HPMCAS-Based Amorphous Solid Dispersions in Clinic: A Review on Manufacturing Techniques (Hot Melt Extrusion and Spray Drying), Marketed Products and Patents.

Today, therapeutic candidates with low solubility have become increasingly common in pharmaceutical research pipelines. Several techniques such as hot melt extrusion, spray drying, supercritical fluid technology, electrospinning, KinetiSol, etc., have been devised to improve either or both the solubility and dissolution to enhance the bioavailability of these active substances belonging to BCS Class II and IV. The principle involved in all these preparation techniques is similar, where the crystal lattice of the drug is disrupted by either the application of heat or dissolving it in a solvent and the movement of the fine drug particles is arrested with the help of a polymer by either cooling or drying to remove the solvent. The dispersed drug particles in the polymer matrix have higher entropy and enthalpy and, thereby, higher free energy in comparison to the crystalline drug. Povidone, polymethaacrylate derivatives, hydroxypropyl methyl cellulose (HPMC) and hydroxypropyl methylcellulose acetate succinate derivatives are commonly used as polymers in the preparation of ASDs. Specifically, hydroxypropylmethylcellulose acetate succinate (HPMCAS)-based ASDs have become well established in commercially available products and are widely explored to improve the solubility of poorly soluble drugs. This article provides an analysis of two widely used manufacturing techniques for HPMCAS ASDs, namely, hot melt extrusion and spray drying. Additionally, details of HPMCAS-based ASD marketed products and patents have been discussed to emphasize the commercial aspect.

Formulation and processing of solid self-emulsifying drug delivery systems (HME S-SEDDS): A single-step manufacturing process via hot-melt extrusion technology through response surface methodology.

The objective of the current study is the formulation development and manufacturing of solid self-emulsifying drug delivery systems (HME S-SEDDS) via a single-step continuous hot-melt extrusion (HME) process. For this study, poorly soluble fenofibrate was selected as a model drug. From the results of pre-formulation studies, Compritol® HD5 ATO, Gelucire® 48/16, and Capmul® GMO-50 were selected as oil, surfactant and co-surfactant respectively for manufacturing of HME S-SEDDS. Neusilin® US2 was selected as a solid carrier. The design of experiments (response surface methodology) was employed to prepare formulations via a continuous HME process. The formulations were evaluated for emulsifying properties, crystallinity, stability, flow properties and drug release characteristics. The prepared HME S-SEDDS showed excellent flow properties, and the resultant emulsions were stable. The globule size of the optimized formulation was 269.6 nm. The DSC and XRD studies revealed the amorphous nature of the formulation and FTIR studies showed no significant interaction between fenofibrate and excipients. The drug release studies showed significant (p < 0.05) improvement in solubility compared to the pure drug (DE15 = 45.04 for the optimized formulation), as >90% of drug release was observed within 15 min. The stability studies for the optimized formulation were conducted for 3 months at 40 °C/75% RH.

Continuous Manufacturing of Oil in Water (O/W) Emulgel by Extrusion Process.

Pharmaceutical industries and drug regulatory agencies are inclining towards continuous manufacturing due to better control over the processing conditions and in view to improve product quality. In the present work, continuous manufacturing of O/W emulgel by melt extrusion process was explored using lidocaine as an active pharmaceutical ingredient. Emulgel was characterized for pH, water activity, globule size distribution, and in vitro release rate. Additionally, effect of temperature (25°C and 60°C) and screw speed (100, 300, and 600 rpm) on the globule size and in vitro release rate was studied. Results indicated that at a given temperature, emulgel prepared under screw speed of 300 rpm resulted in products with smaller globules and faster drug release.

Development of silymarin topical formulation: In vitro and ex vivo dermal kinetics of silymarin.

Silymarin constituents are extensively investigated in the treatment of skin disorders. The main constituents of silymarin include taxifolin (TX), silychristin (ST), silydianin (SDN), silybin A (SA), silybin B (SB), isosilybin A (ISA) and isosilybin B (ISB). The objective of the present study was to determine in-vitro dermal kinetics of individual silymarin constituents in human skin models and to develop a silymarin topical formulation. In-vitro studies indicate human skin binding of silymarin was in the range of 2.09 to 12.3% and half-life of silymarin constituents was > 15.5 h in epidermal and dermal cells. Topical silymarin cream was prepared using sulfobutylether-ß-cyclodextrins as solubilizer and propylene glycol as permeation enhancer. The cream was subjected to ex-vivo human skin permeation studies. In ex-vivo studies, cumulative amount of TX, ST, SDN, SA, SB, ISA and ISB permeated across human cadaver skin at 24 h was 921 ± 13.5, 1992 ± 67.6, 345 ± 39.2, 1089 ± 45.0, 1770 ± 100, 1469 ± 81.5 and 1285 ± 33.1 ng/cm2, respectively. The amount TX, ST, SDN, SA, SB, ISA and ISB retained after 24 h was 60.7 ± 8.2, 376 ± 45.5, 72.3 ± 6.9, 66.4 ± 8.0, 208 ± 31.3, 154 ± 12.4 and 102 ± 6.3 ng/mg of human cadaver skin, respectively. The study results demonstrate silymarin topical formulation could deliver significant amount of silymarin constituents into skin. The developed silymarin formulation could be beneficial for treatment or management of a broad spectrum of dermatological disorders.

Analysis of docosanol using GC/MS: Method development, validation, and application to ex vivo human skin permeation studies.

Docosanol is the only US Food and Drug Administration (FDA) approved over-the-counter topical product for treating recurrent oral-facial herpes simplex labialis. Validated analytical methods for docosanol are required to demonstrate the bioequivalence of docosanol topical products. A gas chromatography/selected ion monitoring mode mass spectrometry (GC/SIM-MS) method was developed and validated for docosanol determination in biological samples. Docosanol and isopropyl palmitate (internal standard) were separated on a high-polarity GC capillary column with (88% cyanopropy)aryl-polysiloxane employed as the stationary phase. The ions of m/z 83 and 256 were selected to monitor docosanol and isopropyl palmitate, respectively; the total run time was 20 min. The GC/SIM-MS method was validated in accordance with US FDA guidelines, and the results met the US FDA acceptance criteria. The docosanol calibration standards were linear in the 100-10000 ng/mL concentration range (R 2>0.994). The recoveries for docosanol from the receptor fluid and skin homogenates were >93.2% and >95.8%, respectively. The validated method was successfully applied to analyze ex vivo human cadaver skin permeation samples. On applying Abreva® cream tube and Abreva® cream pump, the amount of docosanol that penetrated human cadaver skin at 48 h was 21.5 ± 7.01 and 24.0 ± 6.95 ng/mg, respectively. Accordingly, we concluded that the validated GC/SIM-MS was sensitive, specific, and suitable for quantifying docosanol as a quality control tool. This method can be used for routine analysis as a cost-effective alternative to other techniques.

Hot-melt extruded hydroxypropyl methylcellulose acetate succinate based amorphous solid dispersions: Impact of polymeric combinations on supersaturation kinetics and dissolution performance.

Nucleation inhibition and maintenance of drug supersaturation over a prolonged period are desirable for improving oral absorption of amorphous solid dispersions. The present study investigates the impact of binary and ternary amorphous solid dispersions on the supersaturation kinetics of nifedipine using the polymers hydroxypropylmethylcellulose acetate succinate (HPMCAS) LG, and HG, Eudragit® RSPO, Eudragit® FS100, Kollidon® VA64 and Plasdone™ K-29/32. The amorphous solubility, nucleation induction time, and particle size analysis of nifedipine in a supersaturated solution were performed with and without the presence of polymers, alone or in combination. The HPMCAS-HG and HPMCAS-HG + LG combinations showed the highest nifedipine amorphous solubility of 169.47, 149.151 µg/mL, respectively and delay in nucleation induction time up to 120 min compared to other polymeric combinations. The solid dispersions prepared via hot melt extrusion showed the transformation of crystalline nifedipine to amorphous form. The in-vitro non-sink dissolution study revealed that although the binary nifedipine/HPMCAS-LG system had shown the greater supersaturation concentration of 66.1 µg/mL but could not maintain a supersaturation level up to 360 min. A synergistic effect emerged for ternary nifedipine/HPMCAS-LG/HPMCAS-HG, and nifedipine/HPMCAS-LG/Eudragit®FS100 systems maintained the supersaturation level with enhanced dissolution performance, demonstrating the potential of polymeric combinations for improved amorphous solid dispersion performance.

A One-Step Twin-Screw Melt Granulation with Gelucire 48/16 and Surface Adsorbent to Improve the Solubility of Poorly Soluble Drugs: Effect of Formulation Variables on Dissolution and Stability.

Fenofibrate is an effective lipid-lowering drug; however, its poor solubility and high log p (5.2) result in insufficient absorption from the gastrointestinal tract, leading to poor bioavailability. In this study, a one-step continuous twin-screw melt granulation process was investigated to improve the solubility and dissolution of fenofibrate using Gelucire® 48/16 and Neusilin® US2 as the solubilizer and surface adsorbent, respectively. The formulations (granules) were prepared at different ratios of fenofibrate, Gelucire® 48/16, and Neusilin® US2 based on phase-solubility studies and characterized using dissolution, differential scanning calorimetry, powder X-ray diffraction, and scanning electron microscopy analyses and studies on flow properties. In the phase-solubility studies, a linear relation was observed between Gelucire® 48/16 concentration and the amount of fenofibrate dissolved. In contrast, the dissolution rate of the prepared formulations was independent of the fenofibrate: Gelucire® 48/16 ratio and dependent on the Neusilin® US2 levels in the formulation. Increasing Neusilin® US2 levels decreased the rate of dissolution of the granules but improved the stability of the tablets under storage at accelerated stability conditions. Interestingly, higher Gelucire® 48/16 levels in the granules resulted in tablets with a hard matrix, which slowed disintegration and dissolution. All formulations exhibited improved dissolution compared to pure fenofibrate.

Instability of therapeutic proteins - An overview of stresses, stabilization mechanisms and analytical techniques involved in lyophilized proteins.

Solid-state is the preferred choice for storage of protein therapeutics to improve stability and preserve the biological activity by decreasing the physical and chemical degradation associated with liquid protein formulations. Lyophilization or freeze-drying is an effective drying method to overcome the instability problems of proteins. However, the processing steps (freezing, primary drying and secondary drying) involved in the lyophilization process can expose the proteins to various stress and harsh conditions, leading to denaturation, aggregation often a loss in activity of protein therapeutics. Stabilizers such as sugars and surfactants are often added to protect the proteins against physical stress associated with lyophilization process and storage conditions. Another way to curtail the degradation of proteins due to process related stress is by modification of the lyophilization process. Slow freezing, high nucleation temperature, decreasing the extent of supercooling, and annealing can minimize the formation of the interface (ice-water) by producing large ice crystals with less surface area, thereby preserving the native structure and stability of the proteins. Hence, a thorough understanding of formulation composition, lyophilization process parameters and the choice of analytical methods to characterize and monitor the protein instability is crucial for development of stable therapeutic protein products. This review provides an overview of various stress conditions that proteins might encounter during lyophilization process, mechanisms to improve the stability and analytical techniques to tackle the proteins instability during both freeze-drying and storage.

A Rapid Tool to Optimize Process Variables for Continuous Manufacturing of Metronidazole Ointment Using Melt Extrusion Technique.

The use of hot-melt extrusion (HME) technique in the preparation of semi-solid products offers several advantages over conventional processes. However, the optimization of the technique for preparation of semi-solid pharmaceuticals is challenging due to involvement of ingredients with different physical properties. Hence, a simple tool to optimize the mixing of ingredients that results in a target ratio and drug content uniformity is utmost important. In this study, a handheld colorimeter has been explored to optimize the process variables of twin screw processor for preparation of hydrophilic PEG-based ointment. The process parameters which were optimized with use of handheld colorimeter have been used for preparation of polyethylene glycol-based metronidazole ointment. The metronidazole ointment prepared by twin screw processor was compared with commercially available metronidazole gel for in vitro release testing and ex vivo permeation. The flux, ex vivo bioavailability, and Tmax of polyethylene glycol-based metronidazole ointment was found to be similar to that of marketed metronidazole gel.

Topical Pilocarpine Formulation for Diagnosis of Cystic Fibrosis.

Cystic fibrosis is diagnosed in infants by estimating the levels of chloride ions present in the sweat induced by iontophoresis of pilocarpine solution. Elevated levels of chloride (≥60 mMol/L) in sweat are indicative of cystic fibrosis. However, the iontophoretic method of delivering pilocarpine is cumbersome and usually is associated with several side effects such as skin burn, skin rashes, erythema, and so forth. The objective of this study was therefore to develop a topical formulation that delivers adequate amount of pilocarpine. The drug delivery of formulation was compared with iontophoresis of aqueous solution of pilocarpine nitrate in vitro using porcine skin model. The pilocarpine levels in the skin exposed to topical pilocarpine solution under mild hyperthermia was 152.04 ± 52.23 µg/cm2 after 10 min of application, whereas it was 97.05 ± 27.93 µg/cm2 in the skin after 10 min of iontophoresis. The topical formulation was subjected to clinical evaluation to assess the efficacy of the product to induce sweat production. The average amount of the sweat secreted on application of topical formulation was found to be 77.28 ± 18.97 mg. Based on these results, it was found that the topical formulation was successful in delivering pilocarpine and to stimulate sweat secretion.

Xanthan gum stabilized PEGylated gold nanoparticles for improved delivery of curcumin in cancer.

In recent years, gold nanoparticles (AuNPs) have received immense interest in various biomedical applications including drug delivery, photothermal ablation of cancer and imaging agent for cancer diagnosis. However, the synthesis of AuNPs poses challenges due to the poor reproducibility and stability of the colloidal system. In the present work, we developed a one step, facile procedure for the synthesis of AuNPs from hydrogen tetrachloroaurate (III) hydrate (HAuCl4. 3H2O) by using ascorbic acid and xanthan gum (XG) as reducing agent and stabilizer, respectively. The effect of concentrations of HAuCl4, 3H2O, ascorbic acid and methoxy polyethylene glycol-thiol (mPEG800-SH) were optimized and it was observed that stable AuNPs were formed at concentrations of 0.25 mM, 50 µM and 1 mM for HAuCl4.3H2O, ascorbic acid, and mPEG800-SH, respectively. The XG stabilized, deep red wine colored AuNPs (XG-AuNPs) were obtained by drop-wise addition of aqueous solution of ascorbic acid (50 mM) and XG (1.5 mg ml(-1)). Synthesized XG-AuNPs showed λmax at 540 nm and a mean hydrodynamic diameter of 80 ± 3 nm. PEGylation was performed with mPEG800-SH to obtain PEGylated XG-AuNPs (PX-AuNPs) and confirmed by Ellman's assay. No significant shift observed in λmax and hydrodynamic diameter between XG-AuNPs and PX-AuNPs. Colloidal stability of PX-AuNPs was studied in normal saline, buffers within a pH range of 1.2-7.4, DMEM complete medium and in normal storage condition at 4 ˚C. Further, water soluble curcumin was prepared using PVP-K30 as solid dispersion and loaded on to PX-AuNPs (CPX-AuNPs), and evaluated for cellular uptake and cytotoxicity in Murine melanoma (B16F10) cells. Time and concentration dependent studies using CPX-AuNPs showed efficient uptake and decreased cell viability compared to free curcumin.