Formulation strategies to improve the efficacy of intestinal permeation enhancers.

The use of chemical permeation enhancers (PEs) is the most widely tested approach to improve oral absorption of low permeability active agents, as represented by peptides. Several hundred PEs increase intestinal permeability in preclinical bioassays, yet few have progressed to clinical testing and, of those, only incremental increases in oral bioavailability (BA) have been observed. Still, average BA values of ~1% were sufficient for two recent FDA approvals of semaglutide and octreotide oral formulations. PEs are typically screened in static in vitro and ex-vivo models where co-presentation of active agent and PE in high concentrations allows the PE to alter barrier integrity with sufficient contact time to promote flux across the intestinal epithelium. The capacity to maintain high concentrations of co-presented agents at the epithelium is not reached by standard oral dosage forms in the upper GI tract in vivo due to dilution, interference from luminal components, fast intestinal transit, and possible absorption of the PE per se. The PE-based formulations that have been assessed in clinical trials in either immediate-release or enteric-coated solid dosage forms produce low and variable oral BA due to these uncontrollable physiological factors. For PEs to appreciably increase intestinal permeability from oral dosage forms in vivo, strategies must facilitate co-presentation of PE and active agent at the epithelium for a sustained period at the required concentrations. Focusing on peptides as examples of a macromolecule class, we review physiological impediments to optimal luminal presentation, discuss the efficacy of current PE-based oral dosage forms, and suggest strategies that might be used to improve them.

Evaluation of the Stability of Bacteriophages in Different Solutions Suitable for the Production of Magistral Preparations in Belgium.

In Belgium, the incorporation of phages into magistral preparations for human application has been permitted since 2018. The stability of such preparations is of high importance to guarantee quality and efficacy throughout treatments. We evaluated the ability to preserve infectivity of four different phages active against three different bacterial species in five different buffer and infusion solutions commonly used in medicine and biotechnological manufacturing processes, at two different concentrations (9 and 7 log pfu/mL), stored at 4 °C. DPBS without Ca2+ and Mg2+ was found to be the best option, compared to the other solutions. Suspensions with phage concentrations of 7 log pfu/mL were unsuited as their activity dropped below the effective therapeutic dose (6-9 log pfu/mL), even after one week of storage at 4 °C. Strong variability between phages was observed, with Acinetobacter baumannii phage Acibel004 being stable in four out of five different solutions. We also studied the long term storage of lyophilized staphylococcal phage ISP, and found that the titer could be preserved during a period of almost 8 years when sucrose and trehalose were used as stabilizers. After rehydration of the lyophilized ISP phage in saline, the phage solutions remained stable at 4 °C during a period of 126 days.

Elucidating the Molecular Mechanism of Drug-Polymer Interplay in a Polymeric Supersaturated System of Rifaximin.

Supersaturated drug delivery system (SDDS) enables the solubility and sustained membrane transport of poorly water-soluble drugs. SDDS provides higher drug concentration in the dispersed phase and equilibrium in the continuous phase, which corresponds to amorphous solubility of the drug. Rifaximin (RFX) is a nonabsorbable BCS class IV drug approved for the treatment of irritable bowel syndrome and effective against Helicobacter pylori. RFX shows slow crystallization and precipitation in an acidic pH of 1.2-2, leading to obliteration of its activity in the gastrointestinal tract. The objective of the present study is to inhibit the precipitation of RFX, involving screening of polymers at different concentrations, using an in-house developed microarray plate method and solubility studies which set forth hydroxypropyl methylcellulose (HPMC) E15, Soluplus, and polyvinyl alcohol to be effective precipitation inhibitors (PIs). Drug-polymer precipitates (PPTS) are examined for surface morphology by scanning electron microscopy, solid-phase transformation by hot stage microscopy, the nature of PPTS by polarized light microscopy, and drug-polymer interactions by Fourier transform infrared and nuclear magnetic resonance spectroscopy. Besides, the unfathomed molecular mechanism of drug-polymer interplay is discerned at the air-water interface using sum-frequency generation spectroscopy to correlate the interfacial hydrogen bonding properties in bulk water. Surprisingly, all studies disseminate HPMC E15 and Soluplus as effective PIs of RFX.

A novel food-based foam as oral contrast agent with negative Hounsfield units for demarcation of small bowel loops on abdominal CT: tolerability and bowel distension in 25 volunteers.

BACKGROUND: Diseases of the bowel are not always displayed on conventional abdominal computed tomography (CT). The studied oral contrast agent aims to improve this. PURPOSE: To investigate whether the use of a novel oral contrast for abdominal CT enables the same diagnostic advantages as seen in magnetic resonance imaging (MRI). MATERIAL AND METHODS: Twenty-five consented volunteers drank up to 1400 mL of a stable, drinkable foam. Comments on acceptance and side effects were noted immediately and 24 h later. Foam palatability was documented through interviews, and distribution in the small bowel by Hounsfield units from the CT software. The CT results were compared with age- and sex-matched controls, pretreated according to routine. A non-enhanced abdominal CT protocol of lowest possible radiation dose was used. External referees evaluated all data obtained. RESULTS: Foam was considered odd to swallow, and fullness was reported by all volunteers after 950 mL. Five had difficulties in drinking the last 320 mL and two abstained from it. All adverse symptoms were mild. The distribution in the small bowel was on par with standard agents. Foam density revealed stability with intraluminal values of around -550 HU from stomach to terminal ileum, satisfying the requirement of a great bowel lumen-to-wall contrast. External reviewers re-evaluated all our data, and one predicted the foam to offer a potential for improved diagnostics. CONCLUSION: A CT true-negative bowel filling agent was formulated, with high acceptance, few side effects, and a potential to mimic T1-weighted MRI images.

Historical Evolution and Provider Awareness of Inactive Ingredients in Oral Medications.

PURPOSE: A multitude of different versions of the same medication with different inactive ingredients are currently available. It has not been quantified how this has evolved historically. Furthermore, it is unknown whether healthcare professionals consider the inactive ingredient portion when prescribing medications to patients. METHODS: We used data mining to track the number of available formulations for the same medication over time and correlate the number of available versions in 2019 to the number of manufacturers, the years since first approval, and the number of prescriptions. A focused survey among healthcare professionals was conducted to query their consideration of the inactive ingredient portion of a medication when writing prescriptions. RESULTS: The number of available versions of a single medication have dramatically increased in the last 40 years. The number of available, different versions of medications are largely determined by the number of manufacturers producing this medication. Healthcare providers commonly do not consider the inactive ingredient portion when prescribing a medication. CONCLUSIONS: A multitude of available versions of the same medications provides a potentially under-recognized opportunity to prescribe the most suitable formulation to a patient as a step towards personalized medicine and mitigate potential adverse events from inactive ingredients.

Effects of Coformer and Polymer on Particle Surface Solution-Mediated Phase Transformation of Cocrystals in Aqueous Media.

The purpose of the present study was to investigate the effect of the coformer difference on particle surface solution-mediated phase transformation (PS-SMPT) during cocrystal particle dissolution in aqueous media in the absence and presence of polymers. SMPT can occur either in the bulk phase or at the particle surface because drug molecules can be supersaturated at the dissolving cocrystal surface, as well as in the bulk phase. Previously, bulk phase SMPT has been primarily investigated in formulation development. However, little is known about the effects of coformers and polymers on PS-SMPT of cocrystals. In this study, six carbamazepine (CBZ) cocrystals were used as model cocrystals (malonic acid (MAL), succinic acid (SUC), glutaric acid (GLA), adipic acid (ADP), saccharin (SAC), and nicotinamide (NCT); nonsink dissolution tests were performed with or without a precipitation inhibitor (hydroxypropyl methylcellulose (HPMC)) at pH 6.5. The residual particles were analyzed by powder X-ray diffraction, differential scanning calorimetry, polarized light microscopy (PLM), and scanning electron microscopy. Real-time PLM was used to directly observe rapid PS-SMPT. In the absence of HPMC, supersaturation was not observed in the bulk phase for all cocrystals. All cocrystals rapidly transformed to CBZ dihydrate aggregates via PS-SMPT (mostly within 1 min). In contrast, in the presence of 0.1% HPMC, supersaturation was observed for CBZ-SUC, CBZ-ADP, CBZ-SAC, and CBZ-NCT but not for CBZ-MAL and CBZ-GLA. The cocrystals with lower solubility coformers tended to induce higher supersaturation in the bulk phase. The PS-SMPT of CBZ-SUC, CBZ-ADP, and CBZ-SAC was slowed down by HPMC. By suppressing PS-SMPT, the cocrystals exhibited its supersaturation potential, depending on the properties of each coformer. To take advantage of the supersaturation potential of cocrystals to improve oral drug absorption, it is important to suppress particle surface SMPT in addition to bulk phase SMPT.

New Design Strategies for Controlling the Rate of Hydrophobic Drug Release from Nanoemulsions in Blood Circulation.

The intravenous administration of drug-loaded nanoparticles (NPs) is needed to achieve passive or active targeting in disease tissues. However, when the loaded drug is a hydrophobic small molecule, the NPs fail to reach adequate plasma drug concentrations mainly because of premature drug release. The pharmacokinetics of such drugs can be controlled by covalent modification, but this approach could compromise the safety or potency of the drug. In this study, we investigated two formulation parameters that could be used to improve the plasma concentrations of unmodified drugs that are loaded in a nanoemulsion (NE), a core-shell type NP. The first parameter is the loading ratio, and the second is the affinity of the drug to the core. Optimized NEs with reduced drug loading and with a high drug-core affinity resulted in a 12.4- and 11.2-fold increase in the plasma retention of curcumin and paclitaxel, respectively. Our strategy for enhancing the drug-core interaction affinity relied on mixing oils and surfactants to achieve cooperativity in noncovalent interactions, such as hydrophobic interactions, hydrogen bonding, and π-π stacking, which was further confirmed by theoretical calculations of interaction affinities. Finally, we report on the development of a cinnamic acid-derived oil-like material as a novel drug vehicle with exceptional solubilizing ability that could be used in intravenous formulations of NEs.

Can adjuncts to bowel preparation for colonoscopy improve patient experience and result in superior bowel cleanliness? A systematic review and meta-analysis.

BACKGROUND: Bowel preparation for colonoscopy is often poorly tolerated due to poor palatability and adverse effects. This can negatively impact on the patient experience and on the quality of bowel preparation. This systematic review and meta-analysis was carried out to assess whether adjuncts to bowel preparation affected palatability, tolerability and quality of bowel preparation (bowel cleanliness). METHODS: A systematic search strategy was conducted on PubMed, MEDLINE, EMBASE and the Cochrane Database of Systematic Reviews to identify studies evaluating adjunct use for colonoscopic bowel preparation. Studies comparing different regimens and volumes were excluded. Specific outcomes studied included palatability (taste), willingness to repeat bowel preparation, gastrointestinal adverse events and the quality of bowel preparation. Data across studies were pooled using a random-effects model and heterogeneity assessed using I2-statistics. RESULTS: Of 467 studies screened, six were included for analysis (all single-blind randomised trials; n = 1187 patients). Adjuncts comprised citrus reticulata peel, orange juice, menthol candy drops, simethicone, Coke Zero and sugar-free chewing gum. Overall, adjunct use was associated with improved palatability (mean difference 0.62, 95% confidence interval 0.29-0.96, p < 0.001) on a scale of 0-5, acceptability of taste (odds ratio 2.75, 95% confidence interval: 1.52-4.95, p < 0.001) and willingness to repeat bowel preparation (odds ratio 2.92, 95% confidence interval: 1.97-4.35, p < 0.001). Patients in the adjunct group reported lower rates of bloating (odds ratio 0.48, 95% confidence interval: 0.29-0.77, p = 0.003) and vomiting (odds ratio 0.47, 95% confidence interval 0.27-0.81, p = 0.007), but no difference in nausea (p = 0.10) or abdominal pain (p = 0.62). Adjunct use resulted in superior bowel cleanliness (odds ratio 2.52, 95% confidence interval: 1.31-4.85, p = 0.006). Heterogeneity varied across outcomes, ranging from 0% (vomiting) to 81% (palatability), without evidence of publication bias. The overall quality of evidence was rated moderate. CONCLUSION: In this meta-analysis, the use of adjuncts was associated with better palatability, less vomiting and bloating, willingness to repeat bowel preparation and superior quality of bowel preparation. The addition of adjuncts to bowel preparation may improve outcomes of colonoscopy and the overall patient experience.

Liquisolid Technology: A State-of-the-Art Review on the Current State, Challenges, New and Emerging Technologies for Next Generation.

Nowadays, the focus has been shifted to new technologies for improving drug solubility, permeability, and bioavailability, amid unprecedentedly increasing the number of newly discovered Active Pharmaceutical Ingredients (APIs), which are mostly categorized under Biopharmaceutical Classification System (BCS) as class-II and class IV. Traditional technologies and classical formulation strategies often fail to address most of the formulation problems associated with new APIs, particularly solubility and bioavailability. Therefore, exploring new and innovative technologies on an industrial scale is a prerequisite and requires modernization of manufacturing processes, as well as more advanced research and development. Liquisolid technology is a new, innovative industrial technology, particularly designed for either improving the release rates of poorly absorbed drugs or controlling their release pattern by achieving sustained-release profiles with zero-order release kinetics. Besides, it is a promising photoprotective system for photosensitive drugs and can further be used for modulating the drug microenvironmental pH. The next generation of liquisolid systems stems from a set of emerging technologies, such as liqui-pellet technology, which originates from combining liquisolid technology with pelletization technique, particularly extrusion-spheronization technique. This review article highlights the current state of liquisolid technology, ongoing challenges, characterization and applications, possible future prospects, the advent of new and emerging technologies, and the revolution of the next generation of liquisolid technology.

Preparation of ß-CD-Quercetin Complex and its Effects on Ethanol- Damaged BRL-3A Hepatocytes.

OBJECTIVE: To prepare the sustained-release complex, quercetin was incorporated with ß- cyclodextrin (ß-CD) and the effect of ß-CD-quercetin complex on the growth of ethanol-injuried hepatocytes was studied. METHODS: By using scanning electron microscopy, infrared spectroscopy, and release rate analysis, ß- CD-quercetin complex was identified. The effect of different concentrations of ß-CD-quercetin complex on the growth of ethanol-damaged hepatocytes at different time was observed by using MTT assay, and the cell quantity and morphology were observed by using hematoxylin-eosin staining. By using single-cell gel electrophoresis, the prevention of ß-CD-quercetin complex from the DNA damage of ethanol-damaged BRL-3A cells was studied, and Olive tail moment was calculated. RESULTS: ß-CD-quercetin complex as the sustained-release complex was successfully prepared. The ethanol induced damage of BRL-3A cells could be prevented by 20, 40 and 80 mg/L of quercetin complex, and the protection mechanism of hepatocyte was related to the antioxidation of DNA. CONCLUSION: Quercetin sustained-release complex could be prepared with ß-CD, and it might be used to treat alcoholic liver disease.

A Novel Approach to Optimize Hot Melt Impregnation in Terms of Amorphization Efficiency.

In this study, an innovative methodology to optimize amorphization during the hot melt impregnation (HMI) process was proposed. The novelty of this report revolves around the use of thermal analysis in combination with design of experiments (DoEs) to reduce residual crystallinity during the HMI process. As a model formulation, a mixture of ibuprofen (IBU) and Neusilin was used. The main aim of the study was to identify the critical process parameters of HMI and determine their optimal values to assure a robust impregnation process and possibly the highest possible amorphization rate of IBU. In order to realize this, a DoE approach was proposed based on a face-centered composite design involving three factors. The IBU/Neusilin ratio, the feeding rate, and the screw speed were considered as variables, while the residual crystallinity level of IBU, determined using differential scanning calorimetry (DSC), was measured as the response. Additionally, the stability of IBU under HMI was analyzed using high-performance liquid chromatography to estimate the extent of potential degradation. In order to verify the correctness of the DoE model, tested extrudates were manufactured by HMI and the obtained extrudates were thoroughly examined using scanning electron micrography, X-ray powder diffraction, and DSC.

Phycocosmetics and Other Marine Cosmetics, Specific Cosmetics Formulated Using Marine Resources.

Marine resources exist in vast numbers and show enormous diversity. As a result, there are likely many possible applications for marine molecules of interest in the cosmetic industry, whether as excipients or additives, but especially as active substances. It is possible to obtain extracts from active substances; for example, quite a few algae species can be used in moisturizing or anti-ageing products. In the field of topical photoprotection, mycosporine-like amino acids and gadusol are important lines of enquiry that should not be overlooked. In the field of additives, the demonstration that certain seaweed (algae) extracts have antimicrobial properties suggests that they could provide alternatives to currently authorized preservatives. These promising leads must be explored, but it should be kept in mind that it is a long process to bring ingredients to market that are both effective and safe to use.

Enhanced oral bioavailability and anti-diabetic activity of canagliflozin through a spray dried lipid based oral delivery: a novel paradigm.

AIM: Canagliflozin (CFZ), a novel SGLT II antagonist, exhibits erratic absorption after oral administration. The current study entails development and evaluation of spray dried lipid based formulation (solid SMEDDS) for enhancing oral bioavailability and anti-diabetic activity of CFZ. METHODS: Solid SMEDDS developed through spray drying containing Neusilin US2 as an adsorbent. The formed solid SMEDDS were characterized for physicochemical and solid state attributes. Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM) were used to confirm the spherical morphology. In vitro dissolution, ex vivo permeability and in vivo pharmacokinetic studies were conducted to determine the release rate, permeation rate and absorption profile of CFZ, respectively. Pharmacodynamic studies were done as per standard protocols. RESULTS: The optimized solid SMEDDS exhibited acceptable practical yield and flow properties and is vouched with enhanced amorphization, nanoparticulate distribution and acceptable drug content. The spherical morphology of solid SMEDDS and reconstituted SMEDDS were confirmed in SEM and TEM, respectively. In vitro dissolution studies revealed multi-fold release behavior in CFZ in various dissolution media, whereas, remarkable permeability was observed in jejunum segment of rat intestine. Pharmacokinetic studies of CFZ in solid SMEDDS demonstrated 2.53 and 1.43 fold enhancement in Cmax and 2.73 and 1.98 fold in AUC 0-24h, as compared to pure API and marketed formulation, respectively. Pharmacological evaluation of solid SMEDDS revealed enhanced anti-diabetic activity of CFZ through predominant SGLT II inhibition in rats, as evident from evaluation of biochemical levels, urinary glucose excretion studies and SGLT II expression analysis. CONCLUSION: The current work describes significant improvement biopharmaceutical properties of CFZ in solid SMEDD formulation. Graphical abstract Graphical Abstract: Enhanced oral bioavailability and anti-diabetic activity of canagliflozin through a spray dried lipid based oral delivery: a novel paradigm.

Exudate gums: chemistry, properties and food applications - a review.

Gums are complex carbohydrate molecules which have the ability to bind water and form gels at low concentration. These carbohydrates are often associated with proteins and minerals in their structure. Gums are of various types such as seed gums, exudate gums, microbial gums, mucilage gums, seaweeds gums, etc. Exudate gums are plant gums which ooze out from bark as a result of a protection mechanism upon injury. Exudate gums have been used by humans since ancient times for various applications due to their easy availability. The main characteristics which make them fit for use in various applications are viscosity, adhesive property, stabilization effect, emulsification action and surface-active property. Major applications of these gums are in food products, the paper, textile, cosmetics and pharmaceutical industries, oil-well drilling, etc. In the present paper, the chemistry, properties, processing and applications of commercially available exudate gums such as acacia gum or gum arabic, karaya gum, ghatti gum and tragacanth gum are discussed. Recent literature reveals that apart from the above mentioned applications, these gums also have nutritional properties which are being explored. Other gums cannot replace them because of their certain unique characteristics. © 2020 Society of Chemical Industry.

Recent Strategic Developments in the Use of Superdisintegrants for Drug Delivery.

Improving drug bioavailability in the pharmaceutical field is a challenge that has attracted substantial interest worldwide. The controlled release of a drug can be achieved with a variety of strategies and novel materials in the field. In addition to the vast development of innovative materials for improving therapeutic effects and reducing side effects, the exploration of remarkable existing materials could encourage the discovery of diverse approaches for adapted drug delivery systems. Recently, superdisintegrants have been proposed for drug delivery systems as alternative approaches to maximize the efficiency of therapy. Although superdisintegrants are well known and used in solid dosage forms, studies on strategies for the development of drug delivery systems using superdisintegrants are lacking. Therefore, this study reviews the use of superdisintegrants in controlled drug release dosage formulations. This overview of superdisintegrants covers developed strategies, types (including synthetic and natural materials), dosage forms and techniques and will help to improve drug delivery systems.

Transdermal vitamin D supplementation-A potential vitamin D deficiency treatment.

Vitamin D deficiency has high prevalence worldwide. Vitamin D3, the active form of vitamin D, exhibits array of roles in body, from calcium homeostasis and bone mineralization to cancer, neurological disorders, immunomodulatory action, and cardiac health. Current approaches for supplementing vitamin D3 are restricted to oral and parenteral routes. This review highlights recent research in the field of transdermal delivery of vitamin D, its active form and analogues with the aid of penetration enhancers and novel carrier system as nutritional supplement in case of vitamin D deficiency. The penetration of vitamin D3 is challenging; however, by means of reducing hydrophobicity of the active and encapsulating vitamin D3 in a suitable carrier system, penetration is achieved. The results show that penetration of vitamin D3 through skin is feasible. Further clinical trials could strengthen these results. However, the present research till date shows transdermal vitamin D3 a promising way of supplementation.

Solventless-mixing tablet coating technique using a V-shaped blender; investigation using methyl methacrylate and diethylaminoethyl methacrylate copolymer powder.

Our aim was to investigate the feasibility of a tablet coating mixing technique using a V-shaped blender to produce coated tablets by mixing only tablets and polymer powder. Tablet coating was achieved as follows. First, polymethacrylate latex was freeze-dried to prepare a coating powder. Second, tablets and polymer powder were mixed using the blender, yielding coated tablets. Two types of coating powder, composed of colloidal or non-colloidal particles of the same polymer, were prepared and used in the mixing treatment. Colloidal powder was rapidly pulverized due to impact by falling tablets in the blender and adhered to tablet surface. The powder on tablets was easily consolidated due to compression by tumbling tablets, yielding a polymer layer that can suppress drug release after curing. In contrast, non-colloidal powder was insufficiently pulverized and densified, and its deposition did not occur. Therefore, tablets are mechanically coated using a V-shaped blender by using colloidal polymer powder with high grindability and compactability. The impact rose by increasing rotation speed of the blender and promoted deposition of the polymer. Appropriate collision impacts of tablet-tablet and tablet-wall are required for successful tablet coating, although too intense impacts lead to tablet breakage and removal of the membrane.

Effectiveness, Safety, and Economic Comparison of Inhaled Epoprostenol Brands, Flolan and Veletri, in Acute Respiratory Distress Syndrome.

Background: No previous studies exist examining 2 inhaled epoprostenol formulations in an acute respiratory distress syndrome (ARDS) patient population. Objective: The study aim was to evaluate a formulary conversion from inhaled Flolan to Veletri to determine the impact on effectiveness, safety, and cost in patients with ARDS. Methods: This was a single-center, retrospective, matched cohort observational study at a tertiary care academic medical center. Patients included were mechanically ventilated, adult patients with ARDS receiving inhaled Flolan or Veletri for ≥1 hour in the intensive care unit. Results: A total of 132 patients were included in the matched cohort. There was no difference detected in change in partial pressure of arterial O2/fraction of inspired O2 (PaO2/FiO2) ratio after 1 hour of therapy between the inhaled Flolan and Veletri groups (27.2 ± 46.2 vs 30 ± 68 mm Hg, P = 0.78). Significant differences in secondary outcomes included incidence of hypotension (83% vs 95.5%, P = 0.04) and thrombocytopenia (9.1% vs 29.5%, P < 0.01) in the inhaled Flolan and Veletri groups, respectively, with no difference in cost per duration of therapy (P = 0.29). Conclusions and Relevance: There was no difference in the change in PaO2/FiO2 ratio after 1 hour of therapy between inhaled Flolan and Veletri in an ARDS patient population. The formulary conversion from inhaled Flolan to Veletri was likely justified.

Esters of terpene alcohols as highly potent, reversible, and low toxic skin penetration enhancers.

Skin penetration/permeation enhancers are compounds that improve (trans)dermal drug delivery. We designed hybrid terpene-amino acid enhancers by conjugating natural terpenes (citronellol, geraniol, nerol, farnesol, linalool, perillyl alcohol, menthol, borneol, carveol) or cinnamyl alcohol with 6-(dimethylamino)hexanoic acid through a biodegradable ester linker. The compounds were screened for their ability to increase the delivery of theophylline and hydrocortisone through and into human skin ex vivo. The citronellyl, bornyl and cinnamyl esters showed exceptional permeation-enhancing properties (enhancement ratios up to 82) while having low cellular toxicities. The barrier function of enhancer-treated skin (assessed by transepidermal water loss and electrical impedance) recovered within 24 h. Infrared spectroscopy suggested that these esters fluidized the stratum corneum lipids. Furthermore, the citronellyl ester increased the epidermal concentration of topically applied cidofovir, which is a potent antiviral and anticancer drug, by 15-fold. In conclusion, citronellyl 6-(dimethylamino)hexanoate is an outstanding enhancer with an advantageous combination of properties, which may improve the delivery of drugs that have a limited ability to cross biological barriers.

Use of Terahertz-Raman Spectroscopy to Determine Solubility of the Crystalline Active Pharmaceutical Ingredient in Polymeric Matrices during Hot Melt Extrusion.

Polymer-based amorphous solid dispersions (ASDs) comprise one of the most promising formulation strategies devised to improve the oral bioavailability of poorly water-soluble drugs. Exploitation of such systems in marketed products has been limited because of poor understanding of physical stability. The internal disordered structure and increased free energy provide a thermodynamic driving force for phase separation and recrystallization, which can compromise therapeutic efficacy and limit product shelf life. A primary concern in the development of stable ASDs is the solubility of the drug in the polymeric carrier, but there is a scarcity of reliable analytical techniques for its determination. In this work, terahertz (THz) Raman spectroscopy was introduced as a novel empirical approach to determine the saturated solubility of crystalline active pharmaceutical ingredient (API) in polymeric matrices directly during hot melt extrusion. The solubility of a model compound, paracetamol, in two polymer systems, Affinisol 15LV (HPMC) and Plasdone S630 (copovidone), was determined by monitoring the API structural phase transitions from crystalline to amorphous as an excess of crystalline drug dissolved in the polymeric matrix. THz-Raman results enabled construction of solubility phase diagrams and highlighted significant differences in the solubilization capacity of the two polymer systems. The maximum stable API-load was 20 wt % for Affinisol 15LV and 40 wt % for Plasdone S630. Differential scanning calorimetry and XRPD studies corroborated these results. This approach has demonstrated a novel capability to provide real-time API-polymer phase equilibria data in a manufacturing relevant environment and promising potential to predict solid-state solubility and physical stability of ASDs.