Microencapsulation of a probiotic bacteria with alginate–gelatin and its properties

Lactobacillus casei ATCC 393-loaded microcapsules based on alginate and gelatin had been prepared by extrusion method and the product could increase the cell numbers of L. casei ATCC 393 to be 10⁷ CFU g^?1 in the dry state of microcapsules. The microparticles homogeneously distributed with size of 1.1 ± 0.2 mm. Four kinds of microcapsules (S₁, S₂, S₃ and S₄) exhibited swelling in simulated gastric fluid (SGF) while the beads eroded and disintegrated rapidly in simulated intestinal fluid (SIF). Cells of L. casei ATCC 393 could be continuously released from the microcapsules during simulated gastrointestinal tract (GIT) and the release amounts and speeds in SIF were much higher and faster than that in SGF. Encapsulation in alginate–gelatin microcapsules successfully improved the survival of L. casei ATCC 393 and this approach might be useful in delivery of probiotic cultures as a functional food.     

Microencapsulation of gallium–indium (Ga–In) liquid metal for self-healing applications

Abstract

Microcapsules containing a liquid metal alloy core of gallium–indium (Ga–In) are prepared via in situ urea–formaldehyde (UF) microencapsulation. The capsule size, shape, thermal properties, and shell wall thickness are investigated. We prepare ellipsoidal capsules with major and minor diameter aspect ratios ranging from 1.64 to 1.08 and with major diameters ranging from 245?µm to 3?µm. We observe that as the capsule major diameter decreases, the aspect ratio approaches 1. The thermal properties of the prepared microcapsules are investigated by thermogravimetric (TGA) and differential scanning calorimetry (DSC). Microcapsules are shown to survive incorporation into an epoxy matrix and to trigger via mechanical damage to the cured matrix. Microcapsules containing liquid metal cores may have diverse applications ranging from self-healing to contrast enhancement or the demonstration of mechano-adaptive circuitry.     

Drug Release from Ammonio–Methacrylate-Coated Diltiazem Particles: Influence of the Reservoir on Membrane Behavior

Drug-layered sugar spheres 15, 45, and 64% potent were made such that each had the same particle size distribution. The particles were coated to the same coat thickness with an ammonio polymethacrylate formulation, and drug release was measured in two media. The products exhibited a sigmoidal release pattern, where a lag time was followed by relatively rapid drug release. Lag time depended on the applied polymer amount, the media used, and the sugar content, where an increase in sugar content caused greater expansion before drug release. Lag times were related to expansion. Expansion of coated sugar spheres was measured.     

Catanionic Drug–Surfactant Mixtures: Phase Behavior and Sustained Release from Gels

Purpose. To study mixtures of SDS and the drugs diphenhydramine, tetracaine, and amitriptyline to compile phase diagrams and to investigate the use of interesting phases for sustained release from gels. Methods. Phase diagrams were composed by studying large numbers of different compositions of negatively charged SDS and positively charged drug compounds visually, rheologically, and by cryo-transmission electron microscopy. Drug release from Carbopol 940 and agar gels containing interesting phases, e.g., vesicle and branched micelle phases, was measured in vitro by the USP paddle method. Results. Vesicles and elongated and branched micelles were formed on the SDS-rich side in all three systems examined. The tetracaine system differed from the other two in that it showed a vesicle area in the drug-rich side. Release of diphenhydramine from Carbopol 940 gels was slowed by at least a factor of 10 when in the form of vesicles or branched micelles. The same delay was found for both drug-rich and SDS-rich tetracaine vesicles. Conclusions. Mixtures of SDS and positively charged drugs form the same interesting phases as traditional catanionic mixtures. This may prove useful in obtaining functional controlled-release systems when using gels as drug carriers.     

Sustained Release of Naltrexone from Poly(N‐Isopropylacrylamide) Microgels

The release of the opioid antagonist naltrexone from neutral poly(N‐isopropylacrylamide) (PNIPAAM) microgels and negatively charged PNIPAAM microgels containing acrylic acid groups (PNIPAAM‐co‐PAA) has been studied at various microgel and drug concentrations. The release curves were found to be well represented by the Weibull equation. The release rates were observed to be dependent on the microgel concentration. At most conditions, the release from the charged microgels was slower than for the neutral microgels. In addition, the charged microgels exhibited a release lag time, which was dependent on the microgel concentration. No significant lag time could be observed for the neutral microgels. Increasing the naltrexone concentration did not significantly affect the release rates from the neutral microgels, but the release from the charged microgels became faster. The microgels did not exhibit any significant cytotoxic effect on HeLa cells at the tested concentrations. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:227–234, 2014     

Mucoadhesive Films Containing Chitosan‐Coated Nanoparticles: A New Strategy for Buccal Curcumin Release

Mucoadhesive films containing curcumin‐loaded nanoparticles were developed, aiming to prolong the residence time of the dosage form in the oral cavity and to increase drug absorption through the buccal mucosa. Films were prepared by the casting method after incorporation of curcumin‐loaded chitosan‐coated polycaprolactone nanoparticles into plasticized chitosan solutions. Different molar masses of mucoadhesive polysaccharide chitosan and concentrations of plasticizer glycerol were used to optimize the preparation conditions. Films obtained using medium and high molar mass chitosan were found to be homogeneous and flexible. Curcumin‐loaded nanoparticles were uniformly distributed on the film surface, as evidenced by atomic force microscopy and high‐resolution field‐emission gun scanning electron microscopy (FEG‐SEM) images. Analyses of film cross sections using FEG‐SEM demonstrate the presence of nanoparticles inside the films. In addition, films proved to have a good rate of hydration in simulated saliva solution, displaying a maximum swelling of around 80% and in vitro prolonged‐controlled delivery of curcumin. These results indicate that the mucoadhesive films containing nanoparticles offer a promising approach for buccal delivery of curcumin, which may be particularly useful in the treatment of periodontal diseases that require a sustained drug delivery.     

Influence of Preparation Factors on the Sustained Release of Nifedipine from Eudragit RL/RS Microspheres

用乳剂—溶剂挥发法制备硝苯地平的丙烯酸树脂缓释微球。微球中药物的释放速度随丙烯酸树脂ＥｕｄｒａｇｉｔＲＬ／ＲＳ比率的增加以及制备时搅拌速率的增加而增大，随内相聚合物浓度的增加及微球粒径的增加而减小，释药５０％所需时间与微球粒径呈良好线性。微球的释药速率也随药物含量的增加（从４．２％到１６．７％）而增大，并快于药物结晶的溶解速率，但药物含量达２６．６％时，微球释药速率明显下降并低于药物结晶的溶解速率。用差热分析和Ｘ射线衍射分析证明，药物含量为４．２，９．４和１６．７％的微球中药物完全是以非晶态分散的，而含药２６．６％的微球中有药物结晶存在。不同微球释药低于７０％时，释放方式均符合Ｈｉｇｕｃｈｉ时间平方根方程。     

Influence of Formulation Factors and Compression Force on Release Profile of Sustained Release Metoprolol Tablets using Compritol? 888ATO as Lipid Excipient

Tablets containing metoprolol succinate and Compritol^® 888ATO in the ratio of 1:2 yielded the desired sustained release profile in phosphate buffer pH 6.8 when evaluated using USP type II paddle apparatus and was selected as the optimized formulation. Robustness of optimized formulation was assessed by studying the effect of factors like varying source of metoprolol succinate and Compritol^® 888ATO, compression force and hydroalcoholic dissolution medium on the release profile. No significant difference (P>0.05) in release profile was observed when metoprolol succinate from three different sources and Compritol^® 888ATO from two different batches were used. Release profile of sustained release tablets of metoprolol succinate in media containing various concentrations of ethanol was comparable with media devoid of ethanol as evaluated by f2 test. This indicated that release profile of sustained release tablets of metoprolol succinate was reliable with no significant change due to variation in source of active pharmaceutical ingredient, particularly due to particle size distribution. Sustained release tablets of metoprolol succinate yielded release pattern within specifications irrespective of presence or absence of ethanol in the medium indicating that release properties of Compritol^® 888ATO matrix are not affected by ethanol. Tablets compressed at compression force of <100 kg/cm² exhibited low hardness with total porosity of 15.39% and significantly increased (P<0.05) metoprolol succinate release as compared to tablets compressed at 2000 kg/cm² with 6.90% of total porosity revealing influence of compression force. Compritol^® 888ATO holds great potential in providing reliable and controlled release profile of highly water soluble metoprolol succinate.     

Dry Powder Coating of Pellets with Micronized Eudragit® RS for Extended Drug Release

PURPOSE: To develop a novel powder coating technology for extended-release pellets based on the acrylic polymer, Eudragit RS. METHODS: A mixture of micronized Eudragit RS plus talc and a liquid feed (plasticizer plus binder solution) were sprayed separately onto propranolol hydrochloride-loaded pellets in a fluidized bed coater. The coated pellets were heat-cured under different conditions (40 degrees C to 60 degrees C, 2 h to 24 h). The coalescence (film formation) of the polymer particles was studied via the determination of the glass transition and the minimum polymer-softening temperatures (MST). The coated pellets were characterized with respect to their morphologic, release, and stability properties. RESULTS: The optimum plasticizer type and concentration and process temperatures could be identified by the determination of the MST. High concentrations of plasticizer (40% based on the polymer) and a thermal treatment were necessary to achieve complete film formation and extended drug release. Curing the pellets resulted in release profiles, which did not change during storage for 3 years. The coated pellets had a smooth, continuous surface and a dense film structure after curing. CONCLUSIONS: This novel coating technique avoids the use of organic polymer solutions or latex dispersions, has short processing times, and results in stable extended-release profiles.     

Poly(Glycerol Adipate-co-ω-Pentadecalactone) Spray-Dried Microparticles as Sustained Release Carriers for Pulmonary Delivery

Purpose  

The aim of this work was to optimize biodegradable polyester poly(glycerol adipate-co-ω-pentadecalactone), PGA-co-PDL, microparticles as sustained release (SR) carriers for pulmonary drug delivery.     

Core–shell Particles for the Dispersion of Small Polar Drugs and Biomolecules in Hydrofluoroalkane Propellants

Purpose Demonstrate the applicability of a novel particle-based technology for the development of suspensions of small polar drugs and biomolecules in hydrofluoroalkane (HFA) propellants for pressurized metered-dose inhalers (pMDIs). Materials and Methods Emulsification diffusion was used to prepare core–shell particles. The shell consisted of oligo(lactide) grafts attached onto a short chitosan backbone. The active drug was arrested within the particle core. Colloidal Probe Microscopy (CPM) was used to determine the cohesive forces between particles in a model HFA propellant. The aerosol characteristics of the formulations were determined using an Anderson Cascade Impactor (ACI). Cytotoxicity studies were performed on lung epithelial and alveolar type II cells. Results CPM results indicate that particle cohesive forces in liquid HFA are significantly screened in the presence of the polymeric shell and correlate well with the physical stability of suspensions in propellant HFA. The proposed formulation showed little or no cytotoxic effects on both Calu-3 and A549 cells. Conclusions Core–shell particles with a shell containing the lactide moiety as the HFA-phile showed excellent dispersion stability and aerosol characteristics in HFA-based pMDIs. This is a general strategy that can be used for developing novel suspension pMDIs of both small polar drugs and large therapeutic molecules.     

Development of a Thermally Responsive Nanogel Based on Chitosan–Poly(N-Isopropylacrylamide-co-Acrylamide) for Paclitaxel Delivery

A thermally responsive nanogel was developed through the radical polymerization based on chitosan (CTS) and N-isopropylacrylamide (NIPAAm) with acrylamide (AAm) blended to explore the possibility of increasing the volume phase transition temperature (VPTT). The thermally sensitive features of resultant nanogels were studied by determining variance of transmittance and changeable size. The VPTT of the CTS–poly(NIPAAm-co-AAm5.5) nanogel, coplymerized with 5.5% wt. AAm /wt. NIPAAm, was 38°C in contrast to 32°C of the CTS–poly(NIPAAm) polymer and the former was studied thereafter. The critical aggregation concentration of CTS–poly(NIPAAm-co-AAm5.5) nanogels was 1.11 μg/mL, much smaller than CTS–poly(NIPAAm) nanogels (5.00 μg/mL). Paclitaxel (PTX) was encapsulated in CTS–poly(NIPAAm-co-AAm5.5) nanogels with loading efficiency of about 9.06 ± 0.195% (n = 3). Thermally responsive PTX in vitro release fromPTX-loaded nanogels was verified. Coumarin-6-loaded nanogels showed thermally responsive cellular uptake because of electrostatic absorptive endocytosis. Furthermore, the half maximal inhibitory concentration of PTX-loaded nanogels was about 2.025 nmol/L, 10-fold improved relative to PTX solutions against SMMC 7721 cells. In vivo, PTX-loaded nanogels presented remarkably higher antitumor efficacy against human colon carcinoma cells HT-29 xenograft nude mice model after intravenous administration. Accordingly, our results reinforced the potential means of CTS–poly(NIPAAm-co-AAm5.5) nanogels for the combination of thermal therapy and chemotherapy.     

Solid Lipid Particles for Oral Delivery of Peptide and Protein Drugs III — the Effect of Fed State Conditions on the In Vitro Release and Degradation of Desmopressin

The effect of food intake on the release and degradation of peptide drugs from solid lipid particles is unknown and was therefore investigated in vitro using different fed state media in a lipolysis model. Desmopressin was used as a model peptide and incorporated into solid lipid particles consisting of trimyristin (TG14), tripalmitin (TG16), and tristearin (TG18), respectively. Fasted state and fed state media with varying phospholipid and bile salt concentrations, as well as fed state media with milk and oleic acid glycerides, respectively, were used as the release media. The presence of oleic acid glycerides accelerated the release of desmopressin significantly from all solid lipid particles both in the presence and absence of lipase. The presence of oleic acid glycerides also reduced the degradation rate of desmopressin, probably due to the interactions between the lipids and the protease or desmopressin. Addition of a medium chain triglyceride, trilaurin, in combination with drug-loaded lipid particles diminished the food effect on the TG18 particles, and trilaurin is therefore proposed to be a suitable excipient for reduction of the food effect. Overall, the present study shows that strategies to reduce food effect, such as adding trilaurin, for lipid particle formulations should be considered as drug release from such formulations might be influenced by the presence of food in the gastrointestinal tract.     

Combined Study of Biphasic and Zero-Order Release Formulations with Dissolution Tests and ATR–FTIR Spectroscopic Imaging

In this study of multi-layer tablets, the dissolution of biphasic and zero-order release formulations has been studied primarily using attenuated total reflection–Fourier transform infrared (ATR–FTIR) spectroscopic imaging as well as UV–Vis detection of dissolved drug in the effluent stream and USP dissolution testing. Bilayer tablets, containing the excipients microcrystalline cellulose (MCC) and glucose, were used for biphasic release with nicotinamide and buflomedil as model drugs. ATR–FTIR spectroscopic imaging showed the changing component distributions during dissolution. Further experiments studied monolithic and barrier-layered tablets containing hydroxypropyl methylcellulose, MCC and buflomedil dissolving in a USP I apparatus. These data were compared with UV–Vis dissolution profiles obtained online with the ATR flow-through cell. ATR–FTIR imaging data of the biphasic formulations demonstrated that the drug release was affected by excipient ratios and effects such as interference between tablet sections. Tablets placed in the ATR–FTIR flow-through cell exhibited zero-order UV–Vis dissolution profile data at high flow rates, similar to barrier-layered formulations studied using the USP I apparatus. ATR–FTIR spectroscopic imaging provided information regarding the dissolution mechanisms in multi-layer tablets which could assist formulation development. The ability to relate data from USP dissolution tests with that from the ATR–FTIR flow-through cell could help spectroscopic imaging complement dissolution methods used in the industry.     

Sustained Release d-Amphetamine Reduces Cocaine but not ��Speedball'-Seeking in Buprenorphine-Maintained Volunteers: A Test of Dual-Agonist Pharmacotherapy for Cocaine/Heroin Polydrug Abusers

The aim of this study was to determine whether oral sustained release d-amphetamine (SR-AMP) reduces cocaine and opioid/cocaine combination (‘speedball''-like) seeking in volunteers with current opioid dependence and cocaine dependence. Following outpatient buprenorphine (BUP) 8 mg/day stabilization without SR-AMP, eight participants completed a 3-week in-patient study with continued BUP 8 mg/day maintenance and double-blind ascending SR-AMP weekly doses of 0, 30, and 60 mg/day, respectively. After 3 days (Saturday–Monday) stabilization at each SR-AMP weekly dose (0, 15, or 30 mg administered at 0700 and 1225 each day), on Tuesday–Friday mornings (0900–1200 hours), participants sampled four drug combinations in randomized, counterbalanced order under double-blind, double-dummy (intranasal cocaine and intramuscular hydromorphone) conditions: cocaine (COC 100 mg+saline); hydromorphone (COC 4 mg+HYD 24 mg); ‘speedball'' (COC 100 mg+HYD 24 mg); and placebo (COC 4 mg+saline). Subjective and physiological effects of these drug combinations were measured. From 1230 to 1530 hours, participants could respond on a choice, 12-trial progressive ratio schedule to earn drug units (1/12th of total morning dose) or money units (US$2). SR-AMP significantly reduced COC, but not HYD or speedball, choices and breakpoints. SR-AMP also significantly reduced COC subjective (eg, abuse-related) effects and did not potentiate COC-induced cardiovascular responses. This study shows the ability of SR-AMP to attenuate COC self-administration, as well as its selectivity, in cocaine/heroin polydrug abusers. Further research is warranted to ascertain whether SR-AMP combined with BUP could be a useful dual-agonist pharmacotherapy.     

Stable Formulations of Recombinant Human Growth Hormone and Interferon-γ for Microencapsulation in Biodegradable Mircospheres

Purpose. The successful development of controlled release formulations for proteins requires that the protein not be denatured during the manufacturing process. The major objective was to develop formulations that stabilize two recombinant human proteins, human growth hormone (rhGH) and interferon- (rhIFN-), at high protein concentrations (>100 mg/mL) in organic solvents commonly used for microencapsulation, methylene chloride and ethyl acetate. Methods. Several excipients were screened to obtain the maximum solubility of each protein. These formulations (aqueous, lyophilized, milled, spray dried, or isoelectric precipitate) were then rapidly screened by emulsification in the organic solvent followed by recovery into excess buffer. Additional screening was performed with solid protein that was suspended in the organic solvent and then recovered with excess buffer. The recovery of native protein was determined by native size exclusion chromatography (SEC-HPLC) and circular dichroism (CD). The selected formulations were encapsulated in poly-lactic-coglycolic acid (PLGA) microspheres by either water-in-oil-in-water (W/O/W) or solid-in-oil-in-water (S/O/W) methods. The initial protein released from the microspheres incubated at physiological conditions was analyzed by SEC-HPLC, CD, and biological assays. Results. The stability of a given formulation in the rapid screening method correlated well with stability during encapsulation in PLGA microspheres. Formulations of rhGH containing Tween 20 or 80 resulted in lower recovery of native protein, while trehalose and mannitol formulations (phosphate buffer, pH 8.0) yielded complete recovery of native rhGH. Other additives such as carboxymethyl cellulose, gelatin, and dextran 70 were not effective stabilizers, and polyethylene glycol provided some stabilization of rhGH. Trehalose/rhGH (1:4 mass ratio) and mannitol/rhGH (1:2 mass ratio) formulations (potassium phosphate buffer, pH 8.0) were lyophilized, reconstituted to 200 and 400 mg/mL rhGH, respectively, and then encapsulated in PLGA micro-spheres. The protein was released from these microspheres in its native state. Lyophilized formulations of rhGH yielded analogous results indicating the ability of trehalose and mannitol to stabilize the protein. Small solid particles of rhGH generated by spray drying (both air and freeze-drying) formulations containing Tween 20 or PEG were stable in ethyl acetate, but not methylene chloride. Similar results were also obtained with rhIFN- (137 mg/mL in succinate buffer, pH 5.0), where both mannitol and trehalose were observed to stabilize the protein during exposure to the organic solvents resulting in the release of native rhIFN- from PLGA microspheres. Conclusions. The rapid screening method allowed the development of stable concentrated protein solutions or solid protein formulations that could be successfully encapsulated in PLGA microspheres. The excipients observed to stabilize these proteins function by preferential hydration of the protein, and in the dry state (e.g., trehalose) may stabilize the protein via water substitution yielding a protective coating around the protein surface. Studies of other proteins should provide further insight into this mechanism of protein stabilization during encapsulation.     

Effect of Glyceryl Monocaprylate–Modified Chitosan on the Intranasal Absorption of Insulin in Rats

Nasal administration of insulin showed the attractive potential to improve the compliance of diabetic patients and alleviate mild cognitive impairment of Alzheimer's patients. However, the nasal absorption of insulin was not ideal, limiting its therapeutic effect in clinic. This study was to explore the potential of glyceryl monocaprylate–modified chitosan (CS-GMC) on the intranasal absorption of insulin via in vivo pharmacodynamic experiment in conscious rats. It was demonstrated that the absorption-enhancing effect of CS-GMC depended on the existing state of insulin in the formulation, substitution degree of GMC on chitosan and concentration of CS-GMC. Better insulin absorption was achieved when insulin existed in molecular form compared with that in polyelectrolyte complexes. CS-GMC with substitution degree 12% (CS-GMC 12%) was a preferred absorption enhancer, and its absorption enhancing effect increased linearly with the increment of its concentration in the range investigated. Compared with chitosan of the same concentration, CS-GMC12% showed remarkably enhanced and prolonged therapeutic effect up to at least 5 h under the concentration of 0.6% (w/v). CS-GMC12% showed almost no ciliotoxicity to the nasal cilia up to concentration 1.0% (w/v). In conclusion, CS-GMC was a promising absorption enhancer to improve the intranasal absorption of insulin.     

Hydrolytic Degradation and Drug Release of Ricinoleic Acid–Lactic Acid Copolyesters

A systematic study on the degradation and drug release from l-lactic acid and ricinoleic-acid-based copolyesters is reported. These copolyesters were synthesized by ring opening polymerization (ROP), melt condensation (COND) and transesterification (TRANS) of high molecular weight poly(lactic acid) (PLA) with ricinoleic acid (PLA-RA), and repolymerization by condensation to yield random and block copolymers of weight average molecular weights (Mw) between 3000 and 13,000. All polymers showed an almost zero-order weight loss, with a 20–40% loss after 60 days of incubation. Lactic acid release to the degradation solution is proportional to weight loss of the polymer samples. The main decrease in molecular weight was observed during the first 20 days, followed by a slow degradation phase, which kept the number average molecular weight (Mn) at 4000–2000 for another 40 days. Water-soluble 5FU was released from ricinoleic-acid-based polymers faster than slightly water-soluble triamcinolone. Drug release into phosphate-buffered saline (pH 7.4, 0.1 M) at 37°C from P(LA-RA) 60:40 prepared by condensation of the acids was faster than from pasty P(PLA-RA) 60:40 synthesized by transesterification for both drugs.