Sequence-based prediction of pH-dependent protein solubility using CamSol.

Solubility is a property of central importance for the use of proteins in research in molecular and cell biology and in applications in biotechnology and medicine. Since experimental methods for measuring protein solubility are material intensive and time consuming, computational methods have recently emerged to enable the rapid and inexpensive screening of solubility for large libraries of proteins, as it is routinely required in development pipelines. Here, we describe the development of one such method to include in the predictions the effect of the pH on solubility. We illustrate the resulting pH-dependent predictions on a variety of antibodies and other proteins to demonstrate that these predictions achieve an accuracy comparable with that of experimental methods. We make this method publicly available at https://www-cohsoftware.ch.cam.ac.uk/index.php/camsolph, as the version 3.0 of CamSol.

FormulationAI: a novel web-based platform for drug formulation design driven by artificial intelligence.

Today, pharmaceutical industry faces great pressure to employ more efficient and systematic ways in drug discovery and development process. However, conventional formulation studies still strongly rely on personal experiences by trial-and-error experiments, resulting in a labor-consuming, tedious and costly pipeline. Thus, it is highly required to develop intelligent and efficient methods for formulation development to keep pace with the progress of the pharmaceutical industry. Here, we developed a comprehensive web-based platform (FormulationAI) for in silico formulation design. First, the most comprehensive datasets of six widely used drug formulation systems in the pharmaceutical industry were collected over 10 years, including cyclodextrin formulation, solid dispersion, phospholipid complex, nanocrystals, self-emulsifying and liposome systems. Then, intelligent prediction and evaluation of 16 important properties from the six systems were investigated and implemented by systematic study and comparison of different AI algorithms and molecular representations. Finally, an efficient prediction platform was established and validated, which enables the formulation design just by inputting basic information of drugs and excipients. FormulationAI is the first freely available comprehensive web-based platform, which provides a powerful solution to assist the formulation design in pharmaceutical industry. It is available at https://formulationai.computpharm.org/.

Biological activities of drug inactive ingredients.

In a drug formulation (DFM), the major components by mass are not Active Pharmaceutical Ingredient (API) but rather Drug Inactive Ingredients (DIGs). DIGs can reach much higher concentrations than that achieved by API, which raises great concerns about their clinical toxicities. Therefore, the biological activities of DIG on physiologically relevant target are widely demanded by both clinical investigation and pharmaceutical industry. However, such activity data are not available in any existing pharmaceutical knowledge base, and their potentials in predicting the DIG-target interaction have not been evaluated yet. In this study, the comprehensive assessment and analysis on the biological activities of DIGs were therefore conducted. First, the largest number of DIGs and DFMs were systematically curated and confirmed based on all drugs approved by US Food and Drug Administration. Second, comprehensive activities for both DIGs and DFMs were provided for the first time to pharmaceutical community. Third, the biological targets of each DIG and formulation were fully referenced to available databases that described their pharmaceutical/biological characteristics. Finally, a variety of popular artificial intelligence techniques were used to assess the predictive potential of DIGs' activity data, which was the first evaluation on the possibility to predict DIG's activity. As the activities of DIGs are critical for current pharmaceutical studies, this work is expected to have significant implications for the future practice of drug discovery and precision medicine.

Availability and stock-outs of paediatric antiretroviral treatment formulations at health facilities in Kenya and Uganda.

INTRODUCTION: The large number of deaths among children with HIV is driven by poor antiretroviral treatment (ART) coverage among this cohort. The aim of the study was to assess the availability and stock-outs of paediatric and adult ART formulations in Kenya and Uganda across various regions and types of health facilities. METHODS: A survey on availability and stock-outs of paediatric ART at health facilities was adapted from the standardized Health Action International-WHO Medicine Availability Monitoring Tool. All preferred and limited-use formulations, and three phased-out formulations according to the 2021 WHO optimal formulary list were included in the survey, as well as a selection of adult ART formulations suitable for older children, adolescents, and adults. Availability data were collected in June-July 2022 and stock-out data were obtained over the previous year from randomly selected public and private-not-for-profit (PNFP) facilities registered to dispense paediatric ART across six districts per country. All data were analysed descriptively. RESULTS: In total, 144 health facilities were included (72 per country); 110 were public and 34 PNFP facilities. Overall availabilities of preferred paediatric ART formulations were 52.2% and 63.5% in Kenya and Uganda, respectively, with dolutegravir (DTG) 10 mg dispersible tablets being available in 70.2% and 77.4% of facilities, respectively, and abacavir/lamivudine dispersible tablets in 89.8% and 98.2% of facilities. Of note, availability of both formulations was low (37.5% and 62.5%, respectively) in Kenyan PNFP facilities. Overall availabilities of paediatric limited-use products were 1.1% in Kenya and 1.9% in Uganda. At least one stock-out of a preferred paediatric ART formulation was reported in 40.0% of Kenyan and 74.7% of Ugandan facilities. Nevirapine solution stock-outs were reported in 43.1% of Ugandan facilities, while alternative formulations for postnatal HIV prophylaxis were not available. CONCLUSIONS: Recommended DTG-based first-line ART for children across all ages was reasonably available at health facilities in Kenya and Uganda, with the exception of Kenyan PNFP facilities. Availability of paediatric ART formulations on the limited-use list was extremely low across both countries. Stock-outs were reported regularly, with the high number of reported stock-outs of neonatal ART formulations in Uganda being most concerning.

Laser-assisted topical delivery of vismodegib reduces hedgehog gene expression in human basal cell carcinomas in vivo.

BACKGROUND: Systemically delivered hedgehog inhibitors including vismodegib and sonidegib are widely used to treat basal cell carcinomas (BCCs). Ablative fractional laser (AFL)-assisted topical delivery of vismodegib has been demonstrated in preclinical studies. The aim of this explorative clinical study was to evaluate intratumoral vismodegib concentrations and effect on hedgehog pathway gene expression following AFL-assisted topical vismodegib delivery to BCCs. METHODS: In an open-label clinical trial, 16 nodular BCCs (in n = 9 patients) received one application of CO2 -AFL (40 mJ/microbeam, 10% density) followed by topical vismodegib emulsion. After 3-4 days, vismodegib concentrations in tumor biopsies (n = 15) and plasma were analyzed and compared with samples from patients receiving oral treatment (n = 3). GLI1, GLI2, PTCH1, and PTCH2 expression was determined by quantitative polymerase chain reaction (n = 7) and GLI1 additionally by in situ hybridization (n = 3). RESULTS: Following AFL-assisted topical administration, vismodegib was detected in 14/15 BCCs and reached a median concentration of 6.2 µmol/L, which compared to concentrations in BCC tissue from patients receiving oral vismodegib (9.5 µmol/L, n = 3, p = 0.8588). Topical vismodegib reduced intratumoral GLI1 expression by 51%, GLI2 by 55%, PTCH1 and PTCH2 each by 73% (p ≤ 0.0304) regardless of vismodegib concentrations (p ≥ 0.3164). In situ hybridization demonstrated that GLI1 expression was restricted to tumor tissue and downregulated in response to vismodegib exposure. CONCLUSION: A single AFL-assisted topical application of vismodegib resulted in clinically relevant intratumoral drug concentrations and significant reductions in hedgehog pathway gene expressions.

Drug formulation augments the therapeutic response of carboplatin administered through a lymphatic drug delivery system.

Treatment of metastatic lymph nodes (LNs) is challenging due to their unique architecture and biophysical traits. Systemic chemotherapy fails to impede tumor progression in LNs due to poor drug uptake and retention by LNs, resulting in fatal systemic metastasis. To effectively treat LN metastasis, achieving specific and prolonged retention of chemotherapy drugs in the tumor-draining LNs is essential. The lymphatic drug-delivery system (LDDS) is an ultrasound-guided drug-delivery methodology for administration of drugs to LNs that addresses these requirements. However, early-stage metastatic LNs have an additional set of drug transport barriers, such as elevated intranodal pressure and viscosity, that negatively impact drug diffusion. In the present study, using formulations of elevated osmotic pressure and viscosity relative to saline, we sought to favorably alter the LN's physical environment and study its impact on pharmacokinetics and consequently the therapeutic efficacy of carboplatin delivered using the LDDS. Our study confirmed the capability of a drug formulation with elevated osmotic pressure and viscosity to alter the architecture of LNs, as it caused notable expansion of the lymphatic sinus. Additionally, the study delineated an optimal range of osmotic pressure and viscosity, centered around 1897 kPa and 11.5 mPa·s, above and below which therapeutic efficacy was found to decline markedly. These findings suggest that formulation osmotic pressure and viscosity are parameters that require critical consideration as they can both hinder and promote tumorigenesis. The facile formulation reported here has wide-ranging applicability across cancer spectrums and is thus anticipated to be of great clinical benefit.

Exploration of Verticillins in High-Grade Serous Ovarian Cancer and Evaluation of Multiple Formulations in Preclinical In Vitro and In Vivo Models.

Verticillins are epipolythiodioxopiperazine alkaloids isolated from a fungus with nanomolar anti-tumor activity in high-grade serous ovarian cancer (HGSOC). HGSOC is the fifth leading cause of death in women, and natural products continue to be an inspiration for new drug entities to help tackle chemoresistance. Verticillin D was recently found in a new fungal strain and compared to verticillin A. Both compounds exhibited nanomolar cytotoxic activity against OVCAR4 and OVCAR8 HGSOC cell lines, significantly reduced 2D foci and 3D spheroids, and induced apoptosis. In addition, verticillin A and verticillin D reduced tumor burden in vivo using OVCAR8 xenografts in the peritoneal space as a model. Unfortunately, mice treated with verticillin D displayed signs of liver toxicity. Tolerability studies to optimize verticillin A formulation for in vivo delivery were performed and compared to a semi-synthetic succinate version of verticillin A to monitor bioavailability in athymic nude females. Formulation of verticillins achieved tolerable drug delivery. Thus, formulation studies are effective at improving tolerability and demonstrating efficacy for verticillins.

Pharmaceutical Applications of Ionic Liquids: A Personal Account.

Ionic liquids (ILs) have been extensively used in drug formulation and delivery as designer solvents and other components because of their inherent tunability and useful physicochemical and biopharmaceutical properties. ILs can be used to manage some of the operational and functional challenges of drug delivery, including drug solubility, permeability, formulation instability, and in vivo systemic toxicity, that are associated with conventional organic solvents/agents. Furthermore, ILs have been recognized as potential solvents to address the polymorphism, limited solubility, poor permeability, instability, and low bioavailability of crystalline drugs. In this account, we discuss the technological progress and strategies toward designing biocompatible ILs and explore potential biomedical applications, namely the solubilization of small and macromolecular drugs, the creation of active pharmaceutical ingredients, and the delivery of pharmaceuticals.

Learning Relationships Between Chemical and Physical Stability for Peptide Drug Development.

PURPOSE OR OBJECTIVE: Chemical and physical stabilities are two key features considered in pharmaceutical development. Chemical stability is typically reported as a combination of potency and degradation product. Moreover, fluorescent reporter Thioflavin-T is commonly used to measure physical stability. Executing stability studies is a lengthy process and requires extensive resources. To reduce the resources and shorten the process for stability studies during the development of a drug product, we introduce a machine learning-based model for predicting the chemical stability over time using both formulation conditions as well as aggregation curves. METHODS: In this work, we develop the relationships between the formulation, stability timepoint, and the chemical stability measurements and evaluated the performance on a random test set. We have developed a multilayer perceptron (MLP) for total degradation prediction and a random forest (RF) model for potency. RESULTS: The coefficient of determination (R2) of 0.945 and a mean absolute error (MAE) of 0.421 were achieved on the test set when using MLP for total degradation. Similarly, we achieved a R2 of 0.908 and MAE of 1.435 when predicting potency using the RF model. When physical stability measurements are included into the MLP model, the MAE of predicting TD decreases to 0.148. Using a similar strategy for potency prediction, the MAE decreases to 0.705 for the RF model. CONCLUSIONS: We conclude two important points: first, chemical stability can be modeled using machine learning techniques and second there is a relationship between the physical stability of a peptide and its chemical stability.

Fabrication and Applications of Potentiometric Membrane Sensors Based on Specific Recognition Sites for the Measurement of the Quinolone Antibacterial Drug Gemifloxacin.

Supramolecular gemifloxacin (GF) sensors have been developed. Supramolecular chemistry is primarily concerned with noncovalent intermolecular and intramolecular interactions, which are far weaker than covalent connections, but they can be exploited to develop sensors with remarkable affinity for a target analyte. In order to determine the dose form of the quinolone antibacterial drug gemifloxacin, the current study's goal is to adapt three polyvinylchloride (PVC) membrane sensors into an electrochemical technique. Three new potentiometric membrane sensors with cylindric form and responsive to gemifloxacin (GF) were developed. The sensors' setup is based on the usage of o-nitrophenyl octyl ether (o-NPOE) as a plasticizer in a PVC matrix, ß-cyclodextrin (ß-CD) (sensor 1), γ-cyclodextrin (γ-CD) (sensor 2), and 4-tert-butylcalix[8]arene (calixarene) (sensor 3) as an ionophore, potassium tetrakis (4-chlorophenyl) borate (KTpClPB) as an ion additive for determination of GF. The developed method was verified according to IUPAC guidelines. The sensors under examination have good selectivity for GF, according to their selectivity coefficients. The constructed sensors demonstrated a significant response towards to GF over a concentration range of 2.4 × 10-6, 2.7 × 10-6, and 2.42 × 10-6 mol L-1 for sensors 1, 2, and 3, respectively. The sensors showed near-Nernstian cationic response for GF at 55 mV, 56 mV, and 60 mV per decade for sensors 1, 2, and 3, respectively. Good recovery and relative standard deviations during the day and between days are displayed by the sensors. They demonstrated good stability, quick response times, long lives, rapid recovery, and precision while also exhibiting good selectivity for GF in various matrices. To determine GF in bulk and dose form, the developed sensors have been successfully deployed. The sensors were also employed as end-point indicators for titrating GF with sodium tetraphenyl borate.

Administration of medicines to children: a practical guide.

Getting children to take medicines can be difficult. There is no 'one-size-fits-all' approach. When selecting medicines for children, it is important to consider the child's age, swallowing ability, ease of administration and accessibility of the product. Ask the child, parent or caregiver about their preference for formulations and flavours. There are different ways to alter the taste, aftertaste and mouth feel of medicines, which may help improve palatability. Pharmacists or medicines information services can assist with advice on suitable formulations or methods of administration.

Improvement of Skin Permeation of Caffeine, a Hydrophilic Drug, by the Application of Water Droplets Provided by a Novel Humidifier Device.

Recently, a novel humidifier that sprays water fine droplets equipped with a copolymer, poly(3,4-ethylene dioxythiophene)-poly(styrene sulfonate) (PEDOT/PSS) was developed. PEDOT/PSS in the humidifier absorbs water from the environment and releases fine water droplets by heating. In the present study, the effect of hydration on the skin barrier, stratum corneum, was first determined by the application of fine water droplets using the humidifier. The skin-penetration enhancement effect of a model hydrophilic drug, caffeine, was also investigated using the humidifier and compared with a conventional water-evaporative humidifier. More prolonged skin hydration effect was observed after application of the fine water droplet release humidifier using PEDOT/PSS than that using a conventional humidifier. In addition, markedly higher skin permeation of caffeine was observed in both infinite and finite dose conditions. Furthermore, higher skin permeation of caffeine from oil/water emulsion containing caffeine was observed in finite dose conditions by pretreatment with the humidifier using PEDOT/PSS. This device can provide water droplets without replenishing water, so it is more convenient for enhancing the skin permeation of chemical compounds from topical drugs and cosmetic formulations.

Topical NSAIDs for acute local pain relief: in vitro characterization of drug delivery profiles into and through human skin.

OBJECTIVE: The efficacy of topical nonsteroidal anti-inflammatory drugs (NSAIDs) relates not only to the individual NSAID used but also to differences in formulation design. The aim of this study was to investigate the fundamental differences in ibuprofen and diclofenac drug delivery vehicles, specifically gels and plasters, compared to a recently launched 200 mg ibuprofen medicated plaster and characterize the resulting dermatologic-pharmacokinetic profiles into and through ex vivo human skin layers. METHODS: In vitro skin permeation testing over 24 h and sacrificial timepoint penetration experiments (at 1, 4, 8, 12, and 24 h) were conducted using an automated flow-through diffusion cell system. The amount of drug delivered to the epidermis, dermis, and receptor solution (representing deeper tissue) was determined by liquid chromatography-tandem mass spectrometry. Skin protein binding of ibuprofen and diclofenac was investigated by spiking skin homogenate with increasing concentrations of each drug and determining the fraction unbound. RESULTS: Differences were observed in the amount of drug recovered at sacrificial timepoints and rate at which drug was delivered to the target site between plaster and gel formulations of ibuprofen and diclofenac and between plaster formulations of the same drug (ibuprofen). While the amount of drug quantified at sacrificial timepoints did not necessarily determine in vivo flux rates, differences in drug distribution within the skin layers indicated where drug reservoirs were formed. CONCLUSIONS: These findings highlight the importance of intelligent formulation design in determining NSAID delivery through skin layers. Further work is required to quantify drug delivery into deeper tissues and the resultant local anti-inflammatory effects.

Biomedical Applications of Metal Organic Polygons and Polyhedra (MOPs).

Since the discovery and structural characterization of metal organic polygons and polyhedra (MOPs), scientists have explored their potential in various applications like catalysis, separation, storage, and sensing. In recent years, scientists have explored the potential of supramolecular MOPs in biomedical application. Pioneering works by Ehrlich, Rosenberg, Lippard, Stang and others have demonstrated that MOPs have great potential as a novel class of metallo-therapeutics that can deliver cargoes (drugs and dyes) selectively. In this article, we document the progress made over the past two decades on the biomedical applications of MOPs and discuss the future prospects of this emerging field.

Multifunctional Microparticles Incorporating Gold Compound Inhibit Human Lung Cancer Xenograft.

PURPOSE: Gold porphyrin (AuP) is a complex that has been shown to be potent against various tumors. A biocompatible interpenetrating network (IPN) system comprised of polyethyleneglycol diacrylate (PEGdA) and chemically-modified gelatin has been shown to be an effective implantable drug depot to deliver AuP locally. Here we designed IPN microparticles complexed with AuP to facilitate intravenous administration and to diminish systemic toxicity. METHODS: We have synthesized and optimized an IPN microparticle formulation complexed with AuP. Tumor cell cytotoxicity, antitumor activity, and survival rate in lung cancer bearing nude mice were analyzed. RESULTS: IPN microparticles maintained AuP bioactivity against lung cancer cells (NCI-H460). In vivo study showed no observable systemic toxicity in nude mice bearing NCI-H460 xenografts after intravenous injection of 6 mg/kg AuP formulated with IPN microparticles. An anti-tumor activity level comparable to free AuP was maintained. Mice treated with 6 mg/kg AuP in IPN microparticles showed 100% survival rate while the survival rate of mice treated with free AuP was much less. Furthermore, microparticle-formulated AuP significantly reduced the intratumoral microvasculature when compared with the control. CONCLUSION: AuP in IPN microparticles can reduce the systemic toxicity of AuP without compromising its antitumor activity. This work highlighted the potential application of AuP in IPN microparticles for anticancer chemotherapy.

On the Rational Drug Design for Hypertension through NMR Spectroscopy.

Antagonists of the AT1receptor (AT1R) are beneficial molecules that can prevent the peptide hormone angiotensin II from binding and activating the specific receptor causing hypertension in pathological states. This review article summarizes the multifaced applications of solid and liquid state high resolution nuclear magnetic resonance (NMR) spectroscopy in antihypertensive commercial drugs that act as AT1R antagonists. The 3D architecture of these compounds is explored through 2D NOESY spectroscopy and their interactions with micelles and lipid bilayers are described using solid state 13CP/MAS, 31P and 2H static solid state NMR spectroscopy. Due to their hydrophobic character, AT1R antagonists do not exert their optimum profile on the AT1R. Therefore, various vehicles are explored so as to effectively deliver these molecules to the site of action and to enhance their pharmaceutical efficacy. Cyclodextrins and polymers comprise successful examples of effective drug delivery vehicles, widely used for the delivery of hydrophobic drugs to the active site of the receptor. High resolution NMR spectroscopy provides valuable information on the physical-chemical forces that govern these drug:vehicle interactions, knowledge required to get a deeper understanding on the stability of the formed complexes and therefore the appropriateness and usefulness of the drug delivery system. In addition, it provides valuable information on the rational design towards the synthesis of more stable and efficient drug formulations.

Topical delivery of vismodegib using ablative fractional laser and micro-emulsion formulation in vitro.

BACKGROUND AND OBJECTIVE: Hedgehog inhibitors such as vismodegib are targeted drugs widely used for the treatment of basal cell carcinomas; however, their use is significantly limited by frequent systemic side effects due to oral administration route. We aim to use ablative fractional laser (AFL) to enable the topical delivery of vismodegib to relevant dermal depths. MATERIALS AND METHODS: Pig skin was treated in vitro with a fractional 10,600 nm CO2 laser at 0 or 80 mJ/microbeam and exposed to vismodegib (6.4 mmol/L) in Franz-diffusion cells for 0.5, 4, and 24 hours (n = 54 samples), either formulated in a micro-emulsion composed of soybean oil and Tween 80 or dissolved in ethanol as vehicle control. Vismodegib biodistribution was studied at specific skin depths from 0 to 1,800 µm (incremental steps of 300 µm) by mass spectrometry. RESULTS: Combination of AFL and vismodegib emulsion substantially enhanced the delivery of drug into the skin. Emulsion formulation alone yielded higher vismodegib skin concentrations compared to vehicle control in superficial and mid-dermis (0-900 µm, P = 0.002-0.015). The over-all highest concentration found (554.5 µmol/L) was reached at 24 hours in superficial (0-300 µm) AFL exposed skin, 7.6-fold higher than vehicle control (P = 0.002) and 9.7-101.6 fold higher than previously reported steady-state plasma concentrations in patients treated with oral vismodegib (5.5-56.9 µmol/L). Compared to intact skin, AFL exposure significantly increased skin concentrations of vismodegib even in deep skin layers (24 h, 900-1,800 µm, emulsion: 8.7-74.3 µmol/L vs. 0.0-0.0 µmol/L, P = 0.004-0.048; vehicle control: 23.7-50.6 µmol/L vs. 0.0-1.6 µmol/L, P = 0.002). The total delivery of vismodegib-emulsion into mid-deep dermal skin layers from 600 to 1,800 µm was for AFL exposed skin 8.2 fold higher than intact skin. Also, delivery of emulsion vismodegib by AFL was time-dependent as seen by the continuous increase in concentrations found over time, with highest uptake detected after 24 hours (4-24 hours, 0-900 µm, P = 0.002-0.004). CONCLUSION: AFL enhances topical delivery of micro-emulsion formulated vismodegib, reaching concentrations similar to or above plasma concentrations previously reported in patients receiving oral vismodegib. Lasers Surg. Med. 51:79-87, 2019. © 2018 Wiley Periodicals, Inc.

A Decision Support Tool Facilitating Medicine Design for Optimal Acceptability in The Older Population.

PURPOSE: Medicine acceptability, which is of the utmost importance for vulnerable patients' adherence, is driven by both user and product characteristics. Herein, a novel multivariate approach integrating the many aspects of acceptability is used to discriminate positively and negatively accepted medicines in the older population. METHODS: An observational study was carried out in eight hospitals and eight nursing homes to collect a large set of real-life data on medicines uses in older patients (≥65 years). Mapping and clustering explored these multiple observational measures and summarised the main information into an intelligible reference framework. Resampling statistics were used to validate the model's reliability. RESULTS: A three-dimensional map and two clusters defining acceptability profiles, as positive or negative, emerged from the 1079 evaluations. Factors of interest (medicines, user features…) were positioned on the map at the barycentre of their evaluations and assigned to an acceptability profile. Focusing on patients' ability to swallow, we have highlighted the tool's efficacy in demonstrating the impact of user features on medicine acceptability. CONCLUSIONS: This multivariate approach provides a relevant judgement criterion for this multi-dimensional concept. Facilitating the choice of the most appropriate dosage form to achieve optimal acceptability in a targeted population, this tool is of real potential to improve clinical decisions.

Long-Acting Growth Hormone Preparations in the Treatment of Children.

Human growth hormone (hGH), which had been in use since 1958, was supplanted by recombinant human growth hormone (rhGH) in 1985 for those with growth hormone deficiency (GHD). Adherence to daily subcutaneous growth hormone is challenging for patients. Thus, several companies have pursued the creation of long acting rhGH. These agents can be divided broadly into depot formulations, PEGylated formulations, pro-drug formulations, non-covalent albumin binding GH and GH fusion proteins. Nutropin Depot is the only long acting rhGH ever approved by the U.S. Food and Drug Administration, and it was removed from the market in 2004. Of the approximately seventeen candidate drugs, only a handful remain under active clinical investigation or are commercially available.

Soft, chewable gelatin-based pharmaceutical oral formulations: a technical approach.

OBJECTIVE: Hard tablets and capsules for oral drug delivery cause problems for people experiencing dysphagia. This work describes the formulation and properties of a gelatin based, self-preserved, and soft chewable tablet as an alternative and novel drug delivery format. MATERIALS AND METHODS: Gelatin (8.8-10% in 24.7-29% water) constituted the matrix of the soft, semi-solid tablets. Three different pharmaceuticals (Ibuprofen 10%, Acetaminophen 15%, and Meloxicam 1.5%) were tested in this formulation. Microbial stability was controlled by lowering the water activity with a mixture of sorbitol and xylitol (45.6-55%). Rheological properties were tested applying small strain oscillation measurements. Taste masking of ibuprofen soft-chew tablets was achieved by keeping the ibuprofen insoluble at pH 4.5 and keeping the processing temperature below the crystalline-to-amorphous transition temperature. RESULTS: Soft-chew formulations showed good stability for all three pharmaceuticals (up to 24 months), and the ibuprofen containing formulation exhibited comparable dissolution to a standard oral tablet as well as good microbial stability. The rheological properties of the ibuprofen/gelatin formulation had the fingerprint of a true gelatin gel, albeit higher moduli, and melting temperature. CONCLUSIONS: The results suggest that easy-to-swallow and well taste-masked soft chewable tablet formulations with extended shelf life are within reach for several active pharmaceutical ingredients (APIs).