Solid material comminution or disintegration – Processes – With application of fluid or lubricant material
Reexamination Certificate
2001-08-29
2003-10-21
Rosenbaum, Mark (Department: 3725)
Solid material comminution or disintegration
Processes
With application of fluid or lubricant material
C241S184000
Reexamination Certificate
active
06634576
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to compositions of small particles of milled solid materials synergetically commixed with small particulates of milling media of comparable or smaller size, and to milling processes for their preparation employing combinations of two or more milling media materials selected according to their relative fracture toughness, hardness, and brittleness index values.
BACKGROUND OF THE INVENTION
Size reduction to produce small particles of crystalline and amorphous solid materials, now widely used in a variety of industries, can be accomplished by mechanical means using dry or wet milling techniques including jet milling, ball milling, media milling, and homogenization.
Small particles of a solid material, and in particular small particles of a poorly soluble or essentially insoluble solid, find beneficial use in numerous applications related to the increase in surface area achieved as a result of size reduction. When incorporated into a mixture, formula, composition, chemical reaction, dispersion, coating, powder, lyophilizate, suspension, matrix, and the like, a solid material in the form of small particles exhibits greater homogeneity in macroscopic or static properties such as observed or perceived color and uniformity of distribution, and improved microscopic or kinetic properties such as increased rate of dissolution into a volume of solvent or a volume of liquid including a pseudo-infinite solvent pool volume.
In one aspect, with respect to a solid drug substance, a volume of liquid can be a volume of liquid used in or administered with a dosage form of the drug such as from about 100 microliters to about 100 milliliters, often 1 milliliter to about 50 milliliters. In another aspect, with respect to a solid drug substance, a volume of liquid can be a volume of liquid found in a patient to which a dosage form of the drug is administered. For example, the volume of liquid can include the volume of blood in a patient, the volume of urine in a patient, the plasma volume in a patient, the volume of lymph in a patient, the volume of liquid in the stomach of a patient, the volume of liquid in the gastrointestinal tract of a patient, ascites fluid volume in a patient, the volume of liquid in a cyst in a patient, the volume of liquid in the eye of a patient, the volume of liquid in the lung of a patient, and the like. The volume may be the entire volume of a specific kind of fluid or liquid or it can be an aliquot or less than 100% of the total volume.
Small particles of a solid material often require the presence of one or more surface-active substance particularly on the surface of the particles to achieve or augment particle stability especially with respect to particle size increase and stability of a suspension of particles without agglomeration or aggregation in a liquid.
In recent years there has been a transition to the use of small milling media in conventional media mill processes of solid substrates for the preparation of various paints, pigment dispersions, photographic dispersions, pharmaceutical dispersions, and the like. The advantages obtained with the use of smaller size media include faster rates of solid substrate particle size reduction and more rapid attainment of smaller solid substrate particle size distributions as products of the milling process, i.e., more efficient comminution. Improvements in conventional media mill designs such as in Netzsch LMC mills and Drais DCP mills have incorporated smaller screen opening dimensions that allow physical separation (e.g., filtration) of larger milling media from milled substrate particles as small as 250 to 300 micrometers or less. However, even with the best machine designs available, it is generally not possible to use milling media bodies smaller than about 250 to 300 micrometers due to separator screen plugging proximal to the milling chamber and unacceptable pressure build-up due to hydraulic packing of the media. Commonly, for commercial applications, a grinding media size of 350 micrometers is considered the practical lower limit for media particle retention due to media separator screen limitations.
In applications such as pharmaceutical applications it is often desirable to prepare dry formulations of small particles of a solid optionally containing one or more additional ingredients such as an excipient. The ease of resuspension of individual particles rather than agglomerates of particles from dry dosage forms such as capsules, wafers, tablets and powders into fluids such as bodily fluids, for example gastrointestinal fluids and mucosal fluids, and into liquids such as water often in the form of a volume used to administer or comprise a dosage form of a drug is often improved by the presence of such excipients. The subsequent rate of dissolution of drug from resuspended particles in such formulations, and often the bioavailability of a poorly water soluble drug in the form of a resuspended particle rather than as an agglomerate, can increase as a function of increasing surface area and decreasing particle size. Small particles of a solid drug intimately dispersed in a formulation containing one or more excipients can function as isolated sources of the solid substance especially when the particles do not agglomerate or associate strongly with each other to form clusters or agglomerates of small particles. While small particles can sometimes be mixed in bulk formulation processes with other formulation ingredients such as excipients in a pharmaceutical process, it is not always the case that uniform distributions of all ingredients are achieved. In mixing processes involving small particles, it is not always possible to achieve complete separation of small particles that are present in agglomerates or in associated clusters to produce a formulation of separated small particles surrounded by other components of the formulation. Generation of pharmaceutically acceptable excipient particles of molecular clusters or pieces or fragments of excipient during a size reduction process can offer a potential improvement over prior art.
The advantages in drug delivery of water-insoluble drugs formulated as small particles have been described in a review by Pace et al., “Novel injectable formulations of insoluble drugs,” in Pharmaceutical Technology, March 1999 the contents of which are hereby incorporated by reference.
There has been a bias in the pharmaceutical art against wet milling due to concerns associated with contamination from fragments of non-pharmaceutically acceptable or toxic milling media bodies. Contamination by milling media body fragments can introduce non-biocompatible materials into pharmaceutical formulations to produce toxic effects in patients. For example, contamination can produce deleterious effects if formulations containing relatively large size fragments of solid materials (i.e., greater than about 10 microns) are administered by injection and block capillary vessels. Other effects of contamination by media and fragments of media include the introduction of heavy metal ions such as yttrium, and pH changes caused by the introduction of metal oxides that can in turn promote changes in drug substance during storage related to catalyzed reactions such as hydrolysis, oxidation, radical reactions, electron transfer reactions, condensation reactions, and other types of chemical reactions.
Czekai et al. in U.S. Pat. Nos. 5,513,803 and 5,718,388 disclose the use of ultrafine milling media for the preparation of fine particles useful in imaging elements, pigments and pharmaceuticals. Czekai et al. also disclosed simultaneous use of a mixture of large and small size milling media of identical composition wherein the larger size media were retained in the milling chamber while the smaller size media were not retained within the milling chamber. Grinding media in a preferred embodiment comprise particles of a polymeric resin. The use of polymers that are biodegradable is also disclosed with the stated advantage that contaminants from the media can advantageously
Millar Fay
Pace Gary W.
Snow Robert A.
Verhoff Frank
Edwards & Angell LLP
Rosenbaum Mark
RTP Pharma Inc.
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