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
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
• • 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
  • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
  • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
  • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

• the present invention relates to modified release formulations of hidrosmin suitable for once-daily administration and to uses of such formulations.
• Diosmin glycoside is a water-insoluble flavonoid used in the treatment of venous disease.
• Hidrosmin is a synthetic derivative of diosmin, which, in contrast to diosmin, is water soluble and twice as potent.
• 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 ingredient 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.
• the present 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 hydrophobic release agent.
• 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.
• a“reproducible dissolution profile” is to be understood as a dissolution profile with a coefficient of variation or relative standard deviation (RSD) of the in vitro released amount of hidrosmin lower than 10% (RSD ⁇ 10%).
• RSD relative standard deviation
• one aspect of the present invention relates to a modified release pharmaceutical composition
• a modified release pharmaceutical composition comprising:
• At least one diluent selected from silicified microcrystalline cellulose, cellulose, microcrystalline cellulose, maltose, calcium carbonate, magnesium carbonate, magnesium oxide, calcium phosphate, calcium hydrogen phosphate, croscarmellose sodium, crosspovidone, sodium starch glycolate, sucrose, or mixtures thereof.
• the present formulation allows obtaining reproducible (RSD ⁇ 10%) modified release dissolution profiles from directly compressed hidrosmin tablets.
• 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, magnesium carbonate, magnesium 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;
• step (b) compressing the mixture of step (a) to tablets.
• the invention refers to a pharmaceutical composition as defined herein obtainable by the method of the invention.
• the present invention also relates to such pharmaceutical composition for use as a medicament, preferably in the prevention 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.
• a disease selected from chronic venous insufficiency, varicose veins, hemorrhoids, edema, metabolic syndrome, non-alcoholic fatty liver disease or diabetic nephropathy.
• FIG. 1 Hidrosmin in vitro dissolution profile of exemplary pharmaceutical compositions of the invention comprising different glyceride modified release agents.
• Hydrogenated cottonseed oil Libritab®
• Glyceryl palmitostearate Precirol®
• Glyceryl behenate Compritol ®
• 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 immediate release hidrosmin formulation (Venosmil®) given three times a day at a dosing interval of 8 hours.
• 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.
• a composition of a water-soluble active pharmaceutical ingredient (API) with hydrophilic modified release excipients either did not have adequate dissolution profiles or these were not reproducible (RSD ⁇ 10%), or even lacked stability. This was the case when the API is hidrosmin.
• hydrophilic modified release excipients such as hydroxypropyl methylcellulose or carboxymethyl cellulose
• 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 consequent 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. Aguilar-Diaz 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. (201 1 ).
• 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 consideration for development of SeDeM diagram.
• the SeDeM method is based on the experimental study and quantitative determination 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 (Dc), interparticle porosity or sponginess index (le), Carr index (IC), cohesion index (led), Hausner ratio (IH), angle of repose (a), flow rate ( ), relative humidity (%RH), hygroscopicity (%H), particle size (%Pf) and homogeneity index (IQ).
• Da bulk or apparent density
• Dc tapped density
• IC interparticle porosity or sponginess index
• Carr index IC
• cohesion index led
• Hausner ratio IH
• angle of repose a
• flow rate )
• %RH relative humidity
• %H hygroscopicity
• particle size %Pf
• IQ homogeneity index
• Excipients of melting point below 100 °C are known to cause undesirable effects during compression such as adherence, 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.
• the surface of the excipient is known to reach temperatures of 100 °C.
• Lipophilic excipients, of melting point lower than 100 °C are employed as lubricants only if their concentration is below 10%, concentration above which the above-mentioned effects are no longer negligible (Britten JR, Pilpel N., J. Pharm.
• compositions comprising the water-soluble hidrosmin API and hydrophobic 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 have never been selected by the skilled person as viable compression excipients, and even less at the concentrations of the present 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).
• these pharmaceutical compositions provide extended release of hidrosmin.
• the formulation does not allow a modified release at all (see Example 3).
• the release agents are glycerides. Said combination allows obtaining a matrix with adequate solid volume, adequate and with remarkable reproducible (RSD ⁇ 10%) dissolution profiles, and wherein the pharmaceutical solid composition is stable in time.
• modified release agents such as lipids, which comprise glycerides, tend to form unstable solid forms which degrade in time thereby losing the extended release properties (WO 201 1/143118).
• the present invention allows obtaining extended release compositions for a highly soluble active pharmaceutical ingredient, which do not require any additional protective coatings to tune the release thereof.
• 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 have compressibility indexes higher than 9.5) (see Example 2).
• This result advantageously affects the industrial up scaling of the invention.
• one aspect of the present invention relates to a modified release pharmaceutical composition
• a modified release pharmaceutical composition comprising:
• At least one diluent selected from silicified microcrystalline cellulose, cellulose, microcrystalline cellulose, maltose, calcium carbonate, magnesium carbonate, magnesium oxide, calcium phosphate, calcium hydrogen phosphate, croscarmellose sodium, crosspovidone, sodium starch glycolate, sucrose, or mixtures thereof.
• the present formulation allows obtaining reproducible (RSD ⁇ 10%) modified release dissolution profiles from directly compressed hidrosmin tablets.
• modified release is to be understood as opposite to “immediate release” and could also be identified with similar terms such as“extended release” or “delay release”.
• hidrosmin is gradually and continuously liberated over time.
• the term indicates that the system does not release the full dose of hidrosmin immediately after oral dosing and that the formulation allows a reduction in dosing frequency.
• the pharmaceutical composition is a tablet.
• 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, all of the hidrosmin is in a continuous matrix of constant composition.
• 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 derivatives.
• continuous matrix of constant composition is to be interpreted as a homogeneous medium wherein all components comprised therein are distributed throughout the entire volume of the matrix without the presence of defined regions or frontiers.
• 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.
• the pharmaceutical composition of the invention is such that both the hidrosmin and the at least one glyceride are homogeneously distributed in the tablet.
• 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 regions or frontiers. In other words, all regions of the tablet comprise approximately the same amounts of components (i), (ii), and optionally (iii), i.e., all parts of the tablet are equal in composition in terms of components (i), (ii), and optionally (iii).
• the pharmaceutical composition of the invention does not comprise layers or distinguishable regions with different compositions forming frontiers.
• the tablet may comprise further components and/or excipients and in such case, said further components and/or excipients are homogeneously distributed as well.
• 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.
• the pharmaceutical composition of the invention does not comprise hydrophilic modified release agents.
• the pharmaceutical composition of the invention does not comprise hydroxypropyl methylcellulose, carboxymethylcellulose, hydroxyethyl cellulose, methylcellulose, or ethyl cellulose, more preferably cellulose ether derivatives.
• the hidrosmin amount in the pharmaceutical composition of the invention ranges from 200 to 1200 mg. In another particular embodiment, the hidrosmin is present at from 300 mg to 1000 mg. In yet another particular embodiment, the hidrosmin is present 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.
• 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 present from 35 to 85 wt% with respect to the total weight of the composition. In a more preferred embodiment, hidrosmin is present in an amount from 45 to 75 wt%. In an even more preferred embodiment, hidrosmin is present 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 of the total mixture (same mass units), multiplied by 100.
• 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 claims, 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 molecule of glycerol and one fatty acid (monoglyceride), two fatty acids (diglyceride) or three fatty acids (triglyceride).
• 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.
• the pharmaceutical composition of the invention comprises a glyceride at an amount of 23 wt%, relative to the total weight of the composition.
• each glyceride or each excipient is selected from the listed elements independently from any other selected glyceride or excipient.
• 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.
• 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.
• glyceride selected from the group of glyceryl behenate, glyceryl monooleate, glyceryl dioleate, gly
• 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 (C- ) and stearic acid (Cis).
• a hydrogenated vegetable oil is to be understood as a triglyceride extracted from a plant that was submitted to a hydrogenation process.
• the hydrogenation process can be either complete 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.
• Hydrogenated vegetable oils can be solid or liquid at room temperature, and can comprise glycerin as well.
• 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 C15-C18.
• 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.
• the hydrogenated vegetable oil is hydrogenated cottonseed oil or hydrogenated castor oil.
• 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.
• 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 hydrogenation of castor oil.
• a hydrogenated castor oil such as Kolliwax HCO ® predominately contains the triglyceride of 12-hydroxystearic acid.
• the glyceride is ethylated castor oil, such as the one commercially known as Cremophor®.
• 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.
• a glyceride selected from glyceryl behenate, glyceryl palmitostearate, hydrogenated vegetable oil, ethylated castor oil or mixtures thereof.
• the hydrogenated vegetable oil is selected from hydrogenated cottonseed oil or hydrogenated castor oil.
• 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.
• a glyceride selected from glyceryl behenate, glyceryl palmitostearate, hydrogenated vegetable oil, ethylated castor oil or mixtures thereof.
• the 150 to 350 mg of hydrogenated vegetable oil are selected from hydrogenated cottonseed oil or hydrogenated castor oil.
• composition of the invention comprises hidrosmin in the aforementioned amounts and hydrogenated cottonseed oil in the respective aforementioned amounts.
• the composition may further comprise at least one pharmaceutically accepted excipient independently selected from glidants, fillers, disintegrants and binders.
• 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%.
• 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, colloidal 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, magnesium carbonate, magnesium stearate, sodium alginate, calcium alginate, ammonium alginate, xanthan gum, tragacanth, compressible sugar, calcium lactate, or mixtures thereof.
• Preferred diluents and glidants are selected from microcrystalline
• glidant can be understood as lubricant.
• 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, magnesium carbonate, magnesium oxide, calcium phosphate, calcium hydrogen phosphate, croscar
• the pharmaceutical composition comprises a diluent selected from silicified microcrystalline cellulose, cellulose, microcrystalline cellulose, maltose, calcium carbonate, magnesium carbonate, magnesium oxide, calcium phosphate, calcium hydrogen phosphate, croscarmellose sodium, crosspovidone, sodium starch glycolate, sucrose, or mixtures thereof.
• Diluents may comprise at least one disintegrant component.
• the diluents are in an amount of 5 to 50 wt% relative to the total weight of the composition. More preferably, from 1 1 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.
• the diluent is microcrystalline cellulose.
• the diluent is silicified microcrystalline cellulose.
• Silicified microcrystalline cellulose is the silicified product of microcrystalline cellulose.
• the process of silicification leads to the deposition 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).
• the silicified microcrystalline cellulose of the pharmaceutical composition of the invention comprises between 1 and 2 wt% of silicon dioxide.
• the silicified microcrystalline cellulose is characterized by an average particle size of between 100 and 150 pm, more preferably 125 pm.
• 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_.
• 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.
• 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 1 1 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.
• the pharmaceutical composition of the invention comprises silicified microcrystalline cellulose as diluent, at an amount of 14.9%.
• 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 1 1 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.
• the pharmaceutical composition of the invention comprises microcrystalline cellulose as diluent, at an amount of 14.9%.
• the composition further comprises from 0.05 to 5 wt% of a glidant selected from colloidal silicon dioxide, talc mixtures thereof.
• the composition comprises colloidal 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.
• 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.
• the composition further comprises a mixture of 0.1 wt% colloidal silicon dioxide and 2 wt% talc as glidants.
• 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 of the composition.
• 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.
• 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.
• the pharmaceutical composition of the invention is a tablet, i.e., a solid oral dosage form.
• the hardness of said solid form is between 1 10 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 resistance to crushing according to the technique described in European Pharmacopoeia (2.9.8.).
• the technique is intended to determine, under defined conditions, the resistance to crushing of tablets, measured by the force needed to disrupt them by crushing.
• the hardness values have an intrinsic variability of ⁇ 20 N, preferably ⁇ 15 N, more preferably ⁇ 12.5 N. For this reason, in the present description the hardness value is also referred to as target hardness value.
• the solid oral dosage form of the present invention is not in the form of granules. More preferably, the solid oral dosage form of the present invention does not comprise coated granules; even more preferably, does not comprise granules.
• the pharmaceutical composition of the invention provides an in vitro dissolution profile such that:
• the formulation provides the following in vitro dissolution profile:
• the formulation provides the following in vitro dissolution profile:
• the formulation provides the following in vitro dissolution profile:
• the composition of the invention allows remarkably reproducible dissolution profiles (RSD ⁇ 10%).
• RSD coefficient of variation or relative standard deviation
• the coefficient of variation or relative standard deviation (RSD), of the in vitro released amount of hidrosmin between 8 and 14 h is lower than 10%.
• the coefficient of variation or relative standard deviation (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 deviation of various terms from their average in an observation and is defined by the following formula:
• %RSD (sample standard deviation * 100)/ sample mean
• 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.
• 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.
• the solid composition is prepared by direct compression.
• the invention refers to a method of direct compression for preparing a pharmaceutical composition as defined herein, comprising the steps of:
• 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, magnesium carbonate, magnesium 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;
• step (b) compressing the mixture of step (a) to tablets.
• a method for producing the composition of the invention by direct compression can comprise the steps of:
• step (b) compressing the mixture of step (a) to tablets.
• the invention refers to a pharmaceutical composition as defined herein obtainable by the method of the invention.
• 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 medicament.
• 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 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.
• a disease selected from chronic venous insufficiency, varicose veins, hemorrhoids, edema, metabolic syndrome, non-alcoholic fatty liver disease and diabetic nephropathy.
• composition of the invention is advantageously administered once a day.
• the composition is administered once-daily in the form of a solid oral dosage.
• 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 medicament for 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.
• a disease selected from chronic venous insufficiency, varicose veins, hemorrhoids, edema, metabolic syndrome, non-alcoholic fatty liver disease and diabetic nephropathy.
• 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 of the invention.
• a disease selected from chronic venous insufficiency, varicose veins, hemorrhoids, edema, metabolic syndrome, non-alcoholic fatty liver disease and diabetic nephropathy
• Hidrosmin is commercially available. Batch 1000002309 from Laboratorios FAES FARMA S.A. was used.
• Hidrosmin Batch 1000002309 has the following physico-chemical properties:
• 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.
• hidrosmin has deficient 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.
• IRC index of good compression
• a parametric profile of 4.17 closer to the minimum acceptable value of 5
• Suitable direct compression diluents are known in the art as such that have an IGC > 5.
• the inventors have thus surprisingly found that the present 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).
• the tablets were prepared by direct compression defined as follows.
• composition of the tablets is described in the following table.
• the modified release agents used in the present example were: Sample 1. Hydrogenated cottonseed oil (Lubritab®); Sample 2. Glyceryl palmitostearate (Precirol®); and Sample 3. Glyceryl behenate (Compritol ®).
• Hidrosmin Fes Farma S.A., Spain
• Silicified Microcrystalline Cellulose Prosolv ® HD 90, JRS Pharma GmbH&Co. KG, Germany
• Hydrogenated cottonseed oil Libritab ® , JRS Pharma GmbH&Co. KG, Germany
• Glyceryl palmitostearate Precirol®, Gattefosse, USA
• Glyceryl behenate Compritol ®, Gattefosse, USA
• Colloidal silicon dioxide HDK N20P, Wacker Chemie GmbH, Germany
• Talc Imeris Talc Italy S.P.A., Italy
• Turbula T10B Blender (17 L Stainless steel drum).
• step 2 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 T urbula T 10B Blender (17 L Stainless steel drum).
• the dissolution rate of hidrosmin from the tablets prepared in this example shows that the present 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 representation of the table above.
• Example 2 Comparative in vitro dissolution profiles using 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 modified release agent present 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%, Magnesium stearate 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%, Magnesium stearate 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%, Magnesium stearate and Aerosil 200 (fumed silica) 0.1 wt%.
• Each profile corresponds to the averaged measurement of 12 vessels.
• 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:
• the following rates of dissolution of hidrosmin were obtained.
• the profile corresponds to the averaged measurement of 12 vessels.
• Example 4 Formulations of the invention at increasing modified release agent concentrations for tablet target 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 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%, Colloidal Silicon Dioxide 0.1 wt% and Talc 2 wt%).
• the profiles were determined according to the previous examples.
• Figures 4 and 5 show the profiles above at Lubritab® 19%, 21 % and 23%, respectively.
• Figures 5A, 5B and 5C show the samples above at target hardness of 150 N, 175 N and 200 N, respectively.
• the results show that for all 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 concentrations.
• Example 1 of the cited prior art document discloses a formulation of three separate regions, granules, the coating of the granules, and a matrix wherein the coated granules are dispersed.
• 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.
• a formulation as the one disclosed in example 1 of the cited prior 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 2011 1431 18.
• the amounts of each component were adapted so that tablets suitable for oral administration (adequate size, weight and shape) were obtained. A batch of 1 kg was prepared.
• a hydroalcoholic solution (30:70) was prepared by mixing 200 g of deionized water and 475 g of ethanol (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).
• 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®).
• 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.
• 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
• 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 , 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 inadequate, as shown in the table below.
• 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 tablets were successfully prepared and the dissolution profile was adequate as shown in the table below.
• Example 11 Stability of the hidrosmin tablets under temperature and humidity
• Tablets prepared according to example 1 were submitted to three stability tests and their dissolution behavior was measured.
• 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.
• 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.
• Stability test 2 100%, 94% and 94% of the initially obtained values, respectively.
• Stability test 3 97%, 93% and 94% of the initially obtained values, respectively.

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