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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
• • 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
  • A61K9/1682—Processes
  • A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
• • 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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• • 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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
• • 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
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • 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
  • 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 micronized drugs.
• a new method is described for obtaining digoxin in a micronized form, resulting in highly homogeneous powder, compliant with the current regulatory requirements for digoxin and characterized by an enhanced stability of the active principle.
• Digoxin is a cardioactive glycoside naturally present in the leaves of Digitalis purpurea and Digitalis lanata lanata (foxglove). These plants were known and used for long time in traditional medicine, with first written reports of their use dating back to the end of the eighteenth century. The active glycoside was subsequently isolated, characterized and used as active principle in a variety of medicaments. Today, despite the rise in synthetic and semi-synthetic drugs, digoxin still remains a fundamental therapeutic principle, being cited in the World Health Organization's List of Essential Medicines.
• Digoxin has a general tonic effect on cardiac muscle increasing its force of contraction and tone. It is used in therapy in the treatment of various heart conditions, in particular atrial fibrillation and atrial flutter: by slowing down the conduction in the AV node and increasing its refractory period, digoxin can reduce the ventricular rate. Digoxin is also used in the treatment of heart failure, especially in patients unresponsive to diuretic and ACE inhibitor treatment. Digoxin is preferably administered orally. It has a narrow therapeutic window and for these reasons the control of its release is of great importance. In fact, a very rapid release may result in excessively high plasma levels and therefore in a number of side effects; if the release is too slow incomplete absorption occurs, and no therapeutic effect is obtained.
• compositions of digoxin with excipients for gradual and controlled release, making it compliant with the required pharmaceutical standards (for example the United States Pharmacopoeia sets a specification for digoxin requiring that at least 85% digoxin be released in 60 min).
• particle size reduction can be achieved via micronization processes. These are typically mechanical process, performed in dry conditions, whereby a macro-sized raw material undergoes high-impact mechanical treatment, e.g. via milling, grinding, etc; these techniques are based on friction to reduce particle size.
• high-impact mechanical treatment e.g. via milling, grinding, etc
• the standard processes of micronization are not fully satisfactory, especially when used with highly active principles requiring a precise micronization profile: in particular, the degree of homogeneity in particle size may vary from different drug lots, and this reflects into undesired variations in bioavailability and activity.
• digoxin is very labile to mechanical treatments: these were occasionally reported to cause the formation of degradation products, made evident by a colour change of the powder after micronization; the partial degradation of digoxin, is further responsible for an undesired reduction of activity and/or to toxicity due to degradation products.
• the patent US 5 062 959 discloses a process to obtain digoxin as a solid product, via precipitation from a concentrated solution of purified digoxin in methanol/chloroform.
• a first object of the present invention is to develop a new, non-mechanical process of digoxin micronization.
• a further object is to make available a new process for obtaining digoxin in a micronized, highly homogeneous form.
• a further object is to make available a new micronization process for digoxin, having a low impact on the chemical/physical features of this active principle.
• a further object is to obtain a form of digoxin which, once formulated for oral administration, meets the current release standards for digoxin, while not being exposed to degradation.
• a further object is to obtain a stabilized form of micronized digoxin.
• a further object is to obtain a micronized digoxin which is highly pure (i.e. exempt or substantially exempt) from digoxin degradation products.
• the present invention discloses a new, non-mechanical process of micronization, capable to reduce the particle size of digoxin from ordinary level to a selected micrometer range.
• Micronization is obtained via a specific treatment, to be performed on a purified and concentrated digoxin solution in an organic solvent.
• the purified and concentrated digoxin solution is obtainable via a sequence of solvent treatments; then, after reaching the required concentration, the solution is further concentrated, obtaining the precipitation of digoxin; the reaction mixture is then added with methanol under stirring for a suitable time.
• the recovered precipitate consists in a digoxin with particle size comprised between 20 and 30 micrometers fox at least 90%_ by weight of the obtained particles, and is exempt from degradation products.
• concentrate and purified digoxin solution means a concentration of digoxin between 50 and 200 g/ L, preferably 70-150 g/L, most preferably 100-120 g/L.
• the term “purified” means a digoxin with purity of 90.0 - 99.9%, preferably 95.0 - 99.9%, most preferably between 98.0 and . 99.9% (calculated on the digoxin in dry form).
• a preferred, although non-limitative, procedure to obtain the purified concentrated digoxin solution suitable for the present process is the following. a) Crude digoxin, as normally available by known industrial methods, is solubilised with a hydroalcoholic solvent (preferably butanohwater) in presence of a base (preferably sodium carbonate), followed by heating for a suitable time (preferably at least 90°C for 5-15 hours). The solution is then cooled (typically at 5-15°C for a 5-15 hours). The precipitate is filtered and dried.
• a hydroalcoholic solvent preferably butanohwater
• a base preferably sodium carbonate
• c) The precipitate obtained in b) is dissolved in a organic solvent mixture (preferably methanohmethylene chloride), added with carbon and filtered; the filtered solution is passed through one or more beds of alumina, and then concentrated, obtaining a purified concentrated digoxin solution.
• a organic solvent mixture preferably methanohmethylene chloride
• This solution has a concentration typically comprised comprised between 50 and 200 g/ L, preferably 70-150 g/L.
• the purified and concentrated digoxin solution is further concentrated until complete precipitation of the product (i.e. until no further precipitation is observed).
• Concentration is suitably obtained under vacuum, at room temperature, and in stirring conditions; once precipitation is complete, the solution is added with methanol (preferably 1 -2 volumes, more preferably 1 .5 volumes per volume of said further concentrated solution) and stirred at room temperature for a period of 1 -6 hours, preferably 2- 5 hours, most preferably 3-4 hours; the precipitate is then filtered, washed with a polar solvent, preferably acetone, and dried. Drying can be performed e.g. under vacuum, at 20-40°C for 24 hrs, however the drying conditions can be easily varied and adapted in function of the scale of operation.
• the digexin thus obtained has a high purity and is ready to be incorporated in the usual pharmaceutical formulations, typically tablets; it has particle size of 20-30 micrometers for at least 90% of the particles, and is exempt from degradation products, as evident by a wholly neutral colour, and further confirmable analytically.
• the particle size distribution is meant as “number distribution” (thus not “volume distribution” or “mass distribution”); accordingly, any expressions of the type “x-y micrometers for at least m% of the particles” describes a particle distribution characterized in that at least m % of the number of particles making up the product have a size comprised between x and y micrometers; relevant particle size values can be measured by usual techniques, including laser diffraction, dynamic light scattering, dynamic image analysis, suitably equipped with data processing systems. The obtained digoxin can be formulated with common excipients.
• Suitable excipients are cellulose products like microcrystalline cellulose, cellulose ethers like methylcellulose.ethylcellulose, hydroxyethylcellulose, crosslinked polymers (e.g. polyplasdone XL, hyaluronic acid or alginic acid cross-linked with urea), gums from plants, etc. Common diluents like mannitol, fructose, as well as compression aids like magnesium stearate, can also be used. These formulations can be prepared in accordance with conventional methods, like those described in "Remington's Pharmaceutical Handboock” Mack Publishing Co., N.Y. USA, together with suitable excipients. The so- formulated digoxin is suitable to obtain a release rate compliant with the current pharmaceutical standards for digoxin, dissolving at a sufficiently fast rate, while avoiding excessive plasma peaks.
• crosslinked polymers e.g. polyplasdone XL, hyaluronic acid or alginic acid cross-linked with
• the reaction mass was stirred up to 5 hrs at 18-20°C, then filtered and dried under vacuum at 70°C for 12 hrs, obtaining 1 .2 Kgs of dried material.
• the dried material was then dissolved in 20-24 L of a mixture methylene dichloride:methanol (1 :1 v/v) at 35-40°C.
• the mixture was then added with 0.4-0.6 Kg carbon and stirred for 30 minutes at 35-40°C. It was then filtered through Hyflo (diatomaceous earth) bed and the filtered solution was further passed through Alumina (1.5 Kg), Hyflo and Alumina beds; the beds were washed with 6 L of methylene dichloride:methanol (1 :1 v/v).
• This example describes an embodiment of the preparation of a cardiotonic composition (tablet) based on the micronized digoxin according to example 1.

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• 2015
  • 2015-07-23 PL PL15178009T patent/PL3120839T3/pl unknown
  • 2015-07-23 HU HUE15178009A patent/HUE042420T2/hu unknown
  • 2015-07-23 ES ES15178009T patent/ES2716681T3/es active Active
  • 2015-07-23 EP EP15178009.5A patent/EP3120839B1/en active Active
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• 2016
  • 2016-07-21 WO PCT/IB2016/001035 patent/WO2017013485A1/en not_active Ceased
  • 2016-07-21 AU AU2016296162A patent/AU2016296162B2/en not_active Ceased
  • 2016-07-21 ES ES16754316T patent/ES2765675T3/es active Active
  • 2016-07-21 EP EP16754316.4A patent/EP3324942B1/en active Active
  • 2016-07-21 JP JP2018503128A patent/JP6814522B2/ja not_active Expired - Fee Related
  • 2016-07-21 HU HUE16754316A patent/HUE048065T2/hu unknown
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  • 2016-07-21 CN CN201680042406.3A patent/CN108024963A/zh active Pending
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  • 2016-07-21 US US15/746,697 patent/US20180207099A1/en not_active Abandoned
  • 2016-07-21 KR KR1020187003325A patent/KR20180032587A/ko not_active Ceased

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