CA1297006C

CA1297006C - Compositions and methods employing the same for the treatment of viral and cancerous skin lesions and the like

Info

Publication number: CA1297006C
Application number: CA000528088A
Authority: CA
Inventors: Maxwell M. Powell
Original assignee: Exovir Inc
Current assignee: Exovir Inc
Priority date: 1986-02-18
Filing date: 1987-01-23
Publication date: 1992-03-10
Anticipated expiration: 2009-03-10
Also published as: ATE68702T1; DK82287D0; DK82287A; JPS62240627A; AU6879087A; AU598232B2; ZA87702B; DE3773953D1; IL82351A; US4822605A; EP0233629A1; EP0233629B1

Abstract

ABSTRACT OF THE DISCLOSURE

A composition containing an antiviral and an antitumor agent is useful when topically applied for the treatment of tumors and cancers, particularly for the treatment of viral or cancerous skin disorders and skin manifestations thereof. Interferon is usefully employed in these compositions in combination with the antitumor agent. Antitumor agents which are useful include interleukin, such as Interleukin II, tumor necrosis factor (TNF), target cell lysis factor (TCLF) and carcino-breaking factor (CBF). These compositions are especially usefully applied by topical application to the skin manifestation of the viral or cancerous skin disorder.

Description

COÇqPOSITIONS AND MET~ODS EMPLOYING T~l~
SAME FOR T~E TREATMENT OF VIRAI. AND
CANÇ~,~QUS_~BIN LESIONS ANP ~R~

GRQ~ Q~ T~l~. INYE~TIO~l This invention relates to compositions and methods for treating viral or cancerous skin di~orders. In particular, this invention relates to pharmaceutical compositions useful or treating viral and/or cancerous skin di~orders by topical administra~ion of ~aid compositions to the affected area.

Virus-induced skin disorders are widely known.
Dermotropic viruses include poxvirus, measles virus, varicella-zoster, coxsackieviru~, echovirus, herpes sim-plex, rubella adenoviru~, papillomavirus and molluscum contagio~um. A variety of skin disorders, such as psoriasis; eczema, conjunctivitis, keratoconjunctivi-tis, gingivostoma, herpes labialis, herpes keratitis,genital herpes, chicken pox, shingles, milker's nod-ule , cowpox are therapeutically treated with composi-tions of this invention which comprise anti-viral agents for topical applicationO Further, various can-cerous skin disorders such as melanoma, basal cell carcinoma, quamous cell carcinoma, Raposi sarcoma and the like are also amenable to treatment by the topical application of compositions of this invention.

Surface active agents (surfactants) have recently been discovered as effective in reducing the infectivity of certain viruses. Particularly effective are the non-ionic surfactants, tho~e with ether or amide linkages between the hydrophilic and hydrophobic por~ions of the molecule. The therapeutic effect of these surfactants , ~

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~ 2 --probably resldes in their ability to interact with and d~sqolve the lipid containing envelope of the virus, and in their ability to partially destroy the nucleocapsid of the virus.

When so employed, surfactants have been applied to the ~kin surface to contact the uppermost layer of infected cells. Because of al dilu~ion eftec~, cells belo~ the surface do not readily receive sufficient amount~ of the surfactant to destroy the virus particles. Therefore, it would be bene~icial to provide an adjuvant which aids in moving the surfactant or other medicament therewith to infected cells below the skin surface. A suitable such adjuvant is dimethyl sulfoxide.

Perhaps the best known of the antiviral agents are the interferons~ Human interferons are known to protect cells against viral infections. ~uman interferons are produced by cells in reaction to the presence of spe-cific inducers, such as viruses. They may be produced in vivo by the cells of living organisms, or they may be produced in vitro by cell cultures in response to the presence of the inducer. There are now known to be three ma~or varieties of human interferon: leukocyte or alpha, fibroblast or beta, and immune or gamma inter-feron. There are also known to be several sub-variet-ies of human leukocyte and fibroblast interferon.

~ uman interferon is relatively nontoxic and nonanti-genic in humans. It is also extremely effective against a broad spectrum of viruses, including herpes simplex virus 7 even at very low concentrations.

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Various uses of in~erferon for it~ antiviral effect are known, see for example, U.S. Pat:. No. 4~053,582 (Stickl) which disclose~ a method for treating herpes simplex in~ectlons in human3 by administering attenuated fowl pox viru~ to the patient~ The attenuated virus induces the patient to produce his own in~erferon. The herpetic lesions heal within a ~hort time after induction.

U.S. Pat. Nos. 4,061,538 (Dorner et al~) and 4,184,917 (Dorner et al.) disclose a method of tre~ting herpes simplex viral infections by administering ~tructurally modified interferon to the patlent. In these patients~ the modified interferons are administered systematically to the patient.

Further, topical administration of human interferon in compositlons containing antiviral suractants has been shown to be ef~ective in the treatment of skin di~order~ due to herpes simple~ viral infection, see U.S. Pat. No. 4,507,281.

Tumor Necrosis ~ac~or (TNF), an antitumor agent, was recently di~covered by Carswell et al, Proc. Natl. Acad.
Sci. ~.S.A. Vol. 72, Mo. 9 pp. 3666-3670 ~1975)~ TNF
wa~ found in the serum of mice, rats and rabbits which had been sensitized with an immunopotentiator and then treated with an endotoxin. Puriie~ TNF~ while having no toxlc effect on the treated individual, exerts a potent acti~ity against tumor~ transplanted into those individuals; the activity is not species specific. The advantage in having no cytotoxic effect against normal cells while having ~ignificant antitumor activity makes TNF an important candidate for the treatment of the skin manifes~ations of various types o~ cancers. Vses of TNF-.;

and related antitumor or anticancer aqents are disclosedin UOS. Patents 4,309,418; 4,447,355; 4,457,916;
4,481,137; 4,495,282 and 4,5~9,594. U.S~ 4,481,137 discloses that several ~actors considered as promising therapeutic agents for tumors, e.g. lymphotoxin, TNF, interferon, had been obtained from reticulo-endothelial cells and that carcono-br~ak:ing factor (CBF~ as a mixture containing lymphotoxin and T~F has been obtained from a culture of lymphobla~ts grown in immune suppressed hamsters. Another antitumor agent c~lled target cell lysis factor (TCLY) is digclosed in ~.S.
4,495,282 as being comprised of lymphotoxin and human TNF.

Other anti-tumor agents use~ul in ~he practices of this invention, in addition to interferon and TNF, include the interleukins, particularly ~nterleukin II, ~ee U.S. 4,518,584. Interleukin II which has been demonstrated to be an antit~mor agent~ is especially u eful in the practices of this invention.

It is an object of the present invention to provide a pharmaceutical composition usefu~ for the treatment of cancerou~ skin disorders such as by topical administration of said composition to the skin manife~tations of such disorders.

It is another a~pect of the present invention to provide a method for treating~ viral and/or cancerous skin disorders by topically applied therapeutic composi-tions.

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QE~ INvENTIDN

A composition comprising an antitumor agent and an antiviral surfactant i5 useful for the treatment of tumors and cancer~, particularly for the treatment of viral or cancerous skin disorders and skin manifeYtations thereof.

A suitable such composition for the treatment of viral or cancerous skin di~orders would comprise an effective antitumor amount of the antitumor agent, e.g.
about 102 IU to 108 IU of Tumor Necrosis Factor, and about 0.1% to 20% by weigh~ of an antiviral surfactant, together with a physiologically acceptable carrier.
Desirably, these would b~ included in such compositions about 102 to about 108 IU of human interferon~

A method for treating viral or cancerous skin disorders employing the compo8itions of this invention would include topically adminlstering to the skin or the affected area an effective amount of the csmposition.

DETAIL~P DESC~IPTIQN ~F T~ INYENTION

The compositions of one embodiment of thi~ subject in~entlon contains effective amounts o~ Tumor Necrosi~
Factor (TNF), human interferon, an antiviral sur~ace active agent, and a physiologically acceptable carri-er. The TNF may be natural or synthetic TNF, i.e. TNF
produced by recombinant DNA technology. The compositions may also contain any, natural or synthetic, of the known varieties or sub-varieties of human interferon. Thusl the compositions may contain natural and/or synthletic TNF and natural and/or synthe~ic alpha- or husnan leukocyte interferon, and/or beta~ or .,, ~, . . .
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fibroblast interferon, and/or ga~na- or immune interferon. An effective dose of TNF for treatment in accordance with the practices of the subject invention would be about 102 to 10~ 1[~, more or less. An effective do~age of human interferon when present in the compositions in accordance with the practices o~ the subject invention would be about 102 to 108, preferably about 104 to 108, I.~.

Althougb TN~ is the preferr~d antitumor agent in the practices of this inventlon, par~icularly in combination with human interferon, e.g. alpha- and~or beta- and/or gamma-interferon, other antitumor agent~ in combination with the antiviral surfactant, alone or in combination with interferon or with another antitumor agent are also useful. A~ indicated hereinabove~ other antitumor agents usefully employed include interleukin, especially Interleukin II, TCLF and CBF, separately or in any combination. These other antitumor agents are employed in an effective antitumor amount, equivalent to or the same amount as indicated hersinabove with respect to interferon and/or TNF.

Antiviral surfactants useful in the compositions of th~s invent~on include the antiviral anionic, cationic, and nonionic surfactants. Antiviral surface active agents are known, see U.S. Patents 4,147,B03, 4,020,183, 4,139,630 and 4,507,281. Suitable anionic surfactants include sodium alkylsufonates and sodiu~ alkylbenzene-sulfonates. Suitable cationic surfactants include quarternary ammonium detergents, such as cetyl pyri-dinium chloride, and benzalkonium chlorides.

Nonionic surface active agent~ are preferred in the compositions of this invention. In contrast to ' . - , : ' ' . ; .~ . .

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cationic, anionic, and ampholytic surface active agents, the nonionics surface active agents or surfactants contain no ionizable groups and have no surface charge. They depend upon the entire molecule for surface activity. Almost any hydrophobic compound which has in its structure a carboxy, hydroxy, amido or amino group with a free hydrogen attached to the nitrogen, can be reacted with ethylene oxide to form a nonionic sur~actant. At least three groups of nonionic surfactants are recognized (a) those having an ether linkage between the hydrophilic and hydrophobic portions of the molecule, (b) those having an ester or ether-ester linkage, and (c) those having an amide linkage.
Nonionic surfactants having at least one ether or amide linkage are preferred for purposes of the present invention. Examples of preferred nonionic surfactants include the following: nonylphenoxypolyethoxy ethanol (available under the trade name Nononxynol-9)`', p-diisobutylphenoxypolyethoxy ethanol (available under the trade name Triton X-100), polyoxyethylene ~10~; oleyl ether (available under the trade name Brij-97)~, and ony~-ol (available under the trade name Onyx-ol 345):~.

~ or an effective dosage the antiviral surface active agent for the compositions and purposes of this invention comprises about 0.1% to ~0~ by weight of the pharmaceutical composition. The pre~erred range is about l~ to 5% by weight.

The balance of the pharmaceutical compositions comprises a substantially inert, physiologically acceptable carrier. The carrier should not react with the active ingredients and not to reduce their effectiveness. Suitable physiologically acceptable carriers inc}ude water, ethanol, polyethylene glycol, -~Trade-mark , : ' ~3~

mineral oil, petrolatum, propylene glycol, dimethylsulfoxide, and the like. Dimethylsulfoxide is also usefully inclu~ed in the compositions since diemthylsulfoxide is known to effectively carry drugs past the dermal layer of the sk:in and as such wouid be a useful component of the carrier for the co~positlon of this invention. The compositions of this invention, as indicated, are topically applied or administered in formulations suitable for topical application, such as gels, creams, lotions, 6hampoo~, sprays and the like The following are examples of suitable formulations of carriers useful in the preparation of compositions in accordance with this invention:

propylene glycol 24.75 mlO
triethnolamine 1.00 ml.
water 7.00 ml.
oleic acid 1.50 gm.
polyethylene glycol monostearate 10.50 gm.
silicon fluids 10.00 ml.
carbopol-334(2% mucilage) * 50.0 a ml.
Pharmaceutical Cream A
white petrolatum 41.00 gm.
microcrystalline wax 3.00 gm.
fluid lanolin 10.00 gm.
sorbitan monooleate 4.75 gm.
polysorbate-80 0.25 gm.
purified water 41.00 gm.
P~a~maceutical C~eam B
spermaceti 7.5 ~
white wax 12.0 %
mineral oil 56.0 %
sodium borate 0.5 sor~itan monooleate 5.0 water 19.0 ~

In addition to the components listed above, the antitumor agent, e.g. TNF, Interleukin II, TCL~ and/or ~Trade-mark ' , ~ ' , ~

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CBF, preferably in combination with a human interferon in an amount from about 102 I~ to 108 XU, would also be included. Additionally, there would be included an antiviral surfactant in the amount 0.05% to about 20% by w~ight based on the overall composition and, if desirable, a minor amount of dimethylsulfoxide, e.g. an amount in the range about 0.1-10% by weight of the overall composition, Topical administration of compo~itions of the present invention may be effec~ed by applyi~g a small amount (e.g., about 1-5 mls) of the composition3 direc~ly to and onto the area~ adjacent to the site o~
the lesion ~ith a cotton swab, soft brush, sponge or the like. A quantity sufficient to cover the lesion is usually adequate for treatment. ~reatment by topical application of the composition should be regular and, if necessary, fr~quent, for example, every ~-4 hours, f3r about 1-7 days, more or le~s.

The composi~ion~ also display antimicrob~al activity as well as antitumor and antiviral activity.
~or e~ample, ~he compositions are effective in treating certain bacterial infections. As used herein, the term ant~microbial activity refers to activity a~ainst microorgani ~ms othe r than v i ruse s, su ch as bacteria, yea~t and f ungi ~

In addition to direct topical application of the compositions, the composition may be administered topically by various other methods5 for example~ by application to the affected skin area in microencapsulated, temperature and/or pressure sensitiYe form or encapsulated in a film or solid carrier which is soluble in body fluids and the like for subsequent , .. . ' - ' ~ .
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rel@as~ of the compositions. The compositions may also be delivered in a foam, spray, tampon, suppository, etc.

In another embodiment, the antitumor agent is incorporated in a cosmetic composition containing effective amounts of interferon, the an~iviral surfactant, and th0 antitumor agent, such as TNF and/or Interleukin II, and a physiolo~ically acceptable cosmetic careier. Additional components, for example, skin softeners, may be included in the cosmetic formulations.

Cosmetic for~ulations are known in the art and are usually hypoallergenic and pH controlled. The cosmetic formulations of this invention are useful as a prophylactic or for the cosmetic and therapeutic treatment of cancerous skin disorders. Cosmetic formulations according to the present invention gener-ally contain less antitumor agent, human interferon and antiviral surface active agent than the usual therapeutic preparations. The preferred range of the antitumor agent in such compositions is about 102 to about 108 IU. The preferred range of human interferon is 103-105 I.U. and the preferred eange of the antiviral surface active agent is 0.1%-5~. A typical carrier for use in a cosmetic formulation according the the present invention has the formulations:
, ~nsme~ic C~eam beeswax 12.1 %
spermaceti 12.6 %
sweet almond oil 54.4 borax 0-5 rose water 1904 %

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7~ 0 6 The following examples are illustrative of the practices of this inventi.on:

Exa~ple 1 A composition in the form of an aqueous gel and con~aining 2% by weight nonylphenoxypolyethoxy ethanol and a minor amount, about 105 I.U., TNF is applied topically to a cancerous skin lesion, such as a melanoma skin lesion, sufficient to generously cover the skin le ion. After 4 hours another similar application i5 made and this procedure continued for four days and then discontinued for observation and evaluation before another such series oP treatment.

A composition in accordance with Example 1 is prepared bu~ additionally comprising a minor amount, about 105 I.U. Interleukin II, and is applied similarly to a melanoma skin lesion~

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A composition in accordance with Example 1 is prepared but additionally comprising a minor amount, about 105 I~Uo ~ human alpha interferon, and is applied similarly to a melanoma skin lesio~.

As would be apparent from the above, the compositions of this invention are also useful when topically applied in the treatment of disseminated or metastasized cancer or tumors. Accordingly, topical application of the composition provides another approach or technique for, in effect, the systemic treatment of .

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cancer or tumors, rather than the conventional intravenous technique.

As is apparent to those skilled in the art, many changes and modifications and suhstitutions are possible in the practices of this invention without departing from the spirit or scope thereof.

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Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A composition comprising an effective antiviral amount of an antiviral surfactant, an effective antitumor amount of an antitumor agent selected from the group consisting of lymphotoxin, tumor necrosis factor, interleukin, target cell lysis factor and carcino-breaking factor; an effective amount of human interferon and a physiologically acceptable carrier.

2. A composition as in claim 1, wherein the antiviral surfactant is selected from the group consisting of nonylphenoxypolythoxy ethanol, p-dissobutylphenoxypolyethoxy ethanol, polyoxyethylene(10) oleyl ether, and onyx-o1.

3. A composition as in claim 1, wherein the amount of antiviral surfactant is in the range from about 0.1% to about 20%
by weight of said composition.

4. A composition of claim 1, wherein the antitumor agent is tumor necrosis factor.

5. A composition of claim 1, wherein said antiviral surfactant is a non-ionic surfactant.

6. A composition of claim 1, wherein said antiviral surfactant is a non-ionic surfactant wherein said antitumor agent is interleukin II.

7. A composition of claim 1, wherein said carrier is a water dispersible carrier or gel.

8. A composition of claim 1, wherein said composition contains dimethyl sulfoxide.

g. A composition in accordance with claim 1, wherein said antitumor agent is target cell lysis factor.

10. A composition in accordance with claim 1, wherein said antitumor agent is carcino-breaking factor.

11. A composition in accordance with claim 1, wherein said antitumor agent is an interleukin.

12. A composition in accordance with claim 1, wherein said antitumor agent is interleukin II.

13. A composition in accordance with claim 1, wherein said human interferon is alphainterferon.

14. A composition in accordance with claim 1, wherein said human interferon is gamma-interferon.

15. A composition in accordance with claim 1, wherein said human interferon is a mixture of alpha and gamma human interferons.

16. A composition in accordance with claim 1, wherein said antitumor agent comprises a mixture of tumor necrosis factor and interleukin.

17. A composition in accordance with claim 1, wherein said antitumor agent comprises tumor necrosis factor and target cell lysis factor.

18. A composition in accordance with claim 1, wherein said antitumor agent comprises interleukin, target cell lysis factor and carcino-breaking factor.

19. A composition of claim 1 in the form of or provided in a cream, a gel, a lotion, a mouthwash, a spray, a shampoo, a foam, a tampon, or a suppository.