KR20080030835A - Pharmaceutical composition - Google Patents

Abstract

A pharmaceutical composition comprising flavonoids is provided to improve dosage compliance of patients, wetting properties, absorption rate and biological availability, and inhibit unpleasant coarse effects when it is applied to skin or mucosa, so that the composition is useful for treating chronic vein disease. A pharmaceutical composition comprises 70.0 wt.% or more of at least two microcrystalline flavonoids including diosmin and having characteristic parameters: specific surface area of 4-18 m^2/g measured by BET(Brunauer-Emmett-Teller), F/D ratio(F is other flavonoid and D is diosmin) of 0.03-0.1, and water content of 4.0 wt.% or less, and is formulated as tablet, granule, pill, cream or ointment, wherein the microcrystalline flavonoid is selected from isorhoifolin, linarin, diosmetin, hesperitin, quercitin and lutin. Further, a content of the two microcrystalline flavonoids is 4.0%(w/w) or more based on fatty cream.

Description

Pharmaceutical composition {PHARMACEUTICAL COMPOSITION}

Figure 1 shows a typical X-ray powder diffractogram (XRD) of microcrystalline flavonoid fraction batch 2188.

FIG. 2 shows typical X-ray powder diffractograms (XRD) of particular batch 2188 and other similar batches 2189, 2190, 2191, 2192, 2193 of FIG. 1 of the microcrystalline flavonoid fraction.

The present invention relates to flavonoid-containing pharmaceutical compositions for oral or topical administration. The present invention also relates to a process for the production of solid pharmaceutical compositions characterized by marked wettability and improved bioavailability and for the formulation of topical formulations without the unpleasant "rough" effect.

Purified flavonoids such as diosmin, hesperidin, and other natural flavone glycosides, such as isoleuropoline, linarin, diosmetin, individually or together, are used in drugs for the treatment of chronic venous disease are already numerous publications, eg See, for example, Martindale 33rd Ed. page 1611; Vidal 75th Ed., Pages 348, 388, 476, 488, 576, 577, 661, 745, 1155, 1530, 2013; Merck Index 13th Ed. entries 326, 3327, 4690 and 5520. Indeed, flavonoids are capillary protective agents and exhibit venous strengthening and vasoprotective properties. Daily intake can generally vary from 400 to 2000 mg, and may be administered in two to three divided portions per day.

Diosmin, hesperidin, linarin, diosmetin, quercithin, flavonoids such as rutin, and other flavone glycosides are actually insoluble in water (Merck Index 13th Ed., Entries 3326, 3327, 4690, 5520, 8118, 8382). , Eur. Ph. 5th Ed. Page 1452), if systemic drug effects are desired, they are administered alone by the oral route.

Thus, they are generally formulated in conventional pharmaceutical forms of tablets and granules. Topical agents are also used for hemorrhoids (Martindale 33rd Ed. Page 1611.2). However, the most widely used flavonoids, ie diosmin, and also other flavonoids, are hygroscopic substances, and diosmin has been found to contain 4 to 6% water (Eur. Ph. 5th Ed. Page 1452 and also EP 0711560 ( See page 2, lines 50-51).

When formulated into pharmaceuticals in solid form, one experiences a number of difficulties in view of the first, the large mass of flavonoids contained in each dosage unit, and the second, its known water insolubility. Indeed, a wealth of bibliographic references highlight that these are two major technical issues to be solved, particularly when formulating solid compositions of flavonoids. Patent FR 2661610 discloses a new lyophilized pharmaceutical composition administered as a disintegratable and drinkable preparation in water. The composition comprises 30 to 80% of the dry mass, more preferably 40 to 80% of the lyophilized diosmin, up to 60% of the diluent of the dry mass, and various other inert ingredients such as suspending agents, additives, Colorants and optionally surfactants are taught. However, the lyophilized composition appears to be somewhat unsuitable, because the lyophilization of the diosmin is a long and expensive process, especially when large amounts of diosmin have to be processed.

In addition, patients often experience an unpleasant taste when taking flavonoids formulated with this type of drinkable agent. This second drawback is that while venous insufficiency is a chronic disease that requires continuous treatment for months or even years without any interruption, the patient frequently misses treatment, which can lead to treatment failure. To overcome the problem of unpleasant taste, WO 2004/032942 discloses chewable pharmaceutical tablets containing diosmin or granulated diosmin in admixture with auxiliary excipients already known in the art. The embodiment of the prior art invention further provides that the active ingredient diosmin contained in the tablets of the invention has a water content of 1 to 5%, more preferably 2 to 4% and a particle size in the range of 20 to 50 microns. Teach In another embodiment, the active ingredient contained in the tablet is granulated diosmin having a water content of 4-8% and a particle size in the range of 50-150 microns. The main drawback of the formulation is that the total mass of the chewable tablet is very large, in the range of 2.0 to 3.0 g per unit dose, due to the large amount of auxiliary excipients used above the quantity for the purpose of improving the taste of the composition. will be.

More recently, EP 0541874 discloses pharmaceutical preparations for preparing solutions or microsuspensions of diosmin having a grain size of at least 90% between 100 and 400 microns. The patent also (and is commercialized under the trademark "Plurionic F68 ^®") copolymers for the manufacture of powder for sachets and tablets, significant quantities of ethylene oxide and propylene oxide and also disclose the use of povidone or polyethylene glycol. Nevertheless, the patent describes whether it can produce a "solution of diosmin" (diosmin is somewhat insoluble in water) or can provide any indication with regard to the exact herbal benefits derived from the claimed composition. Does not explain. Another patent, EP 0711560, discloses a granulate of tablets or sachets comprising undifferentiated form of diosmin which gives a granule size of 0.1 to 10 microns. However, the patent points out that diosmin has a water content of 4 to 6% and the water indicates a significant inconvenience for the foamable composition. Indeed, Applicants note that spontaneous foaming of the granules occurs when a large amount of bicarbonate, sodium bicarbonate and a significant amount of citric acid (as in the embodiments of 1 to 4) are used simultaneously in the presence of moisture, and thus the moisture The content does not allow good stability of the claimed composition (line 2, lines 51-55).

Furthermore, in order to overcome this inconvenience of herbal medicines, a unique single phase process is also disclosed in which the pellets are prepared without the addition of external water, except for the addition of minimal amounts of ethanol (pages 2, lines 54-58 and 3 Page lines 1-2). However, such a process also presents technical difficulties because the use of organic solvents such as ethanol for the granulation process will require the acquisition and use of expensive antideflagrating equipment. Furthermore, the patent points out that after drying the moisture content of the granules is essentially less than 0.5%, in which the foamable granules of the invention are in stable conditions (page 3 line 2-3). The prior art also specifies that the pharmaceutical composition does not contain tenioactive agents or thickeners (page 3, lines 7-8). The large weight (5000 mg) of the unit dose of the claimed composition is also very strange. Moreover, in the pharmaceutical form of effervescent tablets or sachets, the active ingredient (1000 mg) accounts for only 20% of the total mass of the final composition.

Accordingly, none of the above patents seem to effectively solve the herbal problem for the formulation of solid medications containing flavonoids. Indeed, the inventors consider the solutions presented above to be inadequate, insufficient and contradictory. In particular, the particle size of the flavonoids used is unclear and also large amounts of auxiliary substances and excipients lead to extremely large sized pharmaceutical forms, and in the case of drinking preparations, which results in an unpleasant taste, which is absolutely unsuitable for long-term treatment.

Moreover, the technical solutions of the prior art propose significant limitations and significant disadvantages, to mention a few, for example, an expensive lyophilization process for the active ingredient diosmin, instability of the expandable granules in the presence of water, ethanol The use of ethanol and anti-detonation agents in the granulated process.

Other conventional formulations and general techniques for the preparation of pharmaceutical compositions for oral administration are summarized and are readily found in professional publications such as Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). have. Nevertheless, these conventional teachings are due to various reasons, for example, due to the large size, excessive crushing or hardness of the resulting tablets, low porosity and wettability, unsatisfactory decomposition, scratched or irregular surfaces, and solid oral of flavonoids. No satisfactory result is achieved in the preparation of the composition.

Compared to the above, when formulating flavonoids as topical formulations, only a few formulation problems are faced, but even in this case, it is still difficult to maintain homogeneity in conventional flavonoid formulations and when applied to the skin or mucous membranes The "rough" effect is a discomfort that is well known to skilled personnel.

In light of the unsatisfactory results disclosed in the prior art, the present inventors have studied a whole new approach to overcome and solve the reported herbal problems in particular relating to the preparation of suitable solid formulations of the flavonoids.

The present invention relates to pharmaceutical compositions for oral or topical administration characterized in that they contain microcrystalline flavonoids. The pharmaceutical compositions can be prepared in the form of granules with or without other inert ingredients or auxiliary ingredients, and these granules can be densely packed to produce solid dosage forms suitable for oral administration. The method of making the granules significantly contributes to obtaining the final quality of the solid oral pharmaceutical composition of the present invention which shows significant wettability and good absorption profile. The present invention also relates to pharmaceutical compositions comprising microcrystalline flavonoids, formulated as topical compositions which, in addition to high wettability, do not provide a "rough" effect when applied to the skin or rectal mucosa.

Thus, the present invention contains an active ingredient comprising two or more flavonoids in microcrystalline form, wherein the two or more microcrystalline flavonoids comprise diosmin and one or more other flavonoids; Also provided are pharmaceutical compositions wherein the two or more microcrystalline flavonoids exhibit the following characteristic parameters:

(a) the specific surface area of the microcrystalline flavonoid fraction comprising 4-18 m 2 / g, preferably 9-12 m 2 / g, according to the BET measurement;

(b) a ratio of F / D (F = other flavonoids, D = diocemin) (weight / weight) of 0.03 to 0.1; And

(c) a moisture content of less than 4.0%.

In particularly preferred pharmaceutical compositions of the invention, the two or more microcrystalline flavonoids are "strong" (s) at about 15.32, 19.68 and 21.70, "middle" (m) at 11.90, 15.87, 21.33 and 24.68, and Typical X-ray powder diffraction patterns with a relative intensity peak of diffusion (d) at about 26.35, 27.72 and 28.65.

The present invention also provides a pharmaceutical composition in solid form suitable for oral administration, eg, tablets or granules, wherein the amount of the at least two microcrystalline flavonoids comprises at least 70.0% (w / w) of the total mass of the solid. do. The present invention also provides topical formulations, such as external topical fat creams or ointments, wherein the amount of the two or more microcrystalline flavonoids comprises at least 4.0% of the total mass of the topical formulation.

In a further embodiment of the invention, a disintegrant material is present, wherein the disintegrant material provides a solid pharmaceutical composition in the form of a tablet or granules of at least 15.0% (w / w) of the total mass of the inert or auxiliary component.

Preferably, the tablets or granules according to the invention are obtained by a wet granulation process in which the two or more microcrystalline flavonoids and selected inert and auxiliary ingredients are sprayed, wetted or kneaded with a suitable amount of water in a typical characteristic order. do.

It is particularly preferred that the tablets or granules according to the invention have a water content of more than 2.0% (w / w). Two or more flavonoids in microcrystalline form used in the present invention preferably comprise diosmin as the predominant microcrystalline flavonoid component. Preferably, the diosmin constitutes more than 50%, more preferably more than 90%, by weight of the two or more microcrystalline flavonoids.

The one or more other flavonoids can be selected from one or more of isololypoline, linaline, diosmetin, hesperidin, quercithin and rutin. The pharmaceutical composition according to the invention may comprise two or more microcrystalline flavonoids obtained from separate sources and then combined in the desired ratio. On the one hand, any suitable reaction process can be used which provides a reaction product comprising microcrystalline diosmin and at least one other microcrystalline flavonoid; For example, known reaction processes include the reaction of hesperidin with iodine / potassium acetate in methanol. When using such a reaction process, the preponderance of diosmin in the reaction product can be suitably improved by any technique known in the art, for example by fractional precipitation in water at pH 5-6. Once formed, the mixture of two or more microcrystalline flavonoids is then dried, with vigorous shaking in a vacuum dryer, preferably at a temperature of at least 75 ° C., and then according to the BET measurement, the specific surface area is 4-18 m 2 / g, preferably Preferably 9 to 12 m 2 / g.

When using a reaction process such as the above known process, the microcrystalline flavonoids formed as above may comprise a mixture of monohydrate and dihydrate microcrystalline forms.

Preferably, the monohydrate form is the main component, more preferably the monohydrate form is present in an amount exceeding 50% by weight, with an amount of 60% by weight of the flavonoid mixture being particularly preferred.

Preferred two or more microcrystalline flavonoids for use in the pharmaceutical compositions of the present invention are shown in Fig. N. ° 1 (XRD of a specific production batch is recorded). Indicates. Typical X-ray diffractograms of different production batches of microcrystalline flavonoids are further shown in FIG. Typical X-ray powder diffraction patterns of two or more microcrystalline flavonoids preferred for use in the present invention are "strong" (s) at about 15.32, 19.68 and 21.70, "middle" (m) at 11.90, 15.87, 21.33 and 24.68, And relative intensity peaks of diffusion (d) at about 26.35, 27.72 and 28.65.

Thus, in a preferred embodiment of the present invention, there is provided a reaction process for the preparation of two or more microcrystalline flavonoids, wherein the two or more microcrystalline flavonoids comprise diosmin and one or more other flavonoids, the reaction process It includes the following steps:

a) reacting hesperidin with iodine / potassium acetate in methanol;

b) increasing the amount of diosmin in the reaction product obtained from step a) by fractional precipitation; And

c) drying the reaction product obtained from step b).

Methods and Devices Used in the Analysis of Pharmaceutical Compositions of the Invention

1) "X-ray powder diffractogram (XRD)" (also referred to as "diffraction pattern") of microcrystalline flavonoids, according to known procedures, for example similarly placed in a Pyrex glass holder and copper target X It can be measured by an X-ray diffractometer with a Cu K alpha-1 radiation source, as in the Bruker system type, model AXS, D8 Advanced X-ray diffractometer or Seifert system type model XRD3003 TT using a -ray tube.

2) The "mass" of each component of the F / D ratio of the two or more microcrystalline flavonoids is described in Eur. Ph. 5th Ed. Monograph 01/2005: 1611 page 1452, which can be determined according to liquid chromatography (method 2.2.29) for the quantitative analysis of diosmin (D) and other flavonoids / related substances (F).

3) “Specific surface area” is preferably described in S. Brunauer: "Adsorption of Gas and Vapor", Princetown, 1945], can be measured by the gas adsorption method (BET method). The experimental method used to determine the specific surface area of two or more microcrystalline flavonoids used in the pharmaceutical composition of the present invention is summarized as follows: The apparatus used is a Sorptometer Kelvin 1042, in which the sample is an air stream consisting of a mixture of nitrogen and helium. Analyze using The apparatus uses gas from cylinders guaranteed for gas chromatography to generate a gas mixture at a known concentration. Preheating the sample under a helium flow to remove residual air gas mixture from the sample surface (pretreatment step); The atmospheric gas mixture covering the sample surface may indicate a lower value of the surface area.

The pretreatment of the sample is carried out as indicated herein via temperature increase, the use of a vacuum, the use of helium flow, or, on the other hand, a combination of these techniques:

Temperature + vacuum;

Temperature + Helium (Kelvin Sorptometer).

The use of a vacuum allows for more efficient pretreatment, but can sometimes alter the sample if the sample is sensitive to vacuum. The calculation of the specific surface area value is performed by calculating the amount of nitrogen absorbed by the sample on the surface of the sample; Nitrogen coats the sample surface with a single layer and as a result allows the measurement of the total surface area value.

4) "Moisture" (also referred to as "water content"), Eur. Ph. 5th Ed. It is measured according to the semi-trace method described in Method 2.5.12 page 130].

5) The "weight" (mass) of the two or more microcrystalline flavonoids and inert and auxiliary components (including water used in the wet granulation process) is measured using special balances commonly used in production units in pharmaceutical laboratories. do.

To better recognize the pharmaceutical compositions of the present invention, the "parameters characterizing the present invention" listed will be better illustrated below. More particularly, significant improvements in the two or more microcrystalline flavonoids and their parameters, wet granulation production process, final specifications and properties of the pharmaceutical compositions of the invention used in the pharmaceutical compositions of the invention are described in the following paragraphs. It is well emphasized.

In view of the above, the essential features of the pharmaceutical composition of the present invention are as follows:

a) F / D (flavonoids / Diosmin ) Rain

The preferred F / D ratio (weight / weight) between the total weight of the other flavone glycosides (hesperidin, isoleuropoline, linarine, diosmethine) and the total weight of diosmin is from 0.03 to 0.1. Preferred F / D ratios are direct results from the manufacturing process described above.

b) specific surface area

The specific surface area is a particularly important factor for insoluble substances such as flavone glycosides such as diosmin, hesperidin, isolopoline, linarin and diosmethin.

The specific surface area is the most direct representation of the surface (in square meters / gram, more simply m 2 / g) for each gram of material and is potentially available for binding to water during the dissolution process of the solid pharmaceutical form. Indicates. Thus, the specific surface area of an insoluble material is the most appropriate representation of both its "wetting" and "porosity". Indeed, the greater the number of specific surface areas generated by each gram of material, the greater the water dissolution rate of the insoluble material. Two or more microcrystalline flavonoids used in the pharmaceutical compositions of the present invention exhibit typical specific surface areas of 4 to 8 m 2 / g when obtained directly from the abovementioned reaction process. The product is then milled to yield a mixture of two or more microcrystalline flavonoids having a preferred specific surface area consisting of 9-18 m 2 / g. The grinding process can be carried out in the presence of an inert gas such as nitrogen, helium or argon by conventional apparatus and methods, for example a pin disk mill or a hammer mill or more preferably a fluid energy mill. Microcrystalline flavonoids having a desired specific surface area, the mill speed; It can be obtained by varying the amount and / or grinding period of the product fed, and the impact force and amount of inert gas mixed with the product. If a microcrystalline flavonoid having a relatively high specific surface area, for example about 11 m 2 / g, is desired, it is advantageous to carry out the grinding using a fluid energy mill.

However, by combining the initial specific surface area and selecting the grinding apparatus, methods and conditions, it is possible to obtain microcrystalline flavonoids having the desired specific surface area suitable for the preparation of the pharmaceutical formulations of the present invention.

Moreover, the specific surface area of the microcrystalline flavonoid fraction is also particularly important for improving the bioavailability of humans following single oral administration of the pharmaceutical composition. The bioavailability of a drug administered by this oral route varies depending on its ability to be absorbed by the digestive tract. The main absorption mechanism is mainly passive diffusion, which requires the amphophylic structure of the active ingredient in aqueous solution. As a result, drugs absorbed in this way will dissolve in the digestive fluid before spreading through the digestive tract. The amount of drug absorbed varies with its solubility properties and is measured by the amount dissolved.

The bioavailability of a drug is typically defined as an aliquot of the administered dose that reaches the systemic circulation of a living organism and the rate at which the drug reaches. In certain cases of the pharmaceutical compositions of the invention, the specific surface area is important because it is a major parameter indicative of dissolution rate.

Noise and Witney's law (Remington: The Science and Practice of Pharmacy, 2000, 20th Ed., P654) allows the evaluation of the following parameters:

Dc / Dt = KaS (Cs-Ct)

In the above,

Dc / Dt is the dissolution rate of the drug;

Ka is a constant depending on the dissolution conditions;

S is the contact area between the powder and the solvent;

Cs is the concentration of the drug at saturation;

Ct is the concentration of the amount of drug dissolved in the measurement.

Thus, by increasing S (inversely proportional to the pulverization of the powder), it is possible to contribute significantly to the dissolution rate (Chaumeil JC "Micronization: How to Improve Bioavailability of Insufficiently Soluble Drugs" Meth. Find. Clin. Pharmacol. 20 (3): 211-215, 1998).

Indeed, pharmacokinetic studies conducted on healthy volunteers using the solid pharmaceutical compositions of the present invention surprisingly show that the greater the specific surface area, the greater the absorption of the two or more microcrystalline flavonoids, and thus a surprising improvement in the bioavailability of the tablets of the present invention. This proved to be true.

Moreover, as a result, the value of the volume of distribution (Vd = 62.02 Lt) provides extensive absorption by the walls of vascular tissue, wherein the microcrystalline flavonoid fraction induces its venoenhancing activity. See also publications relating to equivalent formulations in this regard: Cova D. et al., Int. J. Clin. Pharm. Ther. Tox., Vol. 30; No. 1, pages 29-33 (1992) and Garner R.C. et al., J. Pharm. Sci., Vol. 91, No. 1, pages 32-40 (2002).

c) water content (moisture)

Two or more microcrystalline flavonoids used in the pharmaceutical compositions of the present invention are also characterized in that they are stabilized to a water content (moisture) of less than 4.0%.

In addition to these essential features, other features have been found to have a significant effect on the solid pharmaceutical compositions of the present invention; Combinations of these significantly improve the overall process and the final quality of the pharmaceutical composition.

These other features include the amount of flavonoids in the composition according to the invention present in tablets, granules or topical formulations, the amount of disintegrating substances, the use of a wet granulation process, and the final moisture content of the pharmaceutical composition preferably being 2%. It includes more than but less than 2%.

Indeed, the preferred tablets of the present invention exhibit a satisfactory disintegration profile, which on one side exhibits a reduced size (and thus can be swallowed more easily), but also a requirement that can only be achieved by combining the aforementioned manufacturing improvements. . Thus, the wet granulation process described above comprises inert components, wherein the total mass of the solid pharmaceutical composition contains at least 70% (w / w) of at least two microcrystalline flavonoids and the total inert mass of the solid composition is 15% (w). / w) or more disintegrant, while residual water (moisture) will be used to mix in excess of 2% in both the dried granules and the final pharmaceutical composition.

In another embodiment, the preferred disintegrating substance is sodium starch glycolate.

The published literature shows that the amount of flavonoids prescribed for oral administration is 300-2000 mg, more preferably 400-850 mg, and the most commonly used dosage units are 300, 400, 450, 500 and 600 mg of flavonoids. It will be formulated at a dosage. Moreover, conventional pharmaceutical solid forms of flavonoids for oral administration already on the market are generally tablets or sachets. Thus, the unit dose of the solid pharmaceutical composition of the present invention was also designed to contain two or more microcrystalline flavonoids of equivalent or equivalent content.

In another embodiment, the solid pharmaceutical compositions of the present invention in tablet form typically contain two or more microcrystalline flavonoids in a desired unit dose and varying amounts of the following preferred inert and accessory ingredients:

Inert and auxiliary ingredients for wet granulation Preferred range (mg / tablet) Microcrystalline cellulose (Avicel 101 (registered trademark)) 55.00-70.00 Gelatin (vegetable origin) 27.00-35.00 Sodium starch glycolate 25.00-30.00 Magnesium Stearate (vegetable origin) 3.50-4.90 glycerin 0.40-0.50 Sodium lauryl sulfate 0.02-0.04 110.92-140.44 Water (final moisture <2.0%) (*) 10.0-25.0 (*) The greater amount of water used for wet granulation evaporates during the granulation drying step.

Thus, in another embodiment of the present invention, the total weight of the inert and auxiliary components per tablet can vary from 110.92 mg to 140.44 mg (excluding moisture).

In a further embodiment, the tablets of the pharmaceutical composition of the invention are optionally protected by a suitable coating layer, which coating layer is applied according to conventional methods already well known to those skilled in the art. The coating layer mixture applied to the tablet of the present invention exhibits the following composition:

Inert and Auxiliary Components for Coating Mixtures Preferred range (mg / tablet) Hydroxypropylmethyl cellulose (type E5) 3.0-10.0 talc 2.0-10.0 Titanium dioxide 0.5-5.0 Polyethylene Glycol (MW: 4000-6000) 0.1-1.0 Yellow Iron Oxide (E 172) 0.0-0.5 Red Iron Oxide (E 172) 0.0-0.5 5.6-26.5 White lead (final gloss process) 0.0-1.5

Thus, in another embodiment of the present invention, the total amount of coating layer per tablet may vary from 5.6 to 26.5 mg. The tablets of the present invention exhibit a very reduced size and are well suited for easy swallowing. The tablets also show good stability because they do not undergo decomposition. Even if the tablets are stored for extended periods of time under conventional temperature conditions (25 ° C. ± 2 ° C.) in conventional containers, eg, vials sealed with a suitable stopper or heat sealed blisters commonly available on the market. No change in color or scratch was observed on the image.

In addition, the coated tablets of the present invention do not provide a bitter taste on the surface and thus exhibit acceptable sensory properties and also exhibit satisfactory bioavailability as shown in Example 10 below.

In another preferred embodiment, an appropriate amount of solid sweetener (powder or crystal), eg, to obtain granules for administration and packaging as a single dose sealed sachet of the type already available commercially Formulated as granules for granulation, for example obtained by mixing and adding xylitol, fructose, sorbitol powder, binders such as povidone, polyethylene glycol, and flavoring agents such as orange and lemon flavors in suitable amounts already well known in the art. Make up.

The resulting granules containing granules of the pharmaceutical composition of the present invention also exhibit good wettability due to their high specific surface area and thus produce ready-to-drink suspensions when reconstituted with water prior to oral administration. In another embodiment of the invention, the pharmaceutical compositions are formulated in different compositions suitable for topical administration, which are already well known to those skilled in the art. When formulating the pharmaceutical compositions of the present invention as ointments, the active ingredient may be mixed with paraffin based ointments or hydrophilic fatty bases. On the other hand, the active ingredient may be formulated at a concentration of at least 4.0% as a cream based on oil-in-water type. Topical formulations of the invention will exhibit a pH of 6.5 to 7.5. Pharmaceutical compositions produced for topical use exhibit high wettability due to the high specific surface area of the two or more microcrystalline flavonoids used in the present invention, and therefore the topical preparations have an uncomfortable "rough" effect on the skin or anal mucosa, for example It does not provide the effect experienced by some other agents.

EXAMPLE

The invention will now be described in detail with reference to the following experimental examples, which are intended to disclose further details only, rather than to limit the material and scope of the invention itself.

A typical process for preparing microcrystalline (monohydrated) flavonoids with a final specific surface area of greater than 9.0 m 2 / g is shown below:

Reaction of raw flavonoids containing mainly raw diosmin (greater than 80%), hesperidin and other flavonoids by reacting 2 moles of hesperidin and iodine / potassium acetate in industrial methanol (about 5 liters) (as already disclosed in the literature) The mixture was obtained in an amount above the desired ratio. A purer solid microcrystalline mixture (greater than 90% raw diosmin, hesperidin, isoloypoline and others) was fractionated precipitated in a mixture made alkaline (pH 8 or higher) using an equimolar amount of calcium and filtered. . Approximately 1000 g of the resulting precipitate aliquots are again suspended in 4 L of medicinal water (pH 5-6; t ° 15 ° -35 ° C.) and a higher water solvation results in a pureer cake of microcrystalline mixture of flavonoids. Precipitate and filter. In order to obtain the desired microcrystalline flavonoids with a final moisture of less than 4.0% (greater than 66% of untied crystals), the cake is vigorously shaken in a vacuum drier operating at temperatures above 75 ° C.

928 g of the resulting dried microcrystalline mixture having a water content of 2.80% and a specific surface of 4.85 m 2 / g was then jet milled to yield 897 g (1.47 mol) of product having a specific surface of 10.93 m 2 / g. Chromatographic analysis according to the current European Pharmacopoeia demonstrated that the resulting product met this specification.

Example  One

Additional process for preparing microcrystalline flavonoids with final specific surface area exceeding 9.0 m 2 / g

The manufacturing process was carried out in a suitably equipped pharmaceutical facility operating at environmental conditions of relative humidity (R.H.): 25% -40% and temperature (t °): 22 ° ± 3 ° C.

Microcrystalline flavonoids obtained directly from the preparation process as described above and which give an initial specific surface area value of 4.80 m 2 / g (average of three measurements: 4.93; 4.78; 4.70 m 2 / g) measured according to the BET method 2188) 59.980 kg was passed through a conventional fluid-energy mill under nitrogen flow. After the milling process, a mass of at least two microcrystalline flavonoids of 58.884 kg was obtained. The specific surface area is 10.67 m 2 / g (average of three measurements), measured according to the BET method: 9.84; 11.37; 10.81 m 2 / g). Moisture: 2.86%. F / D = 0.078 (other flavonoids: 7.3% / diosmin: 92.7%)

Total yield of this process: 98.17%

Example  2

Preparation of 20,000 tablets containing at least two microcrystalline flavonoids (specific surface area 10.67 m 2 / g) each obtained from 500 mg of Example 1

The manufacturing process was carried out in a pharmaceutical facility suitably equipped for the processes carried out and operated at environmental conditions of relative humidity (R.H.): 35% -50% and temperature (t °): 22 ° ± 3 ° C. The production process was protected from direct sunlight.

Each tablet of the composition contains:

Active, inert and auxiliary ingredients Mg / tablet Microcrystalline Flavonoids (*) 500.000 Microcrystalline cellulose (Avicel 101 (registered trademark)) 62.000 Gelatin (vegetable origin) 31.000 Sodium starch glycolate 27.000 Magnesium Stearate (vegetable origin) 4.426 glycerin 0.426 Sodium lauryl sulfate 0.034 Water (final moisture rated> 2.0%) 11.490 Theoretical mass of each tablet 636.370 (*) Expressed as 100.0% of total inactive ingredients

The amount of each component required to prepare 20,000 batches of the tablet having the above theoretical composition per unit dose:

Active, inert and auxiliary ingredients Weight (kg) Microcrystalline Flavonoids (*) 10.2850 Microcrystalline cellulose (Avicel 101 (registered trademark)) 1.2400 Gelatin (vegetable origin) 0.6200 Sodium starch glycolate 0.5400 Magnesium Stearate (vegetable origin) 0.0885 glycerin 0.0085 Sodium lauryl sulfate 0.0007 Water (for wet granulation) (§) (1.2800) Final Moisture: 2.77% 0.3650 Total weight 13.1477 (*) An amount satisfying 100.0% of the total active ingredient (specific surface area of 10.67 m 2 / g; moisture: 2.85%); (§) The amount of water used for wet granulation (1.280 kg) was then partially removed upon drying of the granules, resulting in a final moisture of 2.77% tablets.

The preparation steps were carried out in the following order:

Step 1)

1.240 kg of microcrystalline cellulose (Avicel 101®) and 10.285 kg of microcrystalline flavonoid fractions were mixed together in a stainless steel powder blender.

Step 2)

The wet solution (binding solution) was prepared separately by mixing together 0.620 kg gelatin, 0.0080 kg glycerin, 0.0007 kg sodium lauryl sulfate and 1.280 kg water in a suitable container.

Step 3)

The powder mixture of step 1 was then sprayed with the binding solution of step 2 until the desired consistency was obtained.

Step 4)

The wet granules obtained were forced into an 8 mesh screen which was then dried using a fluid bed dryer. In order to reduce the electrostatic charge on the particles, it was desirable to obtain about 3% uniform residual moisture. After drying, the granules were passed through a small mesh screen to the desired particle size.

Step 5)

Finally, the dried granules were added to 0.5400 kg of sodium starch glycolate and 0.0885 kg of magnesium stearate and mixed well to obtain a homogeneous powder mixture. The powder mixture was compressed into tablets by a suitable rotary machine equipped with rectangular punches of the desired shape, size and volume to give tablets with an average weight of 657.35 mg. The resulting tablets are described in Eur. Ph. 5th Ed. in accordance with the mass uniformity test described in paragraph 2.9.5. The final moisture of the tablets is described in Eur. Ph. 5th Ed. Method 2.5.12 page 130] measured 2.77% (w / w) according to the semi-trace method.

From this industrial process, 18,783 tablets containing 500 mg of microcrystalline flavonoid fractions were obtained.

Final yield of the above tableting process: 93.91%.

Example  3

Preparation of 20,000 tablets each containing at least 450 mg of two or more microcrystalline flavonoids (specific surface area 10.67 m 2 / g)

Equipment operated in the same sequence, in the same tableting process and in the same environmental conditions as in the preparation step, by using the same quantitative-qualified composition as in Example 2, eg, proportional amounts of microcrystalline flavonoids and the same amount of inert and auxiliary components Using 18,435 tablets containing 450 mg of two or more microcrystalline flavonoids used in the present invention having a final residual mixture of 3.09% (w / w) can be obtained.

Final yield of the tableting process: 92.17%

Example  4

Preparation of 15,000 tablets containing 600 mg or more of two microcrystalline flavonoids (specific surface area 10.67 m 2 / g) each

By using the same quantitative-quantitative composition as in Example 2, for example, proportional amounts of microcrystalline flavonoid fractions and the same amount of inert and auxiliary components, they are operated in the same sequence, same tableting process and same environmental conditions as the preparation steps Using the equipment, 13,978 tablets containing 600 mg of two or more microcrystalline flavonoids of the present invention with a final residual mixture of 2.94% (w / w) could be obtained.

Final yield of the tableting process: 93.18%

Example  5

Preparation of 18,500 film coated tablets of 450 mg of two or more microcrystalline flavonoids (specific surface area 10.67 m 2 / g)

18,435 tablets resulting from the manufacturing process disclosed in Example 3 were subjected to a coating process to improve the pleasant feeling when swallowed.

The film coating process was carried out in a pharmaceutical facility which was suitably equipped with an automatic coating pan and operated at environmental conditions of relative humidity (R.H.): 35% -50% and temperature (t °): 22 ° ± 3 ° C.

Each tablet was coated with a film layer having the following qualitative-quantitative composition:

Inert and Auxiliary Components Mg / coated tablets Hydroxypropylmethyl cellulose (type E5) 7.078 talc 6.000 Titanium dioxide 1.362 Polyethylene Glycol 6000 0.453 Yellow Iron Oxide (E 172) 0.166 Red Iron Oxide (E 172) 0.055 Theoretical mass of individual coating layers 15.114 White lead (gloss process) 0.800 Theoretical mass of coating layer 15.914

The amount of each component required for the excess coating mixture (for 20,000 tablets) for application to the 18,435 tablets of Example 3:

Inert and Auxiliary Components Weight (g) Hydroxypropylmethyl cellulose (type E5) 141.560 talc 120.000 Titanium dioxide 27.240 Polyethylene Glycol 6000 9.060 Yellow Iron Oxide (E 172) 3.320 Red Iron Oxide (E 172) 1.100 Water (removed during the process) 1000.000 Total weight of coating mixture 302.280 Full Back Lead (For Glossy Process) 16.000

Preparation of 20,000 Tablet Coating Mixtures:

Homogeneous suspension of 141.560 g of hydroxypropylmethyl cellulose (type E5), 9.06 g of polyethylene glycol 6000, 120.0 g of talc, 27.240 g of titanium dioxide, 3.320 g of yellow iron oxide (E 172) and 1.1 g of red iron oxide (E 172) It was finely suspended in about 1000 ml of water until it was obtained. The tablets were placed in a coating pan which automatically applied the coating mixture to the tablets until the desired coating layer weight was obtained.

A small amount of residual coating mixture was discarded.

Average weight of tablet sugar coating layer: 15.1 mg

The coated tablets were finally polished by spinning in a special coating pan with 16.0 g of lead.

18,297 coated tablets containing 450 mg of at least two microcrystalline flavonoids were obtained from the coating and polishing process. Final yield of coating and polishing process: 99.25%.

Example  6

Preparation of 13,500 film coated tablets of 600 mg of two or more microcrystalline flavonoids (specific surface area 10.67 m 2 / g)

The film coating process was carried out in a pharmaceutical facility which was suitably equipped with an automatic coating pan and operated at environmental conditions of relative humidity (R.H.): 35% -50% and temperature (t °): 22 ° ± 3 ° C.

13,978 tablets of Example 4 were film coated using proportional amounts of inert and auxiliary components and the same coating and gloss process, as detailed in Example 5 above. 13,634 coated tablets were obtained, each containing 600 mg of two or more microcrystalline flavonoids of the present invention. Final yield of coating and polishing process: 97.53%.

Example  7

Preparation of 60.19 kg of granules containing about 6.94 kg of granules of two or more microcrystalline flavonoids (450 mg per sachet) having a specific surface area of 10.67 m 2 / g

The manufacturing process was carried out in a pharmaceutical facility suitably equipped for the processes performed and operated at environmental conditions of relative humidity (R.H.): 35% -50% and temperature (t °): 22 ° ± 3 ° C.

The manufacturing process was protected from direct sunlight.

Each sachet was designed to contain:

Active, inert and auxiliary ingredients Mg / sachet Microcrystalline Flavonoids (*) 450.00 Xylitol 10.00 Orange flavor 35.00 Theoretical mass of granules 495.00 Sorbitol Fine Powder 3505.00 (*) Expressed as 100.0% of total active ingredient

The amount of each component required for the preparation of a batch of 60.19 kg of granules corresponding to about 15,000 single dose sachets, each administered at 450 mg of two or more microcrystalline flavonoids (specific surface area: 10.67 m 2 / g)

Active, inert and auxiliary ingredients Weight (kg) Microcrystalline Flavonoids (*) 6.94 Xylitol 0.15 Orange flavor 0.53 Total weight of granules 7.62 Sorbitol Fine Powder 52.57 Total weight of granules 60.19 (*) A quantity satisfying 100.0% of the total active ingredient (specific surface area of 10.67 m 2 / g; moisture 2.85%).

The preparation steps were carried out as follows:

Granules containing 52.57 kg of sorbitol fine powder and then 6.94 kg of two or more microcrystalline flavonoids, 0.15 kg of xylitol and 0.53 kg of orange flavor were introduced in a suitable “V” powder mixer. After blending until homogenized, the resulting pellets were subjected to a dose filling process of single dose sachets.

The resulting sachets are described in Eur. Ph. 5th Ed. in accordance with the mass uniformity test described in paragraph 2.9.5.

From this process 14,178 sachets containing 450 mg of at least two microcrystalline flavonoids were obtained. Final yield of process: 94.52%.

Example  8

Preparation of 2,500 tubes (100.0 kg) of 40 g fat cream containing 4.5% or more of two microcrystalline flavonoids (specific surface area 10.67 m 2 / g)

The preparation step was carried out in a pharmaceutical facility suitably equipped for preparation of topical fat cream and operating at environmental conditions of relative humidity (R.H.): 35% -50% and temperature (t °): 22 ° ± 3 ° C.

100 g of topical fat cream containing:

Active, inert and auxiliary ingredients 100 g of fat cream Microcrystalline Flavonoids (*) 4.500 Glyceryl Monostearate 12.000 Polyethylene Glycol Stearate 2.000 Cetylstearyl alcohol 2.000 Polysorbate 20 1.500 Liquid wax 1.000 lanolin 1.000 Methyl-p-hydroxybenzoate 0.150 Propyl-p-hydroxybenzoate 0.050 Essence 0.500 Purified water 75.300 Theoretical mass of fat cream 100.000 (*) Expressed as 100.0% of total active ingredient

The amount of each component necessary for the preparation of a batch of 100.0 kg of fat cream corresponding to about 2,500 tubes of 40 g of fat cream, having a concentration of at least two microcrystalline flavonoids of the present invention of 4.5%.

Active, inert and auxiliary ingredients 100 kg of fat cream Microcrystalline Flavonoids (*) 4.500 Glyceryl Monostearate 12.000 Polyethylene Glycol Stearate 2.000 Cetylstearyl alcohol 2.000 Polysorbate 20 1.500 Liquid wax 1.000 lanolin 1.000 Methyl-p-hydroxybenzoate 0.150 Propyl-p-hydroxybenzoate 0.050 Essence 0.500 Purified water 75.300 Total weight of fat cream 100.000

Preparation of 100.0 kg of fat cream was carried out according to methods well known to those skilled in the topic of topical formulations. After the filling process, 2,327 fat cream 40 g tubes of two or more microcrystalline flavonoid fractions of 4.5% were obtained.

Final yield of the fat cream: 93.08%

Example  9

Preparation of 3,000 tubes (120.0 kg) of an ointment 40 g containing at least 2 microcrystalline flavonoids (specific surface area 10.67 m 2 / g) of 4.0%

The preparation step was carried out in a pharmaceutical facility suitably equipped for topical ointment preparation and operating at environmental conditions of relative humidity (R.H.): 35% -50% and temperature (t °): 22 ° ± 3 ° C.

100 g of topical ointment containing:

Active, inert and auxiliary ingredients g / ointment 100 g Microcrystalline Flavonoids (*) 4.000 Semisynthetic Glyceride (Softisan 100) 12.000 Anionic emulsion wax (Lanetta SX) 6.500 Anhydrous lanolin 1.000 Polysorbate 80 1.500 Dimethylpolysiloxane 100 4.750 Dimethylpolysiloxane 500 4.750 Methyl-p-hydroxybenzoate 0.140 Propyl-p-hydroxybenzoate 0.060 Lemon essence 0.500 Purified water 64.800 Theoretical mass of ointment 100.000 (*) Expressed as 100.0% of total active ingredient

The amount of each component required for the preparation of a batch of ointment 120.0 kg corresponding to about 3,000 tubes of 40 g of formulation having a concentration of at least two microcrystalline flavonoids of the invention of 4.0%

Active, inert and auxiliary ingredients Ointment 120.0 kg Microcrystalline Flavonoids (*) 4.800 Semisynthetic Glyceride (Softisan 100) 14.400 Anionic emulsion wax (Lanetta SX) 7.800 Anhydrous lanolin 1.200 Polysorbate 80 1.800 Dimethylpolysiloxane 100 5.700 Dimethylpolysiloxane 500 5.700 Methyl-p-hydroxybenzoate 0.168 Propyl-p-hydroxybenzoate 0.072 Lemon essence 0.600 Purified water 77.760 Total weight of ointment 120.000

Preparation of ointment 120.0 kg was carried out according to methods well known to those skilled in the topical formulations. After the filling process, 2,812 ointment 40 g tubes of at least 2% microcrystalline flavonoids were obtained.

Final yield of the ointment: 93.93%

Example  10

Investigational pharmacokinetic studies in which volunteers received a single oral dose of the film coated tablets of Example 6 containing 600 mg of two or more microcrystalline flavonoids (specific surface area 10.67 m 2 / g)

Five healthy volunteers (2 males, 3 females) aged 20 to 45 years and weighing between 52 and 68 kg were accommodated in the study after full medical qualification.

Each fasting patient was given a single oral dose of 600 mg of film coated tablets of two or more microcrystalline flavonoids (corresponding to about 10 mg / kg body weight).

Blood samples were taken from the patients at intervals of 0.5, 1, 2, 4, 8, 12, 24 and 48 hours after oral administration using known techniques and centrifuged at 3,000 g immediately. Each plasma sample was individually collected, separated from the blood cell fraction and stored at −20 ° C. until analysis.

The determination of the content of two or more microcrystalline flavonoids was carried out using the following method:

-1 ml of DMSO is added to 1 ml of plasma sample and shaken for 10 minutes;

Centrifuge for 5 min at -2.5 rpm;

Separating the organic phase and evaporating to dryness with nitrogen;

-50 [mu] l methanol is added to the dry residue;

20 μl of the solution was injected into an HPLC apparatus equipped with a PKB 100 column (25 cm × 2.1 mm) using a mixture of methanol / acetic acid / water (40:15:45) and a flow rate of 1.0 ml / min as a mobile phase and;

The absorbance was monitored at 345 nm for the eluate;

The residence time of the microcrystalline flavonoids was about 1.3 minutes.

The following parameters were examined for detailed description of pharmacokinetic parameters:

C _max : the maximum plasma concentration of at least two microcrystalline flavonoids;

T _max : time to reach the maximum plasma concentration;

AUC: area under the plasma concentration-time curve within the dosing interval, calculated by the trapezoidal law;

MRT: mean residence time;

TCI: overall body clearance produced by the ratio of oral dose (D) to AUC;

V _d : distribution volume.

The results are summarized in Table 1 below.

The present invention relates to flavonoid-containing pharmaceutical compositions for oral or topical administration. The present invention also relates to a process for the production of solid pharmaceutical compositions characterized by marked wettability and improved bioavailability and for the formulation of topical formulations without the unpleasant "rough" effect.

Claims (17)

A pharmaceutical composition comprising an active ingredient comprising two or more flavonoids in microcrystalline form, wherein the two or more microcrystalline flavonoids comprise diosmin and one or more other flavonoids; Pharmaceutical compositions wherein said at least two microcrystalline flavonoids also exhibit the following characteristic parameters: Specific surface area, 4-18 m 2 / g, according to the BET measurement; F / D (F = other flavonoids / D = diosmine) (weight / weight) ratio of 0.03 to 0.1; And Moisture content less than 4.0% by weight. The method of claim 1, Pharmaceutical composition wherein at least two microcrystalline flavonoids exhibit a specific surface area of 9-12 m 2 / g according to BET measurements. The method according to claim 1 or 2, A pharmaceutical composition in the form of tablets or granules for oral administration, wherein the amount of two or more microcrystalline flavonoids accounts for at least 70.0% (w / w) of the weight of the tablets or granules. The method according to claim 1 or 2, A pharmaceutical composition in the form of an external topical fat cream or ointment wherein the amount of at least two microcrystalline flavonoids comprises at least 4.0% (w / w) of the weight of the fat cream or ointment. The method according to any one of claims 1 to 4, Two or more microcrystalline flavonoids of "strong" (s) at about 15.32, 19.68, 21.70, "medium" (m) at about 11.90, 15.87, 21.33, 24.68, and diffuse (d) at about 26.35, 27.72 and 28.65 Pharmaceutical composition showing an X-ray powder diffractogram (XRD) pattern with a relative intensity peak. The method according to any one of claims 1 to 5, The pharmaceutical composition of the at least one other microcrystalline flavonoid is selected from at least one of isololypoline, linarin, diosmetin, hesperidin, quercithin and rutin. First in granular form, comprising passing the two or more microcrystalline flavonoids together with the desired inert and auxiliary components through a wet granulation process followed by further steps to homogeneously mix, spray or knead into a suitable compression mixture. Process for the preparation of a pharmaceutical composition according to any one of claims 6 to 6. The method of claim 7, wherein The compression mixture punched into tablets contains other inert and auxiliary components in addition to the two or more microcrystalline flavonoids in the specified weight range (in mg / tablet): Microcrystalline cellulose 55.0-70.0 mg gelatin 27.0-35.0 mg Sodium starch glycolate 25.0-30.0 mg Magnesium stearate 3.50-4.90 mg glycerin 0.40-0.50 mg Sodium lauryl sulfate 0.02-0.04 mg (Total weight of inert and accessory ingredients for each tablet ranged from 110.92 mg to 140.44 mg). The method of claim 8, A process for preparing a compacted mixture characterized in that the content of disintegrant sodium starch glycolate is greater than 15.0% of the total weight of the inert and auxiliary components. The method according to any one of claims 7 to 9, A method comprising the following manufacturing sequence: (a) homogeneously incorporating microcrystalline cellulose into two or more microcrystalline flavonoids (powder mixtures); (b) preparing a binding solution separately by dissolving gelatin, glycerin and sodium lauryl sulfate in a convenient amount of water; (c) conveniently spraying, wetting, or kneading the powder mixture (a) with the binding solution (b) to obtain wet granulates, which are conveniently sieved to granules of suitable consistency and size; (d) the wet granules are dried on a fluid bed dryer (greater than 2.0% moisture) for convenient grinding and sieving; (e) The dry granules (d) are homogeneously blended with sodium starch glycolate to obtain a compacted mixture which is punched into tablets. The method according to any one of claims 7 to 10, The resulting tablet exhibits a residual moisture content of greater than 2.0% (w / w). The coating of any coating on the surface of the tablet obtained according to any one of claims 7 to 11, comprising using an aqueous coating suspension comprising the following components in the specified weight range (in mg / tablet). How to apply: Hydroxypropylmethyl cellulose 3.0-10.0 mg talc 2.0-10.0 mg Titanium dioxide 0.5-5.0 mg Polyethylene glycol 0.1-1.0 mg Yellow Iron Oxide (E 172) 0.0-0.5 mg Red Iron Oxide (E 172) 0.0-0.5 mg White lead (final gloss process) 0.0-1.5 mg (The total weight of the coating layer per tablet ranges from 5.6 mg to 26.5 mg). A method for preparing a pharmaceutical composition in the form of granules for filling a single dose sachet, characterized in that the granules formed according to claim 7 are prepared by mixing with a suitable amount of solid sweetener and flavoring agent. Agent in the form of a fat cream or ointment comprising mixing 4.0% (w / w) of at least two microcrystalline flavonoids with a convenient amount of suitable inert and auxiliary ingredients to produce a physiological pH range of 6.5 to 7.5 A method for the preparation of a pharmaceutical composition according to any one of claims 1 to 4. Orally coated tablets, film coated tablets, granules and granules, or as external topical fat creams or ointments, characterized by marked patient compliance and improved wettability, absorption and bioavailability. A pharmaceutical comprising at least two microcrystalline flavonoids according to any one of claims 1 to 14. The method according to any one of claims 1 to 15, A medicament comprising two or more microcrystalline flavonoids exhibiting venous strengthening and vasoprotective effects, particularly useful in the treatment of chronic venous disease. In the process for the preparation of two or more microcrystalline flavonoids, a. Hesperidin is reacted with iodine / potassium acetate in methanol; b. The amount of diosmin in the reaction product obtained from step a) is increased by fractional precipitation; Drying the product obtained from step b) How to include.

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