MXPA99011899A - Pharmaceutical compositions for oral administration, comprising an active substance and a cyclodextrin - Google Patents

Abstract

The invention concerns pharmaceutical compositions for oral administration, comprising an active substance belonging to the family of substituted benzhydrylpiperazines and at least a cyclodextrin.

Description

, ^ FIELD OF THE INVENTION The present invention relates to orally administrable pharmaceutical compositions containing an active substance which belongs to the family of substituted benzhydrylpiperazines and a cyclodextrin.

"BACKGROUND OF THE INVENTION Numerous substances belonging to the family of substituted benzhydrylpiperazines are known as substances having interesting pharmacological properties. , For example, patent GB 817231 in the name of the applicant describes substituted benzhydrylpiperazms which correspond to the general formula fCHjCRjOJ-- camaya REF. : 32301 in which R and R1 represent independently of one another a hydrogen or halogen atom, an alkyl I or alkoxy group. R and R1 may be in the ortho, meta or para position and n represents the number 1 or 2, as well as their pharmaceutically acceptable T i salts. Among these compounds, there is especially 2- [2- [4- [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] ethanol, also known by the name 1 hydroxyzine and its hydrochloride, well known for its antihistamine and tranquilizing properties. The patent EP 58146 in the name of the applicant describes substituted benzhydrylpiperazines corresponding to the general formula - in which L represents a group -OH or -NH2, X and X ', taken alone, represent a hydrogen atom, a halogen atom, a linear or branched alkoxy radical in Ci or C4 or a trifluoromethyl radical, m is equal to 1 or 2, n is L to 1 or 2, as well as its pharmaceutically acceptable salts. Among these compounds, 2- [2- [4- [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid, also known as cetirizine and its dihydrochloride, are well known for their antihistaminic properties. Until now, the only orally administrable commercial pharmaceutical compositions containing this type of compound are of the conventional type. In the case of coated tablets, administration is made by ingestion thanks to the simultaneous absorption of liquid. When absorption must be done without simultaneous absorption of liquid (pre or post-operative conditions, absence of drinking water, etc.), a conventional mode of administration is not suitable due to the extremely bitter taste of these substituted benzhydrylpiperazines. - - "i ; ___ Different techniques have already been described for the masking of the taste of pharmaceutical substances. For example, US Pat. No. 3,558,600 discloses a method for masking the bitter taste of antihistamines belonging to the family of the substituted 1- (p-chlorobenzhydryl) piperazines which consists in transforming the active substance into the free base form and its salt. of long chain alkyl sulfate, co or stearyl sulfate, for example. Another known method for masking the taste of the active ingredients is to form an inclusion complex between the active principle and a cyclodextrin. In this case, the masking of taste comes from the imprisonment of the active principle that can not be released when it goes through the mouth. However, this solution to the problem of taste masking entails another particular problem of the masking of the taste of active pharmaceutical substances administered orally, namely the problem of the bioavailability and the speed of action of the active principle. Indeed, if the association constant of the inclusion complex is large, there is a risk that the active ingredient will not be released easily enough to allow good absorption in the gastrointestinal tract. obtain the discounted therapeutic effect EP 399902 mentions this dual problem of orally administrable pharmaceutical compositions, namely the "masking of taste associated with good availability. This patent describes lyophilized and porous pharmaceutical forms comprising, in addition to conventional excipients and additives for this type of formulation, the active principle and a cyclodextrin, as well as the methods of preparation of "these pharmaceutical forms." The pharmaceutical compositions containing the following active ingredients are described in the exemplary embodiments of the invention: ketoprofen, trimipramy to methanesulfonate, zopyicone, phenobarbital, vitamin A, lemon essence, pritlnamicin or vitamin D3.

However, this document does not allow to conclude c * .__ t that in all cases there is a good masking of taste and bioavailability_of these active ingredients.

In the case of the pharmaceutical substances belonging to I the family of substituted benzhydrylpiperazines, this problem is of particular importance since, if what is desired is to mask the extremely unpleasant bitter taste of these active ingredients, it is also It is essential that they be released immediately after administration to obtain a fast and effective effect. * Therefore, the applicant has set as, objective to investigate new pharmaceutical compositions that P®rp? and oral administration of the pharmaceutical substances belonging to the family of substituted T-benzhydrylpiperazines more easily than what the current compositions allow, ensuring a good bioavailability of the active substance.

"Recently we have discovered new orally administrable pharmaceutical forms that simultaneously allow to mask the taste of the substances belonging to the family of the substituted benzhydrylpiperazines and obtain a good bioavailability of these compounds by their oral administration, even without _ the simultaneous intake of liquid. In particular, the applicant has set itself the objective of investigating said formulations which are presented in the form of chewable tablets, of dry syrups, granules or sublingual tablets.

DESCRIPTION OF THE INVENTION That is why the present invention relates to orally administrable solid pharmaceutical compositions comprising an active substance belonging to the family of substituted benzhydrylpiperazines and at least one cyclodextrin. The cyclodextrins which can be used according to the present invention can be selected from cyclodextrins a, β or β, or from the alkylated or hydroxyalkylated derivatives of the latter, such as heptakis (2,6-di-o-methyl) -β-cyclodextrin (commonly abbreviated as DIMEB), randomly ethylated ß-cyclodextrin (commonly abbreviated as RAMEB) and hydroxypropyl β-cyclodextrin (commonly abbreviated as HPβCD). - Among the active substances belonging to the family of substituted benzhydrylpiperazines, we will particularly mention 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetic acid (cetirizine), 2- [2- [4- [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] ethanol (hydroxyzine), 2- [2- [4-bis (4-fluorophenyl) methyl] -1-piperazinyl ] ethoxy] -acetic (efletirizine), 1- [(4-chlorophenyl) phenylmethyl] -4- [(3-methylphenyl) methyl] piperazine jmeclizine) 'or l - [(4-tert-butylphenyl) methyl] -4- [(4-chlorophenyl) phenylmethyl] piperazine (buclizine), its optically active isomers I, as well as its pharmaceutically acceptable salts. __ The pharmaceutical compositions according to the present invention can be presented in various orally administrable forms. In particular, the pharmaceutical compositions according to the present invention can be presented in the form of dry syrup, chewable tablets, granules or sublingual tablets which lend especially well to an administration by -_ i orally without simultaneous absorption of fluid. The excipients used are the conventional excipients used for this type of compositions. In the case of dry syrups and granules, diluents such as polyols (mannitol, sorbitol, sucrose, etc.) and flavorings can be used for example. In the case of chewable tablets, any conventional excipient that provides good compression parameters can be used, such as diluents (mannitol, sorbitol, etc.), disintegrating or dispersing agents (polyvinylpyrrolidone, croscaramellose sodium, starches and derivatives, cellulose and derivatives, etc.), lubricating agents (magnesium stearate, etc.), sliding agents (aerosil '200, etc.) and aromas. In the case of sublingual tablets, the excipients cited above can be used by selecting among them those which are water-soluble. - Regarding the methods of preparation, 1 all current methods used by pharmacists can be used for the preparation of this type of compositions. If desired, the complex of active substance I with cyclodextrin? it can preferably be prepared, for example, by mixing the active substance and the cyclodextrin in the presence of water or by preparing an aqueous solution containing the active substance and the cyclodextrin in the desired molar ratio. As an alternative, ~ the active substance and the cyclodextrin can simply be mixed with the other excipients and adjuvants. The following examples illustrate the present invention without limiting it. In these examples, the parts are expressed by weight.

^ Example 1 Test of_amargor __ Different solutions are prepared by adding Table 1 - Bitterness test Molar ratio ß-CD / cetirizine 0.0_ 0.5 1.0 2_.0__4.0 Absence of bitterness 0 0 0 3 7 Very weak bitterness 0 1 6 4 0 Bitterness marked 7 6 1 0 0 There is a reduction in the bitterness of cetirizine dihydrochloride when ß-cyclodextrin is added to the solution of cetirizine dihydrochloride. This reduction is especially notable when the molar ratio between β-cyclodextrin and cetirizine dihydrochloride is between 1.0 and 4.0.

Example 2 - Solubility test The solubility of the hydrophobic molecules in the water increases in the presence of cyclodextrins, as far as the solubilization rate and the amount of active substance solubilized are concerned. Modifying the solubility in water of a hydrophobic active substance in the presence of cyclodextrin is therefore a method commonly used to highlight the formation of an inclusion complex (see J. SZETLI, in VF SMOLEN and LA BALL , Controlled Drug Biovailability, Vol. 3, iley, New York (1985), 365-420). Although cetirizine dihydrochloride has good solubility in water at neutral pH, its solubility is much weaker while the ambient pH is between 2.5 and 3.5 (solubility in the order of 0.3 g / 100 ml). In this test, the modification of the solubility of cetirizine dihydrochloride in water at pH 3_.4 in the presence of β-cyclodextrin in order 1 to f demonstrate the formation of a complex of 1 inclusion between cetirizine has been examined and ß-cyclodextrin. ~ - Two solutions A and B have been prepared. Solution A containing cetirizine dichloride in water "at pH 3.4 and solution B containing cetirizine dihydrochloride and β-cyclodextrin in a 1: 1 molar ratio in water at pH 3.4 These two solutions have been stirred at room temperature until the thermodynamic equilibrium has been reached - After stirring, no solution is dissolved in the solution other than a very small amount of cetirizine (1 g / l). 100 ml of water) As for solution B, it has allowed to solubilize 27 g / 100 ml of cetirizine in the aqueous phase. [_ On the other hand, β-cyclodextrin is poorly soluble I in water (1.85 g / 100 ml Its solubility increases as cetirizine dihydrochloride is added to a molar ratio of β-cyclodextr-ina / cetirizine of 1: 1. At pH 3.4, the solubility of β-cyclodextrin increases by one factor. of at least 30.

Example 3. Demonstration of the formation of a complex by UV spectroscopy. The formation of a complex of a host with a cyclodextrin is generally translated by a slight shift of the maximum absorption in UV spectroscopy and by a modification of the molar extinction coefficient (J. SZETLI in Cyclodextrin Technology, Chapter 2.2.4.2., Kluwer Academic Publishers, 1988). Different solutions containing different molar ratios of cetirizine dihydrochloride / β-cyclodextrin are prepared and the absorbance differences at 230 n have been determined. In fact, cetirizine in water has a maximum absorption at 230 n in the absence of cyclodextrin. A decrease in the absorbance in I is observed as the absorption maximum as the concentration of β-f cyclodextrin increases. This hypochromatic effect indicates the conformation of an inclusion complex.

Example 4 -_ Competition in the_ formation of a complex with color indicators. In this example, modifications of the visible absorption spectrum of a solution containing a complex between a cyclodextrin and a color indicator are observed, while cetirizine is introduced into the solution. In this case, cetirizine enters into competition with the colored indicator for formation I of an inclusion complex. Modifications of the visible spectrum allow to determine if cetirizine forms an inclusion complex with cyclodextrin. Two acid-base indicators have been used: crystal violet and methyl orange. In the case of acid-base indicatorsModifications of the absorption spectrum due to the formation of complexes with a "cyclodextrin" are often important as long as the formation of the complex causes a modification of the pK of the indicator.If the pH of the solution is close to the pK, the addition of a cyclodextrin to a solution of an acid-base indicator causes ionization or deionization of the indicator, which results in a change in the color of the solution, therefore the maximum absorption of the visible spectrum is shifted according to the degree of complex formation JL When the ele - i cetirizine dihydrochloride is introduced into an aqueous solution containing an acid - base indicator and the β - cyclodextrin, a displacement of the absorption maximum is also observed, indicating on the one hand that the indicator has not been more complex with the ß-cyclodextrin, which means that a part of the β-cyclodextrin has served to form a complex with _ I cetirizina introduced in the medium. (J. SZETLI in Cyclodextrin Technology, Chapter 2.2.4.1., Kluwer Academic Publishers, 1998). 4 The mean value of the association constant of 3292 mol-1 is determined for the competition with the violet crystal and of 3587 mol "1 for the competition with the methyl orange.

Example 5 - Identification of the formation of a complex by proton NMR. Nuclear magnetic resonance (NMR) spectroscopy is usually used to demonstrate the formation of inclusion complexes with cyclodextrins (F. DJEDAINI et B. FERLY in D. DUCHENE, i New Trends in Cyclodextrin and Derivatives, Chap. 6, § t 2 &3. Santé Edition, Paris 1991, F. DJEDAINI et al., J.

Pharm. Sciences, 7_9 (7), 643-6416 (1990)). _ _ _ I In this test, different solutions containing varying molar ratios of ß-cyclodextrin / cetirizine dihydrochloride in a mixture of H20 / D20 9: 1 are analyzed. by proton NMR spectroscopy. The observed regions of the spectrum corresponding to the proton resonance frequency zone 2 to 6.6 '(d = 3.0 to 4.0 ppm) of the β-cyclodextrin and to the resonance frequency zone of aromatic protons of cetirizine (d = 7.2 to 7.6 ppm). A single resonance peak is observed with a mean resonance frequency between the resonance frequency of the free molecule and that of the molecule that is forming a complex for each proton. This means that the analyzed system is in a faster rate of change than the time scale of the NMR measurement. ~ When the amount of cetirizine present in solution with the β-cyclodextrin increases, an important shift towards the raised fields is observed for the protons located inside the hydrophobic cavity of the β-cyclodextrin (protons 3 and 5). On the contrary, the resonance frequencies of the protons located on the outside of the cavity of the β-cyclodextrin _. i (protons 2 and 4) practically do not move. This i clearly demonstrates the formation of a complex! inclusion in the cavity of ß-cyclodextrin. As regards the protons of the zirubycin, it is seen that only the aromatic protons suffer a displacement of their resonance frequency. The complete interpretation is complicated by the screening of the resonance signals of the 9 aromatic protons. This observation indicates the inclusion of the aromatic part of the cetirizine in the cavity of the β-cyclodextrin. In addition, the coefficient of stoichiometry of the complex has been determined by the technique of continuous variation also called "Job method" (see F. i DJEDAINI et al., J. Pharm. Sciences, 79 (7), 643-646 (1990), P. JOB, Ann.Chim., 9, 113-134 (1928) Variation of the chemical shift for the proton of the β-cyclodextrin has been taken as variable, by this method, it is determined that the complex formed has a stoichiometry of 1: 1.

Example 6 - Chewable tablets of polyethylene glycol based on polyols. Cetirizine dihydrochloride (10 parts) and β-cyclodextrin (55 parts) are mixed in the presence of water in a planetary mixer for 20 minutes. In this way, the complex is formed between cetirizine dihydrochloride and β-cyclodextrin. This mixture is then dried in an oven. After drying, the complex is mixed with the following excipients: sorbitol (29.45 parts of Acesulfam K (0.7 parts), Aerosil 200 (0.3 parts), elosa croscara Na (2.1 parts), Glycamil (1.2 parts), licorice flavor (0.25 parts). The mixture is then compressed in a conventional manner.

Example 7 - Cetirizine chewable tablets without polyols. The complex dihydrochloride of cetirizine and of β-cyclodextrin is prepared in the same manner as in example 6. The excipients used are the following: polyvinylpyrrolidone (35 parts), Avicel pH 101 (50 parts), Avicel CE 15 (7 parts) , Aerosil 200 (1 part), Magnesium stearate (1.6 parts), Acesulfam K (1.4 parts), flavorings (2.7 parts).

Example 8 - Cetirizine dry syrup. Two compositions A and B are prepared by mixing the ingredients indicated in the table: Component (in parts) A B Cetirizine.2HC1 5 10 I ß-cyclodextrin 27.5 55 Aroma 0.5 0.5 I Mannitol c.s. 1000 c.s. 1000 The mixture is granulated with water in a planetary mixer and then extruded. The obtained extrudate is dried in a bed with air flow.

- Example 9 - Granules of hydroxazine 1 A composition C is prepared by mixing the ingredients indicated in the table: Component (in parts) _C Hydroxyzine.2HC1 25 ß-cyclodextrin 142 Aroma 2 Saccharose impalpable c.s.p.1000 The mixture is granulated with water in a planetary mixer and then extruded. The extrudate is dried in a bed with air flow.

It is noted that in relation to this date, the best method known to the applicant, to carry out the aforementioned invention is that which is clear from the manufacture of the objects to which the same invention relates. refer. - Having described the invention as above, T is claimed as property contained in the following.

Claims (5)

1. - 1. A solid, orally administered pharmaceutical composition comprising an active substance belonging to the family of the substituted benzhydrylpiperazines and at least one cyclodextrin.
2. 2. Pharmaceutical composition according to claim 1, characterized in that it is in the form of a chewable tablet, of a dry syrup, of granules or of a sublingual tablet.
3. 3. Pharmaceutical composition according to claim 1 or 2, characterized in that the active substance is selected from the group consisting of cetirizine, idroxyzine, efletirizine, meclizine and buclizine, their optically active isomers and their pharmaceutically acceptable salts. I
4. 4. Pharmaceutical compositions according to any one of claims 1 to 3, characterized in that the cyclodextrin is selected from the group consisting of cyclodextrins a, β or β? and f-alkylated or hydroxyalkylated derivatives thereof, such as heptakis (2,6-di-o-methyl) -β-cyclodextrin, randomly ethylated β-β cyclodextrin and hydroxypropyl β-cyclodextrin. I
5. 5. Pharmaceutical composition according to claim 1, characterized in that the molar ratio between the cyclodextrin and the active substance ranges from 1.0 to 4.0.