Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2002-05-06
2003-11-11
Acquah, Samuel A. (Department: 1711)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C525S054200, C525S054300, C525S535000, C525S539000, C525S540000, C428S402210, C428S402240, C424S184100, C424S193100, C424S457000, C424S461000, C424S489000, C424S493000, C424S497000, C424S499000, C424S900000, C264S004100, C264S004300, C264S004400, C264S004700, C514S951000, C514S963000, C514S002600, C514S054000
Reexamination Certificate
active
06645525
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to microparticle compositions and methods for making microparticles, and more particularly relates to ionically formed microcarriers for sustained release of biomolecules.
BACKGROUND OF THE INVENTION
Drug delivery systems have evolved greatly in the past ten years. Innovations in drug delivery systems have been driven by medical, technological, and economic factors. One focus has been the development of noninvasive drug delivery systems, which offer an improved quality of life for patients, and can provide improved bioavailability of drugs. Several new areas of development are the use of transdermal technologies and oral administration, both of which avoid the need for injections. Oral administration faces a problem with delivery of biomolecules, such as peptides, which can be rapidly broken down in the gastric cavity.
Another new area of development is delivery via the pulmonary system. Advantages of pulmonary delivery include lowered invasiveness compared to injection, high absorption of undegraded biomolecules, and the ability to target drugs to sites of respiratory disease.
A main focus of research on drug delivery has been providing for controlled release of drugs and continuous maintenance of an acceptable concentration of drugs. A recent success in this area has been an extended-release formulation of nifedipine commercially available as the Procardia XL® nifedipine formulation (Pfizer Inc., New York, N.Y.). The coupling of a biomolecule with a biodegradable polymer can provide controlled release by diffusion out of or degradation of the polymer and can also protect vulnerable drug formulations, such as peptides, from degradation.
Biodegradable polymers can be used for formulation of biomolecules for oral delivery, for implantable delivery systems, for pulmonary delivery, as well as for intravenous injection. Preferred polymers are those that are biodegradable and biocompatible, and that exhibit the desired release characteristics, generally a sustained rate of release without final “dumping” of biomolecule upon final hydrolysis of polymer.
Biodegradable polymers are often used in the form of microcarriers to deliver biomolecules. Advantages of the use of microcarriers include the ability to use appropriately sized carriers to target delivery. For example, microcarriers at least 15 microns in size can be used for regional or depot delivery, whereas delivery via inhalation requires particles in the one to five micron size. Other advantages include the ability to provide protection to delicate biomolecules prior to and during administration and ease of manufacture.
SUMMARY OF THE INVENTION
Compositions for sustained delivery of biomolecules are described herein. The compositions include an anionic polymer (polyanion) and a cationic polymer (polycation) which ionically interact with each other and, optionally, with the biomolecule to form a polymer matrix or complex. Also provided are methods for making the compositions, including the step of combining the negatively charged polymer with the positively charged polymer to form anionic complex. The biomolecule may be complexed with either one of the polymers, depending on the characteristics of the biomolecule, such as the charge of the biomolecule. Then the complex is reacted with the oppositely charged polymer. The complex is exposed to conditions, such as a change in pH or the addition of a complexing molecule, that cause the formation of precipitated microparticles, also referred to herein as microcarriers. The compositions are preferably formulated into microcarriers. The preferred polyanions and polycations are water soluble polymers, available commercially at high purity, that are already known and on the GRAS (generally regarded as safe) list. Alternatively, the polymers are high molecular positively or negatively charged polymers synthesized using polymer chemistry synthesis methods known to those skilled in the art.
In a preferred embodiment, the cationic polymer is polyethyleneimine (PEI), polychitosan, or a cationic polymethacrylate, and the anionic polymer is dextran sulfate, heparin, alginic acid or an anionic polymers are available in a range of molecular weights, typically in the range of 20,000 to 500,000 kD.
Most preferably, insulin, a positively charged protein, is first complexed with dextran sulfate. The cationic polymer, PEI or DEAE dextran, is than added and complexed with the insulin/dextran sulfate complex. Formation of microcarriers is initiated by addition of zinc sulfate.
In another preferred embodiment, the cationic polymer is polyethyleneimine (PEI) and the anionic polymer is dextran sulfate or alginic acid. A negatively charged biomolecule, such as a nucleic acid, is first complexed with the PEI. The biomolecule/PEI complex is than complex with dextran sulfate. Formation of microcarriers is initiated by the addition of zinc sulfate.
Accordingly, it is an object of the invention to provide compositions for the delivery of biomolecules comprising microcarriers that release biomolecules at a sustained, constant rate of release.
It is another object of the present invention to provide compositions for delivery of biomolecules comprising microcarriers that provide stability to biomolecules during formulation and after administration.
It is another object of the present invention to provide microparticle compositions for the delivery of drugs in which the toxic effects of the drugs are minimized by being incorporated in a sustained-release microparticle formulation.
It is another object of the present invention to provide microparticle vaccines for the delivery of antigens in which an immunogenic effect is achieved in the absence of an adjuvant.
It is another object of the present invention to provide microparticle vaccines in which the polymers of the microparticles have an adjuvant effect.
These and other objects of the present invention will become apparent after reading the following detailed description of the disclosed embodiments and the appended claims.
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Acquah Samuel A.
Kilpatrick & Stockton LLP
Sedum Laboratories, Inc.
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