Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2000-05-19
2003-03-25
Pryor, Alton (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
Reexamination Certificate
active
06537579
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods for the production of particulate vehicles for the intravenous administration of pharmacologically active agents, novel compositions produced thereby, and methods for in vivo delivery thereof.
BACKGROUND OF THE INVENTION
The anticancer agent paclitaxel (TAXOL for Injection Concentrate, Bristol Myers Squibb (BMS)) has remarkable clinical activity in a number of human cancers including cancers of the ovary, breast, lung, esophagus, head and neck region, bladder and lymphomas. It is currently approved for the treatment of ovarian carcinoma and non-small cell lung cancer where it is used in combination with cisplatin; for metastatic breast cancer that has failed prior treatment with one combination chemotherapy regimen; and for AIDS-related Kaposi's sarcoma. The major limitation to the use of paclitaxel is its poor solubility and consequently the BMS formulation (TAXOL) contains Cremophor® EL as the solubilizing vehicle. Each vial of TAXOL contains 30 mg of paclitaxel dissolved in Cremophor/ethanol vehicle at a concentration of 6 mg/mL. Prior to intravenous administration, this formulation must be diluted 1:10 in saline to produce a final dosing solution containing 0.6 mg/mL of paclitaxel. The presence of Cremophor in this formulation has been linked to severe hypersensitivity reactions in animals (Lorenz et al., 1987, “Histamine Release in Dogs by Cremphor EL® and its derivatives: Oxethylated oleic acid is the most effective constituent”.
Agents Actions
7:63-67, 1987) and humans (Weiss et al., 1990, “Hypersensitivity reactions from Taxol”,
J Clin Oncol
8:1263-1268, 1990) and consequently requires premedication of patients with corticosteroids (dexamethasone) and antihistamines. The large dilution results in large volumes of infusion (typical dose 175 mg/m
2
) in up to one liter and infusion times ranging from three hours to 24 hours. Thus, there is a need for an alternative, less toxic formulation for paclitaxel.
In a study by Holmes (Holmes F A, Walters R S, Theriault R L, et al: Phase II trial of Taxol, an active drug in the treatment of metastatic breast cancer.
J Natl Cancer Inst
83:1797-1805, 1991) and at MKSCC (Reichman B S, Seidman A D, Crown J P A, et al: Paclitaxel and recombinant human granulocyte colony stimulating factor as initial chemotherapy for metastatic breast cancer.
Clin Oncol
11:1943-1951, 1993) it was shown that higher doses of TAXOL to 250 mg/m
2
produced greater responses (60%) than the 175 mg/m
2
dose (26%) currently approved for TAXOL. These results however, have not been reproduced due to higher toxicities at these higher doses. These studies, however, bear proof to the potential increase in response rate at increased doses of paclitaxel. The invention formulations described herein may allow the administration of highter doses then are possible with TAXOL due to lower toxicity of the formulation, thereby exploiting the full potential of this drug.
Bristol-Myers Squibb tested TAXOL in clinical trials on patients previously treated for ovarian and breast cancer that did not respond to standard therapies. Following are summaries of information as reported in the package insert for TAXOL:
Following intravenous administration of TAXOL, paclitaxel plasma concentrations declined in a biphasic manner. The initial rapid decline represents distribution to the peripheral compartment and elimination of the drug. The later phase is due, in part, to a relatively slow efflux of paclitaxel from the peripheral compartment.
With the 24-hour infusion of TAXOL, it appeared that an increase in dose from 135 mg/m
2
to 175 mg/m
2
(30%) increased the C
max
by 87% whereas the AUC (0-∞) remained proportional. However, with a 3-hour infusion, the dose increase from 135 to 175 mg/m
2
caused an increase in the C
max
and AUC (0-∞) of 68% and 89%, respectively. The mean apparent volume of distribution with the 24-hour infusion of TAXOL ranged from 227 to 688 L/m
2
, indicating extensive extravascular distribution and/or tissue binding of paclitaxel.
In Phase I and II studies, pharmacokinetics of TAXOL were also evaluated in adult cancer patients who received single doses of 15-135 mg/m
2
given by 1-hour infusions (n=15), 30-275 mg/m
2
given by 6-hour infusions (n=36), and 200-275 mg/m
2
given by 24-hour infusions (n=54). Values from these studies were consistent with the findings in the above study.
In vitro studies were used to study the binding of paclitaxel to human serum proteins. Between 89-98% of drug was bound for paclitaxel concentrations ranging from 0.1 to 50 &mgr;g/mL. The presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel.
The disposition of paclitaxel has not been fully elucidated in humans. Mean (SD) values for cumulative urinary recovery of unchanged drug ranged from 1.3% (0.5%) to 12.6% (16.2%) of the dose after intravenous administration, indicating extensive non-renal clearance for 15-275 mg/m
2
doses of TAXOL as 1, 6, or 24-hour infusion. Since TAXOL has been demonstrated to be metabolized in the liver in animals, the evidence suggests hepatic metabolism in humans. In addition, high paclitaxel concentrations have been reported in the bile of patients treated with TAXOL. However, effects of renal or hepatic dysfunction on the disposition of paclitaxel have not been investigated.
Review of recent literature indicates that there are several Phase I and II studies in progress to study possible interactions of paclitaxel with concomitantly administered medications. In general, platinum-based concomitant therapies and sequence/time intervals influence both toxicity and efficacy. Also, paclitaxel can function as a radiosensitizer when used in combination with radiation therapy.
The initial approval of the TAXOL formulation of paclitaxel was based on Phase I and II studies of 189 patients and a Phase III study with 407 patients who had failed initial or subsequent chemotherapy for metastatic carcinoma of the ovary. In the first 2 studies, response rates were 22% (95% Cl=11-37%) and 30% (95% Cl=18-46%) with a total of six complete and 18 partial responses in 92 patients.
The median duration of overall response in these two studies measured from the first day of treatment was 7.2 months (range: 3.5-15.8 months) and 7.5 months (range: 5.3-17.4 months), respectively. The median survival was 8.1 months (range: 0.2-36.7 months) and 15.9 months (range: 1.8-34.5 months).
The Phase III study compared the efficacy and safety of TAXOL, administered at 135 or 175 mg/m
2
paclitaxel with either three or 24 hour infusion schedules. The results are summarized in Table 1.
TABLE 1
Key Efficacy Parameters in the
Phase III Ovarian Carcinoma Study
TAXOL dose (mg/m
2
/hrs)
175/3
175/24
135/3
135/24
Parameter
(N = 96)
(N = 106)
(N = 99)
(N = 106)
Response rate (percent)
14.6
21.7
15.2
13.2
Time to progression
4.4
4.2
3.4
2.8
median (months)
Survival
11.5
11.8
13.1
10.7
median (months)
The most frequently observed adverse events involved myelosuppression with 352 episodes of neutropenia of <2,000/mm
3
and 183 episodes of neutropenia of <500/mm
3
. Episodes of thrombocytopenia with <100,000/m
3
and <50,000/m
3
were 36 and 11, respectively. Episodes of anemia with <11 g/dL and <8 g/dL were 330 and 39, respectively. There were also 93 episodes of infection. There were 169 episodes of hypersensitivity reactions, five of which were severe. Also there were 220 observations of peripheral neuropathy (with three severe cases) and 98 observations of mucositis (with three severe cases).
The initial approval of the TAXOL formulation of paclitaxel for use on patients with breast cancer after failure of combination chemotherapy for metastatic disease or relapse within six months of adjuvant chemotherapy was based on data from 83 patients in three Phase II studies. TAXOL was administered to 53 patients as a 24-hour infusion at initial doses of 250 mg/m
2
(with G-CS
Desai Neil P.
Soon-Shiong Patrick
American BioScience, Inc.
Foley & Lardner
Pryor Alton
Reiter Stephen E.
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