阅读说明：本技术 抗微生物泡沫制品及其制备方法 (Antimicrobial foam articles and methods of making the same ) 是由 彼得拉·L·科赫莱尔里迪 约瑟夫·D·鲁莱 奈穆尔·卡里姆 塞姆拉·克拉克阿坦 张伟 安德 于 2019-07-19 设计创作，主要内容包括：本发明提供了一种制品。该制品包括：聚合物泡沫,该聚合物泡沫具有第一主表面和第二主表面；以及治疗组合物的离散域,该离散域被聚合物泡沫至少部分地围绕；其中每个离散域的外表面基本上适形于聚合物泡沫的第一主表面的一部分；其中该制品包括第一主表面和第二主表面；并且其中聚合物泡沫的第一主表面的一部分和离散域的外表面形成制品的第一主表面。(The present invention provides an article. The article comprises: a polymeric foam having a first major surface and a second major surface; and discrete domains of a therapeutic composition at least partially surrounded by the polymer foam; wherein an outer surface of each discrete domain substantially conforms to a portion of the first major surface of the polymeric foam; wherein the article comprises a first major surface and a second major surface; and wherein a portion of the first major surface of the polymeric foam and the outer surface of the discrete domains form the first major surface of the article.)

1. An article of manufacture, comprising:

a polymeric foam having a first major surface and a second major surface; and

discrete domains of a therapeutic composition at least partially surrounded by the polymer foam;

wherein an outer surface of each discrete domain substantially conforms to a portion of the first major surface of the polymeric foam;

wherein the article comprises a first major surface and a second major surface; and is

Wherein a portion of the first major surface of the polymeric foam and the outer surface of discrete domains form the first major surface of the article.

2. The article of claim 1, wherein the article is a wound dressing.

3. The article of claims 1-2, wherein the discrete domains form a pattern.

4. The article of claims 1 to 3, wherein at least at one plane parallel to the first major surface of the article and between the first and second major surfaces of the article, the cross-section of each discrete domain is greater than the cross-section of the outer surface of the discrete domain.

5. The article of claims 1 to 4, wherein the discrete domains have a diameter of at least about 100 microns.

6. The article of claims 1 to 5, wherein the outer surface of discrete domains covers between 1% and 99% of the first major surface of the article.

7. The article of claims 1 to 6, further comprising a liner on top of or adjacent to the first major surface of the article.

8. The article of claims 1 to 7, further comprising additional discrete domains of the therapeutic composition at least partially surrounded by the polymeric foam.

9. The article of claim 8, wherein an outer surface of each additional discrete domain substantially conforms to a portion of the second major surface of the polymeric foam.

10. The article of claim 8, wherein a portion of the second major surface of the polymeric foam and the outer surface of additional discrete domains form the second major surface of the article.

11. The article of claims 1 to 10, further comprising a second liner on top of or adjacent to the second major surface of the article.

12. The article of claims 1 to 11, wherein the polymeric foam comprises a material selected from the group consisting of polyurethane, polyvinyl acetate, polyvinyl alcohol, polyethylene, and silicone.

13. The article of manufacture of claims 1 to 12, wherein the therapeutic composition is retained in the discrete domains.

14. The article of manufacture of claims 1 to 13, wherein the therapeutic composition comprises an active agent selected from the group consisting of: antimicrobial agents, antibiotics, antioxidants, platelet derived growth factor, vitamin a, vitamin C, vitamin E, corticosteroids, silver sulfadiazine, polymyxin B sulfate, fusidic acid, pirfenidine, interferons, therapeutic oils, plant extracts, animal extracts, drugs, vitamins, hormones, antioxidants, emu oil, aloe vera, lavender oil, rose hip oil, silver sulfadiazine, polymyxin B, fusidic acid, and pirfenidine.

15. The article of manufacture of claims 1 to 14, wherein the therapeutic composition comprises an antimicrobial agent.

16. A method of making a wound dressing, the method comprising:

depositing a therapeutic composition onto a surface of a liner to form a printed surface; and

a foam material is disposed on the printing surface.

17. The method of claim 16, further comprising curing the foam material to form a foam on the printing surface.

18. The method of claims 16-17, wherein depositing the therapeutic composition comprises depositing the therapeutic composition onto the liner in a pattern.

19. The method of claims 16-18, further comprising removing the liner from the foam.

20. A method of making a wound dressing, the method comprising:

depositing a first therapeutic composition onto a surface of a first liner to form a first printed surface;

depositing a second therapeutic composition onto a surface of a second liner to form a second printed surface; and

disposing a foam material between the first printing surface and the second printing surface.

Background

Chronic wounds are often delayed in healing by microbial infection. In these infections, microbes can colonize the wound, and treatment with antimicrobial wound care products can help transfer chronic wounds to the track of healing. These microorganisms are often grown in complex communities known as biofilms. Biofilms occur in more than 80% of chronic wounds and are widely recognized as impeding wound healing.

In treating complex chronic wounds, clinicians are often required to use products that can manage wound exudate. Absorbent foam wound dressings are widely used for exudate management, and antimicrobial foam wound dressings are commercially available. Many commercially available wound dressings contain an antimicrobial component impregnated throughout the foam. A better article to deliver greater amounts of active directly to the wound bed would be desirable.

Disclosure of Invention

In one aspect, the present disclosure provides an article comprising: a polymeric foam having a first major surface and a second major surface; and discrete domains of a therapeutic composition at least partially surrounded by the polymer foam; wherein an outer surface of each discrete domain substantially conforms to a portion of the first major surface of the polymeric foam; wherein the article comprises a first major surface and a second major surface; and wherein a portion of the first major surface of the polymeric foam and the outer surface of the discrete domains form the first major surface of the article.

In another aspect, the present disclosure provides a method of making a wound dressing, the method comprising: depositing a therapeutic composition onto a surface of a liner to form a printed surface; and disposing a foam material on the printing surface.

In another aspect, the present disclosure provides a method of making a wound dressing, the method comprising: depositing a first therapeutic composition onto a surface of a first liner to form a first printed surface; depositing a second therapeutic composition onto a surface of a second liner to form a second printed surface; and disposing a foam material between the first printing surface and the second printing surface.

Various aspects and advantages of exemplary embodiments of the present disclosure have been summarized. The above summary is not intended to describe each illustrated embodiment or every implementation of the present disclosure. Additional features and advantages are disclosed in the following detailed description. The following drawings and detailed description more particularly exemplify certain embodiments using the principles disclosed herein.

Definition of

For the following defined terms, all definitions shall prevail throughout the specification, including the claims, unless a different definition is provided in the claims or elsewhere in the specification based on a specific reference to a modified form of the term as used in the following definition:

the terms "about" or "approximately" with respect to a numerical value or shape mean +/-5% of the numerical value or property or characteristic, but also expressly include any narrow range and exact numerical value within +/-5% of the numerical value or property or characteristic. For example, a temperature of "about" 100 ℃ refers to a temperature from 95 ℃ to 105 ℃, but also expressly includes any narrower temperature range or even a single temperature within that range, including, for example, a temperature of exactly 100 ℃. For example, a viscosity of "about" 1Pa-sec refers to a viscosity from 0.95Pa-sec to 1.05Pa-sec, but also expressly includes a viscosity of exactly 1 Pa-sec. Similarly, a perimeter that is "substantially square" is intended to describe a geometric shape having four lateral edges, wherein the length of each lateral edge is 95% to 105% of the length of any other lateral edge, but also encompasses geometric shapes wherein each lateral edge has exactly the same length.

The term "substantially" with respect to a property or characteristic means that the property or characteristic is exhibited to a greater extent than the opposite side of the property or characteristic. For example, a substrate that is "substantially" transparent refers to a substrate that transmits more radiation (e.g., visible light) than it does not. Thus, a substrate that transmits more than 50% of visible light incident on its surface is substantially transparent, but a substrate that transmits 50% or less of visible light incident on its surface is not substantially transparent.

The terms "a", "an" and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to a material comprising "a compound" includes mixtures of two or more compounds.

Drawings

The disclosure may be more completely understood in consideration of the following detailed description of various embodiments of the disclosure in connection with the accompanying drawings, in which:

FIG. 1 is a cross-sectional view of one embodiment of an article.

Fig. 2A is a photograph of a cross-section of an article.

Fig. 2B is a photograph of a top view of an article.

While the above-identified drawing figures, which may not be drawn to scale, illustrate various embodiments of the disclosure, other embodiments are also contemplated, as noted in the detailed description. In all cases, this disclosure describes the presently disclosed invention by way of representation of exemplary embodiments and not by way of express limitations. It should be understood that numerous other modifications and embodiments can be devised by those skilled in the art that will fall within the scope and spirit of the principles of this disclosure.

Detailed Description

Before any embodiments of the disclosure are explained in detail, it is to be understood that the invention is not limited in its application to the details of the use, construction and arrangement of components set forth in the following description. The invention is capable of other embodiments and of being practiced or of being carried out in various ways that will become apparent to those skilled in the art upon reading this disclosure. Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," or "having" and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items. It is to be understood that other embodiments may be utilized and structural or logical changes may be made without departing from the scope of the present disclosure.

As used in this specification, the recitation of numerical ranges by endpoints includes all numbers subsumed within that range (e.g. 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.8, 4, and 5, etc.).

Unless otherwise indicated, all numbers expressing quantities or ingredients, measurement of properties, and so forth used in the specification and embodiments are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the foregoing specification and attached list of embodiments can vary depending upon the desired properties sought to be obtained by those skilled in the art utilizing the teachings of the present disclosure. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claimed embodiments, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

Many commercially available wound dressings contain an antimicrobial component impregnated throughout the foam. This form makes it difficult to deliver an effective amount of the antimicrobial molecule to the wound bed where bacterial colonization occurs. One way to deliver larger amounts of active directly to the wound bed is to provide a large dose of antimicrobial substance on one surface of the foam wound dressing. However, applying a large amount of material to one side of a wound dressing may potentially prevent the ability of the foam to absorb moisture through the coated surface. The present application provides an article that allows for the incorporation of large amounts of materials into a foam without creating topographical features on the foam.

Fig. 1 is a schematic side view of one embodiment of an article 100. The article 100 can include a polymeric foam 110 having a first major surface 112 and a second major surface 115 and discrete domains 120 of a therapeutic composition. The discrete domains 120 may be at least partially surrounded by the polymer foam 110, as shown in fig. 1. The outer surface 122 of each discrete domain may substantially conform to (in other words, be coplanar with) a portion of the first major surface 112 of the polymeric foam, as shown in fig. 1. Article 100 can have a first major surface 102 and a second major surface 105. A portion of the first major surface 112 of the polymeric foam 110 and the outer surfaces 122 of the discrete domains 120 form the first major surface 102 of the article 100. The outer surface 122 of the discrete domains 120 may cover between 1% and 99%, between 5% and 95%, between 10% and 90%, between 15% and 85%, between 20% and 80%, between 25% and 75%, or between 30% and 70% of the first major surface 102 of the article 100. The article 100 may also include a liner 150 on top of or adjacent to the first major surface 102 of the article 100.

In some embodiments, the article 100 may include additional discrete domains 130 of the therapeutic composition at least partially surrounded by the polymer foam 110. In these embodiments, the outer surface 132 of each additional discrete domain 130 substantially conforms to a portion of the second major surface 115 of the polymeric foam 110. A portion of second major surface 115 of polymeric foam 110 and outer surfaces 132 of additional discrete domains 130 form second major surface 105 of article 100. The outer surface 132 of the discrete domains 130 may cover between 1% and 99%, between 5% and 95%, between 10% and 90%, between 15% and 85%, between 20% and 80%, between 25% and 75%, or between 30% and 70% of the second major surface 105 of the article 100. The article 100 may also include a second liner 160 on top of or adjacent to the second major surface 105 of the article 100.

In some embodiments, at least at one plane parallel to the first major surface 102 of the article 100 and located between the first and second major surfaces of the article, the cross-section of each discrete domain is greater than the cross-section of the outer surface of the discrete domain. For example, at the x-plane as shown in fig. 1, the cross-section 125 of the discrete domains 123 is larger than the cross-section 126 of the outer surface of the discrete domains 123. This may allow, for example, for enhanced mechanical locking of the therapeutic composition domains within the foam. In some embodiments, the therapeutic composition may remain in a discrete domain.

In some embodiments, the discrete domains may form a pattern. The pattern may be continuous or discontinuous. In some embodiments of a continuous pattern, the continuous nature of the discrete domains is less likely to break and, in addition, the shape of the pattern can be more precisely controlled because it does not require wicking within the foam, which can be complex and difficult to control. In some embodiments, the discrete domains may form a predetermined pattern such that they are equally spaced from each other and have a substantially uniform size and shape. In some embodiments, the discrete domains may form a random pattern such that they may be spaced differently from one another and may have generally different sizes and shapes. In some embodiments, the discrete domains may be scattered throughout the article. In some embodiments, the discrete domains may have a diameter of at least about 100 microns, at least about 200 microns, at least about 300 microns, at least about 400 microns, at least about 500 microns, at least about 600 microns, at least about 700 microns, at least about 800 microns, at least about 900 microns, or at least about 1000 microns. In some embodiments, the diameter of the discrete domains may be less than 10 cm. In some embodiments, the diameter of the discrete domains may be in the range of 100 micrometers to 10 cm. In some embodiments, the discrete domains may have an irregularly formed perimeter. This may mean that the discrete domains have an irregular shape (i.e., no line of symmetry). They may have non-smooth edges (e.g., serrated or feathered edges). The irregularly formed discrete domains can also have various thicknesses of the polymer foam surrounding the discrete domains.

In some embodiments, the discrete domains are shaped as channels at least partially surrounded by foam. In some embodiments, the channel has a semi-circular or semi-elliptical cross-sectional shape.

In some embodiments, the discrete domains are shaped as truncated spheres or truncated spheroids. In some embodiments, the discrete domains may be in a striped pattern. The striped pattern may be linear or curved, such as a sinusoidal pattern. In some embodiments, the striped pattern may be oriented in a parallel or non-parallel manner.

In some embodiments, each discrete domain has a portion of the perimeter surface that is curved and a portion of the perimeter surface that is flat. At least a portion of the peripheral surface that is flat is exposed on the surface of the article.

In some embodiments, the cross-section of each discrete domain has a portion of the perimeter that is curved and a portion of the perimeter that is linear. At least a portion of the perimeter that is linear is exposed on the surface of the article.

In some embodiments, a portion of each discrete domain is embedded in the foam, and each discrete domain has an exposed surface at least partially surrounded by the first major surface of the foam. In some embodiments, the liner is in contact with the exposed surface of the discrete domains and also in contact with the first major surface of the foam. In some embodiments, the liner has a slit dividing it into two portions.

Articles according to the present disclosure are useful. For example, they can be applied to the skin and used as wound dressings (including occlusive dressings and pressure dressings, for example) and transdermal patches. In the case of wound dressings, articles according to the present disclosure may allow for high loadings of active to be loaded into foam wound dressings while maintaining a large surface area of the foam wound dressing in contact with the wound to facilitate exudate management. In some embodiments, the articles of the present disclosure may be absorbent foam wound dressings.

Methods of making wound dressing articles of the present disclosure may comprise: depositing a therapeutic composition onto a surface of a liner to form a printed surface; and disposing a foam material on the printing surface.

Alternatively, the method of making a wound dressing article of the present disclosure may comprise: depositing a first therapeutic composition onto a surface of a first liner to form a first printed surface; depositing a second therapeutic composition onto a surface of a second liner to form a second printed surface; and disposing a foam material between the first printing surface and the second printing surface. The first therapeutic composition may be the same as or different from the second therapeutic composition.

In some embodiments, once deposited, the therapeutic composition forms discrete domains of the therapeutic composition on the surface of the liner. The foam material may be disposed on discrete domains of the therapeutic composition. The therapeutic composition may be deposited onto the liner according to any pattern or image. The pattern may comprise any suitable pattern, including, for example, combinations and arrays of dots, squares, diamonds, lines, circles, hexagons, triangles, and combinations thereof.

The method may further include curing the foam material at a temperature in a range from about room temperature to about 300 ° f to form a foam on the printing surface. Lower temperatures may be required to ensure stability of the therapeutic composition. At lower temperatures, the curing time is longer. Curing will take from about 10 minutes to about 15 minutes. At higher temperatures, when some therapeutic compositions remain stable, the cure time is, for example, about 4 to 5 minutes.

In some embodiments, the liner may optionally be removed from the foam after the curing step. When the liner is removed from the foam, discrete domains of the therapeutic composition are subsequently embedded in the foam, thereby forming an article having a flat surface. The method allows for the incorporation of a large amount of a therapeutic composition into the foam without forming topographical features on the foam. The pronounced topographical features of previous foam products make it difficult to handle the foam products.

In some embodiments, the therapeutic composition can be deposited by a non-contact printing process such as a spray or jet process. In other embodiments, the therapeutic composition may be deposited by a solvent coating process or hot melt coating. Useful contact printing methods include, for example, flexographic printing, roll coating, knife coating, and gravure roll coating.

Polymeric foam materials for use in the present disclosure may be selected from hydrophilic or hydrophobic polymers, depending on the nature of the therapeutic composition. Typical hydrophilic polymeric foams can be selected from the group consisting of polyurethane, polyvinyl acetate, polyvinyl alcohol (PVA), polyethylene, and medical grade silicone.

In some embodiments, the therapeutic composition may comprise an active agent. Exemplary useful active agents (e.g., therapeutic agents) include: herbal, anti-inflammatory, both steroidal (e.g., prednisolone, triamcinolone) and non-steroidal (e.g., naproxen, piroxicam); antibacterial agents (e.g., penicillins, cephalosporins, erythromycin, tetracyclines, gentamicin, sulfathiazoles, nitrofurantoin, trimethoprim and quinolones (e.g., norfloxacin, flumequine and ebafloxacin), bacitracin and salts thereof, neomycin and salts thereof, polymyxin B) and preservatives (e.g., chlorhexidine gluconate, biguanidinium, octenidine, antimicrobial quaternary ammonium surfactants such as benzalkonium chloride, cetylpyridinium chloride and cetyltrimethylammonium halides, phenols, cresols, triclosan, antimicrobial natural oils, iodophors, quaternary ammonium compounds, protonated tertiary and secondary amine compounds, certain metal ions (e.g., silver and copper) and their salts (e.g., silver gluconate, silver lactate and silver sulfate), biguanides, triclosan and polymeric antibacterial agents (e.g., polyhexamethylene biguanides, protonated primary amines, polymeric antibacterial agents, and antimicrobial agents, Polymers of secondary and/or tertiary amines, and polyquaternary amines), antimicrobial lipids such as those described in U.S. published patent application 2005/0089539A1(Scholz et al), which includes C of glycerol and propylene glycol₈-C₁₂Alkyl monoesters and monoethers); anti-protozoal drugs (e.g., metronidazole); cardiovascular agents (e.g., amlodipine besylate, glyceryl trinitrate, nifedipine, losartan potassium, irbesartan, diltiazem hydrochloride, clopidogrel hydrogen sulfate, digoxin, abciximab, furosemide, amiodarone hydrochloride, beraprost, theophylline, pirbuterol, salmeterol, isoproterenol, and vitamin E nicotinate); calcium channel blockers (e.g., nifedipine, triazone); enzyme inhibitors such as collagenase inhibitors, protease inhibitors, elastase inhibitors, lipoxygenase inhibitors (e.g., a64077), and angiotensin converting enzyme inhibitors (e.g., captopril, lisinopril); other anti-hypertensive agents (e.g., propranolol); leukotriene antagonists (e.g., ICI204, 219) antiulcer agents such as H2 antagonistsAn anti-agent; steroid hormones (e.g., progesterone, testosterone, estradiol, ethinyl dydrogestrel, mycophenolate mofetil, and methylprednisolone); antiviral agents and/or immunomodulators (e.g., 1-isobutyl-1H-imidazo [4, 5-c)]Quinolin-4-amines, 1- (2-hydroxy-2-methylpropyl) -1H-imidazo [4,5-c]Quinolin-4-amine, acyclovir); cardiotonic agents (e.g., digitalis, digoxin); antitussives (e.g., codeine, dextromethorphan); antihistamines (e.g., diphenhydramine, chlorpheniramine, terfenadine); exfoliating agents (e.g., alpha-hydroxy acids or beta-hydroxy acids); analgesics (e.g., tramadol hydrochloride, fentanyl, analgin, ketoprofen, morphine sulfate, lysine acetylsalicylic acid, acetaminophen, ketorolac tromethamine, morphine, loxoprofen sodium, and ibuprofen); dermatological products (e.g., isotretinoin and clindamycin phosphate); anesthetics (e.g., propofol, imidazodiazepine hydrochloride, and lidocaine hydrochloride); migraine therapeutic agents (e.g., ergotamine, melatonin, sumatriptan, zolmitriptan, and rizatriptan); sedatives and hypnotics (e.g., zolpidem tartrate, triazolam, and scopolamine butylbromide); imaging components (e.g., iohexol, technetium, TC99M, staibietium, iomeprol, gadodiamide, ioversol, and iopromide); peptide hormones (e.g., human or animal growth hormone LHRH); cardiotonic products such as atrial peptides; protein products (e.g., insulin); enzymes (e.g., antipersonnaise, lysozyme, dextranase), antinociceptives (e.g., scopolamine); anticonvulsants (e.g., carbamazepine); immunosuppressive agents (e.g., cyclosporine); psychotherapeutic agents (e.g., benzodiazepine, sertraline hydrochloride, venlafaxine, bupropion hydrochloride, olanzapine, bupropion hydrochloride, alprazolam, methylphenidate hydrochloride, fluvoxamine maleate, and dihydroergotoxine mesylate); sedatives (e.g., sedative hypnotics); anticoagulants (e.g., heparin); analgesics (e.g., acetaminophen); anti-migraine agents (e.g., ergotamine, melatonin, sumatriptan); cholesterol lowering agents (e.g., atorvastatin, calcium, lovastatin, bezafibrate, ciprofibrate, and gemfibrozil); antiarrhythmic agents (e.g., flecainide); antiemetics (e.g., metoclopramide, ondansetron); blood regulationNodal agents (e.g., alfa-liptin, enoxaparin sodium, and antihemophilic factor); anti-arthritic components (e.g., celecoxib, nabumetone, misoprostol, and rofecoxib); AIDS and AIDS-related drugs (e.g., lamivudine, indinavir sulfate, and stavudine); diabetes and diabetes-related therapeutics (e.g., metformin hydrochloride, insulin, troglitazone, and acarbose); biologics (e.g., hepatitis B vaccine and hepatitis a vaccine); immune response modifiers (e.g., purine derivatives, adenine derivatives, and CpGs); anti-cancer agents (e.g., methotrexate, paclitaxel, carboplatin, tamoxifen citrate, docetaxel, epirubicin hydrochloride, leuprolide acetate, bicalutamide, goserelin acetate implant, irinotecan hydrochloride, gemcitabine hydrochloride, and sargrastim); gastrointestinal products (e.g., lansoprazole, ranitidine hydrochloride, famotidine, ondansetron hydrochloride, granisetron hydrochloride, sulfasalazine, and infliximab); respiratory therapeutic agents (e.g., loratadine, fexofenadine hydrochloride, cetirizine hydrochloride, fluticasone propionate, salmeterol, and budesonide); immunosuppressive agents (e.g., cyclosporine); neurological agents, such as anxiolytics; a hemostatic agent; anti-obesity agents; nicotine; algicides; and pharmaceutically acceptable salts and esters of the foregoing.

In some embodiments, the therapeutic composition may comprise an active agent selected from the group consisting of: antimicrobial agents, antibiotics, antioxidants, platelet derived growth factor, vitamin a, vitamin C, vitamin E, corticosteroids, silver sulfadiazine, polymyxin B sulfate, fusidic acid, pirfenidine (pirfennedine), interferons, therapeutic oils, plant extracts, animal extracts, drugs, vitamins, hormones, antioxidants, emu oil, aloe vera, lavender oil, rose hip oil, silver sulfadiazine, polymyxin B, fusidic acid, and pirfenidine.

The active agent may be selected from those that are not reactive with the foam and/or other components of the active composition, although reactive active agents may be used. The antimicrobial agent is generally selected based on the type of microorganism that the article will encounter in a particular use. Exemplary antimicrobial agents may include penicillins, and the like,Cephalosporins, erythromycin, tetracyclines, gentamicin, sulfathiazole, nitrofurantoin, trimethoprim, quinolones (e.g., norfloxacin, flumequine, and ebafloxacin), bacitracin and salts thereof, neomycin and salts thereof, polymyxin B) and preservatives (e.g., chlorhexidine gluconate, bixidine, octenidine, antimicrobial quaternary ammonium surfactants such as benzalkonium chloride, cetylpyridinium chloride, and cetyltrimethylammonium halides, phenols, cresols, triclosan, antimicrobial natural oils, iodophors, quaternary ammonium compounds, protonated tertiary and secondary amine compounds, certain metal ions (e.g., silver and copper) and their salts (e.g., silver gluconate, silver lactate, and silver sulfate), biguanides, triclosans, and polymeric antibacterial agents (e.g., polyhexamethylene biguanides, polymeric primary, secondary, and/or tertiary amines), And polyquaternary amines), and antimicrobial lipids such as those described in U.S. published patent application 2005/0089539a1(Scholz et al), which includes C of glycerol and propylene glycol₈-C₁₂Alkyl monoesters and monoethers, and microbe-inhibiting materials including chelating agents (e.g., EDTA and organic acids). The active agent can be included in the therapeutic composition in any amount. In some embodiments, the active agent may be present in an amount of at least 10 wt.%, 20 wt.%, 30 wt.%, 40 wt.%, or even at least 50 wt.%, based on the total weight of the therapeutic composition.

In some embodiments, the therapeutic composition can comprise a carrier. The carrier may comprise a liquid (aqueous, solvent-based or based on a mixture of solvent and water), a gel (hydrogel), a cream, a paste or a solid. In some embodiments, the carrier may be a liquid at about room temperature.

In other embodiments, the support may be a solid at about room temperature. In some embodiments, the carrier may be a liquid at a temperature of about the human mouth (i.e., at about 37 ℃). In other embodiments, the carrier may be a solid at about the temperature of the human mouth. Exemplary liquid carriers include water, alcohols (e.g., ethanol), glycerin, sorbitol, and liquid silicones. Exemplary solid carriers include crystalline or waxy materials, such as polyethylene glycol.

Each non-carrier component of the therapeutic composition can be independently dissolved, dispersed, suspended, or emulsified in the carrier. In some embodiments, at least one component of the therapeutic composition is dissolved in a carrier. In some embodiments, at least one component of the therapeutic composition is dispersed in a carrier. In some embodiments, at least one component of the therapeutic composition is suspended in the carrier. In some embodiments, at least one component of the therapeutic composition is emulsified in a carrier. In some embodiments, the active agent may be dissolved or dispersed in the aqueous liquid. In some embodiments, the active agent may be dissolved or dispersed in a gel (hydrogel), cream, or paste. In some embodiments, the active agent may be dissolved or dispersed in the thixotropic gel.

In some embodiments, the therapeutic composition can comprise a rheology modifier. The rheology modifier can be any suitable rheology modifier, such as an organic or inorganic material; a soluble or swellable polymer; linear, branched or crosslinked polymers; natural or synthetic polymers, and the like. Rheology modifiers can be used to tailor the rheology of the therapeutic composition to the desired method of depositing the composition on the liner. In some embodiments, the rheology-modifying agent can also affect the release kinetics of the active agent included in the therapeutic composition.

The therapeutic composition comprises a carrier. The carrier may comprise a liquid, a solid, or both. In some embodiments, the carrier may be a liquid at about room temperature. In other embodiments, the support may be a solid at about room temperature. In some embodiments, the carrier may be a liquid at a temperature of about the human mouth (i.e., at about 37 ℃). In other embodiments, the carrier may be a solid at about the temperature of the human mouth. Exemplary liquid carriers include water, alcohols (e.g., ethanol), glycerin, sorbitol, and liquid silicones. Exemplary solid carriers include polymers such as natural rubber, butyl rubber, poly (isobutylene), elastomers, styrene-butadiene rubber, polysaccharides, and waxes (e.g., beeswax).

Each non-carrier component of the therapeutic composition can be independently dissolved, dispersed, suspended, or emulsified in the carrier. In some embodiments, at least one component of the therapeutic composition is dissolved in a carrier. In some embodiments, at least one component of the therapeutic composition is dispersed in a carrier. In some embodiments, at least one component of the therapeutic composition is suspended in the carrier. In some embodiments, at least one component of the therapeutic composition is emulsified in a carrier.

Liners suitable for use in the present disclosure may be made of kraft paper, polyethylene, polypropylene, polyester, or composites of any of these materials. The liner may be coated with a release agent, such as a fluorochemical or silicone. For example, U.S. Pat. No. 4,472,480, the disclosure of which is hereby incorporated by reference, describes a low surface energy perfluorochemical liner. Preferred liners are paper, polyolefin film or polyester film coated with silicone release material. An example of a commercially available silicone coated release paper is POLYSLIK available from James River Division H.P. Smith, James River Co., Bedford Park, Illinois, H.P. Smith Division (Bedford Park,111.))^TMSilicone release paper and silicone release paper supplied by dowert Chemical Co, (Dixon,111.) of Dixon, illinois. The most preferred liner is a 1-60BKG-157 paper liner available from Doubert corporation (Daubert), which is a super calendered kraft paper having a water-based silicone release surface. Alternatively, the wound dressing may be linerless and delivered in roll form such as described in U.S. patent 5,803,086.

The following embodiments are intended to illustrate the disclosure, but not to limit it.

Detailed description of the preferred embodiments

Embodiment 1 is an article comprising: a polymeric foam having a first major surface and a second major surface; and discrete domains of a therapeutic composition at least partially surrounded by the polymer foam; wherein an outer surface of each discrete domain substantially conforms to a portion of the first major surface of the polymeric foam; wherein the article comprises a first major surface and a second major surface; and wherein a portion of the first major surface of the polymeric foam and the outer surface of discrete domains form the first major surface of the article.

Embodiment 2 is the article of embodiment 1, wherein the article is a wound dressing.

Embodiment 3 is the article of embodiments 1-2, wherein the discrete domains form a pattern.

Embodiment 4 is the article of embodiments 1-3, wherein at least at one plane parallel to the first major surface of the article and between the first major surface and the second major surface of the article, the cross-section of each discrete domain is greater than the cross-section of the outer surface of the discrete domain.

Embodiment 5 is the article of embodiments 1-4, wherein the discrete domains have a diameter of at least about 100 microns.

Embodiment 6 is the article of embodiments 1-5, wherein the outer surface of discrete domains covers between 1% and 99% of the first major surface of the article.

Embodiment 7 is the article of embodiments 1-6, further comprising a liner on top of or adjacent to the first major surface of the article.

Embodiment 8 is the article of embodiments 1-7, further comprising additional discrete domains of the therapeutic composition at least partially surrounded by the polymeric foam.

Embodiment 9 is the article of embodiment 8, wherein an outer surface of each additional discrete domain substantially conforms to a portion of the second major surface of the polymeric foam.

Embodiment 10 is the article of embodiment 8, wherein a portion of the second major surface of the polymeric foam and the outer surfaces of additional discrete domains form the second major surface of the article.

Embodiment 11 is the article of embodiments 1-10, further comprising a second liner on top of or adjacent to the second major surface of the article.

Embodiment 12 is the article of embodiments 1-11, wherein the polymeric foam comprises a material selected from the group consisting of polyurethane, polyvinyl acetate, polyvinyl alcohol, polyethylene, and silicone.

Embodiment 13 is the article of embodiments 1-12, wherein the therapeutic composition is retained in the discrete domains.

Embodiment 14 is the article of manufacture of embodiments 1-13, wherein the therapeutic composition comprises an active agent selected from the group consisting of: antimicrobial agents, antibiotics, antioxidants, platelet derived growth factor, vitamin a, vitamin C, vitamin E, corticosteroids, silver sulfadiazine, polymyxin B sulfate, fusidic acid, pirfenidine, interferons, therapeutic oils, plant extracts, animal extracts, drugs, vitamins, hormones, antioxidants, emu oil, aloe vera, lavender oil, rose hip oil, silver sulfadiazine, polymyxin B, fusidic acid, and pirfenidine.

Embodiment 15 is the article of embodiments 1-14, wherein the therapeutic composition comprises an antimicrobial agent.

Embodiment 16 is a method of making a wound dressing, comprising: depositing a therapeutic composition onto a surface of a liner to form a printed surface; and disposing a foam material on the printing surface.

Embodiment 17 is the method of embodiment 16, further comprising curing the foam material to form a foam on the printing surface.

Embodiment 18 is the method of embodiments 16-17, wherein depositing the therapeutic composition comprises depositing the therapeutic composition onto the liner in a pattern.

Embodiment 19 is the method of embodiments 16-18, further comprising removing the liner from the foam.

Embodiment 20 is a method of making a wound dressing, comprising: depositing a first therapeutic composition onto a surface of a first liner to form a first printed surface; depositing a second therapeutic composition onto a surface of a second liner to form a second printed surface; and disposing a foam material between the first printing surface and the second printing surface.

Embodiment 21 is an article, comprising: a polymer film liner; a polymeric foam having a first major surface and a second major surface; and a plurality of discrete domains of a therapeutic composition; wherein a portion of each discrete domain is embedded in the foam and each discrete domain has an exposed surface at least partially surrounded by the first major surface of the foam; wherein the liner is in contact with the exposed surfaces of the discrete domains and also in contact with the first major surface of the foam.

Embodiment 22 is the article of embodiment 21, wherein the liner has a slit dividing it into two portions.

Embodiment 23 is the article of any one of embodiments 21 to 22, wherein the therapeutic composition comprises an antimicrobial agent.

Embodiment 24 is the article of embodiments 15 and 23, wherein the antimicrobial agent is selected from the group consisting of polyhexamethylene biguanide (PHMB), chlorhexidine, benzalkonium chloride, benzethonium chloride, silver salts, neomycin, polymyxin B, bacitracin, and octenidine.

Embodiment 25 is the article of any one of embodiments 15, 23, and 24, wherein the antimicrobial agent is dissolved or dispersed in gels, hydrogels, creams, and paste carriers.

Embodiment 26 is the article of any one of embodiments 1-15 and 21-25, wherein the article is an absorbent wound dressing.

The following working examples are intended to illustrate the disclosure and are not intended to be limiting.

Examples

Material for producing polymer foams

SUPRASEC 9634 isocyanate is a modified methylene diphenyl diisocyanate (MDI) available from Hunsmman Chemical Company, The Woodlands, TX, Woodland, Tex. SUPRASEC 9634 isocyanate is reported to have the following properties: the equivalent weight was 143 g/equivalent, the functionality was 2.15, and the isocyanate content was 29.3%.

The CDB-33143 polyether polyol was prepared from glycerol, propylene oxide and ethylene oxide as a blend, available from Carpenter Company, Richmond, VA, of rieston, VA. According to the manufacturer's report, the CDB-33143 polyether polyol has the following characteristics: the hydroxyl number was 142, the functionality was 3 and the ethylene oxide content was 26%.

The CARPOL GP-700 polyether polyol was prepared from glycerol and propylene oxide and was obtained from Carbotex corporation, Risteman, Va. According to the manufacturer's report, the carbopol GP-700 polyether polyol has the following properties: the average hydroxyl number was 240, the functionality was 3, and the ethylene oxide content was 0%.

The ARCOL E-434 polyether polyol is polyoxypropylene triol modified with ethylene oxide, available from Bayer materials science, Pittsburgh, Va. According to the manufacturer's report, the ARCOL E-434 polyether polyol has the following characteristics: the hydroxyl number is 33.8 to 37.2 and the ethylene oxide content is 15%.

Triethanolamine LFG (low freeze grade) contains 85% triethanolamine and 15% water,

available from Quaker Chemical Corporation, Conshohocken, Pa.

DABCO 33-LV is a solution of triethylenediamine (33% by weight) in dipropylene glycol, available from Air Products Company, Allentown, Pennsylvania, Pa.

The DABCO BL-17 tertiary amine catalyst was purchased from air chemical products.

The DABCO DC-198 silicone glycol copolymer surfactant and the DABCO BA-100 polymeric acid blocking agent were purchased from air chemical products.

Materials for making antimicrobial gels

COSMOCIL PG antimicrobial agents [ polyhexamethylene biguanide (PHMB) in the form of a 20% (w/w) aqueous solution ] were purchased from Longsha, Inc. of Barser, Switzerland.

Poly (ethylene glycol) 4000(PEG4000) was purchased from EMD Millipore corporation of bilrica, massachusetts (EMD Millipore, Billerica, MA).

Polyglycerol-3 was purchased from Solvay s.a., Brussels, Belgium, brussel, Belgium.

Propylene glycol monocaprylate (CAPMUL PG8) was obtained from Abitec Corporation of columbu, ohio (Abitec Corporation, Columbus, OH).

CAB-O-SIL M5 fumed silica was obtained from Cabot Corporation, Boston, Mass.

PLANTAREN 810UP alkyl polyglucoside surfactant is available from BASF Personal Care Company, Florham Park, NJ.

Preparation of antimicrobial gels and pattern coated release liners

Table 1 reports the total amount of each component used to prepare a batch of antimicrobial gel.

TABLE 1：

The mixing vessel of a double planetary mixer [ Charles Ross, Inc. (Charles Ross & Son Company, Hauppauge, NY) ] was heated to 70 ℃ with an external water bath. Polyglycerol-3 was added to the mixing vessel followed by PEG4000 and the mixture was blended for 30 minutes at 25rpm (revolutions per minute). Next, PHMB, propylene glycol monocaprylate (CAPMUL PG8), and PLANTAREN 810UP alkylpolyglycoside surfactant were added sequentially to the mixing vessel and the mixture was blended at 35rpm for 5 minutes. The CAB-O-SIL M5 fumed silica was then added in three equal portions and blended for 5 minutes at 35rpm after each portion was added. Unmixed material on the side of the mixing vessel was scraped into the batch mixture and the mixture was blended for an additional 10 minutes at 25 rpm. The resulting gel was removed from the mixing vessel and heated in an oven at 65 ℃ for one hour. The warmed gel was loaded into a 20mL syringe with a luer tip. The gel was then dispensed on the release surface of the silicone-coated paper release liner in a pattern of non-intersecting lines (about 10cm long and about 4mm apart). Each wire has a diameter of about 2 mm. A pattern was applied to a 10cm x 3.5cm portion of the release liner.

EXAMPLE 1 preparation of foamed articles

Casting an open-cell polyurethane foam layer by: SUPRASEC 9634 isocyanate (58.2 parts) was added to a mixture of CDB-33143 polyether polyol (100 parts), CARPOL GP-700 polyether polyol (3.0 parts), water (1.0 part), triethanolamine LFG (3.7 parts), DABCO DC-198 surfactant (2.0 parts), ARCOL E-434 polyether polyol (4.0 parts), DABCO 33-LV (0.45 parts), DABCO BA-100 polyacid blocking agent (0.12 parts), and DABCO BL-17 tertiary amine catalyst (0.10 parts). The formulation was scaled so that the total reaction mixture weighed 40 grams. The components were mixed in a plastic cup at 3300rpm for 10 seconds using a DAC 150FV high speed mixer [ flaktek, Inc, Landrum, SC, of randlam, south carolina ]. The entire mixture was then immediately poured over the gel pattern that had previously been applied to the silicone-coated release paper liner so that the entire gel pattern was covered by the mixture. The total area of the release liner covered by the foam was about 12cm x 18 cm. A piece of polypropylene coated release paper was placed on the exposed surface of the reactive foam mixture. The foam was allowed to warm and cure at room temperature. An image of a cross-section of the foam article is shown in fig. 2A, and an image of a top view of the foam article is shown in fig. 2B. As shown in fig. 2A and 2B, discrete domains 220 of the antimicrobial gel are surrounded by the polymer foam 210.

Comparative example A.

The same procedure as reported in example 1 was followed except that immediately after mixing, the foam formulation was poured onto a silicone coated release liner without the applied gel pattern of example 1.

Example 2 planktonic microbiological kill assay (Staphylococcus aureus) aureus))

A Culture of Staphylococcus aureus strain number 6538 (purchased from American Type Culture Collection, Manassas, Va.) was grown in tryptic Soy Broth [ Beken-Dickinson, Dickinson and Company, Franklin Lakes, N.J. ] at 37 ℃ for 18 hours. Cultures were diluted 1:100 in sterile Phosphate Buffered Saline (PBS) [ Thermo Fisher Scientific Incorporated, Waltham, MA ] using a 15mL conical centrifuge tube.

Three circular punches (10 mm in diameter) of the foamed article of example 1 were prepared from the area containing the gel-embedded foam. With both release liners removed, 10 microliters of an aliquot of diluted staphylococcus aureus suspension was applied to each foam punch. Each aliquot was applied directly to the surface of the foam article containing the exposed gel. The inoculated punch samples were incubated at room temperature for 5 minutes and then placed into separate 15mL conical centrifuge tubes containing 10mL of Dey-Englay (D/E) neutralization broth [ BD Co., Franklin Lakes, N.J. ]. The process was repeated using three 10mm circular punches of the foam article of comparative example a.

Each tube containing 5mL of D/E broth and foam punch samples was sonicated in a sonication water bath (Branson 2510, available from Emerson Electric Company, st. louis, MO, st.) for one minute, followed by one minute at maximum speed using a VWR micro-vortexer (VWR International, Radnor, PA, ladrono, PA). The neutralized broth was diluted stepwise (10 fold dilution) and plated (1mL) onto 3M PETRIFILM aerobic count plates [ 3M Corporation of meprolid, minnesota (3M Corporation, Maplewood, MN) ]. The plates were incubated at 37 ℃ for 24 to 48 hours. At the end of the incubation period, colonies on each plate were counted visually.

Based on the number of dilutions, the average log (number of colony forming units/sample) recovered from the foam preparation (n-3) was calculated by adjusting the observed plate count. Statistical significance was determined using student two-tailed unpaired t-test, where P-values less than 0.05 were considered statistically significant differences. The results are reported in table 2.

Example 3 planktonic microbiological kill assay (Pseudomonas aeruginosa) aeruginosa))

The same procedure as reported in example 2 was followed, except that instead of staphylococcus aureus, pseudomonas aeruginosa, strain number 15442 (purchased from the american type culture collection) was used. The results are reported in table 2.

Table 2: bacterial count recovered from foam products

All references and publications cited herein are expressly incorporated by reference into this disclosure in their entirety. Illustrative embodiments of the invention are discussed herein and reference is made to possible variations within the scope of the invention. For example, features depicted in connection with one exemplary embodiment may be used in connection with other embodiments of the invention. These and other variations and modifications in the invention will be apparent to those skilled in the art without departing from the scope of the invention, and it should be understood that this invention is not limited to the illustrative embodiments set forth herein. Accordingly, the invention is to be limited only by the claims provided below and equivalents thereof.