Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-07-21
2001-10-02
Geist, Gary (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S492000, C544S261000
Reexamination Certificate
active
06297245
ABSTRACT:
FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
There is no Federally sponsored research and development in this application.
BACKGROUND OF THE INVENTION
Cisplatin (cis-diamminedichloroplatinum, cis-Pt(NH
3
)
2
Cl
12
, molecular weight 300.05) has been used as a chemotherapeutic agent for many years since the discovery of its anti-tumor activity by B. Rosenberg et al. (
Nature
, 1965, 205, 698
; Nature
, 1972, 222, 385).
The physician's Desk Reference (PDR) reports that cisplatin (the commercial name is Platinol®) can be used to treat testicular cancer, ovarian cancer, and bladder cancer.
Rosenberg et al., U.S. Pat. No. 4,177,263, describes methods of treating cancer using cisplatin and cisplatin analogs. The compounds were effective for treating leukemia and tumors induced in mice.
Chemical & Engineering News (Oct. 23, 1995) reported that “[Cisplatin] was first synthesized in the 1800s, but its anticancer activity was not discovered until the 1960s. In 1979, it was approved by the Food & Drug Administration for clinical treatment of testicular and ovarian tumors and cancers of the head and neck. Cisplatin and an analog, carboplatin, are now among the most widely used anticancer drugs.”
After so many years, cisplatin is still being widely used because of its efficacy. However, its major drawback, the toxicity, is still a major concern.
Many attempts have been made to modify the cisplatin molecule in order to reduce its toxicity. Other attempts have been made to understand the interaction between cisplatin and DNA, which is the ultimate target of cisplatin. A few attempts have also been made to modify the composition of cisplatin dosage form to reduce its toxicity or improve its efficacy.
Many articles have been published which suggest modifying the composition of the dosage forms of cisplatin by combining it with other compounds. For example, cisplatin has been used in combination with caffeine by H. Yasutake et al. (
Gan to Kagaku Ryoho
1989, 16, 2031-8) and by H. Tsuchiya (
Kanazawa Daigaku Juzen Igakkai Zasshi
1988, 97, 543-56). Cisplatin has also been used in combination with cytosine arabinoside and the combination has shown some advantages as shown by J. Berek et al. (
Obstet. Gynecol
. 1989, 74, 663-6). Another combination, cisplatin and novobiocin, has also been shown to be advantageous by P. Eder et al. (Cancer Research 1989, 49 595-8, U.S. Pat. No. 5,130,145). This prior art indicates that when cisplatin and L-ascorbic acid are administered simultaneously, the anti-tumor activity is higher.
None of these prior arts suggest or disclose using folic acid along with cisplatin in a pharmaceutical composition for cancer therapy. This may be because folic acid has not been used as a conventional pharmaceutical excipient.
BRIEF SUMMARY OF THE INVENTION
This invention comprises a novel pharmaceutical composition comprising cisplatin and folic acid. Optionally, pharmaceutical excipients can be present.
This composition is different from the conventional pharmaceutical compositions, which do not contain folic acid.
Predominantly, cisplatin binds onto deoxyguanosine of DNA. However, cisplatin also binds onto other deoxynucleosides or nucleosides. Because of the non-selectivity of cisplatin, it can cause lots of side effects. Therefore, reducing the toxicity of cisplatin is a very important issue. In this invention, the novel composition comprising cisplatin and folic acid has been surprisingly demonstrated to be less toxic under lower calcium concentration. This results indicate that the novel composition has a broader dosage range than cisplatin at physiologic calcium concentration. Therefore, this invention is a better pharmaceutical composition than current cisplatin compositions.
Because cisplatin binds onto DNA or RNA, this composition may also be used to treat viruses, such as Human Immunodeficiency Virus (HIV), to bind its DNA or RNA and kill the virus. Thus, the composition may be used for the treatment of Acquired Immune Deficiency Syndrome (AIDS) patient. The composition may also be used in combination with other well known AIDS drugs, such as 3′-azidothymidine (AZT), to interfere with the HIV enzyme reverse transcriptase and achieve the goal of hampering the reproduction of HIV.
DETAILED DESCRIPTION OF THE INVENTION
This invention comprises a novel pharmaceutical composition comprising cisplatin and folic acid. Said pharmaceutical composition has a mole ratio between cisplatin and folic acid in the range of about 1:0.05 to 1:1, preferably 1:0.1 to 1:0.8, most preferably 1:0.2 to 1: 0.5.
Cisplatin is commercially available from many sources such as Sigma Chemical Company and Alfa Aesar. Folic acid is also commercially available from a variety of sources such as Spectrum Quality Products, Inc. and Sigma Chemical Company.
The composition of the present invention may optionally include other pharmaceutically acceptable excipients. Suitable pharmaceutical excipients are customary and physiologically acceptable such as sodium bicarbonate, mannitol, lactose, sodium chloride, phosphates, water, ethanol, hydrochloric acid, magnesium stearate, cellulose, starch, polyethylene glycol, etc. Therefore, the composition may be in a liquid or solid dosage form suitable for parenteral or oral administration to a patient.
The method of preparing the composition comprises the following:
(1) Combining cisplatin and folic acid in a solvent at a molar ratio of about 1:0.05 to 1:1 so that the percentage of cisplatin is 0.005% to 0.25% in the aliquot, whereas said solvent is water containing suitable amount of sodium bicarbonate, 0.1% to 99% methanol in water, 0.1% to 99% ethanol in water, 0.1% to 99% acetone in water, 0.05% to 5.0% sodium chloride in water, 0.0001 N to 1.0 N hydrochloric acid, or a mixture of said solvents.
(2) Stirring the aliquot until it becomes a solution.
(3) Filtering through a filter, preferably a filter with a porosity of between 0.1 &mgr;m to 1.0 &mgr;m, more preferably between 0.2 &mgr;m to 0.45 &mgr;m and collecting the filtrate.
(4) Optionally, drying the filtrate from step (3) under vacuum or by other standard pharmaceutical techniques.
(5) Optionally, reconstituting the dried composition from step (4) into a solution or a suspension by a suitable solvent. Typically, the percentage of cisplatin is 0.005% to 0.25%, preferably 0.01% to 0.1%. Suitable solvents include water containing sodium bicarbonate, ethanol, 0.1% to 90% ethanol in water, 0.05% to 5.0% sodium chloride in water, 0.0001 N to 1.0 N hydrochloric acid, or a mixture of said solvents.
(6) Optionally, blending the dried composition from step (4) with one or more physiologically acceptable pharmaceutical excipient(s). The resulting product can be encapsulated or compressed into capsules or tablets using standard pharmaceutical techniques.
This invention may be used to treat all cancers that may be treated by cisplatin. They include testicular cancer, ovarian cancer, bladder cancer, leukemia, and cancers of the head and neck. This invention may also be used to treat breast cancer as indicated by the in-vitro studies in example 4.
Another part of this invention is related to the method for treating cancer patients by this composition. The composition may be administered to a cancer patient orally, or by subcutaneous or intravenous injection, or by means of an implanted reservoir, or by means of applying on the cancerous skin.
The injectable compositions are normally in the form of an aqueous solution. If necessary, pharmaceutically-acceptable suspensions can be employed. Typically, such a solution contains cisplatin at a concentration of about 0.005%-0.25% (0.05 mg/mL-2.5 mg/mL), more commonly about 0.01%-0.1% (0.1 mg/mL-1 mg/mL). The dosage administered by injection comprises cisplatin in the range of about 5-1,000 mg in the first day of every 1-4 weeks depending upon the patient. Typically, one might administer a dosage of about 50-400 mg in the first day of every 1-4 weeks to a patient having a body weight of about 40-100 kg, although in appropriate cases such dosages may prove usef
Brinks Hofer Gilson & Lione
Crane L. E.
Geist Gary
Unitech Pharmaceuticals
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