Classifications

• • 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
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
• • 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
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• • 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
• • 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
• • 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
  • A61K9/2009—Inorganic compounds
• • 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
  • 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
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

• the invention relates to a new dosage form ("pharmaceutical form") for a tablet containing diosmin.
• Diosmin is a naturally occurring bioflavonoid found, for example, in the peel of citrus fruits. It has already been proposed to use flavonoids other than diosmin in various indications, for example a water-soluble flavonoid combined with a metallic compound, to combat conditions of the ENT sphere, as described in WO- A-02/09699 (Immupharm APS). Diosmin, on the other hand, is specifically known for its veinotonic properties.
• Diosmin used in the pharmaceutical industry is a hemisynthesis product in the form of a hygroscopic powder, practically insoluble in water but soluble in DMSO, obtained from the natural product hesperidin. a series of extraction treatment, processing and purification.
• FR-A-2 760 075 and FR-A-2 760 016 (Innokem) which describe two industrial manufacturing processes for diosmin by oxidation with iodine.
• the semisynthetic resulting product is a pharmaceutical active ingredient described in "Diosmin" monograph of the European Pharmacopoeia, 4 th edition.
• this active ingredient is a mixture of several substances, including pure diosmin and related substances such as hesperidin, linearin, diosmetin.
• the water content of the product obtained is of the order of 1 to 5%, typically of the order of 3%.
• the content of pure diosmin is at least 90% and at most 101% compared to the anhydrous substance.
• the term "native diosmin” will be used subsequently to designate this active principle as described in the European Pharmacopoeia, in the form of the hemisynthesis product available industrially from the various producers of this substance, and by "titrated diosmin" pure diosmin included in the mixture of substances forming the native diosmin.
• Diosmin is known for its venotonic properties by vasoconstrictor action and increase in venous tone, decrease in the volume of venous stasis, lowering of average venous pressure, increase in systolic and diastolic blood pressure in post-operative orthostatic hypotension . It also has vasculoprotective properties by increasing the resistance of vessels and decreasing their permeability.
• venous insufficiency in particular the improvement of symptoms related to venolymphatic insufficiency such as heavy legs, pain, impatience of the primo-decubitus), capillary fragility and the treatment of related functional signs. to hemorrhoidal crisis.
• One solution consists in developing a drinkable liquid form, typically from a powder or granules for oral suspension packaged in sachets, as described by EP-A-0 711 560 (Adir et Cie) for effervescent granules, FR-A-2 661 830 (J. Corbière) for a soluble or dispersible powder or FR-A-2 661 610 (Rhône-Poulenc Santé) for a lyophilized form to disperse or dissolve.
• a first line of research consisted in trying to reduce the total mass of the tablet by reducing the mass of its excipients (while keeping the same dose of active ingredient), for example by trying to reduce the total mass to a value of around 750 mg for a tablet dosed with 600 mg of titrated diosmin.
• the basic idea of the invention consists, on the contrary, in increasing the mass of the excipients to remedy this fragility, with a particular choice of these excipients making it possible to achieve a chewable form.
• the chewable forms are in the form of relatively bulky tablets, typically from 2000 to 3000 mg of unit mass, which makes it easier to choose excipients which can give the tablet the desired mechanical properties.
• the chewable forms are generally very well accepted by patients, since the choice of excipients makes it possible to give them a pleasant flavor and to mask an unpleasant consistency or taste of the active principle (diosmin is indeed present in the mouth a slightly earthy consistency, which should be masked).
• FR-A-2 774 291 (Innothera Laboratory) describes a chewable tablet whose particular composition makes it possible to effectively mask the unpleasant taste of an iron salt present in small amounts to improve it. patient acceptance.
• the object of the invention is to propose a new pharmaceutical form of tablets containing diosmin as active ingredient, the combination of excipients of which meets both technical and patient acceptability constraints.
• the object of the invention is to provide a tablet:
• the invention provides, as a new product, a dry oral formulation for phlebotonic and vasculoprotective purposes for the treatment of venous insufficiency, capillary fragility and hemorrhoidal crisis , this formulation being in pharmaceutical form of tablet comprising, as a mixture, at least one active principle containing diosmin and a combination of excipients, characterized in that said pharmaceutical form is a form of chewable, suckable or chewable tablet .
• the hardness of the tablet is advantageously between 150 and 250 N, preferably between 150 and 200 N.
• the diosmin used can be a native diosmin, the residual water content of which is between 1 and 5%, preferably between 2 and 4%, very preferably of the order of 3%, and the average diameter, between 20 and 50 .mu.m.
• the diosmin used can also be a granulated diosmin, the residual water content of which is between 4 and 8%, and the average diameter, between 50 and 150 ⁇ m.
• the combination of excipients comprises at least one polyol, and the ratio of the mass of the polyol, or of all of the polyols, to the titrated mass of diosmin is then preferably between 2 and 3.
• the polyol, or one of the polyols, is advantageously sorbitol.
• excipients can in particular comprise at least two polyols, advantageously xylitol and sorbitol, in a mass ratio of sorbitol to xylitol preferably greater than 1, very preferably between 1, 20 and 1.50.
• Preferred combinations of excipients include:
• - a polyol a sweetener, a compression agent, a lubricant, an acidifier and a flavor
• the compression agent can be chosen from the group comprising dicalcium phosphate, lactose and their mixtures, preferably dicalcium phosphate.
• the lubricant can be chosen from the group comprising talc, stearic acid, magnesium stearate and mixtures thereof.
• excipients can also comprise, when the active principle is a granulated diosmin, an additional granulating agent, in particular chosen from the group comprising hydroxypropylmethylcellulose, polyvinylpyrrolidone, starches, dextrins, oses, polyols and their mixtures.
• an additional granulating agent in particular chosen from the group comprising hydroxypropylmethylcellulose, polyvinylpyrrolidone, starches, dextrins, oses, polyols and their mixtures.
• one of the sorbitol or xylitol polyols is replaced by mannitol.
• a preferred formulation comprises the following constituents: native diosmin; xylitol; sorbitol; dicalcium phosphate; lubricant selected from the group comprising talc, stearic acid, magnesium stearate and mixtures thereof; acidifier and aroma.
• the preferred quantitative formula is: titrated mass of diosmin 600 mg; xylitol 600 to 800 mg, preferably 700 mg; sorbitol 750 to 950 mg, q.s. one 2400 mg unit mass tablet; dicalcium phosphate 10 to 60 mg, preferably 25 mg; talc 20 to 50 mg, preferably 30 mg; stearic acid 10 to 30 mg, preferably 15 mg; magnesium stearate 30 to 60 mg, preferably 45 mg; flavor 15 to 40 mg, preferably 25 mg; citric acid 3 to 8 mg, preferably 5 mg; or a quantitative homothetic formula.
• diosmin of Pharmacopoeia quality as commercially available
• diosmin is not used as such (native) but after having undergone a preliminary stage of wet granulation before its incorporation into the mixture to be compressed.
• Native diosmin (European Pharmacopoeia, 4 th edition) is a gray to light yellow, hygroscopic powder, practically insoluble in water but soluble in DMSO.
• the native diosmin contains at least 90% and at most 101% of titrated diosmin with respect to the anhydrous substance. Its water content, determined by microdosing, is not more than 6%.
• a native diosmin having a water content of between 1 and 5%, preferably between 2 and 4%, very preferably around 3%.
• water content is determined according to the analytical methods specified in the European Pharmacopoeia, 4th edition, under 2.5.12 "Semi-micro water.”
• Native diosmin is in the form of a sparse powder, its density being of the order of 0.4 to 0.45. Its particle size is a monomodal distribution characterized by an average diameter of the order of 20 to 50 ⁇ m.
• Diosmin is naturally compressible, with a compressibility index varying between 20 and 50, a Hausner ratio greater than 1 and a compaction capacity greater than 20. Although compressible, native diosmin lacks cohesion between particles, so it will be necessary to choose excipients (see below) allowing to bring a satisfactory cohesion. Diosmin, which is not soluble in water as indicated, becomes quite pasty on the palate, with a consistency that can be described as earthy or chalky, which should be masked by a choice appropriate excipients (see also below) for the tablet to be acceptable to the patient.
• the diosmin instead of introducing a native diosmin into the mixture to be compressed, the latter can be subjected to a preliminary treatment of wet granulation. This step is carried out in a conventional manner by mixing the diosmin with an appropriate granulating agent, then granulating proper and finally drying the powder so as to adjust the residual water content.
• the granulation is an aqueous granulation with the addition of a granulating agent, preferably a hydrophilic cellulose derivative such as hydroxypropylmethylcellulose. It is also possible to use, as a variant or in addition, hydrophilic granulation polymers such as polyvinylpyrrolidones, native or modified starches, dextrins, oses, polyols and their mixtures.
• the granulation is carried out so as to increase the particle size of the particles up to an average diameter of the order of 50 to 150 ⁇ m, preferably approximately 50 ⁇ m. A larger, technically possible mean diameter would, however, introduce a grainy, crunchy feeling, generally perceived less pleasant by patients than with a finer grain size.
• the tablet must have acceptable taste and flavor, preferably pleasant for the patient,
• the tablet of the invention comprises as excipients one or more diluents-sweeteners, a compression agent, a lubricating agent, a flavoring, and optionally an acidifier and / or an additional sweetener.
• Thinners-sweeteners one or more polyols, advantageously two different polyols, advantageously a mixture of xylitol and sorbitol, are advantageously used as diluent-sweeteners. These polyols have the advantage of offering a sweet flavor and providing a pleasant sensation of freshness on the palate. They are more acariogenic and very low in calories. They also have binder properties and excellent compressibility properties which make them suitable for manufacture by direct compression. The ratio of the mass of the polyol (if only one polyol is used) or of all the polyols, relative to the titrated mass of diosmin is preferably between 2 and 3.
• the sorbitol / xylitol ratio is adjusted to meet the different technical and taste constraints mentioned above (absence of cleavage and sticking phenomenon, pleasant taste, masking of the earthy consistency of diosmin, etc.). More specifically, this sorbitol / xylitol ratio is greater than 1, preferably between 1.2 and 1.5.
• diluents-sweeteners are as follows:
• - single polyol + dare for example sorbitol + fructose or sucrose, or xylitol + fructose or sucrose.
• Compression agent this excipient brings hardness to the tablet and prevents post-compression cleavage.
• Dicalcium phosphate is preferably used (for example of the Emcompress® type from Pennwest Pharmaceuticals Co.).
• Other compression agents can be used as a variant or as a supplement, for example lactose.
• Lubricant this excipient has the function of avoiding the seizing phenomenon at the level of the dies of the presses to compress and has non-stick properties; it is chosen from conventional lubricants such as stearic acid, magnesium stearate and talc or (preferably) a combination of two or three of these products.
• Flavor this excipient is chosen from conventional additives according to the taste that one wishes to give to the tablet, for example an orange flavor.
• Acidifier it is possible to add a small amount to the preparation of an acidifier such as citric acid to improve its taste qualities.
• Additional synthetic sweetener to increase the sweetness when it is not deemed sufficient, especially when using a single diluent-sweetener such as sorbitol, it is possible to add a small synthetic sweetener powerful such as aspartame, potassium cyclamate, potassium acesulfame or sodium saccharinate.
• a tablet is produced by direct compression.
• the manufacturing operating protocol is conventional, by simple mixing of the active principle (native diosmin or granulated diosmin) with the various excipients then compression on a press.
• the (non-limiting), qualitative and quantitative, formula of this example pre- is as follows, for a tablet dosed with 600 mg of titrated diosmin:
• diosmin 600 mg of titrated mass, corresponding in this example to a mass of native diosmin of 683.45 mg if this native diosmin has a residual water content of 2.95% and a titer of 90.46% over dry pure diosmin,
• - sorbitol type Neosorb® P60W, Roquette
• - dicalcium phosphate type Emcompress®, Pennwest
• - xylitol 600 to 800 mg
• - sorbitol 750 to 950 mg (q.s. a 2400 mg tablet)
• - talc 20 to 50 mg
• - stearic acid 10 to 30 mg
• the tablet obtained has a total mass of 2400 mg per 600 mg of titrated diosmin.
• the unit mass of the tablet is preferably between 2000 and 3000 mg, advantageously between 2200 and 2600 mg, very advantageously 2400 mg, for 600 mg of titrated diosmin.
• Tablet hardness measured according to the analytical methods described in the European Pharmacopoeia, 4th edition, the title 2.9.8 "Tensile strength of the tablets" is 150 N.
• the hardness is preferably between 150 and 250 N, very advanced tagging between 150 and 200 N.
• this formulation is a formulation without sugar (without dare), without sodium and without additional synthetic sweetener (most of them, for example aspartame, having certain contraindications).
• diosmin typically varying between 300 and 1200 mg of titrated diosmin.

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