Spermicide

Details Spermicide Spermicide

1999-09-13

2002-08-13

Travers, Russell (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ketone doai

C514S681000, C514S266400, C514S461000

Reexamination Certificate

active

06433022

ABSTRACT:

This invention relates to a spermicide.
Conventional spermicides have traditionally been active compositions not specifically activated by coitus. The best known spermicide is the detergent nonoxynol-9 (N-9), which is used to impregnate sponges which fit over the cervix, or is used to coat condoms etc. N-9 is believed to act by causing leakage of the intracellular contents, but does not easily diffuse through semen. There are also fears as to its effects on male foetuses, and that it may encourage genital ulcers when used frequently.
Human spermatozoa generate reactive oxygen species (ROS) which are involved in a number of key physiological events within sperm including hyperactivated sperm motility and the acrosome reaction, events intimately associated with oocyte sperm fusion. During spermiogenesis, spermatozoa undergo a peculiar morphological transformation in that most of their cytoplasm is discarded just prior to spermiation (release of sperm into the seminiferous tubules). Consequently they lose much of their intracellular defences against the effects of ROS and are thus left with a diminished amount of antioxidants such as, catalase (CAT), glutathione peroxidase and superoxide dismutase (SOD). Therefore, sperm have the difficult task of ensuring the balanced production of these biologically important modulators of cellular function.
Spermatozoa are uniquely susceptible to peroxidative damage initiated by excess production of reactive oxygen species (ROS). Moreover, ROS can initiate a lipid peroxidation cascade in the plasma membrane of the spermatozoa due to the high unsaturated fatty acid content of these cells. The double bonds found in the membrane weaken C—H bonds on the adjacent carbon atom, thus facilitating the hydrogen abstraction step of lipid peroxidation by ROS. This results in a loss of double bonds, and consequently, membrane fluidity. The direct impact of loss of membrane fluidity on the fusogenicity of the plasma membrane is demonstrated by the failure of peroxidised cells to exhibit normal rates of sperm-oocyte fusion. The activity of key membrane-bound enzymes, such as Ca
2+
-Mg
2+
-ATPases (Ohta et al, 1989) are also disrupted by the loss of membrane fluidity; consequently the spermatozoa lose their capacity to regulate the intracellular concentration of ions involved in the control of sperm movement. The biochemical mechanisms responsible for ROS generation in such cells are poorly understood.
According to the present invention there is provided a spermicidal agent which, upon contact with spermatozoa, is capable of generating reactive oxidizing species, including free radicals and hydrogen peroxide.
The generation of such oxidizing species is preferably in the form of a transient burst; this can overcome the limited endogenous protection mechanisms present in the spermatozoa and rapidly induce a loss of function of the sperm.
By “free radical” we mean any atom or group of atoms with an unpaired electron. Free radicals are generally capable of independent existence in that state.
The spermicidal activity is attributable to the capability of generating oxidizing species including free radicals. Suitable oxidants include any ROS such as superoxide (O
2
−
) or hydrogen peroxide (H
2
O
2
).
The free radicals preferably kill sperm by disrupting the plasma membrane.
One advantage of the invention is that the spermicidal activity of the ROS may be deleterious to pathogenic microorganisms (eg fungi, bacteria and viruses), particularly enveloped viruses, since the ROS may disrupt any membranes present in the virions. Thus, the invention will be of utility to prevent or combat sexually transmitted diseases caused by microorganisms. Particular mention may be made of Chlamydia and HIV.
The invention also has the advantage that the vaginal tissues are not susceptible to damage by ROS such as hydrogen peroxide since the latter is continuously generated by the vaginal microflora, as a means of maintaining sterility.
Preferred examples of spermicidal ROS generators include quinones. Quinones are pharmacological agents with a wide range of clinical applications including use as antitumour agents for example adriamycin and dioxorubicin, antibiotics and antiparasitic drugs.
Multiple molecular mechanisms are involved in the cytotoxic actions of these compounds including the ability to redox cycle producing cytotoxic ROS (Kappus and Sies, 1981; Thor et al, 11982; Hoehsteim, 1983).
By harnessing endogenous sperm flavoprotein reductases such as NAD(P)H cytochrome P450 reductase and DT diaphorase, it is proposed that redox cycling quinones could potentially undergo a series of 1 and 2 electron reductions respectively. One electron reduction of the quinone produces a reactive semiquinone intermediate which redox cycles with O
2
producing superoxide anion radicals. The reaction of this superoxide anion with hydrogen peroxide, previously formed by the enzymatic or spontaneous dismutation of the superoxide anion radical, produces powerful oxidising hydroxy radicals. Indeed quinone-induced production of excessive amounts of ROS may overwhelm the inherent but limited protective mechanisms of the sperm resulting in the lipid peroxidation of polyunsaturated lipids present in the sperm membrane and eventual sperm death.
Whilst the invention is not limited to any particular compound, quinones of the following general formula are of special interest:
wherein each group A independently represents H or an electron releasing moiety. If present each or either of the electron relating moieties may operate by electron induction, in which case A will represent an alkyl group, aryl (especially phenyl)/or alkyl group. More preferably however each or either of the electron releasing moieties (if present) will be electron donating and suitable examples include —OH; —OR; —NH
2
; —NHR; —N(R)
2
; —SH; —SR (where each group R may independently be an alkyl group, especially a C
1-6
alkyl group, for example —CH
3
; —CH
2
CH
3
etc). Where each group A represents H, the quinone is 1,4- napthoquinone. Upon exposure to sperm, this is transiently converted to a semiquinone with an additional H
+
ion. The semiquinone is an unstable molecule and decomposes back to 1,4-napthoquinone with a concomitant release of a single electron. The electron reduces O
2
to superoxide (O
2
−
) which may be converted into hydrogen peroxide (H
2
O
2
) by superoxide dismutase (SOD). Mention may also be made of —OH substituted quinones on the first benzyl ring, for example, juglone.
Thus the present invention also provides a method of affecting the viability of spermatozoa, or their ability to fuse with an ovum, the method comprising producing a biologically effective amount of ROS. Generally the ROS will be generated within the female reproductive tract.
The present invention also provides the use of an agent capable of generating ROS (preferably upon contact with spermatozoa) as a spermicide.
The composition can be augmented by the provision of substances which inhibit enzymes or other agents capable of inhibiting the biologically active amount of ROS or H
2
O
2
. A good example of such substances are inhibitors of the enzyme glutathione peroxidase, such as mercaptosuccinate.
Although we do not wish to be bound by hypothesis, it is feasible that the cytotoxic action of ROS on sperm is due to the modification (eg oxidation or alkylation) of essential thiol groups or other cellular nucleophiles in (or on the surface of) the sperm.
The composition may be employed in a number of different ways, preferred methods being impregnation into sponges, as a coating onto barrier contraceptive devices and as pessaries.
Quinones are probably found in all respiring animal and plant cells. They occur as compounds of potential toxicological significance in foodstuffs and environmental pollutants (Thompson, 1971; Prior et al, 1982). They are also widely used as anticancer, antibacterial or antimalarial drugs as well as fungicides (O'Brien, 1991). Quinones such as adriamycin and dioxorubicin are anticancer a

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