New biodegradable polymers for injectable drug delivery systems.

Many biodegradable polymers were used for drug delivery and some are successful for human application. There remains fabrication problems, such as difficult processability and limited organic solvent and irreproducible drug release kinetics. New star-shaped block copolymers, of which the typical molecular architecture is presented, results from their distinct solution properties, thermal properties and morphology. Their unique physical properties are due to the three-dimensional, hyperbranched molecular architecture and influence microsphere fabrication, drug release and degradation profiles. We recently synthesized thermosensitive biodegradable hydrogel consisting of polyethylene oxide and poly(L-lactic acid). Aqueous solution of these copolymers with proper combination of molecular weights exhibit temperature-dependent reversible sol-gel transition. Desired molecular arrangements provide unique behavior that sol (at low temperature) form gel (at body temperature). The use of these two biodegradable polymers have great advantages for sustained injectable drug delivery systems. The formulation is simple, which is totally free of organic solvent. In sol or aqueous solution state of this polymer solubilized hydrophobic drugs prior to form gel matrix.     

N-sulfonato-N,O-carboxymethylchitosan: a novel polymeric absorption enhancer for the oral delivery of macromolecules.

Chitosan has been shown to act on the mucosal epithelial barriers mainly when protonated at acidic pH values in which it is soluble. Soluble chitosan is able to improve the permeation and absorption of neutral to cationic macromolecules only, as it forms polyelectrolyte complexes with anionic macromolecules. LMWH (Low Molecular Weight Heparin) is an anionic polysaccharide finding clinical application as an improved antithrombotic agent compared to Unfractionated Heparin (UFH). In this study we have employed N-sulfonato-N,O-carboxymethylchitosan (SNOCC) as a potential intestinal absorption enhancer of LMWH, Reviparin. SNOCC was prepared at 3 different viscosity grades 20, 40 and 60 cps and identified as SNOCC-20, SNOCC-40 and SNOCC-60, respectively. SNOCC materials were tested in vitro for their ability to decrease the Trans Epithelial Electrical Resistance (TEER) of Caco-2 cell monolayers. They were further tested as transport enhancers of hydrophilic compounds such as (14)C-mannitol, FITC-Dextran (MW 4400 Da) and Reviparin (LMWH). Solutions of Reviparin, with or without SNOCC, were administered intraduodenally in vivo in rats and the absorption of the drug was assessed by measuring the Anti-Xa levels in rat plasma. In vitro studies showed that SNOCC materials were able to induce a concentration dependent decrease in the TEER of the Caco-2 monolayers. SNOCC-40 and -60 were shown to decrease resistance more readily compared to the low viscosity SNOCC-20. (14)C-mannitol permeation data across intestinal epithelia were in agreement with the observed decrease in TEER; the higher viscosity SNOCC-60 was the most effective demonstrating a 51-fold enhancement of the permeation of the radiolabeled marker. Studies with both FITC-Dextran and Reviparin demonstrated significantly increased permeation across Caco-2 cell monolayers when they were co-incubated at the apical side of the monolayer. Intestinal absorption of Reviparin in rats was increased when it was co-administered with SNOCC-40 and -60, in agreement with in vitro data. Anti-Xa levels were elevated to and above the antithrombotic levels and were sustained for at least 6 h, giving an 18.5-fold increase in the AUC of LMWH in rats. In conclusion, SNOCC-40 and -60 have been shown to enhance both permeation and absorption of Reviparin across intestinal epithelia proving their potential as polymeric absorption enhancers.     

New polymers for drug delivery systems in orthopaedics: in vivo biocompatibility evaluation.

The use of biodegradable polymers for drug delivery systems excluded the need for a second operation to remove the carrier. However, the development of an avascular fibrous capsule, reducing drug release, has raised concern about these polymers in terms of tissue-implant reaction. Five novel polymers were evaluated in vivo after implantation in the rat dorsal subcutis and compared to the reference polycaprolactone (PCL). Poly(cyclohexyl-sebacate) (PCS), poly(L-lactide-b-1,5-dioxepan-2-one-b-L-lactide) (PLLA-PDXO-PLLA), two 3-hydroxybutyrate-co-3-hydroxyvalerate copolymers (D400G and D600G), and a poly(organo)phosphazene (POS-PheOEt:Imidazole) specimens were histologically evaluated in terms of the inflammatory tissue thickness and vascular density at 4 and 12 weeks from surgery. The highest values of inflammatory tissue thickness were observed in D600G (P < 0.01), PCS (P < 0.001) and PLLA-PDXO-PLLA (P < 0.001) at 4 weeks, while POP-PheOEt:Imidazole showed the lowest value of inflammatory tissue thickness (P < 0.05) at 12 weeks. D400G, D600G, PLLA-PDXO-PPLA and POP-PheOEt:Imidazole showed higher (P < 0.001) values of vascular density near the implants in comparison to PCL at 4 weeks. Finally, D400G and D600G increased their vessel densities while POP-PheOEt:Imidazole and the synthetic polyester PLLA-PDXO-PLLA presented similar vessel density values during experimental times. These different behaviours to improve neoangiogenesis without severe inflammatory tissue-responses could be further investigated with drugs in order to obtain time-programmable drug delivery systems for musculoskeletal therapy.     

Evaluation of bioadhesive polymers as delivery systems for nose to brain delivery: in vitro characterisation studies.

There is an increasing need for nasal drug delivery systems that could improve the efficiency of the direct nose to brain pathway especially for drugs for treatment of central nervous system disorders. Novel approaches that are able to combine active targeting of a formulation to the olfactory region with controlled release bioadhesive characteristics, for maintaining the drug on the absorption site are suggested. If necessary an absorption enhancer could be incorporated. Low methylated pectins have been shown to gel and be retained in the nasal cavity after deposition. Chitosan is known to be bioadhesive and also to work as an absorption enhancer. Consequently, two types of pectins, LM-5 and LM-12, together with chitosan G210, were selected for characterisation in terms of molecular weight, gelling ability and viscosity. Furthermore, studies on the in vitro release of model drugs from candidate formulations and the transport of drugs across MDCK1 cell monolayers in the presence of pectin and chitosan were also performed. Bioadhesive formulations providing controlled release with increased or decreased epithelial transport were developed. Due to their promising characteristics 3% LM-5, 1% LM-12 pectin and 1% chitosan G210 formulations were selected for further biological evaluation in animal models.     

Oral delivery of macromolecules using intestinal patches: applications for insulin delivery.

Oral drug delivery, though attractive compared to injections, cannot be utilized for the administration of peptides and proteins due to poor epithelial permeability and proteolytic degradation within the gastrointestinal tract. A novel method is described that utilizes mucoadhesive intestinal patches to deliver therapeutic doses of insulin into systemic circulation. Intestinal patches localize insulin near the mucosa and protect it from proteolytic degradation. In vitro experiments confirmed the secure adhesion of patches to the intestine and the release of insulin from the patches. In vivo experiments performed via jejunal administration showed that intestinal insulin patches with doses in the range of 1-10 U/kg induced dose-dependent hypoglycemia in normal rats with a maximum drop in blood glucose levels of 75% observed at a dose of 10 U/kg. These studies demonstrate that reduction in blood glucose levels comparable to that induced by subcutaneous injections can be achieved via enteral insulin absorption with doses only 2-10-fold higher than subcutaneous doses.     

Floating drug delivery systems: an approach to oral controlled drug delivery via gastric retention.

In recent years scientific and technological advancements have been made in the research and development of rate-controlled oral drug delivery systems by overcoming physiological adversities, such as short gastric residence times (GRT) and unpredictable gastric emptying times (GET). Several approaches are currently utilized in the prolongation of the GRT, including floating drug delivery systems (FDDS), also known as hydrodynamically balanced systems (HBS), swelling and expanding systems, polymeric bioadhesive systems, modified-shape systems, high-density systems, and other delayed gastric emptying devices. In this review, the current technological developments of FDDS including patented delivery systems and marketed products, and their advantages and future potential for oral controlled drug delivery are discussed.     

Acetaldehyde-modified-cystine functionalized Zr-MOFs for pH/GSH dual-responsive drug delivery and selective visualization of GSH in living cells

In recent years, the construction of drug carriers that integrate diagnosis and treatment has become a new trend. In this article, a metal–organic framework (Zr-MOF) was synthesized and functionalized using acetaldehyde-modified-cystine (AMC) to form the functional drug carrier Zr-MOF/AMC which could be used to determine the concentration of glutathione (GSH) for cancer diagnosis, and to achieve pH/GSH dual-responsive release of methotrexate (MTX) for cancer therapy. The cleavage of the AMC disulfide bond by GSH generates two fluorescent molecules that produce strongly enhanced fluorescence, and the intensity is proportional to the GSH concentration. The green fluorescence of Zr-MOF/AMC in cancer cells proves that it can be applied in cell imaging to detect abnormal GSH concentrations for early diagnosis. In addition, MTX loaded on the Zr-MOF/AMC is released by the cleavage of the –S–S– and –C N– bonds at the high GSH concentration and low pH in cancer cells. This dual-responsive drug release helps to deliver drugs to cancer cells more precisely. All the experiments suggest that this novel type of pH/GSH dual-responsive Zr-MOF/AMC nanoparticle may serve as a new drug delivery system for cancer diagnosis and treatment.

In recent years, the construction of drug carriers that integrate diagnosis and treatment has become a new trend.     

Novel delivery systems: oral transmucosal and intranasal transmucosal

During the past 2 decades, anesthesiologists have been provided with a number of new, potent opioid analgesics and sedative/hypnotics, as well as an increased understanding of the pharmacokinetic and pharmacodynamic principles that govern their action and disposition. These developments have suggested that the skin and the buccal and nasal mucous membranes may have use as alternate routes of analgesic and anesthetic drug delivery. A novel transmucosal delivery system for fentanyl has recently been developed by incorporating the drug into a dissolvable matrix on a stick called an "oralete." Oral transmucosal fentanyl citrate has been evaluated as a premedication in the pediatric population and as an analgesicfor acute postoperative and emergency room pain, procedural pain, and breakthrough cancer pain by using fentanyl. Increases in plasma fentanyl and onset of clinical effect are rapid (20-40 min) with this formulation. A potential advantage is the apparent ease of titration to a sedative or analgesic end point. This system may improve premedication, acute postoperative analgesia, and chronic pain therapy in various clinical settings. Delivery of opioids through the nasal mucosa also has been recently investigated. In one study, sufentanil was administered (1.5, 3.0, or 4.5 mu/kg) to 80 children ranging in age from 6 mo to 7yr. Easy separation from parents was achieved in 86% of the children 10 min following administration of the premedication. Unfortunately, 61% of the children cried after drug administration, and side effects included reduced ventilatory compliance (chest-wall rigidity) with higher doses (3.0 and 4.5 microg/kg). Nevertheless, nasal transmucosal drug delivery may have value, especially in frightened or uncooperative children.     

Nanotechnological approaches for the delivery of macromolecules.

In this overview, novel approaches are described for the controlled release and/or for the targeted delivery of macromolecules such as proteins and DNA. The building stones of these highly complex systems are (phospho)lipids and/or (biodegradable) polymers. They should be carefully chosen and preparation protocols should be rationally designed to maximize chances for success.     

Thiolated chitosans: development and in vitro evaluation of a mucoadhesive, permeation enhancing oral drug delivery system.

It was the aim of this study to develop a mucoadhesive, permeation enhancing delivery system for orally administered poorly absorbed drugs. Chitosan was modified by the immobilisation of thiol groups utilising 2-iminothiolane (Traut's reagent). The permeation enhancing effect of the resulting chitosan-4-thio-butylamidine conjugate (chitosan-TBA conjugate) in combination with the permeation mediator glutathione (GSH) was evaluated in Ussing chambers on freshly excised small intestinal mucosa from guinea pigs using rhodamine 123 as marker for passive drug uptake. The mucoadhesive properties of the chitosan-TBA conjugate adjusted to pH 3, 5 and 7 were evaluated via the rotating cylinder method and via tensile studies. Release studies were performed with tablets comprising 10% cefadroxil used as model drug, 10% GSH and 80% chitosan-TBA conjugate pH 3 in 100 mM phosphate buffer pH 6.8 at 37 degrees C. Results showed a 3-fold higher permeation enhancing effect of the chitosan-TBA conjugate/GSH system in comparison to unmodified chitosan. Mucoadhesion studies revealed that the lower the pH of the thiolated chitosan is, the higher are its mucoadhesive properties. Release studies showed a sustained release of both cefadroxil and GSH over several hours. This delivery system might represent a promising novel tool in order to improve the therapeutic efficacy of various drugs which are poorly absorbed from the gastrointestinal tract.     

Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs.

The oral delivery of hydrophobic drugs presents a major challenge because of the low aqueous solubility of such compounds. Self-emulsifying drug delivery systems (SEDDS), which are isotropic mixtures of oils, surfactants, solvents and co-solvents/surfactants, can be used for the design of formulations in order to improve the oral absorption of highly lipophilic drug compounds. SEDDS can be orally administered in soft or hard gelatin capsules and form fine relatively stable oil-in-water (o/w) emulsions upon aqueous dilution owing to the gentle agitation of the gastrointestinal fluids. The efficiency of oral absorption of the drug compound from the SEDDS depends on many formulation-related parameters, such as surfactant concentration, oil/surfactant ratio, polarity of the emulsion, droplet size and charge, all of which in essence determine the self-emulsification ability. Thus, only very specific pharmaceutical excipient combinations will lead to efficient self-emulsifying systems. Although many studies have been carried out, there are few drug products on the pharmaceutical market formulated as SEDDS confirming the difficulty of formulating hydrophobic drug compounds into such formulations. At present, there are four drug products, Sandimmune and Sandimmun Neoral (cyclosporin A), Norvir (ritonavir), and Fortovase (saquinavir) on the pharmaceutical market, the active compounds of which have been formulated into specific SEDDS. Significant improvement in the oral bioavailability of these drug compounds has been demonstrated for each case. The fact that almost 40% of the new drug compounds are hydrophobic in nature implies that studies with SEDDS will continue, and more drug compounds formulated as SEDDS will reach the pharmaceutical market in the future.     

Improved intestinal absorption of sulpiride in rats with synchronized oral delivery systems.

The goals of this study were to examine whether formulations, capable of releasing sulpiride (SP) in synchrony with the p-Glycoprotein (P-gp) inhibitors, verapamil (Ver) or quinidine (Qn) can increase SP relative bioavailability and to suggest a rationale approach for oral administration of SP. Jejunum of anesthetized rats was perfused with 200 or 400 microg/ml of SP either alone or together with 98 microg/ml of Ver. It was observed that while an increasing SP concentration did not cause an increase in SP blood levels, the addition of Ver or Qn to the perfusion solution caused a profound increase in SP absorption. Erodible matrix tablets, exhibiting a range of erosion rates, were prepared by manipulating the ratios of hydroxypropylmethylcellulose (HPMC) in the matrices. The tablets were designed to release the low water soluble SP and the highly water soluble Qn concomitantly over 1, 2 or 4 h. In all cases, the synchronous release increased SP bioavailability after intra-intestinal administration. The increase varied from 2.6- to 3.9-fold for the fast and the slow release formulations, respectively (compared with a control administration of a powdered mixture of SP and Qn). It is speculated that the poor oral bioavailability of SP was caused by brush border P-gp efflux. Synchronous release delivery systems of SP containing also the P-gp inhibitor Qn were able to increase SP bioavailability after intestinal administration in the rat. It is concluded that oral bioavailability of poorly absorbed drugs, in which absorption is restricted by gut wall secretory transport, may be improved by formulating them with functional adjuvants in synchronous release drug carriers.     

Formulation aspects in the development of osmotically controlled oral drug delivery systems.

Osmotically controlled oral drug delivery systems utilize osmotic pressure for controlled delivery of active agent(s). Drug delivery from these systems, to a large extent, is independent of the physiological factors of the gastrointestinal tract and these systems can be utilized for systemic as well as targeted delivery of drugs. The release of drug(s) from osmotic systems is governed by various formulation factors such as solubility and osmotic pressure of the core component(s), size of the delivery orifice, and nature of the rate-controlling membrane. By optimizing formulation and processing factors, it is possible to develop osmotic systems to deliver drugs of diverse nature at a pre-programmed rate. In the present review, different types of oral osmotic systems, various aspects governing drug release from these systems, and critical formulation factors are discussed.     

Chitosan delivery systems for the treatment of oral mucositis: in vitro and in vivo studies.

Oral mucositis is a frequent and potentially severe complication of radiation or chemotherapy for cancer. Associated with atrophy and ulceration of the oral mucosa is an increased risk of infection, and the most common pathogenic agent is Candida. Chitosan is an excellent candidate for the treatment of oral mucositis. Its bioadhesive and antimicrobial properties offer the palliative effects of an occlusive dressing and the potential for delivering drugs, including anti-candidal agents. The aim of this study was to develop an occlusive bioadhesive system for prophylaxis and/or treatment of oral mucositis. Gel and film formulations were prepared using chitosans at different molecular weights and in different solvents. Nystatin, which is considered as a prophylactic agent for oral mucositis was incorporated into the formulations. The in vitro release of nystatin from the formulations was decreased with the increasing molecular weight of chitosan. The effect of the formulations was investigated in vivo in hamsters with chemotherapy-induced mucositis. Mucositis scores in groups treated with nystatin incorporated into gel and suspension formulations were significantly lower (p < 0.05) than those treated with the chitosan gel alone. Survival of animals in the treated groups was higher than that in the control group. The retention time and distribution of the gels in the oral cavity were investigated in healthy volunteers. A faster distribution of nystatin in the oral cavity was obtained using the suspension compared to the gels, but the nystatin saliva level decreased rapidly as well. A drug concentration above the minimum inhibitory concentration (MIC) value for Candida albicans (0.14 microg/ml) was maintained for longer periods of time at the application site (90 min) than at the contralateral site (45 min) in the oral cavity.     

Nanoparticles as potential oral delivery systems of proteins and vaccines: a mechanistic approach.

Peptides and proteins remain poorly bioavailable upon oral administration. One of the most promising strategies to improve their oral delivery relies on their association with colloidal carriers, e.g. polymeric nanoparticles, stable in gastrointestinal tract, protective for encapsulated substances and able to modulate physicochemical characteristics, drug release and biological behavior. The mechanisms of transport of these nanoparticles across intestinal mucosa are reviewed. In particular, the influence of size and surface properties on their non-specific uptake or their targeted uptake by enterocytes and/or M cells is discussed. Enhancement of their uptake by appropriate cells, i.e. M cells by (i) modeling surface properties to optimize access to and transport by M cells (ii) identifying surface markers specific to human M cell allowing targeting to M cells and nanoparticles transcytosis is illustrated. Encouraging results upon in vivo testing are reported but low bioavailability and lack of control on absorbed dose slow down products development. Vaccines are certainly the most promising applications for orally delivered nanoparticles.     

Water soluble polymers in tumor targeted delivery.

The rationales for the use of water soluble polymers for anticancer drug delivery include: the potential to overcome some forms of multidrug resistance, preferential accumulation in solid tumors due to enhanced permeability and retention (EPR) effect, biorecognizability, and targetability. The utility of a novel paradigm for the treatment of ovarian carcinoma in an experimental animal model, which combines chemotherapy and photodynamic therapy with polymer-bound anticancer drugs is explained. Research and clinical applications as well as directions for the future development of macromolecular therapeutics are discussed.     

The quest for non-invasive delivery of bioactive macromolecules: a focus on heparins.

The development of a non-invasive drug delivery system for unfractionated heparin (UFH) and low molecular weight heparins (LMWHs) has been the elusive goal of several research groups since the initial discovery of this glycosaminogylcan by McLean in 1916. After a brief update on current parenteral formulations of UFH and LMWHs, this review revisits past and current strategies intended to identify alternative routes of administration (e.g. oral, sublingual, rectal, nasal, pulmonary and transdermal). The following strategies have been used to improve the bioavailability of this bioactive macromolecule by various routes: (i) enhancement in cell-membrane permeabilization, (ii) modification of the tight-junctions, (iii) increase in lipophilicity and (iv) protection against acidic pH of the stomach. Regardless of the route of administration, a simplified unifying principle for successful non-invasive macromolecular drug delivery may be: "to reversibly overcome the biological, biophysical and biochemical barriers and to safely and efficiently improve the in vivo spatial and temporal control of the drug in order to achieve a clinically acceptable therapeutic advantage". Future macromolecular drug delivery research should embrace a more systemic approach taking into account recent advances in genomics/proteomics and nanotechnology.     

Setting bioequivalence requirements for drug development based on preclinical data: optimizing oral drug delivery systems.

The recently proposed Biopharmaceutics Classification System can be used to classify drugs and set standards for scale-up and post-approval changes as well as standards for in vitro/in vivo correlation for immediate and controlled release products. This classification scheme is based on determining the underlying process that is controlling the drug absorption rate and extent, namely, drug solubility and intestinal membrane permeability. Theoretical analysis and experimental results suggest that a permeability/solubility classification scheme can be used to set more rationale drug standards. In particular, high solubility/high permeability, rapidly dissolving drugs may be regulated on the basis of a single point rapid dissolution test while low solubility dissolution rate limited drugs can be regulated based on an in vitro dissolution test that reflects the in vivo dissolution process. This dissolution test may include multiple time points, media change, as well as surfactants in order to reflect the in vivo dissolution process and would be used by the manufacturer for requesting a waiver from a bioequivalence (BE) trial. For controlled release products, the regulation of bioequivalence standards is more complex due to the potential differences in position-dependent permeability/solubility and metabolism of drugs along the gastrointestinal tract. These differences may result in drug absorption rates that are highly transit time dependent. This paper will present the current status of the biopharmaceutic drug classification scheme, the underlying developed data base and its application to optimizing IR and CR products.     

Programmable delivery of hydrophilic drug using dually responsive hydrogel cages.

Micro-capsules normally encapsulate therapeutic agents only inside their cavities. In this paper, we report on the synthesis of dually responsive poly(N-isopropylacrylamide) (PNiPAM)-co-acrylic acid (AA) hydrogel cages sub-micrometer in size and the use of these cages as drug carriers. The cavity structure of the cages can enhance volume phase transition compared to solid gel particles, thus favoring drug loading and release. TEM images and FT-IR spectra confirmed that the model drug isoniazid (INH) is located in two regions: within the shell and inside the cavity of the cages. The drugs residing in the shell can form hydrogen bonds with the cage matrix, while the drugs in the cavity are interaction free with the carrier. This difference from the residency of drugs exploited to a structure induced drug release which was programmable controlled by external pH and temperature. In vitro drug release studies showed that in a neutral medium (pH=7.4), major drugs were preserved within the shell, while in an acidic medium (pH=1.2), nearly all of the drugs were released due to the dissociation of hydrogen bonds.