Design of Montelukast Nanocrystalline Suspension for Parenteral Prolonged Delivery.

Background: Montelukast (MTK), a representative leukotriene receptor antagonist, is currently being investigated as a potential candidate for treating Alzheimer's disease. For potent and effective dosing in elderly patients, a parenteral prolonged delivery system is favored, with improved medication adherence with reduced dosage frequency. Purpose: This study aimed to design a nanocrystalline suspension (NS)-based MTK prolonged delivery system and evaluate its pharmacokinetics profile and local tolerability following subcutaneous administration. Methods: To decelerate the dissolution rate, the amorphous MTK raw material was transformed into a crystalline state using a solvent-mediated transformation method and subsequently formulated into NS using a bead-milling technique. The MTK NSs were characterized by morphology, particle size, crystallinity, and in vitro dissolution profiles. The pharmacokinetic profile and local tolerability at the injection site following subcutaneous injection of MTK suspension were evaluated in rats. Results: Microscopic and physical characterization revealed that the amorphous MTK powder was lucratively transformed into a crystalline form in acidic media (pH 4). MTK crystalline suspensions with different diameters (200 nm, 500 nm, and 3 µm) were uniformly prepared using bead-milling technology, employing polysorbate 80 as suspending agent. Prepared crystalline suspensions exhibited analogous crystallinity (melting point, 150°C) and size-dependent in vitro dissolution profiles. MTK NSs with particle sizes of 200 nm and 500 nm provided a protracted pharmacokinetic profile for up to 4 weeks in rats, with a higher maximum drug concentration in plasma than the 3 µm-sized injectable suspensions. Histopathological examination revealed that MTK NS caused chronic granulomatous inflammation at the injection site, which resolved after 4 weeks. Conclusion: The MTK parenteral NS delivery system is expected to be a valuable tool for treating Alzheimer's disease with extended dose intervals.

Effect of particle size on in vivo performances of long-acting injectable drug suspension.

Herein, entecavir-3-palmitate (EV-P), an ester prodrug of entecavir (EV), was employed as a model drug, and the effect of drug particle size on in vivo pharmacokinetic profiles and local inflammatory responses, and those associations were evaluated following intramuscular (IM) injection. EV-P crystals with different median diameters (0.8, 2.3, 6.3, 15.3 and 22.6 µm) were prepared using the anti-solvent crystallization method, with analogous surface charges (-10.7 ~ -4.7 mV), and crystallinity (melting point, 160-170 °C). EV-P particles showed size-dependent in vitro dissolution profiles under sink conditions, exhibiting a high correlation between the median diameter and Hixon-Crowell's release rate constant (r2 = 0.94). Following IM injection in rats (1.44 mg/kg as EV), the pharmacokinetic profile of EV exhibited marked size-dependency; 0.8 µm-sized EV-P particles about 1.6-, 3.6-, and 5.6-folds higher systemic exposure, compared to 6.3, 15.3, and 22.6 µm-sized particles, respectively. This pharmacokinetic pattern, depending on particle size, was also highly associated with histopathological responses in the injected tissue. The smaller EV-P particles (0.8 or 2.3 µm) imparted the larger inflammatory lesion after 3 days, lower infiltration of inflammatory cells, and thinner fibroblastic bands around depots after 4 weeks. Conversely, severe fibrous isolation with increasing particle size augmented the drug remaining at injection site over 4 weeks, impeding the dissolution and systemic exposure. These findings regarding the effects of formulation variable on the in vivo behaviors of long-acting injectable suspension, provide constructive knowledge toward the improved design in poorly water-soluble compounds.

Montelukast microsuspension with hypromellose for improved stability and oral absorption.

Oral montelukast (MTK) is prescribed to treat asthma or rhinitis, and is clinically investigated as new medication in the treatment of Alzheimer's dementia. Herein, in order to better patient's compliance, microsuspensions (MSs)-based oral liquid preparations of montelukast (MTK) were formulated with polymeric suspending agents including hypromellose (HPMC), and those drug-polymer interaction, physicochemical stability, dissolution, and in vivo pharmacokinetic profile was evaluated. When amorphous MTK particle was suspended in aqueous vehicle, it was readily converted into crystalline form and grown into aggregates, drastically lowering dissolution rate. However, the addition of HPMC polymer markedly suppressed the crystal growth, providing both improved drug stability and profound dissolution profile. Raman spectrometry denoted the inter-molecular hydrogen boding between MTK particle and HPMC polymer. The crystal growth or dissolution profile of MSs was markedly affected by pharmaceutical additives (sucrose or simethicone) in the preparations or storage temperature. The optimized HPMC-based MS exhibited over 80% higher bioavailability, compared to marketed granule (Singulair®) in rats. Therefore, novel MTK-loaded MS can be a promising liquid preparation, bettering oral absorption and patient's compliance.

Development of a Novel Controlled-Release Tablet of Pregabalin: Formulation Variation and Pharmacokinetics in Dogs and Humans.

BACKGROUND: Novel three-layered (TL) tablet systems were compared with both monolithic matrix (MM) formulations and a commercial immediate-release (IR) capsule to develop once-a-day (OAD) pregabalin tablets. METHODS: The physical properties of the TL tablets, including dissolution and swelling rates, were compared with those of the MM tablets and the pharmacokinetic parameters of the TL tablet were compared with those of an IR capsule in beagles and humans. RESULTS: Our results indicated that the same amount of a hydrophilic polymer in the formulations had similar dissolution profiles at 12 h, regardless of the tablet geometry. However, the degree of tablet swelling differed, with larger amounts of polymer in the tablets showing a greater degree of swelling. In addition, TL tablets swelled more rapidly compared with MM tablets. For the pharmacokinetic study of the TL tablet, the beagles demonstrated absorption results similar to those of an IR capsule, whereas the humans demonstrated low total absorption compared with an IR capsule. The time of the peak plasma concentration at 6 h in the fed state of humans coincided with the results of the study on beagles. CONCLUSION: The novel TL tablet system of pregabalin may prove to be helpful in developing improved formulations with better continuous drug absorption for OAD administration.

In situ intestinal permeability and in vivo oral bioavailability of celecoxib in supersaturating self-emulsifying drug delivery system.

In order to characterize the in situ intestinal permeability and in vivo oral bioavailability of celecoxib (CXB), a poorly water-soluble cyclooxygenase (COX)-2 inhibitor, various formulations including the self-emulsifying drug delivery system (SEDDS) and supersaturating SEDDS (S-SEDDS) were compared. The S-SEDDS formulation was obtained by adding Soluplus as a precipitation inhibitor to SEDDS, composed of Capryol 90 as oil, Tween 20 as surfactant, and Tetraglycol as cosurfactant (1:4.5:4.5 in volume ratio). An in situ single pass intestinal perfusion study in rats was performed with CXB-dissolved solutions at a concentration of 40 µg/mL. The effective permeability (Peff) of CXB in the control solution (2.5 v/v% Tween 20-containing PBS) was 6.39 × 10(-5) cm/s. The Peff value was significantly increased (P < 0.05) by the lipid-based formulation, yielding 1.5- and 2.9-fold increases for the SEDDS and S-SEDDS solutions, respectively, compared to the control solution. After oral administration of various formulations to rats at the equivalent dose of 100 mg/kg of CXB, the plasma drug level was measured by LC-MS/MS. The relative bioavailabilities of SEDDS and S-SEDDS were 263 and 355 %, respectively, compared to the CXB suspension as a reference. In particular, S-SEDDS revealed the highest Cmax and the smallest Tmax, indicating rapid and enhanced absorption with this formulation. This study illustrates the potential use of the S-SEDDS formulation in the oral delivery of poorly water-soluble compounds.

Enhanced dissolution of celecoxib by supersaturating self-emulsifying drug delivery system (S-SEDDS) formulation.

A supersaturating self-emulsifying drug delivery system (S-SEDDS) was prepared and evaluated for enhanced dissolution of celecoxib (CXB), a poorly water-soluble drug. The selected CXB-dissolved SEDDS formulation consisting 10 % Capryol 90 (oil), 45 % Tween 20 (surfactant), and 45 % Tetraglycol (cosurfactant) had the characteristics of small droplet size and great solubility as 208 nm and 556.7 mg/mL in average, respectively. CXB dissolution from SEDDS in simulated gastric fluid was increased to about 20 % for the initial period of 5 min, but decreased to a half level as time elapsed. Thus, precipitation inhibitors were screened to stabilize the supersaturation. The stabilizing effect of Soluplus, an amphiphilic copolymer, was concentration-dependent, revealing the greatest dissolution of approximately 90 % level with delayed drug crystallization by the addition of the copolymer. CXB dissolution from S-SEDDS was pH-independent. We concluded that S-SEDDS formulation would be very useful in the future for developing oral delivery product of poorly water-soluble drugs.

Immediate release of ibuprofen from Fujicalin®-based fast-dissolving self-emulsifying tablets.

BACKGROUND: Drug release from a solid form of self-emulsifying drug delivery system (SEDDS) has greatly been limited due to strong adsorption and physical interaction with carriers. To facilitate drug release process in the stomach, an acid-soluble powderizing carrier, Fujicalin(®) was evaluated together with different disintegrants and hydrophilic lubricants. METHOD: Immediate-release self-emulsifying tablets (IR-SETs) of ibuprofen (IBU) was prepared with solidified SEDDS of IBU, various disintegrants, and lubricants, and drug release was evaluated to develop IR-SET that can release IBU with a similar IBU release rate to that obtained with liquid SEDDS. RESULTS: The liquid SEDDS consisted of Capryol 90, Cremophor EL, Labrasol, and IBU at a ratio of 3:4:3:3, and was solidified with various adsorbents. The powderized SEDDS was tabletted by a direct compression. Fujicalin(®)-based SEDDS tablets demonstrated remarkably higher dissolution rate of IBU compared with Neusilin(®) and Neosyl(®)-based SEDDS tablets. The IR-SET formula of IBU prepared with Fujicalin(®) as an adsorbent, Polyplasdone(®) as a disintegrant, and sodium bicarbonate as a co-disintegrant showed over 90% of initially loaded dose of IBU released within 5 min in a stimulated gastric juice (pH 1.2), exhibiting almost equivalent rate of IBU release to that shown by liquid SEDDS. The particle size analysis revealed no significant differences in droplet sizes of the microemulsions formed from liquid (116 nm) and IR-SET (110 nm). CONCLUSION: The novel IR-SET can be promising as a fast-releasing SEDDS tablet of IBU for fast onset of action.

Solid dispersion formulations of megestrol acetate with copovidone for enhanced dissolution and oral bioavailability.

In order to enhance the dissolution profile and oral bioavailability of megestrol acetate (MA), solid dispersions of MA (MASDs) were formulated with copovidone and crystal sugar as a hydrophilic polymeric carrier and an inert core bead, respectively. Solvent evaporation method and fluidized bed coating technique were employed. MASDs were categorized as crystalline solid dispersion by the characterization of differential scanning calorimetry and X-ray diffraction. The mass-median diameters of MASDs were in a range of 1.4 to 2.6 µm. Based on drug to polymer ratio, MASD (1:1) and (1:2) were considered as optimized formulations, resulting in a smooth-surfaced homogeneously coated layer with enhanced dissolution rate. Dissolution of MASD was gradually increased up to 15 min, after which it reached a plateau. For the initial period, dissolution rates were in the decreasing order of MASD (1:2) ≥ MASD (1:1) > MASD (1:3) > MASD (1:5) > MASD (1:0.5) > MA powder. In the comparative pharmacokinetic study with Megace OS, a reference drug product, MASD (1:1) showed improved bioavailability of over 220% with 2-fold higher C(max) and 30% faster T(max). We conclude that MASD (1:1) is a good candidate for the development of oral solid dosage forms.

Pharmacologically active metabolites of currently marketed drugs: potential resources for new drug discovery and development.

Biotransformation is the major clearance mechanism of therapeutic agents from the body. Biotransformation is known not only to facilitate the elimination of drugs by changing the molecular structure to more hydrophilic, but also lead to pharmacological inactivation of therapeutic compounds. However, in some cases, the biotransformation of drugs can lead to the generation of pharmacologically active metabolites, responsible for the pharmacological actions. This review provides an update of the kinds of pharmacologically active metabolites and some of their individual pharmacological and pharmacokinetic aspects, and describes their importance as resources for drug discovery and development.