Composite microparticles with in vivo reduction of the burst release effect

The aim of this study was to develop microparticles containing nanoparticles (composite microparticles) for prolonged drug delivery with reduced burst effect in vitro and in vivo. Such composite microparticles were prepared with hydrophobic and biodegradable polymers [poly(ε-caprolactone), poly(lactic-co-glycolic) acid]. Ibuprofen was chosen as the model drug, and microparticles were prepared by the extraction technique with ethyl acetate as the solvent. Nanoparticles and microparticles and an ibuprofen solution (Pedea^®) were administered subcutaneously at the dose of 1 mg of ibuprofen per kg to overnight-fasted rats (male Wistar). Composite microparticles showed prolonged ibuprofen release and less burst effect when compared to simple microparticles (without nanoparticles inside) or nanoparticles both in vitro (PBS buffer) and in vivo. Moreover, ibuprofen was still detected in the plasma after 96 h with composite microparticles. Consequently, it has been demonstrated that composite microparticles were able to reduce burst release and prolong the release of ibuprofen for a long period of time.     

A novel gastroretentive porous microparticle for anti-Helicobacter pylori therapy: Preparation, in vitro and in vivo evaluation

Gastroretentive drug delivery system is a promising option for the treatment of Helicobacter pylori infection, which can prolong gastric residence time and supply high drug concentration in the stomach. In the present study, a low density system of metronidazole-loaded porous Eudragit^® RS microparticle with high drug loading capacity (>25%) was fabricated via electrospray method. The porous structure and size distribution of microparticles were affected by polymer concentration and flow rate of solution. FTIR and XRD analyses indicated that drug has been entrapped into the porous microparticles. In addition, sustained release profiles and slight cytotoxicity in vitro were detected. Gamma scintigraphy study in vivo demonstrated that ¹³¹I-labeled microparticles retained in stomach for over 8 h, and about 65.50% radioactive counts were finally detected in the region of interest. The biodistribution study confirmed that hotspot of radioactivity was remaining in the stomach. Furthermore, metronidazole-loaded porous microparticles can eradicate H. pylori completely with lower dose and administration frequency of antibiotic compared with pure drug, which were also more helpful for the healing of mucosal damages. These results suggest that prepared porous microparticle has the potential to provide better treatment for H. pylori infection.     

Sustained release formulations of rhVEGF165 produce a durable response in a murine model of peripheral angiogenesis

Local delivery of therapeutic angiogenic agents that stimulate blood vessel formation represents a promising strategy for the treatment of peripheral vascular disease (PVD). At present, requirements for temporal and spatial parameters for localized delivery are unclear, with a variety of sustained delivery approaches being examined. Two polymer-based sustained formulations containing the 165 amino acid isoform of human recombinant vascular endothelial growth factor-A (rhVEGF₁₆₅) were evaluated for their potential application in the treatment of PVD following intramuscular injection. Microspheres prepared from a 50:50 ratio of polylactic-co-glycolic acid (PLGA) and a gel of PLGA polymer solubilized in N-methyl pyrrolidone (PLGA:NMP) were each loaded with rhVEGF₁₆₅ and tested in vitro and in vivo. PLGA microspheres averaged ∼30 μm in diameter and contained 8.9% (w/w) rhVEGF₁₆₅, while the PLGA:NMP gel was formulated with varying amounts of spray freeze-dried rhVEGF₁₆₅ to result in final gel formulations having concentrations of 0.36, 0.72, or 3.6 mg/mL rhVEGF₁₆₅. In vitro release of rhVEGF₁₆₅ from PLGA microspheres showed ∼10% cumulative release by day 6, whereas the cumulative release of rhVEGF₁₆₅ from the PLGA:NMP gel matrices (0.65% w/w loading) was less than 0.25% at this same time point. While the in vitro release characteristics of these two sustained release formulations were broadly different, the plasma rhVEGF₁₆₅ concentration-time profiles following hind-limb intramuscular (IM) injection of these formulations in non-compromised rats revealed similar in vivo pharmacokinetics. Three-dimensional resin casts of vascular architecture were prepared at days 3, 7, 14, 21, 28, 60, and 75 following a single IM dosing of these sustained release microsphere and gel matrix formulations in the gastrocnemius muscle of immune-compromised mice. Scanning electron microscopic visualization of these vascular casts demonstrated spatial arrangement of capillary sprouts and vessel enlargement consistent with profound vascular changes occurring within 3 days of dosing that persisted for 2 months, approximately 1 month beyond the anticipated completion of rhVEGF₁₆₅ release from these sustained delivery formulations. Vascular re-modeling events were correlated with histological and immunohistochemical parameters attributed to known biological actions of rhVEGF₁₆₅ signaling. Together, these pharmacokinetic and pharmacodynamic results support the use of sustained release PLGA-based formulations for the local delivery of rhVEGF₁₆₅ to achieve a durable vascular re-modeling response.     

A novel pH-sensitive interferon-β (INF-β) oral delivery system for application in multiple sclerosis

pH-sensitive microparticles were prepared using trimethyl-chitosan (TMC), poly(ethylene glycol)dimethacrylate (PEGDMA) and methacrylic acid (MAA) by free radical suspension polymerization, for the oral delivery of interferon-β (INF-β). The microparticles were subsequently compressed into a suitable oral tablet formulation. A Box–Behnken experimental design was employed for generating a series of formulations with varying concentrations of TMC (0.05–0.5 g/100 mL) and percentage crosslinker (polyethylene glycol diacrylate) (3–8%, w/w of monomers), for establishment of an optimized TMC-PEGDMA-MAA copolymeric microparticles. For pragmatism, insulin was initially employed as the model peptide for undertaking the preliminary experimentation and the optimized formulation was subsequently evaluated using INF-β. The prepared copolymeric microparticulate system was characterized for its morphological, porositometric and mucoadhesive properties. The optimized microparticles with 0.5 g/100 mL TMC and 3% crosslinker had an INF-β loading efficiency of 53.25%. The in vitro release of INF-β was recorded at 74% and 3% in intestinal (pH 6.8) and gastric (pH 1.2) pH from the oral tablet formulation, respectively. The tablet was further evaluated for plasma concentration of INF-β in the New Zealand White rabbit, and compared to a known subcutaneous formulation. The system showed an astounding effective release profile over 24 h with higher INF-β plasma concentrations compared with the subcutaneous injection formulation.     

Preparation,In Vitro Characterization,and In Vivo Pharmacokinetic Evaluation of Respirable Porous Microparticles Containing Rifampicin

This study aimed to prepare and evaluate rifampicin microparticles for the lung delivery of rifampicin as respirable powder. The microparticles were prepared using chitosan by the spray-drying method and evaluated for aerodynamic properties and pulmonary drug absorption. To control the drug release, tripoly-phosphate in different concentrations 0.6, 0.9, 1.2, and 1.5 was employed to get a sustained drug release profile. The microparticles were evaluated for drug loading, % entrapment efficiency, tapped density, morphological characteristics, and in vitro drug release studies. Aerosol properties were determined using the Andersen cascade impactor. Porous microparticles with particle sizes (d_0.5) less than 10 μm were obtained. The entrapment of rifampicin in microparticles was up to 72%. In vitro drug release suggested that the crosslinked microparticles showed sustained release for more than 12 hrs. The drug release rate was found to be decreased as the TPP concentration was increased. The microparticles showed a fine particle fraction in the range of 55–63% with mass median aerodynamic diameter (MMAD) values below 3 μm. The in vivo pulmonary absorption of the chitosan microparticles suggested a sustained drug release profile up to 72 hrs with an elimination rate of 0.010 per hr. The studies revealed that the spray-dried porous microparticles have suitable properties to be used as respirable powder in rifampicin delivery to the lungs.     

Surface chemistry and pore size affect carrier properties of mesoporous silicon microparticles

Six different types of mesoporous silicon microparticles were prepared to evaluate the effect of surface treatment and pore sizes on their properties as drug carriers. The studied porous silicon particles were as-anodized, thermally carbonized (TCPSi) and thermally oxidized (TOPSi) in addition to three novel ones: annealed TCPSi, annealed TOPSi and thermally hydrocarbonized porous silicon (THCPSi). Drug dissolution at pH 5.5 and physical and chemical stabilities after 3 months of storage were used as experimental models to investigate the loaded particles. Loading degrees of ibuprofen in the particles were determined by several methods before and after storage, and the results were in good agreement with each other. Loading improved the dissolution rate of ibuprofen in all the studied cases, while the hydrophilic TCPSi material resulted in the fastest dissolution and the most stable mesoporous microparticles. The release profiles of ibuprofen did not change markedly during storage. The effect of storage on the loading degrees of the other PSi microparticles than the unstable (easily oxidized) as-anodized porous silicon was not notable.     

Methylated N-(4-N,N-dimethylaminocinnamyl) chitosan-coated electrospray OVA-loaded microparticles for oral vaccination

The purpose of this study was to prepare microparticles entrapping ovalbumin (OVA) as a model antigen to induce immune responses in mice following oral vaccination. In this study, calcium-alginate and calcium-yam-alginate microparticles were prepared by crosslinking alginate with calcium chloride solution using an electrospraying technique. 0.1% (w/v) of methylated N-(4-N,N-dimethylaminocinnamyl) chitosan (TM₆₅CM₅₀CS) was used to coat microparticles entrapping an initial OVA of 20% w/w to polymer. The results indicated that the coated microparticles were spherical and had a smooth surface, with an average size of 1–3 μm, and were positively charged. In addition, the particles demonstrated a greater swelling and mucoadhesive properties than did uncoated microparticles. The in vitro release from the microparticles indicated that the coated microparticles resulted in more sustained release than uncoated microparticles. The cytotoxicity results showed that all of the formulations were safe. The in vivo oral administration demonstrated that at the same amount of 250 μg OVA, coated microparticles exhibited the highest in vivo adjuvant activity in both IgG and IgA immunogenicity.     

Enhanced in vitro transdermal delivery of caffeine using a temperature- and pH-sensitive nanogel,poly(NIPAM-co-AAc)

Temperature- and pH-responsive poly(N-isopropylacrylamide) (polyNIPAM) copolymerised with 5% (w/v) of acrylic acid (AAc), termed as poly(NIPAM-co-AAc) nanogel was investigated as a novel multi-responsive topical drug delivery carrier, using caffeine as a model permeant. The role of a pH modulator (citric acid) on the nanogel system was also studied. The loading was carried out in deionised water at two different temperatures, which were 2–4 °C and 25 °C (room temperature, RT) over 3 days. The loading of caffeine into the poly(NIPAM-co-AAc) nanogel was found to be significantly higher at 2–4 °C than at RT (p = 0.0072). As for the control nanogel (polyNIPAM), a similar pattern of loading level can be observed (p = 0.0005). This enhanced loading at low temperatures could be attributed to the hydrophilic behaviour of the polyNIPAM network in response to temperatures lower than its lower critical solution temperature (LCST). In vitro diffusion studies across epidermis porcine skin were carried out at 32 °C for the saturated solution of caffeine as well as caffeine-loaded poly(NIPAM-co-AAc) and polyNIPAM nanogels. The in vitro permeation data of caffeine-loaded poly(NIPAM-co-AAc) at 2–4 °C were shown to enhance the delivery of the loaded caffeine across the epidermis in comparison to the saturated solution of caffeine, by 3.5 orders of magnitude. Additionally, the study demonstrated that the effect of pH modulator on the release of loaded permeant was insignificant.     

Poly(δ-valerolactone-co-allyl-δ-valerolactone) cross-linked microparticles: Formulation,characterization and biocompatibility

A novel polymeric material, poly(δ-valerolactone-co-allyl-δ-valerolactone) (PVL-co-PAVL), was used to manufacture microparticles (MPs) for sustained drug delivery. PVL-co-PAVL MPs were formulated using a modified oil-in-water approach, followed by a UV-initiated cross-linking process. Prepared MPs had a smooth spherical morphology and cross-linking of the copolymer was found to improve the integrity and thermal stability of the MPs. Paclitaxel (PTX) was successfully loaded into the MPs at a high drug loading capacity, using a post-loading swelling-equilibrium method. In vitro evaluation showed that the PVL-co-PAVL MPs provide sustained release of PTX, which exhibited first-order release kinetics. A subsequent pilot pharmacokinetic study was carried out on the PTX-loaded PVL-co-PAVL MPs. During this study, serum levels of PTX were monitored following subcutaneous administration of the MPs to Sprague-Dawley rats. Overall, the in vivo release of PTX from the MPs was lower than expected based on the in vitro release studies. Detectable serum levels of PTX suggest that sustained release of drug was achieved in vivo. Minimal changes in subcutaneous tissue were observed at the site of injection. Future studies will further examine the localized and systemic distribution of drug following administration in this new polymer-based MP system.     

Alginate coated chitosan core shell nanoparticles for oral delivery of enoxaparin: In vitro and in vivo assessment

The objective of present research work was to develop alginate coated chitosan core shell nanoparticles (Alg-CS-NPs) for oral delivery of low molecular weight heparin, enoxaparin. Chitosan nanoparticles (CS-NPs) were synthesized by ionic gelation of chitosan using sodium tripolyphosphate. Core shell nanoparticles were prepared by coating CS-NPs with alginate solution under mild agitation. The Alg-CS-NPs were characterized for surface morphology, surface coating, particle size, polydispersity index, zeta potential, drug loading and entrapment efficiency using SEM, Zeta-sizer, FTIR and DSC techniques. Alginate coating increased the size of optimized chitosan nanoparticles from around 213 nm to about 335 nm as measured by dynamic light scattering in zeta sizer and further confirmed by SEM analysis. The performance of optimized enoxaparin loaded Alg-CS-NPs was evaluated by in vitro drug release studies, in vitro permeation study across intestinal epithelium, in vivo venous thrombosis model, particulate uptake by intestinal epithelium using fluorescence microscopy and pharmacokinetic studies in rats. Coating of alginate over the CS-NPs improved the release profile of enoxaparin from the nanoparticles for successful oral delivery. In vitro permeation studies elucidated that more than 75% enoxaparin permeated across the intestinal epithelium with Alg-CS-NPs. The Alg-CS-NPs significantly increased (p < 0.05) the oral bioavailability of enoxaparin in comparison to plain enoxaparin solution as revealed by threefold increase in AUC of plasma drug concentration time curve and around 60% reduction in thrombus formation in rat venous thrombosis model. The core shell Alg-CS-NPs showed promising potential for oral delivery and significantly enhanced the in vivo oral absorption of enoxaparin.     

Mesoporous Silicon (PSi) for Sustained Peptide Delivery: Effect of PSi Microparticle Surface Chemistry on Peptide YY3-36 Release

Purpose  

To achieve sustained peptide delivery via mesoporous silicon (PSi) microparticles and to evaluate the effects of different surface chemistries on peptide YY3-36 (PYY3-36) delivery.     

Dexamethasone-containing biodegradable superparamagnetic microparticles for intra-articular administration: Physicochemical and magnetic properties, in vitro and in vivo drug release

Compared with traditional drug solutions or suspensions, polymeric microparticles represent a valuable means to achieve controlled and prolonged drug delivery into joints, but still suffer from the drawback of limited retention duration in the articular cavity. In this study, our aim was to prepare and characterize magnetic biodegradable microparticles containing dexamethasone acetate (DXM) for intra-articular administration. The superparamagnetic properties, which result from the encapsulation of superparamagnetic iron oxide nanoparticles (SPIONs), allow for microparticle retention with an external magnetic field, thus possibly reducing their clearance from the joint. Two molecular weights of poly(lactic-co-glycolic acid) (PLGA) were used, 12 and 19 kDa. The prepared batches were similar in size (around 10 μm), inner morphology, surface morphology, charge (neutral) and superparamagnetic behaviour. The SPION distribution in the microparticles assessed by TEM indicates a homogeneous distribution and the absence of aggregation, an important factor for preserving superparamagnetic properties. DXM release profiles were shown to be quite similar in vitro (ca. 6 days) and in vivo, using a mouse dorsal air pouch model (ca. 5 days).     

Incorporation of quercetin in lipid microparticles: Effect on photo- and chemical-stability

Lipid microparticles loaded with the flavonoid, quercetin were developed in order to enhance its stability in topical formulations. The microparticles were produced using tristearin as the lipid material and phosphatidylcholine as the emulsifier. The obtained lipoparticles were characterized by release studies, scanning electron microscopy and powder X-ray diffractometry. The quercetin loading was 12.1% (w/w). Free or microencapsulated quercetin was introduced in a model cream formulation (oil-in-water emulsion) and irradiated with a solar simulator. The extent of photodegradation was measured by high-performance liquid chromatography. The light-induced decomposition of quercetin in the cream vehicle was markedly decreased by incorporation into the lipid microparticles (the extent of degradation was 23.1 ± 3.6% for non-encapsulated quercetin compared to 11.9 ± 2.5% for the quercetin-loaded microparticles) and this photostabilization effect was maintained over time. Moreover, the chemical instability of quercetin, during 3-month storage of the formulations at room temperature and in the dark, was almost completely suppressed by the lipid microparticle system. Therefore incorporation of quercetin in lipoparticles represents an effective strategy to enhance its stability in dermatological products.     

Lipomer of doxorubicin hydrochloride for enhanced oral bioavailability

The present study discusses design of doxorubicin hydrochloride (Dox) loaded lipid based nanocarrier (LIPOMER) for oral delivery. High entrapment (>90%) and high loading (38.11 ± 0.37% w/w) of hydrophilic Dox in lipid nanocarrier of polyglyceryl-6-distearate was achieved using poly(methyl vinyl ether-co-maleic anhydride) (Gantrez^® AN 119) and a modified nanoprecipitation method. Dox-LIPOMER revealed nanosize (314 ± 16.80 nm) and negative zeta potential (−25.00 ± 2.41 mV). Dox-LIPOMER exhibits sustained release in vitro and was influenced by ionic strength of dissolution medium. DSC and XRD studies suggested amorphous nature of Dox in LIPOMER. TEM revealed spherical morphology of Dox-LIPOMER. Dox-LIPOMER was stable up to 12 months at 25 °C/60% RH. A 384% enhancement in oral bioavailability compared to Dox solution was observed following Dox-LIPOMER administration at 10 mg/kg body weight. Superoxide dismutase (SOD), catalase (CAT) and malondialdehyde (MDA) assay data of heart and kidney tissues of rats treated with Dox-LIPOMER were comparable with untreated rats. Dox-LIPOMER represents a potential safe drug delivery system for oral administration.     

Preparation and evaluation of alginate-chitosan microspheres for oral delivery of insulin

The alginate-chitosan microspheres with narrow size distribution were prepared by membrane emulsification technique in combination with ion (Ca²⁺) and polymer (chitosan) solidification. The preparation procedure was observed, and the physical properties (particle size distribution, surface morphology, chitosan distribution, zeta potential) of the microspheres were characterized. Subsequently, the microspheres were employed to load model peptide of insulin. The effect of loading ways on the loading efficiency and immunological activity of insulin were investigated. It was shown that the higher loading efficiency (56.7%) and remarkable activity maintenance (99.4%) were obtained when the insulin was loaded during the chitosan solidification process (Method B). Afterward, the release profile in vitro for the optimal insulin-loaded microspheres was investigated. Under the pH conditions of gastrointestinal environment, only 32% of insulin released during the simulated transit time of drug (2 h in the stomach and 4 h in the intestinal). While under the pH condition of blood environment, insulin release was stable and sustained for a long time (14 days). Furthermore, the chemical stability of insulin released from the microspheres was well preserved after they were treated with the simulated gastric fluid containing pepsin for 2 h. Finally, the blood glucose level of diabetic rats could be effectively reduced and stably kept for a long time (∼60 h) after oral administration of the insulin-loaded alginate-chitosan microspheres. Therefore, the alginate-chitosan microspheres were found to be promising vectors showing a good efficiency in oral administration of protein or peptide drugs.     

Encapsulation of poorly soluble basic drugs into enteric microparticles: a novel approach to enhance their oral bioavailability

Poorly water soluble basic drugs are very sensitive to pH changes and following dissolution in the acidic stomach environment tend to precipitate upon gastric emptying, which leads to compromised or erratic oral bioavailability. In this work, we show that the oral bioavailability of a model poorly soluble basic drug (cinnarizine) can be improved by drug encapsulation within highly pH-responsive microparticles (Eudragit L). The latter was prepared by emulsion solvent evaporation which yielded discrete spherical microparticles (diameter of 56.4 ± 6.8 μm and a span of 1.2 ± 0.3). These Eudragit L (dissolution threshold pH 6.0) microparticles are expected to dissolve and release their drug load at intestinal conditions. Thus, the enteric microparticles inhibited the in vitro release of drug under gastric conditions, despite high cinnarizine solubility in the acidic medium. At intestinal conditions, the particles dissolved rapidly and released the drug which precipitated out in the dissolution vessel. In contrast, cinnarizine powder showed rapid drug dissolution at low pH, followed by precipitation upon pH change. Oral dosing in rats resulted in a greater than double bioavailability of Eudragit L microparticles compared to the drug powder suspension, although C_max and T_max were similar. The higher bioavailability with microparticles contradicts the in vitro results. Such an example highlights that although in vitro results are an indispensable tool for formulation development, an early in vivo assessment of formulation behaviour can provide better prediction for oral bioavailability.     

Evaluation of the immunogenicity and in vivo toxicity of the antimicrobial peptide P34

Immunogenicity and toxicity of antimicrobial peptide P34 were evaluated in vivo. BALB/c mice were inoculated intraperitoneally with peptide P34 alone and associated with Freund's adjuvant. For acute toxicity testing, different concentrations of the peptide P34 (82.5, 165.0, 247.5 and 330.0 mg/kg) were orally administered. To evaluate the sub-chronic toxicity the tested dose of 0.825 mg/kg/day of the peptide P34 or nisin were administered for 21 days. There were no hypersensitivity reactions or significant increase in antibody titer during the immunogenicity experiment or death of animals during the acute or sub-chronic toxicity tests. The LD₅₀ was higher than 332.3 ± 0.76 mg/kg. No significant changes in serum biochemical parameters were observed in the animals treated with the peptide P34 unlike nisin-treated group showed a significant increase in alanine transaminase levels in comparison to controls. The group treated with 0.825 mg/kg/day of nisin showed histological changes in the spleen, skin and liver. In the group treated with peptide P34 histological changes in the spleen were observed, with the presence of megakaryocytes. Few studies report the use of animal models to evaluate the in vivo toxicity of antimicrobial peptides and such investigation is an essential step to ensure it safe use in foods.     

A novel dendritic mesoporous silica based sustained hydrogen sulfide donor for the alleviation of adjuvant-induced inflammation in rats

PurposeS-propargyl-cysteine (SPRC), an excellent endogenous hydrogen sulfide (H₂S) donor, could elevate H₂S levels via the cystathionine γ-lyase (CSE)/H₂S pathway both in vitro and in vivo. However, the immediate release of H₂S in vivo and daily administration of SPRC potentially limited its clinical use.MethodsTo solve the fore-mentioned problem, in this study, the dendritic mesoporous silica nanoparticles (DMSN) was firstly prepared, and a sustained H₂S delivery system consisted of SPRC and DMSN (SPRC@DMSN) was then constructed. Their release profiles, both in vitro and in vivo, were investigated, and their therapeutical effect toward adjuvant-induced arthritis (AIA) rats was also studied.ResultsThe spherical morphology of DMSN could be observed under scanning Electron Microscope (SEM), and the transmission electron microscope (TEM) images showed a central-radiational pore channel structure of DMSN. DMSN showed excellent SPRC loading capacity and attaining a sustained releasing ability than SPRC both in vitro and in vivo, and the prolonged SPRC releasing could further promote the release of H₂S in a sustained manner through CSE/H₂S pathway both in vitro and in vivo. Importantly, the SPRC@DMSN showed promising anti-inflammation effect against AIA in rats was also observed.ConclusionsA sustained H₂S releasing donor consisting of SPRC and DMSN was constructed in this study, and this sustained H₂S releasing donor might be of good use for the treatment of AIA.     

A dynamic topical hydrofluoroalkane foam to induce nanoparticle modification and drug release in situ

Topical nanoparticles are usually applied using semi-solid formulations, but the delivery process is often inefficient due to the poor drug release from the particles. The aim of this study was to investigate the capability of a dynamic foam to break open nanoparticles upon application to the skin and enhance drug delivery efficiency. Vitamin E acetate (VEAc) was selected as a model drug and loaded into lipid nanoparticles (50-60 nm) prepared by phase inversion. The highest drug loading was 18.9 ± 1.2 mg/ml and the corresponding encapsulation efficiency was 81.5 ± 4.1%. Dynamic foams were generated by emulsifying VEAc-loaded nanoparticle suspensions with hydrofluoroalkane using pluronic L62D. An in vitro permeation study demonstrated that VEAc did not release from the nanoparticles when administered as an aqueous suspension, but attained a flux of 18.0 ± 2.1 (μg cm⁻² h⁻¹) when applied using the foam. Drug release from the foam was shown to be a consequence of nanoparticle modification after dose administration and this led to the foam delivering 0.7 ± 0.3% VEAc into the stratum corneum (SC) when applied to human skin.     

A novel strategy to design sustained-release poorly water-soluble drug mesoporous silica microparticles based on supercritical fluid technique

Background

The organic solvent solution immersion method was often used to achieve the loading of the drugs into mesoporous silica, but the drugs that have loaded into the pores of the mesoporous silica would inevitable migrate from the inside to the external surface or near the outside surface during the process of drying. Hence, it often leads to the pores of mesoporous materials not be fully utilized, and results in a low drug loading efficiency and a fast releasing rate.

Objective

The purpose of this study was to develop a novel drug loading strategy to avoid soluble component migration during the process of drying, then, to prepare poorly water-soluble drug mesoporous silica microparticles with higher drug loading efficiency and longer sustained-release time.

Method

Ibuprofen was used as model drug. The microparticles were prepared by a novel method based on mesoporous silica and supercritical fluid (SCF) technique. The drug-loaded mesoporous silica microparticles prepared by SCF technique were analyzed by thermogravimetric analysis (TGA), N₂ adsorption/desorption, scanning electron microscopy (SEM), powder X-ray diffraction (XRD) and differential scanning calorimetry (DSC). In vitro releasing study was used to evaluate the sustained-release effect of the drug-loaded microparticles.

Results

By virtue of the high diffusibility and the high dissolving capacity of the supercritical carbon dioxide (SCF-CO₂), the poorly water-soluble drugs, ibuprofen, entered the pores of the mesoporous silica. The amount and the depth of ibuprofen entered the pores of the mesoporous silica by SCF technique were both larger than those by the solution immersion method. It was found that ibuprofen loaded into the mesoporous silica by SCF technique was amorphous and the largest amount of the ibuprofen loaded into the mesoporous silica by SCF technique could reach 386 mg/g (w/w, ibuprofen/SiO₂), it was more than that by the solution immersion method. In vitro releasing study showed that the sustained-release effect of ibuprofen in the samples prepared by SCF technique was 50% in 15 min and 90% in 60 min. It was longer than that prepared by the solution immersion method.

Conclusion

Present study showed that sustained-release poorly water-soluble drug mesoporous silica microparticle based on SCF technique has twofold advantages. One is the larger drug loading amount in internal pores of the mesoporous silica, the other is the longer drug releasing time.