Hydrogel formulations containing inula viscosa extract for wound care

Abstract

A formulation for the treatment of wounds comprises an extract of Inula viscosa in a hydrogel form. The extract of Inula viscosa may be an extract of Inula viscosa AGS-RIED. The hydrogel may comprise a natural or synthetic polymer selected from the group consisting of cellulose, hyaluronic acid, polyvinyl alcohol, polyethylene glycol, polyurethane, poly(lactic-co-glycolic) acid and combinations and co-polymers thereof. The extract of Inula viscosa may the product of extraction with at least one organic solvent, such as methanol, ethyl acetate, and chloroform. The formulation may be used as a wound dressing such as a diabetic wound or ulcer dressing. A method of manufacture of a wound dressing comprises extraction of Inula viscosa with solvents methanol, ethyl acetate, and chloroform, removing the solvents to provide a powdered form of Inula viscosa extract, and incorporating the powdered Inula viscosa into a hydrogel.

Description

HYDROGEL FORMULATIONS CONTAINING INULA VISCOSA EXTRACT FOR WOUND CARE CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of pending U.S. Provisional Application No. 63 / 675,620 filed on July 25, 2024, the contents of which are incorporated by reference herein. BACKGROUND OF THE INVENTION

[0002] This invention relates to formulations for wound care. More particularly, this invention relates to hydrogel formulations for wound care. Even more particularly, this invention relates to hydrogel formulations for wound care that contain Inula viscosa extract.

[0003] A superficial wound / ulcer in a diabetic patient can quickly become more serious due to the adverse impact of diabetes on the skin, circulatory system, and overall health. The usual poor wound healing associated with diabetes can manifest as an inability of skin tissue to regenerate, which can increase the risk for wound infection. In turn, infection in the wound reduces its ability to heal, and may also spread through the blood. Meanwhile, ulcers in diabetics are far more likely to be non-healing. Antimicrobial drug resistance, allergies to specific antibiotics, and diverse prescription drug interactions can preclude the effective treatment of a diabetic person with a superficial wound. These may contribute to chronicity and progressive worsening of the wound.

[0004] Skin wounds are a major complication of diabetes, with patients having a lifetime diabetic foot ulcer (DFU) risk of 19 to 34%. Within five years of foot ulceration, at least 5% proceed to amputation due to gangrene. Moreover, after amputation, the overall patient mortality rate skyrockets to 50-70%. Another concern is the fact that patients with diabetes and foot or leg ulcers have a decreased quality of life and lower long-term survival rate than diabetic patients without ulcers. Elevated blood glucose levels leading to impaired neural and vascular function are prime causal factors in the reduced skin tissue integrity and poor skin ulcer healing that often occurs in these patients. Persistently elevated blood glucose is additionally linked to an increased risk ofbacterial over-colonization with organisms such as Staphylococcus aureus, including methicillin- resistant Staphylococcus aureus (MRSA), Streptococcal sp., Escherichia coli, Pseudomonas aeruginosa, and drug-resistant Acinetobacter, Bacillus, and Citrobacter species. Excessive bioburden with these pathogens stalls wound healing and increases the risk of infection, amputation, and even patient demise.

[0005] Chronic non-healing wounds pose a special clinical challenge. Diabetes-related microvascular dysfunction, impaired angiogenesis, chronic inflammation, and impaired immune cell function pose significant healing obstacles for patients with chronic wounds. In addition to impacting the patient’s overall health and well-being, hard-to-heal wounds incur significant treatment costs. Furthermore, they may cause a significant economic burden to both the patient and the healthcare sector. The availability and access to cost-effective therapies have been shown to directly impact the reduction of morbidities in chronic wounds, with a recent US study highlighting a 33% reduction in amputation rates in diabetic patients with access to affordable medical interventions. Thus, there is a significant need for cost-effective, readily available wound therapies to overcome current limitations in care.

[0006] Standard of care treatment of diabetic foot ulcers includes debridement, exudate management, advanced wound dressings, wound pressure avoidance (off-loading), and topical pharmaceutical and / or biologic agents; for poorly- or non-healing ulcers, treatment also often include antibiotics to control infection, the use of fibrin or other autologous patches, cellular, acellular and matrix-like products (CAMPs), skin grafting, hyperbaric oxygen, and negative pressure wound therapy. Existing treatments for diabetic foot ulcers can be expensive, vary in efficacy, and have not shown consistent wound-healing efficacy.

[0007] Adjunctive management of non-healing diabetic skin ulcers may also include the use of antimicrobial creams / ointments containing zinc hyaluronate, silver sulfadiazine, tretinoin, pexiganan cream, and / or chloramine; and / or naturopathic agents composed of plant-based constituents such as Curcumin or Aloe vera. While these naturally derived products may seeminglyhave multiple advantages over synthetic agents, there is a paucity of research publications focused on the use of natural molecules in wound healing.

[0008] Diabetic foot wounds can also be painful. Patients with wound pain have been shown to have a higher incidence of missed follow-up appointments and non-adherence to treatment plans. Pain creates several barriers to treatment, including anticipatory anxiety, coping exhaustion, and physical mobility limitations. Inconsistent or inadequate follow-up can directly contribute to poor wound healing outcomes. Thus, treatments that minimize pain offer significant benefits to patients.

[0009] Hydrogels are versatile biomaterials that can be used to treat a variety of wounds, including DFUs. Cross-linked polymer chains in hydrogels create a mesh-like structure that enables them to maintain a water content of about 90% up to 95%, facilitating the maintenance of a beneficial moist wound environment. Hydrogels also act as a protective barrier, safeguarding the wounded tissue by conforming to the wound bed and filling irregular contours. Hydrogel-based dressings have the advantage of being easily tunable, allowing for the incorporation of antibacterial and antimicrobial agents, cells, biomolecules, and growth factors. A hydrogel can be formulated using any hydrophilic natural polymer, such as cellulose or hyaluronic acid, or synthetic polymer, such as polyvinyl alcohol (PVA), polyethylene glycol (PEG), polyurethane (PU) or poly(lactic-co- glycolic) acid (PLGA) for example, through a tailored cross-linking technique, which offers considerable promise in the treatment of hard-to-heal DFUs.

[0010] Ongoing clinical research on these products continues to explore and expand hydrogels' potential uses and functionalities in wound management.

[0011] There is, therefore, a need for alternative wound care treatments for persistent wounds such as diabetic foot ulcers.BRIEF SUMMARY OF INVENTION

[0012] It is, therefore, an aspect of the present invention to provide a hydrogel formulation for wound care. It is another aspect of the present invention to provide a hydrogel for diabetic wound care. It is still another aspect of the present invention to provide a wound care hydrogel comprising extract of Inula viscosa.

[0013] Inula viscosa is a perennial herb of the Asteraceae family. These plant species have been used in Middle Eastern traditional medicine for centuries to treat skin injuries and diabetes. An Inula viscosa cultivar extract, ‘AGS-RIED’, has been developed to have a higher content of anti- inflammatory, vasodilatory, and anti-microbial compounds in the plant and is the primary plant- based ingredient in the present botanical hydrogel developed by Lavior Pharma, Inc. Inula viscosa- extract may be prepared by cleaning the plant with water to eliminate soil and dust particles, prior to being air-dried and powdered. For extract preparation, any of four different solvents may be used, namely ethanol, methanol, ethyl acetate, and chloroform, with ethanol being a typical solvent; the extraction process may be conducted using the Soxhlet apparatus. In one example, powdered sample (50 g) may be extracted with 250 mL of solvent, afterward, the extracts obtained were eliminated of solvent using a rotary evaporator. The obtained crude extracts may be refrigerated (−4 °C) in airtight bottles.

[0014] The data presented herein evaluate differential healing rates between the present inventive hydrogel, LAVIOR Diabetic Wound Gel (LDWG) (Lavior Pharma Inc., Hallandale Beach, FL) and a prior hydrogel: SoloSite Wound Gel (SSWG) (Smith and Nephew Inc., Andover, Massachusetts) in the treatment of DFUs. Herein, we report the results of a double-blinded randomized controlled clinical trial of LDWG versus SSWG with the primary objectives of comparing time-to-heal between study groups, rates of complete healing, and other clinical factors associated with more rapid healing.

[0015] Current treatments for diabetic foot ulcers (DFUs) mainly target only one complication of the ulcer at a time, such as inflammation, resulting in multiple treatments being prescribed toaddress other wound issues with little or no guarantee of success. Other treatments may focus on bacterial colonization / infection or target vascularization. Novel therapies, such as those derived from natural botanical sources, may have expedited healing capabilities, are safe, effective, accessible, and affordable. These new therapies provide alternatives to existing and conventional treatments. A botanical-based hydrogel, incorporating Inula viscosa AGS-RIED, has been designed to address known challenges to wound healing. By focusing on inflammation, microbial burden, vascularization, and hypoxia, the hydrogel supports expedited wound healing, especially in those with diabetes.

[0016] In general, the present invention provides a wound care formulation comprising an extract of Inula viscosa in a hydrogel form. The extract of Inula viscosa may be an extract of Inula viscosa AGS-RIED. The hydrogel may comprise a natural polymer selected from the group consisting of cellulose and hyaluronic acid, or a synthetic polymer selected from the group consisting of polyvinyl alcohol (PVA), polyethylene glycol (PEG), polyurethane (PU), poly(lactic- co-glycolic) acid (PLGA) and combinations and co-polymers thereof. The extract of Inula viscosa may be the product of extraction with at least one organic solvent, such as ethanol, methanol, ethyl acetate, and chloroform.

[0017] The formulation may be used as a wound dressing such as a diabetic wound or diabetic ulcer dressing. A method of manufacture of a wound dressing comprises an extraction of Inula viscosa with solvents methanol, ethyl acetate, and chloroform, removing the solvents to provide a powdered form of Inula viscosa extract, and incorporating the powdered Inula viscosa into a hydrogel. BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0018] Figure 1 is a graph of incidence (%) of subjects achieving a complete wound closure at FU 5 / Week 4 and FU 6 / Week 5 for each treatment group. FU denotes Follow-Up, SSWG denotes SoloSite Wound Gel, and LDWG denotes Lavior Diabetic Wound Gel.Figure 2 is a graph of incidence (%) of > 75% relative reduction in ulcer volume at FU 6 / Week 5 for each treatment group. FU denotes Follow-Up, SSWG denotes SoloSite Wound Gel, and LDWG denotes Lavior Diabetic Wound Gel. Figure 3 is a graph of mean relative percent change in wound surface area from FU 1 / Week 0 to each of FU 2 / Week 1, FU 3 / Week 2, FU 4 / Week 3, FU 5 / Week 6 for each treatment group. FU denotes Follow-Up, SSWG denotes SoloSite Wound Gel, and LDWG denotes Lavior Diabetic Wound Gel. Figure 4 is a graph of mean pain severity scores out of ten (10) between FU 1 / Week 0, FU 2 / Week 1, FU 3 / Week 2, FU 4 / Week 3, FU 5 / Week 4, and FU 6 / Week 5 for the SSWG treatment group. FU denotes follow-up, and SSWG denotes SoloSite Wound Gel. Figure 5 is a graph of mean pain severity scores out of ten (10) between FU 1 / Week 0, FU 2 / Week 1, FU 3 / Week 2, FU 4 / Week 3, FU 5 / Week 4, and FU 6 / Week 5 for the LDWG treatment group. FU denotes follow-up, and LDWG denotes Lavior Diabetic Wound Gel. Figure 6 is a graph of mean diabetic foot ulcer out of (290) between FU 1 / Week 0, FU 2 / Week 1, FU 3 / Week 2, FU 4 / Week 3, FU 5 / Week 4, and FU 6 / Week 5 for the SSWG treatment group. FU denotes follow-up, and SSWG denotes SoloSite Wound Gel. Figure 7 is a graph of mean diabetic foot ulcer out of (290) between FU 1 / Week 0, FU 2 / Week 1, FU 3 / Week 2, FU 4 / Week 3, FU 5 / Week 4, and FU 6 / Week 5 for the LDWG treatment group. FU denotes follow-up, and LDWG denotes Lavior Diabetic Wound Gel. DETAILED DESCRIPTION OF THE INVENTION

[0019] The present invention is directed toward a hydrogel for wound treatment comprising Inula viscosa extract, particularly extract of Inula viscosa AGS-RIED. The following examples should not be viewed as limiting the scope of the invention. The claims will serve to define the inventions.

[0020] The invention will be better understood by reference to the following examples which are included for the purpose of illustration and not limitation.

[0021] A prospective, double-blinded, randomized, controlled, parallel-group, multi-center clinical trial was conducted to compare healing outcomes in patients with chronic lower extremity diabetic foot ulcers. All patients received standard of care (SOC) for DFUs, including debridement, exudate management, off-loading, and topical pharmaceutical and / or biologic agents. Participants received the hydrogel of the present invention, Lavior Diabetic Wound Gel (LDWG) or the prior art Smith & Nephew’s SoloSite Wound Gel (SSWG). The study followed enrolled subjects for up to 7 weeks. LDWG contains water, glycerin, alcohol, xanthan gum, phenoxyethanol, Inula viscosa flower / leaf / stem extract, allantoin, tocopheryl acetate (Vitamin E), propanediol, ethylhexylglycerin, sodium gluconate, citric acid, sodium hyaluronate and potassium sorbate.

[0022] Patients with Type 1 or Type 2 diabetes presenting to the clinic for care of a DFU were screened for study eligibility based on inclusion and exclusion criteria. For inclusion in the study, patients needed to have a foot wound in the setting of diabetes mellitus (with or without prior surgery), a minimum wound surface area of 0.7 x 0.7 cm (0.49 cm2), and the ability to comprehend and provide written informed consent. Patients were excluded from the study if they were <18 years of age; noncompliant with the study protocol, visit schedule, or follow-up; had gangrene and / or untreatable peripheral arterial disease; had malignancy in the wound; used any other hydrogels not included in this investigation within one month of enrollment; were simultaneously participating in competing clinical trials; or were pregnant or nursing mothers. Additionally, patients with dry, uninfected, stable pressure ulcers of the heel and dry, stable eschar in arterial wounds were excluded.

[0023] Patients who met the requirements and were willing to participate in the clinical study were randomized into two treatment groups. Participants were randomized dynamically within each center by wound size, with 36 patients in the LDWG group and 32 in the SSWG group. Both gels were used as directed by the manufacturer. A clinician and / or trained staff member performed thehydrogel application during initial and follow-up visits, and patients were instructed to apply the given treatment every 2-3 days between each weekly follow-up visit. Both patients and clinicians were blinded to the products being used.

[0024] Strict confidentiality was maintained throughout the study. Patient survey responses were provided with no identifying patient information. Clinicians could withdraw study participants based on their clinical assessments, including wound deterioration not remediated with temporary therapy hiatus or any medical condition that precluded or contraindicated continued study participation; patients could withdraw at will. Any withdrawn participants were considered a treatment failure. Data collected prior to study termination on safety, quality of life, and healthcare economic resource utilization were included in the study’s follow-up phase. Patients were provided with the treatment at no cost and received compensation for participation in the form of a retail gift card.

[0025] Following enrollment, clinicians conducted standard weekly wound assessments, including: • Wound surface area, measured with a standardized ruler provided to the investigators • Wound depth using a graduated cotton-tipped applicator provided to the investigators • Wound photographs • Wound exudate: amount, appearance, consistency, odor • Percent of granulation tissue, epithelialization, and necrotic tissue present in the wound • Signs and symptoms of infection • Condition of the wound edge and periwound • Peripheral tissue edema Any adverse events or findings

[0026] All study subjects were asked to complete a validated symptom scale questionnaire each week (i.e., the Diabetic Foot Scale (DFS)) at baseline (day 0) and up to 7 weeks post-enrollment. The 58-item DFS included questions covering 11 domains: leisure, physical health, daily activities,emotions, noncompliance, family, friends, positive attitude, treatment, satisfaction, and financial impacts. The scale has demonstrated adequate test-retest reliability and sensitivity to changes in wound status over time, indicating its appropriateness for inclusion in clinical trials. Subjects were asked to answer additional survey questions regarding patient satisfaction, quality of life, and resumption of their everyday activities.

[0027] The topical wound treatment (LDWG or SSWG) was applied every 2 to 3 days, depending upon clinician preference. At each weekly follow-up study visit, the clinician or clinician-trained staff completed standard wound care, cleansed the wound with normal saline, and applied the assigned treatment. Bordered gauze dressings were used as a secondary dressing. Study participants were instructed to change the dressing every 2-3 days between clinic visits, applying the assigned product to the entire wound bed and wound edges as a thin layer (approximately 2 mm thick). If the dressing became soiled or wet, the subject was instructed to discard and replace the dressing. Primary endpoints The primary endpoint of this trial was the duration of the wound prior to closure (i.e., time to heal), defined as the time (number of days) to achieve complete wound closure as noted in clinical notes and photos in study participants before the end of the study at day 49. Complete wound closure was defined as: 100% epithelialization No drainage from the wound No need for adjuvant therapy or dressing No presence of sutures Secondary Endpoints Percent reduction of wound area over the study period Incidence of wound closures by the end of the study at day 49 Exploratory Endpoints Patient responses to DFS

[0028] Descriptive statistics were calculated for all variables, including frequencies and percentages for categorical variables and means with standard deviation (SD) for continuous variables. The maximum sample size available was used for each statistical analysis. Three wound surface area outliers at Week 0 with Z-scores ±3 or more were removed from the study and all analyses: two from the LDWG group and one from the SSWG group. A two-tailed alpha was set to 0.05 for all statistical comparisons. SPSS v.27 was used for all analyses.

[0029] Changes in mean wound surface area from baseline (Week 0) to each follow-up visit (Week 1, 2, 3, 4, 5) were calculated and then analyzed using the paired t-test to identify any statistically significant differences between the SSWG and LDWG test groups. An unpaired t-test was used to identify any statistically significant differences between the groups for mean relative percent change in wound surface area from Week 0 to Weeks 1, 2, 3, 4, and 5.

[0030] The difference between SSWG and LDWG in the incidence of relative reduction >40% in ulcer area at each of Weeks 1, 2, 3, 4, and 5 was analyzed using the chi-square test. Similarly, differences between SSWG and LDWG in the incidence of relative reductions of >40%, >50%, >60%, and >70% at Week 4 and separately at Week 5 were analyzed.

[0031] The paired t-test was also used to compare mean pain severity scores and mean diabetic foot ulcer scale scores from Week 0 to each of Week 1, 2, 3, 4, and 5 within each of the SSWG and LDWG.

[0032] A total of 65 subjects were enrolled in this study. One ulcer on each patient was identified as the index ulcer for treatment in the study [LDWG (N=34) and SSWG (N=31)]. There were no significant differences in patient age (Table 1) and gender (Table 2) between the two treatment groups. A majority of subjects were male in both cohorts, with 70.6% in the LDWG cohort and 61.3% in the SSWG cohort. The mean age of the LDWG cohort was 64.4 years, while the SSWG cohort was 67.1 years. The mean baseline ulcer area was 7.32 cm2in the LDWG group and 8.18cm2in the SSWG group. Ulcers in the LDWG and SSWG groups had a mean ulcer depth of 5.0 mm versus 7.3 mm and mean ulcer volumes of 4.89 cm3versus 11.74 cm3, respectively. Table 1: Patient ages (yr) at baseline LDWG SSWG (N=34 (N=31) Mean 64.4 67.1 SD 12.8 9.7 Median 65.4 66.0 Minimum 41.0 49.8 Maximum 88.1 84.7 Table 2: Patient gender at baseline LDWG SSWG

[0033] The primary for LDWG-treated ulcers was greater than SSWG at 4 weeks (14.7% vs. 12.9%; p = 0.834) and 5 weeks (20.6% vs. 16.1%; p = 0.6), respectively (Figure 1). For the wounds from follow-up (FU) / Week 0 through FU / Week 5, the median time to wound closure for LDWG-treated ulcers was 4 weeks. For SSWG-treated ulcers, the median time to wound closure was also 4 weeks.

[0034] DFUs treated in the study showed an incidence of achieving a greater than 60% relative reduction in baseline area (56.3% vs. 41.2%; P=0.387) and depth (55.6% vs. 14.3%; P=0.066) for the LDWG-treated and the SSWG-treated wounds, respectively, at Week 5. In addition, the incidence of ulcers demonstrating greater than a 75% reduction in baseline volume by Week 5 was more significant in the LDWG-treated subjects compared with the SSWG-treated subjects (55.6% vs. 42.9%; P=0.680) (Figure 2).

[0035] Group comparisons (Figure 3) showed that the LDWG-treated group demonstrated a more significant relative mean percent surface area reduction in wound size at the end of the study from baseline in ulcer area compared with the SSWG group. In Fig. 3, each pair of bars in the chart provides the percentage change relative to the first follow up appointment for the subsequent follow up appointment. In each pair of bars, the number of patients changes as patients either drop out or are cured and the data for such patients are eliminated. The difference between the LDWG treated group and the SSWG-treated group was statistically significant at three weeks (P=0.036); however, the cumulative difference between groups was not statistically significant.

[0036] The mean pain severity scores at baseline and study completion, comparing both cohorts, are as follows. SSWG-treated group paired pain severity scores are illustrated in Figure 4, where at baseline, pain = 4.71 out of 10 (N=17), at Week 5 = 3.00 out of 10 (N=17), P=0.002. In Figure 4, each pair of bars in the chart provides the mean pain severity score for the first follow up appointment and for a subsequent follow up appointment. The number of patients changes from week to week as patients either drop out or are cured. Similarly, the LDWG-treated group’s paired mean pain severity scores are illustrated in Figure 5, where baseline pain was 4.82 out of 10 (N=17), at Week 5 = 1.76 out of 10 (N=17), P<0.001.

[0037] The mean diabetic foot ulcer scale scores at baseline and study completion, comparing both cohorts. (Figures 6 and 7) Again, each pair of bars in the chart provides the mean diabetic foot ulcer score for the first follow up appointment and for a subsequent follow up appointment. The number of patients changes from week to week as patients either drop out or are cured. The SSWG-treated group (Figure 6) at baseline = 207 out of 290 (N=14), at Week 5 = 225 out of 290 (N=14), P=0.001. The LDWG-treated group (Figure 7) at baseline = 192 out of 290 (N=12), at Week 5 = 219 out of 290 (N=12), P=0.001.

[0038] Wound care providers have many treatment options and products available for use. When considering novel therapies, clinicians should be confident that the product provides at least as much benefit as standard therapy. In all variables measured in this study, LDWG performed at least as well as SSWG, with wound surface area and wound pain showing significantly more improvement in the LDWG-treated cohort. Complete wound healing did not differ between the groups, nor did the study participants’ quality of life measures.

[0039] Other research has demonstrated the action of Inula viscosa cultivar ‘AGS-RIED’ in reducing inflammation, wound bioburden, and vasodilation of the wound bed. These three effects may explain the rapid decrease in surface area from wounds treated with the Inula viscosa ‘AGS-RIED’ extract-containing hydrogel (LDWG) compared to standard wound care hydrogel (SSWG). The results of this preliminary study suggest that botanical hydrogels may offer significant benefits to patients with diabetic foot wounds over traditional hydrogels.

[0040] Wound-related pain represents a significant morbidity for patients with wounds, impacting both healing outcomes and quality of life. At 5 weeks, pain reduction was significantly more pronounced in the LDWG cohort than the SSWG cohort, achieving a substantially larger decrease in mean pain score. This significant alleviation of pain suggests an important benefit of LDWG in clinical settings. Decreased wound pain can dramatically improve patient compliance with treatment and follow-up with healthcare providers, leading to better wound surveillance and detection of deterioration, which facilitates better healing outcomes.

[0041] The diabetic foot ulcer scale was used to evaluate the study participants’ overall health and quality of life more broadly. Improvement was seen in both treatment groups from baseline to Week 5, suggesting that both treatments positively impacted these critical metrics.

[0042] This study evaluated the performance of a novel botanical hydrogel with a widely used hydrogel. In general, both products demonstrated positive results in treating diabetic foot ulcers. The botanical gel performed at least as well as traditional hydrogel in all variables measured, but demonstrated superior pain management with a trend toward more rapid improvement in wound surface area.

[0043] Existing treatments for diabetic foot ulcers can be expensive, vary in efficacy, and have not shown consistent wound-healing efficacy. The results reported here suggest that the natural, botanical-based, and non-synthetic LDWG, with Inula viscosa AGS RIED extract, elicits a faster response for the reduction of wound size when compared to wounds treated with a prior Wound Gel.

[0044] Inula viscosa AGS-RIED includes a wide array of sesquiterpenoids, especially Sesquiterpene Lactones (SLs). SLs and have been shown to exhibit antimicrobial, antitumor, anti- inflammatory, antifungal, and antimalarial activity. LDWG specializes in addressing chronic wounds mired in the prolonged inflammatory stage, impeding proper healing. The gel, incorporating Inula viscosa, which has vasodilation effects, encourages oxygen to the wound. Interestingly, data reported in this manuscript shows a smaller initial reduction in wound surface area for the LDWG treated group compared to the SSWG treated group (-1.3 vs. -1.8 cm2) during the first week after initial application (Figure 2). This would be expected. It has been widely recognized that providing oxygen to the wound area while promoting blood flow, or tissue perfusion, are important aspects of the healing process. Oxygen plays an important role in collagen formation, promoting growth of new capillaries and cell proliferation, bacterial defense and infection control. Without oxygen and associated blood flow to the tissues, the healing cascade will be impaired. During this phase of wound healing, the wound may initially get larger due to increased blood flow to the tissue.

[0045] Both studied products, LDWG and SSWG have allantoin and glycerin in their formulation. Allantoin is known to stimulate cell proliferation and is hydrolyzed in the skin to form urea, providing a moisturizing effect and keratolytic action which activates wound healing. Glycerin is known to be chemotactic and encourages leukocytes, encourages angiogenesis, promotes autolytic debridement, and may prevent necrosis while favoring the formation of granulation tissue. As allantoin has no irritating effect when applied to the skin, incorporating it in hydrogel-based dressings is positive because it binds to the stratum corneum and increases the affinity of keratin for water. This allows hydration to occur in the wound bed, which facilitates debridement of the wound and contributes to the healing process.

[0046] The expedited healing that contributes to a better quality of life, as shown in these results, can also manifest in reduced healthcare costs, reduced hospitalizations, and a lowering of the risk and necessity of diabetic complications, including limb amputation.

[0047] Complications from diabetes affect millions of people in the U.S. and tens of millions around the world. Early clinical interventions that promote diabetes management and prevention along with the identification of emerging, novel, efficacious, and safe therapies, such as Lavior Diabetic Wound Gel, will assist in reducing diabetic related complications, including amputations. Successful chronic wound management is not without challenges. Recent published literature has illustrated the disparities among ethnic and minority communities prone to higher diabetes rates and the differences in healthcare management in these populations. As the results here suggest, new and affordable OTC therapies with multimodal healing properties that show superiority to existing commercial and conventional treatments, are very encouraging and allow for broader patient access that will address existing healthcare disparities and promote expedited wound healing.

[0048] Based upon the foregoing disclosure, it should now be apparent that the claimed Diabetic Wound Gel is a cost-effective OTC novel, efficacious, botanical-based product and is a viable, efficacious, safe, and affordable alternative to existing therapies. The claimed inventionshows expedited healing in diabetic foot ulcers when compared to another commercially available OTC wound care hydrogel. The plant-based hydrogel has been shown to promote vascularization of the wound, elicit anti-toxic, anti-inflammatory, and anti-bacterial properties, and improve quality of life while reducing pain severity scores in patients presenting with complicated and variously sized diabetic wounds. Results reported suggest that this commercially available and affordable OTC plant-based hydrogel may be effectively used as a first-line, clinician-preferred and recommended treatment option and as part of a multimodal treatment approach. It is, therefore, to be understood that any variations evident fall within the scope of the claimed invention and thus, the selection of specific component elements can be determined without departing from the spirit of the invention herein disclosed and described.

[0049] The word “comprising” and forms of the word “comprising” as used in this description and in the claims does not limit the invention claimed to exclude any variants or additions.

Claims

CLAIMS We claim:

1. A formulation for the treatment of wounds, comprising an extract of Inula viscosa in a hydrogel form.

2. The formulation of claim 1, wherein the extract of Inula viscosa is an extract of Inula viscosa AGS-RIED. 3 The formulation of claim 2, wherein the hydrogel comprises a polymer selected from the group consisting of cellulose, hyaluronic acid, polyvinyl alcohol, polyethylene glycol, polyurethane, poly(lactic-co-glycolic) acid, and combinations and co-polymers thereof. 4 The formulation of claim 3, wherein the polymer comprises hyaluronic acid. 5 The formulation of any one of the preceding claims, wherein the extract of Inula viscosa is the product of extraction with at least one organic solvent. 6 The formulation of claim 5, wherein the at least one organic solvent is selected from the group consisting of ethanol, methanol, ethyl acetate, and chloroform. 7 The formulation of claim 5 for use as a wound dressing. 8 The formulation of claim 7, for use as a diabetic wound dressing. 9 The formulation of claim 7, for the treatment of diabetic wounds. 10 A method of treating wounds, the method comprising administering a wound dressing comprising a hydrogel and an extract of Inula viscosa. 11 The method of claim 10, wherein the extract of Inula viscosa is an extract of Inula viscosa AGS- RIED.

12. The method of claim 11, wherein the hydrogel comprises a polymer selected from the group consisting of cellulose, hyaluronic acid, polyvinyl alcohol, polyethylene glycol, polyurethane, poly(lactic-co-glycolic) acid, and combinations and co-polymers thereof.

13. The method of claim 12, wherein the extract of Inula viscosa is the product of extraction with at least one organic solvent.

14. The method of claim 13, wherein the at least one organic solvent is selected from the group consisting of ethanol, methanol, ethyl acetate, and chloroform.

15. A method of manufacture of a wound dressing comprising extraction of Inula viscosa with solvents ethanol, methanol, ethyl acetate, and chloroform, removing the solvents to provide a powdered form of Inula viscosa extract, and incorporating the powdered Inula viscosa extract into a hydrogel.

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