Semi-solid extrusion 3D printing ODFs: an individual drug delivery system for small scale pharmacy.

Orodispersible films (ODFs) are promising drug delivery systems for customized medicines as it provide an alternative approach to increase consumer acceptance by advantages of rapid dissolution and administration without water. The aim of this study was to develop a platform to support the realization of tailored treatments suitable for the extemporaneous production of ODFs by semi-solid extrusion (SSE) 3D printing (3DP). Hydroxypropyl methyl cellulose (HPMC) was used as the polymer of ODFs, and levocetirizine hydrochloride was used as the model drug. The optimal formulation was HPMC:API:PS:maltitol:sucralose at a ratio of 64:10:10:15:1. Seventeen percent HPMC solution and optimal formulation were used to prepare film precursors. The impact of dynamic viscosities and fluid mechanics difference on printing applicability was discussed. The ODFs of cube designs with aimed dose of 1.25 mg, 2.5 mg, and 5 mg were printed by SSE 3DP. Good linear relationship between theoretical model volume and drug content (R2 = 0.999) and good dose accuracy indicate that 3DP is a suitable method for preparing individualized ODFs.

Synthesis and characterization of amphiphilic star-shaped copolymers based on ß-cyclodextrin for micelles drug delivery.

PURPOSE: A series of ß-CD amphiphilic star-shaped copolymers with exceptional characteristics were synthesized and their potential as carriers for micelles drug delivery was investigated. METHODS: A series of amphiphilic copolymers based on ß-CD were synthesized by introducing poly (acrylic acid)-co-poly(methyl methacrylate)-poly (vinyl pyrrolidone) or poly (acrylic acid)-co-poly(methyl methacrylate)-co-poly(monoacylated-ß-CD)-poly (vinyl pyrrolidone) blocks to the primary hydroxyl group positions of ß-CD. The micellization behavior of the copolymers, the synthesis conditions, characteristics, drug release in vitro and tissue distribution of vinpocetine (VP) micelles in vivo were investigated. RESULTS: Around 60 types of ß-CD amphiphilic star-shaped copolymers were successfully synthesized and the critical micelle concentration ranged from 9.80 × 10-4 to 5.24 × 10-2g/L. The particle size, drug loading and entrapment efficiency of VP-loaded ß-CD-P4 micelles prepared with optimal formulation were about 65 nm, 21.44 ± 0.14%, and 49.05 ± 0.36%, respectively. The particles had good sphericity. The cumulative release rates at 72 h of VP-loaded ß-CD-P4 micelles in pH 1.0, pH 4.5, pH 6.5, or pH 7.4 media were 93%, 69%, 49%, and 43%, respectively. And, the lung targeting efficiency of VP-loaded ß-CD-P4 micelles was 8.98 times higher than that of VP injection. CONCLUSION: The VP-loaded ß-CD-P4 micelles exhibited controlled-release property, pH-induced feature and lung targeting capacity compared with VP injection, suggesting that the ß-CD-P4 copolymers are an excellent candidate for micelles drug delivery.

Oral disintegrating patient-tailored tablets of warfarin sodium produced by 3D printing.

Individualized medicine is a new direction in the field of modern pharmacy. In this study, we assessed the feasibility and accuracy of 3D printing techniques for the preparation of individualized doses of mouth-disintegrating tablets of warfarin. Warfarin sodium, D-sucrose, pregelatinized starch, povidone K30, microcrystalline cellulose, and silicon dioxide (at a ratio of 1:42.45:46.15:5.1:4.9:0.4) were mixed and used as the printing powder in the 3D printer; preset parameters were used. The dosage of the tablet was controlled by the number of printing layers. The content, dose uniformity, dose accuracy, hardness, friability, disintegration time, dissolution, and the microstructural and overall appearance were determined to evaluate the printed tablets. For the doses of 3, 2, and 1 mg that were produced in the experiment, the disintegration times were 50.0 ± 5.2, 35.7 ± 4.3, and 11.0 ± 2.2 s, respectively, and the relative errors of the dose were -2.33, -1.50, and 0%, respectively. The other indicators were consistent with the preparation requirements of pharmaceutical tablets. It is possible to prepare tablets with excellent properties and controlled drug doses by using 3D printing techniques. This technology will be an important means to achieve individualized medicine.

[Study on formulation of naoxuekang dispersible tablets].

OBJECTIVE: To study the formulation of Naoxuekang dispersible tablets. METHODS: The formulation was determined by pre-processing leech extractum prior to a series of experiments used to screen excipients like bulking agents and disintegrants and so on, and by adding disintegrants within and without. RESULTS: Microcrystalline cellulose was determined as the bulking agent, and carboxymethyl cellulose and low-substituted hydroxypropyl cellulose were determined as the disintegrants of Naoxuekang dispersible tablet formula. The average disintegration time and nitrogen content of one tablet were 52 seconds and 5.47 milligrams, respectively. Also disperse homogeneity, weight variation and microbial limit all met the requirements in Ch. P. CONCLUSION: The prepared Naoxuekang dispersible tablet is reasonable in formula, feasible in technology, which meets the quality standards.

Incorporation of ion exchange functionalized-montmorillonite into solid lipid nanoparticles with low irritation enhances drug bioavailability for glaucoma treatment.

Montmorillonite-loaded solid lipid nanoparticles with good biocompatibility, using Betaxolol hydrochloride as model drug, were prepared by the melt-emulsion sonication and low temperature-solidification methods and drug bioavailability was significantly improved in this paper for the first time to application to the eye. The appropriate physical characteristics were showed, such as the mean particle size, Zeta potential, osmotic pressure, pH values, entrapping efficiency (EE%) and drug content (DC%), all showed well suited for possible ocular application. In vitro release experiment indicated that this novel system could continuously release 57.83% drugs within 12 h owing to the dual drug controlled-release effect that was achieved by ion-exchange feature of montmorillonite and structure of solid lipid nanoparticles. Low irritability and good compatibility of nanoparticles were proved by both CAM-TBS test and cytotoxicity experiment. We first discovered from the results of Rose Bengal experiment that the hydrophilicity of the drug-loaded nanoparticles surface was increased during the loading and releasing of the hydrophilic drug, which could contribute to prolong the ocular surface retention time of drug in the biological interface membrane of tear-film/cornea. The results of in vivo pharmacokinetic and pharmacodynamics studies further confirmed that increased hydrophilicity of nanoparticles surface help to improve the bioavailability of the drug and reduce intraocular pressure during administration. The results suggested this novel drug delivery system could be potentially used as an in situ drug controlled-release system for ophthalmic delivery to enhance the bioavailability and efficacy.

Controlled drug delivery for glaucoma therapy using montmorillonite/Eudragit microspheres as an ion-exchange carrier.

BACKGROUND: Glaucoma is a serious eye disease that can lead to loss of vision. Unfortunately, effective treatments are limited by poor bioavailability of antiglaucoma medicine due to short residence time on the preocular surface. MATERIALS AND METHODS: To solve this, we successfully prepared novel controlled-release ion-exchange microparticles to deliver betaxolol hydrochloride (BH). Montmorillonite/BH complex (Mt-BH) was prepared by acidification-intercalation, and this complex was encapsulated in microspheres (Mt-BH encapsulated microspheres [BMEMs]) by oil-in-oil emulsion-solvent evaporation method. The BH loaded into ion-exchange Mt was 47.45%±0.54%. After the encapsulation of Mt-BH into Eudragit microspheres, the encapsulation efficiency of BH into Eudragit microspheres was 94.35%±1.01% and BH loaded into Eudragit microspheres was 14.31%±0.47%. RESULTS: Both Fourier transform infrared spectra and X-ray diffraction patterns indicated that BH was successfully intercalated into acid-Mt to form Mt-BH and then Mt-BH was encapsulated into Eudragit microspheres to obtain BMEMs. Interestingly, in vitro release duration of the prepared BMEMs was extended to 12 hours, which is longer than both of the BH solution (2.5 hours) and the conventional BH microspheres (5 hours). Moreover, BMEM exhibited lower toxicity than that of BH solution as shown by the results of cytotoxicity tests, chorioallantoic membrane-trypan blue staining, and Draize rabbit eye test. In addition, both in vivo and in vitro preocular retention capacity study of BMEMs showed a prolonged retention time. The pharmacodynamics showed that BMEMs could extend the drug duration of action. CONCLUSION: The developed BMEMs have the potential to be further applied as ocular drug delivery systems for the treatment of glaucoma.

The efficacy of nimodipine drug delivery using mPEG-PLA micelles and mPEG-PLA/TPGS mixed micelles.

OBJECTIVE: In order to develop and compare mPEG-PLA micelles and mPEG-PLA/TPGS mixed micelles, with the intention to develop a highly efficient formulation for nimodipine (NIM), NIM-loaded micelles and mixed micelles were made and their pharmacokinetics were studied. METHODS: Single factor experiments and orthogonal experiments were designed to optimize the final preparation process, characterizations and drug release behaviors were studied. Pharmacokinetics of NIM micelles, NIM mixed micelles were researched and were compared to NIM solution. RESULTS: Micelles and mixed micelles were prepared by solvent evaporation method, with relatively high drug loading efficiency and within nano-particle size range. The CMC value of mPEG-PLA was lower than that of mPEG-PLA/TPGS. The results of FTIR and TEM confirmed the spherical core-shell structure of micelles as well as mixed micelles, and the encapsulation of NIM inside the cores. In vitro release showed that micelles and mixed micelles had sustained release effect in the forms of passive diffusion and dissolution process, respectively. Following intraperitoneal administration (5mg/kg), micelles and mixed micelles were absorbed faster than solution, and with larger MRT(0-t), smaller CLz and larger AUC(0-t) as compared to that of solution, which showed micelles and mixed micelles had higher retention, slower elimination and higher bioavailability. This experiment also showed that mixed micelles released NIM more stably than micelles. By evaluate the bioequivalence, NIM micelles and NIM mixed micelles were testified non-bioequivalent to NIM solution. CONCLUSION: Micelles and mixed micelles could sustain the NIM concentrations more efficiently in plasma as compared to solution. Mixed micelles were the best ones since they had high loading content and released more stably. Thus, apprehending micelles and mixed micelles were suited as poor aqueous solubility drug carriers, and mixed micelles were better due to their high loading content and more stable release.