JP5134818B2 - Method for the manufacture of lipid controlled drug formulations - Google Patents

Description

  The present invention relates to a novel process for producing solid formulations of lipid controlled drugs.

  2- [4- (4-Chlorobenzoyl) phenoxy] -2-methyl-propanoic acid 1-methylethyl ester, also known as fenofibrate, has a wide variety of pharmaceutical utilities as lipid control drugs. It is representative of compounds. More specifically, this compound is one of the lipid-regulating drug compounds commonly known as fibrate and is disclosed in US Pat. No. 4,058,552.

  Fenofibrate has been manufactured in several different formulations, see US Pat. No. 4800079 and US Pat. No. 4,895,726. A formulation of finely ground fenofibrate and solid surfactant is disclosed in US Pat. No. 4,895,726.

  U.S. Pat. No. 4,961,890 discloses a method for producing a controlled release formulation in which fenofibrate is in the form of fine particles in an intermediate layer and contained in an inert matrix pore. This formulation wets the inert core with a binder-based solution, then extrudes fenofibrate microparticles onto the moistened core, and then the fenofibrate microparticles are a binder-based solution. It is produced by a method comprising sequential steps of drying before dissolving in and repeating the above three steps until an intermediate layer is formed.

  European Patent Publication No. 793958 discloses a method for producing a fenofibrate solid preparation using fenofibrate, a surfactant, and polypinylpyrrolidone, wherein the fenofibrate microparticles are mixed with a polypinylpyrrolidone solution. Mix. The mixture thus obtained is granulated with one or more aqueous surfactant solutions, and the particles thus produced are dried.

  PCT Publication WO 82/01649 discloses a fenofibrate formulation consisting of particles comprising a neutral core that is a mixture of sucrose and starch. The neutral core is coated with a first layer of fenofibrate mixed with excipients and a microporous second outer layer of edible polymer.

  US Pat. No. 5,645,856 discloses the use of carriers for hydrophobic agents including fenofibrate, and pharmaceutical compositions based thereon. The carrier comprises a digestible oil and a surfactant component consisting of a pharmaceutically acceptable hydrophilic surfactant for dispersing the oil in vivo upon administration of the carrier, the surfactant component being a fat component in vivo of the digestible oil. It is a class that does not substantially inhibit degradation.

  US Pat. No. 6,383,517 describes a solid formulation of fenofibrate comprising dissolving fenofibrate in a surfactant solution, mixing the excipients, wet granulating the mixture, drying and forming the final dosage form. A method of manufacturing is disclosed.

  Prior art methods obtain fine particles of fenofibrate and / or require the presence of a surfactant by using a step of comminuting together. These methods result in formulations that may not exhibit maximum dissolution properties and may cause gastrointestinal inflammation.

  It is an object of the present invention to exhibit dissolution and absorption characteristics comparable to particles of similar drugs produced by the prior art without the need to micronize lipid controlled drugs or use surfactants. It is to provide lipid control drugs of small particles, more preferably fenofibrate.

  The present invention is directed to a method for producing a solid formulation of a lipid controlled drug.

  This method involves dissolving a lipid-controlling drug in a surfactant-free solvent, premixing one or more excipients into a mixture, wet granulating the lipid-controlling drug solution and premix. Forming a granulated drug mixture and drying the mixture. The dry granulation mixture may then be sized to form the final dosage form.

  The mixture may be granulated by techniques well known in the prior art, preferably by a fluidized bed or by a low shear or high shear mixer.

  The final oral dosage form is prepared as a final oral dosage form, preferably a tablet or capsule, by adjusting the particle size of the mixture by techniques well known to those skilled in the art, and dry-mixing the resulting particles with excipients. May be.

  The formulation thus prepared can be administered directly as a granulated product, diluted in a suitable medium for administration, encapsulated in a hard gelatin shell or capsule for administration, or the skilled artisan. May be administered by other methods obvious.

  The lipid control drug may be any suitable and pharmaceutically active compound, preferably a fibrate, more preferably a fenofibrate.

  The lipid-controlled drug bulk can be produced by any possible method, for example, the fenofibrate compound can be prepared by the means disclosed in US Pat. No. 4,658,552 or US Pat. No. 4,739,101 (both by reference). Which is incorporated by reference herein).

  Next, the lipid-controlling drug is added to a solution containing a suitable solvent such as acetone, methylene chloride, ethanol or chloroform, and the lipid-lowering agent is 0.5 to 8.0, preferably 1.0 to 5.0 parts by weight. Dissolve so that

  Excipient premixes are produced by conventional methods. Suitable excipients include, for example, binders, fillers, and disintegrants such as lactose, starch, polyvinyl pyrrolidone, sodium starch glycolate and crystalline cellulose.

  Next, the lipid control drug solution and excipient premix are combined and mixed. The resulting mixture is then granulated, for example in a fluidized bed or low or high speed shear mixer, and well-known solvent evaporation techniques such as spray drying, fluidized bed, tray drying, rotary spraying. Drying by rotating disk drying method or evaporation method under atmospheric pressure or reduced pressure. The resulting material may then be sized, if necessary, to form the final dosage form, such as a tablet or capsule, by conventional techniques such as direct compression or other methods.

  Excluding surfactants reduces raw material and funding costs, facilitates production, has the potential to reduce gastrointestinal side effects, and provides a method that may make tablets and capsules easier to manufacture. It is done. The invention will be more clearly understood by the following non-limiting exemplary examples.

Fenofibrate (25 g) was dissolved in 10 mL of acetone. Anhydrous lactose (67 g), popidone K30 (4 g), and sodium starch glycolate (4 g) were premixed. The premix was granulated with the above solution. The wet granules were tray dried overnight in a dryer of about 40-55 ^> C. The dried granules were sieved through a screen and the 30-120 mesh portion was collected and filled into hard gelatin capsules.

The in vitro dissolution rate of the capsules was compared with the rate of Ripanple, a commercial capsule product containing the same amount of active ingredient as the reference product. A United States Pharmacopeia Type II device was used for testing. Test conditions were paddle speed = 50 rpm, dissolution test solution = 50 mM SDS solution, temperature = 37 ^> C. Eluted samples were taken at predetermined time points and analyzed at 286 nm by UV spectroscopy.

Fenofibrate (25 g) was dissolved in 10 mL of acetone. Anhydrous lactose (57 g), Aircel pH 101 (10 g), popidone K30 (4 g), and sodium starch glycolate (4 g) were premixed. This premix was mixed with the solution. The wet mass was tray dried in a 40-55 ^> C dryer.

  The dried solid was pulverized and sieved through a screen to recover a 30-120 mesh portion. The collected particles were filled into hard gelatin capsules.

The in vitro dissolution rate of the capsules produced in Examples 1 and 2 was compared to the rate of Ripanple, a commercial capsule product containing the same amount of active ingredient as the reference product. A United States Pharmacopeia Type II device was used for testing. Test conditions were paddle speed = 50 rpm, dissolution test solution = 50 mM SDS solution, temperature = 37 ^> C. A 5 mL elution sample was removed at a given time and examined at 286 nm by UV spectroscopy.

The in vitro dissolution profiles of the reference capsule and the capsule of the present invention are shown in FIG. This data shows that the elution rate of a representative capsule of the present invention is comparable to that of a reference capsule. Based on US Pat. No. 4,895,726, in vitro elution results can be correlated with in vivo absorption in humans. Thus, in vitro equivalent or increased elution can result in bioavailability comparable to a reference product in humans.

2 is a graph showing elution characteristics of a representative composition produced by the method of the present invention and a prior art composition.

Claims (14)

Dissolving a fibrate in a surfactant-free solvent to form a drug solution, wherein the drug solution comprises the fibrate and the solvent;
Premixing excipients to form a mixture;
A method for producing a drug formulation, comprising wet granulating the mixture and the drug solution to form a granulated drug mixture, and drying the granulation mixture. The method of claim 1 , wherein the fibrate is fenofibrate.   The method of claim 1, wherein the drying step comprises evaporating the solvent. The method of claim 3 , wherein the evaporating is performed under reduced pressure.   The method of claim 1, wherein the drying step is performed using a fluidized bed, tray dryer or rotary atomizer.   The method of claim 1 including the additional step of adding other excipients.   The method of claim 1 including the additional step of forming a final dosage form. Dissolving a fibrate in a surfactant-free solvent to form a drug solution;
Premixing excipients to form a mixture;
Wet granulating the mixture and the drug solution to form a granulated drug mixture;
A method for producing a drug formulation comprising: drying the granulation mixture; and tableting the dry granulation mixture. Dissolving a fibrate in a surfactant-free solvent to form a drug solution;
Premixing excipients to form a mixture;
Wet granulating the mixture and the drug solution to form a granulated drug mixture;
A method for producing a drug formulation comprising: drying the granulation mixture; and filling capsules with the dry granulation mixture.   The method of claim 1, wherein the excipient is one or more members selected from the group consisting of lactose, starch, polyvinylpyrrolidone, magnesium stearate, and other pharmaceutically acceptable excipients. .   The method of claim 1, wherein the mixture is granulated in a fluidized bed.   The method of claim 1, wherein the mixture is granulated in a low shear or high shear mixer.   A composition produced by the method of claim 1. A composition produced by the method of claim 2 .

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