WO2023230509A2

WO2023230509A2 - Extended-release composite wound dressing

Info

Publication number: WO2023230509A2
Application number: PCT/US2023/067402
Authority: WO
Inventors: Brett Hale DAVIS; Caleb Adrian LADE; Susan Alice WOJTALEWICZ; Michael Beeman; Stefan Julius NIEDERAUER; Sierra Nichelle ERICKSON
Original assignee: Rebel Medicine Inc
Priority date: 2022-05-24
Filing date: 2023-05-24
Publication date: 2023-11-30
Also published as: WO2023230509A3

Abstract

Various aspects disclosed relate to a film. The film includes a polymer. The film further includes one or more polysaccharides distributed about the polymer. The film further includes at least one local anesthetic distributed about the polymer. At least one pore extends between opposed major surfaces of the film.

Description

EXTENDED-RELEASE COMPOSITE WOUND DRESSING

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 63/365,232 entitled “EXTENDED-RELEASE COMPOSITE WOUND DRESSING,” filed May 24, 2022, the disclosure of which is incorporated herein in its entirety by reference.

BACKGROUND

[0002] Dermal injuries can result in severe pain that can last from days to several weeks. Patients healing from these injuries often cite wound pain as their primary concern. While there are numerous types of wound dressings that are used to aid in the healing process of dermal injuries, there are no existing dressings that effectively address wound pain. Consequently, opioids remain the primary analgesics used to manage this pain, exposing patients to numerous adverse effects which can negatively impact outcomes and cost of care.

SUMMARY OF THE INVENTION

[0003] The present disclosure relates to a composite wound contact film comprising a synthetic polymer component, a polysaccharide component and a local anesthetic component. These components are combined to create a composite film where the synthetic polymer creates a scaffold and the local anesthetic and polysaccharide components are dispersed (e.g., substantially homogenously) within the polymer scaffold. The composite films can be used in both human and veterinary wound applications for the treatment and/or management of wounds and wound-related pain. Examples of wound applications include, but are not limited to, superficial wounds, partial-thickness wounds (e.g., a wound is confined to the skin layers; damage does not penetrate below the dermis and may be limited to the epidermal layers only), and fullthickness wounds (e.g., a wound indicating that damage extends below the epidermis and dermis (all layers of the skin) into the subcutaneous tissue or beyond (into muscle, bone, tendons, etc.)) in humans and animals. The films can also be used for transdermal applications or mucous membrane applications. Examples include, but are not limited to, as a transdermal or mucous membrane patch for painful cutaneous conditions, mucosal conditions or deeper tissue damage.

[0004] Various aspects disclosed relate to a film. The film includes a polymer. The film further includes one or more polysaccharides distributed about the polymer. The film further includes at least one local anesthetic distributed about the polymer. At least one pore or perforation extends between opposed major surfaces of the film.

[0005] Various aspects disclosed relate to a method of treating a wound. The method includes applying a film of the instant disclosure on the wound. The film includes a polymer. The film further includes one or more polysaccharides distributed about the polymer. The film further includes at least one local anesthetic distributed about the polymer. At least one pore extends between opposed major surfaces of the film.

[0006] Various aspects disclosed relate to an assembly. The assembly includes a film of the instant disclosure. The film includes a polymer. The film further includes one or more polysaccharides distributed about the polymer. The film further includes at least one local anesthetic distributed about the polymer. At least one pore extends between opposed major surfaces of the film. The assembly further includes a secondary dressing such as a bandage in contact with the film and a dressing in contact with the secondary dressing.

BRIEF DESCRIPTION OF THE FIGURES

[0007] In the drawings, which are not necessarily drawn to scale, like numerals describe substantially similar components throughout the several views. The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments of the present invention.

[0008] FIG. l is a perspective view of a film.

[0009] FIG. 2 is a partial sectional view of the film taken along line AA of FIG. 1.

[0010] FIG. 3 A is a graph showing results of a Porcine Evoked Pain Scale study.

[0011] FIG. 3B is a graph showing results of a Glasgow Pain Score study. [0012] FIG. 4 is a graph showing plasma ropivacaine concentrations in treated animals.

DETAILED DESCRIPTION OF THE INVENTION

[0013] Reference will now be made in detail to certain embodiments of the disclosed subject matter, examples of which are illustrated in part in the accompanying drawings. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter.

[0014] Throughout this document, values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a range of “about 0.1% to about 5%” or “about 0.1% to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement “about X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise. Likewise, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z,” unless indicated otherwise.

[0015] In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. The statement “at least one of A and B” has the same meaning as “A, B, or A and B.” In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting; information that is relevant to a section heading may occur within or outside of that particular section.

[0016] In the methods described herein, the acts can be carried out in any order without departing from the principles of the invention, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process.

[0017] The term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range. The term “substantially” as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. The term “substantially free of’ as used herein can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that about 0 wt% to about 5 wt% of the composition is the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than or equal to about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 0 wt%.

[0018] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or portion of the body to another organ or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the composition, not injurious to the patient, and substantially non-pyrogenic. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other nontoxic compatible substances employed in pharmaceutical compositions. Pharmaceutical compositions of the present disclosure are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient. [0019] As used herein, the term “medical device” means any instrument, apparatus, implant, in vitro reagent or similar or related article that is used to diagnose, prevent, or treat a disease of other condition, and does not achieve its purpose through pharmacological action within or on the body.

[0020] At least some ingredients in the pharmaceutical composition can be defined as being Generally Recognized as Safe (“GRAS”). A full list of GRAS ingredients can be found in the GRAS Substances (SCOGS) Database maintained by the United States Food and Drug Administration. About 50% to about 100% of the ingredients in the pharmaceutical composition can be classified as being GRAS ingredients, about 75% to about 100%, about 90% to about 100%, less than, equal to, or greater than about 50%, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100% of the ingredients in the pharmaceutical composition can be classified as being GRAS ingredients.

[0021] According to various aspects, a film can be used to deliver a therapeutically effective amount of a local anesthetic to a dermal wound for a desired amount of time. FIG. 1 is a perspective view of film 100. FIG. 2 is a partial sectional view of film 100 taken along line AA of FIG. 1. FIGS. 1 and 2 include many of the same components and will be discussed concurrently. Unexpectedly, it was shown that the polysaccharide component can alter the release of the local anesthetic component from the wound contact material. Polysaccharide-containing dressings demonstrated increases drug release rates. Without intending to be bound to any theory, the addition of polysaccharide is thought to draw fluid into the film matrix which increases the fluid-matrix interface that governs the diffusion-based release of the local anesthetic.

[0022] Film 100 is a medical device that has a thickness defined between opposed major surfaces 102 and 104. An average thickness of film 100 can be in a range of from about 50 pm to about 2 mm, about 200 pm to about 800 pm, less than, equal to, or greater than about 50 pm, 100 pm, 200 pm, 500 pm, 600 pm, 700 pm, 800 pm, 1 mm, or about 2 mm. A length and width of film 100 can be dimensioned to sufficiently cover a wound on a subject. Although film 100 is shown as a quadrilateral, many other shapes such as a circular shape, triangular shape, or other polygonal shape are possible.

[0023] Film 100 is porous and includes a plurality of pores or perforations 106 that each extend from opposed major surface 102 to opposed major surface 104. Pores 106 can account of any percentage of the total surface area of film 100. For example, pores 106 can range from about 1 to about 99 percent of a total surface area of film 100, about 1 to about 70 percent of the total surface area of film 100, about 2 to about 20 percent of the total surface area of film 100, less than, equal to, or greater than about 1 percent of a total surface area of film 100, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 99 percent of a total surface area of film 100.

[0024] Each of pores 106 can have a generally circular profile, or a generally polygonal profile. In some aspects, at least two of pores 106 can have different profiles. An average diameter of pores 106 can be substantially the same or an average major dimension of at least two pores can be different. As an example, an average diameter of the at least one pore is in a range of from about 50 pm to about 1000 pm, about 200 pm to about 500 pm, less than, equal to, or greater than about 50 pm, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or about 1000 pm. The diameter of each of pores 106 can be constant along the thickness of film 100. In other words, the diameter of an individual pore 106 can narrow towards the center of film 100’s thickness and then widen towards either of major surfaces 102, 104, or both. Alternatively, a diameter of any individual pore 106 can be larger at major surface 102 than at major surface 104 or larger at major surface 104 than at major surface 102. Any of pores 106 can be a through pore.

[0025] As shown, pores 106 are arranged according to a predetermined pattern. But it is possible, in other examples, for pores 106 (or a portion of the total amount of pores 106) to be randomly arranged.

[0026] Pores 106 can serve many different functions. For example, pores 106 can allow for moisture to have a channel to evaporate through and away from the film and the wound. Pores 106 can also serve as a channel to wick moisture up to film 100 to interact with polysaccharide 110. Additionally, pores 106 allow wound fluid (e.g., exudate) to readily pass through film 100 into a secondary dressing (e.g., bandage or waterproof dressing) thus preventing buildup of wound fluid under film 100. The shape, average major dimension, and pattern of pores 106 can all be varied to affect these properties.

[0027] Film 100 includes three primary components. The components include polymer 103, polysaccharide 110, and local anesthetic 112. Polymer 103 forms the bulk of film 100 and contributes to forming the structure or matrix of film 100. Each of polysaccharide 110 and local anesthetic 112 are distributed about polymer 103.

[0028] Polymer 103 can be a natural polymer, a synthetic polymer or a blend of a natural polymer and a synthetic polymer. The synthetic polymer, natural polymer, or blend is biocompatible. In some examples, polymer 103 is a biodegradable polymer. If polymer 103 is a biodegradable polymer, it can be possible for film 100 to degrade at an acceptable rate while the local anesthetic is delivered. In that manner, film 100 can be considered to be a biodegradable film. [0029] A suitable polymer 103, will be a polymer, or mixture of polymers, that result in film 100 being strong enough to maintain its structure during use, yet have enough flexibility to not cause unreasonable discomfort to a user. As non-limiting examples, suitable Young’s elastic modulus values can be in a range of from about 50 to about 800 MPa and suitable tensile strength values can be in a range of from about 1 to about 10 MPa. The selection of mechanical properties is driven by being able to have film 100 having enough flexibility to conform to the uneven, contoured nature of the body, and therefore act to aid adequate attachment and surface-dressing connection. Moreover, polymer 103 should have compatibility with polysaccharide 110 and local anesthetic 112, such that it does not react with polysaccharide 110 or local anesthetic 112 in such a way that either material is rendered unstable, loses its structural integrity or loses its therapeutic effectiveness.

[0030] Examples of suitable polymers for polymer 103 include a polyester, a polyurethane, a silicone, a poly(ethylene glycol), a (PEG)-based polymer, a polyacrylamide, a polyvinylpyrrolidone, a polyethylene oxide, a pallulan, a homoglycan, a beta-glucan, a dextran derivative, a cellulose, a chitin, an alginate, an agar, a pectin, a collagen, a carrageenan, a copolymer thereof, or a mixture thereof. Examples of suitable polyesters include a poly(lactic-co- glycolic acid), a poly(caprolactone), a poly(lactide), or a mixture thereof. In a particular example, polymer 103 is a poly(lactide-co-caprolactone). According to some examples, a lactide monomer molar ratio of the poly(lactide-co- caprolactone) is in a range of from about 30% to about 90 %, about 60% to about 80%, less than, equal to, or greater than about 30%, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or about 90%. According to some examples, polymer 103 is biodegradable.

[0031] Polysaccharide 110 is distributed about polymer 103.

Polysaccharide 110 can be chosen to be one that can wick up moisture at a desired rate when exposed to fluid. The fluid can be supplied via evaporated perspiration. It was surprisingly and unexpectedly found that the presence of polysaccharide 110 had a beneficial effect on the release of local anesthetic 108. Without intending to be bound to any theory, it is thought that polysaccharide 110, wicks fluid into the matrix of film 100 (e.g., polymer 103) which leads to an increase in the area of the interface between the fluid and matrix that affects the diffusion-based release of local anesthetic 108. The increase in the area of the interface provides adequate fluid to allow the drug to diffuse from film 100 to the wound. Additionally, the increased interface can be helpful to keep the wound moist and promote good wound healing. In some examples, the increased interface can also help to increase the tackiness of film 100, such that it can feel soft to the touch and have at least some adhesive properties.

[0032] Additionally, polysaccharide 110 helps to provide suitable adhesion to the wound site. The adhesion can be described as a mucoadhesion. Mucoadhesion generally describes the attractive forces between a biological material and mucus or mucous membrane. Mucous membranes adhere to epithelial surfaces. An advantage of the adhesion provided by polysaccharide is that it is somewhat gentle and allows for a degree of lateral movement on the wound site. Compared to a dressing that uses a stronger adhesive (e.g., glue) the mucoadhesion of polysaccharide 110 causes less mechanical damage to the wound, thus promoting better healing while still allowing for sufficient adhesion to the wound site. As understood the wound site includes the wound and possibly at least some tissue proximate to the wound. [0033] Examples of suitable polysaccharides can include calcium alginate, sodium alginate, carboxymethylcellulose, chitosan, sodium hyaluronate, or a mixture thereof. Polysaccharide 110 can be present in film 100 in a concentration ranging from about 1 wt% to 15 wt%, about 1 wt% to about 10 wt%, about 3 wt% to about 10 wt% less than, equal to, or greater than about 1 wt%, 2, 3, 4, 5, 6, 7, 8, 9, or about 10 wt%. In some examples, using calcium alginate can be particularly helpful in increasing the tackiness of film 100 as mentioned herein above.

[0034] Polysaccharide 110 can be fully dispersed within film 100. That is, in some examples, substantially no polysaccharide 110 is present on either of opposed major surfaces 102 and 104. In other examples, polysaccharide 110 can be fully dispersed about an external surface of one or more of opposed major surfaces 102 and 104. In still other examples, a first portion of the total number of polysaccharide 110 can be dispersed within film 100 and a second portion of the total number of polysaccharide present can be disposed about one or more of opposed major surfaces 102 and 104. Similarly, at least a portion of the total number of polysaccharide 110 present can be located on an external surface of at least one pore 106. A possible benefit to locating at least some of polysaccharide on at least one of opposed major surfaces 102 and 104 or an external surface of at least one pore 106 is that moisture can be wicked into film 100 quicker and start the release of local anesthetic 108.

[0035] Polysaccharide 110 can be evenly (e.g., substantially homogenously) distributed about the thickness of film 100. However, in some examples, polysaccharide 110 is unevenly (e.g., substantially heterogeneously) distributed about the thickness of film 100. For example, a major portion of the total amount of saccharide 110 may be located proximate to whichever of major surface 102 or 104 is in contact, or nearest to contact, with a user (e.g., a human or animal subject). Such a configuration can be helpful to create a burst release (e.g., an unpredictable and uncontrolled release of a drug from a carrier) of local anesthetic in that a large amount of moisture is wicked to film quicky. Alternatively, a major portion of the total amount of saccharide 105 may be located distal to whichever of major surface 102 or 104 is in contact, or nearest to contact, with a user (e.g., a human or animal subject). Such a configuration can be helpful if a delayed release is desired. This can be accomplished because the comparatively smaller amount of polysaccharide located proximate to whichever of major surface 102 or 104 is in contact, or nearest to contact, with a user (e.g., a human or animal subject) will slow down the rate at which moisture is wicked to film 100. Thus, less moisture is immediately available to participate in the release of local anesthetic 108. However, once the moisture reaches the point where more polysaccharide 110 is located, the release of local anesthetic 108 is accelerated. If constant release (e.g., a controlled amount of drug release from a carrier over a period of time) of local anesthetic 108 is desired, polysaccharide 110 can be distributed (e.g., substantially homogenously) about film 100. It is noted these are only examples and that it is well within the skill in the art to modulate the location and amounts of the various components to achieve the desired release profile.

[0036] The at least one local anesthetic 108 is present in an amount sufficient to reduce pain in a subject (e.g., a human or other animal subject). That is, film 100 can include one or more local anesthetics 108 in an amount such that the one or more local anesthetics can be released in an amount sufficient to reduce pain in a subject. As an example, the at least one local anesthetic can be in a range of from about 5 wt% to about 50 wt% of film 100, about 15 wt% to about 40 wt% of film 100, about 25 wt% to about 35 wt% of film 100, less than, equal to, or greater than about 5 wt%, 10, 15, 20, 25, 30, 35, 40, 45, or about 50 wt% of film 100.

[0037] Suitable examples of local anesthetics include an ester-based anesthetic, an amide-based anesthetic, or a mixture thereof. Non-limiting examples of ester-based anesthetics include procaine, amethocaine, benzocaine, tetracaine, a salt thereof, or a mixture thereof. Non-limiting examples of amide-based anesthetic include lidocaine, prilocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, dibucaine, etidocaine, a salt thereof, or a mixture thereof. The amide-based anesthetics can include the freebase form of the amide-based anesthetic, a hydrochlorinated form of the amide-based anesthetic, or additional salt forms of the amide-based anesthetic including lipophilic salts. A lipophilic salt of the amide-based anesthetic involves pairing the protonated amid-based anesthetic with a lipophilic counterion, which can enhance the lipid solubility of the amide-based anesthetic. This can be beneficial in increasing the loading of the anesthetic agent in the pharmaceutical composition. Additionally, the lipophilic salt of the local anesthetic can increase the ability of the local anesthetic to reach the target nerves within the dermal tissues. For example, a lipophilic salt of the amide- based anesthetic can include a docusate counterion. As an example, the lipophilic salt of the amide-based anesthetic can be ropivacaine docusate. Local anesthetic 108 can be dispersed in a pharmaceutically acceptable excipient or pharmaceutically acceptable carrier.

[0038] While any of the aforementioned amide-based anesthetics are desirable, ropivacaine can be desirable for use because it includes several known clinical advantages such as good patient safety and good analgesic properties such as sensory selectivity.

[0039] Film 100, can be applied to a wide range of different wounds applications such as transdermal applications and mucous membrane applications. For example film 100 can be applied to a superficial dermal wound, a partial-thickness dermal wound, or a full-thickness dermal wound. In some examples, the wound can be a burn, a skin graft donor site, an abrasion, an ulcer, an incision, or the like. Film 100 can be applied to a subject immediately for treatment although in some examples, film 100 can be applied at a later stage of treatment. For example, if a subject has suffered a third-degree burn, there may not be an immediate need for a wound dressing to include a local anesthetic as the nerve endings at the burn site are destroyed. However, as the healing process progresses and nerves are regenerated, the subject may begin to feel pain and will benefit from the application of film 100.

[0040] In operation, film 100 is applied to a subject as part of an assembly. For example, film 100 is usually applied directly to the subject. In some examples a cream, ointment, or the like may be disposed between the subject and film 100. A secondary dressing (e.g., a bandage and/or semiocclusive film) can be applied over film 100. The secondary dressing can serve to protect film 100, but can primarily serve to absorb wound fluid and/or to help secure film 100 to the subject. There are many different suitable secondary dressings s that can be used. A gauze bandage is a suitable example of the secondary dressings that can be used with film 100. In some examples, the secondary dressing itself may be waterproof. If the secondary dressing is not waterproof another dressing (e.g., a third dressingjean be applied over the secondary dressing. The additional dressing can serve to provide an extra layer of protection to the wound site and film 100 and to secure film 100 and secondary dressing to the subject. In some examples the further dressing is waterproof. As a specific example, a clinician can apply the film 100 as a primary dressing to a wound, then adds 1 more layers of gauze to absorb the fluid coming through film 100 (collectively a secondary dressing) then secures everything with a third dressing (e.g., a tegaderm-like film). In the case of a tegaderm film, the tegaderm film both secures the other dressings to the patient and can help keep the wound and other dressings/films from completely drying out.

[0041] Film 100 can affect a prolonged release of local anesthetic 108 to the subject. Thus, film 100 can be used for a prolonged period of time without being changed. Indeed, film 100 can be configured to release the at least one local anesthetic over a period of time ranging from about 1 day to about 40 days, about 1 day to about 14 days, about 1 day to about 7 days, less than, equal to, or greater than about 1 day, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or about 40 days.

[0042] Film 100 can be fabricated according to any suitable method. For example, a method of making film 100 can include solubilizing polymer 103. Following solubilization, an appropriated amount of local anesthetic 108 and polysaccharide 110 to achieve the desired concentration is added to the solubilized polymer. The mixture of the solubilized polymer and local anesthetic and polysaccharide is mixed for a set amount of time, casted, and the left to allow the solvent (e.g., a volatile organic solvent) to evaporate thus leaving a casted film. Pores 106 are formed in the casted film with a cutter such as a laser cutter. The laser cutter forms pores 106. The operation of the laser cutter can be guided by an AutoCAD file that includes the desired hole pattern. Other methods of manufacture can include extruding film 100 and laser cutting or perforating film 100. Extrusion can be accomplished through blown film extrusion, hot-melt extrusion, or the like.

Examples [0043] Various embodiments of the present invention can be better understood by reference to the following Examples which are offered by way of illustration. The present invention is not limited to the Examples given herein.

Example 1: Manufacturing the Film

[0044] A film was prepared according to the following protocol. Poly(lactide-co-caprolactone) (PLC) was brought to room temperature and placed in a fume hood. Dichloromethane (DCM) was added to the PLC to bring a volume in the container to 60 mL. A respective mass of Ropivacaine free base as well as calcium alginate was added to the container to achieve a desired concentration. The container was placed on a laboratory shaker for mixing at 150 RPM for 30 minutes. The suspension was then further mixed for at least 24 hours. A liner was prepared with a polytetrafluoroethylene (PTFE)-coated side facing up. The mixture of PLC, calcium alginate and Ropivacaine free base was placed on the liner and casted with a casting knife. The casted mixture was left overnight to dry to form the film. The dried film was laser cut to form 100 cm² square films. Through pores were formed in the film using an AutoCAD file with a desired hole pattern.

Example 2: In Vivo Study of Film

Porcine Partial Thickness Skin Wound Model

[0045] The safety and efficacy of the analgesic wound dressing was tested in a swine partial thickness skin wound model. Six conventional nulliparous female Yorkshire swine (Premier BioSource, Ramona, CA, USA) aged approximately 12-16 weeks and weighing 24-36 kg were used for this 14- day study.

[0046] Following a standard one-week pre-study quarantine, swine were acclimated to pain testing procedures over a three-week period prior to split thickness wound creation. At study initiation, fasted animals were sedated using a combination of drugs. Following endotracheal intubation and maintenance isoflurane (VetOne, Boise, ID, USA) anesthesia, an electric dermatome (Model B, Integra Life Sciences, Princeton, NJ, USA) was used to create one 10x10 cm split thickness wound approximately 635 microns deep over the left dorsolateral aspect of the abdomen. A central venous access port (CP2, Norfolk Access Technologies, Skokie, Illinois, USA) was placed in the right external jugular vein for subsequent pharmacokinetic blood collection. Swine received either a nonadherent silicone wound dressing (AdapticTouch™, KCI, St. Paul, Minnesota, USA) (denoted as a “control” in FIGS. 3A and 3B), or analgesic wound dressing formed according to the protocol of Example 1 (denoted as “treated” in FIGS. 3 A and 3B). The analgesic wound dressing was formed to have calcium alginate (BD7JFKA, TCI America, Portland, OR, USA) incorporated into the polymer matrix at 5% w/w PLC to promote dressing wettability and mucoadhesion. The analgesic wound dressing was loaded with 33.5% ropivacaine (w/w to PLC) and 400 um thick. The analgesic wound dressing were perforated with 300 pm holes spaced 3 mm in a square pattern. A secondary protective bandage comprised of gauze padding (Medline Industries Inc, Northfield, IL, USA), Tegaderm™ (3M, St. Paul Minnesota, USA), cotton roll bandage (McKesson Corp., Irving, TX, USA), Coban™ (Medline Industries Inc, Northfield, IL, USA) and Elastikon® (Johnson & Johnson, Somerville, NJ, USA) was applied over top the primary. Secondary bandages were changed at all primary dressing evaluation time points. The primary dressing was left in direct contact over the split thickness wound site for the duration of the study.

Pain Assays

[0047] The pain management efficacy of the dressings was evaluated using a single pinprick assay and Glasgow composite pain scores. Single pin prick utilized a single use sensory testing device (Medipin, US Neurologicals LLC, Poulsbo, WA, USA) to elicit a painful response at a location 2 cm dorsal from the wound edge. The pin prick test was repeated two times, with an interstimulus interval of at least 1 minute. Animal investigators were blinded to treatment and scored pinprick response by the Porcine Evoked Pain Scale (PEPS), ranging from 0=no pain to 10=extreme pain. For the single pinprick assay, a pre-treatment baseline was collected, and then the assays were performed at 4, 24, 72, 120, and 168 hours post-treatment. PEPS scores were normalized to each animals’ pre-surgery response. The Glasgow pain response was adapted for swine and includes five behavioral categories: comfort, social behavior, target site activity, movement, and response to site palpation. Scores from 0 to 3 are given for each category and summed to produce a final score that ranged from 0 (no pain) to 15 (extreme pain). All Glasgow evaluations were made with wound bandaging in place by a single trained blinded animal investigator. Glasgow composite pain scores were measured at 1, 2, 4, 8, 24, 72, 120, and 168 hours post-treatment.

Results

[0048] Single pinprick scores, shown in Figure 3 A, showed significantly improved pain management in the treatment group for the whole testing period (p<0.001). Glasgow pain scores, shown in Figure 3B, also exhibited a statistically significant reduction in pain in the treatment animals over the testing period (p=0.0014). Use of the ropivacaine-eluting wound dressing enhanced pain management compared to the clinical control dressing.

Pharmacokinetic Assessment

[0049] Plasma pharmacokinetics were measured to evaluate systemic exposures to the ropivacaine in the dressing. Blood samples were collected at 0 (pre-treatment), 4, 8, 24, 72, 120, 168, 216, 264, and 336 hours after treatment into K2EDTA vacutainer tubes (BD, Franklin Lakes, NJ, USA). Blood was immediately refrigerated at 4 °C for 15 min, then centrifuged at 1500 x g for 15min at 4 °C to separate plasma. Plasma was isolated into cryotubes and stored at -80 °C until completion of the study. At the conclusion of the study, all plasma samples were analyzed for ropivacaine concentration using a ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. Briefly, internal standard (500ng/mL ropivacaine-d7) was added to 50pL of plasma and the sample extracted using a basified (0.5 mL of 5% ammonium hydroxide) methyl-tert-butyl ether (MTBE) liquid-liquid extraction. MTBE was decanted, dried under lab air, and reconstituted in lOOpL of 5:95 methanol: water. A Waters Acquity UPLC coupled with a ThermoSci entific TSQ Quantum Access was used for instrumental analysis. The UPLC used a gradient elution with methanol and 0.1% formic acid on a Phenom enex Luna Omega 3pm PS C18 (2.1 x 100mm) column. A mass transition of 275.1 to 126.1 (collision energy 30 V) was used to monitor for ropivacaine. The calibration curve was fit with linear regression between 5 and 5000 ng/mL.

Results

[0050] Plasma ropivacaine concentrations in the treatment animals, demonstrate peak systemic exposures occur at 8 hours post-treatment, with a maximum concentration (Cmax) between 160-295 ng/mL (see figure 5). These peak concentrations are approximately 10-fold lower than the reported toxicity threshold in humans (3000 ng/mL). Ropivacaine concentrations steadily decreased after this peak, but persisted throughout the entire study, supporting the sustained release of ropivacaine from the wound dressing. Two of the 3 animals demonstrated concentration increases approximately one week into the study, though neither of these increases approached the anticipated toxicity threshold.

[0001] The terms and expressions that have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the embodiments of the present invention. Thus, it should be understood that although the present invention has been specifically disclosed by specific embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those of ordinary skill in the art, and that such modifications and variations are considered to be within the scope of embodiments of the present invention.

Exemplary Embodiments.

[0002] The following exemplary embodiments are provided, the numbering of which is not to be construed as designating levels of importance: [0003] Aspect 1 provides a film comprising: a polymer; one or more polysaccharides distributed about the polymer; at least one local anesthetic distributed about the polymer; and at least one through pore extends between opposed major surfaces of the film.

[0004] Aspect 2 provides the film of Aspect 1, wherein the polymer comprises a polyester, a polyurethane, a silicone, a poly(ethylene glycol), a (PEG)-based polymer, a polyacrylamide, a polyvinylpyrrolidone, a polyethylene oxide, a pallulan, a homoglycan, a beta-glucan, a dextran derivative, a cellulose, a chitin, an alginate, an agar, a pectin, a collagen, a carrageenan, or a mixture thereof.

[0005] Aspect 3 provides the film of any one of Aspects 1 or 2, wherein the polyester comprises poly(lactic-co-glycolic acid), Poly(caprolactone), a poly(lactide), or a mixture thereof.

[0006] Aspect 4 provides the film of any one of Aspects 1 or 3, wherein the polymer comprises a poly(lactide-co-caprolactone).

[0007] Aspect 5 provides the film of Aspect 4, wherein a lactide monomer molar ratio of the poly(lactide-co-caprolactone) is in a range of from about 30% to about 90 %.

[0008] Aspect 6 provides the film of Aspect 5, wherein a lactide monomer molar ratio of the poly(lactide-co-caprolactone) is in a range of from about 60% to about 80%.

[0009] Aspect 7 provides the film of any one of Aspects 1-6, wherein the one or more polysaccharides comprises calcium alginate, sodium alginate, carboxymethylcellulose, chitosan, sodium hyaluronate, or a mixture thereof.

[0010] Aspect 8 provides the film of any one of Aspects 1-7, wherein the one or more polysaccharides comprises 1 wt% to 10 wt%.

[0011] Aspect 9 provides the film of any one of Aspects 1-8, wherein the polymer is doped with the one or more polysaccharides, a portion of the one or more polysaccharides is disposed about a surface of the polymer, or both.

[0012] Aspect 10 provides the film of any one of Aspects 1-9, wherein the polymer is doped with the one or more polysaccharides.

[0013] Aspect 11 provides the film of any one of Aspects 1-10, wherien the one or more polysaccharides comprises about 1 wt% to about 10 wt% of the film. [0014] Aspect 12 provides the film of any one of Aspects 1-11, wherien the one or more polysaccharides comprises about 1 wt% to about 15 wt% of the film.

[0015] Aspect 13 provides the film of any one of Aspects 1-12, wherien the one or more polysaccharides comprises about 3 wt% to about 10 wt% of the film.

[0016] Aspect 14 provides the film of any one of Aspects 1-13, wherein the at least one local anesthetic comprises an ester-based anesthetic, an amide- based anesthetic, a salt thereof, or a mixture thereof.

[0017] Aspect 15 provides the film of Aspect 14, wherein the ester-based anesthetic comprises procaine, amethocaine, benzocaine, tetracaine, a salt thereof, or a mixture thereof.

[0018] Aspect 16 provides the film of any one of Aspects 14 or 15, wherein the amide-based anesthetic comprises lidocaine, prilocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, dibucaine, etidocaine, a salt thereof, or a mixture thereof.

[0019] Aspect 17 provides the film of any one of Aspects 14-16, wherein the amide-based anesthetic comprises bupivacaine, ropivacaine, a salt thereof, or a mixture thereof.

[0020] Aspect 18 provides the film of any one of Aspects 14-17, wherien the at least one local anesthetic comprises bupivacaine docusate, ropivacaine docusate, or a mixture thereof.

[0021] Aspect 19 provides the film of any one of Aspects 1-18, wherein the at least one local anesthetic is present in an amount sufficient to reduce pain in a subject.

[0022] Aspect 20 provides the film of any one of Aspects 1-19, wherein the polymer is doped with the local anesthetic.

[0023] Aspect 21 provides the film of any one of Aspects 1-20, wherien the local anesthetic comprises about 5 wt% to about 50 wt% of the film.

[0024] Aspect 22 provides the film of any one of Aspects 1-21, wherien the local anesthetic comprises about 15 wt% to about 40 wt% of the film.

[0025] Aspect 23 provides the film of any one of Aspects 1-22, wherien the local anesthetic comprises about 25 wt% to about 35 wt% of the film. [0026] Aspect 24 provides the film of any one of Aspects 1-23, wherien an average thickness of the film is in a range of from about 50 micrometers to about 2 millimeter.

[0027] Aspect 25 provides the film of any one of Aspects 1-24, wherien an average thickness of the film is in a range of from about 200 micrometers to about 800 micrometers.

[0028] Aspect 26 provides the film of any one of Aspects 1-25, wherien the film is configured to effectuate a prolonged release of the at least one local anesthetic.

[0029] Aspect 27 provides the film of any one of Aspects 1-26, wherien the film is configured to release the at least one local anesthetic over a period of time ranging from about 1 day to about 40 days.

[0030] Aspect 28 provides the film of any one of Aspects 1-27, wherien the film is configured to release the at least one local anesthetic over a period of time ranging from about 1 day to about 14 days.

[0031] Aspect 29 provides the film of any one of Aspects 1-28, wherien the film is configured to release at least one local anesthetic over a period of time ranging from about 1 day to about 7 days.

[0032] Aspect 30 provides the film of any one of Aspects 1-29, wherein the at least one pore comprises from about 1 to about 99 percent of a total surface area of the film.

[0033] Aspect 31 provides the film of any one of Aspects 1-30, wherein the at least one pore comprises from about 1 to about 70 percent of the total surface area of the film.

[0034] Aspect 32 provides the film of any one of Aspects 1-31, wherein the at least one pore comprises from about 2 to about 20 percent of the total surface area of the film.

[0035] Aspect 33 provides the film of any one of Aspects 1-32, wherein an average major dimension of the at least one pore is substantially the same.

[0036] Aspect 34 provides the film or any one of Aspects 1-33, wherien an average major dimension of the at least one pore is in a range of from about 50 pm to about 1000 pm. [0037] Aspect 35 provides the film of any one of Aspects 1-34, wherien an average major dimension of the at least one pore is in a range of from about 200 pm to about 500 pm.

[0038] Aspect 36 provides the film of any one of Aspects 1-35, wherien the at least one pore independently comprises a generally circular profile, or a generally polygonal profile.

[0039] Aspect 37 provides the film of any one of Aspects 1-36, wherien the at least one pore is arranged according to a predetermined pattern.

[0040] Aspect 38 provides the film of any one of Aspects 1-37, wherien the at least one pore is randomly arranged.

[0041] Aspect 39 provides the film of any one of Aspects 1-38, wherien the polymer is a synthetic polymer.

[0042] Aspect 40 provides the film of any one of Aspects 1-39, wherien the polymer is a biodegradable polymer.

[0043] Aspect 41 provides the film of any one of Aspects 1-40, wherein the film is a biodegradable film.

[0044] Aspect 42 provides a method of treating a wound, the method comprising applying the film of any one of Aspects 1-41, on the wound.

[0045] Aspect 43 provides the method of Aspect 42, wherein the wound comprises a superficial dermal wound, a partial-thickness dermal wound, or a full-thickness dermal wound.

[0046] Aspect 44 provides the method of any one of Aspects 42 or 43, wherein the wound comprises a burn, a skin graft donor site, or both.

[0047] Aspect 45 provides an assembly comprising: the film of any one of Aspects 1-44; a secondary dressing in contact with the film; and a dressing in contact with the secondary dressing.

[0048] Aspect 46 provides the assembly of Aspect 45, wherein the secondary dressing comprises a gauze bandage.

[0049] Aspect 47 provides the assembly of any one of Aspects 45 or 46, wherein the secondary dressing is substantially waterproof.

Claims

CLAIMS What is claimed is:

1. A film comprising: a polymer; one or more polysaccharides distributed about the polymer; at least one local anesthetic distributed about the polymer; and at least one pore extends between opposed major surfaces of the film.

2. The film of claim 1, wherein the polymer comprises a polyester, a polyurethane, a silicone, a poly(ethylene glycol), a (PEG)-based polymer, a polyacrylamide, a polyvinylpyrrolidone, a polyethylene oxide, a pullulan, a homoglycan, a beta-glucan, a dextran derivative, a cellulose, a chitin, an alginate, an agar, a pectin, a collagen, a carrageenan, or a mixture thereof.

3. The film of claim 2, wherein the polyester comprises poly(lactic-co- glycolic acid), Poly(caprolactone), a poly(lactide), poly(glycolic acid), or a mixture thereof.

4. The film of claim 1, wherein the polymer comprises a poly(lactide-co- caprolactone).

5. The film of claim 4, wherein a lactide monomer molar ratio of the poly(lactide-co-caprolactone) is in a range of from about 30% to about 90 %.

6. The film of claim 5, wherein a lactide monomer molar ratio of the poly(lactide-co-caprolactone) is in a range of from about 60% to about 80%.

7. The film of claim 1, wherein the one or more polysaccharides comprises calcium alginate, sodium alginate, carboxymethylcellulose, chitosan, sodium hyaluronate, or a mixture thereof.

8. The film of claim 1, wherein the one or more polysaccharides comprises 1 wt% to 10 wt%.

9. The film of claim 1, wherein the polymer is doped with the one or more polysaccharides, a portion of the one or more polysaccharides is disposed about a surface of the polymer, or both.

10. The film of claim 1, wherein the polymer is doped with the one or more polysaccharides.

11. The film of claim 1, wherein the one or more polysaccharides comprises about 1 wt% to about 10 wt% of the film.

12. The film of claim 1, wherein the one or more polysaccharides comprises about 1 wt% to about 15 wt% of the film.

13. The film of claim 1, wherein the one or more polysaccharides comprises about 3 wt% to about 10 wt% of the film.

14. The film of claim 1, wherein the at least one local anesthetic comprises an ester-based anesthetic, an amide-based anesthetic, a salt thereof, or a mixture thereof.

15. The film of claim 14, wherein the ester-based anesthetic comprises procaine, amethocaine, benzocaine, tetracaine, a salt thereof, or a mixture thereof.

16. The film of claim 14, wherein the amide-based anesthetic comprises lidocaine, prilocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, dibucaine, etidocaine, a salt thereof, or a mixture thereof.

17. The film of claim 14, wherein the amide-based anesthetic comprises bupivacaine, ropivacaine, a salt thereof, or a mixture thereof.

18. The film of claim 14, wherein the at least one local anesthetic comprises bupivacaine docusate, ropivacaine docusate, or a mixture thereof.

19. The film of claim 1, wherein the at least one local anesthetic is present in an amount sufficient to reduce pain in a subject.

20. The film of claim 1, wherein the polymer is doped with the local anesthetic.

21. The film of claim 1, wherein the local anesthetic comprises about 5 wt% to about 50 wt% of the film.

22. The film of claim 1, wherein the local anesthetic comprises about 15 wt% to about 40 wt% of the film.

23. The film of claim 1, wherein the local anesthetic comprises about 25 wt% to about 35 wt% of the film.

24. The film of claim 1, wherein an average thickness of the film is in a range of from about 50 micrometers to about 2 millimeter.

25. The film of claim 1, wherein an average thickness of the film is in a range of from about 200 micrometers to about 800 micrometers.

26. The film of claim 1, wherein the film is configured to effectuate a prolonged release of the at least one local anesthetic.

27. The film of claim 1, wherein the film is configured to release the at least one local anesthetic over a period of time ranging from about 1 day to about 40 days.

28. The film of claim 1, wherein the film is configured to release the at least one local anesthetic over a period of time ranging from about 1 day to about 14 days.

29. The film of claim 1, wherein the film is configured to release at least one local anesthetic over a period of time ranging from about 1 day to about 7 days.

30. The film of claim 1, wherein the at least one pore comprises from about 1 to about 99 percent of a total surface area of the film.

31. The film of claim 1, wherein the at least one pore comprises from about 1 to about 70 percent of the total surface area of the film.

32. The film of claim 1, wherein the at least one pore comprises from about 2 to about 20 percent of the total surface area of the film.

33. The film of claim 1, wherein an average major dimension of the at least one pore is substantially the same.

34. The film of claim 1, wherein an average major dimension of the at least one pore is in a range of from about 50 pm to about 1000 pm.

35. The film of claim 1, wherein an average major dimension of the at least one pore is in a range of from about 200 pm to about 500 pm.

36. The film of claim 1, wherein the at least one pore independently comprises a generally circular profile, or a generally polygonal profile.

37. The film of claim 1, wherein the at least one pore is arranged according to a predetermined pattern.

38. The film of claim 1, wherein the at least one pore is randomly arranged.

39. The film of claim 1, wherein the polymer is a synthetic polymer.

40. The film of claim 1, wherein the polymer is a biodegradable polymer.

41. The film of claim 1, wherein the film is a biodegradable film.

42. A method of treating a wound, the method comprising applying the film of claim 1, on the wound.

43. The method of claim 42, wherein the wound comprises a superficial dermal wound, a partial-thickness dermal wound, or a full-thickness dermal wound.

44. The method of claim 42, wherein the wound comprises a burn, a skin graft donor site, or both.

45. An assembly comprising: the film of claim 1; a secondary dressing in contact with the film; and a third dressing in contact with the secondary dressing.

46. The assembly of claim 45, wherein the secondary dressing comprises a gauze bandage.

47. The assembly of claim 45, wherein the third dressing is substantially waterproof.