Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1998-10-09
2004-04-27
Travers, Russell (Department: 1619)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S485000, C424S496000, C424S484000, C424S488000, C424S451000, C424S450000, C435S178000
Reexamination Certificate
active
06726934
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the fields of pharmaceutical sciences, protein chemistry, polymer chemistry, colloid chemistry, immunology, and biomedical engineering. More specifically, the present invention relates to a novel microparticulate and nanoparticulate system for drug and antigen delivery, for gene (plasmid DNA) delivery and antisense RNA and DNA oligonucleotide delivery.
2. Description of the Related Art
Microparticulate systems are solid particles having a diameter of 1-2,000 &mgr;m (2 mm) and more preferably 1-10 &mgr;m (microparticles). Nanoparticulate system are submicroscopic colloidal particles (nanoparticles) having a diameter of preferably 50-500 nm (1,000 nm=1 &mgr;m). Both microparticles and nanoparticles can be formed from variety of materials, including synthetic polymers and biopolymers (proteins and polysaccharides). Both microparticles and nanoparticles are used as carriers for drugs and other biotechnology products, such as antigens, genes and antisense oligonucleotides.
In the controlled drug and antigen delivery area, microparticles and nanoparticles are formed in a mixture with molecules to be encapsulated within the particles, for subsequent sustained release. A number of different techniques are routinely used to make these particles from synthetic or natural polymers, including phase separation, precipitation, solvent evaporation, emulsification, and spray drying, or a combination of thereof [Desay, P.B., Microencapsulation of drugs by pan and air suspension technique.
Crit. Rev. Therapeut. Drug Carrier Syst
., 5: 99-139 (1988); Berthold, A., Cremer, K., Kreuter, J. Preparation and characterization of chitosan microspheres as drug carrier for prednisolone sodium phosphate as model anti-inflammatory drugs.
J. Controlled Release
39: 17-25 (1996); Watts, P. J., Davies, H. C., Melia, C. D. Microencapsulation using emulsification/solvent evaporation: An overview of techniques and applications.
Crit. Rev. Therapeut. Drug Carrier Syst
. 7: 235-159 (1990); Cowsar, D. R., Tice, T. R., Gilley, R. M., English, J. P. Poly(lactide-co-glycolide) microcapsules for controlled release of steroids.
Methods Enzymol
. 112: 101-116 (1985); Genta, I., 5 Pavanetto, F., Conti, B., Ginnoledi, P., Conte, U. Spray-drying for the preparation of chitosan microspheres.
Proc. Int. Symp. Controlled Release Mater
. 21: 616-617 (1994)].
Microparticles and nanoparticles can be prepared either from preformed polymers, such as polylactic acid, polylactic-glycolic acid [Cohen, et al., Controlled delivery systems for proteins based on poly(lactic/glycolic acid) microspheres.
Pharm. Res
. 8: 713-720 (1991)], or from a monomer during its polymerization, as is the case of polyalkylcyanoacrylates [Al-Khouri-Fallouh, et al., Development of new process for the manufacture of polyisobutylcyanoacrylate nanoparticles. Int.
J. Pharm
. 28: 125-132 (1986)]. Both of the above technologies have limited application because of the use of organic solvents during their preparation which leave residual organic solvents in the final product. Although the polyalkylcyanoacrylate nanoparticulate technology is also available as a water-based [Couvreur, et al., Biodegradable submicroscopic particles containing a biologically active substance and compositions containing them, U.S. Pat. No. 4,329,332 (1982)], animal studies demonstrated a presence of toxic degradation products [Cruz, et al., Interaction between polyalkylcyanoacrylate nanoparticles and peritoneal macrophages: MTT metabolism, NBT reduction, and NO production.
Pharm. Res
. 14: 73-79 (1997)].
Cell encapsulation [Chang, T. M. Hybrid artificial cells:
Microencapsulation of living cells.
ASAIO Journal
38: 128-130 (1992)] is a related technology which has been also explored for the purpose of making microparticles and nanoparticles. Such particles can be formed either by polymer precipitation, following the addition of a non-solvent or by gelling, following the addition of a small inorganic ion (salt) and of a complexing polymer (of an opposite charge). If enough time is allowed, the particle interior (core) can be completely gelled. Usually, the inner core material is typically of a polyanionic nature (negatively charged polymer), the particle membrane (corona) is made from a combination of polycation (positively charged polymer) and polyanion. The core material is usually atomized (nebulized) into small droplets and collected in a receiving bath containing a polycationic polymer solution. The reverse situation is also possible in which case the core material is polycationic and the receiving bath is polyanionic.
Several binary polymeric encapsulation systems have been described. An undesirable side effect of these encapsulation systems is that the membrane parameters are tied by a single chemical complex resulting from the ionic interactions. The inability to adjust particle parameters independently has limited the success of this system.
To overcome these limitations, a new multicomponent polymeric particle was designed which allows for independent modification of mechanical strength and permeability. Over one thousand combinations of polyanions and polycations were examined as polymer candidates suitable for encapsulation of living cells. Thirty-three combinations were found to be usable. However, the composition and concentrations do not allow for generating of small microparticles and nanoparticles, suitable for drug and antigen delivery.
The prior art is deficient in the lack of effective means of drug and antigen delivery, as well as plasmid and oligonucleotide delivery. The present invention fulfills this longstanding need and desire in the art.
SUMMARY OF THE INVENTION
To overcome the limitations of the prior art, the present invention provides new combinations of multicomponent water-soluble polymers which allow for modification of the particle size down to a desirable size, adequate mechanical strength, and desirable permeability and surface characteristics.
In one aspect, the present invention provides a method of preparing of microparticles and nanoparticles by means of a hollow ultrasonic device and a combination of polymers at relatively low concentrations. In another aspect, the present invention provides a method of production of micro- and nanoparticles in a single step process. In another aspect, the present invention provides a composition of matter of micro- and nanoparticles whereas the multicomponent combination of polymers is composed of a structural (gelling) polymer and a polymer providing the mechanical strength (crosslinking) and permeability control. In another aspect, the present invention provides a composition of matter and method of incorporation of antigens as an integral part of the particulate matter. In another aspect, the present invention provides a composition of matter and method of electrostatic and steric stabilization of particles whereas the stabilizing polymers are integral part of the particulate matter. Also provided is a method of direct use of particles generated in the single step as a vaccine delivered orally, nasally, rectally or vaginally, through inhalation to the lung, and by injection into muscle or skin or underneath the skin.
In another aspect, the present invention provides a composition of matter and method of production whereas the particles comprise of anionic DNA or oligonucleotide incorporated as an integral part of the matter. Further provided is a method of post-production processing of particles, composed of recovery and washing steps.
In another embodiment, the present invention provides a method of stabilization and composition of matter of particles by means of physiological crosslinking agents. Also provided is a method of cryoprotection and stabilization by means of lyophilization. In addition, the present invention provides methods of adjustment of biodegradation and composition of matter of particles by means of incorporation of sui
Adler Benjamin Aaron
Sharareh Shahnam
Travers Russell
Vanderbilt University
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