Preparation of PLGA Nanoparticles by Milling Spongelike PLGA Microspheres.

Currently, emulsification-templated nanoencapsulation techniques (e.g., nanoprecipitation) have been most frequently used to prepare poly-d,l-lactide-co-glycolide (PLGA) nanoparticles. This study aimed to explore a new top-down process to produce PLGA nanoparticles. The fundamental strategy was to prepare spongelike PLGA microspheres with a highly porous texture and then crush them into submicron-sized particles via wet milling. Therefore, an ethyl formate-based ammonolysis method was developed to encapsulate progesterone into porous PLGA microspheres. Compared to a conventional solvent evaporation process, the ammonolysis technique helped reduce the tendency of drug crystallization and improved drug encapsulation efficiency accordingly (solvent evaporation, 27.6 ± 4.6%; ammonolysis, 65.1 ± 1.7%). Wet milling was performed on the highly porous microspheres with a D50 of 64.8 µm under various milling conditions. The size of the grinding medium was the most crucial factor for our wet milling. Milling using smaller zirconium oxide beads (0.3~1 mm) was simply ineffective. However, when larger beads with diameters of 3 and 5 mm were used, our porous microspheres were ground into submicron-sized particles. The quality of the resultant PLGA nanoparticles was demonstrated by size distribution measurement and field emission scanning electron microscopy. The present top-down process that contrasts with conventional bottom-up approaches might find application in manufacturing drug-loaded PLGA nanoparticles.

Protein Loading into Spongelike PLGA Microspheres.

A self-healing microencapsulation process involves mixing preformed porous microspheres in an aqueous solution containing the desired protein and converting them into closed-pore microspheres. Spongelike poly-d,l-lactide-co-glycolide (PLGA) microspheres are expected to be advantageous to protein loading through self-healing. This study aimed to identify and assess relevant critical parameters, using lysozyme as a model protein. Several parameters governed lysozyme loading. The pore characteristics (open-pore, closed-pore, and porosity) of the preformed microspheres substantially affected lysozyme loading efficiency. The type of surfactant present in the aqueous medium also influenced lysozyme loading efficiency. For instance, cetyltrimethylammonium bromide showing a superior wetting functionality increased the extent of lysozyme loading more than twice as compared to Tween 80. Dried preformed microspheres were commonly used before, but our study found that wet microspheres obtained at the end of the microsphere manufacturing process displayed significant advantages in lysozyme loading. Not only could an incubation time for hydrating the microspheres be shortened dramatically, but also a much more considerable amount of lysozyme was encapsulated. Interestingly, the degree of microsphere hydration determined the microstructure and morphology of closed-pore microspheres after self-healing. Understanding these critical process parameters would help tailor protein loading into spongelike PLGA microspheres in a bespoke manner.

Assessment of Residual Solvent and Drug in PLGA Microspheres by Derivative Thermogravimetry.

Thermogravimetry does not give specific information on residual organic solvents in polymeric matrices unless it is hyphenated with the so-called evolved gas analysis. The purpose of this study was to apply, for the first time, derivative thermogravimetry (DTG) to characterize a residual solvent and a drug in poly-d,l-lactide-co-glycolide (PLGA) microspheres. Ethyl formate, an ICH class 3 solvent, was used to encapsulate progesterone into microspheres. DTG provided a distinct peak, displaying the onset and end temperatures at which ethyl formate started to evolve from to where it completely escaped out of the microspheres. DTG also gave the area and height of the solvent peak, as well as the temperature of the highest mass change rate of the microspheres. These derivative parameters allowed for the measurement of the amount of residual ethyl formate in the microspheres. Interestingly, progesterone affected not only the residual solvent amount but also these derivative parameters. Another intriguing finding was that there was a linear relationship between progesterone content and the peak height of ethyl formate. The residual solvent data calculated by DTG were quite comparable to those measured by gas chromatography. In summary, DTG could be an efficient and practical quality control tool to evaluate residual solvents and drugs in various polymeric matrices.

Qualification of Non-Halogenated Organic Solvents Applied to Microsphere Manufacturing Process.

As a non-halogenated dispersed solvent, ethyl acetate has been most commonly used for the manufacturing of poly-d,l-lactide-co-glycolide (PLGA) microspheres. However, ethyl acetate-based microencapsulation processes face several limitations. This study was aimed at proposing ethyl formate as an alternative. Evaluated in this study was the solvent qualification of ethyl formate and ethyl acetate for microencapsulation of a hydrophobic drug into PLGA microspheres. An oil-in-water emulsion solvent extraction technique was developed to load progesterone into PLGA microspheres. Briefly, right after emulsion droplets were temporarily stabilized, they were subject to primary solvent extraction. Appearing semisolid, embryonic microspheres were completely hardened through subsequent secondary solvent extraction. Changes in process parameters of the preparative technique made it possible to manipulate the properties of emulsion droplets, progesterone behavior, and microsphere quality. Despite the two solvents showing comparable Hansen solubility parameter distances toward PLGA, ethyl formate surpassed ethyl acetate in relation to volatility and water miscibility. These features served as advantages in the microsphere manufacturing process, helping produce PLGA microspheres with better quality in terms of drug crystallization, drug encapsulation efficiency, microsphere size homogeneity, and residual solvent content. The present ethyl formate-based preparative technique could be an attractive method of choice for the production of drug-loaded PLGA microspheres.

Merits of sponge-like PLGA microspheres as long-acting injectables of hydrophobic drug.

Our study was initiated to challenge the preconception that nonporous PLGA microspheres with compact matrices should be used to develop long-acting depot injectables of hydrophobic drugs. A simple, new oil-in-water emulsion technique was utilized to produce porous PLGA microspheres with a sponge-like skeleton. Then, their applicability to developing sustained-release depots of hydrophobic drugs was explored in this study. As control, nonporous microspheres with a compact matrix were produced following a typical solvent evaporation process. Both microsphere manufacturing processes used non-halogenated isopropyl formate and progesterone as a dispersed solvent and a model hydrophobic drug, respectively. Various attempts were made to evaluate critical quality attributes of the porous microspheres and the nonporous ones. Surprisingly, the former displayed interesting features from the viewpoints of manufacturability and microsphere quality. For example, the spongy microspheres improved drug encapsulation efficiency and particle size uniformity, inhibited drug crystallization during microencapsulation, and minimized the residual solvent content in microspheres. Furthermore, the porous microspheres provided continual drug release kinetics without a lag time and much faster drug release than the non-porous microspheres did. In summary, the porous and sponge-like PLGA microspheres might find lucrative applications in developing sustained release dosage forms of hydrophobic drugs.

Applicability of non-halogenated methyl propionate to microencapsulation.

Applicability of methyl propionate to microencapsulation was evaluated with regard to volatility, capability of forming emulsions, and their quality. An emulsion-based technique was then developed to encapsulate progesterone into poly-d,l-lactide-co-glycolide microspheres. Their characteristics were compared with those prepared using ethyl acetate. Our results demonstrated that methyl propionate had greater evaporative tendency and less water miscibility than ethyl acetate did. The former allowed us to prepare good microspheres. Their average volume mean diameter was 68.3 ± 1.7 µm with a span index of 0.91 ± 0.13. Progesterone did not undergo polymorphic transition during microencapsulation, and its encapsulation efficiency ranged from 41.80 ± 1.83 to 85.64 ± 1.95%. Residual methyl propionate in various microspheres was found to be 0.97 ± 0.03 to 1.54 ± 0.07%. Such microsphere characteristics were quite similar to those prepared by the ethyl acetate-based microencapsulation process. Overall, our findings reflect that methyl propionate has a potential to become an invaluable solvent for microencapsulation.

Concepts and practices used to develop functional PLGA-based nanoparticulate systems.

The functionality of bare polylactide-co-glycolide (PLGA) nanoparticles is limited to drug depot or drug solubilization in their hard cores. They have inherent weaknesses as a drug-delivery system. For instance, when administered intravenously, the nanoparticles undergo rapid clearance from systemic circulation before reaching the site of action. Furthermore, plain PLGA nanoparticles cannot distinguish between different cell types. Recent research shows that surface functionalization of nanoparticles and development of new nanoparticulate dosage forms help overcome these delivery challenges and improve in vivo performance. Immense research efforts have propelled the development of diverse functional PLGA-based nanoparticulate delivery systems. Representative examples include PEGylated micelles/nanoparticles (PEG, polyethylene glycol), polyplexes, polymersomes, core-shell-type lipid-PLGA hybrids, cell-PLGA hybrids, receptor-specific ligand-PLGA conjugates, and theranostics. Each PLGA-based nanoparticulate dosage form has specific features that distinguish it from other nanoparticulate systems. This review focuses on fundamental concepts and practices that are used in the development of various functional nanoparticulate dosage forms. We describe how the attributes of these functional nanoparticulate forms might contribute to achievement of desired therapeutic effects that are not attainable using conventional therapies. Functional PLGA-based nanoparticulate systems are expected to deliver chemotherapeutic, diagnostic, and imaging agents in a highly selective and effective manner.

Core-shell-type lipid-polymer hybrid nanoparticles as a drug delivery platform.

The focus of nanoparticle design over the years has evolved toward more complex nanoscopic core-shell architecture using a single delivery system to combine multiple functionalities within nanoparticles. Core-shell-type lipid-polymer hybrid nanoparticles (CSLPHNs), which combine the mechanical advantages of biodegradable polymeric nanoparticles and biomimetic advantages of liposomes, have emerged as a robust and promising delivery platform. In CSLPHNs, a biodegradable polymeric core is surrounded by a shell composed of layer(s) of phospholipids. The hybrid architecture can provide advantages such as controllable particle size, surface functionality, high drug loading, entrapment of multiple therapeutic agents, tunable drug release profile, and good serum stability. This review focuses on current research trends on CSLPHNs including classification, advantages, methods of preparation, physicochemical characteristics, surface modifications, and immunocompatibility. Additionally, the review deals with applications for cancer chemotherapy, vaccines, and gene therapeutics. FROM THE CLINICAL EDITOR: This comprehensive review covers the current applications of core-shell-type lipid-polymer hybrid nanoparticles, which combine the mechanical advantages of biodegradable polymeric nanoparticles and biomimetic advantages of liposomes to enable an efficient drug delivery system.

Utilization of catalytic hydrolysis of ethyl acetate for solvent removal during microencapsulation.

The objective of this study was to apply the specific acid-catalysed hydrolysis of ethyl acetate to completing solvent extraction during an emulsion-based microencapsulation process. The dispersed phase consisting of poly-D,L-lactide-co-glycolide and ethyl acetate was emulsified in an acid catalyst containing aqueous phase. Catalytic hydrolysis of ethyl acetate led to its continual leaching from the dispersed phase of the emulsion, thereby triggering microsphere hardening with high efficiency. Ketoprofen was successfully encapsulated into microspheres via this technique, and liquid chromatography-mass spectrometry showed that its structural integrity was preserved during microencapsulation. Compared to typical solvent extraction approaches, the acid-catalysis technique helped minimize the consumption of a quench liquid. Also, the resultant microspheres displayed excellent dispersibility and decreased propensity for aggregation. Furthermore, the new method provided better drug encapsulation efficiency and lower levels of residual ethyl acetate in microspheres. In conclusion, the acid-catalysis approach had great potential for the preparation of versatile microspheres and nanoparticles.

Application of acid-catalyzed hydrolysis of dispersed organic solvent in developing new microencapsulation process technology.

The aim of this study was to evaluate a new microencapsulation technology employing an acid-catalyzed solvent extraction method in conjunction to an emulsion-based microencapsulation process. Its process consisted of emulsifying a dispersed phase of poly(D,L-lactide-co-glycolide) and isopropyl formate in an aqueous phase. This step was followed by adding hydrochloric acid to the resulting oil-in-water emulsion, in order to initiate the hydrolysis of isopropyl formate dissolved in the aqueous phase. Its hydrolysis caused the liberation of water-soluble species, that is, isopropanol and formic acid. This event triggered continual solvent leaching out of emulsion droplets, thereby initiating microsphere solidification. This new processing worked well for encapsulation of progesterone and ketoprofen that were chosen as a nonionizable model drug and a weakly acidic one, respectively. Furthermore, the structural integrity of poly(D,L-lactide-co-glycolide) was retained during microencapsulation. The new microencapsulation technology, being conceptually different from previous approaches, might be useful in preparing various polymeric particles.

Nonhalogenated solvent-based solvent evaporation process useful in preparation of PLGA microspheres.

The objective of this study was to develop an isopropyl formate-based evaporation process useful in producing poly-D,L-lactide-co-glycolide microspheres. Surprisingly, the evaporating tendency of isopropyl formate was comparable to that of methylene chloride and far better than that of ethyl acetate. After optimization of the isopropyl formate-based process, progesterone was encapsulated into microspheres. Under our conditions, its encapsulation efficiency ranged from 75.1% to 92.6%. Even though all microspheres took spherical geometry, their external and internal morphologies were greatly influenced by progesterone payloads. A GC analysis demonstrated that residual isopropyl formate in various microspheres was 1.8% to 4.0%. Interestingly, progesterone underwent polymorphic transition during the microencapsulation process - the ß form was present in microspheres with lower progesterone payloads, whereas the α form predominated over the ß one at higher progesterone loads. In terms of human safety and environmental toxicity, isopropyl formate might have an edge over halogenated organic solvents for solvent evaporation.

Investigation on structural integrity of PLGA during ammonolysis-based microencapsulation process.

The objective of this study was to gain insights into the structural integrity of PLGA during an ammonolysis-based microencapsulation process. PLGA (lactide:glycolide ratio=75:25; M(w)=25,925 g/mol) was dissolved in ethyl acetate or isopropyl formate (3-6 ml), which was emulsified in an aqueous phase. Ammonia, being added to the emulsions, reacted with the dispersed solvents to yield water-miscible solvents. Consequently, emulsion droplets were solidified into microspheres. To evaluate the impact of ammonia upon PLGA, the molar ratio of ammonia to a dispersed solvent varied from 1 to 2 and 3. After preparation of microspheres by the ammonolysis-based procedure, the lactide:glycolide composition and Mw of PLGA were analyzed by (1)H NMR and GPC. Our results demonstrated that ammonia did indeed catalyze the cleavage of PLGA ester bonds during microencapsulation. Strikingly, PLGA degradation was affected by solvent type and volume, as well as ammonia concentration. For instance, when 6 ml of ethyl acetate was used and the molar ratio of ammonia to the solvent was 3, the glycolide content and M(w) of the microspheres considerably decreased to 17.56% and 10,814 g/mol, respectively. There were little changes in these terms, however, when microspheres were prepared using 3 ml of isopropyl formate and an equimolar amount of ammonia. Depending upon microencapsulation conditions, progesterone encapsulation efficiency ranged from 71.6 to 98.8%. Also, its release behavior was significantly influenced by ammonolysis-related process parameters. Our study demonstrated that all these contrasting results arose from differences in solvent reactivity toward ammonolysis, the rate of microsphere solidification, and the availability of ammonia to PLGA ester linkages.

Another paradigm in solvent extraction-based microencapsulation technologies.

The objectives of this study were to apply a base-driven reaction to developing a new microencapsulation technique to prepare progesterone-containing poly-D,L-lactide-co-glycolide microspheres. Nonhalogenated ester solvents such as ethyl acetate and ethyl formate were used as dispersed solvents. After an oil-in-water emulsion was prepared, a sodium hydroxide solution was added to trigger base-catalyzed hydrolysis of organic solvents dissolved in the aqueous phase. Their rapid depletion provided a sink condition and drove the continual diffusion of the organic solvents residing in emulsion droplets into the aqueous phase. These events led to the solidification of emulsion droplets into microspheres over 15-30 min, without the use of a quenching liquid. The rate of the base-driven reaction observed with ethyl formate was 2.3 times faster than that attained with ethyl acetate. The drug encapsulation efficiency was >or=93.2%, and solvent residues in the microspheres ranged from 1.87 to 2.69%. GPC and FTIR results demonstrated that the structural integrity of the polymer and progesterone remained unchanged during the base-catalyzed microencapsulation process. This method might serve as a promising alternative for preparing nanoparticles and microspheres.

Ammonolysis-based microencapsulation technique using isopropyl formate as dispersed solvent.

The objectives of this study were to develop an ammonolysis-based microencapsulation technique using a nonhalogenated isopropyl formate and to evaluate its feasibility in preparing poly-D,L-lactide-co-glycolide microspheres. The choice of isopropyl formate was based on its great reactivity toward ammonolysis and acceptance as a flavoring agent for human food by regulatory agencies. Progesterone was used as a model drug for microencapsulation. In the practice of this microencapsulation process, a dispersed phase consisting of isopropyl formate, the polymer and progesterone was emulsified in an aqueous phase. Solvent removal from emulsion droplets was rapidly achieved by ammonolysis at ambient conditions, not by typical solvent evaporation and/or extraction. Depending upon microsphere formulations, its encapsulation efficiency ranged from 88.0+/-3.6 to 97.0+/-3.6%. Analysis of FTIR spectra suggested that there were no significant chemical interactions between prednisolone and the polymer. Both DSC and XRD data substantiated that the magnitude of an actual progesterone loading influenced its physical status in the microspheres. Interestingly, the microspheres prepared in this study contained noticeably lower levels of solvent residues: a gas chromatographic analysis demonstrated that the levels of residual isopropyl formate found in different microspheres were not more than 0.34+/-0.07%. It was seen to be feasible from these results that the ammonolysis-based approach using isopropyl formate might have a potential as an alternative microencapsulation technique.

Application of column-switching HPLC method in evaluating pharmacokinetic parameters of zaltoprofen and its salt.

The objective of this study was to compare the pharmacokinetic parameters of zaltoprofen and those of its sodium salt in rats. Zaltoprofen, a potent non-steroidal anti-inflammatory agent, was virtually insoluble in water, but its sodium salt had excellent water solubility. To investigate the effect of aqueous solubility differences upon their pharmacokinetic parameters, minicapsules containing the drug powders were administrated orally to rats, and blood samples were taken via the common carotid artery. A column-switching high-performance liquid chromatographic analytical procedure was developed and validated for the quantitation of zaltoprofen in rat plasma samples. Our study demonstrated that the time required to reach maximum plasma concentration (T(max)) of zaltoprofen sodium was significantly reduced and its maximum plasma concentration (C(max)) was increased 1.5-fold, relative to the values for zaltoprofen. It is anticipated that the sodium salt of zaltoprofen will allow the rapid onset of the drug's action in the treatment of inflammatory diseases.

Effect of pharmaceutical excipients on aqueous stability of rabeprazole sodium.

The chemical stability of a proton-pump inhibitor, rabeprazole sodium, was evaluated in simulated intestinal fluid (pH 6.8) containing various 'Generally Recognized As Safe (GRAS)'-listed excipients, including Brij 58, Poloxamer 188, Cremophor RH40, Gelucire 44/14 and PEG 6000. After incubation at 37 and 60 degrees C, the amounts of rabeprazole and its degradation product, thioether-rabeprazole, were quantitated by HPLC analysis. The main degradation product was separated and characterized by LC/MS. The degradation of rabeprazole followed first-order kinetics. In the absence of any excipients, the rate constants (k) obtained at 37 and 60 degrees C were 0.75 and 2.78h(-1), respectively. In contrast, the addition of excipients improved its stability. Among several excipients tested in this study, Brij 58 displayed the greatest stabilizing effect. For instance, at 37 and 60 degrees C, Brij 58 reduced the k values to 0.22 and 0.53h(-1), respectively. The stabilizing mechanisms of these hydrophilic polymeric excipients with optimal HLB values could be partially explained in terms of their solubilizing efficiency and micellar formation for thioether-rabeprazole. In conclusion, rabeprazole formulations that contain suitable excipients would improve its stability in the intestinal tract, thereby maximizing bioavailability.

Ammonolysis-induced solvent removal: a facile approach for solidifying emulsion droplets into PLGA microspheres.

An ammonolysis-based microencapsulation technique useful for the preparation of biodegradable microspheres was described in this study. A dispersed phase consisting of poly- d, l-lactide- co-glycolide, progesterone, and methyl chloroacetate was emulsified in an aqueous phase. Upon addition of ammonia solution, the emulsion droplets were quickly transformed into poly- d, l-lactide- co-glycolide microspheres laden with progesterone. Rapid solvent removal was accompanied by ammonolysis. The chemical reaction converted water-immiscible methyl chloroacetate to water-miscible chloroacetamide and methanol. Chloroacetamide formation was proved by (1)H NMR and ESI-MS studies. Thermogravimetric analysis showed that the microspheres contained only small amounts of residual methyl chloroacetate. Incorporation efficiencies of progesterone ranged from 64.3 +/- 1.1 to 72.8 +/- 0.3%, depending upon microsphere formulations. X-ray powder diffractometry analysis substantiated that no polymorphic transition of progesterone occurred during microencapsulation. To evaluate the feasibility of this new method against the commonly used microencapsulation method, microspheres were also prepared by a typical dichloromethane-based solvent evaporation process. The important attributes of microspheres prepared from both methods were characterized for comparison. The new ammonolysis-based microencapsulation process showed interesting features distinct from those of the solvent evaporation process. The microencapsulation process reported in this study might be applicable in loading pharmaceuticals into various polymeric microspheres.

Characterization of dual layered pellets for sustained release of poorly water-soluble drug.

The aim of this study was to develop pellet formulations that could be used to improve the dissolution and bioavailability of a poorly water-soluble model drug, cisapride. Six different types of pellets were prepared by coating sugar spheres in a fluidized bed coater. When the sugar spheres were single layered containing cisapride and solubilizer such as polysorbate 80, the resulting pellets provided an instant release of cisapride in the simulated gastric fluid. Dissolution tests carried out in the simulated intestinal fluid showed that there were negligible amounts of cisapride released, regardless of the pellet formulation. To succeed in attaining dissolution and the sustained release of cisapride at a neural pH, the single layered pellets were coated again with a coating suspension containing Eudragit RS 30D and L 30D. Scanning electron microscopy revealed that the dual layered pellets had a crack-free and spherical surface. Interestingly, the dual layered pellets provided the sustained release of cisapride in both the simulated gastric and intestinal fluids. The composition and components of the dual layers were found to be key parameters affecting the pattern of cisapride dissolution. Significant improvement in the bioavailability of cisapride was achieved when the dual layered pellets were administered orally to dogs. Overall, these results suggest that the dual layered pellets have potential as a sustained release dosage form for poorly water-soluble drugs.

Reverse micelle-based microencapsulation of oxytetracycline hydrochloride into poly-d,l-lactide-co-glycolide microspheres.

The objectives of this study were to solubilize oxytetracycline hydrochloride (HCl) in reverse micelles to prepare poly-d,l-lactide-co-glycolide (PLGA) microspheres and to explore parameters affecting its encapsulation efficiency. Oxytetracycline HCl was dissolved in the reverse micelles consisting of cetyltrimethylammonium bromide, water, and ethyl formate. A PLGA polymer was then dissolved in the reverse micellar solution, and a modified solvent quenching procedure was carried out to prepare PLGA microspheres. Encapsulation efficiencies of oxytetracycline HCl ranged from 2.3 +/- 0.2 to 24.9 +/- 4.6%, depending on experimental conditions. Important parameters affecting its encapsulation efficiency included the amounts of water used to prepare the reverse micelles and PLGA polymer. With regard to microsphere morphology, the reverse micellar process produced the microspheres with smooth and pore-free surfaces. In particular, their internal matrices did not possess hollow cavities that were frequently observed when a typical double emulsion technique was used to make microspheres. In summary, it was possible to encapsulate oxytetracycline HCl into PLGA microspheres via the ethyl formate-based reverse micellar technique. We also anticipate that the use of ethyl formate could avoid environmental and human toxicity issues associated with methylene chloride.

Characterization of itraconazole semisolid dosage forms prepared by hot melt technique.

The objective of this study was to formulate itraconazole semisolid dosage forms and characterize their physicochemical properties. Itraconazole and excipients such as polysorbate 80, fatty acids, fatty alcohols, oils and organic acids were melted at 160 degrees C. The fused solution was then cooled immediately at -10 degrees C to make wax-like semisolid preparations. Their physicochemical attributes were first characterized using differential scanning calorimetry, Fourier transform infrared spectroscopy and nuclear magnetic resonance spectrometry. The solubility of itraconazole in semisolid preparations and their dispersability in the simulated gastric fluid were also determined. Our semisolid preparations did not show any distinct endothermic peak of a crystalline form of itraconazole around 160-163 degrees C. This suggested that it was changed into amorphous one, when it was formulated into semisolid preparations. In addition, the distinctive functional peaks and chemical shifts of itraconazole were well retained after processing into semisolid preparations. It could be inferred from the data that itraconazole was stable during incorporation into semisolid preparations by the hot melt technique. In particular, itraconazole semisolid preparations composed of polysorbate 80, fatty acids and organic acids showed good solubility and dissolution when dispersed in an aqueous medium. It was anticipated that the semisolid dosage forms would be industrially applicable to improving the bioavailability of poorly water-soluble drugs.