Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1998-06-25
2001-07-24
McGarry, Sean (Department: 1635)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S006120, C435S455000, C536S024100, C536S024500, C424S484000, C424S486000, C424S487000, C424S488000, C424S489000
Reexamination Certificate
active
06265389
ABSTRACT:
BACKGROUND OF THE INVENTION
Antisense oligonucleotides are modified synthetic oligonucleotides which can inhibit gene expression. For example, antisense oligodeoxynucleotides (ODNs) are modified oligodeoxynucleotides which can inhibit gene expression by interfering with messenger RNA (mRNA) translation. More specifically, many antisense ODNs are designed to bind tightly to mRNA that serves as a template to synthesize a protein. Since the RNA template is known as the “sense” strand, the complementary sequence that binds to it is called the antisense strand. An antisense drug can act, for example, by destroying the targeted mRNA as a result of binding to it, thereby invoking the activity of a ubiquitous cellular enzyme ribonuclease H (RNase H). This enzyme will cleave RNA that is bound to DNA. As such, antisense ODNs are useful, for example, in the treatment of diseases where a particular protein has been identified as critical for a disease to flourish. Many antisense ODNs are modified by replacement of one of the phosphate oxygens in the backbone by a sulfur, so that the antisense ODN is not a poly(phosphodiester) but a poly(phosphorothioate). Antisense ODNs of this type are typically designated [S]ODNs.
Antisense ODNs and other therapeutic oligonucleotides such as, ribozymes, antisense oligoribonucleotides, peptide nucleic acids, decoy RNAs and “dumbbell” DNAs, also known as transcription factor decoy DNAs, are typically administered intravenously. Many conditions which can be treated by oligonucleotide drug therapy require repetitive administration of the oligonucleotide, such as an antisense ODN, which can be problematic with regard to patient compliance.
Therefore, a need exists for a means of delivering oligonucleotides, such as antisense ODNs, which eliminates the need for repetitive administration without inordinately reducing the activity or potency of the ODN released.
SUMMARY OF THE INVENTION
This invention relates to a composition, and method of forming and using said composition, for the sustained release of oligonucleotides, in particular, antisense ODNs. The sustained release composition of this invention comprises a polymeric matrix of a biocompatible polymer and stabilized oligonucleotide, for example, a stabilized antisense ODN, wherein the stabilized oligonucleotide is dispersed within the biocompatible polymer. In a particular embodiment, the oligonucleotide is a stabilized antisense ODN. In a more particular embodiment, the stabilized antisense ODN is in the form of particles.
The method of the invention, for forming a composition for the sustained release of oligonucleotides, includes dissolving a polymer in a polymer solvent to form a polymer solution, dispersing or dissolving the stabilized oligonucleotide, for example, a stabilized antisense ODN in the polymer solution, and then solidifying the polymer to form a polymeric matrix as microparticles containing the stabilized oligonucleotide.
The method of using the sustained release composition of the present invention comprises providing a therapeutically effective blood level of oligonucleotide, such as an antisense ODN, in a subject for a sustained period by administering to the subject a dose of the sustained release composition described herein.
The sustained release composition of the invention overcomes the problem of high initial release of an oligonucleotide in vivo, which is exhibited when the oligonucleotide, in particular an antisense ODN, is not stabilized prior to incorporation into the polymeric matrix. Further, loss of activity of the oligonucleotide, such as an antisense ODN due to instability of the medicament, and chemical interactions between the oligonucleotide and other components contained in or used in formulating the sustained release composition are substantially absent.
The advantages of the sustained release formulation for oligonucleotides, for example, antisense ODNs, as described herein, include increased patient compliance and acceptance by eliminating the need for repetitive administration, increased therapeutic benefit by eliminating fluctuations in oligonucleotide concentration in blood levels by providing a desirable release profile, and a potential lowering of the total amount of the oligonucleotide, in particular an antisense ODN, necessary to provide a therapeutic benefit, by reducing these fluctuations.
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Alkermes Controlled Therapeutics Inc.
Hamilton Brook Smith & Reynolds P.C.
McGarry Sean
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