Liquid-filled Capsules Research Articles

Liquid- and Semisolid-Filled Hard Gelatin Capsules Containing Alpha-Lipoic Acid as a Suitable Dosage Form for Compounding Medicines and Dietary Supplements.

Liquid-filled hard gelatin capsules may have pertinent advantages both for therapeutic effect and extemporaneous preparations of medicines. Alpha lipoic acid is a substance used in medicines and dietary supplements and there is a need for creating an appropriate formulation which would be suitable for each individual patient or consumer. Based on its biopharmaceutical and physical chemical characteristics, eight different capsule formulations were designed and characterized. Silicon dioxide was added to form a semisolid content and prevent leakage. The formulation filled with alpha lipoic acid solution in polyethylene glycol 400 showed the best performance. Although the addition of silicon dioxide to the formulation with polyethylene glycol 400 led to a change in both flow character and viscosity, the release rate did not show a statistically significant decrease (more than 85% of content was released after 5 min testing). Applied technique is a simple and an appropriate approach for compounding and could be used for other substances with similar properties.

Clinical validation of a fast-acting acetaminophen: a randomized, active and placebo controlled dental pain study

Objectives To address the need for faster pain relief of over-the-counter (OTC) analgesic users, a novel drug delivery technology was developed to achieve faster absorption of orally administered acetaminophen with the goal of delivering earlier onset of pain relief. Previous development studies suggested that a 1000 mg dose of this fast-acting acetaminophen (FA-acetaminophen) formulation provided faster absorption and onset of action versus, commercially available OTC fast-acting analgesics, 1000 mg of extra-strength acetaminophen (ES-acetaminophen) or 400 mg of liquid-filled ibuprofen capsules (LG-ibuprofen). This study was designed as the definitive trial evaluating the onset of pain relief of FA-acetaminophen versus these same OTC comparators. Methods This single-dose, randomized, double-blind, placebo- and active-controlled clinical trial compared analgesic onset, overall efficacy, and safety of FA-acetaminophen 1000 mg, ES-acetaminophen 1000 mg, LG-ibuprofen 400 mg, and placebo over 4 h in a postsurgical dental pain model. Following removal of 3 to 4 impacted third molars, 664 subjects with moderate-to-severe pain were randomized in a 4:4:2:1 ratio to FA-acetaminophen (249), ES-acetaminophen (232), LG-ibuprofen (124), or placebo (59). Mean age was 18.9 years; 45.5% were male; 57.5% had severe baseline pain intensity. Subjects stopped a first stopwatch if/when they had perceptible pain relief and a second stopwatch if/when their pain relief became meaningful to them. Pain intensity difference (PID) and pain relief (PAR) were obtained using an 11-point numerical rating scale. Findings FA-acetaminophen 1000 mg had faster median time to onset of pain relief (15.7 min) compared to ES-acetaminophen 1000 mg (20.2 min, p = 0.035), LG-ibuprofen 400 mg (23.2 min, p < 0.001), and placebo (non-estimable), statistically greater mean PAR and PID scores than other treatment groups at 15 and 30 min, and a statistically greater percentage of subjects with confirmed perceptible pain relief at 15 and 20 min. At 25 min, FA-acetaminophen 1000 mg had a statistically significantly greater percentage of subjects with confirmed perceptible pain relief than LG-ibuprofen 400 mg and placebo. No clinically significant adverse events were reported. Conclusions This study supports previous studies, demonstrating faster onset of analgesia with FA-acetaminophen 1000 mg compared to OTC ES-acetaminophen 1000 mg and OTC LG-ibuprofen 400 mg. ClinicalTrials.gov Identifier NCT03224403 https://clinicaltrials.gov/ct2/show/NCT03224403

Analgesic onset and efficacy of a fast-acting formulation of acetaminophen in a postoperative dental impaction pain model

Objectives Speed of onset can be critical to an analgesic’s efficacy treating acute pain. To enhance onset, a new oral acetaminophen formulation intended to be fast acting was developed. Two studies evaluated the analgesic onset, efficacy, and safety of this fast-acting acetaminophen (FA-acetaminophen) tablet relative to commercial acetaminophen caplets (ES-acetaminophen) and commercial ibuprofen liquid-filled gelatin capsules (LG-ibuprofen). Methods Two single-center, single-dose, inpatient, randomized, double-blind, triple-dummy, placebo-controlled, parallel group design clinical trials were conducted using the postoperative dental impaction pain model. Subjects were healthy men and women aged 17–50 years experiencing moderate-to-severe pain after surgical extraction of at least three impacted third molars. In both studies, four treatment groups were evaluated: 1,000 mg acetaminophen as two 500 mg FA-acetaminophen tablets, 1,000 mg as two 500 mg ES-acetaminophen caplets, 400 mg ibuprofen as two 200 mg LG-ibuprofen capsules, and placebo. To maintain blinding, each subject received six units of study medication. Times to confirmed perceptible pain relief (TCPR) and meaningful pain relief (TMPR) were obtained using the double-stopwatch method. Pain intensity and relief were measured over 6 h following drug administration using a 0–10 numerical rating scale. Time to use of rescue medication (naproxen sodium) and subject global evaluations of study medications at 6 h were collected. Pharmacokinetic blood sampling and safety assessments were performed. Results Studies 1 and 2 enrolled 240 and 420 subjects, respectively. No clinically important differences among treatment groups were observed for any demographic or baseline characteristics. Efficacy results showed all active treatments statistically superior to placebo. In Study 1, TCPR was statistically significantly shorter for FA-acetaminophen compared to ES-acetaminophen and LG-ibuprofen. In Study 2, no statistically significant differences in TCPR were noted across the active treatment groups. In Study 1, FA-acetaminophen 1,000 mg provided significantly shorter TMPR compared with LG-ibuprofen but not compared with ES-acetaminophen. In Study 2, no significant differences in TMPR were noted across the active treatment groups. In both Study 1 and 2 at 15 min after administration of study drug, PID and PAR scores were greater for FA-acetaminophen than LG-ibuprofen. Conclusions Both studies suggested FA-acetaminophen had faster onset of action compared to ES-acetaminophen and LG-Ibuprofen. In light of the difference in TCPR and TMPR results between Study 1 and 2, an additional study is needed to further investigate time to analgesic onset of FA-acetaminophen compared with ES-acetaminophen and LG-Ibuprofen. Study registry numbers Study 1: NCT02735122; Study 2: NCT03224403

Interplay of liquid particles and interphases on the macroscopic elastic response of Liquid-filled composites

This paper deals with providing the effective elastic response of three-phase composites consist of a matrix filled with a random suspension of liquid-filled capsules firmly bonded to the matrix in the realm of small deformation theory. The capsules shell (interphases) and the matrix are considered to be elastic solids and the liquid is considered ideal. For this purpose, the solution for dilute concentrations of the interphases and the liquid particles are derived analytically. Then, the dilute solution is passed to an iterative technique to generate the non-dilute version of the solution. The non-dilute response is available in terms of a system of two nonlinear-coupled-ODE-initial-value problems. The results are confronted with the results of a 3D full-field FE analysis and experimental data and a good agreement is observed. The solution, provided here for polydisperse microstructures, allows for considering different thicknesses for the interphases and in turn can possibly account for different physical phenomena like the size and the surface tension effects. A comprehensive study on the effects of interphases (capsules shell) thickness and mechanical properties as well as the volume concentration of the capsules and the liquid particles on the overall elastic properties of three-phase liquid-filled composites are carried out. We show that although the addition of liquid particles to the matrix has deteriorating effects on the overall elastic properties of the composites, proper selection of the interphases can compensate for these negative effects.

The preparation of cellulose acetate capsules using emulsification techniques: high-shear bulk mixing and microfluidics

Abstract This work describes an emulsification-solvent-evaporation method for the preparation of liquid-filled capsules made from cellulose acetate. Two different emulsification techniques were applied: bulk emulsification by high-shear mixing, and droplet generation using microfluidics. The bulk emulsification method resulted in the formation of oil-in-water emulsions composed of an organic mixture of isooctane and cellulose acetate in methyl acetate, and an aqueous phase of high-molecular-weight polyvinyl alcohol (PVA). Upon the solvent evaporation, the emulsion droplets evolved into isooctane-filled cellulose acetate capsules. In contrast, microfluidics led to the formation of monodisperse droplets composed of the aqueous PVA solution dispersed in the organic phase. Upon the solvent evaporation, the emulsion droplets evolved into water-filled cellulose acetate capsules. Owing to the thermoplastic properties of the cellulose acetate, the capsules formed with the bulk mixing demonstrated a significant expansion when exposed to an increased temperature. Such expanded capsules hold great promise as building blocks in lightweight materials.

Liquid-filled hard capsule formulation of choline alfoscerate: preparation and in vitro/in vivo evaluation

Liquid-filled hard capsule formulation of choline alfoscerate: preparation and in vitro/in vivo evaluation

3D-Printed, Liquid-Filled Capsules of Concentrated and Stabilized Polyphenol Epigallocatechin Gallate, Developed in a Clinical Trial

In vitro studies have shown that epigallocatechin gallate (EGCG), the most potent antioxidant of the green tea polyphenol catechins, is able to effectively prevent the formation of amyloid plaques and induce their clearance. However, its high chemical reactivity promotes high chemical instability, which represents a major obstacle for the development of pharmaceutical forms containing solubilized EGCG, an essential condition for a better systemic passage via the oral route. After discovering that EGCG forms a deep eutectic with choline chloride, we exploited this property to formulate and patent liquid-filled capsules containing 200-800 mg of soluble EGCG in easy-to-administer sizes. The gelatin envelopes used are of the conventional type and their filling has been achieved using 3D printing technology. Not only did the EGCG-choline complex allow the formulation of hydrophilic solutions with a high concentration of active substance but it also contributed significantly to its chemical stability, since after at least 18 months of storage at 25 °C/60% RH and one year at 40 °C/75% RH, the capsules show unchanged hardness, chromatographic profiles and antioxidant activity compared to T0. Preclinical studies in monkeys showed that bioavailability was increased by a factor of 10 compared to marketed capsules comprising EGCG powder. This pharmaceutical development was conducted in the context of upcoming clinical trials to evaluate EGCG alone or in combination when treating transthyretin and light-chain cardiac amyloidosis.

Importance of Gastric Secretion and the Rapid Gastric Emptying of Ingested Water along the Lesser Curvature ("Magenstraße") in Predicting the In Vivo Performance of Liquid Oral Dosage Forms in the Fed State Using a Modeling and Simulation.

The objective of the present study was to develop an in silico model of the stomach for predicting oral drug absorption in fed humans. We focused on a model capable of simulating dynamic fluid volume changes and included a simulated Magenstraße "stomach road," a route along the lesser curvature that often carries fluids rapidly to assess the gastric emptying of drugs. Two types of model liquid drug formulations, liquid-filled soft gelatin capsules (enzalutamide, cyclosporine, and nifedipine) and oral solutions (levofloxacin and fenfluramine), were used. An in silico model was assembled, and simulations were performed using Stella Professional software. The secretion rate of the gastric juice induced by food ingestion was assessed along with the gastric emptying of the ingested water via the Magenstraße in the fed state. The model for the fed state successfully described the in vivo performance of the model drug formulations. These results clearly indicate the importance of including gastric secretion and the kinetics of Magenstraße when predicting the in vivo performance of dosage forms using an in silico modeling and simulation of fed humans. This simulation model should be further optimized to allow for the different physiological mechanisms following the ingestion of different types of meals, as well as modifications for interindividual and intraindividual variabilities in gastrointestinal physiology in the fed state in the future.

Study to Compare Capsule and Liquid Formulations of Enzalutamide After Single-Dose Administration Under Fasting Conditions in Prostate Cancer.

Limited evidence suggests an acceptable pharmacokinetic profile when enzalutamide is administered via a liquid formulation extracted from the commercially available liquid-filled soft-gelatin capsules. Tolerability may limit use in clinical practice. Enzalutamide is an established standard-of-care treatment for advanced prostate cancer with a commercially available formulation that may be inconvenient for some patients. We proposed a study to evaluate the bioequivalence of a liquid formulation to provide an alternative method of administration. This was a single-dose, randomized, open-label, two-way crossover pilot bioequivalence study to compare two oral formulations of enzalutamide: four enzalutamide 40 mg liquid-filled soft-gelatin capsules (commercially available) administered whole versus enzalutamide 160 mg liquid (extracted from capsules) administered via oral syringe. To assess bioequivalence, patients were randomized to receive a single dose of one formulation, then cross over to receive the alternative formulation following a 42-day washout period; serial plasma samples were collected over the course of 24 hours, followed by collections at 3, 8, and 42 days after the dose for both formulations. Bioequivalence of the formulations was assessed via comparisons of area under the plasma concentration-time curve (AUC) calculations per U.S. Food and Drug Administration (FDA) guidance. The study also assessed the safety and tolerability of the formulations. The study failed to meet proposed accrual, with only one patient enrolled, thus limiting the bioequivalence evaluation. Based on the data from a single patient, the drug exposure (measured by AUC) of enzalutamide and N-desmethyl enzalutamide (primary active metabolite) for the liquid formulation was 112% and 117%, respectively, compared with the capsule formulation. Although both formulations appeared well tolerated with no adverse events reported, the tolerability assessment questionnaire revealed an unpleasant taste of the liquid formulation. Preliminary evidence suggests a similar pharmacokinetic profile when administering liquid extracted from enzalutamide soft-gelatin capsules compared with intact capsules in patients with prostate cancer.

Design and characterisation of an amorphous formulation of nifedipine for the treatment of autonomic dysreflexia.

Current treatment for autonomic dysreflexia (AD) involves rupturing a liquid-filled soft capsule of nifedipine to aid rapid drug release and absorption, however, this application is not covered under the manufacturer's license. The objective of the current work was to design a rapidly dissolving solid dosage formulation for the treatment of AD as an alternative to the off-license "bite and swallow" use of currently available commercial products. Amorphous solid dispersions (ASDs) of nifedipine were prepared by spray-drying using three different polymers: hydroxypropyl methyl cellulose (HPMC), polyvinyl pyrrolidone (PVP) and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (Soluplus), at a 15% w/w drug loading and were formulated and compressed into tablets. Dissolution testing was performed in the paddle dissolution apparatus using either a monophasic or biphasic medium. The PVP-nifedipine ASD tablets exhibited rapid dissolution, with 35% of the total nifedipine dose dissolving within 15 min in the monophasic dissolution medium. The HPMC-nifedipine ASD exhibited a very slow dissolution, while the Solupus-nifedipine system exhibited no nifedipine release over 120 min. When tested in the biphasic dissolution medium, the PVP-nifedipine ASD tablets exhibited a release profile comparable to that of the pre-split/ruptured nifedipine soft capsule product. This study demonstrates that a nifedipine-PVP ASD is a promising formulation strategy in the treatment of AD.

PCV39 ECONOMIC IMPACT OF SWITCHING FROM ENTERIC COATED ASPIRIN TABLETS TO LIQUID FILLED CAPSULES WITH A NOVEL PHARMACEUTICAL LIPID-ASPIRIN COMPLEX IN PATIENTS SURVIVING AN ACUTE CARDIOVASCULAR EVENT

A new, pharmaceutical lipid-aspirin complex (PL-ASA) formulation has been specifically developed to reduce the risk of aspirin-induced gastric injury. In clinical studies PL-ASA liquid-filled capsules were shown to have significantly higher rates of complete aspirin response compared with the current standard of care (enteric coated aspirin tablets [EC-ASA]). Aspirin response has been linked to avoidance of ischemic events such as myocardial infarction MI) or stroke. In the current analysis we sought to determine the economic impact of switching patients from EC-ASA to PL-ASA for the first year following an index MI or stroke.

Bioavailability of aspirin in fasted and fed states of a novel pharmaceutical lipid aspirin complex formulation

Dyspeptic symptoms are common with aspirin and clinicians frequently recommend that it be taken with food to reduce these side effects. However, food can interfere with absorption, especially with enteric-coated aspirin formulations. We evaluated whether food interferes with the bioavailability of a new, pharmaceutical lipid-aspirin complex (PL-ASA) liquid-filled capsule formulation. In this randomized, open label, crossover study, 20 healthy volunteers fasted for ≥ 10 h and then randomized as either “fasted”, receiving 650 mg of PL-ASA, or as “fed”, with a standard high-fat meal and 650 mg of PL-ASA 30 min later. After a washout of 7 days, participants crossed over to the other arm. The primary outcome was comparison of PK parameters of the stable aspirin metabolite salicylic acid (SA) between fasted and fed states. Mean age of participants was 36.8 years and 55% were male. The ratios for the fed to fasted states of the primary SA PK parameters of AUC0−t and AUC0−∞ were 88.7% and 88.8% respectively, with 90% confidence intervals between 80 and 125%, which is consistent with FDA bioequivalence guidance. Mean peak SA concentration was about 22% lower and occurred about 1.5 h later in the fed state. Food had a modest effect on peak SA levels and the time required to reach them after PL-ASA administration, but did not impact the extent of exposure (AUC) compared with intake in a fasted state. These data demonstrate that PL-ASA may be co-administered with food without significant impact on aspirin bioavailability.Clinical Trial Registration:http://www.clinicaltrials.gov Unique Identifier: NCT01244100

Abstract TP432: Bioavailability of Aspirin in Fasted and Fed States of a Novel Formulation of a Pharmaceutical Lipid-Aspirin Complex

Introduction: Lifelong aspirin therapy is recommended after a TIA or stroke, but dyspeptic symptoms frequently lead to non-adherence. Clinicians often recommend that daily doses be taken with food to reduce these side effects. However, food can interfere with absorption, especially with enteric coated aspirin tablets. Hypothesis: We evaluated whether food interferes with bioavailability of a new, pharmaceutical lipid-aspirin complex (PL-ASA) liquid-filled capsule formulation. Methods: This was a randomized, open label, crossover study in 20 healthy volunteers. Participants fasted for ≥10 hours prior to randomization; if assigned to “fasting” they then received the single 650 mg dose of PL-ASA. If they were randomized to “fed”, they first ate a standard high-fat meal and were dosed 30 minutes later. After a washout period of 10 days each participant crossed over to the other arm and was again dosed with a 650 mg dose of PL-ASA. The primary outcome was the comparison of PK parameters of the primary metabolite salicylic acid (SA) between fasting and fed states. Results: Mean age of participants was 36.8 years and 55% were male. The primary SA PK parameters of AUC 0-t and AUC 0- infinity in the fed state were within 88.7% and 88.8% of concentrations in the fasting state consistent with bio-equivalence (FDA guidance &gt;80%). Mean peak SA concentration was about 25% lower and occurred about 1.5 hours later in the fed state (Figure). Conclusions: Food had a modest effect on the time required to reach peak SA concentration and on the actual peak SA levels after PL-ASA administration, but did not impact the extent of exposure (area under the curve) compared with intake in a fasting state. These data demonstrate that PL-ASA may be co-administered with food without significant variability in absorption, a recognized limitation of coated aspirin formulations.

The Headache Pipeline: Excitement and Uncertainty.

There are many new treatment options available for migraine and more are coming. Three calcitonin gene-related peptide (CGRP) antagonist monoclonal antibodies have been approved and a 4th is due in early 2020. Small molecule CGRP receptor-blocking oral compounds, both for acute care and prevention, are also coming. Four neurostimulators are available, with others on the way. New acute treatments coming soon include the 5HT1F agonist lasmiditan, a zolmitriptan intradermal micro-needle patch, and a nasal mist sumatriptan with a permeability enhancer. Farther out, three novel dihydroergotamine delivery systems, and a liquid-filled capsule of celecoxib show early promise. A new, safer form of methysergide is in the works, as is a longer-duration onabotulinumtoxinA. As always with new products, questions regarding safety, tolerability, cost, and insurance coverage will need to be addressed. Despite these concerns and uncertainties, a robust headache treatment pipeline is good for patients who are not satisfied with the results of their treatment and/or cannot tolerate existing treatments.

Liquid Filled Hard Gelatin Capsule

Novel dosage forms emerges more and more in recent years. One of them is liquid-filled hard gelatin capsules, which have gelatin or the hydroxypropyl methyl cellulose (HPMC) as capsule shell. The liquid-filled hard gelatin capsule is gradually getting attention because of its new-concept dosage form design, which bring liquid drugs by solid form. The paper mostly presents application, pharmaceutical manufacturing, quality assessment, vision of liquid-filled hard gelatin capsules and emphases on the application and pharmaceutical manufacturing of liquid-filled capsule. It is recommended that the capsule is suitable for many liquid or semi-solid natural plant extract and achieve different release profiles. The preparation adopted liquid-filled hard capsules technology. The impact factors concluded property of shell and device of filling. The quality was frequently evaluated by moisture content of capsule shell, dissolution rate. At the same time, it was pointed out that the new dosage form has remarkable marketing prospect and bring profits for enterprises. Keywords: Liquid filled capsule, Capsule Shell, Gelatin, HPMC, Dissolution rate.

Color-Tunable White-Light-Emitting Materials Based on Liquid-Filled Capsules and Thermally Responsive Dyes.

Color-tunable white-light-emitting materials are currently attracting much attention because of their potential applications in artificial lighting, sensing, and imaging. However, preparation of these systems from organic emitters is often cumbersome due to the interchromophoric interactions occurring upon solvent drying in the final solid materials, which can be hardly predicted and may lead to detrimental effects. To circumvent these obstacles, we have developed a new fabrication methodology that relies on dye encapsulation within liquid-filled capsules, thus enabling direct transfer of the luminescent properties from solution to the solid state and as such, rational design of miniaturized white-light-emitting materials. By introducing a thermally responsive chromophore into the capsules, these materials are further endowed with color tunability, which does not only allow ample modulation of the emitted color but also facilitate external fine control of the system so as to ensure precise realization of white light at the desired temperature and excitation wavelength.

Liquid Nanosize Emulsion-Filled Enteric-Coated Capsules for Colon Delivery of Immunosuppressant Peptide.

Present study aims at solubilizing slightly water-soluble peptide into a nanosize emulsion which is filled into a hard gelatin capsule in the form of preconcentrate. Further, liquid-filled capsule was dip-coated with ethyl cellulose and Eudragit S100 for colon targeting. An in vitro release profile was studied for selected formulations, i.e., Formulation A (5mg ethyl cellulose and 40mg Eudragit S100), Formulation B (10mg ethyl cellulose and 30mg Eudragit S100), and Formulation C (10mg ethyl cellulose and 20mg Eudragit S100). Formulations B and A showed an immediate release after 5 and 6h, respectively, which represents ileo-ceacal transit time. The nanosize of emulsion, i.e., below 100nm, was confirmed by transmission electron microscopy. Also, a phase transition of nanosize emulsion from water in oil to oil in water on dilution with water was observed through TEM. This novel approach of filling poorly water-soluble protein in solubilized form of nanosize emulsion preconcentrate into coated hard gelatin capsules for colon targeting has been reported first time. This approach could be a breakthrough for the better management of local intestinal pathologies.

Improving the drug release of Naproxen Sodium tablets by preparing granules and tablets with a preferred mixing ratio of hydrates

Naproxen is a typical and well-known analgesic classified as non-steroidal anti-inflammatory drug (NSAID) and is commercialized as tablets or liquid-filled capsules. Naproxen is typically used asa sodium salt because of its better processability compared to Naproxen free acid. This entails hygroscopicity and gives rise to the existence of four different hydrates, which show polymorphic and pseudopolymorphic properties. Solid dosage forms containing Naproxen Sodium often have to be processed in an applicable dosage form by granulation and tablet compression. During granulation, Naproxen Sodium will be in contact with water and is exposed to the drop and rise in temperature and to mechanical stress. The result could be a mixture of different hydrates of Naproxen Sodium.This study showed that a modified designed fluid bed granulation was not affected by differences in the mixing ratio of hydrates when using different water contents after spraying and at the end with the finished granules. Here, X-ray diffraction combined with Rietveld refinement was used to analyze the ratio of the hydrates and its identity. All granulation batches showed a large amount of Naproxen Sodium Monohydrate (>87%) and no differences could be observed during tablet compression. Quantities of other hydrates were negligibly small.Furthermore, this study also demonstrated the influence of tablet compression by transforming the hydrates of the granules. In addition to Naproxen Sodium Monohydrate, a large quantity of amorphous structures has also been found. Rietveld evaluation combined with the preliminary studies of the raw hydrates provided conclusions on the drug release of the tablets containing hydrates of Naproxen Sodium which were influenced by tablet compression.Fast drug release was obtained when a maximum water content of about 21% was used after spraying during granulation, independently of the final water content of the finished granules. A maximum water content of less than 21% after spraying yielded a high quantity of amorphous components after tablet compression and thus worsened the drug release.

Deformation and buckling of microcapsules in a viscoelastic matrix.

In this paper, we numerically study the dynamics of (1) a Newtonian liquid-filled capsule in a viscoelastic matrix and that of (2) a viscoelastic capsule in a Newtonian matrix in a linear shear flow using a front-tracking method. The numerical results for case (1) indicate that the polymeric fluid reduces the capsule deformation and aligns the deformed capsule with the flow direction. It also narrows the range of tension experienced by the deformed capsule for case (1), while the tank-treading period significantly increases. Interestingly, the polymeric fluid has an opposite effect on the tank-treading period and the orientation angle of case (2), but its effect on the deformation is similar to case (1).

Transformation of Biopharmaceutical Classification System Class I and III Drugs Into Ionic Liquids and Lipophilic Salts for Enhanced Developability Using Lipid Formulations

Higher lipid solubility of lipophilic salt forms creates new product development opportunities for high-dose liquid-filled capsules. The purpose of this study is to determine if lipophilic salts of Biopharmaceutical Classification System (BCS) Class I amlodipine and BCS Class III fexofenadine, ranitidine, and metformin were better lipid formulation candidates than existing commercial salts. Lipophilic salts were prepared from lipophilic anions and commercial HCl or besylate salt forms, as verified by 1H-NMR. Thermal properties were assessed by differential scanning calorimetry and hot-stage microscopy. X-ray diffraction and polarized light microscopy were used to confirm the salt's physical form. All lipophilic salt forms were substantially more lipid-soluble (typically >10-fold) when compared to commercial salts. For example, amlodipine concentrations in lipidic excipients were limited to <5-10 mg/g when using the besylate salt but could be increased to >100 mg/g when using the docusate salt. Higher lipid solubility of the lipophilic salts of each drug translated to higher drug loadings in lipid formulations. In vitro tests showed that lipophilic salts solubilized in a lipid formulation resulted in dispersion behavior that was at least as rapid as the dissolution rates of conventional salts. This study confirmed the applicability of forming lipophilic salts of BCS I and III drugs to promote the utility of lipid-based delivery systems.