A Self-Immolative Linker for the pH-Responsive Release of Amides.

The administration of therapeutics using bioconjugation has been mainly limited to drugs containing amine, alcohol, or thiol functional groups. Here, we report a general procedure for the preparation of benzylic N-acyl carbamates suitable for masking the amide group in important drugs such as Linezolid, Enzalutamide, or Tasimelteon in good to acceptable yields. These N-acyl carbamates appear to be stable in plasma, while a qualitative analysis of further drug uncage demonstrates that, at pH values of 5.5, a classical 1,6-benzyl elimination mechanism takes place, releasing more than 80% of the drug in 24 h.

Kinetic buffers.

This paper proposes a new type of molecular device that is able to act as an inverse proton sponge to slowly decrease the pH inside a reaction vessel. This makes the automatic monitoring of the concentration of pH-sensitive systems possible. The device is a composite formed of an alkyl chloride, which kinetically produces acidity, and a buffer that thermodynamically modulates the variation in pH value. Profiles of pH versus time (pH-t plots) have been generated under various experimental conditions by computer simulation, and the device has been tested by carrying out automatic spectrophotometric titrations, without using an autoburette. To underline the wide variety of possible applications, this new system has been used to realize and monitor HCl uptake by a di-copper(II) bistren complex in a single run, in a completely automatic experiment.

Implantation of In Situ Gelling Systems for the Delivery of Chemotherapeutic Agents.

Implantation is a modern method of administering chemotherapeutic agents, with a highly targeted effect and better patient tolerance due to the low frequency of administration. Implants are capable of controlled release, which makes them a viable alternative to infusional chemotherapy, allowing patients to enjoy a better quality of life without the need for prolonged hospitalization. Compared to subcutaneous implantation, intratumoral implantation has a number of significant advantages in terms of targeting and side effects, but this area of chemotherapy is still poorly understood in terms of clinical trials. At the same time, there are more known developments of drugs in the form of implants and injections for intratumoral administration. The disadvantages of classical intratumoral implants are the need for surgical intervention to install the system and the increased risk of tumor rupture noted by some specialists. The new generation of implants are in situ implants-systems formed in the tumor due to a phase transition (sol-gel transition) under the influence of various stimuli. Among this systems some are highly selective for a certain type of malignant neoplasm. Such systems are injected and have all the advantages of intratumoral injections, but due to the phase transition occurring in situ, they form depot forms that allow the long-term release of chemotherapeutic agents.

Recent Developments in Ion-Sensitive Systems for Pharmaceutical Applications.

Stimuli-responsive carriers of pharmaceutical agents have been extensively researched in recent decades due to the possibility of distinctively precise targeted drug delivery. One of the potentially beneficial strategies is based on the response of the medical device to changes in the ionic environment. Fluctuations in ionic strength and ionic composition associated with pathological processes may provide triggers sufficient to induce an advantageous carrier response. This review is focused on recent developments and novel strategies in the design of ion-responsive drug delivery systems. A variety of structures i.e., polymeric matrices, lipid carriers, nucleoside constructs, and metal-organic frameworks, were included in the scope of the summary. Recently proposed strategies aim to induce different pharmaceutically beneficial effects: localized drug release in the desired manner, mucoadhesive properties, increased residence time, or diagnostic signal emission. The current state of development of ion-sensitive drug delivery systems enabled the marketing of some responsive topical formulations. Concurrently, ongoing research is focused on more selective and complex systems for different administration routes. The potential benefits in therapeutic efficacy and safety associated with the employment of multi-responsive systems will prospectively result in further research and applicable solutions.

Targeting joint inflammation for osteoarthritis management through stimulus-sensitive hyaluronic acid based intra-articular hydrogels.

Numerous therapeutic strategies have been developed for osteoarthritis (OA) management, including intra-articular (IA) injections. The ideal IA formulation should control cartilage degradation and restore synovial fluid viscosity. To this end, we propose to combine thermo-sensitive polymers (poloxamers) with hyaluronic acid (HA) to develop suitable beta-lapachone (ßLap) loaded IA formulations. The development of IA formulations with these components entails several difficulties: low ßLap solubility, unknown ßLap therapeutic dose and the bonded commitment of easy administration and viscosupplementation. An optimized formulation was designed using artificial intelligence tools based on the experimental results of a wide variety of hydrogels and its therapeutic capacity was evaluated on an ex vivo OA model. The formulation presented excellent rheological properties and significantly decreased the secretion of degradative (MMP13) and pro-inflammatory (CXCL8) molecules. Therefore, the developed formulation is a promising candidate for OA treatment restoring the synovial fluid rheological properties while decreasing inflammation and cartilage degradation.

Recent Advances in the Development of In Situ Gelling Drug Delivery Systems for Non-Parenteral Administration Routes.

In situ gelling drug delivery systems have gained enormous attention over the last decade. They are in a sol-state before administration, and they are capable of forming gels in response to different endogenous stimuli, such as temperature increase, pH change and the presence of ions. Such systems can be administered through different routes, to achieve local or systemic drug delivery and can also be successfully used as vehicles for drug-loaded nano- and microparticles. Natural, synthetic and/or semi-synthetic polymers with in situ gelling behavior can be used alone, or in combination, for the preparation of such systems; the association with mucoadhesive polymers is highly desirable in order to further prolong the residence time at the site of action/absorption. In situ gelling systems include also solid polymeric formulations, generally obtained by freeze-drying, which, after contact with biological fluids, undergo a fast hydration with the formation of a gel able to release the drug loaded in a controlled manner. This review provides an overview of the in situ gelling drug delivery systems developed in the last 10 years for non-parenteral administration routes, such as ocular, nasal, buccal, gastrointestinal, vaginal and intravesical ones, with a special focus on formulation composition, polymer gelation mechanism and in vitro release studies.

Smart Freeze-Dried Bigels for the Prevention of the Sexual Transmission of HIV by Accelerating the Vaginal Release of Tenofovir during Intercourse.

Sub-Saharan African women are still at risk from the human immunodeficiency virus (HIV), and sex with men is the main route of transmission. Vaginal formulations containing antiretroviral drugs are promising tools to give women the power to protect themselves. The aim of this work was to obtain freeze-dried bigels containing pectin, chitosan, or hypromellose for the vaginal controlled release of Tenofovir, which is accelerated in the presence of semen. Nine batches of bigels were formulated using different proportions of these polymers in the hydrogel (1, 2, and 3% w/w). The bigels obtained were freeze-dried and then underwent hardness and deformability, mucoadhesion, swelling, and drug release tests, the last two in simulated vaginal fluid (SVF) and SVF/simulated seminal fluid (SSF) mixture. The formulation containing 3% pectin (fd3P) has the highest values for hardness, resistance to deformation, and good mucoadhesivity. Its swelling is conditioned by the pH of the medium, which is responsive to the controlled release of Tenofovir in SVF, with the fastest release in the SVF/SSF mixture. fd3P would be an interesting smart microbicidal system to allow faster release of Tenofovir in the presence of semen, and thus increase women's ability to protect themselves from the sexual transmission of HIV.

Environmentally Responsive Systems for Drug Delivery.

BACKGROUND: In recent decades, the development of the environmentally responsive systems for drug delivery has been well regarded, with enormous potential in different applications. <P><P> Methods: These environmentally sensitive, smart, intelligent formulations have the ability to alter their physical properties in response to small changes in physical or chemical conditions, such as temperature, glucose, pH, ultrasound, light, electric field and redox potential with a huge potential in drug delivery systems. The use of formulations containing smart materials enables to carry the drug to the target tissue, cells and release in a triggered way. Consequently, they have demonstrated several advantages like decreased dose frequency, ease of preparation and administration, prolonged release with reduced side effects, as well as, reduced costs when compared to conventional processes for industrial applications. In this sense, many patents have deposited, displaying different pharmaceutical devices using responsive systems. <P><P> Results: There are more than twenty-five patents deposited about thermoresponsive systems. Furthermore, a few number of patents within glucose responsive, ultrasound responsive and light responsive deposited. There also are about eight patents that are pH-responsive, four as electric-field responsive. Most of them cover more than one type of stimuli. <P><P> Conclusion: Therefore, in this review, since 1975 to 2016, we have categorized, reviewed and discussed the patents, applications, pharmaceutical dosage forms, the importance and perspectives of this environmentally responsive approach as potentially useful therapeutic modality.