JPS6365050B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compositions and methods for treating herpes simplex infections in humans. More specifically, the present invention provides a pharmaceutical composition comprising interferon and an antiviral surfactant, and a method for treating herpes simplex infection in humans by locally administering the pharmaceutical composition to the affected area. It is about the method.

Infections caused by herpes simplex virus are extremely common in humans. the virus is transmitted by direct contact by infected individuals;
It is estimated that more than half of the entire population has been infected by the herpes simplex virus at one time or another.

Once an individual is infected, the virus itself manifests as inflammation or disease in various parts of the body. Herpes labialis is the most clinical form of herpes simplex virus infection. The symptoms include not only oral rash (herpes herpes) but also inflammation of the mouth and gums.
Cold sores are often very painful and disfiguring.

In another common clinical presentation, herpes genitalis rash occurs on the vulva. It often causes severe psychological and social problems in affected individuals. It can even be fatal for patients with compromised immune systems. In addition, infected mothers pose a risk of transmission to their newborns, and the disease is often fatal to infants.

Herpes simplex virus also infects the eyes, causing acute keratitis, and infects the central nervous system, causing severe encephalitis.

Although it was once thought that there was only one type of herpes simplex virus, it is now known that there are two main types of virus.
Herpes simplex virus type 1 (hereinafter HSV-1) is commonly associated with herpes labialis. Herpes simplex virus type 2 (hereinafter referred to as HSV-2)
is usually associated with herpes genitalis. However, HSV-1 has been isolated from vulvar lesions in some instances, whereas HHSV-2 has been isolated from affected areas of other body parts than the vulva.
In some reports, HSV-1 has been associated with lip cancer, while HSV-2 has been associated with cervical and vulvar cancer.

Following initial infection with HSV-1 or HSV-2, disease may or may not develop. However, the virus does not die and continues to exist in a latent form in ganglia. Relapses can occur throughout life in response to non-specific stimuli, such as changes in body temperature, stress, ultraviolet radiation, and hormonal changes. It is also believed by some that relapse occurs when the host's immune system is suppressed. At that time,
The latent virus in the ganglion travels along the nerve cells without damaging them until it exits the nerve terminal. Then, as it leaves the house, the virus infects neighboring cells and begins to multiply.

Viral multiplication proceeds in two stages that result in disease. In the first stage, known as the progenitor stage, the number of virus particles increases until a first maximum is reached. During this stage, the patient will feel pain at the site of viral multiplication. The number of virus particles then decreases. Approximately 2 to 3 days after the progenitor stage, the virus particles undergo a second stage of multiplication. In the second stage, the number of virus particles multiplies until it reaches a second maximum value, which is much larger than the first maximum value. The second stage of proliferation causes the death of many cells;
Causes disease. Usually the disease subsides within 10 to 14 days, but in some cases the disease persists for an extended period of time.

Many demands have been made for effective antiherpetic compositions. No doubt, the efficacy demonstrated by many of these compositions in in vivo tests would be considered modest. This effect is 50% against herpes simplex virus infection.
It would be something like that. In in vitro tests,
One set of chemical reagents that has demonstrated effectiveness against herpes simplex virus is that of anionic and cationic surfactants dissolved in lipids. The effectiveness of these reagents has been demonstrated for HSV-1 and
It is believed that this is due to their ability to dissolve the lipid-containing membrane that surrounds both nucleocapsids of HSV-2.

More recently, one of the inventors, in collaboration with others, has discovered that nonionic surfactants also have the effect of reducing the infectivity of herpes simplex virus. For example, Asculai, SS, etc.
Antimicrobial Agents and Chemotherapy
13686 (1978), certain nonionic surfactants inhibited HSV-1 and HSV-1 in vitro.
It has been reported that the infectivity of P. 2 can be rapidly reduced. Nonionic surfactants that inactivate the infectivity of herpes simplex virus have an ether bond or amide bond between the hydrophilic and hydrophobic portions of the molecule. US4020183 (Asculai
See also U.S.4139630 (Asculai et al.). The therapeutic efficacy of these nonionic surfactants is also believed to be due to their ability to dissolve the lipid-containing shell of the herpes simplex virus. The nonionic surfactants have also been reported to partially disrupt viral nucleocapsids. The nonionic surfactants have found use as spermicides in vaginally inserted contraceptives.
Contraceptive formulations containing nonionic surfactants have also been demonstrated to be effective against herpes simplex virus. Treatment of herpes simplex virus infections by local administration of surfactants, whether anionic, cationic, or nonionic, is not completely satisfactory. The most effective results are obtained when the surfactant is applied during the prodromal stage before the appearance of the disease. However, it is often difficult to discern when viruses are in the progenitor stage of replication. Additionally, the surfactant is applied to the top layer of infected cells.
Because of the dilution effect, cells below the top layer are not exposed to a sufficient amount of the detergent to kill virus particles. Thus, cells below the superficial layer are not afforded protection, and herpes simplex virus continues to multiply in these cells below the superficial layer. In addition, treatment with antiviral surfactants does not appear to reduce the frequency of relapses. However, recurrence may be prevented if a significant number of replicating virus particles are killed.

It would thus be desirable to provide a pharmaceutical composition that would reduce the herpes simplex virus load and therefore prevent recovery of the latent state.

It would also be desirable to provide a pharmaceutical composition that prevents the spread of the virus to cells below the surface layer.

Human interferons are known to protect cells against viral infections. Human interferons are produced by cells in reaction in the presence of specific derivatives, such as viruses. It may be produced in vivo by cells of a living organism or in vitro by cell culture in the presence of the derivative. It is currently known that there are three main types of human interferons: leukocyte or alpha, fibroblast or beta, and immune or gamma interferon.

Human interferon is relatively non-toxic and non-antigenic in humans. It is also highly effective against a wide range of viruses, including herpes simplex virus, even at very low concentrations. To date, the treatment of herpes diseases with human interferon has involved two main challenges: (a) medical induction of endogenous interferon in the patient, and (b) administration of exogenous interferon to the patient. I came willingly.

For example, US4053582 (Stickl) discloses a method for treating herpes simplex virus infection in humans by administering to the patient a weakened fowlpox virus. The weakened virus induces the patient to produce his own interferon. The herpes disease is cured within a short time after induction.

US4061538 (Dorner et al.) and 4184917
(Dorner et al.) disclose a method of treating herpes simplex virus infection by administering to a patient a structurally modified interferon. In these patents, the modified interferon is administered systematically to a patient.

Several published reports also disclose the treatment of herpes eye infections by topical administration of human interferon. For example, D.
Naumann-Haefelin et al., Infection and
Immunity, 17468 (1977) and BRJones et al.
See Lancet II, 128 (1976).

None of these disclosures disclose herpes labialis and herpes sores in humans by locally administering a pharmaceutical composition containing interferon.
Genitalis treatment is not implied. Furthermore, none of these disclosures suggest the treatment of herpes simplex virus infections by locally administering a combination of human interferon and antiviral surfactants.

The present invention also provides squamous cell carcinoma, basic cell carcinoma,
The present invention relates to methods of treating malignant and premalignant skin diseases including actinic keratosis and leukoplakia. This invention also relates to methods of treating psoriasis and herpes zoster.

Basal cell carcinoma, which manifests as a small shiny hard nodule or an ulcerated skin-covered disease on the skin, is commonly treated with electrode desiccation and curettage, surgical excision, or x-ray therapy. Measures will be taken accordingly. Approximately 5 in those cases
% will recur. Such recurrences are treated locally by further excision or Mo's chemical surgery, ie, microscopically controlled excision after chemical fixation of the tissue.

Scaloid cell carcinoma arises from the Malpiki cells of the epithelium. The tumor typically begins as small red pimples or plaques with a scaly or hard crusted surface. Then it becomes a nodule. Eventually the disease ulcerates and erodes the subcutaneous tissue. As with basic cell carcinoma, squamous cell carcinoma is treated by electrode drying and curettage, surgical excision, or x-ray therapy.

A precancerous keratinizing disease, actinic keratin fibers are the result of repeated overexposure to sunlight over many years. Keratinous fibers are usually hard and gray to dark in color. Such diseases are commonly treated by topical application of uracil fluoride (uracil pentafluoride). However, if the disease becomes malignant, topical application of uracil fluoride is not recommended as the rate of recurrence is higher than such treatment is acceptable.

Leukoplakia, excessive keratinization of the oral mucosa, is commonly caused by chronic irritation from sources such as tobacco, alcohol, chewing on the cheeks, ill-fitting dentures, sharp, broken or worn teeth, or Spicy foods, syphilis,
It is believed that vitamin deficiencies, hormonal changes, and several factors acting locally or systematically, such as Candida, Albicans, each acting independently or in combination, are responsible.
Leukoplachial disease can range from small, very localized white spots to widespread areas involving most of the oral mucosa, and from smooth flat or slightly raised translucent white plaques to thick fissured palpable plaques. There are various types of diseases, including papilloma-like diseases that feel stiff and hard. Treatment of leukoplakia generally involves removal or elimination of obvious irritants, such as tobacco or defective restorations or prostheses, chemical irritants, and general treatment of the localized disease. Consists of excision or cauterization. Major disease will be removed by a series of "stripping" operations. In addition, patients are periodically re-examined and any subsequent disease found undergoes biopsy due to the pre-cancerous nature of the disease. Additionally, leukoplakia is included in vaginal and anal diseases. If involved in the vagina, leukoplakia is treated with a total vaginal excision.

Psoriasis is characterized by a skin disease that consists of erythematous pimples or plaques, usually with sharp edges and without pruritus, covered with superimposed silvery or slightly opalescent shiny scales. . The typical course of psoriasis is chronic mild symptom flare-ups that change periodically and continuously. Psoriasis can vary in severity from single or double disease to large scale skin disease, to psoriatic arthritis or scaling. Treatment depends on the extent of the disease and the severity of symptoms. The simplest modes of treatment were initially used, such as lubricants, keratotherapy, and topical application of corticosteroids and the like. Systemic antimetabolites should be used only in severely affected skin or joints because of their possible side effects. Exposure to ultraviolet light has been found to be useful in the treatment of psoriasis. Methotrexate taken orally is an effective treatment in severe and disabling psoriasis that is generally refractory to topical treatments. However, due to the toxicity of methotrexate, the patient's hematological
Renal or liver function must be carefully monitored.

Herpes zoster is a virus-associated acute CNS infection that primarily involves dorsal rhizomas and is characterized by a vesicular rash and neuralgia in the skin area fed by peripheral sensory nerves that occurs in the affected rhizomas. can be attached. Herpes zoster may be activated by local or systemic disease, among other reasons. Prodromal symptoms such as chills and fever, malaise and gastrointestinal disturbances are characteristic features of disease progression within 3 or 4 days.
It will have been there for a while now. At about the fourth or fifth day, characteristic vesicles develop one after another on the erythematous base, followed by the distribution of one or more dorsal radiculomas into the skin. There is no specific treatment for herpes zoster. However, initial systemic application of corticosteroids generally relieves pain.

It would thus be desirable to provide a method for the treatment of malignant and premalignant skin diseases that consists of local administration of effective agents.

It would also be desirable to provide effective methods for the treatment of malignant and premalignant skin diseases using topical application of non-toxic agents.

It would also be desirable to provide an effective method for the treatment of psoriasis that consists of local administration of non-toxic and relatively non-antigenic agents.

It would also be desirable to provide a method for the treatment of herpes zoster that consists of local administration of an effective therapeutic agent.

Human interferons are known to protect cells against viral infections. Human interferons are produced by cells in reaction in the presence of specific derivatives, such as viruses. It may be produced in vivo by cells of a living organism or in vitro by cell culture in the presence of the derivative. There are three main types of human interferons: leukocyte (α), fibroblast (β), and immune (γ).
is currently known to exist. Additionally, it is also known that several subtypes of human leukocyte (α) and fibroblast (β) interferons exist.

Human interferon is relatively non-toxic and non-antigenic in humans. It is an effective drug against a wide range of viruses, including herpes simplex virus. For example, USPat.No.
4061538 (Dorner et al.) and USPat.No.4184917
(Dorner et al.) disclose a method of treating herpes simplex virus infection by administering to a patient a structurally modified interferon. The method of administration disclosed in the Dorner patent is systemic.

Several published reports also disclose the treatment of herpes eye infections by topical administration of human interferon. For example D.Naumann
−Haefelin et al., Infection and Immunity, 17468
(1977) and BR Jones et al. Lancet II, 128 (1976)
See.

Also recently non-ionic surfactants (e.g. used as spermicides in vaginally inserted contraceptives)
has been found to be effective in treating viral skin diseases. For example, Asculai, SS, etc.
Antimicrobial Agents and Chemotherapy
13686 (1978), it was reported that certain nonionic surfactants rapidly reduce the infectivity of herpes simplex viruses (HSV-1 and HSV-2) in vitro. The nonionic surfactant that inactivates the infectivity of the virus has an ether bond or an amide bond between the hydrophilic and hydrophobic portions of the molecule.

US4020183 (Asculai et al.) and US4139630
See also (Asculai et al.). The therapeutic efficacy of such nonionic surfactants is also believed to be due in part to their ability to lyse the lipid-laden foreskin of the virus. The nonionic surfactant has also been reported to partially disrupt the nucleocapsid of the virus.

It is therefore an object of the present invention to provide a new pharmaceutical composition comprising human interferon and an antiviral surfactant.

It is also an object of the present invention to provide a method for treating diseases caused by herpes simplex virus by locally administering the above pharmaceutical composition.

Furthermore, it is an object of the present invention to provide a composition for curing herpes diseases that will not only cure the disease but also reduce its recurrence.

Furthermore, it is an object of the present invention to provide a method for the treatment of malignant and pre-malignant skin diseases, herpes zoster and psoriasis.

It is also an object of the present invention to provide a method for the treatment of malignant and pre-malignant skin diseases, which consists in treating the affected skin area locally with a pharmaceutical composition.

It is also an object of the present invention to provide a method for the treatment of malignant and pre-malignant skin diseases by local administration of non-toxic pharmaceutical compositions.

It is also an object of the present invention to treat skin diseases caused by scaly cell carcinoma, basal cell carcinoma, actinic keratosis, leukoplakia, psoriasis, and herpes zoster by administering relatively non-antigenic pharmaceutical preparations. It provides a method for

How these and other objects of the invention are achieved will become apparent from the following description and claims.

A composition for treating herpes simplex virus infection comprises about 10 ² to 10 ⁸ IU of human interferon, about 0.1% to 20% by weight of an antiviral surfactant, and a physiologically acceptable carrier. Consisting of More specifically, compositions for treating herpes simplex virus infections range from about 10 ⁴ to
10 ⁶ IU of human leukocyte interferon, about 1% to 5% by weight of a nonionic surfactant having at least one ether or amide bond;
and a physiologically acceptable carrier. A method of treating herpes simplex virus infectivity in humans comprises administering an effective amount of the composition locally to the affected area. More particularly, the method of treating herpes simplex virus infection in humans comprises administering an effective amount of the composition locally to the affected area during the prodromal phase of viral replication.

A method for treating malignant skin diseases, premalignant skin diseases, and diseases associated with psoriasis and herpes zoster uses 10 ^to 10 ⁸ IU of human interferon, approx.
It consists of administering locally to the affected area of the skin an effective amount of a composition consisting of 0.1% to 20% by weight of an antiviral surfactant and a physiologically acceptable carrier. The local administration could be accomplished by direct application of the pharmaceutical product with or without an occlusive dressing. Methods of treatment for malignant and pre-malignant skin diseases desirably include daily application of a composition comprising human interferon and an antiviral surfactant in conjunction with an occlusive dressing. Treatment of such diseases is preferably continued for 10 days during which treatment can be evaluated.

The novel pharmaceutical compositions of the present invention include an effective amount of human interferon, an antiviral surfactant, and a physiologically acceptable carrier. The pharmaceutical composition will include any known type or subtype of human interferon. Thus, the composition may include human leukocytes, fibroblasts, or immune interferons.
Additionally, the interferon may be prepared by classical culture methods or recombinant DNA methods. An effective dosage of human interferon for treating herpes diseases according to the practice of this invention is about 10 ² to 10 ⁸ , preferably about 10 ⁴ to 10 ⁶ IU.

The antiviral surfactant is anionic, cationic, or preferably nonionic.
Antiviral surfactants are known in the art. These surfactants dramatically reduce the infectivity of HSV-1 and HSV-2 by damaging or disrupting the lipid envelope of the virus. Suitable anionic surfactants include sodium alkylsulfonates and sodium alkylbenzenesulfonates. Suitable cationic surfactants include, for example, cetyl pyridinium chloride, and quaternary ammonium detergents such as benzalkonium chloride.

Nonionic surfactants are desirable in the pharmaceutical formulations of this invention. In contrast to cationic, anionic, and amphoteric surfactants, the nonionic surfactants do not contain ionizable groups;
It also has no interfacial charge. Their surface activity is due to their entire molecule. Almost any hydrophobic compound that has an amide or amino group in its structure with a free hydrogen atom attached to a carboxy, hydroxy, or nitrogen atom can react with ethylene oxide to form a nonionic surfactant. I can do it. At least three groups of nonionic surfactants are recognized.
(a) those with an ether bond between the hydrophilic and hydrophobic portions of the molecule, (b) those with an ester or ether-ester bond, and (c) those with an amide bond. Nonionic surfactants having at least one ether or amide bond are desirable for purposes of this invention. Examples of desirable nonionic surfactants include: Nonyl-phenoxy-polyethoxyethanol (marketed under the trade name Nonoxynol-9), P-diisobutylphenoxypolyethoxyethanol (marketed under the trade name TritonX-100), polyoxyethylene (10) Oleyl ether (marketed under the trade name Brij-97),
and Onyx-ol (marketed under the trade name Onyx-ol 345).

For purposes of this invention, an effective amount of antiviral surfactant comprises from about 0.1% to 20% by weight of the pharmaceutical composition. The preferred range is about 1% to 5% by weight.

The balance of the pharmaceutical composition consists of an inert, physiologically acceptable carrier. The carrier should not react with the active ingredients and should not reduce their efficacy. A suitable physiologically acceptable carrier is water,
Contains ethanol, polyethylene glycol, mineral oil, semi-solid mineral oil, propylene glycol, etc. The pharmaceutical composition is desirably administered in a lotion, cream, oil, or emulsion formulation.

The following is an example of a suitable formulation containing a nonionic surfactant and human interferon.

Medicated lotion Propylene glycol 24.75ml Triethanolamine 1.00ml Water 7.00ml Oleic acid 1.50gm Polyethylene glycol monostearate
10.50gm Fluid silicone 10.00ml Carbopol-934 (2% mucus) 50.00ml Human leukocyte interferon 10 ⁶ - ^{10 8} IU Medicated cream A White petrolatum 41.00gm Microcrystalline wax 3.00gm Fluid lanolin 10.00gm Sorbitan monooleate 4.75gm Polysorbate-80 0.25gm Purified water 41.00gm Human leukocyte interferon 10 ⁶ - ^{10 8} IU Medicated cream B Whale wax 7.5% White wax 12.0% Mineral oil 56.0% Sodium borate 0.5% Sorbitan monooleate 5.0% Water 19.0% Human leukocyte interferon Ron 10 ⁵ to 10 ⁷ IU Local administration of the pharmaceutical composition of the present invention involves applying a small amount (e.g., about 1 ml) of the composition directly and in close proximity to the location of the disease with a cotton swab, soft brush, sponge, etc. brought about by. Any amount sufficient to cover the diseased area will be effective.
Treatment with the pharmaceutical compositions disclosed herein should often be administered, for example, every 2 to 4 hours for about 3 to 4 days. Desirably, the pharmaceutical composition should be applied early in the growth of the virus. For example, the composition will be applied during the prodromal phase to the area where the sensation of pain is felt. When the composition is applied to the diseased area, the pain is substantially reduced within one hour in almost all cases. The area improves significantly within 4 to 12 hours and heals completely within 4 to 5 days with little or no residual scarring. When the composition is applied at the prodromal stage, the pain sensation usually disappears within one hour and the composition provides protection against the appearance of the disease. In some cases, no disease appears at all. In other cases, small blisters appear that disappear within two to three days.
Furthermore, treatment of herpes simplex virus infections according to the present invention appears to reduce the frequency of relapses, and in some cases apparently eliminates the virus altogether. No contraindications have been found.

The pharmaceutical composition of the invention exhibits not only antiviral but also antimicrobial activity. For example, they are effective in treating warts as well as bacterial infections. As used here, the term antimicrobial activity refers to activity against microorganisms other than viruses, such as bacteria and fungi.

In addition to direct application, the pharmaceutical compositions may be administered locally by a variety of other methods. For example, the composition may be delivered to the affected area in microencapsulated form. They are also delivered in foam form, by spray, in tampons, vaginal suppositories, and the like.

Although not fully understood, it is believed that the pharmaceutical compositions disclosed herein work in the following manner. The antiviral surfactant dissolves the lipid-containing outer shell of the herpes simplex virus, thereby destroying its ability to infect. The interferon rescues cells in preventing viral reproduction. In addition, since very small amounts of interferon molecules are required to protect cells, interferon prevents the spread of the virus to cells below the top layer. Thus, the combination of a surfactant, such as a nonionic surfactant and human interferon, may be more effective against herpes simplex virus than would be expected by simply adding the potency of the two active ingredients. more effective. This synergistic effect appears to prevent recurrence of the virus.

In another embodiment, the invention comprises a cosmetic composition comprising an effective amount of human interferon, an antiviral surfactant, and a physiologically acceptable cosmetic carrier. Further compositions may be included in the cosmetic formulation, such as skin softeners.

Cosmetic formulations are known in the art and are generally hypoallergenic and PH controlled. The cosmetic formulation of the present invention is used as a prophylactic agent to prevent the occurrence of herpetic diseases.
These will be applied every night. Cosmetic formulations according to the invention generally contain less human interferon and antiviral surfactants than pharmaceutical formulations. The desirable range for human interferon is 10 ³ to 10 ⁵ IU, and the above desirable range for the antiviral surfactant is also desirable. A typical cosmetic formulation according to the invention is as follows.

Cosmetic Cream 12.1% Whale Wax 12.6% Aromatic Almond Oil 54.4% Borax 0.5% Rose Water 19.4% Onyx All 1.0% Human Leukocyte Interferon 10 ³ - 10 ⁵ IU The following examples illustrate practical improvements of the present invention. This is an explanation.

Example 1 To determine whether human interferon is compatible with antiviral surfactants, monolayers of human fetal cells were cultured. Human leukocyte interferon (10 ⁵ IU) was added to a 1% solution of nonylphenoxypolyethoxyethanol (without carrier) and 1%
It was mixed with a proprietary cream formulation (Stearox) containing 1% nonylphenoxypolyethoxyethanol. The interferon was kept in contact with the nonionic antiviral surfactant overnight and the mixture was then washed 1:1 with standard media salt solution.
Diluted to 10 ⁴ . The mixture was then applied to a monolayer of human fetal cells overnight at 37°C. The next day, the human fetal cells were exposed to vesiculostomatitis virus and after an appropriate time the cultures were assayed for viral plaque plaque. The assay compares assays performed when the cells were exposed to vesicular stomatitis virus without the benefit of any antiviral reagent and with the benefit of human leukocyte interferon (diluted as above). It was hot. The results show that there is no decrease in the activity of human interferon when the nonionic surfactant is bound.

Example 2 A procedure similar to Example 1 was performed except that human fetal cells were exposed to herpes simplex virus types 1 and 2 instead of vesicular stomatitis virus. The results show that human interferon maintains its activity against herpes simplex virus even in the presence of antiviral surfactants. The test shows that human interferon is compatible with antiviral surfactants.

Example 3 Patient A, a female, suffered from recurrent herpes simplex virus infection on the face. The disease covered most of her face and occurred approximately every three to four months. She then felt a pain that indicated the precursor stage of viral replication.
She applied the above medicinal lotion directly to her entire face. The lotion was applied every 2 hours while she was awake for 3 days. The pain sensation disappeared within 1 hour after the first application. Two days after the first application, small vesicles appeared on her lips. The vesicles disappeared without a trace after one day. The patient reported no subsequent symptoms.

Example 4 Patient B, a female, had a recurrence of herpes genitalis. On average, symptoms occurred every 8 weeks and symptoms lasted about 2 weeks. She was treated with the above-mentioned pharmaceutical cream A during the prodromal stage of her next symptom. The cream was applied every 4 hours for 3 days. The pain sensation disappeared almost immediately and no further development of symptoms was observed. No recurrence of symptoms has also been reported.

Example 5 Patient C, a male, had a recurrence of herpes genitalis. Breakouts occurred on average every 3 to 4 months and lasted about 10 to 14 days. At the onset of the following symptoms, the above medicated cream was applied as soon as pimples began to appear. The medicinal cream was applied every 2 hours. The breakouts were smaller and fewer in number than would normally occur, and lasted only two days. Patient C then applied the cosmetic cream described above once a day.
No subsequent symptoms were reported.

A novel method for the treatment of malignant skin diseases, premalignant skin diseases, and skin diseases associated with psoriasis and herpes zoster provides a pharmaceutical composition containing human interferon and an antiviral surfactant in a physiologically acceptable carrier. consists of local administration of an effective amount of a substance. The interferon used in the pharmaceutical composition may be any known type or subtype of human interferon. Thus, the pharmaceutical composition may include human leukocyte (α), fibroblast (β), or immune (γ) interferon. Additionally, the interferon may be prepared by classical culture methods or recombinant DNA methods. An effective dosage of human interferon for treating skin disorders according to the practice of this invention is about 10 ² to 10 8 , preferably about 10 2 to 10 ⁸ .
10 ⁴ to 10 ⁶ IU.

The antiviral surfactant is anionic, cationic, or preferably nonionic.
Antiviral surfactants are known in the art. Suitable anionic surfactants include sodium alkylsulfonates and sodium alkylbenzenesulfonates. Suitable cationic surfactants include, for example, cetyl pyridinium chloride, and quaternary ammonium detergents such as benzalkonium chloride.

Nonionic surfactants are desirable in pharmaceutical formulations used in the methods of the invention. In contrast to cationic, anionic (and also amphoteric) surfactants, nonionic surfactants do not contain ionizable groups and have no surface charge. Their surfactants are due to their entire molecule. Almost any hydrophobic compound that has an amide or amino group in its structure with a free hydrogen atom attached to a carboxy, hydroxy, or nitrogen atom can react with ethylene oxide to form a nonionic surfactant. I can do it. At least three groups of nonionic surfactants are recognized. (a) those with an ether bond between the hydrophilic and hydrophobic portions of the molecule, (b) those with an ester or ether-ester bond, and (c) those with an amide bond. Nonionic surfactants having at least one ether or amide bond are desirable for purposes of this invention. Examples of such desirable nonionic surfactants include: Nonylphenoxy-polyethoxyethanol (marketed under the trade name Nonoxynol-9),
P-diisobutylphenoxy-polyethoxyethanol (marketed under the trade name Triton X-100), polyoxyethylene (10) oleyl ether (marketed under the trade name Brij-97), and Onyx- All (marketed under the trade name Onyx-ol345).

In the pharmaceutical compositions used in the methods of the invention, the effective amount of antiviral surfactant comprises from about 0.1% to 20% by weight of the pharmaceutical composition. The preferred range is about 1% to 5% by weight.

The balance of the pharmaceutical composition used in the method of the invention consists of an inert, physiologically acceptable carrier.
The carrier should not react with the active ingredients or otherwise reduce their efficacy. Suitable physiologically acceptable carriers are water, ethanol,
Including polyethylene glycol, mineral oil, semi-solid mineral oil, propylene glycol, etc. For administration according to the invention, the pharmaceutical composition preferably comprises a lotion,
Prepared in cream, oil, or emulsion formulations.

The method of treating malignant skin diseases, such as scaly cell carcinoma and basal cell carcinoma, and premalignant skin diseases, such as actinic keratosis and leukoplakia, according to the invention comprises an effective amount of human interferon as described above. It encompasses the topical application of pharmaceutical compositions containing antiviral surfactants. Although the topical application could be accomplished with or without an occlusive dressing, it is preferred to use an occlusive dressing. Preferably, the disease is treated daily for a period of about 10 days by topical administration of a pharmaceutical composition comprising interferon and an antiviral surfactant. The disease is then evaluated and further treatment determined. For example, observations should be made in the course of a disease or for the possible cure of a new disease.

The method of treatment of the present invention is also useful when a scaly or basal cell carcinoma has been surgically removed, but tumor cells are found at the periphery of the tumor in the specimen. This method may be used as a form of prophylactic therapy with monitoring for recurrence.

Although a 10-day course of daily application with occlusive dressings is desirable for the treatment of malignant and premalignant skin diseases, modifications are readily made as necessary for the treatment of special cases.

In the treatment of herpes zoster according to the present invention, topical application, preferably using an occlusive dressing, will be done with a pharmaceutical composition comprising interferon and an antiviral surfactant as described above. Applications are made two to three times daily until evidence of healing is observed. By using the method of the present invention, herpes zoster pain is relieved due to local healing. Furthermore, it has been found that use of the method of the invention in the treatment of herpes zoster prevents postherpetic neuralgia. It has been determined that the disease associated with herpes zoster heals faster than if it remained untreated using the methods of the invention.

Treatment of psoriasis according to the invention will require repeated tasks of topical application of interferon and antiviral surfactant in a physiologically acceptable carrier according to the invention. Psoriasis is a chronic, relapsing condition for which there is no known treatment.
Since large areas of skin are often involved, a plastic occlusive dressing is preferably used to ensure absorption of the pharmaceutical composition comprising human interferon and antiviral surfactant into the skin.
Furthermore, since a large area is involved and therefore treatment is required, a significant amount of human interferon will be absorbed into the blood stream. This would have a positive effect on the systemic symptoms of psoriasis, ie psoriatic arthritis.

Local administration according to the invention involves applying a small amount (e.g., about 1 ml) of the composition containing human interferon and an antiviral surfactant directly and using a cotton swab, soft brush, sponge, etc. to the area in close proximity to the location of the disease. It is brought about by applying it. The amount applied will depend on the size of the disease being treated. Any amount sufficient to cover the diseased area is effective.

In addition to direct application, the pharmaceutical compositions comprising human interferon and antiviral surfactants may be administered locally by a variety of other methods. For example, the composition may be delivered to the affected area in microencapsulated form. The pharmaceutical composition may also be delivered in foam form, by spray, in tampons, and the like.

In another embodiment, the invention comprises the treatment of a malignant or premalignant skin disease with a cosmetic composition comprising an effective amount of human interferon, an antiviral surfactant, and a physiologically acceptable cosmetic carrier. . Further compositions may be included in the cosmetic formulation, such as skin softeners. Cosmetic formulations are known in the art and are generally hypoallergenic and PH
is being adjusted. The cosmetic formulation according to the invention contains less human interferon and antiviral surfactants than the pharmaceutical formulation. The desired range of human interferon dosage is from 10 ^{to 3}
10 ⁵ IU, and the desired range for the amount of antiviral surfactant is 0.1% to 1% by weight of the composition. Nonionic antiviral surfactants are preferred.

As indicated above, interferon-containing compositions of the present invention are useful as prophylactic agents and in the treatment of in situ cervical carcinoma. In this application, the interferon-containing composition would be applied directly to the cervix or genital area.

Although the invention has been described by reference to specific embodiments, this is to be construed for purposes of illustration only and to limit the spirit or scope of the invention disclosure. Shouldn't.

Claims (1)

[Scope of Claims] 1. Treatment of herpes simplex virus infection in humans, comprising an antiviral effective amount of human interferon, an antiviral effective amount of an antiviral surfactant, and a physiologically acceptable carrier. A therapeutic composition for. 2 The amount of human interferon is from about 10 ² to
10 ⁸ IU and the amount of antiviral surfactant is from about 0.1% to about 20% by weight. 3 The amount of human interferon is from about ¹⁰⁴ to
The composition of Claim 1 which is 10 ⁶ IU. 4. The composition of claim 1, wherein the amount of antiviral surfactant is about 1% to 5%. 5. The composition of claim 1, wherein the antiviral surfactant is nonionic. 6. The composition of claim 5, wherein the nonionic surfactant has at least one ether or amide bond. 7. The composition of claim 5, wherein the nonionic surfactant is nonylphenoxy-polyethoxyethanol. 8. The composition of claim 5, wherein the nonionic surfactant is P-diisobutylphenoxy-polyethoxyethanol. 9. The composition of claim 5, wherein the nonionic surfactant is polyoxyethylene (10) oleyl ether. 10. The composition of claim 5, wherein the nonionic surfactant is onyx-ol. 11. The composition of claim 1, wherein the human interferon is leukocyte interferon. 12. The composition of claim 1, wherein the carrier is water, ethanol, polyethylene glycol, mineral oil, semisolid mineral oil, or propylene glycol.