Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-05-01
2002-10-22
Russel, Jeffrey E. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C514S021800, C514S108000, C514S126000, C514S127000, C514S369000, C514S563000, C514S578000, C514S592000
Reexamination Certificate
active
06468963
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to pharmaceutical formulations of a reducible disulfide compound and a diabetes treatment agent. The invention also includes a method of reducing the risks associated with the administration of anti-diabetes agents by administration of a reducible disulfide compound.
BACKGROUND OF THE INVENTION
Treatments for diabetes mellitus are dependent upon the type and severity of the disease in individual patients. Insulin is still the treatment of choice for type I diabetes, and is now often combined with an oral anti-diabetic agent to better provide control of the patient's blood sugar levels and reduce the risk of complications due to either dangerously high or low levels.
Type II diabetes mellitus is normally controlled with oral anti-diabetic agents, and if the disease worsens insulin may be employed for better control of the disease. Although insulin and most oral anti-diabetic agents are well tolerated by most patients, the risk of toxic reactions remains. Further, since diabetics usually administer their own medications and must remain on these medications for life, the risks are multiplied over the course of a number of years.
The main danger with insulin therapy is the risk of acute hypoglycemia and of subsequent diabetic rebound reactions, either of which can mitigate complications ranging from skin flushing to stroke and coma, even death.
Use of oral anti-diabetic agents can also result in acute hypoglycemia and rebound reactions, and these agents have also resulted in unwanted toxic effects such as GI disturbances, hepatotoxicity, skin rashes and other allergic reactions, hematologic toxicity and others. At times the adverse effects are serious enough to warrant a drop in dosage or discontinuance of the drug.
Mesna (sodium 2-mercaptoethane sulfonate) and dimesna (disodium 2,2′-dithiobis ethane sulfonate) are known therapeutic compounds, which have heretofore demonstrated a wide variety of therapeutic uses. Both mesna and dimesna have been shown to be effective protective agents against certain specific types of toxicity associated with the administration of cytotoxic drugs used to treat patients for various types of cancer.
In particular, mesna has been used in humans with some success in mitigating the toxic effects of certain antineoplastic alkylating agents such as if osfamide, cyclophosphamide, melphalane, trofosfamide, sulfosfamide, chlorambucil, busulfan, triaziquone, triethylene thiophosphamide, and others, as disclosed in U.S. Pat. No. 4,220,660, issued Sep. 2, 1980.
The near absence of toxicity of dimesna further underscores the usefulness of this compound, as large amounts can be given to a patient without increasing the risk of adverse effects from the protective agent itself.
Further, pharmacological profiles of each compound indicate that, if proper conditions are maintained, mesna and dimesna do not prematurely inactivate the main drug to any significant degree. Thus, neither compound will significantly reduce activity of the chemotherapeutic agent, and in many cases, act to potentiate the effect of the main drug on targeted cancer cells.
The structures of both mesna and dimesna are shown below.
Mesna—HS—CH
2
—CH
2
—SO
3
Na
Dimesna—NaSO
3
—CH
2
—CH
2
—S—S—CH
2
—CH
2
—SO
3
Na
As shown, dimesna is a dimer of mesna, with the optimum conditions for oxidation occurring in the slightly basic (pH~7.3), oxygen rich environment found in blood plasma. In mildly acidic, low oxygen conditions, in the presence of a reducing agent such as glutathione reductase, conditions prevalent in the kidneys, the primary constituent is mesna.
Mesna and dimesna act as protective agents for a number of cytotoxic agents by substituting a nontoxic sulfhydryl moiety for a toxic hydroxy (or aquo) moiety. This action is particularly evidenced in the co-administration of mesna and an oxazaphosphorine, and in the administration of dimesna in conjunction with cisplatin and/or paclitaxel.
Mesna and dimesna, as well as most analogues of these compounds, have excellent toxicity profiles in mammalian species. Dimesna and other disulfide analogues have much better safety profiles than the mesna analogues having free thiol moieties. In fact, dimesna has been given to mice and dogs in doses higher than the accepted LD
50
for common table salt (3750 mg/kg), with no adverse effects. Dimesna has also been administered to humans in doses exceeding 40 g/m
2
, with no adverse effects.
Mesna, and other analogues with free thiol moieties, constitute the more physiologically active form of the two types of compounds described in this specification. These compounds manifest their activity by providing free thiol moieties for terminal substitution at locations where a terminal leaving group of appropriate configuration is located.
Also, it is known that compounds with one or more free thiols tend to be highly water soluble, which means that their activity is generated mainly in the extracellular space. This significantly decreases drug-induced cell damage, which is common with other compounds of this general type that are more prone to pass through cell walls.
This profile is especially significant in explaining the success of dimesna in controlling and mitigating the toxic effects of platinum complex and taxane antitumor drugs. The mechanism for action in the case of cisplatin (cis-diammine dichloro platinum) is explained in U.S. Pat. No. 5,789,000, which is incorporated herein by reference.
Mesna, dimesna, and analogues of these compounds have been the subject of several prior pharmaceutical uses described in the literature and in prior patents, both in the United States and around the world. In addition to the cytotoxic agent protection uses, one or more of these compounds have proven effective, in vitro, against a multiplicity of biological targets, and have been effective, in vivo, in the treatment of sickle cell disease, radiation exposure, chemical agent exposure, and other uses.
Mesna, dimesna, and analogues thereof are synthesized from commonly available starting materials, using acceptable routes well known in the art. One such method involves the two-step, single pot synthetic process for making dimesna and like compounds of the following formula:
R
1
—S—R
2
;
wherein:
R
1
is hydrogen, X-lower alkyl, or X-lower alkylene-R
3
;
R
2
is -lower alkylene-R
4
;
R
3
and R
4
are each individually SO
3
M or P0
3
M
2
;
X is absent or X is sulfur; and
M is hydrogen or an alkali metal.
The process essentially involves a two-step single pot synthetic process, which results in the conversion of an alkenyl sulfonate salt or acid to the desired formula I compound. The process in the case of mesna is a single step process, which converts the alkenyl sulfonate salt to mesna or a mesna derivative by reacting with an alkali metal sulfide or with hydrogen sulfide.
If the desired end product is dimesna or a dimesna analogue, a two-step single pot process is involved. Step 1 is as described above. Step 2 of the process is performed in the same reaction vessel as Step 1 without the need to purify or isolate the mesna formed during that step. Step 2 includes the introduction of oxygen gas into the vessel, along with an increase in pressure and temperature above ambient values, at least 20 pounds per square inch (psi) and at least 60° C. Dimesna or a derivative thereof is formed in essentially quantitative yield.
Other processes, well known and documented in the prior art, may be employed to make either mesna or dimesna, or derivatives and analogues thereof.
SUMMARY OF THE INVENTION
The formulations and methods of this invention are employed to reduce the toxic effects and related complications associated with the administration of insulin and oral anti-diabetic agents used to treat patients with diabetes mellitus.
The compounds used in within the context of this invention are of the following formula I:
R
1
—S—R
2
; (I)
wherein:
R
1
is hydrogen, X-lower alkyl, or X-lower alkylene-R
3
;
R
2
is -lower alkylene-R
4
;
R
3
and R
4
are each individually SO
Hamilton Susan E.
Hausheer Frederick H.
Parker Aulma
BioNumerik Pharmaceuticals, Inc.
Dodd Thomas J.
Russel Jeffrey E.
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