Assessment of Pain, Healing Time, and Wound Contraction in Postoperative Auricular Defects Healing Secondarily With and Without the Use of a Porcine Xenograft, a Pilot Study.

BACKGROUND: Postoperative auricular defects heal well with secondary intention healing (SIH); however, potential complications include postoperative pain, perichondritis, and chondritis. OBJECTIVE: To compare postoperative pain and wound healing in auricular defects healing by secondary intention with and without the placement of a porcine xenograft. MATERIALS AND METHODS: Twenty-one subjects were enrolled in the study. The primary outcome was self-reported pain, measured on a 0 to 10 scale for 14 postprocedure days. Secondary outcomes included time to greater than 90% of reepithelialization and degree of wound contraction. RESULTS: There was a 1 to 2 point difference in median pain scores between the porcine graft and control groups during postoperative days 4 to 7, 12, and 13. Time to 90% or greater reepithelialization was not statistically different between groups (p = .94). The average wound contraction was 34.1% for the porcine group and 34.0% for the control group (p = .95). CONCLUSION: In this pilot study, overall pain scores were low in both groups. Placement of a porcine xenograft resulted in a slight reduction of median pain compared with traditional SIH. Patients in the control group were more likely to require analgesics. Similar rates of reepithelialization and degree of wound contracture were observed.

Amorphous solid dispersion of nisoldipine by solvent evaporation technique: preparation, characterization, in vitro, in vivo evaluation, and scale up feasibility study.

The present study was designed to determine the applicability of a newly derived dimensionless number precipitation parameter, "supersaturation holding capacity (SHC)" in development of amorphous solid dispersion (ASD) of a rapidly crystallizing drug, nisoldipine. Also, ASD preparation from lab scale formulation technique to scalable spray drying technique followed by oral bioavailability study was demonstrated. Solution state screening of polymers was performed by determining nucleation induction time (tin) and SHC. With screened polymers, lab scale ASDs of nisoldipine were prepared using rotary evaporation (solvent evaporation) method, and the optimized stable ASDs were scaled up by spray drying. The ASDs were characterized by DSC, PXRD, and FTIR for amorphous nature and evaluated for apparent solubility, dissolution, and solid-state stability improvement. The spray dried ASDs were additionally evaluated for micrometric properties and oral bioavailability study.PVP grades demonstrated superior crystal growth inhibition properties (with 2-4-fold enhancements in SHC). ASDs prepared by both lab scale and scale-up technique using PVP stabilized the amorphous nisoldipine via antiplasticization effect that maintained the stability under accelerated stability conditions (40 °C/75% RH) for 6 months. Additionally, FTIR study confirmed the role of intermolecular interactions in amorphous state stabilization of PVP-based solid dispersions. PVP-based spray dried ASDs improved the apparent solubility 4-fold for PVP K17 and more than 3-fold for remaining spray dried ASDs. The enhanced solubility was translated to improved dissolution of the drug when compared with crystalline and amorphous form complementing the outcome of the solution state study. The spray dried ASD showed 2.3 and > 3-fold the improvement in Cmax and AUC (0-24 h) respectively when compared with crystalline nisoldipine during oral bioavailability study which highlights the significance of SHC parameter of polymers. The spray dried ASD has shown improved micromeritics properties then crystalline nisoldipine in terms of flow behavior.This unique study provides a rational strategy for selection of appropriate polymer in development of ASDs that can tackle both precipitation during dissolution and amorphous state stabilization in solid state and also considers the SHC in scale-up study. Graphical abstract.

Mechanistic Insights of Formulation Approaches for the Treatment of Nail Infection: Conventional and Novel Drug Delivery Approaches.

Onychomycosis is a chronic disorder that is difficult to manage and hard to eradicate with perilous trends to relapse. Due to increased prevalence of HIV, use of immunosuppressant drugs and lifestyle-related factors, population affected with fungal infection of nail (Onychomycosis) happens to increase extensively in last two decades. Modalities available for the treatment of onychomycosis include systemically administered antifungals, mechanical procedures, and topical drug therapy. But the efficacy of the most of approaches to deliver drug at targeted site, i.e., deep-seated infected nail bed is limited due to compact and highly keratinized nail structure. A series of advanced formulation approaches, such as transfersomes, liposomes, nano/micro emulsion, nail lacquers etc., have been attempted to improve the drug penetration into nail plate more efficiently. The manuscript reviews these formulation approaches with their possible mechanisms by which they improve the drug penetration.Comparative analysis of available treatment modalities for onychomycosis has been provided with pros and cons of each alternatives. Additionally, ongoing research about the application of biological materials such as modified cationic antimicrobial peptides (AMPs), plant-derived proteins, and synthetic antimicrobial peptidomimetics have also been explored.

Classification of the crystallization tendency of active pharmaceutical ingredients (APIs) and nutraceuticals based on their nucleation and crystal growth behaviour in solution state.

Supersaturated drug delivery systems are commonly used to address the problems of poor aqueous solubility posed by most of the active pharmaceutical ingredients (APIs). However, the supersaturated systems are highly unstable due to their high free energy levels and demonstrate a tendency to precipitate. Understanding the crystallization tendency based on the mechanisms of crystallization, that is nucleation and crystal growth, is imperative to design formulation strategies and select appropriate precipitation inhibitors. This study aims to provide a classification system, based on both the nucleation and crystal growth tendency in the solution state of 60 APIs and nutraceuticals (in absence of polymer) from their desupersaturation profiles monitored by UV-Visible spectroscopy. The APIs and nutraceuticals are divided into four classes based on their induction time (tind) and crystal growth rate as fast nucleators-fast crystal growth (class I), fast nucleators-slow crystal growth (class II), slow nucleators-fast crystal growth (class III) and slow nucleators-slow crystal growth (class IV). Most of the molecules fall in the class I and class IV. An easy-to-use protocol for nucleation and crystal growth studies has been optimized. This protocol will find application to assess the crystallization tendency of the molecules in the preliminary screening stages, enabling appropriate formulation strategies to inhibit crystallization.

Metastatic Multiple Myeloma to the Skin.

Cutaneous involvement of multiple myeloma (MM) is uncommon, typically occurs in late stage disease, and is a poor prognostic indicator with an approximate eight month median survival. We present a 51-year-old man with relapsed lambda light chain MM who developed abrupt asymptomatic skin metastases. Biopsy revealed a dermis replete of atypical plasma cells, positive for CD138 and CD45. In situ hybridization confirmed lambda light chain restriction. Despite rescue antimyeloma therapy with the anti-CD38 drug daratumumab, he rapidly declined clinically and succumbed to the disease four weeks after presentation. A standard treatment approach for cutaneous MM does not currently exist; however, various techniques to detect cytogenetic abnormalities are emerging and will provide additional prognostic value and direct individualized therapy.

Co amorphous valsartan nifedipine system: Preparation, characterization, in vitro and in vivo evaluation.

Co amorphous systems are supersaturated drug delivery systems which offer a basic platform for delivery of multicomponent adducts (combination of more than one active pharmaceutical ingredient (API)) and/or as a fixed dose combination therapy, in addition to their potential to improve the apparent solubility, dissolution rate and ultimately bioavailability of poorly water soluble APIs. In the present work, a new drug-drug co amorphous system namely valsartan-nifedipine was prepared by quench cooling technique. Prepared co amorphous system was characterized for its solid state behavior with the help of Fourier Transform Infrared spectroscopy (FTIR), Differential Scanning Calorimetry (DSC) and Powder X Ray Diffractometry (PXRD). The optimized co amorphous system was stable for 1 month when exposed to accelerated stability condition (40 ±â€¯2 °C and 75 ±â€¯5% RH). The improved stability of amorphous nifedipine in co amorphous system was attributed to improved miscibility and intra and intermolecular non-covalent interactions mainly due to presence of hydrogen bonding between valsartan and nifedipine which was studied by FTIR analysis. Co amorphous systems were evaluated by mainly in vitro dissolution and in vivo benefit. In vitro dissolution study showed nearly 5.66 folds and 1.61 folds improvement which was translated to 3.63 and 2.19 times enhancement in vivo Cmax for nifedipine and valsartan respectively.

Quantification of niclosamide polymorphic forms - A comparative study by Raman, NIR and MIR using chemometric techniques.

Niclosamide, an anthelmintic drug recently repurposed for its activity against cancer, crystallizes into three solvated forms, two monohydrates (NHa, NHb) and one anhydrous (NAn) form. NAn is sensitive to pseudopolymorphic transformations that affect its dissolution and consequently, its bioavailability. NAn exhibits a polymorphic conversion to metastable monohydrate (NHa) form during high-energy milling in presence of poorly soluble solvents like water. It is hence very important to quantify polymorphic conversion from NAn to NHa, as water is a commonly used solvent during various processing like ball milling and wet granulation. This main objective of the study was to examine the feasibility of Raman, NIR and MIR spectroscopic techniques for identification and quantification of polymorphic forms of niclosamide in binary mixtures and multicomponent mixtures. Calibration models were developed and validated by vibrational spectroscopic techniques in binary mixtures of NAn and NHa and in multicomponent mixtures by chemometric techniques. These techniques were further used to identify and quantify NHa during ball milling, granulation and in presence of other polymorphic forms of niclosamide. Identification and quantification of pseudopolymorphs in binary and multicomponent mixtures with an acceptable recovery of 100.13-102.99% for Raman and 100.07-101.28% for NIR with low % RSD of 2.38-3.12 for both techniques were obtained. The % NHa determined during ball milling and granulation was similar by NIR and Raman. Raman spectroscopy however showed a greater advantage over other techniques in determining the NHa in presence of NHb due to significant difference in the spectral region of hydrates, when compared to NIR and MIR.

Formulation and evaluation of cyclodextrin complexes for improved anticancer activity of repurposed drug: Niclosamide.

Niclosamide, previously used as an anthelmintic drug is currently being repurposed for its anticancer activity. Niclosamide is a brick like biopharmaceutical classification system (BCS) class II drug with poor aqueous solubility and dissolution consequently leading to low bioavailability. By considering the physicochemical properties and geometry of niclosamide, inclusion complex with cyclodextrin was prepared by freeze drying method and characterized using FT-IR, DSC, PXRD, and 1HNMR. In silico molecular modeling study was performed to study the possible interactions between niclosamide and cyclodextrin. The anticancer activity of niclosamide formulation was evaluated through in vitro cell cytotoxicity study using various cancer cell lines. The potential of niclosamide complex for improvement of the bioavailability was evaluated in male BALB/c mice. In vitro cytotoxicity studies indicated significantly higher cytotoxicity at lower concentrations and the pharmacokinetic studies showed significant improvement in Cmax and Tmax of niclosamide from cyclodextrin complex in comparison to pure niclosamide alone.

Cellulose based polymers in development of amorphous solid dispersions.

Cellulose derivatives have gained immense popularity as stabilizers for amorphous solid dispersion owing to their diverse physicochemical properties. More than 20 amorphous solid dispersion-based products that have been approved for marketing consist of cellulose derivatives as stabilizers, thus highlighting their importance in generation of amorphous solid dispersions. These polymers offer numerous advantages like drug solubilization, crystallization inhibition and improvement in release patterns of drugs. Exploring their potential and exploiting their chemistry and pH responsive behaviour have led to the synthesis of new derivatives that has broadened the scope of the use of cellulose derivatives in amorphous formulation development. The present review aims to provide an overview of different mechanisms by which these cellulose derivatives inhibit the crystallization of drugs in the solid state and from supersaturated solution. A summary of different categories of cellulose derivatives along with the newly explored polymers has been provided. A special segment on strengths, weaknesses, opportunities, and threats (SWOT) analysis and critical quality attributes (CQAs) which affect the performance of the cellulose based amorphous solid dispersion will aid the researchers in identifying the major challenges in the development of cellulose based solid dispersion and serve as a guide for further formulation development.

Differentially expressed serum host proteins in hepatitis B and C viral infections.

Hepatitis B virus (HBV) and Hepatitis C virus (HCV) infection often lead to hepatocellular carcinoma (HCC), which is mostly detected in advanced stage. Hence, its early detection is of paramount importance using a biomarker having sensitivity and specificity both. The present study highlights differentially expressed host proteins in response to HBV/HCV infection at different stages. Comparative proteomic study was done by two-dimensional gel electrophoresis followed by mass spectrometry. Sera from each of chronically infected, liver cirrhosis and HCC in HBV or HCV infection along with controls were selected. Analysis of functional association between differentially expressed proteins with viral hepatitis was extensively carried out. Forty-three differentially expressed spots (≥ 1.5 fold; P < 0.05) on two-dimensional gel electrophoresis were corresponded to 28 proteins by mass spectrometry in variable liver diseases. Haptoglobin protein levels were decreased upon disease progression to HCC due to HBV infection. The other proteins expressed differentially are ceruloplasmin, serum paraoxonase 1, retinol binding protein and leucine rich alpha 2 proteins in plasma maybe associated to HBV HCC. Whereas, upregulation of C4a/C4b showed it as a reliable marker in patients with end stage liver disease related to HCV infection. ApolipoproteinA1 levels in liver diseases in both HBV and HCV infection corresponding to healthy controls may be a common marker for early diagnosis and disease monitoring. Protein interaction studies by extensive pathway analysis using bioinformatics tools such as EnrichNet application and STRING revealed significant associations with specific infections.

Determination of precipitation inhibitory potential of polymers from amorphous solid dispersions.

Precipitation inhibitory potential of polymers screened from precipitation study may be altered once it is formulated in amorphous solid dispersions (ASDs). OBJECTIVE: Present study was embarked with an objective to determine whether the polymers retain the same inhibitory potential after formulating them into ASDs. METHODS: Screening of polymers was based on a new dimensionless parameter 'Supersaturation Holding Capacity (SHC)' calculated from the precipitation study. Nifedipine ASDs were formulated using HPMC E3 and HPMC E50 (high SHC values), and HPMC K100M, PVP K25, and HPC M (low to moderate SHC values). Generated ASDs were characterized by DSC, FTIR, and PXRD and evaluated for stability under accelerated conditions (40˚C and 75% RH) for 6 months. RESULTS: Thermal analysis of the ASDs and theoretical prediction of the glass transition temperature (Tg) suggested a linear dependency of Tg on the content of HPMC E3 and HPMC E50. Under accelerated stability conditions, all ASDs of nifedipine with HPMC E3 and HPMC E50 (except ASDs with 70% drug load) were stable, which could be attributed to the molecular level dispersion of the drug in these polymers. SHC parameter calculated from the apparent solubility profile gave following rank order HPMC E50 (3.4) > HPMC E3 (3.2) > HPMC K100M (1.29) > PVP K25 (1.09) > HPC M (0.99). SHC calculated from the apparent solubility profile of ASDs demonstrated good agreement between the solution state and solid state screening of the polymers for precipitation inhibition. During dissolution study, nearly four-fold enhancement has been observed with ASDs comprising HPMC E3 and HPMC E50. CONCLUSIONS: The outcome of the study concluded that SHC can be a promising parameter in the screening of polymers for the development of the ASDs.

Continuous manufacturing of co-crystals: challenges and prospects.

The last decade has witnessed extensive growth in the field of co-crystallization for mitigating the solubility and dissolution-related issues of poorly soluble drugs. This is largely because co-crystals can modify the physicochemical properties of drugs without any covalent modification in the drug molecules. The US Food and Drug Administration (FDA) now considers drug products that are designed to contain a new co-crystal, analogous to new polymorph of the active pharmaceutical ingredient (API). This positive change in regulatory perspective coupled with successful commercialization of valsartan-sacubitril co-crystal (Entresto, Novartis) has now brought co-crystals into focus, in both industries as well as academia. Co-crystal prediction, screening, and synthesis have been reported in literature; however, co-crystal production at a larger scale needs further investigations. With this aim, the article describes various continuous methods for co-crystal production, along with in-line monitoring during co-crystal production, emphasizing on process analytical technology (PAT). In addition, the scale-up issues of continuous and batch co-crystallization and other suitable techniques for pharmaceutical scale up are detailed. Quality control aspects and regulatory viewpoint crucial for commercial success are elaborated in the future perspective.

Rufinamide: Crystal structure elucidation and solid state characterization.

Rufinamide (R) is a triazole derivative approved for the management of partial seizures and seizures associated with Lennox-Gastaut Syndrome, in November 2007. Crystal structure, solid state characterization, drug-excipient compatibility and solubility play a pivotal role in formulation development. This work deals with the crystal structure elucidation of R by single crystal X-ray diffraction and solid state characterization by thermal, spectroscopic and crystallographic techniques. Drug- excipient compatibility was assessed by differential scanning calorimetry (DSC). New RP-HPLC method for quantification of R was developed with improved retention time. Solubility and dissolution of drug in different media was determined. Additionally, the flow behavior of the drug was evaluated by measuring Carr's index and Hausner's ratio, while the compressibility behavior was studied using Well's protocol. R crystallized from dimethylformamide (R-DMF) was utilized for single crystal analysis. The drug crystallized in triclinic crystal system with P-1 space group. Asymmetric unit cell consists of two molecules of R held by intermolecular hydrogen bond (connected by NH⋯O, which forms the catemeric chain). Analytical outcomes from DSC, thermogravimetric analysis (TGA) and powder X-ray diffraction (PXRD) revealed that the drug was present in pure crystalline form and was devoid of any polymorphic or pseudopolymorphic impurities. Influence of pH on the solubility and dissolution of R-DMF was found to be insignificant. The drug exhibited poor aqueous solubility, which was improved nearly 4.6 fold with the addition of 2% sodium lauryl sulphate (SLS). The drug exhibits poor flow and elastic compression nature. Excipients such as poly ethylene glycol (PEG) 8000, SLS, lactose monohydrate, starch and Hydroxypropyl methylcellulose (HPMC) E15 were incompatible with R-DMF as identified by thermal analysis. It is envisaged that these information regarding solid state properties of R-DMF would aid in identifying a logical path for formulation development.

Near infra red spectroscopy: a tool for solid state characterization.

Physical characterization of solid form of drug is of paramount importance as its biopharmaceutical properties and/or its processing behavior may be altered. Early identification and monitoring of solid state transformation is a critical requirement for pharmaceutical product development. In combination with chemometrics, a non destructive and non invasive technique like NIR is a powerful tool for solid state characterization. Main focus of this review is application of NIR for qualitative and quantitative analysis of solid forms of drugs and excipients. In addition, this review also sheds light on recent advancement in NIR, such as NIR chemical imaging and NIR based hyphenated techniques.

Preparation, characterization, and cytotoxicity studies of niclosamide loaded mesoporous drug delivery systems.

Recent reports on the anticancer potential of niclosamide have opened new avenues for anticancer treatment. Niclosamide belongs to the BCS class II, which is indicative of poor solubility and dissolution rate limited absorption. The aim of this study was to improve the dissolution rate of the drug by mesoporous drug delivery system. Porous silica grades (ordered and nonordered) with different pore size, pore volume and surface area were used in the study. The drug was loaded on silica carriers by the solvent evaporation method and characterized by BET surface area analysis, SEM, P-XRD, DSC, and FTIR. A discriminatory dissolution medium was developed for performing the in vitro dissolution of niclosamide. In comparison to the plain drug, all silica based formulations showed improvement in the dissolution rate. Maximum enhancement in the dissolution rate was observed in 1:2 drug:carrier loading ratio when compared to 1:1 ratio. Different properties of mesoporous silica like structural geometry, pore size and microenvironment pH demonstrated a significant impact on drug release from the formulations. Cytotoxicity of the optimized mesoporous formulations of niclosamide was explored in HCT-116, HCT-15, NCI, MDA-MB-231 and A549 cancer cell lines. Nearly 3 fold and 2 fold increase in% cytotoxicity of drug loaded Syloid-244 and Sylysia 350 at 1:2 ratio respectively, were observed when compared to the plain drug.

Fast dissolving drug-drug eutectics with improved compressibility and synergistic effects.

Combinational therapy has become increasingly popular in recent times due to various advantages like greater therapeutic effect, reduced number of prescriptions, lower administrative costs, and an increase in patient compliance. Drug-drug multicomponent adducts could help in combination of drugs at supramolecular level. Two drug-drug eutectics of etodolac with paracetamol (EP) and etodolac with propranolol hydrochloride (EPHC) were successfully designed and synthesized for the first time. These eutectics significantly improved dissolution and material properties. A 6 to 9 fold enhancement in % dissolution efficiency was found at 1min suggesting the fast dissolving capabilities of the eutectic mixtures when compared to plain drug. In addition, eutectic mixtures have shown improved hardness compared to plain drugs. EP and EPHC have shown around 5 fold and 3 fold improvements in hardness respectively at 10MPa when compared to plain etodolac. Cell culture studies have shown improved effects of EP. Western blotting analysis revealed that the said combination successfully reduced various inflammatory mediators like TNF-α, COX-2 and IL-6. Whereas, the eutectic combination EPHC has shown enhanced cytotoxic effects with synergistic combination index and favorable dose reduction index. The generated multi-component systems EP and EPHC with fast dissolving capabilities, improved hardness at lower pressures and synergistic effects represent prospective combinations for effective treatment of osteoarthritis and cancer chemotherapy respectively.

Benign Glandular Schwannoma With Ancient Change.

Benign glandular schwannomas are rare and should be distinguished from malignant peripheral nerve sheath tumors with similar divergent tissue differentiation. The authors present a benign glandular schwannoma with ancient change that developed in the subcutis of a 46-year-old man's posterior calf. He lacked stigmata of neurofibromatosis type 1 (NF1). The glandular elements stained positively for epithelial membrane antigen and pancytokeratin. The spindled cells stained positively for SOX10 and S100 protein, supporting schwannian (neural crest) differentiation. The tumor's location and histopathology suggest that the pathogenesis stems from entrapment of sweat glands. Finally, it must be recognized that ancient change may mimic malignancy in these neoplasms as the malignant counterparts have a greater association with NF1 and a poorer prognosis.

Type I Cutaneous Meningioma (Rudimentary Meningocele) With Intradural Attachment to the Phylum Terminale.

Cutaneous meningiomas (CM) are a small subset of meningiomas, further classified into three subtypes. The authors present a 15-year-old male with a symptomatic congenital type I CM and describe the histopathological and immunohistochemical findings. To the authors' knowledge, this is the first report of an extraspinal lumbar type I CM with intradural attachment to the phylum terminale.

Co amorphous systems: A product development perspective.

Solubility is one of the major problems associated with most of the new chemical entities that can be reasonably addressed by drug amorphization. However, being a high-energy form, it usually tends to re-crystallize, necessitating new formulation strategies to stabilize amorphous drugs. Polymeric amorphous solid dispersion (PASD) is one of the widely investigated strategies to stabilize amorphous drug, with major limitations like limited polymer solubility and hygroscopicity. Co amorphous system (CAM), a new entrant in amorphous arena is a promising alternative to PASD. CAMs are multi component single phase amorphous solid systems made up of two or more small molecules that may be a combination of drugs or drug and excipients. Excipients explored for CAM preparation include amino acids, carboxylic acids, nicotinamide and saccharine. Advantages offered by CAM include improved aqueous solubility and physical stability of amorphous drug, with a potential to improve therapeutic efficacy. This review attempts to address different aspects in the development of CAM as drug products. Criterion for co-former selection, various methods involved in CAM preparation, characterization tools, stability, scale up and regulatory requirements for the CAM product development are discussed.