Stock material or miscellaneous articles – Coated or structually defined flake – particle – cell – strand,... – Particulate matter
Reexamination Certificate
2003-03-19
2004-07-27
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
06767637
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 controlled release of easily denatured drugs utilizing microcapsules.
BACKGROUND OF THE INVENTION
Microencapsulation technologies have advanced significantly during the last few decades and the current technologies are at such a level that drugs can be delivered at predetermined rates for days and years depending on applications. These advances, however, usually apply only to low molecular weight drugs. Microencapsulation of high molecular weight drugs, such as peptides and proteins, is still complicated due to the intricate nature of their physical and chemical properties. Of these, protein-based pharmaceuticals have become especially important since mass production of such drugs has been enabled by recombinant DNA technology. Furthermore, completion of the human genome project is expected to bring about an improved understanding of the therapeutic roles of specific proteins, which should lead to numerous new protein drugs.
Since the early promise of sustained delivery of proteinaceous drugs [1], studies on protein microencapsulation have increased exponentially. Some of the early efforts succeeded in bringing the first microparticle product for peptide delivery (LUPRON DEPOT) onto the market [2, 3]. Not long after the commercial success of this product, however, it was recognized that the susceptibility of most proteins to environmental stresses would pose serious barriers to development of microparticle systems for proteins. Despite all the obstacles, protein microencapsulation is still an attractive approach, especially when such pharmaceuticals cannot be delivered via oral routes. Also, the need for infusions or frequent drug injections calls for the development of long-term delivery systems.
Current technologies commonly used in the preparation of microparticles for controlled drug delivery are summarized below, each of which has its own advantages and limitations.
Emulsion—solvent evaporation or extraction
Coacervation (Simple and complex coacervation)
Hot melt microencapsulation (congealing)
Interfacial cross-linking and interfacial polymerization
Spray drying
Supercritical fluid
The emulsion (solvent evaporation or extraction) methods utilize volatile organic solvents for dissolving water-insoluble polymers, such as poly (lactic acid-co-glycolic acid) (PLGA). Microdrops are produced when a mixture of a drug and a polymer solution is emulsified in a continuous phase, which is usually water. The microdrops become microparticles after solvent removal. A double emulsion process is commonly used for encapsulation of water-soluble drugs such as protein or peptide. Both solid/oil/water (s/o/w) and water/oil/water (w/o/w) systems are used depending on the type of protein drug. In the solvent evaporation method, the organic solvent is removed by evaporation at a raised temperature and/or under vacuum. See, for example, U.S. Pat. No. 3,523,906 (issued to Vrancken, et al. [41]). In the solvent extraction method, the organic solvent is extracted into a large volume of continuous phase, thereby turning the emulsion drops into solid polymer microspheres. See, for example, U.S. Pat. No. 4,389,330 (issued to Tice, et al. [5]). The organic solvents conventionally employed in this method are typically chlorinated hydrocarbons, such as methylene chloride. In both methods, the use of chlorinated solvents often becomes a substantial drawback for environmental and human safety reasons. FDA guidelines for the residual solvents limits the permitted daily exposure to 6 mg per day for methylene chloride. In addition, the loading capacity of microspheres prepared by this method is in general very low. Furthermore, the way emulsions are created increases not only the total interfacial area the bioactive substances are subjected to, but also extensive shear and cavitation stress, which may be destructive to bioactive substances [6].
To minimize such loss of activity of the bioactive substances, it is proposed to make microspheres at very low temperatures. See, e.g., U.S. Pat. No. 5,019,400 (issued to Gombotz, et al. [7]). Biodegradable polymer is dissolved in an organic solvent, such as methylene chloride, together with a protein powder and then atomized over a bed of frozen ethanol overlaid with liquid nitrogen. The microdrops 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. The methylene chloride solvent in the microspheres then thaws and is slowly extracted into ethanol, resulting in hardened microspheres containing proteins and polymer matrix. Clearly, this method can be costly and laborious, especially for scaled-up production.
The coacervation method is based on salting out (or phase separation) of polymers from a homogeneous solution into small drops of a polymer-rich phase upon addition of extra substances. For example, when an aqueous polymer solution (e.g., gelatin or carboxymethylcellulose) is partially dehydrated (or desolvated) by adding a strongly hydrophilic substance (e.g., sodium sulfate) or a water-miscible non-solvent (e.g., ethanol, acetone, dioxane, isopropanol, or propanol), the water-soluble polymer is concentrated to form the polymer-rich phase. This is known as simple coacervation. If water-insoluble drug particles are present as a suspension or as an emulsion, the polymer-rich phase is formed on the drug particle surface to afford a capsule. In complex coacervation, the polymer-rich complex (coacervate) phase is induced by interaction between two dispersed hydrophilic polymers (colloids) of opposite electric charges. Since electrostatic interactions are involved, it is important to control the pH of the medium in order to control the charges of the polymers.
In hot melt microencapsulation (also called congealing), a drug is mixed with a polymer, which is melted at high temperatures. The mixture is then suspended in a non-miscible solvent with continuous stirring at a temperature several degrees above the melting point of the polymer. After the emulsion is stabilized, the system is cooled until the polymer particles are solidified. This method requires the drug to be stable at the polymer melting temperature.
Interfacial cross-linking and interfacial polymerization employ two reactive phases that can form a solid boundary at their interface, which becomes the surface of microparticles. For interfacial cross-linking, the polymer must possess functional groups that can be cross-linked by ions or multi-functional molecules contained in a continuous phase. Interfacial polymerization requires two reactive monomers dissolved in immiscible solvents that can be polymerized at the interfaces. Capsules are collected after quenching the polymerization reaction with a third phase.
Spray-drying involves spraying a mixture of a drug and a polymer and evaporating the solvent in a drying chamber to solidify the atomized drops. This seemingly simple process has not been widely used in the pharmaceutical industry due at least in part to difficulties in the scale-up process. The parameters optimized in the laboratory scale spray dryer do not usually work for the industrial scale spray dryer. Moreover, the temperature of inlet gas that is used for drying the microdrops can reach 90-150° C. [9, 10], which may not be tolerable for encapsulation of heat-sensitive biomaterials.
Ultrasonic atomizers have reportedly been used for microparticle formation in connection with the spray-drying or spray-congealing techniques discussed hereinabove. In one example, the ultrasound energy was used to break up drug and carrier mixture into microparticles [11]. A lipid excipient and a drug were mixed at a temperature higher than the melting point of the excipient. The resulting fluid was poured onto the oscillating surface, and the liquid was
Park Kinam
Yeo Yoon
Acquah Samuel A.
Meadows James H.
Medicus Associates
Purdue Research Foundation
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