难溶性药物固体分散体研究新进展

如何改善难溶性药物溶出度和口服生物利用度,业已成为药剂学研究的重点,而将其制成固体分散体,作为一种行之有效的改善方法,备受关注.综述近年来用于制备难溶性药物固体分散体的新型载体材料和新技术的研究进展.     

Hydrotropic Solubilization of Poorly Water-Soluble Drugs

The solubilizing ability of two aromatic hydrotropes, N,N-diethylnicotinamide (DENA) and N,N-dimethylbenzamide (DMBA), was investigated using a set of 13 poorly soluble, structurally diverse drugs. The number of aromatic rings in the solute molecule has a very strong effect on the solubility enhancement produced by either hydrotrope. However, although solubility enhancements in the order of 1000- to 10,000-fold were obtained with each of the hydrotropic agents, important differences were found between the two. DMBA is more hydrophobic and undergoes more extensive self-association than DENA, as determined by vapor osmometry. As a result, DMBA is generally a more powerful solubilizer of hydrophobic drugs. DENA, on the other hand, is more polar and its self-association is essentially limited to dimer formation. However, despite being less hydrophobic, DENA is an extremely powerful solubilizer of paclitaxel, a highly hydrophobic compound. Such a result is attributed to the higher hydrogen bonding ability of DENA over DMBA and the very high hydrogen bonding ability of paclitaxel. These observations in turn illustrate the strong interplay between specific and hydrophobic interactions on the observed solubilization by hydrotropic agents. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3953–3965, 2010     

Physicochemical Properties of Solid Phospholipid Particles as a Drug Delivery Platform for Improving Oral Absorption of Poorly Soluble Drugs

Purpose

A novel drug delivery platform, mesoporous phospholipid particle (MPP), is introduced. Its physicochemical properties and ability as a carrier for enhancing oral absorption of poorly soluble drugs are discussed.

Methods

MPP was prepared through freeze-drying a cyclohexane/t-butyl alcohol solution of phosphatidylcholine. Its basic properties were revealed using scanning electron microscopy, x-ray diffraction, thermal analysis, hygroscopicity measurement, and so on. Fenofibrate was loaded to MPP as a poorly soluble model drug, and effect of MPP on the oral absorption behavior was observed.

Results

MPP is spherical in shape with a diameter typically in the range of 10–15 μm and a wide surface area that exceeds 10 m²/g. It has a bilayer structure that may accommodate hydrophobic drugs in the acyl chain region. When fenofibrate was loaded in MPP as a model drug, it existed partially in a crystalline state and improvement in the dissolution behavior was achieved in the presence of a surfactant, because of the formation of mixed micelles composed of phospholipids and surfactants in the dissolution media. MPP greatly improved the oral absorption of fenofibrate compared to that of the crystalline drug and its efficacy was almost equivalent to that of an amorphous drug dispersion.

Conclusion

MPP is a promising option for improving the oral absorption of poorly soluble drugs based on the novel mechanism of dissolution improvement.

     

Characterization of Supersaturatable Formulations for Improved Absorption of Poorly Soluble Drugs

With the increasing number of poorly water-soluble compounds in contemporary drug discovery pipelines, the concept of supersaturation as an effective formulation approach for enhancing bioavailability is gaining momentum. This is intended to design the formulation to yield significantly high intraluminal concentrations of the drug than the thermodynamic equilibrium solubility through achieving supersaturation and thus to enhance the intestinal absorption. The major challenges faced by scientists developing supersaturatable formulations include controlling the rate and degree of supersaturation with the application of polymeric precipitation inhibitor and maintenance of post-administration supersaturation. This review is intended to cover publications on this topic since April 2009. Scientific publications associated with characterization of supersaturatable systems and related preclinical and clinical pharmacokinetics (PK) studies are reviewed. Specifically, this review will address issues related to assessing the performance of supersaturatable systems including: (1) Diversified approaches for developing supersaturatable formulations, (2) meaningful in vitro test methods to evaluate supersaturatable formulations, and (3) in vivo PK study cases which have demonstrated direct relevance between the supersaturation state and the exposure observed in animal models and human subjects.     

Spectrophotometric Determination of Poorly Water Soluble Drug Rosiglitazone Using Hydrotropic Solubilization technique

In the present investigation, hydrotropic solution of urea was employed as a solubilizing agent for spectrophotometric determination of poorly water-soluble drug rosiglitazone maleate. In solubility determination study, it was found that there was more than 14-folds enhancement in solubility of rosiglitazone maleate in a 6M solution of urea. Rosiglitazone maleate obeys Beer's law in concentration range of 5-300 μg/ml. Linearity of rosiglitazone maleate was found in the range of 80-120% of the label claim. The proposed method has been applied successfully to the analysis of the cited drug in pharmaceutical formulations with good accuracy and precision. The method herein described is new, simple, eco-friendly, economic, and accurate and can be utilized in routine analysis of rosiglitazone maleate in bulk drug and tablet dosage form.     

A Step Toward Development of Printable Dosage Forms for Poorly Soluble Drugs

The purpose of this study was to formulate printable dosage forms for a poorly soluble drug (piroxicam; PRX) and to gain understanding of critical parameters to be considered during development of such dosage forms. Liquid formulations of PRX were printed on edible paper using piezoelectric inkjet printing (PIJ) and impression printing (flexography). The printed dosage forms were characterized using scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM–EDX) and the amount of drug was determined using high-performance liquid chromatography. Solutions of PRX in polyethylene glycol 400 (PEG-400):ethanol (40:60) and in PEG-400 were found to be optimal formulations for PIJ and flexography, respectively. SEM–EDX analysis revealed no visible solid particles on the printed dosage forms indicating the drug most likely remained in solution after printing. More accurate drug deposition was obtained by PIJ as compared with flexography. More than 90% drug release was achieved within 5 min regardless of printing method used. The solubility of drug in solvents/cosolvents, rheological properties of formulations, properties of substrate, feasibility and accuracy of the printing methods, and detection limit of analytical techniques for characterization of printed dosage forms are some of the concerns that need to be addressed for development of printable dosage forms of poorly soluble drugs. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3694–3704, 2013     

Enhancement of Transdermal Penetration and Bioavailability of Poorly Soluble Acyclovir Using Solid Lipid Nanoparticles Incorporated in Gel Cream

The objective of this work was to increase the amount of acyclovir in the basal epidermis, site of herpes virus simplex infection, using the solid lipid nanoparticles loaded gel cream as carriers. Solid lipid nanoparticles were prepared by high pressure homogenisation method and incorporated in a semisolid submicron gel cream. Acyclovir distribution into rat skin after topical application of solid lipid nanoparticles loaded gel cream was determined by fabricated Franz diffusion cell. The results showed that, the quantity of the acyclovir in the basal epidermis with the solid lipid nanoparticles loaded submicron gel cream was two folds times more than marketed acyclovir gel cream. This type of carrier can improve acyclovir loaded therapy since it increases drug retention in the basal epidermis.     

New Formulation Technique for Solubility and Dissolution Rate Enhancement of Poorly Soluble Drugs

Pharmaceutical Chemistry Journal - Ebastine (EBS) is a second-generation non-sedating antihistamine used for the prevention and treatment of allergic rhinitis and chronic idiopathic urticaria. It...     

难溶性药物渗透泵控释制剂的研究现状

将渗透泵制剂技术应用于难溶性药物传递系统,目前已经成为药剂学研究领域的一大热点。从处方工艺等方面,分类综述推挽式、单室单层型以及夹芯式等难溶性药物渗透泵制剂的研究现状。     

Analysis of a Diffusion Dryer for the Respiratory Delivery of Poorly Water Soluble Drugs

Purpose. The purpose of this study was to analyze a diffusion dryer as a means to remove organic solvents from aerosol particles of poorly water soluble drugs. Methods. Aerosols of methanol, ethanol, and ethyl acetate were generated with an ultrasonic nebulizer, and inflow to outflow concentration ratio of vapor in a annular charcoal column was determined as a function of time by gas chromotography at two to four different airflow rates. In addition, the particle transmission efficiency was determined with an ethanol solution of the test compound, budesonide. The results were analyzed with equations originally developed for assessing the loss of drug from intravenous tubing along with independent measures of the adsorption isotherm of the vapors onto charcoal. Results. Aerosol production was relatively constant with time, and the transmission of solid particles through the column occurred with efficiency nearing 100%. The inlet to outlet vapor concentration ratio was adequately described by a model of three resistances in series composed of the inner tube, the screen mesh, and the charcoal bed. Conclusions. The diffusion dryer was found to be satisfactory for the removal of methanol, ethanol, and ethyl acetate and the efficiency may be assessed from the adsorption isotherms on charcoal and the geometry of the dryer.     

Supercooled Smectic Nanoparticles: A Potential Novel Carrier System for Poorly Water Soluble Drugs

PURPOSE: The possibility of preparing nanoparticles in the supercooled thermotropic liquid crystalline state from cholesterol esters with saturated acyl chains as well as the incorporation of model drugs into the dispersions was investigated using cholesteryl myristate (CM) as a model cholesterol ester. METHODS: Nanoparticles were prepared by high-pressure melt homogenization or solvent evaporation using phospholipids, phospholipid/ bile salt, or polyvinyl alcohol as emulsifiers. The physicochemical state and phase behavior of the particles was characterized by particle size measurements (photon correlation spectroscopy, laser diffraction with polarization intensity differential scattering), differential scanning calorimetry, X-ray diffraction, and electron and polarizing light microscopy. The viscosity of the isotropic and liquid crystalline phases of CM in the bulk was investigated in dependence on temperature and shear rate by rotational viscometry. RESULTS: CM nanoparticies can be obtained in the smectic phase and retained in this state for at least 12 months when stored at 230C in optimized systems. The recrystallization tendency of CM in the dispersions strongly depends on the stabilizer system and the particle size. Stable drug-loaded smectic nanoparticles were obtained after incorporation of 10% (related to CM) ibuprofen, miconazole, etomidate, and 1% progesterone. CONCLUSIONS: Due to their liquid crystalline state, colloidal smectic nanoparticles offer interesting possibilities as carrier system for lipophilic drugs. CM nanoparticles are suitable model systems for studying the crystallization behavior and investigating the influence of various parameters for the development of smectic nanoparticles resistant against recrystallization upon storage.     

Formulation and Antitumor Activity Evaluation of Nanocrystalline Suspensions of Poorly Soluble Anticancer Drugs

Purpose. Determine if wet milling technology could be used to formulate water insoluble antitumor agents as stabilized nanocrystalline drug suspensions that retain biological effectiveness following intravenous injection. Methods. The versatility of the approach is demonstrated by evaluation of four poorly water soluble chemotherapeutic agents that exhibit diverse chemistries and mechanisms of action. The compounds selected were: piposulfan (alkylating agent), etoposide (topoisomerase II inhibitor), camptothecin (topoisomerase I inhibitor) and paclitaxel (antimitotic agent). The agents were wet milled as a 2% w/v solids suspension containing 1 % w/v surfactant stabilizer using a low energy ball mill. The size , physical stability and efficacy of the nanocrystalline suspensions were evaluated. Results. The data show the feasibility of formulating poorly water soluble anticancer agents as physically stable aqueous nanocrystalline suspensions. The suspensions are physically stable and efficacious following intravenous injection. Conclusions. Wet milling technology is a feasible approach for formulating poorly water soluble chemotherapeutic agents that may offer a number of advantages over a more classical approach.     

Application of Drug Nanocrystal Technologies on Oral Drug Delivery of Poorly Soluble Drugs

The limited solubility and dissolution rate exhibited by poorly soluble drugs is major challenges in the pharmaceutical process. Following oral administration, the poorly soluble drugs generally show a low and erratic bioavailability which may lead to therapeutic failure. Pure drug nanocrystals, generated by “bottom up” or “top down” technologies, facilitate a significant improvement on dissolution behavior of poorly soluble drugs due to their enormous surface area, which in turn lead to substantial improvement in oral absorption. This is the most distinguished achievement of drug nanocrystals among their performances in various administration routes, reflected by the fact that most of the marketed products based on the nanocrystals technology are for oral application. After detailed investigations on various technologies associated with production of drug nanocrystals and their in vitro physicochemical properties, during the last decade more attentions have been paid into their in vivo behaviors. This review mainly describes the in vivo performances of oral drug nanocrystals exhibited in animals related to the pharmacokinetic, efficacy and safety characteristics. The technologies and evaluation associated with the solidification process of the drug nanocrystals suspensions were also discussed in detail.     

Use of 1-Methyl-Pyrrolidone as a Solubilizing Agent for Determining the Uptake of Poorly Soluble Drugs

Pharmaceutical Research -     

Microfluidic Preparation of Nanoparticles Using Poly(ethylene Glycol)-distearoylphosphatidylethanolamine for Solubilizing Poorly Soluble Drugs

Microfluidic systems have shown promise for the production of nanoparticles from mixtures of aqueous and organic solutions, including liposomes, oil-in-water nanoemulsions, and lipid nanoparticles. They offer important practical advantages, including low reagent consumption, parallelization, and automation, and are ideally suited to high-throughput optimization and scale-up. In this study, we developed a new method for the formulation of nanoparticles of poorly soluble drug compounds. The nanoparticles, prepared by microfluidic mixing using only poly(ethylene glycol)-distearoylphosphatidylethanolamine (PEG-DSPE), were highly stable and uniform in size. By mixing an organic solution of poorly soluble cyclosporine A and PEG-DSPE with water in the microfluidic device, amorphous cyclosporine A nanoparticles (CsA-NPs), with an encapsulation efficiency of approximately 90% and a particle size of 100–200 nm, were obtained. Analysis of the microfluidic process parameters revealed that particle size distribution was significantly controlled by the flow rate ratio. The obtained CsA-NPs were stable for up to 150 days at room temperature, and the pharmacokinetic profile was similar to that of the commercial formulation containing Cremophor EL, which has been reported to induce serious adverse effects after intravenous administration. These findings provide a useful technical platform for the safe solubilization of poorly soluble compounds and their subsequent pharmaceutical development.     

Solubilization of a Poorly Soluble B-Raf (Rapidly Accelerated Fibrosarcoma) Inhibitor: From Theory to Application

The oral bioavailability of a drug candidate is influenced by its permeability, metabolism, and physicochemical properties. Among the physicochemical properties, solubility and dissolution rate often are the most critical factors affecting the oral bioavailability of a compound. The increasing challenge for the pharmaceutical industry is to achieve reasonable oral bioavailability of poorly water-soluble drug candidates. G-F is a potent and selective B-Raf (rapidly accelerated fibrosarcoma) inhibitor with poor water solubility and moderate permeability, which resulted in an absorption-limited exposure in preclinical safety studies. The intrinsic solubility of G-F is 8 μg/mL (i.e., 0.0188 nM). In this study, pH adjustment combined with cosolvency, micellization, or complexation was applied as a technique to enhance the solubility of G-F. pH 9.5 and 4 buffers were selected to combine with the solubilization agents based on G-F's acidic pKa of 7.47. The solubilization power of each solubilization agent was determined based on the experimental data. The solubility G-F can be increased up to 4000-fold in a selected combination. The advantage of combination over individual solubilization agent was demonstrated. In this study, the understanding of the solubilization power of each solubilization agent played an important role in the formulation development of this development candidate.