Title of Invention	SUSTAINED-RELEASE PHARMACEUTICAL FORMULATIONS CONTAINING MIZOLASTINE
Abstract	The present invention discloses sustained-release pharmaceutical formulation containing mizolastine, characterized in that it contains a core formed of a sustained-release tablet containing mizolastine combined with a fatty matrix and with an organic acid the said tablet being coated.

Full Text

The present invention relates to novel sustained-release pharmaceutical formulations containing 2-[[l-[1-[(4-fluorophenyl) methyl]-lH-benzimidazol-2-yl]piperid-4-yl]methylamino]-pyrimidin-4-ol or 2-[[l-[l-[(4-fluorophenyl)methyl]-lH-benzimidazol-2-yl] piperid-4-yl] methylamino]-pyrimidine-4(lH)-one, or mizolastine, as active principle. This application is divided out of our patent Application No.358CAL97. Mizolastine is described in European patent EP 0,217,700. The chemical structure of Mizolastine is : Mizolastine binds to the Hi histamine receptor and inhibits the degranulation of mastocytes in vitro and in vivo. It can thus be used for the treatment of respiratory, cutaneous or ocular allergies and various allergic manifestations. During the oral administration of immediate-release formulations containing mizolastine, undesirable sedative effects have been observed which are associated with the existence of a high peak in the plasma. Consequently, it was necessary to find formulations for an oral administration which have a profile of release of the active principle such that it is possible to obtain a lower peak in the plasma without decreasing the bioavailability. The Applicant Company has based its research of such formulations on the study of the kinetics of dissolution of mizolastine. The reason for this is that mizolastine is a weak base (pK 5.6) which is sparingly soluble in water (13 mg/1 at neutral pH) but much more soluble at acidic pH (11 g/1 at pH 3); the first gelatin capsules released 100 % of mizolastine over 30 minutes in a dissolution medium at pH 2 whereas only 40 % were dissolved at pH 6.8. Moreover, the release of mizolastine from the sustained-release pharmaceutical form according to the invention did not need to be influenced by the differences in pH in the gastrointestinal tract. The aim of the present invention is to propose formulations containing mizolastine whose dissolution profile is as follows: - about 30 to 70 % of mizolastine dissolved in 1 hour, - 100 % of mizolastine dissolved in 3 to 5 hours, and - pH-independent profile. The Applicant Company has shown that tablets containing a core formed of a sustained-release tablet containing mizolastine combined with a fatty matrix and with an acid of low pK, the said tablet being coated to prevent degradation of the product by light, are entirely suitable. Accordingly, the present invention provides a sustained-release pharmaceutical formulation containing mizolastine, characterized in that it contains a core formed of a sustained-release tablet containing mizolastine combined with a fatty matrix and with an organic acid, the said tablet being coated. The tablets according to the invention contain from 1 mg to 25 mg of mizolastine. These doses correspond to concentrations of from 0.5 % to .12 % by-weight of mizolastine. The fatty matrix is made with hydrogenated castor oil or with hydrogenated lecithins or long-chain fatty acids such as behenic acid or triglycerides esterified with medium-chain fatty acids, for example C8-C18 fatty acids. The acid of low pK is chosen from maleic, tartaric, malic, fumaric, lactic, citric, adipic and succinic acids in the form of racemates or isomers. According to the invention, the acid 10 particularly preferred is L-tartaric acid. The weight ratio between the mizolastine and the acid of low pK should be between 0.3 and 1. With L-tartaric acid, this ratio is preferably equal to 0.5. The tablets are prepared by granulation using 15 the active principle, the agent constituting the fatty matrix, the acid of low pK and other excipients such as, for example, lactose, mannitol and sugars or similar sugar-alcohols, microcrystalline cellulose, starch, calcium phosphates and sulphates, polyvidone, 20 and substituted celluloses such as hydroxypropyl- cellulose, hydroxypropylmethylcellulose or methylcellulose. The granulation may be carried out in a wet phase, for example in the presence of water or alcohol, 2 or may be performed by fusion or by compacting. The granulation step may optionally be left out and the tablets prepared by direct tableting of the mixture .of mizolastine and the excipients. Anhydrous colloidal silica and magnesium stearate are added to the granules obtained and the mixture is tableted. The tablets are then covered with a coating film by spraying them with a coating solution 5 in a machine with a fluidized-air bed or in a coating turbine. The example which follows illustrates the invention without limiting it: Tablet 11) ¦ % (weight) mizolastine 4.8 hydrogenated castor oil 12.0 lactose 60.0 microcrystalline cellulose 9.6 1) L-tartaric acid 9.6 polyvidone 2.9 anhydrous colloidal silica 0.2 magnesium stearate 0.9 purified water Q.S. 2) Total 100.0 Coating methylhydroxypropylcellulose 74.0 titanium dioxide (E171) 18.5 propylene glycol 7.5 2 5 purified water " .Q.S. Total 100.0 The dissolution profile obtained with a formulation according to the invention is given in Figure 1. This profile gives about 50 % of product 5 dissolved in 1 hour, 100 % of product dissolved in 3 to 5 hours, and it is independent of the pH. The dissolution profile obtained with a formulation identical to that of the invention but containing no L-tartaric acid is given in Figure 2. 10 The plasma kinetics of a pharmaceutical form according to the invention containing 10 mg of mizolastine were studied in a healthy volunteer after a single oral administration, compared with a standard immediate-release gelatin capsule containing 10 mg of 15 mizolastine. Table 1 presents the kinetic parameters and Figure 3 the curves of the plasma kinetics, obtained respectively with each formulation; the plasma kinetics obtained with the pharmaceutical form according to the 20 invention makes it possible to prevent any peak in the plasma without losing bioavailability. The plasma kinetics of a pharmaceutical form according to the invention were also studied in comparison with the same formulation without L-tartaric 25 acid. The study was performed on twelve healthy volunteers after a single oral administration of a tablet according to the invention containing 10 mg of mizolastine or the same tablet without L-tartaric acid. Table 2 shows that the bioavailability of the formulation containing no L-tartaric acid represents only 43 % of that observed with the formulation according to the invention containing L-tartaric acid. The values of Cmax and the AUC values (0-8) are respectively 1.5 and 2 times as high for the formulation containing L-tartaric acid as for that not containing any. In addition, for the formulation with L-tartaric acid, the min.-max. variation indices are much lower, which suggests great uniformity in the release. The results altogether show that the formulations according to the invention have: - a pH-independent dissolution profile, - an in vivo release which prevents any peak in the plasma, - a bioavailability which is not decreased relative to an immediate-release formulation, - lower variability of the plasma kinetics results. WE CLAIM: 1. Sustained-release pharmaceutical formulation containing mizolastine, characterized in that it contains a core formed of a sustained-release tablet containing mizolastine combined with a fatty matrix and with an organic acid, the said tablet being coated. 2. Sustained-release pharmaceutical formulation as claimed in claim 1, wherein the weight ratio between the mizolastine and the organic acid is between 0.3 and 1. 3. Sustained-release pharmaceutical formulation as claimed in either of claims 1 or 2, wherein the fatty matrix is made with hydrogenated castor oil or with hydrogenated lecithins or long-chain fatty acids or triglycerides esterified with medium-chain fatty acids. 4. Sustained-release pharmaceutical formulation as claimed in any one of claims 1 to 3, wherein the organic acid is chosen from maleic, tartaric, malic, fumaric, lactic, citric, adipic and succinic acids in the form of racemates or isomers. 5. Sustained-release pharmaceutical formulation as claimed in any one of claims 1 to 4, wherein the organic acid is L-tartaric acid. 6. Sustained-release pharmaceutical formulation as claimed in claim 5, wherein the ratio between the mizolastine and the L-tartaric acid is 0.5. 7. Formulation as claimed in any one of claim 1 to 6, wherein it contains from 1 to 25 mg of mizolastine. 8. Sustained-release pharmaceutical formulation containing mizolastine, substantially as herein described, particularly with reference to the foregoing examples, and as illustrated in the accompanying drawings. The present invention discloses sustained-release pharmaceutical formulation containing mizolastine, characterized in that it contains a core formed of a sustained-release tablet containing mizolastine combined with a fatty matrix and with an organic acid, the said tablet being coated.

Documents:

00079-cal-2001-abstract.pdf

00079-cal-2001-claims.pdf

00079-cal-2001-correspondence.pdf

00079-cal-2001-description complete.pdf

00079-cal-2001-drawings.pdf

00079-cal-2001-form 1.pdf

00079-cal-2001-form 13.pdf

00079-cal-2001-form 2.pdf

00079-cal-2001-form 3.pdf

00079-cal-2001-form 5.pdf

00079-cal-2001-form-18.pdf

00079-cal-2001-gpa.pdf

00079-cal-2001-letters patent.pdf

00079-cal-2001-priority document others.pdf

00079-cal-2001-priority document.pdf

00079-cal-2001-reply f.e.r.pdf

79-CAL-2001-FORM-27.pdf