MXPA01012225A

MXPA01012225A - Novel formulations comprising lipid-regulating agents.

Info

Publication number: MXPA01012225A
Application number: MXPA01012225A
Authority: MX
Inventors: Devalina Law
Original assignee: Abbott Lab
Priority date: 1999-05-28
Filing date: 2000-05-23
Publication date: 2002-08-12
Also published as: JP2003500439A; EP1183017A1; WO2000072829A1; CA2374117A1

Abstract

The present invention is directed to a solid formulation comprising the mixture of a lipid-regulating agent and an excipient, in which said agent and said excipient form a eutectic mixture.

Description

FORM ULACION IS NOVEDOSAS WHAT THEY BUY D IN AGENTS REGÍADORES DE LÍPI DO CAM PO OF THE INVENTION The present invention relates to novel formulations comprising lipid regulating agents.

BACKGROUND OF THE INVENTION The 2- [4- (4-chlorobenzoyl) phenoxy] -2-methylpropanoic acid methyl ester, also known as fenofibrate, is representative of a broad class of compounds which have pharmaceutical utility as lipid regulating agents. More specifically, this compound is part of a class of compounds lipid regulating agents, commonly known as fibrates, and is described in US Patent No. 4,058,552. Fenofibrate has been prepared in several different formulations; see U.S. Patent No. 4,800,079 and U.S. Patent No. 4,895,726. U.S. Patent 4,895,726 describes a co-micronized formulation of fenofibrate and a solid surfactant. U.S. Patent No. 4,961,890 describes a process for preparing a controlled release formulation, . a.tj containing fenofibrate in an intermediate layer, in the form of crystalline microparticles included within the pores of an inert matrix. The formulation is prepared by a process comprising the sequential steps of wetting the inert core with a solution based on the binder; then project the fenofibrate microparticles in a single layer, over the moistened core, and then dry before the binder-based solution dissolves the fenofibrate particles, and repeat these three steps in sequence until the intermediate layer is formed. European Patent Application No. EPO 793958 A2 describes a process for producing a solid dosage form of fenofibrate, which uses fenofibrate, a surfactant and polyvinylpyrrolidone, where the fenofibrate particles are mixed with a solution of polyvinylpyrrolidone. The mixture thus obtained is granulated with an aqueous solution of one or more surfactants, and the granules thus produced are dried. The publication of TCP No. WO 82/01649 describes a fenofibrate formulation having granules consisting of a neutral core which is a mixture of sucrose and starch. The neutral core is covered with a first layer of fenofibrate, mixed with an excipient, and with a second microporous outer layer of an edible polymer. U.S. Patent No. 5,645,856 describes the use of a carrier for hydrophobic drugs, which includes J iiU fenofibrate; and pharmaceutical compositions based thereon. The carrier comprises a digestible oil and a pharmaceutically acceptable surfactant component to disperse the oil in vivo when the carrier is administered; comprising a hydrophobic surfactant agent; the surfactant component being such that it does not substantially inhibit the in vivo lipolysis of the digestible oil. Sheu, M. T. and co-authors, Int. J. Pharma. , 103 (1994) 1 37-146, reported that it is possible that the increase in the rate of dissolution, obtained by PEG 6000, could be due to the 10 Reduction in particle size and / or increase in wetting capacity. Palmieri, G. F., Pharma Sciences 6 (1966), 188-194, reported that solid drug solutions are formed when the amount of fenofibrate present in the powder is less than 15%. 15 percent, and the solubility of the drug is increased by the formation of a solid dispersion, particularly for the carrier: drug ratio of 90: 1. Gemfibrozi is another member of the fibrate class of lipid regulating agents. U.S. Patent No.

No. 4,927,639 discloses a disintegrable gemfibrozil formulation, which provides both immediate and sustained release, comprising a tablet compressed from a mixture of a first and a second granulation, and a disintegrating excipient operable to effect partial or complete disintegration in the 25 stomach. The first granulation comprises particles finely ^ ^. ^ aa. .i »-. divided from pure gemfibrozil, granulated with at least one cellulose derivative; and the second granulation comprises finely divided particles of pure gemfibrozil, granulated with a pharmaceutically acceptable, water soluble or insoluble polymer, which is then uniformly coated with a pharmaceutically acceptable (meth) acrylate copolymer, before being mixed with the first granulation. The first and second granulations are present in the final composition in an approximate ratio of 10: 1 to 1:10. U.S. Patent No. 4,925,676 discloses a disintegrable gemfibrozil tablet that provides immediate and enteric release, which is compressed from a mixture of a first granulation of gemfibrozil with at least one binder disintegrable with acid, and a second granulation formed from the first granulation, but again granulated or coated with an alkali-disintegrable formulation, of at least one polymer substantially soluble in alkali and substantially insoluble in acid. Another class of lipid regulating agents is commonly known as statins, of which pravastatin and atorvastatin are members. U.S. Patents 5,030,447 and 5,180,589 describe stable pharmaceutical compositions which, when dispersed in water, have a pH of at least 9, and include a medicament that is sensitive to a low pH environment, such as pravastatin; one or more fillers, such as lactose and / or microcrystalline cellulose; one or more binders, such as microcrystalline cellulose (dry binder) or polyvinylpyrrolidone (wet binder); one or more disintegrating agents, such as croscarmellose sodium; one or more lubricants, such as magnesium stearate, and one or more basifying agents, such as magnesium oxide. It is an object of the present invention to provide formulations of lipid regulating agents having increased bioavailability, as compared to commercially available formulations.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to a solid formulation comprising the mixture of a lipid regulating agent and an excipient, such as polyethylene glycol, in which the agent and excipient form a eutectic mixture. The reduction in size obtained during the preparation of a dispersion is usually difficult to obtain. However, using a melting technique or a solvent evaporation technique, a dispersion of the crystalline lipid regulating agent is prepared in the excipient; so that the agent and the excipient form a eutectic mixture.

The resulting formulation results in an increase in the solubility of the drug and oral bioavailability, and an improved dissolution rate.

"- • - • - '^ -» "- The formulation can be administered directly, diluted in a suitable vehicle for administration, encapsulated in hard gelatin capsules or capsules, or compressed to tablets for administration; or it can be administered by other means, obvious to those who are experts in the field.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph showing plasma concentration in dogs fed the formulation of Example 1 and with a reference compound.

DETAILED DESCRIPTION OF THE INVENTION The bulk lipid regulating agent can be prepared by any available means, such as, for example, the fenofibrate compound can be prepared by the process described in US Patent No. 4,058,552, or by the process described in U.S. Patent No. 4,739,101, both incorporated here by means of this reference. The composition comprising the lipid regulating agent and the excipient is first determined, in such a ratio, that the melting point of the lipid regulating agent and the excipient are reduced to a single value, below the melting point 1 j. of any of the components. This composition, that is, the composition in which the two components exhibit a single melting point, is called a eutectic mixture. A composition of the lipid regulating agent and excipient, ranging from about 0.5% (w / w) to 10% above the eutectic mixture, is then heated to a temperature sufficient to obtain a clear solution. Then the solution is cooled until a solid mass is formed. As an alternative method, these components in the composition scale 10 mentioned above can be dissolved in a suitable solvent to obtain a clear solution. In this last case it is necessary to separate the solvent to obtain the solid mass. The solid mass is then ground, brought to the desired size and, optionally, formulated into an appropriate delivery system. The delivery system of the present invention results in an increased dissolution rate and greater bioavailability, and an improved dissolution rate of the lipid regulating agent. The term "eutectic mixture" refers to a system 20 biphasic crystalline having a melting point that is lower than that of any of the pure components of the mixture. The presence of a eutectic mixture can be determined by thermal analysis and X-ray powder diffractometry. Suitable excipients include, for example: 25 polyethylene glycol (PEG), pentaerythritol, pentaerythritol tetraacetate, S &R-S succinic acid, urea, polyoxyethylene stearates and poly-e-caprolactone or, more preferably, PEG. If a solvent evaporation technique is used, suitable solvents include, for example: methanol-water, ethanol-water or other water-miscible organic solvent, in which the lipid-regulating agent and the polymers have appreciable solubility. Other pharmaceutically acceptable excipients may be added to the formulation before forming the desired final product. Suitable excipients include, for example, lactose, starch, magnesium stearate or other fillers, other diluents, lubricants or pharmaceutically acceptable disintegrants, which may be necessary to prepare a capsule or tablet. The resulting composition comprising the lipid regulating agent can be dosed directly for oral administration, can be diluted in a vehicle suitable for oral administration, can be introduced into capsules or formed into tablets for oral administration, or can be supplied by other obvious means for those who are experts in the field. Said composition can be used to improve oral bioavailability and solubility of the lipid regulating agent. The invention will be understood more clearly from the following representative, non-limiting examples: EXAMPLE 1 Fenofibrate and PEG were heated at a ratio of 15:85, at about 85 ° C until a clear solution was obtained. The solution was then cooled on an ice bath, which resulted in the formation of a solid mass. The resulting dry, solid mass was then ground and milled to a size passing through a 60-100 mesh screen. 446.7 mg of the granulated formulation (containing 67 mg fenofibrate) was introduced into 10 individual capsules EXAMPLE 2 Mixtures of a statin and PEG are prepared and the melting point of each of these mixtures is determined to locate the eutectic composition. The statin and PEG are then melted in a ratio which, preferably, is approximately 10 percent greater than the eutectic composition, to obtain a clear solution; The solution is then cooled in an ice bath to form a solid mass. This solid mass is milled and sieved between 60 and 100 mesh, and filled into capsules containing the appropriate desired dose.

EXAMPLE 3 25 * -wr i _J Capsules prepared by the process described in Example 1 were administered, and from a commercial composition of fenofibrate, Lipanthyl 67M (Groupe Fournier) (as a reference), to a group of dogs, at a dose of 67 mg fenofibrate / dog. The concentrations of fenofibric acid in the plasma were determined by means of HPLC. The concentrations were normalized at a dose of 6.7 mg / kg in each dog. Figure 1 presents the resulting data in the form of a graph. The results provided as the mean ± standard deviation were the following: 10 Lipanthyl 67M (reference): Cmax = 2.83 ± 1.40 mcg / ml Tmax = 1.7 ± 0.6 hr t1 / 2 = 14.5 hr AUC (0-24) = 16.36 ± 6.93 mcg.hr/ml 15 Capsule of example 1: Cmax = 5.20 ± 1.15 mcg / ml Tmax = 1.3 ± 0.6 hr t1 / 2 = 10.8 hr AUC in relation to the reference = 149.08% & "R -" "-f ?? - k

Claims

1. - A composition, characterized in that it comprises the mixture of a lipid regulating agent and an excipient; where the agent and the excipient form a eutectic mixture.

2. A composition according to claim 1, further characterized in that the lipid regulating agent is present in the composition in an amount ranging from approximately 0.5% w / w to 10% w / w, above the eutectic mixture. .

3. A composition according to claim 1, further characterized in that the lipid regulating agent is a fibrate.

4. A composition according to claim 3, further characterized in that the fibrate is fenofibrate.

5. A composition according to claim 1, further characterized in that the lipid regulating agent is a statin.

6. A composition according to claim 5, further characterized in that the statin is prevastatin.

7. A composition according to claim 5, further characterized in that the statin is atorvastatin.

8. - A composition according to claim 1, further characterized in that the excipient is selected from polyethylene glycol, pentaerythritol, pentaerythritol tetraacetate, succinic acid, urea, polyoxyethylene stearates and poly-e-caprolactam.

9. A composition according to claim 8, further characterized in that the excipient is polyethylene glycol.

10. A supply system, characterized in that it comprises a composition of claim 1. 11 - A supply system according to claim 10, further characterized in that the delivery system is a capsule or a tablet. 12. A method for treating hyperlipidemia, characterized in that it comprises administering to a patient a composition of claim 1. 13. A method for treating hyperlipidemia, characterized in that it comprises administering to a patient a composition of claim 4. 14.- A method for treating hyperlipidemia, characterized in that it comprises administering to a patient a composition of claim 11. ., .... jfc. ",