Innovative Strategies and Advances in Drug Delivery Systems to Address Poor Solubility: A Comprehensive Review.

Rheumatoid arthritis (RA) is a long-term inflammatory disease that causes synovial joint inflammation, which causes pain, stiffness, and gradual joint destruction. In addition to having a major effect on quality of life, the illness may result in systemic problems. The goal of current treatment approaches, which include biologics, corticosteroids, disease-modifying antirheumatic medications (DMARDs), and nonsteroidal anti-inflammatory medicines (NSAIDs), is to manage symptoms and halt the course of the disease. These treatments, however, frequently have problems like poor effectiveness, systemic side effects, and exorbitant expenses. Advanced, tailored medication delivery methods like nanocarriers are necessary because managing RA is made more difficult by poor patient adherence and limited targeting of inflammatory areas. Berberine and curcumin are bioactive natural compounds with significant therapeutic potential, particularly in managing inflammatory and autoimmune conditions like rheumatoid arthritis (RA). Berberine exhibits potent anti-inflammatory, immunomodulatory, and antioxidant properties, effectively suppressing pro-inflammatory cytokines and oxidative stress Curcumin, a polyphenol derived from turmeric, also demonstrates strong anti-inflammatory and antioxidant effects, inhibiting key molecular pathways involved in RA pathogenesis, such as NF-κB activation. Despite their promising pharmacological profiles, both compounds face challenges like poor water solubility, low bioavailability, and rapid metabolism. Advanced drug delivery systems, such as nanostructured lipid carriers, offer a solution to enhance their therapeutic efficacy and clinical applicability. Nanostructured lipid carriers (NLCs) are advanced drug delivery systems offering numerous advantages for therapeutic applications. Their unique structure, combining solid and liquid lipids, enhances drug solubility, stability, and bioavailability. NLCs enable controlled and sustained drug release, reducing dosing frequency and improving patient compliance. They can protect sensitive drugs like berberine and curcumin from degradation, extending their shelf life. Additionally, NLCs can be functionalized for targeted delivery, increasing drug accumulation at inflamed joints in conditions like rheumatoid arthritis while minimizing systemic side effects. Their biocompatibility and scalability make NLCs a promising platform for improving the clinical efficacy of challenging therapeutic agents. Berberine and curcumin exhibit remarkable anti-inflammatory and antioxidant properties, making them promising candidates for managing rheumatoid arthritis (RA). However, their clinical potential is limited by poor solubility and bioavailability. Nanostructured lipid carriers (NLCs) address these limitations by enhancing drug stability, targeted delivery, and controlled release. Preclinical studies demonstrate improved therapeutic efficacy of NLC formulations in RA models, though clinical translation remains limited. Future research should focus on optimizing NLC designs for enhanced targeting, scalability, and regulatory compliance. Combining these carriers with advanced therapeutic strategies offers a pathway to more effective and patient-friendly RA treatments, bridging lab discoveries to clinical practice

Objective The fabrication of furosemide (FSM) with enhanced oral bioavailability and encapsulation was achieved using a nanostructured lipid carriers (NLCs) drug delivery system. Significance The uniform drug distribution is a barrier due to its low dose. The lipid-based delivery system was selected based on its poor solubility and permeability, limiting its poor partitioning and solubility in water-based polymeric delivery systems. The lipophilicity of the FSM makes it favorable to partition with triglyceride-based Compritol 888 ATO and oleic acid with minimized drug expulsion, high drug payload, and sustained release over extended time frames. Methods The Organic and aqueous phases of the microemulsion were stabilized using Tween 80, a hydrophilic surfactant. Box-Behnken design-based optimization was done using alteration in various formulation variables to obtain nano-formulation with the lowest particle size and polydispersity, maximal zeta potential and entrapment efficiency. Results Design-Expert yielded several optimized formulations with the desirability function. Maximum desirability was obtained at a particle size of around 178 nm, a surface charge of −19.6 mV, and an EE of above 85%. The in vitro release profile depicted 86.5% of cumulative release after 24 h whereas, in vivo pharmacokinetic study revealed an increase in Cmax from 0.48 µg/mL (FSM-Suspension) to 0.77 µg/mL (FSM NLCs) to increase the bioavailability to approx. 241% in FSM NLCs. The half-life escalation demonstrated that the residence time of the nanoparticles prolonged at the physiologic pH. Conclusions FSM-NLCs exhibited sustained release over a prolonged period, improved residence time in the body, and their action was prolonged.

In pharmaceutical field, many drugs are being invented to combat the existing new diseases. The winds of change in the drug scenario are blowing forcefully worldwide. The emergence of new technologies provides an unique opportunities to exploit novel approaches in drug delivery. A shift from conventional drug delivery to novel drug delivery is noticed as shift from conventional drug delivery suffers from various drawbacks, But these new mighty compounds in drug therapy solely are not sufficient to meet the today’s need. There is an urgent need for the smart technology, as the drugs available suffer from serious problems like poor solubility and poor bioavailability. Most of the drugs that are available therapeutically comes under BCS class II ie, poorly soluble and high lipophilc. To assure progress in drug therapy, the development of new drugs merely is not sufficient. Issues arising in delivery of new drugs should also be addressed. Thus there is an emergent need to improve the bioavailability of these drugs, the only remedy or boon for such drugs is the discovery of some smart technologies which can improve the bioavailability of these drugs. Nano drug delivery systems are the one such universal approach which fulfills the lacuna, which exists in conventional drug delivery systems. These Nano drug delivery systems, improves the pharmacokinetic profiles of many drugs. In 1980 K. Eric Drexler developed and popularized the concept of nanotechnology. In this review a deep insight on Nano structured lipid carriers is discussed elaborating its birth, significant qualities compared to other colloidal systems, its structure, characteristics, preparation and application are spotted.
 Key words: BCS class, Lipophilic, Nano technology, Nano structured lipid carrier.

Structural and Dynamic Properties of Amorphous Solid Dispersions: The Role of Solid-State Nuclear Magnetic Resonance Spectroscopy and Relaxometry

With the advent of modern technologies, a large number of drugs have been discovered which have a better efficiency but their clinical application is restricted due to poor water solubility. Nearly 40% of the drugs in the pipeline and around 60% of compounds coming directly from synthesis have poor solubility. Poor water solubility has become a leading challenge for the formulation of these compounds. Poor solubility is generally associated with poor bioavailability. Nanocrystals have the potential to overcome this issue. Change of materials into the nanodimension dramatically changes its physical properties which were used in pharmaceutics to develop a new innovative formulation principle for poorly soluble drugs: the drug nanocrystals. Drug nanocrystals are crystals with a size in the nanometer range (mean diameter < 1000 nm). The present article describe the details about the drug nanocrystals. Drug nanocrystals consist of poorly soluble drug without matrix material means carrier free drug delivery system. The review article includes method of preparation, properties, advantages of nanocrystals and application of nanocrystals through all routes of administration.

Poor aqueous drug solubility and therefore poor oral bioavailability is a source of attrition in drug development, preventing potentially efficient drug candidates from further development towards the benefit for patients. Therefore, drug delivery systems to increase the oral bioavailability of such drugs is of great interest. Amorphous solid dispersions (ASDs) are a promising delivery platform to address these challenges. In ASDs, the drug substance is molecularly dispersed in a solid polymer matrix. Although their potential to enhance drug absorption has been proven, they are not yet frequently used in drug development. Reasons are the complexity of ASDs concerning their production and formulation development as well as the poor predictability of technical feasibilities and clinical outcomes. Up to date, underlying mechanisms in these areas are incompletely understood, which impedes the rational application of ASDs in drug development. This PhD thesis aimed to gain mechanistic insights related to the use of ASDs in drug development and thereby to facilitate their application as enabling formulation for poorly soluble drug candidates. Concretely, this was accomplished by: i. Establishing a mechanistic model of the production of ASDs though hot-melt extrusion, facilitating rational and efficient process development. ii. Analyzing current literature on mechanisms whereby ASDs increased bioavailability, proposing mechanistic concepts of increased bioavailability to assist in formulation development and research on ASDs. iii. Optimizing an exemplary ASDs through the addition of excipients and investigating their impact on formulation performance in silico, in vitro and in vivo. iv. Analyzing mechanisms of increased bioavailability through ASDs in a prospective clinical study in humans, aiming to validate translational approaches in formulation development. The results of this thesis contribute to the advanced scientific understanding in the use of ASDs for drug delivery and the facilitation of the rational and translational development of ASDs as an enabling formulation platform for the oral delivery of poorly soluble drugs.

Breviscapine (BVP) is one of the extracts of several flavonoids of Erigeron breviscapus, which has been widely used in the treatment of cerebral infarction and its sequelae, cerebral thrombus, coronary heart disease, and angina pectoris. But BVP has poor solubility. The objective of the study is to develop mesoporous silica nanoparticles (MSNs) that can be loaded with a drug with poor water solubility. The MSNs, which were designed for oral administration, enhanced both the dissolution rate and drug loading capacity. The use of MSNs as an oral drug delivery system was investigated by SEM, TEM, BETBJH, XRD, FT-IR, and HPLC. Additionally, we examined the oral bioavailability of BVP loaded onto MSNs and examined the cellular cytotoxicity of MSNs. The results indicate that the oral bioavailability of BVP after loading onto MSNs was greater than that of a marketed product. Furthermore, we studied the mechanism by which MSNs enhance the oral absorption of BVP. MSNs have the potential to enhance the oral bioavailability of poorly water-soluble drugs by accelerating the drug dissolution rate.

Epidermal growth factor receptors (EGFRs) have potential to be considered as therapeutic target for cancer treatment especially in cancer patients with overexpression of EGFR. Cetuximab as a first monoclonal antibody and Imatinib as the first small molecule tyrosine kinase inhibitor (SMTKI) were approved by FDA in 1998 and 2001. About 28 SMTKIs have been approved until 2015 and a large number of compound with kinase inhibitory activity are at the different phases of clinical trials. Although Kinase inhibitors target specific intracellular pathways, their tissue or cellular distribution are not specific. So treatment with these drugs causes serious dose dependent side effects. Targeted delivery of kinase inhibitors via dendrimers, polymeric nanoparticles, magnetic nanoparticles and lipid based delivery systems such as liposomes, solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) can lead to reduction of side effects and improving therapeutic efficacy of the drugs in the target organs. Furthermore formulation of these drugs is challenged by their physicochemical properties such as solubility and dissolution rate. The main approaches in order to increase dissolution rate, are particle size reduction, self-emulsification, cyclodextrin complexation, crystal modification and amorphous solid dispersion. Synergistic therapeutic effect, decreased side effects and drug resistant, reduced cost and increased patient compliance are the advantages associated with using combination therapy especially in the treatment of cancer. Combination of TKIs with chemotherapeutic agents or biopharmaceuticals such as monoclonal antibodies and oligonucleotides and also combination of two TKIs within one formulation is possible by new targeting delivery systems. This article reviews the recent advances in the design and development of delivery systems for TKIs.

Nano drug delivery system is the latest technology employed in various medicinal applications. This technology can be adapted to the conventional drug administration due to its site-specific targeting phenomena. The oral lipophilic drug administration has its drawbacks due to poor solubility and bioavailability. Lipid-based carrier systems are now widely popular due to improved efficiency, especially for lovastatin delivery. Lovastatin is an important drug which arrests the rate-limiting step of the cholesterol cascade. This drug has short half-lives, poor oral-administered bioavailability, poor solubility, and is rapidly metabolizable. Based on the composition, the drug delivery carriers are classified into solid lipid nanoparticles (SLNs), lipid emulsions (LEs), and nanostructured lipid carriers (NLCs). Among them, NLCs are a smarter generation of drug delivery carriers for lovastatin. The selection of various lipid systems and their formulation are discussed in this paper. Moreover, the characterization of these carrier systems to achieve the optimal characteristic features is discussed in a concise manner.

Curcumin is a phytochemical achieved from the plant turmeric. It is extensively utilized for the treatment of several types of diseases such as cancers. Nevertheless, its efficiency has been limited because of rapid metabolism, low bioavailability, poor water solubility, and systemic elimination. Scientists have tried to solve these problems by exploring novel drug delivery systems such as lipid-based nanoparticles (NPs) (e.g., solid lipid NPs, nanostructured lipid carriers, and liposomes), polymeric NPs, micelles, nanogels, cyclodextrin, gold, and mesoporous silica NPs. Among these, liposomes have been the most expansively studied. This review mainly focuses on the different curcumin nanoformulations and their use in cancer therapy in vitro, in vivo, and clinical studies. Despite the development of curcumin-containing NPs for the treatment of cancer, potentially serious side effects, including interactions with other drugs, some toxicity aspects of NPs may occur that require more high-quality investigations to firmly establish the clinical efficacy.

Background: The combination of moxifloxacin hydrochloride (MOX) and dexamethasone sodium phosphate (DEX) is widely available in the conventional commercial market for treating ocular infections and inflammations. Traditional ocular delivery systems are inferior to nanostructured lipid carriers (NLCs) due to their poor drug bioavailability, rapid tear drainage, and limited drug penetration. In contrast, NLCs offer sustained release, enhanced corneal absorption, and improved drug stability. Thus, the research aims to develop moxifloxacin and dexamethasone-loaded NLC for effective drug release. Methodology: In this study, a combination of MOX and DEX drugs was loaded in an NLC. The NLC was prepared using standard methods and evaluated for characteristic properties, including particle size (PS), polydispersity index (PDI), entrapment efficiency (EE), and drug loading (DL), as well as drug encapsulation and in vitro studies. Results and Discussion: The optimized formulation of NLC possessed a particle size of 190.58 nm and a polydispersity index of 26.7%. The fabricated drug exhibited a KP model release kinetics, indicating that drug release occurred via a combination of diffusion and polymer reaction. The NLC also exhibited a PDI of 26.7%, indicating a moderately uniform particle size distribution, which further suggests a consistent particle size, an acceptable characteristic for nano-carrier systems. The FT-IR analysis revealed optimal encapsulation of drugs inside the lipids, thereby achieving the desired objectives of drug fabrication. Conclusion: The formulated NLC has a particle size that falls within the ideal range for a smooth surface in commercial NLC formulations. Additionally, the prepared NLCs' adherence to the KP model underscores their potential as an advanced drug delivery system.

Poor water solubility of newly discovered compounds has become the most common challenge in the drug development process. Indeed, poor solubility is considered as the root cause of failure of drug during drug development phases. Moreover, it has also been reported to be the main reason for bioavailability issues such as poor, inconsistent, incomplete and highly variable bioavailability of the marketed products. As per an estimate, approximately 90% of drug molecules suffer with poor water solubility at early stage and approximately 40% of the marketed drugs have bioavailability problems mainly due to poor water solubility. Solubility enhancement of the newly discovered compounds is primary research area for the pharmaceutical industries and research institutions. The conventional techniques to improve aqueous solubility of drugs employ salt formation, prodrug formation, co-crystallization, complexation, amorphous solid dispersion and use of co-solvent, surfactants or hydrotropic agents. Current advancement in the science and technology has enabled the use of relatively new techniques under the umbrella of nanotechnology. These include the development of nanocrystals, nanosuspensions, nanoemulsions, microemulsions, liposomes and nanoparticles to enhance the solubility. This review focuses on the conventional and current approaches of multifold enhancement in the solubility of poorly soluble marketed drugs, including newly discovered compounds.

Cancer is the second leading cause of death globally, with every sixth death being attributable to cancer. Nevertheless, the efficacy of conventional chemotherapeutic drugs is often limited due to their poor solubility, unfavorable pharmacokinetic profile, and lack of tumor selectivity. The use of nanotechnology provides an opportunity to enhance the efficacy of a chemotherapeutic drug by improving its bioavailability and pharmacokinetic profile while facilitating preferential accumulation at the tumor tissue. To date, a variety of platforms have been investigated as nanocarriers in oncology, which include lipid-based, polymer-based, inorganic materials, and even viruses. Among different nanocarriers, lipid-based delivery systems have been extensively used in oncology because of their biocompatibility, biodegradability, ability to encapsulate diverse drug molecules, high temporal and thermal stability, and offer prolonged and controlled drug release. This review discusses the current status of the lipid-based nanocarriers and their applications in cancer treatment as well as an overview of the different liposomal formulations commercially available for cancer therapy.

Lowering lattice forces of crystalline bases

Lopinavir, a key protease inhibitor in antiretroviral therapy, faces significant challenges related to its poor solubility, low bioavailability, and low stability, which limit its therapeutic efficacy. This review explores a range of advanced formulation strategies developed to overcome these limitations, enhancing lopinavir’s delivery and effectiveness. Nanoparticle-based systems such as solid lipid nanoparticles, nanostructured lipid carriers, and lipid-polymer hybrid systems demonstrate notable improvements in bioavailability, drug release, and lymphatic targeting. Additionally, solid dosage formulations like amorphous solid dispersions and proliposomes have been shown to significantly enhance solubility and stability, improving lopinavir’s pharmacokinetic profile. By reviewing the preparation techniques, in vivo results, and comparative advantages of these innovative delivery systems, this article provides insight into their potential to optimize lopinavir-based therapies. Furthermore, the review discusses the role of these strategies in addressing adherence issues, ultimately improving patient outcomes. Continued research into the novel approaches is essential for advancing lopinavir delivery and enhancing its clinical efficacy in the treatment of HIV.