OA20151A - Once-daily formulation of hidrosmin. - Google Patents

Abstract

The present invention relates to a formulation comprising hidrosmin characterized by a modified release rate suitable for once-daily administration. The use of said composition in the prevention or treatment of a disease selected from chronic venous insufficiency, varicose veins, hemorrhoids, edema, metabolic syndrome, non-alcoholic fatty liver disease and diabetic nephropathy is also provided.

Description

ONCE-DAILY FORMULATION OF HIDROSMIN

Field of the Invention

The présent invention relates to modifiée! release formulations of hidrosmin suitable for once-daily administration and to uses of such formulations.

Background of the Invention

Diosmin glycoside is a water-insoluble flavonoid used in the treatment of venous disease. Hidrosmin is a synthetic dérivative of diosmin, which, in contrast to diosmin, is water soluble and twice as potent. Hidrosmin is a mixture composed primarily of 5-0-(2hydroxyethyl)diosmin (Ri=CH₂CH₂OH and R₂=H), 3’-O-(2-hydroxyethyl)diosmin (R^H and R₂=CH₂CH2OH) and 5,3’-di-O-(2-hydroxyethyl)diosmin (Ri=R₂=CH₂CH₂OH). CAS number 12050-44-4.

Hidrosmin is a vasoprotective that has been approved in several countries for the treatment of chronic venous insufficiency. It is available in oral capsules commercialized under the name of Venosmil®. These capsules contain 200 mg of hidrosmin as the active ingrédient and are administered three times a day.

Such formulations provide a fast release of hidrosmin, giving rise to a plasma high concentration peak of hidrosmin short after oral intake. This occurs due to the high water solubility of hidrosmin.

However, there is still a need in the art for improved formulations containing increased doses of hidrosmin that could be administered once-daily without undergoing fast release. This would offer an obvious advantage for patients as compared to the presently available formulations which require three times daily use.

Up to now, the State of the art clearly points towards the use of hydrophilic compounds for the modified release of hydrophilic drugs. International PCT application

WO 2011/143118 even teaches that lipids such as fatty acids or triglycérides should not be used for the purpose of obtaining a modified release formulation of active pharmaceutical ingrédients. Bose A. et al., Saudi Pharmaceutical Journal, 2013, 21, 201-213 teaches the use of the hydrophilic hydroxypropyl methylcellulose polymer for obtaining a modified release formulation of Itopride, a water soluble drug. International PCT application WO 2017/062027 teaches that the preferred way of improving the modified release of water soluble Naproxen is to employ matrix-forming hydrophilic agents such as cellulose dérivatives, gelatin or alginic acid. However, there is not a single prior art disclosure which enables modified release formulations comprising hidrosmin.

The présent invention now provides the first modified release formulation of hidrosmin with a reproducible dissolution profile and which is stable in time. As will become apparent from the description below, and in contrast to the State of the art teachings, this is only achievable by using a hydrophobie release agent.

Summary of the Invention

The invention faces the problem of providing a modified release formulation of hidrosmin that achieves the desired therapeutic effect by once-daily administration, with a reproducible dissolution profile and in a dosage form which is stable in time. In the context of the présent invention, a “reproducible dissolution profile” is to be understood as a dissolution profile with a coefficient of variation or relative standard déviation (RSD) of the in vitro released amount of hidrosmin lower than 10% (RSD < 10%). The inventors hâve found that said problem is solved by the pharmaceutical composition of the invention.

Accordingly, one aspect of the présent invention relates to a modified release pharmaceutical composition comprising:

(i) from 200 mg to 1200 mg of hidrosmin;

(ii) at least one glyceride, consisting of an ester derived from glycerol and one to three fatty acids; and (iii) at least one diluent selected from silicified microcrystalline cellulose, cellulose, microcrystalline cellulose, maltose, calcium carbonate, magnésium carbonate, magnésium oxide, calcium phosphate, calcium hydrogen phosphate, croscarmellose sodium, crosspovidone, sodium starch glycolate, sucrose, or mixtures thereof.

The présent formulation allows obtaining reproducible (RSD < 10%) modified release dissolution profiles from directly compressed hidrosmin tablets.

In a second aspect, the invention refers to a method of direct compression for preparing a pharmaceutical composition as defined herein, comprising the steps of:

(a) mixing hidrosmin with at least one glyceride, consisting of an ester derived from glycerol and one to three fatty acids, at least one diluent selected from silicified microcrystalline cellulose, cellulose, microcrystalline cellulose, maltose, calcium carbonate, magnésium carbonate, magnésium oxide, calcium phosphate, calcium hydrogen phosphate, croscarmellose sodium, crosspovidone, sodium starch glycolate, sucrose, or mixtures thereof and optionally at least one pharmaceutically accepted excipient independently selected from glidants, fillers, disintegrants and binders;

(b) compressing the mixture of step (a) to tablets.

In a third aspect, the invention refers to a pharmaceutical composition as defined herein obtainable bythe method ofthe invention.

In a fourth aspect, the présent invention also relates to such pharmaceutical composition for use as a médicament, preferably in the prévention and/or treatment of a disease selected from chronic venous insufficiency, varicose veins, hemorrhoids, edema, metabolic syndrome, non-alcoholic fatty liver disease or diabetic nephropathy.

Brief description of the drawinqs

Figure 1. Hidrosmin in vitro dissolution profile of exemplary pharmaceutical compositions ofthe invention comprising different glyceride modified release agents. 1. Hydrogenated cottonseed oil (Lubritab®); 2. Glyceryl palmitostearate (Precirol®); and 3. Glyceryl behenate (Compritol ®).

Figure 2. Hidrosmin in vitro dissolution profile for comparative compositions comprising different hydrophilic modified release excipients: 1. Metolose 4000SR 5%; 2. Metolose 1500SR 5%; and 3. Retardcel 5%.

Figure 3. Hidrosmin in vitro dissolution profile for comparative composition comprising stearic acid as lipophilie modified release excipient.

Figure 4. Hidrosmin in vitro dissolution profile of exemplary pharmaceutical compositions ofthe invention at increasing target hardness for: A. 19% Lubritab; B. 21% Lubritab; and C. 23% Lubritab.

Figure 5. Hidrosmin in vitro dissolution profile of exemplary pharmaceutical compositions of the invention at increasing Lubritab concentrations for tablets with a target hardness of: A. 150 N; B. 175 N; and C. 200 N.

Figure 6. Préparation of tablets according to the procedure in WO 2011143118. A Blend of sieved hidrosmin, Methocel® K100M, ethyl cellulose and glyceryl behenate; B and C - Hydroalcoholic solution with ethyl cellulose; D and E - Paste resulting from 10 minutes mix of the sieved hidrosmin, Methocel® K100M, ethyl cellulose and glyceryl behenate with the hydroalcoholic solution containing ethyl cellulose.

Detailed Description of the Invention

The pharmaceutical composition of the invention can be administered once a day at a dosing interval of 24 h with a similar systemic bioavailability as that obtained after administration of the immédiate release hidrosmin formulation (Venosmil®) given three times a day at a dosing interval of 8 hours. Hence, the modified release formulation of the invention allows for once-daily administrations, greater convenience for the patient with better chances of proper patient compliance, while providing the same systemic bioavailability without increasing the side effects.

The inventors hâve found out that, contrary to the teachings of the art, a composition of a water-soluble active pharmaceutical ingrédient (API) with hydrophilic modified release excipients (such as hydroxypropyl methylcellulose or carboxymethyl cellulose) either did not hâve adéquate dissolution profiles or these were not reproducible (RSD < 10%), or even lacked stability. This was the case when the API is hidrosmin. It is common practice in the pharmaceutical sciences that a water-soluble API can be obtained as modified release formulations if a hydrophilic polymer is used, since the polymer will swell when in contact with water and the entrapped API is allowed to slowly permeate to the exterior of the formulation. However, this is not applicable when hidrosmin is the pharmaceutically active ingrédient.

Hidrosmin displays average apparent density values of 0.30-0.60 g/mL and tapped 0.50-0.70 g/mL, which means that the necessary dosage form to administrate hidrosmin in the desired formulation (600 mg) will occupy a greater volume than 1 mL. That is why minigranules type multiparticulate pharmaceutical forms or “pellets” should be discarded due to the large volume they would represent and the conséquent oral administration difficulty; in the same way, the pharmaceutical capsules formed in its prolonged release combination should be discarded. Consequently, the pharmaceutical oral dosage form will preferably be from direct compression, which allows reducing the volume occupied by hidrosmin. However, the hidrosmin has poor direct compression properties, as will become apparent from the following paragraphs.

The SeDeM® expert System indicates the suitability of a material for direct compression (P. Perez et al., Eur. J. Pharm. Biopharm. 2006, 64, pp. 351-359; J.M. Sune-Negre et al., Eur. J. Pharm. Biopharm. 2008, 69, pp. 1029-1039; J. E. AguilarDiaz et al., Eur. J. Pharm. Biopharm. 2009, 73, pp. 414-423; A. Khan et al., Saudi Pharm. J. 2014, 22, pp. 433-444; J. M. Sune Negre et al. (2011). SeDeM Diagram: A New Expert System for the Formulation of Drugs in Solid Form. Expert Systems for Human, Materials and Automation, Prof. Petrica Vizureanu (Ed.), InTech). Certain powder characteristic parameters are taken into considération for development of SeDeM diagram. The SeDeM method is based on the experimental study and quantitative détermination of the characterization parameters of powdered substances that provide the necessary information about the ability of a substance to be used for direct-compression technology. The considered parameters are as follows: bulk or apparent density (Da), tapped density (De), interparticle porosity or sponginess index (le), Carr index (IC), cohésion index (lcd), Hausner ratio (IH), angle of repose (a), flow rate (°°), relative humidity (%RH), hygroscopicity (%H), particle size (%Pf) and homogeneity index (ΙΘ). Hence, the SeDeM diagram method is a mathematical and graphical représentation of powder characteristic parameters for studying direct compression suitability of various active and inactive ingrédients. Example 1 shows a SeDem diagram for hidrosmin. The poor results obtained for hidrosmin were indicative that it is not suitable for direct compression unless suitable excipients are carefully chosen.

Excipients of melting point below 100 °C are known to cause undesirable effects during compression such as adhérence, clumps, irregular displacement or dosing. These effects are intensified at increasing excipient concentration values. The compressibility index is an indication of how well a pharmaceutical component inside a mixture responds to compression, and is calculated from the ratio between the melting point and concentration of said component inside said mixture. When submitted to compression, the surface of the excipient is known to reach températures of 100 °C. Lipophilie excipients, of melting point lower than 100 °C, are employed as lubricants only if their concentration is below 10%, concentration above which the abovementioned effects are no longer negligible (Britten JR, Pilpel N., J. Pharm. Pharmacol.,

1978, 30(11), 673-677; Graf E, Nada A. Studies on the direct compression of pharmaceuticals, XXIII. Pancreatin, 1) Effect of lubricants on enzyme activity after storage. Arch Pharm (Weinheim). 1986, 319 (9), 808-14; Edward J. Hanus, Louis D. K., Journal of Pharmaceutical Sciences, 1968, 57 (4), 677-684; E. Nürnberg and A. Hopp., Pharm. Technol., 1981, 168, 81-101; Handbook of Pharmaceutical Excipients, 6 Ed. 2009 p. 286). Taking 100 °C as reference température, together with the maximum workable concentration of lipophilie excipients (10%), the compressibility index is calculated to yield: (melting point of 100 °C) / (concentration of 10%) = 10. This value of 10 is the optimal compressibility index an excipient would hâve for the purpose of good compression. Compounds with such values are difficult to find, thus, in the context of the présent invention, a compressibility value of 5 is considered as the minimum value an excipient must hâve for it to be considered as a possible excipient for compression. Excipients with compressibility values lower than 5 would be rejected as industrially not viable excipients, since this would mean adhesion or heterogeneity issues upon compression.

Surprisingly, it has now been found that pharmaceutical compositions comprising the water-soluble hidrosmin API and hydrophobie modified release agents of compressibility index lower than 5 (of compressibility values as low as 2) can be adequately compressed into industrially viable tablets. These excipients would hâve never been selected by the skilled person as viable compression excipients, and even less at the concentrations of the présent invention, since 10% is the maximum recommended concentration according to the literature (Britten JR, Pilpel N., J. Pharm. Pharmacol., 1978, 30(11), 673-677; Graf E, Nada A. Studies on the direct compression of pharmaceuticals, XXIII. Pancreatin, 1) Effect of lubricants on enzyme activity after storage. Arch Pharm (Weinheim). 1986, 319 (9), 808-14; Edward J. Hanus, Louis D. K., Journal of Pharmaceutical Sciences, 1968, 57 (4), 677-684; E. Nürnberg and A. Hopp., Pharm. Technol., 1981, 168, 81-101; Handbook of Pharmaceutical Excipients, 6 Ed. 2009 p. 286).

In addition, it has also been surprisingly found that these pharmaceutical compositions provide extended release of hidrosmin. However, this was not achievable for ail hydrophobie modified release agents. If, for example, stearic acid is used, the formulation does not allow a modified release at ail (see Example 3). Thus, in particular, the release agents are glycerides. Said combination allows obtaining a matrix with adéquate solid volume, adéquate and with remarkable reproducible (RSD < 10%) dissolution profiles, and wherein the pharmaceutical solid composition is stable in time. The latter is also surprising as it is also known that modified release agents such as lipids, which comprise glycerides, tend to form unstable solid forms which dégradé in time thereby losing the extended release properties (WO 2011/143118).

Furthermore, the présent invention allows obtaining extended release compositions for a highly soluble active pharmaceutical ingrédient, which do not require any additional protective coatings to tune the release thereof.

As mentioned above, the inventors hâve also found that the pharmaceutical composition of the invention, which comprises low compressibility index value glycerides, shows modified release profiles of reduced variability, preferably less than 10% variability, with regard to other tested known excipients which were expected to provide good results (such as hydroxypropyl methylcellulose or carboxymethyl cellulose which hâve compressibility indexes higher than 9.5) (see Example 2). This resuit advantageously affects the industrial up scaling ofthe invention.

Accordingly, one aspect of the présent invention relates to a modified release pharmaceutical composition comprising:

(i) from 200 mg to 1200 mg of hidrosmin;

(ii) at least one glyceride, consisting of an ester derived from glycerol and one to three fatty acids; and (iii) at least one diluent selected from silicified microcrystalline cellulose, cellulose, microcrystalline cellulose, maltose, calcium carbonate, magnésium carbonate, magnésium oxide, calcium phosphate, calcium hydrogen phosphate, croscarmellose sodium, crosspovidone, sodium starch glycolate, sucrose, or mixtures thereof.

The présent formulation allows obtaining reproducible (RSD < 10%) modified release dissolution profiles from directly compressed hidrosmin tablets.

The term “modified release” as used herein is to be understood as opposite to “immédiate release and could also be identified with similar terms such as “extended release” or “delay release”. In the présent invention, hidrosmin is gradually and continuously liberated over time. In particular, the term indicates that the System does not release the full dose of hidrosmin immediately after oral dosing and that the formulation allows a réduction in dosing frequency.

In a particular embodiment, the pharmaceutical composition is a tablet.

In another particular embodiment, at least 10 wt%, at least 20 wt%, at least 30 wt%, at least 40 wt%, at least 50 wt%, at least 60 wt%, at least 70 wt%, at least 80 wt%, preferably at least 90 wt%, more preferably at least 95 wt%, of the total weight of hidrosmin is in a continuous matrix of constant composition. In a preferred embodiment, ail of the hidrosmin is in a continuous matrix of constant composition.

In a preferred embodiment, said matrix is devoid of hydroxypropyl methylcellulose, more preferably devoid of any hydrophilic polymers. Hydrophilic polymer, in this context can also be understood as hydrophilic release agent or hydrophilic modified release agent. Examples of hydrophilic polymers are hydroxypropyl methylcellulose, carboxymethylcellulose, hydroxyethyl cellulose, methylcellulose, or ethyl cellulose, more preferably cellulose ether dérivatives.

The term “continuous matrix of constant composition” is to be interpreted as a homogeneous medium wherein ail components comprised therein are distributed throughout the entire volume of the matrix without the presence of defined régions or frontiers.

In another particular embodiment, the pharmaceutical composition is a tablet wherein at least 60 wt%, preferably at least 70%, more preferably at least 80%, even more preferably at least 90% of the total weight of hidrosmin is in a continuous matrix of constant composition devoid of a hydrophilic polymer selected from the group consisting of hydroxypropyl methylcellulose, carboxymethylcellulose, hydroxyethyl cellulose, methylcellulose and ethyl cellulose.

In a preferred embodiment, the pharmaceutical composition of the invention is such that both the hidrosmin and the at least one glyceride are homogeneously distributed in the tablet.

In another preferred embodiment, the pharmaceutical composition of the invention is such that the hidrosmin, the at least one glyceride and the at least one diluent are homogeneously distributed in the tablet.

The term “homogeneously distributed in the tablet”, referring to components (i), (ii) and optionally (iii), of the pharmaceutical composition of the invention, means that said components are distributed throughout the entire volume of the tablet without the presence of defined régions or frontiers. In other words, ail régions of the tablet comprise approximately the same amounts of components (i), (ii), and optionally (iii), i.e., ali parts of the tablet are equal in composition in terms of components (i), (ii), and optionally (iii).

Preferably, the pharmaceutical composition of the invention does not comprise layers or distinguishable régions with different compositions forming frontiers.

In a particular embodiment, the tablet may comprise further components and/or excipients and in such case, said further components and/or excipients are homogeneously distributed as well.

In another particular embodiment, the tablet may comprise further components and/or excipients and in such case, said further components and/or excipients are not homogenously distributed in the tablet.

In a preferred embodiment, the pharmaceutical composition of the invention does not comprise hydrophilic modified release agents. Preferably, the pharmaceutical composition of the invention does not comprise hydroxypropyl methylcellulose, carboxymethylcellulose, hydroxyethyl cellulose, methylcellulose, or ethyl cellulose, more preferably cellulose ether dérivatives.

The term “once-daily” or “once a day” administration is well known to those skilled in the art and intends to mean the administration of a dosage form to a subject a single time per day, i.e., once approximately every 24 hours.

Hidrosmin is a mixture composed primarily of 5-O-(2-hydroxyethyl)diosmin (R₁=CH₂CH₂OH and R₂=H), 3’-O-(2-hydroxyethyl)diosmin (Ri=H and R₂=CH₂CH₂OH) and 5,3’-di-O-(2-hydroxyethyl)diosmin (Ri=R₂=CH₂CH₂OH), CAS number 12050-44-4.

In a particular embodiment, the hidrosmin amount in the pharmaceutical composition of the invention ranges from 200 to 1200 mg. In another particular embodiment, the hidrosmin is présent at from 300 mg to 1000 mg. In yet another particular embodiment, the hidrosmin is présent at from 400 mg to 1200 mg, preferably from 400 mg to 1000 mg, more preferably from 400 mg to 900 mg. Preferably, the hidrosmin amount in the pharmaceutical composition of the invention ranges from 500 mg to 700 mg, more preferably from 550 mg to 650 mg. In a most preferred embodiment, the pharmaceutical composition comprises 600 mg of hidrosmin.

In another particular embodiment, the amount of hidrosmin in the pharmaceutical composition of the invention is from 20 to 85 wt% with respect to the total weight of the composition. In a preferred embodiment, hidrosmin is présent from 35 to 85 wt% with respect to the total weight of the composition. In a more preferred embodiment, hidrosmin is présent in an amount from 45 to 75 wt%. In an even more preferred embodiment, hidrosmin is présent in an amount from 50 to 70 wt%. In this context, wt% (mass fraction) is the ratio of the mass of one substance (such as hidrosmin, for example) to the mass ofthe total mixture (same mass units), multiplied by 100.

In a particular embodiment, the hidrosmin has a density of between 0.30 and 0.60 g/mL, preferably between 0.35 and 0.55 g/mL, more preferably between 0.40 and 0.50 g/mL. The density values aforementioned are obtained by known techniques in the art such as, measurement of bulk density of powders in a graduated cylinder as it is described in the European Pharmacopoeia (2.9.34).

A glyceride, as already defined in the daims, consists of an ester derived from glycerol and one to three fatty acids. Therefore, a glyceride is as commonly understood in the field. The glyceride of the invention consists in the ester derived from one molécule of glycerol and one fatty acid (monoglyceride), two fatty acids (diglyceride) or three fatty acids (triglycéride). The composition of the invention can comprise one or more glycerides as long as the total amount of glyceride or mixture of glycerides in the composition is between 10 and 50 wt%, preferably from 15 to 35 wt%, more preferably from 15 to 32 wt%, more preferably from 15 to 25 wt%, even more preferably from 20 to 25 wt%, relative to the total weight of the composition. In a preferred embodiment, the pharmaceutical composition of the invention comprises a glyceride at an amount of 23 wt%, relative to the total weight ofthe composition.

The expression independently selected, when used in the context of multiple sélections such as at least one glyceride or one or more pharmaceutically accepted excipients, means that each glyceride or each excipient is selected from the listed éléments independently from any other selected glyceride or excipient.

Thus, in another particular embodiment of the invention, the pharmaceutical composition comprises at least one glyceride wherein the one to three fatty acids are independently selected from C₁₂-C₃2 fatty acids, preferably from C15-C22 fatty acids.

In yet another particular embodiment of the invention, the pharmaceutical composition comprises at least one glyceride selected from the group of glyceryl behenate, glyceryl monooleate, glyceryl dioleate, glyceryl trioleate, glyceryl monostearate, glyceryl distearate, glyceryl tristearate, glyceryl palmitostearate, vegetable oil, hydrogenated vegetable oil, ethylated castor oil, glyceryl monolaurate, glyceryl dilaurate, glyceryl trilaurate, glyceryl monomyristate, glyceryl dimyristate, glyceryl trimyristate, glyceryl palmitate, glyceryl dipalmitate, glyceryl tripalmitate, and mixtures thereof.

Glyceryl behenate, also known by its commercial name Compritol 888 ATO®, is a mixture of various esters of the saturated fatty C22 behenic acid and glycerol, the mixture containing predominately glyceryl dibehenate.

Glyceryl palmitostearate, also known by its commercial name Precirol®, is a mixture of mono-, di-, and triglyceryl esters between glycerol, palmitic acid (Ο₁₈) and stearic acid (Ci₈).

In the context of the présent invention, a hydrogenated vegetable oil is to be understood as a triglycéride extracted from a plant that was submitted to a hydrogénation process. In the hydrogénation process, double bonds on the fatty acids are reduced to single bonds. The hydrogénation process can be either complété or partial, thus leading to totally hydrogenated vegetable oils or partially hydrogenated vegetable oils, with an increased melting point with regard to the vegetable oil precursor. As the degree of hydrogénation increases, the oil's viscosity and melting point increase. Hydrogenated vegetable oils can be solid or liquid at room température, and can comprise glycerin as well.

In another preferred embodiment, the hydrogenated vegetable oil has a melting point of from 10 to 90 °C. In another preferred embodiment, the hydrogenated vegetable oil is a mixture of totally hydrogenated and partially hydrogenated fatty acids characterized by carbon-chain lengths of Ci₅-C₁₈.

In a particular embodiment, the hydrogenated vegetable oil is selected from: coconut oil; safflower oil; canola oil; sunflower oil; peanut oil; corn oil; palm oil; soybean oil; cottonseed oil; castor oil, rapeseed oil or mixtures thereof.

In a preferred embodiment, the hydrogenated vegetable oil is hydrogenated cottonseed oil or hydrogenated castor oil.

In a particular embodiment, the hydrogenated vegetable oil is a hydrogenated cottonseed oil with a melting point of from 20 to 85 °C, such as those under the registered trademarks Sterotex, NF or Lubritab. Lubritab may act also as a glidant. Lubritab can be purchased by, for example, Jrspharma. In another particular embodiment, the glyceride is hydrogenated castor oil, such as the one formerly commercially known as Cutina HR® and now commercially available as Kolliwax HCO®.

Kolliwax HCO® is obtained by hydrogénation of castor oil. A hydrogenated castor oil such as Kolliwax HCO® predominately contains the triglycéride of 12-hydroxystearic acid.

In another particular embodiment, the glyceride is ethylated castor oil, such as the one commercially known as Cremophor®.

In a particular embodiment, the composition of the invention comprises hidrosmin in an amount of from 200 to 1200 mg of hidrosmin, and from 150 to 800 mg of a glyceride selected from glyceryl behenate, glyceryl palmitostearate, hydrogenated vegetable oil, ethylated castor oil or mixtures thereof. In another particular embodiment, the hydrogenated vegetable oil is selected from hydrogenated cottonseed oil or hydrogenated castor oil.

In a particular embodiment, the composition of the invention comprises hidrosmin in an amount of from 500 to 700 mg of hidrosmin, and from 150 to 350 mg of a glyceride selected from glyceryl behenate, glyceryl palmitostearate, hydrogenated vegetable oil, ethylated castor oil or mixtures thereof. In another particular embodiment, the 150 to 350 mg of hydrogenated vegetable oil are selected from hydrogenated cottonseed oil or hydrogenated castor oil.

More preferably, the composition of the invention comprises hidrosmin in the aforementioned amounts and hydrogenated cottonseed oil in the respective aforementioned amounts.

In an embodiment, the composition may further comprise at least one pharmaceutically accepted excipient independently selected from glidants, fillers, disintegrants and binders. In a particular embodiment, the composition may further comprise at least one pharmaceutically accepted excipient independently selected from glidants, fillers, disintegrants and binders in an amount of 0.05 to 50 wt%. In another particular embodiment, the at least one pharmaceutically accepted excipient is independently selected from glidants, fillers, disintegrants and binders in an amount of from 0.001 to 10 wt%, more preferably from 0.001 to 5 wt%, even more preferably from 0.001 to 2 wt% relative to the total weight of the composition.

Diluents, glidants, fillers, disintegrants and binders may be selected from calcium carbonate, calcium phosphate, calcium sulfate, cellulose, cellulose acetate, ethylcellulose, microcrystalline cellulose, colloïdal Silicon dioxide, dextrates, dextrose, fructose, trehalose, lactose, starch, corn starch, rice starch, pregelified starch (200 and

1500), erythritol, xylitol, sorbitol, mannitol, sucrose, talc, maltose, isomaltose, lactitol, cyclodextrins, maltodextrin, magnésium carbonate, magnésium stéarate, sodium alginate, calcium alginate, ammonium alginate, xanthan gum, tragacanth, compressible sugar, calcium lactate, or mixtures thereof. Preferred diluents and glidants are selected from microcrystalline cellulose, silicified microcrystalline cellulose, colloïdal Silicon dioxide and talc.

In the context of the présent invention, the term glidant can be understood as lubricant.

In a particular embodiment, the pharmaceutical composition further comprises a diluent selected from silicified microcrystalline cellulose, cellulose, microcrystalline cellulose, povidone, isomalt, pharmaburst (consisting of mannitol, starch 1500, crospovidone, croscarmellose and S1O2), microcelac (consisting of lactose and microcrystalline cellulose), Ludipres (consisting of povidone, crospovidone and lactose), PanexcealMH300G (consisting of microcrystalline cellulose, hidroxipropil methylcellulose and crospovidone), Parteck (consisting of mannitol), Parteck ODT (consisting of mannitol and sodium croscarmellose), Sorbcel (consisting of mannitol, PEG-4000, povidone, citric acid and bicarbonate), maltose, calcium carbonate, magnésium carbonate, magnésium oxide, calcium phosphate, calcium hydrogen phosphate, croscarmellose sodium, crosspovidone, sodium starch glycolate, sucrose, or mixtures thereof. In a preferred embodiment, the pharmaceutical composition comprises a diluent selected from silicified microcrystalline cellulose, cellulose, microcrystalline cellulose, maltose, calcium carbonate, magnésium carbonate, magnésium oxide, calcium phosphate, calcium hydrogen phosphate, croscarmellose sodium, crosspovidone, sodium starch glycolate, sucrose, or mixtures thereof. Diluents may comprise at least one disintegrant component.

In a preferred embodiment, the diluents are in an amount of 5 to 50 wt% relative to the total weight of the composition. More preferably, from 11 to 23 wt%. Even more preferably, from 12 to 17 wt%, relative to the total weight of the composition. In a most preferred embodiment, the diluents are in an amount of 14.9 wt% relative to the total weight of the composition.

In a preferred embodiment, the diluent is microcrystalline cellulose.

In another preferred embodiment, the diluent is silicified microcrystalline cellulose.

Silicified microcrystalline cellulose is the silicified product of microcrystalline cellulose. The process of silicification leads to the déposition of Silicon, presumably in the form of Silicon dioxide, both on the outer envelope surface of the particle and on exposed surfaces within the particle (M.J. Tobyn et al., International Journal of Pharmaceutics, 1998, 183-194).

In a preferred embodiment, the silicified microcrystalline cellulose of the pharmaceutical composition of the invention comprises between 1 and 2 wt% of Silicon dioxide. In a particular embodiment, the silicified microcrystalline cellulose is characterized by an average particle size of between 100 and 150 pm, more preferably 125 pm. In yet another particular embodiment, the silicified microcrystalline cellulose of the pharmaceutical composition of the invention has a bulk density of between 0.20 to 0.70 g/mL, preferably from 0.30 to 0.60 g/mL, even more preferably from 0.38 to 0.50 g/mL. In an embodiment, the silicified microcrystalline cellulose has a Silicon dioxide content of between 1 and 2 wt%, an average particle size of between 90 and 160 pm, and a bulk density of between 0.20 to 0.70 g/mL.

In yet another preferred embodiment, the silicified microcrystalline cellulose is in an amount of 5 to 50 wt% relative to the total weight of the composition. More preferably, the silicified microcrystalline cellulose is in an amount from 11 to 23 wt%. Even more preferably, the silicified microcrystalline cellulose is in an amount from 12 to 17 wt%, relative to the total weight of the composition.

In a preferred embodiment, the pharmaceutical composition of the invention comprises silicified microcrystalline cellulose as diluent, at an amount of 14.9%.

In yet another preferred embodiment, the microcrystalline cellulose is in an amount of 5 to 50 wt% relative to the total weight of the composition. More preferably, the microcrystalline cellulose is in an amount from 11 to 23 wt%. Even more preferably, the microcrystalline cellulose is in an amount from 12 to 17 wt%, relative to the total weight of the composition.

In a preferred embodiment, the pharmaceutical composition of the invention comprises microcrystalline cellulose as diluent, at an amount of 14.9%.

In a particular embodiment of the invention, the composition further comprises from 0.05 to 5 wt% of a glidant selected from colloïdal Silicon dioxide, talc mixtures thereof. In another preferred embodiment, the composition comprises colloïdal Silicon dioxide in an amount of from 0.01 to 5 wt%, preferably from 0.05 to 2 wt%, more preferably from 0.1 to 2 wt%, relative to the total weight of the composition. In another preferred embodiment, the composition further comprises talc in an amount of from 0.5 to 10 wt%, preferably from 1 to 5 wt%, more preferably from 1 to 3 wt%, relative to the total weight of the composition. In yet another preferred invention, the composition further comprises a mixture of 0.1 wt% colloïdal Silicon dioxide and 2 wt% talc as glidants.

In an embodiment, the pharmaceutical composition of the invention comprises hidrosmin in an amount of 35 to 85 wt%, preferably from 45 to 75 wt%, more preferably from 50 to 70 wt%, hydrogenated vegetable oil in an amount of 10 to 50 wt%, preferably from 15 to 35 wt%, more preferably from 20 to 25 wt%, and silicified microcrystalline cellulose in an amount of 5 to 50 wt%, preferably from 10 to 30 wt%, more preferably from 10 to 20 wt%, relative to the total weight ofthe composition.

In a particular embodiment, the composition of the invention comprises from 500 to 700 mg of hidrosmin, 15 to 30 wt% of hydrogenated vegetable oil and 12 to 17 wt% of silicified microcrystalline cellulose. Preferably, the pharmaceutical composition of the invention comprises 600 mg of hidrosmin, from 19 wt% to 23 wt% of a glyceride selected from hydrogenated cottonseed oil, hydrogenated castor oil, glyceryl behenate and glyceryl palmitoestearate, and from 14.9 wt% to 18.9 wt% of a diluent selected from silicified microcrystalline cellulose.

As defined in the claims, the pharmaceutical composition of the invention is a tablet, i.e., a solid oral dosage form. The hardness of said solid form is between 110 and 250 N, preferably from 120 and 220 N, more preferably between 130 and 200 N, even more preferably between 140 and 175 N, measured by résistance to crushing according to the technique described in European Pharmacopoeia (2.9.8.). The technique is intended to détermine, under defined conditions, the résistance to crushing of tablets, measured by the force needed to disrupt them by crushing.

In the context of the présent invention, the hardness values hâve an intrinsic variability of ± 20 N, preferably ± 15 N, more preferably ± 12.5 N. For this reason, in the présent description the hardness value is also referred to as target hardness value.

In a preferred embodiment, the solid oral dosage form of the présent invention is not in the form of granules. More preferably, the solid oral dosage form of the présent invention does not comprise coated granules; even more preferably, does not comprise granules.

In a particular embodiment, the pharmaceutical composition of the invention provides an in vitro dissolution profile such that:

(a) an amount of 25 wt% to 50 wt% of hidrosmin relative to the total hidrosmin content of the composition is released within 2 h, (b) an amount of 50 wt% to 80 wt% of hidrosmin relative to the total hidrosmin content of the composition is released within 8 h, and (c) an amount of more than 70 wt% of hidrosmin relative to the total hidrosmin content of the composition is released within 14 h, when the in vitro release of hidrosmin is measured according to United States Pharmacopeia (chapter 711) and European Pharmacopeia 2.9.3 dissolution apparatus 2 (paddles), in 900 mL at pH 6.8 (EP or USP), 50 rpm and 37°C

Preferably, and for the same aforementioned experimental conditions, the formulation provides the following in vitro dissolution profile:

(a) an amount of 25 wt% to 45 wt% of hidrosmin relative to the total hidrosmin content of the composition is released within 2 h, (b) an amount of 55 wt% to 75 wt% of hidrosmin relative to the total hidrosmin content of the composition is released within 8 h, and (c) an amount of more than 75 wt% of hidrosmin relative to the total hidrosmin content of the composition is released within 14 h.

More preferably, and for the same aforementioned experimental conditions, the formulation provides the following in vitro dissolution profile:

(a) an amount of 25 wt% to 45 wt% of hidrosmin relative to the total hidrosmin content of the composition is released within 2 h, (b) an amount of 55 wt% to 80 wt% of hidrosmin relative to the total hidrosmin content of the composition is released within 8 h, and (c) an amount of more than 75 wt% of hidrosmin relative to the total hidrosmin content of the composition is released within 14 h.

Even more preferably, and for the same aforementioned experimental conditions, the formulation provides the following in vitro dissolution profile:

(a) an amount of 25 wt% to 45 wt% of hidrosmin relative to the total hidrosmin content of the composition is released within 2 h, (b) an amount of 60 wt% to 80 wt% of hidrosmin relative to the total hidrosmin content of the composition is released within 8 h, and (c) an amount of more than 80 wt% of hidrosmin relative to the total hidrosmin content ofthe composition is released within 14 h.

The inventors hâve found that the composition of the invention allows remarkably reproducible dissolution profiles (RSD < 10%). Thus, in a preferred embodiment, the coefficient of variation or relative standard déviation (RSD), of the in vitro released amount of hidrosmin between 8 and 14 h is lower than 10%. In a more preferred embodiment, the coefficient of variation or relative standard déviation (RSD), of the in vitro released amount of hidrosmin throughout the entire release is lower than 10%. %RSD is a statistical measurement that describes the déviation of various terms from their average in an observation and is defined by the following formula:

%RSD = (sample standard déviation *100)/ sample mean

Therefore a %RSD lower than 10% between 8 and 14 h means that each measurement of the in vitro release of hidrosmin between 8 and 14 h deviates by less than 10% from the mean of the data set at that time.

The composition of the invention provides a modified release pharmacokinetic profile as shown in the examples.

The pharmaceutical composition of the invention can be prepared by a method selected from direct compression, dry granulation, wet granulation, melt extrusion and melt embedding. Preferably, the solid composition is prepared by direct compression.

In another aspect, the invention refers to a method of direct compression for preparing a pharmaceutical composition as defined herein, comprising the steps of:

(a) mixing hidrosmin with at least one glyceride, consisting of an ester derived from glycerol and one to three fatty acids, at least one diluent selected from silicified microcrystalline cellulose, cellulose, microcrystalline cellulose, maltose, calcium carbonate, magnésium carbonate, magnésium oxide, calcium phosphate, calcium hydrogen phosphate, croscarmellose sodium, crosspovidone, sodium starch glycolate, sucrose, or mixtures thereof , and optionally at least one pharmaceutically accepted excipient independently selected from glidants, fillers, disintegrants and binders;

(b) compressing the mixture of step (a) to tablets.

More preferably, a method for producing the composition of the invention by direct compression can comprise the steps of:

(a) mixing hidrosmin with a triglycéride, silicified microcrystalline cellulose or microcrystalline cellulose, and optionally at least one pharmaceutically accepted excipient independently selected from diluents, glidants, fillers, disintegrants and binders;

(b) compressing the mixture of step (a) to tablets.

In another aspect, the invention refers to a pharmaceutical composition as defined herein obtainable by the method of the invention.

In another aspect, the invention refers to a pharmaceutical composition as defined herein or to a pharmaceutical composition obtainable by the method of the invention, for use as a médicament.

In another aspect, the invention refers to a pharmaceutical composition for use as defined herein or to a pharmaceutical composition obtainable by the method of the invention, in the prévention or treatment of a disease selected from chronic venous insufficiency, varicose veins, hemorrhoids, edema, metabolic syndrome, non-alcoholic fatty liver disease and diabetic nephropathy.

The composition of the invention is advantageously administered once a day. In a particular embodiment, the composition is administered once-daily in the form of a solid oral dosage.

In another aspect, the invention refers to the use of a pharmaceutical composition as defined herein or to a pharmaceutical composition obtainable by the method of the invention, in the manufacture of a médicament for the prévention or treatment of a disease selected from chronic venous insufficiency, varicose veins, hemorrhoids, edema, metabolic syndrome, non-alcoholic fatty liver disease and diabetic nephropathy.

In another aspect, the invention refers to a method or treating or preventing a disease selected from chronic venous insufficiency, varicose veins, hemorrhoids, edema, metabolic syndrome, non-alcoholic fatty liver disease and diabetic nephropathy, method which comprises administering to a patient in need of such a treatment a pharmaceutical composition as defined herein or a pharmaceutical composition obtainable by the method ofthe invention.

The following examples illustrate the invention and should not be considered as limitative of the invention.

Examples

Example 1 - Préparation of tablets

a. Préparation of hidrosmin

Hidrosmin is commercially available. Batch 1000002309 from Laboratories FAES FARMA S.A. was used.

Said batch showed the following particle size distribution: dio = 6.107 pm, d₅₀ = 21.020 pm, d₉o = 48.091 pm.

Hidrosmin Batch 1000002309 has the following physico-chemical properties:

- Apparent density: 0.474 g/mL (Ph. Eur. 2.9.34)

- Tapped density: 0.544 g/mL (Ph. Eur. 2.9.34)

- Sponginess index (le): 0.27

- Carr index (IC): 12.87%(Ph. Eur. 2.9.36)

- Cohesiveness index (IcD): 382.6 N

- Hausner index (IH): 1. (Ph. Eur. 2.9.36)

- Angle of repose (a): 24 ⁰ (Ph. Eur. 2.9.36)

- Flow rate: ⁰⁰ (Ph. Eur. 2.9.16)

- Relative humidity (%RH): 3.43

- Hygroscopicity (%H): 17.78

- Particle percentage of détermination < 50pm (%Pf): 66.20 p

- Homogeneity index (ΙΘ): 0.006

Considering the above properties for hidrosmin (Batch 1000002309) and after application of the SeDeM® expert System, the following SeDeM® diagram was obtained:

(a)

The above hidrosmin SeDeM® diagram reveals that the average of the parameters associated with the compressibility (comprised by the sponginess index, Carr index and cohesiveness index) falls just under 5. Regarding the compressibility characteristics, hidrosmin has déficient sponginess index (2.26 of radius) and Carr index (2.57 of radius) values, which must be compensated using for example diluent excipients which enable the direct compression of the product. Indeed, displaying an index of good compression (IGC) of 3.97 (poor but close to the minimum acceptable value of 5) and a parametric profile of 4.17 (doser to the minimum acceptable value of 5), it is possible to directly compress the hidrosmin whenever it is combined with suitable direct compression diluents that compensate the déficient parameters. Suitable direct compression diluents are known in the art as such that hâve an IGC > 5. The inventors hâve thus surprisingly found that the présent invention only shows reproducible (RSD < 10%) modified release of hidrosmin when compression diluents of IGC values lower than 5 (such as glycerides), are used (Negre s, et al., Cienc. Tecnol. Pharm., 2005, 15(3), 125-136).

b. Préparation of hidrosmin modified release tablets

The tablets were prepared by direct compression defined as follows.

The composition ofthe tablets is described in the following table.

Ingrédient	Quantity (mg/tablet)	% w/w
Drug Substance:
Hidrosmin	600	60.0
Excipients:
Silicified Microcrystalline Cellulose (Prosolv® HD 90)	149	14.9
Modified release agent*	230	23.0
Colloïdal Silicon Dioxide	1	0.1
Talc	20	2.0
Total:	1000	100.0

* The modified release agents used in the présent example were: Sample 1. Hydrogenated cottonseed oil (Lubritab®); Sample 2. Glyceryl palmitostearate (Precirol®); and Sample 3. Glyceryl behenate (Compritol ®).

Materials

The following materials were used: Hidrosmin (Faes Farma S.A., Spain); Silicified

Microcrystalline Cellulose (Prosolv® HD 90, JRS Pharma GmbH&Co. KG, Germany); Hydrogenated cottonseed oil (Lubritab®, JRS Pharma GmbH&Co. KG, Germany); Glyceryl palmitostearate (Precirol®, Gattefossé, USA); Glyceryl behenate (Compritol ®, Gattefossé, USA); Colloïdal Silicon dioxide (HDK N20P, Wacker Chemie GmbH, Germany); and Talc (Imeris Talc Italy S.P.A., Italy).

Equipment and additional material

EQUIPMENT

Hand sieve: 1.0 mm sieve size

Stainless Steel scoop and spatula

Turbula T10B Blender with 17 L stainless Steel drum

FETTE P1200 iC Tablet Press, 16 stations rotor, no. 14 feed cam and oval shape format (20.00 x 10.00 mm)

Sartorius CP423S Balance

HANHART Compact digital chronometer

PHARMA TEST PTB 311 Durometer

Manufacturing process

1. Sieving of ail raw materials except modified release agents in the following order: % Hidrosmin, Silicified microcrystalline cellulose, colloïdal Silicon dioxide, talc, % hidrosmin were sifted through a 1.0 mm sieve size.

2. Blending of raw materials previously sieved during 10 minutes at 23 rpm in a Turbula T10B Blender (17 L Stainless Steel drum).

3. The blend from step 2 was blended with the modified release agent (depending on sample 1,2 or 3) previously sifted through a 1.0 mm sieve size during 10 minutes at 23 rpm in a Turbula T10B Blender (17 L Stainless Steel drum).

4. The above obtained blend was compressed into tablets of average weight of 1000 mg. Average tablet hardness 144 N (132-158 N).

Tablet press speed 20,000 t/h (42 rpm), F-O-M speed 12 rpm.

The rates of dissolution of hidrosmin from the prepared tablets were measured. The profiles were determined by the following dissolution test conditions:

Equipment: USP (711 )-EP (2.9.3) apparatus 2 (paddles)

Volume: 900 mL

Medium: Buffer pH 6.8 (USP or EP)

Speed: 50 rpm ± 2 rpm

Température: 37°C ± 0.5 °C.

The following rates of dissolution of hidrosmin for the tablets Samples 1 to 3 were obtained. Each profile corresponds to the averaged measurement of 12 vessels.

	S1	S2	S3
Time (hrs)	% hidros.	% RSD	% hidros.	% RSD	% hidros.	% RSD
0	0	0	0	0	0	0
0.25	12	6.4	12	5.1	11	1.5
0.5	17	5.7	17	4.5	16	1
1	24	5.2	23	4.4	22	0.8
2	33	4.8	32	4.1	30	0.8
3	41	4.6	38	4.1	36	0.9
4	46	4.4	44	4.0	41	0.9
6	55	4.1	52	4.0	49	0.9
8	62	4.2	59	3.9	56	1.0
10	68	4.2	65	3.9	61	1.0
12	73	4.1	70	3.8	66	1.0
14	78	4.3	74	3.8	70	1.0
16	81	4.1	78	3.6	73	1.0

The dissolution rate of hidrosmin from the tablets prepared in this example shows that the présent invention allows obtaining a remarkably reproducible (RSD < 10%) hidrosmin modified release formulation. This is observed when the modified release agent is a glyceride.

Figure 1 is a graphical représentation of the table above.

Example 2 - Comparative in vitro dissolution profiles usine hydrophilic agents

This example shows the rates of dissolution of hidrosmin from tablets prepared according to the procedure in Example 1 but instead of a modified release agent based on a glyceride, the comparative compositions comprised: 1. Metolose 4000SR 5%; 2. Metolose 15000SR 5%; or 3. Retardcel 5%.

Metolose 4000SR (Shin-Etsu Chemical Co., Ltd., Japan) is the brand name for Hydroxypropyl methylcellulose (HPMC) of 4000 viscosity (USP). Metolose 15000SR (Shin-Etsu Chemical Co., Ltd., Japan) is the brand name for Hydroxypropyl methylcellulose (HPMC) of 15000 viscosity (USP). Retardcel (BIOGRUND GmbH, Germany) is the brand name for a mixture of HPMC and Carboxymethylcellulose.

The profiles were determined by the following dissolution test conditions:

Equipment: USP (37 édition) apparatus 2 (paddles)

Volume: 900 mL

Medium: Buffer pH 6.8 (USP)

Speed: 50 rpm ± 2 rpm

Température: 37°C ± 0.5 °C.

The modified release agent présent at a concentration of 5 wt%

Comparative sample 1 (C1): hidrosmin 60 wt%, Metolose 4000SR 5 wt%, Prosolv HD90 (silicified crystalline cellulose) 31.9 wt%, Talc 2 wt%, Magnésium stéarate and Aerosil 200 (fumed silica) 0.1 wt%.

Comparative sample 2 (C2): hidrosmin 60 wt%, Metolose 15000SR 5 wt%, Prosolv HD90 (silicified crystalline cellulose) 31.9 wt%, Talc 2 wt%, Magnésium stéarate and Aerosil 200 (fumed silica) 0.1 wt%.

Comparative sample 3 (C3): hidrosmin 60 wt%, RetardCel 5 wt%, Prosolv HD90 (silicified crystalline cellulose) 31.9 wt%, Talc 2 wt%, Magnésium stéarate and Aerosil 200 (fumed silica) 0.1 wt%.

The following rates of dissolution of hidrosmin for the tablets C1-C3 were obtained. Each profile corresponds to the averaged measurement of 12 vessels.

	C1	C2	C3
Time (hrs)	% hidros.	% RSD	% hidros.	% RSD	% hidros.	% RSD
0	0	0	0	0	0	0
0.25	8	19.6	7	14.3	13	13.0
0.5	17	21.2	14	14.7	23	13.7

1	32	23.7	24	17.6	34	14.9
2	54	25.9	39	20.2	44	16.7
3	67	26.0	49	25.5	48	18.1
4	72	22.0	55	26.3	50	17.6
6	80	16.6	63	21.6	54	16.4
8	85	12.5	70	18.1	59	14.6
10	88	9.9	75	15.7	64	14.1
12	91	7.8	78	14.3	70	10.1
14	—	—	83	12.7	74	9.1

Although the formulations were able to be adequately compressed and did form a matrix formulation, the modified release profiles were far from reproducible.

The dissolution rate of hidrosmin from the tablets prepared in this comparative example shows that for several points in time, a variability between tablets (n = 12) was obtained with a RSD greater than 10%. Changing the composition did not solve this problem. Figure 2 is a graphical représentation ofthe table above.

Example 3 - Comparative in vitro dissolution profile using stearic acid as modified release agent

This example shows the rates of dissolution of hidrosmin from tablets prepared according to the procedure in Example 1 but instead of a modified release agent based on a glyceride, the comparative composition comprised stearic acid. The profiles were determined by the following dissolution test conditions:

Equipment: USP (711 )-EP (2.9.3) apparatus 2 (paddles)

Volume: 900 mL

Medium: Buffer pH 6.8 (USP or EP)

Speed: 50 rpm ± 2 rpm

Température: 37°C ± 0.5 °C.

The following rates of dissolution of hidrosmin were obtained. The profile corresponds to the averaged measurement of 12 vessels.

	C4
Time (hrs)	% hidros.	% RSD
0	0.0	0.0
0.25	20	2.9
0.5	35	4.1
1	60	4.7
2	93	1.8
3	98	1.6
4	98	1.5
6	98	1.3
8	99	1.3
10	99	1.3
12	99	1.3
14	99	1.4
16	99	1.4

Although the hidrosmin dissolution profile for a formulation comprising stearic acid is reproducible (%RSD < 5% for n = 12), this is only because the formulation does not allow the proper compression of the tablets. The conséquence is that the profile is not 5 modified release but immédiate release, as shown in Figure 3.

Example 4 - Formulations of the invention at increasinq modified release agent concentrations for tablet tarqet hardness of 150 N, 175 N and 200 N.

This example shows rates of dissolution of hidrosmin from tablets prepared according to the procedure in Example 1 but at different concentrations of the modified 10 release agent Lubritab® and at tablet target hardness of 150 N, 175 N and 200 N. The remaining components were maintained as in example 1 (Hidrosmin 60 wt%, Prosolv® HD 90 14.9%, Colloïdal Silicon Dioxide 0.1 wt% and Talc 2 wt%). The profiles were determined according to the previous examples.

Sample 4. Lubritab® 19%. Target hardness = 150 N.

Sample 5. Lubritab® 21 %. Target hardness = 150 N.

Sample 6. Lubritab® 23%. Target hardness = 150 N.

Sample 7. Lubritab® 19%. Target hardness = 175 N.

Sample 8. Lubritab® 21%. Target hardness = 175 N.

Sample 9. Lubritab® 23%. Target hardness = 175 N.

Sample 10. Lubritab® 19%. Target hardness = 200 N.

Sample 11. Lubritab® 21 %. Target hardness = 200 N.

Sample 12. Lubritab® 23%. Target hardness = 200 N.

	S4	S5	S6
Time (hrs)	% hidros.	% RSD	% hidros.	% RSD	% hidros.	% RSD
0.00	0.0	0.0	0.0	0.0	0.0	0.0
0.25	13	2.9	15	2.1	14	1.5
0.50	21	1.4	21	2.3	20	1.1
1.00	33	1.7	31	2.8	29	1.2
2.00	50	2.4	46	3.3	43	2.3
3.00	63	1.7	58	3.4	53	2.8
4.00	74	2.1	68	3.7	62	2.6
6.00	93	2.0	83	3.7	76	3.1
8.00	98	1.0	94	2.7	87	2.4
10.00	99	1.4	98	0.7	94	2.5
12.00	99	1.5	99	1.9	97	1.9
14.00	99	1.5	99	2.1	99	1.2
16.00	99	1.5	99	0.7	99	1.3

	S7	S8	S9
Time (hrs)	% hidros.	% RSD	% hidros.	% RSD	% hidros.	% RSD
0.00	0.0	0.0	0.0	0.0	0.0	0.0
0.25	11	1.5	14	2.4	15	3.8
0.50	20	2.1	20	2.6	20	3.1
1.00	29	2.4	29	3.0	28	2.4
2.00	42	2.3	41	3.5	39	2.1
3.00	54	2.1	52	4.0	47	2.2
4.00	63	2.1	60	3.6	54	2.2
6.00	78	2.1	74	3.9	66	2.1
8.00	91	2.2	86	4.2	75	2.1

10.00	100	0.7	94	2.7	83	2.3
12.00	102	0.6	98	1.6	90	2.5
14.00	102	0.8	99	2.1	96	2.9
16.00	102	0.9	98	1.3	99	1.9

	S10	S11	S12
Time (hrs)	% hidros.	% RSD	% hidros.	% RSD	% hidros.	% RSD
0.00	0.0	0.0	0.0	0.0	0.0	0.0
0.25	15	1.3	14	5.2	14	5.0
0.50	21	1.5	20	4.1	19	3.3
1.00	28	1.4	27	3.2	26	2.8
2.00	40	1.5	37	2.4	36	2.7
3.00	49	1.6	45	1.9	43	2.7
4.00	57	1.6	52	1.6	50	2.8
6.00	69	7.3	62	1.6	60	3.2
8.00	82	2.5	71	1.4	69	3.0
10.00	91	1.9	79	1.8	76	2.9
12.00	97	1.8	86	2.2	83	3.1
14.00	100	1.3	91	2.2	88	3.4
16.00	100	2.1	95	2.8	92	2.7

The profiles are shown in Figures 4 and 5. Figures 4A, 4B and 4C show the samples above at Lubritab® 19%, 21% and 23%, respectively. Figures 5A, 5B and 5C show the samples above attarget hardness of 150 N, 175 N and 200 N, respectively.

The results show that for ail of the tested parameters, the variability (% RSD) of the profiles is always less than 10% (for n > 12). The results also show that the release profile can be tuned by adjusting the modified release agent concentration and the tablet compression force.

Example 5 - Formulations of the invention at varying modified release agent 10 concentrations.

This example adds up to the data shown in example 4, wherein further concentrations of Lubritab were tested. The variation in the concentration of Lubritab is compensated by the concentration of Prosolv® HD90 so that the other concentrations (see example 1) are maintained.

Sample 13. Lubritab® 15%. Target hardness - 240 N.

Sample 14. Lubritab® 20%. Target hardness = 240 N.

Sample 15. Lubritab® 25%. Target hardness = 240 N.

	S13	S14	S15
Time (hrs)	% hidros.	% RSD	% hidros.	% RSD	% hidros.	% RSD
0.00	0.0	0.0	0.0	0.0	0.0	0.0
0.25	15	2.8	13	3.2	13	1.1
0.50	20	2.5	18	0	19	0.7
1.00	28	1.5	25	0	26	0.8
2.00	38	2	34	1.2	36	0.9
3.00	45	2.3	41	1.3	42	0.8
4.00	50	2.7	46	1.1	48	0.8
6.00	59	2.3	54	1	57	0.8
8.00	66	1.5	60	1.3	63	0.9
10.00	72	1.4	66	1.1	69	0.9
12.00	77	1.3	71	1.5	74	0.9
14.00	82	1	75	1.4	78	0.9
16.00	85	0.9	78	1.3	82	0.9

The results show that for ail of the tested parameters, the variability (% RSD) of the profiles is always less than 10% (for n > 6). The results also show that the release 10 profile can be tuned by adjusting the modified release agent concentration and the tablet compression force.

Example 6 - Préparation of comparative tablets following the prior art disclosure This example reveals the attempt in the préparation of comparative tablets following the teachings of example 1 in prior art WO 2011143118.

Example 1 of the cited prior art document discloses a formulation of three separate régions, granules, the coating of the granules, and a matrix wherein the coated granules are dispersed. According to said example, granules comprising the drug Venlafaxine are formed in a first step, followed by a coating step and, finally, a step of blending the coated granules with the components of the matrix. The resulting mixture is then compressed to form tablets.

For the purposes of the présent comparative example, a formulation as the one 5 disclosed in example 1 ofthe cited prier art was prepared with slight modifications. The drug Venlafaxine was replaced with hidrosmin (aiming at 300 mg/tablet) and glycerol behenate (20% by weight relative to the granule) was included as granule excipient. Glycerol behenate is explicitly disclosed in prior art WO 2011143118. The amounts of each component were adapted so that tablets suitable for oral administration (adéquate 10 size, weight and shape) were obtained. A batch of 1 kg was prepared.

The following table shows the target composition for the comparative tablets of the présent example:

Uncoated granules composition	Relative weight
Hidrosmin	50%
Methocel® K100M	15%
Ethyl cellulose	15%
Compritol® 888 ATO (Glyceryl behenate)	20%
Coated granules composition
Hidrosmin	86.95%
Ethyl cellulose	8.70%
Magnésium stéarate	4.35%
Dosage form (matrix) composition
Coated granule	50.86%
Lactose monohydrate	30.96%
Methocel® K100M	17,69%
Magnésium stéarate	0.49%

500 g of sieved hidrosmin, 150 g of sieved Methocel® K100M, 75 g of sieved ethyl 15 cellulose and 200 g of glyceryl behenate were blended in a double cône blender for 15 minutes at 20 rpm. The resulting blend was then introduced in a double sigma mixer (see Figure 6A).

In parallel, a hydroalcoholic solution (30:70) was prepared by mixing 200 g of deionized water and 475 g of éthanol (96°) and, in a 2 paddle mixer, 75 g of ethyl cellulose were added to obtain a hydroalcoholic solution comprising 10% of ethyl cellulose. The resulting solution was highly viscous and its manipulation was difficult (see Figures 6B and 6C).

Then, the highly viscous 10% hydro-ethanolic (30:70) solution of the remaining 75 g of ethylcellulose was slowly added to the double sigma mixer which contained the sieved hidrosmin and excipients and mixed for 10 minutes. A highly heterogeneous mass started to develop upon mixing which was not typical of these type of mixing procedures. It was observed that, upon mixing, the once loose blend of hidrosmin was now an agglomerated, paste-like mass (see Figures 6D and 6E).

The consistency of the mix did not allow the step of milling. Therefore, this step was skipped and the mass was dried with the purpose of reducing the agglomérâtes.

However, the resulting dried mass proved to be extremely compact and hard. This rendered impossible the process of obtaining the granules and the process of manufacturing tablets according to the prior art but using Hidrosmin instead of Venlafaxine could not be reproduced.

This comparative example shows that pursuing the teachings of the prior art could and would not help the skilled person to solve the problem of the présent invention. The replacement of Venlafaxine with Hidrosmin and the addition of the glyceride glyceryl behenate rendered the teachings of the prior art useless since the resulting mass was not workable.

Example 7 - Hidrosmin modified release tablets with different hidrosmin quantities

The tablets were prepared in the same manner as described above in example 1, but by modifying the quantity of hidrosmin and adapting the quantities of the remaining excipients. Also, in the tablets of this example the modified release agent was Hydrogenated cottonseed oil (Lubritab®).

When the hidrosmin quantities were 400, 500, 550 and 900 mg (total tablet weights 800, 900, 1000 and 1500 mg, respectively), the tablets were successfully compressed and performed adequately.

Sample 16. Hidrosmin 400 mg (50% w/w); Prosolv 149 mg (18.625% w/w); Lubritab® 230 mg (28.75% w/w); Talc 20 mg (2.5% w/w) and aerosil®200 1 mg (0.125% w/w). Hardness = 147 N.

Sample 17. Hidrosmin 500 mg (55.56% w/w); Prosolv 149 mg (16.55% w/w); Lubritab® 230 mg (25.56% w/w); Talc 20 mg (2.22% w/w) and aerosil®200 1 mg (0.11% w/w). Hardness = 164 N.

Sample 18. Hidrosmin 550 mg (55% w/w); Prosolv 149 mg (14.9% w/w); Lubritab® 280 mg (28% w/w); Talc 20 mg (2% w/w) and aerosil®200 1 mg (0.1% w/w). Hardness = 174 N.

Sample 19. Hidrosmin 500 mg (50% w/w); Prosolv 159 mg (15.9% w/w); Lubritab® 320 mg (32% w/w); Talc 20 mg (2% w/w) and aerosil®200 1 mg (0.1% w/w). Hardness = 164 N.

Sample 20. Hidrosmin 900 mg (60% w/w); Prosolv 223.5 mg (14.9% w/w); Lubritab® 345 mg (23% w/w); Talc 30 mg (2% w/w) and aerosil®200 1.5 mg (0.1 % w/w).

Hardness = 246 N.

	S16	S17	S18	S19	S20
Time	%	%	%	%	%	%	%	%	%	%
(hrs)	hidros.	RSD	hidros.	RSD	hidros.	RSD	hidros.	RSD	hidros.	RSD
0	0	0	0	0	0	0	0	0	0	0
0.25	13	2.3	13	1.6	11	3.2	11	1.5	11	1.3
0.5	19	2.1	18	2.2	17	1.4	16	1.6	16	1.1
1	26	2.1	26	1.9	24	0.8	22	1.2	24	2
2	36	2	36	1.8	33	0.9	31	1.0	35	3.1
3	43	1.8	45	2.1	40	1.0	37	1.2	43	3.5
4	49	1.7	51	2	45	0.9	42	1.3	50	3.8
6	58	1.7	63	1.8	54	0.9	50	1.3	61	3.9
8	66	1.8	74	2.8	62	0.9	57	1.2	69	4
10	73	2	83	3.8	69	1.2	63	1.4	76	4
12	78	1.8	90	4	76	1.9	68	1.6	82	3.9
14	83	1.9	95	2.8	81	2.4	73	1.6	87	3.7
16	87	2	98	1.8	86	2.7	77	1.8	91	3.4

The results show that the variability (% RSD) of the profiles is always less than

10% (for n > 6).

Example 8 - Hidrosmin modified release tablets with Vivapur instead of Prosolv

The tablets were prepared in the same manner as described above in example 1, but by replacing the diluent Prosolv with Vivapur® 102. Prosolv is the commercial name of silicified microcrystalline cellulose and Vivapur is the commercial name of microcrystalline cellulose. In this example, the modified release agent was the same as in Sample 1 of example 1: Hydrogenated cottonseed oil (Lubritab®). The tablets were successfully compressed and performed adequately.

	Same as Sample 1 but with Vivapur instead of Prosolv
Time (hrs)	% hidros.	% RSD
0	0	0
0.25	12	1.4
0.5	18	1.4
1	25	1.4
2	34	1.5
3	42	1.1
4	56	1.2
6	64	1.3
8	71	1.8
10	76	2
12	81	2.1
14	81	2.1
16	85	2.1

The results show that the variability (% RSD) of the profiles is always less than 10% (forn > 6).

Example 9 - Hidrosmin modified release tablets with non-glyceride release agents

The tablets were prepared in the same manner as described above in example 1, 10 but by using cetyl alcohol as modified release agent (instead of Lubritab®, Precirol® or Compritol®). Cetyl alcohol is a non-glyceride compound. The tablets were successfully compressed but their dissolution profile was inadéquate, as shown in the table below.

	Same as Sample 1 but with cetyl alcohol as modified release agent
Time (hrs)	% hidros.	% RSD
0	0	0
0.25	17	2.4
0.5	26	2.1
1	41	4.4
2	71	3.1
3	91	4
4	97	1.4
6	98	0.9
8	98	0.9
10	98	0.9
12	98	1
14	98	0.9
16	99	1

An alternative attempt using Carnauba wax revealed that this compound is not suitable as release agent for the purposes of the présent invention because the wax cannot be manipulated without forming a melted wax cover while sieving. Therefore, 5 tablets could not be prepared using the non-glyceride carnauba wax.

Example 10 - Hidrosmin modified release tablets with hydrogenated castor oil as glyceride release agent

The tablets were prepared in the same manner as described above in example 1, but by using a hydrogenated castor oil (Kolliwax® HCO) as modified release agent. The 10 tablets were successfully prepared and the dissolution profile was adéquate as shown in the table below.

	Same as Sample 1 but with hydrogenated castor oil as modified release agent
Time (hrs)	% hidros.	% RSD

0	0	0
0.25	12	0
0.5	17	2.4
1	24	2.2
2	32	1.6
3	39	1.9
4	44	1.7
6	52	1.5
8	58	1.3
10	64	1.6
12	69	1.5
14	73	1.4
16	76	1.7

The results show that the variability (% RSD) of the profiles is always less than 10% (for n > 6).

Example 11 - Stability of the hidrosmin tablets under température and humidity

Tablets prepared according to example 1 were submitted to three stability tests and their dissolution behaviorwas measured.

In stability test 1, the tablets were submitted, as prepared, to an accelerated stability test (40 °C and 75 RH% conditions). The dissolution profile was measured at the time the tablets were prepared and, after 5 months of bulk storage below 25°C and further 6 months in PCV/PVDC 120/AI blisters, the dissolution profile was measured again and compared to the initially obtained values.

The results obtained for the released hidrosmin concentration at time 2h, 8h and 14h, were pharmaceutically acceptable: 92%, 93% and 93% of the initially obtained values, respectively.

In stability tests 2 and 3, the tablets were submitted, as prepared, to long-term stability at:

Stability test 2: 30 °C and 75 RH%; and

Stability test 3: 30 °C and 65 RH%.

The dissolution profile was measured at the time the tablets were prepared and, after 5 months of bulk storage below 25°C and further 12 months in PCV/PVDC 120/AI blisters, the dissolution profile was measured again and compared to the initially obtained values.

The results obtained for the released hidrosmin concentration at time 2h, 8h and

14h, were pharmaceutically acceptable:

Stability test 2: 100%, 94% and 94% of the initially obtained values, respectively; and

Stability test 3: 97%, 93% and 94% of the initially obtained values, respectively.

The accelerated and long-term stability results thus show that the tablets remain stable upon exposure to forced température and humidity conditions.

Claims (16)

1. Modified release pharmaceutical composition comprising:

(i) from 200 mg to 1200 mg of hidrosmin;

(ii) at least one glyceride, consisting of an ester derived from glycerol and one to three fatty acids independently selected from Ci₂-C₃₂ fatty acids; and (iii) at least one diluent selected from silicified microcrystalline cellulose, cellulose, microcrystalline cellulose, maltose, calcium carbonate, magnésium carbonate, magnésium oxide, calcium phosphate, calcium hydrogen phosphate, croscarmellose sodium, crosspovidone, sodium starch glycolate, sucrose, or mixtures thereof, wherein the pharmaceutical composition is a tablet.

2. Pharmaceutical composition according to claim 1, wherein both the hidrosmin and the at least one glyceride are homogeneously distributed in said tablet.

3. Pharmaceutical composition according to anyone of daims 1 to 2, wherein the at least one glyceride is présent in an amount of 10 to 50 wt%, relative to the total weight of the composition.

4. Pharmaceutical composition according to anyone of daims 1 to 3, wherein the at least one glyceride is présent in an amount of 15 to 35 wt%, relative to the total weight of the composition.

5. Pharmaceutical composition according to anyone of daims 1 to 4, wherein the at least one glyceride is selected from the group of glyceryl behenate, glyceryl monooleate, glyceryl dioleate, glyceryl trioleate, glyceryl monostearate, glyceryl distearate, glyceryl tristearate, glyceryl palmitostearate, vegetable oil, hydrogenated vegetable oil, ethylated castor oil, glyceryl monolaurate, glyceryl dilaurate, glyceryl trilaurate, glyceryl monomyristate, glyceryl dimyristate, glyceryl trimyristate, glyceryl palmitate, glyceryl dipalmitate, glyceryl tripalmitate, and mixtures thereof.

6. Pharmaceutical composition according to anyone of daims 1 to 5, comprising from 500 to 700 mg of hidrosmin.

7. Pharmaceutical composition according to anyone of daims 1 to 6, further comprising one or more pharmaceutically accepted excipients independently selected from the group formed by glidants, fillers, disintegrants and binders.

8. Pharmaceutical composition according to anyone of daims 1 to 7, comprising from 11 wt% to 23 wt% of the at least one diluent, wherein wt% corresponds to the percentage mass weight ratio of said diluent relative to the total weight of the composition.

9. Pharmaceutical composition according to claim 8, comprising from 12% wt% to 17% wt% of diluent.

10. Pharmaceutical composition according to anyone of daims 1 to 9, comprising a diluent selected from silicified microcrystalline cellulose or microcrystailine cellulose, or mixtures thereof.

11. Pharmaceutical composition according to anyone of daims 7 to 10, further comprising from 0.05 to 5 wt% of a glidant selected from colloïdal Silicon dioxide, talc, or mixtures thereof.

12. Method of direct compression for preparing a pharmaceutical composition as defined in anyone of daims 1 to 11, comprising the steps of:

(a) mixing hidrosmin with at least one glyceride, consisting of an ester derived from glycerol and one to three fatty acids independently selected from C₁₂-C₃₂ fatty acids, at least one diluent selected from silicified microcrystalline cellulose, cellulose, microcrystailine cellulose, maltose, calcium carbonate, magnésium carbonate, magnésium oxide, calcium phosphate, calcium hydrogen phosphate, croscarmellose sodium, crosspovidone, sodium starch glycolate, sucrose, or mixtures thereof;

(b) compressing the mixture of step (a) to tablets.

13. Modified release pharmaceutical composition obtainable by the method according to claim 12.

14. Pharmaceutical composition according to anyone of daims 1 to 11, or 13, characterized by an in vitro dissolution profile such that:

(a) an amount of 25 wt% to 50 wt% of hidrosmin relative to the total hidrosmin content ofthe composition is released within 2 h, >8 (b) an amount of 50 wt% to 80 wt% of hidrosmin relative to the total hidrosmin content of the composition is released within 8 h, and (c) an amount of more than 70 wt% of hidrosmin relative to the total hidrosmin content of the composition is released within 14 h,

5 where in the in vitro release of hidrosmin is measured according to United States Pharmacopeia (711)-EP (2.9.3) dissolution apparatus 2 (paddles), in 900 mL at pH 6.8 (USP or EP), 50 rpm and 37°C.

15. Pharmaceutical composition as defined in anyone of daims 1 to 11, or 13 or 14, for 10 use as a médicament.

16. Pharmaceutical composition as defined in anyone of daims 1 to 11, or 13 or 14, for use in the prévention and/or treatment of a disease selected from chronic venous insufficiency, varicose veins, hemorrhoids, edema, metabolic syndrome, non15 alcoholic fatty liver disease and diabetic nephropathy.