Sustained release hydrophobic bioactive PLGA microspheres

Details Sustained release hydrophobic bioactive PLGA microspheres Sustained release hydrophobic bioactive PLGA microspheres

1997-08-21

2002-09-10

Criares, Theodore J. (Department: 1617)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C424S426000, C424S457000, C424S468000

Reexamination Certificate

active

06447796

ABSTRACT:

GOVERNMENT INTEREST
The invention described herein may be manufactured, licensed and used by or for governmental purposes without the payment of any royalties to us thereon.
FIELD OF THE INVENTION
This invention relates to providing novel pharmaceutical compositions for local delivery and burst-free programmable sustained release of hydrophobic drugs from biocompatible, biodegradable poly (DL-lactide-co-glycolide) (PLGA) microspheres. The resulting product is administered locally into soft tissues by sub-cutaneous or intra-muscular injection where it will locally sustain release the drug.
This invention relates generally to providing novel blend of end-capped and uncapped providing novel biocompatible and biodegradable PLGA microspheres for burst-free programmable sustained release of hydrophobic biologically active agents which degrade over a period of up to 100 days in an aqueous physiological environment. The active agents contemplated within the scope of this invention includes the delivery of poly-peptide antibiotics, antimalarials, antituberculosis drugs, anesthetics, analgesics, anticancer agents, antiparasitic agents, antibacterial agents, antifungal agents, antiinflammatory agents, immunosuppressive agents, immunostimulatory agents, dentinal desensitizers, odor masking agents, nutritional agents, antioxidants, and insulins.
The invention also relates especially to providing novel pharmaceutical compositions for sustained release of compounds for treating cancer, inflammatory and/or autoimmune disorders from PLGA microspheres.
BACKGROUND OF THE INVENTION
This invention is particularly effective for the localized delivery of chemotherapeutic hydrophobic anticancer agents, inclusive of paclitaxel(taxol)doxorubicin, 5-fluorouracil, campthothecin, cisplatin, and metronidazole, their corresponding derivatives and functionally equivalents, and combinations thereof from PLGA microspheres.
One-third of all individuals in the United States of America (U.S.) alone will develope cancer.
Although the five-year survival rate has risen dramatically to nearly fifty percent as a resulting progress in early diagnosis and the therapy, cancer still remains second only to cardiac disease as a cause of death in the U.S. Twenty percent of Americans die from cancer, half due to lung, breast, and colon-rectal cancer.
Breast cancer is the second leading cause of death in women in the U.S. Approximately 135,000 women are diagnosed with and 42,000 women die from breast cancer annually (1). Breast cancer treatment plans include a combination of surgery, radiotherapy, and chemotherapy (CT). The general treatment plan for stage I and II breast cancer is conservative surgery and radiotherapy (2,3,4,5). The general treatment plan for stage III and IV breast cancer is a combination of surgery, radiotherapy, and systemic CT using chemotherapeutic agents such as taxol (6,7,8,9,10).
Taxol treatment is recommended for the treatment of breast cancer when CT for metastatic disease has failed or when disease relapse has occurred within 6 months of adjuvant CT. Advantages of taxol treatment include: (1) lack of cardiotoxicity; (2) a mechanism of action, the stabilization of microtubules, which targets a large percentage of tumor cells, as opposed to normal cells; and (3) inhibition of angiogensis (11,12). Taxol is systemically administered intravenously (i.v.), primarily as a bolus administration. Systemic CT using taxol, as well as other chemotherapeutic drugs, is highly effective, in terms of additional years of life gained as a result of therapy; however, there are many problems associated with this treatment regimen. CT drugs are high by cytotoxic (13), and typically, large doses of CT drugs are needed to produce an optimal therapeutic response (13, 14); therefore, CT drugs have a low therapeutic index (13). Side effects commonly seen with taxol CT include: nausea, vomiting, fever, weight changes, musculoskeletal pain, neuropathy, general malaise, immune dysfunction, and the development of tumor resistance to taxol (9,15,16). An additional side effect seen in patients treated with taxol is a severe hypersensitivity reaction due to Cremophor EL, taxol's solubilizing agent (17). This side effect is controlled via patient pre-medication using a combination of corticosteroids, antihistamines, and histamine receptor antagonists. Often, patients become so ill during therapy that they are removed from treatment regimens or that-drug dosages are lowered. The consequence of these regimen changes is fluctuating drug levels, which equates to decreased efficacy. The problems associated with systemic taxol treatment signal the need for the development of a drug delivery system which offers a safer and a more effective means of administering toxic agents, such as taxol, to breast cancer patients, as well as to other cancer patients.
Delivery systems based on prolonged exposure to taxol have been investigated as a means to overcome the problems associated with bolus administration of taxol. These systems include infusional administration of taxol over 1,3,24, or 96 hours and administration of taxol via polymeric carrier vehicle. Infusional data suggests that cytotoxicity may be enhanced due to the increased exposure of cycling cells and has shown, in vitro, 4.4 fold less resistance in multi-drug resistant MCP-7 human breast carcinoma cells exposed to taxol for 24 hours as compared to 3 hours (16). A 96-hour taxol infusion study in patients with metastatic breast cancer showed that this infusion schedule: (1) was better tolerated than bolus administration of taxol, as evidenced by mild side effects, such as nausea and myalgia; (2) did not cause significant hypersensitivity reactions despite the omission of corticosteroid pre-treatment; (3) did not result in any cardiac, renal, or hepatic toxicity, and (4) resulted in major objective responses in 7/26 patients (26.9%), with a 6 month median response duration (16). In this trial, the predominant toxic side effect was granulocytopenia which resulted in taxol dose reduction in 3/26 patients (11.54%) and in hospitalization of 4/26 patients (15.38%). Taxol infusion regiments offer significant advantages over bolus administration of taxol in terms of systemic toxicity, efficacy, and resistance; however, immune dysfunction still appears to be the major limiting factor in the success of this treatment regimen.
Certain chemotherapeutics such as paclitaxel (taxol) and camptothecin, which are efficacious when administered systemically must be delivered at very high dosages in order to avoid toxicity due to poor bioavailability. For example, paclitaxel (taxol) has been used systemically with efficacy in treating several human tumors, including ovarian, breast, and non-small cell lung cancer. However, maintenance of sufficient systemic levels of the drug for treatment of tumors has been associated with severe, in some cases “life-threatening” toxicity, as reported by Sarosy and Reed, J.Nat. Med. Assoc. 85(6):427-431 (1993). Paclitaxel is a high molecular weight (854), highly lipophilic deterpenoid isolated from the western yew, Taxus brevifolia, which is insoluble in water. It is normally administered intravenously by dilution into saline of the drug dissolved or suspended in polyoxyethylated castor oil. This carrier has been reported to induce an anaphylactic reaction in a number of patients (sarosy and Reed (1993) so alternative carriers have been proposed, such as a mixed micellar formulation for parenteral administration, described by Alkan-Onyuksel, et al., Pharm. Res. 11(2), 206-212 (1994). There is also extensive non-renal clearance, with indications that the drug is removed and stored peripherally. Pharmacokinetic evidence from clinical trials (Rowinsky, E. K., et al., Cancer Res. 49:4640-4647 (1989) and animal studies (Klecker, R. W., Proc. Am. Assoc. Cancer Res. 43:381 (1993) indicates that paclitaxel penetrates the intact blood-brain barrier poorly, if at all, and that there is no increased survival from systemic intraperitoneal injections of paclitaxel into rats with

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