# Patent

## Title
In situ film-forming bioactive solutions of absorbable multiblock copolymers

## Abstract

An in situ film-forming methyl acetate-based solution of at least one absorbable, segmented block copolymer with amorphous and semi-crystalline segments contains at least one bioactive agent which exhibits antimicrobial, anti-inflammatory, antiviral, anesthetic, hemostatic, and/or antineoplastic activity. The absorbable polymers can be a polyaxial copolyester, polyether-ester and polyether-ester urethane. The solution can be applied (e.g., sprayed or swabbed) onto animal and human skin or accessible body cavities to prevent or treat one or more disorders preventable or treatable by the bioactive agent therein.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
The present application is a continuation-in-part of co-pending application U.S. Ser. No. 12/931,279, filed Jan. 29, 2011, which claims priority to provisional application U.S. Ser. No. 61/337,295, filed Feb. 2, 2010, both of which applications are incorporated herein in their entirety.


FIELD OF THE INVENTION
This invention is directed to an in situ film-forming methyl acetate-based solution of an absorbable segmented block copolymer with amorphous and semi-crystalline segments containing at least one soluble or microdispersed bioactive agent. Depending on the application site, the tissue adherent and compliant film produced by spraying or swabbing the solution is designed to display a one hundred to six hundred percent elongation and can be applied on animal or human skin and walls of accessible body cavities for controlled release of a variety of bioactive agents including antifungals and antibacterials to treat or prevent the respective infections.
BACKGROUND OF THE INVENTION
Interest in developing a practical form of bandages or covers that are formed in situ on a wound by spraying or swabbing a solution or dispersion of a polymer(s) in a liquid carrier dates back to the early 1970s, when for instance the preparation of a spray-on bandage was described in U.S. Pat. No. 3,577,516. In the latter the inventors outlined the requirements for a fully acceptable spray-on bandage to include the following:

    
    
        (1) It protects the wound from air borne bacteria and dirt.
        (2) It has moisture vapor permeability sufficient to prevent accumulation of aqueous fluid under the bandage.
        (3) It must be non-toxic and non-irritating to the skin.
        (4) It should not adhere to the wound area or permit infiltration by regenerating tissue.
        (5) It should not cause a burning or stinging sensation when applied.
        (6) It should not be water soluble or rendered tacky by contact with water to avoid dirt accumulation.
        (7) It should be readily removable when desired.
    
    


Those inventors also noted that prior art spray-on products suffer from a number of disadvantages with respect to the above criteria. Thus prior art materials having the desired moisture vapor permeability coupled with water resistance must be applied as a spray from alcohol or similar solvent solution which causes a strong burning sensation in the wound area. Hence, the objective of U.S. Pat. No. 3,577,516 was to develop a spray-on bandage having all seven of the above set forth desirable characteristics while avoiding the disadvantages of prior art spray-on bandages. More specifically U.S. Pat. No. 3,577,516 dealt primarily with a method of forming a powdery bandage in situ on skin having a wound therein which is readily removable therefrom after soaking, the improvement comprising the steps of (a) applying, as a powder, a hydrophilic water insoluble hydroxyl or lower alkoxy lower alkyl acrylate or methacrylate polymer or a copolymer of 20 to 70% of a lower acrylate or methacrylate and 80 to 30% of acrylamide, methacrylamide, N-lower alkyl acrylamide or methacrylamide, or N-vinylpyrrolidone as a powder and (b) applying, simultaneous or in succession, a high boiling liquid plasticizer or solvent therefore which does not cause a burning or stinging sensation when applied on the skin resulting from adherence of the powder to the wound area wet with the non-stinging plasticizer solvent thereby covering said wound wherein the polymer powder and plasticizer are sprayed from separate containers in succession, or wherein the polymer powder and plasticizer are simultaneously sprayed from separate chambers in a single container, or wherein the polymer powder and plasticizer are sprayed simultaneously from the same chamber in a single container, the plasticizer and polymer powder being kept separate by the propellant which prevents salvation and agglomeration of the polymer powder by the plasticizer, wherein the polymer is in finely divided form, substantially uncrosslinked and has a moisture vapor permeability of at least 200 grams/sq. meter/24 hours/mil and the application is accomplished by spraying as an aerosol with the aid of a propellant.
Extension of the in situ-forming film technology was described in U.S. Pat. No. 6,958,154 and dealt with a spray-on bandage and drug delivery system. This provided the so called patch-in-a-bottle technology in which a fluid composition, e.g., an aerosol spray, is applied onto a surface as a fluid, but then dries to form a covering element, such as a patch, having a tack-free outer surface covering an underlying adhesive that helps to adhere the patch to the substrate. The fluid compositions have a unique chemical formulation that allows such composite patches to form in situ. Specifically, the fluid compositions include a tacky component, such as an adhesive, and a film-forming, non-tacky component. The non-tacky and tacky components are selected to be immiscible with each other so that the components undergo phase separation as the fluid composition dries. Accordingly, U.S. Pat. No. 6,958,154 claimed a fluid composition suitable for in situ forming and adhering to a touch-dry, non-tacky covering element onto a surface, comprising:
(a) an effective amount of a tacky component such that the formed covering element adheres to the surface, wherein the tacky component comprises a pressure sensitive adhesive comprising a methacrylate polymer, further wherein the methacrylate polymer is a copolymer of monomers comprising about 40 to about 100 weight percent of an alkyl methacrylate and 0 to about 60 weight percent of a free radically 20 copolymerizable monomer;
(b) a film-forming, non-tacky component, wherein said film-forming; non-tacky component comprises at least one low surface energy, surface seeking moiety, wherein said film-forming, non-tacky component is incompatible with the tacky component, and wherein the film-forming, non-tacky component is present in an effective amount such that upon application it undergoes phase separation from the tacky component such that an outer surface of the in situ formed covering element is non-tacky when the covering element is touch dry; and
(c) a sufficient amount of at least one volatile solvent such that the fluid composition has a coatable viscosity allowing the fluid composition to be coated onto said surface.
In a series of disclosures (U.S. Pat. Nos. 4,987,893, 5,103,812, and U.S. patent application Ser. No. 11/465,237), conformable solvent-based bandage and coating materials were discussed by the inventors, specifically, combinations of alky siloxy siloxane-containing polymers admixed with liquid polydimethylsiloxanes are excellent non-stinging, non-irritating liquid coating material for forming films, which act as conformable bandages adhering to and protecting nails, skin and mucous membrane wounds from abrasion, contamination, and desiccation, while stopping pain from exposed nerve ends and allowing body fluid evaporation U.S. Pat. Nos. 4,987,893 and 5,103,812). In one primary claim (U.S. Pat. No. 4,987,893) the inventors described a liquid polymer-containing bandage material comprising 1 to 40 weight percent siloxane containing polymer, 59.9 to 98.9 weight percent volatile polydimethylsiloxane liquid, and 0.1 to 10 weight percent polar liquid; said bandage material being substantially non-stinging and film forming at room temperature to form an adherent conformable moisture vapor permeable bandage directly on a user. In a second major claim (U.S. Pat. No. 5,103,812), the inventors described a liquid polymer-containing coating material comprising from 1 to 40 weight percent siloxane containing polymer, 59.9 to 98.9 weight percent volatile polydimethylsiloxane, and 0.1 to 10 weight percent polar liquid; said coating material being substantially non-stinging and film forming at room temperature to form an adherent conformable moisture 35 vapor permeable coating directly on a user, wherein said siloxane-containing polymer is soluble in hexamethyldisiloxane and comprises a monomer component that is a silane derivative, a monomer component that when provided as a homopolymer would prepare a hard polymer, and a monomer component that, when provided as a homopolymer would prepare a soft polymer. In a subsequent disclosure, those inventors described liquid hemostatic coating materials that comprise a cyanoacrylate monomer and a solvent system comprising a volatile, non-reactive liquid that is non-stinging and non-irritating to a user. The material forms a coating or bandage in the form of a film that when applied and adhered to a surface or to the skin of a user inhibits the application surface from adhering to another surface (U.S. patent application Ser. No. 11/465,237). Specifically, the primary claims described a liquid coating material comprising about 0.1 to about 99.9 weight percent polymerizable cyanoacrylate monomer and about 0.1 to about 99.9 weight percent non-stinging, non-irritating, volatile, non-reactive liquid; said coating material being hemostatic on bloody, moist and non-moist surfaces to form an adherent, conformable polymer coating, which adherent, conformable coating does not adhere to a second surface, wherein the liquid coating comprises about 0.01 to about 99.5 percent by weight siloxysilane-containing polymer, about 0.1 to about 99.5% by weight polymerizable cyanoacrylate monomer and about 0.5 to about 99.9% by weight non-stinging, non-irritating, volatile hydrophobic liquid; said coating materials being film-forming on bloody, moist and non-moist surfaces to form an adherent, conformable, moisture vapor permeable, hemostatic, interpenetrating polymer coating, which coating does not adhere to a second surface, and wherein said polymerizable cyanoacrylate monomer component comprises alpha-cyanoacrylates.
Growing interest in exploring new biomedical applications of the absorbable polymer technology coupled with existing experience with in-situ forming non-absorbable film as discussed above directed the attention of Tipton et al. (U.S. Pat. Nos. 5,632,727 and 5,792,469) to the preparation of a biodegradable film dressing with or without additional therapeutic agents, an apparatus for spray delivery and a method for formation of the film dressing on a human or animal tissue. The film dressing is formed from a liquid composition of at least one biodegradable/bioerodible thermoplastic polymer in a pharmaceutically acceptable solvent. The spray apparatus includes a vessel containing the liquid composition with a dispensing means. The film is formed by dispensing, preferably by spraying, the liquid composition onto a tissue site and contacting the liquid composition with an aqueous-based fluid to coagulate or solidify the film onto the human or animal tissue. The biodegradable film can be used to protect and to promote healing of injured tissue and/or to deliver biologically active agents. The primary claims of these disclosures deal with a biodegradable microporous film dressing comprised of a skin and a core portion, the skin portion having pores with a smaller diameter than pores of the core portion; wherein the film dressing is formed by contacting a composition comprising a biodegradable thermoplastic polymer that is insoluble in aqueous or body fluids, and an organic solvent that is soluble in aqueous or body fluids, with an aqueous or body fluid whereupon the composition coagulates or solidifies to form the microporous film dressing, wherein the film dressing is formed by administering the composition onto tissue, and the core portion of the film dressing is orientated under the skin portion and in contact with the tissue, and further wherein the film dressing is formed by administering the composition onto a tissue and the skin portion of the film dressing is orientated under the core portion and in contact with the tissue. Meanwhile, the biodegradable thermoplastic polymer is selected from the group consisting of polylactides, polyglycolides, polycaprolactones, polyethylene glycols, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(amino acids), poly (methyl vinyl ether) and copolymers, terpolymers, and combinations thereof. The solvent used in dissolving the polymers included N-methyl-2-pyrrolidone, 2-pyrrolidone, acetone, acetic acid, ethyl acetate, ethyl lactate, methyl acetate, methyl ethyl ketone, dimethylformamide, dimethylsulfoxide, dimethyl sulfone, tetrahydrofuran, caprolactam, decylmethylsulfoxide, oleic acid, propylene carbonate, N,N-diethyl-m-toluamide, and 1-dodecylazacycloheptan-2-one, and mixtures thereof. A second primary claim made by those inventors dealt with a liquid composition suitable for forming an in situ biodegradable film dressing on a human or animal tissue, comprising: a liquid formulation of a biodegradable thermoplastic polymer that is insoluble in aqueous or body fluids and an organic solvent that is soluble in aqueous or body fluids; wherein the composition comprises about 0.01-2 g polymer per mL solvent, and has a viscosity of about 45 0.1-2000 cps which effectively allows for aerosolization, and wherein the amount and molecular weight of said polymer is such that the composition is capable of coagulating or solidifying to form a film dressing upon contact with an aqueous or based fluid. Meanwhile, (1) the solvent is a liquid aerosol propellant that can be selected from the group consisting of trichloromonofluoromethane, dichlorodifluoromethane, dichloromonofluoromethane, 2-tetrafluoroethane, 1,1dichloro-1,2,2-tetrafluoroethane, 1-chloro-1,1difluoroethane, 1,1-difluoroethane, octofluorocyclobutane, propane, isobutane, N-butane, and mixtures thereof and (2) “biodegradable thermoplastic polymer is selected from the group consisting of polylactides, polyglycolides, polycaprolactones, polyethylene glycols, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(amino acids), poly (methyl vinyl ether), and copolymers, terpolymers, and combinations thereof.
The use of a natural gum resin as a carrier for topical application of pharmacologically active agents was the subject of U.S. Pat. No. 6,899,897, which described a biological dressing for treatment of a dermatological disease comprised of a gum resin, a topically acceptable volatile solvent, and a pharmacologically active agent. The gum resin is present in a suitable amount that the composition, when the solvent evaporates, will dry to form a solid coating that sticks to the skin or mucosal membrane to which the composition is applied and maintain the pharmacologically active agent over a sustained period of time in contact with sites on the skin or mucosal membranes exhibiting symptoms of the disease. Methods are provided for treating symptoms of dermatological diseases with such a pharmacological composition. Biological dressings including tincture of benzoin and clotriconazole are shown to be efficacious for the long-term amelioration of symptoms of athlete's foot.
The primary claims of U.S. Pat. No. 6,899,897 dealt with a pharmacological composition comprising: (1) a gum resin, wherein said gum resin comprises benzoin; (1) at least one topically acceptable pharmacologically active agent other than said gum resin that is effective as a treatment for ameliorating symptoms of a disease of skin or a mucous membrane of a mammal wherein said pharmacologically active gent can remain in contact with said skin or said mucous membrane greater than 6 hours without toxic effects to said mammal; and (3) a topically acceptable volatile solvent for said gum resin and said pharmacologically active agent, wherein said topical acceptable volatile solvent is ethanol and the pharmacological active agent is the antimicrobial agent, clotriconazole.
All patents and patent applications noted in this specification are indicative of the level of skill of those skilled in the art to which the instant invention pertains. However, none of the prior art disclosures dealt with uniquely tailored in situ-formed bioactive tissue adherent films based, specifically, on absorbable multiblock coolymers in a non-irritating, highly volatile organic solvent to ensure optimum applicability, performance as a flexible tissue-adherant, conforming and stretchable protective cover that is also capable of a timely delivery of its drug payload and undergoing biodegradation thereafter. This and the availability of proprietary absorbable polymers in our laboratory that can be processed towards meeting the requirements of such film provided an incentive to pursue the study subject of the instant invention.
SUMMARY OF THE INVENTION
This invention deals in general with an in situ film-forming methyl acetate-based solution of at least one absorbable, segmented block copolymer with amorphous and semi-crystalline segments, comprising at least one bioactive agent selected from the group exhibiting antimicrobial, anesthetic, antiviral, anti-inflammatory, hemostatic, and antineoplastic activities, wherein the methyl acetate represents from about fifty to one hundred weight percent of the solvent component of the methyl acetate-based solution, the balance being a secondary organic solvent, preferably a ketone and wherein said solution can be sprayed or swabbed on animal or human skin and accessible body cavities to form an adherent, flexible, conformable, stretchable, dimensionally stable film with tack-free outer surface and when tested in the tensile mode, exhibits an elongation of 100 to 600 percent, tensile strength of 3-10 MPa and a tensile modulus of 5-20 MPa, and further wherein the copolymer represents 0.1 to 20 weight volume percent of the solution. The secondary organic solvent may be acetone, methyl ethyl ketone, ethyl isopropyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, or 3 pentanone. Acetone is preferred.
Another aspect of this invention deals with an in situ film-forming methyl acetate-based solution of at least one absorbable, segmented block copolymer with amorphous and semi-crystalline segments comprising at least one bioactive agent selected from the group exhibiting antimicrobial, anesthetic, antiviral, anti-inflammatory, hemostatic, and antineoplastic activities, wherein the methyl acetate represents from about fifty to one hundred weight percent of the solvent component of the methyl acetate-based solution, the balance being a secondary organic solvent, preferably a ketone, and wherein the at least one absorbable segmented block copolymer with amorphous and semi-crystalline segments exhibits a heat of fusion (ΔHf) of 1 to 20 J/g and is selected from the group consisting of polyaxial copolyesters, polyether-esters and polyether-ester-urethanes, and further wherein the at least one bioactive agent represents 0.1 to 15 weight percent of the copolymer and is in said solution as a soluble entity or partially soluble microparticles or colloids. More specifically, (a) the polyaxial copolyester is derived from at least two cyclic monomers selected from the group consisting of p-dioxanone, 1,5-dioxapan-2-one, glycolide, l-lactide, ε-caprolactone, trimethylene carbonate and a morpholinedione; (b) the polyether-ester is an end-grafted product of a polyethylene glycol and at least one monomer selected from the group of p-dioxanone, 1,5-dioxapan-2-one, glycolide, l-lactide, ε-caprolactone, trimethylene carbonate and a morpholinedione; and (c) the polyether-ester urethane is an end-grafted product of a polyethylene glycol and at least one monomer selected from the group consisting of p-dioxanone, 1,5-dioxapan-2-one, glycolide, l-lactide, ε-caprolactone, trimethylene carbonate and a morpholinedione, the end-grafted product being further interlinked with an aliphatic diisocyanate selected from the group consisting of 1,4-butane diisocyanate, 1,6-hexane diisocyanate, and a lysine diisocyanate.
Yet another aspect of this invention deals with an in situ film-forming methyl acetate-based solution of at least one absorbable, segmented block copolymer with amorphous and semi-crystalline segments comprising at least one bioactive agent selected from the group exhibiting antimicrobial, anesthetic, antiviral, anti-inflammatory, hemostatic, and antineoplastic activities, wherein the methyl acetate represents about fifty to one hundred volume percent of the solvent component of the methyl acetate-based solution, the balance being a secondary organic solvent and wherein the at least one absorbable segmented block copolymer with amorphous and semi-crystalline segments exhibits a heat of fusion (ΔHf) of 1 to 20 J/g and is selected from the group consisting of polyaxial copolyesters, polyether-esters and polyether-ester-urethanes, and further wherein the at least one bioactive agent wherein said agent represents 0.1 to 15 weight percent of the copolymer and is in said solution as a soluble entity or partially soluble microparticles. More specifically, the at least one bioactive agent is selected from the group consisting of miconazole, ketoconazole, metronidazole, fluconazole, a silver salt, chlorhexidine, curcumin, capsaicin, lidocaine, benzocaine, 8-hydroxyquinaline, triclosan, and paclitaxel. The silver salt may be any reasonably soluble compound, such as, for example, silver nitrate, silver acetate, silver sulfadiazine, and the like. Chlorhexidine is preferably used in the form of the free base.
From a clinical perspective, this invention deals with an in situ film-forming, sprayable or swabable methyl acetate-based solution of at least one absorbable, segmented block copolymer with amorphous and semi-crystalline segments comprising at least one bioactive agent selected from the group exhibiting antimicrobial, antifungal, anesthetic, antiviral, anti-inflammatory, hemostatic, and antineoplastic activities and said solution is useful for treating or preventing at least one of the following fungal infection, bacterial infection, viral infection, acne, pain, and bleeding.
The solution of the invention may be used, for example, in a surgical setting to form a sprayed or applied barrier on a closed wound, in a hospital setting to cover an intravenous line, indwelling port, catheter, or the like to retard infection, or in a first aid setting to cover a minor cut or scrape.


DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Since the earliest history, tools for wound protection and repair have been used in progressively different forms. However, significant changes in these tools have taken place in the last 60 to 70 years, where gauzes and adhesive bandages began to share the wound care market with adhesive tapes and more recently the so-called liquid bandages. The latter are classified into two main categories. The first category entails skin protectants and over-the-counter gels and sprays that can shield superficial scrapes as well as large chronic bedsores. The second category encompasses the family of tissue adhesives which are used to cover more serious skin lacerations and yet to be widely used in tissue repair as legitimate replacements for mechanical wound closure devices, such as sutures and staples. Most pertinent to the present invention are the tools of the first category. The instant invention provides unique transient compositions for tissue protection and treatment of wounds during a finite period of time through using novel in situ-formed bioactive tissue adherent films of absorbable, segmented block copolymers with amorphous and semi-crystalline segments.
The uniqueness of the in situ-formed bioactive films can be illustrated as follows:
1. The film-forming polymers are absorbable in nature and their absorption profiles can be modulated by controlling their chemical composition to permit controlling their effective residence time at the application site.
2. The absorbable film-forming polymers are designed to be soluble in the previously unexpected, useful methyl acetate-based solvent that (a) provides the necessary solvating power of a broad range of difficult-to-dissolve film-forming polymers having a broad range of solubility parameters; (b) is capable of dissolving highly potent drugs with established efficacy in a variety of key indications including the treatment of skin and mucus membrane microbial and viral infections; (c) has a low boiling point and can be easily lead to film formation using a simple sprayer; (d) is non-stinging and has a pleasant odor to permit its use on large tissue areas having variable amounts of nerve endings; and (e) is capable of dissolving or effectively dispersing nano- and/or microparticulate sun-screening compounds to allow their use in protecting against sun rays and then are removable at will by wiping with a drug-free solvent in a soft pad.
3. The absorbable film-forming polymers are designed to have (a) sufficiently high percentages of ultimate elongation to circumvent breakage upon stretching of the application site; (b) sufficiently low modulus and hence, high compliance to prevent unwanted mechanical incompatibility with application sites such as high-compliance soft skin or mucus membranes; (c) low degrees of crystallinity to provide in-use dimensional stability without compromising the compliance or softness of the film; (d) a high degree of light transmission, in spite of the presence of a crystalline fraction to allow a desirable levels of film transparency—the small size of crystallites, as evidenced by pertinent analytical methods, is responsible for such transparency; (e) a range of solvating capacities and absorption profiles to allow their use as depots for the timely and controlled release of the different bioactive agents therein; and (f) the necessary structure to allow their sterilization by one or a combination of traditional means such as ethylene oxide, gamma radiation, electron beam, and less traditional means such as gas plasma and radiochemical sterilization.
4. The in situ film-forming methyl acetate-based solution of at least one segmented block copolymer with amorphous and semi-crystalline segments loaded with antimicrobial agents can be used as an absorbable barrier/sealent with or without specific antibiotics to be applied on any minor laceration, in the setting of wound re-approximation after any major or minor surgery, or to protect the site of an intravenous line, port, catheter, or the like. The aforementioned advantages are as follows:
(1) Off-the-shelf use in the operating room or a first aid setting without any timely preparation.
(2) Ease of application as a “sprayed” on film to various sized incisions with 100% coverage given it film forming properties regardless of surface incongruency.
(3) May display “mild adhesive” properties if used after skin re-approximation with subcuticular closures (i.e. suture placed under skin).
(4) Broad use in a variety of medical applications, such as surgeries as in abdominal surgery (GI-colorectal, GYN, Urologic), obstetrics (skin closure after C-sections), breast surgery for cancer, vascular surgery where amputations are performed due to peripheral vascular disease, hand surgery, foot (podiatric) surgery, plastic surgery (abdominoplasty, breast reduction or augmentation, and fascial surgery), trauma surgery, and emergent surgery where an infection is apparent (ruptured appendix, small or large bowel perforation, gynecologic infections), or to provide a protective barrier over intravenous lines, ports, catheters, or the like, as well as for in-home first aid use on minor cuts, scrapes, and the like.
(5) Minimize post-op wound infection and provide a barrier system that will exhibit the necessary compliance or stretch as patient activity level increases without comprising skin healing and repair.
(6) Proprietary formulation may display optimal oxygen transmission to the wound based on the hydrophilic properties that retain moisture.
(7) Provides a protective coating and sealant and minimizes drainage at incision sites when there is excessive edema and inflammation whereby the excess fluid may leak in-between the suture-line or of staple line.
(8) May contain antimicrobial compounds as an adjunct to its protective coating. This is relevant to a variety of medical situations, such as (a) small or large bowel surgery where bowel contents have entered the surgical field—or in the case of ruptured infectious processes such as appendix, tubo-ovarian abscesses, or in the setting trauma where emergent surgery is needed, (b) patients with poor wound healing potential such as morbidly obese and/or diabetic patients, as well as patients with peripheral vascular disease, (c) as a protective anti-infective covering over indwelling intravenous lines, ports, catheters, and the like, and (d) for in-home first aid use.
(9) May contain anti-inflammatory agents to minimize swelling and improve pain control with less need for narcotic use post-operatively.
In one particular embodiment of the invention the solution comprises:

    
    
        a) a polymer component comprising at least one absorbable, segmented block copolymer with amorphous and semi-crystalline segments made from ε-caprolactone, trimethylene carbonate, glycolide, and l-lactide;
        b) a solvent component comprising methyl acetate and an optional secondary organic solvent; and
        c) a bioactive agent selected from a silver salt, chlorhexidine, and combinations thereof.
    
    


In this embodiment, the solvent component may, for example, be 100% methyl acetate if the bioactive agent is only chlorhexidine. However, if the bioactive agent is a silver salt or the combination of chlorhexidine and a silver salt, the solvent component should be a mixture of methyl acetate and a secondary organic solvent suitable for increasing the solubility of the silver salt in the solvent component. Suitable secondary organic solvents are, for example, ketones, such as acetone, methyl ethyl ketone, ethyl isopropyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, or 3 pentanone. Acetone is preferred. Silver salts are essentially insoluble in methyl acetate but certain silver salts are somewhat soluble in other organic solvents such as ketones. Therefore, if the bioactive agent comprises a reasonably soluble silver salt (such as silver nitrate, silver acetate, silver sulfadiazine, or the like), sufficient secondary organic solvent should be present in the solvent component so that when the solvent component is saturated with the silver salt, the solution has the desired concentration of silver salt. On the other hand, since some organic solvents, such as ketones, can sting when applied to a wound, the solvent component should preferably not contain excess secondary organic solvent beyond the amount needed to dissolve the desired amount of silver salt. Typically, the solvent component may comprise up to about 50 volumer % of the secondary organic solvent and the balance methyl acetate.
In a further embodiment of the invention, the solution comprises:

    
    
        a) a polymer component comprising a segmented copolyester made of approximately 35/14/34/17/ε-caprolactone/trimethylene carbonate/l-lactide/glycolide;
        a) a solvent component comprising about 70 wt % methyl acetate and 30 wt % acetone; and
        b) a bioactive agent comprising chlorhexidine and either silver nitrate or silver acetate, or a combination thereof.
    
    


In the above embodiments, the chlorhexidine prefereably comprises about 3 wt % based on the weight of the polymer component and the polymer component comprises about 7.5 wt-vol % based on the polymer and solvent components.
A further embodiment of the invention comprises a method of preparing the solution of the invention by the sequential steps of:

    
    
        a) preparing a solvent component comprising methyl acetate and acetone;
        b) dissolving chlorexidine base in the solvent component to form a chlorhexidine solution;
        c) dissolving a polymer component in the chlorhexidine solution, the polymer component comprising at least one absorbable, segmented block copolymer with amorphous and semi-crystalline segments made from ε-caprolactone, trimethylene carbonate, glycolide, and l-lactide;
        d) adding excess silver salt to the resulting solution and allowing a saturated solution of silver salt to form in the resulting solution; and
        e) removing the undissolved silver salt.
    
    


In the above embodiment, the silver salt may be silver nitrate, silver acetate, or silver sulfadiazine. Silver nitrate and silver acetate are preferred. Silver nitrate is more preferred. A saturated solution of the silver salt in the resulting solution is typically formed by stirring the silver salt in the solution for a prolonged period (e.g., twelve to sixteen hours) at ambient temperature. The appropriate time needed to form a saturated solution of the silver salt can readily be determined by one of ordinary skill in the chemical art. When saturation of silver salt (e.g., silver nitrate) is attained, the concentration of silver salt comprises between about 100 ppm and 500 ppm. The excess silver salt may be removed by filtration, centrifugation, or the like. In this embodiment, steps b) and c) may be interchanged, so that the polymer component may be initially dissolved in the solvent component and the chlorhexidine base then dissolved in the polymer solution. However, it is important that step d), the step of adding excess silver salt, occur after steps b) and c), in whichever order steps b) and c) occur. Applicants believe that the order of addition of components described herein produces unexpected results in that a film formed from the solution made as described above has a significantly higher silver concentration compared to a film formed from a similar solution in which step b), dissolving chlorhexidine base, is omitted or in which step d) is performed before steps b) and c). Without intending to be bound thereby, Applicants believe that in the method described above the silver ion forms a complex with the chlorhexidine or the chlorhexidine and the polymer, thus accounting for the surprisingly increased concentration of silver ion in the CH/Ag solution compared to a solution of silver nitrate alone.
In a still further embodiment of the method, the solvent component comprises about 70 wt % methyl acetate and about 30 wt % acetone. In another embodiment of the method, the polymer component comprises a segmented copolyester made of approximately 35/14/34/17/ε-caprolactone/trimethylene carbonate/l-lactide/glycolide. In yet another embodiment, the chlorhexidine comprises about 3 wt % based on the weight of the polymer component and the polymer component comprises 7.5 wt-vol % based on the polymer and solvent component. In any of these embodiments, the silver salt may be either silver nitrate or silver acetate.
Further illustrations of the present invention are provided by the following examples:
EXAMPLE 1
Synthesis and Properties of a Typical l-Lactide-Based Polyaxial Copolyester
The polymer was prepared using the general procedure for the synthesis of crystalline, segmented, polyaxial copolyesters as described earlier (U.S. Pat. No. 7,348,364 and U.S. patent application Ser. No. 11/598,427). An amorphous polymeric initiator comprising 35/14/9 (molar) ε-caprolactone/trimethylene carbonate/glycolide was made and end-grafted to form crystalline end-grafts comprising 34/8 (molar) l-lactide/glycolide to yield a copolyester made of 35/14/34/17 (molar) caprolactone/trimethylene carbonate/l-lactide/glycolide. The polymer was characterized for identity (IR, NMR), molecular weight (in terms of inherent viscosity), and thermal property (DSC). It was shown to have an inherent viscosity of 1.45 dL/g, melting temperature of 109° C., and heat of fusion of 7.4 J/g.
EXAMPLE 2
Film Tensile Properties of Polyaxial Copolyester from Example 1
A sample of the polymer from Example 1 (10.0 g) was dissolved in methyl acetate (100 mL). The resulting solution was cast uniformly on a Teflon coated plate to provide a liquid film. This was allowed to dry at room temperature for 2 hours to yield a solid film having a thickness of 0.5 mm. The mechanical properties of the film were determined using a MTS Synergie 200 tensile tester. The procured data are summarized in Table I.







TABLE I





Mechanical Properties of a Polyether-ester Film Based on the


Polymer of Example 1
















Thickness, mm
0.5


Peak Stress, MPa
5.2


Tensile Modulus, MPa
8.9


Elongation at Break, %
484









EXAMPLE 3
Preparation of a Model Construct of a Typical Bioactive Spray-On Film and Study of its In Vitro Release Profile
In order to prepare the model bioactive construct, fluconazole was mixed into methyl acetate at a 0.5% concentration. Follow dissolution of the fluconazole, polyaxial copolyester from Example 1) was dissolved in the methyl acetate solution by rolling at room temperature for three hours to provide a 10% solution. The drug/polymer solution was sprayed onto a pre-weighed, non-woven polyethylene fabric of known weight per unit area and allowed to dry overnight. The dried piece of the sprayed fabric was weighed to determine loading. The loaded piece was submerged in 10 mL of 7.2 pH phosphate buffer and placed in a 37° C. incubator. At time points of 21, 28, and 48 hours, the buffer was poured off and collected and replaced with 10 mL of fresh buffer. The collected eluent was filtered through 0.45 μm filters and analyzed by HPLC. The HPLC analysis was done using a C18 column and a gradient method involving acetonitrile and HPLC grade water both containing 0.1% triflouroacetic acid. The release data are summarized in Table II:







TABLE II





Release Data of Fluconazole from the Model Construct


















Time period (Hours)
21  
28  
48  


Drug Released (mg)*
 1.09
 0.16
 0.26


Cumulative Percentage of Estimated 
62%  
71%  
86%  


Total Loading*





*Initial loading of 1.752 mg/test specimen






EXAMPLE 4
Preparation of a Model Construct of a Typical Bioactive Spray-On Film for Study of its In Vitro Bactericidal Activity
Chlorhexidine (“CH”)/Silver Nitrate (“Ag”) Formulation Preparation
The chlorhexidine/silver nitrate formulation was prepared by dissolving 22.5 mg of chlorhexidine (3% w/w based on the dried film weight) in 10 ml of a methyl acetate/acetone solvent mixture (70/30, vol/vol) at room temperature with gentle swirling. The chlorhexidine dissolved quickly to yield a clear solution. Next, 750 mg of the polymer of Example 1 (7.5% weight/volume) was added to the solution. The solution was agitated and shaken gently to facilitate dissolution of the polymer. Upon complete dissolution of the polymer after approximately 6 hours, 150 mg of silver nitrate crystals (excess) was added to the solution in a roller bottle. The roller bottle was wrapped with aluminum foil and placed on a rolling apparatus for sufficient time to permit dissolved silver nitrate to come to equilibrium with the remaining solid silver nitrate to produce a saturated silver nitrate solution. After approximately 16 hours, the solution was filtered through 0.45 μm Acrodisc filters to remove the undissolved silver nitrate and collected in a clean vial for future use. The vial containing the filtered solution was wrapped with aluminum foil to avoid contact with light and stored at 4° C.
Chlorhexidine (“CH”) Only Formulation Preparation
The formulation containing only Example 1 polymer (7.5% weight/volume) and chlorhexidine (3% w/w based on the films dried weight) was prepared by dissolving 22.5 mg of chlorhexidine in 10 ml of a methyl acetate/acetone solvent mixture (70/30, v/v) at room temperature with gentle swirling. The chlorhexidine dissolved quickly to yield a clear solution. Next, 750 mg of the polymer was added to the solution. The solution was agitated and shaken gently over a six-hour period to facilitate dissolution of the polymer. The vial containing the solution of chlorhexidine and the polymer was wrapped with aluminum foil and stored at 4° C.
Silver Nitrate (“Ag”) Only Formulation Preparation
The formulation containing only Example 1 polymer (7.5% weight/volume) and silver nitrate (excess) was prepared by dissolving 750 mg of the polymer in 10 ml of a methyl acetate/acetone solvent mixture (70/30, v/v) at room temperature with gentle swirling and agitation over a 6 hour period. Upon complete dissolution after approximately 6 hours, 150 mg of silver nitrate crystals (excess) was added to the solution in a roller bottle. The roller bottle was wrapped with aluminum foil and placed on a rolling apparatus for sufficient time to allow a saturated silver nitrate solution to form. After approximately 16 hours, the solution was filtered through 0.45 μm Acrodisc filters to remove undissolved silver nitrate and collected in a clean vial for future use. The vial containing the filtered solution was wrapped with aluminum foil and stored at 4° C.
Film Preparation for Chemical Analysis and Analysis Results
Films were prepared from each formulation by adding 9 ml of the solution to a Petri dish inside a chemical fume hood. The solvent was allowed to evaporate for approximately 16 hours. The dried film was weighed and submitted for chemical analysis (nitrogen and silver). Typical chemical analysis of CH/Ag formulation films yielded 2.5-3.5% for chlorhexidine content and  ̃200-550 ppm for silver content. The same analysis performed on chlorhexidine-only film yielded 2.96% for chlorhexidine content, while chemical analysis of a silver-only film yielded 30 ppm for silver content.
EXAMPLE 5
Study of In Vitro Bactericidal Activity of the Materials of Example 4
The materials prepared in Example 4 were tested for bactericidal activity as described below. The solution was the CH/Ag solution before formation of a film.
Materials


    Mueller-Hinton II or TSA agar
    Appx 1.5×108 CFU/mL cultures of:
    
        Staphylococcus epidermidis ATCC 12228
        Staphylococcus aureus ATCC 25923
        Candida albicans ATCC 90029
        Pseudomonas aeruginosa ATCC 27853
    
    
    Pipettes (200-1000 μl)
    Sterile pipette tips
    Test Articles:
    
        CH/Ag Solution vial
        12 sterile individually cast CH/Ag films
        4 sterile individually cast CH only films
        4 sterile individually cast Ag only films
        Blank discs for control
    
    
    Sterile forceps

Procedure

Test Articles



The solution was kept wrapped in foil and out of light at room temperature until use. The film containers were kept in freezer and out of light until 30 minutes prior to use, when they were removed from the freezer and allowed to come to room temperature.
Bacterial Culture
The initial cultures were grown in 20 mL sterile Trypticase Soy Broth (TSB) for 16-24 hours at 37° C. The resulting cultures were grown on Mueller Hinton Agar plate for 24 hours at 37° C. The broth concentration was 1.5×108 CFU/mL—prepared using BD BBLTM PromptTM Inoculation system Cat#226306, which is specific for standardized suspensions of bacteria for Kirby Bauer antimicrobial susceptibility method, per manufacturer's instructions.
Plate Inoculation
The surface of the agar medium was inoculated with 0.1 mL (or volume determined to achieve desired plate inoculum concentration) of bacterial broth with a sterile swab.
Test Article Application
Solution
For each plate, 200 μl of solution was slowly pipetted into the center of the plate, forming a circle. The solution was allowed to dry for 5 minutes, forming a film.
Film
The test film is removed from its sterile packaging with sterile forceps and placed on center of plate. A sterile swab was used to apply light pressure and flatten film on agar surface.
Sterile Disks
Sterile discs (control) were placed on center of plate with sterile forceps and light pressure was applied with a sterile swab to secure it to agar surface.
Incubation and Measurement of Results
The plates were inverted and incubated for 24 hours at 37° C. After incubation, the zone of inhibition was measured to the nearest mm from outermost edge of test article to outermost edge of the zone of inhibition. If the test article was not a perfect circle, the zone of inhibition was measured from 3 different points and averaged. The results are given in Table III below.
Results







TABLE III







Zone of Inhibition (mm)














S.

C. 
P.


Description
Replicate
epidermidis
S. aureus
albicans
aeruginosa















CH/Ag Film
1
4.3
3.0
2.0
0.8


CH/Ag Film
2
4.0
3.0
2.7
0.0


CH only
1
4.0
3.3




Film







Ag only Film
1
0.0
0.0




CH/Ag
1
5.5
5.7
5.0
1


Solution







CH/Ag
2
6.0*
4.7
4.0
1.3


Solution







Control**
1
Growth
Growth
Growth
Growth





*mean of three measurements


**Control plates were test cultures with nothing added to the plate. All showed evenly confluent growth on plates with no inhibition and no areas of more dense growth.






EXAMPLE 6
Study of In Vitro Bactericidal Activity of the Materials of Example 4
Following the test methods of Example 5, the following tests were performed. The solutions were the solutions of Example 4 prior to film formation. The dyed solution was prepared by dissolving approximately 0.5-1.0 mg of D&C violet #2 in 20 ml of the CH/Ag solution from Example 4.
Materials


    Mueller-Hinton II or TSA agar
    Appx 1.5×108 CFU/mL cultures of:
    
        Staphylococcus epidermidis ATCC 12228
        Staphylococcus aureus ATCC 25923
    
    
    Pipettes (200-1000 μl )
    Sterile pipette tips
    Test Articles:
    
        CH/Ag Solution
        CH only Solution
        Ag only Solution
        CH/Ag dyed Solution
        6 sterile individually cast CH/Ag films
        6 sterile individually cast CH only films
        6 sterile individually cast Ag only films
        6 sterile individually cast CH/Ag dyed films
        Blank discs for control
    
    
    Sterile forceps

Procedure



The test articles and plates were prepared, the plates inoculated, the test articles applied, and the resulting plates and test articles incubated and measured as in Example 5. The results are given in Table IV below.
Results







TABLE IV







Zone of Inhibition (mm)












S. epi
S. aureus


Description
Replicate
(mm)
(mm)













CH/Ag Film
1
5
4


CH/Ag Film
2
5
3.5


CH/Ag Film
3
4
4.9


CH only Film
1
5.67
4.2


CH only Film
2
5.83
5.2


CH only Film
3
6.33
5.1


Ag only Film
1
1
0


Ag only Film
2
0
0


Ag only Film
3
0
0


Dyed CH/Ag
1
5.83
3.9


Film





Dyed CH/Ag
2
No growth 
4.1


Film

—



Dyed CH/Ag
3
7.17
3.1


Film





CH/Ag Solution
4
7.17
6.5


CH/Ag Solution
5
7
7


CH/Ag Solution
6
6.67
5.1


CH only Solution
4
8.5
6


CH only Solution
5
8
8.1


CH only Solution
6
12.67
7


Ag only Solution
4
3
1.5


Ag only Solution
5
5
2.4


Ag only Solution
6
3
2.4


Dyed CH/Ag
4
7.83
5.6


Solution





Dyed CH/Ag
5
7.83
5.1


Solution





Dyed CH/Ag
6
7
5.1


Solution












Although the present invention has been described in connection with the preferred embodiments, it is to be understood that modifications and variations may be utilized without departing from the principles and scope of the invention, as those skilled in the art will readily understand. Accordingly, such modifications may be practiced within the scope of the following claims. Moreover, Applicants hereby disclose all subranges of all ranges disclosed herein. These subranges are also useful in carrying out the present invention.

## Claims

1. An in situ film-forming solution comprising
at least one absorbable, segmented block copolymer with amorphous and semi-crystalline segments wherein the copolymer is a polyaxial coplolyester made from trimethylene carbonate and at least one cyclic monomer selected from the group consisting of p-dioxanone, 1,5-dioxapan-2-one, glycolide, l-lactide, ε-caprolactone, and a morpholinedione;
a solvent comprising methyl acetate; and
at least one bioactive agent selected from the group consisting of chlorhexidine and silver nitrate antimicrobial agents, anesthetic agents, antiviral agents, anti-inflammatory agents, hemostatic agents, and antineoplastic agents.

2. The in situ film-forming solution as in claim 1 wherein the solvent consists essentially of methyl acetate.

3. The in situ film-forming solution as in claim 2 wherein said solution can be sprayed or applied on animal or human skin and accessible body cavities to form an adherent, flexible, conformable, stretchable, dimensionally stable film having a tack-free outer surface, the film exhibiting an elongation of 100 to 600 percent, a tensile strength of 3-10 MPa and a tensile modulus of 5-20 MPa.

4. The in situ film-forming solution as in claim 2 wherein the segmented copolymer comprises from about 0.1 to about 20 weight/volume percent of the solution.

5. The in situ film-forming solution as in claim 2 wherein the at least one bioactive agent comprises from about 0.1 to about 15 weight percent of the absorbable copolymer and comprises a soluble entity or partially soluble microparticles or colloids.

6. The in situ film-forming solution as in claim 5 wherein the at least one bioactive agent is chlorhexidine.

7. The in situ film-forming solution as in claim 2 wherein the segmented copolymer comprises from about 0.1 to about 20 weight percent of the solution.

8. The in situ film-forming solution as in claim 6 wherein the at least one bioactive agent comprises from about 0.1 to about 15 weight percent of the absorbable copolymer and comprises a soluble entity or partially soluble microparticles.

9. The in situ film-forming solution as in claim 2 wherein the bioactive agent comprises silver nitrate and chlorhexidine.

10. The in situ film-forming solution as in claim 9 wherein the polyaxial copolyester consists of ε-caprolactone/trimethylene carbonate/l-lactide/glycolide. at a molar ratio 35/14/34/17.

11. The in situ film-forming solution as in claim 1 which consists of a methylacetate solution of a polyaxial ε-caprolactone/trimethylene carbonate/l-lactide/glycolide copolymer at a molar ratio of 35/14/34/17and silver nitrate.

12. The in situ film-forming solution as in claim 1 which consists of a methylacetate solution of a polyaxial ε-caprolactone/trimethylene carbonate/l-lactide/glycolide copolymer at a molar ratio of 35/14/34/17and chlorhexidine.

13. The in situ film-forming solution as in claim 1 which consists of a methylacetate solution of a polyaxial ε-caprolactone/trimethylene carbonate/l-lactide/glycolide copolymer at a molar ratio of 35/14/17, silver nitrate, and chlorhexidine.