Polymeric Films for the Encapsulation, Storage, and Tunable Release of Therapeutic Microbes.
ABSTRACT: Microbe-based therapeutics (MBTs) are an emerging therapeutic modality for treating gastrointestinal infections and inflammatory bowel diseases. Current formulations for oral delivery of MBTs use capsules to achieve safe gastric transit, but oral formulations that control the spatiotemporal concentration of MBTs are yet to be developed, despite well-established connections between all therapeutics and their location, concentration, and distribution at sites of action. The development of a multi-functional polymer-based encapsulation system to formulate MBTs for enhanced storage and delivery through formulation of a model MBT, Lactobacillus casei ATCC393, is reported here. This approach enables the additive inclusion of excipients and polymers to grant specific functions, toward the development of a modular MBT platform. Through addition of established excipients, the formulation provides long-term storage of the encapsulated MBT. By adding higher molecular weight polymers, the release kinetics of the encapsulated MBTs can be modified. The inclusion of a mucoadhesive polymer significantly increases the adhesion force between the formulation and the intestinal tissue. Together, mucoadhesive and sustained release properties can be used to modulate the spatiotemporal concentration of MBTs. The formulation is compatible with standard oral capsules, thus maintaining existing clinical advantages of oral capsules while providing new functions from film encapsulation.
Project description:An <i>E.coli</i>-specific phage was encapsulated in three different pH responsive polymer formulations using the process of membrane emulsification. Small 100 µm capsules were fabricated and shown to afford phages suitable acid protection upon exposure to pH 1.5. Selection of polymer formulations allowed controlled release of phages at pH 5.5, pH 6 and pH 7. Other aspects of phage encapsulation including factors affecting encapsulation yield, release kinetics, acid and storage stability were evaluated. The work presented here would be useful for future evaluation of new therapeutic strategies including microbiome editing approaches allowing pH-triggered release of phages and delivery of encapsulated cargo to different intestinal compartments. The size of the capsules were selected to permit ease of delivery using small bore oral gavage tubes typically used in pre-clinical studies for evaluation of drug substances using small animal vertebrate models such as in mice and rats.
Project description:The encapsulation ?-carotene in whey protein concentrate (WPC) capsules through the emulsion electrospraying technique was studied, using deep eutectic solvents (DES) as solvents. These novel solvents are characterized by negligible volatility, a liquid state far below 0 °C, a broad range of polarity, high solubilization power strength for a wide range of compounds, especially poorly water-soluble compounds, high extraction ability, and high stabilization ability for some natural products. Four DES formulations were used, based on mixtures of choline chloride with water, propanediol, glucose, glycerol, or butanediol. ?-Carotene was successfully encapsulated in a solubilized form within WPC capsules; as a DES formulation with choline chloride and butanediol, the formulation produced capsules with the highest carotenoid loading capacity. SEM micrographs demonstrated that round and smooth capsules with sizes around 2 µm were obtained. ATR-FTIR results showed the presence of DES in the WPC capsules, which indirectly anticipated the presence of ?-carotene in the WPC capsules. Stability against photo-oxidation studies confirmed the expected presence of the bioactive and revealed that solubilized ?-carotene loaded WPC capsules presented excellent photo-oxidation stability compared with free ?-carotene. The capsules developed here clearly show the significant potential of the combination of DES and electrospraying for the encapsulation and stabilization of highly insoluble bioactive compounds.
Project description:Buccal mucosal membrane offers an attractive drug-delivery route to enhance both systemic and local therapy. This review discusses the benefits and drawbacks of buccal drug delivery, anatomical and physiological aspects of oral mucosa, and various in vitro techniques frequently used for examining buccal drug-delivery systems. The role of mucoadhesive polymers, penetration enhancers, and enzyme inhibitors to circumvent the formulation challenges particularly due to salivary renovation cycle, masticatory effect, and limited absorption area are summarized. Biocompatible mucoadhesive films and patches are favored dosage forms for buccal administration because of flexibility, comfort, lightness, acceptability, capacity to withstand mechanical stress, and customized size. Preparation methods, scale-up process and manufacturing of buccal films are briefed. Ongoing and completed clinical trials of buccal film formulations designed for systemic delivery are tabulated. Polymeric or lipid nanocarriers incorporated in buccal film to resolve potential formulation and drug-delivery issues are reviewed. Vaccine-enabled buccal films have the potential ability to produce both antibodies mediated and cell mediated immunity. Advent of novel 3D printing technologies with built-in flexibility would allow multiple drug combinations as well as compartmentalization to separate incompatible drugs. Exploring new functional excipients with potential capacity for permeation enhancement of particularly large-molecular-weight hydrophilic drugs and unstable proteins, oligonucleotides are the need of the hour for rapid advancement in the exciting field of buccal drug delivery.
Project description:This study reports the development of nanostructured hydrogels for the sustained release of the eutectic mixture of lidocaine and prilocaine (both at 2.5%) for intraoral topical use. The local anesthetics, free or encapsulated in poly(?-caprolactone) nanocapsules, were incorporated into CARBOPOL hydrogel. The nanoparticle suspensions were characterized in vitro in terms of particle size, polydispersity, and surface charge, using dynamic light scattering measurements. The nanoparticle concentrations were determined by nanoparticle tracking analysis. Evaluation was made of physicochemical stability, structural features, encapsulation efficiency, and in vitro release kinetics. The CARBOPOL hydrogels were submitted to rheological, accelerated stability, and in vitro release tests, as well as determination of mechanical and mucoadhesive properties, in vitro cytotoxicity towards FGH and HaCaT cells, and in vitro permeation across buccal and palatal mucosa. Anesthetic efficacy was evaluated using Wistar rats. Nanocapsules were successfully developed that presented desirable physicochemical properties and a sustained release profile. The hydrogel formulations were stable for up to 6 months under critical conditions and exhibited non-Newtonian pseudoplastic flows, satisfactory mucoadhesive strength, non-cytotoxicity, and slow permeation across oral mucosa. In vivo assays revealed higher anesthetic efficacy in tail-flick tests, compared to a commercially available product. In conclusion, the proposed hydrogel has potential for provision of effective and longer-lasting superficial anesthesia at oral mucosa during medical and dental procedures. These results open perspectives for future clinical trials.
Project description:<h4>Lessons learned</h4>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.<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.
Project description:<b>Background</b>: The study aimed at assessing the mucoadhesive properties and the barrier effect of a formulation, labelled as AL2106, containing sodium chondroitin sulfate (ChS), xyloglucan from tamarind seed extract, and glycerol, by evaluating the capacity to adhere to a layer of mucin, the rheological synergism and the barrier effect in comparison to the marketed Esoxx One medical device. AL2106 is a medical device distributed by Alfasigma SpA, Italy with REF FTP57 (Manufacturer: Labomar SpA); it is analogous to Esoxx One medical device: the two products are drinkable solutions that, after swallowing, adhere to the esophageal mucosa, protecting it from the corrosive effect of the gastric acid reflux. AL2106 has been conceived to be better performing in terms of duration of the barrier effect compared to Esoxx One. <b>Methods</b>: The mucoadhesive properties, rheological behavior, buffering capacity against acidity, and film-forming ability with the resultant protecting effect on esophagus mucosa (caffeine permeation test) was compared between the two products. <b>Results</b>: The mucoadhesivity of the formulations was shown in vitro: both remained adherent to a mucin layer, also when the support was rotated by 90°, and when the film layer was washed with water, intended to simulate the washout due to swallowing. AL2106 showed a good buffering efficacy, being able to absorb at least 50% of its weight of 0.03 M HCl while maintaining the pH above 4. The film-forming effect and barrier properties of AL2106 and Esoxx One were confirmed by an in vitro study on reconstructed human esophageal epithelium. A greater film-forming efficacy of AL2106, lasting for at least 5 h, than Esoxx One was observed. Noteworthy, the barrier function of esophageal tissues was shown to be preserved after the application of both formulations. <b>Conclusions</b>: The combination of ChS with the mucoadhesive glycerol-xyloglucan complex and other excipients, which contribute to the barrier effect and to mucoadhesion, contained in AL2106, allowed a longer-lasting protective effect than Esoxx One, proving its effectivity and safety for oral use.
Project description:The objective of this study is to improve and optimize the formulation of Genistein in capsules in order to result in a better pharmacokinetic profile comparing to existing commercial products. In order to do this, five different formulations of Genistein capsules were developed and examined by reviewing their disintegration and dissolution properties. Furthermore, flowability of the powder along with potent incompatibilities between Genistein and its excipients were monitored through their thermal properties. The final formulation of Genistein was quantified using HPLC analysis and then its stability was evaluated thoroughly in real time and accelerated conditions. Finally, with the target to have a product with actual results, in vitro and in vivo studies were conducted. The final product proved to have better results in disintegration and dissolution. Moreover, R.G.C.C.'s capsules exhibited enhanced action in human cell lines as well as impressive pharmacokinetic results in animal models. The in vitro results showed an advantage of the R.G.C.C. product compared to the commercial one, whereas its maximum concertation in vivo was determined 34% higher than the commercial one.
Project description:Sodium alginate and its oligosaccharides through potential antifungal properties might improve the activity of antifungal drugs enhancing their efficacy and potentially reducing the frequency of application. Mucoadhesive buccal films are oral dosage forms designed for maintaining both local or systemic drug effects and seem to be a very promising alternative to conventional oral formulations. Hence, in this study, mucoadhesive buccal films based on the alginate and its oligosaccharide oligomer composed predominantly of mannuronic acid for the administration of posaconazole-antifungal drug from the azole group were developed. As the polymer gelation method, a relatively new freeze-thaw technique was chosen. All prepared formulations were examined for pharmaceutical tests, swelling, mechanical, and mucoadhesive properties. In addition, the influence of sodium alginate (ALG) and alginate oligosaccharides (OLG) on POS antifungal activity on Candida species was performed. It was observed that film formulation containing 1% ALG and 1% OLG (F2) was characterized by optimal mucoadhesive and swelling properties and prolonged drug release up to 5 h. Additionally, it was shown that OLG affected the growth reduction of all tested Candida spp. The obtained data has opened the way for future research for developing OLG-based dosage forms, which might increase the activity of antifungal drugs.
Project description:There is a clinical need for a liquid formulation of atomoxetine. We assessed the safety and bioequivalence of an atomoxetine oral solution.This was an open-label, randomized, crossover study. Healthy adult male Japanese subjects (n = 42) with a cytochrome P450 2D6 extensive (including intermediate and ultrarapid) metabolizer genotype were administered atomoxetine 50 mg as oral solution and capsules once each, with a washout period >5 days between doses. Blood samples were used to analyze pharmacokinetic parameters, particularly maximum observed drug concentration (C max) and area under the concentration vs. time curve from time zero to the last time point with a measurable concentration (AUC0-last). Bioequivalence was concluded if the 90 % confidence interval of the ratio of geometric means between formulations for both C max and AUC0-last were within the interval of 0.8-1.25. Safety assessments included determination of adverse events. Taste was evaluated via a five-item questionnaire immediately and 10 min after taking atomoxetine oral solution.Forty subjects completed the study. Plasma concentration-time profiles of atomoxetine oral solution and capsules were similar, and the statistical analysis of systemic exposure showed that the two formulations were bioequivalent. Adverse events were mild and similar in type and frequency between the formulations. For taste acceptability, only 7.1 % of subjects responded that the oral solution would be difficult to take every day.Atomoxetine oral solution is bioequivalent to atomoxetine capsules and potentially fulfills the need for an oral solution atomoxetine formulation that will facilitate treatment of children with attention-deficit hyperactivity disorder.
Project description:High-resolution measurement of medication adherence is essential to personalized drug therapy. A US Food and Drug Administration (FDA)-cleared device, using an edible ingestion sensor (IS), external wearable patch, and paired mobile device can detect and record ingestion events. Oral medications must be combined with an IS to generate precise "digitized-medication" ingestion records. We developed a Good Manufacturing Practice protocol to repackage oral medications with the IS within certified Capsugel capsules, termed co-encapsulation (CoE). A randomized bioequivalence study of CoE-IS-Rifamate (Isoniazid/Rifampin 150/300 mg) vs. native-Rifamate was conducted in 12 patients with active Mycobacterium tuberculosis and demonstrated bioequivalence using the population method ratio test (95% confidence interval). Subsequently, CoE-IS-medications across all biopharmaceutical classes underwent in vitro dissolution testing utilizing USP and FDA guidelines. CoE-IS medications tested met USP dissolution specifications and were equivalent to their native formulations. CoE combines oral medications with the IS without altering the quality of the native formulation, generating "digitized" medications for remote capture of dosing histories.