Chondroitin sulfate-liposome: clustering toward high functional efficiency.

Chondroitin sulfate (CS) is a linear polysaccharide chain of alternating residues of glucuronic acid (GlcA) and N-acetylgalactosamine (GalNAc), modified with sulfate groups. Based on the structure, CS chains bind to bioactive molecules specifically and regulate their functions. For example, CS whose GalNAc is sulfated at the C4 position, termed CSA, and CS whose GalNAc is sulfated at both C4 and C6 positions, termed CSE, bind to a malaria protein VAR2CSA and receptor type of protein tyrosine phosphatase sigma (RPTPσ), respectively in a specific manner. Here, we modified CSA and CSE chains with phosphatidylethanolamine (PE) at a reducing end, attached them to liposomes containing phospholipids, and generated CSA- and CSE-liposomes. The CS-PE was incorporated into the liposome particles efficiently. Inhibition ELISA revealed specific interaction of CSA and CSE with recombinant VAR2CSA and RPTPσ, respectively, more efficiently than CS chains alone. Furthermore, CSE-liposome was specifically incorporated into RPTPσ-expressing HEK293T cells. These results indicate CS-liposome as a novel and efficient drug delivery system, especially for CS-binding molecules.

Regional variations and sex-related differences of stiffness in human tracheal ligaments.

PURPOSE: There have been numerous studies focused on the stiffness of tracheal cartilage. However, no research has been conducted specifically on the annular ligament, nor have any regional differences in the annular ligament been identified. The purpose of this study was to investigate the stiffness of the ligaments present between the thyroid, cricoid and tracheal cartilages. METHODS: The ligaments were identified in the cervical region of living subjects with ultrasonography. The stiffness of the ligaments was measured from the body surface using a digital palpation device (MyotonPRO). Since it is impossible to measure the entire trachea in a living subject, an additional measurement was performed on human cadavers. RESULTS: Both in vivo and cadaveric investigations found that the stiffness of annular ligaments decreased gradually from the superior to inferior parts. There was no difference in the stiffness between males and females in the superior part of the trachea. However, the stiffness of the middle and inferior parts was predominantly higher in females than in males. Furthermore, males showed significant differences in stiffness between the superior and middle parts, while females showed no significant differences. CONCLUSION: These results reveal that there are regional and sex-related differences in the stiffness of human tracheal ligaments.

A rat model for acute limb ischemia using microsized gelatin beads.

OBJECTIVE: Acute limb ischemia (ALI) is a rapid decrease in lower limb blood flow due to acute occlusion of peripheral arteries or bypass grafts. This study aimed to establish an ALI model using microsized gelatin beads and to investigate the pathophysiological conditions. METHODS: Male Sprague-Dawley rats were anesthetized, and a low or high dose of microsized gelatin beads was administered into the left femoral artery on days 0 and 7. A control, that is, normal saline (NS) group in which NS was administered in the left femoral artery, a femoral artery cut (FAC) group in which the left femoral artery was cut, and a sciatic nerve cut (SNC) group in which the left sciatic nerve was cut were prepared. After 21 days, the temperature changes and the muscle weights in the lower limbs were measured. To assess nerve damage, the L1-6 sympathetic ganglia were immunostained with activating transcription factor 3 (ATF3) antibody. RESULTS: In the Low-dose, High-dose, and FAC groups, a decrease in temperature was predominantly observed in the left limb. In the High-dose and SNC groups, the weight of the soleus muscle and extensor digitorum longus in the left limb decreased; however, no weight changes were observed in the Low-dose and FAC groups. Conversely, the weight of the gastrocnemius muscle significantly decreased in the Low-dose, High-dose, FAC, and SNC groups. In the High-dose and SNC groups, the number of ATF3-positive cells in the sympathetic ganglia significantly increased, and in the Low-dose, a small number of ATF3-positive cells were observed. However, ATF3-positive cells were rarely observed in the FAC and NS groups. CONCLUSION: We established an ALI rat model using microsized gelatin beads. The results of this study suggest that autonomic neuropathy in ALI is related to both muscle damage and peripheral neuropathy.

Assessing site-specificity of the biomechanical properties of hamstring aponeuroses using MyotonPRO: A cadaveric study.

BACKGROUND: Hamstring muscles are the most frequently reported sites of muscle strain injuries, especially near the bi-articular muscles' myotendinous junction, where aponeurosis provides a connective tissue network linking muscle fibers to the tendon. This study aimed to investigate the reliability and site-specific differences of hamstring aponeuroses under different conditions (formalin and urea) using MyotonPRO. METHODS: Eight hamstring muscle groups were dissected from four human cadavers (two males and two females) aged 83-93 years. Measurements of the mechanical properties of the aponeuroses from the superficial and deep regions of biceps femoris long head, semitendinosus, and semimembranosus (after formalin solution immersion) were done using MyotonPRO (intra-rater reliability was examined within a 24-h interval), following which the hamstring aponeuroses were measured using a similar procedure after urea solution immersion. FINDINGS: Test-retest (intra-rater) results revealed that the MyotonPRO measurement of tone, stiffness, relaxation, and creep of cadaveric aponeuroses presented good to excellent reliability (ICC: 0.86 to 0.98). There were no significant differences in tone, stiffness, elasticity, relaxation, and creep among the six sites of hamstring aponeuroses under both formalin and urea conditions. Significant differences between formalin and urea conditions were found in the tone, stiffness, relaxation, and creep of hamstring aponeuroses (P < 0.05). INTERPRETATION: These results suggested that the biomechanical properties of hamstring aponeuroses showed homogeneity between the sites using MyotonPRO. Urea solution could potentially neutralize the effect of formalin on the biomechanical properties of cadaveric muscle-aponeurosis-tendon units. The present findings might influence the design of subsequent cadaveric studies on hamstring muscle strains.

Thickness of the Medial Pretarsal Adipose Tissue in the Upper Eyelid among the Japanese Population.

PURPOSE: To investigate the medial pretarsal adipose tissue thickness of the upper eyelid in the Japanese population. METHODS: Sixty-two whole upper eyelids were harvested from 35 Japanese cadavers and fixed in paraffin. The samples were cut into 5 µm sagittal microsections and stained with hematoxylin and eosin, as well as Masson's trichrome. Data obtained from images and measurements were taken with Aperio ScanScope and ImageScope software and underwent statistical analysis. RESULTS: The samples were divided into 3 shapes sagittal cross-sections of the eyelid (triangular, rectangular, and flat) corresponding to the shape of the medial pretarsal adipose tissue. Type I (triangular shape, 48.4%) had a ratio of fat thickness at 1/2 tarsal height to peak fat thickness of <0.9, and type IIa (rectangular shape, 30.6%) and IIb (flat shape, 21.0%) had pretarsal adipose tissue thickness to tarsal height ratio of ≥0.2 and <0.2, respectively. The mean values of tarsal thickness at 1/2 tarsal height were 1021 µm for the type I group, 1100 µm for the type IIa group, and 764.4 µm for the type IIb group ( p = 0.01). The mean values of fat thickness at 1/2 tarsal height were 410.6 µm for the type I group, 303.3 µm for the type IIa group, and 242.6 µm for the type IIb group ( p = 0.26). CONCLUSIONS: The thickness of the medial pretarsal adipose tissue was different according to the shape of the sagittal cross-section of the eyelid. Awareness of the medial pretarsal adipose tissue thickness contributes to effective suture placement and safe suture depth during blepharoptosis surgery.

Biomechanical assessment of gastrocnemii and Achilles tendon using MyotonPRO: in vivo measurements, and preliminary in situ measurements using formalin-fixed tissues.

PURPOSE: This study aims to evaluate the reliability and validity of using MyotonPRO to quantify the mechanical properties of the muscle-tendon unit through in vivo measurements and preliminary in situ measurements using formalin-fixed tissues. MATERIALS AND METHODS: The mechanical properties of gastrocnemii and the Achilles tendon of 12 healthy adults (six males and six females, 34.9 ± 5.8 years) were examined for in vivo test twice within a day and once post-24 hours using MyotonPRO, while nine human cadavers (formalin-fixed, 3 males and 6 females, 89.9 ± 5.1 years) were assessed for preliminary in situ test with identical time schedule to evaluate the within-day and inter-day reliability and validity. RESULTS: In vivo tests had very high within-day (ICC: 0.96-0.99) and inter-day reliability (ICC: 0.83-0.96), while in situ tests (formalin-fixed tissues) showed high within-day (ICC: 0.87-0.99) and inter-day reliability (ICC: 0.76-0.98) for the results of tone and stiffness. There was no significant difference in the stiffness of the free part of the Achilles tendon between in vivo and in situ conditions. The stiffness of the lateral gastrocnemius (r = 0.55, p = 0.018), proximal part of the Achilles tendon (r = 0.56, p = 0.015), and free part of the Achilles tendon (r = 0.47, p = 0.048) before removing the skin was significantly correlated with that after removing the skin condition. CONCLUSIONS: The findings of the current study suggest that MyotonPRO is reliable and valid for evaluating tendon stiffness both in vivo and in situ (formalin-fixed tissues).

Effect of interprofessional education on cadaver dissection seminar.

In 2010, WHO published a "Framework for action on interprofessional education and collaborative practice." Interprofessional education (IPE) is now being conducted in various ways. We have been holding cadaver dissection seminars to provide opportunities for medical students, nursing students, and nurse practitioner (NP) students to learn together. In this study, we investigated the effect of learning about IPE in cadaver dissection seminars. The seminars were held for 5 days each in 2021 and 2022 (the number of days of participation was arbitrary). In the seminars, teams of 3-5 participants with the same theme collaborated to dissect a single donated cadaver. Teams were made up of participants with different departments: 29 medical students, 12 NP students, and 20 nursing students participated in the seminar, and participants were surveyed before and after the seminars. The Readiness for Interprofessional Learning Scale (RIPLS) scores before and after the dissection seminar increased significantly overall. The scores of medical and nursing students increased significantly, but those of NP students did not significantly change. In terms of the number of days of participation, a significant increase in scores was found for participants who participated for ≥ 2 days. Overall, a significant positive correlation was found between intrinsic motivation to learn and RIPLS scores. For medical students, a significant negative correlation was noted between extrinsic motivation and RIPLS scores. Cadaver dissection seminars conducted by medical, nursing, and NP students demonstrated IPE learning effect on medical students and undergraduate nursing students.

Specific acupuncture stimulation of Shenshu (BL23) affects sympathetic nervous activity-associated plasma renin concentration changes.

OBJECTIVE: To examine whether specific stimulation of Shenshu (BL23) affects sympathetic nervous activity (SNA)-associated plasma renin concentration (PRC). METHODS: Eight healthy volunteers participated in three pattern conditions in random order: control (Cont), stimulation of Shenshu (BL23), and stimulation of sham point (Sham). All participants were initially in the supine position for > 60 min, and then remained in the standing position during the experimental procedure to increase SNA. An electrocardiogram was used to calculate low frequency/high frequency (LF/HF) ratio; blood was collected to analyze PRC. RESULTS: The LF/HF ratio was significantly increased in the standing position when compared with the supine position ( 0.01). There was no difference in LF/HF ratio during or after stimulation of Shenshu (BL23) in the standing position when compared with before the stimulation in the supine position; however, the LF/HF ratio was significantly increased in Cont and Sham conditions ( 0.01). There was no difference in PRC after stimulation of Shenshu (BL23) in the standing position when compared with before the stimulation in the supine position; however, there was a significant increase in PRC in the Cont and Sham conditions (Cont 0.05, Sham 0.01). CONCLUSION: Our results demonstrated that specific acupuncture stimulation of Shenshu (BL23) in the standing position decreased SNA-associated PRC, which was not observed during acupuncture stimulation of the sham point.

Nerve branches to the anterior tibial artery: Clinical application.

Arteries receive vascular branches (VBs) from peripheral nerves. VBs are thought to be involved in arterial constriction. Although the anterior tibial artery (ATA) receives VBs, information on their branching patterns and distribution areas remains limited. The aim of this study was to investigate the anatomical structures of the VBs reaching the ATA. Forty cadaver limbs were examined to assess the branching patterns and distribution areas of the VBs reaching the ATA. The VBs reaching the ATA ramified from the deep fibular nerve (DFN), and the ATA received two or three VBs in each limb. The following mean distances from the head of fibula to the points at which the VBs reached the ATA were measured: all the VBs, 1st VB, 2nd VB and 3rd VB. The measurements were 51.5 ± 23.2 mm, 33.3 ± 3.7 mm, 53.3 ± 18.6 mm, and 72.2 ± 24.5 mm, respectively. In all limbs, the DFN and the ATA converged after the DFN branched into the 1st VB. The 2nd VB in 38 of 40 limbs and the 3rd VB in 20 of 32 limbs were distributed in the ATA proximal to the convergence point of the ATA and the DFN. These findings revealed that all VBs reaching the ATA ramified from the DFN in all limbs. The ATA received two or three VBs, and all the 1st VBs distributed to the ATA proximal to the convergence point.

Recurrent position and innervation pattern of recurrent peroneal nerve: A cadaveric study.

BACKGROUND: The recurrent peroneal nerve (RPN) branches from the common peroneal nerve or the deep peroneal nerve and it innervates to the lower patellar region. It has recently been reported that damage to the RPN causes pain in the lower patellar region; therefore, this study examined the recurrent position and the innervation pattern of the RPN. METHODS: Cases of knee deformity or atrophy were excluded, and 50 legs (25 males and 25 females) of 34 cadavers (15 males and 19 females) were examined to assess the recurrent position and the innervation pattern of the RPN. RESULTS: The recurrent position of the RPN was 27.9 ± 3.6 mm from the tip of the fibula. The RPN innervated to the patellar tendon in five of the 50 legs (10%), to the infrapatellar fat pad in 13 legs (26%), and to both the patellar tendon and the infrapatellar fat pad in 20 legs (40%), and to neither the patellar tendon nor the infrapatellar fat pad in 12 legs (24%). No significant sex differences were observed in the recurrent position and the innervation pattern of the RPN. CONCLUSIONS: In all cases, the recurrent position of the RPN was almost fixed from the tip of the fibula. The RPN frequently innervated to the patellar tendon or the infrapatellar fat pad (76%) in both males and females. These findings would be useful in knee surgery to preserve the RPN or for the diagnosis of pain in the lower patellar region.

Physical disuse contributes to widespread chronic mechanical hyperalgesia, tactile allodynia, and cold allodynia through neurogenic inflammation and spino-parabrachio-amygdaloid pathway activation.

Physical disuse could lead to a state of chronic pain typified by complex regional pain syndrome type I due to fear of pain through movement (kinesiophobia) or inappropriate resting procedures. However, the mechanisms by which physical disuse is associated with acute/chronic pain and other pathological signs remain unresolved. We have previously reported that inflammatory signs, contractures, disuse muscle atrophy, spontaneous pain-like behaviors, and chronic widespread mechanical hyperalgesia based on central plasticity occurred after 2 weeks of cast immobilization in chronic post-cast pain (CPCP) rat model. In this study, we also demonstrated dystrophy-like changes, both peripheral nociceptive signals and activation of the central pain pathway in CPCP rats. This was done by the following methods: (1) vascular permeability (Evans blue dye) and inflammatory- and oxidative stress-related messenger RNA changes (real-time quantitative polymerase chain reaction); (2) immunofluorescence of pERK and/or c-Fos expression in the spino-parabrachio-amygdaloid pathway; and (3) blockade of nociceptive-related signals using sciatic nerve block. Furthermore, we demonstrated tactile allodynia using an optogenetic method in a transgenic rat line (W-TChR2V4), cold allodynia using the acetone test, and activation of dorsal horn neurons in the chronic phase associated with chronic mechanical hyperalgesia using c-Fos immunofluorescence. In addition, we showed that nociceptive signals in the acute phase are involved in chronic pathological pain-like behaviors by studying the effects of sciatic nerve block. Thus, we conclude that physical disuse contributes to dystrophy-like changes, spontaneous pain-like behavior, and chronic widespread pathological pain-like behaviors in CPCP rats after 2 weeks of cast immobilization.

Developing spray-freeze-dried particles containing a hyaluronic acid-coated liposome-protamine-DNA complex for pulmonary inhalation.

The liposome-protamine-DNA complex (LPD) is an effective cationic carrier of various nucleic acid constructs such as plasmid DNA and small interfering RNA (siRNA). Hyaluronic acid coated on LPD (LPDH) reduces cytotoxicity and maintains the silencing effect of LPD-encapsulated siRNA. Herein, we aim to develop LPD- or LPDH-containing spray-freeze-dried particles (SFDPs) for therapeutic delivery of siRNA to the lungs. LPD- or LPDH-containing SFDPs (LPD- or LPDH-SFDPs) were synthesized and their structure and function as gene carriers were evaluated using physical and biological methods. The particle size of LPDH, but not of LPD, was constant after re-dispersal from the SFDPs and the amount of siRNA encapsulated in LPDH was larger than that in LPD after re-dispersal from the SFDPs. The in vitro pulmonary inhalation properties of LPDH-SFDPs and LPD-SFDPs were almost the same. The cytotoxicity of LPDH-SFDPs in human umbilical vein endothelial cells (HUVEC) was greatly decreased compared with that of LPD-SFDPs. In addition, Bcl-2 siRNA in LPDH-SFDPs had a significant gene silencing effect in human lung cancer cells (A549), whereas Bcl-2 siRNA in LPD-SFDPs had little effect. These results indicate that compared with LPD, LPDH is more useful for developing SFDPs for siRNA pulmonary inhalation.

High-Pressure Carbon Monoxide and Oxygen Mixture is Effective for Lung Preservation.

(1) Background: Heme oxygenase-1 (HO-1) degrades heme and generates carbon monoxide (CO), producing various anti-inflammatory, anti-oxidative, and anti-apoptotic effects. This study aimed to confirm the effects of CO on the ischemia-reperfusion injury (IRI) of donor lungs using a high-pressure gas (HPG) preservation method. (2) Methods: Donor rat and canine lungs were preserved in a chamber filled with CO (1.5 atm) and oxygen (O2; 2 atm) and were ventilated with either CO and O2 mixture (CO/O2 group) or air (air group) immediately before storage. Rat lungs were subjected to heterotopic cervical transplantation and evaluated after reperfusion, whereas canine lungs were subjected to allogeneic transplantation and evaluated. (3) Results: Alveolar hemorrhage in the CO/O2 group was significantly milder than that in the air group. mRNA expression levels of HO-1 remained unchanged in both the groups; however, inflammatory mediator levels were significantly lower in the CO/O2 group than in the air group. The oxygenation of graft lungs was comparable between the two groups, but lactic acid level tended to be higher in the air group. (4) Conclusions: The HO-1/CO system in the HPG preservation method is effective in suppressing IRI and preserving donor lungs.

Different effects of partial pressure in a high-pressure gaseous mixture of carbon monoxide and oxygen for rat heart preservation.

We maintained the function of an extracted rat heart after 24-48 h preservation in a high-pressure gaseous mixture of carbon monoxide (CO) and oxygen (O2). Here, we assessed the effects of different partial pressures of hyperbaric CO and O2 for 24-48 h at 4 °C on rat heart preservation and compared conditions including immersion in University of Wisconsin solution. Preserved hearts were transplanted into recipient rats via heterotopic cervical heart transplantation for in vivo evaluation and perfused using the Langendorff system for ex vivo evaluation. The survival rate of transplanted hearts was 100% at postoperative day 7 in the CO + O2 (PCO:PO2 = 1.5:2.0 atm) group but only 33% in the CO + O2 (PCO:PO2 = 2.0:1.5 atm) group. Langendorff system and histopathological analysis revealed that the left ventricular pressure of preserved hearts in the CO + O2 (PCO:PO2 = 1.5:2.0 atm) group was better than the CO + O2 (PCO:PO2 = 2.0:1.5 atm). We demonstrate that exposure of rat hearts to hyperbaric CO and O2 is superior to the immersion method and that partial pressure of hyperbaric CO and O2 is crucial to preservation.

Preparation of Curcumin-Containing α-, ß-, and γ-Cyclodextrin/Polyethyleneglycol-Conjugated Gold Multifunctional Nanoparticles and Their in Vitro Cytotoxic Effects on A549 Cells.

Gold nanoparticles (GNPs) have promising properties such as photothermal effects and could be useful for imaging and as multifunctional nanocarriers for various drugs. In this study, we synthesized polyethyleneglycol (PEG)-grafted GNPs and conjugated them with cyclodextrin (CD) to incorporate curcumin. Curcumin has anticancer effects but its therapeutic application is limited due to poor water solubility. Three types of CDs (α-, ß-, and γ-CDs) were conjugated with PEGylated GNPs and the curcumin-containing CD/PEG-conjugated GNPs (cur-CD-GNPs) were characterized. Transmission electron microscopy and dynamic light scattering results showed that these cur-CD-GNPs have a small gold nanocore (approximately 5 nm) and the average size of the three cur-CD-GNPs was approximately 25-35 nm. Curcumin was efficiently incorporated into the ß-CD solution and the loading efficiency of curcumin in ß-CD-GNPs was the highest of the three types of CD-GNPs prepared. The cytotoxic effect of cur-CD-GNPs was investigated using a human lung cancer cell line. All cur-CD-GNPs exhibited cytotoxic effects comparable to that of curcumin solution and CD-GNPs without curcumin were not cytotoxic. These results suggest that cur-CD-GNPs may be a useful multifunctional nanomedicine, although in vivo investigations are required.

Defined drug release from 3D-printed composite tablets consisting of drug-loaded polyvinylalcohol and a water-soluble or water-insoluble polymer filler.

3D-printed tablets are a promising new approach for personalized medicine. In this study, we fabricated composite tablets consisting of two components, a drug and a filler, by using a fused deposition modeling-type 3D printer. Polyvinylalcohol (PVA) polymer containing calcein (a model drug) was used as the drug component and PVA or polylactic acid (PLA) polymer without drug was used as the water-soluble or water-insoluble filler, respectively. Various kinds of drug-PVA/PVA and drug-PVA/PLA composite tablets were designed, and the 3D-printed tablets exhibited good formability. The surface area of the exposed drug component is highly correlated with the initial drug release rate. Composite tablets with an exposed top and a bottom covered with a PLA layer were fabricated. These tablets showed zero-order drug release by maintaining the surface area of the exposed drug component during drug dissolution. In contrast, the drug release profile varied for tablets whose exposed surface area changed. Composite tablets with different drug release lag times were prepared by changing the thickness of the PVA filler coating the drug component. These results which used PVA and PLA filler will provide useful information for preparing the tablets with multi-components and tailor-made tablets with defined drug release profiles using 3D printers.

3D Printing Factors Important for the Fabrication of Polyvinylalcohol Filament-Based Tablets.

Three-dimensional (3D) printers have been applied in many fields, including engineering and the medical sciences. In the pharmaceutical field, approval of the first 3D-printed tablet by the U.S. Food and Drug Administration in 2015 has attracted interest in the manufacture of tablets and drugs by 3D printing techniques as a means of delivering tailor-made drugs in the future. In current study, polyvinylalcohol (PVA)-based tablets were prepared using a fused-deposition-modeling-type 3D printer and the effect of 3D printing conditions on tablet production was investigated. Curcumin, a model drug/fluorescent marker, was loaded into PVA-filament. We found that several printing parameters, such as the rate of extruding PVA (flow rate), can affect the formability of the resulting PVA-tablets. The 3D-printing temperature is controlled by heating the print nozzle and was shown to affect the color of the tablets and their curcumin content. PVA-based infilled tablets with different densities were prepared by changing the fill density as a printing parameter. Tablets with lower fill density floated in an aqueous solution and their curcumin content tended to dissolve faster. These findings will be useful in developing drug-loaded PVA-based 3D objects and other polymer-based articles prepared using fused-deposition-modeling-type 3D printers.

Fabrication of nanocomposite particles using a two-solution mixing-type spray nozzle for use in an inhaled curcumin formulation.

A unique two-solution mixing-type spray nozzle is useful for producing nanocomposite particles (microparticles containing drug nanoparticles) in one step. The nanocomposite particles can prevent nanoparticle aggregation. Curcumin has many reported pharmacological effects. Curcumin was entrapped in mannitol microparticles using a spray dryer coupled with a two-solution mixing-type spray nozzle to prepare "curcumin nanocomposite particles" and the application of these particles for inhalation formulations was investigated. Spray drying conditions (flow rate, concentration and inlet temperature) affected the size of both the resulting curcumin nanocomposite particles and the curcumin nanoparticles in the nanocomposite particles. The aerosol performance of the curcumin nanocomposite particles changed depending on the spray drying conditions and several conditions provided better deposition compared with the curcumin original powder. The curcumin nanocomposite particles showed an improved dissolution profile of curcumin compared with the original powder. Furthermore, the curcumin nanocomposite particles showed a higher cytotoxic effect compared with the curcumin original powder towards three cancer cell lines. Curcumin nanocomposite particles containing curcumin nanoparticles show promise as an inhalation formulation for treating lung-related diseases including cancer.

Enhanced dissolution of inhalable cyclosporine nano-matrix particles with mannitol as matrix former.

This study aims to improve the dissolution of inhalable cyclosporine A nanoparticles by formulating the drug with mannitol as a hydrophilic nano-matrix former. The effect of mannitol content on the aerosol performance of the nano-matrix particles was also examined. Cyclosporine A nanosuspensions were produced by anti-solvent precipitation using a multi-inlet vortex mixer. Various amounts of mannitol were dissolved into the suspensions before spray drying to obtain micron-sized aggregates (nano-matrix powders). Dissolution properties of the powders in an aqueous medium, with the drug content, aggregate size distribution, surface roughness, physicochemical properties and aerosol performance were determined. The powders contained amorphous cyclosporine A and α-crystalline mannitol, with drug content being very close to the theoretical doses. Inclusion of mannitol enhanced the dissolution rate of the drug, without significantly affecting the aggregate size distribution, surface roughness and aerosol performance. This formulation approach may be applicable to improving the dissolution rate and bioavailability of hydrophobic drugs.