Preparation and evaluation of zinc-pectin-chitosan composite particles for drug delivery to the colon: role of chitosan in modifying in vitro and in vivo drug release

Zinc-pectin-chitosan composite microparticles were designed and developed as colon-specific carrier. Resveratrol was used as model drug due to its potential activity on colon diseases. Formulations were produced by varying different formulation parameters (cross-linking pH, chitosan concentration, cross-linking time, molecular weight of chitosan, and drug concentration). Single-step formulation technique was compared with multi-step technique. Effect of these parameters was investigated on shape, size, weight, weight loss (WL), moisture content (MC), encapsulation efficiency (EE), drug loading (L), and drug release pattern of the microparticles. The formulation conditions were optimized from the drug release study. In vivo pharmacokinetics of the zinc-pectinate particles was compared with the zinc-pectin-chitosan composite particles in rats. Formulations were spherical with 920.48-1107.56 μm size, 21.19-24.27 mg weight of 50 particles, 89.83-94.34% WL, 8.31-13.25% MC, 96.95-98.85% EE, and 17.82-48.31% L. Formulation parameters showed significant influence on drug release pattern from the formulations. Formulation prepared at pH 1.5, 1% chitosan, 120 min cross-linking time, and pectin:drug at 3:1 ratio demonstrated colon-specific drug release. Microparticles were stable at 4 °C and room temperature. Pharmacokinetic study indicated in vivo colon-specific drug release from the zinc-pectin-chitosan composite particles only.     

Polyethyleneimine-modified pectin beads for colon-specific drug delivery: In vitro and in vivo implications

Calcium-pectinate (Ca-pectinate) beads have shown immense potential as colon-specific drug carrier. However, Ca-pectinate itself is unable to prevent its swelling/degradation in the upper gastro-intestinal (GI) conditions. Hence, polyethyleneimine (PEI) was added in the cross-linking solution to strengthen the Ca-pectinate network. Resveratrol was used as a model drug due to its promising therapeutic activity towards several colonic diseases. Beads were prepared by varying cross-linking solution pH and other formulation variables. The effects of these formulation variables were investigated on the bead's characteristics. Furthermore, surface morphology, drug–polymer interaction, stability, and in vivo pharmacokinetic study of the optimized formulation were performed. The optimized PEI-modified beads prevented drug release in the upper GI conditions, while released the drug in simulated colonic fluid. Furthermore, in vivo pharmacokinetics studies in rats demonstrated delayed appearance of drug in blood after oral administration. The optimized Ca-pectinate beads demonstrated both in vitro and in vivo colon-specific drug release.     

Influence of polymers on the bioavailability of microencapsulated celecoxib

Celecoxib, a selective COX-2 inhibitor, primarily used in treatment of osteoarthritis, rheumatoid arthritis and acute pain was encapsulated in microparticles composed of various polyesters, polymethacrylates or cellulose derivatives used alone or blended. The influence of polymers on microparticle mean diameter, encapsulation efficiency and in vitro and in vivo celecoxib release was investigated. Microparticles were in the size range 11–37?µm. Encapsulation efficiency was optimal due to poor aqueous solubility of celecoxib. Considering in vitro release, microparticles could be divided into drug delivery systems with fast and slow release profiles. Microparticles prepared with poly-ε-caprolactone, Eudragit® RS and low viscosity ethylcellulose, together with physical mixture of celecoxib with lactose and Celebrex®, were tested in vivo. Relative bioavailability of celecoxib was below 20% in all cases and was probably the consequence of a slow in vivo release of celecoxib from microparticles or low wettability in the case of Celebrex® and physical mixture.     

Shape,optimization and in vitro evaluation of colon-specific multi-particulate system based on low-methoxy amidated pectin and polycarbophil

Natural polysaccharides are widely used for development of colon-specific drug delivery systems. The present study was carried out to develop multi-particulate calcium pectinate (Ca-pectinate) formulations for colon-targeted delivery of lornoxicam. The formulations were developed using a combination of polycarbophil and low-methoxy amidated pectin. The beads were prepared using an ionotropic gelation technique. The effects of the polycarbophil and low-methoxy amidated pectin concentrations on the beads characteristics, encapsulation efficiency, swelling study and drug release performance were investigated. The optimized formulation was evaluated for its morphological characteristics. The in vitro drug release of the optimized formulation over a period of 12 h was 96.78 ± 1.35 %. The concentration of the polycarbophil was a decisive factor in sustaining drug release in the colon. The study revealed that optimized Ca-pectinate beads prepared with polycarbophil can efficiently encapsulate lornoxicam. It also showed that these beads can potentially be used for colon-specific delivery of lornoxicam.     

Methacrylate micro/nano particles prepared by spray drying: a preliminary in vitro/in vivo study

Delivery systems controlling drug release only in the colon holds great promises since they improve utilization of drug and decrease the dosing times comparison with conventional forms. The aim of the present study was to prepare polymeric microparticles on the basis of Ciprofloxacin via oral route for the treatment of inflammatory bowel disease. Ciprofloxacin was selected because of its extensive coverage for intestinal flora, relatively favorable side-effect profile and preliminary data suggesting its efficacy in the treatment of active Crohn's Disease. Microparticles were prepared using different acrylic compounds, namely Eudragit® RL (PO) and RS (PO) and a mixture of both. Spray-drying was used as a preparation method of Ciprofloxacin/Eudragit® microparticles using a Mini Spray Dryer B-290 (Büchi, Postfach, Switzerland). In vitro dissolution studies were performed to choose the best formulation and selected microparticles were characterized by size and morphology by environmental scanning electron microscopy. Yield and encapsulation efficiency were calculated and in vivo/ex vivo experiments were investigated both of which suggest that selected microparticles can be used for colon targeting of drugs increasing residence time of the drug in the affected area.     

Preparation of naproxen–ethyl cellulose microparticles by spray-drying technique and their application to textile materials

Abstract

The objective of this study is to develop a new textile-based drug delivery system containing naproxen (NAP) microparticles and to evaluate the potential of the system as the carrier of NAP for topical delivery. Microparticles were prepared by spray-drying using an aqueous ethyl cellulose dispersion. The drug content and entrapment efficiency, particle size and distribution, particle morphology and in vitro drug release characteristics of microparticles were optimized for the application of microparticles onto the textile fabrics. Microparticles had spherical shape in the range of 10–15?μm and a narrow particle size distribution. NAP encapsulated in microparticles was in the amorphous or partially crystalline nature. Microparticles were tightly fixed onto the textile fabrics. In vitro drug release exhibited biphasic release profile with an initial burst followed by a very slow release. Skin permeation profiles were observed to follow near zero-order release kinetics.     

Preparation and characterization of D,L-PLA loaded 17-β-Estradiol valerate by emulsion/evaporation methods

PLA microparticles containing 17-β-estradiol valerate were prepared by an emulsion/evaporation method in order to sustain drug release. This system was characterized concerning particle size, particle morphology and the influence of formulation and processing parameters on drug encapsulation and in vitro drug release. The biodegradation of the microparticles was observed by tissue histological analysis. Scanning electron microscopy and particle size analysis showed that the microparticles were spherical, presenting non-aggregated homogeneous surface and had diameters in the range of 718–880 nm (inert micro-particles) and 3–4 µm (drug loaded microparticles). The encapsulation efficiency was ～80%. Hormone released from microparticles was sustained. An in vivo degradation experiment confirmed that microparticles are biodegradable. The preparation method was shown to be suitable, since the morphological characteristics and efficiency yield were satisfactory. Thus, the method of developed microparticles seems to be a promising system for sustained release of 17-β-estradiol.     

Preparation and characterization of nanocapsules for colon-targeted drug delivery system

Context: Nanoparticles for colon-specific drug delivery system are known for their specific accumulation in the inflamed tissue in the colon and may therefore allow a selective delivery to the site of inflammation for the treatment of inflammatory bowel disease (IBD).

Objective: The objective of this study was to formulate and evaluate nanocapsules (NC), an oral system designed to achieve site-specific and instant drug release in colon for effective treatment of IBD.

Materials and methods: Prednisolone (PD), a typical glucocorticoid, has been widely used for the treatment of IBD. In this study, nanoprecipitation method was used to prepare polymeric NC of PD with pH responsive polymer Eudragit S100. The effect of several formulation variables such as surfactant, oil, and polymer on the PD-NC properties (average size, drug release rate, and drug entrapment) was investigated. In vitro drug release study was done by changing pH method and an in vivo study on rat was done to ascertain efficiency of PD-NC to release drug specifically in colon.

Results and discussion: The optimized formulations lead to the preparation of PD-NC with a mean size of 567.87?nm, high encapsulation efficiency of 90.21%. In vitro studies reveal that NC releases the drug after 4.5-h lag time corresponding to time to reach colonic region, and in vivo studies show that NC release drug after 3-h lag time in rat corresponds to arrival in colon.

Conclusion: The above NC formulation of PD is the targeted drug to the colon and may provide effective way of treatment of colonic disease.     

Preparation and characterization of chitosan-treated alginate microparticles incorporating all-trans retinoic acid

Chitosan treated alginate microparticles were prepared with the purpose of incorporating all-trans retinoic acid (ATRA) using an inexpensive, simple and fast method, enhancing dermal localization and sustaining the release of ATRA into the skin. Microparticles characterization, drug–polymer interaction, release profile and in vitro skin retention were investigated. Microparticles presented spherical shape and drug loading capacity of 47%. The drug content of these microparticles was affected by ATRA concentration and by the solvent used and it was more weakly affected by chitosan concentration. The release of ATRA was also affected by chitosan concentration. Microparticles prepared with 0.4% chitosan (w/w) resulted in drug release with a more sustained profile. The results of in vitro retention studies showed that chitosan treated alginate microparticles decreased the drug retention in the stratum corneum (SC), where occur the skin irritation, but maintained the ATRA concentration in the deeper skin layers, where occur the pathologies treated with ATRA. Then, the microparticles developed in this work can be a good candidate to improve the topical therapy with retinoid.     

Preparation and evaluation of pectin-based colon-specific pulsatile capsule in vitro and in vivo

The purpose of this study was to develop and evaluate a colon-specific, pulsatile drug delivery system, which consists of an impermeable capsule body filled with a 5-aminosalicylic acid rapid-disintegrating tablet and a pectin-based erodible plug placed in the opening of the capsule body. To obtain an appropriate gel-forming ability and suitable lag time for the colon-specific drug delivery, high-methoxy pectin (HM-pectin) was formulated with lactose and lowmethoxy pectin (LM-pectin) with HPMC to prepare the plug tablet. In order to evaluate the lag time, prior to the rapid drug release, both the formulation of the plug tablet and in vitro release medium were studied. The lag time prior to the rapid drug release was mainly determined by the HM-pectin/lactose or LM-pectin/HPMC ratio. The addition of pectinase or rat cecal content into the release medium shortened the lag time significantly, which predicted the probable enzyme sensitivity of pectin plug tablet. In vivo studies showed that the plasma concentration of drug can only be detected 6h after oral administration of the pulsatile capsule, which indirectly proved the colon-specific characteristics. These results show that the pulsatile capsule may have the therapeutic action for colon-specific drug delivery.     

Factors Effecting the Morphology of Eudragit S-100 Based Microsponges Bearing Dicyclomine for Colonic Delivery

The purpose of this study was to design microsponge-based novel colon-specific drug delivery system bearing dicyclomine. Eudragit S-100-based microsponges containing the drug in varying amount were prepared using quasi-emulsion solvent diffusion method. The microsponges were prepared by optimizing various process parameters. Differential scanning calorimetry and Fourier transform infrared studies indicated compatibility and stability of the drug in various formulations. Shape and surface morphology of the microsponges were examined using scanning electron microscopy. The formulations were subjected to in vitro release studies, and the results were evaluated kinetically and statistically. In vitro release data showed a biphasic pattern with an initial burst effect. In the first hour, drug release from microsponges was found to be between 17% and 31%. The cumulative percent release at the end of eighth hour was noted to be between 53% and 83%. The release kinetics showed that the data followed Higuchi model and the main mechanism of drug release was diffusion. The colon-specific tablets were prepared by compressing the microsponges followed by coating with pectin:hydroxypropylmethylcellulose mixture. In vitro release studies exhibited that compression-coated colon-specific formulations started releasing the drug at the sixth hour corresponding to the arrival time at colon. The study presents a new approach for colon-specific drug delivery.     

Development and in vitro/in vivo evaluation of Zn-pectinate microparticles reinforced with chitosan for the colonic delivery of progesterone

The colon is a promising target for drug delivery owing to its long transit time of up to 78?h, which is likely to increase the time available for drug absorption. Progesterone has a short elimination half-life and undergoes extensive first-pass metabolism, which results in very low oral bioavailability (～25%). To overcome these shortcomings, we developed an oral multiparticulate system for the colonic delivery of progesterone. Zn-pectinate/chitosan microparticles were prepared by ionotropic gelation and characterized for their size, shape, weight, drug entrapment efficiency, mucoadhesion and swelling behavior. The effect of cross-linking pH, cross-linking time and chitosan concentration on progesterone release were also studied. Spherical microparticles having a diameter of 580–720?µm were obtained. Drug entrapment efficiency of ～75–100% was obtained depending on the microparticle composition. Microparticle mucoadhesive properties were dependent on the pectin concentration, as well as the cross-linking pH. Progesterone release in simulated gastric fluids was minimal (3–9%), followed by burst release at pH 6.8 and a sustained phase at pH 7.4. The in vivo study revealed that the microparticles significantly increased progesterone residence time in the plasma and increased its relative bioavailability to ～168%, compared to the drug alone. This study confirms the potential of Zn-pectinate/chitosan microparticles as a colon-specific drug delivery system able to enhance the oral bioavailability of progesterone or similar drugs.     

Preparation and evaluation of double-walled microparticles prepared with a modified water-in-oil-in-oil-in-water (w1/o/o/w3) method

Abstract

In this study, a modified water-in-oil-in-oil-in-water (w₁/o/o/w₃) method was developed to prepare double-walled microparticles containing ovalbumin (OVA). The microparticles were characterized with respect to their morphology, particle size, encapsulation efficiency, production yield, thermal properties and in vitro drug release. Microscopy observations clearly showed that microparticles have spherical shape and smooth surface. These microparticles were characterized to have double-walled structure, with a cavity in the centre. By using w₁/o/o/w₃ method, a significant decrease in mean particle size and a significant increase in encapsulation efficiency were obtained. The mean particle size and the encapsulation efficiency of double-walled microparticles were also affected by the changing amount of OVA and mass ratio of polymers. Microparticles prepared with two polymers exhibited a significantly lower initial burst release followed by sustained release compared to microparticles made from poly(d,l-lactide-co-glycolide) 50/50 only. It can be concluded that these microparticles can be a potential delivery system for therapeutic proteins.     

<Emphasis Type="BoldItalic">In Vitro</Emphasis> and <Emphasis Type="BoldItalic">In Vivo</Emphasis> Drug Release from a Novel <Emphasis Type="BoldItalic">In Situ</Emphasis> Forming Drug Delivery System

Purpose The objective of this work was to investigate the influence of various preparation and formulation parameters on the in vitro and in vivo release of bupivacaine hydrochloride from an injectable in situ forming microparticle system (ISM). Methods The in vitro drug release of ISM was investigated as a function of various formulation and process parameters and was compared to the drug release from in situ forming implants and conventional microparticles. In vivo studies were carried out in male Sprague–Dawley rats. Results Upon contact with an aqueous medium, the internal polymer phase of the ISM system solidified and formed microparticles. The initial drug release from ISM systems was reduced with decreasing polymer phase/external oil phase ratio. An advantage of the ISM system compared to in situ implant systems was the significantly reduced burst effect, resulting in drug release profiles comparable to microparticles prepared by conventional methods. The in vivo drug release studies were in good agreement with the in vitro drug release. With the ISM system, the analgesic effect of the bupivacaine hydrochloride was prolonged when compared to the injection of a drug solution or drug-polymer solution. Conclusions ISM are an attractive alternative for parenteral drug delivery systems.     

Collagen-coated polycaprolactone microparticles as a controlled drug delivery system

Objective: Polycaprolactone (PCL) microparticles coated with acetylated collagen have been assessed for use as a controlled drug delivery system.

Method: The surface morphology, drug encapsulation and release profile of PCL microparticles and collagen-coated PCL microparticles containing doxycycline hydrochloride (DH) have been investigated in order to develop a controlled release system which would in addition act as a scaffold for cell attachment. PCL microparticles were prepared by emulsion solvent evaporation technique and loaded with DH. Since the encapsulation was found to be low, PCL microparticles were coated with acetylated collagen containing DH, to increase the drug availability. Collagen was modified by acetylation to shift its isoelectric point and to have acetylated collagen solution at pH 7.0. The microparticles were characterized using a scanning electron microscope (SEM) and the in vitro drug release profile was determined using HPLC.

Results: Uniform sized (～1000 nm) PCL microparticles were prepared using 4% PVA in the external water phase. Acetylated collagen at pH 7.0 was coated onto the PCL microparticles. This resulted in microparticles of uniform size at neutral pH. PCL acts as a support for collagen which acts as a scaffold for cell attachment. In vitro drug release studies show that collagen-coated PCL microparticle is a promising candidate for controlled drug delivery system having release duration of over 10 days. In vitro fibroblast culture studies reveal that collagen is a good substrate for cell attachment and would provide a stable environment for cell proliferation and regeneration. Thus, this system would be ideal for a short-term drug delivery to create an aseptic environment where cells can adhere and proliferate to regenerate the site.     

Formulation,development, and performance evaluation of metoclopramide HCl oro-dispersible sustained release tablet

The present study was undertaken to develop and evaluate an oro-dispersible, sustained release tablet of metoclopramide HCl. The technology was comprised of developing sustained release microparticles, and compression of resultant microspheres into a fast dispersible tablet by direct compression. The microspheres of metoclopramide HCl were prepared by an emulsification-solvent evaporation method using ethylcellulose as the matrix polymer. The prepared microspheres were evaluated for morphology, particle size, entrapment efficiency, and in vitro drug release characteristics. Scanning electron microscopy demonstrated spherical particles with a mean diameter of 81.27 ± 5.87 μm and the drug encapsulation efficiency was found to be 70.15 ± 3.06%. The process and formulation variables such as rotation speed, polymer concentration, and drug concentration influenced the drug encapsulation efficiency and in vitro drug release. Optimized microspheres were compressed into tablets which were comprised of metoclopramide HCl microspheres, 53% (w/v) of D-mannitol granules, 7% (w/w) of Polyplasdone XL 10, and 0.5% (w/w) of calcium stearate. The tablets demonstrated a hardness of 59 ± 3 N, friability of 0.21% and disintegration time of 27 ± 3 sec. The formulations were subjected to stability studies as per ICH guidelines and were found to be stable after a 6 month study. In vivo experiments conducted in rats demonstrated that a constant level of metoclopramide HCl in plasma could be maintained for up to 20 h at a suitable concentration for antiemetic activity. An appropriate combination of excipients made it possible to obtain orally disintegrating sustained release tablets of metoclopramide HCl using simple and conventional techniques.     

Design of composite microparticle systems based on pectin and waste material of propolis for modified l-alanyl-l-glutamine release and with immunostimulant activity

Catabolic conditions like acquired immunodeficiency syndrome, cancer, and burn can cause immunosuppression. Amino acids such as alanine and glutamine are essential for the activity of the immune system. Propolis is immunostimulant and the waste of propolis extraction has been reused with technological and therapeutic purposes. Therefore, this study describes the association of propolis byproduct extract (BPE) with pectin to prepare spray-dried microparticles containing the dipeptide l-alanyl-l-glutamine as stimulant systems of neutrophils. The use of a factorial design allowed selecting the best formulation, which was characterized by morphology, size, and entrapment efficiency analyses. In addition, the systems were characterized by thermal and X-ray diffraction analysis, Fourier-transform infrared spectroscopy, in vitro drug release, and in vitro cytotoxicity and stimulation test of neutrophils. Small well-structured microparticles with good entrapment efficiency values were achieved. Thermal stability of formulation was observed, and it was proved that pectin, BPE and l-alanyl-l-glutamine were dispersed throughout the matrix. The drug was released from the microparticles during 24?h governed by swelling and diffusion. The drug-loaded formulations showed a significant stimulating effect on neutrophils. These structures could increase the activity of immune cells, and other in vitro and in vivo studies should be performed in the future.     

Assessment of formulated amodiaquine microparticles in Leishmania donovani infected rats

The aim of this study was to formulate, characterise and evaluate the activity of amodiaquine microparticles against Leishmania donovani. Microparticles were formulated by encapsulating the drug in bovine serum albumin using the spray-dryer method. The microparticles were evaluated for size, zeta potential, drug content, encapsulation efficiency and in vitro release profile. The size range of the microparticles formulated was between 1.9 and 10?μm with an average zeta potential of ?25.5?mV. Of the expected 20% drug loading, an average of 18.27% was obtained giving an encapsulation efficiency of 91.35%. Pharmacokinetic profile of amodiaquine improved with microencapsulation of the drug with C_max, AUC_0→48 and t_1//2 all significantly higher than amodiaquine solution. Amodiaquine microparticles showed an overall higher bioavailability and hence were more effective in eliminating intra-tissue parasites than the drug solution. It would therefore be expected that the formulated microparticles will be more effective in treating visceral leishmaniasis.     

Formulation and evaluation of novel solid lipid microparticles as a sustained release system for the delivery of metformin hydrochloride

Abstract

The low encapsulation efficiency of conventional solid lipid microparticles (SLMs) especially for hydrophilic drugs has remained a challenge to drug formulation experts. This work seeks to address the issue of inefficient delivery of metformin hydrochloride (MTH), a potent hydrophilic oral antihyperglycemic agent, using novel SLMs based on solidified reverse micellar solutions (SRMS) prepared by melt-emulsification using a lipid derived from Capra hircus and Phospholipon® 90H. Characterization based on size, morphology, zeta potential, polydispersity index, encapsulation efficiency (EE%), loading capacity (LC) and time-resolved stability were carried out on the SLMs. The in vitro release of MTH from the SLMs was performed in phosphate buffer (pH 7.4) while the in vivo antidiabetic properties were investigated in alloxan-induced diabetic rats. Stable, spherical and smooth SLMs were obtained. Loading of MTH into the SLMs had no effect on the surface charge of the particles. The SLMs with 1.0%w/w PEG 4000 resulted in significantly (p?<?0.05) higher EE% while those with 2.0%w/w gave the least. The LC values ranged from 20.3 to 29.1 and 14.6 to 24.1 for SLMs containing 500?mg and 250?mg of MTH, respectively. The in vitro release studies revealed significant release of MTH from the SLMs whereas the in vivo antidiabetic studies indicated that novel SLMs containing 500?mg of MTH gave significantly (p?<?0.05) higher glucose reduction than glucophage®. This research has shown that SLMs based on SRMS offer a new and better approach of delivering MTH, thus encouraging further development of this formulation.     

Formulation and optimization of alkaline extracted ispaghula husk microparticles of isoniazid – in vitro and in vivo assessment

Microparticles containing isoniazid were prepared by the emulsification internal ionic gelation method using a novel, alkaline extracted ispaghula husk as a wall forming material. A four-factor three-level Box–Behnken design was employed to study the effect of independent variables on dependent variables. Sodium alginate concentration (X₁), alkaline extraction of ispaghula husk (AEISP) concentration (X₂), concentration of cross-linking agents (X₃) and stirring speed (X₄) were four independent variables considered in the preparation of microparticles, while the particle size (Y₁) and entrapment efficiency (Y₂) were dependent variables. Optimized microparticles exhibited 83.43% drug entrapment and 51.53?µm particle size with 97.80% and 96.37% validity, respectively, at the following conditions – sodium alginate (3.55% w/v), alkaline extracted ispaghula husk (3.60% w/v), cross-linker concentration (7.82% w/v) and stirring speed (1200?rpm). The optimized formulation showed controlled drug release for more than 12?h by following Higuchi kinetics via non-Fickian diffusion. The gamma scintigraphy of the optimized formulation in Wistar rats showed that microparticles could be observed in the intestinal lumen after 1?h and were detectable in the intestine up to 12?h, with decreased percentage of radioactivity (t_1/2 of ^99mTc 4–5?h).