Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2002-03-15
2004-05-04
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S182000
Reexamination Certificate
active
06730664
ABSTRACT:
The present invention relates to pharmaceutical formulations of estramustine phosphate for parenteral use and, more particularly, to formulations of estramustine phosphate for parenteral use further comprising sulfoalkyl ether cyclodextrins.
Estramustine phosphate (The Merck Index, XII Ed., No. 3749, 1996) is an estradiol-17 &bgr;-phosphate derivative widely known in the art as antitumor agent, currently used in the treatment of advanced adenocarcinoma of the prostate.
The drug is usually administered orally, preferably at a dose of 10-15 mg/kg/day. Intravenous administration, however, is also adopted in some particular cases.
For example, initial intravenous administration of estramustine phosphate, followed by oral administration, has been reported at dosages paralleling the oral administration for the drug, i.e. 300-600 mg daily given intravenously and usually repetitively over for several consecutive days (see, for a reference, British Journal of Urology, 1977, 49, 73-79; J. Urol.108:303-306, 1972; Eur. Clin. Pharmacol. 26(1), 113-119, 1984; Eur. Urol. 1990, 17, 216-218).
Estramustine phosphate as well as other well-known cytotoxic compounds used in antitumor therapy are known to cause, or potentially cause, vascular damages at the site of injection when parenterally, in particular intravenously, administered.
As an example, studies in patients treated with estramustine phosphate administered as a slow intravenous injection or as a bolus, at 300 mg/day, revealed thrombophlebitis and local irritations at the peripheral intravenous injection sites.
These drawbacks are considered major limitations for the intravenous administration of estramustine phosphate, thus requiring, in many patients, the establishment of central line administration or, in some cases, even discontinuation of the treatment.
With the aim of minimising the unwanted effects associated with the intravenous administration of cytotoxic agents, a few means are reported in the art.
Among them is the use of hydroxypropyl-cyclodextrin, in the preparation of formulations for parenteral administration of cytotoxic known to cause ulcerative lesions. See, for a reference, U.S. Pat. No. 5,804,568 in the name of Supergen Inc.
Sulfoalkyl ether cyclodextrins are known in the art as solubilizing agents for insoluble or poorly soluble drugs (see, for a reference, U.S. Pat. No. 5,134,127 in the name of the University of Kansas).
In this respect, we found formulations for parenteral use comprising estramustine phosphate together with sulfoalkyl ether cyclodextrins which, unexpectedly, resulted to achieve optimal protection from side-effects associated with estramustine administration.
It is therefore the object of the present invention a formulation for parenteral use comprising estramustine phosphate in admixture with a sulfoalkyl ether cyclodextrin.
Once administered intravenously to patients, the formulations object of the present invention do not provoke ulcerative damages, nor thrombophlebitis, at the site of injection.
In the present invention, unless otherwise specified, with the term formulation comprising estramustine phosphate, as the active ingredient, we intend any formulation comprising estramustine phosphate either in the acid form or as a pharmaceutically acceptable salt for parenteral administration such as, for instance, a salt with a basic amino acid or with N-methyl glucamine, otherwise referred to as meglumine.
Preferably, estramustine phosphate is in the form of its meglumine salt. With the term sulfoalkyl ether cyclodextrin we refer to any cyclodextrin of the above type wherein alkyl stands for straight or branched C
1
-C
6
alkyl group such as methyl, ethyl, n.propyl, isopropyl, n.butyl, isobutyl, sec-butyl, tert-butyl, n.pentyl, n.hexyl and the like.
Preferably, the formulations of the present invention comprise estramustine phosphate in admixture with sulfobutyl ether &bgr;-cyclodextrin.
According to a preferred embodiment of the invention, the above formulations are advantageously used for intravenous use.
As such, these formulations of the invention can be administered to patients either as a slow injection, e.g. over about 30 minutes to about 3 hours, or as a bolus injection, also referred to as IV (intravenous) push.
Preferably, these formulations comprise estramustine phosphate in admixture with a sulfoalkyl ether cyclodextrin wherein the weight ratio between estramustine phosphate and sulfoalkyl ether cyclodextrin is from about 1:1 to about 1:5, respectively.
Formulations containing even higher amounts of sulfoalkyl ether cyclodextrin with respect to the active, are however still effective and thus comprised within the scope of the present invention.
In addition, it is herewith provided a very advantageous method for delivering estramustine phosphate intravenously, even when high doses of the active are needed.
It is therefore a further object of the invention a formulation for parenteral use comprising estramustine phosphate, as a single infusion dosage of the active exceeding 1300 mg, in admixture with a sulfoalkyl ether cyclodextrin.
According to another preferred embodiment of the invention, it is further provided a formulation for parenteral use comprising estramustine phosphate, as a single infusion dosage of the active exceeding 950 mg/m
2
, in admixture with a sulfoalkyl ether cyclodextrin.
In a yet further preferred embodiment, the estramustine phosphate is provided in lyophilised form and the sulfoalkyl ether cyclodextrin is provided in physiological solution. Formulations of this type may typically be presented as a kit.
The formulations object of the present invention allow the administration of the active either as a single agent or, alternatively, in combination with known anticancer treatments such as radiation therapy or chemotherapy regimen in combination with cytostatic or cytotoxic agents, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, e.g. aromatase inhibitors, immunological agents, interferon-type agents, cyclooxygenase inhibitors (e.g. COX-2 inhibitors), metallomatrixprotease inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti-growth factor receptor agents, anti-HER agents, anti-EGFR agents, anti-angiogenesis agents, farnesyl transferase inhibitors, ras-raf signal transduction pathway inhibitors, cell cycle inhibitors, other cdks inhibitors, tubulin binding agents, topoisomerase I inhibitors, topoisomerase II inhibitors, and the like.
As an example, the above formulations can be administered in combination with one or more chemotherapeutic agents, optionally within liposomal formulations thereof.
Examples of chemotherapeutic agents are, for instance, taxane, taxane derivatives, CPT-11, camptothecin and derivatives thereof, anthracycline glycosides, e.g. doxorubicin, idarubicin or epirubicin, etoposide, navelbine, vinblastine, carboplatin, cisplatin and the like, optionally within liposomal formulations thereof.
In addition, the above formulations can be also administered in combination with protein kinase inhibitors such as, for instance, the indolinone derivatives disclosed by Sugen in the international patent applications WO 96/40116 and WO 99/61422, which are herewith incorporated by reference.
In this respect, the formulations object of the invention can be preferably administered in combination with 3-[4-(2-carboxyethyl-3,5-dimethylpyrrol-2-yl)methylidenyl]-2-indolinone and 3[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone, better known as Sugen SU 6668 and SU 5416, respectively.
The formulations of the invention may be administered sequentially with known anticancer agents when a combination formulation is inappropriate.
Therefore, it is a further object of the present invention a product containing a formulation for parenteral use of estramustine phosphate in admixture with a sulfoalkyl ether cyclodextrin and one or more chemotherapeutic agents, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.
Toxicology
To study the local irritant effects of est
Buzzi Giovanni
Colombo Paolo
Martini Alessandro
Muggetti Lorena
Maier Leigh C.
McDonnell Boehnen & Hulbert & Berghoff LLP
Pharmacia Italia S.p.A.
Wilson James O.
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