NON-MECHANICAL PROCESS FOR THE MICRONIZATION OF DIGOXIN

FIELD OF INVENTION 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.

BACKGROUND OF THE INVENTION

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. Many literature reports and patents disclose 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).

An important parameter responsible for the solubility and, indirectly, for the bioavailablity of digoxin, is the drug particle size. In particular, substances like digoxin, being poorly soluble in aqueous environment, might benefit from a reduction in particle size and consequent increase of specific surface; these interrelations are summarized in the following equation, where dM/dt is the dissolution rate, A the specific surface area of the drug particle, D the diffusion coefficient, h the diffusion layer thicknes C _s the saturation solubility, and C _t the drug concentration at time t. dM _ AD (Cs - Ct)

dt ^~ h

It will be noted that, since the surface area increases with decreasing particle size, a higher dissolution rate may be achieved through the reduction of the particle size of the drug substance.

In the case of digoxin, micronization to a particle size of below 50 micrometers is particularly appreciated, since it easily allows to process it in formulations with a delivery time compliant with the above referred pharmaceutical standards for digoxin; an example thereof is disclosed in US2004/0048809.

In pharmaceutical technology, 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. However, 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. Moreover 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. These and further objectives are obtained by the invention described below.

SUMMARY OF THE INVENTION

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.

DETAILED DESCRIPTION OF THE INVENTION

In the expression "concentrated and purified digoxin solution", the term "concentrated" means a concentration of digoxin between 50 and 200 g/ L, preferably 70-150 g/L, most preferably 100-120 g/L.

In the expression "concentrated and purified digoxin solution", 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.

b) The precipitate obtained in a) is dissolved in an organic solvent mixture (preferably methanohmethylene chloride), then reprecipitated by addition of water under stirring (preferably at 15-25°C for 3-7 hours); the precipitate is filtered and drie_d.

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. This solution has a concentration typically comprised comprised between 50 and 200 g/ L, preferably 70-150 g/L. In accordance with the present invention, 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. In the present invention, 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.

The invention is now described by reference to the following non-limitative examples.

Example 1

Crude digoxin (1 ,5 Kg) obtained by industrial traditional methods (digoxin content 85%) was dissolved in 3 times butanol/water mixture (88: 12) ( 4,5 L) . 30,0 g solid sodium carbonate were added and the mixture was refluxed (95±2°C) for 10 hrs. The reaction mass was then cooled to 10°C and then maintained for 10 hrs at temperature below 10°C. The material was filtered and dried under vacuum at 70°C for 12 hrs. The material so obtained was dissolved in 30 L of a mixtrure methylene dichloride: methanol (1 : 1 v/v). After complete dissolution, further 30 L of methylene dichloride were added, followed by slow addition of 30 L of water. 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). The combined filtrates were concentrated up to 10 L without vacuum. The resulting solution was further concentrated under vacuum and stirring up to 4 L, observing the formation of a precipitate; once the precipitation was complete, the solution was added with 6 L of methanol under stirring for 3-4 hours; the precipitate was finally filtered, washed with acetone and dried under vacuum at 25-40°C for 24 hrs; digoxin ( 0.95 Kg) with particle size 20-30 micrometers for > 90% of the particles was obtained. Example 2

This example describes an embodiment of the preparation of a cardiotonic composition (tablet) based on the micronized digoxin according to example 1.

Micronized digoxin 0,200 mg

Microcristalline cellulose 100 mg

Mannitol 20 mg

Fructose 40 mg

Polyplasdone XL 8 mg

Magnesium stearate 4 mg