Drug – bio-affecting and body treating compositions – Plant material or plant extract of undetermined constitution... – Containing or obtained from labiatae
Reexamination Certificate
1997-11-05
2001-09-04
Naff, David M. (Department: 1651)
Drug, bio-affecting and body treating compositions
Plant material or plant extract of undetermined constitution...
Containing or obtained from labiatae
C514S544000, C514S643000
Reexamination Certificate
active
06284289
ABSTRACT:
The present invention relates to a pharmaceutical composition for the treatment of herpes.
Herpes simplex infection on the skin causes superficial painful spots and blisters, which eventually open, thereby causing lesions. Herpes is mainly caused by Herpes simplex virus (HSV) type 1, but can also be the result of HSV type 2 which usually causes genital herpes. Conversely, genital herpes is caused in about 30% of cases by HSV 1.
Infections of the mouth are designated with the term herpes labialis, also called cold sore (feverblister). Other parts of the face, such as eyes and nose, can also be affected. This is then referred to as facial herpes simplex. The infection can also manifest itself on other parts of the body.
About 70-90% of the population is primarily infected with HSV. These people are then carriers of the virus. Once an individual has been infected with the HSV, this virus will thereafter remain latently present in the body. In latent state the virus is situated in nerve cell bodies in the ganglia. Due to particular stimuli, such as influenza infection or other respiratory disorders, gastro-intestinal infections, stress, fatigue, menstruation, pregnancy, allergy, sunlight and fever, the latent virus can be activated. It will travel from the ganglia along well-defined nerve paths to the skin surface and there multiply and cause the symptoms. This recurrent form of herpes occurs in about 40% of the infected individuals.
A per se reasonably innocuous herpes simplex infection can lead to much more serious infections, such as keratitis and encephalitis. It is therefore important that the virus niduses, at the location of the infection, are efficiently destroyed.
At the moment the most frequently used remedy against HSV infections is acyclovir, which is sold for instance under the brand name Zovirax. Acyclovir is a guanine analog which interferes with the DNA polymerase of the virus and thereby inhibits viral DNA replication. The virus is prevented from multiplying but the virus itself is however not killed. The virus can therefore withdraw to the ganglia, thus resulting once again in latency.
Transmission of HSV-1 occurs through direct contact via saliva or the infected spot on the skin. This transmission is also not prevented by acyclovir.
Another problem is the occurrence of secondary bacterial infections, for instance impetigo, caused by staphylococci and/or streptococci.
On account of these problems of herpes infection, which may or may not be attendant, there is an obvious need for a pharmaceutical preparation which can diminish or even prevent the occurrence of latency as well as the transmission and secondary bacterial infections.
According to the present invention it has now been found that a pharmaceutical composition consisting of a quaternary ammonium compound as a first component and/or an antiviral agent as a second component and/or a plant extract as a third component, wherein the three components are mutually compatible, in a pharmaceutically acceptable base, can resolve the above stated problems.
In order to break the vicious circle of latency, recurrence and renewed latency of the virus, it is necessary to kill the virus itself. Less or even no latency can hereby reoccur in the case of primary or recurrent infection since the dead virus cannot withdraw into the ganglia. The most important component of the present composition according to the invention is therefore a virucidal substance whereby the virus is killed.
Antiviral agents can be subdivided into a number of categories (Colgate, S. M. & Molyneux, R. J., Bio-active natural products, 410, CRC Press, Inc. (1993)), designated with the classification group Ia to group Vb. According to the invention it has now been found that, in order to deal with HSV infections to the fullest possible extent, preferably one or more substances from group IVb must be combined with one or more substances from group Va. Substances from group IVb exhibit virucidal activity, while compounds from group Va display virustatic and antiviral activity. By the combination of both types of substance the virus replication is inhibited and in addition the viruses already present are killed.
In order to ensure that the secondary infection of the lesion caused by HSV infection by other micro-organisms such as bacteria is prevented, it is recommended that either the first component and/or the second component has disinfecting properties.
In order to alleviate the associated symptoms of pain and inflammation a plant extract is preferably also used. This extract preferably also has a soothing effect in addition to inflammation-inhibiting properties.
Products from group IVb which also have a disinfecting activity and can therefore be used in the pharmaceutical composition according to the invention can be selected in a manner known to the skilled person. Use is herein made of the end point titration technique (EPTT) as described by Colgate & Molyneux (supra. p. 413), with which the virucidal activity of a product can be tested. The activity is expressed in virus titre reduction which is determined in vitro by incubation of a herpes virus suspension with dilutions of the product for testing at 37° C. for 5 minutes. A good product will give a minimal titre reduction of 10
3
.
From a general screening of known disinfectants for their virucidal action against Herpes simplex type 1 and Herpes simplex type 2 strains (clinical isolates) it has been found according to the invention that a few products display very high activity, even at 25° C. This is very advantageous because the temperature on the skin is generally lower than 37° C. and even lower than 34° C. It has been found that the quaternary ammonium compounds cetrimide and benzalkonium chloride in a concentration of 50-200 &mgr;g/ml and 100-200 &mgr;g/ml respectively showed a titre reduction of at least 10
3
for a test period of 5 minutes at 25° C. Other known disinfectants, such as alcohols, phenols, peroxides, biguanides, aldehydes, chlorine compounds etc. displayed an activity which was a minimum of five times lower. Only mercury compounds and determined heavy metal compounds have a better activity. However, due to their high toxicity these compounds are not suitable for the intended application.
All quaternary ammonium compounds can in principle be used with the general formula:
wherein R
1
, R
2
, R
3
, and R
4
can be the same or different and represent an aliphatic or aromatic group, wherein at least one of R
1
, R
2
, R
3
or R
4
is an aliphatic chain of 8 or more carbon atoms; and
wherein X is a low molecular weight inorganic anion or a high molecular weight organic anion. A survey of suitable quaternary ammonium compounds is given for instance by A. Dauphin & J. C. Darbord in “Hygiëne hospitalière pratique”, Editions medicales internationales, Paris (1988). Cetrimide is highly recommended.
Quaternary ammonium compounds are well soluble in water and alcohol but cannot be combined with any random other product. An important requirement for the second component is therefore that it must be compatible with the first component. Anionic products, soaps, nitrates, heavy metals, oxidizing products, rubber, proteins and the like are not compatible with quaternary ammonium compounds. Such products are therefore not suitable for use in the composition according to the invention. The second component is preferably not teratogenic and can be given in a high dosage without being toxic therein. In preference the second component further shows a good penetration of the skin.
As second component known antiviral products can be used, such as acyclovir, BVDU, 3FT, Idoxuridine etc., as long as they are compatible with the first component. In addition non-toxic natural products with antiviral activity can be used.
The suitability of the second component can likewise be tested with a per se known EPTT method (Colgate & Molyneux, supra, p. 414). Use is herein made of VERO cells. According to the invention it has thus been found that gallates have a good antiviral activity in vitro. Propyl gallate
Bio Pharma Sciences B.V.
Meller Mike
Naff David M.
Webb Ziesenheim & Logsdon Orkin & Hanson, P.C.
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