Stock material or miscellaneous articles – Coated or structually defined flake – particle – cell – strand,... – Particulate matter
Reexamination Certificate
2001-12-13
2003-07-29
Acquah, Samuel A. (Department: 1711)
Stock material or miscellaneous articles
Coated or structually defined flake, particle, cell, strand,...
Particulate matter
C264S004100, C264S004300, C264S004330, C427S213300, C427S213360, C428S402200, C428S403000
Reexamination Certificate
active
06599627
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to pharmaceutical compositions and methods of drug delivery. The invention especially relates to methods and compositions for providing controlled release of proteinaceous drugs.
BACKGROUND OF THE INVENTION
Controlled drug delivery technologies have advanced significantly over the last few decades and current technologies afford delivery of drugs at predetermined rates for days and years depending on the application. These advances, however, are applicable mostly to low molecular weight drugs. It is still difficult to develop controlled release formulations for long-term delivery of high molecular weight drugs, such as peptides, proteins, oligonucleotides, and genes. The delivery of high molecular weight drugs has become especially significant since the development of recombinant DNA technology, which has made possible large-scale production of such protein drugs as tissue plasminogen activator (TPA), erythropoietin (EPO), interferon, insulin, and a number of growth factors. Furthermore, completion of the genome project is expected to result in an improved understanding of the therapeutic roles of many different proteins, which should lead to numerous new protein drugs.
Almost all protein drugs are short acting, requiring repeated injections to maintain therapeutic efficacy. Many drugs, such as human growth hormone, luteinizing hormone-releasing hormone, interferons, cyclosporins, and TPA, are therapeutically useful only by following a therapeutic regimen that may require multiple injections daily. This means that therapeutic applications and commercialization of these drugs rely heavily on the successful development of viable delivery systems, which can improve their biochemical and biophysical stability and systemic bioavailability. Development of nonparenteral routes of administration, such as oral, nasal, pulmonary, ocular, buccal, vaginal, rectal, and transdermal routes, are highly desirable, but to date delivery through such routes is very difficult, if not impossible. The high molecular weights and enzymatic degradations of protein drugs make them particularly difficult to deliver non-parenterally.
Currently, the main goal in delivery of protein-based pharmaceuticals is to develop controlled release formulations that permit long-term delivery ranging from weeks to months from a single administration. For such applications, biodegradable polymers are very attractive, especially when their degradation products are known to be innocuous or biocompatible. They need not be surgically removed at the end of a treatment. Commonly used biodegradable polymers, which have been investigated for the controlled delivery of protein drugs, include homopolymers of poly(lactic acid) (PLA) or poly(glycolic acid) (PGA), poly(lactic acid-co-glycolic acid) (PLGA), poly(ortho esters), and polyanhydrides. Of these, PLGA has been used most frequently. Due to the long history of clinical applications of PLGA, it has become a polymer of choice for developing most protein drug delivery systems. A number of excellent reviews discuss currently available microencapsulation methods (1,2).
In discussing different approaches of microencapsulation, it is useful to understand the terminologies commonly used in the microencapsulation field. The process of microencapsulation results in “microparticles.” Microparticles can be divided into “microspheres” and “microcapsules,” which are different from each other. Microspheres usually refer to a monolithic type formulation in which the drug molecules are dispersed throughout the polymeric matrix (1, 2). On the other hand, microcapsules refer to reservoir devices in which the drug core is surrounded by a continuous polymeric layer or membrane. The drug core can be single (mononuclear) or multiple (multinuclear) inside the polymer membrane (3-5), but mononuclear microcapsules are generally preferred for drug delivery.
There are a number of advantages of microcapsules over microspheres. First of all, microcapsule formulations provide much more drug reservoir space than microspheres. In microcapsules only a minimal amount of the drug compound is in contact with organic solvent during processing and with the polymer coating after the microcapsules are formed. In contrast, protein drugs in microspheres are dispersed throughout the polymer matrix, but the large contact areas between protein drugs and solid polymer component may be unfavorable for protein stability. In microcapsules, protein drugs can be further protected from degrading polymers using another layer of a hydrophilic material or matrix before microencapsulation. For example, drug-containing nanoparticles made of gelatin, agarose, or poly(vinyl alcohol) suspended in an organic solvent containing a dissolved polymer (e.g., PLGA in methylene chloride) form multinuclear microcapsules by phase separation methods (6, 7) or by solvent extraction methods (8, 9). Microcapsules also provide desirable zero-order release as compared to the ever-decreasing release rate obtained by microspheres.
The current methods used for the preparation of microencapsulated pharmaceutical products are listed below, each of which has its own advantages, limitations and drawbacks. While the methods listed have been used to produce successful commercial products, many protein drugs cannot be formulated using such methods. Considering that a large number of protein drugs are available now and will be produced in the near future, it is clear that new, improved protein delivery systems need to be developed.
Solvent evaporation and solvent extraction
Coacervation (Simple and complex coacervation)
Hot melt microencapsulation (congealing)
Interfacial cross-linking and interfacial polymerization
Spray drying
Supercritical fluid
Solvent evaporation and solvent extraction methods utilize volatile organic solvents for dissolving water-insoluble polymers, such as PLGA. Commonly used organic solvents are methylene chloride, ethyl acetate, and methyl ethyl ketone. A double emulsion process is commonly used for producing PLGA microspheres containing water-soluble drugs, including protein drugs. Both solid/oil/water (s/o/w) and water/oil/water (w/o/w) systems are used depending on the type of drug (10). A drug in soluble or dispersed form is added to the polymer solution, and the mixture is then emulsified in an aqueous phase containing a surface-active agent, such as poly(vinyl alcohol). In the solvent evaporation method, the organic solvent is evaporated by raising the temperature and/or by applying vacuum. See, for example, U.S. Pat. No. 3,523,906 (issued to Vrancken, et al.). In the solvent extraction method, the organic solvent diffuses into the water phase to make emulsion droplets into solid polymer microspheres. See, for example, U.S. Pat. No. 4,389,330 (issued to Tice, et al.). In both methods, the continuous phase can be non-miscible oils. The organic solvent conventionally employed in this method is a chlorinated hydrocarbon, such as methylene chloride, of which a residual amount is strictly controlled under 600 ppm for the known toxicities. In addition, the loading capacity of microspheres prepared by the solvent extraction and solvent evaporation is in general low. Furthermore, the way emulsions are created increases not only the total interfacial area the bioactive materials are subjected to, but also the extent of shear and cavitation stress which may be destructive to bioactive materials (12).
To minimize the loss of activity of the bioactive materials, it has been proposed to make microspheres at very low temperatures. See, e.g., U.S. Pat. No. 5,019,400 (issued to Gombotz, et al.). Biodegradable polymer is dissolved in an organic solvent, such as methylene chloride, together with protein powders, and then atomized over a bed of frozen ethanol overlaid with liquid nitrogen. The microdroplets freeze upon contacting the liquid nitrogen, and then sink onto the frozen ethanol layer. As the ethanol layer thaws, the frozen microspheres sink into the ethanol. Methylene chloride, the solve
Basaran Osman A.
Chen Alvin Un-Teh
Park Kinam
Yeo Yoon
Acquah Samuel A.
Meadows James H.
Medicus Associates
Purdue Research Foundation
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