WO2017039670A1 - Composition pharmaceutique de vinpocétine - Google Patents

Composition pharmaceutique de vinpocétine Download PDF

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Publication number
WO2017039670A1
WO2017039670A1 PCT/US2015/048295 US2015048295W WO2017039670A1 WO 2017039670 A1 WO2017039670 A1 WO 2017039670A1 US 2015048295 W US2015048295 W US 2015048295W WO 2017039670 A1 WO2017039670 A1 WO 2017039670A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
pharmaceutical composition
vinpocetine
cellulose
use according
Prior art date
Application number
PCT/US2015/048295
Other languages
English (en)
Inventor
Miguel Angel ESPINOSA ALFARO
Maria Sitges Berrondo
Original Assignee
Neolpharma Inc
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 Neolpharma Inc filed Critical Neolpharma Inc
Priority to PCT/US2015/048295 priority Critical patent/WO2017039670A1/fr
Priority to MX2018002786A priority patent/MX2018002786A/es
Publication of WO2017039670A1 publication Critical patent/WO2017039670A1/fr

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Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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

Definitions

  • the present invention relates to the field of pharmaceutical products, particularly referred to a pharmaceutical composition comprising vinpocetine as active principle, the composition pharmacokinetics and its use in treatment of central nervous system diseases such as refractory epilepsy.
  • Epilepsy is a central nervous system disease affecting people worldwide and characterized by relapsing convulsions. Those patients with epilepsy which convulsions do not respond satisfactorily to treatment with anti-epilepsy drugs are considered to have drug-resistant epilepsy or refractory epilepsy .
  • Vinpocetine 3a, 16 a-apovincaminic acid ethyl ester
  • Vinpocetine is an alkaloid derived from vincamine which was introduced into clinical practice more than 30 years ago for treating patients with brain flow loss resulting in oxygen brain deficiency, and has also been promoted as a supplement for cognitive function and memory and also considered as a nootropic.
  • Vinpocetine increases brain blood flow and glucose transportation and intake by neurons (Daniel, Mark, Maier, Steven F., y Einstein, Gilles 0. Psychological Science in the Public Interest Vol. 3, No. 1, Mayo 2002, pages 12-38).
  • Vinpocetine is generally used in the treatment of cerebrovascular disorders and is generally available in 5 mg tablets of active ingredient.
  • vinpocetine has an anticonvulsant effect in convulsions induced by 100 mg/kg Pentylene tetrazole injection in unanesthetized animals (V. Nekrassov, M. Sitges / Epilepsy Research 60 (2004) 63-71) .
  • said studies in clinical practice have not been capable of demonstration as vinpocetine has a very short half-life of only 2 hours (L. Vlase, B. Bodiu, SE . Leucuta / Arzneim. -Forsch/Drug Research 11 (2005) 664-668; M. Vatsova, S. Tzevetanov, A. Drenska, J. Goranscheva, N. Tyutyulkova / Journal of Chromatography B 702 (1997) 221-226) .
  • vinpocetine is an effective anticonvulsive agent it is desirable to have a pharmaceutical composition capable of eliciting a suitable therapeutic response against refractory epilepsy .
  • Figure 1 shows the typical release profile with the dissolved drug percentage equivalent to the amount of released drug versus measured time in hours
  • Figure 2 shows an example of 60-mg dose pharmacokinetic curve of the pharmaceutical composition of the present invention, in a logarithmic plot.
  • Figure 3 shows a percentage median of crisis reduction observed at three months of treatment with a 95% probability range .
  • composition refers to a defined pharmaceutical form by its physical, chemical and biological characteristics.
  • composition and formulation are used herein indistinctly.
  • therapeutic use As detailed in the present invention the terms “therapeutic use”, “method of treatment”, and “use for preparation of a drug” are indistinct and referred to the same matter.
  • the present invention provides a vinpocetine composition for treatment of epilepsy. In another embodiment, the present invention provides a method of treatment of epilepsy comprising administering a pharmaceutical composition comprising vinpocetine to a patient .
  • the formulation according to the invention is useful for treatment of refractory epilepsy. In one further embodiment, the formulation is also effective for treating effects associated with epilepsy such as cognitive impairment .
  • the sustained-release formulation according to the invention is capable of releasing vinpocetine in a predetermined time.
  • the vinpocetine is released at the required rate to reach and maintain an active principle therapeutic concentration in blood, sufficient to exert a pharmacological effect against epilepsy.
  • the formulation according to the invention provides a pharmaceutical formulation adapted to release vinpocetine, which release rate is independent of the vinpocetine amount which is included within the dosage form, said release rate further being constant over a determined period .
  • a pharmaceutical formulation adapted to release vinpocetine is provided, allowing plasma levels of this active principle to be therapeutically and constantly maintained during 12 hours, for treatment of epilepsy.
  • the composition according to the invention is adapted to be administrable by digestive, parenteral, respiratory and topical route.
  • the pharmaceutical formulation according to the invention is an oral formulation; more preferably, the oral formulation is a tablet or caplet.
  • composition according to the invention comprises vinpocetine or a pharmaceutically acceptable salt thereof.
  • the vinpocetine amount in the formulation is from 10 mg to 150 mg.
  • the formulation preferably comprises 15 to 90 mg of vinpocetine.
  • the formulation according to the invention comprises pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients are selected from the group consisting of release- modifying agents, diluent agents, and lubricant agents.
  • the release-modifying agent is a cellulose polymer.
  • the cellulose polymer is hydroxypropylmethyl cellulose, hydroxypropylcellulose, sodium carboxymethyl cellulose, ethyl cellulose, microcrystalline cellulose, carbomer, and mixtures or combinations thereof.
  • the release- modifying agent is a carbomer.
  • the release- modifying agent is hydroxypropylmethyl cellulose.
  • the diluent agents which may be used in the pharmaceutical composition according to the invention are such as, silicified microcrystalline cellulose, microcrystalline cellulose, co-processed cellulose and lactose, powdered cellulose, lactose, corn starch, mannitol, and mixtures thereof.
  • the diluent is silicified microcrystalline cellulose.
  • the lubricants included in the composition are magnesium stearate, stearic acid, sodium stearyl fumarate, sodium benzoate, transcutol, polyethylene glycol, silicon dioxide and mixtures thereof.
  • the diluent is magnesium stearate.
  • the release-modifying agent is present in the pharmaceutical composition in an amount from 10 to 45% by weight, based on total composition weight.
  • the release-modifying agent is in an amount from 30% by weight of total composition.
  • the diluent is present in the pharmaceutical composition in an amount from 20 to 70% by weight, based on total composition weight.
  • the release-modifying agent is in an amount from 56.46% by weight of total composition.
  • the lubricant is present in the pharmaceutical composition in an amount from 0.25 to 2% by weight, based on total composition weight.
  • the present invention provides a sustained-release vinpocetine pharmaceutical composition
  • a sustained-release vinpocetine pharmaceutical composition comprising the following components by weight based on total composition :
  • the composition comprises an acidifying agent.
  • the acidifying agents which may be used in the pharmaceutical composition according to the invention are such as, citric acid, fumaric acid, ascorbic acid, malic acid, tartaric acid, and mixtures thereof.
  • the acidifying agent is anhydrous citric acid.
  • the acidifying agent is present in the pharmaceutical composition in an amount from 1 to 15% by weight, based on total composition weight. Preferably, the acidifying agent is present in an approximate amount of 7 % by weight.
  • the composition according to the invention keeps a 1:9 vinpocetine ratio in respect of total excipients.
  • the vinpocetine composition in accordance with the 1:9 vinpocetine to total excipient ratio, has a size such that it may be orally administered without difficulty.
  • the pharmaceutical formulation according to the present invention reaches release rates from 5.9 to 6.5 ng/h of vinpocetine with a 50% bioavailability, during a period of 12 hours according to a bioavailability in vivo profile. In one further embodiment, the pharmaceutical formulation according to the invention reaches release rates from 0.2 to 6 mg/h during 24 hours according to a dissolution in vitro profile.
  • the pharmaceutical composition reaches a maximum concentration from 22 ng/mL to 125 ng/mL in plasma, 1 to 4 hours after administration, preferably 1.5 hours after administration.
  • the composition reaches a vinpocetine active metabolite bioavailability of 50% during 12 hours, (procedure calculated taking the area under the curve (ABC) and dose as reference data (Chen J, Cai J, Tao W, Mei N, Cao S, Jiang X. Journal of Chromatography B. 830, 2006, 201-206) and a complete removal of active principle within 24 hours.
  • the active ingredient release rate of the present invention allows the release profile to include up to 24 hours and being specific to achieve the intended therapeutic effect for at least 12 hours.
  • the concentrations of present invention achieve equivalent percentage release rates within a period of 24 hours making this pharmaceutical composition to reach the same release rate regardless of vinpocetine dose .
  • the permanence of vinpocetine active metabolite in a patient's plasma is at least 12 hours.
  • the pharmaceutical formulation according to the invention is adapted to be administered to a patient at a rate from 1 to 4 mg per kg per day, preferably 1 a 3 mg per kg per day.
  • composition is adapted to be administered one to three times per day.
  • composition according to the invention pharmacokinetic parameters of certain embodiments of the composition according to the invention were obtained from clinical trials.
  • Dissolution profiles developed for the pharmaceutical composition demonstrate that the active principle is fully released from composition within 24 hours from being administered .
  • vinpocetine is a useful anti-epilepsy agent for treatment of refractory epilepsy; however in other embodiments, the present invention is also directed to the treatment of central nervous system diseases.
  • Silicon dioxide 2.60 1.00%
  • Silicon dioxide 1. 30 1. 00%
  • Results from in vitro behavior from above compositions are shown in Figure 1, showing a typical release profile (released drug amount [Q] versus time) obtained from examples at different dosages of the present invention, 15mg, 30mg, 45mg and 60 mg of vinpocetine.
  • the test was conducted by a dissolution tester equipped with apparatus II (paddles) according to the method disclosed in 2013 USP36-NF31 (United States Pharmacopeia-National Formulary) at 50 rpm keeping bath temperature at 37°C ⁇ 0.5 °C.
  • a Varian Model 7025 dissolution tester with apparatus II (paddles) equipped with a Varian Mod VK810 peristaltic pump, coupled automatedly with a Varian Mod Cary 50 Tablet UV/Vis spectrophotometer was used.
  • Vinpocetine quantification a series of 6 vinpocetine solutions dissolved in 0.1 N hydrochloric acid from 0.024 mg/mL to 0.144 mg/mL was prepared representing from 20% to 120% of vinpocetine nominal concentration.
  • the equipment was programmed to take a volume of 5 mL at 3h, 6h, 9h, 12h, 18h and 24h by means of a peristaltic pump with recycling from the sample to the dissolution cup thus the medium volume keeps constant.
  • a peristaltic pump with recycling from the sample to the dissolution cup thus the medium volume keeps constant.
  • samples were filtered and sample and solution absorbance was determined from the calibration curve at 224 nm in 0.1 cm continuous flow cells.
  • Results show that all compositions reach a similar dissolution percentage for a period of 24 hours at release rates from 0.2 to 6 mg/h during 24 hours, confirming a constant release during this determined time period and dose- independent .
  • Different vinpocetine doses are derived from the dissolution profile reaching a constant release rate in a range from 0.2 to 6.00 mg/h during a time close to 24 hours. Release rate is similar for different doses of present invention formulation.
  • FIG. 1 A pharmacokinetic study in patients treated with a sustained- and controlled-release dosage form pharmaceutically adapted to release vinpocetine of the present invention was conducted, using a 60 mg composition at single dose.
  • Figure 2 shows the pharmacokinetic curve of the 60 mg vinpocetine pharmaceutical composition, plotted in logarithmic form.
  • a phase III multi- center, double-blind, randomized, parallel-group, placebo controlled trial lasting 12 weeks was conducted in children and adult population with refractory epilepsy; to assess the efficacy and safety of the sustained- and controlled-release dosage form of the present invention vs placebo as added therapy to a treatment.
  • Patients were diagnosed with partial refractory epilepsy, having a regular use of CBZ, lamotrigine (LMT) , topiramate (TPM) , AVP or any combination thereof.
  • the vinpocetine composition of the present invention may be effective in treatment of refractory epilepsy.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique à libération prolongée comprenant de la vinpocétine comme principe actif. La présente invention concerne également la pharmacocinétique de la composition pharmaceutique. La composition selon la présente invention a trait au traitement de maladies du système nerveux central, telles que l'épilepsie et l'épilepsie réfractaire. Dans un mode de réalisation, la présente invention concerne une composition de vinpocétine pour le traitement de l'épilepsie. Dans un autre mode de réalisation, la présente invention concerne un procédé de traitement de l'épilepsie comprenant l'administration d'une composition pharmaceutique comprenant de la vinpocétine à un patient.
PCT/US2015/048295 2015-09-03 2015-09-03 Composition pharmaceutique de vinpocétine WO2017039670A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/US2015/048295 WO2017039670A1 (fr) 2015-09-03 2015-09-03 Composition pharmaceutique de vinpocétine
MX2018002786A MX2018002786A (es) 2015-09-03 2015-09-03 Composicion farmaceutica de vinpocetina.

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2015/048295 WO2017039670A1 (fr) 2015-09-03 2015-09-03 Composition pharmaceutique de vinpocétine

Publications (1)

Publication Number Publication Date
WO2017039670A1 true WO2017039670A1 (fr) 2017-03-09

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MX (1) MX2018002786A (fr)
WO (1) WO2017039670A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4904476A (en) * 1986-03-04 1990-02-27 American Home Products Corporation Formulations providing three distinct releases
US20050096369A1 (en) * 2003-11-04 2005-05-05 Hoang Ba X. Compositions and methods for treating cellular proliferation disorders
US20070135470A1 (en) * 2003-10-28 2007-06-14 Universidad Nacional Autonoma De Mexico Utilization of vinpocetine to avoid complications in particular those associated to hearing which occur with epilepsy, and treatment thereof
US20120231010A1 (en) * 2008-07-03 2012-09-13 Osteogenex Inc. Vinpocetine and eburn amonine derivatives for promoting bone growth

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4904476A (en) * 1986-03-04 1990-02-27 American Home Products Corporation Formulations providing three distinct releases
US20070135470A1 (en) * 2003-10-28 2007-06-14 Universidad Nacional Autonoma De Mexico Utilization of vinpocetine to avoid complications in particular those associated to hearing which occur with epilepsy, and treatment thereof
US20050096369A1 (en) * 2003-11-04 2005-05-05 Hoang Ba X. Compositions and methods for treating cellular proliferation disorders
US20120231010A1 (en) * 2008-07-03 2012-09-13 Osteogenex Inc. Vinpocetine and eburn amonine derivatives for promoting bone growth

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SITGES ET AL.: "Effects of carbamazepine, phenytoin, valproic acid, oxcarbazepine, lamotrigine, topiramate and vinpocetine on the presynaptic Ca2+ channel-mediated release of [3H] glutamate: Comparison with the Na+ channel-mediated release", NEUROPHARMACOLOGY, vol. 53, no. 7, 26 August 2007 (2007-08-26), pages 854 - 862, XP022325177 *
SITGES ET AL.: "Vinpocetine inhibits glutamate release induced by the convulsive agent 4-aminopyridine more potently than several antiepileptic drugs", EPILEPSY RESEARCH, vol. 96, no. 3, 7 July 2011 (2011-07-07), pages 257 - 266, XP028312301 *

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