Mechanical, optical, and physicochemical properties of HPMC-based doxazosin mesylate orodispersible films

Abstract In this study, orodispersible films formed from hydroxypropyl methylcellulose (HPMC) E6 (2, 2.5, and 3%) and plasticizers ((glycerin (Gly), propylene glycol (PP), or polyethylene glycol (PEG)), containing doxazosin mesylate, were prepared by the solvent casting method and characterized. Design of experiments (DoE) was used as a statistical tool to facilitate the interpretation of the experimental data and allow the identification of optimal levels of factors for maximum formulation performance. Differential scanning calorimetry (DSC) curves and X-ray powder diffraction (XRPD) diffractograms showed doxazosin mesylate amorphization, probably due to complexation with the polymer (HPMC E6), and the glass transition temperature of the polymer was reduced by adding a plasticizer. Fourier transformed infrared (FTIR) spectroscopy results showed that the chemical structure of doxazosin mesylate was preserved when introduced into the polymer matrix, and the plasticizers, glycerin and PEG, affected the polymer matrix with high intensity. The addition of plasticizers increased the elongation at break and adhesiveness (Gly > PEG > PP), confirming the greater plasticizer effect of Gly observed in DSC and FTIR studies. Greater transparency was observed for the orodispersible films prepared using PP. The addition of citric acid as a pH modifier was fundamental for the release of doxazosin mesylate, and the desirability formulation had a release profile similar to that of the reference product

Mechanical properties and immunotherapeutic effects of dissolving microneedles with different drug loadings based on hyaluronic acid

Abstract Improving vaccine immunity and reducing antigen usage are major challenges in the clinical application of vaccines. Microneedles have been proven to be painless, minimally invasive, highly efficient, and have good patient compliance. Compared with traditional transdermal drug delivery, it can effectively deliver a large-molecular-weight drug into the skin, resulting in a corresponding immune response. However, few studies have examined the relationship between microneedle loading dose and immune effects. In this study, the hyaluronic acid (HA) conical and pyramidal dissolving microneedles were prepared by the two-step vacuum drying method, respectively. The model drug ovalbumin (OVA) was added to HA to prepare dissolving microneedles with different loading amounts. The mass ratios of HA to OVA were 5:1, 5:3, and 5:5. The mechanical properties of the dissolving microneedles were characterized using nanoindentation and in vitro puncture studies. The immune effects of the matrix and drug content were studied in Sprague-Dawley (SD) rats. Finally, the diffusion behavior of OVA and the binding mode of HA and OVA in the microneedles were simulated using Materials Studio and Autodocking software. The experimental results showed that the conical microneedles exhibited better mechanical properties. When the mass ratio of HA to OVA was 5:3, the immune effect can be improved by 37.01% compared to subcutaneous injection, and achieved a better immune effect with relatively fewer drugs. This conclusion is consistent with molecular simulations. This study provides theoretical and experimental support for the drug loading and efficacy of microneedles with different drug loadings

An evaluation of dermal microcirculatory occlusion under repeated mechanical loads: Implication of lymphatic impairment in pressure ulcers.

OBJECTIVE: Pressure ulcers are caused by prolonged mechanical loads deforming the underlying soft tissues. However, the mechanical loads for microcirculatory occlusion are unknown. The present study was designed to characterize the simultaneous response of microvascular and lymphatic structures under repeated mechanical loading. METHODS: The effects of two distinct loading/unloading cycles involving (a) incremental pressures 30, 60, and 90 mmHg and (b) three repeated cycles of 30 mmHg were evaluated on a cohort of able-bodied volunteers. Microvascular response involved the monitoring of transcutaneous gas tensions, while dermal lymphatic activity was estimated from near-infrared imaging. Responses were compared during each load and recovery cycle. RESULTS: Changes in microvascular response were dependent on the load magnitudes, with 30 mmHg resulting in a reduction in oxygen tension only, while 90 mmHg affected both oxygen and carbon dioxide values in most cases (54%). By contrast, lymphatics revealed near total occlusion at 30 mmHg. Although there were intersubject differences, temporal trends consistently revealed partial or full impairment under load, with recovery during off-loading. CONCLUSIONS: The pressure required to cause microcirculatory occlusion differed between individuals, with lymphatic impairment occurring at a lower pressure to that of microvascular vessels. This highlights the need for personalized care strategies and regular off-loading of vulnerable tissues.

Establishing a measurement array to assess tissue tolerance during loading representative of prosthetic use.

BACKGROUND: In the early stages of rehabilitation after primary amputation, residual limb soft tissues have not been mechanically conditioned to support load and are vulnerable to damage from prosthetic use. There is limited quantitative knowledge of skin and soft tissue response to prosthetic loading. METHODS: An in-vivo protocol was developed to establish suitable measures to assess tissue tolerance during loading representative of early prosthesis use. Ten participants without amputation one participant with trans-tibial amputation were recruited, and pressure applied to their calf in increments from 20 to 60 mmHg. Measurements were recorded at relevant skin sites including interface pressures, transcutaneous oxygen (TCPO2) and carbon dioxide (TCPCO2) tensions and inflammatory biomarkers. FINDINGS: At the maximum cuff pressure, mean interface pressures were between 66 and 74 mmHg, associated with decreased TCPO2 values. On the release of pressure, the ischaemic response was reversed. Significant upregulation (p < 0.05) in inflammatory biomarker IL-1α and its antagonist IL-1RA were observed at all sites immediately following loading. INTERPRETATION: The protocol was successful in applying representative prosthetic loads to lower limb tissues and monitoring the physiological response, both in terms of tissue ischemia and skin inflammation. Results indicated that the measurement approaches were sensitive to changes in interface conditions, offering a promising approach to monitor tissue status for people with amputation.

A Helmholtz resonator on elastic foundation for measurement of the elastic coefficient of human skin.

A new sensing mechanism is proposed for the measurement of elasticity of human skin by utilizing Helmholtz resonator with a flexible membrane mounted at the bottom and putting on an elastic foundation. Elastic coefficient of human skin is modeled as the elastic foundation modulus, based on the assumption that human skin is equivalent to the Winkler foundation. For the Helmholtz resonator, the acoustic transmission loss (by which resonant frequency can be acquired) was derived by using the receptance coupling method, based on the theories of conventional Helmholtz resonator and fixed-edge membrane on elastic foundation. The fundamental resonant frequency of the proposed Helmholtz resonator was proved to be related with the elastic foundation modulus, and was used as the indicator of elastic foundation modulus to be measured. Theoretical derivation for measuring elastic foundation modulus and analytical example were presented. Experiments measuring the elastic foundation modulus of the phantoms were carried out by utilizing phantoms with different stiffness using gelatin with corresponding different concentrations. The analytical and experimental results verified the effectiveness of the proposed method. Nanoindentation test was conducted for comparison, and relative errors ranged from 9.24% to 20.06% were obtained, which tends to be higher with the increasing concentration of gelatin.

A multi-purpose force-controlled loading device for cartilage and meniscus functionality assessment using advanced MRI techniques.

Response to loading of soft tissues as assessed by advanced magnetic resonance imaging (MRI) techniques is a promising approach to evaluate tissue functionality beyond (statically obtained) structural and compositional features. As cartilage and meniscus pathologies are closely intertwined in osteoarthritis (OA) and beyond, both tissues should ideally be studied to elucidate further the underlying mechanisms involved in load transmission and its failure leading to OA. Hence, we devised, constructed and validated a dedicated MRI-compatible pneumatic force-controlled loading device to study cartilage and meniscus functionality in a standardized and reproducible manner and in reference to alternative tissue evaluation methods. Mechanical reference measurements using digital force sensors confirmed the reproducible application of forces in the range of 0-76N. To demonstrate the device's utility in a basic research context, MRI measurements of human articular cartilage (obtained from the lateral femoral condyle, n = 5) and meniscus (obtained from lateral meniscus body, n = 5) were performed in the unloaded (δ0) and loaded configurations (δ1: [cartilage] 0.75 bar corresponding to 15.1 N, [meniscus] 2 bar corresponding to 37.1 N; δ2: [cartilage] 1.5 bar corresponding to 28.6 N, [meniscus] 4 bar corresponding to 69.1 N). Cartilage samples were directly indented, while meniscus samples were subject to torque-induced compression using a dedicated lever compression device. Morphological MR Imaging using Proton Density-weighted sequences and quantitative MR Imaging using T2 and T1ρ mapping were performed serially and at high resolution. For reference, samples underwent subsequent biomechanical and histological reference evaluation. In conclusion, the force-controlled loading device has been validated for the non-invasive response-to-loading assessment of human cartilage and meniscus samples by advanced MRI techniques. Hereby, both tissues may be functionally evaluated in combination, beyond mere static analysis and in reference to histological and biomechanical measures.