Lipid-based vehicle for oral drug delivery

With an increasing number of lipophilic drugs under development, homolipids and heterolipids have gained renewed interests as excipients for oral drug delivery systems. Oral administration has many advantages for chronic drug therapy. It is relatively safe, convenient for the patient and allows self administration. This article is not intended to review the broad area of lipid-based vehicle for oral drug delivery comprehensively. The rationale behind choosing lipids materials for pharmaceutical dosage forms and their applications is discussed. It also comments on the methods for monitoring the physicochemical properties of vehicles and formulations and describes a range of pharmacopoeial excipients suitable for these purposes. The excipients selected here are pharmacopoeial in European Pharmacopoeia 4th Ed., United States Pharmacopoeia 24th Ed./National Formulary 19th Ed. and Japanese Pharmacopoeia 13th Ed. or are drafted in Pharmaeuropa and Pharmacopoeial Forum. Widening availability of lipidic excipients with specific characteristics offer flexibility of application with respect to improving the bioavailability of poorly water-soluble drugs and manipulating release profiles.     

Polypeptide multilayer film co-delivers oppositely-charged drug molecules in sustained manners

The current state-of-the-art for drug-carrying biomedical devices is mostly limited to those that release a single drug. Yet there are many situations in which more than one therapeutic agent is needed. Also, most polyelectrolyte multilayer films intended for drug delivery are loaded with active molecules only during multilayer film preparation. In this paper, we present the integration of capsules as vehicles within polypeptide multilayer films for sustained release of multiple oppositely charged drug molecules using layer-by-layer nanoassembly technology. Calcium carbonate (CaCO(3)) particles were impregnated with polyelectrolytes, shelled with polyelectrolyte multilayers, and then assembled onto polypeptide multilayer films using glutaraldehyde. Capsule-integrated polypeptide multilayer films were obtained after decomposition of CaCO(3) templates. Two oppositely charged drugs were loaded into capsules within polypeptide multilayer films postpreparation based on electrostatic interactions between the drugs and the polyelectrolytes impregnated within capsules. We determined that the developed innovative capsule-integrated polypeptide multilayer films could be used to load multiple drugs of very different properties (e.g., opposite charges) any time postpreparation (e.g., minutes before surgical implantation inside an operating room), and such capsule-integrated films allowed simultaneous delivery of two oppositely charged drug molecules and a sustained (up to two weeks or longer) and sequential release was achieved.     

Biodegradable chitosan matrix for the controlled release of steroids.

Chitosan, a polysaccharide, having structural characteristics similar to glycosaminoglycans, seems to be nontoxic and bioabsorbable. This study highlights the use of chitosan matrix for controlled drug delivery systems. The steroid drugs, namely testosterone, progesterone and beta-oestradiol were mixed with chitosan and the films were prepared by evaporation technique. The in vitro release profile of these steroids from the film matrix was monitored, as a function of time, in phosphate buffered saline (PBS, pH 7.4) at 37 degree C using a U-V-spectrophotometer. The degradation, of these chitosan and drug loaded chitosan films, was also investigated by weight loss and tensile strength studies. The steroid release from chitosan films was compared with the release of these drugs from their microbeads. It appears, the films and the microbeads stayed intact during the dissolution study of 90 days and the possibility of using these systems in contraceptive applications and novel drug delivery systems are discussed.     

Multifunctional nanoparticles from albumin for stimuli-responsive efficient dual drug delivery

In this project methotrexate (MTX) conjugated albumin based nanoparticles (MTX-BSA) loaded with curcumin (CUR) drug (CUR-MTX-BSA) for simultaneous delivery of multi-chemotherapeutic drugs and combination cancer therapy were designed. Co-delivery is a new strategy which minimize the amount of each drug, reduce of side effects and also to achieve the synergistic effect for cancer therapies. The MTX was conjugated to albumin via covalent bond. Next, this synthesized prodrug loaded with CUR. Afterward, the formulations were evaluated for physical and chemical properties by DLS, TEM, FTIR, UV/Vis, DSC analysis, in vitro cytotoxicity and in vivo biocompatibility studies. Furthermore, the drug loading and release study were evaluated. Proteinase K enzyme was used to break amid bond between MTX and BSA and also amidic bonds in BSA structure. Administration of up to 2000 mg/kg of BSA to healthy animals was non-toxic and all treated mice were still alive after 24 h. The result of this study proved that CUR-MTX-BSA can be used as a proficient vehicle for effective co-delivery of CUR and MTX in the treatment of cancer.     

Synthesis of amphiphilic alternating polyesters with oligo(ethylene glycol) side chains and potential use for sustained release drug delivery

Novel amphiphilic alternating polyesters, poly((N-phthaloyl-l-glutamic anhydride)-co-(2-(2-(2-methoxyethoxy)ethoxy)methyl)oxirane) (P(PGA-co-ME(2)MO)), were synthesized by alternating copolymerization of PGA and ME(2)MO. The structures of the synthesized polyesters were characterized by (1)H NMR, (13)C NMR, FT-IR, and GPC analyses. Because of the presence of oligo(ethylene glycol) (OEG) side chains, the polyesters could self-assemble into thermosensitive micelles. Dynamic light scattering (DLS) showed that these micelles underwent thermoinduced size decrease without intermicellar aggregation. In vitro methyl thiazolyl tetrazolium (MTT) assay demonstrated that the polyesters were biocompatible to Henrietta Lacks (HeLa) cells, rendering their potential for drug delivery applications. Two hydrophobic drugs, rifampin and doxorubicin (DOX), were loaded into the polyester micelles and observed to be released in a zero-order sustained manner. The sustained release could be accelerated in lower pH or in the presence of proteinase K, due to the degradation of the polyester under these conditions. Remarkably, in vitro cell experiments showed that the polyester micelles accomplished fast release of DOX inside cells and higher anticancer efficacy as compared with the free DOX. With enhanced stability during circulation condition and accelerated drug release at the target sites (e.g., low pH or enzyme presence), these novel polyesters with amphiphilic structures are promising to be used in sustained release drug delivery systems.     

Polymer micelles for delayed release of therapeutics from drug-releasing surfaces with nanotubular structures

A new approach to engineer a local drug delivery system with delayed release using nanostructured surface with nanotube arrays is presented. TNT arrays electrochemically generated on a titanium surface are used as a model substrate. Polymer micelles as drug carriers encapsulated with drug are loaded at the bottom of the TNT structure and their delayed release is obtained by loading blank micelles (without drug) on the top. The delayed and time-controlled drug release is successfully demonstrated by controlling the ratio of blank and drug loaded-micelles. The concept is verified using four different polymer micelles (regular and inverted) loaded with water-insoluble (indomethacin) and water-soluble drugs (gentamicin).     

Melatonin delivery from PCL scaffold enhances glycosaminoglycans deposition in human chondrocytes – Bioactive scaffold model for cartilage regeneration

The therapeutic potential of an engineered cartilage construct can be enhanced by sustained delivery of chondrogenic drug like melatonin from 3D porous scaffolds embedded with melatonin loaded bovine serum albumin nanoparticles (MNP). In this study, MNP was synthesized and loaded into polycaprolactone (PCL) scaffolds. 12 % (w/v) and 10 % (w/v) PCL scaffolds were fabricated with different concentrations of MNP. X- ray diffraction and Raman analysis of MNP and scaffolds revealed amorphization of melatonin which is highly desired in drug delivery applications. Additionally, Fourier Transform Infrared spectroscopic analysis confirmed the drug to be chemically inert to fabrication process. Field emission scanning electron microscopic analysis suggested highly interlinked porous scaffold (diameter 50 μm – 300 μm) and MNP diameters in the range of 110−200 nm. Importantly, UV spectrophotometric analysis showed that all groups of scaffolds showed sustained release for 21 days, wherein MNP concentration had an influence on release behaviour of melatonin from scaffolds. Drug release kinetics studied using mathematical models revealed, diffusion and dissolution mechanism of release. Furthermore, in vitro evaluation of MNP loaded scaffolds with Human chondrocytes for 21 days increased glycosaminoglycans deposition significantly. In brief, sustained release of melatonin from polycaprolactone scaffolds increased the therapeutic potential of the engineered construct.     

Porous bioactive glass scaffolds for local drug delivery in osteomyelitis: development and in vitro characterization

A new bioactive glass-based scaffold was developed for local delivery of drugs in case of osteomyelitis. Bioactive glass having a new composition was prepared and converted into porous scaffold. The bioactivity of the resulting scaffold was examined by in vitro acellular method. The scaffolds were loaded with two different drugs, an antibacterial or antifungal drug. The effects of the size of the scaffold, drug concentration, and dissolution medium on drug release were studied. The scaffolds were further coated with a degradable natural polymer, chitosan, to further control the drug release. Both the glass and scaffold were bioactive. The scaffolds released both the drugs for 6 weeks, in vitro. The results indicated that the bigger the size and the higher the drug concentration, the better was the release profile. The scaffolds appeared to be suitable for local delivery of the drugs in cases of osteomyelitis.     

The use of zeolites as slow release anthelmintic carriers

This work examines the ability of commercial zeolite Y to act as a slow release agent for a number of anthelmintic drugs. Administration to rats, dosed with Nippostrongylus brasiliensis, of pyrantel and/or fenbendazole and pigs, dosed with Ascaris and Oesophagostomum, of dichlorvos (DDVP) loaded onto zeolite Y was more successful in killing adult worms than administration of the pure drug alone. The zeolite Y was used as supplied for initial studies and then later dealuminated for further studies. The drug loadings were monitored by thermal analysis and the loaded zeolites were used in several field trials. The results indicate that zeolite Y is a suitable vehicle for the slow release of some anthelmintics. The slow release of drug from the zeolite matrix improved its efficacy.     

Release characteristics of three model drugs from chitosan/cellulose acetate multimicrospheres

Chitosan/cellulose acetate multimicrospheres (CCAM) loaded different model drugs were prepared by the method of w/o/w emulsion. Model drugs with different hydrophilicity were selected to investigate the delivery system, such as hydrophilic ranitidine hydrochloride (RT), amphoteric acetaminophen (ACP) and hydrophobic 6-mercaptopurine (6-MP). The size of CCAM loaded RT or ACP were almost the same of 200–280 μm and the size of CCAM loaded 6-MP was only 50–80 μm. With the increasing of hydrophobicity of drug, the holes in the appearance of microspheres became smaller and the loading efficiency increased. The loading efficiency of 6-MP was more than 30% whereas that of RT and ACP was only 10%. The CCAM system had good effect on the controlled release in vitro of all model drugs of different hydrophobicity. However, the release rate was affected by the hydrophobicity of model drug. It became slower with the increasing of hydrophobicity of drugs. The highest release rate was almost 60% during 48 h which was for the hydrophilic drug of RT and the release rate of hydrophobic drug (6-MP) was not more than 30% in the same time.     

Temperature-Tunable Iron Oxide Nanoparticles for Remote-Controlled Drug Release

Herein, we report the successful development of a novel nanosystem capable of an efficient delivery and temperature-triggered drug release specifically aimed at cancer. The water-soluble 130.1 ± 0.2 nm iron oxide nanoparticles (IONPs) were obtained via synthesis of a monodispersed iron oxide core stabilized with tetramethylammonium hydroxide pentahydrate (TMAOH), followed by coating with the thermoresponsive copolymer poly-(NIPAM-stat-AAm)-block-PEI (PNAP). The PNAP layer on the surface of the IONP undergoes reversible temperature-dependent structural changes from a swollen to a collapsed state resulting in the controlled release of anticancer drugs loaded in the delivery vehicle. We demonstrated that the phase transition temperature of the prepared copolymer can be precisely tuned to the desired value in the range of 36°C–44°C by changing the monomers ratio during the preparation of the nanoparticles. Evidence of modification of the IONPs with the thermoresponsive copolymer is proven by ATR-FTIR and a quantitative analysis of the polymeric and iron oxide content obtained by thermogravimetric analysis. When loaded with doxorubicin (DOX), the IONPs-PNAP revealed a triggered drug release at a temperature that is a few degrees higher than the phase transition temperature of a copolymer. Furthermore, an in vitro study demonstrated an efficient internalization of the nanoparticles into the cancer cells and showed that the drug-free IONPs-PNAP were nontoxic toward the cells. In contrast, sufficient therapeutic effect was observed for the DOX-loaded nanosystem as a function of temperature. Thus, the developed temperature-tunable IONPs-based delivery system showed high potential for remotely triggered drug delivery and the eradication of cancer cells.

Electronic supplementary material

The online version of this article (doi:10.1208/s12249-014-0131-x) contains supplementary material, which is available to authorized users.KEY WORDS: drug delivery, IONPs, remote-triggered drug release, thermoresponsive copolymer, tunable LCST     

Slow-release Drug Delivery through Elvax 40W to the Rat Retina: Implications for the Treatment of Chronic Conditions

Diseases of the retina are difficult to treat as the retina lies deep within the eye. Invasive methods of drug delivery are often needed to treat these diseases. Chronic retinal diseases such as retinal oedema or neovascularization usually require multiple intraocular injections to effectively treat the condition. However, the risks associated with these injections increase with repeated delivery of the drug. Therefore, alternative delivery methods need to be established in order to minimize the risks of reinjection. Several other investigations have developed methods to deliver drugs over extended time, through materials capable of releasing chemicals slowly into the eye. In this investigation, we outline the use of Elvax 40W, a copolymer resin, to act as a vehicle for drug delivery to the adult rat retina. The resin is made and loaded with the drug. The drug-resin complex is then implanted into the vitreous cavity, where it will slowly release the drug over time. This method was tested using 2-amino-4-phosphonobutyrate (APB), a glutamate analogue that blocks the light response of the retina. It was demonstrated that the APB was slowly released from the resin, and was able to block the retinal response by 7 days after implantation. This indicates that slow-release drug delivery using this copolymer resin is effective for treating the retina, and could be used therapeutically with further testing.     

Facile fabrication of thermo-responsive and reduction-sensitive polymeric micelles for anticancer drug delivery

The development of thermo-responsive and reduction-sensitive polymeric micelles based on an amphiphilic block copolymer poly[(PEG-MEMA)-co-(Boc-Cyst-MMAm)]-block-PEG (denoted PEG-P-SS-HP) for the intracellular delivery of anticancer drugs is reported. PTX, as model drug, was loaded into the PEG-P-SS-HP micelles with an encapsulation efficiency >90%, resulting in a high drug loading content (up to 35?wt%). The PTX-loaded PEG-P-SS-HP micelles show slow drug release in PBS and rapid release after incubation with DTT. The PTX-loaded micelles display a better cytotoxic effect than the free drug, whereas empty micelles are found to be non-toxic. The thermo-responsive and reduction-sensitive polymeric micelles described may serve as promising carriers for cytostatic drugs.     

树突状细胞对海藻酸钙纳米胶囊的吞噬作用与功能诱导

本研究采用量子点标记方法,证实了人外周血来源树突状细胞对海藻酸钙纳米胶囊的吞噬作用,并对其体外成熟诱导和接受偶联有牛血清白蛋白的纳米胶囊刺激之后的自体T淋巴细胞免疫作用进行了探讨。实验结果表明,树突状细胞在吞噬海藻酸钙纳米胶囊后被诱导成熟,而且偶联有牛血清白蛋白的纳米胶囊可诱导自体T淋巴细胞增殖,显示该海藻酸钙纳米胶囊可能成为具有载体功能的癌症细胞免疫治疗佐剂。     

Agarose bioplastic‐based drug delivery system for surgical and wound dressings

We have developed an agarose‐based biocompatible drug delivery vehicle. The vehicle is in the form of thin, transparent, strong and flexible films. The biocompatibility and haemocompatibility of the films is confirmed using direct and indirect contact biological assay. Contact angle measurement exhibits hydrophilic nature of the films, and protein adsorption test shows low protein adsorption on the film surface. Drugs, antibiotics and antiseptics, retain their potency after their incorporation into the films. Our bioplastic films can be a versatile medium for drug delivery applications, especially as wound and surgical dressings where a fast drug release rate is desired.     

Pectin Matrix as Oral Drug Delivery Vehicle for Colon Cancer Treatment

Colon cancer is the fourth most common cancer globally with 639,000 deaths reported annually. Typical chemotherapy is provided by injection route to reduce tumor growth and metastasis. Recent research investigates the oral delivery profiles of chemotherapeutic agents. In comparison to injection, oral administration of drugs in the form of a colon-specific delivery system is expected to increase drug bioavailability at target site, reduce drug dose and systemic adverse effects. Pectin is suitable for use as colon-specific drug delivery vehicle as it is selectively digested by colonic microflora to release drug with minimal degradation in upper gastrointestinal tract. The present review examines the physicochemical attributes of formulation needed to retard drug release of pectin matrix prior to its arrival at colon, and evaluate the therapeutic value of pectin matrix in association with colon cancer. The review suggests that multi-particulate calcium pectinate matrix is an ideal carrier to orally deliver drugs for site-specific treatment of colon cancer as (1) crosslinking of pectin by calcium ions in a matrix negates drug release in upper gastrointestinal tract, (2) multi-particulate carrier has a slower transit and a higher contact time for drug action in colon than single-unit dosage form, and (3) both pectin and calcium have an indication to reduce the severity of colon cancer from the implication of diet and molecular biology studies. Pectin matrix demonstrates dual advantages as drug carrier and therapeutic for use in treatment of colon cancer.     

Controlled Delivery of Vancomycin via Charged Hydrogels

Surgical site infection (SSI) remains a significant risk for any clean orthopedic surgical procedure. Complications resulting from an SSI often require a second surgery and lengthen patient recovery time. The efficacy of antimicrobial agents delivered to combat SSI is diminished by systemic toxicity, bacterial resistance, and patient compliance to dosing schedules. We submit that development of localized, controlled release formulations for antimicrobial compounds would improve the effectiveness of prophylactic surgical wound antibiotic treatment while decreasing systemic side effects. Our research group developed and characterized oligo(poly(ethylene glycol)fumarate) / sodium methacrylate (OPF/SMA) charged copolymers as biocompatible hydrogel matrices. Here, we report the engineering of this copolymer for use as an antibiotic delivery vehicle in surgical applications. We demonstrate that these hydrogels can be efficiently loaded with vancomycin (over 500 μg drug per mg hydrogel) and this loading mechanism is both time- and charge-dependent. Vancomycin release kinetics are shown to be dependent on copolymer negative charge. In the first 6 hours, we achieved as low as 33.7% release. In the first 24 hours, under 80% of total loaded drug was released. Further, vancomycin release from this system can be extended past four days. Finally, we show that the antimicrobial activity of released vancomycin is equivalent to stock vancomycin in inhibiting the growth of colonies of a clinically derived strain of methicillin-resistant Staphylococcus aureus. In summary, our work demonstrates that OPF/SMA hydrogels are appropriate candidates to deliver local antibiotic therapy for prophylaxis of surgical site infection.     

Poly (DL-lactide-co-glycolide) based delivery systems for vaccines and drugs

Current vaccination and drug delivery strategies emphasize on the development of controlled release techniques for persistent and sustained effects. In the recent years, polymer based systems for the delivery of bioactive agents have gained considerable attention due to their marked adjuvanticity, established biodegradability and biocompatibility, excellent mechanical strength and controlled release profiles. This review deals with the potential applications of synthetic polymers mainly PLG polymers in delivery of vaccines and drugs.     

Development of hydrocortisone succinic acid/and 5-fluorouracil/chitosan microcapsules for oral and topical drug deliveries

Recently, we demonstrated the safety use of calendula oil/chitosan microcapsules as a carrier for both oral and topical deliveries. We also reported the improved biological activity towards skin cells and Staphylococcus aureus of phyllanthin containing chitosan microcapsules. However, the possibility of both oral and topical applications was still necessary to be further studied. Here we investigated that both oral and topical applications of chitosan-based microcapsules were tested using hydrocortisone succinic acid (HSA) and 5-fluorouracil (5-FU), respectively. The drug loading efficiency, particle size, surface morphology and chemical compositions of both drug loaded microcapsules were confirmed by UV-vis spectrophotometer, particle size analyzer, scanning electron microscope and Fourier transform infrared spectroscopy. The in vitro release studies revealed that both HSA and 5-FU could be released form chitosan microcapsules. The mean adrenocorticotropic hormone concentration in HSA loaded microcapsule mice plasma was detected to be lower than that of water control. One hundred micrograms per milliliter of 5-FU containing microcapsules exhibited a stronger growth inhibition towards skin keratinocytes than that of free 5-FU. In vitro drug delivery model demonstrated the delivery of 5-FU from microcapsule treated textiles into nude mice skin. Further uses of the drug loaded microcapsules may provide an efficiency deliverable tool for both oral and topical applications.     

The release dynamics of salicylic acid and tetracycline hydrochloride from the psyllium and polyacrylamide based hydrogels (II)

Psyllium, a medicinally active natural polysaccharide, has been modified with polyacrylamide to develop the hydrogels; those can act as the potential candidate for novel drug delivery systems. In the present studies, the release dynamics of model drugs (salicylic acid and tetracycline hydrochloride) from the drug-loaded hydrogels have been discussed, for the evaluation of the drug release mechanism and diffusion coefficients. It has been observed that diffusion exponent ‘n’ have 0.68 and 0.74 values and gel characteristic constant ‘k’ have 1.625 × 10⁻² and 1.272 × 10⁻² values, respectively, for the release of salicylic acid and tetracycline hydrochloride in distilled water from the drug loaded hydrogels. Therefore, drug release from the drug loaded hydrogels through Non-Fickian or Anomalous diffusion mechanism where the rate of drug diffusion and rate of polymer relaxation were comparable. The effect of pH on the release pattern of tetracycline has been studied by varying the pH of the release medium. However, in each release medium, the Initial diffusion coefficient was observed to be more than the late time diffusion coefficient.