Therapies for wound treatment

Abstract

The present specification concerns therapeutic approaches for the treatment of wounds, especially chronic wounds experienced by patients whose ability to heal skin is impaired (e.g. diabetes sufferers). The therapies are based on the use of resorbable glass beads (for example calcium phosphate glass microspheres) alone or in combination with an 11β-hydroxysteroid dehydrogenase type I (11β-HSD1) inhibitor such as (S)-2-(1-(5-(cyclohexylcarbamoyl)-6-(propylthio)pyridin-2-yl)piperidin-3-yl)acetic acid (AZD4017, compound (I) below).

Description

[0001] 201395-PCT01-NP Therapies for Wound Treatment CROSS‑REFERENCE TO RELATED PATENT APPLICATION

[0001] This specification claims the benefit of priority to GB Patent Application No.2408335.4 (filed 11 June 2024). The entire text of the above-referenced patent application is incorporated by 5 reference into this specification. FIELD

[0002] The present specification concerns therapeutic approaches for the treatment of wounds, especially chronic wounds experienced by patients whose ability to heal skin is impaired (e.g. diabetes sufferers). The therapies are based on the use of resorbable glass beads (for example calcium 10 phosphate glass microspheres) alone or in combination with an 11β-hydroxysteroid dehydrogenase type I (11β-HSD1) inhibitor such as (S)-2-(1-(5-(cyclohexylcarbamoyl)-6-(propylthio)pyridin-2- yl)piperidin-3-yl)acetic acid (AZD4017, compound (I) below, first disclosed in WO2008 / 053194). BACKGROUND 15

[0003] Wound healing is a dynamic, complex process involving coagulation, inflammation, tissue formation and tissue remodelling. Patients with diabetes mellitus are observed to be more susceptible to infection and other complications during the wound healing process. One reason for this may be that the high blood sugar levels that are characteristic of diabetes can inhibit the delivery of nutrients and oxygen to skin cells, which in turn can impair the functioning of the immune system and increase 20 inflammation at the cellular level.

[0004] In addition, high blood sugar levels can damage nerves and vessels, resulting in numbing. This numbing, or diabetic neuropathy, has been cited as a common cause of injury and complications in diabetic wound healing, with, for instance, a lack of feeling in the feet being associated with foot ulcers which are allowed to develop unnoticed. As a consequence, impaired wound healing is a common 25 cause of morbidity (including amputation) and mortality among diabetic patients. 201395-PCT01-NP

[0005] In 2009 chronic wounds to the skin affected 6.5 million people in the United States and led to $25 billion in annual treatment costs. Rising rates of obesity and diabetes, combined with an ageing population, leads to an expectation that the number of people affected by chronic wounds will continue to rise. Accordingly, treatment of patients with chronic wounds is a significant unmet clinical 5 need.

[0006] WO2021 / 094390 discloses that orally-administered 11β-HSD1 inhibitors such as (S)-2-(1-(5- (cyclohexylcarbamoyl)-6-(propylthio)pyridin-2-yl)piperidin-3-yl)acetic acid can be used as wound treatments, effecting improved healing and general improvements in skin properties such as epidermal thickness and hydration that increase resistance to wounds. 10

[0007] In a further effort to provide wound treatments, this specification discloses an alternative method of therapy that involves topically treating wounds with a resorbable glass. Without wishing to be bound by theory, the resorbable glass may assist in the formation of an extracellular matrix (or temporary “scaffold”) that the body’s natural healing factors can utilise, allowing them to regrow into the wound, thus speeding up the wound healing process. 15

[0008] Surprisingly, yet further improvements in the wound healing efficacy of resorbable glass can be obtained by administering them in combination with 11β-HSD1 inhibitors. As shown in the examples, such combinations deliver synergistic healing effects compared to treatments using either of the individual components alone. Again, this is hypothesised to be because the resorbable glass provides a temporary scaffold upon which the body’s natural healing factors can build while the 11β- 20 HSD1 inhibitor reduces the local cortisol concentrations delivering a wound environment ideally set up for rapid wound healing. SUMMARY

[0009] It is an object of the present specification to provide new therapies for the topical treatment 25 of wounds.

[0010] In a first aspect of the present specification there is provided a resorbable glass for use in the topical treatment of wounds.

[0011] In a second aspect of the present specification there is provided the use of a resorbable glass in the manufacture of a medicament for the topical treatment of wounds. 201395-PCT01-NP

[0012] In a third aspect of the present specification there is provided a method of topical treatment of wounds in a human or animal patient in need thereof, comprising administering to the patient a therapeutically effective amount of a resorbable glass.

[0013] In a fourth aspect of the present specification there is provided a resorbable glass for use in 5 the topical treatment of wounds, where the resorbable glass is administered in combination with an 11β-HSD1 inhibitor.

[0014] In a fifth aspect of the present specification there is provided the use of a resorbable glass in the manufacture of a medicament for the topical treatment of wounds, where the resorbable glass is administered in combination with an 11β-HSD1 inhibitor. 10

[0015] In a sixth aspect of the present specification there is provided a method of topical treatment of wounds in a human or animal patient in need thereof, comprising administering to the patient a therapeutically effective amount of a resorbable glass, where the resorbable glass is administered in combination with an 11β-HSD1 inhibitor.

[0016] In a seventh aspect of the present specification there is provided a pharmaceutical 15 composition comprising a resorbable glass and a pharmaceutically acceptable excipient.

[0017] In an eight aspect of the present specification there is provided a pharmaceutical composition for use in the topical treatment of wounds.

[0018] In a ninth aspect of the present specification there is provided a pharmaceutical composition comprising a resorbable glass, an 11β-HSD1 inhibitor and optionally a pharmaceutically acceptable 20 excipient.

[0019] In a tenth aspect of the present specification there is provided a kit comprising: - A resorbable glass in a first dosage form; - An 11β-HSD1 inhibitor in a second dosage form; and optionally - Instructions for use. 25 FIGURES

[0020] So that the specification may be better understood, reference is made to the following figures.

[0021] Figure 1: Initiation of neo-dermal tissue formation at various time points.

[0022] Figure 2: Terminology for measurement of wound closure and its components wound contraction & wound re-epithelialisation: a) original wound day 0 (immediately post-wounding), b) 201395-PCT01-NP the same wound at day 10 demonstrating both contraction and re-epithelialisation. Photographs approximately equally scaled to visualise wound closure.

[0023] Figure 3: Low power photomicrograph of a hematoxylin and eosin (H&E)-stained diabetic mouse wound section granulation tissue depth (GTD) measurement. 5

[0024] Figure 4: Appearance of group 3 wounds (i.e. control / DMSO-saline vehicle group) on day 8.

[0025] Figure 5: Appearance of group 2 wounds (i.e. bead monotherapy group) on day 8.

[0026] Figure 6: Plot of wound area remaining over time after treatment with resorbable glass bead monotherapy.

[0027] Figure 7: Plot of wound contraction over time after treatment with resorbable glass bead 10 monotherapy.

[0028] Figure 8: Plot of wound re-epithelisation over time after treatment with resorbable glass bead monotherapy.

[0029] Figure 9: Plot of wound re-epithelisation on day 8 and day 20 after treatment with resorbable glass bead monotherapy. 15

[0030] Figure 10: Plot of granulation tissue formation on day 8 and day 20 after treatment with resorbable glass bead monotherapy.

[0031] Figure 11: Histology of wound following resorbable glass bead monotherapy, showing wound healing components.

[0032] Figure 12: Appearance of group 5 wounds (i.e. control / kleptose vehicle group) on day 8. 20

[0033] Figure 13: Appearance of group 4 wounds (i.e. compound (II) [“AZT”] monotherapy group) on day 8.

[0034] Figure 14: Plot of wound area remaining over time after treatment with compound (II) monotherapy.

[0035] Figure 15: Plot of wound contraction over time after treatment with compound (II) 25 monotherapy.

[0036] Figure 16: Plot of wound re-epithelisation over time after treatment with compound (II) monotherapy.

[0037] Figure 17: Appearance of group 1 wounds (i.e. resorbable glass bead and compound (II) combination therapy group) on day 8. 30

[0038] Figure 18: Plot of wound area remaining over time after treatment with resorbable glass bead and compound (II) combination therapy. 201395-PCT01-NP

[0039] Figure 19: Plot of wound contraction over time after treatment with resorbable glass bead and compound (II) combination therapy.

[0040] Figure 20: Plot of wound re-epithelisation over time after treatment with resorbable glass bead and compound (II) combination therapy. 5 DESCRIPTION

[0041] The invention detailed in this specification should not be interpreted as being limited to any of the recited embodiments or examples. Other embodiments will be readily apparent to a reader 10 skilled in the art.

[0042] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure is related. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the 15 Oxford Dictionary of Biochemistry and Molecular Biology, Revised, 2000, Oxford University Press, provide one of skill with a general dictionary of many of the terms used in this disclosure. Units, prefixes, and symbols are generally denoted in their Systeme International de Unites (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range (for example, “between XX and YY” includes XX and YY, as well as the range between XX and YY). 20

[0043] In any embodiment defined by a physical parameter (for example, density, particle diameter, porosity, pore diameter, and / or surface area per unit mass), the physical parameter may be as measured using any experimental technique or procedure described or referenced in the experimental section (for example a technique or procedure described in Hossain et al., Acta Biomaterialia 2018, 72, 396-406, the contents of which reference are incorporated entirely herein). 25

[0044] “A” or “an” mean “at least one”.

[0045] When an embodiment includes “a” or “an” feature X, subsequent referrals to “the” feature X do not imply only one of the feature is present. Instead the above interpretation of “a” or “an” continues to apply so that “the” also means “at least one”.

[0046] “Comprising” means that a given embodiment may contain other features. For example, in 30 any embodiment where a material “comprising” certain materials or elements is mentioned, the given 201395-PCT01-NP material may be formed of at least 10% w / w, at least 20% w / w, at least 30% w / w, or at least 40% w / w of the materials or elements (or combination of materials or elements).

[0047] In some embodiments “comprising” may also mean “consisting of” (or “consists of”) or “consisting essentially of” (or “consists essentially of”). 5

[0048] “Consisting of” or “consists of” means a given material or element is formed entirely of the material or element (or combination of materials or elements). In any embodiment where “consisting of” or “consists of” is mentioned the given material or element may be formed of 100% w / w of the material or element.

[0049] In any embodiment where “consisting essentially of” or “consists essentially of” is mentioned 10 the given material or element may be formed of at least 60% w / w, at least 70% w / w, at least 80% w / w, at least 90% w / w, at least 95% w / w or at least 99% w / w of the material or element.

[0050] In any embodiment where “is” or “may be” is used to define a claim element, “is” or “may be” may mean the element “consists of” or “consists essentially of” the element.

[0051] When it is mentioned that “in some embodiments…” a certain feature may be present, the 15 feature may be present in a suitable embodiment in any part of the specification, not just a suitable embodiment in the same section or textual region of the specification.

[0052] “About” may mean + / -0% (i.e. no variance around a value), + / - 10%, + / - 20%, or + / - 30% of a given value. In some embodiments “about” means + / -0% (i.e. no variance around a value). 20 Resorbable Glass in Wound Therapy

[0053] In one embodiment there is provided a resorbable glass for use in the topical treatment of wounds.

[0054] A “resorbable” glass refers to one which may be assimilated by the body, i.e. degraded in the physiological environment such that its by-products are eliminated or completely bioabsorbed. 25

[0055] “Topical treatment” of a wound means local treatment of a wound, for example by applying a material or compound to a wound (such as a skin wound) surface.

[0056] “Treatment” (and similar terms such as “treat” and “treating”) refer to at least partially alleviating, inhibiting and / or ameliorating a condition, such as a wound. In the context of wound healing it specifically refers to speeding up or otherwise improving wound healing. 201395-PCT01-NP

[0057] In some embodiments a wound may be a skin wound (i.e. a breaking, rupture or opening of the skin, such that the normal epidermal and / or dermal barrier layers are compromised, including skin ulcers).

[0058] In one embodiment there is provided the use of a resorbable glass in the manufacture of a 5 medicament for the topical treatment of wounds.

[0059] In one embodiment there is provided a method of topical treatment of wounds in a human or animal patient in need thereof, comprising administering to the patient a therapeutically effective amount of a resorbable glass.

[0060] A “therapeutically effective amount” refers to that amount of a compound or combination of 10 compounds that is sufficient to effect the intended application including, but not limited to, wound treatment. A therapeutically effective amount may vary depending upon the intended application (in- vitro or in-vivo), or the subject and disease condition being treated (e.g., the weight, age and gender of the subject), the severity of the disease condition, the manner of administration, and other factors which can readily be determined by one of ordinary skill in the art. The term also applies to a dose 15 that will induce a particular response in target cells (e.g. improved re-epithelisation). The specific dose needed to effect therapy will vary depending on the particular treatments chosen, the dosing regimen to be followed, whether the therapeutic materials are administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried. 20

[0061] In some embodiments treatment may be administered once weekly. Patient Selection

[0062] In some embodiments treatment may be of a diabetic patient.

[0063] In some embodiments treatment may be of a diabetic patient at elevated risk of a diabetic 25 foot injury (for example a foot ulcer).

[0064] “Elevated risk” may for example be diagnosed by a suitable medical professional.

[0065] In some embodiments treatment may be of a diabetic patient having wounds showing little or no healing (for example as judged by a suitable medical professional) four weeks after wound diagnosis. 201395-PCT01-NP

[0066] In some embodiments treatment may be of a patient 60 years old or over, optionally wherein the patient has been diagnosed as suffering dry skin, has a history of developing chronic wounds and / or has been identified as at risk of developing chronic wounds. 5 Resorbable Glass

[0067] In some embodiments a resorbable glass may comprise phosphate glass, silicate glass (for example a bioactive silicate glass such as bioglass, e.g. bioglass 45S5 [also known as 45S5 Bioglass®] or bioglass S53P4), borosilicate glass and / or borate glass.

[0068] Bioglass 45S5 has the following composition: SiO2 (46.1 mol%), P2O5 (2.6 mol%), CaO (26.9 10 mol%) and Na2O (24.4 mol%). Bioglass S53P4 has the following composition: SiO2 (53.8 mol%), P2O5 (1.7 mol%), CaO (21.8 mol%) and Na2O (22.7 mol%).

[0069] Examples of Bioglass 45S5 and Bioglass S53P4 suitable for use in the therapies and combinations disclosed herein are described in Towhidul Islam Md et. Al., J. Biomater. Appl. 2022, 36(8), 1427. 15

[0070] In some embodiments a resorbable glass may consist essentially of phosphate glass, silicate glass, borosilicate glass and / or borate glass.

[0071] In some embodiments a resorbable glass may be selected from phosphate glass, silicate glass, borosilicate glass and borate glass.

[0072] In some embodiments a resorbable glass may comprise phosphate glass. 20

[0073] In some embodiments a resorbable glass may consist essentially of phosphate glass.

[0074] In some embodiments a resorbable glass may comprise calcium phosphate glass.

[0075] In some embodiments a resorbable glass may consist essentially of calcium phosphate glass.

[0076] In some embodiments a resorbable glass may comprise at least about 20mol% P2O5. In some embodiments a resorbable glass may comprise at least about 30mol% P2O5. In some embodiments a 25 resorbable glass may comprise at least about 35mol% P2O5. In some embodiments a resorbable glass may comprise from about 20mol% to about 60mol% P2O5. In some embodiments a resorbable glass may comprise from about 30mol% to about 60mol% P2O5. In some embodiments a resorbable glass may comprise from about 35mol% to about 55mol% P2O5. In some embodiments a resorbable glass may comprise from about 35mol% to about 45mol% P2O5. 30

[0077] In some embodiments a resorbable glass may comprise from about 5mol% to about 40mol% CaO. In some embodiments a resorbable glass may comprise from about 10mol% to about 30mol% 201395-PCT01-NP CaO. In some embodiments a resorbable glass may comprise from about 10mol% to about 20mol% CaO.

[0078] In some embodiments a resorbable glass may further comprise MgO. In some embodiments a resorbable glass may comprise from about 10mol% to about 40mol% MgO. In some embodiments a 5 resorbable glass may comprise from about 20mol% to about 30mol% MgO.

[0079] In some embodiments a resorbable glass may further comprise Na2O. In some embodiments a resorbable glass may comprise from about 10mol% to about 30mol% Na2O.In some embodiments a resorbable glass may comprise from about 15mol% to about 25mol% Na2O.

[0080] In some embodiments further oxides may be present in the resorbable glass, for example, in 10 order to provide beneficial properties. For example, in some embodiments, a resorbable glass may comprise CuO. This may lead to increased angiogenesis in the wound.

[0081] In some embodiments a resorbable glass may have the formulation 40P2O5.16CaO.24MgO.20Na2O (in mol%).

[0082] In some embodiments a resorbable glass may be selected from glass codes P40, P55, P52.5 15 and P52.5-Cu of Table 1.

[0083] In some embodiments a resorbable glass may be glass code P40 of Table 1.

[0084] In some embodiments a resorbable glass may comprise microspheres (i.e. beads) of resorbable glass. Microspheres need be only generally spherical in shape rather than completely symmetrical. 20

[0085] In some embodiments a resorbable glass may consist essentially of microspheres of resorbable glass.

[0086] In some embodiments microspheres may have a diameter between about 20μm and about 250μm.

[0087] In some embodiments microspheres may have a diameter between about 45μm and about 25 250μm.

[0088] In some embodiments microspheres may have a diameter between about 50μm and about 200μm.

[0089] In some embodiments microspheres may have a diameter between about 50μm and about 150μm. 30

[0090] In some embodiments microspheres may have a diameter between about 125μm and about 200μm. 201395-PCT01-NP

[0091] In some embodiments microspheres may have a diameter between about 125μm and about 150μm.

[0092] In some embodiments microspheres may have a diameter of about 25μm, 50μm, 100μm, 150μm or 200μm. 5

[0093] In some embodiments the resorbable glass may comprise microspheres with differing diameter ranges, for example, if it is desirable to achieve higher packing density.

[0094] In some embodiments microspheres may be non-porous.

[0095] In some embodiments microspheres may be porous (i.e. may comprise voids or empty spaces or regions). Porous microspheres may comprise internal and / or surface pores. 10

[0096] In some embodiments microspheres may comprise internal pores.

[0097] In some embodiments microspheres may comprise surface pores.

[0098] In some embodiments microspheres may comprise surface pores with a diameter between about 10μm and about 100μm.

[0099] In some embodiments microspheres may comprise surface pores with a diameter between 15 about 40μm and about 70μm.

[0100] In some embodiments microspheres may comprise surface pores with a diameter between about 47μm and about 63μm.

[0101] In some embodiments microspheres may comprise surface pores with a mean diameter between about 0.1μm and about 100μm. 20

[0102] In some embodiments microspheres may comprise surface pores with a mean diameter between about 45μm and about 60μm.

[0103] In some embodiments microspheres may comprise surface pores with a mean diameter of about 55μm.

[0104] In some embodiments microspheres may comprise surface pores with a mean diameter 25 between about 1μm and about 5μm.

[0105] In some embodiments microspheres may comprise surface pores with a mean diameter of about 2.8μm.

[0106] In some embodiments microspheres may comprise surface pores with a median diameter of about 1.9μm. 201395-PCT01-NP

[0107] In some embodiments microspheres may have a porosity of at least 40%, at least 50%, at least 60%, at least 70% at least 75% or at least 80%. Porosity refers to the amount of void space within a given body.

[0108] In some embodiments microspheres may have a porosity of at least 60%. 5

[0109] In some embodiments microspheres may have a porosity between about 65% and about 85%.

[0110] In some embodiments microspheres may have a porosity of about 76%.

[0111] In some embodiments microspheres may have a mean porosity between about 60% and about 90%.

[0112] In some embodiments microspheres may have a mean porosity between about 70% and 10 about 80%.

[0113] In some embodiments microspheres may have a mean porosity of about 76%.

[0114] In some embodiments microspheres may have an apparent density between about 2g / cm3and about 3g / cm3, optionally between about 2.3g / cm3and about 2.8g / cm3(for example as measured using Helium Pycnometry). 15

[0115] In some embodiments microspheres may have an apparent density between about 2.4g / cm3and about 2.8g / cm3(for example as measured using Helium Pycnometry).

[0116] In some embodiments, microspheres may have a density between about 2.518g / cm3and about 2.522g / cm3(for example as measured using Helium Pycnometry).

[0117] In some embodiments microspheres may have an apparent density of about 2.52 g / cm3(for 20 example as measured using Helium Pycnometry).

[0118] In some embodiments microspheres may have a tap density between about 0.5g / cm3and about 2g / cm3.

[0119] In some embodiments microspheres may have a tap density between about 0.5g / cm3and about 0.7g / cm3. 25

[0120] In some embodiments microspheres may have a tap density between about 0.57g / cm3and about 0.61g / cm3.

[0121] In some embodiments microspheres may have a tap density of about 0.59g / cm3.

[0122] In some embodiments microspheres may have a surface area per unit mass between about 0.1m2 / g and about 2m2 / g. 30

[0123] In some embodiments microspheres may have a surface area per unit mass between about 0.3m2 / g and about 1m2 / g. 201395-PCT01-NP

[0124] In some embodiments microspheres may have a surface area per unit mass between about 0.3m2 / g and about 0.9m2 / g.

[0125] In some embodiments microspheres may have a surface area per unit mass between about 0.34m2 / g and about 0.90m2 / g. 5

[0126] In some embodiments microspheres may have a surface area per unit mass of about 0.4m2 / g.

[0127] In some embodiments microspheres may have a surface area per unit mass of about 0.4187m2 / g.

[0128] In some embodiments the resorbable glass comprises microspheres: - having a diameter between about 45μm and about 250μm; 10 - comprising surface pores with a diameter between about 0.1μm and about 100μm; - having a porosity of at least 70%; - having an apparent density between about 2.3g / cm3and about 2.8g / cm3as measured by Helium Pycnometry; and - having a surface area per unit mass between about 0.1m2 / g and about 2m2 / g. 15 Therapeutic Combinations

[0129] In one embodiment there is provided a resorbable glass for use in the topical treatment of wounds, where the resorbable glass is administered in combination with an 11β-HSD1 inhibitor. The treatment and the resorbable glass may be as described in any of the embodiments herein. 20

[0130] An “11β-HSD1 inhibitor” is any compound that can reduce or attenuate the activity of the 11β- hydroxysteroid dehydrogenase type I enzyme, for example in converting cortisone to cortisol.

[0131] When a component is “administered in combination” with another component, the combination may comprise the sequential or simultaneous administration of the components. Where treatment is sequential, the interval between the doses of the two components may be chosen to 25 ensure the production of a combined therapeutic effect.

[0132] In some embodiments the combination of resorbable glass and an 11β-HSD1 inhibitor is administered sequentially or simultaneously.

[0133] In some embodiments the combination of a resorbable glass and an 11β-HSD1 inhibitor is administered sequentially. 30

[0134] In some embodiments the combination of a resorbable glass and an 11β-HSD1 inhibitor is administered simultaneously. 201395-PCT01-NP

[0135] In one embodiment there is provided the use of a resorbable glass in the manufacture of a medicament for the topical treatment of wounds, where the resorbable glass is administered in combination with an 11β-HSD1 inhibitor.

[0136] In one embodiment there is provided a method of topical treatment of wounds in a human or 5 animal patient in need thereof, comprising administering to the patient a therapeutically effective amount of a combination of a resorbable glass and an 11β-HSD1 inhibitor.

[0137] In one embodiment there is provided a method of topical treatment of wounds in a human or animal patient in need thereof, comprising administering to the patient a resorbable glass in a first amount and an 11β-HSD1 inhibitor in a second amount, where the first amount and second amount 10 together comprise a therapeutically effective amount.

[0138] In some embodiments the 11β-HSD1 inhibitor may be administered orally or parenterally.

[0139] In some embodiments the 11β-HSD1 inhibitor may be administered orally.

[0140] In some embodiments the 11β-HSD1 inhibitor may be administered parenterally.

[0141] In some embodiments the 11β-HSD1 inhibitor may be administered topically (for example as 15 a salve, cream, ointment, gel or paste, such as any of the formulations prepared and used in the experimental section).

[0142] In some embodiments both the resorbable glass and the 11β-HSD1 inhibitor may be administered topically. 20 11β-HSD1 inhibitors

[0143] In some embodiments an 11β-HSD1 inhibitor may be a selective inhibitor. A selective 11β- HSD1 inhibitor may be at least 10-fold, at least 100-fold, or at least 1000-fold more potent at inhibiting a target than at least one other metabolic enzyme (for example 1, 10 or 100 other metabolic enzymes, such as 11beta HSD2). 25

[0144] In some embodiments an 11β-HSD1 inhibitor may be selected from a compound listed in Table A, or a pharmaceutically acceptable salt thereof. 201395-PCT01-NP Table A 201395-PCT01-NP 201395-PCT01-NP 201395-PCT01-NP 201395-PCT01-NP 201395-PCT01-NP 201395-PCT01-NP 201395-PCT01-NP

[0145] The compounds of Table A may be found in Almeida, C. et al., Sci. Pharm. 2021, 89, 5 and references therein, Kupczyk et al., J. Clin. Med.2022, 11, 6190 and references therein, Scott et al., J. Med. Chem., 2014, 57, 4466-4486 and references therein, and Leiva et al., Bioorg. Med. Chem. Lett.,5 2015, 25, 4250-4253 and references therein, Na, Yoon-Ju et al., Int. J. Mol. Sci.2020, 21(10), 3729 (KR- 67606), Gillespie, P. et al., Biorg. Med. Chem. Lett.2014, 24(12), 2707, Hu, Guo-Xin et al., PLOS One 2013, 8(3): e49976, Suda, H. et al., ABS MEDI-82 “Identification of urea derivatives as novel and 201395-PCT01-NP selective 11beta-HSD1 inhibitors”, American Chemical Society National Meeting and Exposition March 16, 2014 (DSP-0011), Udagawa S. et al., Biorg. Med. Chem. Lett.2013, 23(6), 1617 (HIS601), Ye, Xiang- Yang et al., Bioorg. Med. Chem. Lett.2014, 24(2), 654-60 (BMS-816336), WO2011 / 135276 (UE-2343), Yoon et al., Biorg. Med. Chem. Lett. 2014, 24(21), 5045-5049 (compound 8h), Ning, Ruo-Nan et al., 5 Biorg. Med. Chem. Lett.2014, 24, 5395-5398 (lithocarpic acid O), Lee, YounHo et al., Biorg. Med. Chem. Lett.2014, 24, 1421 (Compound 8j), WO2020 / 106337 (ASP-3662), Ye, Xiang-Yang et al., Bioorg. Med. Chem. Lett. 2022, 73, 128884 (INCB-019808), Bohme et al., Bioorg. Med. Chem. Lett. 2013, 23(16), 4685 (SR184841), Sun, Daqing et al., Bioorg. Med. Chem. Lett.2011, 21(1), 405, Goldberg et al, J. Med. Chem.2014, 57, 970-986. In some embodiments, an 11β-HSD1 inhibitor may be selected from any of 10 the 11β-HSD1 inhibitors described in the preceding references (or references therein).

[0146] In some embodiments, an 11β-HSD1 inhibitor may be selected from any of the 11β-HSD1 inhibitors described in Almeida, C. et al., Sci. Pharm.2021, 89, 5, Kupczyk et al., J. Clin. Med.2022, 11, 6190, Scott et al., J. Med. Chem., 2014, 57, 4466-4486, and Leiva et al., Bioorg. Med. Chem. Lett., 2015, 25, 4250-4253. 15

[0147] In some embodiments an 11β-HSD1 inhibitor may be selected from BI 187004 (CAS No. 1303515-32-3) or a pharmaceutically acceptable salt thereof, BI 135585 (CAS No.1114561-85-1) or a pharmaceutically acceptable salt thereof, RO5093151 (RO-151) or a pharmaceutically acceptable salt thereof, ABT-384 or a pharmaceutically acceptable salt thereof, MK-0916 (CAS No.633317-53-0) or a pharmaceutically acceptable salt thereof and (S)-2-(1-(5-(cyclohexylcarbamoyl)-6- 20 (propylthio)pyridin-2-yl)piperidin-3-yl)acetic acid or a pharmaceutically acceptable salt thereof.

[0148] In some embodiments an 11β-HSD1 inhibitor may be (S)-2-(1-(5-(cyclohexylcarbamoyl)-6- (propylthio)pyridin-2-yl)piperidin-3-yl)acetic acid or a pharmaceutically acceptable salt thereof.

[0149] In some embodiments an 11β-HSD1 inhibitor may be (S)-2-(1-(5-(cyclohexylcarbamoyl)-6- (propylthio)pyridin-2-yl)piperidin-3-yl)acetic acid in a salt-free form (for example in a neutral or 25 zwitterionic form).

[0150] In some embodiments an 11β-HSD1 inhibitor may be a pharmaceutically acceptable salt of (S)-2-(1-(5-(cyclohexylcarbamoyl)-6-(propylthio)pyridin-2-yl)piperidin-3-yl)acetic acid.

[0151] The term "pharmaceutically acceptable" is used to specify that an object (for example a salt, dosage form or excipient) is suitable for use in patients. An example list of pharmaceutically acceptable 30 salts can be found in the “Handbook of Pharmaceutical Salts: Properties, Selection and Use”, P. H. Stahl and C. G. Wermuth, editors, Weinheim / Zurich:Wiley-VCH / VFiCA, 2002 or subsequent editions. 201395-PCT01-NP

[0152] A suitable pharmaceutically acceptable salt of (S)-2-(1-(5-(cyclohexylcarbamoyl)-6- (propylthio)pyridin-2-yl)piperidin-3-yl)acetic acid is, for example, an acid-addition salt. An acid addition salt of (S)-2-(1-(5-(cyclohexylcarbamoyl)-6-(propylthio)pyridin-2-yl)piperidin-3-yl)acetic acid may be formed by bringing the compound into contact with a suitable inorganic or organic acid 5 under conditions known to the skilled person.

[0153] A suitable pharmaceutically-acceptable salt of (S)-2-(1-(5-(cyclohexylcarbamoyl)-6- (propylthio)pyridin-2-yl)piperidin-3-yl)acetic acid is, for example, an acid-addition salt with hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid.

[0154] A further suitable pharmaceutically acceptable salt of (S)-2-(1-(5-(cyclohexylcarbamoyl)-6- 10 (propylthio)pyridin-2-yl)piperidin-3-yl)acetic acid is, for example, a base-addition salt. An base addition salt of (S)-2-(1-(5-(cyclohexylcarbamoyl)-6-(propylthio)pyridin-2-yl)piperidin-3-yl)acetic acid may be formed by bringing the compound into contact with a suitable inorganic or organic base under conditions known to the skilled person.

[0155] A suitable pharmaceutically-acceptable salt of (S)-2-(1-(5-(cyclohexylcarbamoyl)-6- 15 (propylthio)pyridin-2-yl)piperidin-3-yl)acetic acid is, for example a salt with methylamine, dimethylamine, trimethylamine, tert-butylamine, piperidine, morpholine or tris-(2- hydroxyethyl)amine.

[0156] A further suitable pharmaceutically acceptable salt of (S)-2-(1-(5-(cyclohexylcarbamoyl)-6- (propylthio)pyridin-2-yl)piperidin-3-yl)acetic acid is, for example, a salt formed within the human or20 animal body after administration of (S)-2-(1-(5-(cyclohexylcarbamoyl)-6-(propylthio)pyridin-2- yl)piperidin-3-yl)acetic acid to said human or animal body. Pharmaceutical Compositions

[0157] In one embodiment there is provided a pharmaceutical composition comprising a resorbable 25 glass and a pharmaceutically acceptable excipient. The resorbable glass may be as described in any of the embodiments herein.

[0158] In one embodiment there is provided a pharmaceutical composition comprising a resorbable glass and an 11β-HSD1 inhibitor. The resorbable glass and the 11β-HSD1 inhibitor may be as described in any of the embodiments herein. 201395-PCT01-NP

[0159] In one embodiment there is provided a pharmaceutical composition comprising a resorbable glass, an 11β-HSD1 inhibitor, and a pharmaceutically acceptable excipient. The resorbable glass and the 11β-HSD1 inhibitor may be as described in any of the embodiments herein.

[0160] In one embodiment there is provided a pharmaceutical composition comprising a resorbable 5 glass and a pharmaceutically acceptable excipient for use in the topical treatment of wounds. The treatment and the resorbable glass may be as described in any of the embodiments herein.

[0161] In one embodiment there is provided a pharmaceutical composition comprising a resorbable glass and an 11β-HSD1 inhibitor for use in the topical treatment of wounds. The treatment, the resorbable glass and the 11β-HSD1 inhibitor may be as described in any of the embodiments herein. 10

[0162] In one embodiment there is provided a pharmaceutical composition comprising a resorbable glass, an 11β-HSD1 inhibitor and a pharmaceutically acceptable excipient for use in the topical treatment of wounds. The treatment, the resorbable glass and the 11β-HSD1 inhibitor may be as described in any of the embodiments herein. 15 Kits

[0163] In one embodiment there is provided a kit comprising: - A resorbable glass in a first dosage form; - An 11β-HSD1 inhibitor in a second dosage form; and optionally - Instructions for use. 20 The resorbable glass and the 11β-HSD1 inhibitor may be as described in any of the embodiments herein. Combined Embodiments

[0164] In one embodiment there is provided a resorbable glass for use in the treatment of wounds, 25 where treatment is of a diabetic patient, and the resorbable glass comprises microspheres of calcium phosphate glass: - having a diameter between about 45μm and about 250μm; - comprising surface pores with a diameter between about 0.1μm and about 100μm; - with a porosity of at least 70%; 30 - having an apparent density between about 2.4g / cm3and about 2.8g / cm3as measured by Helium Pycnometry; and 201395-PCT01-NP - with a surface area per unit mass between about 0.1m2 / g and about 2m2 / g.

[0165] In one embodiment there is provided a resorbable glass for use in the treatment of wounds, where treatment is of a diabetic patient, the resorbable glass comprises microspheres of calcium phosphate glass: 5 - having a diameter between about 125μm and about 200μm; - comprising surface pores with a mean diameter of about 55μm; - with a porosity of about 76%; - having an apparent density of about 2.52g / cm3as measured by Helium Pycnometry; and - with a surface area per unit mass of about 0.4m2 / g; 10 and where the resorbable glass is administered in combination with (S)-2-(1-(5- (cyclohexylcarbamoyl)-6-(propylthio)pyridin-2-yl)piperidin-3-yl)acetic acid or a pharmaceutically acceptable salt thereof.

[0166] In one embodiment there is provided the use of a resorbable glass in the manufacture of a medicament for the topical treatment of wounds, where treatment is of a diabetic patient, the 15 resorbable glass comprises microspheres of calcium phosphate glass: - having a diameter between about 45μm and about 250μm; - comprising surface pores with a diameter between about 0.1μm and about 100μm; - with a porosity of at least 70%; - having an apparent density between about 2.4 / cm3and about 2.8g / cm3as measured by 20 Helium Pycnometry; and - with a surface area per unit mass between about 0.1m2 / g and about 2m2 / g; and where the resorbable glass is administered in combination with an 11β-HSD1 inhibitor.

[0167] In one embodiment there is provided the use of a resorbable glass in the manufacture of a medicament for the topical treatment of wounds, where treatment is of a diabetic patient, the 25 resorbable glass comprises microspheres of calcium phosphate glass: - having a diameter between about 125μm and about 200μm; - comprising surface pores with a mean diameter of about 55μm; - with a porosity of about 76%; - having an apparent density of about 2.52g / cm3as measured by Helium Pycnometry; and 30 - with a surface area per unit mass of about 0.4m2 / g; 201395-PCT01-NP and where the resorbable glass is administered in combination with (S)-2-(1-(5- (cyclohexylcarbamoyl)-6-(propylthio)pyridin-2-yl)piperidin-3-yl)acetic acid or a pharmaceutically acceptable salt thereof.

[0168] In one embodiment there is provided a method of topical treatment of wounds in a human or 5 animal patient in need thereof, comprising administering to the patient a therapeutically effective amount of a resorbable glass, where treatment is of a diabetic patient, the resorbable glass comprises microspheres of calcium phosphate glass: - having a diameter between about 45μm and about 250μm; - comprising surface pores with a diameter between about 0.1μm and about 100μm; 10 - with a porosity of at least 70%; - having an apparent density between about 2.4g / cm3and about 2.8g / cm3as measured by Helium Pycnometry; and - with a surface area per unit mass between about 0.1m2 / g and about 2m2 / g; and where the resorbable glass is administered in combination with an 11β-HSD1 inhibitor. 15

[0169] In one embodiment there is provided a method of topical treatment of wounds in a human or animal patient in need thereof, comprising administering to the patient a therapeutically effective amount of a resorbable glass, where treatment is of a diabetic patient, the resorbable glass comprises microspheres of calcium phosphate glass: - having a diameter between about 125μm and about 200μm; 20 - comprising surface pores with a mean diameter of about 55μm; - with a porosity of about 76%; - having an apparent density of about 2.52 / cm3as measured by Helium Pycnometry; and - with a surface area per unit mass of about 0.4m2 / g; and where the resorbable glass is administered in combination with (S)-2-(1-(5- 25 (cyclohexylcarbamoyl)-6-(propylthio)pyridin-2-yl)piperidin-3-yl)acetic acid or a pharmaceutically acceptable salt thereof. EXAMPLES The following examples relate to the preparation of resorbable glass beads and 11β-HSD1 inhibitors, 30 and their use in a diabetic mouse wound model. 201395-PCT01-NP Example 1 - Resorbable Glass Beads

[0170] Resorbable glass in the form of bead microspheres was prepared according to the methods described in Hossain et al., Acta Biomaterialia 2018, 72, 396-406 (see for example section 2.1).

[0171] Phosphate based glass (PBG) production. Phosphate glasses are prepared using the following 5 precursors; sodium dihydrogen phosphate (NaH2PO4), calcium hydrogen phosphate (CaHPO4), calcium carbonate (CaCO3) and magnesium hydrogen phosphate trihydrate (MgHPO4·3H2O, Sigma Aldrich, UK). The above precursors are weighed according to the composition and mixed thoroughly before being heated in a platinum crucible at 350°C for 30 minutes. This initial heating phase is performed to dehydrate the samples and remove CO2 which is then followed by melting at 1150°C at a heating rate 10 of 10°C / min and held at this temperature for 90 minutes. The molten glass is then quenched between two stainless steel plates at room temperature or on plates that may have been kept in a fridge at - 20°C for 4 hours prior to casting (which is composition dependant to prevent surface crystallisation). Once the glass had cooled it is broken up and then ground into particles using a Retsch PM100 milling machine and the ground glass samples are sieved to obtain particles in the range of 63-125µm. 15

[0172] Manufacturing solid (dense) and porous PBG microspheres. Microspheres are produced using a flame spheroidisation process utilising a thermal spray gun (MK74, Metallisation Ltd, B’ham, UK). For solid microspheres, ground glass particles (usually in a size range between 63-125 µm) are fed into an oxy-acetylene flame at a gas ratio of 3:3. Calcium carbonate (CaCO3) is used as the porogen to manufacture porous PBG microspheres (NB: other carbonate based porogens can also be used). 20 CaCO3is mixed homogenously with the ground glass particles using a bench top vortex mixer in a 1:3 ratio. The mixed glass and porogen particles are then fed into the flame and collected post exiting the flame as porous microspheres. These microspheres are then submerged in 5M acetic acid for 2 minutes (to remove any potential porogen remnants) and then further washed in deionised water for 5 minutes. The solution is then filtered using a funnel and filter paper and dried overnight at 50 °C. 25

[0173] Example beads prepared from the given compositions using these procedures include those shown in Table 1. Table 1: Example Beads 201395-PCT01-NP

[0174] Bead Characterisation. The beads (for example P40 beads) were characterised according to methods for example as described in Acta Biomaterialia 2018, 72, 396-406 (see for example section 2.2 therein). P40 beads prepared according to the porous microsphere method were found to have 5 the following properties: - Particle diameter: sieving obtained particles with a particle diameter ranging from 125µm to 200µm - Porosity: 71-81% - Mean porosity: 76% 10 - Surface pore diameter: 47µm to 63µm - Mean surface pore diameter: 55µm - Density: The apparent density of the glass microspheres was determined using a Micromeritics AccuPyc 1330 helium pycnometer (Norcross, GA, USA). The equipment was calibrated using a standard calibration ball (3.18551 cm3) with errors of ±0.03%. Glass 15 microspheres with an average weight of approximately 1g were used for the density measurements, and the process was repeated three times. Tap density of the glass microspheres were measured using a 10 mL graduated cylinder. The microspheres were placed into the cylinder and then tapped 15 times at 2 second intervals. The tap density was then obtained by dividing the weight of the sample in grams by the final 20 tapped volume in cm3of the sample contained in the cylinder. The process was repeated 10 times and an average tap density was calculated using the equation: where M is weight in grams and Vp is final tapped volume in cm3. Table 2 below shows the apparent density (measured by He pycnometer) and tap density of 25 P40 porous beads. Table 2: Density Properties of P40 Beads Glass Code 28 201395-PCT01-NP - Surface area: 0.4187 m2 / g Example 2 - 11β-HSD1 Inhibitors 5

[0175] Compound (I) [(S)-2-(1-(5-(cyclohexylcarbamoyl)-6-(propylthio)pyridin-2-yl)piperidin-3- yl)acetic acid] was synthesised according to the methods disclosed in WO 2008 / 053194. Compound (I) is a potent human 11β-HSD1 inhibitor shown to be effective in wound healing (see J. Med. Chem., 2012, 55, 5951-5964; WO2021 / 094390). However, Compound (I) is much less potent against murine 11β-HSD1, so was not suitable to be used in the mouse wound model of Example 3. Instead, an 11β- 10 HSD1 inhibitor that was developed to explore preclinical efficacy of 11β-HSD1 inhibitors in rodent models (J. Med. Chem.2014, 57, 970-986) was used in the mice wound healing experiments: Compound (II).

[0176] Compound (II) [N-(trans-5-hydroxy-2-adamantyl)-4-[(2R)-tetrahydrofuran-2-yl]-2- 15 tetrahydropyran-4-yloxythiazole-5-carboxamide] was synthesised according to the methods disclosed in J. Med. Chem. 2014, 57, 970-986. The potency of Compound (II) against 11β-HSD1 (human and murine) is similar to that of Compound (I) against human 11β-HSD1.

[0177] For the wound healing experiments in mice, Compound (II) was formulated in two different vehicles (1% DMSO-saline and 30% w / v Kleptose® HPB [hydroxypropyl β-cyclodextrin; CAS 128446- 20 35-5]), suitable for a dosing of 10µg of Compound (II) per wound in 100µL vehicle (note that in the Figures compound (II) is labelled “AZT”).

[0178] Kleptose formulation: 300 mg Kleptose HPB was made up to 0.8mL volume using MilliQ water and stirred until a clear solution was obtained. The volume was then made up to 1mL. Up to 0.5 mg / mL Compound (II) was weighed into an appropriate vial before addition of the Kleptose vehicle up to 201395-PCT01-NP 90% of the final volume and the compound dissolved with sonication, before being made up to final volume with the vehicle.

[0179] DMSO-saline formulation: 1mg Compound (II) was dissolved in 0.1mL DMSO and the volume made up to 10 mL in phosphate buffered saline (PBS). 5 Example 3 - Diabetic Mouse Wound Model

[0180] Animal Husbandry: 36 diabetic mice (BKS.Cg-m Dock7m + / + Leprdb / J, The Jackson Laboratory, USA), all male and aged 9 weeks were used. Mice were housed in groups of 2 animals 10 according to Home Office regulations and the specific requirements of diabetic animals. After experimental wounding, animals were housed in individual cages (cage dimensions 500 cm2with sawdust bedding, changed three times per week), in an environment maintained at an ambient temperature of 23°C with 12-hour light / dark cycles. They were provided with food (Standard Rodent Diet) and water ad libitum. To acclimatise the animals to their surroundings, prior to experimentation, 15 they were housed for a period of 5 - 7 days without disturbance, other than to refresh their bedding and to replenish their food and water provisions. Following all anaesthetic events, animals were placed in a warm environment and monitored until fully recovered from the procedure.

[0181] All animals received appropriate analgesia (Vetergesic® [buprenorphine]) after surgery and additional analgesics as required. Animals also received prophylactic antibiotics (in the form of20 enrofloxacin [Baytril®] subcutaneous) on the day of wounding and subsequently on every 4thpost- operative day (with the exception of day 4 where no dressing removal was planned).

[0182] All animal procedures were carried out in a UK Home Office licensed establishment under UK Home Office Licences ((PCD: 50 / 2505; PPL:P81E9540D; PIL: IBCEFDF55; PIL: I34817249). The health status of animals was be monitored on a daily basis throughout the study (change in body weight was 25 monitored every fourth day post-wounding).

[0183] Creation of full-thickness experimental wounds & topical treatment: Animals were randomized to one of 5 treatment regimens using appropriate software. On day 0, animals were anaesthetised (isofluorane & air) and the dorsum was shaved and cleaned with Chlorhexidine gluconate 0.5% w / v in 70% IMS (VetaSept®). Wound sites were swabbed with 70% IMS, and a single 30 standardised full-thickness wound (10.0mm x 10.0mm) was created in the left dorsal flank skin of each 201395-PCT01-NP experimental animal. Wounds were then digitally photographed (together with a calibration / identity plate).

[0184] The materials under test were then applied directly to the surface of wounds according to Table 3. Phosphate glass beads used corresponded to glass code P40 in Table 1. 5 Table 3 - Treatment Groups

[0185] For animals in groups 1 and 2 phosphate glass beads (65mg) were applied to the surface of all wounds. Tegaderm® Film dressing (3M Deutschland GmbH, Germany) was then applied over the 10 wounds.100µL of either: i) drug in 1% DMSO-saline vehicle (Group 1), or ii) 1% DMSO-saline vehicle alone (group 2), was then injected through the film dressing (using a 30G hypodermic needle) onto the phosphate glass beads. 201395-PCT01-NP

[0186] Animals in groups 3, 4 and 5 were dressed with Tegaderm® Film, after which they received 100µL of either i) 1% DMSO-saline (group 3), ii) drug in 30% kleptose vehicle (group 4), or iii) 30% kleptose vehicle alone (group 5), by injection through the film dressing (using a 30G hypodermic needle). Animals were then allowed to recover in a warm environment. 5

[0187] At various time points after treatment (2, 6, 24 hours, 8- and 20-days), two animals from group 1 were re-anaesthetised their film dressings were removed and wounds were cleaned, assessed and digitally photographed, after which the animals were terminated. A terminal blood sample was taken by cardiac puncture and wound and marginal tissue was harvested and processed for: i) PK analysis and ii) to facilitate histological investigation. Where possible, animals received BrdU by i.p. injection 10 one hour prior to harvesting to facilitate IHC determination of cellular proliferation.

[0188] On post-wounding days 4, 8, 12 & 16 all remaining animals were re-anaesthetised and their dressings and any free wound surface debris was removed. Their wound margins were then gently cleaned using saline- soaked sterile gauze and any free debris removed from the wound surface (taking care not to disturb the bead system) before being mopped dry with sterile gauze. Wounds were 15 assessed and digitally photographed (together with a calibration / identity plate). Tegaderm® Film dressings were re-applied and the animals were allowed to recover under warmed conditions.

[0189] On post-wounding day 20, all remaining animals were re-anaesthetised the film dressing was removed and wounds were cleaned, assessed and digitally photographed. Animals were then terminated and wound and marginal tissue was harvested and processed to facilitate histological 20 investigation. As noted above, terminal blood samples and wound / marginal tissue was taken from remaining animals in group 1 for PK analysis. One hour prior to harvesting all animals received BrdU by i.p. injection (to facilitate IHC determination of cellular proliferation).

[0190] Criteria for assessment of initiation of neo-dermal response: All wounds were assessed in terms of ‘initiation of neo-dermal tissue formation’ on a daily basis until day 8 and on alternate days 25 thereafter. Neo-dermal tissue formation was considered to have initiated when blood vessels within the fascia of the wound base were concealed by overlying “material”. This concealment may have resulted from the formation of cloudy exudate, polymerised / semi-polymerised fibrin or granulation tissue. Invariably, the first sign of neo-dermal tissue initiation is the formation of a reddish exudate within the wound void. Figure 1 shows three wounds with different initiation characteristics. 30

[0191] Image analysis of wound closure (contraction & re-epithelialisation): Image Pro Plus image analysis software (version 4.1.0.0, Media Cybernetics, USA) was used to calculate wound closure from 201395-PCT01-NP wound images in each of the experimental groups over time. For each wound at each time point - open wound area was measured and expressed in terms of % wound area relative to day 0. As the process of wound closure results from the combined effects of wound contraction (the inward movement of marginal tissue) and re-epithelialisation (wound resurfacing by the inward migration of epithelial 5 cells), wound closure over time was also considered with respect to these components (Figure 2).

[0192] Harvesting & processing of wound tissues for histology: On the day of harvesting animals were painlessly killed by a UK Home Office compliant method. Wounds and surrounding normal tissue were excised and fixed in 10% buffered formalin (Sigma, UK) for possible future histological assessment. One hour prior to termination all animals received an i.p. injection (30µg / g) of 5- bromo- 10 2′-deoxyuridine (Sigma B5002) for possible assessment of cellular proliferation. Excised tissue was sandwiched between two pieces of foam prior to being placed in fixative, to reduce the extent of tissue curling. Fixed specimens were trimmed and bisected in a cranio-caudal direction, generating two half wounds per site. The dorsal half was processed and embedded in paraffin wax. Specimens that are too small to bisect were embedded whole. Specimens were orientated in such a fashion as to 15 ensure that appropriate transverse sections of the wound could be taken.

[0193] Histological Evaluations: Wax embedded wounds were sectioned (6μm) and stained with Haematoxylin & Eosin and stained sections were digitally scanned. The scans of Haematoxylin & Eosin and stained sections were used to assess the tissue response to the presence of the treatments and to quantify the impact of treatment on granulation tissue formation and re-epithelialisation (at the 20 histological level) as described below.

[0194] Measurement of granulation tissue deposition (in terms of granulation tissue depth): Granulation tissue deposition was measured in terms of granulation tissue depth using H&E stained sections (see measure ‘d’ in Figure 3). GTD was measured at 9 different sites across the width of each wound using NPD.View2 image analysis software (Hamamatsu). These measurements were then 25 averaged to give a single granulation tissue depth measurement for each wound under study.

[0195] Measurement of wound re-epithelialisation: The extent of re-epithelialisation from the left and right margins of each wound was measured from H&E stained sections using NPD.View2 image analysis software (Hamamatsu). Wound re-epithelialisation is expressed as the percentage of the total wound surface epithelialized (Figure 3). 30

[0196] Statistical analysis: Fisher’s Exact test (for proportionate data) was used to analyse the impact of treatment on initiation of neo- dermal tissue repair activity. Non-parametric analysis (Kruskall Wallis 201395-PCT01-NP multi-group analysis followed by ad hoc two sample Mann Whitney U-test) was used to test the significance of any inter-group differences in wound closure and its components contraction and re- epithelialisation and in each of the histological parameters. All data was additionally investigated for normality, and where found to be normally distributed was additionally analysed using appropriate 5 multi-group and two sample parametric analysis techniques.

[0197] Results - resorbable glass bead monotherapy: Figure 5 shows that when bead monotherapy is applied, healing is improved at the same timepoint compared to the control group 4, treated with DMSO / saline vehicle alone. Figures 6 to 8 show wound recovery over time as measured by remaining wound area, wound contraction, and re-epithelisation for wounds treated with resorbable glass alone. 10 The plots all show that topical treatment with the resorbable beads promotes overall wound closure (and its components) compared to vehicle. Figures 9 and 10 also show that bead monotherapy improves wound re-epithelisation and granulation tissue formation over time compared to the control. Figure 11 shows an example histology slide from the bead monotherapy group, qualitatively highlighting that aspects of wound-healing are present. 15

[0198] Results - compound (II) monotherapy: Figure 13 shows that when compound monotherapy is topically applied, healing is slightly improved at the same timepoint compared to the control group (Figure 12). Quantitative data shown in Figures 14-16 confirm that compound (II) appears to have a supplemental effect on wound healing when delivered in kleptose.

[0199] Results - resorbable glass bead / compound (II) combination therapy: Figure 17 shows that 20 when a combination of resorbable glass beads and compound (II) is applied, healing is visually very significantly improved at the same timepoint compared to the control group (Figure 12), with clear wound re-epithelisation and granulation visible. Quantitative data shown in Figures 18-20 also show that compound (II) enhances the wound healing effects of the resorbable glass beads significantly. Overall data suggests that the inhibitor and beads appear to work synergistically. 25 Specific Embodiments a. A resorbable glass for use in the topical treatment of wounds. b. Use of a resorbable glass in the manufacture of a medicament for the topical treatment of 30 wounds. 201395-PCT01-NP c. A method of topical treatment of wounds in a human or animal patient in need thereof, comprising administering to the patient a therapeutically effective amount of a resorbable glass. d. The resorbable glass for use, the use or the method as described in any of the preceding 5 specific embodiments where the resorbable glass comprises phosphate glass, silicate glass, borosilicate glass and / or borate glass. e. The resorbable glass for use, the use or the method as described in specific embodiment d, where the resorbable glass comprises phosphate glass. f. The resorbable glass for use, the use or the method as described in specific embodiment e, 10 where the phosphate glass comprises calcium phosphate glass. f1. The resorbable glass for use, the use or the method as described in specific embodiment e or f, where the resorbable glass comprises at least about 20mol% P2O5; optionally at least about 30mol% P2O5; optionally at least about 35mol% P2O5. f2. The resorbable glass for use, the use or the method as described in specific embodiment e or 15 f, where the resorbable glass comprises from about 20mol% to about 60mol% P2O5; optionally from about 30mol% to about 60mol% P2O5; optionally from about 35mol% to about 55mol% P2O5; optionally from about 35mol% to about 45mol% P2O5. f3. The resorbable glass for use, the use or the method as described in any of specific embodiments e to f2, where the resorbable glass comprises from about 5mol% to about 20 40mol% CaO; optionally from about 10mol% to about 30mol% CaO; optionally from about 10mol% to about 20mol% CaO. f4. The resorbable glass for use, the use or the method as described in any of specific embodiments e to f3, where the resorbable glass further comprises MgO; optionally from about 10mol% to about 40mol% MgO; optionally from about 20mol% to about 30mol% MgO. 25 f5. The resorbable glass for use, the use or the method as described in any of specific embodiments e to f4, where the resorbable glass further comprises Na2O; optionally from about 20mol% to about 30mol% Na2O; optionally from about 15mol% to about 25mol% Na2O. f6. The resorbable glass for use, the use or the method as described in specific embodiment e or f, where a resorbable glass is selected from glass codes P40, P55, P52.5 and P52.5-Cu of Table 30 1. 201395-PCT01-NP g. The resorbable glass for use, the use or the method as described in any of the preceding specific embodiments, where the resorbable glass comprises microspheres of resorbable glass. h. The resorbable glass for use, the use or the method as described in specific embodiment g, 5 where the microspheres have a diameter between about 20μm and about 250μm. h1. The resorbable glass for use, the use or the method as described in specific embodiment h, where the microspheres have a diameter between about 45μm and about 250μm. i. The resorbable glass for use, the use or the method as described in specific embodiment h, where the microspheres have a diameter between about 50μm and about 200μm. 10 j. The resorbable glass for use, the use or the method as described in any of specific embodiments g to i, where the microspheres have a mean diameter between about 90μm and about 120μm. k. The resorbable glass for use, the use or the method as described in specific embodiment j, where the microspheres have a mean diameter of about 100μm. 15 l. The resorbable glass for use, the use or the method as described in any of specific embodiments g to k, where the microspheres are porous. m. The resorbable glass for use, the use or the method as described in specific embodiment l, where the microspheres comprise surface pores and internal pores. n. The resorbable glass for use, the use or the method as described in specific embodiment m, 20 where the surface pore diameter is between about 10μm and about 100μm. o. The resorbable glass for use, the use or the method as described in specific embodiment n, where the surface pore diameter is between about 40μm and about 70μm. p. The resorbable glass for use, the use or the method as described in specific embodiment o, where the surface pore diameter is between about 47μm and about 63μm. 25 q. The resorbable glass for use, the use or the method as described in specific embodiment p, where the surface pore diameter is between about 0.1μm and about 100μm. r. The resorbable glass for use, the use or the method as described in specific embodiment q, where the mean surface pore diameter is about 55μm. s. The resorbable glass for use, the use or the method as described in any of specific 30 embodiments l to r, where the median pore diameter is about 1.9μm. 201395-PCT01-NP t. The resorbable glass for use, the use or the method as described in any of specific embodiments l to s, where the microspheres have a porosity of at least 40%, at least 50%, at least 60%, at least 70%, at least 75% or at least 80%. u. The resorbable glass for use, the use or the method as described in any of specific 5 embodiments l to t, where the microspheres have a porosity of at least 60%. v. The resorbable glass for use, the use or the method as described in any of specific embodiments l to u, where the microspheres have a porosity between 65% and 85%. w. The resorbable glass for use, the use or the method as described in any of specific embodiments l to v, where the microspheres have a porosity of about 76%. 10 x. The resorbable glass for use, the use or the method as described in any of specific embodiments l to w, where the microspheres have a surface area per unit mass between about 0.1m2 / g and about 2m2 / g. y. The resorbable glass for use, the use or the method as described in specific embodiment x, where the microspheres have a surface area per unit mass between about 0.3m2 / g and about 15 0.9m2 / g. z. The resorbable glass for use, the use or the method as described in specific embodiment y, where the microspheres have a surface area per unit mass of about 0.4m2 / g. aa. The resorbable glass for use, the use or the method as described in any of specific embodiments l to z, where the microspheres have an apparent density between about 2g / cm320 and about 3g / cm3, as measured using Helium Pycnometry. bb. The resorbable glass for use, the use or the method as described in any of specific embodiments l to z, where the microspheres have an apparent density between about 2.3g / cm3and about 2.8g / cm3, as measured using Helium Pycnometry. cc. The resorbable glass for use, the use or the method as described in any of specific 25 embodiments l to z, where the microspheres have an apparent density between about 2.4g / cm3and about 2.8g / cm3,as measured using Helium Pycnometry. dd. The resorbable glass for use, the use or the method as described in any of specific embodiments l to z, where the microspheres have an apparent density between about 2.518g / cm3and about 2.522g / cm3as measured by Helium Pycnometry. 201395-PCT01-NP ee. The resorbable glass for use, the use or the method as described in any of specific embodiments l to z, where the microspheres have an apparent density of about 2.52g / cm3as measured by Helium Pycnometry. ff. The resorbable glass for use, the use or the method as described in any of specific 5 embodiments l to ee, where the microspheres have a tap density between about 0.5g / cm3and about 2g / cm3. gg. The resorbable glass for use, the use or the method as described in any of specific embodiments l to ee, where the microspheres have a tap density between about 0.5g / cm3and about 0.7g / cm3. 10 hh. The resorbable glass for use, the use or the method as described in any of specific embodiments l to ee, where the microspheres have a tap density between about 0.57g / cm3and about 0.61g / cm3. ii. The resorbable glass for use, the use or the method as described in any of specific embodiments l to ee, where the microspheres have a tap density of about 0.59g / cm3. 15 jj. The resorbable glass for use, the use or the method as described in any of the preceding specific embodiments where the resorbable glass is material P40 from Table 1. kk. The resorbable glass for use, the use or the method as described in any of the preceding specific embodiments where the resorbable glass is administered in combination with an 11β- HSD1 inhibitor. 20 ll. The resorbable glass for use, the use or the method as described in specific embodiment kk, where the combination of resorbable glass and an 11β-HSD1 inhibitor is administered sequentially or simultaneously. mm. The resorbable glass for use, the use or the method as described in specific embodiment ll, where the combination is administered simultaneously. 25 nn. The resorbable glass for use, the use or the method as described in any of specific embodiments kk to mm, where the 11β-HSD1 inhibitor is selected from a compound listed in Table A, or a pharmaceutically acceptable salt thereof. oo. The resorbable glass for use, the use or the method as described in specific embodiment nn, where the 11β-HSD1 inhibitor is (S)-2-(1-(5-(cyclohexylcarbamoyl)-6-(propylthio)pyridin-2- 30 yl)piperidin-3-yl)acetic acid or a pharmaceutically acceptable salt thereof. 201395-PCT01-NP pp. The resorbable glass for use, the use or the method as described in specific embodiment oo where the 11β-HSD1 inhibitor is (S)-2-(1-(5-(cyclohexylcarbamoyl)-6-(propylthio)pyridin-2- yl)piperidin-3-yl)acetic acid in a salt-free form. qq. The resorbable glass for use, the use or the method as described specific embodiment oo, 5 where the 11β-HSD1 inhibitor is a pharmaceutically acceptable salt of (S)-2-(1-(5- (cyclohexylcarbamoyl)-6-(propylthio)pyridin-2-yl)piperidin-3-yl)acetic acid. rr. The resorbable glass for use, the use or the method as described in any of specific embodiments kk to qq, where both the resorbable glass and the 11β-HSD1 inhibitor are administered topically. 10 ss. The resorbable glass for use, the use or the method as described in any of the preceding specific embodiments where treatment is of a diabetic patient. tt. The resorbable glass for use, the use or the method as described in any of the preceding specific embodiments where treatment is of a patient 60 years old or over, optionally wherein the patient has been diagnosed as suffering dry skin, has a history of developing chronic 15 wounds and / or has been identified as at risk of developing chronic wounds. uu. The resorbable glass for use, the use or the method as described in any of the preceding specific embodiments where treatment is administered once weekly. vv. The resorbable glass for use, the use or the method as described in specific embodiment a, b or c, where treatment is of a diabetic patient, the resorbable glass comprises microspheres of 20 calcium phosphate glass: - having a diameter between about 45μm and about 250μm; - comprising surface pores with a diameter between about 0.1μm and about 100μm; - having a porosity of at least 70%; - having an apparent density between about 2.4g / cm3and about 2.8 g / cm3, as measured 25 by Helium Pycnometry; and - having a surface area per unit mass between about 0.1m2 / g and about 2m2 / g; and where the resorbable glass is administered in combination with an 11β-HSD1 inhibitor. ww. A pharmaceutical composition comprising a resorbable glass and a pharmaceutically acceptable excipient. 30 xx. The pharmaceutical composition as described in specific embodiment ww where the resorbable glass is as described in any of specific embodiments d to jj. 201395-PCT01-NP yy. A pharmaceutical composition comprising a resorbable glass, an 11β-HSD1 inhibitor and optionally a pharmaceutically acceptable excipient. zz. The pharmaceutical composition as described in specific embodiment yy where the resorbable glass is as described in any of specific embodiments d to jj and / or the11β-HSD1 5 inhibitor is as described in any of specific embodiments nn to qq. aaa. A pharmaceutical composition as described in specific embodiments ww to zz for use in the topical treatment of wounds. bbb. The pharmaceutical composition for use as described in specific embodiment aaa, where the treatment is as described in any of specific embodiments ll, mm or ss to uu. 10 ccc. A kit comprising: - A resorbable glass in a first dosage form; - An 11β-HSD1 inhibitor in a second dosage form; and optionally - Instructions for use. ddd. The kit as described in specific embodiment ccc, wherein the resorbable glass is as 15 described in any of specific embodiments d to jj and / or the11β-HSD1 inhibitor is as described in any of specific embodiments nn to qq.

Claims

201395-PCT01-NP CLAIMS 1. A resorbable glass for use in the topical treatment of wounds.

2. Use of a resorbable glass in the manufacture of a medicament for the topical treatment of wounds.

3. A method of topical treatment of wounds in a human or animal patient in need thereof, comprising administering to the patient a therapeutically effective amount of a resorbable glass.

4. The resorbable glass for use, the use or the method as claimed in any of the preceding claims, where the resorbable glass comprises phosphate glass, silicate glass, borosilicate glass and / or borate glass.

5. The resorbable glass for use, the use or the method as claimed in claim 4, where the resorbable glass comprises calcium phosphate glass.

6. The resorbable glass for use, the use or the method as claimed in any of the preceding claims, where the resorbable glass comprises microspheres of resorbable glass.

7. The resorbable glass for use, the use or the method as claimed in claim 6, where the microspheres have a diameter between about 45μm and about 250μm.

8. The resorbable glass for use, the use or the method as claimed in claim 6 or claim 7, where the microspheres are porous.

9. The resorbable glass for use, the use or the method as claimed in claim 8, where the microspheres comprise surface pores with a mean diameter between about 0.1μm and about 100μm.201395-PCT01-NP 10. The resorbable glass for use, the use or the method as claimed in claim 9, where the microspheres comprise surface pores with a mean diameter of about 55μm.

11. The resorbable glass for use, the use or the method as claimed in any of claims 8 to 10, where the microspheres have a porosity of at least 40%, at least 50%, at least 60%, at least 70%, at least 75% or at least 80%.

12. The resorbable glass for use, the use or the method as claimed in any of claims 6 to 11, where the microspheres have a surface area per unit mass between about 0.1m2 / g and about 2m2 / g.

13. The resorbable glass for use, the use or the method as claimed in any of claims 6 to 12, where the microspheres have an apparent density between about 2.4g / cm3and about 2.8g / cm3as measured by Helium Pycnometry.

14. The resorbable glass for use, the use or the method as claimed in any of claims 6 to 13, where the microspheres have a tap density between about 0.5g / cm3and 0.7g / cm3.

15. The resorbable glass for use, the use or the method as claimed in any of the preceding claims where the resorbable glass is material P40 from Table 1.

16. The resorbable glass for use, the use or the method as claimed in any of the preceding claims where the resorbable glass is administered in combination with an 11β-HSD1 inhibitor.

17. The resorbable glass for use, the use or the method as claimed in claim 16, where the combination of resorbable glass and an 11β-HSD1 inhibitor is administered simultaneously.

18. The resorbable glass for use, the use or the method as claimed in claim 16 or claim 17, where the 11β-HSD1 inhibitor is selected from a compound listed in Table A, or a pharmaceutically acceptable salt thereof.201395-PCT01-NP 19. The resorbable glass for use, the use or the method as claimed in claim 18, where the 11β- HSD1 inhibitor is (S)-2-(1-(5-(cyclohexylcarbamoyl)-6-(propylthio)pyridin-2- yl)piperidin-3-yl)acetic acid or a pharmaceutically acceptable salt thereof.

20. The resorbable glass for use, the use or the method as claimed in any of claims 16 to 19, where both the resorbable glass and the 11β-HSD1 inhibitor are administered topically.

21. The resorbable glass for use, the use or the method as claimed in any of the preceding claims where treatment is of a diabetic patient.

22. The resorbable glass for use, the use or the method as claimed in any of the preceding claims where treatment is administered once weekly.

23. The resorbable glass for use, the use or the method as claimed in claim 1, 2 or 3, where treatment is of a diabetic patient, the resorbable glass comprises microspheres of calcium phosphate glass: - having a diameter between about 45μm and about 250μm; - comprising surface pores with a mean diameter between about 0.1μm and about 100μm; - with a porosity of at least 70%; - having an apparent density between about 2.4g / cm3and about 2.8g / cm3as measured by Helium Pycnometry; and - with a surface area per unit mass between about 0.1m2 / g and about 2m2 / g; and where the resorbable glass is administered in combination with an 11β-HSD1 inhibitor.

24. A pharmaceutical composition comprising a resorbable glass and a pharmaceutically acceptable excipient.201395-PCT01-NP 25. A pharmaceutical composition comprising a resorbable glass, an 11β-HSD1 inhibitor and optionally a pharmaceutically acceptable excipient.

26. A pharmaceutical composition as claimed in claim 24 or claim 25 for use in the topical treatment of wounds.

27. A kit comprising: - A resorbable glass in a first dosage form; - An 11β-HSD1 inhibitor in a second dosage form; and optionally - Instructions for use.

Images