Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2001-06-28
2003-07-29
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S400000, C424S402000, C424S451000, C424S184100, C424S422000, C424S423000, C424S489000, C424S486000, C424S487000, C424S484000
Reexamination Certificate
active
06599519
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a biocompatible and biodegradable block copolymer of poly(alkylene oxide) and poly(p-dioxanone) which is soluble in organic solvents. More particularly, the invention relates to a composition comprising the block copolymer for delivering bioactive agents and methods of use thereof.
BACKGROUND ART
The concept of using polymers for the controlled release of active drugs and other therapeutic compounds in medical applications has emerged and been developed extensively in the last two decades. When polymers are used for the delivery of pharmacologically active agents in vivo, it is essential that the polymers themselves be nontoxic and degrade into non-toxic products as the polymer is eroded by the body fluids. Many synthetic biodegradable polymers, however, upon erosion in vivo yield oligomers and monomers that adversely interact with the surrounding tissue. To minimize the toxicity of the intact polymer carrier and its degradation products, polymers have been designed based on naturally occurring metabolites.
Poly(lactic acid)(PLA), poly(glycolic acid)(PGA), and copolymers thereof, have been used as drug carriers in the form of microspheres, nanospheres, implants and fibers. These polymers are polyesters that, upon implantation in the body, undergo simple hydrolysis. The products of such hydrolysis are biologically compatible and metabolizable moieties (i.e. lactic acid and glycolic acid), which are eventually removed from the body by the citric acid cycle. Drug release from these polymers occurs by two mechanisms. First, diffusion results in the release of drug molecules from the implant surface. Second, subsequent release occurs by the cleavage of the polymer backbone, defined as bulk erosion. Several implant studies have proven these polymers safe in drug delivery applications when used in the form of matrices, microspheres, bone implant materials, surgical sutures, and also as long term contraceptives. Thus, these polymers have been time-tested in various applications and proven safe for human use. Most importantly, these polymers are FDA-approved for human use.
However, these polymers do have drawbacks. For example, due to their strong hydrophobicity they undergo hydrolysis slowly in vivo which may cause an undesirably slow rate of drug release. When the drug to be delivered is a high molecule weight protein drug, the activity of the protein drug is significantly lowered due to the relatively long binding duration of the protein drug to the hydrophobic polymer. In order to solve such problems a number of studies have been conducted to impart a suitable degree of hydrophilicity to the predominantly hydrophobic PLA, PGA or other hydrophobic biodegradable polymers by way of introducing hydrophilic polymer moieties therein. In these studies, block copolymers of PLA, PGA or other biodegradable polymers containing bicompatible poly(ethylene oxide) in the form of a hydrophilic polymer block, have been developed to obtain an improved drug delivery polymer composition (see U.S. Pat. Nos. 4,862,168, 4,452,973, 4,716,203, 5,683,723, 4,942,035, 5,384,333, 5,476,909, 5,548,035, 5,702,717, 5,449,513, 5,510,103, and 5,543,158)
Doddi et al. (U.S. Pat. No. 4,052,988) have reported that poly(p-dioxanone), a polymer of 1,4-dioxane-2-one, is a new class of biodegradable polymer which has superior properties over other existing biodegradble polymers that are used for the purpose of preparing surgical sutures. To further improve the rheological properties of poly(dioxanone) for suture applications there have also been developed poly(p-dioxanone) copolymers (see U.S. Pat. Nos. 4,643,191, 5,080,665, and 5,019,094).
However, the above-mentioned homopolymers and copolymers of p-dioxanone are not soluble in common organic solvents which renders them not suitable to be used as biocompatible/biodegradable drug carriers.
DISCLOSURE OF THE INVENTION
The present invention provides a biocompatible and biodegradable block copolymer of p-dioxanone and alkylene oxide, which is soluble in common organic solvents and is suitable for use as a drug delivery carrier.
The present invention also provides a composition and a formulation for drug delivery comprising said block copolymer.
The block copolymer of the present invention, which is soluble in pharmaceutically acceptable solvents, comprises one or more poly(alkylene oxide) blocks and one or more blocks of a p-dioxanone homopolymer or copolymer, wherein the amount of the poly(alkylene oxide) blocks is within a range of 25 to 85% by weight, based on the total amount of the block copolymer.
Before the present block compolymer composition and method of use in delivery of a bioactive agent are disclosed and described, it is to be understood that this invention is not limited to the particular configurations, process steps, and materials disclosed herein as such configurations, process steps, and materials may vary somewhat. It is also to be understood that the terminology employed herein is used for the purpose of describing particular embodiments only and is not intended to be limiting since the scope of the present invention will be limited only by the appended claims and equivalents thereof.
It must be noted that, as used in this specification and the appended claims, the singular form “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a polymer containing a “block” includes reference to two or more of such blocks, and reference to “a drug” includes reference to two or more of such drugs.
As used herein, the term “drug” or “bioactive agent” or any other similar term means any chemical or biological material or compound suitable for administration by methods previously known in the art and/or by the methods taught in the present invention and that induce a desired biological or pharmacological effect, which may include but is not limited to (1) having a prophylactic effect on the organism by preventing an undesired biological effect, such as preventing an infection, (2) alleviating a condition caused by a disease, for example, alleviating pain or inflammation caused as a result of disease, and/or (3) either alleviating, reducing, or completely eliminating a disease from the organism. The effect may be local, such as providing for a local anaesthetic effect, or it may be systemic. This invention is not drawn to novel drugs or to new classes of bioactive agents. Rather it is limited to the compositions and methods of delivery of agents that exist in the state of the art or that may later be established as active agents and that are suitable for delivery by the present invention. Such substances include broad classes of compounds normally delivered into the body. In general, this includes but is not limited to antiinfective such as antibiotics and antiviral agents; analgesics and analgesic combinations; anorexics; antihelminthics; antiarthritics; antiasthmatic agnets; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihistamines; antiinflammatory agents; antimigraine preparations; antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations including potassium and calcium channel blockers, beta-blockers, alpha-blockers, and antiarrhythmics; antihypertensives; diuretics and antidiuretics; vasodilators including general coronary, peripheral and cerebral, central nervous system stimulants;vasoconstrictors; cough and cold preparations, including decongestants; hormones such as estradiol and other steroids, including corticosteriods, hypnotics, immunosuppressive, muscle relaxants; parasympatholytics, psychostimulants; sedatives; and tranquilizers. By the method of the present invention, both ionized and nonionized drugs may be delivered, as can drugs of either high or low molecular weight. Also included in the scope of these terms are nucleic acids, such as DNA, RNA, and oligonucleotid
Choi In-Ja
Seo Min-Hyo
Fubara Blessing
Samyang Corporation
Thorpe North & Western LLP
LandOfFree
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