Male oral contraceptive

A simple, nontoxic, effective male oral contraceptive is disclosed which directly effects the metabolism of the sperm by causing an acidotic state in the fluid medium surrounding the sperm thereby inhibiting the sperm's activity.

BACKGROUND OF THE INVENTION 
Social scientists recognize that over population is one of the most serious 
problems which mankind must face and solve. As an example, in the United 
States the Department of Health, Education and Welfare released statistics 
recently which showed that 3.3 million babies were born in the United 
States in 1977, up 5% from the previous year. This marked an increase in 
the nation's birth rate for the first time since 1970. (1) The problem is 
even more critical in underdeveloped countries. 
In order to control our increasing world population, there exists a myriad 
of contraceptive devices to prevent unwanted pregnancy. 
Each method attempts to achieve a contraceptive possessing the qualities of 
simplicity, acceptability, efficacy, nontoxicity and absence of adverse 
side effects. One class of such measures are mechanical contraceptives, 
such as the diaphragm, which are inserted into the vagina to completely 
occlude the orifice of the cervix, thus obstructing the migration of 
spermatozoa upward into the fallopian tubes. Such contraceptives have 
serious application problems due to the wide variation in size and 
geometry of the vaginal canal and the cervical opening. These devices 
often require special insertion instruments and careful fitting, usually 
by a trained physician. Furthermore, since trained help in application is 
often necessary, these devices are ill-suited for the underdeveloped 
countries where they are needed most. 
Chemical or spermicidal contraceptives are another well known method for 
attempting to prevent pregnancy. These devices consist of a carrier agent 
such as jellies and creams which provide partial obstruction of the cervix 
and in addition contain nontoxic chemical agents that immobilize sperm. 
The creams and jellies can be inserted high into the vagina with an 
applicator or can be encapsulated as capsules or suppositories. Capsules 
or suppositories are placed in the vagina shortly before coitus to allow 
sufficient time for them to melt and disperse their active ingredients. 
However, the use of these devices have resulted in unwanted pregnancies 
because the spermicidal material is not held for a sufficient length of 
time (which may be several hours) in the desired location in relation to 
the cervical opening. As a result of this inability to be effective alone, 
creams and jellies are often used in conjunction with other contraceptive 
devices. In addition, suppositories require skill in positioning the 
device in the depth of the vagina in order to prevent flow back out the 
vaginal opening. 
Another type of mechanical device is the condom, a rubber device that 
surrounds the penis and contains the sperm after ejaculation. This widely 
used device suffers from an unnatural or desensitizing feeling to the male 
and female. In addition, the possibility of a perforation in the sheath 
and the problem of disposing of spent condoms, make the device less than 
the ultimate answer to unwanted pregnancy. 
Recently, oral contraceptives have gained prominence. The "pill" is a 
female contraceptive which works by suppressing ovulation. One type of 
"pill" contains a combination of estrogen and progestogen. The Food and 
Drug Administration has recently published a brochure which reports that 
estrogen causes cancer in some animals, but studies have not confirmed 
that it causes cancer in humans. This brochure also states that the pill 
doubles a woman's change of having a heart attack as well as increasing 
the risk of other circulatory problems. 
Risk of heart attack is further increased if the woman is a smoker. Pill 
users who smoke are three times more likely to die of a heart attack than 
nonsmokers on the pill and ten times more likely than nonsmokers who do 
not use the pill. (2) 
The pill should not be taken by females who have certain ailments. In 
addition, undesirable side effects will sometimes occur when the female 
first takes the oral contraceptive. These include nausea and vomiting, 
increase in breast tenderness and engorgement, accentuation of acne, fluid 
retention, weight gain, increased vaginal discharge and breakthrough 
bleeding. Finally, there is documentation to the effect that the risk of 
death to the user may be on the order of 3 per 100,000. (3) 
Given these problems with an oral female contraceptive, much 
pharmacological research has been focused recently upon producing male 
oral contraceptives. Alkylating agents and hormones to regulate 
spermatogenesis and thereby bring about a temporary or controlled 
sterility have been the subject of experimentation. However, alkylating 
agents are considered dangerous due to possible irreversible side effects 
and toxicity. Many unanswered questions remain with the use of hormones 
also. (4) 
Due to the above deficiencies in prior contraceptive methods, recently 
there has been an attempt to begin discovering new fertility-control 
agents developed from plant extracts. In the January, 1978, issue of 
PHARMACEUTICAL TECHNOLOGY, the editors write that: 
"In light of evidence that primitive people in certain parts of the world 
have been able to limit population growth by using plant extracts, the 
World Health Organization has approved an international program to find 
new fertility-regulating agents in plants. In 1978, the Department of 
Pharmacognosy and Pharmacology of the College of Pharmacy at the 
University of Illinois Medical Center, along with centers in London, 
Brazil, Hong Kong, South Korea, and Ceylon, will receive funds from WHO 
for this purpose. 
Professor Norman R. Farnsworth, Ph.D., head of the Pharmacognosy and 
Pharmacology Department, stresses that plants are a key ingredient in our 
health-care system: at least 25% of all prescriptions dispensed by 
community pharmacies contain active principles still extracted from 
plants. `Most of these plant drugs,` he says, `have been discovered by 
scientists studying folklore uses of plants.` Other University of Illinois 
projects involve studying published articles on plants for new sources of 
drugs to treat cancer, pain and high blood pressure." 
The invention disclosed is an oral contraceptive formulation which will 
obviate many of the deficiencies in the prior art. It is the first male 
oral contraceptive which has proven effectiveness by providing a carefully 
controllable, temporary sterility, and yet is simple, completely nontoxic, 
and possesses no side effects. 
SUMMARY OF THE INVENTION 
The invention is a male oral contraceptive whose active ingredient is an 
aqueous disiccated extract from a plant, Ecballium elaterium, Linn. The 
active ingredient is extracted from the plant with an acetone, toluene, 
hexane, absolute alcohol solution, concentrated by column chromatography, 
dried over a steam bath, desiccated over sulfuric acid, pulverized and 
mixed with a carrier to produce a contraceptive in the form of a dose for 
human consumption. 
The extraction and concentration process is a sophisticated mechanism which 
converts a flower of nature, whose value heretofore was only aesthetic, 
into a drug beneficial to mankind, with a utility to induce controlled 
temporary sterility in human males. 
DESCRIPTION OF THE PREFERRED EMBODIMENT 
The plant which provides the active ingredient of the present invention is 
the Ecballium elaterium, Linn. It inhabits several countries, including 
the United States, but particularly the middle eastern countries of 
Lebanon and Syria. It grows exclusively on the rocky mountainous areas. It 
blossoms in the spring and lasts until the end of September. The flowers 
are yellow and belong to the composite family and its petals are serrated. 
Before the claimed invention there was no indication that the flower had 
any properties which could be useful in contraceptives. Thus, the use of 
the flower in producing a new contraceptive is highly surprising. 
In order to prepare the claimed invention, the plant is collected, dried 
for two weeks, and the leaves and stem ground up in a mortar and pestle 
until they become powder. Next follows the extraction of the active 
ingredient. This extraction is a highly sophisticated process which is 
necessary in order to isolate and purify the active ingredient into a form 
which will be suitable for human consumption as a male contraceptive. This 
extraction and purification process took months of rigorous 
experimentation to develop and therefore is a significant contribution to 
the invention. In fact, over 100 experiments were performed in order to 
perfect the process which will now be described. 
Approximately 500 mg. of the powdered plant material is weighed into a 250 
ml. volumetric flask and extracted with 50 ml. of a solution consisting of 
acetone, toluene, hexane, and absolute alcohol for about two hours with 
the optimum ratios being 14:14:20:12, respectively. The flask is left in a 
dark box for 24 hours after wrapping it with aluminum foil. 
Next, a solution of alcoholic hydroxide is added to the flask, preferably 5 
ml. of 40% methanolic potassium hydroxide. The flask is swirled for a few 
minutes and allowed to stand in the dark for another two hours. The 
methanol acts as a surfactant with solvent-like properties to extract the 
necessary pigments. The potassium hydroxide increases the pH and thereby 
facilitates extraction. The active ingredient is further extracted with an 
immiscible solvent, preferably 50 ml. of hexane is added to the flask 
which is then diluted to volume with a high ionic strength salt, 
preferably a 20% sodium sulfate solution. The sodium sulfate is a base 
which causes precipitation. The solution is filtered and allowed to stand 
for another two hours in the dark. 
A chromatograhic column 12.5 mm..times.30 cm. is assembled with bottom 
capillary tube 2 mm..times.10 cm. extending into the neck of a collecting 
flask. The column is placed on a filtrator and the bottom is plugged with 
glass wool. The column is filled with a slurry of silica gel G and hyflo 
super-cel (l/l w/w), to about the 20 cm. layer. The slurry is filtered by 
vacuum and a layer of anhydrous sodium sulfate is then added to the top of 
the adsorbent and pressed firmly. 
10 ml. of the plant solution is added to the column and eluted on the 
column with flow adjusted at one drop per second. The eluant is a 
hexane-acetone (94/4) solution. After all the solution is eluted, another 
layer of adsorbent is added and blended from activated magnesia and 
diatomaceous earth (1:1 w/w). The eluation is continued with a solution 
consisting of hexane, methylalcohol and acetone in a ratio of 80:10:10, 
respectively. The concentrated solution should then be checked on a 
Beckman DBG spectrophotometer at a wavelength maximum between 470-480 and 
a split width at 0.03. The reading should be a maximum. 
Finally, the solution is dried over a steam bath, desiccated over sulfuric 
acid for ten days, pulverized, and mixed with a carrier. The large number 
of suitable excipients which could be used as carrier agents in the 
present invention are well known to those of ordinary skill in the art. As 
one embodiment lactose and dicalcium phosphate are used as excipients to 
form a tablet. 
A pharmaceutically active amount of active ingredient is mixed with the 
carrier. The acceptable range for effectiveness in human males is 1 
microgram to 1000 micrograms. In the preferred embodiment, one microgram 
of active material is mixed with a suitable amount of carrier. The amount 
of carrier added can be adjusted depending upon the size of table desired. 
One tablet consisting of a dosage of one microgram of the pharmaceutically 
active material would have an effectiveness for an 8-12 hour period. 
Without attempting to be bound by any particular theory, it is suggested 
that the temporary and controlled sterility which results from the active 
ingredients of the claimed invention is produced through the following 
mechanism. The active ingredient is absorbed and transmitted through the 
blood to the vesticular tissue such as the epididymis and seminiferous 
tubules. Sperm are formed in the seminiferous tubules of the testes. 
Following formation in the seminiferous tubules, the sperm pass through 
the vasa recta into the epididymis. After the sperm have been in the 
epididymis for some eighteen hours or more, they mature, develop the power 
of motility, and thus become capable of fertilizing the ovum. 
A small quantity of sperm can be stored in the epididymis, but probably 
most sperm are stored in the vas deferens. Normally, the sperm in these 
areas would become motile if released to the exterior. However, the active 
ingredients of the claimed invention induce the cells surrounding the 
sperm to secrete carbon dioxide which in the aqueous medium will produce 
carbonic acid. This production of an acidic state has a direct effect upon 
the metabolism of the sperm. The sperm's metabolism is greatly increased 
and thereby activates the sperm to begin utilizing the nutrient substances 
contained in the fluid surrounding the sperm such as glucose, lactose, 
glulactose and most of the monosaccharides. This induced hyperactivity of 
the sperm rapidly depletes the nutrient substances from the surrounding 
fluid until a point is reached at which the nutrients are essentially 
exhausted resulting in the complete death of the sperm. 
This theory is supported by experimental results which indicated hat the pH 
of the semen which is normally 7.5 is reduced by the drug to 1.5, thereby 
dropping the motility of the sperm from the normal level at 95% to 0% and 
also dropping the number of viable sperms remaining in the ejaculate. 
Vaginal secretions in the female are quite acidic in nature (pH of 3.5 to 
4.0) and through the action of the active ingredients the semenal fluid 
would decrease this pH even further rather than neutralizing it as it 
would in the normal state. Tests conducted on samples from subject's 
tested 24 hours after taking the capsule showed that the semenal fluid 
returns to normal. 
The contraceptive of the claimed invention possesses no toxic or side 
effects. Pharmacological tests, such as the pyrogen, histamine-like 
effect, pressor-like effect and tests for undue toxicity all reported 
negative results.

The following working and experimental examples provide further insights 
into the experimental mechanism and conclusively prove the effectiveness 
of the claimed invention. 
EXPERIMENT I 
A random sample of mature male rabbits were used in this study. They were 
given a capsule containing 1 mg. of the test material with some lactose 
and dicalcium phosphate as excipients, through a gastric tube. One hour 
after the capsule was injected, those rabbits that did not ejaculate 
spontaneously were mechanically stimulated, and the ejaculate was 
collected in a small test tube, and the following results were obtained: 
Table 1: 
______________________________________ 
Normal values of the rabbit's ejaculate. 
______________________________________ 
Amount 0.02-0.05 .+-. 0.001 ml. 
Number 2000-3500 / cc 
Motility 85-98% in first hour 
75-55% in second hour 
50-25% in third hour 
25-5% in fourth hour 
Morphology 100% normal forms 
pH 6.2 .+-. 0.05 
______________________________________ 
Table 2: 
______________________________________ 
One hour after taking the capsule. 
______________________________________ 
Amount 0.02-0.5 .+-. 0.001 ml. 
Number 2000-35000 / cc 
Motility 15-2% in first hour 
0% in second hour 
Morphology 90-100% normal forms 
pH 1.4 .+-. 0.01 
______________________________________ 
Twenty-four hours later the values returned back to normal. 
EXPERIMENT 2 
In-vitro studies were conducted on the frozen ox semen, which when mixed 
with the test powder, showed complete liquification with 90% drop in 
motility. 
EXPERIMENT 3 
A random sample of men of various nationalities were selected with ages 
ranging between 18-40 years. Samples of their semen were collected, as a 
control. One hour after injestion of the capsule containing 1 mg. of the 
test powder with the excipients, the following results were obtained: 
Table 3: 
______________________________________ 
Normal values of the man's ejaculate. 
______________________________________ 
Amount 2-4 ml. 
Number 80,000,000-120,000,000 / cc 
Motility 80-95% in first hour 
80-55% in second hour 
55-35% in third to eighth hour 
35-15% in eighth to fourteenth hour 
Morphology 85-95% normal forms 
pH 7.2-7.6 .+-. 0.05 
______________________________________ 
After taking the capsule by one hour, another sample from the same subjects 
were tested. 
The average results were as follows: 
Table 4: 
______________________________________ 
One hour after taking the capsule. 
______________________________________ 
Amount 2-4 ml. 
Number 5,000,000-15,000,000 / cc 
Motility 25-35% in first hour 
25-5% in second hour 
5-9% in third hour 
Morphology 85-95% normal forms 
pH 1.5-2.0 .+-. 0.05 
______________________________________ 
Twenty-four hours later, all the values were back to normal. 
Various experiments were conducted with samples varying in concentrations 
between one microgram and one milligram and all concentrations were proven 
to be effective. 
References 
1. Los Angeles Times, p. 26, Friday, March 24, 1978. 
2. Los Angeles Herald Examiner, p. A-6, Monday, April 3, 1978. 
3. Boyd, W., A Textbook of Pathology, Structure and Function in Disease, 
8th Ed., pp. 967-1006, 1974. 
4. Van Nostrand's Scientific Encyclopedia, 5th Ed., p. 661.