Integrated in silico formulation design of self-emulsifying drug delivery systems

The drug formulation design of self-emulsifying drug delivery systems (SEDDS) often requires numerous experiments, which are time- and money-consuming. This research aimed to rationally design the SEDDS formulation by the integrated computational and experimental approaches. 4495 SEDDS formulation datasets were collected to predict the pseudo-ternary phase diagram by the machine learning methods. Random forest (RF) showed the best prediction performance with 91.3% for accuracy, 92.0% for sensitivity and 90.7% for specificity in 5-fold cross-validation. The pseudo-ternary phase diagrams of meloxicam SEDDS were experimentally developed to validate the RF prediction model and achieved an excellent prediction accuracy (89.51%). The central composite design (CCD) was used to screen the best ratio of oil-surfactant-cosurfactant. Finally, molecular dynamic (MD) simulation was used to investigate the molecular interaction between excipients and drugs, which revealed the diffusion behavior in water and the role of cosurfactants. In conclusion, this research combined machine learning, central composite design, molecular modeling and experimental approaches for rational SEDDS formulation design. The integrated computer methodology can decrease traditional drug formulation design works and bring new ideas for future drug formulation design.     

Application of chitosan/alginate nanoparticle in oral drug delivery systems: prospects and challenges

Oral drug delivery systems (ODDSs) have various advantages of simple operation and few side effects. ODDSs are highly desirable for colon-targeted therapy (e.g. ulcerative colitis and colorectal cancer), as they improve therapeutic efficiency and reduce systemic toxicity. Chitosan/alginate nanoparticles (CANPs) show strong electrostatic interaction between the carboxyl group of alginates and the amino group of chitosan which leads to shrinkage and gel formation at low pH, thereby protecting the drugs from the gastrointestinal tract (GIT) and aggressive gastric environment. Meanwhile, CANPs as biocompatible polymer, show intestinal mucosal adhesion, which could extend the retention time of drugs on inflammatory sites. Recently, CANPs have attracted increasing interest as colon-targeted oral drug delivery system for intestinal diseases. The purpose of this review is to summarize the application and treatment of CANPs in intestinal diseases and insulin delivery. And then provide a future perspective of the potential and development direction of CANPs as colon-targeted ODDSs.     

Optimizing drug delivery systems using systematic "design of experiments." Part II: retrospect and prospects

The first study on application of Design of Experiments (DoE) in optimizing drug formulation appeared in 1967. Since then the number of literature reports on the use of DoE optimization in development of drug delivery technologies has been piling up steadily. Such systematic techniques find their use in every type of conventional dosage form and modern drug delivery system. The drug delivery devices investigated for optimization using response surface methodology include controlled release compressed matrices, microparticulates, macroparticulates, vesicular systems, floating systems, bioadhesive systems, semisolids, transdermals, and inhalations. The optimized processes mainly include extrusion-spheronization, pelletization, microencapsulation, coating, granulation, and tableting. Part I of this article [Crit Rev Ther Drug Carrier Syst 2005; 22(1):27-106] dealt with the salient steps involved in the DoE optimization methodology using diverse experimental designs. Part II deals with various retrospective literature findings as well as the prospective application of such DoE procedures while optimizing varied drug delivery technologies. A vast account of various DoE reports on optimization of diverse drug delivery system and processes along with the critical graphical analysis of various designs, input, and response variables have been presented here in a categorical form. Such an explicit and updated review on drug delivery optimization has not been published anywhere else in the recent past.     

Lipid drug delivery and rational formulation design for lipophilic drugs with low oral bioavailability, applied to cyclosporine

By using a rational formulation approach, we have tried to find the general characteristics for promising self-emulsifying drug delivery systems (SEDDS) based on natural lipid components, for the oral delivery of lipophilic drugs. Galactolipids, which are polar lipids commonly found in the chloroplast membranes of green plants, and a natural part of the human diet, were the main surfactants in these formulations. This was done in three clinical studies: a screening study, followed by a prediction study and, finally, a confirmatory study; in all 17 experimental formulations were investigated. The clinical trials were performed in healthy volunteers. Cyclosporine, a well-known lipophilic peptide, was incorporated in different SEDDS, and administered orally, followed by the measurement of the blood concentration of the drug over time. The pharmacokinetic parameters, which describe the rate and extent of absorption, were estimated. We found that fractionated oat oil (FOO) and medium chain monoglycerides (60:30:10 mono-, di- and tri-glycerides) promoted absorption, and resulted in a formulation with absorption characteristics nearly equal to the commercial formulation of cyclosporine, Sandimmun Neoral^®.     

Enhanced transdermal drug delivery of zaltoprofen using a novel formulation

Zaltoprofen is a non-steroidal anti-inflammatory drug (NSAID) belonging to the propionic acid class. It has strong inhibitory effects on acute and chronic inflammation. Although zaltoprofen is well tolerated orally compared to other NSAIDs, it has to be administered in three to four doses per day and was associated with ulcerogenicity, bellyache and indigestion. This makes administration of zaltoprofen unsuitable for patients with gastric ulcer and is also associated with drug interactions. Therefore, it is important to develop an alternative dosage form which is easier to administer and avoids first-pass metabolism. The transdermal route meets all the above advantages. In this study, zaltoprofen gels were prepared using carbomer with mixture solution of polyethylene glycol (PEG) 400, Tween 80 and (2-hydroxypropyl)-β-cyclodextrin (HPCD) (called as T2), subsequently oleic acid as a penetration enhancer was added. Zaltoprofen gel containing T2 and oleic acid could promote the percutaneous absorption of zaltoprofen and increase AUC by 183% compared to zaltoprofen gel without T2 and oleic acid. Also, there was a finding zaltoprofen gel containing T2 and oleic acid did not cause dermal irritations in an experimental animal.     

Polymeric nanofibers: targeted gastro-retentive drug delivery systems

Background: Conventional oral dosage forms exhibit poor/low bioavailability due to incomplete release of drug and short residence time at the absorption site. Gastro-retentive drug delivery system (GRDDS) is particularly used to improve bioavailability of the drugs, which have narrow absorption window down in the levels of gastrointestinal tract and also to treat local disorders.

Purpose: The purpose of this review is to describe the utility of the nanofibers as gastro-retentive dosage form. From last few decades, formulation scientists have put extensive efforts to develop suitable gastro-retentive drug delivery system, which is appropriate for commercialization. Current approaches used for preparation of gastro-retentive drug delivery system offers limited functional features to control the floating behavior. Recently, an extensive research has been developed to improve the gastric residence time by using nanofibers, which ultimately leads to the increased bioavailability of the drug. Multiple functional features and unique properties of nanofibers improve its gastro retention.

Conclusion: Nanofiber system provides stomach-specific drug release for longer duration; moreover, increased local action of the drug due to prolonged contact time with the gastric mucosa. Thus, the nanofiber system promises to be the potential approach for gastric retention drug delivery system.     

Application of Box-Behnken design in understanding the quality of genistein self-nanoemulsified drug delivery systems and optimizing its formulation

The purpose of the present study was to understand the effect of formulation variables of self- nanoemulsified drug delivery systems (SNEDDS) on the rapid dissolution of a model drug, genistein (GN). A three-factor, three-level Box-Behnken design was used to explore the main and interaction effect of several independent formulation variables including the amount of Maisine 35-1 and Labrafac Lipophile WL 1349 (1:1, w/w) (X₁), Cremophor EL and Labrasol (3:1, w/w) (X₂), and Transcutol P (X₃). Droplet size (Y₁), turbidity (Y₂), and dissolution percentage of GN after 5 (Y₃) and 30 (Y₄) min were the dependent variables. A mathematical relationship, Y₃?=???89.3447?+?5.9524X₁?+?1.0683X₂?+?0.462X₃???0.0825X₁²???0.0075X₂²???0.0009X₃²?+?0.0104X₁X₂ ??0.0113X₁X₃?+?0.0009X₂X₃ (r2?=?0.9604), was obtained to explain the effect of all factors and their co-linearities on the dissolution of GN at 5?min. Formulation optimization was then performed to maximize dissolution percentage of GN at 5?min (Y₃). The optimized formulation was predicted to dissolution 93.34% of GN at 5?min, when X₁, X₂ and X₃ values were 37.1, 101.7 and 77.3?mg, respectively. A new batch was prepared according to the optimized formulation, and the observed and predicted values of Y₃ were in close agreement. In conclusion, the Box-Behnken experimental design allowed us to understand the effect of formulation variables on the rapid dissolution of GN from SNEDDS, and optimize the formulation to obtain a rapid drug dissolution at 5?min.     

口服结肠靶向释药系统的制备及应用

目的由于在治疗肠道或某些全身性疾病中具有特殊的优点,口服结肠靶向给药系统受到更多的关注。但消化道的复杂性导致影响药物在结肠靶向释药的因素较多,重现性不好。本文对经口服药物结肠靶向释药的生理因素、目前已有的制备技术及应用进行综述。     

Overview on zein protein: a promising pharmaceutical excipient in drug delivery systems and tissue engineering

Introduction: Natural pharmaceutical excipients have been applied extensively in the past decades owing to their safety and biocompatibility. Zein, a natural protein of plant origin offers great benefit over other synthetic polymers used in controlled drug and biomedical delivery systems. It was used in a variety of medical fields including pharmaceutical and biomedical drug targeting, vaccine, tissue engineering, and gene delivery. Being biodegradable and biocompatible, the current review focuses on the history and the medical application of zein as an attractive still promising biopolymer.

Areas covered: The current review gives a broadscope on zein as a still promising protein excipient in different fields. Zein- based drug and biomedical delivery systems are discussed with special focus on current and potential application in controlled drug delivery systems, and tissue engineering.

Expert opinion: Zein as a protein of natural origin can still be considered a promising polymer in the field of drug delivery systems as well as in tissue engineering. Although different researchers spotted light on zein application in different industrial fields extensively, the feasibility of its use in the field of drug delivery replenished by investigators in recent years has not yet been fully approached.     

Self-emulsifying drug delivery systems in oral (poly)peptide drug delivery

Introduction: Oral administration of most therapeutic peptides and proteins is mainly restricted due to the enzymatic and absorption membrane barrier of the GI tract. In order to overcome these barriers, various technologies have been explored. Among them, self-emulsifying drug delivery systems (SEDDS) received considerable attention as potential carriers to facilitate oral peptide and protein delivery in recent years.

Areas covered: This review article intends to summarize physiological barriers which limit the bioavailability of orally administrated peptide and protein drugs. Furthermore, the potential of SEDDS to protect incorporated peptides and proteins towards peptidases and proteases and to penetrate the mucus layer is reviewed. Their permeation-enhancing properties and their ability to release the drug in a controlled way are described. Moreover, this review covers the results of in vivo studies providing evidence for this promising approach.

Expert opinion: As SEDDS can: i) provide a protective effect towards a presystemic metabolism; ii) efficiently permeate the intestinal mucus gel layer in order to reach the absorption membrane; and iii) be produced in a very simple and cost-effective manner, they are a promising tool for oral peptide and protein drug delivery.     

Novel engineered systems for oral,mucosal and transdermal drug delivery

Abstract

Technological advances in drug discovery have resulted in increasing number of molecules including proteins and peptides as drug candidates. However, how to deliver drugs with satisfactory therapeutic effect, minimal side effects and increased patient compliance is a question posted before researchers, especially for those drugs with poor solubility, large molecular weight or instability. Microfabrication technology, polymer science and bioconjugate chemistry combine to address these problems and generate a number of novel engineered drug delivery systems. Injection routes usually have poor patient compliance due to their invasive nature and potential safety concerns over needle reuse. The alternative non-invasive routes, such as oral, mucosal (pulmonary, nasal, ocular, buccal, rectal, vaginal), and transdermal drug delivery have thus attracted many attentions. Here, we review the applications of the novel engineered systems for oral, mucosal and transdermal drug delivery.     

Ophthalmic drug delivery systems

New ophthalmic drug delivery systems are curently receiving increased attention, in part because of the expected emergence of new drugs with short biological half-lives whose usefulness may depend on a more continuous drug supply than eyedrops can provide, but also because of the potential of some delivery systems to reduce the side effects of the more potent drugs recently introduced or presently under investigation. Some ophthalmic delivery systems extend the duration of drug action by enhancement of corneal absorption; these systems include soluble gels and emulsions, hydrophilic ocular inserts, ion-pair associations, prodrugs, and liposomes. Since these systems enhance the “pulse entry” of the drug, they are limited to use with drugs whose dose-related side effects are not serious. Other delivery systems provide for a controlled release of drugs and therefore minimize the pulse entry with which side effects are associated. They can be based on any of several different mechanisms and include both erodible and nonerodible matrices. The various delivery systems that have recently been developed and those that are currently known to be under investigation are described in this paper, along with some observations regarding the future outlook of ophthalmic drug delivery systems.     

口服结肠定位给药系统

综述了近年来口服结肠定位给药系统的发展状况 ,并评价了各类结肠定位给药系统的优、缺点和发展前景     

Stimuli-sensitive drug delivery systems for site-specific antibiotic release

Site-specific delivery of antibiotics has always been a high-priority area in pharmaceutical research. Conventionally used antibiotics suffer several limitations, such as low accumulation and penetration in diseased cells/tissues, limited bioavailability of drugs, drug resistance, and off-target toxicity. To overcome these limitations, several strategies have been exploited for delivering antibiotics to the site of infection, such as the use of stimuli-responsive antibiotic delivery systems, which can release antibiotics in a controlled and timely fashion. These stimuli can either be exogenous (light, magnetism, ultrasound, and electrical) or endogenous (pH, redox reactions, and enzymatic). In this review, we present a summary of recent developments in the field of stimuli-based targeted drug delivery systems for the site-specific release of antibiotics.     

Thermo-responsive systems for controlled drug delivery

Controlled drug delivery systems represent advanced systems that can be tightly modulated by stimuli in order to treat diseases in which sustained drug release is undesirable. Among the many different stimuli-sensitive delivery systems, temperature-sensitive drug delivery systems offer great potential over their counterparts due to their versatility in design, tunability of phase transition temperatures, passive targeting ability and in situ phase transitions. Thus, thermosensitive drug delivery systems can overcome many of the hurdles of conventional drug delivery systems in order to increase drug efficacies, drug targeting and decrease drug toxicities. In an effort to further control existing temperature-responsive systems, current innovative applications have combined temperature with other stimuli such as pH and light. The result has been the development of highly sophisticated systems, which demonstrate exquisite control over drug release and represent huge advances in biomedical research.     

叶酸受体介导的靶向纳米给药系统研究进展

叶酸受体在许多恶性肿瘤细胞表面过度表达,而在正常细胞中则几乎不表达或只有少量表达。利用叶酸受体表达的特性,通过将叶酸修饰于药物载体表面,可使药物靶向输送至叶酸受体过度表达的肿瘤细胞中,从而避免对正常细胞产生毒性,提高药物疗效;而纳米给药系统因粒径较小等原因可使药物在肿瘤部位浓集。本文对近年来叶酸受体介导的靶向纳米给药系统进行了综述。     

Erythrocyte-based drug delivery

The use of a physiological carrier to deliver therapeutics throughout the body to both improve their efficacy while minimising inevitable adverse side effects, is an extremely fascinating perspective. The behaviour of erythrocytes as a delivery system for several classes of molecules (i.e., proteins, including enzymes and peptides, therapeutic agents in the form of nucleotide analogues, glucocorticoid analogues) has been studied extensively as they possess several properties, which make them unique and useful carriers. Furthermore, the possibility of using carrier erythrocytes for selective drug targeting to differentiated macrophages increases the opportunities to treat intracellular pathogens and to develop new drugs. Finally, the availability of an apparatus that permits the encapsulation of drugs into autologous erythrocytes has made this technology available in many clinical settings and co-mpetitive with other drug delivery systems.     

黄芩素自微乳的制备及大鼠体内生物利用度研究

目的:制备黄芩素自微乳化制剂(SMEDDS),考察其大鼠体内生物利用度。方法:采用伪三元相图法筛选自微乳的油相、表面活性剂及助表面活性剂;采用HPLC法测定大鼠血浆中药物浓度,与原料比较,对黄芩素自微乳进行大鼠体内生物利用度评价。结果:通过使用混合油相、混合表面活性剂及助表面活性剂,可获得较为理想的黄芩素自微乳。大鼠体内血药浓度-时间曲线结果表明,黄芩素自微乳的AUC是原料的3.77倍,且药时曲线的形状发生一定的改变。结论:自微乳系统可显著增加黄芩素的溶解度,有利于提高口服生物利用度,且自微乳可能改变其胃肠道吸收行为。     

Application of freeze-drying in the development of oral drug delivery systems

ABSTRACT

Introduction: With continual focus on oral drug delivery systems (ODDS), the role of freeze-drying becomes increasingly valuable. While freeze-drying is fundamentally a desiccation process, the advantageous material properties attributed to freeze-drying extend far beyond the preparation of stable pharmaceutical products. The formulation and process variables are important considerations as they affect the final freeze-dried product characteristics. It is of interest to expound on the principles and effects of freeze-drying in the hope of introducing novel products for applications in the development of ODDS.

Areas covered: In this review, basic principles, general formulation and process variables associated with freeze-drying will be covered. The application of freeze-drying in 3 areas: modification of active ingredients, development of novel freeze-dried excipients and development of freeze-dried final dosage forms will be discussed.

Expert opinion: As a pharmaceutical unit operation, freeze-drying has created new dimensions in the area of oral drug delivery, where the properties of the drugs, excipients and characteristics of the final solid dosage form can be modified by the freeze-drying process. With the emergence of new applications, the role of freeze-drying technology in ODDS is indeed a relevant and promising one.