Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2001-04-10
2003-05-27
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S484000, C424S486000, C424S499000, C424S400000, C424S426000
Reexamination Certificate
active
06569459
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the field of delivery of anti-tumor chemotherapeutics and more particularly to delivery of the anti-tumor chemotherapeutic, paclitaxel.
BACKGROUND
Paclitaxel is a high molecular weight (854 g/mole), highly lipophilic cytotoxic chemotherapeutic used as an anti-tumor agent in the treatment of carcinomas of the ovary, breast, lung and in the treatment AIDS related Karposi's sarcoma. Paclitaxel is currently used to treat breast cancer by pre-operatively administering the drug systemically. The pre-operation treatment reduces tumor burden prior to surgery, thus potentially improving the post-surgery prognosis. Although impressive success has been achieved using this approach, the treatment requires prolonged hospitalization and is accompanied by severe side-effects. Moreover, a significant number of cases (30%) do not result in a clinically satisfactory outcome either because the tumors are not reduced or because the side effects require that paclitaxel dosing be discontinued.
Paclitaxel's cytotoxic and anti-tumor properties derive from its ability to promote apoptosis (programed cell death) by inducing the assembly of microtubules from tubulin dimers and preventing microtubules from depolymerization. The stabilized microtubules inhibit normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic functions. In addition paclitaxel induces abnormal arrays or “bundles” of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.
Paclitaxel Formulations
Paclitaxel is substantially water insoluble and must be administered using a solubilizing carrier. The currently approved paclitaxel carrier formulation, marketed as TAXOL®, comprising pacitaxel dissolved in ethanol and CREMOPHOR®EL (polyoxyethylated castor oil).
The TAXOL® carrier CREMOPHOR®EL can cause side effects, such as anaphylaxis and severe hyper-sensitivity. (Sarosy and Reed,
J Natl Med Assoc
(1993) 85(6):427-31.) To reduce the side effects, current recommended treatment with TAXOL® includes pre-medication with corticosteroids, diphenhydramine and H
2
antagonists.
Several alternative carriers have been proposed to address the anaphylaxis and severe hyper-sensitivity caused by the CREMOPHOR®EL. For example, U.S. Pat. No. 5,684,169, which is incorporated by reference, discloses unbranched cyclodextrin or branched cyclodextrin inclusion complexes of paclitaxel which improves the solubility of paclitaxel in water. The complex is produced by adding an unbranched cyclodextrin or a branched cyclodextrin to paclitaxel at a molar ratio of 1-20 times with respect to paclitaxel. By improving solubility, the cyclodextrin inclusion complex improves paclitaxel absorption in cancer patients.
U.S. Pat. No. 5,415,869, which is incorporated by reference, discloses paclitaxel or paclitaxel tumor-active analogs solubilized using one or more negatively charged phospholipids and one or more zwitterionic phospholipids. The phospholipid mixture entraps paclitaxel or the analog in a liposome. The liposome is in the form of particles having a size of 0.025 to 10 microns, with substantially no crystals of paclitaxel or the analog.
U.S. Pat. No. 5,580,575, which is incorporated by reference, discloses a therapeutic drug delivery system comprising gas-filled microspheres and a therapeutic drug, as well as, methods for employing such microspheres in therapeutic drug delivery. The preferred microspheres of the disclosure are gas-filled liposomes with an encapsulated drug. Methods of preparing such liposomes in drug delivery applications are also disclosed.
WO 99/13914, incorporated herein by reference, discloses that paclitaxel, and other slightly water soluble drugs can be formulated without CREMOPHOR®EL or other toxic solubilizers by forming a water soluble homogeneous complex with plasma proteins, such as human serum albumin (HSA) or human gamma globulin (&ggr;-globulin). As disclosed by WO 99/13914 homogeneous aqueous solutions up to at least 4.68 mM paclitaxel (4 mg/mL) can be formulated using HSA. The plasma proteins act as a slow release depot of paclitaxel. WO 99/13914 further discloses a dosage range of paclitaxel-HSA complex containing 70-280 mg of paclitaxel per treatment. Such formulations can be made bio-equivalent to the conventional CREMOPHOR®EL containing formulations.
Other formulations for administering paclitaxel are disclosed in U.S. Pat. Nos. 5,504,102 and 5,407,683, incorporated herein by reference.
In addition, the slow infusion of CREMOPHOR®EL solutions has been studied as a means of avoiding or ameliorating the side effects of the CREMOPHOR®EL vehicle. The most common dosage is 135-175 mg/m
2
CREMOPHOR®EL, which is administered over a 3 hour, 6 hour, or 24 hour dosage schedule. (See U.S. Pat. Nos. 5,641,803, and 5,621,001, both incorporated herein by reference.) Other dosing schedules have been suggested to reduce toxic side effects, including 96 hour infusion every 21 days (U.S. Pat. No. 5,496,846, incorporated herein by reference) and 60-180 minutes, repeated a plurality of times during a 21 day period, each infusion separated by an interval of between 4 to 5 days. (U.S. Pat. No. 5,696,153, incorporated herein by reference).
Paclitaxel Chemotherapy Reservoir
An alternative method of administering paclitaxel is using a chemotherapy reservoir. U.S. Pat. Nos. 5,846,565, 5,626,862 and 5,651,986, which are incorporated by reference, discloses a method and devices for localized delivery of a chemotherapeutic agent to solid tumors, where the chemotherapeutic agent does not cross the blood-brain barrier and is characterized by poor bioavailability and/or short half-lives in vivo. The devices consist of reservoirs which release the chemotherapeutic over an extended period while at the same time preserving the bio-activity and bio-availability of the agent. The preferred embodiment is biodegradable polymeric matrices. Alternatively reservoirs can be made from non-biodegradable polymers or reservoirs connected to implanted infusion pumps. The devices are implanted within or immediately adjacent to the tumors to be treated or the site where tumors have been surgically removed. The patents further disclose the efficacy of paclitaxel and camptothecin delivered in polymeric implants prepared by compression molding of biodegradable and non-biodegradable polymers, respectively.
U.S. Pat. No. 5,888,530, which is incorporated by reference, discloses a method of enhancing the amount of a pharmaceutical composition delivered to a target tissue site in a mammal, by creating a transient differential between the hydrostatic pressure in the target site and a region near the target tissue site. An apparatus for performing the method is provided. In one form that apparatus includes a pharmaceutical reservoir, pump, and an agent reservoir and pump.
Chemotherapy reservoirs are also disclosed in U.S. Pat. No. 5,470,311 incorporated herein by reference.
Initial results testing such chemotherapy reservoirs have been disappointing. While a significantly lowered side effect profile has been demonstrated, there are no indications of clinical improvement.
The limitations of current chemotherapy reservoir technology is probably due to the retention of the chemotherapeutic drug only on the tumor periphery or at the injection site due to the poor penetration and distribution of the drug as a result of the neoplasm's high interstitial fluid pressure. A more potent anti-tumor effect can be achieved by targeting the chemotherapy directly to the tumor, i.e., intratumorally, rather than by systemic infusion.
We now report a method of delivering an anti-cancer chemotherapeutic, such as paclitaxel, by first administered paclitaxel by intratumoral injection and thereafter administering paclitaxel by intravenous injection. This invention takes advantage of the lower toxicity and side effects of paclitaxel/plasma solutions, and the ability of plasma proteins, such as HSA, to act as a slow release depot for paclitaxel.
SUMMARY
Bennett Rachel M.
Kenyon & Kenyon
Page Thurman K.
Teva Pharmaceutical Industries Ltd.
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