CA2216377A1 - Methods to inhibit acute radiation-induced skin damage - Google Patents

Abstract

Disclosed are methods for inhibiting acute radiation-induced skin damage during treatment of a patient with ionizing radiation by application of a layer of biocompatible polymer to the skin surface prior to exposure of the surface to ionizing radiation.

Description

~ r W O 96/34610 PCTrUS96/06340 METHODS TO INHIBIT
ACUTE RADIATION-INDUCED SKIN DAMAGE

BACKGROUND OF THE ~VENTION
Field of the Invention This invention is directed to methods for inhibiting acute radiation-induced skin damage during treatment of a patient with ionizing radiation.
Specifically, the methods of this invention involve formation of a layer of biocompatible polymer over the skin surface prior to exposure of the surface to ionizing radiation.
In one embodiment, the biocompatible polymer layer can be formed by solvent casting or by the in. sit.u. polymer formation on the skin surface.

References The following publications, patent applica~ions and patents are cited in this application as superscript numbers:
' Sitton, "Early and Lot.e Radiation-lnduced Skin Alterations Parr l:Mechanisms of Skin C~1anges", Oncology Nursing Forum, 19(5):801-807 (l99~i 2 Sitton, "Early and l ate Radiation-lnduced Skin Alt.erations Part lI:Nursing Care of Irradiated Skin", Oncology Nursing Forum, 19(6):907-912 (1992) 3 Dini, et al., "Management of Acute Radiodermatitis", Cancer Nursing, 16(5):366 370 (1993) 4 Barley, "Methods for Retarding Blister Formation by Use of Cyanoacrylare Adhesives", U.S. Patent No. 5,306,490, issued April 26, 1994.
Rubin et al., Clinical Radiotion and Pathology, Chapter 3, Skin and Adnexa, pp. 62- 119 (1986) ' CA 02216377 1997-09-24 W 096/34610 PCTrUS9~'Ofl1 6 Perez, et al., Principles a.nd Practice of Ra,diation Oncology, Second Edition, J.B. Lippincott Company, Phil~elr~hia, PA, pp. 104-105 ~1987) 7 Barley, et al., Methods for Treating Suturable Wou.nds by Use of Sutures an~ ~yanoacrylate Adhesives, U.S. Patent No. 5,254,132, issued October 19, 1993 8 Robertson, et al., Flu.orocyanoacryla.t.es, U.S. Patent No. 3,722,599, issued March 27, 1973 9 Barley, et al., International Patent Application Publication No. WO
93/25196, for Me~10ds f~r Treating Non-Sut.urable Woun~s by Use of Cyanoacrylate Adhesives, published December 23, 1993 Barley, et al., U.S. Patent Application Serial No. 08/200,953, for Methods for Reducing Skin Irritation From Art.ificial Devices by Use of Cyanoacrylate Adhesives, filed February 24, 1994 ll Tighe, et al., U.S. Patent No. 5,403,591, for Methods for In~ibitin.g Skin Ulcera.tion. by Use of Cyanoacrylate Adhesives issued April 4, 1995 2 Tighe, et al., U.S. Patent Application Serial No. 08/299,935, for Use of ~yanoacrylates for Providing a Prot.ective Barrier, filed September 1, 1994.

All of the above publications, patent applications and patents are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent application or p~ent was s~ecifically and individually indicated to be incorporated by rei~rence in its entirety.

State of the Art Treatment regimens for many tumors (e.g., tumors of the head, neck, chest, breasts, prostate, etc.) currently include daily exposure of the tumor toionizing radiation repeated over a period of time where application of the radiation to the site of the tumor is through the skin.' Typical regimens include daily (e.g., five times per week) exposure of the tumor with ionizing radiation 30 for about 5 or more weeks wherein both the length of treatment and the total dosage of radiation are dictated by the tumor size, location, etc. For example, ' CA 02216377 1997-09-24 W O96/34610 PCTnUS96/06340 treatment regim~n~ for small microscopic tumors typically include daily e,~o~.ure of the tumor to ionizing r~ tion for a~lu,~imately 5 weeks with a cumulative ionizing radiation dosage of about 4500-5000 rads [45-50 Gray (Gy)]. Treatment r~im~nc for larger tumors as well as tumors located in the 5 head and neck typically are extended to 8 or more weeks and can employ a cumulative ionizing radiation dosage of about 7400 or more rads (74 or more Gy). Treatment of tumors located in the head and neck are particularly troublesome because stem cells associated with such tumors will exhibit maximal recruitment of tumor cells approximately half way through the 10 treatment schedule. To compensate for this recruitment, there is some interest in hyperfractionation of the ionizing radiation where the radiation is applied more than once daily to the patient. Hyperfractionation requires, however, that acute radiation-induced skin damage be within tolerable limits during the treatment regimen.6 Contrarily, interruptions for any significant period of time in the daily schedule of ionizing radiation reduces the effectiveness of the radiation on thetumor. Moreover, for tumors located in the head and neck, such interruptions can actually exacerbate the cancer by ~e~ ing recruitment of tumor cells by stem cells associated with the tumor. Accordingly, maintenance of the daily 20 radiation schedule is clinically significant in effective treatment of the tumor with ionizing radiation.
Notwithstanding the benefits in maintaining the daily s~nedule of ionizing radiation for the entire length of the prescribed treatment regimen, acute radiation-induced skin injuries, such as erythema, dry desquamation, 25 moist desquamation, epilation and ulceration, often dictate an interruption in this schedule in order to permit the skin to heal sufficiently to resume the daily schedule of ionizing radiation. Such acute radiation-induced skin injuries arisebecause ionizing radiation has sufficient energy to break chemical bonds therebydegrading/destroying tissues and has a particularly adverse affect on rapidly 30 dividing cells, including the basal cells found at the base of the epidermis.

' CA 02216377 1997-09-24 wo 96134610 Pcr/uss-~o~ Ic Basal cells rapidly divide to provide a renewed cell population to co",pensate for cell lose at the surface of the epidermis. When a basal cell divides, two cells are formed. One of these cells begins the progressive process of terminal dirrt;1cntiation into mature, dead, ker~tini7ed or cornifiedcells. From the outermost layer of the epidermis, cornified cells detach and desqu~m~t~ The average turnover time of the entire epidermis is about 3-4 weeks. Accordingly, acute radiation-induced skin conditions arising from damage to basal cell is evident approximately 3-5 weeks after initiation of the ionizing radiation regimen and can continue for approximately 4 weeks after cessation of this regimen.5 The degree of skin injury depends on a large number of well known factors such as the ionizing radiation source, the dose, the treatment schedule,the site of irradiation on the patient, individual sensitivity of the patient, etc.
It is estim~t.od, however, that approximately one-third of patients undergoing lS ionizing radiation therapy for tumors will experience an interruption in the therapy schedule, typically of about 1-2 weeks, to permit the skin to heal sllfflciçntly to resume the therapy. This interruption typically occurs at 3-5 weeks after initiation of the therapy where damage to basal cells in the epidermis manifests itself at the skin surface.
Heretofore, the art has addressed acute radiation-induced skin damage by use ~ ointments, lotions, powders, occlusive dressings, etc. on the damaged =skin.l 2 Lilcewise, Dini, et al.3 discloses the use of a foam emulsion containing hydrophilic (propylene glycol, glycerol and polyunsaturated alcohols) and hydrophobic (stearic acid) components which was applied to radiation-induced damaged skin in order to enhance recovery of the damaged skin.
It is apparent, then, that there is a continuing need in the art of radiation oncology to inhibit the degree of skin damage induced by exposure to ionizing radiation during the treatment regimen.
This invention is directed, in part, to the discovery that formation of a biocompatible polymer layer over the surface of the skin area which is tO be exposed to ionizing radiation followed by exposure to ionizing radiation through ' CA 02216377 1997-09-24 W O 96/34610 PCTrUS96106340 this layer reduces the degree of acute radiation-incluced skin damage in the patient. Surprisingly, the reduction in the degree of acute radiation-induced skin damage by the biocompatible polymer layer is achieved notwith~t~n-~ing the te~hin~ in the art that tapes (presumably adhesive tapes) should not be 5 applied directly on the treated skin.2 The biocompatible polymer layer is preferably formed by solvent casting or by the in sit.u polymer formation on the skin surface. When in situ polymto-ri7~tion is employed, a reactive monomer or oligomer (i.e., prepolymer) is applied onto the skin which, in situ, polymerizes to form the polymer layer.
10 A particularly preferred reactive monomer or oligomer is that obtained from cyanoacrylates which in situ form a cyanoacrylate polymer on the skin surface.
Such use of cyanoacrylate polymers per this invention is in contrast to their known medical uses as an alternative or adjunct to sutures' or as a hemostat8. Other described uses of cyanoacrylate polymers include their use to 15 prevent friction blister formation4; to inhibit pressure ulcer formation", to form a barrier layer in the treatment of incontinencel2; to treat small non-suturablewounds~; and to inhibit surface skin irritation arising from friction between the skin surface and artificial devices such as tapes, prosthetic devices, casts? and the like.'~

SUMMARY C)F THE ~VENTION
This invention is directed to methods for inhibiting acute radiation-inducel skin damage during treatment of a patient with ionizing radiation by application of a biocompatible polymer layer over the surface of the skin area which is to be exposed to ionizing radiation followed by exposure to ionizing radiation through this layer.
Accordingly, in one of its method aspects, this invention is directed to a method for inhibiting acute radiation-induced skin damage to a human patient during treatment of that patient with ionizing radiation wherein application of the radiation is through a portion of the skin thereby exposing the epidermal layer of that skin portion to said ionizing radiation which method comprises:

' CA 02216377 1997-09-24 wo 96/34610 PCTIU~.9~

(a) applying a layer of biocompatible polymer to the surface of the skin area which is to be exposed to ionizing radiation; and (b) exposing the patient to ionizing radiation through the layer of bioco,l,~lible polymer.
Application of the layer of bioco~palible polymer is preferably made onto the surface of intact skin. More preferably, the intact skin is further ~h~ractPri7ed as lacking any infection, open wounds, etc. which would permit the polymer to penetrate from the surface of the epidermis to or beyond the dermal layer.
In one pler~ d embodiment, the layer of biocompatible polymer is formed on the skin surface by solvent casting. In this embodiment, a suitable biocompatible polymer is dissolved or dispersed in a biocompatible solvent and applied onto the surface of the skin. Upon t~ ip~.tion of the solvent, a thin polymer layer forms on the skin surface.
In another preferred embodiment, the layer of biocompatible polymer is formed by the in sit.u polymerization of a reactive monomer or oligomer (prepolymer) on the skin surface. Suitable reactive monomers and oligomers include, by way of example, cyanoacrylates, urethanes, silicones, and the like.
Preferred reactive monomers and oligomers are cyanoacrylates and, particularly, n-butyl cyanoacrylate.
In this preferred embodiment, this invenlion is ~irected to a method for inhibiting acute radiation-induced skin dama~e to a human patient during treatment of that patient with ionizing radiation wherein application of the radiation is through a portion of the skin thereby exposing the epidermal layer of that skin portion to said ionizing radiation which method comprises:
(a) applying a layer of cyanoacrylate polymer to the surface of the skin area which is to be exposed to ionizing radiation; and , (b) exposing the patient to ionizing radiation through the layer of cyanoacrylate polymer.
In a further l~efe"~d embodiment, the cyanoacrylate, in monomeric form, is represented by formula I:

' CA 02216377 1997-09-24 W O 96/34610 PCTnUS96/06340 CH2= C-C OR
C N

where R iSS~lPctf~cl from the group concicting of:
alkyl of 2 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, cycloalkyl groups of from S to 8 carbon atoms, phenyl, 2-ethoxyethyl, 3-methoxybutyl, and a substituent of the formula:
R' O
l ll - C - C-OR"
R' wherein each R'is independently selected from the group con.ci.cting of:
hydrogen and methyl, and R"is selected from the group consisting of:
alkyl of from 1 to 6 carbon atoms, alkenyl of from 2 to 6 carbon atoms, alkynyl of from 2 to 6 carbon atoms, cycloalkyl of from 3 to 8 carbon atoms, aralkyl selected from the group consisting of benzyl, methylbenzyl and phenylethyl, ~ phenyl, and phenyl substituted with 1 to 3 substituents selected from the group consisting of hydroxy, chloro, bromo, nitro, alkyl of 1 to 4 carbon atoms, and alkoxy of from 1 to 4 carbon atoms.

' CA 02216377 1997-09-24 wo 96134610 pcrluss~J~ o In still another of its method aspects, this invention is directed to a method for inhibiting acute radiation-in~uce~ skin ~i~m~ge to a human patient during treatment of that patient with ionizing radiation wherein application of the radiation is through a portion of the skin thereby exposing the epidermal 5 layer of that skin portion to said ionizing radiation which method comprises:
(a) applying to skin surface area(s) which will be exposed to ionizing radiation a sufficient amount of a cyanoacrylate adhesive so as to cover said area(s);
(b) polymerizing the cyanoacrylate adhesive so as to form a flexible, 10 waterproof, adhesive polymer layer which adheres to the area(s) where the adhesive was applied; and (c) exposing the patient to ionizing radiation through the layer of cyanoacrylate polymer wherein the cyanoacrylate adhesive, in monomeric form, is represented 15 by formula I above.
Preferably, in the cyanoacrylates of formula I, R is alkyl of from 2 to 10 carbon atoms and more preferably alkyl of from 2 to 8 carbon atoms. Even more preferably, R is butyl, pentyl or octyl and most preferably, R is n-butyl.
In another preferred embodiment, the biocompatible polymer layer has a 20 thickness of no more than about 1 millimeter so as to avoid a bolus affect onthe skin whi~h would exacerbate the skin damage induced by the radiation.
More preferably, the biocompatible polymer has a thickness of from about 0.1 to about 0.5 millimeters and still more preferably from about 0.3 to about 0.5 millimete-rs.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
This invention relates to methods for inhibiting acute radiation-induced skin damage during treatment of a patient with ionizing radiation. However, prior to discussing this invention in further detail, the following terms will first be defined.

WO g6/34610 PCT/~9 Definitions As used herein, the following terms have the following me~nin~c:
The term "ionizing radiation" refers to radiation commonly employed in the tr~tmçnt of tumors (whether benign or cancerous) which radiation, either 5 as a large single dosage or as repeated smaller dosages, will cause acute skin~~m~ge in at least a portion of the p~ti~nt~ exposed to this dosage of r~ tion.
Ionizing radiation includes, by way of example, x-rays, electron beams, -y-rays,and the like.
The term "acute radiation-induced skin damage" refers to the damage to 10 the epidermal layer of the skin caused by either a single large dosage or repeated smaller dosages of ionizing radiation which damage can manifest itself about 3-5 weeks after treatment with ionizing radiation. Acute radiation-induced skin damage is sometimes referred to as early radiation induced skin damage and includes, by way of example, erythema, dry desquamation, moist 15 desquamation, epilation and ulceration. Acute radiation-indllced skin damage can be particularly severe in skin folds and areas of high friction, e.g., groin, buttocl~, the folds of the breast, neck, etc. and the like.
The term "biocompatible polymer" refers to a polymer which can form a water-insoluble polymeric layer over the skin, which is compatible with the skin20 as measured by the lack of skin irritation and which can be removed from the skin by conventional means, ~ ~ ~ sloughing off with the epidermal layer.
Preferably, the polymer has a number average molecular weight of at least about 10,000, more preferably from about 10,000 to about 500,000 and still more preferably from about 50,000 to about 250,000. Suitable biocompatible 25 polymers are well known in the art and include, by way of example, cyanoacrylate polymers, cellulosics, polyurethane, poly(C,-C6alkyl)meth-acrylate, polyhydroxyalkyl acrylates, polyhydroxyalkyl alkacrylates (e.g., HEMA -- polyhydroxyethyl methacrylate), polyesters, and the like, as well as mixtures and copolymers thereof including the butyl ester of polyvinyl alcohol 30 maleic anhydride copolymer, mixtures of 1:1 n-butyl & iso-butyl methacrylate,and the like. Biocompatible polymers are also found in conventional skin care ' CA 02216377 1997-09-24 W O 96134610 PCTAUS9~'0~0 products such as Smith & Nephew Skin PrepTM, Mentor Shield SkinTM, BardTM
& AllkareTM P,oL~;live Barrier, and 3MTM No Sting Barrier Film, as disclosed by Lutz, in Per~om.~ance Assessment of Film Fom.ing Skin Protectants (Sealants).
The term "cyanoacrylate adhesive" refers to polymerizable adhesive formul~tion~ comprising cyanoacrylate monomers or polymerizable oligomers which in their monomer form are compounds l~lcsented by formula I as described above.
Preferably, in formula I, R is an alkyl group of from 2 to lQ carbon atoms including ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, n-pentyl, iso-pentyl, n-hexyl, iso-hexyl, 2-ethylhexyl, n-heptyl, octyl, nonyl, and decyl. More preferably, R is butyl, pentyl or octyl and most preferably, R
is n-butyl.
These cyanoacrylate adhesives are known in the art and are described in, lS for example, U.S. Patent Nos. 3,527,224; 3,591,676; 3,667,472; 3,995,641;
4,035,334; and 4,650,826 the disclosures of each are incorporated herein by reference in their entirety.
A preferred cyanoacrylate adhesive for use in the invention is n-butyl-2-cyanoacrylate.
The cyanoacrylate adhesives described herein rapidly polymerize in the presence of water vapor or tissue protein, and the n-bu~YJ-cvanoacrylate is capable of bonding human skin tissue without causing histoxicity or cytotoxicity.
The term "biocompatible plasticizer" refers to any material which is soluble or dispersible in the prepolymer or polymer composition, which increases the flexibility of the resulting polymer coating on the skin surface, and which is compatible with the skin as measured by the lack of s'cin irritation.
Suitable plasticizers are well known in the art and include those disclosed in U.S. Patent Nos. 2,784,127 and 4,444,933 the disclosures of both of which are incorporated herein by reference in their entirety. Specific plasticizers include, by way of example only. acetyl tri-n-butyl citrate, butyl benzyl phthalate, ' . CA 02216377 1997-09-24 W O96/34610 PCTrUS9~'Q~71~

dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dioctylphthalate, n-butyryl tri-n-hexyl citrate, ben7o~tP esters of di- and poly-hydroxy branched aliphatic compounds, tri(p-cresyl) phosphate, and the like. The particular pl~ ti~.i7er employed is not critical and ~ f~ d pl~ctici7~rs include alkyl phth~ tP~ indepen~iently having from 1 to 10 carbon atoms in each alkyl group.
A particularly pref~:lled plasticizer is dioctylphth~l~tP.
The term "bioco~-~paLible solvent" refers to those solvents or mixture of solvents which dissolve or disperse the biocompatible polymer, which ~iC~ip~tP
from the skin upon application, and which are compatible with the skin as measured by the lack of skin irritation. Examples of suitable biocompatible solvents include, by way of example only, DMSO, acetone, ethanol, iso~r~panol, hex~methyl disiloxane, etc.

Methods The methods of this invention comprise application of a layer of a biocompatible polymer onto surface skin areas prior to exposure to ionizing radiation. The biocompatible polymer layer or coating can be applied onto the skin surface as a polymer solution or as prepolymeric formulation comprising polymerizable monomers and oligomers. Preferably, the skin area is clean and dry prior to application of the polymer layer.
When a polymer solution is employed, a requisite amount of the solution or dispersion of the polymer in a biocompatible solvent is applied to the skin surface and, upon dissipation of the solvent, a waterproof layer of polymer is formed thereon. In this embodiment, the thickness of the polymer layer is controlled by the concentration of the polymer in solution and the amount of solution applied to the skin. Such factors are well within the skill of the art.Dissipation of the biocompatible solvent is achieved typically by evaporation upon contact with the skin and, accordingly, low boiling point solvents (b.p. ~--100~C) are preferred for this purpose. Dissipation can also be achieved by bioabsorption of the solvent across the skin barrier such as in W O96~4~10 PCTrUS9flO~

the case of DMSO. The particular method for dissipating the solvent is not ~riti~l In a plcrellc:d embodiment, the solution can further comprise a biocompatible plasticizer and other optional additives. Typically, the solution 5 will comprise from about 1 to about lO weight percent of a biocompatible polymer based on the total weight of the solution.
More preferably, a prepolymeric formulation comprising polymerizable monomers and/or oligomers is employed. Upon application of the monomers and/or oligomers to the skin, polymerization occurs. Such polymerization can 10 be initiated by, for example, surface skin moisture, tissue protein, etc.
Alternatively, a conventional polymerization initiator can be included just prior to application of the prepolymeric formulation to the skin. Thereafter, the skinsurface is maintained under suitable conditions to allow polymerization to proceed to formation of the polymer layer. In general, the particular length of 15 time required for polymerization will vary depending on factors such as the amount and type of prepolymer formulation applied, the surface area of skin to which the adhesive was applied, and the like. However, in a L)l~f~lled embodiment, polymerization is generally complete within about 10 to about 60 seconds while the skin is maintained at ambient conditions. During this period, 20 the person to whom application of the prepolymeric formulation has been made merely allows the formulation to form a polymer layer while minimizing ~ny action to prevent the formulation from being dislodged from that portion of the skin where it was applied or to adhere to unintended objects.
A particularly pl~fe~led prepolymer is a composition comprising a 25 cyanoacrylate prepolymer ("adhesive") which, upon application to the skin, the surface skin moisture, tissue protein, and temperature are sufficient to initiate polymerization of the adhesive upon application. Thereafter, the skin surface ismaintained under suitable conditions to allow polymerization to proceed to formation of the polymer layer. As before, the particular length of time 30 required for polymerization will vary depending on factors such as the amountof adhesive applied, the temperature of the skin, the moisture content of the wo 96/34610 PCT/US96/06340 skin, the surface area of skin to which the adhesive was applied, and the like.
However, in a l)ler~ d embodiment, polymerization is generally complete within about 10 to about 60 seconds while the skin is m,.int,.ined at ambient conditions. During this period, the person to whom application of the 5 cyanoacrylate adhesive has been made merely allows the adhesive to form a polymer layer while minimi7ing any action to prevent the adhesive from being dislodged from that portion of the skin where it was applied or to adhere to nintPn-'ed objects.
Whether the polymer layer is formed from a solution comprising the 10 polymer or by in situ polymerization of a prepolymer on the skin surface, sufficient amounts of applied composition are employed to cover (i.e., coat) theentire surface skin area to be exposed to ionizing radiation with a layer of thecyanoacrylate polymer. The specific manner of application and location of the polymer layer is typically determined by the radiation oncologist or other health 15 care professionals. Preferably, the layer is extended beyond the area to be exposed by preferably at least about 1 centimeter and more preferably by at least about 5 centimeters. When the polymer is cyanoacrylate, excess polymer can be removed with acetone (nail polish remover) which can be readily conducted except in the case where the adhesive polymer binds to a sensitive 20 skin part (e.g., the eye lids) where it should be removed by a health care professional.
After forrnation of the polymer layer on ~he surface of the skin, the polymer adheres to the skin, is flexible and waterproof, thereby forming a protective coating which enhances the integrity of the underlying skin.
25 Adherence to the skin is enhanced by in situ formation of the polymer layer preferably from a cyanoacrylate adhesive.
While not being limited to any theory, we believe that the polymer layer inhibits acute radiation-induced skin damage by minimizing moisture loss to the covered skin areas; by preventing mctional contact of the covered skin with, 30 for example, clothing; and by enhancing the underlying skin integrity. By ' CA 02216377 1997-09-24 Wo 96/34610 Pcrlussf ~ lo inhibiting initial skin damage, further and more acute skin damage due to the infl~mm~tory response of the initial skin damage is prevented.
In general, the polymer layer will adhere to the skin for a period of about 2-4 days after which time it sloughs off. Accordingly, the polymer layer 5 need not be removed in the manner of other adhesives/dressings whose removal results in skin irritation.
The polymer layer is formed over the skin surface prior to exposure of that surface with ionizing radiation. Preferably, the polymer layer is maintained during periods between radiation exposure merely by reapplication 10 of the layer as nece~s~ry in the manner described above. In a particularly preferred embodiment, the polymer layer is maintained continuously throughout the period of ionizing radiation treatment. Moreover, because damage to the basal cells of the epidermis can manifests itself up to 4 weeks after termination of the treatment, the polymer layer is preferably maintained for up to 4 weeks 15 after treatment termination. Preferably, prior to reapplication of the polymer layer to the skin, the skin surface is again cleaned.
The polymer layer should be maintained in a unbroken manner over the entire skin area to be exposed to ionizing radiation. This can be assured by careful application of the polymer (either as a polymer solution or as the 20 polymerizable monomer or oligomer) onto the skin. Additionally, the use of a plasticizer will facilitate the maintenance of the polymer coating in an unbroken manner.
In a plerell~d embodiment, after application of the initial polymer layer, a second, preferably thinner, layer is applied over the coating. Additional 25 amounts of polymer solution or the prepolymer can be applied as needed to maintain an unbroken coating covering over the surface skin areas.
Application is conducted under conditions wherein the polymer layer has a thickness of no more than about 1 millimeter and preferably has a thickness of from about 0.1 to about 0.5 millimeters. Such a thickness will ensure that 30 the polymer does not act in the manner of a bolus. The amount of polymer W O 96134610 PCTrUSg~ 10 solution or prepolymer applied to obtain this thickness is well within the skill of the art.
The polymer layer applied onto the skin surface area can be readily controlled by the amount of polymer solution or prepolymer packaged in a S single dose product or by use of a multiple use ~lispt~ncPr which governs the amount of m~fPri~l applied onto a unit area of surface skin. In this regard, therli~p~n~r described by Otake, U.S. Patent No. 4,958,748, which is incol~olated by reference in its entirety, is particularly advantageous because it dispenses the prepolymer or polymer solution in a controlled dropwise manner.
10 Other methods for the controlled dispersement include, by way of example, a spray applicator, a brush or solid paddle applicator, applicators for repeated and int~ iLLc:nt use of the cyanoacrylate composition and the like.
A preferred applicator for repeated and intermittent usage is an applicator suitable for the non-sterile storage and metered dispersement of the 15 composition after opening of the applicator wherein the applicator is characterized as having a resealable opening of no more than about 0.008 square inches (0.0516 square centimeters) so as to permit the metered dispersement of the composition from the applicator and which is capable of multiple a~lministrations of the composition and is further characterized as 20 having resealing means such as a cap which either tightly mates with the licator ~r which screws onto the applicator.
Prererably, the opening of the applicator is about 0.0016 to about 0.003 square inches (about 0.0103 to about 0.0194 square centimeters).
In another preferred embodiment, the walls of the applicator are made of 25 a pliable material, so that upon application of pressure onto the walls, the walls depress sufficiently to force the composition contained in the applicator through the opening. Preferably, the applicator is manufactured with its opening covered by a metal foil or other similar construction which closes this opening until the device is ready for use. The opening is then reinstated by use of a pin 30 or similar device which punctures the covering.

W O96/34610 PCT~US9''0~?1~

When a cyanoacrylate prepolymer composition is employed in applicators suitable for repe~t~d intermittent uses, the alkyl cyanoacrylate co,l,~osiLion is stored at ambient conditions and can be selected to be bacteriostatic. See, for example, Rabinowitz et al., U.S. Patent No. 3,527,224.
S When the selected composition is bacteriostatic, prolonged storage at ambient conditions is without regard to the sterility of the formulation because there is no adverse buildup of bacteria during storage.
Rer~llse the polymer layer is waterproof, the patient is not prevented from bathing and other activities involving exposure to water during the period the polymer layer protects this skin area.
In a plefelled but optional embodiment, the methods described herein can be used in conjunction with conventional treatment regimens to inhibit and/or treat acute radiation-induced skin damage. For example, it is contemplated that conventional anti-inflammatory agents, e.g., steroids, could be applied to the skin prior to application of the cyanoacrylate adhesive.
Alternatively, it is contemp]ated that the anti-inflammatory agent can be incorporated into the cyanoacrylate composition whereupon it will be released into/onto the skin over time. Suitable anti-inflammatory agents include, by way of example, anti-inflammatory steroids well known in the art which steroids include hydrocortisone (11,17,21 -trihydroxypregn-4-ene-3,20-dione), betamethasone (9-fluoro- l l,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione), clobetasol (21-chloro-9-fiuoro-11,17-dihydroxy-16-methylpregna-1,4-diene-3,20-dione), clobetasone (21 -chloro-9-fluoro- 17-hydroxy- 16-methylpregna-1,4-diene-3,11,20-trione), and the like. The anti-inflammatory agent is incorporated into the cyanoacrylate composition in sufflcient quantities such that, upon application of the cyanoacrylate polymer layer to the skin, the anti-inflammatory agent will be released in sufficient quantities into/onto the skin as to be therapeutically effective.

Compositions W O96/34610 PCTnUS96/06340 The polymer or prepolymer compositions described herein are ~lepaled by conventional methods of mixing the a~r~.iate components until homogenous.
The specific viscosity of these prepolymer and polymer compositions ~Ppenric, in part, on the intended application of the composition. For example, relatively low vi~co~ititos are often preferred where application is to be made to a large surface area. This plerclcllce results from the fact that those forms are less viscous and, accordingly, will permit more facile large surface area application of a thin application. Contrarily, where application is to be made to a specific position on the skin, higher viscosity materials are preferred to prevent "running" of the material to unintended locations.
Accordingly, these compositions have a viscosity of from about 2 to 50,000 centipoise at 20~C. Preferably from about 2 to 1,500 centipoise at 20~C. More preferably, when a prepolymer is employed, the prepolymer is almost entirely in monomeric form and the composition has a viscosity of from about 5 to about 100 centipoise at 20~C.
A thickening agent is optionally employed to increase the viscosity of the composition which thickening agent is any biocompatible material which increases the viscosity of the composition whether as a prepolymer composition or as a polymeric composition. Suitable thickening agents include, by way of example, polymethyl methacrylate (PMMA) -~r othe~ ei~erormed polymers soluble or dispersible in the composition, a suspending agent such as fumed silica and the like with PMMA being plefelled. Fumed silica is particularly useful in producing a gel for topical application having a viscosity of from about 1500 to 50,000. Suitable thickening agents for prepolymeric compositions also include a partial polymer of the alkyl cyanoacrylate as disclosed in U.S. Patent Nos. 3,654,239 and 4,038,345 both of which are incorporated herein by reference in their entirety.
Thickening agents are deemed to be biocompatible if they are both soluble or dispersible in the composition and are compatible with the skin as measured by the lack of skin irritation.

' CA 02216377 1997-09-24 WO 96134610 PCTrUS96/06340 . -18-The prepolymer and polymer compositions preferably include a biocompatible pl~ctici7~r and such pl~ctici7~rs are preferably included from about 10 to 30 weight percent and more preferably from about 18 to 25 weight percent based on the weight of the composition in the absence of any solvent.
Additionally, in prepolymeric compositions such as cyanoacrylate prepolymers, a polymerization inhibitor is also preferably employed and, in a particularly l,refel,ed embodiment, this inhibitor is sulfur dioxide which is employed at from about 50 to 500 ppm based on the total weight of the composition.
The prepolymer and polymer compositions may additionally contain one or more optional additives such as colorants, perfumes, anti-diffusion agents, rubber modifiers, modifying agents, etc. In practice, each of these optional additives should be both miscible and compatible with the prepolymer and the polymer. Compatible additives are those that do not prevent the use of the prepolymers and polymers in the manner described herein.
In general, colorants are added so that the polymer layer formed on the skin will contain a discrete and discernable color. Perfumes are added to provide a pleasant smell to the formulation. Rubber modifiers are added to further enhance the flexibility of the resulting polymer layer. The amount of each of these optional additives employed in the composition is an amount neces5~ry to achieve the desired effect.
Preferred cyanoacrylate compositions useful in the practice of this invention are also disclosed by Greff, et al., U.S. Patent No. 5,480,935, which application is incorporated herein by reference in its entirety.

Utilitv The methods described herein are useful in inhibiting acute radiation-induced skin damage during radiation treatment of malignant and benign tumors. Such tumors include, by way of example only, tumors associated with breast cancer, tumors ~c50cj~ted with prostate cancer, tumors associated with rectal cancer, brain tumors, tumors associated with Iymph node cancer of the W O 96~4610 P~~ 10 head and neck, and any other tumors where ionizing radiation forms a part of the tre~tment regimen.
These methods are particularly useful in prophylactic methods to inhibit the skin damage due to radiation treatment by either reducing the severity of the 5 skin damage and/or by delaying the onset of the damage. These methods can also be used with skin irritated by ionizing radiation but yet unbroken to inhibit the onset of more severe skin damage or to reduce the severity thereof.

The following examples illustrates certain embo~ime~ of the invention but is not meant to limit the scope of the claims in any way.

The treatment regimen for a female patient, age 49, suffering from an in situ breast cancer in the right breast included daily (5 times per week) radiation treatments of the breast. The radiation protocol comprises 28 sessions of 180 rads (1.8 Gy) of X-ray photon radiation to the whole breast over approximately 15 a 6 week period. The radiation was spatially applied equally from the left and right directions of the breast. Following this treatment, an additional 5 treatments were given to the original tumor site using an electron beam [200 rads (2 Gy)]. All treatments were given using a Siemens Mevatron 12 linear accelerator.
Prior to each day of radiation treatment, the patient applied a cyanoacrylate adhesive formulation comprising n-butyl ~-cyanoacrylate in monomeric form, 20 weight percent of dioctyl phthalate as a plasticizer and 200 ppm SO2 over the entire breast and then allowed this composition to polymerize whereby a polymer layer was formed. Upon completion of the treatment procedure, the patient exhibited little, if any, skin damage during the treatment.
The patient was able to complete the treatment without interruption.

' CA 02216377 1997-09-24 W O96/34610 PCTrUS96/06340 Fifty-nine (59) cancer patients (including cancers of the breast, chest wall, and head and neck) were evaluated to coll,pa.~ the effect on acute radiation-induced skin damage during radiation therapy. These results were S co-,-pal~d against a historical control group of 225 breast cancer patients.
In this example, each of the 59 p,.tit-nt~ applied a cyanoacrylate adhesive composition comprising n-butyl a!-cyanoacrylate in monomeric form, 20 weight percent of dioctyl phthalate as a plasticizer and 200 ppm S~ over the entire area to be exposed to radiation. The composition was then allowed to 10 polymerize whereby a polymer layer was formed. Application of this composition was conducted prophylactically on day 1 and every other day during radiation treatment and for up to 4 weeks post therapy. Radiation therapy was delivered using standard fractionation techniques to total doses of 50-60 Gy.
Weekly, patients were evaluated by the nurse or physician to score the skin for the level of acute radiation-induced sKin damage.
Approximately 7 months after initiation of this study, one of the 59 patients (1.69%) required a treatment interruption and/or field modification dueto excessive skin toxicity. In contrast, 83 of 225 (36.9%) in the historical control group required either a treatment break and/or modification.
Additionally, in the study group, 4/59 patients (6.78%) exhibited a grade 2 or higher skin desquamation during treatment as compared to 41/225 p~ti~nts(l8~2%) in the historical group. Seven additional patients in the study group progressed to grade 2 desquamation during the post treatment period.
From the foregoing description, various modifications and changes in the composition and method will occur to those skilled in the art. All such modifications coming within the scope of the appended claims are intended to be included therein.

Claims (44)

WHAT IS CLAIMED IS:

1. A method for inhibiting acute radiation-induced skin damage to a patient arising from treatment of that patient with ionizing radiation wherein application of the radiation is through a portion of the skin thereby exposing the epidermal layer of that skin portion to said ionizing radiation which method comprises:
(a) applying a layer of biocompatible polymer to the surface of the skin area which is to be exposed to ionizing radiation; and (b) exposing the patient to ionizing radiation through the layer of biocompatible polymer.

2. The method according to Claim 1 wherein the treatment comprises exposing the patient to ionizing radiation up to 5 times per week over 4-10 weeks.

3. The method according to Claim 1 wherein said layer of biocompatible polymer is maintained over the skin throughout the entire treatment period.

4. The method according to Claim 3 wherein said layer of biocompatible polymer is maintained over the skin for up to 4 weeks after exposure to ionizing radiation terminates.

5. The method according to Claim 1 wherein said biocompatible polymer is applied onto the intact skin surface as a prepolymer which polymerizes in situ to provide for the layer of biocompatible polymer.

6. The method according to Claim 5 wherein said biocompatible polymer is applied onto the intact skin surface as a polymer solution comprisinga biocompatible solvent and the biocompatible polymer which is either dissolved or dispersed therein and the biocompatible solvent is permitted to dissipate from the skin surface leaving a polymer layer thereon.

7. The method according to Claim 1 wherein said polymer further comprises a biocompatible plasticizer.

8. The method according to Claim 7 wherein said biocompatible plasticizer is dioctyl phthalate.

9. The method according to Claim 5 wherein the prepolymer further comprises a polymerization inhibitor.

10. The method according to Claim 9 wherein said polymerization inhibitor is SO2.

11. The method according to Claim 1 wherein the polymer layer has a thickness of no more than about 1 millimeter.

12. A method for inhibiting acute radiation-induced skin damage to a patient arising from treatment of that patient with ionizing radiation wherein application of the radiation is through a portion of the skin thereby exposing the epidermal layer of that skin portion to said ionizing radiation which method comprises:
(a) applying to skin surface area(s) which will be exposed to ionizing radiation a sufficient amount of a prepolymer composition so as to cover said area(s);
(b) polymerizing the prepolymer so as to form a flexible, waterproof, adhesive polymer layer which adheres to the area(s) where the adhesive was applied; and (c) exposing the patient to ionizing radiation through the layer of polymer layer.

13. The method according to Claim 12 wherein the treatment comprises exposing the patient to ionizing radiation up to 5 times per week over 4-10 weeks.

14. The method according to Claim 12 wherein said layer of polymer is maintained over the skin throughout the entire treatment period.

15. The method according to Claim 14 wherein said layer of polymer is maintained over the skin for up to 4 weeks after exposure to ionizing radiation terminates.

16. The method according to Claim 12 wherein the prepolymer composition comprises a cyanoacrylate monomer or oligomer.

17. The method according to Claim 16 wherein the cyanoacrylate is n-butyl cyanoacrylate.

18. The method according to Claim 12 wherein said polymer comprises a biocompatible plasticizer.

19. The method according to Claim 18 wherein said biocompatible plasticizer is dioctyl phthalate.

20. The method according to Claim 18 wherein said prepolymer further comprises a polymerization inhibitor.

21. The method according to Claim 20 wherein said polymerization inhibitor is SO2.

22. The method according to Claim 12 wherein the polymer layer has a thickness of no more than about 1 millimeter.

23. A method for inhibiting acute radiation-induced skin damage to a patient arising from treatment of that patient with ionizing radiation wherein application of the radiation is through a portion of the skin thereby exposing the epidermal layer of that skin portion to said ionizing radiation which method comprises:
(a) applying a layer of cyanoacrylate polymer to the surface of the skin area which is to be exposed to ionizing radiation; and (b) exposing the patient to ionizing radiation through the layer of cyanoacrylate polymer.

24. The method according to Claim 23 wherein the treatment comprises exposing the patient to ionizing radiation up to 5 times per week over 4-10 weeks.

25. The method according to Claim 23 wherein said layer of cyanoacrylate polymer is maintained over the skin throughout the entire treatment period.

26. The method according to Claim 25 wherein said layer of cyanoacrylate polymer is maintained over the skin for up to 4 weeks after exposure to ionizing radiation terminates.

27. The method according to Claim 23 wherein said cyanoacrylate polymer, in monomeric form, is selected from the group consisting of octyl cyanoacrylate and butyl cyanoacrylate.

28. The method according to Claim 27 wherein said cyanoacrylate polymer, in monomer form, is n-butyl cyanoacrylate.

29. The method according to Claim 23 wherein said polymer further comprises a biocompatible plasticizer.

30. The method according to Claim 29 wherein said biocompatible plasticizer is dioctyl phthalate.

31. The method according to Claim 29 wherein said prepolymer still further comprises a polymerization inhibitor.

32. The method according to Claim 31 wherein said polymerization inhibitor is SO2.

33. The method according to Claim 32 wherein the polymer layer has a thickness of no more than about 1 millimeters.

34. A method for inhibiting acute radiation-induced skin damage to a patient arising from treatment of that patient with ionizing radiation wherein application of the radiation is through a portion of the skin thereby exposing the epidermal layer of that skin portion to said ionizing radiation which method comprises:
(a) applying to skin surface area(s) which will be exposed to ionizing radiation a sufficient amount of a cyanoacrylate adhesive so as to cover said area(s);
(b) polymerizing the cyanoacrylate adhesive so as to form a flexible, waterproof, adhesive polymer layer which adheres to the area(s) where the adhesive was applied; and (c) exposing the patient to ionizing radiation through the layer of cyanoacrylate polymer wherein the cyanoacrylate adhesive, in monomeric form, is represented by formula I:

I

where R is selected from the group consisting of:
alkyl of 2 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, cycloalkyl groups of from 5 to 8 carbon atoms, phenyl, 2-ethoxyethyl, 3-methoxybutyl, and a substituent of the formula:

wherein each R' is independently selected from the group consisting of:
hydrogen and methyl, and R" is selected from the group consisting of:
alkyl of from 1 to 6 carbon atoms, alkenyl of from 2 to 6 carbon atoms, alkynyl of from 2 to 6 carbon atoms, cycloalkyl of from 3 to 8 carbon atoms, aralkyl selected from the group consisting of benzyl, methylbenzyl and phenylethyl, phenyl, and phenyl substituted with 1 to 3 substituents selected from the group consisting of hydroxy, chloro, bromo, nitro, alkyl of 1 to 4 carbon atoms, and alkoxy of from 1 to 4 carbon atoms.

35. The method according to Claim 34 wherein the treatment comprises exposing the patient to ionizing radiation up to 5 times per week over 4-10 weeks.

36. The method according to Claim 34 wherein said layer of cyanoacrylate polymer is maintained over the skin throughout the entire treatment period.

37. The method according to Claim 34 wherein said layer of cyanoacrylate polymer is maintained over the skin for up to 4 weeks after exposure to ionizing radiation terminates.

38. The method according to Claim 34 wherein R is selected from the group consisting of octyl and butyl.

39. The method according to Claim 38 wherein R is n-butyl.

40. The method according to Claim 34 wherein said polymer comprises a biocompatible plasticizer.

41. The method according to Claim 40 wherein said biocompatible plasticizer is dioctyl phthalate.

42. The method according to Claim 40 wherein said cyanoacrylate adhesive further comprises a polymerization inhibitor.

43. The method according to Claim 42 wherein said polymerization inhibitor is SO2.

44. The method according to Claim 34 wherein the polymer layer has a thickness of no more than about 1 millimeters.