WO1993020828A1

WO1993020828A1 - Methods for the multiple, intermittent, non-sterile use of cyanoacrylate adhesives

Info

Publication number: WO1993020828A1
Application number: PCT/US1993/003715
Authority: WO
Inventors: Leonard V. Barley, Jr.; Linda M. Barley; J. Royce Renfrow; Michael M. Byram
Original assignee: Medlogic, Inc.
Priority date: 1992-04-20
Filing date: 1993-04-20
Publication date: 1993-10-28
Also published as: AU4032993A

Abstract

Disclosed are methods for the multiple, intermittent, non-sterile application of cyanoacrylate adhesives (2) onto human skin.

Description

METHODS FOR THE MULTIPLE, INTERMITTENT, NON-STERILE USE OF CYANOACRYLATE ADHESIVES

BACKGROUND OF THE INVENTION

Field of the Invention

This invention is directed to methods for the multiple, intermittent, non-sterile application of cyanoacrylate adhesives onto human skin. Such applications include, by way of example, inhibiting blister formation, treating small, non-suturable wounds, and the like.

State of the Art

Cyanoacrylate adhesives have been suggested for a variety of adhesive purposes including glues and surgical adhesives. In particular, cyanoacrylate adhesives of Formula I:

O

CH₂=C- ICIOR I

wherein R is methyl are known in the art as super glues and are commercially available in applicators for multiple, intermittent use. One such applicator is disclosed in U.S. Patent No. 4,958,748.

Likewise, cyanoacrylate adhesives of formula

I above wherein R is butyl or another suitable substituent are known in the art as adhesives for living tissue. See, for example, U.S. Patent Nos. 3,527,224; 3,591,676; 3,667,472; 3,995,641; 4,035,334; and 4,605,826. The suggested medical uses for cyanoacrylate adhesives have been limited to suturing situations wherein the cyanoacrylate adhesives are utilized by physicians as an alternative or an adjunct to sutures such as in surgical environments. See, for example, Halpern, U.S. Patent No. 3,667,472 and Barley et al., in allowed U.S. Patent Application Serial No. 07/938,838; both disclosures being incorporated herein by reference in their entirety.

When so employed, the cyanoacrylate adhesive is necessarily utilized in a sterile environment and is typically utilized in a single dose form wherein, after use, any remaining adhesive is discarded. Mizrahi et al.. Journal for Pediatric Surgery, Vol. 23, No. 4, pp. 312-313 (1988) . however, discloses that after use of the cyanoacrylate adhesive in one sterile environment, i.e., in pediatric surgery, the rest of the vial may be safely used in another sterile environment, i.e., in the emergency room.

As noted in commonly-assigned U.S. Patent

Application Serial Nos. 07/871,558 and 07/895,589, it has now been discovered that cyanoacrylate adhesives can be used in methods to inhibit blister formation and to treat and/or protect small, non-suturable wounds. Such small wounds are characterized as superficial wounds including cuts generally less than 0.5 centimeters in depth and from about 0.2 centimeters to about 10 centimeters in length. The disclosures of both of these applications are incorporated herein by reference in their entirety.

While methods relating to blister formation and small wound treatment and/or protection by use of a cyanoacrylate adhesive are amenable to single dose methodologies and devices in a sterile environment in a medical setting (e.g., by a doctor or a nurse), it would be particularly advantageous if these adhesives could be repeatedly used in a non-sterile environment by non-medically trained individuals«_

SUMMARY OF THE INVENTION

This invention is directed to methods for the multiple, intermittent application of cyanoacrylate adhesives on human skin surfaces (i.e., the epidermis of the skin) under non-sterile conditions.

Specifically, in one of its method aspects, this invention is directed to a method for the multiple, intermittent, non-sterile application of cyanoacrylate adhesive onto human skin which method comprises the steps of:

(a) selecting an applicator suitable for the non- sterile storage and metered dispensement of a cyanoacrylate adhesive after opening of the applicator which applicator comprises: a resealable opening of no more than about

0.25 square inches ( millimeters square) so as to permit the metered dispensement of the adhesive from the applicator and which is capable of multiple administrations of the stored adhesive; resealing means; and a cyanoacrylate adhesive contained therein, which in monomeric form, is represented by Formula I:

O CH₂=C- ICIOR I

where R is butyl and is preferably n-butyl; and (b) dispensement of the cyanoacrylate adhesive from the applicator selected in step (a) above onto the human skin.

Preferably, the opening of -the applicator is from about 0.02 to about 0.10 square inches (about to about millimeters square) in area. Such an opening area permits the facile but metered dispensement of the cyanoacrylate adhesive from the applicator.

The viscosity of the cyanoacrylate adhesive is chosen, in part, relative to the applicator employed and the rate of dispensement desired. For example, adhesives having a high viscosity coupled with a relatively narrow opening in the applicator will result in the slower, more readily metered application of the adhesive onto the skin. Contrarily, adhesives having a low viscosity and a relatively wide opening in the applicator will result in the more rapid application of the adhesive onto the skin. In a preferred embodiment, the applicator opening permits the metered dispensement of at least 0.02 milliliter of cyanoacrylate adhesive per cm² of skin to be covered.

In any event, the cyanoacrylate adhesive to be stored in the applicator for dispensement onto human skin (epidermis) preferably has a viscosity of from about 2 to about 1000 centipoise at 20°C. Preferably, when the cyanoacrylate adhesive is to be employed to inhibit blister formation, it has a viscosity of from about 2 to about 1000 centipoise and more preferably from about 2 to about 20 centipoise at 20°C. When used to treat small, non-suturable wounds, the cyanoacrylate adhesives described herein preferably have a viscosity of from about 2 to about 100 centipoise and more preferably from about 2 to about 20 centipoise at 20°C.

The cyanoacrylate adhesive to be applied onto the skin can be monomeric or partially polymeric. In general, partially polymerized cyanoacrylate adhesives are liquid polymers having a higher viscosity than that of the corresponding monomer and, therefore, are better suited for those applications which are intended to be specific for a particular skin area. In other words, less viscous materials are more likely to "run" (i.e., flow) into areas where application was not intended. Methods for preparing partially polymerized cyanoacrylate adhesives are disclosed, for example, in Rabinowitz, U.S. Patent No. 3,527,224 which is incorporated herein by reference in its entirety.

The cyanoacrylate adhesive compositions employed in the methods described herein may additionally contain one or more optional additives such as colorants, perfumes, stabilizers, bactericides, and the like. In practice, each of these optional additives should be both miscible and compatible with the cyanoacrylate adhesive. Compatible additives is those that do not prevent the use of the cyanoacrylate adhesives for their intended use.

In general, colorants are added so that the polymerized film will contain a discrete and discernable color. Perfumes are added to provide a pleasant smell to the formulation. Stabilizers are added to minimize in situ polymerization in containers during storage. Bactericides are added to inhibit bacterial growth. Each of these additives is conventional. For example, suitable stabilizers are disclosed in U.S. Patent No. 4,650,826 the disclosure of which is incorporated herein by reference in its entirety.

As used herein, the following terms have the following meanings:

The terra "cyanoacrylate adhesive" refers to adhesives based on cyanoacrylate monomers of formula I:

CH₂=C-COR CN

where R is butyl (e.g., n-butyl, iso-butyl, sec-butyl, and t-butyl) . Preferably, R is n-butyl.

These cyanoacrylate adhesives are known in the art and are described in, 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 of which are incorporated herein by reference in its entirety.

These cyanoacrylate adhesives rapidly polymerize in the presence of water vapor and/or tissue protein found on the surface of human skin (i.e., epidermis) . The n-butyl-cyanoacrylate is capable of bonding to human skin without causing histoxicity and/or cytotoxicity.

BRIEF DESCRIPTION OF THE DRAWING

Figure 1 illustrates one embodiment of an applicator suitable for use in this invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

This invention is directed to methods for the multiple intermittent application of cyanoacrylate adhesives onto human skin. These methods employ devices suitable for the non-sterile storage of cyanoacrylate adhesives after opening of the device, thereby permitting the multiple, intermittent dispensement of these adhesives by non-medically trained individuals.

The devices employed in the herein described methods are particularly suited for storing the cyanoacrylate adhesive in a home medicine cabinet for repeated uses over a period of days, weeks or months. These storage conditions are invariably non-sterile, and, accordingly, the dispensement devices described herein are constructed to permit the non-sterile storage of these adhesives after the device is opened while still permitting their subsequent application onto the surface of human skin days, weeks or months after opening.

While it is noted that the cyanoacrylate adhesives employed in the devices described herein are bacteriostatic, repeated use of these adhesives in an applicator can result in the inclusion of water (via condensation) and other contaminants in the applicator as well as in adhesive composition. The inclusion of such contaminants in the adhesive is detrimental to the repeated intermittent use of the adhesive over a period of time. For example, it is known that cyanoacrylate adhesives are prone to polymerization in the presence of water which can result in the undesired in situ polymerization of the adhesive in the applicator. Likewise, the inclusion of contaminants in the applicator can result in the presence of bacterial populations in the applicator notwithstanding the bacteriostatic nature of the adhesive.

The methods of this invention are directed, in part, to the discovery that the devices described herein are capable of storing cyanoacrylate adhesives under non-sterile conditions while still permitting their subsequent application onto human skin days, weeks or months after opening the applicator.

The dispensement devices of this invention are specifically characterized by an opening of no more than 0.25 square inches ( millimeters square) and preferably of from about 0.02 to about 0.10 square inches (about to about millimeters square) which opening is resealable. In particular, it is noted that such a narrow opening area minimizes the circulation of ambient air into the device during unsealing of the device (e.g., during dispensement of the adhesive) , thereby limiting the amount of moisture and other contaminants which can enter the device during dispensement. Additionally, the narrow opening coupled with the viscosity of the adhesive, as recited above, permits the metered application of the adhesive onto the skin.

The resealable feature of the described applicator permits resealing the applicator after, for example, dispensement of the adhesive, which further limits the amount of moisture and other contaminants which can enter the device.

Figure 1 illustrates one embodiment of an applicator suitable for use in the methods of this invention. Specifically, in Figure 1, applicator 1 contains cyanoacrylate adhesive 2 which has an applicator region 3 which is tapered to provide for portal 4. Preferably, when manufactured, the cyanoacrylate adhesive 2 fills most of the space within applicator 1 so that the amount of dead space (the air between the cyanoacrylate adhesive and the container opening) is minimal. This is illustrated by the cut away portion 7 of wall 5 which illustrates adhesive 2 filling most of applicator 1. Walls 5 of applicator 1 are made of a pliable material, preferably a pliable plastic, so that upon the application of pressure onto walls 5, the walls depress sufficiently to force adhesive 2 up through the applicator region 3 and through opening or portal 4.

Applicator region 3 is constructed in a manner to permit resealing of the opened applicator. In one preferred embodiment, the resealing means comprises a cap 6 which is sized to tightly mate with applicator region 3 when attached to the top of applicator 1, as shown by the arrows. In another preferred embodiment, applicator region 3 is constructed as a thread (not shown) , and the resealing means comprises a cap (not shown) which screws on. Other resealing means relative to the applicator region are well known in the art.

In a preferred embodiment, the resealable opening is manufactured in non-opened (closed) configuration so as to enclose the cyanoacrylate adhesive, thereby inhibiting accidental spillage during storage. For example, during manufacture, the opening can be covered with a metal foil or the like which, at the time of use, can be punctured by the consumer. Such coverings are well known in the art and are typically punctured by a pin enclosed with the applicator. In this embodiment, closure of the opening together with the resealing means reduces the likelihood of spillage during storage.

Other suitable applicators suitable for use in the devices of this invention are described, for example, by Otake, U.S. Patent No. 4,958,748, which patent is incorporated herein by reference in its entirety.

By combining these features, it has been found that the applicators described herein are suitable for use in methods comprising the intermittent repeated application of cyanoacrylate adhesives onto human skin.

The methods of this invention are particularly suited for intermittent, multiple uses described in the methods of commonly-assigned U.S. Patent Application Serial Nos. 07/895,589 and 07/871,588, the disclosures of which are incorporated herein by reference in their entirety.

For example, the methods described in these applications include the treatment of small non- suturable wounds. Such wounds are characterized by superficial wounds, generally less than about 0.5 cm in depth and preferably less than about 0.1 cm in depth and of varying lengths, although generally ranging from about 0.2 cm to about 10 cm in length. Such superficial wounds include cuts where the skin is separated and can be joined together, as well as abrasions such as "nicks" or "scrapes" where the skin is removed. However, non-suturable wounds generally do not include puncture wounds. The cyanoacrylate adhesive is applied to a wound area under conditions suitable for polymerizing the adhesive so as to form a protective coating. In general, the wound is usually first cleaned (soap/water and optionally a disinfectant) , and then sufficient amounts of cyanoacrylate adhesive are employed to cover or encase the entire scrape, scratch or nick area. For cuts, an amount sufficient to join the opposing skin edges is applied as well as to encase the entire cut area. Where the adhesive is applied to cover a wound, the adhesive coating is at least less than about 0.5 mm thick and more preferably at least about 0.1 mm thick. Such coatings are formed by applying at least about 0.02 ml of cyanoacrylate adhesive per square centimeter of skin surface area.

Upon application of the cyanoacrylate adhesive, the surface skin moisture, tissue protein, and temperature are sufficient to initiate polymerization of the adhesive upon application. Thereafter, the skin surface is maintained under suitable conditions to allow polymerization to proceed to formation of an adhesive coating.

In general, the particular length of time required for polymerization will vary depending upon factors such as the amount of adhesive applied, the temperature of the skin, the moisture content of the skin, the surface area of the wound and the like. However, in a preferred embodiment, polymerization is generally complete within about 10 to about 60 seconds while the skin is maintained at ambient conditions.

During this period, the person to whom application of the cyanoacrylate adhesive has been made merely allows the adhesive to form a coating while minimizing any action to prevent the adhesive from being dislodged from that portion of the skin where it was applied or to adhere to unintended objects. After the adhesive coating has formed, the coating strongly adheres to the skin and is flexible and waterproof, thereby protecting the wound area and promoting healing.^*

It is important to note that the adhesive coating of the invention can be applied in a non- sterile environment to a non-sterile surface. This is directly contrary to the use of cyanoacrylates as surgical adhesives which requires one-time use in a sterile environment. The invention provides for storage of the adhesive in a dispenser for repeated intermittent uses in a non-sterile environment.

In general, the coating will adhere to the skin- for a period of about 2-3 days after which time it sloughs off. Additional applications can be made if desired.

The coating protects non-suturable wounds because the adhesive forms a polymer coating which extends ever the entire surface of the wound to protect the wound in much the way a bandage does while, in the case of cuts, it also joins together the separated skin surfaces.

The methods of this invention are also suited for inhibiting blister formation by forming an artificial callus over an area of uncut skin by the application of at least about 0.2 ml of cyanoacrylate adhesive per square centimeter of skin so as to inhibit blister formation. The cyanoacrylate adhesive is applied onto the skin surface area under conditions suitable for polymerizing the adhesive so as to form an artificial callus. In general, sufficient amounts of cyanoacrylate adhesive are employed to permit formation of an artificial callus having a sufficient thickness to inhibit blister formation. In a preferred embodiment, the artificial callus has a thickness of at least about 0.1 mm and more preferably at least about 0.3 mm. Such artificial calluses are formed by applying at least about 0.02 ml of cyanoacrylate adhesive per square centimeter .of skin surface area.

In another preferred embodiment, the amount of cyanoacrylate adhesive employed should not exceed about 0.05 ml per square centimeter. At concentrations in excess of that maximum preferred concentration, it takes too long for the artificial callus to form, and the resulting callus is subject to shear forces. Additionally, higher concentrations of adhesive create polymers having less than desirable skin adherence and durability characteristics.

For inhibiting the formation of blisters, the cyanoacrylate adhesive is applied prior to blister formation. That is, the cyanoacrylate adhesive is applied onto the blister prone areas of uncut and uninjured skin prior to initiation of physical activity which would be expected to result in the formation of blisters. Additionally, the cyanoacrylate adhesive can be applied onto uncut blister prone areas of the skin at some point during physical activity when blister prone areas begin exhibiting some of the classic signs of blister formation (i.e., irritation, perceived heat and so forth) .

Upon application of the cyanoacrylate adhesive, the surface skin moisture and temperature are sufficient to initiate polymerization of the adhesive upon application. Thereafter, the skin surface is maintained under suitable conditions to allow polymerization to proceed to formation of an artificial callus.

In general, the particular length of time required for polymerization will vary depending upon factors such as the amount of adhesive applied, the temperature of the skin, the moisture content of the skin and the like. However, in a preferred embodiment, polymerization is generally complete within about 10 to about 60 seconds while the skin is maintained at ambient conditions. During this period, the person to whom application of the cyanoacrylate adhesive has been made merely allows the adhesive to form a callus while minimizing any action to prevent the adhesive from being dislodged from that portion of the skin where it was applied (e.g., washing his hands, placing socks on his feet) . After the artificial callus has formed, the callus strongly adheres to the skin and is flexible and waterproof, thereby permitting the person to conduct the intended activity.

In general, the artificial callus will adhere to the skin for a period of about 2-3 days after which time it sloughs off. However, if it is desirable to remove the artificial callus prior to its sloughing off, the artificial callus can be removed with acetone (nail polish remover) .

From the foregoing description, various modifications and changes in the composition and method described herein 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

WHAT IS CLAIMED IS:

1. A method for the multiple, intermittent, non-sterile application of cyanoacrylate adhesive onto human skin which method comprises the^* steps of: (a) selecting an applicator suitable for the non- sterile storage and metered dispensement of a cyanoacrylate adhesive after opening of the applicator which applicator comprises: a resealable opening of no more than about 0.25 square inches ( millimeters square) so as to permit the metered dispensement of the adhesive from the applicator and which is capable of multiple administrations of the stored adhesive; resealing means; and a cyanoacrylate adhesive contained therein, which in monomeric form, is represented by Formula I:

O

where R is butyl and is preferably n-butyl; and

(b) dispensement of the cyanoacrylate adhesive from the applicator selected in step (a) above onto the human skin.

2. The method according to Claim 1 wherein the resealable opening is from about 0.02 to about 0.10 square inches (about to about millimeters square) .

3. The method according to Claim 2 wherein the cyanoacrylate adhesive is n-butyl cyanoacrylate.

4. The method according to Claim 1 wherein the viscosity of the cyanoacrylate adhesive is from about 2 to about 1000 centipoise at 20°C.

5. The method according to^* Claim 4 wherein the cyanoacrylate adhesive is dispensed at a rate of at least 0.02 ml per square centimeter of skin.