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WO2002056883A1 - Preparation de particules de felodipine microscopiques par microfluidisation - Google Patents

Preparation de particules de felodipine microscopiques par microfluidisation Download PDF

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Publication number
WO2002056883A1
WO2002056883A1 PCT/US2001/001635 US0101635W WO02056883A1 WO 2002056883 A1 WO2002056883 A1 WO 2002056883A1 US 0101635 W US0101635 W US 0101635W WO 02056883 A1 WO02056883 A1 WO 02056883A1
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WO
WIPO (PCT)
Prior art keywords
cyclodextrin
felodipine
composition
dosage form
cellulose
Prior art date
Application number
PCT/US2001/001635
Other languages
English (en)
Inventor
Vinay K. Sharma
Arun K. Srivastav
Javed Hussain
Habil F. Khorakiwala
Original Assignee
Wockhardt Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wockhardt Limited filed Critical Wockhardt Limited
Priority to PCT/US2001/001635 priority Critical patent/WO2002056883A1/fr
Publication of WO2002056883A1 publication Critical patent/WO2002056883A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine

Definitions

  • felodipine undergoes acid-catalyzed, solvolytic oxidation in a solid state due to the degradation of dicalcium phosphate dihydrate to form dehydrogenated felodipine (Impurity A).
  • Other impurities Impurity B and Impurity C were not significantly increased during the testing of the current formulation placed at accelerated conditions.
  • Impurity B is the dimethyl ester of felodipine, dimethyl 4-(2,3-dichloropentyl)-l,4-dihydro-2,6- dimethypyridine-3,5-dicarboxylate
  • Impurity C is the diethyl ester of felodipine, diethyl 4-(2,3-dichloropentyl)-l,4-dihydro-2,6-dimethypyridine-3,5- dicarboxylate.
  • the present invention provides a method for preparing a unit dosage form of a stable felodipine composition.
  • the method comprises forming a drug containing core by compressing a composition comprising granulated microparticles, of felodipine and cyclodextrin, having a diameter of from about 0.5 microns to about 9 microns, and a carrier comprising cyclodextrin particles, a water-insoluble alkaline component and a swellable polymer.
  • the unit dosage form can be optionally coated with a resilient membrane coating.
  • the composition includes felodipine, non-covalently bound to ⁇ -cyclodextrin, a source of hydroxide ions, and an optional binder as a moisture carrier component for the migration of hydroxide ions to the non-covalently bound felodipine and ⁇ -cyclodextrin.
  • Inorganic excipients such as dicalcium phosphate (DCP) dihydrate can undergo hydrolysis and thereby serve as a source of hydrogen ions which can cause solid-state, solvolytic oxidation of felodipine into "Impurity A".
  • DCP dicalcium phosphate
  • the present invention discloses that ⁇ -cyclodextrin can be used as a primary stabilizing component in a formulation containing felodipine. Therefore, dicalcium phosphate dihydrate is eliminated and replaced by ⁇ -cyclodextrin.
  • Felodipine particles can be non-covalently bound to ⁇ -cyclodextrin, for example, during microfluidization.
  • the felodipine particle is protected from acid-catalyzed oxidation (including abnormal acidity from water or air) because in the ⁇ -cyclodextrin micro-environment, the pH is intentionally designed to be alkaline in nature.
  • the aqueous process of granulation is environmentally compatible, in contrast with solvent-based granulation processes disclosed in the prior art.
  • the use of cyclodextrins, and especially ⁇ -cyclodextrin to stabilize pharmaceutical compounds and compositions, especially during microfluidization of Felodipine has not been reported in the literature. Brief Description of the Figures
  • Figure 1 is a graphic illustration of a comparison of heat treatment and screening of suspensions of various excipients, combinations of excipients and combinations of felodipine and excipients to determine the source of hydrogen ions.
  • Figures 2 and 2A schematically illustrate the process for the preparation of the Felodipine compositions of the invention.
  • Figure 3 is a graphic illustration of the comparative data of two discreetly different, drug particle diameters.
  • Figure 4 is a graphic illustration of the release profile of the formulation 9C, tested in the Bioequivalence Study 1.
  • Figure 5 is a graphic illustration of the effect of concentration of magnesium trisilicate on drag release by locating the magnesium trisilicate in the "bowl charge” of the Fluid Bed Granulator Dryer.
  • Figure 6 is a graphic illustration of the influence of locating unmicronized and powder magnesium trisilicate in the "bowl charge” vs. Spraying it as a non-microfluidized slurry along with drug dispersion, on RSD of drug release.
  • Figure 7 is a graphic illustration of the influence of the ratio of ⁇ -cyclodextrin to felodipine in microfluidized dispersion on drug release for 5 mg dosage using the tablets prepared in examples 6 and 7.
  • Figure 8 is a graphic illustration of the bioequivalence of felodipine tablet of the invention compared to a commercial felodipine tablet, Plendil. Detailed Description of the Invention
  • the present invention is motivated by the undesirability of Cremophor ® in pharmaceutical compositions where it can be eliminated.
  • the invention involves a novel use of the process known as "Microfluidization" for achieving bioequivalence to Plendil ® .
  • the process is described in copending U.S. Patent Application Serial No. 09/340,917, filed June 28, 1999, titled “Preparation of Micron-Size Pharmaceutical Particles by Microfluidization.”
  • the application describes a process where micronized feed materials are microfluidized at low pressures (e.g., about 3,500 to 7,000 or 4,000 to 6,000 pounds per square inch) to effectively prepare particles in the 6-12 micron size range, using from 1-3 passes through the microfluidizer.
  • compositions of the present invention are substantially free of dicalcium phosphate.
  • substantially free means less than about 1%, and typically less than 0.6%, of the composition by weight is dicalcium phosphate.
  • the present invention provides a drug delivery system for drugs having low water solubility, such as, for example, felodipine.
  • the invention uses a monophasic particle size distribution, ranging from 1-3 microns, to provide a swellable, erosion rate-controlled drug delivery system. This system uses a combination of a highly swellable non-ionic polymer and hydrophilic insoluble excipients.
  • the present invention provides a process for preparing a kinetically stable, controlled release formulation of felodipine by preparing dispersions of hydrophilized alkaline material and the hydrophobic drug non-covalently bonded to a cyclodextrin.
  • the sequential processing may comprise the granulating of a blend of a macroparticulate cyclodextrin and a medium viscosity (1,000-6,500 cps), highly swellable hydroxyalkyl cellulose using dispersions of alkaline material and hydrophobic drug (felodipine).
  • a compressed core is formed by conventional core pressing of a mixture comprising granulated microparticles of felodipine and cyclodextrin, having a diameter of from about 0.5 microns to about 9 microns and an optional binder; wherein the felodipine particles are non-covalently bonded to the cyclodextrin; and a carrier comprising cyclodextrin particles, a water-insoluble alkaline component, and a (medium viscosity) swellable polymer.
  • the tablets of the invention are compressed granules prepared from a microfluidized latex formed from felodipine, a binder, such as hydroxypropyl cellulose (HPC), a dissolution enhancer, such as ⁇ -cyclodextrin ( ⁇ -CD) and a polydimethylsiloxane-silicon dioxide defoamer, such as simethicone in water.
  • a binder such as hydroxypropyl cellulose (HPC)
  • a dissolution enhancer such as ⁇ -cyclodextrin ( ⁇ -CD)
  • ⁇ -CD ⁇ -cyclodextrin
  • a polydimethylsiloxane-silicon dioxide defoamer such as simethicone in water.
  • the latex is granulated in a fluidized bed with an alkaline agent, such as magnesium trisilicate, additional ⁇ -CD, HPC, hydroxyethyl cellulose (HEC) (swellable polymer for release control) and simethicone, to provide granules having a matrix that erodes uniformly.
  • an alkaline agent such as magnesium trisilicate, additional ⁇ -CD, HPC, hydroxyethyl cellulose (HEC) (swellable polymer for release control) and simethicone
  • HEC hydroxyethyl cellulose
  • simethicone simethicone
  • the geometry of the drag delivery system (e.g., the tablet), at a constant polymer (binder):excipient:drag ratio, can be modified from a generally spherical matrix (e.g., diameter of 10.6 mm and thickness of 6.46 mm, approximately 288 mm 2 ) to provide a more cylindrical form (e.g., diameter of 12.92 mm and a thickness of 4.58 mm, approximately 342 mm 2 ) to generate a larger surface area and a shorter distance for erosion or diffusion of the delivery system.
  • the resultant effect of this particular modification is an acceleration of matrix erosion.
  • the success of any drug delivery system is governed by the drug absorption performance, which is in turn at least a partial function of the drug release rate and characteristics. This is particularly true where the drug permeability after oral administration is not a rate-limiting step in the process of the distribution of drug in the body.
  • an aqueous medium is used for wet-micronization of the drug/excipient mixture, based on the particle size distribution (PSD) of the feed material (unmicronized vs. micronized) and the targeted particle size distribution of the outflow micro-suspension.
  • PSD particle size distribution
  • a granulated drug containing material is subsequently obtained by preparing two phases.
  • the first phase is a microfluidized mixture of the drug (latex) a cyclodextrin, such as, ⁇ -cyclodextrin and a water soluble binder, in water.
  • the microfluidized phase (latex) is subsequently blended with a separately prepared dispersion of hydroxypropyl cellulose in water, and an optional antifoaming agent, such as simethicone.
  • Microfluidization facilitates the reduction of the mean particle size of the drag and ⁇ -cyclodextrin mixture and creates a smooth latex-like micro- suspension.
  • resulting particle sizes are in the nanometer range, preferably less than 400 nm, more preferably less than 500 nm, and most preferably less than 1000 nm.
  • the preferred range of particle sizes is from about 500 to about 4000 nm. More preferable are particle sizes from about 1000 to about 3000 nm. Most preferable are particle sizes from about 1000 to about 1500 nm. Mixtures within these ranges can be produced according to the process described herein (with or without the presence of surface-active agents or surface modifying-agents).
  • the cyclodextrins as noted herein, remain as particles within the microfluidized system and the resultant product.
  • the cyclodextrin particles may or may not be separable from the pharmaceutical particles.
  • CDS cyclodextrins
  • the dissolution rate expressed in the above equation is termed the intrinsic dissolution rate and is characteristic of each solid compound in a given solvent under fixed hydrodynamic conditions.
  • the intrinsic dissolution rate in a fixed volume of solvent is generally expressed as mg dissolved in min "1 cm “2 .
  • the sizes are weight average particle sizes.
  • the ranges may alternatively be applied to number average particle sizes, usually where fewer than 10% by number of the particles exceed the stated average size by more than 25%.
  • the aqueous solubility of felodipine was determined to be about
  • felodipine 0.0001% at all pH levels, respectively.
  • the intrinsic dissolution rate of felodipine was calculated to be 0.00086 mg min l cm "2 .
  • the media used was a 500 ml phosphate buffer, Type II, and dissolution was assisted by using a paddle. Based on this data, a 10-20 micron range for felodipine will exhibit dissolution rate-limited absorption.
  • antifoaming agents such as silicone compounds, fluorinated compounds, such as simethicone and FC-40 manufactured by Minnesota Mining and Manufacturing Co. (although there are many chemical classes of materials known in the art for this purpose) has already been briefly referred to. These compounds provide a benefit to processing performance. The benefit is unrelated to any surface-active effect between the drag and the liquid carrier used in the microfluidization process.
  • aqueous carrier When particles are provided in the aqueous carrier, significant amounts of air or other gas can be carried with the particles. Because of the small size of the particles, the air or other gas is not easily shed from the surface of the small particles. Thus, it can be carried into the carrier liquid, and foaming can occur in the suspension.
  • Defoaming may occur directly in the storage or feed tank used in the microfluidization system or may be carried out at another time, prior to introduction of the suspension into the microfluidizer.
  • the defoaming agents are preferably used in amounts that are much smaller than the concentrations or volumes that are usually necessary for effective surface-active properties.
  • defoaming agents may be used in weight/weight percentages of the solution in a range of from about 0.005 to about 0.08% by weight of the total solution/dispersion.
  • the defoaming agents are used in a range of from about 0.005 to about 0.1%.
  • the defoaming agents are used in a range of from about 0.0005% to about 0.2%.
  • Conventional surface-active agents are typically used in higher concentrations.
  • the cyclodextrin is introduced into the carrier drag particle system as a solid particle.
  • the cyclodextrin remains as solid particles in the process, even if there is some breakdown or minor dissolution of the cyclodextrin.
  • the cyclodextrin does not act as a surface-modifying agent, i.e., it does not form a coating on the surface of the pharmaceutical particle, and remains only associated with the hydrophobic, water-insoluble drag particle, in a non-covalent mixture, during and after the microfluidization process.
  • the pharmaceutical hydrophobic, relatively water-insoluble drug, the cyclodextrin or both may be added to the suspension or used to form the suspension in any size particles, such as, for example, from about 1 to about 50, preferably from about 1 to about 100, and most preferably from about 1 to about 200 micrometers in size.
  • the cyclodextrin particles may be larger or smaller than the drug particles.
  • the cyclodextrin (preferably ⁇ -cyclodextrin) may be added to the drag in a ratio of drug to cyclodextrin of from about 1 : 50 to about 50:1.
  • a preferred ratio of drug to cyclodextrin is from about 1 :50 to about 20:1.
  • a more preferred ratio of drug to cyclodextrin is from about 1:30 to about 5:1. Even more preferred is a ratio of drug to cyclodextrin from about 1 :25 to about 1:1. The most preferred ratio of drug to cyclodextrin is from about 1 : 15 to about 1 :2.
  • a stable felodipine composition may be based on micronized and microfluidized felodipine, a cyclodextrin, preferably ⁇ -cyclodextrin, a binder (e.g., hydroxypropyl cellulose, preferably Klucel ® LF) and a matrix-forming material or gelling agent (e.g., hydroxyethyl cellulose , preferably (Natrosol ® 250M)), and optionally preferably an alkaline excipient, preferably magnesium trisilicate, and an optional lubricant, preferably magnesium stearate (stearic acid is preferably specifically avoided).
  • a binder e.g., hydroxypropyl cellulose, preferably Klucel ® LF
  • a matrix-forming material or gelling agent e.g., hydroxyethyl cellulose , preferably (Natrosol ® 250M)
  • an alkaline excipient preferably magnesium trisilicate
  • the granules are prepared by placing ⁇ -cyclodextrin and hydroxyethyl cellulose in a FBGD (Fluid Bed Granulator Dryer) insert of GPCG-5 (a chemical processing unit [Model 5] sold by Glatt Air Techniques, Mahwah, New Jersey).
  • FBGD Fluid Bed Granulator Dryer
  • the microfluidized drug dispersion containing the binder, (e.g., hydroxypropyl cellulose), and magnesium trisilicate is sprayed onto the blended material in the GPCG-5 FBGD (Fluid Bed Granulator Dryer) container.
  • the granules are dried to a moisture content of not more than about 2%.
  • the granules are lubricated with colloidal silicon dioxide, and magnesium stearate.
  • the product is compressed into single dosage forms (tablets) using 11 mm standard concave punches.
  • the compressed core can be film coated with a combination of low viscosity (5-125 cps) hydroxyalkyl cellulose polymers, appropriately plasticized to form a resilient membrane that will not rapture due to the various stresses that may be created within the film structure and the core matrix.
  • the core matrix is intentionally designed to include a swellable polymer, which has viscoelastic tableting behavior. By using this type of polymer, the matrix develops an elastic recovery-related stress after ejection from the tablet machine. Hence, a resilient film is useful to minimize film rapture.
  • a suitable core coating is a cosmetic membrane composed of low viscosity hydroxyethyl cellulose (Natrosol ® 250 L), described in U.S. Patent Application Serial No.
  • the amount of drag, such as, for example, felodipine in each dosage form is preferably from about 0.5 mg to about 25.0 mg. More preferred are dosage forms containing from about 1 mg to about 15 mg of drug. Most preferred are dosage forms containing from about 2.5 mg to about 10 mg of drug.
  • the cyclodextrins useful in the present invention include but are not limited to ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, dimethyl - ⁇ -cyclodextrin and hydroxypropyl - ⁇ -cyclodextrin.
  • the preferred cyclodextrin is ⁇ -cyclodextrin.
  • the amount of cyclodextrin in the composition is from about 50 to about 80 weight percent of the composition based on the total weight of the composition based on the weight of the composition.
  • the amount of cyclodextrin is from about 60 % to about 75%.
  • the most preferred amount of cyclodextrin is from about 60 to about 70 weight percent of the composition based on the total weight of the composition.
  • the matrix forming material is water soluble (or water-dispersible) and swellable.
  • a preferred matrix-forming material or swellable polymer comprises a hydroxy alkyl cellulose which is commercially available as various grades such as Natrosol ® 250 M ( ⁇ 720,000, MPA 4500-6500 for a 2% aqueous dispersion), and Natrosol ® 250 H ( 1,000,000, MPA 1500-2500 for a 1% aqueous dispersion).
  • the preferred grade is Natrosol ® 250M.
  • the concentration of matrix-forming material in the granules may range from 10-40 % of the weight of the granules. Preferred proportions are 12-18% and most preferred is a range of 15-16%.
  • the basic alkaline agents useful in the present invention can be selected from the group consisting of oxides, or hydroxide, carbonate, and trisilicate salts of strong basic cations such as Mg 2+ , Ca 2+ , Al 3+ and the like. These are preferably pH 9 or greater.
  • suitable alkaline materials include materials such as, magnesium oxide, magnesium trisilicate, aluminum hydroxide, magnesium hydroxide, magnesium aluminum silicate (Veegum ® ) and the like.
  • the preferred basic alkaline material is magnesium trisilicate.
  • the concentration of the alkaline agent in the granule may range from about 0.5 to about 15% of the weight of the composition (granule).
  • concentration of the alkaline agent in the composition is from about 2 to about 10 %. More preferably the concentration of the alkaline agent in the composition is from about 3 to about 8 %. Most preferably the concentration of the alkaline agent in the composition is about 5 %.
  • the process of the present invention enhances the effective dissolution rate of drugs such as felodipine which has an M x (Log 10 ) x P computed value of 3.22, a MW (molecular weight) of 384.26, and an extremely low aqueous solubility of 0.5 mg/ml.
  • drugs such as felodipine which has an M x (Log 10 ) x P computed value of 3.22, a MW (molecular weight) of 384.26, and an extremely low aqueous solubility of 0.5 mg/ml.
  • Microfluidizer processors rely upon the forces of shear, impact and agitation to deagglomerate and disperse a solid into a liquid. The process takes place at relatively high energy conditions within an interaction chamber (IXC) and may employ an additional chamber called an Auxiliary Processing Module (APM).
  • IXC interaction chamber
  • ABM Auxiliary Processing Module
  • the core of the delivery system comprises microparticulate felodipine with a particle diameter of 0.5 to 10.0 microns, in a matrix comprised of highly swellable hydroxyethyl cellulose, a cyclodextrin such as, for example, ⁇ -cyclodextrin, and hydrophilized magnesium trisilicate.
  • a microfluidized dispersion can have a specific surface area of 5.5 m 2 /g or greater.
  • Felodipine may be complexed with cyclodextrin, ⁇ -cyclodextrin, dimethyl- ⁇ -cyclodextrin, and hydroxypropyl ⁇ -cyclodextrin to enhance solubility and stability.
  • the preferred cyclodextrin is ⁇ -cyclodextrin and is present as 30-80 percent w/w of the active core of a delivery system.
  • the general range for felodipine is about 0.5-3 % w/w whereas the preferred range is 0.6-2.1 % w/w.
  • the general range for the highly swellable matrix binder e.g., the hydroxyethyl cellulose
  • a pharmaceutically acceptable binder is used to prepare a mass of suitable consistency, which after drying will retain its structure until compressed.
  • binders include natural and synthetic adhesives, by way of non-limiting examples including materials such as sodium alginate, soluble cellulosic materials such as sodium carboxymethyl cellulose, methyl cellulose, and hydroxypropyl cellulose, and polyvinyl pyrrolidone. All dissolve in water to give clear, viscous preparations.
  • the preferred binder is hydroxypropyl cellulose and the preferred range is 3-6% w/w.
  • the composition of this invention can contain a swellable polymer, which is hydrophilic in nature.
  • the polymer is based on hydroxypropylmethyl cellulose or hydroxyethyl cellulose or other gelling agents such as alginates, carrageenan, pectin, guar gum, xanthan gum, modified starch, sodium carboxymethyl cellulose and hydroxypropyl cellulose. This list is not meant to be exclusive.
  • the preferred swellable polymer is hydroxyethyl cellulose.
  • the preferred grade is Natrosol 250M (traded by Aqualon, Wilmington, Delaware). The preferred range is 10-30% w/w.
  • magnesium trisilicate in its hydrophilized form. This is achieved either by preparing a slurry of about 100 mesh fine magnesium trisilicate powder in a 2% dispersion of hydroxypropyl cellulose (HPC) or microfluidizing it to a finer particle size such as 10-20 microns resembling a viscous suspension in feel and consistency.
  • HPC hydroxypropyl cellulose
  • a hydrophilizing agent for magnesium trisilicate may be a low viscosity polymer such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose or hydroxyethyl cellulose.
  • the role of the hydrophilizing agent in case of magnesium trisilicate is to decrease the anti-bonding influence of magnesium trisilicate on the compaction of the matrix.
  • magnesium trisilicate acts as an anti-bonding lubricant.
  • Magnesium trisilicate may be used in a concentration of 1-15 percent based on the weight of the tablet. The preferred concentration is 3-5 % w/w.
  • the magnesium trisilicate is located as a fine powder or as a slurry and then sprayed into the bowl.
  • the preferred way of locating it is in the slurry or even better as a microfluidized, viscous suspension.
  • a further preferred approach is to locate magnesium trisilicate in the slurry prepared by microfluidization in the presence of ⁇ -cyclodextrin (1:1 to 1:3).
  • Magnesium trisilicate should not be included in the granulating medium because it counterbalances the binding influence of the granulating medium by behaving as a lubricant. For example, when it was included at a concentration 3-5% of the tablet weight in the granulating medium, the tablet structure became softer regardless of the moisture content and its particle size.
  • the act of compression presses the granules against the die wall and punch faces will such a force so that the core can be difficult to eject and can have a rough surface if the lubricant is not included.
  • External lubricants such as stearates of divalent metals like magnesium, calcium and zinc function by coating the surface of the granules with a film, which reduces interfacial friction between the granules and the compressing surfaces.
  • the preferred lubricant for this invention is magnesium stearate and the preferred range is 0.25-0.75% w/w of the tablet or core.
  • antifoaming agents such as silicone compounds can provide a benefit to the process performance that is unrelated to any surface active effect they may have on the relationship of the pharmaceutical to the liquid carrier in the microfluidization process.
  • silicone compounds When particles are provided in the aqueous carrier, significant amounts of air or other gas is carried with the particles.
  • the particles and/or to the particles and liquid (water) carrier it is desirable, either before any microfluidization occurs or shortly after initiation of the microfluidization process, to introduce an anti-foaming agent to the particles and/or to the particles and liquid (water) carrier. It is particularly desirable to add the particles and antifoaming agent to the liquid carrier and allow a significant dwell time (e.g., at least 5 minutes, preferably at least 10 or 15 minutes, up to an hour or more) to allow the air or other gas to disassociate itself from the surface of the particles.
  • a significant dwell time e.g., at least 5 minutes, preferably at least 10 or 15 minutes, up to an hour or more
  • defoaming may occur directly within storage or feed tank for use in the microfluidization system or may be done at another time prior to introduction of the suspension into the microfluidizer.
  • the defoaming agents some of which are surfactants, may also be used, and are preferably used in amounts that are much smaller than the concentrations or volumes that are usually necessary for effective surface active properties.
  • defoaming agents may be used in wt/wt percentages of the dispersion in ranges, for example, of about 0.010- 0.030 by weight of the total dispersion.
  • the defoaming agent is less than about 0.030 wt %.
  • compositions and methods of the present invention will be more fully apparent from consideration of the following specific, non-limiting examples of preferred embodiments of the invention.
  • Felodipine BP micronized (175 g), ⁇ -cyclodextrin ( ⁇ -CD) micronized (1487.5 g) and simethicone emulsion (3.5 g) were added to the Klucel LF dispersion from Step 1.
  • the dispersion from Step 2 was passed through a microfluidizer (M-210 EH) at 10,000 psi, single pass. 4.
  • a second Klucel dispersion was prepared by adding Klucel LF, 105 g, to purified water 1187.5 g, while stirring vigorously, to obtain clear mucilage.
  • the drag dispersion from Step 3 is added to this Klucel dispersion.
  • a third Klucel dispersion was prepared by adding Klucel LF (87.5 g) to 2,333 g of purified water while stirring vigorously, to obtain clear mucilage.
  • Magnesium trisilicate, 350 g (100 mesh), 350 g of micronized ⁇ -cyclodextrin, and simethicone (3.5 g) were added to the third Klucel dispersion and mixed. 6.
  • the drag dispersion from Step 4 and magnesium trisilicate dispersion from Step 5 were transferred into two separate measuring cylinders. The cylinders were connected, sequentially, to a Glatt (GPCG-5) through a peristaltic pump.
  • the material from Step 7 was granulated with the magnesium trisilicate dispersion from Step 5, and followed by the drug dispersion from Step 4. 9.
  • drag dispersion is complete, the granules were dried to a moisture content of less than 2.5 percent. Stop drying and discharge the product.
  • the magnesium stearate is added to the granules from Step 9 and blend using an appropriate blender.
  • the lubricated granules, from Step 10, are compressed into tablets using a rotary or depression machine equipped with 11 mm standard concave tooling.
  • the tablets are finished by initially applying a resilient base coat comprising hydroxyethyl cellulose and hydroxypropyl methyl cellulose followed by a outer coat.
  • Felodipine was micronized using a (Alpine Jet Mill, Model Hosokawa, Alpine AG, Type K20 M-S60 DR). It was then added, with mixing, to a 3.87 % w/w dispersion of hydroxypropyl cellulose in water (Klucel ® LF, traded by Alkaline, Division of Hercules, Delaware) along with micronized ⁇ -cyclodextrin (24% w/w of the dispersion), using a Lightning Mixer with a propeller stirrer at medium speed.
  • the particle size distribution, computed using Malvern Mastersizer ® was from about 5-7 microns.
  • the mixture is microfluidized at 10,000 PSI (MicrofluidizerTM M-210 EH) in order to achieve a target particle diameter of 2.5-4.0 microns (90% of the particle size is below this range and 50% of the particles are below 1.5-2 microns).
  • Magnesium Trisilicate Dispersion Preparation Magnesium trisilicate hydrate (100 mesh) was dispersed in a dispersion of about 10 % w/w, hydroxypropyl cellulose and about 45 % w/w, unmicronized ⁇ -cyclodextrin (100 mesh) and Simethicone emulsion (0.05% w/w). The dispersion was continuously stirred using a Lightning Mixer with a propeller stirrer at medium speed. The purpose of treating magnesium trisilicate with ⁇ - cyclodextrin was to hydrophilize it in order to create a uniformly wettable dispersion in the fluid bed granulation drying (FBGD) bowl ("bowl charge").
  • FBGD fluid bed granulation drying
  • the fluid bed granulation drying was conducted using a GPCG- 5 processing unit (Model 5) traded by Glatt Air Techniques, Mahwah, New Jersey.
  • the FBGD bowl is one of the inserts which permits spray granulation operation and drying.
  • the "bowl charge” is composed of micronized ⁇ -cyclodextrin (CavitronTM 8900, 25 ⁇ ) and hydroxyethyl cellulose (Natrosol ® 250 M) in about a 3 : 1 ratio.
  • the magnesium trisilicate dispersion was sprayed into the "bowl” in order to prime the "bowl charge” as well as microdisperse magnesium trisilicate in the materials of the "bowl charge”.
  • the plenum was preheated to 70 °C.
  • the plenum was pre-heated to 70 degree C.
  • Exemplary results of the size distribution of the particles prepared as described herein are reported in Table 5 .
  • the granular particles were sieved using 30 mesh, 40 mesh and 60 mesh sieves.
  • the granular density was determined and illustrated in Table 5A.
  • the Hauser ratio was used to determine compaction. It was determined that 60 mesh particles were the optimum size for compaction.
  • the Hausner ratio (Tap density/Bulk Density) should be greater than 1.2.
  • the granules were lubricated with 0.5% magnesium stearate (HyQual ® ), based on the weight of the unlubricated granules.
  • the granules were compressed according to the conditions provided in Table 6.
  • the tablets were coated using a suitable R&D coating pan such as LDCS 3.75L (Vector Corporation, New Jersey).
  • the machine configuration included standard nozzle type, a.2 mm nozzle port, and standard air pattern. Pan rotation was 20 RPM.
  • Tables 7 describes the coating compositions and Table 8 describes the processing conditions.
  • the dissolution profiles referred to herein were conducted using the method as described in the US Pharmacopeia, Volume XXII, utilizing a Type 2 paddle assembly at 50 rpm.
  • the media used was a pH 6.5 phosphate buffer containing 1% sodium lauryl sulfate (wt/wt).
  • FERT refers to Felodipine Extended Release Tablets.
  • EXAMPLE 9 Following the general procedure described herein the felodipine formulations in Table 9 were prepared and tableted.
  • Formulation 9C used dibasic calcium phosphate dihydrate, in step 6, in place of magnesium trisilicate, used in formulation 9A.
  • FERT refers to Felodipine Extended Release Tablets.
  • the formulation using magnesium trisilicate, 9A was found to have increased stability over the formulation using dibasic calcium phosphate dihydrate, 9C.
  • the comparison of the particle size distributions for two drug dispersions after microfluidization are illustrated in Figure 3, where SSA is the Specific Surface Area.
  • the dissolution profiles for the experimental dosage form 9C and a reference dosage form used in the pilot bioequivalence study are illustrated in Figure 4.
  • the particle size distribution of FERT 9A and FERT 9C are compared and reported in Figure 3. Although release profiles are similar, the particle size was not optimum for achieving statistical bioequivalence between these dosage forms, FERT 9C and Plendil.
  • Colloidal silicon dioxide (Aerosil ® 200), Stearic acid (Hystren ® ), and total blend
  • Example 11 A study was conducted to determine the pH of several combinations of excipients with and without felodipine to identify hydrogen ion (H "1" ) sources. The heat treatment step involved heating the mixture at reflux for 15 minutes and allowing the mixture to stand over night.
  • Example 11 A study was conducted to confirm, in actual product formulations, the results from Example 11, after heat treatment of suspensions of various excipients, combinations of excipients and combinations of felodipine and excipients was conducted.
  • the basic formulation used was magnesium trisilicate 64.0 g, felodipine 180.0 g, ⁇ -cyclodextrin 1529.5 g ( ⁇ -CD), hydroxypropyl cellulose 246.91 g and about 4380 g, remainder, purified water, for a final slurry weight of about 6400 g.
  • the slurry had the 3.09 g simethicone added.
  • the additional ⁇ -CD or DCP were added to this basic drug slurry.
  • the heat treatment step involved heating the mixture at reflux for 15 minutes and allowing the mixture to stand over night. Table 12 Heat Treatment and Screening of Raw Materials in Product Formulation.
  • the formulation FERT-015 was prepared using the basic felodipine slurry described above with ⁇ -cyclodextrin and DCP.
  • the formulation FERT-016 was prepared using the basic felodipine slurry described above with ⁇ -cyclodextrin alone.
  • the formulation FERT-017 was prepared using the basic felodipine slurry described above with DCP alone.
  • Formulation FERT 16 contained 1% Magnesium Trisilicate in slurry-spray form.
  • Formulation FERT 2 contained 8% Magnesium Trisilicate in bowl charge.
  • Formulation FERT 3 contained 4.8% Magnesium Trisilicate in bowl charge.
  • Formulation FERT 4 contained a 10.5% Magnesium Trisilicate in bowl charge
  • the results from this experiment confirmed that use of ⁇ -cyclodextrin alone provided a more stable combination than the formulations that used DCP alone or DCP in combination with ⁇ -CD.
  • Example 13 A study was conducted to determine the quantity of magnesium trisilicate required to neutralize the acid generated by degradation of DCP after heat treatment in a formulation. The mixtures, except the initial felodipine, B-CD and DCP formulation, were subjected to a heat treatment step that involved heating the mixture at reflux for 15 minutes and allowing the mixture to stand over night.
  • Example 14 The foraiulation, FERT- 16 containing ⁇ -cyclodextrin was prepared. A small amount, 1%, of magnesium trisilicate, in slurry form, as a water insoluble alkaline excipient was added. An accelerated study was performed by heating the formulation at 60 °C for 7 days and for 15 days. The impurities, Impurity A, dehydrogenated felodipine (pyridine) and the other impurities, Impurity B, the dimethyl ester of felodipine and Impurity C, the diethyl ester of felodipine were not significantly increased during the testing of the current formulation placed at accelerated conditions. The results of an are presented in Table 14. Table 14 Product - Stability using ⁇ -Cyclodextrin
  • the bowl charge comprised unmicronized ⁇ -cyclodextrin (CavitronTM 8900) and hydroxyethyl cellulose (Natrosol (R) 250 M) in a 3:1 weight ratio.
  • Formulation FERT-018 (Table 15B) was prepared using 3.5% of magnesium trisilicate in the FBGD bowl and no magnesium trisilicate in the slurry. The degradation of felodipine was monitored and the results are illustrated in Table 15, Table 15A and Table 15B:
  • Example 16 Formulation FERT-019 contained ⁇ -cyclodextrin along with a larger amount of magnesium trisilicate (13.3%) as the water insoluble alkaline excipient in the FBGD bowl ("bowl charge"). The results of accelerated study are presented below in Table 16.
  • Bioequivalence studies were conducted.
  • two dosage forms (one test and Plendil, reference) containing 10 mg of felodipine were administered as single doses in a crossover protocol to a group of 10 healthy male subjects on a fasted stomach.
  • the test formulation 9C was a 10 mg felodipine tablet prepared according to the present invention as described in example 9.
  • the reference formulation was a 10 mg Plendil ® Extended Release felodipine Tablet.
  • the plasma concentrations of felodipine were compared with the plasma concentration after a single dose of Plendil ® Extended Release Tablets.
  • the particle diameter of the microfluidized dispersion was 7.05 micrometers (0.9) and 1.53 micrometers (0.5) for the Test Formulation in Pilot Bio 1.
  • the parameters of bioequivalence are listed in terms of test to reference ratios and 90 percent confidence intervals 2-One Sided in Table 17 below:
  • AUC 0. ⁇ indicates area under the plasma-time curve and is computed using either trapezoidal rale or by defining the curve as a mathematical function (y as a function of x) and then integrating the function. (Nanogram-hours/ml) .
  • Ln C max is the natural logarithm of the C max value. (Nano gram/ml) 5. T max indicates the time on the x-axis where the peak value for drag concentration on the y-axis occurs.
  • Bioequivalence Study 2 was conducted with 15 fasted subjects.
  • the test formulation 9 A was a 10 mg felodipine tablet prepared according to the present invention as described in example 9.
  • the reference formulation was a lO mg Plendil ® Extended Release felodipine Tablet.
  • the results for the parameters of bioequivalence are presented in Table 18:
  • the release of felodipine is illustrated in Figure 8 where the results of the bioequivalence comparison of felodipine tablets, prepared in Example 9A is compared with the reference Plendil tablets.

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Abstract

La présente invention concerne les composants d'une composition de félodipine stable et un processus de préparation de cette composition. Cette composition comprend de la félodipine non liée par covalence à la ß cyclodextrine, et un liant optionnel comme composant porteur d'humidité destiné à la migration des ions hydroxydes vers la félodipine et la ß-cyclodextrine non liées par covalence. Cette composition de félodipine est combinée avec un porteur comprenant des particules de cyclodextrine, un composant alcalin non soluble dans l'eau et un polymère à intumescence.
PCT/US2001/001635 2001-01-18 2001-01-18 Preparation de particules de felodipine microscopiques par microfluidisation WO2002056883A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101953837A (zh) * 2010-09-20 2011-01-26 山西康宝生物制品股份有限公司 一种非洛地平缓释片及其制备方法
US8846901B2 (en) 2005-10-26 2014-09-30 Cydex Pharmaceuticals, Inc. Sulfoalkyl ether cyclodextrin compositions and methods of preparation thereof
CN105326806A (zh) * 2015-12-15 2016-02-17 西南药业股份有限公司 一种非洛地平缓释片及其制备方法
US10117940B2 (en) 2004-04-23 2018-11-06 Cydex Pharmaceuticals, Inc. DPI formulation containing sulfoalkyl ether cyclodextrin
JP2019507127A (ja) * 2016-01-28 2019-03-14 ホビオネ サイエンティア リミテッド 医薬品有効成分の連続的な錯体化

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EP0249587A1 (fr) * 1986-04-11 1987-12-16 Aktiebolaget Hässle Composition pharmaceutique solide à libération prolongée et procédé de préparation
EP0566142A1 (fr) * 1992-04-16 1993-10-20 LEK, tovarna farmacevtskih in kemicnih izdelkov, d.d. Complexes d'inclusion de dérivés optiquement actifs et racémiques de la 1,4-dihydropyridine et de cyclodextrines
WO2000059475A1 (fr) * 1999-04-06 2000-10-12 Lipocine, Inc. Compositions et procedes d'administration amelioree d'agents therapeutiques hydrophobes ionisables

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0249587A1 (fr) * 1986-04-11 1987-12-16 Aktiebolaget Hässle Composition pharmaceutique solide à libération prolongée et procédé de préparation
EP0566142A1 (fr) * 1992-04-16 1993-10-20 LEK, tovarna farmacevtskih in kemicnih izdelkov, d.d. Complexes d'inclusion de dérivés optiquement actifs et racémiques de la 1,4-dihydropyridine et de cyclodextrines
WO2000059475A1 (fr) * 1999-04-06 2000-10-12 Lipocine, Inc. Compositions et procedes d'administration amelioree d'agents therapeutiques hydrophobes ionisables

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10117940B2 (en) 2004-04-23 2018-11-06 Cydex Pharmaceuticals, Inc. DPI formulation containing sulfoalkyl ether cyclodextrin
US10668160B2 (en) 2004-04-23 2020-06-02 Cydex Pharmaceuticals, Inc. DPI formulation containing sulfoalkyl ether cyclodextrin
US11464862B2 (en) 2004-04-23 2022-10-11 Cydex Pharmaceuticals, Inc. DPI formulation containing sulfoalkyl ether cyclodextrin
US8846901B2 (en) 2005-10-26 2014-09-30 Cydex Pharmaceuticals, Inc. Sulfoalkyl ether cyclodextrin compositions and methods of preparation thereof
US9617352B2 (en) 2005-10-26 2017-04-11 Cydex Pharmaceuticals, Inc. Sulfoalkyl ether cyclodextrin compositions and methods of preparation thereof
US10202468B2 (en) 2005-10-26 2019-02-12 Cydex Pharmaceuticals, Inc. Sulfoalkyl ether cyclodextrin compositions and methods of preparation thereof
US10703826B2 (en) 2005-10-26 2020-07-07 Cydex Pharmaceuticals, Inc. Sulfoalkyl ether cyclodextrin compositions and methods of preparation thereof
CN101953837A (zh) * 2010-09-20 2011-01-26 山西康宝生物制品股份有限公司 一种非洛地平缓释片及其制备方法
CN105326806A (zh) * 2015-12-15 2016-02-17 西南药业股份有限公司 一种非洛地平缓释片及其制备方法
JP2019507127A (ja) * 2016-01-28 2019-03-14 ホビオネ サイエンティア リミテッド 医薬品有効成分の連続的な錯体化
JP7038057B2 (ja) 2016-01-28 2022-03-17 ホビオネ サイエンティア リミテッド 医薬品有効成分の連続的な錯体化

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