form according to the present invention are manufactured preferably as per the following procedure: i) Blending the active agent, pH-independent binder(s), acid (s) and one or more pharmaceutically acceptable excipient(s),
  • the pharmaceutical dosage forms of the invention may further be coated.
  • the coating may be a functional or non-functional coating.
  • the preferred coating of this invention is comprised of a commercial film-coating product designed for aqueous film coating containing the water-soluble, film-forming resin, such a product is commercially available under the trade name Opadry White.
  • These coating comprises one or more excipients selected from the group comprising coating agents, opacifiers, fillers, polishing agents, colouring agents, antitacking agents and the like.
  • Table- 1 shows the comparative dissolution profile of Ranolazine sustained release tablets of Example 3 of the present invention (Test) & Ranexa ® 1 gm tablets (Reference) carried out in-vitro by USP Apparatus II (Paddle) method of U.S. Pharmacopoeia at 100 rpm, at 37 °C in 900 ml of phosphate buffer, pH 6.8.
  • the release profile (cumulative % of drug released) is given in Table 1.
  • Table-2 shows the comparative dissolution profile of Ranolazine sustained release tablets of Example 4 of the present invention (Test) & Ranexa ® 1 gm tablets (Reference) carried out in-vitro by USP Apparatus II (Paddle) method of U.S. Pharmacopoeia at 100 rpm, at 37 °C in 900 ml of phosphate buffer, pH 6.8.
  • the release profile (cumulative % of drug released) is given in Table 2.
  • Table 2 shows the comparative dissolution profile of Ranolazine sustained release tablets of Example 4 of the present invention (Test) & Ranexa ® 1 gm tablets (Reference) carried out in-vitro by USP Apparatus II (Paddle) method of U.S. Pharmacopoeia at 100 rpm, at 37 °C in 900 ml of phosphate buffer, pH 6.8.
  • the release profile (cumulative % of drug released) is given in Table 2.
  • Table-3 shows the comparative dissolution profile of Ranolazine sustained release tablets of Example 5 of the present invention (Test) & Ranexa ® 1 gm tablets (Reference) carried out in-vitro by USP Apparatus II (Paddle) method of U.S. Pharmacopoeia at 100 rpm, at 37 °C in 900 ml of phosphate buffer, pH 6.8.
  • the release profile (cumulative % of drug released) is given in Table 3.
  • Table-4 shows the comparative dissolution profile of Ranolazine sustained release tablets of Example 6 of the present invention (Test) & Ranexa 1 gm tablets (Reference) carried out in-vitro by USP Apparatus II (Paddle) method of U.S. Pharmacopoeia at 100 rpm, at 37 °C in 900 ml of phosphate buffer, pH 6.8.
  • the release profile (cumulative % of drug released) is given in Table 4.
  • Example 7 Ranolazine sustained release tablet composition
  • Blend for compression layer 1 Blend for compression layer 1
  • Blend for compression layer 2 Blend for compression layer 2
  • Blend for compression layer 1
  • Blend for compression layer 2 is a blend for compression layer 2:
  • Table-5 shows the comparative dissolution profile of Ranolazine sustained release tablets of Example 7 of the present invention (Test) & Ranexa ® 1 gm tablets (Reference) carried out in-vitro by USP Apparatus II (Paddle) method of U.S. Pharmacopoeia at 100 rpm, at 37 °C in 900 ml of phosphate buffer, pH 6.8.
  • the release profile (cumulative % of drug released) is given in Table 5.
  • Example 8 Ranolazine sustained release tablet composition
  • Blend for compression layer 2 Blend for compression layer 2
  • Blend for compression layer 1
  • Blend for compression layer 2 5. Sifting: Ranolazine, Microcrystalline cellulose PH 101 and sodium starch glycolate was sifted through a specific mesh,
  • Table-6 shows the comparative dissolution profile of Ranolazine sustained release tablets of Example 8 of the present invention (Test) & Ranexa ® 1 gm tablets (Reference) carried out in-vitro by USP Apparatus II (Paddle) method of U.S. Pharmacopoeia at 100 rpm, at 37 °C in 900 ml of phosphate buffer, pH 6.8.
  • the release profile (cumulative % of drug released) is given in Table 6.
  • a single dose, open-label, randomized, 2-period, 2-treatment, 2-way crossover bioavailability study was made with the Ranolazine Sustained release tablets of Example 5 under fasted conditions. Twenty Four healthy subjects were randomly assigned to a treatment sequence and received two separate single - dose administrations of study medication, one treatment per period, according to the randomized schedule. The subjects received Treatment T (test product of Example 5, Ranolazine Sustained release tablets) and Treatment R (reference product, Ranexa ® 1 Gm tablets) following an overnight fast of at least ten hours. Blood samples were collected, pre-dose and after administration of the dose, for 12 hours.
  • Example 8 exhibits a geometric mean ratio of Cmax, AUClast and AUCinf of within 80% to 125% limits for Ranolazine.

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  • Health & Medical Sciences (AREA)
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  • Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques de ranolazine ou de sels, polymorphes, solvates, hydrates, énantiomères pharmaceutiquement acceptables de celle-ci. En particulier, la présente invention concerne des formes posologiques à libération prolongée de ranolazine comprenant une combinaison de liants indépendants du pH et d'acides, et éventuellement un ou plusieurs excipients pharmaceutiquement acceptables.
PCT/IN2018/050113 2017-03-06 2018-03-03 Compositions de ranolazine à libération prolongée Ceased WO2018163199A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111000818A (zh) * 2020-01-04 2020-04-14 东莞市东阳光仿制药研发有限公司 一种雷诺嗪组合物及其制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000336032A (ja) * 1999-05-26 2000-12-05 Kissei Pharmaceut Co Ltd ピペラジンアセトアミド誘導体を含有する徐放性経口医薬品組成物

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000336032A (ja) * 1999-05-26 2000-12-05 Kissei Pharmaceut Co Ltd ピペラジンアセトアミド誘導体を含有する徐放性経口医薬品組成物

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111000818A (zh) * 2020-01-04 2020-04-14 东莞市东阳光仿制药研发有限公司 一种雷诺嗪组合物及其制备方法

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