Three Dimensional Printing and Its Applications Focusing on Microneedles for Drug Delivery.

Microneedles (MNs) are considered to be a novel smart injection system that causes significantly low skin invasion upon puncturing, due to the micron-sized dimensions that pierce into the skin painlessly. This allows transdermal delivery of numerous therapeutic molecules, such as insulin and vaccines. The fabrication of MNs is carried out through conventional old methods such as molding, as well as through newer and more sophisticated technologies, such as three-dimensional (3D) printing, which is considered to be a superior, more accurate, and more time- and production-efficient method than conventional methods. Three-dimensional printing is becoming an innovative method that is used in education through building intricate models, as well as being employed in the synthesis of fabrics, medical devices, medical implants, and orthoses/prostheses. Moreover, it has revolutionary applications in the pharmaceutical, cosmeceutical, and medical fields. Having the capacity to design patient-tailored devices according to their dimensions, along with specified dosage forms, has allowed 3D printing to stand out in the medical field. The different techniques of 3D printing allow for the production of many types of needles with different materials, such as hollow MNs and solid MNs. This review covers the benefits and drawbacks of 3D printing, methods used in 3D printing, types of 3D-printed MNs, characterization of 3D-printed MNs, general applications of 3D printing, and transdermal delivery using 3D-printed MNs.

Preparation of Sustained Release Formulation of Verapamil Hydrochloride Using Ion Exchange Resins.

The purpose of this investigation was to formulate and evaluate the interaction between cation exchange resins and verapamil hydrochloride. The uptake studies were conducted using the rotating bottle apparatus. The Langmuir-like equation was applied to the experimental data and the maximum drug loading was determined from the Langmuir-like parameters. The drug-resin complexes were evaluated using XRD, SEM, and particle size analysis. Release studies were performed using USP dissolution apparatus 2. The resin with the lowest percentage of cross-linking had the highest uptake capacity. The percent increase in particle size due to complexation was found to be associated with drug loading; the highest drug loading had the highest increase in particle size. The X-ray diffraction patterns of the resins and the drug-resin complexes showed that they were both amorphous. The maximum drug release was approximately 40% when conventional dissolution testing was used. Results showed that sink conditions could not be maintained using conventional dissolution methods. Maximum drug release increased dramatically by increasing the volume of samples withdrawn and fresh dissolution medium added. Excellent correlation was obtained between sample volume and drug release rate with an R-value of 0.988. Particle diffusion-controlled model and film diffusion-controlled model were both applied to the experimental data. The results indicated that the rate-limiting step is the diffusion of the exchanging cations through the liquid film. The modified release formulation was prepared successfully and correlated very well with the USP monograph for verapamil hydrochloride extended release capsules.

Enhancement of the Solubility of Asenapine Maleate Through the Preparation of Co-Crystals.

BACKGROUND: Asenapine maleate, an anti-schizophrenic drug, is a class II drug with low solubility and high permeability. This exerts a rate-limiting effect on drug bioavailability. OBJECTIVE: To improve the solubility/dissolution rate of asenapine maleate and hence the bioavailability using the co-crystal approach. METHODS: Co-crystals were prepared using the solvent evaporation method. Since the drug has Hbond acceptor count of 6, and H-bond donor count of 2, several co-formers (nicotinamide, urea, succinic, benzoic, and citric acid) were investigated in different ratios. The optimized co-crystals (drug-nicotinamide in a ratio of 1:3) were evaluated using PXRD, DSC, FTIR spectroscopy, and SEM. Additionally, in vitro dissolution and stability studies were conducted. RESULTS: Preparation of the co-crystals was successful except when citric and benzoic acids were used. PXRD patterns showed that the co-crystals were crystalline. FTIR spectroscopy confirmed the formation of H-bond between the drug and the co-former. DSC indicated a lower melting point than that of the components followed immediately by an exothermic peak, which confirmed the formation of co-crystals. SEM showed the formation of crystals with different size and habit. The dissolution of the drug from all the prepared co-crystals was almost similar and much enhanced compared to that of the unprocessed drug. The initial dissolution of the drug from the optimized batch was much faster than that from the other co-crystals and the physical mixture with the same ratio. The optimized batch exhibited long term stability. CONCLUSION: Co-crystals with improved solubility/dissolution rate of asenapine maleate were prepared successfully and were expected to enhance the bioavailability of the drug.

Solid self-nanoemulsifying drug delivery system filled in enteric coated hard gelatin capsules for enhancing solubility and stability of omeprazole hydrochloride.

Omeprazole has poor water solubility, low stability in acidic solutions, and is subject to first pass metabolism resulting in low bioavailability. The objective was to enhance the dissolution and stability by preparing a solid-self nanoemulsifying drug delivery system (SNEDDS) and filling it in enteric coated HGCs. Drug solubility in many oils, surfactants, and cosurfactants was studied. Different SNEDDS were prepared and ternary phase diagrams were constructed. The optimum SNEDDS was evaluated. It was converted into solid by adsorption onto Neusilin® US2, and evaluated. Emulsions formed using Capryol 90, Cremophor RH 40, and ethanol formed spontaneously and were clear. Droplet size was 19.11 ± 3.11 nm, PDI was 0.18 ± 0.05, and zeta potential was -3.9 ± 1.56 mV. Non-medicated SNEDDS was thermodynamically stable. Cloud point was 88 ± 2 °C. Encapsulation efficiency and drug loading of solid-SNEDDS were 98.56 ± 0.44 and 1.29 ± 0.01%, respectively. Flow properties were much enhanced. Crystalline drug was adsorbed/precipitated onto Neusilin® US2 in amorphous form. Dissolution rate was enhanced as compared to commercial products and unprocessed drug. The drug was unstable at the accelerated stability conditions. Accordingly, the traditional stability study at 25 °C should be conducted. In conclusion, the solid-SNEDDS filled in enteric coated HGCs enhanced the dissolution rate and stability in acidic pH.

Preparation and Characterization of an Oral Norethindrone Sustained Release/Controlled Release Nanoparticles Formulation Based on Chitosan.

Norethindrone has short half-life and low bioavailability. The objective was to prepare an oral Sustained Release/Controlled Release (SR/CR) Liquid Medicated Formulation (LMF) to enhance bioavailability and improve patient compliance. Norethindrone was solubilized in HP-ß-CD then complexed with different concentrations of Low Molecular Weight Chitosan (LMWC) (mucoadhesive). PolyElectrolyte Complexes (PECs) were homogenized with oleic acid using different concentrations of tween 80 to form LMFs (nanoemulsions). PECs and LMFs were characterized using different techniques. LMF 2 (optimum formula containing 2.5% w/v LMWC 11 kDa) was administered orally to dogs and mice for pharmacokinetic and adhesion evaluation. DSC, FTIR spectroscopy and SEM images indicated complex formation. Mean diameters of PECs were 183-425 nm, mean zeta potentials were + 18.6-+ 31 mV, and complexation efficiencies were 18.0-20.6%. Ten to fifteen percent tween was needed to prepare homogenous LMFs. Mean diameter of LMF 2 was 10.5 ± 0.57 nm, mean zeta potential was - 11.07 ± - 0.49 mV, encapsulation efficiency was 95.28 ± 1.75%, and each mL contained 145.5 µg norethindrone. SEM images showed spherical homogeneous oil droplets. All of these parameters were affected by molecular weight and concentration of chitosan. Norethindrone release from LMFs was controlled (zero order) for 96 h. It was little affected by molecular weight and concentration of chitosan but affected by concentration of tween 80. LMF 2 adhered to GIT for 48 h and enhanced the bioavailability. It showed no cytotoxicity after considering dilution in GIT and was stable for 3 months refrigerated. In conclusion an effective SR/CR LMF was prepared.

Effect of Moisture Content of Chitin-Calcium Silicate on Rate of Degradation of Cefotaxime Sodium.

Assessment of incompatibilities between active pharmaceutical ingredient and pharmaceutical excipients is an important part of preformulation studies. The objective of the work was to assess the effect of moisture content of chitin calcium silicate of two size ranges (two specific surface areas) on the rate of degradation of cefotaxime sodium. The surface area of the excipient was determined using adsorption method. The effect of moisture content of a given size range on the stability of the drug was determined at 40°C in the solid state. The moisture content was determined at the beginning and the end of the kinetic study using TGA. The degradation in solution was studied for comparison. Increasing the moisture content of the excipient of size range 63-180 µm (surface area 7.2 m2/g) from 3.88 to 8.06% increased the rate of degradation of the drug more than two times (from 0.0317 to 0.0718 h-1). While an opposite trend was observed for the excipient of size range < 63 µm (surface area 55.4 m2/g). The rate of degradation at moisture content < 3% was 0.4547 h-1, almost two times higher than that (0.2594 h-1) at moisture content of 8.54%, and the degradation in solid state at both moisture contents was higher than that in solution (0.0871 h-1). In conclusion, the rate of degradation in solid should be studied taking into consideration the specific surface area and moisture content of the excipient at the storage condition and it may be higher than that in solution.

Preparation and Optimization of Sertraline Hydrochloride Tablets with Improved Dissolution Through Crystal Modification.

Sertraline hydrochloride has low solubility and undergoes first-pass metabolism resulting in low bioavailability. The main objective of this research was to enhance the dissolution rate of the drug. The drug was recrystallized in the presence of polymers and surfactant. The formulation was optimized by studying the effects of drug/polymer ratio, concentration of SLS, and type of polymer on particle size and drug release. The optimized formulation was characterized using different techniques and by evaluating in vitro release, stability, and flow properties. A tablet was compressed and evaluated for hardness, friability, and in vitro dissolution. Release profile of the drug from the optimum formulation (poloxamer 407, drug/polymer ratio 1:2/3, and 0.05% SLS) was higher (96%) than that from processed drug alone (56%). After storage of the optimum formulation for 6 months in a desiccator containing silica gel at room temperature, the drug remained crystalline and did not interact with additives, and almost the same cumulative amount (%) of the drug was released as compared to that from the freshly prepared formulation. Flow proprieties were slightly improved. Compressed tablets exhibited acceptable hardness and friability, and the release profile was better (faster and higher) than that from commercial tablet (Zoloft®). In conclusion, the optimum formulation was successful in enhancing the dissolution.

The Effect of Specific Surface Area of Chitin-Metal Silicate Coprocessed Excipient on the Chemical Decomposition of Cefotaxime Sodium.

Chitin-metal silicates are multifunctional excipients used in tablets. Previously, a correlation between the surface acidity of chitin-calcium and chitin-magnesium silicate and the chemical decomposition of cefotaxime sodium was found but not with chitin-aluminum silicate. This lack of correlation could be due to the catalytic effect of silica alumina or the difference in surface area of the excipients. The objective of this study was to investigate the effect of the specific surface area of the excipient on the chemical decomposition of cefotaxime sodium in the solid state. Chitin was purified and coprocessed with different metal silicates to prepare the excipients. The specific surface area was determined using gas adsorption. The chemical decomposition was studied at constant temperature and relative humidity. Also, the degradation in solution was studied. A correlation was found between the degradation rate constant and the surface area of chitin-aluminum and chitin-calcium silicate but not with chitin-magnesium silicate. This was due to the small average pore diameter of this excipient. Also, the degradation in solution was slower than in solid state. In conclusion, the stability of cefotaxime sodium was dependent on the surface area of the excipient in contact with the drug.