Ionic liquids in transdermal drug delivery system: Current applications and future perspectives

The transdermal drug delivery(TDD) shows considerable advantages over other administration pathways.However, conventional enhancing permeation methods face a series of challenges owing to barrier function provided by the skin, of which enhancing abilities either are so strong that it results in toxicity and irritation, or too weak to achieve desirable therapeutical effects. To address these issues, it is an urgent need to develop a novel method to overcome the limitations of current measures. Fo...     

Synthesis and Characterization of Novel Amphiphilic Polymers as Drug Delivery Nano Carriers

Polymer nano-particles have been widely investigated in the last decade due to a variety of potential applications. In particular, polymers which can self assemble into micellar nano-particles can be effectively used as vehicles for drug delivery. Considerable efforts are underway to develop better drug delivery nano carriers for high drug loading capacity for a wide variety of bioactive compounds. In this study, several new polymers were synthesized in bulk (solventless condition) by a chemo-enzymatic methodology using Candida antarctica lipase B (Novozyme 435) and molecular sieves (MS). The synthesized polymers demonstrated high drug loading capacity and the potential to encapsulate drugs which are poorly soluble in aqueous solvents.     

Molecular Simulation and Statistical Learning Methods toward Predicting Drug–Polymer Amorphous Solid Dispersion Miscibility,Stability, and Formulation Design

Amorphous solid dispersions (ASDs) have emerged as widespread formulations for drug delivery of poorly soluble active pharmaceutical ingredients (APIs). Predicting the API solubility with various carriers in the API–carrier mixture and the principal API–carrier non-bonding interactions are critical factors for rational drug development and formulation decisions. Experimental determination of these interactions, solubility, and dissolution mechanisms is time-consuming, costly, and reliant on trial and error. To that end, molecular modeling has been applied to simulate ASD properties and mechanisms. Quantum mechanical methods elucidate the strength of API–carrier non-bonding interactions, while molecular dynamics simulations model and predict ASD physical stability, solubility, and dissolution mechanisms. Statistical learning models have been recently applied to the prediction of a variety of drug formulation properties and show immense potential for continued application in the understanding and prediction of ASD solubility. Continued theoretical progress and computational applications will accelerate lead compound development before clinical trials. This article reviews in silico research for the rational formulation design of low-solubility drugs. Pertinent theoretical groundwork is presented, modeling applications and limitations are discussed, and the prospective clinical benefits of accelerated ASD formulation are envisioned.     

Prospects of Curcumin Nanoformulations in Cancer Management

There is increasing interest in the use of natural compounds with beneficial pharmacological effects for managing diseases. Curcumin (CUR) is a phytochemical that is reportedly effective against some cancers through its ability to regulate signaling pathways and protein expression in cancer development and progression. Unfortunately, its use is limited due to its hydrophobicity, low bioavailability, chemical instability, photodegradation, and fast metabolism. Nanoparticles (NPs) are drug delivery systems that can increase the bioavailability of hydrophobic drugs and improve drug targeting to cancer cells via different mechanisms and formulation techniques. In this review, we have discussed various CUR-NPs that have been evaluated for their potential use in treating cancers. Formulations reviewed include lipid, gold, zinc oxide, magnetic, polymeric, and silica NPs, as well as micelles, dendrimers, nanogels, cyclodextrin complexes, and liposomes, with an emphasis on their formulation and characteristics. CUR incorporation into the NPs enhanced its pharmaceutical and therapeutic significance with respect to solubility, absorption, bioavailability, stability, plasma half-life, targeted delivery, and anticancer effect. Our review shows that several CUR-NPs have promising anticancer activity; however, clinical reports on them are limited. We believe that clinical trials must be conducted on CUR-NPs to ensure their effective translation into clinical applications.     

DNA纳米结构在药物转运载体和智能载药中的应用进展

纳米材料具有荷载效率高、靶向性能好、半衰期较长等优点, 非常适于作为药物转运载体, 可有效提高药物的水溶性、稳定性和疾病治疗效果.目前, 开发具有良好生物相容性、可控靶向释放能力和精确载药位点的理想药物转运载体, 仍是该领域存在的挑战性问题和当前研究的重点.自组装DNA纳米结构是一类具有精确结构、功能多样的纳米生物材料, 具有良好的生物相容性和稳定性、较高的膜渗透性和可控靶向释放能力等优点, 是理想的药物转运载体和智能载药材料.本文总结了DNA纳米结构的发展历程、DNA纳米结构作为药物转运载体的研究现状、动态DNA纳米结构在智能载药中的应用进展, 并对其发展前景进行了展望.     

Ocular Delivery of Polyphenols: Meeting the Unmet Needs

Nature has become one of the main sources of exploration for researchers that search for new potential molecules to be used in therapy. Polyphenols are emerging as a class of compounds that have attracted the attention of pharmaceutical and biomedical scientists. Thanks to their structural peculiarities, polyphenolic compounds are characterized as good scavengers of free radical species. This, among other medicinal effects, permits them to interfere with different molecular pathways that are involved in the inflammatory process. Unfortunately, many compounds of this class possess low solubility in aqueous solvents and low stability. Ocular pathologies are spread worldwide. It is estimated that every individual at least once in their lifetime experiences some kind of eye disorder. Oxidative stress or inflammatory processes are the basic etiological mechanisms of many ocular pathologies. A variety of polyphenolic compounds have been proved to be efficient in suppressing some of the indicators of these pathologies in in vitro and in vivo models. Further application of polyphenolic compounds in ocular therapy lacks an adequate formulation approach. Therefore, more emphasis should be put in advanced delivery strategies that will overcome the limits of the delivery site as well as the ones related to the polyphenols in use. This review analyzes different drug delivery strategies that are employed for the formulation of polyphenolic compounds when used to treat ocular pathologies related to oxidative stress and inflammation.     

Stable Polymer Nanoparticles with Exceptionally High Drug Loading by Sequential Nanoprecipitation

Poor solubility often leads to low drug efficacy. Encapsulation of water‐insoluble drugs in polymeric nanoparticles offers a solution. However, low drug loading remains a critical challenge. Now, a simple and robust sequential nanoprecipitation technology is used to produce stable drug‐core polymer‐shell nanoparticles with high drug loading (up to 58.5 %) from a wide range of polymers and drugs. This technology is based on tuning the precipitation time of drugs and polymers using a solvent system comprising multiple organic solvents, which allows the formation of drug nanoparticles first followed by immediate precipitation of one or two polymers. This technology offers a new strategy to manufacture polymeric nanoparticles with high drug loading having good long‐term stability and programmed release and opens a unique opportunity for drug delivery applications.     

Nano-formulations for transdermal drug delivery: A review

The different applications of nano-formulations (vesicles or nanoparticles and nanoemulsions) have been widely studied. Here, the classification, characteristics, transdermal mechanism, and application of the most popular nano-formulations in transdermal drug delivery system are reviewed.     

Novel PEGylated Amphiphilic Copolymers as Nanocarriers for Drug Delivery: Synthesis,Characterization and Curcumin Encapsulation

Amphiphilic polymers can self assemble into micellar nano-particles and can be effectively used as nano carriers for drug delivery. A number of macromolecular delivery systems are under investigation to improve the efficacy of prospective drugs. In this study, seven new co-polymers were synthesized under mild reaction conditions in bulk (without solvent) by chemoenzymatic approach using Candida antarctica lipase (Novozyme 435) and molecular sieves, subsequently these polymers were treated with different long chain bromoalkanes and acid chlorides for attachment of the lipophilic moieties to the backbone polymer via an ether or an ester linkage, respectively in order to make them amphiphilic. These synthesized nano-particles demonstrated high drug loading capacity and have the potential to encapsulate hydrophobic drugs.     

Cyclodextrin Complexed Generic Drugs are Generally not Bio-equivalent with the Reference Products: Therefore the Increase in Number of Marketed Drug/Cyclodextrin Formulations is so Slow

Taking into consideration the numerous advantages of the cyclodextrin (CD) complexation of drugs, it is not evident why are not approved and marketed many more long known (generic) drugs in CD-complexed form. The price and approval status of the CDs is not any more a serious restricting factor for their use. The crucial problem is, that for approval of any new formulation of a known (generic) drug a bioequivalence test has to be performed. A CD-formulated drug is practically never bioequivalent with the reference product (the old, earlier approved formulation), but significantly better, results in improved solubility, faster and more complete absorption, in enhanced biological activity, etc. The average increase of AUC values of 35 orally (or sublingually) administered drug/CD complexes (as compared with the plain drug, or its classical formulation, of course at identical drug doses) in different species (human, rat, rabbit, dog, pig) is 1.81 ± 0.53 fold, the average increase in c _max of 26 drugs is 1.71 ± 0.47 fold, attained in an 0.55-fold shorter time after oral administration. The CD-formulated drug will not be a simple generic but a ‘super generic’ drug¹. In this case the authorities are requesting the repetition of the largest part of the long lasting and very costly clinical studies. This is why the costs of development will be nearly as high as in case of an original drug, nevertheless its market generally will be considerably narrower. If it is acceptable that, the absorption of a drug (in reduced dose!) from its CD-complex is faster than from its original formulation (lower T _max ) then a simple Clinical I. phase should have to be satisfying for the regulatory authorities. All deviation between the pharmacological effect of the original formulation and the CD-formulated drug is resulted by the quicker and more complete absorption of the last one. No any further significant change in pharmacodynamics or therapeutic effect of the drug might arise in consequence of the CD complexation.Deceased.When the patents and other exclusivities for an original drug are expired (both for the chemical entity as well as for its approved formulation), a clone of this drug (generally produced and marketed by other companies) is called a “generic drug” (or commodity generic). It must be a perfect copy of the original, must contain the same active ingredient (amount, dose unit), formulation (tablet or injectable or liquid, etc.), containing the same vehicles, must perform identical dissolution, stability, biological absorption and effectivity. If the formulation (other ingredients) or the route of delivery (e.g. injection instead of tablet) are different, then this drug is not a simple (generic) but is called a ‘specialty generic’ or ‘super generic’. If a drug (a well known, long used one) in form of a CD-complex is incorporated into a new formulation, it is not a generic. It seems to be evident to consider a CD-complex containing drug formulation as a ‘super generic’ – except of course those cases when the drug substance is itself an original drug.This revised version was published online in July 2005 with a corrected issue number.     

Factors Contributing to Solubility Synergism of Some Basic Drugs with β-Cyclodextrin in Ternary Molecular Complexes

Ternary complexes exploiting solubility synergism (SSn) between basic drugs and β-cyclodextrin (β-CD) in the presence of an organic hydoxy acid have been reported to provide the pharmaceutical technology with highly soluble ternary complexes, even with the least soluble β-CD. In this work, phase solubility techniques were used to study factors affecting SSn in aqueous solution, which may help in understanding the mechanism involved in ternary complex formation in solution, under equilibrium conditions. The equilibrium solubility of both β-CD and each of 8 structurally unrelated drugs were measured in tandem in the presence of different acid types at low and high pHs, and at different time intervals over a period of 1–40 days. The results indicate that SSn is evident regardless of acid type (organic and inorganic) at low pH, but the extent of SSn is acid type dependant and is limited by the drug salt solubility product constant (pK _sp). Among different drugs, no apparent trend exists between drug salt solubility and the extent of SSn, but lowering drug salt solubility by increasing pH depresses SSn. The results also reveal no apparent trend between the magnitude of the complex formation constant (K _ij) and SSn. For example, drugs of low K _ij values such as astemizole, cisapride and sildenafil do not show any SSn, yet ketotifen and pizotifen, which also have low K _ij values, exhibit substantial SSn. However, the solublizing power of β-CD represented by the slope of phase solubility diagram can be used as a marker for SSn (slopes exceeding 0.4 induce SSn).     

Gelation characteristics and applications of poly(ethylene glycol) end capped with hydrophobic biodegradable dipeptides

Poly(ethylene glycol) (PEG) end capped with biodegradable hydrophobic dipeptides shows versatile gelation behavior in a wide range of aqueous and organic solvents. This gelation characteristic is attributed to the aggregation of polymer chains induced by dipeptide end groups. Both PEG molecular weight and molecular structure of end groups control this aggregation by striking a balance between two opposing molecular interactions: solubility of the PEG segment which tends to dissolve the polymer while hydrophobic and intermolecular noncovalent interactions between the end groups induce aggregation. Morphologically, this aggregated structure forms interpenetrating nano sheets with characteristic microstructural features. These gels are biodegradable and possess physicomechanical characteristics suitable for biomedical applications. Furthermore, proteins and hydrophobic model drugs can be encapsulated within the gels from aqueous and organic solvents, respectively, and can be released in a controlled fashion which indicates the applicability of the gels as drug delivery vehicles. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 1917–1928     

Skin permeability of water-soluble drugs

The permeabilities of several water-soluble drugs through excised hairless rat skin from their aqueous suspensions were investigated by using newly designed two-chamber diffusion cells. Disodium cromoglycate, diclofenac sodium, dopamine hydrochloride, isoproterenol hydrochloride, diltiazem hydrochloride and papaverine hydrochloride were selected as water-soluble drugs. Indomethacin, a lipophilic drug, and deuterium oxide (D2O) were used for comparison. The skin permeability coefficients of these water-soluble drugs were 100--1000 times lower than that of indomethacin. Since these drugs have high solubility in the donor solution (distilled water or lactate buffer), however, the skin permeation rates, which are in general proportional to the product of skin permeability coefficient and solubility of drugs in the drug-donor compartment, were comparable to or higher than that of indomethacin (1.7 micrograms/cm2/h): the skin permeation rate of dopamine hydrochloride (458 micrograms/cm2/h) was about 300 times higher than that of indomethacin. The water-soluble drugs with lower molecular weight and higher solubility in water showed higher skin permeation rates. These results suggest that some water-soluble drugs with low molecular weight and high solubility in water might be good candidates for transdermal drug delivery.     

The effect of solvent composition on vancomycin hydrochloride and free base vancomycin release from in situ forming implants

In situ forming drug delivery systems that are formed by solvent‐induced phase inversion have attracted extensive attention in sustained delivery of peptides and proteins. Based on the findings of our previous studies, N‐methyl‐2‐pyrrolidone (NMP) and acetone are two solvents that could improve the release profile of vancomycin from in situ forming systems based on poly(D,L‐lactide‐co‐glycolic acid). In this study, the effect of different compositions of these solvents on the release profile of hydrochloride and free base forms of vancomycin was investigated. To this end, several formulations with vancomycin (either hydrochloride or free base form) and different proportions of NMP and acetone were prepared. The cumulative drug release at specified time was determined and tested against conventional kinetic models. The surface and cross‐sectional morphology of implants were investigated by SEM. The experimental results showed that as solvent composition changed, the amount of vancomycin release during the first 12 h changed, too. The use of free base vancomycin resulted in an extended vancomycin release profile with less initial burst release. The formulation containing free base vancomycin and mixed solvents of acetone and NMP in 2:1 ratio released 70% of loaded drug in 6 weeks with near zero‐order kinetic. The best kinetic model to fit the in vitro release profiles was found to be Peppas–Sahlin model. Copyright © 2016 John Wiley & Sons, Ltd.     

Solubility enhancement of ibuprofen using tri-ureasil-PPO hybrid: structural,cytotoxic, and drug release investigation

Herein, we used tri-ureasil organic–inorganic hybrid material (tU5000) in order to enhance the solubility of nonsteroidal anti-inflammatory drugs and fine tuning the drug delivery profile. For the first time, we used tU5000 as a film-forming agent in order to provide an alternative vehicle for transdermal drug delivery systems which the cell viability of practically 100 % for the highest and the lowest tested concentrations of pure tU5000 indicated that the material was not cytotoxic. The physicochemical properties of the tU5000 drug carrier and drug-loaded hybrids were systematically studied using powder X-ray diffraction, differential scanning calorimetry, small-angle X-ray scattering, and Fourier-transform infrared spectroscopy. The structural changes of tU5000 as well as the relationships between the drug content and in vitro drug release behaviors were investigated. The results showed that the ibu molecules were homogeneously distributed in the tU5000 xerogels contributing to fine-tuning the drug delivery profile. Considering the ability to incorporated high drug content, simple and mild preparation procedure by one-pot sol–gel route, high stability of the materials, sustained-release property, this class of hybrid based on polymers and inorganic compounds may have potential applications in the design of pharmaceutical formulation as ophthalmic (contact lenses), transdermal (patches) and implantable (soft tissue) drug delivery systems.     

Polyurethanes as Carriers of Antitumorous Drugs

Drug delivery systems on a polyurethane base with various antitumorous drugs, such as cyclophosphane, thiophosphamide and vincristine, have been prepared. An in vitro technique was used to determine the release characteristics of the drugs into model biological media. It was shown the drug release occurs in accordance with first-order kinetics, as well a maximum degree for the drug loading were studied. The thermodynamic parameters of drug release has been determined. It was illustrated that the activation energies were 4.3, 3.9 and 3.2 kcal/mole for cyclophosphane, thiophosphamide and vincristine respectively, corresponding to a diffuse-controlled mechanism of release. © 1998 John Wiley & Sons, Ltd.     

Supersaturation-Based Drug Delivery Systems: Strategy for Bioavailability Enhancement of Poorly Water-Soluble Drugs

At present, the majority of APIs synthesized today remain challenging tasks for formulation development. Many technologies are being utilized or explored for enhancing solubility, such as chemical modification, novel drug delivery systems (microemulsions, nanoparticles, liposomes, etc.), salt formation, and many more. One promising avenue attaining attention presently is supersaturated drug delivery systems. When exposed to gastrointestinal fluids, drug concentration exceeds equilibrium solubility and a supersaturation state is maintained long enough to be absorbed, enhancing bioavailability. In this review, the latest developments in supersaturated drug delivery systems are addressed in depth.     

Synthesis and characterization of a multiarm poly(acrylic acid) star polymer for application in sustained delivery of cisplatin and a nitric oxide prodrug

Functionalized polymeric nanocarriers have been recognized as drug delivery platforms for delivering therapeutic concentrations of chemotherapies. Of this category, star‐shaped multiarm polymers are emerging candidates for targeted delivery of anticancer drugs, due to their compact structure, narrow size distribution, large surface area, and high water solubility. In this study, we synthesized a multiarm poly(acrylic acid) star polymer via macromolecular design via the interchange (MADIX)/reversible addition fragmentation chain transfer (MADIX/RAFT) polymerization and characterized it using nuclear magnetic resonance (NMR) and size exclusion chromatography. The poly(acrylic acid) star polymer demonstrated excellent water solubility and extremely low viscosity, making it highly suited for targeted drug delivery. Subsequently, we selected a hydrophilic drug, cisplatin, and a hydrophobic nitric oxide (NO)‐donating prodrug, O²‐(2,4‐dinitrophenyl) 1‐[4‐(2‐hydroxy)ethyl]‐3‐methylpiperazin‐1‐yl]diazen‐1‐ium‐1,2‐diolate, as two model compounds to evaluate the feasibility of using poly(acrylic acid) star polymers for the delivery of chemotherapeutics. After synthesizing and characterizing two poly(acrylic acid) star polymer‐based nanoconjugates, poly(acrylic acid)–cisplatin (acid–Pt) and poly(acrylic acid–NO (acid–NO) prodrug, the in vitro drug release kinetics of both the acid–Pt and the acid–NO were determined at physiological conditions. In summary, we have designed and evaluated a polymeric nanocarrier for sustained‐delivery of chemotherapies, either as a single treatment or a combination therapy regimen. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Multistimuli‐Responsive Bilirubin Nanoparticles for Anticancer Therapy

Although stimuli‐responsive materials hold potential for use as drug‐delivery carriers for treating cancers, their clinical translation has been limited. Ideally, materials used for the purpose should be biocompatible and nontoxic, provide “on‐demand” drug release in response to internal or external stimuli, allow large‐scale manufacturing, and exhibit intrinsic anticancer efficacy. We present multistimuli‐responsive nanoparticles formed from bilirubin, a potent endogenous antioxidant that possesses intrinsic anticancer and anti‐inflammatory activity. Exposure of the bilirubin nanoparticles (BRNPs) to either reactive oxygen species (ROS) or external laser light causes rapid disruption of the BRNP nanostructure as a result of a switch in bilirubin solubility, thereby releasing encapsulated drugs. In a xenograft tumor model, BRNPs loaded with the anticancer drug doxorubicin (DOX@BRNPs), when combined with laser irradiation of 650 nm, significantly inhibited tumor growth. This study suggests that BRNPs may be used as a drug‐delivery carrier as well as a companion medicine for effectively treating cancers.     

Pectin in controlled drug delivery – a review

Controlled drug delivery remains a research focus for public health to enhance patient compliance, drug efficiency and reduce the side effects of drugs. Pectin, an edible plant polysaccharide, has been shown to be useful for the construction of drug delivery systems for specific drug delivery. Several pectin derived formulations have been developed in our laboratory and tested in vitro, ex vivo, and in vivo for the ability to deliver bioactive substances for therapeutic purposes in the context of interactions with living tissues. Pectin derivatives carrying primary amine groups were more mucoadhesive and have shown potential in nasal drug delivery and other mucosal drug delivery. Pectin derivatives with highly esterified galacturonic acid residues are more hydrophobic and able to sustain the release of incorporated fragrances for a prolonged duration. Less esterified pectin derivatives are able to penetrate deeper into the skin and may be useful in aromatherapy formulations. Pectin, in combination with zein, a corn protein, forms hydrogel beads. The bound zein restricts bead swelling and retains the porosity of the beads; the pectin networks shield the zein from protease attack. The complex beads are ideal vehicles for colon-specific drug delivery. Studies presented in this paper indicate the flexibility and possibility to tailor pectin macromolecules into a variety of drug delivery systems to meet different clinical requirements. Mention of trade names or commercial products in this article is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the US Department of Agriculture.