Title:  Drug delivery system for enhanced bioavailability of hydrophobic active ingredients

United States Patent:  6,531,158

Issued:  March 11, 2003

Inventors:  Teng; Ching-Ling (Fremont, CA); Hsiao; Charles (Livermore, CA); Gatts; Joshua (Hayward, CA)

Assignee:  Impax Laboratories, Inc. (Haywood, CA)

Appl. No.:  635234

Filed:  August 9, 2000

The present invention provides a drug delivery system for the oral administration of a hydrophobic active ingredient. The active ingredient's post-ingestion dissolution rate and its corresponding bioavailability can be optimized by intimately mixing a micronized hydrophobic drug with suitably sized inert particles to a dispersion that will facilitate desired bioavailability. In a particular embodiment, the hydrophobic active ingredient is fenofibrate. Suitably sized inert particles include microcrystalline cellulose and lactose. Dispersion may be monitored by microscopic visualization.

DETAILED DESCRIPTION OF THE INVENTION

The advantages of the present invention are obtained, e.g., when using hydrophobic pharmaceutical substances that are not readily dissolved in water, although the degree of water solubility can vary with the type of substance used, and the intention is not that the solubility of the active pharmaceutical substance or substances shall constitute a limitation of the invention. One skilled in the art may easily establish, by routine experimentation, whether a pharmaceutical substance can be used in a pharmaceutical composition according to this invention.

Examples of active ingredients that are considered hydrophobic, poorly water-soluble or water-insoluble include benzodiazepines, clofibrate, chlorpheniramine, dinitirate, digoxin, digitoxin, ergotamin tartate, estradiol, fenofibrate, griseofulvin, hydrochlorothiazide, hydrocortisone, isosorbide, medrogeston, oxyphenbutazone, prednisolone, prednisone, polythiazide, progensterone, spironolactone, tolbutamide, 10,11-dihydro-5H-dibenzo[a,d]cyclo-heptene-5-carboxamide; 5H-dibenzo[a,d]cycloheptene-5-carboxamide, fish oil and the like. This recitation is in no way exhaustive.

Many hydrophobic active ingredients are available commercially in micronized form, or may be micronized by methods well known to those skilled in the art. For example, micronized active ingredients may be reduced to a fine powder by use of conventional methods such as an air-jet micronizer. The fenofibrate of the instant invention may be purchased in micronized form.

Inert particles of suitable size, as embodied in the present invention, may be any pharmaceutically acceptable excipient. Water-soluble excipients include, but are not limited to, for example, sugars such as lactose, mannitol, dextrose and sorbitol. Water-insoluble excipients include, but are not limited to, for example, microcrystalline cellulose, calcium phosphate, and many synthetic or organic polymers. Inert substrates that are suitable particles for the present invention are well known in the art. See, e.g., Wade & Waller, Handbook of Pharmaceutical Excipinets (2^nd ed. 1994).

In particular, microcrystalline cellulose is a highly crystalline, insoluble, particulate cellulose consisting primarily of crystalline aggregates obtained by removing amorphous (fibrous cellulose) regions of a purified cellulose source material derived from, for example, wood pulp or cotton linters. Various methods for producing microcrystalline cellulose include steam explosion, acid hydrolysis, and pressure treatment. See, e.g., U.S. Pat. No. 5,769,934, Ha et al. Microcrystalline cellulose is considered insoluble.

Another example, the disaccharide sugar lactose, is well known in the art as a water soluble excipient in pharmaceutical preparations. Lactose can be milled to the appropriate minute size by standard methodologies, e.g., passing through a suitably sized screen, or various particle sizes can be obtained commercially.

The size of inert substrate particles preferred in the present invention may range from about 1 micron to 500 microns. Preferably, the inert substrate particles are smaller than about 100 microns in size. Most preferably, the inert substrate particles are less than about 50 microns in size. Particles having irregular surface areas are also preferred. Microcrystalline cellulose is available commercially as, for example, EMCOCEL.RTM. from Edward Mendell Co., Inc. (Cedar Rapids, Iowa.) and AVICEL.RTM. from FMC BioPolymer. (Philadelphia, Pa.). Lactose is available commercially from numerous sources, such as FMC BioPolymer. It may be milled, e.g., through an appropriately sized mesh screen, to a suitable particle size.

In a preferred embodiment of the invention, the ratio of inert ingredient to active ingredient is between 0.1 to 10.0 weight/weight. More preferably, the ratio of the inert substrate to the hydrophobic drug is between about 0.1 and 4.0. Most preferably, the ratio of the inert substrate to the hydrophobic drug is between about 0.3 and 2.0.

Different types of equipment can be used to achieve the desired degree of dispersion. Dispersion of the active ingredient and the inert particles may be monitored easily by visualization. Accordingly, a sample is removed from the batch being mixed, placed on a microscope slide with water or a very low concentration of surfactant solution, and viewed under magnification. Agglomerates or aggregates of poorly dispersed active ingredient absorb light and appear as opaque bodies. Visualization also provides for standardized and uniform dispersion levels among different batches.

Other methods of monitoring dispersion include scanning electron microscopy which visually presents the degree of dispersion; analyzing the dissolution rate of the preparation; testing the light obscuration particle count; and measuring the wetting time, i.e., timing how long it takes for the powder blend to sink after being placed on a solution surface.

The pharmaceutical compositions produced in accordance with this invention may be used in different types of pharmaceutical preparations. The preparations will preferably be intended for enteral administration, primarily for oral administration. The preparations may be in solid form, for instance, in capsule, powder or granule, or tablet form or in the form of suppositories for rectal administration. Alternatively, the formulation may be dispersed into a suitable liquid for, e.g., pediatric use. Pharmaceutical compositions prepared in accordance with the invention may also be used in preparations for external use, such as in ointments and creams.

The pharmaceutical preparations can be formulated by combining the inventive pharmaceutical compositions with the conventional pharmaceutical additives and excipients, normally used in the desired forms of the preparations, with the aid of known methods. Such additions may comprise, for example, additional carriers, binders, preservatives, lubricants, glidants, disintegrants, flavorants, dyestuffs and like substances, all of which are well known in the art.

The pharmaceutical preparations herein may be prepared by wet granulation. The wet granulation procedure includes mixing the microcrystalline cellulose and the micronized active ingredient to be incorporated into a dosage form with a suitable solvent in, for example, a high shear granulator, twin shell blender or double-cone blender, or a simple planetary mixer, and thereafter adding solutions of a binding agent to the mixed solution to obtain a granulation. Suitable solvents include water, or other polar organic solvents such as alcohols. After mixing, the damp mass, optionally, can be screened through a suitably sized mesh screen, and then dried via, for example, tray drying, the use of a fluid-bed dryer, spray dryer, radio-frequency dryer, microwave, vacuum, or infra-red dryer. A Fitzmill or Co-mill or oscillating mill may be used to control granule size. A V-blender or double cone blender may be used for final blending.

Alternatively, the mixed microcrystalline cellulose/micronized active agent may be mixed with solvent for wet granulation in the presence of a suitable surfactant. Suitable surfactants may be ionic or nonionic, and are well-known to those practicing the art.

Disintegrants are often added to ensure that the ultimate prepared solid dosage form has an acceptable disintegration rate in the environment of use, such as the gastrointestinal tract. Typical disintegrants include starch derivatives and salts of carboxymethyl cellulose such as croscarmellose.

The milled granule may optionally be blended with a lubricant. Lubricants include magnesium stearate, sodium stearate, magnesium sulfate, steric acid or talc. Such lubricants are commonly included in the final tableted or capsuled product.

Bioavailability refers to the degree to which the therapeutically active medicament becomes available in the body after administration. Typically, bioavailability is measured in patients who fasted overnight before being dosed with the test preparation. Plasma samples are then taken and analyzed for the plasma concentration of the parent compound and/or its active metabolite. These data may be expressed as Cmax, the maximum amount of active ingredient found in the plasma, or as AUC, the area under the plasma concentration time curve. Shargel & Yu, Applied Biopharmaceutics adf Pharmacokinetics ch. 10 (3rd Ed. 1996); see also APPLIED Pharmacokinetics: Principles of Therapeutic Drug Monitoring (Evans et al., eds., 3rd ed. 1992).

It will be appreciated by those skilled in the art that although the invention is illustrated with particularly hydrophobic drugs, the composition and method of this invention is also applicable to more soluble drugs in need of enhanced bioavailability.

Claim 1 of 19 Claims

We claim:

1. A drug delivery system comprising micronized fenofibrate or a pharmaceutically acceptable salt thereof and an inert substrate of suitable particle size, selected from microcrystalline cellulose or lactose, which when orally administered as a single 67 mg dose in adults maintains post ingestion blood plasma levels of fenofibric acid of:

at least about 100 mg/ml at one hour;

at least about 350 mg/ml at two hours;

at least about 750 mg/ml at four hours;

at least about 850 mg/ml at five hours; and

at least about 650 mg/ml at twenty-four hours.
 

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