Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Patent
1998-08-26
2000-12-26
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
424480, 424484, 514272, A61K 922, A61K 936, A61K 914, A61K 31505
Patent
active
061655074
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel sustained-release pharmaceutical formulations containing 2-[[1-[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]piperid-4-yl]methyl amino]-pyrimidin-4-ol or 2-[[1-[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]piperid-4-yl]methyl amino]-pyrimidine-4(1H)-one, or mizolastine, as active principle.
Mizolastine is described in European patent EP 0,217,700.
Mizolastine binds to the H.sub.1 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.
Applicant have based their 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/l at neutral pH) but much more soluble at acidic pH (11 g/l 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:
Applicants have shown that tablets containing 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 to prevent degradation of the product by light, are entirely suitable.
FIG. 1 shows the dissolution profile obtained with a formulation according to the invention;
FIG. 2 shows the dissolution profiled obtained with a formulation identical to that of the invention but containing no L-tartaric acid; and
FIG. 3 shows the curves of the plasma kinetics of a pharmaceutical form according to the invention containing 10 mg of mizolastine studied in a healthy volunteer after a single oral administration, compared with a standard immediate-release gelatin capsule containing 10 mg of mizolastine.
FIG. 4 present the kinetic parameters of the plasma kinetics in table form.
FIG. 5 provides a tabular comparison of the bioavailability of the formulations with and without L-tartaric acid.
DETAILED DESCRIPTION OF THE INVENTION
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, for example C.sub.12 -C.sub.28 long chain fatty acids such as behenic acid, or triglycerides esterified with medium-chain fatty acids, for example C.sub.8 -C.sub.18 fatty acids.
The organic acid preferably having a pK of 2 or more 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 particularly preferred is L-tartaric acid.
The weight ratio between the mizolastine and the organic acid 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 the active principle, the agent constituting the fatty matrix, the organic acid and other excipients such as, for example, lactose, mannitol and sugars or similar sugar-alcohols, microcrystalline cellulose, starch, calcium phosphates and sulphates, polyvidone, and substituted celluloses such as hydr
REFERENCES:
patent: 5681583 (1997-10-01), Conte et al.
patent: 5686105 (1997-11-01), Kelm et al.
Derwent. Mosques, R. et al. Antihistamines for the treatment of nasal congestion. Allergy. 51(31):157, 1996.
Chemical Abstracts, vol. 107, No. 1, 1987, Abstract No. 7211.
Chariot Maryvonne
Lewis Gareth
Montel Jean
Berman Alysia
Page Thurman K.
Synthelabo
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