Preparation, Characterization, and In Vivo Pharmacokinetic Evaluation of Polyvinyl Alcohol and Polyvinyl Pyrrolidone Blended Hydrogels for Transdermal Delivery of Donepezil HCl.

Transdermal delivery systems are emerging platforms for the delivery of donepezil hydrochloride (DH) for treating Alzheimer's disease. The primary aim of this study was to develop polyvinyl alcohol and polyvinyl pyrrolidone blended hydrogels and to evaluate their feasibility for delivering DH via a transdermal route. Physicochemical properties, such as gel fraction (%), swelling ratio (%), weight loss (%), mechanical strength, elongation at break, and Young's modulus of the prepared hydrogels were evaluated. Furthermore, in vitro skin permeation and in vivo pharmacokinetic studies were performed. With an increased concentration of propylene glycol (PG), the gel fraction (%), maximum strength, and elongation at break decreased. However, the swelling ratio (%) and weight loss (%) of hydrogels increased with increased PG content. The 26% PG-hydrogel was superior, with an enhancement ratio of 12.9 (*** p < 0.001). In addition, the 11% PG-hydrogel and 1% PG-hydrogel exhibited an enhancement ratio 6.30-fold (*** p < 0.001) and 2.85-fold (* p < 0.05) higher than that exhibited by control, respectively, indicating a promising effect of PG on skin permeation. In addition, in vivo pharmacokinetic studies on hairless rats assessed the expediency for transdermal delivery of DH. The transdermal delivery of optimized hydrogel-patches with two different doses of DH revealed that the maximum plasma concentration and area under the curve were dose dependent, and the time to reach the maximum concentration was 8 h. Thus, optimized hydrogels have the potential to enhance the transdermal delivery of DH and could be a novel clinical approach.

Preparation, characterization, and evaluation of celecoxib eutectic mixtures with adipic acid/saccharin for improvement of wettability and dissolution rate.

Celecoxib (CEL) is a selective cyclooxygenase-2 (COX-2) inhibitor therapeutically indicated for the treatment of rheumatoid arthritis, osteoarthritis, acute pain, and inflammation. However, its poor solubility and dissolution rate significantly hinders its broader application. In this study, eutectic mixtures, as binary pharmaceutical compositions of CEL with adipic acid (ADI) and saccharin (SAC), were identified through a phase diagram and Tammann's triangle intended to improve the wettability and dissolution rate of poorly water-soluble CEL. The contact angles at 0s in the liquid-solid interface were approximately θs (theta) 79.7 ±â€¯0.50° and 86.65 ±â€¯0.45° for CEL-ADI and CEL-SAC, respectively, which were much lower than the value obtained for CEL (92.05 ±â€¯0.75° θ). Moreover, a comparison of the disk intrinsic dissolution rate and powder dissolution properties demonstrated that eutectic mixtures significantly increased the dissolution rate compared with CEL and physical mixtures. A general relationship was elucidated and indicated that the dissolution rate was increased as the contact angle decreased (correlation coefficient, r = 0.9966 ±â€¯0.0031). Therefore, CEL-ADI and CEL-SAC eutectics may offer a novel formulation strategy to enhance the solubility and oral bioavailability of CEL.

Does Rapid Eye Movement Sleep Aggravate Obstructive Sleep Apnea?

OBJECTIVES: To investigate the apnea-hypopnea index (AHI) according to the sleep stage in more detail after control of posture. METHODS: Patients who underwent nocturnal polysomnography between December 2007 and July 2018 were retrospectively evaluated. Inclusion criteria were as follows: age >18 years, sleep efficacy >80%, and patients who underwent polysomnography only in the supine position (100% of the time). Patients were classified into different groups according to the methods the first, rapid eye movement (REM)-dominant group (AHIREM/AHINREM >2), non-rapid eye movement (NREM)-dominant group (AHINREM/AHIREM >2), and non-dominant group; and the second, light sleep group (AHIN1N2>AHISWS) and slow wave sleep (SWS) group (AHISWS>AHIN1N2). RESULTS: A total of 234 patients (mean age, 47.4±13.9 years) were included in the study. There were 108 patients (46.2%) in the REM-dominant group, 88 (37.6%) in the non-dominant group, and 38 (16.2%) in the NREM-dominant group. The AHI was significantly higher in the NREM-dominant group than in the REM-dominant group (32.9±22.9 events/hr vs. 18.3±9.5 events/hr, respectively). There were improvements in the AHI from stage 1 to SWS in NREM sleep with the highest level in REM sleep. A higher AHISWS than AHIN1N2 was found in 16 of 234 patients (6.8%); however, there were no significant predictors of these unexpected results except AHI. CONCLUSION: Our results demonstrated the highest AHI during REM sleep stage in total participants after control of posture. However, there were 16.2% of patients showed NREM-dominant pattern (AHINREM/AHIREM >2) and 6.8% of patients showed higher AHISWS than AHIN1N2. Therefore, each group might have a different pathophysiology of obstructive sleep apnea (OSA), and we need to consider this point when we treat the patients with OSA.

Correction of Short Nose.

To correct an Asian short nose with low dorsum, short columella, and poorly defined nose tip, augmentation rhinoplasty has been popularized. A simple augmentation no longer is considered an efficient rhinoplasty approach for Asians aesthetically; most surgeons simultaneously perform nasal elongation and augmentation during rhinoplasty. To extend the nose length successfully, important factors are cartilages, mucosal and skin conditions, and presence and degree of fibrotic changes. In addition, surgeons should consider preoperatively how much should be extended from an aesthetics perspective. This article introduces the current practice of surgical correction of the short nose in Asians.

Enhancing the solubility and bioavailability of poorly water-soluble drugs using supercritical antisolvent (SAS) process.

Poor water solubility and poor bioavailability are problems with many pharmaceuticals. Increasing surface area by micronization is an effective strategy to overcome these problems, but conventional techniques often utilize solvents and harsh processing, which restricts their use. Newer, green technologies, such as supercritical fluid (SCF)-assisted particle formation, can produce solvent-free products under relatively mild conditions, offering many advantages over conventional methods. The antisolvent properties of the SCFs used for microparticle and nanoparticle formation have generated great interest in recent years, because the kinetics of the precipitation process and morphologies of the particles can be accurately controlled. The characteristics of the supercritical antisolvent (SAS) technique make it an ideal tool for enhancing the solubility and bioavailability of poorly water-soluble drugs. This review article focuses on SCFs and their properties, as well as the fundamentals of overcoming poorly water-soluble drug properties by micronization, crystal morphology control, and formation of composite solid dispersion nanoparticles with polymers and/or surfactants. This article also presents an overview of the main aspects of the SAS-assisted particle precipitation process, its mechanism, and parameters, as well as our own experiences, recent advances, and trends in development.

Cyclosporine Amicellar delivery system for dry eyes.

BACKGROUND: The objectives of this study were to develop stable cyclosporine A (CsA) ophthalmic micelle solutions for dry-eye syndrome and evaluate their physicochemical properties and therapeutic efficacy. MATERIALS AND METHODS: CsA-micelle solutions (MS-CsA) were created by a simple method with Cremophor EL, ethanol, and phosphate buffer. We investigated the particle size, pH, and osmolarity. In addition, long-term physical and chemical stability for MS-CsA was observed. To confirm the therapeutic efficacy, tear production in dry eye-induced rabbits was evaluated using the Schirmer tear test (STT). When compared to a commercial product, Restasis, MS-CsA demonstrated improvement in goblet-cell density and conjunctival epithelial morphology, as demonstrated in histological hematoxylin and eosin staining. RESULTS: MS-CsA had a smaller particle size (average diameter 14-18 nm) and a narrow size distribution. Physicochemical parameters, such as particle size, pH, osmolarity, and remaining CsA concentration were all within the expected range of 60 days. STT scores significantly improved in MS-CsA treated groups (P<0.05) in comparison to those of the Restasis-treated group. The number of goblet cells for rabbit conjunctivas after the administration of MS-CsA was 94.83±8.38, a significantly higher result than the 65.17±11.51 seen with Restasis. The conjunctival epithelial morphology of dry eye-induced rabbits thinned with loss of goblet cells. However, after 5 days of treatment with drug formulations, rabbit conjunctivas recovered epithelia and showed a relative increase in the number of goblet cells. CONCLUSION: The results of this study indicate the potential use of a novel MS for the ophthalmic delivery of CsA in treating dry eyes.

Surgical Techniques for the Correction of Postrhinoplasty Depressed Scars on the Nasal Tip.

IMPORTANCE: Augmentation rhinoplasty is common in the Asian population and the lack of suitable autologous material for augmentation has led to the use of alloplastic materials. Many of these patients develop complications, including a depressed dimple-like scar of the nasal tip. Causes of such dimpling include the use of large implants, infection, extrusion, and surgeon incompetence. OBJECTIVE: To describe the various techniques that can be used to correct dimpling of the nasal tip. DESIGN, SETTING, AND PARTICIPANTS: Data were retrospectively reviewed from 28 patients who had undergone surgical procedures from January 1, 2013, through July 31, 2014, in a rhinoplasty clinic in Seoul, Korea, for the correction of a contracted nose with nasal scars secondary to previous rhinoplasties. Data analysis was conducted from August 1, 2014, through February 16, 2015. INTERVENTIONS: Before surgery, a complete rhinological examination was conducted, digital photographs were taken, and an assessment was made regarding the severity of the dimpling, the condition of the nasal skin, and the underlying supporting structures. Based on these factors, the appropriate type of procedure was planned. MAIN OUTCOMES AND MEASURES: Patient satisfaction with change after surgery was assessed using a 3-point Likert scale (3 indicates satisfied; 2, fairly satisfied; and 1, dissatisfied). Outcomes were also reviewed by 2 surgeon-peers who gave an outcome score ranging from 1 to 10 (1 indicates a poor cosmetic outcome; 10, the best possible outcome). RESULTS: The nasal contour and tip symmetry were restored to aesthetic standards with these relatively simple techniques. Eleven patients (39.2%) were treated with unilobed flap, 4 (14.2%) with a bilobed flap, 3 (10.7%) with Z-plasty, 9 (32.1%) with soft-tissue interposition, and 1 (3.5%) with a transposition flap. Twenty-four of the 28 patients (85.7%) were satisfied with their outcomes and 4 (14.3%) patients were dissatisfied and were given a revision procedure, following which they were satisfied with their outcomes. The follow-up period ranged between 6 to 32 months (mean, 12.3 months). The mean surgeon-reviewed outcome score for soft-tissue interposition procedure was 8.0 of 10; for the unilobed flap, 8.0 of 10; for the bilobed flap, 7.5 of 10; for the transposition flap, 8.0 of 10; and for Z-plasty, 7.8 of 10. CONCLUSIONS AND RELEVANCE: These techniques are reproducible and the choice of the technique depends on the shape, size, and location of the scar; skin condition; patient expectations; and the surgeon's experience and comfort level with the procedure. LEVEL OF EVIDENCE: 4.

The Seesaw Technique for Correction of Vertical Alar Discrepancy.

Alar vertical discrepancy including alar base has been viewed as one of the most challenging reconstructive problems in rhinoplasty. The authors have created a simple technique that consistently gives aesthetically acceptable results. The authors have designed the seesaw technique to correct alar discrepancy (type 1 to 3). Type 1 has been used in 14 patients, type 2 has been used in three patients, and type 3 has been used in seven patients. Alar discrepancy was corrected satisfactorily in all cases, with good cosmetic outcome. One case required scar revision and another case required revision for overcorrection; satisfactory results were ultimately achieved in both cases. This new technique is quite easy to design and is effective in the correction of alar discrepancy. It yields good postoperative results along with satisfactory aesthetic outcomes.

Treatment outcomes of saddle nose correction.

IMPORTANCE: Many valuable classification schemes for saddle nose have been suggested that integrate clinical deformity and treatment; however, there is no consensus regarding the most suitable classification and surgical method for saddle nose correction. OBJECTIVES: To present clinical characteristics and treatment outcome of saddle nose deformity and to propose a modified classification system to better characterize the variety of different saddle nose deformities. DESIGN, SETTING, AND PARTICIPANTS: The retrospective study included 91 patients who underwent rhinoplasty for correction of saddle nose from April 1, 2003, through December 31, 2011, with a minimum follow-up of 8 months. Saddle nose was classified into 4 types according to a modified classification. MAIN OUTCOME AND MEASURE: Aesthetic outcomes were classified as excellent, good, fair, or poor. RESULTS: Patients underwent minor cosmetic concealment by dorsal augmentation (n = 8) or major septal reconstruction combined with dorsal augmentation (n = 83). Autologous costal cartilages were used in 40 patients (44%), and homologous costal cartilages were used in 5 patients (6%). According to postoperative assessment, 29 patients had excellent, 42 patients had good, 18 patients had fair, and 2 patients had poor aesthetic outcomes. No statistical difference in surgical outcome according to saddle nose classification was observed. Eight patients underwent revision rhinoplasty, owing to recurrence of saddle, wound infection, or warping of the costal cartilage for dorsal augmentation. CONCLUSIONS: We introduce a modified saddle nose classification scheme that is simpler and better able to characterize different deformities. Among 91 patients with saddle nose, 20 (22%) had unsuccessful outcomes (fair or poor) and 8 (9%) underwent subsequent revision rhinoplasty. Thus, management of saddle nose deformities remains challenging. LEVEL OF EVIDENCE: 4.

Normative diameters and effects of aging on the cochlear and facial nerves in normal-hearing Korean ears using 3.0-tesla magnetic resonance imaging.

OBJECTIVES/HYPOTHESIS: To assess the normative size of the cochlear nerve (CN) and facial nerve (FN) in normal-hearing ears and to determine whether nerve size varies with age. STUDY DESIGN: Cross-sectional. METHODS: We included 169 ears with normal hearing between 2005 and 2010. The height, width, and cross-sectional area (CSA) of the CN and FN in the middle of the internal auditory canal were measured on oblique sagittal images of 3.0-T magnetic resonance imaging. Results were compared by age. Young subjects were divided into three age groups, 0-5, 6-10, and 11-15 years. Subjects over age 40 years were divided into groups at 10-year intervals. RESULTS: Mean age was 32.6 years (range, 0.75-79 years). We found that the CN had significantly greater vertical (1.10 ± 0.21 mm vs. 0.95 ± 0.21 mm) and horizontal (1.11 ± 0.20 mm vs. 1.03 ± 0.22 mm) diameters than the FN. The CSA of the CN was larger than that of the FN (0.98 ± 0.33 mm(2) vs. 0.79 ± 0.31 mm(2) ). Except for the CN vertical diameter, there were no significant differences between right and left ears. Sex did not affect the nerve size. Although the CN was not affected by age, the FN vertical diameter and CSA of children <5 years were significantly smaller than those of children aged >5 years. The size of the two nerves did not differ among groups over age 40 years. CONCLUSIONS: The CN is not affected by age in normal-hearing ears. The FN vertical diameter and CSA of children <5 years are smaller than those of older children.

Impact of combined prophylactic unilateral central neck dissection and hemithyroidectomy in patients with papillary thyroid microcarcinoma.

BACKGROUND: Lymph node metastases occur frequently in patients with papillary thyroid carcinoma (PTC), and the central compartment of the neck is the most frequently involved site. Some authors advocate prophylactic central neck dissection (CND) during total thyroidectomy. However, little is known about the effects of prophylactic unilateral CND in papillary thyroid microcarcinoma (PTMC) patients who undergo hemithyroidectomy. This study was designed to investigate the impact of prophylactic unilateral CND in this population. METHODS: The clinical records of 152 patients with a PTMC ≤1 cm according to preoperative ultrasonography who underwent hemithyroidectomy between 2002 and 2009 were assessed retrospectively. Outcomes were compared between the 65 (43%) patients who underwent hemithyroidectomy with elective unilateral CND (CND+ group) and the 87 (57%) patients who underwent hemithyroidectomy only (CND- group). RESULTS: In the CND- group, 37 patients (43%) had microscopic extrathyroidal extension (ETE). In the CND+ group, 33 patients (50.7%) had ETEs or nodal metastases. During follow-up, recurrence was observed in 14 patients (n = 1, CND+ group; n = 13, CND- group). Prophylactic unilateral CND was associated with a significantly lower rate of locoregional recurrence (P = 0.017). CONCLUSIONS: Compared with hemithyroidectomy alone, prophylactic unilateral CND may decrease the rate of locoregional recurrence in patients with PTMC.