Changes in Tablet Color Due to Light Irradiation: Photodegradation of the Coating Polymer, Hypromellose, by Titanium Dioxide.

The color of the tablets and capsules produced by pharmaceutical companies is important from the perspectives of product branding and counterfeiting. According to some studies, light can change tablet color during storage. In this study, tablets comprising amlodipine besylate (AB), a well-known light-sensitive drug, were coated with commonly used coating materials and exposed to light. Compared to the tablets that were not exposed to light, the color of those exposed to light changed over time. In fact, a faster and more pronounced color change was observed in the tablets exposed to light; however, the amount of AB did not decrease significantly in these tablets. The coating materials and their amounts were varied to clarify the materials involved in the color change. Based on the results, titanium dioxide and hypromellose may be involved in the color change process. As titanium dioxide is a photocatalyst, it may induce or promote chemical changes in hypromellose upon light irradiation. Overall, care should be exercised during selection of the coating polymer because titanium dioxide may promote photodegradation of the coatings while protecting the tablet's active ingredient from light.

Phosphorylated Serine-Modified Polyamidoamine Dendrimer as an Osteoid Surface-Targeting Drug Carrier.

The aim of this study was to develop a polyethylene glycol (PEG)-conjugated third-generation polyamidoamine dendrimer (PAMAM) with phosphorylated serine as an osteoid surface-targeting drug carrier for the treatment of bone diseases. We conjugated PAMAM backbones to l-serine and obtained Ser-PAMAM. Then, phosphoric acid and PEG were covalently bound to the Ser-PAMAM to generate PEGylated phosphorylated Ser-PAMAM (PEG-phosSer-PAMAM). Using osteoblast-like cells (MC3T3-E1 cells) cultured in 3D collagen gels, we showed that phosSer-PAMAM adsorbed both the hydroxyapatite and type I collagen components of the bone matrix. Fourier transform infrared spectroscopy analysis indicated that the phosphoryl side chains of phosSer-PAMAM formed electrostatic interactions and hydrogen bonds with the anionic amino acid residues of type I collagen. Mice were intravenously injected with the foregoing molecules, and a tissue distribution study disclosed that the lower limb bone took up about twice as much 111In-labeled PEG-phosSer-PAMAM as 111In-labeled nonphosphorylated PEG-Ser-PAMAM or unmodified PAMAM. An intrabone distribution experiment showed that fluorescein isothiocyanate (FITC)-labeled PEG-phosSer-PAMAM accumulated on the osteoid surfaces, which is associated with bone pathogenesis such as skeletal dysplasias and osteoporosis to a far greater extent than nonphosphorylated PEG-Ser-PAMAM. Our findings indicated that PEG-phosSer-PAMAM is a promising carrier for efficient drug targeting to osteoid surfaces.

Topical Xerostomia Treatment with Hyaluronate Sheets Containing Pilocarpine.

Sjogren's syndrome and radiation therapy for head and neck cancers are often accompanied by xerostomia. Oral pilocarpine (PCP) to treat xerostomia produces systemic side effects, such as runny nose and lacrimation. To improve the therapeutic efficacy of PCP and reduce the aforementioned side effects, we developed a topical delivery system for PCP using freeze-dried sheets of hyaluronic acid (HA). The advantages of HA sheets over conventional oral formulations were examined through in vivo pharmacokinetic and pharmacodynamic studies after their application to oral tissues and salivary glands. The concentration of PCP in the submucosal tissue of the oral cavity was determined using the microdialysis (MD) method after buccal application of HA sheets containing PCP to hamsters. The concentration of PCP in the MD outflow was quite low after gastric administration, whereas the PCP concentration in plasma was high. In contrast, after buccal application of HA sheets containing PCP, the concentration of the drug in the MD outflow increased, despite the negligible concentration in plasma. These findings indicated that both enhancement of saliva secretion and the avoidance of systemic side effects could be achieved through buccal administration of PCP-loaded HA sheets. In addition, the pharmacodynamic study showed that when compared with intravenous and gastric administration, salivary application of HA sheets containing PCP resulted in similar volumes of saliva secretion and reduced lacrimal secretions. In conclusion, freeze-dried HA sheets allow for the development of a novel buccal delivery system with enhanced therapeutic efficacy and safety to treat xerostomia.

Simultaneous Determination of Active Pharmaceutical Ingredients and Water-Soluble Polymers: Analysis of Dissolution Profiles from Sustained-Release Formulations and Mechanisms Involved.

The dissolution behaviors of base excipients from sustained-release formulations have been investigated using various methodologies. However, the dissolution of polymers has not been fully evaluated because differences between formulations are still verified only by the release of active pharmaceutical ingredients (APIs). In our previous study, we proposed a quick and simultaneous analysis of dissolved APIs and water-soluble polymers by ultra HPLC using charged aerosol and photodiode array detectors. The purpose of this study was to verify whether the analysis system could be adapted to other water-soluble polymers. Dissolution tests were conducted using matrix model tablets prepared from three polymers and three APIs (propranolol, ranitidine, and cilostazol) with different solubilities. The dissolution profiles of the polymers and APIs were determined using the proposed analysis system and compared. The results clarified differences in the dissolution behaviors of the APIs and polymers. The polymers, especially hydroxypropyl cellulose, exhibited the dissolution properties characteristic of each model formulation. Propranolol and ranitidine showed the diffusion type, while cilostazol showed the erosion type release mechanism due to their different solubilities. The release of cilostazol was delayed in all models compared to the polymer, which may be due to the aggregation of cilostazol in the gel layer. This analytical method can be used to study the dissolution behavior (diffusion or erosion) of APIs from matrix tablets containing various polymers. This method will provide useful information on release control, which will make it easier and more efficient to design appropriate formulations and analyze the release mechanisms.

Sunitinib decreases the expression of KRT6A and SERPINB1 in 3D human epidermal models.

Hand-foot skin reaction (HFSR) is a common side effect caused by several tyrosine kinase inhibitors, including sunitinib. However, the nature of the cornifying factors related to the molecular biological mechanisms underlying HFSR remains poorly understood. We used human keratinocyte models to investigate the key cornifying factors for dermatological and biological abnormalities induced by sunitinib. On the basis of the results of microarray analysis using the three-dimensional (3D) human epidermal model, keratin (KRT)6A, serine protease inhibitor (SERPIN)B1, KRT5, and SERPIN Kazal-type 6 were selected as candidate genes related to HFSR. Sunitinib treatment significantly decreased the expression of SERPINB1 and KRT6A in the immunohistochemical staining of the 3D epidermal model. In PSVK1 cells, but not in normal human epidermal keratinocyte cells, both of which are human normal keratinocyte cell lines, sunitinib decreased the expression of KRT6A with a concomitant decrease in levels of phosphorylated extracellular signal-regulated kinases (ERK)1/2 and phosphorylated p38 mitogen-activated protein kinase (MAPK). Inhibitors of the ERK and p38 MAPK signal pathways also significantly decreased KRT6A expression. Sunitinib-induced decrease in KRT6A expression was suppressed by the inhibition of glycogen synthase kinase-3ß by enhancing ERK1/2 and p38 MAPK phosphorylation. Thus, sunitinib reduces the expression of KRT6A and SERPINB1 by inhibiting the ERK1/2 and p38 MAPK signalling pathways in the skin model. These changes in expression contribute to the pathology of HFSR.

l-Serine-modified polyamidoamine dendrimer as a highly potent renal targeting drug carrier.

Effective delivery of drug carriers selectively to the kidney is challenging because of their uptake by the reticuloendothelial system in the liver and spleen, which limits effective treatment of kidney diseases and results in side effects. To address this issue, we synthesized l-serine (Ser)-modified polyamidoamine dendrimer (PAMAM) as a potent renal targeting drug carrier. Approximately 82% of the dose was accumulated in the kidney at 3 h after i.v. injection of 111In-labeled Ser-PAMAM in mice, while i.v. injection of 111In-labeled unmodified PAMAM, l-threonine modified PAMAM, and l-tyrosine modified PAMAM resulted in kidney accumulations of 28%, 35%, and 31%, respectively. Single-photon emission computed tomography/computed tomography (SPECT/CT) images also indicated that 111In-labeled Ser-PAMAM specifically accumulated in the kidneys. An intrakidney distribution study showed that fluorescein isothiocyanate-labeled Ser-PAMAM accumulated predominantly in renal proximal tubules. Results of a cellular uptake study of Ser-PAMAM in LLC-PK1 cells in the presence of inhibitors [genistein, 5-(N-ethyl-N-isopropyl)amiloride, and lysozyme] revealed that caveolae-mediated endocytosis, micropinocytosis, and megalin were associated with the renal accumulation of Ser-PAMAM. The efficient renal distribution and angiotensin-converting enzyme (ACE) inhibition effect of captopril (CAP), an ACE inhibitor, was observed after i.v. injection of the Ser-PAMAM-CAP conjugate. These findings indicate that Ser-PAMAM is a promising renal targeting drug carrier for the treatment of kidney diseases. Thus, the results of this study demonstrate efficient renal targeting of a drug carrier via Ser modification.

Quick and Simultaneous Analysis of Dissolved Active Pharmaceutical Ingredients and Formulation Excipients from the Dissolution Test Utilizing UHPLC and Charged Aerosol Detector.

The objective of the study is to develop a quick and simultaneous analysis system for the dissolution of the active pharmaceutical ingredient (API) and the formulation excipient in samples from the dissolution test by UHPLC using the charged aerosol and PDA detectors. The combination of two columns for size-exclusion chromatography (SEC) and the equipment of the charged aerosol detector allowed the quick determination of various water-soluble polymers. Three model sustained-release tablets, each containing a different API of different water solubility (propranolol (soluble), ranitidine (very soluble), and cilostazol (practically insoluble)), were prepared from polyethylene oxide (PEO) matrix to verify the applicability and utility of the analysis system. The dissolution of propranolol was the same as that of PEO, indicating that the diffusion rate of propranolol was consistent with the erosion rate of the PEO and that the dissolution of PRO was based on diffusion. Ranitidine was released faster than PEO, suggesting that ranitidine was diffused through the gel layer of PEO early upon contact with the dissolution medium and before PEO gel erosion. Cilostazol was released slower as compared to PEO, indicating that cilostazol dissolution was based on the polymer's erosion. These results suggested that the analysis system developed in this study is a precise and valid tool to study the dissolution behavior of both APIs and excipients. Optimization of the SEC column for the appropriate separation of APIs and excipients makes the analysis system more efficient and convenient to study the drug release mechanisms and to design formulations.

Effect of Cerebrospinal Fluid Circulation on Nose-to-Brain Direct Delivery and Distribution of Caffeine in Rats.

Direct drug delivery from nose to brain has drawn much attention as an effective strategy for the treatment of central nervous system diseases. After intranasal administration, drug molecules can be directly delivered from the nose to the brain. However, the detailed mechanism for this direct delivery to the brain has not been elucidated. In the present study, the effect of the activation of the cerebral fluid circulation (the glymphatic system) on the efficacy of direct delivery from nose to brain was investigated. Because the glymphatic system is activated by some anesthetic regimens, the differences in brain delivery and the pharmacokinetics under anesthetic and conscious conditions were compared in rats. Under urethane anesthesia, direct delivery from the nose to the brain was facilitated, whereas the brain uptake from the systemic circulation via the blood-brain barrier was decreased. In addition, both the brain uptake of caffeine injected into the subarachnoid cerebrospinal fluid (CSF) and the extracerebral clearance of caffeine after intrastriatal injection were enhanced under anesthesia. For intranasal administration, caffeine was transported directly from the nose to the CSF and then delivered into the brain parenchyma by the CSF circulation. The results obtained in the present study clarified that the direct delivery from nose to brain could be facilitated by anesthesia. These findings suggest that fluid circulation in the brain can contribute to a wider cerebral distribution of the drug after direct delivery from nose to brain.

Transnasal Delivery of the Peptide Agonist Specific to Neuromedin-U Receptor 2 to the Brain for the Treatment of Obesity.

Obesity and metabolic syndrome are threats to the health of large population worldwide as they are associated with high mortality, mainly linked to cardiovascular diseases. Recently, CPN-116 (CPN), which is an agonist peptide specific to neuromedin-U receptor 2 (NMUR2) that is expressed predominantly in the brain, has been developed as a new therapeutic candidate for the treatment of obesity and metabolic syndrome. However, treatment with CPN poses a challenge due to the limited delivery of CPN to the brain. Recent studies have clarified that the direct anatomical connection of the nasal cavity with brain allows delivery of several drugs to the brain. In this study, we confirm the nasal cavity as a promising CPN delivery route to the brain for the treatment of obesity and metabolic syndrome. According to the pharmacokinetic study, the clearance of CPN from the blood was very rapid with a half-life of 3 min. In vitro study on its stability in the serum and cerebrospinal fluid (CSF) indicates that CPN was more stable in the CSF than in the blood. The concentration of CPN in the brain was higher after nasal administration, despite its lower concentrations in the plasma than that after intravenous administration. The study on its pharmacological potency suggests the effective suppression of increased body weight in mice in a dose-dependent manner due to the direct activation of NMUR2 by CPN. This results from the higher concentration of corticosterone in blood after nasal administration of CPN as compared to nasal application of saline. In conclusion, the above findings indicate that the nasal cavity is a promising CPN delivery route to the brain to treat obesity and metabolic syndrome.

A chemically stable peptide agonist to neuromedin U receptor type 2.

Neuromedin U (NMU) is a peptide with appetite suppressive activity and other physiological activities via activation of the NMU receptors NMUR1 and NMUR2. In 2014, we reported the first NMUR2 selective agonist, 3-cyclohexylpropionyl-Leu-Leu-Dap-Pro-Arg-Asn-NH2 (CPN-116). However, we found that CPN-116 in phosphate buffer is unstable because of Nα-to-Nß acyl migration at the Dap residue. In this study, the chemical stability of CPN-116 was evaluated under various conditions, and it was found to be relatively stable in buffers such as HEPES and MES. We also performed a structure-activity relationship study to obtain an NMUR2-selective agonist with improved chemical stability. Consequently, CPN-219 bearing a Dab residue in place of Dap emerged as a next-generation hexapeptidic NMUR2 agonist.

Hepatic and Intrahepatic Targeting of Hydrogen Sulfide Prodrug by Bioconjugation.

Hydrogen sulfide (H2S) is an endogenous gaseous transmitter known to play an important role in biological functions. For the hepatic and intrahepatic targeting of H2S prodrug at the cellular level, we developed two types of sulfo-albumins, in which five sulfide groups (source of H2S) were covalently bound to succinylated (Suc) or galactosylated (Gal) bovine serum albumin (BSA). Sulfo-BSA-Suc and polyethylene glycol (PEG)-Sulfo-BSA-Gal, both released H2S in the 5 mM glutathione solution, but not in the plasma. Sulfo-BSA-Suc and PEG-Sulfo-BSA-Gal were taken up by RAW264.7 cells (mouse macrophage-like cells) and Hep G2 cells (human hepatocellular carcinoma cells), respectively, and H2S was released. These results indicate that Sulfo-BSA-Suc and PEG -Sulfo-BSA-Gal selectively released H2S intracellularly. In a biodistribution study, up to 80% of 111In-labeled Sulfo-BSA-Suc and PEG-Sulfo-BSA-Gal rapidly accumulated in the liver, 30 min after intravenous injection in mice. Furthermore, 111In-labeled Sulfo-BSA-Suc and PEG-Sulfo-BSA-Gal predominantly accumulated in liver nonparenchymal (endothelial cells and Kupffer cells) and parenchymal cells (hepatocytes), respectively. These findings suggest that targeted delivery of H2S prodrug to a specific type of liver cells was successfully achieved by bioconjugation.

A New Method for Classification of Salts and Cocrystals Using Solid-State UV Spectrophotometry.

Salt and cocrystal formulations are widely used as techniques to improve physicochemical properties of compounds. Some spectrometric techniques to distinguish cocrystals from salts have been reported; however, it has not been possible to adapt these formulations with many compounds, because of limitations, high difficulty, and exceptions. Therefore, we focused on the possibility of UV spectrometry, which had not been reported as a classification technique for salts and cocrystals. The integration values of solid-state UV/visible (Vis) spectra of indomethacin salts were larger than those of physical mixtures of indomethacin and counter molecules, while that of indomethacin cocrystal was not large compared with that of the physical mixture. From these results, differences between a salt and a cocrystal were observed in their solid-state UV/Vis absorption spectra for indomethacin complexes. Therefore, it is suggested that solid-state UV/Vis absorption spectra can be used as a new technique to classify salts and cocrystals.

Improving the Solid-State Photostability of Furosemide by Its Cocrystal Formation.

The photostability of three types of furosemide (FUR) cocrystal (FUR-caffeine, FUR-urea, and FUR-nicotinamide cocrystals) was studied under irradiation with a D65 fluorescent lamp. The coloration of the FUR-urea pellets was significantly faster than that of the intact FUR, whereas the coloration of FUR-nicotinamide was suppressed compared with that of intact FUR and the other cocrystals. In the case of FUR-urea, the chemical degradation of FUR increased by approximately 6.6% after irradiation for 90 d. On the other hand, FUR-nicotinamide showed better chemical stability, with only 1.3% of FUR degraded, which was significantly lower than the other cocrystals. The FUR-urea pellets showed a UV-Visible absorption spectrum similar to that of intact FUR, while the absorption range of FUR-nicotinamide shifted to a shorter wavelength. The light sensitivity of FUR-nicotinamide was improved because of the much lower emission of the D65 fluorescent lamp in the absorption range of the cocrystal.

Application of a Microreactor to Pharmaceutical Manufacturing: Preparation of Amorphous Curcumin Nanoparticles and Controlling the Crystallinity of Curcumin Nanoparticles by Ultrasonic Treatment.

Amorphous nanoparticles of curcumin (ANC) with primary particle sizes of 50 to 100 nm were prepared using a forced thin film reactor (FTFR). An ethanolic solution of curcumin and polyvinylpyrrolidone was mixed with purified water in an FTFR to precipitate the curcumin nanoparticles. In order to obtain amorphous particles, the solvent used and the operation conditions of FTFR such as the rotation speed of the disk and the flow rate of solutions were adjusted. According to powder X-ray diffraction (XRD) analysis and Fourier transform infrared spectroscopy (FT-IR), amorphous curcumin nanoparticles were obtained. To control the crystallinity, ultrasonic treatment was carried out on ANC suspended in water or hexane to which a polymer or a surfactant was added to prevent the growth of the particles. Transmission electron microscopy, XRD, and FT-IR analyses indicated that the treatment enabled the transformation of ANC to crystalline form 1 (a fundamental curcumin structure) and then to crystalline form 2 or crystalline form 3 without any change in the size of the primary particles. These findings suggest the possibility of preparing solid particles with a desired particle size and crystallinity.

Quantitative Estimation of the Effect of Nasal Mucociliary Function on in Vivo Absorption of Norfloxacin after Intranasal Administration to Rats.

Nasal drug delivery has attracted significant attention as an alternative route to deliver drugs having poor bioavailability. Large-molecule drugs, such as peptides and central nervous system drugs, would benefit from intranasal delivery. Drug absorption after intranasal application depends on the nasal retention of the drug, which is determined by the nasal mucociliary clearance. Mucociliary clearance (MC) is an important determinant of the rate and extent of nasal drug absorption. The aim of the present study was to clarify the effect of the changes in MC on in vivo drug absorption after nasal application, and to justify the pharmacokinetic model to which the MC parameter was introduced, to enable prediction of bioavailability after intranasal administration. The pharmacokinetics of norfloxacin (NFX) after intranasal administration were evaluated following the modification of nasal MC by pretreatment with the MC inhibitors propranolol and atropine and the MC enhancers terbutaline and acetylcholine chloride. From the relationship between nasal MC and bioavailability after nasal application, prediction of drug absorption was attempted on the basis of our pharmacokinetic model. Propranolol and atropine enhanced the bioavailability of NFX by 90 and 40%, respectively, while the bioavailability decreased by 30% following terbutaline and 40% following acetylcholine chloride. As a result of changes in the MC function, nasal drug absorption was changed depending on the nasal residence time of the drug. On the basis of our pharmacokinetic model, the nasal drug absorption can be precisely predicted, even when the MC is changed. This prediction system allows the quantitative evaluation of changes in drug absorption due to changes in nasal MC and is expected to contribute greatly to the development of nasal formulations.

Delivery of Oxytocin to the Brain for the Treatment of Autism Spectrum Disorder by Nasal Application.

Oxytocin (OXT) is a cyclic nonapeptide, two amino acids of which are cysteine, forming an intramolecular disulfide bond. OXT is produced in the hypothalamus and is secreted into the bloodstream from the posterior pituitary. As recent studies have suggested that OXT is a neurotransmitter exhibiting central effects important for social deficits, it has drawn much attention as a drug candidate for the treatment of autism. Although human-stage clinical trials of the nasal spray of OXT for the treatment of autism have already begun, few studies have examined the pharmacokinetics and brain distribution of OXT after nasal application. The aim of this study is to evaluate the disposition, nasal absorption, and therapeutic potential of OXT after nasal administration. The pharmacokinetics of OXT after intravenous bolus injection to rats followed a two-compartment model, with a rapid initial half-life of 3 min. The nasal bioavailability of OXT was approximately 2%. The brain concentration of OXT after nasal application was much higher than that after intravenous application, despite much lower concentrations in the plasma. More than 95% of OXT in the brain was directly transported from the nasal cavity. The in vivo stress-relief effect by OXT was observed only after intranasal administration. These results indicate that pharmacologically active OXT was effectively delivered to the brain after intranasal administration. In conclusion, the nasal cavity is a promising route for the efficient delivery of OXT to the brain.

Novel Strategy for the Systemic Delivery of Furosemide Based on a New Drug Transport Mechanism.

We reported a novel transport mechanism of curcumin, independent of improved solubility, which involved direct contact of amorphous solid particles with the cell membrane. This mechanism has potential as a novel systemic delivery system of poorly water-soluble drugs. In this study, the transport mechanism of furosemide (FUR), which is transported by the same novel mechanism, was examined. In vitro cell permeation studies under air-interface conditions (AICs) revealed that the permeation from powders sprayed on cell monolayers was significantly higher than that under liquid-covered conditions (LCCs) from their solutions. The permeation from amorphous solid particles was faster than that from crystals. Similar results were derived from in vitro studies using an artificial membrane, with which the permeation of FUR could be examined without water. These findings clearly indicated that the transport mechanism of FUR is the same as that of curcumin. For the application of this new transport mechanism, the in vivo absorption of FUR was examined after pulmonary insufflation, which allows the solid particles to make direct contact with the epithelial cells. Pulmonary absorption of FUR from the amorphous powder was almost complete and was faster than that after intragastric administration of the solution, suggesting that FUR was absorbed from the lung by the same mechanism as the in vitro study. This new transport mechanism, which is independent of water dissolution, could be exploited to develop a novel delivery system for poorly water-soluble drugs, using pulmonary powder inhalation.

Utility of Solid-State UV/Vis Spectra on the Evaluation of Photostability of Indomethacin Crystals.

Evaluating the stability of drugs over ranges of various environmental conditions is necessary to ensure the quality of the drug throughout the shelf life. In this study, we used indomethacin, which is well known as a photosensitive drug, and evaluated the photostability of prepared crystals. HPLC analysis revealed that all the indomethacin crystals were degraded by light exposure. However, the indomethacin crystals involving solvates had different degrees of photodegradation and different solid-state UV/Vis spectra. The value of the absorption integral in the UVA range related closely to the photodegradation of indomethacin crystals involving solvates. Therefore, it is easy to compare the photosensitivity among the crystals without actual analytical data, by use of a suitable analytical method and using light exposure samples. Moreover, it is possible to predict the value of photodegradation ratio from the solid-state UV/Vis spectra of indomethacin crystals. Therefore, this method may provide key information for selecting the most appropriate crystal form of photosensitive drugs.

Improvement of the Solubility and Intestinal Absorption of Curcumin by N-Acyl Taurates and Elucidation of the Absorption-Enhancing Mechanisms.

In this study, the effects of N-acyl taurates (NATs) on the intestinal absorption of curcumin (CUR), a water-insoluble and poorly absorbed compound, were examined in rats. Sodium methyl lauroyl taurate (LMT) and sodium methyl cocoyl taurate (CMT) were the most effective in increasing the solubility and intestinal absorption of CUR. The intestinal membrane toxicity of the NATs was also evaluated by measuring the activity of lactate dehydrogenase (LDH), a toxicity marker. NATs did not increase the activity of LDH, suggesting that they may be safely administered orally. We further elucidated the absorption-enhancing mechanisms of NATs by using Caco-2 cells. In cellular transport studies, LMT and CMT reduced the transepithelial electrical resistance value of Caco-2 cells and increased the transport of 5(6)-carboxyfluorescein and CUR. Hence, the intestinal absorption enhancement by LMT and CMT was attributed to the synergistic effect of higher solubility and greater permeability of the cell layer towards CUR in the presence of the surfactants. In summary, co-administration of CUR with either LMT or CMT is a simple and effective method to enhance oral delivery of CUR.

Nasal Drug Absorption from Powder Formulations: Effect of Fluid Volume Changes on the Mucosal Surface.

The effect of changes in the mucosal fluid volume on the nasal drug absorption of powder formulations was evaluated using warfarin (WF), piroxicam (PXC), and norfloxacin (NFX) as model drugs. Lactose and sodium chloride (NaCl), which are water soluble and small-sized chemicals that increase osmotic pressure after dissolution, were used as excipients to change the mucosal fluid volume. The in vitro study using a Madin-Darby canine kidney (MDCK) cell monolayer indicated that lactose and NaCl, sprayed over the surface of air interface monolayers, increased the fluid volume on the monolayer surface and enhanced the transepithelial transport of the model drugs. The in vivo animal study indicated that the nasal absorption of PXC is enhanced by lactose and NaCl after nasal administration of the powder formulations. This is likely due to the enhanced dissolution of PXC on fluid-rich nasal mucosa and an increase in the effective surface area for drug permeation, which lead to better nasal absorption. However, both excipients failed to increase the nasal absorption of WF and NFX. To clarify the mechanism of the drug-dependent effect of lactose and NaCl, the nasal residence of the formulation was examined using FD70 as a non-absorbable marker. The nasal clearance of FD70 was enhanced by lactose and NaCl, leading to a decrease in the nasal drug absorption. Lactose and NaCl caused no damage to the nasal tissue. These results indicate that the addition of water-soluble excipients such as lactose to powder formulations can enhance the nasal absorption of highly permeable but poorly soluble drugs.