Pharmaceutical composition for oral administration

 

(57) Abstract:

The invention relates to medicine, specifically to pharmacology. The proposed solid pharmaceutical composition for oral administration containing an active substance from the group of substituted benzhydrylpiperazine and at least one cyclodextrin without the formation of a complex with the active substance, which provides a good bioavailability of the active substance. 4 C.p. f-crystals, 3 tables.

The invention relates to pharmaceutical compositions for oral administration containing an active substance group substituted benzhydrylpiperazine and cyclodextrin.

It is known that many substances belonging to the group of substituted benzhydrylpiperazine, have useful pharmacological properties.

For example, in the United Kingdom patent 817231 the applicant describes substituted benzhydrylpiperazine General formula

< / BR>
in which R and R' denote, independently of each other a hydrogen atom or chlorine or alkyl or CNS group, R and R' may be in ortho-, meta - or paraprotein, and n denotes the number 1 or 2, and their pharmaceutically acceptable salts.

These compounds belong, in particular, 2-[2-[4-[(4- chlorine is known, with antihistaminic properties and the properties of the tranquilizer.

In the European patent 58146 the applicant describes substituted benzhydrylpiperazine General formula

< / BR>
in which L is-HE-or-NH2group, X and X' individually mean a hydrogen atom, halogen atom, linear or branched C1- or4group, m is 1 or 2 and n is 1 or 2, and their pharmaceutically acceptable salts.

Among these compounds 2-[2-[4-[(4- chlorophenyl)-phenylmethyl]-1 - piperazinil]ethoxy]-acetic acid, also known as cetirizine, and its dichlorhydrate, as is well known, possess antihistaminic properties.

To date the only commercially available pharmaceutical compositions for oral administration, containing compounds of this type are those of the traditional type. In the case of coated tablets accept them, swallowing, and at the same time washed down with liquid. When you want to take the medicine without simultaneous fluid intake (before or after surgery, the lack of drinking water and so on), the traditional method is not suitable due to the extremely bitter taste of these substituted benzhydrylpiperazine.

For example, in U.S. patent 3558600 describes a method of masking the bitter taste antihistamine substances related to substituted 1-(p-chlorobenzhydryl) piperazines, consisting in the transfer of the active substance in the free base is liberated too easy to ensure a good absorption in the gastrointestinal tract. In this case, there can be achieved the expected therapeutic effect.

In the European patent 399902 mentioned this dual problem associated with the pharmaceutical compositions for oral administration, namely masking of taste, combined with good bioavailability. This patent describes and lyophilized porous pharmaceutical form, containing, besides the usual for this type of formulations of excipients and additives, active component and the cyclodextrin, as well as methods of preparing these pharmaceutical forms. In examples of embodiments of methods according to the invention describes a pharmaceutical composition containing the following active ingredients: Ketoprofen, trimipramine methanesulfonate, zopiclone (zopiclone), phenobarbital, vitamin a, lemon essence, pristinamycin or vitamin D3.

However, this document cannot be concluded, dig substances of the class of substituted benzhydrylpiperazine this problem is especially important, because, although it is desirable to mask the extremely bitter, unpleasant taste of the active ingredients, it is also significant that they stood out immediately after the introduction, in order to ensure prompt and effective action.

Thus, it is an urgent task of the search for new pharmaceutical compositions that facilitate oral administration of pharmaceutical drugs belonging to the group of the substituted benzhydrylpiperazine compared to modern compositions, but it will provide a good bioavailability of the active substance. When it comes to the search for such formulations, which may be in the form of chewable tablets, dry syrups, granules or tablets under your tongue.

Accordingly, the present invention is to create an oral input of a solid pharmaceutical compositions containing the active substance, which is substituted by benzhydrylpiperazine, and at least one cyclodextrin, without the formation of a complex with the active substance.

Cyclodextrins that can be used in this invention, it is possible to choose from , or-cyclodextrins or their alkyl or hydroxyalkyl derivatives, such as heptanes (2,6-di-o-methyl) - cyclodextrin is about referred to as RAMEB) and hydroxypropyl--cyclodextrin (usually referred to as HPbCD).

Among the active substances related to substituted benzhydrylpiperazine, which will be discussed are, in particular, 2-[2-[4-[(4- chlorophenyl)phenylmethyl] - 1-piperazinil] ethoxy]-acetic acid (cetirizine), 2-[2-[4-[(4- chlorophenyl)phenylmethyl] -1-piperazinil]- ethoxy]ethanol (hydroxyzine), 2-[2-[4-[bis-(4 - forfinal)-methyl] -1-piperazinil]-ethoxy] -acetic acid (efletirizine), 1-[(4-chlorophenyl) -phenylmethyl]-4-[(3 - were)methyl] piperazine (meclizine) or 1-[(4-tert-butylphenyl) methyl]-4-[(4 - chlorophenyl)-phenylmethyl] piperazine (buclizine), their optically active isomers and pharmaceutically acceptable salts.

The pharmaceutical compositions according to this invention can be in various forms for oral administration. In particular, the pharmaceutical compositions according to this invention can be in the form of dry syrups, chewable tablets, granules or tablets under the tongue, which is especially appropriate for oral administration, if not to accept the liquid. Used excipients are conventional fillers used in such compositions.

In the case of dry syrup and granules can be applied thinners, such as polyols (mannitol, sorbitol, sucrose, and so on) and corrigentov.

Mirovaya, for example diluting agents (mannitol, sorbitol and so on ), leavening agents or substances that promote inflammation (polyvinylpyrrolidone, nitrocresols, starches and their derivatives, cellulose and its derivatives), lubricants (magnesium stearate, and so on), substances that contribute to turnover (Aerosil 200, and so on), and flavorings (corrigentov).

In the case of sublingual tablets may apply the above-mentioned fillers from which to choose water-soluble.

No need to prepare a complex of cyclodextrin with an active substance according to the present invention can significantly simplify and reduce the cost of the technology of preparation of pharmaceutical compositions than those used in the preparation of the complex. It can be reduced to a simple mixing of the active substance and cyclodextrin together with other excipients and adjuvants.

The following experiments illustrate the invention without limiting it. In these experiments, the composition is given in weight parts.

Example 1. Test the degree of bitterness.

Prepare various solutions, adding a cyclodextrin to a solution of cetirizine dihydrochloride with a concentration of 2 mg/ml so that the molar ratio of the ditch was tested in a group of 7 people.

The results of this test are given in table 1.

Reducing the bitterness of cetirizine dihydrochloride is observed when the solution of cetirizine dihydrochloride add-cyclodextrin. This reduction is particularly noticeable when the molar ratio of cyclodextrin and cetirizina diclorhidrato ranges from 1.0 to 4.0.

Example 2. Test solubility.

The solubility of hydrophobic molecules in water is increased in the presence of cyclodextrins. This applies to both the dissolution rate and the amount of dissolved active substance. This change of water solubility of hydrophobic active substances in the presence of cyclodextrin is the usual way to prove the formation of inclusion complex (see J. Szetli, V. F. Smolen and L. A. Ball, Controlled Drug Bioavailability, vol 3, Wiley, New York (1985), 365-420).

Although the cetirizine dihydrochloride it is soluble in water at neutral pH, its solubility is significantly reduced when the pH in the range between 2.5 and 3.5 (solubility of about 1 g/100 ml). In this test examined the change in the solubility of cetirizine hydrochloride in water at pH 3.4 in the presence of-cyclodextrin in order to show the formation of inclusion complex between cetirizine and-cyclodextrin.

G is n dihydrochloride and-cyclodextrin in a molar ratio of 1: 1 in water at a pH of 3.4. These two solution was stirred at room temperature until the establishment of thermodynamic equilibrium.

After stirring only a very small amount of cetirizine (1 g/100 ml water) is in solution A. on the other hand, in the aqueous phase of a solution dissolved In 27 g/100 ml

Moreover, the cyclodextrin laboratory in water (1.85 g/100 ml). Its solubility increases gradually as the addition of cetirizine dihydrochloride until the molar ratio of cycloketocain/cetirizine of 1:1. At pH 3.4 solubility-cyclodextrin increases at least 30 times.

Example 3. Evidence of complex formation by means of UV-spectroscopy.

The formation of complex molecules of the basic substance (molecule-master) with cyclodextrin is usually expressed in a weak shift of the maximum absorption in the UV spectrum and/or the change of molar absorption coefficient (J. Szetli in Cyclodextrin Technology, Chapter 2.2.4.2, Kluwer Academic Publishers, 1988).

Prepare solutions with different molar ratio of the cetirizine dihydrochloride/-cyclodextrin and determine the difference absorption at 230 nm. The reason is that in maximum water absorption of cetirizine in the absence of cyclodextrin the maximum absorption with increasing concentration of cyclodextrin. This gipohloremicski effect indicates the formation of inclusion complex.

Example 4. Competitive complexation with colored indicators.

In this example, the observed changes in the absorption spectrum in the visible region of the solution containing the complex of cyclodextrin and a color indicator when added to a solution of cetirizine. In this case cetirizine competes in the formation of inclusion complex with a color indicator. Changes in the spectrum of the visible region, thus, provide an opportunity to determine forms whether cetirizine, the inclusion complex with cyclodextrin or not.

Use two acid-base indicator - crystal violet and methyl orange. In the case of acid-base indicator that changes in the absorption spectrum due to the formation of a complex with cyclodextrin often large, reflected in the fact that the complexation leads to a change in RK indicator. If the pH of the solution close to the RoK, adding cyclodextrin to a solution of an acid-base indicator causes the dissociation of the indicator molecules to ions or their Association, indicated by a color change of the solution. Accordingly, the maximum absorption in the visible region offset the aqueous solution, containing the acid-base indicator and a-cyclodextrin, also observed shift of the maximum, this indicates that part of the indicator is no longer forms a complex with the cyclodextrin. This means that part-cyclodextrin is involved in the formation of the complex with cetirizine added to the environment (J. Szelti in Cyclodextrin Technology, Chapter 2.2.4.1, Kluwer Academic Publishers, 1988).

Found the average value of the dissociation constants is 3292 mol-1in the case of competition with crystal violet and 3587 mol-1in the case of competition with methyl orange.

Example 5. Evidence of complex formation method1H NMR.

Spectroscopy nuclear magnetic resonance (NMR) is usually used to prove the formation of inclusion complexes with cyclodextrins (F. Djedaini Century and Perly in D. Duchene, New Trends in Cyclodextrin and Derivatives, Chap. 6, 2 and 3, Edition de Santu, Paris 1991, F. Djedaini et al. J. Pharm. Sciences, 79 (7), 643-646 (1990)).

In this example, the solutions with varying molar ratios of b-cyclodextrin/citiesunlimited in a mixture with a ratio of H2O/D2O equal to 9: 1, analyse method1H NMR. Signals are observed in the region of resonance frequencies corresponding to protons 2 and 6.6' (d = from 3.0 to 4.0 M. D.) -cyclade.

For every proton there is only one signal in the middle of the resonance frequencies between the resonance frequencies of the free molecules and those molecules of the complex.

This means that the exchange rate is analyzed in the system of higher frequency RF field NMR.

When the number of cetirizine in solution with a-cyclodextrin increases, there is a strong shift in the strong field of signals from protons located inside the hydrophobic part of the molecule-cyclodextrin (protons 3 and 5). On the other hand, the signals (resonance frequency) of the protons located on the outside of the molecule-cyclodextrin (protons 2 and 4), virtually unchanged. This clearly confirms participation-cyclodextrin in the formation of inclusion complex. As for the protons of cetirizine, is found to change only the signals of aromatic protons. Full interpretation of the spectrum is difficult due to overlapping signals 9 aromatic protons. This observation indicates that the aromatic protons of cetirizine included in the field-cyclodextrin.

In addition, the stoichiometric coefficient for the complex is determined by the method of continuous variations, also called the "method of job" (Job) (see F. Djedaini et a is codextron. By this method it was found that the stoichiometry of the complex is 1:1.

Example 6. Chewable tablets cetirizine-based polyols.

Of the cetirizine dihydrochloride (10 parts) and-cyclodextrin (55 parts) are mixed in the presence of water using a planetary mixer for 20 minutes. This forms a complex of cetirizine dihydrochloride and-cyclodextrin. Then this mixture is dried in a drying Cabinet.

After drying, the complex is mixed with the following excipients: sorbitol (29,45 parts), Acesulfam K (0.7 parts), Aerosil 200 (0.3 part), nutritionnelles (2.1 part), glycemil (part 1,2), Supplement with a taste of licorice (0,25).

The mixture is then tabletirujut in the usual way.

Example 7. Chewable tablet cetirizine, not containing polyols.

The complex of cetirizine dihydrochloride and-cyclodextrin prepared as in example 6.

The following fillers:

Polyvinylpyrrolidone (35 casts); Avicel pH 101 (50 parts), Avicel CE 15 (7 parts), Aerosil 200 (1 part), magnesium stearate (1,6 part), Acesulfam K (1.4 parts), flavorings (2,7).

Example 8. Dry syrup of cetirizine.

Prepare two compositions a and b by mixing the ingredients shown in table 2.

Example 9. Granules hydroxyzine.

The composition is prepared by mixing the ingredients according to table 3.

From a mixture of preparing granules with water using a planetary mixer and then extruded. The extrudate is kept in the fluidized bed.

1. Solid pharmaceutical composition for oral administration containing an active substance from the group of substituted benzhydrylpiperazine, characterized in that it contains at least one cyclodextrin without the formation of a complex with the active substance.

2. The pharmaceutical composition under item 1, characterized in that it has the form of chewable tablets, dry syrup and granules or sublingual tablets.

3. The pharmaceutical composition under item 1 or 2, characterized in that the active substance is selected from the group consisting of cetirizine, hydroxyzine, efletirizine, meclizine and buclizine, their optically active isomers and pharmaceutically acceptability of salts.

4. The pharmaceutical composition according to any one of paragraphs. 1-3, characterized in that the cyclodextrin is selected from the group consisting of -, - or-cyclodextrins and their alkyl or hydroxyalkyl derivatives, such as heptanes (2,6-di-o-methyl--cyclodextrin, P> 5. The pharmaceutical composition according to any one of paragraphs. 1-4, characterized in that the molar ratio of the cyclodextrin and the active substance is 1.0 to 4.0.

 

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EFFECT: improved preparing method, valuable biochemical and medicinal properties of compounds.

14 cl, 36 ex

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