Opportunities and challenges of three-dimensional printing technology in pharmaceutical formulation development

Three-dimensional printing is a technology that prints the products layer-by-layer, in which materials are deposited according to the digital model designed by computer aided design (CAD) software. This technology has competitive advantages regarding product design complexity, product personalization, and on-demand manufacturing. The emergence of 3D technology provides innovative strategies and new ways to develop novel drug delivery systems. This review summarizes the application of 3D printing technologies in the pharmaceutical field, with an emphasis on the advantages of 3D printing technologies for achieving rapid drug delivery, personalized drug delivery, compound drug delivery and customized drug delivery. In addition, this article illustrates the limitations and challenges of 3D printing technologies in the field of pharmaceutical formulation development.

Study on intralymphatic-targeted hyaluronic acid-modified nanoliposome: influence of formulation factors on the lymphatic targeting.

In this study, hyaluronic acid-modified docetaxel-loaded liposomes were prepared to evaluate the lymphatic targeting after subcutaneous administration, and formulation factors affecting the lymphatic targeting were examined, including free hyaluronic acid, molecular weight, hyaluronic acid-density and particle diameter. The high molecular weight hyaluronic acid-modified docetaxel-loaded liposomes (HA-LPs) and low molecular weight hyaluronic acid-modified docetaxel-loaded liposomes (LMWHA-LPs) were prepared via electrostatic attraction. The physicochemical properties and in vitro drug release were evaluated. The lymphatic drainage and the lymph node uptake were investigated by pharmacokinetics and distribution recovery of docetaxel in lymph nodes, injection site and plasma. The lymphatic targeting ability of optimized Cy7-loaded LMWHA-LPs (LMWHA-LPs/Cy7) was evaluated by near-infrared fluorescence imaging technique. The result showed that HA-LPs and LMWHA-LPs with suitable and stable physicochemical properties could be used for in vivo lymphatic targeting studies. Hyaluronic acid-modified liposome significantly increased the docetaxel recovery in lymph nodes, and displayed higher AUC(0-24h) and longer retention time compared to unmodified liposomes in vivo. In contrast, the presence of free hyaluronic acid hindered the lymphatic drainage and increased the plasma-drug concentration. Importantly, LMWHA-modification improved lymphatic drainage and lymph node uptake of liposomes compared with HA-modification. And Lymph node uptake of LMWHA-LPs depended mainly on LMWHA-density instead of particle size. The results of in vivo imaging showed that LMWHA-LPs/Cy7 significantly located in the lymphatic system. And both DTX-loaded and Cy7-loaded LMWHA-LPs had similar and stable lymphatic target level. Our investigation showed that LMWHA-LPs were a highly promising lymphatic targeting carrier for chemotherapy drugs and diagnostic fluorescence agents.

Anti-tumor activity of folate receptor targeting docetaxel-loaded membrane-modified liposomes / 药学学报

The anti-tumor activity of folate receptor targeting docetaxel-loaded membrane-modified liposomes (FA-PDCT-L) was investigated in vitro and in vivo. FA-PDCT-L was prepared by organic solvent injection method. Transmission electron microscope, dynamic light scattering and electrophoretic light scattering were employed to study the physicochemical parameters of FA-PDCT-L. The inhibitory effects of docetaxel injection (DCT-I), non-modified DCT liposomes (DCT-L) and FA-PDCT-L on the growth of MCF-7 and A-549 cells at different incubation times were detected by CCK-8 assay; and the hemolytic test was employed in vitro. Tumor mice were randomized into 4 groups: DCT-I, DCT-L, FA-PDCT-L and control group (normal saline), and given drugs at 10 mg x kg(-1) x d(-1) through tail vein. The tumor volume, mice weight, inhibition rate of tumor and life span were measured at the end of experiments. The IC50 of the FA-PDCT-L for MCF-7 and A549 cell lines were significantly lower than that of DCT-I and DCT-L, without hemolysis reaction observed. Compared with control group, the weights of tumor in DCT-I, DCT-L and FA-PDCT-L were decreased, especially for FA-PDCT-L, with inhibitory rates at 79.03 % (P < 0.05). The life span and median survival time of FA-PDCT-L treated mice were significantly higher than that of DCT-I and DCT-L. In conclusion, FA-PDCT-L shows a good anti-tumor activity, indicating that it is potential carriers for DCT in the treatment of tumor.

Intestinal absorption kinetics of flurbiprofen in rats / 药学学报

To study the in situ intestinal absorption kinetics of flrubiprofen in rats, the absorption of flurbiprofen in small intestine (duodenum, jejunum and ileum) and colon of rats was investigated using in situ single-pass perfusion method and the drug content was measured by HPLC. The effects of drug concentration on the intestinal absorption were investigated. The K(a) and P(app) values of flurbiprofen in the small intestine and colon had no significant difference (P > 0.05). Drug concentration (4.0, 10.0 and 16.0 mg x L(-1)) had no significant influence on the K(a) values (P > 0.05). However, when concentration was 4.0 mg x L(-1) and 10.0 mg x L(-1), significant effect on the P(app) values (P 0.05). The K(a) and P(app) values of flurbiprofen on the perfusion flow rate had significant difference (P < 0.05). Flurbiprofen could be absorbed at all segments of the intestine in rats and had no special absorption window. The absorption of flurbiprofen complies with the facilitated diffusion in the general intestinal segments, and accompany with the cytopsistransport mechanism probably. The perfusion flow rate had significant effect on the K(a) and P(app).

Preparation of valsartan nanosuspensions and its in vitro dissolution / 药学学报

To increase the dissolution rate and extent of valsartan, valsartan nanosuspensions have been prepared. Controlled precipitation assisted with sonication is utilized to prepare valsartan nanosuspensions, the concentration of the drug, stabilizer and costablizer had a great effect on the stability of the preparation according to the pre-experiment. So the method of central composite design-response surface is used to optimize the prescription based on the above three factors and the particle size as the response value. The software Origin 8.0 is used to draw the view of the three-dimensional effects and 2D contour map, to get the optimal prescription area. Valsartan nanosuspensions were prepared. The mean diameter and zeta potential are about 216.6 nm and -57.7 mV, respectively. Compared with the microsuspensions and commercial preparation, the dissolution of valsartan nanosuspensions was faster and the bioavailability can be enhanced to some extent.

Comparison of the characteristics of several polymer materials used in hydrophilic matrix tablets / 药学学报

Pure and drug hydrophilic matrix tablets were prepared by direct compression method with theophylline as a model drug. The characteristics of four hydrophilic matrix polymers, hydroxypropylmethylcellulose (HPMC), polyethylene oxide (PEO), sodium alginate (NaAlg) and xanthan gum (XG), were compared by investigating the water absorption, swelling, erosion and gel layer strength. The sequence of water absorption rate was XG >> NaAlg (H) > PEO > NaAlg (L) >> HPMC; The sequence of swelling index was XG >> PEO >> HPMC >> NaAlg; The sequence of erosion rate was NaAlg (L) > NaAlg (H) >> PEO80 > PEO200 > PEO300 > XG approximately PEO400 approximately K4M > K15M > PEO600 approximately K100M; The sequence of the gel layer strength was PEO > HPMC > XG >> NaAlg. For the PEO and HPMC matrix tablets, with the polymer molecular weight increased, the drug release mechanism was gradually transferred from mainly depending on the erosion to the diffusion; for SAL matrix tablets, the drug release mainly depends on erosion mechanism; and for XG matrix tablets, the drug release mainly depends on non-Fick diffusion mechanism. Comparison of the performance difference between the polymer materials will contribute to rational design and prediction of drug release behaviors from matrix tables and ultimately to achieve clinical needs.

Design push-pull osmotic pump tablets of famotidine based on an expert system for the formulation design of osmotic pump of poor water-soluble drug / 药学学报

The purpose of this study is to design push-pull osmotic pump (PPOP) tablets of famotidine using the expert system for the formulation design of osmotic pump of poor water-soluble drug which had been established by the authors. Firstly, the parameters which were requisite of the system input were obtained from literatures and experimental tests. Then the parameters were input into the system, and the program was run. The system displayed the designed formulations sequential. Finally, famotidine PPOP was prepared according to the designed formulations and the in vitro dissolution was carried out. It was found out that the target formulation of famotidine PPOP which could release for 24 hours was obtained in a very short period. Meanwhile, the practicability of the established expert system was proved.

Preparation and Optimization of Formulation of PLGA Microspheres Containing Chinese Herbal Extract Cucurbitacin B / 中国药房

OBJECTIVE: To prepare Polylactic-co-glycolic acid)(PLGA) microspheres loaded with Chinese herbal extract cucurbitacin B.METHODS: Cucurbitacin B loaded by PLGA microspheres were prepared by modified emulsification-solvent evaporation method.Central composite design-response surface method was applied to optimize the formulation with PVA concentration and ratio of drug to polymer as independent variables,and with yield of microspheres(Y1),drug loading amount(Y2),encapsulation efficiency(Y3),mean particle diameter(Y4),and the cumulative percentage of the drug release in 24 hr(Y5) as indexes to conduct multiple linear regression and second-order polynomial equation fitting.In vitro release test was performed by modified immediate release method.RESULTS: The results showed that all response variables were greatly fitted by a second-order polynomial equation.The optimal formulation was proved to be as follows: PVA concentration was 0.014 and ratio of drug to polymer was 0.066 5.The microspheres prepared in the optimal formulation were spherical and had smooth surface.Y1,Y2,Y3,Y4,and Y5 were 79.9%,7.83%,80.5%,56.18 ?m and 6.98%,respectively.The cumulative release from microspheres within 35 days reached 86.73%.CONCLUSION: Cucurbitacin B-PLGA microspheres are characterized by prolonged action and sustained-release.Furthermore,the established model has satisfactory predictability.

In vitro and in vivo evaluation of two extended release preparations of combination metformin and glipizide.

A system that can deliver multi-drugs at a prolonged rate is very important to the treatment of various chronic diseases such as diabetes, asthma, and heart disease. Two controlled-release systems, which exhibited similar release profiles of metformin and glipizide, i.e., elementary osmotic pump tablets (EOP) and bilayer hydrophilic matrix tablet (BT), were designed. The effects of pH and hydrodynamic conditions on drug release from two formulations were investigated. It was found that both drug releases from EOP were not sensitive to dissolution media pH and hydrodynamics change, while the release of glipizide from BT was influenced by the stirring rate. Moreover, in vivo evaluation was performed, relative to the equivalent dose of conventional metformin tablet and glipizide tablet, by a three-crossover study in six Beagle dogs. Cumulative percent input in vivo was compared to in vitro release profiles. The linear correlations of metformin and glipizide between fraction absorbed in vivo and fraction dissolved in vitro were established for EOP-a true zero-order release formula, whereas only nonlinear correlations were obtained for BT. In conclusion, drug release from EOP was both independent of in vitro and in vivo conditions, where the best sustained release effect was achieved, whereas the in vitro dissolution test employed for BT needed to be further optimized to be biorelevant.

Study on Base Material Optimization of Oxaprozin Gel / 中国药房

OBJECTIVE: To observe the effects of different types of carbomers on percutaneous permeability of oxaprozin gels in vitro and to opitmize the formulation of oxaprozin gel. METHODS: The permeability test in vitro was carried out by using Franz diffusion cell with rats' ex vivo skin as barrier. RESULTS: The ex vivo permeability of oxaprozin gel was the best when the carbomer 940 used as its base material with its ex vivo permeability coefficient at 22.77?g/ (cm2?h) . CONCLUSION : The optimized gel base material can act as bases for the production of oxaprozin gel.

Optimization of the Formulation of Bezafibrate Osmotic Pump Tablets by Central Composite Design-response Surface Methodology / 中国药房

OBJECTIVE: To prepare bezafibrate osmotic pump tablets(BOPT) and optimize its formulation by central composite design-response surface methodology(CCDRSM).METHODS: The amount of polyoxyethylene(PEO) N80 which used as an adjuvant of Bezafibrate osmotic pump tablets(A),the amount of Na2CO3(B),and the coating weight increase(C) were used as 3 factors for investigation,and the cumulative release amount at 1 h and 6 h respectively,and the linear correlation coefficient(r) of the cumulative release amount versus time were taken as indexes.The formulation of BOPT was optimized by CCDRSM and the optimized formulation was verified.RESULTS: The optimized formulation obtained was as follows: A 40 mg,B 20 mg,and C 29 mg.The tablets prepared in optimized formulation demonstrated good release behavior,with the absolute value of deviation of each index being less than 5%.CONCLUSION: The CCDRSM can be applied to optimize the formulation of BOPT and the established model is of satisfactory predictive value.

Quantitative determination of salvianolic acid A in rat plasma by HPLC / 中草药

Object To develop a method for the quantitative determination of salvianolic acid A in rat plasma. Methods HPLC method and Hypersil ODS column (4 6 mm?200 mm, 10 ?m) were used, the mobile phase was acetontrile water (1∶2 65, adjusted pH to 2 5 with formic acid), at a flow rate of 0 9 mL/min, the UV detection wavelength was 285 nm. Cinnamic acid was used as internal standard. Results The recovery of the method was in the range of 98 9%～106 9%, the recovery of the extraction was over 83%. The within day precision and the day to day precision were both lower than 8 4%. Conclusion The method is appropriate for the determination of salvianolic acid A when pharmacokinetics of salvianolic acid A is studied in rat plasma.