Cocrystals are long known yet recently applied molecular entities. In the past decade, a significant potential has been demonstrated by these novel solids in terms of modifying the physicochemical ...and pharmacokinetic properties of drugs. Thus far, publications have outlined various aspects of cocrystals at the molecular level concentrating on their design, growing techniques, and physicochemical characterizations. However, to take cocrystals from bench to bedside, they have to be incorporated into suitable formulations notwithstanding that the attention paid to cocrystal formulations is so diminutive. This is the first systematic review based exclusively on cocrystals formulation. In this contribution, the impact of cocrystals on essential pharmaceutical properties is glanced at before shining the spotlight on cocrystals formulation. The findings suggest that preformulation characteristics play a significant role, however, after which a number of approaches are desired in order to develop successful cocrystal formulations. It further highlights the main hurdles encountered with cocrystals formulation and other challenges to the transformation of cocrystals into viable medicines to have the full picture. There are marketed cocrystal products now, and it can be said it is only a matter of time before cocrystals are added to the main selection toolbox alongside salts for developing medicinal products.
The uniqueness of structure and physiology of the lymphatic system make it challenging to delineate all its contributions in the maintenance of our health. However, in the past two decades, the ...understanding of the importance of the function of this system has evolved and more appreciation has been drawn to the distinctive role it plays in health and disease. The lymphatic system has been linked to the pathophysiology of numerous ailments including cancer, various metabolic diseases, inflammatory conditions, and infections. Moreover, it has also been revealed that lymphatic targeted formulations can enhance the delivery of drugs through the lymphatic system to the bloodstream, bypassing the hepatic first-pass metabolism if taken orally, thus increasing the bioavailability, and improving the pharmacokinetic and toxicological profiles in general. Engineering lymphotropic preparations requires the understanding of many factors, the most important one being that of the physiological environment which they will encounter. Therefore, in this review, we detail the basic structure of the lymphatic system, then highlight the therapeutic and the pharmacokinetic benefits of drug delivery into the lymphatic system. The criteria for drugs and formulations used for lymphotropic delivery are also detailed with a contemporary overview of various studies undertaken in this field.
The lymphatic system plays a crucial role in the absorption of lipophilic drugs, making it an important route for drug delivery. In this study, an in vitro model using Intralipid® was developed to ...investigate the lymphatic uptake of drugs. The model was validated using cannabidiol, halofantrine, quercetin, and rifampicin. Remarkably, the uptake of these drugs closely mirrored what would transpire in vivo. Furthermore, adding peanut oil to the model system significantly increased the lymphatic uptake of rifampicin, consistent with meals containing fat stimulating lymphatic drug uptake. Conversely, the inclusion of pluronic L-81 was observed to inhibit the lymphatic uptake of rifampicin in the model. This in vitro model emerges as a valuable tool for investigating and predicting drug uptake via the lymphatic system. It marks the first phase in developing a physiologically based predictive tool that can be refined further to enhance the precision of drug interaction predictions with chylomicrons and their subsequent transport via the lymphatic system. Moreover, it can be employed to explore innovative drug formulations and excipients that either enhance or hinder lymphatic drug uptake. The insights gained from this study have significant implications for advancing drug delivery through the lymphatic system.
The law of superposition underpins first-order linear pharmacokinetic relationships. Most drugs, therefore, after a single dose can be described by first-order or linear processes, which can be ...superposed to understand multiple-dose regimen behavior. However, there are a number of situations where drugs could display behaviors after multiple dosing that leads to capacity-limited or saturation non-linear kinetics and the law of superposition is overruled. This review presents a practical guide to understand the equations and calculations for single and multiple-dosing regimens after intravenous and oral administration. It also provides the pharmaceutical basis for saturation in ADME processes and the consequent changes in the area under the concentration–time curve, which represents drug exposure that can lead to the modulation of efficacy and/or toxic effects. The pharmacokineticist must implicitly understand the principles of superposition, which are a central tenet of drug behavior and disposition during drug development.
Drug absorption via chylomicrons holds significant implications for both pharmacokinetics and pharmacodynamics. However, a mechanistic understanding of predicting in vivo intestinal lymphatic uptake ...remains largely unexplored. This study aimed to delve into the intestinal lymphatic uptake of drugs, investigating both enhancement and inhibition using various excipients through our previously established in vitro model. It also examined the applicability of the model by assessing the lymphatic uptake enhancement of a lymphotropic formulation with linoleoyl polyoxyl-6 glycerides using the same model. The model successfully differentiated among olive, sesame, and peanut oils in terms of lymphatic uptake. However, it did not distinguish between oils containing long-chain fatty acids and coconut oil. Coconut oil, known for its abundance of medium-chain fatty acids, outperformed other oils. This heightened uptake was attributed to the superior emulsification of this oil in artificial chylomicron media due to its high content of medium-chain fatty acids. Additionally, the enhanced uptake of the tested formulation with linoleoyl polyoxyl-6 glycerides underscored the practical applicability of this model in formulation optimization. Moreover, data suggested that increasing the zeta potential of Intralipidsup.® using sodium lauryl sulfate (SLS) and decreasing it using (+/−) chloroquine led to enhanced and reduced uptake in the in vitro model, respectively. These findings indicate the potential influence of the zeta potential on intestinal lymphatic uptake in this model, though further research is needed to explore the possible translation of this mechanism in vivo.
Scientists have developed and employed various models to investigate intestinal lymphatic uptake. One approach involves using specific blocking agents to influence the chylomicron-mediated lymphatic ...absorption of drugs. Currently utilized models include pluronic L-81, puromycin, vinca alkaloids, colchicine, and cycloheximide. This review offers a thorough analysis of the diverse models utilized, evaluating existing reports while delineating the gaps in current research. It also explores pharmacokinetic related aspects of intestinal lymphatic uptake pathway and its blockage through the discussed models. Pluronic L-81 has a reversible effect, minimal toxicity, and unique mode of action. Yet, it lacks clinical reports on chylomicron pathway blockage, likely due to low concentrations used. Puromycin and vinca alkaloids, though documented for toxicity, lack information on their application in drug intestinal lymphatic uptake. Other vinca alkaloids show promise in affecting triglyceride profiles and represent possible agents to test as blockers. Colchicine and cycloheximide, widely used in pharmaceutical development, have demonstrated efficacy, with cycloheximide preferred for lower toxicity. However, further investigation into effective and toxic doses of colchicine in humans is needed to understand its clinical impact. The review additionally followed the complete journey of oral lymphatic targeting drugs from intake to excretion, provided a pharmacokinetic equation considering the intestinal lymphatic pathway for assessing bioavailability. Moreover, the possible application of urinary data as a non-invasive way to measure the uptake of drugs through intestinal lymphatics was illustrated, and the likelihood of drug interactions when specific blockers are employed in human subjects was underscored.
Conventional dissolution tests only assess the aqueous release of drugs to ensure quality and performance, without indicating whether absorption occurs through the portal or the lymphatic ...circulation. To address this issue, this study aimed to develop novel first-generation dissolution models that could investigate the release and uptake of oral lymphotropic drugs and examine relevant formulation issues. Dissolution of three commercial lymphotropic drug products (Terbinafina, Apo-terbinafine, and Lamisil) was done using modified versions of USP Apparatus II and IV. The developed models contained a lymphatic compartment filled with artificial chylomicrons to account for absorption through intestinal lymphatic pathway. The various products exhibited different release profiles into the aqueous media and the lymphatic media across the two tested models. The modified USP IV apparatus demonstrated greater distinction in aqueous release patterns. However, the release pattern into the lymphatic media remained similar in both models. This work represents a progress in meeting the challenges posed by the increasing complexity of pharmaceutical products containing lipophilic drugs or formulations, and has the potential to contribute towards the development of
in-vitro
bioequivalence standards for formulations targeting intestinal lymphatics.
Graphical Abstract
Display omitted
Dissolution testing is important in assessing the in vitro drug release performance for oral administration dosage forms. However, currently, a simple and efficient in vitro test to ...investigate critical factors that may impact the drug release and bioavailability at the development stage of a drug-loaded nanoemulsion (NE) is lacking. Thus, in this study, we developed a new combined biphasic and modified cylinder (BP + MC) method to evaluate the dissolution profile of NEs. Flubendazole (FLZ), a Biopharmaceutical Classification System (BCS) Class II drug, offers a new prospective for drug repositioning for treating lung cancer and cryptococcal meningitis. We compared the drug release profiles of three different FLZ formulations (micronized as a suspension, loaded in NE, and solubilized in oil) by using three different methods (dialysis bag, modified cylinder method, and a new BP + MC method). The results showed potential higher drug release of FLZ from the suspension compared to FLZ-loaded NE at pH 1.2, and higher drug release from FLZ-loaded NE compared to other forms in octanol phase. These results correlate well with the in vivo test performed in mice carried out in our previous works. Furthermore, the partition mechanism of the drug released from the NE is discussed in-depth in this article, as well as the advantage of drug-loaded NEs over other preparations in creating supersaturable conditions. Based on the results, we provide new insights into how dissolution methods for a poorly water-solubility drug can be designed. Therefore, we present this new combined BP + MC method as a potential new discriminative dissolution test for future studies when developing drug-loaded NE and comparing with other dosage forms.
Background: First-Episode Psychosis (FEP) is defined as the first treatment contact with psychiatric service, regardless of the duration of symptoms. This study aims to determine the antipsychotics ...prescription patterns in FEP patients at three psychiatric hospitals in Khartoum. Method: A descriptive cross-sectional retrospective hospital-based study was conducted at Eltigani Elmahi, Taha Baasher, and Abd Elaal Aledrissi Psychiatric hospitals in Khartoum State, Sudan, during the period March to July 2018. Medical records of patients with FEP were identified and reviewed to look for demographic data, the onset of symptoms, investigations requested, and medications prescribed. Data were recorded and subjected to statistical analysis using the Statistical Package for Social Sciences. Result: Reviewing the medical records of the 98 FEP patients (66 males and 32 females) included in the study showed that the majority of patients (94.8%) were medicated with combinations of psychotropic medications. The most commonly used combination was Haloperidol, Olanzapine, Promethazine, and Benzodiazepines. And only 5.1% of the whole population was treated with an atypical antipsychotic (Olanzapine) as a monotherapy. Conclusion: Based on prescription patterns and requested investigations, there was a wide gap between the actual practice regarding antipsychotics prescriptions for FEP at the three psychiatric hospitals and the evidence-based guidelines in this respect.
PDF
