WO2021123341A1

WO2021123341A1 - Composition comprising diosmin

Info

Publication number: WO2021123341A1
Application number: PCT/EP2020/087263
Authority: WO
Inventors: Katja ŠKRLEC; Andrejka Kramar; Milena; PAVLIN; Grega Hudovornik
Original assignee: Krka, D.D., Novo Mesto
Priority date: 2019-12-20
Filing date: 2020-12-18
Publication date: 2021-06-24

Abstract

The present invention provides a chewable tablet comprising diosmin, microcrystalline cellulose, mannitol, an acidulant and a flavoring agent and a process for preparing the same.

Description

COMPOSITION COMPRISING DIOSMIN

FIELD OF THE INVENTION

The present invention relates to a chewable tablet comprising diosmin.

BACKGROUND OF THE INVENTION

Diosmin is a glycosylated flavonoid that belongs to the group of flavones. Flavonoids are the largest group of plant-derived polyphenols. Diosmin was first isolated in 1925 and has been used therapeutically since 1960s. It was first marketed in Europe in 1970s and a new micronized formulation (smaller particle size) was introduced in 1986. Diosmin is converted in the intestinal lumen into its diosmetin derivative, an aglycone with phlebotonic properties, increasing venous tone, improving lymphatic drainage and protecting the microvascularisation of inflammatory processes and apoptosis.

Diosmin can be manufactured by extracting hesperidin from citrus rinds and converting hesperidin to diosmin by dehydrogenation reaction.

Diosmin is available as a diosmin (European Pharmacopoeia) and as a micronized purified flavonoid fraction (MPFF) containing 90 % diosmin and 10 % other flavonoids expressed as hesperidin. Diosmin formulations are used to treat chronic venous insufficiency and other venocapillary disorders. The dose of diosmin in commercially available solid oral dosage forms is relatively large with doses up to 1000 mg. The inventors of the present invention are not aware, at the time of filing of the present patent application, of any commercially available chewable tablets comprising diosmin. EP541874 teaches the preparation of diosmin solid preparations such as powders, granules and tablets, which disperse in water.

EP711560 describes an effervescent granulate in the form of a tablet or a sachet comprising diosmin.

W02004032942 describes a pharmaceutical chewable tablet comprising diosmin.

EP1707192 describes a pharmaceutical composition comprising an active ingredient comprising two or more flavonoids in microcrystalline form.

RU2314812 relates to tablets comprising diosmin and red grape leaf extract. Chewable tablets are not disclosed.

W02014096740 relates to oral suspensions comprising diosmin and xanthan gum.

JP6253393 describes preparation of effervescent chewable tablets of hesperidin and hesperidin derivatives comprising a carbonate and an organic acid. Compositions comprising diosmin are not disclosed.

SUMMARY OF THE INVENTION

Diosmin requires relatively large doses with oral doses up to 1000 mg. It is well known that large tablets pose a problem because they can be difficult to swallow. On the other hand, tablets in general are simple and convenient to use and in this regard are preferable to other dosage forms such as solutions and dispersible dosage forms. Furthermore, diosmin has an unpleasant taste and requires taste masking if exposed to taste buds. In addition, in case of large doses, it is desirable to maximize the content of active ingredient as to reduce the tablet size, i.e., to increase the drug load. The inventors of the present invention have developed a chewable tablet that can solve the above-mentioned problems.

Although the problem of large doses of diosmin and consequently of its large dosage forms is discussed in EP541874, EP711560 and W02004032942, the prior art does not teach the specific composition with advantageous properties of the present invention. EP541874 and EP711560 do not disclose chewable tablets and are focused on the preparation of water dispersible preparations. W02004032942 teaches the preparation of diosmin chewable tablets, however, the tablets in the examples have a drug load of only 25 % and the amount of diosmin of only 600 mg. Furthermore, specific combination of excipients of the present invention is not disclosed.

The chewable tablets according to the present invention can have a drug load of at least 40 % and can comprise more than 800 mg of diosmin. The novel excipient base of the present invention provides chewable tablets with improved properties, including consistency in the mouth for chewing, taste and mouthfeel. Chewable tablets have an improved compliance, as they can be easily chewed, even for those who experience difficulties swallowing conventional tablets. With the selected excipients, the processability of the tablets was improved with neither cracking problems after compression nor picking and sticking problems during tableting.

More specifically, the present invention accomplishes the above objectives by providing the chewable tablets as specified in the appended claims. Further embodiments of the invention are described hereinbelow. DETAILED DESCRIPTION OF THE INVENTION

The object of the present invention is a chewable tablet comprising diosmin, microcrystalline cellulose, mannitol, an acidulant and a flavoring agent.

The term "chewable tablet" as used herein means an oral dosage form intended to be chewed and then swallowed by the patient rather than swallowed whole. Chewable tablet is palatable and may be chewed and ingested with little or no water.

Chewable tablet may be prepared by any suitable process, such as a process that comprises direct compression, wet granulation and/or dry granulation. Preferably, chewable tablet is prepared by wet granulation.

The term "diosmin" as used herein refers to diosmin and a mixture of diosmin with not more than 10 % (w/w) of other flavonoids. For example, such a mixture is a micronized purified flavonoid fraction (MPFF) which is a combination of about 90 % diosmin and about 10 % other flavonoids expressed as hesperidin. This means that 1000 mg of MPFF contains about 900 mg of diosmin and about 100 mg of other flavonoids.

The amount of diosmin in the chewable tablet can be from 700 to 1300 mg, preferably from 800 to 1200 mg and even more preferably from 900 to 1100 mg. Most preferably, the amount of diosmin is 1000 mg. Diosmin can be incorporated into the chewable tablet intragranularly and/or extragranularly, preferably intragranularly, even more preferably only intragranularly. Preferably, diosmin granules are prepared by wet granulation.

The term "drug load" as used herein means a mass fraction of diosmin in a given formulation expressed as percentage by mass. Preferably, the drug load is at least 40 %, most preferably at least 45 %. Even more preferably, the drug load is in the range from 45 % to 60 %, more preferably from 45 to 55 % and most preferably from 45 % to 50 %.

Mannitol is a sweetener and a diluent and has a pleasant cooling sensation in the mouth. Preferably, mannitol is present in the form of highly compressible and compactible grade, such as particle-engineered type as spray dried and/or granulated type. Mannitol is preferably selected from mannitol with average particle size 50-300 pm, more preferably from 100 to 250 pm. For example, mannitol commercially available under the trade name such as Mannitol Parteck M200, Mannitol Parteck M100, Mannogem Mannitol XL, Mannitol Pearlitol 160C can be used. Preferably, mannitol is incorporated extragranularly, even more preferably only extragranularly. Preferred amount of mannitol in the chewable tablet is in the range from 5 % to 40 % by weight, more preferably from 10 to 30 % by weight and most preferably from 10 % to 25 % by weight of the chewable tablet.

Microcrystalline cellulose (MCC) can be diluent, binder, lubricant and/or disintegrant. MCC used in the present invention can be of any type, for example, it can be MCC commercially available under the trade name Avicel PH-101, Avicel PH-102, Avicel PH-200 and/or Avicel PH-301. MCC can be incorporated in the tablets also as a mixture with other excipients, for example as co-processed MCC. Co-processed MCC can be a mixture of MCC with silicone dioxide (silicified MCC or SMCC), mannitol, guar gum, sodium carboxymethyl cellulose, calcium carbonate and/or lactose. Preferably, the co-processed mixture is a mixture of MCC and guar gum, for example, such a mixture is commercially available under the trade name Avicel CE-15 that contains about 85 % of MCC and about 15 % of guar gum. MCC can be incorporated intragranularly and/or extragranularly . Preferably, MCC is incorporated intragranularly and extragranularly. More preferably, MCC incorporated extragranularly is co-processed MCC. Most preferably, MCC incorporated extragranularly is a mixture of MCC and guar gum. Preferably, the amount of MCC in the chewable tablet is in the range from 1 % to 40 %, more preferably from 5 % to 30 %, and most preferably from 5 % to 25 % by weight of the chewable tablet. Preferred amount of MCC incorporated intragranularly in the chewable tablet is in the range from 1 % to 30 % by weight, most preferably in the range from 5 % to 15 % by weight of the chewable tablet. Preferred amount of MCC incorporated extragranularly in the chewable tablet of the present invention is in the range from 1 % to 30 % by weight, most preferably in the range from 5 % to 20 % by weight of the chewable tablet. In a particularly preferred embodiment, amount of MCC incorporated intragranularly in the chewable tablet is in the range from 5 % to 25 % by weight and the amount incorporated extragranularly in the chewable tablet of the present invention is in the range from 5 % to 20 % by weight. In one embodiment, if co-processed MCC as specified above is used, the above amount indications apply to the entire co-processed substance.

It has been surprisingly found that the use of a mixture of microcrystalline cellulose and mannitol gives not only superior flow properties of formulation, but that this combination of diluents allows to prepare chewable tablet with lessened grittiness, minimized chalkiness, reduced toothpacking and improved overall palatability.

The term "acidulant" as used herein refers to a pharmaceutically acceptable excipient having a pH of 1 % (w/w) aqueous solution of less than 4.0. The acidulant is usually added to enhance the taste. For example, the acidulant can be selected from the group consisting of citric acid, tartaric acid, fumaric acid, lactic acid, malic acid, succinic acid, phosphoric acid and/or acetic acid. Preferably, the acidulant is selected from the group consisting of citric acid, tartaric acid, fumaric acid, lactic acid and/or malic acid. More preferably, the acidulant is citric acid. Preferred amount of acidulant in the chewable tablet of the present invention is in the range from 0.5 % to 10 % by weight, more preferably from 1 % to 5 % by weight and most preferably from 3 % to 5 % by weight of the chewable tablet. Preferably, the acidulant is incorporated extragranularly.

The term "flavoring agent" as used herein is intended to mean a compound which imparts taste and/or odor to the chewable tablet or a compound which modifies taste and/or odor of the chewable tablet. Substances with exclusively sweet, sour or salty taste are not flavoring agents according to the present invention. Preferably, the flavoring agent is of natural origin. More preferably, the flavoring agent is a fruit flavoring agent. For example, the flavoring agent can be selected from the group consisting of citrus, lime, orange, apple, pear, peach, lemon, cherry, grape, strawberry, plum, pineapple, raspberry, passion fruit, banana, caramel, chocolate, vanilla, anise, peppermint, eucalyptus, maple and/or honey flavoring agent. Preferably, the flavoring agent is selected from the group consisting of orange, citrus, lime and lemon flavoring agent. Most preferably, the flavoring agent is orange flavoring agent. Preferably, the amount of flavoring agent in the chewable tablet is in the range from 0.1 to 15 % by weight, more preferably from 0.5 to 10 % by weight and most preferably from 1 to 5 % by weight of the chewable tablet. Preferably, the flavoring agent is incorporated extragranularly. The chewable tablet according to the present invention can in addition comprise other excipients, such as sweeteners, diluents, disintegrants, binders, lubricants and glidants.

Sweetener can be selected from the group consisting of xylitol, fructose, sucrose, erythritol, polydextrose, cyclodextrin, thaumatin, steviol glycoside, a synthetic sweetener such as aspartame, sucralose, acesulfame potassium, saccharine and its salts, cyclamic acid and its salts, dihydrochalcones, thaumatin, monellin and/or alitame. Preferably, the sweetener is sucralose. Preferred amount of sweetener in the chewable tablet is in the range from 0.01 % to 20 % by weight, most preferably in the range from 0.05 % to 10 % by weight of the chewable tablet.

Diluents can be selected from the group consisting of simple carbohydrates or their derivatives such as glucose, lactose, and sucrose, starch and its derivatives such as corn starch, pregelatinized starch, and dextrates, sugar alcohols such as erythritol, xylitol, and sorbitol, metal salts of phosphoric acid such as calcium hydrogenphosphate in anhydrous or hydrated form, or other diluents and combinations thereof not specifically listed herein. Particularly preferred diluents are dextrates such as a commercially available product sold under the tradename Emdex. Preferred amount of diluent in the chewable tablet is in the range from 1 % to 40 % by weight, most preferably in the range from 3 % to 20 % by weight of the chewable tablet. Preferably, the diluents in the chewable tablet are dextrates and the amount of dextrates is preferably in the range from 3 % to 20 % by weight of the chewable tablet. If a diluent also has sweetening function, it is preferably used in an amount such that a fraction thereof is in accordance with the above-mentioned preferred diluent amount and the remaining fraction is in accordance with the above-mentioned preferred sweetener amount. Preferably, diluents are incorporated extragranularly.

Disintegrants can be selected from the group consisting of crospovidone, pregelatinized starch, sodium croscarmellose, carmellose sodium or calcium, low substituted hydroxypropyl cellulose, sodium starch glycolate, salts of polacrilin such as potassium polacrilin, and silicate derivatives such as calcium silicate or other disintegrants or combinations thereof not specifically listed herein. Preferably, the disintegrant is sodium starch glycolate and/or crospovidone. Preferred amount of disintegrant in the chewable tablet is in the range from 1 % to 50 %, more preferably from 1 % to 40 %, and most preferably from 2 % to 30 % by weight of the chewable tablet. Disintegrants can be incorporated intragranularly and/or extragranularly.

Binders can be selected from the group consisting of hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, methyl cellulose, povidone, copovidone, polyvinyl alcohol, polyethylene glycol, starch and/or pregelatinized starch. Preferably the binder is povidone and/or polyvinyl alcohol. Preferred amount of binder in the chewable tablet is in the range from 1 % to 20 % by weight, most preferably in the range from 2 % to 10 % by weight of the chewable tablet. Binders can be incorporated intragranularly and/or extragranularly, preferably they are incorporated intragranularly.

Lubricants can be selected from the group consisting of fatty acid such as stearic acid, a metal salt of fatty acid such as magnesium stearate, calcium stearate, fumed silica, a wax variety such as cetyl ester waxes or hydrogenated castor oil, sodium stearyl fumarate, sodium lauryl sulphate, magnesium lauryl sulphate, talc and/or other lubricants or combinations thereof not specifically listed herein. Preferably, the lubricant is magnesium stearate, talc, and/or combinations thereof. Most preferably, the lubricant is a combination of magnesium stearate and talc. Preferred amount of lubricant in the chewable tablet is in the range from 0.2 % to 8 % by weight, more preferably from 0.5 % to 5 % by weight and most preferably in the range from 1.0 % to 3 % by weight of the chewable tablet. Preferably, lubricants are incorporated extragranularly .

Glidants can be selected from the group consisting of talc, silicon dioxide (fumed silica, colloidal silica,...) magnesium oxide, silicates such as magnesium silicate, polyethylene glycols and/or other glidants or combinations thereof not specifically listed herein. Preferably, the glidant is silicon dioxide, and most preferably, the glidant is colloidal silicon dioxide. For example, colloidal silicon dioxide sold under the tradename Aerosil can be used. Preferred amount of glidant in the chewable tablet is in the range from 0.01 % to 5 % by weight, most preferably in the range from 0.05 % to 2.5 % by weight of the chewable tablet. Preferably, glidants are incorporated extragranularly.

Particularly preferred chewable tablet according to the present invention is a chewable tablet which comprises diosmin, microcrystalline cellulose, mannitol, citric acid, orange flavoring agent and sucralose. Even more preferred is a chewable tablet of this type, which additionally contains a disintegrant and especially sodium starch glycolate and/or crospovidone . The invention also relates to a process for preparation of the chewable tablet. The process is simple, reliable, straightforward, economical and may be conducted using standard formulation methods. It was found out that optimal process and final composition properties are achieved if firstly diosmin comprising granules are produced and afterwards extra-granular excipients are admixed to the granules .

The process for the preparation of chewable tablet according to the present invention comprises the following steps: i) mixing diosmin with pharmaceutical excipients to form a powder mixture; ii) granulating the powder mixture using a solvent to form granules; iii) drying the granules; iv) mixing granules with extragranular excipients to obtain a compression mixture; and v) compressing the compression mixture into chewable tablets.

Mixing (homogenization) and granulation can be performed using a high shear granulator. The solvent used in the granulation process can be any suitable solvent such as water, ethanol and/or isopropanol. Preferably, the solvent is water. The solvent preferably comprises a dissolved binder, which is sprayed onto the powder mixture. Alternatively, a part or whole amount of binder can be put into the powder mixture and water is sprayed over this mixture. The obtained granules can be dried in a fluid-bed dryer. The obtained granules may be screened and/or milled to obtain a blend with specified technological properties and processability. The optimum specific bulk volume of the compression mixture is between 1.0 and 2.5 ml/g and the optimum specific tapped volume between 0.8 and 1.9 ml/g. Preferably, at least 20 %, more preferably at least 30 %, even more preferably at least 35 % of granules produced in step iii) are in the particle size range from 71 to 250 pm determined by sieve analysis. Such particle size distribution of the granules enables good flow properties and appropriate compression and compaction properties of the compression mixture.

The optimal and thus preferred loss on drying (LOD) value of the diosmin granules obtained in step iii) is in the range from 0.5 % to 3.0 %, more preferably from 1.0 % to 2.5 % (w/w).

The granules of step iii) are in the next manufacturing step blended with the extra-granular excipients using the blending equipment known from the state of the art such as for example container blender, V-shaped blender, biconical blender, conical blender, horizontal blender, high turbulence blender or high shear mixer.

Final stage of the chewable tablet manufacturing is compressing the compression mixture using the state of the art tableting equipment. The preferred tablet core shape is a round shape with a diameter of 18-22 mm and preferably 20 mm. Hardness of the chewable tablet can be from 50 to 250 N, preferably from 100 to 200 N, more preferably from 110 to 160 N, and most preferably from 120 to 140 N. Hardness must be sufficient to prevent the tablet break in its package. Disintegration time of the tablet is preferably less than 15 minutes measured in purified water according to the method described in Ph. Eur. The desired friability of the tablet is preferably less than 1.0 %.

The physical characteristics of the tablets are suitable for packaging on a conventional packaging line. The tablets of the present invention preferably correspond to all pharmacopoeial standards for uncoated tablets or chewable tablets. Analytical methods

Specific bulk volume was measured using Method 1 (Measurement in a Graduated Cylinder) as prescribed in European Pharmacopoeia 9.0, chapter 2.9.34, Bulk Density and Tapped Density of Powders, paragraph Bulk density. Specific bulk volume was calculated by dividing measured volume with the weight of the applied material.

Particle size measurements of both granulates and compression mixture were conducted using air jet sieve particle size analyzer (Hosokawa Alpine 200 LS). Sieves with mesh size 71, 125, 250, 500, 710 pm and 1000 pm were used to carry out the analysis .

Specific tapped density was measured using Method 1 as prescribed in European Pharmacopoeia 9.0, chapter 2.9.34. Bulk Density and Tapped Density of Powders, paragraph Tapped density. Volume was read after 1250 taps had been applied. Specific tapped volume was calculated by dividing measured volume with the weight of the applied material.

LOD measurements were done on a 10 g sample using Mettler Toledo halogen moisture analyzer set at 105 °C for 5 min. Disintegration testing was carried out in apparatus A or B (European Pharmacopoeia) using purified water at 37°C as disintegration medium. The test was carried out in accordance with European Pharmacopoeia 9.0, chapter 2.9.1.

Tablet hardness was measured using the method described in European Pharmacopoeia (Ph.Eur 10.0, 2.9.8).

The examples described herein below are not intended to be limiting, but rather as exemplary of the chewable tablet formulations of the present invention.

EXAMPLES Examples 1-5: Preparation of diosmin granules

The solid components (without binder) were homogenized in a high shear granulator. Afterwards, binder dissolved in water was sprayed onto the powder mixture. The obtained granules were dried in a fluid bed dryer.

Examples 6-30: Preparation of tablets

The components were mixed in the container mixer to obtain the compression mixtures. The compression mixtures were compressed into round tablets with a theoretical weight of 2000 mg or 2200 mg. Compression force from 10 to 45 kN was applied during the process and tablet cores with hardness between 50 and 250 N were obtained. For Examples 16, 18, 20, 22, 27, and 33-39 all tablets showed hardness of 120-140 N.

In the chewable tablets according to present invention, the combination of mannitol, microcrystalline cellulose, acidulant and flavoring agent significantly improved the taste and palatability. By carefully selecting these ingredients and the percentile range of these ingredients, it is possible to prepare chewable tablets with diosmin that have improved taste, mouthfeel, stability, and greater likelihood for dosage compliance and use, particularly among patients, who have difficulties swallowing large tablets. The formulation of the reference example was determined to be poor, gritty and bitter tasting. Diosmin has in mouth an unpleasant taste and earthly and chalky consistency.

Claims

1. A chewable tablet comprising diosmin, microcrystalline cellulose, mannitol, an acidulant and a flavoring agent.

2. The chewable tablet according to claim 1, wherein the acidulant is selected from the group consisting of citric acid, tartaric acid, fumaric acid, lactic acid and/or malic acid.

3. The chewable tablet according to claim 1, wherein the acidulant is citric acid.

4. The chewable tablet according to anyone of claims 1-3, wherein the flavoring agent is selected from the group consisting of orange, citrus, lime and lemon flavoring agent.

5. The chewable tablet according to claim 4, wherein the flavoring agent is orange flavoring agent.

6. The chewable tablet according to anyone of claims 1-5, wherein the drug load is at least 45 %.

7. The chewable tablet according to anyone of claims 1-6, wherein the amount of diosmin is from 700 to 1300 mg.

8. The chewable tablet according to anyone of claims 1-7, wherein the chewable tablet is prepared by wet granulation.

9. The chewable tablet according to anyone of claims 1-8, wherein microcrystalline cellulose is a mixture of microcrystalline cellulose with guar gum.

10. The chewable tablet according to anyone of claims 1-9, wherein the microcrystalline cellulose is incorporated intragranularly and extragranularly.

11. The chewable tablet according to claim 10, wherein the microcrystalline cellulose incorporated extragranularly is a mixture of MCC and guar gum.

12. The chewable tablet according to anyone of claims 1-11, wherein the chewable tablet further comprises a sweetener, which is sucralose.

13. The chewable tablet according to anyone of claims 1-12, which comprises diosmin, microcrystalline cellulose, mannitol, citric acid, orange flavoring agent and sucralose.

14. The chewable tablet according to anyone of claims 1-13, wherein the hardness of the chewable tablet is from 50 to

250 N.

15. A process for preparation of the chewable tablet according to anyone of claims 1-14, wherein the process comprises the following steps: i) mixing diosmin with pharmaceutical excipients to form a powder mixture; ii) granulating the powder mixture using a solvent to form granules; iii) drying the granules; iv) mixing the granules with extragranular excipients to obtain a compression mixture; and v) compressing the compression mixture into chewable tablets .