In Vitro Development of Enteric-Coated Tablets of the Probiotic Lactobacillus fermentum LF-G89: A Possible Approach to Intestinal Colonization.

BACKGROUND: Probiotics must be able to withstand the demanding environment of the gastrointestinal system to adhere to the intestinal epithelium, promoting health benefits. The use of probiotics can prevent or attenuate the effects of dysbiosis that have a deleterious effect on health, promoting anti-inflammatory, immunomodulatory, and antioxidant effects. OBJECTIVE: The aim of the study was to prepare tablets containing Lactobacillus fermentum LF-G89 coated with 20% Acryl-Eze II® or Opadry® enteric polymers. METHOD: Tablet dissolution was evaluated under acidic and basic pH conditions, and aliquots of the dissolution medium were plated to count the Colony-forming Units (CFU). The free probiotic's tolerance to pH levels of 1.0, 2.0, 3.0, and 4.0, as well as to pepsin, pancreatin, and bile salts, was assessed. RESULTS: The probiotic was released from tablets coated after they withstood the pH 1.2 acid stage for 45 minutes. The release was higher with the Acry-Eze II® polymer in the basic stage. The amount of CFU of free probiotics at pH 1.0 to 4.0 as well as pepsin reduced over time, indicating cell death. Conversely, the CFU over time with pancreatin and bile salts increased, demonstrating the resistance of L. fermentum to these conditions due to hydrolases. CONCLUSION: Both coating polymers were able to withstand the acid step, likely ensuring the release of the probiotic in the small intestine, promoting colonization. Coating with enteric material is a simple and effective process to increase the survival of probiotics, offering a promising alternative to mitigate the negative effects of the dysbiosis process.

Transdermal Therapeutic Systems for the Treatment of Alzheimer's Disease: A Patent Review.

BACKGROUND: Two classes of medications are used to treat Alzheimer's disease (AD); donepezil, galantamine, and rivastigmine are acetylcholinesterase inhibitors, and memantine is a non-competitive antagonist of the N-methyl-D-aspartate receptor. Although these are typically taken orally, there are transdermal therapeutic systems (TTSs) commercially available for rivastigmine and donepezil. The transdermal route has been preferable for guardians/caregivers due to ease of use, reduced side effects, and improved adherence to therapy. OBJECTIVE: The study aimed to obtain knowledge of the properties of these drugs and to search for patents relating to the TTS for AD using the Espacenet platform. METHODS: The search terms were "rivastigmine AND transdermal AND skin delivery AND Alzheimer's", changing the drugs "memantine", "donepezil", and "galantamine", between January 2015 and January 2022. Title and abstract were used to choose patents. RESULTS: TTSs present some limit factors in terms of absorption due to skin physiology and the size of the molecules with established limits of percutaneous penetration (molecular mass of 500 g/mol and log P of 5). We found 1, 4, 4, and 2 patents for galantamine, rivastigmine, donepezil, and memantine, respectively. Galantamine TTS seems to be more challenging due to the molecular mass of 287.35 g/mol and logP of 1.8. The permeator of absorption is necessary. Memantine, rivastigmine, and donepezil present logP of 3.28, 2.3, and 4.27 and molecular weights of 179.30, 250.34, and 415.96 g/mol, respectively. CONCLUSION: TTSs are primarily effective for delivering small molecules. The use of absorption enhancers and irritation mitigators can be necessary to enhance the performance. The development of these technologies is essential for the convenience of patients and caregivers.

Functional properties of thermally tampered poly(ethylene oxide).

Introduction: Poly(ethylene oxide) (PEO) is the most common polymer used in commercial abuse-deterrent tablets. Due to its vulnerability to high-temperature manipulation, we investigated abuse-deterrent capability and the toxicity of this polymer upon thermal treatments at 80°C and 180°C for 1 hour. Methods: Tablets (200 mg PEO and 300 mg Avicel®) were directly compressed under 2000 lb. The thermally manipulated PEOs were evaluated for their viscosity, crushability, structural changes, and cell toxicity. Results: Our findings showed that 180°C-treated tablets underwent some degrees of oxidative degradation with profound toxicity in both mesenchymal stem cells and MG63 cells. The 180°C-treated tablets exhibited almost no resistance against crushing and were prone to abuse. While thermal processing of PEO at around its melting temperature is a common approach to enhance crush resistance of its dosage forms, thermal manipulation at close to the PEO's oxidation temperature can lead to structural changes, dramatic loss of crush and extraction resistance, and significant cell toxicity. Conclusion: Similar to the low molecular weight PEO, when thermally manipulated at its thermo-oxidative temperature, the high molecular weight PEO loses its deterrence performance and causes severe cell toxicity.

In vitro evaluation of adhesion and mechanical properties of oral thin films.

Oral drug delivery is often challenged with enzymatic degradation of drug molecules in the gastrointestinal tract and high first-pass metabolism, resulting in low bioavailability. Delivery of drug molecules via the oral cavity mucosa is considered a viable option to enhance bioavailability. One of the relatively new dosage forms for transmucosal drug delivery is the oral thin film (OTF) with mucoadhesive properties that offers several advantages over conventional dosage forms, including faster dissolution, higher patient compliance, and extended oral retention by reduced salivary washout. Mucoadhesive OTFs should have sufficient muco-adhesiveness as well as suitable mechanical properties for their best performance, thus such characterization is critical in the successful design and development of OTFs. However, there is currently no FDA or USP-recommended analytical procedure or standard available for evaluating adhesiveness and mechanical properties of mucoadhesive OTFs. Therefore, we aimed to develop a fast and reliable in vitro method capable of differentiating various OTFs in terms of their adhesive strengths using a texture analyzer. We found that an in vitro gel substrate composed of 4% w/v gellan gum and 2% w/v glycerin could be used to discriminate between the adhesive features of the tested film samples. Also, our studies show that the adhesion test parameters of 0.96 N target force, probe speed of 0.1 mm/s, holding time of 15 s, and conditioning medium volume of 200 µL while using the said substrate could successfully differentiate between the adhesion strength of the OTF samples. We further examined the film samples for their physicomechanical properties to obtain a tangible and practical range of mechanical values for pharmaceutical OTFs using the puncture test and folding endurance test. We found a breaking factor above 34.5 N/mm, elongation to puncture less than 5.55% and folding endurance of at least 50 folds can be used as a starting point when designing and manufacturing OTFs.

Abuse-deterrent properties and cytotoxicity of poly(ethylene oxide) after thermal tampering.

Poly(ethylene oxide) (PEO) is the most common deterring agent used in the abuse-deterrent formulations (ADFs). In this study, we investigated the PEO's abuse-deterrent properties and its potential cytotoxicity after being heated at high temperatures (80 °C and 180 °C). The results indicated a significant loss in both crush and extraction resistance features of the polymer, which is primarily associated with the polymer degradation at the higher temperatures. The heat-treated PEO at the high temperature was also found to lose its controlled-release feature, upon which over 80% of the drug was released after one hour in the simulated gastric fluid. The cytotoxicity of the PEO was further assessed to evaluate the safety of the polymer following the thermal treatment. Our findings revealed a substantial loss in the viability of the cells exposed to the PEO treated at higher temperatures. Taken all, heating PEO at high temperatures can lead to a significant loss in both the crush/extraction resistance characteristics and the safety of the polymer. These findings reemphasize the fact that more appropriate and stricter test and regulations will be needed to assure that the abuse deterrent formulations are safe and effective under severe conditions of abuse.

Mucoadhesion and Mechanical Assessment of Oral Films.

Aligned with efforts to overcome shortcomings of conventional oral dosage forms, mucoadhesive oral thin films have been the focus of drug development. Transmucosal drug delivery through oral cavity is a popular alternative to deliver many drugs due to several advantages over conventional oral delivery including greater bioavailability due to bypassing the first-pass effect and avoiding enzymatic or acid-related degradation in the gastrointestinal tract, faster onset of action, and better patient compliance particularly in geriatric and pediatric patients. Furthermore, among solid transmucosal delivery platforms, buccal and sublingual strips or patches are more attractive due to their flexibility, ease of administration, high patient compliance, and fast dissolution. They are also more stable compared to oral gels making them a desirable candidate to deliver many small and large molecules locally or systemically. Mucoadhesion and mechanical properties of oral films are crucial in their performance, and therefore ways to measure these properties are also similarly important. Since they are relatively new to the pharmaceutical market, there are currently no FDA-recommended or USP standard methods available to characterize such dosage forms. This review intends to cover and discuss various methods cited in the literature to measure and evaluate mucoadhesive and mechanical properties of oral films.

Enhancement of The Stability of Human Growth Hormone by Using Tris(hydroxymethyl)aminomethane: Molecular Docking and Experimental Analysis.

OBJECTIVE: It is so difficult to formulate human growth hormone (hGH) in a solution with high stability and new drug delivery system (NDDs) due to physiochemical instability. The purpose of this study was to investigate the possibility of using Tris as a hGH stabilizer. MATERIALS AND METHODS: In this experimental study, the role of tris(hydroxymethyl)aminomethane (Tris) was evaluated as a hGH stabilizing agent in phosphate buffer, as a practical aqueous solution and a media to release NDDs. Highperformance liquid chromatography (HPLC) and enzyme-linked immune sorbent assay (ELISA) were applied to investigate the stability of hGH in solutions and dynamic light scattering (DLS) was used to measure the effect of Tris on the hydrodynamic size of hGH in aqueous solutions. Ultra violet (UV) spectrophotometry was used to check the hGH spectrum. In computational study, formation of ligand-protein complex of the Tris-hGH, and the intermolecular interactions between Tris and hGH were studied by molecular docking modeling. RESULTS: The results demonstrated that Tris at the optimum concentration, increases hGH stability in aqueous solutions. Also, molecular docking modeling confirmed that amino acid residues such as tyrosine (Tyr), proline (Pro), glutamic acid (Glu), aspartic acid (Asp), leucine (Leu), and phenylalanine (Phe) in hGH structure, were linked with Tris as a ligand. CONCLUSION: It seems that interactions between hGH and Tris are the most important reason for increment of the physicochemical stability of hGH in aqueous solutions containing Tris.

ChABC-loaded PLGA nanoparticles: A comprehensive study on biocompatibility, functional recovery, and axonal regeneration in animal model of spinal cord injury.

Spinal Cord Injury (SCI) is one of the leading causes of physical disability. In this study, spherical PLGA nanoparticles (NPs) containing ChABC enzyme were manufactured and fully characterized for SCI therapy. The NPs were used in the rat's contused spinal cord to assess the functional improvement and scar digestion. Twenty-three adult male Wistar rats (275 ± 25 g) were assigned into four groups of control, sham, blank-treated particle, and ChABC-treated particle. Throughout the survey, the BBB scores were obtained for all the groups. Finally, the injured sections of animals were dissected, and histological studies were conducted using Luxol fast blue and Bielschowsky. The biocompatibility and non-toxicity effects of the NPs on olfactory ensheathing cells (OECs) were confirmed by the MTT test. The flow-cytometry revealed the purity of cultured OECs with p75+/GFAP+ at around 87.9 ± 2.4%. Animals in the control and the blank-treated groups exhibited significantly lower BBB scores compared with the ChABC-treated particle group. Histological results confirmed the induced contusion models in the injured site. Myelin was observed in the treated groups, especially when the ChABC-loaded nanoparticles were utilized. The immunohistochemistry results indicated the scar glial degradation in animals treated by the ChABC-loaded particles. According to this study, the loaded particles can potentially serve as a suitable candidate for spinal cord repair, functional recovery and axonal regeneration.

A cellulose-based therapeutic polymer to deter intravenous drug abuse.

Prescription opioids have widely been abused as an epidemic. In this research, we developed a drug composition based on the crosslinked carboxymethylcellulose (XCMC) and a drug model that can effectively deter abuse by injection via multiple mechanisms. The anionic nature of the XCMC is responsible for complexing the cationic opioids in aqueous solutions, minimizing the free drug amount accessible for extraction. The crosslinked nature of the polymer is responsible for its swelling and partial containment of the drug solution within the swollen polymer's network, thus minimizing the available volume for subsequent injection. We have shown that XCMC can efficiently interact with cationic drugs in the form of physical blends and chemical complexes in different aqueous solvents, forming abuse-deterrent complexes. The complexation efficiency was affected by the solution pH and ionic strength, as well as the drug to polymer ratio in the formulation. The in vitro dissolution studies were conducted in two stages, the stage I in 0.1 M HCl and the stage II in water and pH 7.5 phosphate buffer. These studies confirmed the proper drug release under the legitimate conditions of use. Therefore, the XCMC polymers have a great potential to be used as deterring agents in developing opioid medications with abuse-deterrent properties.

Development and in vitro evaluation of an abuse-deterrent formulation based on a crosslinked starch derivative.

An innovative abuse-deterrent composition was developed to deter the most dangerous route of drug abuse, the intravenous route. The composition is based on a crosslinked sodium starch glycolate (X-SSG) that can effectively complex with cationic drugs in aqueous solutions and minimize the amount of the free drug available for extraction. Furthermore, the crosslinked polymer swells in and entraps a portion of the drug solution by which it reduces the available volume for syringing and subsequent injection. Two deterrent compositions were prepared, a drug-polymer physical blend and a drug-polymer chemical complex. The composition in its complexed form showed greater deterrence capacity than the physical blend except in solvents with ionic moieties, where the deterrence remained almost the same. The studies revealed that the complexation with the drug played a major role in total drug entrapment. Tablets prepared from the drug-polymer complex showed a complete and immediate drug release in 0.1 N HCl within the first 15 min. Moreover, the dissolution studies in the simulated intestinal media ruled out the re-complexation potential between the drug and the polymer. The proposed X-SSG composition provides a desirable drug release in the gastric and intestinal media under the legitimate use while deterring an intravenous abuse.

Multifunctional Cosmetic Containing Blueberry and Tinosorb M®-Loaded Microparticles Improves Sunscreen Performance.

Purpose: We aimed to evaluate the effect of blueberry extract and microparticles (MP) on sunscreen performance of multifunctional cosmetics. Octocrylene (OCT), benzophenone-3 (BENZ-3) and Tinosorb® M (MBBT) were employed as UV filters. Methods: An in-silico modeling was used to determine the UV filters concentrations to obtain high values of sunscreen protection factor (SPF) and UVA protection factor (UVA-PF). MBBT and blueberry-loaded microparticles (MPMB+B) and MBBT-loaded microparticles (MPMBBT) were prepared by spray-drying. OCT and BENZ-3 were added in the oil phase of cosmetics. Cosmetics A and B contained MPMB+B and MPMBBT, respectively, and cosmetic C was prepared without MP. Characterization, physicochemical stability and in vitro SPF was performed. UV filters distribution in human stratum corneum (SC) for each cosmetic was performed. Anti-oxidant activity of blueberry extract was evaluated. Results: Sunscreen combination with the highest SPF was selected for formulations. Formulations A and B maintained their rheological behavior over time, unlike formulation C. In-vitro SPFs for formulations A, B and C were 51.0, 33.7 and 49.6, respectively. We also developed and validated a method for analysis of the UV filters by HPLC/ PDA suitable for the in-vivo assay. In Tape stripping test, MBBT showed SC distribution similar for all cosmetic formulations. OCT and BENZ-3 distribution to formulation A and C was also similar. Blueberry extract showed antioxidant capacity of 16.71 µg/mL equivalent to vitamin C. Conclusion: Cosmetics containing MPs presented better physical stability. Blueberry increased the photoprotective capacity of the formulations and added extra benefits due to its anti-oxidant and anti-aging properties.

Safety and performance of current abuse-deterrent formulations.

INTRODUCTION: Prescription opioid abuse is now an epidemic that has forced the government and industries to take initiatives. These include developing abuse-deterrent formulations (ADFs), issuing regulatory guidances and allocating massive budgets to ensure the safety and effectiveness of these medications. Areas covered: This review covers the regulatory guidance on evaluation and labeling of the branded and generic ADFs. It also includes the relevant patents and technologies, the in-vitro, in-vivo, the post-marketing data, the FDA reviews, and the products' labeling of the FDA-approved products with abuse-deterrent features. Expert opinion: Despite the development of a dozen products with abuse-deterrent features, most of these technologies rely on the same deterrent agent, making it easier for abusers to focus their manipulation efforts and share their experience to defeat the technology. Further advancement in the field requires developing more robust, more diverse, safer, and affordable deterrent technologies for the extended- and immediate-release opioid products. Moreover, advances in the reporting of the post-market results, issuance of policies in support of the ADFs, and concurrent monitoring of the illicit opioid market are other considerations that can further help in confronting the epidemic.

Determining Abuse Deterrence Performance of Poly (ethylene oxide) Using a Factorial Design.

Purpose: The purpose of this study was to determine the effects of thermal processing and antioxidant formulation variables on the abuse deterrence performance of a high molecular weight poly(ethylene oxide) (PEO) polymer. Methods: A 24 factorial design with one categorical factor (antioxidant type) and three continuous factors (curing time, curing temperature, % antioxidant) was used. Abuse deterrence performance was evaluated using solution viscosity, surface melting temperature, and mechanical strength. Thermal degradation of PEO powders before compaction was also studied using DSC, FTIR spectroscopy, and viscosity analysis. Results: Our results showed that curing temperature and type of antioxidant can significantly affect the deterrence performance of PEO. The main effect plot for viscosity shows the most prominent factors affecting viscosity are curing temperature and type of antioxidant. However, curvature in the linear model obtained was not sufficient to completely describe the behavior. For surface melting temperature, butylated hydroxytoluene was associated with higher surface melting temperatures compared to ascorbic acid. Additionally, higher percent of antioxidant resulted in higher melting temperature. Particle size distribution to indicate mechanical strength showed no significant effects of tested factors. This suggests that comminution method has more prominent effect on tablet fragment size than the formulation and processing factors studied. Conclusion: While heat confers the mechanical strength to the polymer, it can diminish its physical stability and solution state viscosity. The experimental studies showed that prolonged exposure to high temperatures, even in the presence of antioxidants, can severely hamper polymer deterrence performance in both solid and solution states.