Aqueous pharmaceutical composition for treatment of herpes viral diseases comprising diaminoargentum ions

AQUEOUS PHARMACEUTICAL COMPOSITION. FOR TREATMENT OF HERPES VIRAL DISEASES COMPRISING DIAMINOARGENTUM IONS

The present invention relates to a pharmaceutical composition. More particularly the present invention relates to an antiviral pharmaceutical composition and to a method of preventing viral diseases caused by a member of the Herpes family.

As is known different members of the herpes simplex virus are responsible for various diseeses.

What makes herpes virus unique is that unlike influenza and other viruses, it survives in the human body long after an attack has subsided.

This perplexing persistence is characteristic of all five members of the human herpes family. After herpes simplex 1 and 2, the best known is the varicella-zoster virus, the cause of chicken pox, the third most common ailment in the U.S. today. Three-quarters of the U.S. population gets chicken pox by age 15. Most are never bothered by the virus again, though it will linger in their nerv/bus systems for the rest of their lives. Some will not be so lucky. They will be victims of shingles, a painful, blistering rash that is triggered in adults when, for reasons unknown, the varicella-zoster virus reawakens.

Cytomegalovirus (CMV), another type of herpes, infects up to 80% of the U.S population, and nearly 100% of male homosexuals. Though not usually a problem for adults, CMV can be deadly to cancer patients and others whose immune systems have been suppressed by drugs. It also causes a wide range of birth defects and is the most common cause of infectious retardation in infants. Epstein-Barr virus is the herpes associated with mononucleosis. More tragically, it is believed to sJri mainly₍contribute to Burkitt’s lymphoma, a cancer thatnttarhtlyirtfcrikgs JAfricans.

Herpes simplex is almost always transmitted by intimate contact, between infected and noninfected skin surfaces. Once inside, herpes reproduces by taking over the protein-producing apparatus of the host cell.

Once the attack has been brought under control by the immunological system, the virus retreats. In oral herpes, which is generally caused by herpes simplex Type 1, it travels through nerve fibers into the trigeminal ganglia, a group of nerve cells located near the brain. In genital herpes, usually caused by Type 2, the virus withdraws to the sacral ganglia, nerve cell clusters near the spinal cord. Lodged in the nerve cells, the herpes simplex virus is beyond the reach of the body's immune system and enters a latent stage. This stage may last forever, or it may be broken when the virus reawakens and reinfects the original site. Such recurrences may take place as often as twice a month or as rarely as once a decade.

On rare occasions, herpes in the trigeminal ganglia will journey to the brain, where it causes a generally fatal form of encephalitis. Or, in about 500,000 cases a year (including recurrences), it may follow the trigeminal nerve to the eye, provoking an infection that can seriously damage vision if left untreated. Similarly, Type 2 located in the sacral ganglia will sometimes travel to the spinal cord, producing a mild form of meningitis.

Up to several years ago the most common herpes infection was the herpes simplex labialis otherwise known as the simple cold sore.

As is known, however, in recent years herpes simplex genitalis or genital herpes has spread in epidemic proportions throughout the world.

Genital herpes is a painful sexualjy transmitted disease which according to recent figures afflicts approximately 15 to 20 million people in the United States alone.

While a majority of the people afflicted with this disease have only rare or occasional occurances of active symptoms a significant number experience symptoms every few weeks.

Not only is this a painful and embarrasing disease which is readily sexually transmitted but it is also dangerous for pregnant women since an active infection at the time of delivery can be passed along, via the birth canal, to a newborn child. Although this happens infrequently because of the high rate of contraception and/or abortion among infected women, it can cause eye or brain damage to the newborn infant and in 50 percent of cases death. Furthermore, because neonatal herpes is generally acquired during passage through an infected birth canal, a caesarean is necessary if the mother has an active infection.

The only proven treatment for genital herpes and the only one approved by the FDA is ac^ovir, a creamy salve marketed by Burroughs (R) Wellcome Co. under the trade name Zovirax. Acyclovir, which retails for about $20 a tube, works by interfering with viral replication. Applied during the initial episode of herpes, acyclovir will alleviate symptoms and speed up healing. Unfortunately, it is less effective in treating subsequent episodes and will not reduce the frequency of outbreaks.

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Thus today thousands of people use the topical form of acyclovir to lessen the severity and duration of the intial episode of genital herpes, however, despite the widespread epidemic proportions of this disease over the last years and the search by most major pharmaceutical companies and academic and research institutions for a cure for this disease no cure has yet been reported.

As is known previous genital diseases such as syphilis were caused by bacterial microorganisms and were treatable with such antimicrobial antibacterial drugs as penicillin and similar drugs.

In this context it is important to note that penicillin and similar drugs do their job by killing the single-celled bacteria that float around in the bloodstream and cause the infection. But viruses can't be destroyed without risk to body cells, for they cannot live outside a host cell. Between infections they are nothing more than inert chemical particles. To produce infectious agents they must penetrate a normal cell, subvert its genetic machinery and turn it into a viral replicating factory. The active viruses turned out this way then invade still more healthy cells.

Just controlling a viral disease can produce wondrous results for people who are suffering from disabling or life-threatening forms of it. This is particularly true in cancer and transplant patients. With their immune systems suppressed by chemotherapy, they are especially vulnerable to herpes infections. A simple cold sore (‘herpes simplex labialis) in a child receiving treatment for leukemia may spread to the mouth, nose, face, eyes and brain sometimes ending in fatal encephalitis. With the antivirals, though, most of these runaway infections can be controlled.

As indicated even the powerful antimicrobial and antibiotic penicillins and related drugs have proven ineffective in .dealing with herpes infections and therefor the search for a :cure for herpes diseases is sought in new potentially antiviral compositions.

It is in this context that it has been discovered according to the present invention that a composition previously described as having effect against fungal infections and having antimicrobial activity against gram positive and gram negative pathogens can kill herpes virus without damage to the host cell.

Thus according to the present invention there is now provided an antiviral pharmaceutical composition for use in the treatment or prevention of virus diseases in mammals caused by a member of the Herpes family comprising silver ions and ammonia dissolved in a major proportion of water.

The invention also provides a method of treating or preventing viral disease caused by a member of the Herpes family which comprises administering to a mammal an effective antiviral amount of pharmaceutical composition comprising silver ions and ammonia, dissolved in a major proportion of water.

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In its preferred form the present invention provides a concentrated antiviral pharmaceutical composition adapted for further dilution with water to prepare predetermined dosage unit concentrations comprising about 0.01 g to about 2.5 g silver salts, about 2 cc to about 50 cc of a solution of and about 55 to about 98 cc water.

In preferred embodiments of the present invention said source of NHj is a 25^ solution of and said silver salt is silver nitrate. A preferred concentrated pharmaceutical composition according to the invention comprises about 0.8 to about 1.2 g silver salts, about 20 to about 40 cc of a 25^ solution of NH^, and about 55 to about 80 cc water.

Such a concentrated solution is combined in a ratio of about 1 part of a concentrated composition and about 1,000 to about 20,000 parts water, to form unit dosage pharmaceutical compositions.

Thus the present invention also provides an antiviral pharmaceutical composition for use in the treatment or prevention of virus diseases in mammals caused by a member of the Herpes family comprising silver ions and ammonia dissolved in a major proportion of f 'י י water, t׳&g׳et+ief^wvi-t+1--iffs^jt1ⁿti-et4«f«-fer-^jt-he-ths-e-t-he-ree^jf--ifl-the-ⁱtFetitfflefit<rf-+ιβ.Γρβ.5-eh’seeies.: |

In Israel Patent 67 237 there is described and claimed an anti-bacterial oral and/or ingestible composition comprising silver ions, ammonia and fluoride ions.

a In Israel Patent 58 537 there is described and claimed an antimicrobial composition possessing a broad spectrum of antimicrobial activity covering the majority of commonly encountered gram positive and gram negative pathogens, prepared by combining silver ions, ammonia, vitamin C and vitamin P in a major proportion of water. More specifically, the said Patent described and claimed a concentrated antimicrobial pharmaceutical composition adapted for further dilution with water to prepare predetermined dosage.

unit concentrations comprising about 0.01 g to about 1.2 g silver salts, about 2 cc to about 40 cc of a solution of NHj, about 0.15 to about 1.0 g vitamin C, about 0.005 to about 0.05 mg vitamin P and about 55 to about 98 cc water.

In Extra Pharmacopoeia Martindale, 25th Ed. p. 1325, there is also described a solution of diamminosi Tver nitrate prepared from silver nitrate 704 g. water 245 ml and strong ammonia solution to dissolve all but the last trace of precipitate (about 680 ml). It contains 28.5 to 30.5 % w/w of Ag and 9 to 9.7% w/w of NH₃. It is stated that said solution may be employed in the treatment of fungus infections of the nails and also in dental surgery to deposit silver in exposed dentine or to fill up small crevices in the teeth. Said publications, however, neither teach nor suggest the specific antiviral compositions of the present invention and their surprising effectiveness in the treatment and cure of virus diseases caused in mammals by a member of the herpes family and especially the heretofor unachievable cure of genital herpes.

The invention will now be described in connection with certain preferred embodiments in the following examples so that it may be more fully understood, however, it is not intended to limit the invention to these particular embodiments. On the contrary, it^sintended to cover all alternatives, modifications and equivalents as may be included within the scope of the invention as defined by the appended claims. Thus, the following examples which include preferred embodiments will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purposes of illustrative discussion of preferred embodiments of the present invention only and is are presented in the cause of providing whatlvV believed to be the most useful and readily understood description of formulation procedures as well as of the principles and conceptual aspects of the invention.

EXAMPLES 1-25 - Concentrated antiviral solutions of silver, ammonia

Using the procedure described hereinafter, concentrated solutions according to the invention were prepared having the following ingredients and proportions:

<td> Example</td><td> Ag no₃</td><td> NH₃%</td><td> Water</td>

<td> ו</td><td> 9 ו</td><td> 35 cc 25%</td><td> 64 cc</td>

<td> 2</td><td> 1g .</td><td> 30 cc </td><td> 70 cc</td>

<td> 3</td><td> 1g</td><td> . 20 cc </td><td> 79 cc</td>

<td> 4</td><td> g ו</td><td> 40 cc 20%</td><td> 59 cc</td>

<td> 5</td><td> 0.4 g</td><td> 15 cc 25%</td><td> 84 cc</td>

<td> 6</td><td> 0.5 g</td><td> 15 cc 25%</td><td> 84 cc</td>

<td> 7</td><td> 0.7 g</td><td> 20 cc 20%</td><td> 79 cc</td>

<td> 8</td><td> 0.1 g</td><td> 2 cc 25%</td><td> 97 cc</td>

<td> 9</td><td> 0.1 g</td><td> 8 cc ¹¹</td><td> 90 cc</td>

<td> 10</td><td> 0.2 g</td><td> 10 cc 20%</td><td> 89 cc</td>

<td> וו</td><td> 0.25 g</td><td> 15 cc .25%</td><td> 83 cc</td>

<td> 12</td><td> 0.35 g</td><td> 25 cc 20%</td><td> 74,5 cc</td>

<td> 3ו</td><td> 0.35 g</td><td> . 29 cc 15%</td><td> 70 cc</td>

<td> 14</td><td> 1.2 g</td><td> . 39 cc 25%</td><td> 59 cc</td>

<td> 15</td><td> 1.3 g</td><td> 40 cc .25%</td><td> 58 cc</td>

<td> 16</td><td> 1.2 g</td><td> 30 cc 20%</td><td> 69 cc</td>

<td> 17 ,</td><td> 1. g</td><td> 45 cc 25%</td><td> 54 cc</td>

<td> 18</td><td> : 1.4 g</td><td> 38 cc 25%</td><td> 61 cc</td>

<td> 19</td><td> 1.2 g</td><td> 40 cc 20%</td><td> 58 cc</td>

<td> 20</td><td> 1.5 g</td><td> 48 cc 25%</td><td> 51 cc</td>

<td> 21</td><td> 1.7 g</td><td> 43 cc 25%</td><td> 54 cc</td>

<td> 22</td><td> 1.9 g</td><td> 46 cc 24%</td><td> 53 cc</td>

<td> .23</td><td> 2 g</td><td> 50 cc 25%</td><td> 49' cc</td>

<td> 24</td><td> 2.5 g</td><td> 52 cc .25%</td><td> 47 cc</td>

<td> 25'</td><td> 2.3 g</td><td> 50 cc 25%</td><td> 49 cc</td>

Said compositions were each prepared as follows:

a) Crystals of the silver salt» Ag NOp are weighed and placed in a yellow glass vessel.

b) The chosen quantity of NH^ is measured and poured into the vessel containing the silver salts and after a short time said salts dissolve in said ammonia.

It is important that in the making of the said preparation it must be severely observed that its preparation be effected in a dark place, with red light, and also that the pouring of the solution, and the transfer of the solution from one vessel to the other, and the subsequent guarding and storing of the preparation must be in a dark place. The preparation must be stored in a place guarded against light, and direct penetration of sunlight and daylight must be avoided.

The period of storing the preparation from the beginning of its making is between 15 and 30 days. The sterilizationof the preparation is in an autoclave.

The concentrated solutions of the present invention are then diluted to prepare predetermined dosage unit concentrations depending on the intended use and manner of administration. Thus, 1 part of concentrated solution is diluted with between TOO and 45,000 parts distilled water and preferably 1 part of coneentrated solution will be diluted with between about:!,000 and about 20,000 parts water. The diluted preparations can be administered orally, subcutaneously in the veins or muscles or in the form of transdermal delivery compresses in manner known per se.

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EXAMPLE 26

The concentrated composition of Example 1 was submitted for testing to the virology department of the Academy of Science at Kirgiz SSR.

The preparation was administered to animals having genital herpes. Both biopsy of cells and histological testing of blood was carried out to confirm the existence of the herpes virus. Observation and examination with electron microscope and microbiopsy was also carried out.

After administration of the composition, clinical, veterinariological and biochemical observations and tests were carried out on the treated animals. The above tests were also repeated and it was found that the composition had arrested the spread of genital herpes in the treated animal.

Preferably in the treatment of genital herpes the composition will be formulated as an injectable antiviral composition dissolved in a major proportion of sterile water.

For treatment of children a first injected dosage of 50 cc in a dilution of 1:10,000 followed by further injected doses of up to 75 cc in a dilution of between about 1:7000 and 1:3000 is recommended.

For treatment of adults a first injected dosage of 50 cc in a dilution d-Het-ifi of 1:5000 followed by subsequent dosages of 75-100 cc in a dilution of between about 1:3000 to about 1:1000 is recommended.

For treatment of children it is also preferable to first inject lidocaine or novocaine to reduce discomfort caused by the injection of the compositions of the present invention.

It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples a . .

and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be illustrative . . considered in all respects as -i-Htrs+rtri-ve and not restrictive, ' reference being made to the appended claims, rather than to the foregoing description, and all changes which come with the meaning and range of equivalency of the claims are therefore intended to be embraced therein.