Hyaluronic Acid Formulations Research Articles

The role of high molecular weight hyaluronic acid in mucoadhesion on an ocular surface model

Hyaluronic acid (HA) is frequently formulated in eye drops to improve the stability of the tear film by hydration and lubrication. Mucoadhesion is related to the ocular residence time and therefore to the effectiveness of the eye drops. The ocular residence time of the HA formulation is correlated with the ability of HA to create specific strong interactions in the ocular surface with the mucus layer, mainly composed of a mixture of secreted mucins (MUC; gel forming MUC5AC and MUC2) and shed membrane-bound soluble mucins (MUC1, MUC4, and MUC16). Dry eye disease (DED) is a multifactorial pathology of the preocular tear film with possible damage to the ocular surface classified in two types: (1) aqueous-deficient dry eye and (2) evaporative dry eye, caused by a decrease in goblet cell density that reduces MUC expression and/or by meibomian gland dysfunction, that results in a drop in the lipidic fraction of the tear film.In this work, the binding affinity between HA and MUC2 has been evaluated with three complementary approaches because the secreted MUCs play a pivotal role in the viscoelastic properties of the tear film: 1. Rheological analysis, measuring the mucoadhesive index and the complex viscosity in relation to MM (Molecular Mass) and concentration; 2. Fluorescence analysis, using a fluorescent hydrophobic probe, to investigate the conformational change of MUC2 during the interaction with the HA polymer; 3. Surface plasmon resonance analysis, used to measure the affinity between MUC2 (immobilized on the surface of a sensor chip) and the HA polymers that flowed on it at the molecular level.For all these tests, the mucoadhesive performance of the natural HA linearly increases with the MM, whereas cross-linked HA and other emollient and gelling agents (formulated in artificial tears) do not show the same mucoadhesive properties (with the exception of xanthan gum). The mucoadhesive performance of high MM HA has also been confirmed in conditions that simulate the pathological condition of the tear film during DED by decreasing the MUC2 or oleic acid concentration. Physico-chemical analysis of a series of marketed artificial tears confirms the linear correlation between the MM of the HA used in the products and the mucoadhesive index measured on the ocular surface model.

Niosomal Curcumin Suppresses IL17/IL23 Immunopathogenic Axis in Skin Lesions of Psoriatic Patients: A Pilot Randomized Controlled Trial.

Psoriasis (PS) is characterized by hyperplasia of epidermis and infiltration of immune cells in the dermis. A negligible susceptibility of hypodermic permeation for local anti-inflammatory remedies is one of the major causes of medication failures. Although curcumin (CUR) has indicated effectiveness in treatment of inflammation, its successful permeation through the stratum corneum is yet a challenging issue. Therefore, niosome (NIO) nanoparticles were used as curcumin carriers to enhance its delivery and anti-inflammatory effects. Curcumin-niosome (CUR-NIO) formulations were constructed by the thin-film-hydration (TFH) technique and were added to hyaluronic acid and Marine-collagen gel-based formulation. Five mild-to-moderate PS patients (18-60 years) with PASI scores < 30 with symmetrical and similar lesions were included in the study. The prepared formulation (CUR 15 µM) was topically administered for 4 weeks on the skin lesions, in comparison to the placebo. Clinical skin manifestations were monitored and skin punches were obtained for further gene expression analyses. There was a significant reduction in redness, scaling, and an apparent improvement in CUR-NIO-treated group in comparison to the placebo-treated counterpart. The gene expression analyses resulted in significantly downregulation of IL17, IL23, IL22, and TNFα, S100A7, S100A12, and Ki67 in CUR-NIO-treated lesions. Consequently, CUR-NIO could provide therapeutic approaches for the patients with mild-to-moderate PS by suppressing the IL17/IL23 immunopathogenic axis.

The Effectiveness of Injectable Hyaluronic Acid in the Improvement of the Facial Skin Quality: A Systematic Review.

Several studies have evaluated the role of various injectable formulations of hyaluronic acid (HA) in the improvement of the quality of facial skin. It is important to systematically summarize the available evidence in this regard. Relevant databases were searched for clinical studies that evaluated the therapeutic role of any injectable formulation of HA in improving the quality of facial skin in adult humans until 31 December 2022. The available studies were critically analyzed and the data were extracted. A total of 2996 articles were screened and 13 studies were finally included. Eight studies evaluated the effect of various formulations of HA alone, while five evaluated the effect of various formulations of HA along with other active ingredients (cocktails) on the quality of facial skin. All types of HA formulations cause a significant improvement in facial skin quality, in terms of hydration, firmness, skin-tiring effect/fatigue, brightness, texture, radiance, and elasticity. The effect of HA monotherapy was more pronounced than that of the cocktail ingredients. HA treatment was quite safe and the patient satisfaction level was high. The clinical evidence on the use of injectable HA alone in the improvement of the quality of facial skin, in terms of hydration, firmness, skin-tiring effect/fatigue, brightness, texture, radiance, and elasticity, is quite promising. Large randomized controlled trials are required in this regard.

Utilization of experimental design in the formulation and optimization of hyaluronic acid–based nanoemulgel loaded with a turmeric–curry leaf oil nanoemulsion for gingivitis

Numerous problems affect oral health, and intensive research is focused on essential oil–based nanoemulsions that might treat prevent or these problems. Nanoemulsions are delivery systems that enhance the distribution and solubility of lipid medications to targeted locations. Turmeric (Tur)- and curry leaf oil (CrO)–based nanoemulsions (CrO-Tur-self-nanoemulsifying drug delivery systems [SNEDDS]) were developed with the goal of improving oral health and preventing or treating gingivitis. They could be valuable because of their antibacterial and anti-inflammatory capabilities. CrO-Tur-SNEDDS formulations were produced using the response surface Box-Behnken design with different concentrations of CrO (120, 180, and 250 mg), Tur (20, 35, and 50 mg), and Smix 2:1 (400, 500, and 600 mg). The optimized formulation had a bacterial growth inhibition zone of up to 20 mm, droplet size of less than 140 nm, drug-loading efficiency of 93%, and IL-6 serum levels of between 950 ± 10 and 3000 ± 25 U/ml. The optimal formulation, which contained 240 mg of CrO, 42.5 mg of Tur, and 600 mg of Smix 2:1, was created using the acceptable design. Additionally, the best CrO-Tur-SNEDDS formulation was incorporated into a hyaluronic acid gel, and thereafter it had improved ex-vivo transbuccal permeability, sustained in-vitro release of Tur, and large bacterial growth suppression zones. The optimal formulation loaded into an emulgel had lower levels of IL-6 in the serum than the other formulations evaluated in rats. Therefore, this investigation showed that a CrO-Tur-SNEDDS could provide strong protection against gingivitis caused by microbial infections.

The Comparative Study of the Administration of the Combination Preparation of Isoflavones and Hyaluronic Acid in Menopausal Women for the Treatment of the Symptoms of Menopause, Urogenital Atrophy and Oteoporosis in Relation to Existing Hormone Replacement Therapies.

Menopause is characterized by a series of symptoms and effects from the various systems and organs, for which, the decline in estrogen production from the ovaries is considered responsible. The aim of this study was to make comparative study of the administration of the combination preparation of isoflavones and hyaluronic acid in menopausal women for the treatment of the symptoms of menopause, urogenital atrophy and osteoporosis in relation to existing hormone replacement therapies. In this five-year, double-blind, placebo-controlled clinical study, a total of 274 postmenopausal women were enrolled and classified into three groups. Participants in group A, were 96 women who did not receive Hormone Replacement Therapy (HRT), in the second group, 92 received daily treatment with tibolone (2.5 mg) as monotherapy, and in the third group, 86 received treatment with a pharmaceutical formulation of hyaluronic acid 120 mg and isoflavones. MF11RCE 80 mg. In the postmenopausal women of our study, a significant reduction of postmenopausal symptoms was found in both groups B and C of participants who received hormone replacement preparations compared to group A who did not receive HRT. Furthermore, no difference in efficacy was observed between the administered preparations of isoflavones and tibolone. The combination of isoflavones and hyaluronic acid has the same efficacy as tibolone in menopausal symptoms.

Formulation and Characterization of Hyaluronic Acid Anchored Polycaprolactone Nanoparticles for Delivery of Anticancer Drugs

Methotrexate (MTX), a stoichiometric inhibitor of dihydrofolate reductase, is a chemotherapeutic agent for treating a variety of neoplasms. The objective of the present study was to synthesize nanoparticles of MTX using hyaluronic acid-polyethyleneglycol-polycaprolactone (HA-PEG-PCL) copolymer for tumor targeting. Targeting efficiency of HA-PEG-PCL nanoparticles was compared with non-HA-containing nanoparticles polycaprolactone. The copolymers were chemically synthesized and characterized by IR and Nuclear Magnetic Resonance (NMR) spectroscopes. The nanoparticles were characterized for shape and morphology by transmission electron microscopy (TEM), particle size, percentage of drug entrapment and in-vitro drug release profile. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) studies were also performed to appraise the crystalline or amorphous nature of MTX inside the polymer matrix. Formulations were prepared using different MTX: polymer ratios (1:0.05-3:0.15 w/w) and the optimum formulation with the drug: polymer ratio of 1:0.05 showed the mean particle size of 185 ± 2.21 nm and entrapment efficiency of 93.16 ± 2.1% in the case of HA-PEG-PCL nanoparticles, while the values were 140 ± 1.24 nm and 90.12 ± 1.3%, respectively, in the case of PCL nanoparticles. The nanoparticles prepared using copolymers HA-PEG-PCL showed their potential to sustain the MTX release. MTX-HA-PEG-PCL nanoparticles showed 95.08 ± 2.50% release of MTX in 96 hours while MTX-PCL nanoparticles released almost 100% of the drug in the same duration. The stability was evaluated in terms of particle size and residual drug content, the nanoparticles formulations were found to be more stable at 5 ± 3°C and then 40 ± 2°C. These results suggest that HA-PEG-PCL nanoparticles could be an efficient delivery system for MTX for targeted therapy of cancer.

Cysteamine Eye Drops in Hyaluronic Acid Packaged in Innovative Single-Dose Systems: Stability and Ocular Biopermanence.

Cystinosis is a rare genetic disorder characterized by the accumulation of cystine crystals in different tissues and organs causing, among other symptoms, severe ocular manifestations. Cysteamine eye drops are prepared in hospital pharmacy departments to facilitate access to treatment, for which vehicles that provide adequate biopermanence, as well as adaptable containers that maintain its stability, are required. Difficulties related to cysteamine preparation, as well as its tendency to oxidize to cystamine, show the importance of conducting rigorous galenic characterization studies. This work aims to develop and characterize an ophthalmic compounded formulation of cysteamine prepared with hyaluronic acid and packaged in innovative single-dose systems. For this task, the effect of different storage temperatures and the presence/absence of nitrogen on the physicochemical stability of the formulation and its packaging was studied in a scaled manner, until reaching the optimal storage conditions. The results showed that 0.55% cysteamine, prepared with hyaluronic acid and packaged in single-dose containers, is stable for 30 days when stored at −20 °C. In addition, opening vials every 4 h at room temperature after 30 days of freezing maintains the stability of the cysteamine formulation for up to 16 h. Moreover, ocular biopermanence studies were conducted using molecular imaging, concluding that the biopermanence offered by the vehicle is not affected by the freezing process, where a half-life of 31.11 min for a hyaluronic acid formulation stored for 30 days at −20 °C was obtained, compared with 14.63 min for 0.9% sodium chloride eye drops.

Efficacy and Tolerability of Hybrid Complexes of High- and Low-Molecular-Weight Hyaluronan Intradermal Injections for the Treatment of Skin Roughness and Laxity of the Neck.

This study aimed to evaluate the efficacy of a well-characterized formulation of hyaluronic acid (HA), Profhilo®, in the treatment of roughness and laxity of the neck skin. The study was performed on 25 subjects ranging in age from 40 to 65 years. Two injections of the studied product at 30-day intervals were performed, with evaluations conducted 1 and 4 months after the first injection. The efficacy was determined by clinical and multilevel instrumental evaluations. In addition, at the end of the study, the subjects completed a questionnaire related to the efficacy and tolerability of the product. The studied product was shown to induce a clear and statistically significant improvement in the skin of the neck in all the subjects, with concordant results between the clinical, instrumental, and subjects' evaluations. The positive effects, present after the first injection, were further increased in the second and last evaluation. Notably, the product was reported to have a very high tolerability by both clinicians and subjects. In conclusion, two injections of the studied product safely induced skin amelioration in subjects with mild to moderate neck skin roughness and laxity.

Multicenter evaluation of a topical hyaluronic acid serum.

A new hyaluronic acid (HA) formulation was developed based on high molecular weight (MW) compounds used on the surface of the skin while using peptides to stimulate the high MW HA production by fibroblasts and keratinocytes from within the skin layers. Detailed science has been submitted to this journal in a previous publication. This multicenter study aims to validate the science by demonstrating the safety and efficacy of the product in the clinical realm. This study evaluated the efficacy and safety of a topical HA serum in facial skin. An open-label clinical study was undertaken over 4months from November 2021 to March 2022. Participants applied the topical serum twice daily and were provided a gentle cleanser and an SPF 30+ to use in the morning. Follow-up visits were conducted at weeks 2, 4, and 8. At every visit, participants were measured for hydration post 15 minutes of cleansing the skin and post 15 minutes of product application for cumulative skin hydration sensor measurements. Additional procedures included participant assessments and satisfaction, investigator assessments, biopsies, and photography. At each follow-up visit, there was an increase in hydration measurements compared to baseline, in both immediate scores and cumulative long-term scores. At weeks 4 and 8, there was a statistically significant increase in hydration compared to baseline and the prior visit. Participants' assessments progressively increased over 2-, 4-, and 8-week intervals with significantly favorable ratings in all measured parameters. Similarly, investigator assessment grades were statistically significant (p < 0.0001) for decreased fine lines/wrinkling, crepiness, texture, erythema, and dryness, and increased (p < 0.0001) for moisture/hydration. Histology revealed increased CD44 staining in 6 of the 7 participants biopsied, denoting increased HA stimulation. In all of the participant biopsies, H&E staining demonstrated improvement in solar elastosis. Photography revealed remarkable improvement in erythema, tone, and texture. The study results demonstrated that the formulation produced significant improvements in immediate and long-term hydration effects on the skin as measured by the skin hydration sensor, 'wearifi' technology, comparison of before and after biopsies, and participant and investigator assessments. This high MW HA formulation produced excellent clinical improvement in skin health and hydration.

Oral Preparation of Hyaluronic Acid, Chondroitin Sulfate, Curcumin, and Quercetin (Ialuril® Soft Gels) for the Prevention of LUTS after Intravesical Chemotherapy.

Intravesical chemotherapy may cause chemical cystitis and related lower urinary tract symptoms (LUTS). The aims of this study were to evaluate the efficacy and safety of an oral preparation of hyaluronic acid (HA), chondroitin sulfate (CS), curcumin, and quercetin (Ialuril® Soft Gels) to reduce the severity of LUTS in patients with a history of bladder cancer (BCa) undergoing intravesical chemotherapy. We designed a monocentric, randomized, double-blind, placebo-controlled pilot trial. Patients referred to our institute between November 2016 and March 2018 were enrolled. All subjects had non-muscle-invasive BCa and received intravesical chemotherapy with mitomycin C (MMC). Patients were randomized 1:1 in two groups (intervention vs. control). All subjects underwent oral administration (Ialuril® Soft Gels or placebo) starting one week before the first weekly instillation and ending 30 days after the last one, subsequently starting one week before each monthly instillation and ending 14 days after it. International prostate symptom score (IPSS) and 0-100 visual analogue scale (VAS) were used to assess the efficacy of the treatment. Adverse events were also described. Patients were evaluated at baseline and after 1, 4, 7, and 13 months of intravesical chemotherapy. A total of 34 patients were enrolled. The median IPSS score was significantly lower in the intervention group compared to the control group at 4 (13 vs. 17 points; p = 0.038), 7 (10 vs. 18 points; p < 0.001), and 13 (10 vs. 17 points; p = 0.002) months. The median VAS score was significantly lower in the intervention group compared to the control group at 7 (22 vs. 37 points; p = 0.021) and 13 (20 vs. 35 points; p = 0.024) months. No AE specifically related to supplement or placebo was recorded. Oral formulation of HA, CS, quercetin, and curcumin could be an effective and safe supportive therapy against chemical cystitis in patients receiving intravesical chemotherapy for BCa.

Use of Hyaluronic Acid in Periodontal Disease Treatment: A Systematic Review

The main purpose of the present study was to investigate the potential benefit of local use of hyaluronic acid as an adjunct to periodontal therapy, since commercial products of hyaluronic acid (HA), due to its anti-inflammatory and anti-bacterial actions and its significant role in wound repair, have been proposed as adjuncts to either nonsurgical or surgical periodontal therapy. A total of 19 electronic databases were searched and the appropriate studies were identified with the use of specific eligibility criteria, according to PRISMA guidelines. Two reviewers independently screened and selected the studies and made the data extraction and the assessment of risk of bias, by using the Cochrane risk of bias tool. Out of 3,186 papers, 38 randomized clinical trials (8 related to gingivitis therapy, 20 related to nonsurgical periodontal therapy, and 10 related to surgical periodontal therapy) were finally included in the review. The outcomes were categorized as primary (that answered the focus question) and secondary (regarding additional quality characteristics). The adjunct use of HA combined to all treatment modalities shows improvement of patients' postoperative course, in terms of decreased inflammatory reactions, and changes in periodontal pocket depth and clinical attachment level. No side effects were reported in any of the included studies. Among the secondary outcomes were the variety of HA formulations and chemical forms, the variety in application, follow-up protocol and blinding design, the uneven geographic distribution of the studies, and the low bibliometric characteristics of most studies. Overall and despite the positive effects reported, further research is needed to define the ideal HA compound, formulation, and regimen characteristics for periodontal disease treatment. The adjunct use of HA may lead in the reduction of the prescription of nonsteroid anti-inflammatory drugs and achieve improved clinical parameters, including periodontal probing depth, periodontal inflammation, and clinical attachment level.

Novel Hyaluronic Acid ethosomes based gel formulation for topical use with reduced toxicity, better skin permeation, deposition, and improved pharmacodynamics

Hyaluronic Acid (HA) has been applied as an anti-ageing molecule in the form of topical products. Current topical commercial formulations of HA face the limitations of very small and stagnant skin permeation, thereby demanding enduring administration of the formulation to sustain its action. In this study, Lipid-based nanocarriers in the form of ethosomes were formulated in a 1% w/w HA strength and were extensively evaluated in vitro, ex-vivo, and in vivo parameters along with a comparison to it’s commercial counterpart. The optimised ethosomes-based HA gel formulation revealed required pH (6.9 ± 0.2), small globule size (1024 ± 9 nm), zeta potential of −6.39 ± 0.2 mV, and 98 ± 1.1% HA content. The ex vivo skin permeation and deposition potenwere conferred on synthetic membrane Strat-M, Human cadaver skin, mice skin, rat skin, and pig skin, and both parameters were found to be much higher in comparison to the commercial topical formulation. Skin deposition capacity of the optimised HA formulation was further confirmed by Scan Electron Microscopy (SEM) and Confocal Laser Scanning Microscopy (CLSM) and it was observed that the developed ethosomal gel formulation got deposited more on the treated skin. The in vivo anti-ageing effect of optimised ethosomal gel on rats was found to be greater when compared to commercial formulation of HA and the developed carrier-based system proved to deliver the HA molecule in very small amounts into the systemic circulation. The results endorse the ethosomal carrier-based formulation of HA as a attractive technique for better local bioavailability of HA.

Abstract 5990: Targeted nanoparticles reduce tumor progression and lung metastasis by limiting DNA damage repair and immune suppression in metastatic triple-negative breast cancer

Abstract Background: Metastatic triple-negative breast cancer (TNBC), especially with BRCA1/2 mutations, is a deadly subtype of breast cancer with ~12% of 5-year survival. Despite their FDA approval, the therapeutic benefits of poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) are limited to BRCA1/2 mutated malignancies. Moreover, the PARPi olaparib has been shown to upregulate the expression of programmed death-ligand 1 (PD-L1) leading to immune suppression. The purpose of this study is to investigate if a novel nanoparticle formulation of oligomer hyaluronic acid (oHA) and doxorubicin (DOX) co-loaded in an iRGD-conjugated polymer-lipid nanocarrier (iRGD-DOX-oHA-PLN) can inhibit DNA damage repair and suppress PD-L1 in both mutant and non-mutant TNBC cells and reduce tumor progression and lung metastasis compared to the PARPi olaparib. We postulate that the co-administered oHA will block the signaling pathways of native hyaluronic acid (HA) receptors, the cluster of differentiation 44 (CD 44) and receptor for HA mediated motility (RHAMM), that regulate DNA damage repair and immunosuppression and enhance DOX efficacy. Methods: In vitro cellular uptake of various DOX formulations by TNBC MDA-MB-231-luc-D3H2LN cells and MDA-MB-436 (BRCA1 mutant) cells was examined using confocal laser scanning microscopy or spectrophotometer. The expression level of RHAMM, PD-L1, and PARP1 parylation (PAR) was evaluated after treatment with iRGD-DOX-oHA-PLN or olaparib in both cell lines using western blot or confocal laser scanning microscopy. The therapeutic efficacy of iRGD-DOX-oHA-PLN compared to olaparib was determined by monitoring the tumor progression and lung metastasis development in orthotopic breast tumor models of MDA-MB-231-luc-D3H2LN or MDA-MB-436 cell line. Results: The expression of native HA receptor RHAMM was profoundly reduced by ~5 folds in vivo and the DNA DSB was significantly increased by the iRGD-DOX-oHA-PLN treatment with 40% of γH2AX positive cells in tumor tissue sections. The iRGD-functionalized PLN enhanced DOX cellular uptake compared to DOX free drug or non-targeted NPs by ~3- and ~1.5-fold, in MDA-MB-231 and MDA-MB-436 cells, respectively. While olaparib upregulated PD-L1 and free DOX increased PAR level, the iRGD-DOX-oHA-PLN reduced the parylation and PD-L1 expression in both TNBC cell lines. The iRGD-DOX-oHA-PLN treatment (two dose of 10 mg/kg i.v. biweekly) outperformed olaparib (twenty doses of 50 mg/kg i.p 5x/week) in preventing tumor progression and lung metastasis in vivo over a 4-week period. Conclusion: The results suggest that the iRGD-DOX-oHA-PLN can effectively inhibit DNA damage repair and immunosuppression of cancer cells and could be a promising multitargeted nanomedicine for the treatment of both BRCA1-mutant and non-mutant metastatic TNBC. Citation Format: Ibrahim Alradwan, Pei Zhi, Tian Zhang, HoYin Lip, Abdulmutalib Zetrini, Chunsheng He, Jeffery Henderson, Andrew Rauth, Xiao Yu Wu. Targeted nanoparticles reduce tumor progression and lung metastasis by limiting DNA damage repair and immune suppression in metastatic triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5990.

Health Economic Evaluation of a High and Low Molecular Weight Hyaluronic Acid Formulation for the Treatment of Knee Osteoarthritis. Post Hoc Analyses from a Randomized Clinical Trial.

IntroductionIn a recent randomized placebo-controlled trial, a single intra-articular injection of a high and low molecular weight hyaluronic acid formulation (HA–HL) was shown to be effective in providing a clinically meaningful reduction in pain and functional limitation up to 24 weeks in subjects with painful knee osteoarthritis (OA). The objective of this post hoc analyses is to assess the cost-effectiveness of HA–HL compared with placebo using individual patient data from this clinical trial in a Swiss health care perspective.MethodsA total of 692 patients fulfilling the inclusion criteria were randomly allocated to HA–HL or placebo groups. Each patient received one intra-articular injection of HA–HL or placebo at baseline and was then followed-up for a total duration of 24 weeks with five follow-up visits (i.e., after weeks 1, 6, 12, 18, and 24). The EQ-5D-5L five-point verbal Likert scale was used to calculate the health utility and the related quality-adjusted life-years (QALYs) using the area-under-the-curve (AUC) method. For the costs, the price of HA-HL in Switzerland was used. The primary threshold for the incremental cost/effectiveness ratio (ICER) below which HA-HL was considered as cost-effective was 91,540 Swiss francs (CHF) per QALY (i.e., US $100,000).ResultsNo significant difference between the baseline characteristics of the HA–HL group and the placebo group was observed. With a mean ICER of 27,212 CHF per QALY (95% CI 20,135–34,289), HA–HL was considered as cost-effective compared to placebo. Sensitivity analyses (e.g., using lower or upper limit prices or using other threshold values) gave similar results, i.e., ICERs far below the threshold values of cost-effectiveness.ConclusionsThese results confirm the role of HA–HL as a cost-effective therapeutic option in the management of OA. However, more studies taking into account the utilization of other health care resources are needed.

Hyaluronic acid in the treatment of dry eye disease.

Dry eye disease (DED) is a highly prevalent and debilitating condition affecting several hundred million people worldwide. Hyaluronic acid (HA) is a naturally occurring glycosaminoglycan commonly used in the treatment of DED. This review aims to critically evaluate the literature on the safety and efficacy of artificial tears containing HA used in DED treatment. Literature searches were conducted in PubMed, including MEDLINE, and in Embase via Ovid with the search term: "(hyaluronic acid OR hyaluronan OR hyaluronate) AND (dry eye OR sicca)". A total of 53 clinical trials are included in this review, including eight placebo-controlled trials. Hyaluronic acid concentrations ranged from 0.1% to 0.4%. Studies lasted up to 3 months. A broad spectrum of DED types and severities was represented in the reviewed literature. No major complications or adverse events were reported. Artificial tears containing 0.1% to 0.4% HA were effective at improving both signs and symptoms of DED. Two major gaps in the literature have been identified: 1. no study investigated the ideal drop frequency for HA-containing eyedrops, and 2. insufficient evidence was presented to recommend any specific HA formulation over another. Future investigations assessing the optimal drop frequency for different concentrations and molecular weights of HA, different drop formulations, including tonicity, and accounting for DED severity and aetiology are essential for an evidence-based, individualized approach to DED treatment.

Abstract P028: Effects of histone deacetylase inhibition on major histocompatibility compatibility complex (MHC) class I expression, growth, and migration of cancer cells

Abstract Background: Cancer is a devastating scourge, causing morbidity and mortality in both adult and pediatric populations. In this study, we analyzed the effects of histone deacetylase (HDAC) inhibitors on the MHC class I expression, growth, and migration of cancer cells. Within cancer cells, MHC class I molecules bind to fragments of tumor-associated peptides, and then migrate to the cell surface to present the peptides to T lymphocytes and induce lysis of the tumor cells, thereby preventing further spread of the malignancy. Pancreatic cancer, a disease afflicting older adults, is now the third most common cause of cancer-related death overall in the U.S. Neuroblastoma is the third most common childhood cancer and results in 12% of cancer-associated deaths in children less than 15 years of age. In both of these cancers, HDAC expression has been shown to be dysregulated and abnormally high. Although several HDAC inhibitors have been extensively investigated in preclinical studies and have entered clinical trials, the two HDAC inhibitors that we are evaluating in our research (M344 and RGFP966) have been the focus of only a few prior studies, and much remains to be discovered about their therapeutic effects. Methods: We treated cancer cell lines with HDAC inhibitors over a range of concentrations for multiple timepoints. Our investigations included analysis of MHC class I expression by immunoblotting for total subunit protein levels and flow cytometric monitoring of MHC class I levels at the cell surface, immunoblotting for the co-inhibitory protein PD-L1, transwell assays for migration, and MTT assays for cell growth. New collaborative studies have been initiated to develop two varieties of nanoformulations for optimization of the delivery of these HDAC inhibitors to tumors. Results: Our flow cytometry analysis demonstrated that the expression of the cell-surface human MHC class I molecules detected by antibodies recognizing HLA-A and both HLA-B and –C was elevated on S2-013 cells following M344 treatment. Increased total MHC class I heavy chain protein expression was induced in S2-013 cells by both M344 and RGFP966, and RGFP966 also increased PD-L1 expression. In addition, M344 and RGFP966 reduced S2-013 pancreatic cancer cell growth, and M344 slowed S2-013 migration and Neuro2a neuroblastoma cell growth. Analysis of M344 efficacy in an S2-013 orthotopic xenograft mouse model showed significant reduction of the tumor growth rate. Novel nanoparticles have been generated for M344 delivery using block copolymer and hyaluronic acid formulation strategies. Conclusions: Our evidence indicates that the HDAC inhibitors M344 and RGFP966 have anti-tumor potential via boosting MHC class I molecule expression to improve T cell recognition, as well as by tumor-intrinsic effects (i.e., down-regulation of proliferation and migration). Thus, both of these HDAC inhibitors warrant further analysis in adult and pediatric tumor mouse models, and may have potential for future clinical testing in patients. Citation Format: Shelby M. Knoche, Gabrielle L. Brumfield, Benjamin T. Goetz, Bailee H. Sliker, Cecilia Barbosa, Svetlana Romanova, Tatiana Bronich, Donald W. Coulter, Joyce C. Solheim. Effects of histone deacetylase inhibition on major histocompatibility compatibility complex (MHC) class I expression, growth, and migration of cancer cells [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P028.

Assessment of the Efficiency of HP-Guar and hyaluronic Acid Tear Supplements to Control Tear Film Evaporation Rate in Dry Eye Subjects

Background: The most common factor that could lead to dryness is the accelerated tear evaporation rate. Controlling the tear evaporation rate is increasingly used as a method to control dry eye complications. The present study explores the effects of different tear supplements formulations on tear film evaporation rate. Objective: This study aimed to evaluate the short-term effects of Systane ULTRA and Artelac Advanced eye drops on the tear film evaporation rate. Methods: Fifteen male dry eye subjects were enrolled in the current study. Tear film parameters were observed at several time points post installation (10, 20, 30, and 60 min). The tear film parameters observed in the current study were tear evaporation rate, noninvasive breakup time (NITBUT) and tear meniscus height (TMH). Two visits were required to conduct this study. One visit was conducted to assess the physiological tear film parameters with the use of Systane® ULTRA eye drop. The other visit was conducted to assess tear film parameters with the use of Artelac Advanced eye drop. Results: The mean tear evaporation rate at baseline was 52.58 ± 23.24 g/m2 h. A box plot of tear evaporation showed a reduction in tear film evaporation rate after instillation of Systane eye drop. A drop in tear film evaporation rate of 14% was observed at 20 and 60 min time point after instillation of Systane ULTRA eye drop. A significant increase in NITBUT was found after instillation of Systane ULTRA (P = 0.01) and Artelac Advanced (P = 0.02). Conclusion: The current study indicates a significant improvement in the tear film parameters using both HP-Guar and hyaluronic acid formulations. However, it was apparent that the use of HP-Guar was superior to hyaluronic acid in controlling the tear evaporation rate in dry eye subjects.

Hyaluronic Acid Injections for Knee Osteoarthritis: Has Utilization Among Medicare Beneficiaries Changed Between 2012 and 2018?

The utilization of hyaluronic acid (HA) for the management of knee osteoarthritis (OA) remains controversial, and more information is needed regarding how its utilization and financial burden have changed over recent years. The purpose of our analysis was to evaluate changes in overall utilization and health-care costs associated with HA injections among Medicare beneficiaries over a contemporary time frame. The 2012 to 2018 Medicare Fee-for-Service Provider Utilization and Payment Public Use Files (PUFs) were utilized for our analysis. Organized by Healthcare Common Procedure Coding System (HCPCS) codes, these files capture 100% of Medicare Part B claims. Payment and utilization data were collected for all HCPCS codes corresponding to injection of an HA formulation. The number of services involving HA as well as the total cost of HA administration in 2020 U.S. dollars were tabulated. Mann-Kendall trend tests were used to evaluate trends in utilization for providers nationally and when segregated by specialty. Total HA utilization increased significantly from 2012 (n = 1,090,503) through 2018 (n = 1,209,489; p = 0.04). Although orthopaedic surgeons did not demonstrate significant changes in total utilization rates (p = 0.23), the average number of services per orthopaedic surgeon increased significantly (p = 0.02). Reflecting a substantial growth in the number of advanced practice providers (APPs) providing injections, there was a significant increase in utilization and associated costs among physician assistants (p < 0.01) and nurse practitioners (p < 0.01). Total costs associated with HA services increased significantly from $290.10 million to $325.02 million (p < 0.01). Despite the 2013 American Academy of Orthopaedic Surgeons clinical practice guideline recommending against the clinical utility of these injections, HA services continued to be widely implemented among Medicare beneficiaries. Although there were variations across specialties when evaluating overall utilization rates as well as rates per provider, APPs largely contributed to the increase seen in the U.S. over this study period. More data are needed to support continued implementation and spending on this low-value care.

In vivo joint synovial fluid disposition of a novel sustained-release formulation of diclofenac and hyaluronic acid in horses.

Intra-articular administration of sustained-release anti-inflammatory drugs is indicated in horses suffering from joint inflammation, but no such drugs are labelled for veterinary use. To obtain initial data on synovial disposition and safety of a new sustained-release formulation of diclofenac (SYN321) in the joints of horses, an experimental interventional study of elimination and side effects of intra-articular administration of SYN321 was conducted. Nine clinically sound horses were included in the study, and SYN321 was administered by the intra-articular route. Dose ranges and sampling intervals were established in a pilot study with two horses, and then applied in a main study involving seven horses treated in the fetlock joint. Diclofenac was detected above lower limit of quantification (LOQ: 0.5ng/ml) in synovial fluid throughout the study period (14days), and below LOQ (0.1ng/ml) in plasma after 4days and in urine after 14days. No obvious clinical side effects were detected. Clinical examination and objective lameness evaluation suggested that SYN321has potential as a local joint NSAID treatment with sustained release in horses, but further studies on synovial fluid exposure, safety and clinical efficacy are warranted.

EFFECTIVENESS AND SAFETY OF INTRA-ARTICULAR HYALURONIC ACID IN ATHLETES WITH ARTICULAR LESIONS: A MULTICENTER, PROSPECTIVE OBSERVATIONAL STUDY

Objective: To evaluate the effectiveness and safety of a novel intra-articular formulation of hyaluronic acid (HA) to treat athletes with articular lesions. Methods: Multicenter, prospective, interventional, observational study analyzing the clinical evolution of athletes who received 2 or 3 intra-articular injections of HA. The study was scheduled in Visit 1 (week 0), Visit 2 (week 1), Visit 3 (week 2), Visit 4 (week 3), and Visit 5 (end of follow up, week 24). The change in Visual Analog Scale (VAS) of pain and in Knee Injury and Osteoarthritis Outcome Score (KOOS) and the rate of return to physical activity were evaluated upon treatment initiation for up to 24 weeks. The incidence of adverse events was recorded throughout the study. Results: Sixty patients were recruited: 28 (46.7%) in the 2-injection group and 32 (53.3%) in the 3-injection group. Mean VAS gradually decreased across the visits, with statistically significant reductions in both groups from Visit 2 to Visit 3 and to Visit 5 (P &lt; 0.0001). Inter-group differences in the change in VAS from Visit 2 to Visit 5 were statistically comparable (P = 0.8271). At Visit 5, the KOOS of all subscales statistically improved in both treatment groups. At the end of follow-up (Visit 5), 75.9% of patients returned to sport in the overall population. Only one patient reported an adverse event. Conclusion: This novel formulation of HA is effective and safe for at least 24 weeks, resulting in a promising treatment option for athletes with articular lesions.