Challenges of cannabinoid delivery: how can nanomedicine help? (original) (raw)
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Cannabinoid Delivery Systems for Pain and Inflammation Treatment
Molecules, 2018
There is a growing body of evidence to suggest that cannabinoids are beneficial for a range of clinical conditions, including pain, inflammation, epilepsy, sleep disorders, the symptoms of multiple sclerosis, anorexia, schizophrenia and other conditions. The transformation of cannabinoids from herbal preparations into highly regulated prescription drugs is therefore progressing rapidly. The development of such drugs requires well-controlled clinical trials to be carried out in order to objectively establish therapeutic efficacy, dose ranges and safety. The low oral bioavailability of cannabinoids has led to feasible methods of administration, such as the transdermal route, intranasal administration and transmucosal adsorption, being proposed. The highly lipophilic nature of cannabinoids means that they are seen as suitable candidates for advanced nanosized drug delivery systems, which can be applied via a range of routes. Nanotechnology-based drug delivery strategies have flourished...
Drug development and industrial pharmacy, 2015
This work aims at developing and optimizing a valuable oral delivery carrier for the cannabinoid derivative CB13, which presents a high therapeutic potential in chronic pain states that respond poorly to conventional analgesics, but also shows highly unfavorable physicochemical properties. CB13-loaded lipid nanoparticles (LNP) formulations were developed through solvent-emulsion evaporation and optimized in terms of physicochemical properties, long-term stability, integrity under gastric simulated conditions and in vitro interaction with NIH 3T3, HEK 293T and Caco-2 cells. An optimized formulation of LNP containing CB13 was obtained from a wide range of conditions assayed and analyzed. The selection of the lipid core, production conditions and the inclusion of lecithin proved to be key factors for the final properties of encapsulation, integrity and performance of the carriers. The LNP formulation proposed proved to be a promising carrier for the oral delivery of CB13, a cannabinoid...
Materials Science and Engineering: C, 2015
This study describes the preparation, characterization, and in vivo evaluation in rats of nanostructured lipid carriers (NLCs) encapsulating rimonabant (RMN) as prototypical cannabinoid antagonist. A study was conducted in order to optimize NLC production by melt and ultrasonication method. NLCs were prepared by alternatively adding the lipid phase into the aqueous one (direct protocol) or the aqueous phase into the lipid one (reverse protocol). RMN-NLCs have been characterized by cryogenic transmission electron microscopy (cryo-TEM), X-ray, photon correlation spectroscopy (PCS) and sedimentation field flow fractionation (SdFFF). Reverse NLCs were treated with polysorbate 80. RMN release kinetics have been determined in vitro by dialysis method. In vivo RMN biodistribution in rats was evaluated after intranasal (i.n.) administration of reverse RMN-NLC. The reverse protocol enabled to prevent the lost of lipid phase and to achieve higher RMN encapsulation efficacy (EE) with respect to the direct protocol (98% w/w versus 67% w/w). The use of different protocols did not affect NLC morphology and dimensional distribution. An in vitro dissolutive release rate of RMN was calculated. The in vivo data indicate that i.n. administration of RMN by reverse NLC treated with polysorbate 80 increased RMN concentration in the brain with respect to the drug in solution. The nanoencapsulation protocol presented here appears as an optimal strategy to improve the low solubility of cannabinoid compounds in an aqueous system suitable for in vivo administration.
Cannabinoid Formulations and Delivery Systems: Current and Future Options to Treat Pain
Drugs
The field of Cannabis sativa L. research for medical purposes has been rapidly advancing in recent decades and a growing body of evidence suggests that phytocannabinoids are beneficial for a range of conditions. At the same time impressing development has been observed for formulations and delivery systems expanding the potential use of cannabinoids as an effective medical therapy. The objective of this review is to present the most recent results from pharmaceutical companies and research groups investigating methods to improve cannabinoid bioavailability and to clearly establish its therapeutic efficacy, dose ranges, safety and also improve the patient compliance. Particular focus is the application of cannabinoids in pain treatment, describing the principal cannabinoids employed, the most promising delivery systems for each administration routes and updating the clinical evaluations. To offer the reader a wider view, this review discusses the formulation starting from galenic preparation up to nanotechnology approaches, showing advantages, limits, requirements needed. Furthermore, the most recent clinical data and meta-analysis for cannabinoids used in different pain management are summarized, evaluating their real effectiveness, in order also to spare opioids and improve patients' quality of life. Promising evidence for pain treatments and for other important pathologies are also reviewed as likely future directions for cannabinoids formulations.
Design and function of targeted endocannabinoid nanoparticles
Scientific Reports
Nanoparticles and nano-delivery systems are constantly being refined and developed for biomedical applications such as imaging, gene therapy, and targeted delivery of drugs. Nanoparticles deliver beneficial effects by both release of their cargo and by liberation of their constitutive structural components. The N-acylethanolamines linoleoyl ethanolamide (LEA) and oleoyl ethanolamide (OEA) both exhibit endocannabinoid-like activity. Here, we report on their ability to form nanoparticles that when conjugated with tissue-specific molecules, are capable of localizing to specific areas of the body and reducing inflammation. The facilitation of pharmacological effects by endocannabinoids at targeted sites provides a novel biocompatible drug delivery system and a therapeutic approach to the treatment, patient management and quality of life, in conditions such as arthritis, epilepsy, and cancer.
The Transdermal Delivery of Therapeutic Cannabinoids
Pharmaceutics
Recently, several studies have indicated an increased interest in the scientific community regarding the application of Cannabis sativa plants, and their extracts, for medicinal purposes. This plant of enormous medicinal potential has been legalised in an increasing number of countries globally. Due to the recent changes in therapeutic and recreational legislation, cannabis and cannabinoids are now frequently permitted for use in clinical settings. However, with their highly lipophilic features and very low aqueous solubility, cannabinoids are prone to degradation, specifically in solution, as they are light-, temperature-, and auto-oxidation-sensitive. Thus, plant-derived cannabinoids have been developed for oral, nasal-inhalation, intranasal, mucosal (sublingual and buccal), transcutaneous (transdermal), local (topical), and parenteral deliveries. Among these administrations routes, topical and transdermal products usually have a higher bioavailability rate with a prolonged steady...
International Journal of Molecular Sciences
Opportunities for developing innovative and intelligent drug delivery technologies by targeting the endocannabinoid system are becoming more apparent. This review provides an overview of strategies to develop targeted drug delivery using the endocannabinoid system (ECS). Recent advances in endocannabinoid system targeting showcase enhanced pharmaceutical therapy specificity while minimizing undesirable side effects and overcoming formulation challenges associated with cannabinoids. This review identifies advances in targeted drug delivery technologies that may permit access to the full pharmacotherapeutic potential of the ECS. The design of optimized nanocarriers that target specific tissues can be improved by understanding the nature of the signaling pathways, distribution in the mammalian body, receptor structure, and enzymatic degradation of the ECS. A closer look at ligand-receptor complexes, endocannabinoid tone, tissue distribution, and G-protein activity leads to a better und...
Phytocannabinoids: Chromatographic Screening of Cannabinoids and Loading into Lipid Nanoparticles
Molecules
Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC) are receiving increasing interest as an approach to encapsulate natural extracts to increase the physicochemical stability of bioactives. Cannabis extract-derived cannabidiol (CBD) has potent therapeutic properties, including anti-inflammatory, antioxidant, and neuroprotective properties. In this work, physicochemical characterization was carried out after producing Compritol-based nanoparticles (cSLN or cNLC) loaded with CBD. Then, the determination of the encapsulation efficiency (EE), loading capacity (LC), particle size (Z-Ave), polydispersity index (PDI), and zeta potential were performed. Additionally, the viscoelastic profiles and differential scanning calorimetry (DSC) patterns were recorded. As a result, CBD-loaded SLN showed a mean particle size of 217.2 ± 6.5 nm, PDI of 0.273 ± 0.023, and EE of about 74%, while CBD-loaded NLC showed Z-Ave of 158.3 ± 6.6 nm, PDI of 0.325 ± 0.016, and EE of about 70%. T...
Molecular Pharmaceutics, 2019
Diseases affecting the central nervous system (CNS) should be regarded as a major health challenge due to the current lack of effective treatments given the hindrance to brain drug delivery imposed by the blood-brain barrier (BBB). Since efficient brain drug delivery should not solely rely on passive targeting, active targeting of nanomedicines into the CNS is being explored. The present study is devoted to the development of lipid nanocapsules (LNCs) decorated with non-psychotropic cannabinoids as pioneering non-immunogenic brain targeting molecules and to the evaluation of their brain targeting ability both in vitro and in vivo. Noticeably, both the permeability experiments across the hCMEC/D3 cell-based in vitro BBB model and the biodistribution experiments in mice consistently demonstrated that the highest brain targeting ability was achieved with the smallest-sized cannabinoiddecorated LNCs. Importantly, the enhancement in brain targeting achieved with the conjugation of CBD to LNCs outperformed by 6-fold the enhancement observed for the G-Technology ® (the main brain active strategy that has already entered clinical trials for the treatment of CNS diseases) As the transport efficiency across the BBB certainly determines the efficacy of the treatments for brain disorders, small cannabinoiddecorated LNCs represent auspicious platforms for the design and development of novel therapies for CNS diseases.
Anticancer Research, 2015
shown a promise as an anticancer agent but causes psychoactive side-effects. In the present study, nano-micelles of styrene maleic acid (SMA)-conjugated WIN were synthesized to reduce side-effects and increase drug efficacy. SMA-WIN micelles were characterised and their in vitro cytotoxic effect was compared to that of free WIN against triple-negative breast cancer (MDA-MB-231), hormone receptor-positive breast cancer (MCF-7) and castrationresistant prostate cancer (PC3) cell lines. SMA-WIN micelles were synthesised with a ~15% loading, 132.7 nm average diameter, -0.0388 mV charge, and pH-dependent release rate. A dose-dependent inhibition of cell growth was observed in all three cell lines treated with both free and micellar WIN, with both formulations demonstrating equal cytotoxicity. Cancer is among the leading causes of death worldwide. Breast cancer is the most common cancer in women, contributing to 25% of all cancers diagnosed in 2012 (1), while prostate cancer is the second most common cancer in men, accounting for 15% of cancer diagnosed in men in 2012 (2). Triple-negative breast cancer (TNBC) accounts for approximately 15-20% of all breast cancer (3), and is associated with a younger age of disease onset, larger tumor size, increased lymph node positivity, high risk of metastasis, and decreased overall survival. This particular subtype of breast cancer lacks all three receptors [oestrogen (ER), progesterone (PR) and human epidermal growth factor 2 (Her2/neu)] exploited by currently available hormonal and targeted therapies (4). Similarly in the prostate, the androgen receptor mediates cell growth. Androgen-independent prostate cancer does not respond to androgen-deprivation therapy. Hence, chemotherapy remains the mainstay of treatment for these hormone-resistant cancer types (5). Traditional chemotherapeutic agents exert their anticancer effects via inhibiting the growth of rapidly dividing cells. The non-specific nature of these drugs means that they also affect the growth of normal rapidly-dividing cells, such as those found in the bone marrow and the gastrointestinal mucosa, resulting in side-effects such as myelosuppression, hair loss, nausea and vomiting (6). Therefore, a safer and more targeted approach for the treatment of TNBC is desperately needed. Cannabinoid is a term given to a class of chemical compounds that act on cannabinoid receptors and includes the endogenous cannabinoids anandamide and 2-arachidonyl glycerol (7). Cannabinoids potentially have anticancer effects in models of breast, prostate, and pancreatic cancer, glioma, and lymphoma (8-10). The broad efficacy of cannabinoids is paired with the observation that the cannabinoid receptors CB1 and CB2 show increased expression in some types of tumor cells when compared to normal tissue, implying a selectivity of the drug for these cancer types (9, 10). Although the medicinal use of cannabis and its associated compounds have been known since antiquity, its place in modern medicine has remained controversial, due in part to the psychoactive effects of cannabinoids, mediated by CB1 receptors found in the central nervous system (CNS) (11). The incorporation of cannabinoids into a micellar system is a strategy to improve drug solubility, and reduce CNS side-effects by increasing the drug diameter sufficiently such that it is unable to pass through the blood-brain barrier ( ) to act on central CB1 receptors.