Pharmaceutical composition in the form of a drinkable oral suspension in a sachet comprising a flavonoid fraction and a xanthan gum.

Abstract

Oral composition in the form suspension comprises diosmin as an active ingredient, and optionally flavonoid derivatives and xanthan gum as excipient. ACTIVITY : Anticoagulant; Antiinflammatory. MECHANISM OF ACTION : None given.

Description

[001] The present invention relates to a high-dose oral suspension comprising diosmin, and optionally other flavonoid compounds, and xanthan gum as an excipient, and also to its use in the treatment of venous insufficiency.

[002] Preferably, the present invention relates to a high-dose suspension of a flavonoid fraction and xanthan gum for oral administration, and also to its use in the treatment of venous insufficiency.

[003] The flavonoid fraction is obtained from an extract of Rutaceae. The purified and micronized flavonoid fraction used in the invention contains 87% to 93% diosmin and other flavonoids concomitantly. Those other flavonoids, which constitute about 10% of the content, comprise 2.5% to 5.0% hesperidin, 0.9% to 2.8% isorhoifolin, 0.9% to 2.8% linarin, and less than 1% diosmetin. The particle size of the micronized flavonoid fraction is strictly less than 5 µm, preferably less than 4 µm, 3 µm, 2 µm, and most preferably less than 1.6 µm.

[004] The flavonoid fraction according to the invention is administered at daily doses ranging from 1000 mg to 3000 mg in order to treat the manifestations of chronic venous insufficiency of the lower limbs. Due to the high degree of metabolization of the flavonoid fraction in the gastrointestinal tract, a high dose of this active ingredient must be given with each administration. Furthermore, treatments based on a flavonoid fraction are long-term treatments that require simple administration in order to encourage patient compliance with the treatment. Consequently, preference is given to formulations under development which, in the case of Petition 870260053784, dated 03 / 06 / 2026, page 28 / 45 2 / 9 elderly, they are easy to take and, in the case of patients who take the medication outside the home, do not require water to be added.

[005] The therapeutic use, according to the invention, of the flavonoid fraction extracted from Rutaceae was described in patent application EP 0 711 560. This patent application describes a high-dose effervescent granulated composition containing 1000 mg of flavonoid fraction. However, those effervescent granules must be dissolved in water before being taken.

[006] Drinkable solutions comprising flavonoids and a xanthan gum were described in US patent application 5,240,732. That patent application discloses a solution in which the flavonoids were dissolved in an alcohol, unlike the present invention which relates to an aqueous solution in which the flavonoid fraction is homogeneously distributed.

[007] Drinkable suspensions comprising polyphenols and dispersion stabilizers were described in US patent application 2012 / 0070475. The suspensions according to US application 2012 / 0070475 contain low doses of quercetin and exclusively use gellan gum as a dispersion stabilizer.

[008] The object of the present invention is a pharmaceutical composition in the form of a high-dose oral suspension comprising diosmin as the active ingredient, and optionally other flavonoid compounds, and xanthan gum as an excipient.

[009] Preferably, the object of the present invention is the pharmaceutical composition in the form of a high-dose oral suspension comprising as the active ingredient a flavonoid fraction and as an excipient xanthan gum.

[0010] The percentage of flavonoid fraction in the pharmaceutical composition is between 7% w / w and 20% w / w.

[0011] The amount of flavonoid fraction in the composition Petition 870260053784, dated 03 / 06 / 2026, page 29 / 45 3 / 9 pharmaceutical dosage ranges from 1000 mg to 3000 mg, including, for example, 2000 mg, 1500 mg, and 2500 mg.

[0012] The oral suspension having a high dose of the active ingredient according to the present invention must have a viscosity that is suitable, on the one hand, to allow the suspension to flow in the production machines and, upon administration, to flow out of the sachet and, on the other hand, to prevent the flavonoid fraction from settling in the sachet and to allow it to remain stable for a period of time.

[0013] In order to satisfy all those functional properties, the oral suspension must satisfy specific rheological properties.

[0014] The viscosity of the suspension should not be dependent on the time for which it is subjected to shear forces. It is necessary for the suspension to recover its initial viscosity after the application of stress, regardless of the duration of its application. The viscosity of the suspension must therefore be reversible over the shear range of 0.01 to 1000 s-1. The rheological property, that is, the fact that the suspension fully recovers its viscosity during periods at rest, is essential in the pumping and pre-packaging stages, up to transport and storage, and until the oral suspension in sachets is being used by the end consumer.

[0015] Furthermore, it seems necessary that the viscosity of the suspension be independent of temperature over the range of 15°C-60°C, the ad hoc temperature range at the end of production and during the transport, processing and packaging stages of the final product.

[0016] Viscosity measurements are performed using the Anton Paar rheometer or the Brookfield rheometer. The results obtained with those two types of rheometers are fully compatible. Petition 870260053784, dated 03 / 06 / 2026, page 30 / 45 4 / 9

[0017] The stability and rheological properties required for the oral suspension according to the invention are obtained with the aid of thickening of the pharmaceutical composition. Thickening of the pharmaceutical composition is achieved by means of the use of a thickening agent.

[0018] The thickening agent according to the invention is xanthan gum. Xanthan gum is a high molecular weight anionic polysaccharide comprising D-glucoses and D-mannoses as predominant hexoses. In solution, xanthan gum molecules associate with each other to form a network of intertwined molecules.

[0019] The concentration of xanthan gum in the pharmaceutical composition according to the invention is between 0.45% w / v and 0.55% w / v, inclusive. The concentration of xanthan gum may be, for example, 0.50% w / v, 0.47% w / v, 0.53% w / v.

[0020] The amount of xanthan gum in the pharmaceutical composition is between 0.30% w / w and 0.60% w / w.

[0021] The pharmaceutical composition in the form of an oral suspension having a high content of flavonoid fraction according to the invention is free of surfactants. Surfactants are generally used in oral suspensions in order to improve the dispersion and wettability of the suspended particles.

[0022] In addition to the flavonoid fraction and xanthan gum, the pharmaceutical composition according to the invention comprises one or more pharmaceutically acceptable excipients such as preservatives, flavorings, sweeteners or pH adjusters.

[0023] Examples of excipients include: as preservatives: sodium benzoate, benzalkonium chloride, methyl parahydroxybenzoate, propyl parahydroxybenzoate; Petition 870260053784, dated 03 / 06 / 2026, page 31 / 45 5 / 9 aromas: orange aroma, lemon aroma, soft caramel aroma, vanilla / lemon aroma; as sweeteners: maltitol, sorbitol, aspartame, xylitol, acesulfame potassium, sodium saccharin; pH adjusters include: citric acid, ascorbic acid, and tartaric acid.

[0024] The pharmaceutical composition according to the invention is in the form of a drinkable suspension in a sachet. The sachet or stick packaging preferably has a unit volume of 10 ml containing the daily dose of flavonoid fraction. For better patient compliance, the unit volume of the sachet would not be excessively large, for example, 10 ml, 12 ml, 15 ml, 17 ml or, at most, 20 ml.

[0025] The present invention also relates to the use of the pharmaceutical composition according to the invention in the treatment of venous disease, more specifically venous insufficiency. These pharmaceutical compositions are used as venotonics and vasculoprotectors.

[0026] The examples below illustrate the invention in a non-limiting way. Example 1: Pharmaceutical composition for a sachet containing a 1 g suspension of flavonoids. Sodium benzoate 0.015 g / 10 ml Citric acid 0.0125 g / 10 ml Orange flavor 0.015 g / 10 ml Maltitol 1.8 g / 10 ml Flavonoid fraction 1.0 g / 10 ml Xanthan gum 0.05 g / 10 ml Purified water q.s.p. 10 ml Preparation of the suspension of Example 1: Petition 870260053784, dated 03 / 06 / 2026, page 32 / 45 6 / 9 For approximately 100,000 sachets:

[0027] 700 liters of purified water and 1.5 kg of sodium benzoate are carefully mixed at 20°C until complete dissolution. 1.25 kg of citric acid and 1.5 kg of orange flavoring are added to the solution. 180 kg of maltitol powder are added to the solution and carefully mixed. 100 kg of the flavonoid fraction are added to the mixture very slowly until a homogeneous suspension is formed. 5 kg of xanthan gum are very slowly introduced directly into the suspension. Purified water is added q.s. to obtain a final volume of 1100 liters. Example 2: Oral suspension stability from Example 1 (LP02 load)

[0028] The stability of the pharmaceutical composition of example 1 according to the invention in sachets was tested under various humidity and temperature conditions.

[0029] The sachets are made of a multi-layered composite (PET12 polyethylene / AL12 aluminum / PE50 extruded polyethylene composite). Sachet T Density (Eur. Ph.) 25°C / 60% RH 30°C / 65% RH 30°C / 75% RH 40°C / 75% RH T0 1.11 T0 + 1 month 1.10 1.10 1.10 1.10 T0 + 3 months 1.10 1.10 1.10 1.10

[0030] The table above, referring to the density of the suspension in the sachet over time, shows that the density is completely stable even under conditions of high humidity and temperature (40°C / 75% RH). This density stability shows that Petition 870260053784, dated 03 / 06 / 2026, pp. 33 / 45 7 / 9 the suspension does not separate for a period of time under conditions of high humidity and temperature. Sachet T Particle size of flavonoid fraction 25°C / 60% RH 30°C / 65% RH 30°C / 75% RH 40°C / 75% RH T0 d10 0.658 d50 2.581 d90 6.642 T0 + 1 month d10 0.723 d50 2.679 d90 6.969 d10 0.741 d50 2.692 d90 6.675 d10 0.739 d50 2.694 d90 6.698 d10 0.760 d50 2.726 d90 6.685 T0 + 3 months d10 0.726 d50 2.663 d90 6.670 d10 0.746 d50 2.779 d90 6.862 d10 0.751 d50 2.708 d90 6.690 d10 0.798 d50 2.818 d90 6.739

[0031] The particle size distribution of the flavonoid fraction is expressed in terms of the diameters d10, d50 and d90 where d10 = d(v,0,1) corresponds to the 10% value on the cumulative particle size distribution curve in terms of volume; d50 = d(v,0,5) corresponds to the value at 50% on the cumulative particle size distribution curve in terms of volume; d90 = d(v,0,9) corresponds to the 90% value on the cumulative particle size distribution curve in terms of volume.

[0032] The table above shows that the particle size in the flavonoid fraction according to the invention does not increase over time under conditions of high humidity and temperature. The particles of the micronized flavonoid fraction neither clump together nor Petition 870260053784, dated 03 / 06 / 2026, pp. 34 / 45 8 / 9 undergo sedimentation in the oral suspension according to the invention. Sachet T Viscosity in cP 25°C / 60% RH 30°C / 65% RH 30°C / 75% RH 40°C / 75% RH T0 321 T0 + 1 month 293 298 294 296 T0 + 3 months 293 293 294 298

[0033] The table above, referring to the viscosity of the suspension in the sachet, shows that the viscosity is extremely stable over time under conditions of high humidity and temperature.

[0034] Finally, a visual inspection of the suspension under various temperature and humidity conditions after 1 month and 3 months of evaluation shows an absence of lumps and bubbles in the sachets. Example 3: Uniformity of content of the pharmaceutical composition according to Example 1

[0035] The test is performed on 10 sachets. The contents of each sachet are analyzed; a diosmin reference solution is used as a control.

[0036] The average content Xm is expressed as follows: Xm = (Σ Xi) / 10

[0037] The acceptance value (AV), expressed as a percentage of the theoretical value, is given by the following formula: AV = (M-Xm) + kxs where: Xm is the average content expressed as a percentage of the theoretical value; M is the reference value expressed as a percentage of the theoretical value: M=98.5 if Xm < 98.5; M=Xm if 98.5 < Xm< 101.5; M=101.5 if Xm>101.5; Petition 870260053784, dated 03 / 06 / 2026, pages 35 / 45 9 / 9 k is the acceptability constant (k = 2.4 for 10 sachets); s is the standard deviation of the Xi levels. Uniformity parameters of content (diosmin) LP02 load 1000 liters (sachet) according to Example 1 Start of sachet filling End of sachet filling Average content 100.5 102.1 Standard deviation 0.9 0.7 Acceptance value (AV) 2.2 2.3

[0038] According to the European Pharmacopoeia, article 2.9.40, an acceptance value of less than 15 means that the uniformity of content is agreed (L1 level).

[0039] The table above therefore shows that the uniformity of diosmin content contained in the formulation according to the invention satisfies the regulatory requirements.

Claims

1. Pharmaceutical composition in the form of a drinkable oral suspension in a sachet, characterized in that it comprises diosmin as the active ingredient, and optionally flavonoid compounds, and xanthan gum as an excipient, wherein the active ingredient is a purified and micronized flavonoid fraction, wherein the flavonoid fraction comprises diosmin, hesperidin, isorhoifolin, linarin and diosmetin, wherein the amount of the flavonoid fraction is between 7% w / w and 20% w / w, inclusive, wherein the amount of xanthan gum is between 0.30% w / w and 0.60% w / w, inclusive.

2. Pharmaceutical composition, according to claim 1, characterized in that the concentration of xanthan gum is between 0.45% w / v and 0.55% w / v, inclusive.

3. Pharmaceutical composition, according to claim 2, characterized in that the concentration of xanthan gum is 0.5% w / v.

4. Pharmaceutical composition, according to any one of claims 1 to 3, characterized in that the amount of the flavonoid fraction is between 1000 and 3000 mg, inclusive.

5. Pharmaceutical composition, according to claim 4, characterized in that the amount of the flavonoid fraction is 1000 mg.

6. Pharmaceutical composition, according to any one of claims 1 to 5, characterized in that it comprises one or more pharmaceutically acceptable excipients selected from sweeteners, flavorings, preservatives and pH adjusters.

7. Pharmaceutical composition, according to any one of claims 1 to 6, characterized by the fact that it is for use in the treatment of venous insufficiency.