Powder composition of hydroxypropyl betacyclodextrin and process for preparing the same

“HYDROXIPROPIL-CYCLODEXTRIN PULVERIFORM COMPOSITION AND PROCESS FOR PREPARATION”

The invention relates to a novel hydroxypropyl cyclodextrin β pulveriform composition which has a particular particle size and also an excellent dissolution rate.

The invention further provides a particular process for obtaining such a composition and also its uses for industrial purposes.

Cyclodextrins, which are macrocycles having 6, 7 or 8 glucose motifs depending on whether they are α, β or γ cyclodextrins, are perfectly described in the literature, in particular the aspects concerning their solubilizing and stabilizing properties of various compounds. Such properties, essentially due to their ability to form a complex in the presence of compounds capable of housing all or part of such macrocycles, have a very important interest in the food, pharmaceutical and phytosanitary industries. Cyclodextrin derivatives have also been studied, in particular in order to increase the solubility of cyclodextrins in water, as their solubility is not very high: in reality this value does not, for example, exceed 1.8 g per 100 mL for cyclodextrin β. Among said derivatives, cyclodextrin ethers and more particularly hydroxyalkyl cyclodextrins have received particular attention due to their high water solubility, their harmlessness and ease of manufacture.

These hydroxyalkyl cyclodextrins correspond to cyclodextrins in which all or part of the hydroxy groups have been etherified with hydroxyalkyl radicals.

The characteristics of these derivatives led scientists to test them in different domains, namely in the pharmaceutical, cosmetic and phytosanitary domains.

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Indeed, the good solubility of these derivatives in water is of particular particular interest for the production of water-soluble forms of pharmaceutical active ingredients which are poorly soluble or even water-insoluble by themselves, but also have great stability.

Thus, U.S. Patent No. 4,727,064, filed by ΡΙΊΉΑ, protects pharmaceutical compositions containing an amorphous complex of a pharmaceutical agent with a cyclodextrin compound, in particular hydroxypropyl cyclodextrin β. This complex allows to improve the solubility of the active ingredient and consequently its absorption by the body.

JANSSEN PHARMACEUTICA has also been granted a European patent EP 149 197 which relates to pharmaceutical preparations consisting of water-soluble, or water-unstable, drug inclusion compounds together with a partially etherified β cyclodextrin and in particular hydroxypropyl cyclodextrin β for the purpose of improving the solubility and stability of such medicinal products in water.

The European patent granted to SHISEIDO under EP 366154 protects the use of hydroxypropyl cyclodextrin β in a cosmetic product. Complexes obtained with low-water-soluble compounds, which are UV filters, preservatives and perfumes, have very good water solubility and the cosmetic products containing them show satisfactory stability without the need for solubilizing agents. irritating to the skin.

Finally, it should also be noted that there are uses of hydroxypropyl cyclodextrin β in the phytosanitary domain which are described, inter alia, in Japanese Patent Nos. SUN OIL No. 1068303 and NIHON NOYAKU No. 63079802. There is particular interest to the level of the toxicity of the chemical compound as a complex and also in terms of the solubility and stability of such complexes.

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Furthermore, there are still many references in the literature specifically describing complexes of a particular active agent with hydroxypropyl cyclodextrin β.

Hydroxyalkylated derivatives of cyclodextrins are generally obtained in accordance with the process of reacting, under particular temperature, pressure and time conditions, propylene oxide with a cyclodextrin β in aqueous medium at an alkaline pH. Generally sodium hydroxide is chosen as the reaction catalyst.

This reaction generally proceeds at a temperature of not less than 70 ° C.

Following the completion of the reaction, the reaction medium is neutralized and the hydroxypropyl cyclodextrin β compound is isolated, purified and recovered as an aqueous solution.

If you want to get a solid form then you can practice various techniques that have already been used. Thus, in Chapter 2 on hydroxypropyl cyclodextrin β, published by Professor DUCHENE in 1991 and entitled “New trends in Cyclodextrins and derivatives”, L. SZENTE and CE STRATTAN cite lyophilization, atomization and evaporation.

Lyophilization and atomization are also the means suggested by AMERICAN MAIZE PRODUCTS in French Patent No. 2,597,485 for recovering cyclodextrin ethers.

However, as pointed out by L. SZENTE and CE STRATTAN in the above cited reference, powders obtained according to these different techniques have many defects and in particular are found to have poor dissolution.

On the other hand, such powders hardly flow and have poor compression characteristics.

Moreover, such techniques lead to the obtainment of very fine particles, which represents a notable drawback in filling and emptying operations of hoppers and feed ducts as well as packaging bags. In addition, such

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Fine particles may be the source of explosions and also represent a potential source of irritation to the operator handling.

In view of this, the applicant company therefore sought to develop a spray composition of hydroxypropyl cyclodextrin β which had a high dissolution rate and was more compatible with all industrial requirements, without the flow and compression defects of the spray forms. hydroxypropyl cyclodextrin β, and which was not also a source of dust or explosions at production sites.

The applicant company has been successful in preparing a pulverulent hydroxypropyl cyclodextrin β composition free of the above-mentioned defects and at the same time having a fine-centered “centered” particle size and a remarkably better ability to dissolve in an aqueous medium.

Thus, the invention relates to a hydroxypropyl cyclodextrin β pulveriform composition, characterized in that it has less than about 25% of particles smaller than 100 μη and whose dissolution rate in aqueous medium, measured according to a test I, is less than 5 minutes at 21 ° C for a solution containing 20% ​​dry matter.

The invention also relates to a process for the preparation of a hydroxypropyl cyclodextrin β pulveriform composition having the physical and functional characteristics indicated above.

According to the first essential feature of the hydroxypropyl cyclodextrin β-spray composition according to the invention, hereinafter referred to as ΉΡΟϋβ only¹Such a composition has a particular and centered grain size. In fact, it contains less than about 25% particles smaller than 100 µm in size.

Preferably, the ββ spray composition does not contain more than about 10% particles smaller than 50 µm and even more preferably contains less than about 40% particles larger than 315 µm.

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As regards the absence of very fine particles, which represents a particular advantage characteristic of the compositions according to the invention, such an advantage has been demonstrated using the DUSTMETER apparatus (configuration No. 2) marketed by the HENBACH ENGINEERING Company. 0 The principle of measurement is based on a procedure whereby the product to be tested is moved in a rotating drum. The fine particles present are then entrained by an air stream and then collected on a filter. The weighing of this filter before and after said movement gives the amount of fine particles accumulated in it.

In the case of the powdered composition of ΗΡΟϋβ according to the invention, the amount of dust used was 100 g, the air flow rate was 8 L / min and the duration of the moving operation was 5 minutes. The results clearly demonstrate the negligible amount of fine particles present in the compositions according to the invention compared to a prior art composition.

The second essential feature of the HPCD1 pulveriform composition according to the invention is its ability to dissolve very rapidly.

Accordingly, the dissolution time measured under the conditions of test I, which will be described below, is less than 5 minutes, preferably less than 3 minutes and more preferably less than 2 minutes at a temperature of 21 ° C and to a ΗΡΟΏβ solution with 20% dry matter, which is an important improvement over the dissolution rate of the known ΗΡΟϋβ powders. This improvement is particularly noteworthy in that a rapid dissolution rate conditions an even greater use of HPCDfl.

In order to measure the dissolution rate which is therefore the second essential feature of the ββ-spray composition according to the present invention, proceed as described in Test I, which consists in measuring the time required for complete solubilization to take place in accordance with the present invention. demineralized water of different amounts of HPCDP corresponding to compositions containing 5%, 10%, 20%, 30% and 40% dry matter. For this measurement, the amount of demineralized water required to obtain 100 g of composition with an HPCDp content of 5%, 10%, 20%, in a high capacity 150 ml capacity beaker. 30% or 40% and then subjected to a stirring operation at 1250 rpm with a magnetic rod (length: 25 mm; diameter 6 mm) and the retained amount of HPCDp added. This test is performed at two temperatures: 21 ° C and 60 ° C.

The time taken for dissolution is that which corresponds to obtaining perfect visual clarity of the suspensions thus prepared.

Whether working at room temperature or at a high temperature, whatever the concentration of the HPCDP, the dissolution times of the spray compositions according to the invention are always markedly shorter than those of the prior art compositions.

On the other hand, it should be noted that with the compositions according to the prior art surface dust accumulation occurs in the case of the higher dry matter, which accumulation is eventually followed by an overflow. This problem requires that the addition of HPCDfl be done in a fractional manner.

In addition to the dissolution time, the applicant has also shown other particularly advantageous functional characteristics of the composition according to the invention, such as its flowability and compressibility.

The flow capacity was evaluated with the device sold by the HOSOKAWA Company. This device allows measuring the flowability of a powder under standard and reproducible conditions and calculating a flow parameter also known as the CARR index. The HPCDP powdered composition according to the invention has an excellent flow rate, from 60 to 90. Preferably, this rate will be from 70 to 85. The flow of the powders according to the invention therefore appears to be markedly better than that of the prior art powders.

This feature is particularly interesting in industrial practice as it facilitates the filling and emptying of hoppers and containers or of pharmaceutical forms such as sachets and glands.

With the same apparatus and according to the method indicated by the manufacturer, the aerated bulk density was also measured. The values ​​obtained for the compositions according to the invention are always between 300 and 650 g / l and preferably between 350 and 600 g / l, whereas for prior art compositions the aerated bulk density is less than 300 g / l. g / l.

Compressibility is determined according to Test II, which is to measure the force, expressed in Newton (N), which is required to break a tablet prepared from the composition to be tested, that is, to cause the appearance of lines of rupture within its constituent mass. This strength thus reflects the fracture strength of a convex-faced cylindrical tablet with a diameter of 13 mm, a thickness of 5 mm and a mass of 0,499 g, ie a density or density of 1, 15 g / ml, said force being exerted against the peripheral surface of the tablet in the direction of its axis of revolution by means of a movable abutment that applies against said surface along a geratrix; said tablet being immobilized against a fixed abutment also applied against the peripheral surface of that tablet along a diametrically opposite generatrix to that against which the movable abutment is applied.

For the preparation of these tablets an amount of 0.5% by weight of a lubricating agent, namely magnesium stearate, is added to the composition studied.

These two products are mixed homogeneously with the aid of a 'TURBULA T2C' mixer (marketed by

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“WILLY A. BACHOFEN AG”, Switzerland) for 5 minutes at 42 rpm.

The obtained mixture is compressed using an alternative 'FROGERAL' type AM press. This press is equipped with round concave punches with a diameter of 13 mm.

In order to achieve the characteristics of the above tablets, the depth displacement of the upper punch and the filling volume of the die are adjusted in the press, allowing the latter arrangement to fix the mass amount of the desired spray mixture, in this case 0.499 g.

To assess the fracture resistance of these tablets a 'SCHLEUNIGER 2E' durometer (marketed in France by the company 'FROGERAIS') is used.

Contrary to prior art compositions obtained according to known techniques, with which it is not possible to produce tablets because of the bonding and cleavage problems that arise at the time of application of pressure, the iformβ pulveriform compositions according to invention have a completely satisfactory compressibility. This translates to a tablet hardness which is in all cases greater than 30 N, preferably greater than 60 N and even more preferably greater than 100 N, for a tablet density of 1.15 g. / ml.

This compressibility is intended for the preparation of sucking or chewing tablets, either in the pharmaceutical or confectionery field.

The powdered HPCDp compositions according to the invention may be obtained according to a process similar to spraying, under particular conditions, a hydroxypropyl cyclodextrin β solution, although this technique has not hitherto allowed to obtain a hydroxypropyl cyclodextrin pulveriform composition having the particle size and functional characteristics of the composition according to the invention. This process consists essentially of spraying a solution of ΗΡΟϋβ onto a moving spray bed made up of HPCDp particles.

In particular, the process used to obtain compositions according to the invention comprises the following steps:

- preparation of a ΗΡΟϋβ solution with a dry matter content of not less than 30%,

fine spraying of this solution onto a spray bed of moving ΗΡΟΌβ particles, the temperature of said bed being between 40 ° C and 110 ° C, and such that the mass of that bed permanently represents at least 0,5 times mass of spray solution per hour,

- drying the spray bed and the solution to obtain the spray composition of ΗΡΟΏβ,

- partial recycling of the composition to form a new pulverβ spray bed.

This technique thus enables a pulverulent composition of ΗΡΟΏβ having a particular and centered particle size while having an excellent dissolution rate. These characteristics, as well as their flowability and compressibility, can be adjusted by modifying the dry matter of the ΗΡΟϋβ solution to be solubilized, the degree of fineness of the spray, the means for moving the particles, the temperature of the bed. , the drying temperature and the respective masses of the bed and the spray solution.

For dry matter of ΗΡΟΏβ solution, it is preferable that the amount is greater than or equal to 50%.

On the other hand, it is preferable to avoid coarse spraying of the solution, in which case the particles stick together.

In addition, in order for the ββ pulveriform composition to have the specific properties described above, it is important to use a material which allows very fine droplets to be formed from the solution, ie a cloud of droplets.

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With regard to the nature of the ΗΡΟϋβ particles constituting the pulveriform bed, it is ideal to use for that bed ΗΡΟΟβ particles having all the characteristics of the HPCDp spray composition according to the invention. This can be achieved by partially recycling the composition according to the invention, which will therefore perform the function of the β-particle spray bed.

In order to set in motion the particles constituting the spray bed can be used by mechanical means or this can be achieved by means of a draft. The latter possibility is preferable since it is easy, by selecting the air temperature, to adjust the bed temperature to between 40 ° C and 110 ° C.

In general, it is preferable for the bed temperature to be between 50 ° C and 80 ° C.

Drying of the spray bed on which the solution has been sprayed should be carried out to a final water content of not more than 5% and preferably not more than 3% of the composition.

The applicant has shown that it is advantageously possible to continuously manufacture the pulverulent composition of HPCDp by, for example, using a 'Multi-Effect' or MSD-type 'NIRO ATOMIZER' atomization column or tower. The latter type is preferable. Such atomization columns or towers allow, by their design, to reproduce all the essential steps of the process according to the invention.

In fact, this equipment makes it possible to spray a solution at a temperature of 30 ° C to 100 ° C and having a dry matter content of 30% to 70%, with the aid of the injector mounted on it. over a bed of HPCDP particles, placed and kept moving by air. In addition, this equipment allows simultaneous drying by means of hot air. Advantageously, it is possible to

Γ choose an air inlet temperature of between 160 ° C and 300 ° C with permitted material flow rates such that the outlet air temperature is between 45 ° C and 130 ° C and better still is between 60 ° C and 90 ° C. This equipment also allows to partially recycle the HPCDp spray composition and to disperse it very finely in the column, preferably around the solution spray nozzle.

Due to its particular properties, the HPCDP powdered composition according to the invention may also be advantageously used as an agent for improving the solubility and / or stability in water of active compounds in the formulation of powders to be dissolved or in tablets. in the pharmaceutical, cosmetic and agrochemical fields.

The advantages of the present invention will be better understood upon reading of the following illustrative examples which are by no means limiting, taking into consideration particular embodiments of the HPCDp spray composition according to the invention.

EXAMPLE

Preparation of three β-spray compositions according to the invention and comparison with a prior art product.

A solution of ΗΡΟϋβ is prepared according to a classical procedure under the following conditions.

A solution of 1275 g of commercial cyclodextrin β (corresponding to 1134 g of the same anhydrous product) in 1600 g of a 6% sodium hydroxide solution (96 g of sodium hydroxide in 1504 g of demineralised water) is prepared. keeping the temperature at about 80 ° C.

The solution is placed in a nitrogen ionized reactor equipped with a stirring device and a condenser. 406 g of propylene oxide is introduced dropwise into the reactor, keeping the temperature between 80 ° C and 100 ° C and allowing the reaction to proceed for 4 hours following the completion of the propylene oxide addition. The reaction mixture is then cooled and neutralized by the addition of concentrated hydrochloric acid.

Eventually the reaction mixture will be purified depending on the desired degree of purity using known prior art methods (filtration, decolorization by activated charcoal treatment, demineralization, ethanol washing, acetone extraction and dialysis). .

For each of the three compositions according to the invention, respectively, then operate as follows.

Composition # 1

The dry matter (DM) content of the solution is adjusted to 60% and the temperature is brought to 50 ° C before spraying the solution on a NIRO ATOMIZER 'Multiple Effect' column.

This solution is then finely sprayed onto a spray bed of moving particles corresponding to the particles formed at the beginning of the operation.

The temperature of the moving particle bed is adjusted to 50 ° C.

The temperature of the drying air admitted to the upper inlet of the column is from 175 ° C to 195 ° C and the temperature of the air leaving the column is from 45 ° C to 60 ° C.

Composition No. 2

The MS content of the solution is adjusted to 35% and the temperature is brought to 70 ° C before spraying the solution onto a NIRO ATOMIZER MSD-type column.

The temperature of the moving particle bed is adjusted to 75 ° C.

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The temperature of the drying air admitted to the upper inlet of the column is between 200 ° C and 230 ° C and the temperature of the air leaving the column is between 65 ° C and 85 ° C.

Composition No. 3

The solution is adjusted to 55% and brought to 70 ° C before spraying the solution onto a NIRO ATOMIZER MSD column.

The temperature of the moving particle bed is adjusted to 62 ° C.

The temperature of the drying air admitted to the upper inlet of the column is between 180 ° C and 200 ° C and the temperature of the air leaving the column is between 60 ° C and 80 ° C.

Composition according to the prior art

This composition is obtained according to a classical atomization technique which consists of a simple spray of a 35% dry matter HPCDp solution onto a classic atomization column in the absence of any particle bed of ΗΡΟϋβ.

The temperature of the drying air admitted to the upper inlet of the column is between 230 ° C and 280 ° C and the temperature of the air leaving the column is between 100 ° C and 130 ° C.

The main physical and functional characteristics of compositions No. 1, No. 2 and No. 3 obtained under the conditions described above are grouped in the following table.

PAINTING

<td rowspan="2"></td><td colspan="6">Compositions according to the invention</td><td colspan="2">Prior Art Composition</td>

<td colspan="2">| # 1</td><td colspan="2">No. 2</td><td colspan="2">No. 3</td><td colspan="2"></td>

<td>Granulometry &lt;40 pm &lt;100 μιη &gt; 315 μιη</td><td colspan="2"> 0% 9% 25%</td><td colspan="2"> 0% 21% 6%</td><td colspan="2"> 0% 1% 11%</td><td colspan="2"> 50% 100% 0%</td>

<td>Airy bulk density in g / L</td><td colspan="2"> 478</td><td colspan="2"> 386</td><td colspan="2"> 381</td><td colspan="2"> 263</td>

<td>Dissolution Time</td><td>at 21 ° C</td><td>at 60 ° C</td><td>at 21 ° C</td><td>at 60 ° C</td><td>at 21 ° C</td><td>at 60 ° C</td><td>at 21 ° C</td><td>at 60 ° C</td>

<td>5% solution 10% 20% 30% 40%</td><td>0mnl5 0mn35 Qmn50 2mnl5 4mn</td><td>&lt;10 s OmnlO 0mnl5 0mn35 lmnlO</td><td>0mnl5 0mn30 0mn45 lmnlO 2mn30</td><td>&lt;10 s OmnlO 0mn20 0mn35 lmnlO</td><td>0mnl5 0mn35 0mn50 lmnl5 2mn40</td><td>&lt;10 s OmnlO 0mn20 0mn35 lmnlO</td><td>lmnl5 4mn 8mn * llmn * 17mn *</td><td>0mn40 linnlO 4mn 6mnl5 * 8mn50 *</td>

<td>Amount of dust in g</td><td colspan="2"> 0,15</td><td colspan="2"> 0,03</td><td colspan="2"> 0,03</td><td colspan="2"> 0,64</td>

<td>flow rate</td><td colspan="2"> 77</td><td colspan="2"> 76</td><td colspan="2"> 78</td><td colspan="2"> 44</td>

<td>Compressibility</td><td colspan="2">34 N</td><td colspan="2">147 N</td><td colspan="2">116 N</td><td colspan="2">Impossible to compress it</td>

* It is necessary to fractionate the addition of ΗΡΟΟβ

Contrary to the prior art composition, the compositions according to the invention advantageously combine properties which to date have never been found simultaneously. In fact, they simultaneously have the characteristics of dissolving very rapidly in water, being compressible, easily flowing and not generating very fine particles.