Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-10-12
2004-03-09
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S422000, C424S433000, C604S890100, C604S891100
Reexamination Certificate
active
06703037
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to methods for administering biologically active substances, and biodegradable compositions for administering these substances.
The rapid advances in the fields of genetic engineering and biotechnology have led to the development of an increasing number of proteins and peptides that are useful as pharmaceutical agents. The development of methods for administering these new pharmaceutical agents is thus gaining increasing importance. In particular, the local or systemic administration of biologically active substances, such as proteins, is a current concern.
The delivery of proteins can be complicated, as proteins will degrade in many of the carriers that have traditionally been used for the administration of small molecules. In many cases, the active forms of proteins are difficult to formulate in biodegradable polymers. Synthetic materials, such as biodegradable hydrogels, can be used to deliver proteins. In many methods, however, the delivery of the protein to the systemic and local circulation is relatively rapid, and is determined primarily by the rate of dissolution of the protein particles. These methods can be of limited utility, as drug release can occur in an initial “burst” rather than at a sustained, controlled rate.
SUMMARY OF THE INVENTION
In a first aspect, the invention features a method for delivering a biologically active substance including the steps of: (a) combining the active substance with a macromer; (b) forming a mixture of the combination formed in step (a); (c) polymerizing the mixture to form articles; and (d) administering the articles, or a portion thereof, to a mammal, where step (c) takes place in the absence of a polymerizable monovinyl monomer.
In a second aspect, the invention features a method for delivering a biologically active substance including the steps of: (a) combining the active substance with a macromer; (b) forming a mixture of the combination formed in step (a); (c) polymerizing the mixture to form articles; and (d) administering the articles, or a portion thereof, to a mammal, where step (c) takes place in the absence of a water soluble polymerizable monovinyl monomer.
In a third aspect, the invention features a method for delivering a biologically active substance including the steps of: (a) combining the active substance with a macromer; (b) forming a mixture of the combination formed in step (a); (c) polymerizing the mixture to form articles; and (d) administering the articles, or a portion thereof, to a mammal, where step (c) takes place in the absence of a vinyl pyrrolidone monomer. The invention also features compositions formed by these methods.
In a fourth aspect, the invention features a method for delivering a biologically active substance including the steps of: (a) combining the active substance with a macromer; (b) forming a mixture of the combination formed in step (a); (c) polymerizing the mixture to form articles; and (d) administering the articles, or a portion thereof, to a mammal, where the articles release at least 80% of the active substance at a time 2.5 times greater than t
50
.
In a fifth aspect, the invention features a method for delivering a biologically active substance including the steps of: (a) combining the active substance with a macromer; (b) forming a mixture of the combination formed in step (a); (c) polymerizing the mixture to form articles; and (d) administering the articles, or a portion thereof, to a mammal, where the articles release a therapeutic dose of the active substance for a period of time at least 2.5 times greater than t
50
.
In a sixth aspect, the invention features a composition for delivering a biologically active substance, the composition including particles including a hydrogel and a biologically active substance, where the release kinetics of the particles are independent of particle size, where the particles have a mass mean diameter of about 50 nm to about 1 mm.
In a seventh aspect, the invention features a method for making articles for the controlled release of a biologically active substance including the steps of: (a) combining the active substance with a biodegradable, polymerizable macromer, the macromer including at least one water soluble region, at least one degradable region which is hydrolyzable under in vivo conditions, and polymerizable end groups having the capacity to form additional covalent bonds resulting in macromer polymerization, where the polymerizable end groups are separated by at least one degradable region, in the presence of an initiator; (b) polymerizing the macromer in the absence of light to form a hydrogel and to incorporate the active substance into the hydrogel; and (c) forming the hydrogel into articles capable of controlled release of the active substance. The initiator may be a radical initiator or an ionic initiator.
In an eighth aspect, the invention features a method for making a polymerized hydrogel, the method including the steps of: (a) combining a hydrophobic, water insoluble macromer, an initiator, and water; (b) allowing the macromer to swell; (c) mixing the macromer to form a homogenous mixture; and (d) polymerizing the macromer to form a hydrogel. Preferably, the method further includes adding a biologically active substance to the mixture before step (d).
In a ninth aspect, the invention features a method for making a polymerized hydrogel including the steps of: (a) combining a hydrophilic macromer and a hydrophobic, water insoluble macromer; (b) heating and stirring the combination formed in step (a) to form a homogenous mixture; (c) cooling the mixture to room temperature (d) adding water and an initiator to the mixture and allowing the mixture to swell; and (e) polymerizing the macromer to form a hydrogel. Preferably, the method further includes adding a biologically active substance to the mixture before step (e).
In a tenth aspect, the invention features a method for delivering a protein including the steps of: (a) combining the protein with a polymerizable hydrophilic polymer; (b) forming a mixture of the combination formed in step (a); (c) polymerizing the mixture to form articles; and (d) administering the articles, or a portion thereof, to a mammal, where the protein remains intact, and where at least 70% of the protein is released from the articles.
In an eleventh aspect, the invention features a method for delivering a biologically active substance, the method including the steps of: (a) combining the active substance with a biodegradable, polymerizable macromer in an aqueous solution, in the presence of a free radical initiator; (b) dispersing the solution to form fine droplets including the macromer and the biologically active substance; (c) polymerizing the macromer in the droplets, thereby forming hydrogel particles having the biologically active substance incorporated therein, where the particles are capable of controlled release of the biologically active agent; and (d) administering the articles, or a portion thereof, to a mammal, where step (c) takes place in the absence of a vinyl pyrrolidone monomer. Preferably, at least 80% of the particles have a particle size of smaller than about 5 &mgr;m.
In a twelfth aspect, the invention features a composition including a biologically active substance enclosed within a biodegradable, polymerizable macromer, the macromer including at least one water soluble region, at least one degradable region which is hydrolyzable under in vivo conditions, and polymerizable end groups having the capacity to form additional covalent bonds resulting in macromer polymerization, where the polymerizable end groups are separated by at least one degradable region, where the composition contains at least 5% by weight of the active substance.
In a thirteenth aspect, the invention features an insoluble macromer including at least one water soluble region, at least one degradable region which is hydrolyzable under in vivo conditions, and polymerizable end groups having the capacity to form additional covalent bonds resulting in macromer po
Hubbell Jeffrey A.
Kieras Mark T.
Ron Eyal S.
Rowe Stephen C.
Bieker-Brady Kristina
Clark & Elbing LLP
Pelias Technologies, Inc.
Ware Todd D
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