Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-06-28
2003-04-29
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C514S777000, C514S781000, C514S951000
Reexamination Certificate
active
06555139
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to processes for preparing small particles, preferably spherical particles, usually in the range of about 1 to 30 microns, with the size controllable in narrow ranges of from 1-5 micrometers, 5-15 micrometers, or 15 to 30 micrometers. These particles, referred to herein as “micronized particles,” have the advantage of controlled sizing, even size distribution of particles, controlled dissolution rates, and more consistent drug release properties. The invention also relates to new micronized particles obtained by the process of the invention and to their use in human or animal pharmacy. The present invention also relates to a process for the microfluidization of hydrophobic drugs and the use of the microfluidized product in a drug delivery system to provide controlled swellability and erosion-rate control. The drug release properties may also be modified as desired by using the microfluidization process to alter the product (pellet or particle) design or geometry.
2. Background of the Art
Bioavailability is the degree to which a drug becomes available to the target tissue after administration. Many factors can affect bioavailability including the dosage form and various properties, e.g., dissolution rate of the drug. Poor bioavailability is a significant problem encountered in the development of pharmaceutical compositions, particularly those containing an active ingredient that is poorly soluble in water. Poorly water soluble drugs, i.e., those having a solubility less than about 15 mg/ml or less than 10 mg/ml, tend to be eliminated from the gastrointestinal tract before being absorbed into the circulation. Moreover, poorly water soluble drugs tend to be unsafe for intravenous administration techniques, which are used primarily in conjunction with fully soluble drug substances.
It is known that the rate of dissolution of a particulate drug can increase with increasing surface area, i.e., decreasing particle size. Consequently, methods of making finely divided drugs have been studied and efforts have been made to control the size and size range of drug particles in pharmaceutical compositions. For example, dry milling techniques have been used to reduce particle size and hence influence drug absorption. However, in conventional dry milling, as discussed by Lieberman et al,
Pharmaceutical Dosage Forms: Tablets
, Volume 2, Chapter 3, “Size Reduction”, p. 132, (1990), the limit of fineness is reached in the region of 100 microns (100,000 nm) when material cakes on the milling chamber. Lachman et al note that wet grinding is beneficial in further reducing particle size, but that flocculation restricts the lower particle size limit to approximately 10 microns (10,000 nm). However, there tends to be a bias in the pharmaceutical art against wet milling due to concerns associated with contamination. Commercial airjet milling techniques have provided particles ranging in average particle size from as low as about 1 to 50 .mu.m (1,000-50,000 nm). However, such dry milling techniques can cause unacceptable levels of dust.
Other techniques for preparing pharmaceutical compositions include loading drugs into liposomes or polymers, e.g., during emulsion polymerization. However, such techniques have problems and limitations. For example, a lipid soluble drug is often required in preparing suitable liposomes. Further, unacceptably large amounts of the liposome or polymer are often required to prepare unit drug doses. Further still, techniques for preparing such pharmaceutical compositions tend to be complex. A principal technical difficulty encountered with emulsion polymerization is the removal of contaminants, such as unreacted monomer or initiator, which can be toxic, at the end of the manufacturing process. U.S. Pat. No. 4,540,602 (Motoyama et al) discloses a solid drug pulverized in an aqueous solution of a water-soluble high molecular substance using a wet grinding machine. However, Motoyama et al teach that as a result of such wet grinding, the drug is formed into finely divided particles ranging from 0.5 .mu.m (500 nm) or less to 5 .mu.m (5,000 nm) in diameter.
EPO 275,796 describes the production of colloidally dispersible systems comprising a substance in the form of spherical particles smaller than 500 nm. However, the method involves a precipitation effected by mixing a solution of the substance and a miscible non-solvent for the substance and results in the formation of non-crystalline nanoparticles. Furthermore, precipitation techniques for preparing particles tend to provide particles contaminated with solvents. Such solvents are often toxic and can be very difficult, if not impossible, to adequately remove to pharmaceutically acceptable levels to be practical.
U.S. Pat. No. 4,107,288 describes particles in the size range from 10 to 1,000 nm containing a biologically or pharmacodynamically active material. However, the particles comprise a crosslinked matrix of macromolecules having the active material supported on or incorporated into the matrix.
U.S. Pat. No. 5,145,684 discloses a process for preparing particles consisting of a crystalline drug substance having a surface modifier or surface active agent adsorbed on the surface of the particles in an amount sufficient to maintain an average particle size of less than about 400 nanometers. The process of preparation comprises the steps of dispersing the drug substance in a liquid dispersion medium and applying mechanical means in the presence of grinding media to reduce the particle size of the drug substance to an average particle size of less than 400 nm. The particles can be reduced in the presence of a surface active agent or, alternatively, the particles can be contacted with a surface active agent after attrition. The presence of the surface active agent prevents flocculation/agglomeration of the nanoparticles.
The mechanical means applied to reduce the particle size of the drug substance is a dispersion mill, the variety of which include a ball mill, an attrition mill, a vibratory mill and media mill, such as sand mill, and a bead mill.
The grinding media for the particle size reduction is spherical or particulate in form and includes: ZrO.sub.2 stabilized with magnesia, zirconium silicate, glass, stainless steel, titania, alumina and ZrO.sub.2 stabilized with yttrium. Processing time of the sample can be several days long. This patent is incorporated herein in its entirety by reference.
To a more limited extent the prior art also utilized microfluidizers for preparing small particle-size materials in general. Microfluidizers are relatively new devices operating on the submerged jet principle. In operating a microfluidizer to obtain nanoparticulates, a premix flow is forced by a high pressure pump through a so-called interaction chamber consisting of a system of channels in a ceramic block which split the premix into two streams. Precisely controlled shear, turbulent and cavitational forces are generated within the interaction chamber during microfluidization. The two streams are recombined at high velocity to produce shear. The so-obtained product can be recycled into the microfluidizer to obtain smaller and smaller particles.
The prior art has reported two distinct advantages of microfluidization over conventional milling processes (such as reported in U.S. Pat. No. 5,145,684, supra): substantial reduction of contamination of the final product, and the ease of production scaleup.
Numerous publications and patents were devoted to emulsions, liposomes and/or microencapsulated suspensions of various substances including drug substances produced by the use of microfluidizers. See, for example:
1) U.S. Pat. No. 5,342,609, directed to methods of preparing solid apatite particles used in magnetic resonance imaging, x-ray and ultrasound.
2) U.S. Pat. No. 5,228,905, directed to producing an oil-in-water dispersion for coating a porous substrate, such as wood.
3) U.S. Pat. No. 5,039,527 is drawn to a process of producing hexamethyhnelamine conta
Spear James M.
Wockhardt Europe Limited
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