Title:  Thermogelling biodegradable aqueous polymer solution

United States Patent:  6,841,617

Issued:  January 11, 2005

Inventors:  Jeong; Byeong Moon (Richland, WA); Gutowska; Anna (Richland, WA)

Assignee:  Battelle Memorial Institute (Richland, WA)

Appl. No.:  833460

Filed:  April 11, 2001

Abstract

Disclosed is a thermogelling biodegradable aqueous polymer solution useful in providing a bioactive agent delivery system. The present invention provides a thermogelling biodegradable aqueous polymer solution with a polyethylene glycol (PEG) block and a biodegradable polyester block, where the blocks are linked to form a polymer of a general structure comprising the formula of A_n (B), where n is greater than 2 and A is selected from the group consisting of a polyethylene glycol block and a biodegradable polyester block, B is selected from the group consisting of a polyethylene glycol block and a biodegradable polyester block, and A is different from B.

Description of the Invention

FIELD OF THE INVENTION

The disclosure relates to a thermogelling biodegradable aqueous polymer solution composition and methods of use of such polymers for providing in situ forming, biodegradable implants.

BACKGROUND OF THE INVENTION

Materials that gel in situ have recently gained attention as promising implantable drug delivery systems as well as injectable matrices for tissue engineering. There is an emerging need for materials that are biocompatible, promote cellular proliferation and biosynthesis, support physiological loads, and are easily manipulated and synthesized. Materials that gel in situ are promising as they are easily handled and permit cell seeding, they offer the ability to form any desired implant shape, and may be engineered to be biodegradable and biocompatible.

In situ gelation is the bases of injectable systems that eliminate the need for surgical procedures and offers the advantage of the ability to form any desired implant shape. The change in molecular association can be driven by changes in temperature, pH, or solvent composition. Among the candidates of stimuli sensitive systems, organic solvent-free injectable systems are designed by using the thermosensitive sol-to-gel transition of aqueous solution. Such a system enables bioactive agents to be easily entrapped.

To perform as an ideal injectable system, the aqueous solution of a polymer should exhibit low viscosity at formulation conditions and gel quickly at physiological conditions. Considering the biomedical applications, the biocompatibility of the polymers is also an important issue. Therefore, the material should be biodegradable, and by keeping water-rich hydrogel properties it should not induce tissue irritation during the degradation.

In situ gelling of aqueous Poloxamer 407 and N-isopropylacrylamide copolymers have been studied as candidate materials for injectable drug delivery systems and also tissue engineering applications. These materials are, however, non-biodegradable and animal studies demonstrated an increase in triglyceride and cholesterol after intraperitoneal injection of the aqueous Poloxamer 407 solution.⁹

Recently, Jeong et al. reported biodegradable, in situ gelling poly(ethylene glycol-b-(DL-lactic acid-co-glycolic acid)-b-ethylene glycol), (PEG-PLGA-PEG), triblock copolymers. (See U.S. Pat. No. 6,117,949) They exhibited promising properties as an injectable drug delivery system. In vivo studies in rats demonstrated that the copolymer gels were still present after one month. During the degradation, the initially transparent gel became opaque due to preferential mass-loss of hydrophilic PEG rich segments. This change in morphology and the generation of an interface or phase might denature the protein drugs or cause cell deterioration in tissue engineering. In vitro release of porcine growth hormone (PGH) and insulin from the in-situ formed gel stopped after releasing 40-50% of loaded proteins.

Recently, several protein/peptide drugs demonstrated excellent efficacy in clinical trials and have been introduced to the market. With the advent of genetic engineering, proteins/peptides will soon become much more common drugs. However, due to the short plasma half-life and instability of proteins, there are urgent needs for suitable delivery vehicles. Certain drug formulations need a one to two-week delivery system. Moreover, a one to two-day delivery system may be required. For example, ifosfamide, a drug used for germ cell testicular cancer, is administered intravenously for 5 consecutive days. This treatment is repeated every three weeks or after recovery from hematological toxicity. In order to prepare such a short-term delivery system, poly(ethylene glycol) grafted with poly(lactic acid-co-glycolic acid) (PEG-g-PLGA), where hydrophilic PEG is a backbone, is designed. This material is expected to show a different gelation and degradation behavior, and consequently, a different drug release profile as compared to PEG-PLGA-PEG.

The following references disclose processes or compounds useful in this art:

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SUMMARY OF THE INVENTION

The present invention provides a thermogelling biodegradable aqueous polymer solution with a polyethylene glycol (PEG) block and a biodegradable polyester block, where the blocks are linked to form a polymer of a general structure comprising the formula of A_n (B), where n is greater than 2 and A is selected from the group consisting of a polyethylene glycol block and a biodegradable polyester block, B is selected from the group consisting of a polyethylene glycol block and a biodegradable polyester block, and A is different from B.

It is an object of the present invention to provide a thermogelling biodegradable polymer solution having utility as a bioactive agent delivery system.

A further object of this invention is to provide a drug delivery system that can be injected parenterally.

Another object of this invention is to provide a drug delivery system that allows control of polymer degradation rate or duration of a sustained gel by controlling the number of branches linked to the backbone of the structure or by mixing a first polymer comprising the formula A_n (B) with at least one other polymer comprising the formula A_n (B), wherein the first polymer is different from said at least one other polymer.

Still another object of this invention is to provide a drug delivery system that allows control of the stability of drugs and drug dosage from one day to two months.

Another object of this invention is to provide block copolymer drug delivery systems that are biodegradable.

Still another object of this invention is to provide block copolymer drug delivery systems that demonstrate desirable release rates.

Another object of this invention is to provide injectable block copolymer drug delivery systems that are in solution at room temperature or lower and gel at or about physiological temperature.

Yet another object of this invention is to provide injectable drug delivery systems that eliminate the need for surgical procedures and offers the advantage of the ability to form any desired implant shape.

Still another object of this invention is to provide stimuli sensitive, organic solvent-free injectable drug delivery systems that are designed by using the thermosensitive sol-to-gel transition of aqueous solutions.

Yet another object of this invention is to provide an aqueous solution of a polymer that exhibits low viscosity at formulation conditions and gels quickly at physiological conditions.

Still yet another object of this invention is to provide drug delivery systems that can provide desired release rates by varying the ratio of polyethylene glycol (PEG) block and a biodegradable polyester block.

Additional objects and advantages of this invention will become apparent from the following summary and detailed description of the various embodiments making up this invention.

There is an emerging need for materials that are biocompatible, promote cellular proliferation and biosynthesis, support physiological loads, and are easily manipulated and synthesized. Materials that gel in situ are promising as they are easily handled, permit cell seeding, and they offer the ability to form any desired implant shape. The present invention is well suited for delivery of cells, whereby the thermogelling biodegradable aqueous polymer solution provides a scaffold for tissue repair and organ regeneration. The present invention offers several advantages including: the flowability of the thermogelling biodegradable aqueous polymer solutions can fill any shape of a defect, promotion of tissue integration, easily incorporates live cells and various therapeutic agents (e.g. growth factors), and finally enables minimally invasive placement.

Therefore, another object of this invention is to provide a thermogelling biodegradable polymer solution having utility in tissue engineering.

Still another object of this invention is to provide a thermogelling biodegradable polymer solution having utility as a cell delivery system.

Yet still another object of this invention is to prepare biodegradable solubilizes for hydrophobic drugs. Due to surfactant nature of the PEG-g-PLGA and PLGA-g-PEG, this polymer can be used as a solubilizer for hydrophobic drug formulations.

For a clear and concise understanding of the specification and claims, including the scope given to such terms, the following definitions are provided:

Bioactive Agent: As used herein, a "bioactive agent" shall mean any drug, molecule, biomolecule, or cell.

Drug: As used herein, a "drug" shall mean any organic compound or substance having bioactivity and adapted or used for a therapeutic purpose.

Polypeptide: As used herein, a "polypeptide" shall mean any peptide, polypeptide, oligopeptide, and/or protein used as a drug and shall not be limited by molecular weight, sequence, length, activity or use.

Parenteral: Administering into the body or administered in a manner other than through the digestive tract, as by intravenous or intramuscular injection.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is a biodegradable polymer solution, comprising a polyethylene glycol (PEG) block, and a biodegradable polyester block linked to form a polymer of a general structure comprising the formula of A_n (B), where n is greater than 2 and A is selected from the group consisting of a polyethylene glycol block and a biodegradable polyester block, B is selected from the group consisting of a polyethylene glycol block and a biodegradable polyester block, and A is different from B.

The present invention further provides a thermogelling biodegradable aqueous polymer solution which comprises a biodegradable polymer solution, comprising a polyethylene glycol (PEG) block, and a biodegradable polyester block linked to form a polymer of a general structure comprising the formula of A_n (B), where n is greater than 2 and A is selected from the group consisting of a polyethylene glycol block and a biodegradable polyester block, B is selected from the group consisting of a polyethylene glycol block and a biodegradable polyester block, and A is different from B, and an aqueous solution.

The thermogelling biodegradable aqueous polymer solution is preferred when prepared with the formula A_n (B) as described previously and n is between 3 and 10.

The biodegradable polyester block is preferably a member selected from the group consisting of poly(DL-lactic acid), poly(L-lactic acid), poly(glycolic acid), poly(.epsilon.-caprolactone), poly(.gamma.-butyrolactone), poly(.alpha.-valerolactone), poly(.beta.-hydroxybutyric acid), and their copolymers or terpolymers. It is also preferred that the copolymers and/or terpolymers are selected from the group consisting of poly(DL-lactic acid-co-glycolic acid), poly(L-lactic acid-co-glycolic acid), poly(.epsilon.-caprolactone-co-DL-lactic acid), copoly(.epsilon.-caprolactone-co-DL-lactic acid-glycolic acid). The above listing of suggested biodegradable polyester blocks is not intended to be all-inclusive. The biodegradable polyester blocks can have a maximum molecular weight of 100,000 with a preferred range of about 1,000 and 30,000, and most preferably between about 1,000 and 10,000. The biodegradable polyester blocks are limited as a result of the desire to accommodate a solubility limit and not because of degradability

It is preferred that the polyethylene glycol (PEG) block have an average molecular weight of between about 300 and 20,000 and is more preferably between about 500 and 10,000. The PEG block with a higher molecular weight than 10,000 is hard to be filtered through glomeruli filtration.

The present invention provides an effective biodegradable bioactive agent delivery liquid, comprising an effective amount of bioactive agent contained in thermal gelling biodegradable aqueous polymer solution comprising a polyethylene glycol (PEG) block, and a biodegradable polyester block linked to form a polymer of a general structure comprising the formula of A_n (B), where n is greater than 2 and A is selected from the group consisting of a polyethylene glycol block and a biodegradable polyester block, B is selected from the group consisting of a polyethylene glycol block and a biodegradable polyester block, and A is different from B.

It is understood that the present invention can make use of any bioactive agent, which can be any drug, molecule, biomolecule, or cell. As well, the present invention can provide as a delivery system for other matter requiring a sustained release rate.

The thermogelling biodegradable aqueous polymer solutions of the present invention are useful as drug delivery systems that provide as a carrier for drugs. A drug is an organic compound or substance having bioactivity and adapted or used for a therapeutic purpose including but not limited to anti-cancer agents, hormones, antibiotics, narcotic antagonists, analgesics, anti-inflammatory agents, anti-depressants, anti-epileptics, anti-malarial agents, immunoactivators, growth factors, gene therapy agents, oligonucleotides, therapeutic peptides and proteins, and combinations thereof. In particular, the present invention provides a very useful delivery system for polypeptide and protein drugs that require a short biodegradation period to accommodate the requirement for a specific sustained release rate due to the short plasma half-life and instability.

Because the polymers of the present invention are composed of hydrophobic and hydrophilic blocks and the surfactant nature, this polymer can be used as a solubilizer for hydrophobic drug formulations. This property enables these polymers to be used as a solubilizer of hydrophobic drugs. Typical cancer drugs, such as Taxol, have good efficacy while they tend to have low solubility in water. The polymers of the present invention can be used as biocompatible solubilizers for such drugs.

The present invention is well suited for delivery of anti-cancer agents. It is preferred that the anti-cancer agents be selected from the group consisting of adriamycin, mitomycin, bleomycin, cisplatin, carboplatin, doxorubicin, daunorubicin, 5-fluouroacil, methotrexate, taxol, taxotere, and actinomycin D. It is understood that other anti-cancer agents may work as well with this invention and the preceding list is not meant to be all-inclusive.

The present invention is equally well suited for delivery of polypeptides. It is preferred that that polypeptides be selected from the group consisting of oxytocin, vasopressin, adrenocorticotropic growth factor (PDGF), prolactin, luliberin or luteinising hormone releasing hormone (LHRH), growth hormone, growth hormone releasing factor, insulin, somatostatin, glucagons, interleukin-2 (IL-2), interferon-.alpha.,.beta.,.gamma. (IFN-.alpha.,.beta.,.gamma.), gastrin, tetragastrin, pentagastrin, urogastroine, secretin, cacitonin, enkephalins, endorphins, angiotensins, thyrotropin releasing hormone (TRH), tumor necrosis factor (TNF), nerve growth factor (NGF), granulocyte-colony stimulating factor (G_CSF), granulocyte macrophage-colony stimulating factor (M-CSF), rennin, bradykinin, bacitracins, polymixins, colistins, tyrocidin, gramicidines, and synthetic analogues, modifications and pharmacologically active fragments thereof, monoclonal antibodies and soluble vaccines. This list is not all-inclusive and it is understood that other proteins can be used as well.

The present invention is well suited for delivery of cells. The thermogelling biodegradable aqueous polymer solution comprising cells provides a scaffold for tissue repair and organ regeneration as well as for therapeutic use.

A useful aspect of the present invention is method for the delivery of a bioactive agent in a thermogelling polymer matrix to a warm-blooded animal for the controlled release of the bioactive agent. Fundamental to this aspect of the invention is to provide an injectable thermogelling biodegradable aqueous polymer solution which comprises a polyethylene glycol (PEG) block, a biodegradable polyester block, wherein the blocks are linked to form a polymer of a general structure comprising the formula of An(B), where n is greater than 2 and A is selected from the group consisting of a polyethylene glycol block and a biodegradable polyester block, B is selected from the group consisting of a polyethylene glycol block and a biodegradable polyester block, and A is different from B. The thermogelling biodegradable aqueous polymer solution is then mixed with an effective amount of a bioactive agent to form a polymer-bioactive agent mixture, maintained at a temperature below the gelling temperature of the polymer, and provided into a warm blooded animal to form a gel depot as the temperature is raised by the body temperature of the animal to be above the gelling temperature of the polymer. It is recognized that this aspect of the present invention can have various forms of application. For example, it is well suited to use this method of application when it is desired to apply a bioactive agent to a warm-blooded animal during a surgical procedure where a portion of the body of the warm-blooded animal is exposed. By applying the polymer-bioactive agent mixture to an area exposed during surgery will allow the formation of a depot to a specific/desired area.

Another aspect of the present invention is method for the parenteral delivery of a bioactive agent in a thermogelling polymer matrix to a warm-blooded animal for the controlled release of the bioactive agent. Fundamental to this aspect of the invention is to provide an injectable thermogelling biodegradable aqueous polymer solution which comprises a polyethylene glycol (PEG) block, a biodegradable polyester block, wherein the blocks are linked to form a polymer of a general structure comprising the formula of An(B), where n is greater than 2 and A is selected from the group consisting of a polyethylene glycol block and a biodegradable polyester block, B is selected from the group consisting of a polyethylene glycol block and a biodegradable polyester block, and A is different from B. The injectable thermogelling biodegradable aqueous polymer solution is then mixed with an effective amount of a bioactive agent to form a polymer-bioactive agent mixture, maintained at a temperature below the gelling temperature of the polymer, and injected into a warm blooded animal to form a gel depot as the temperature is raised by the body temperature of the animal to be above the gelling temperature of the polymer. This aspect of the invention provides well when it is desired to provide a bioactive agent under controlled release without having to surgically expose a warm-blooded animal. Several injectable routes including intradermal or intracutaneous, subcutaneous or hypodermic, intramuscular, intravenous, and intraspinal can administer the polymer-bioactive agent mixture parenterally.

Claim 1 of 17 Claims

We claim:

1. A thermogelling biodegradable aqueous polymer solution, comprising:

a. a biodegradable graft polymer, comprising:

i. a polyethylene glycol (PEG) block, and

ii. a biodegradable polyester block, wherein

iii. said blocks are linked to form a polymer of a general structure comprising the formula of A_n (B), where n is greater than 2 and A is selected from the group consisting of a polyethylene glycol block and a biodegradable polyester block, B is selected from the group consisting of a polyethylene glycol block and a biodegradable polyester block, and A is different from B;and

b. an aqueous solution.

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