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WO2021118403A1 - Système d'administration de 2-éthyl-6-méthyl-3-hydroxyopyridine succinate pour prise orale - Google Patents

Système d'administration de 2-éthyl-6-méthyl-3-hydroxyopyridine succinate pour prise orale Download PDF

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Publication number
WO2021118403A1
WO2021118403A1 PCT/RU2020/000665 RU2020000665W WO2021118403A1 WO 2021118403 A1 WO2021118403 A1 WO 2021118403A1 RU 2020000665 W RU2020000665 W RU 2020000665W WO 2021118403 A1 WO2021118403 A1 WO 2021118403A1
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WIPO (PCT)
Prior art keywords
ethyl
methyl
hydroxypyridine
succinate
emhps
Prior art date
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Ceased
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English (en)
Russian (ru)
Inventor
Дамир Хизбуллаевич САЛАХЕТДИНОВ
Александр Александрович ЗАБОЗЛАЕВ
Александр Викторович РОЖДЕСТВЕНСКИЙ
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Obshchestvo S Ogranichennoy Otvetstvennostiyu "nauchno Proizvodstvennaya Kompaniya "pharmasoft"
Original Assignee
Obshchestvo S Ogranichennoy Otvetstvennostiyu "nauchno Proizvodstvennaya Kompaniya "pharmasoft"
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Publication of WO2021118403A1 publication Critical patent/WO2021118403A1/fr
Anticipated expiration legal-status Critical
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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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/25—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids with polyoxyalkylated alcohols, e.g. esters of polyethylene glycol
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4425—Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
    • 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

Definitions

  • the invention relates to the chemical-pharmaceutical industry, medicine and veterinary medicine and describes a delivery system for 2-ethyl-6-methyl-3-hydroxypyridine succinate (hereinafter EMHPS) for oral administration in the form of a tablet.
  • EMHPS 2-ethyl-6-methyl-3-hydroxypyridine succinate
  • the invention can be used in medicine or veterinary medicine as a drug for oral administration of EMHPS for the treatment and prevention of various diseases and pathological conditions of the human or animal organism.
  • EMHPS (trade name - Mexidol®, etc.) are widely used as an antioxidant and antihypoxic agent, characterized by a wide spectrum of pharmacological action and high efficiency (nootropic and tranquilizing action - patent RU2065299, anti-ischemic and antiatherosclerotic action - patent RU 2144822, antianginal - patent RU 2168993, hepatoprotective - patent RU 2189817, antibacterial - US Pat. RU 2157686 and others).
  • EMHPS is used in the treatment of the following human diseases / conditions:
  • compositions based on EMHPS in the form of various dosage forms solution for parenteral administration (Mexidol® 5% solution for injection P N002161 / 01, patents RU2205640, 2380089, 2398583), tablets (Mexidol® coated tablets, 0.125 g LSR-002063 / 07), capsules (patent RU 2144822, 2145855).
  • dosage forms for injection are most preferred.
  • a number of disadvantages of this route of administration are well known - the risk of infection, the need for the presence of qualified personnel, the painfulness of injections, and how as a consequence, the impossibility of long-term (more than 3-4 weeks) treatment with parenteral dosage forms.
  • the injectable form does not provide a long-term nootropic effect, while there is a change in the spectrum of the pharmacological activity of the drug, which is expressed in an increase in aggressiveness, emotional reactivity, and a decrease in anti-stress action [see. description RU 2065299].
  • the objective of the invention is to develop a system for the delivery of EMHPS for oral administration in the form of a tablet, providing increased bioavailability with simultaneous long-term maintenance of the required concentration of the active substance in the blood plasma.
  • the authors of the invention described in patent RU 2444359 which can be indicated as the closest analogue, have attempted to solve this problem. They have developed the composition of tablets with modified release EMHPS.
  • the described dosage form is are tablets having in their structure, spheroids with an active substance, coated. Depending on the composition of the shells, forms with different solubility of the active substance were created. For each group of obtained spheroids, the dissolution profile was determined and, based on the data obtained, the required ratio of spheroids in the finished dosage form was calculated to achieve the required dissolution profile.
  • the dissolution profile was obtained using USP Apparatus 2 (USP Apparatus 2): volume of dissolution medium 900 ml; stirrer rotation speed 50 rpm; bath temperature 37 ⁇ 0.5 ° C. Dissolution medium 0.1 N HC1 0 for 2 hours, the rest of the time - phosphate buffer, pH 6.8.
  • Dosage forms are formed to provide and control the required release and dissolution of the active ingredient.
  • the dissolved the substance in this regard, the dissolution process (the amount and rate of transition of the drug into the solution) is one of the most significant factors in ensuring the required bioavailability of the pharmacologically active substance from the finished dosage form.
  • the dissolution process (the amount and rate of transition of the drug into the solution) is one of the most significant factors in ensuring the required bioavailability of the pharmacologically active substance from the finished dosage form.
  • solubility there are other biopharmaceutical factors that can significantly modify the final properties of the tableted microsystem, which ultimately can lead to significant differences in bioavailability (see S.B. Setkina et al. Biopharmaceutical aspects of drug technology and ways of modifying bioavailability, Bulletin VSMU, 2014, volume 13, No4, pp. 62-172).
  • bioavailability can be increased as a result of creating an EMHPS delivery system capable of retaining the active substance for more than 6 hours in the stomach. Also it has been proven that bioavailability when using dosage forms with prolonged action is comparable to immediate release tablets. Our studies have refuted the opinion of experts that using a prolonged form with EMHPS can increase bioavailability. Sustained-release formulations begin to release EMHPS in different parts of the gastrointestinal tract (from the stomach to the rectum), which does not contribute to an increase in its bioavailability.
  • the present invention provides a novel drug delivery technology (EMHPS) with a gastro-retentive (gastro-retention) delivery system.
  • EHPS novel drug delivery technology
  • gastro-retentive (gastro-retention) delivery system gastro-retentive (gastro-retention) delivery system.
  • EMHPS drug delivery
  • EMHPS which is highly soluble, can be administered orally in a manner that prolongs its release time in order to distribute its absorption rate more evenly over time. This will significantly reduce the problems of temporary overdose caused by an initial spike in concentration entering the bloodstream immediately after administration and subsequent underdosing, and instead monitors the dosage to safer and more effective levels over an extended period of time.
  • EMHPS has been found to be problematic due to its release in the lower gastrointestinal tract due to its poor absorption capacity into the bloodstream in the lower gastrointestinal tract.
  • the invention relates to a gastro-retentive delivery system for EMHPS, providing a long residence time in the stomach.
  • Gastro-retentive delivery systems in the form of stomach swellable tablets, as well as methods for their preparation, are described in patents EP 1886665, US6340475 and international application W003035177.
  • Polymers used in gastro-retentive gastric swellable tablets are known from these documents. Retention in the stomach can result from swelling and / or mucoadhesion of the delivery system. However, the suitability, much less the effectiveness of these delivery systems for EMHPS with improved bioavailability has not been previously described.
  • polymers for such a delivery system is within the skill of the art and depends on the properties of the polymers, their molecular weight and the desired rate of release of EMHPS and the duration of retention in the stomach.
  • a properly selected combination of polymers can provide a more controlled release and absorption of EMHPS, which leads not only to an increase in bioavailability, but also to a reduction in the number of doses of the drug.
  • the object of the invention is a system for the oral delivery of 2-ethyl-6-methyl-3-hydroxypyridine succinate in the form of a gastro-retentive tablet.
  • the agent for preparing an EMHPS delivery system contains at least one polymer that combines gastric swelling control, gastric EMHPS release and mucoadhesive properties.
  • the system can contain one polymer with such properties or a combination of polymers, providing the necessary properties. Examples of polymers are shown in Table 1.
  • polyapkylene oxides polyethylene oxide and polypropylene oxide; copolymers of ethylene oxide and propylene oxide
  • PEO polyethylene oxide
  • the weight ratio of 2-ethyl-6-methyl-3-hydroxypyridine succinate to polyethylene oxide is preferably 2.6: 1 to 1.3: 1.
  • the invention also relates to a gastric retained tablet in which the matrix is a delivery agent and EMHPS in a therapeutically effective amount.
  • the tablet may contain from 125 mg to 1500 mg of EMHPS.
  • the tablet according to the invention optionally contains additional pharmaceutically acceptable excipients to aid in the production, compressibility, appearance and taste of the formulation.
  • Such agents include, for example, diluents or fillers, glidants, binders, granulating agents, release agents, lubricants, flavors, colorants, and preservatives. Other common excipients known in the art may also be included. Table 1.
  • the filler can be selected from soluble fillers, for example sucrose, lactose, in particular lactose monohydrate, trehalose, maltose, mannitol and sorbitol.
  • a lubricant can be used to enhance the release of the tablet from the device on which it is formed.
  • Suitable lubricants include magnesium stearate, calcium stearate, canola oil, glyceryl palmitostearate, hydrogenated vegetable oil, magnesium oxide, mineral oil, poloxamer, polyethylene glycol, polyvinyl alcohol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, and the like. ...
  • composition of the tablets can be developed taking into account the technological properties of the pharmaceutical substance, as well as its compatibility with various excipients.
  • the choice of auxiliary components and production technology can be carried out experimentally.
  • the new dosage form provides the concentration of the active substance in the blood in the range of therapeutic activity, if possible, without short-term peaks Cmax.
  • the dosage form by keeping the EMHPS in the area of absorption, shows an improvement in bioavailability due to a slow release rate. Controlled release has several distinct advantages over conventional formulations immediate release. In addition, the controlled release dosage form lowers the maximum plasma concentration.
  • the action of the active substance in the stomach occurs due to the swelling of the tablet and its adhesive capacity (mucoadhesion).
  • the gastro-retentive tablet can have the following degree of swelling up to 243% in 6 hours, and the prolonged 60% in 6 hours.
  • the prolonged form does not have mucoadhesive ability, while the gastro-retentive form can maintain this ability for 14 hours.
  • the invention also relates to a method for increasing the bioavailability of EMHPS, which provides for the administration of a tablet once a day to a subject in need thereof.
  • Increased bioavailability and prolonged action can reduce the frequency of taking EMHPS to 1 time per day.
  • FIG. 1-6 Solubility curve of EMHPS from different compositions (on the abscissa axis - time in hours, on the ordinate axis EMHPS release in%).
  • the methods for preparing gastro-retentive tablets are no different from those for conventional tablets.
  • the delivery system and tablets can be produced by the following methods: direct compression technology, wet granulation technology, dry granulation technology, etc.
  • the most preferred adjuvants are as follows.
  • Microcrystalline cellulose 102 This brand of microcrystalline cellulose has an average particle size of 130 microns, which makes it possible to use it to improve flowability and compressibility.
  • Microcrystalline cellulose is used as a filler and diluent, which improves flowability and adhesion between particles during tableting.
  • Cellulose microcrystalline ensures the preservation of the integrity of the tablet shape under mechanical stress.
  • the content of microcrystalline cellulose will be selected experimentally. The content of microcrystalline cellulose is limited due to the large geometry of the tablets.
  • Carmellose sodium grade CMC 7H4F in concentration was selected based on Ashland's recommendations for use in sustained release tablets by wet granulation.
  • Carmellose sodium acts as a binding agent in wet granulation.
  • Carmellose sodium has mucoadhesive (mucoadhesive) properties.
  • Povidone is a well-known and readily available high performance binder. Depending on the concentration in the formulation, it can be used: 1) to form complexes with the substance, in order to improve its dissolution; 2) for binding the components in order to agglomerate them (obtaining granules); 3) to impart technological properties to the tablet cores (hardness and abrasion strength of the tablets).
  • Povidone is a universal component and is used in drug production technologies using the direct pressing, dry granulation, wet granulation, compacting. The 90 F grade was selected based on the manufacturer's recommendations, BASF, as a binding agent for wet granulation.
  • This component is included in the formulation of the medicinal product as a binding agent in order to impart abrasion and chipping resistance to the tablets so that a film coating can be applied to the tablet cores, as well as to increase the degree of swelling in combination with polyethylene oxide.
  • Hypromellose provides the desired dissolution profile.
  • POLYOX TM Water Soluble Resins are nonionic poly (ethylene oxide) polymers. They are hydrophilic polymers available in a wide range of molecular weights and are supplied as white free flowing powders. POLYOX provides fast wetting and swelling for use in osmotic pump technologies and forms a gel in a hydrophilic matrix. Polyethylene oxide is used as a hydrophilic matrix in gastro-retentive dosage forms and has mucoadhesive (mucoadhesive) properties. Magnesium stearate
  • Magnesium stearate was chosen because of the large tablet size, which has a high tablet end, which can cause high ejection forces when tableted at high speed on an industrial scale.
  • Magnesium stearate is a hydrophobic lubricant in nature and is used to prevent mixtures from sticking to the press tool.
  • a casing of the Colorcon company of the Opadry II brand based on polyvinyl alcohol is proposed.
  • the polyvinyl alcohol-based film coat spreads quickly and evenly over the tablet surface, and also reduces the risk of chipping due to greater adhesion and lower viscosity than the hypromellose-based film coat.
  • the shell based on polyvinyl alcohol ensures easy swallowing of tablets, which is important for large tablets of the drug.
  • wet granulation To obtain tablets, two production technologies have been proposed: wet granulation and direct compression.
  • wet granulation To obtain tablets, two production technologies have been proposed: wet granulation and direct compression.
  • wet granulation technology allows:
  • the pharmaceutical substance EMHPS has unsatisfactory technological properties, which complicates the use of direct compression technology.
  • one of the variants of gastro-retentive tablets can be obtained by the method described below. Description of the production process Preparation of raw materials Sifting of raw materials EMHPS is sieved manually through a 1.0 mm sieve.
  • the rest of the raw materials are sieved on a CISA RP 200N vibrating sieve through a 0.5 mm sieve.
  • Each type of raw material is weighed into separate clean containers.
  • Sifted EMHPS, sieved MCC, polyethylene oxide and / or sifted sodium carmellose are loaded into a modular installation with a fluidized bed. The components are mixed until homogeneous (visual control).
  • the granulate is dried in a fluidized bed dryer to a residual moisture content of no more than + 0.5% to the original at a temperature of 50-55 ° C.
  • the granulate is sieved on a CIS A RP 200N vibrating sieve through a 1.0 mm sieve.
  • the screening of the granulate is rubbed manually through a 1.0 mm sieve.
  • Granulate, Hypromellose 2208 or Polyethylene oxide and Hypromellose 2208 are introduced into the mixer. Mixing is carried out until homogeneous (visual control).
  • the tabletting mixture is discharged into a labeled container.
  • the tableting process is carried out on a Fasttab 3000 tablet press.
  • the tableting process is carried out on a press tool with a geometry of 19x8 (18x10) mm.
  • the tablet press is tuned for production of average weight. After adjusting the average weight of the tablets, the tablet press is adjusted according to the rest of the indicators:
  • tablets are collected in labeled containers.
  • the tablets are heated to 37-39 ° C with periodic stirring in the drum of the coater.
  • spraying of the film suspension is started.
  • the appearance of tablets and the weight gain of the shell are controlled.
  • the coating process is carried out until the average weight of the tablets is obtained.
  • the process is stopped and the tablets are cooled to a temperature not higher than 33 ° C. After the end of the process, the containers are closed.
  • a tablet composition with gastro-retention properties can be the following:
  • composition and ratio of the components help to achieve the desired release profile in the stomach (in-vitro test).
  • dissolution curves of EMHPS of the following tablet compositions were obtained: The solubility curve at pH 1, 2 is shown in FIG. one.
  • Solubility curves at pH 1.2 and 6.8 are shown in FIG. 4 and 5 respectively.
  • the solubility curve at pH 1.2 is shown in FIG. 6.
  • This composition allows to obtain the required release profile and the necessary additional parameters (degree of swelling, mucoadhesiveness) for a gastro-retentive tablet, as well as satisfactory technological properties (flowability of the mixture, strength and abrasion of the tablet).
  • Wet granulation technology makes the tabletting process stable and controlled. Study of the comparative pharmacokinetics of three experimental finished dosage forms of EMHPS in dwarf pigs.
  • Mexidol of the following composition: EMHPS 125 mg, excipients: lactose monohydrate - 97.5 mg, povidone - 25.0 mg, magnesium stearate - 2.50 mg. Sheath: opadry II white - 7.5 mg.
  • Dwarf pigs are a standard subject of pharmacokinetic studies (Guidelines for the maintenance and use of laboratory animals. Eighth edition / translated from English. Edited by IV Belozertseva, DV Blinov, MS Krasilytsikova. - M .: IRBIS , 2017 - 362 s). Before the start of the study, laboratory animals were kept in enclosures for adaptation.
  • the duration of the adaptation period for animals was 5 days. During the adaptation period, the animals were monitored daily for clinical condition by visual inspection. No deviations were found.
  • the distribution of animals into groups was not carried out, because only 3 animals were involved in the experiment.
  • the introduction of objects JVb 1, 2 was carried out sequentially after the introduction of the object of comparison: the tested object No. 1 was introduced 2 days after the introduction of the object of comparison; tested object - 4 days after the introduction of the test object N ° l.
  • EMHPS 1 * 375 mg 375 mg / day.
  • VTD therapeutic dose
  • 375/60 6.25 mg / kg.
  • the tested objects represent a dosage form of prolonged action, which implies its minimal destruction when introduced into the test system during the study and does not allow crushing of the dosage form. Therefore, this study provides for the introduction of the EMHPS preparation without destroying the integrity of the dosage form.
  • the peculiarities of the dosage form of the EMHPS preparation determine the selected dose, 1 tablet, as the minimum and the closest possible to VTD in terms of dwarf pigs, taking into account the interspecific coefficients.
  • EMHPS The selected dose made it possible to assess the main parameters of the EMHPS pharmacokinetics after a single administration of the test objects.
  • test objects were administered to miniature pigs unchanged orally, once, before the morning feed distribution at a dose of 1 tablet / animal using a tablet.
  • the comparison drug was administered 3 times a day, 1 tablet with an interval of 2.5 hours, to each animal, which is equivalent to the dose of administration for the tested objects (EMHPS drug).
  • Each animal was placed a 22G intravenous catheter (KD Medical GmbH Hospital Products, Germany) into the ear vein, through which blood samples were taken in a volume of 2.0 ml per exposure point.
  • a 22G intravenous catheter KD Medical GmbH Hospital Products, Germany
  • the analysis was performed on a high-pressure liquid chromatograph (Shimadzu, Japan) with a diode array detector and a Luna Cl 8 (2) 4.6x150 mm column (sorbent particle size 5 ⁇ m) and a guard column (3 mm) filled with the same sorbent (Phenomenex, USA ) in isocratic mode of elution with a mixture of 0.03% solution of trifluoroacetic acid and acetonitrile in a ratio of 95: 5, the flow rate of the eluent is 1 ml / min, the dosed volume of samples is 20 ⁇ L, the detection wavelength is 295 nm. Registration and processing of chromatograms was performed using the LabSolutions LCSolution Version 1.25 software (Shimadzu, Japan). Statistical data processing
  • Tables 3-5 show the arithmetic mean values (X), their corresponding standard deviations (SD), standard errors of the mean (ST).
  • Pharmacokinetic parameters (maximum concentration C max, time to maximum concentration is the T x, area under the curve "concentration-time» AUC, MRT the average retention time, half-life T 1/2 and rate of absorption speed C max / AUC t) calculated by vnemodelnym statistical moments (Piotrovsky V.K. Method of statistical moments and integral model-independent parameters of pharmacokinetics // Pharmacology and toxicology. - 1986. - T. 49, N ° 5. - S. 118-127). To statistically evaluate the differences between pharmacokinetic parameters, a two-sample t-test for means was used (assessed at a 95% confidence level).
  • the content of EMHPS in the blood plasma of dwarf pigs after a single oral administration of object No. 2, ng / ml The kinetics of detecting EMHPS in blood plasma differed in the shape of the curves, but was characterized by the presence of the analyte in the blood for 6-8 hours.
  • Pharmacokinetic profiles of a pharmacological agent in the blood when administered orally should be characterized by such parameters as maximum concentration (C max ), time to reach maximum concentration (T max ), area under the concentration-time curve (AUC), mean retention time (MRT ), period elimination half-life (T) and rate of absorption C max / AUC t [13].
  • Pharmacokinetic parameters were calculated by the non-model method - the method of statistical moments (Piotrovsky V.K. Method of statistical moments and integral model-independent parameters of pharmacokinetics // Pharmacology and toxicology. - 1986. - T. 49, Ne5. - P. 118-127), vol. .to.
  • the invention can be used in medicine or veterinary medicine as a drug for oral administration of 2-ethyl-6-methyl-3-hydroxypyridine succinate for the treatment and prevention of various diseases and pathological conditions of the human or animal body.
  • Medicinal preparations with 2-ethyl-6- methyl 3-hydroxypyridine succinate are effectively used in various fields of clinical medicine: neurology, psychiatry, cardiology, ophthalmology, surgery, dentistry, endocrinology, etc.

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  • Health & Medical Sciences (AREA)
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Abstract

L'invention se rapporte au domaine de l'industrie chimique et pharmaceutique, de la médecine et de la médecine vétérinaire, et concerne un agent d'administration de 2-éthyl-6-méthyl-3-hydroxyopyridine succinate pour prise orale assurant un effet gastro-rétentif, ainsi qu'une forme médicamenteuse sur la base de celui-ci. L'agent comprend au moins un polyalkylènoxyde. L'invention permet d'augmenter la biodiversité de l'agent actif, et de diminuer la fréquence de prise de l'agent médicamenteux.
PCT/RU2020/000665 2019-12-10 2020-12-07 Système d'administration de 2-éthyl-6-méthyl-3-hydroxyopyridine succinate pour prise orale Ceased WO2021118403A1 (fr)

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RU2019140742A RU2734970C1 (ru) 2019-12-10 2019-12-10 Система доставки 2-этил-6-метил-3-гидроксипиридина сукцината для перорального применения в форме гастроретентивной таблетки
RU2019140742 2019-12-10

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2444359C1 (ru) * 2010-12-06 2012-03-10 Общество с ограниченной ответственностью "Научно-производственная компания "ФАРМАСОФТ" (ООО "НПК "ФАРМАСОФТ") Фармацевтическая композиция с 2-этил-6-метил-3-гидроксипиридина сукцината для перорального применения и способ ее получения
WO2018112078A1 (fr) * 2016-12-14 2018-06-21 Amgen Inc. Formes pharmaceutiques à libération modifiée et à rétention gastrique pour oprozomib et leur procédé de fabrication

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2491070C2 (ru) * 2011-10-11 2013-08-27 Общество с ограниченной ответственностью "Фармамед" Фармацевтическая композиция для профилактики и лечения сердечно-сосудистых заболеваний
GB201300304D0 (en) * 2013-01-08 2013-02-20 Kalvista Pharmaceuticals Ltd Benzylamine derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2444359C1 (ru) * 2010-12-06 2012-03-10 Общество с ограниченной ответственностью "Научно-производственная компания "ФАРМАСОФТ" (ООО "НПК "ФАРМАСОФТ") Фармацевтическая композиция с 2-этил-6-метил-3-гидроксипиридина сукцината для перорального применения и способ ее получения
WO2018112078A1 (fr) * 2016-12-14 2018-06-21 Amgen Inc. Formes pharmaceutiques à libération modifiée et à rétention gastrique pour oprozomib et leur procédé de fabrication

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