FIELD OF THE INVENTION
The present invention relates to microparticles of drugs, especially drugs that are poorly soluble in water, and to methods for making them.
BACKGROUND OF THE INVENTION
Many important drugs have poor oral bioavailability because they are poorly soluble in water. Many approaches have been suggested to overcome this problem. Although some approaches have been used, with limited commercial success, each approach has its own drawbacks and limitations.
In one approach, a water-soluble prodrug of a poorly water-soluble drug is made [1-4]. The prodrug approach is limited to those molecules that have functionality amenable to facile removal in the body to form the drug. Not all poorly water-soluble drugs are so endowed. Furthermore, the prodrug would likely be considered a new chemical entity and require separate approval from regulatory agencies, adding considerable time and cost to bringing the product to market.
The bioavailability of poorly water-soluble drugs has been improved by decreasing the particle size of the drug to increase the surface area. Milling [5-6], high pressure homogenization [7-8], spray drying , lyophilization of solutions in water—organic solvent mixtures , and lyophilization of solutions inorganic solvents [11-12] have been tried. Size reduction is, in principal, generally applicable for improving bioavailability, but achieving size reduction by, for example, high energy milling, requires special equipment and is not always applicable. High pressure homogenization requires special equipment and requires organic solvents that can remain in the comminuted product. Spray drying also requires solvents and generally produces particles that are too large.
Lyophilization is usually limited to materials that are soluble in water in any event, although there have been some efforts at using organic solvents.
The solubility of poorly soluble antibiotics has been improved by complexation with polymers or cyclodextrins. Polymer complexes have been formed with PVP in organic solvent [13a], or with PVP in heated water . Other drugs have been complexed with cyclodextrins and polymers [14-15].
The bioavailability of poorly soluble drugs has been improved by dispersing the drug in a soluble polymer, often with addition of surfactants [16-24].
Some combinations of techniques have shown added improvement. For example spraying and drying a dispersion of drug and polymer or cyclodextrin on pellets in a fluidized bed dried [25-26]. The combination of solid dispersion and lyophilization to improve solubility has been demonstrated , and the use of solid dispersions absorbed on a carrier having a large surface area has also been demonstrated .
Clearly, there is a need for a simpler and generally applicable means of making and delivering particles of drugs having a size below 10 μm and especially below 1 μm.
Many of the above-described techniques require forming particles by solvent removal which, in turn, entails concentration of a solution. During solution concentration, solute molecules, which in solution are statistically separated into individual molecules and small clusters or aggregates, are drawn together to form larger molecular aggregates. When the solute drug eventually precipitates, relatively larger crystals are formed.
Lyophilization (freeze drying) has the advantage of allowing the solvent to be removed whilst keeping the solute relatively immobile, thereby suppressing enlargement of clusters or aggregates. When the solvent is removed, the formed crystals are smaller or the material is amorphous, reflecting the separation of the molecules in the frozen solution state. Molecular separation can be improved and aggregate formation still further suppressed by lyophilizing a more dilute solution, although one pays a hefty price in energy requirements for removing more solvent. Lyophilization is usually a very slow, energy intensive process and usually requires high vacuum equipment. Furthermore, there is a tendency for the crystals formed to aggregate in the free state, undoing the job that the freeze drying did. This tendency can sometimes be overcome with additives, but these must be compatible with the entire system.
Amorphous or nanoparticulate materials tend to show poor bulk flow properties as powders, requiring formulation work to be able to fill them into capsules. While these problems are not insurmountable, they add further limitations in the usefulness of the system. Many of the existing limitations are overcome by the present invention.
SUMMARY OF THE INVENTION
The present invention relates to a drug delivery vehicle including a pharmaceutical carrier particle, especially a pharmaceutical carrier particle that is a sugar particle, a starch particle, a lactose particle, or a particle of microcrystalline cellulose, bearing microparticles of a drug, especially a drug having poor solubility in water, wherein the microparticles of the drug are deposited on the pharmaceutical carrier particle from a solid solution of the drug in a sublimable carrier such as menthol, thymol, camphor, t-butanol, trichloro-t-butanol, imidazole, coumarin, acetic acid (glacial), dimethylsulfone, urea, vanillin, camphene, salicylamide, and 2-aminopyridine. The drug delivery vehicle of the present invention is useful for delivering a drug, especially a drug that has poor solubility in water, to a mammal, especially a human, in need of treatment with that drug.
In another aspect, the present invention relates to a method of making a microparticle including the steps of forming a solid solution of the drug in a sublimable carrier and removing the sublimable carrier from the solid solution by, for example, sublimation. Sublimation can be accomplished in a fluidized bed apparatus.
In another aspect, the present invention relates to a method of making a drug delivery vehicle including the steps of forming a solid solution of the drug and a sublimable carrier on the surface of a pharmaceutical carrier particle, especially a pharmaceutical carrier particle that is a sugar particle, a starch particle, a lactose particle, or a particle of microcrystalline cellulose, and removing the sublimable carrier from the solid solution, for example by sublimation, to deposit microparticles of the drug on the pharmaceutical carrier particle. The solid solution can be formed on the carrier particle by, for example, combining drug, sublimable carrier, and a solvent (for example ethanol), applying the combination to the carrier particle, and removing the solvent. The solid solution can also be formed by applying a combination of drug and molten sublimable carrier to the particle and allowing the combination to cool to form the solid solution on the carrier particle.
In yet another aspect, the present invention relates to pharmaceutical compositions that include microparticles of the present invention, which microparticles can be born by a drug delivery vehicle of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides microparticles of a pharmacologically active substance, i.e. a drug, and a method for making them. The invention also provides a drug delivery vehicle for administering a pharmacologically active substance, and methods for making it, wherein the delivery vehicle includes at least one pharmaceutical carrier particle bearing microparticles of the drug, which microparticles are made according to the present invention.
Microparticles of the present invention are formed as described hereinbelow and generally have mean dimensions on the order of about 100 nm, up to about 10 μm. Microparticles according to the present invention can have a regular shape, e.g. essentially spherical, or they can have an irregular shape. The material of which microparticles are comprised can be crystalline or it can be at least partly amorphous. Preferably the material is at least partly amorphous.
As used herein in connection with a measured quantity, the term about refers to the normal variation in that measured quantity that would be expected by the skilled artisan making the measurement and exercising a level of care commensurate with the objective of the measurement and the precision of the measuring equipment used.
Any pharmagologically active substance (drug) can be used in the practice of the present invention. However, drugs having poor water solubility (poorly water soluble drugs), and hence relatively lower bioavailability, are preferred and the advantages of the present invention are more fully realized with poorly water-soluble drugs. For purposes of the present invention, a drug is considered to be poorly water soluble if it has a solubility of less than about 20 mg/per milliliter of water. Examples of drugs having poor water solubility include fenofibrate, itraconazole, bromocriptine, carbamazepine, diazepam, paclitaxel, etoposide, camptothecin, danazole, progesterone, nitrofurantoin, estradiol, estrone, oxfendazole, proquazone, ketoprofen, nifedipine, verapamil, and glyburide, to mention just a few. The skilled artisan knows other drugs having poor water solubility.
Pharmaceutical carrier particles useful for making the delivery vehicle of the present invention are made of comestible substances and are well known in the art. Examples of useful pharmaceutical carrier particles include particles, that can be non-pariel pellets, typically between about 0.1 mm. and about 2 mm. in diameter, and made of, for example, starch, particles of microcrystalline cellulose, lactose particles or, particularly, sugar particles. Suitable sugar particles (pellets, e.g. non-panel 103, Nu-core, Nu-pariel) are commercially available in sizes from 35 to 40 mesh to 18 to 14 mesh. Particles of microcrystalline cellulose are preferred pharmaceutical carrier particles. The skilled artisan knows other pellets or spheres useful as pharmaceutical carrier particles.
The microparticles of the drug or pharmacologically active substance of the present invention are obtained by removing a sublimable carrier from a solid solution of the drug in the sublimable carrier. The drug or pharamaceutically active substance can be present with the sublimable carrier in the solid solution as discrete molecules, or it can be present in aggregates of a few hundred, a few thousand, or more molecules. The drug need only be dispersed on a sufficiently small scale so that sufficiently small, discrete microparticles are ultimately obtained. Preferably, the drug or pharmagolocigally active substance in the solid solution is dissolved in the sublimable carrier.
Sublimable carriers useful in the practice of the present invention form solid solutions with the drug at an easily accessible temperature and can be removed from the solid solution without heating the solid solution to a temperature above the melting point of the solid solution, for example by sublimation. Sublimable carriers have a measurable vapor pressure below their melting point. Preferred sublimable carriers have a vapor pressure of at least about 10 Pascal, more preferably at least about 50 Pascal at about 10° or more below their normal melting points. Preferably, the sublimable carrier has a melting point between about −10° C. and about 200° C., more preferably between about 20° C. and about 60° C., most preferably between about 40° C. and about 50° C. Preferably, the sublimable carrier is a substance that is classified by the United States Food and Drug Administration as generally recognized as safe (i.e., GRAS). Examples of suitable sublimable carriers include menthol, thymol, camphor, t-butanol, trichloro-t-butanol, imidazole, coumarin, acetic acid (glacial), dimethylsulfone, urea, vanillin, camphene, salicylamide, and 2-aminopyridine. Menthol is a particularly preferred sublimable carrier.
The solid solutions of the present invention can exist as a true homogeneous crystalline phase of the interstitial or substitutional type, composed of distinct chemical species occupying the lattice points at random, or they can be a dispersion of discrete molecules or aggregates of molecules in the sublimable carrier.
The solid solutions can be made by combining a drug with molten sublimable carrier, then cooling the combination to below the melting point of the solid solution. The solid solutions can also be formed by combining drug and sublimable carrier in an organic solvent and evaporating the organic solvent to obtain a solid solution of drug in sublimable carrier. Ethanol is an example of a preferred organic solvent that can be used in the practice of the present invention.
The solid solution can also include a compound or polymer that forms a dispersion with the drug.
In a preferred embodiment, the solid solution is formed on the surface of at least one pharmaceutical carrier particle and preferably a plurality of pharmaceutical carrier particles. For example, a molten combination of drug and carrier can be applied to the surface of a pharmaceutical carrier particle where it is allowed to cool to form the solid solution on the surface of the pharmaceutical carrier particle. A solid solution can also be formed at the surface of a pharmaceutical carrier particle by applying a combination of solvent, drug, and sublimable carrier to at least one, and preferably a plurality of, pharmaceutical carrier particle(s) and evaporating the organic solvent to obtain the solid solution on the surface of the pharmaceutical carrier particle.
Application to the pharmaceutical carrier particles can be by any particle coating technique known in the art, for example using fluidized bed equipment or a spray coater. When used, organic solvent is removed after application by exposing the coated carrier particles to vacuum or a stream of heated or non-heated air using particle handling equipment well known in the art.
When no solvent is used, application is at a temperature above the melting point of the sublimable carrier. When drug and sublimable carrier are combined with solvent, application is at a temperature such that drug and sublimable carrier remain in solution in the solvent.
The microparticles of the present invention are formed by removal of sublimable carrier from a solid solution, made as described above, at a temperature below the melting point of the solid solution. The solid solution must be kept at a temperature below its melting point to preserve the solid solution during the process of removing the sublimable carrier. The sublimable carrier can be removed from the solid solution by, for example, treating the solid solution, deposited on a pharmaceutical carrier particle where applicable, in a stream of air, preferably heated air, in, for example, a fluidized bed drier.
In those embodiments in which the solid solution is coated on the surface of a pharmaceutical carrier particle, the sublimable carrier can be removed by exposing the coated particles to heat, vacuum, heat and vacuum, or to a stream of heated or non-heated air, for example in a fluidized bed dryer. Exposing coated pharmaceutical carrier particles to a stream of air (heated or not) in a fluidized bed dryer is a preferred means of removing sublimable carrier from solid solution coated on pharmaceutical carrier particles in order to form the microparticles of the present invention on the surface of the carrier particles.
Removal of sublimable carrier from the solid solution, whether coated on a pharmaceutical carrier particle or not, results in formation of the microparticles of the present invention.
In another embodiment of the present invention, the microparticles of drug or the pharmaceutical carrier particles bearing microparticles of a drug are formulated into pharmaceutical compositions that can be made into dosage forms, in particular oral solid dosage forms such as capsules and compressed tablets, as are well known in the art.
Compressed tablets are formulated from pharmaceutical compositions containing the microparticles of the pharmacologically active substance or drug, or using pharmaceutical carrier particles bearing such microparticles, and pharmacologically inert (pharmaceutically acceptable) additives or excipients.
For making a tablet, it will typically be desirable to include one or more benign pharmaceutical excipients in the pharmaceutical composition. The pharmaceutical composition of the present invention may contain one or more diluents added to make the tablet larger and, hence, easier for the patient and caregiver to handle. Common diluents are microcrystalline cellulose (e.g. Avicel®), microfine cellulose, lactose, starch, pregelitinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
Binders also may be included in tablet formulations to help hold the tablet together after compression. Some typical binders are acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate and starch.
The tablet may further include a disintegrant to accelerate disintegration of the tablet in the patient's stomach. Disintegrants include alginic acid, carboxymethyl cellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium (e.g. Ac-Di-Sol®, Primellose®), crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab®) and starch.
A pharmaceutical composition for making compressed tablets may further include glidants, lubricants, flavorings, colorants and other commonly used excipients.
Pharmaceutical carrier particles bearing microparticles of a drug made in accordance with the present invention have excellent bulk flow properties and can be used directly, alone or in combination with carrier particles that do not carry a drug, to make capsule dosage forms. If necessary, diluents such as lactose, mannitol, calcium carbonate, and magnesium carbonate, to mention just a few, can be formulated with the microparticle-bearing pharmaceutical carrier particles when making capsules
Liquid oral pharmaceutical compositions of the present invention comprise microparticles or microparticle-bearing pharmaceutical carrier particles and a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin, most preferably water.
Liquid oral pharmaceutical compositions may contain emulsifying agents to disperse uniformly throughout the composition the active ingredient, drug delivery vehicle, or excipient having low solubility in the liquid carrier. Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol.
Liquid oral pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.
The liquid oral pharmaceutical composition also may contain sweetening agents, such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar; preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid; and buffers such as guconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate.