Article

The effect of Pro NanoLipospheres (PNL) formulation containing natural absorption enhancers on the oral bioavailability of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in a rat model

Authors:
  • Teva Pharmaceutical Industries Ltd. Israel
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Abstract

The lipophilic phytocannabinoids cannabidiol (CBD) and Δ⁹-tetrahydrocannabinol (THC) show therapeutic efficacy in various medical conditions. Both molecules are poorly water soluble and subjected to extensive first pass metabolism in the gastrointestinal tract, leading to a limited oral bioavailability of approximately 9%. We have developed an advanced lipid based Self-Emulsifying Drug Delivery System termed Advanced Pro-NanoLiposphere (PNL) pre-concentrate. The PNL is composed of lipid and emulsifying excipients of GRAS status and are known to increase solubility and reduce Phase I metabolism of lipophilic active compounds. Advanced PNLs are PNLs with an incorporated natural absorption enhancers. These molecules are natural alkaloids and phenolic compounds which were reported to inhibit certain phase I and phase II metabolism processes. Here we use piperine, curcumin and resveratrol to formulate the Advanced-PNL formulations. Consequently, we have explored the utility of these Advanced-PNLs on CBD and THC oral bioavailability. Oral administration of CBD-piperine-PNL resulted in 6-fold in AUC compared to CBD solution, proving to be the most effective of the screened formulations. The same trend was found in pharmacokinetic experiments of THC-piperine-PNL with resulted in a 9.3-fold increase in AUC as compared to THC solution. Our Piperine-PNL can be used as a platform for synchronized delivery of piperine and CBD or THC to the enterocyte site. This co-localization provides an increase in CBD and THC bioavailability by its effect at the pre-enterocyte and the enterocyte levels of the absorption process. The extra augmentation in the absorption of CBD and THC by incorporating piperine into PNL is attributed to the inhibition of Phase I and phase II metabolism by piperine in addition to the Phase I metabolism and P-gp inhibition by PNL. These novel results pave the way to utilize piperine-PNL delivery system for other poorly soluble, highly metabolized compounds that currently cannot be administered orally.

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... The PNL formulation serves as the basis for the development of a more sophisticated formulation, an Advanced PNL, with the added value of containing the natural absorption enhancer piperine [13]. We have found that the PNL excipients not only aid in increasing solubility in the GI tract, but they also inhibit first pass metabolism mechanisms such as CYP family enzymes and the P-gp efflux pump [10]. ...
... In the freely moving rat model, incorporating THC and CBD into the piperine-PNL vehicle results in a 9 and 6-fold increase in oral bioavailability, respectively, when compared to THC and CBD solution and an additional 1.47 and 2-fold increase when compared to THC/CBD-PNL administration [13]. We maintain that this enhanced absorption is result of P-PNL's ability to increase solubility of the cannabinoids, inhibit Phase I and Phase II metabolism as well as efflux mechanisms. ...
... THC-CBD-piperine-PNL was prepared by the pre-concentrate method. This preparation process was based on the formulation design of CBD-piperine-PNL and THC-piperine-PNL described before [13]. Briefly, an amphiphilic co-solvent (ethyl lactate) and soy phospholipid (lecithin) were initially placed in a clean scintillation tube at a ratio of 4:1 respectively, and heated to 40°C until completely dissolved. ...
Article
Nowadays, therapeutic indications for cannabinoids, specifically Δ9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) are widening. However, the oral consumption of the molecules is very limited due to their highly lipophilic nature that leads to poor solubility at the aqueous environment. Additionally, THC and CBD are prone to extensive first pass mechanisms. These absorption obstacles render the molecules with low and variable oral bioavailability. To overcome these limitations we designed and developed the advanced pro-nanolipospheres (PNL) formulation. The PNL delivery system is comprised of a medium chain triglyceride, surfactants, a co-solvent and the unique addition of a natural absorption enhancer: piperine. Piperine was selected due to its distinctive inhibitory properties affecting both Phase I and Phase II metabolism. This constellation self emulsifies into nano particles that entrap the cannabinoids and the piperine in their core and thus improve their solubility while piperine and the other PNL excipients inhibit their intestinal metabolism. Another clear advantage of the formulation is its composition of materials approved for human consumption. The safe nature of the excipients enabled their direct evaluation in humans. In order to evaluate the pharmacokinetic profile of the THC-CBD-piperine-PNL formulation, a two-way crossover, single administration clinical study was conducted. The trial comprised of 9 healthy volunteers under fasted conditions. Each subject received a THC-CBD (1:1, 10mg) piperine (20mg)-PNL filled capsule and an equivalent dose of the oromucosal spray Sativex® with a washout period in between treatments. Single oral administration of the piperine-PNL formulation resulted in a 3-fold increase in Cmax and a 1.5-fold increase in AUC for THC when compared to Sativex®. For CBD, a 4-fold increase in Cmax and a 2.2-fold increase in AUC was observed. These findings demonstrate the potential this formulation has in serving as a standardized oral cannabinoid formulation. Moreover, the concept of improving oral bioavailability described here, can pave the way for other potential lipophilic active compounds requiring enhancement of their oral bioavailability.
... The particles entrap the drug and piperine in their core, improving their solubility in water. 17 In addition, excipients of the formulation, such as the surfactants and phospholipids, inhibit first pass metabolism mechanisms that affect the model molecules. 18−22 Unlike THC or any other cannabinoid, a prominent metabolic route of CBD is direct glucuronidation of the parent compound, leading to the formation of an O-glucuronide. ...
... 23,24 We have shown that piperine-PNL increased CBD oral bioavailability by a further 2-fold in comparison to PNL while it enhanced THC's bioavailability by 1.47-fold compared to PNL administration. 17 We hypothesize that this difference might be a result of the effect piperine-PNL has on intestinal direct phase II metabolism, specifically, glucuronidation. In order to investigate this hypothesis, we selected the model molecule raloxifene. ...
... PNL and piperine-PNL were prepared by a preconcentrate method as previously described. 17 Briefly, an amphiphilic cosolvent (ethyl lactate) and soy phospholipid (lecithin) were placed in a clean scintillation tube at a ratio of 4:1, respectively. The mixture was heated to 40°C until completely dissolved. ...
Article
Full-text available
In recent years, Phase II metabolism, as a first pass metabolism process occurring to the parent drug, is gaining more and more attention. This is due to its acknowledged significance in drug development as well as drug-drug interactions. However, the predominant role of Phase I metabolism has always overshadowed Phase II metabolism, resulting in insufficient data regarding its mechanisms. In this paper, we investigate the effect of an advanced lipid based drug delivery system on Phase II metabolism at the intestinal level of the enterocytes monolayer. Specifically, we focus on Phase II metabolism of compounds that are cleared primarily by direct glucuronidation without the requirement of P450 enzymes. The investigated formulation is a self-emulsifying drug delivery system, termed pro-nano lipospheres, which contains the natural absorption enhancer piperine. To evaluate the effect of this formulation on direct Phase II metabolism we chose the model molecule raloxifene. First, glucuronidation is the main clearance pathway of this compound without involvement of preceding mechanisms. Secondly, raloxifene's extensive glucuronidation site is primarily at the intestine. Raloxifene's oral bioavailability was determined in a series of pharmacokinetic experiments using the freely moving rat model. In order to test the effect of the formulation directly on the relevant UGT enzymes reported in the clinic, we used the in-vitro method UGT-glo TM assay. Co-administration of raloxifene and piperine-pro-nano lipospheres to rats resulted in a 2-fold increase in the relative oral bioavailability of raloxifene. However, Co-administration of raloxifene with blank pro-nano lipospheres had no effect on its oral bioavailability. In contrast to the difference found in-vivo between the two vehicles, both formulations extended an inhibitory effect on UGT enzymes in-vitro. Ultimately, these findings prove the ability of the formulation to diminish intestinal direct Phase II metabolism. Pro-nano lipospheres is a formulation that serves as a platform for the simultaneous delivery of the absorption enhancer and a required drug. The discrepancy found between the in-vivo and in-vitro models demonstrates that the in-vitro method may not be sensitive enough to distinguish the difference between the formulations.
... Cannabinoids, such as Δ9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) have received great attention lately due to their therapeutic advantages [467,468]. Recently, Hoffman et al. ...
... studied the encapsulation of these compounds in piperine-pro-nanolipospheres (PPNs), as a novel oral delivery system, where piperine works as an absorption enhancer [467,468]. PPNs appear to improve the oral bioavailability of these poorly water-soluble compounds since they inhibit first-pass intestinal metabolism and allow better delivery of the compounds [467,468]. ...
... studied the encapsulation of these compounds in piperine-pro-nanolipospheres (PPNs), as a novel oral delivery system, where piperine works as an absorption enhancer [467,468]. PPNs appear to improve the oral bioavailability of these poorly water-soluble compounds since they inhibit first-pass intestinal metabolism and allow better delivery of the compounds [467,468]. ...
Thesis
In recent years, the scientific community has seen an increasing interest in the use of natural compounds in medicines, food supplements, cosmetics and dermatological products. An important example is Sambucus nigra L. whose flowers (elderflowers) and berries (elderberries) have been widely used in traditional medicine. The traditional use of elderflowers in the relief of early symptoms of common cold has been officially recognised by the European Union, where several products in the form of herbal tea, tincture or liquid extract, are available on the market. Elderberries have also been traditionally used in the form of herbal tea, syrup or juice. Nevertheless, no single herbal substance/herbal preparation is registered as medicine. In line with the need for comprehensive pharmacological studies to validate the traditional use of S. nigra, namely its anti-inflammatory activity, one of the aims of this PhD thesis was to screen and characterize biological activities of S. nigra L. extracts obtained using different extraction methodologies. Then, to optimize the biological activity of the best extract (i.e. with high interest for therapeutic uses), different extract-loaded nanocarriers were prepared. Different materials were applied in this task such as polymeric and lipid-based materials. In this specific context, the purpose of using nanotechnology as strategy was to increase the stability of bioactive compounds and to modulate their release, creating a potential topical formulation. Due to the harvesting time of elderflowers and elderberries, in a first part of this PhD thesis, initial nanoencapsulation studies were performed using hyaluronic acid as model drug. Hyaluronic acid is commonly used through intraarticular administration for viscosupplementation in osteoarthritis and other inflammation disorders. Therefore, the first studies consisted of producing an characterising polymeric nanoparticles made of poly(lacticco-glycolic acid) (PLGA) were prepared with and without hyaluronic acid. The inclusion of hyaluronic acid was achieved with an efficiency higher than 70%, but resulted in a marked particle size increase. Particles revealed an in vitro sustained release profile and in vitro cell compatibility, as well as a risk of haemolysis less than 1%, ensuring their safety. In vivo antiinflammatory studies showed a higher inhibition for hyaluronic acid-loaded PLGA particles when compared to hyaluronic acid suspension (78% versus 60%). Results were not so different from the positive control, clearly suggesting that this formulation may be a promising alternative to the current hyaluronic acid injectable dosage form. Having characterised the intended particulate carrier, different extraction methods were studied to obtain the S. nigra extracts from elderflowers and elderberries. For this purpose, fresh flowers, and fresh and dried berries were considered, resulting in eighteen S. nigra extracts. Several parameters were considered for selecting the extraction method, i.e. yield of extraction, type of solvent, flavonoid content and biological activity of the resultant extracts (antioxidant activity, total polyphenol content, collagenase, elastase, tyrosinase and acetylcholinesterase inhibition). The most promising extracts were characterized for in vitro and in vivo antiinflammatory activity and cytotoxicity (skin and monocytic cells). The most promising extracts were those obtained from fresh flowers using ultrasounds method with methanol. Specifically, these extracts showed results similar to positive controls, particularly the antioxidant activity (75 ± 2%), collagenase inhibition (94 ± 1%) and in vitro anti-inflammatory activity (97 ± 3%). Nevertheless, extracts of fresh flowers using ultrasounds/ethanol presented higher collagenase inhibition (88 ± 3%) and in vitro anti-inflammatory activity (102 ± 2%). Cytotoxicity testing confirmed their safety. The second aim of the present PhD thesis was to optimize the activity of the resultant methanolic extracts through encapsulation in different types of nanocarriers: polymeric nanoparticles based on PLGA and poly-Ɛ-caprolactone (PCL) and lipid-based nanoparticles (ethosomes). The so obtained nanoparticulate formulations were analysed in terms of particle size and morphology, physicochemical stability over the time, extract encapsulation efficiency, release profile and biological activities (e.g., anti-inflammatory activity, collagenase inhibition, antioxidant activity). Small and well-defined polymeric nanoparticles and ethosomes were prepared. The highest encapsulation efficiency (76%) was found in PLGA nanoparticles. The same happened for the anti-inflammatory activity (60.7 ± 9.0%). On the other hand, ethosomes presented a very promising value of collagenase inhibition. At the end, this thesis validates and supports the scientific evidence of potential uses of S. nigra as a therapeutic agent, in the case of polymeric nanoparticles, or as cosmetic ingredient, in the case of ethosomes. However, further studies should be carried out, hopefully attracting interest from pharmaceutical and cosmetic industries.
... While a growing body of research indicates that the CBD molecule promises a host of pharmacological effects such as anticancer, analgesic, anti-anxiety, or anti-inflammatory properties there are only a few medicinal-grade products in use [2]. Although CBD may have a high potency, its efficacy is limited by poor oral bioavailability ranging between 13 and 19% [3][4][5] due to rapid metabolism, gastric instability poor chemical stability (photoand thermo-sensitive), and low water solubility, resulting in reduced and unpredictable absorption [3,6]. Therefore, alternative strategies to the development of more effective CBD-loaded drug delivery systems are needed to realize the beneficial pharmacological effects of the CBD molecule by overcoming its biopharmaceutical shortcomings. ...
... The films were thereafter rehydrated using PBS (pH: 7.4 under vigorous stirring; volume: 15 mL) (3), and then left for two hours which yielded multilamellar vesicles (MLVs) (4). The resultant MLVs were placed into sonicator bath (Sonics Vibra Cell, Newtown, CT, USA) at ambient temperature for 15 min to produce unilamellar vesicles (5). To obtain uniform size distribution, unilamellar vesicles were gradually filtered through a membrane filter (0.22 µm) [31]. ...
... Q = k·t n for Koresmeyer-Peppas model (5) where Q is the cumulative amount of medication released at time t, t denotes the time in minutes, and K 0 denotes the zero order rate constant. K 1 denotes the first order constant. ...
Article
Full-text available
Current cannabidiol (CBD) formulations are challenged with unpredictable release and absorption. Rational design of a rectal colloid delivery system can provide a practical alternative. In this study the inherent physiochemical properties of transferosomes were harnessed for the development of a nano-sized transfersomes to yield more stable release, absorption, and bioavailability of CBD as a rectal colloid. Transfersomes composed of soya lecithin, cholesterol, and polysorbate 80 were synthesized via thin film evaporation and characterized for size, entrapment efficiency (%), morphology, CBD release, ex vivo permeation, and physicochemical stability. The optimized formulation for rectal delivery entrapped up to 80.0 ± 0.077% of CBD with a hydrodynamic particle size of 130 nm, a PDI value of 0.285, and zeta potential of −15.97 mV. The morphological investigation via SEM and TEM revealed that the transfersomes were spherical and unilamellar vesicles coinciding with the enhanced ex vivo permeation across the excised rat colorectal membrane. Furthermore, transfersomes improved the stability of the encapsulated CBD for up to 6 months at room temperature and showed significant promise that the transfersomes promoted rectal tissue permeation with superior stability and afforded tunable release kinetics of CBD as a botanical therapeutic with inherent poor bioavailability.
... Based on this rationale, Cherniakov and colleagues (2017) developed PNLs with THC and CBD (drug load > 99%), which improved the in vivo oral absorption of the drugs when compared to Sativex ® due to the aforementioned physicochemical characteristics of PNLs [33][34][35]. ...
... These authors also developed CBD and TCH-advanced-PNLs by adding absorption enhancers (resveratrol, piperine, or curcumin) to improve system absorption [33]. However, the low solubility of curcumin in the system probably disrupts the nanoemulsion, stimulating drug precipitation [32,36]. ...
... On the other hand, resveratrol and piperine-CBD-PNLs produced homogeneous, clear, and stable oil-in-water (O/W) nanoemulsions after their addition to a water medium in vitro. Nonetheless, only the piperine-advanced-PNL enhanced the oral bioavailability of CBD and THC compared to PNL formulations and free cannabinoids in vivo [33,34]. Indeed, because the gastrointestinal tract is profoundly supplied by lymph and blood vessels, the higher the lipophilicity of a drug delivery system (attributed to piperine incorporation), the greater the extent of lymphatic transport. ...
Article
Introduction Cannabidiol (CBD), a phytocannabinoid from Cannabis sativa, has several therapeutic properties. However, its high lipophilicity, metabolization, and instability impair its bioavailability and translational use in clinical settings. Several advanced drug delivery systems (ADDSs) have been evaluated as CBD carriers to overcome these drawbacks. These systems can improve the CBD dissolution profile, protect it against metabolization, and produce a site-specific release, increasing its bioavailability and making CBD administration clinically effective. Areas covered This review summarizes scientific reports on cannabidiol advanced delivery systems (CBD-ADSs) that have been (i) developed, and (ii) applied therapeutically; reports published in the main scientific databases until January 2020 were included. Studies without experimental data and/or published in languages other than English were excluded. Moreover, pharmaceutical technology tools in CBD therapeutic use have been discussed, emphasizing the clinical translation of CBD carrier use. Expert opinion Studies reporting CBD-ADS use for medicinal applications were reviewed and revealed multifaceted systems that can overcome the physicochemical drawbacks of CBD and improve its biological activities. Therefore, researchers concluded that the developed CBD-ADS can be used as an alternative to traditional formulations because they show comparable or superior effectiveness in treatment protocols. Although several criteria remain to be met, our findings emphasize the potential of CBD-ADSs for translational therapeutics, particularly for neurological-disorders.
... Bioavailability showed a 2-fold increase in the CBD-piperine-PNL formulation compared to the CBD solution. 40 Piperine-pro-NanoLipospheres This extract has been used to treat arthritic pains in the Middle East in creams, ointments, pastes, microemulsions, and gels. CBD has a relatively well-known anti-inflammatory effect which is thought to emulate the activity of acetylsalicylic acid. ...
... 3.5.7. Pro-NanoLipospheres 40 Cherniakov et al. designed a formulation that created a nanoliposphere that enhanced oral absorption in rats. The self-emulsifying product was developed by taking Pro Nanoliposphere (PNL) pre-concentrates to enhance phase I metabolism and bioavailability. ...
... Future CBD/THC formulations could utilize piperine as a simple biological hack, disabling liver enzymes responsible for metabolism, functionally slowing metabolism, and then increasing serum concentrations as a downstream effect. 40 This is a suggested conclusion for ethylcellulose and electrospun fibers containing pyrrolidone, having excellent dreg loading at 80% and 90%, respectively. 44,47 Classically, buccal or sublingual formulations are thought to increase serum concentrations the most and most rapidly. ...
Article
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img src=” https://s3.amazonaws.com/production.scholastica/article/30706/large/prnano_742021ga.jpg?1639119402”>This review article provides a comprehensive overview and analysis of current and experi-mental cannabidiol (CBD) delivery methods and examines the pharmacological significance of various dosage forms and delivery systems. There are a limited number of CBD-based drugs on the market, many of them utilizing conventional dosage forms, i.e., capsules, oils, creams. The objective of this review is to evaluate various CBD formulations and analyze their formulation, bioavailability, and therapeutic effectiveness. CBD formulations were classified as conventional, transdermal, emulsion, nanoparticle, and miscellaneous. It also provides an exhaustive review of all CBD formulations from research articles, patent publications, and commercial products. In addition, studies data provided by inquiries to contrast new dosage forms with those currently available, like Epidiolex, dronabinol, and various over-the-counter formulations. The expected outcome of this review article is to better inform the scientific community on advancements in delivering CBD, which may improve patient outcomes.
... Cannabinoid nanodelivery systems have been applied in vitro and in vivo to serve as therapeutic strategies. A number of studies are building nanoparticles for nanodelivery of cannabis, cannabinoids and ECS components as nanotherapeutics [6,[16][17][18][19][20][21][22][23][24][25][26]. They include strategies for creating cannabinoid delivery systems incorporating cannabinoid nanoconjugates in a multifunctional nanocarrier. ...
... In order to avoid the intestinal first-pass effect, solubility, absorption and high lipophilicity of cannabinoids, advanced pro nanolipospheres and self-nano emulsifying drug delivery systems containing natural absorption enhancers on the oral bioavailability of tetrahydrocannabinol (THC) and CBD have been used in a rat model [7,24]. Cannabinoid-loaded poly(lactic-co-glycolic acid) PLGA nanoparticles also have potential for theranostic applications, for example, CBD-loaded PLGA nanoparticles were effective at inhibiting tumor growth following intraperitoneal administration in a model of ovarian cancer [25]. ...
... Their attractive features are (i) enhanced encapsulation efficiency or drug solubilization capacity for safe and targeted delivery, (ii) presence of surface functional groups that can be modified to improve stability and internalization, (iii) potential for superior pharmacokinetics, increased bioavailability, and minimal clearance from the body, and (iv) controlled, stimuli-responsive, remote actuation, and on-demand drug release properties [43,44,116,117]. Several studies have reported the development of nanoparticle-based delivery systems for cannabis, cannabinoids, and ECS components delivery [118][119][120][121][122][123][124][125][126][127][128]. Cannabinoid delivery systems based on nanoconjugates consist of nano-conjugated cannabinoids in a multifunctional metallic nanocarrier, classified as inorganic, organic, or hybrid nano systems, depending upon the specific requirements and administration route. ...
... The absorption of lipid-based nano-formulations in healthy rats was quick, whereas the absorption of oily preparations took longer, lasting 4-6 h [137]. PTL4 is a self-emulsifyingbased formulation of THC and CBD (1:1) with polysorbate 20, sorbitan monooleate 80, polyoxyethylene hydrogenated castor oil 40, glyceryl tridecanoate, lecithin, and ethyl lactate [119,126]. Namisol TM , an oral tablet formulation of dronabinol, was produced using Alitra TM , an emulsifying drug delivery technology. In this method, THC microgranules (size 30 micron) were coated with the surfactant sucrose monolaurate to increase the solubility of THC. ...
Article
Full-text available
Cannabis and its natural derivatives have emerged as promising therapeutics for multiple pathological and nonpathological medical conditions. For example, cannabinoids, the most popular and biologically active chemicals in cannabis, aid in many clinical ailments, including pain, inflammation, epilepsy, sleep disturbances or insomnia, multiple sclerosis, anorexia, schizophrenia, neurodegenerative diseases, anti­nausea, and most importantly, cancer. Despite the comprehensive benefits, certain aspects of cannabis present unique challenges in the medical cannabis landscape. Recent studies have highlighted the inherent challenges associated with cannabinoids' formulation like low solubility, rapid metabolism, poor bioavailability, and erratic pharmacokinetics – all of which contribute to the limited efficacy of cannabinoids. Several efforts are underway to address the bottlenecks and modify the formulations along with the delivery systems to achieve greater solubility/bioavailability, potency, and efficacy in treatment settings while minding the necessary standards for purity associated with the pharmaceutical industry. The current article presents a perspective on (1) a working knowledge of cannabinoids and their mechanisms of action, (2) the landscape of using medicinal cannabis for cancer-related medical conditions along with adversities, (3) current approaches, formulations, and challenges in medicinal cannabis delivery systems (oral, transdermal, pulmonary, and transmucosal), and lastly, (4) emerging approaches to improve delivery systems.
... PTL401 is the proprietary PNL-based formulation of THC and CBD. The PTL401 formulation is composed of THC-CBD (1:1) in a formulation with polysorbate 20, sorbitan monooleate 80, polyoxyethylene hydrogenated castor oil 40, glyceryl tridecanoate, lecithin and ethyl lactate [129,130]. The CBD-THC PNL formulation also allows absorption enhancers, such as curcumin, resveratrol and piperine, to be incorporated. ...
... The CBD-THC PNL formulation also allows absorption enhancers, such as curcumin, resveratrol and piperine, to be incorporated. PK evaluations in a rat model have indicated that only piperine enhanced the oral bioavailability of CBD in-vivo [130]. Moreover, the enhanced oral bioavailability can be attributed to the inhibition of intestinal processes, rather than those of hepatic first-pass metabolism, while additional increases in the AUC of CBD prove that piperine-PNL also has an effect on phase II, and not on just phase I, metabolism. ...
Article
Full-text available
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 in several therapeutic fields in recent years and numerous drugs have reached the market. This review explores the most recent developments, from preclinical to advanced clinical trials, in the cannabinoid delivery field, and focuses particularly on pain and inflammation treatment. Likely future directions are also considered and reported.
... This phytocannabinoid is a highly lipophilic molecule (logP = 6.64) and is sparingly soluble in aqueous media. It is classified as a Class II substance according to the Biopharmaceutical Classification System (Gaston and Friedman, 2017;Cherniakov et al., 2017;Paudel et al., 2010). The low aqueous solubility of CBD, associated with the extensive metabolism that it undergoes in the first passage through the liver, makes its oral bioavailability low and variable (6-13%) (WHO, 2018;Cherniakov et al., 2017). ...
... It is classified as a Class II substance according to the Biopharmaceutical Classification System (Gaston and Friedman, 2017;Cherniakov et al., 2017;Paudel et al., 2010). The low aqueous solubility of CBD, associated with the extensive metabolism that it undergoes in the first passage through the liver, makes its oral bioavailability low and variable (6-13%) (WHO, 2018;Cherniakov et al., 2017). ...
Article
The therapeutic potential of cannabidiol (CBD) has been explored to treat several pathologies, including those in which pain is prevalent. However, the oral bioavailability of CBD is low owing to its high lipophilicity and extensive first-pass metabolism. Considering the ability of the nasal route to prevent liver metabolism and increase brain bioavailability, we developed nanostructured lipid carriers (NLCs) for the nasal administration of CBD. We prepared particles with a positively charged surface, employing stearic acid, oleic acid, Span 20ࣨ, and cetylpyridinium chloride to obtain mucoadhesive formulations. Characterisation of the CBD-NLC dispersions showed uniform nano-sized particles with diameters smaller than 200 nm, and high drug encapsulation. The mucoadhesion of cationic particles has been related to interactions with negatively charged mucin. Next, we added in-situ gelling polymers to the CBD-NLC dispersion to obtain a CBD-NLC-gel. A thermo-reversible in-situ forming gel was prepared by the addition of Pluronicsࣨ. CBD-NLC-gel was characterised by its gelation temperature, rheological behaviour, and mucoadhesion. Both formulations, CBD-NLC and CBD-NLC-gel, showed high mucoadhesion, as assessed by the flow-through method and similar in vitro drug release profiles. The in vivo evaluation showed that CBD-NLC dispersion (without gel), administered intranasally, produced a more significant and lasting antinociceptive effect in animals with neuropathic pain than the oral or nasal administration of CBD solution. However, the nasal administration of CBD-NLC-gel did not lessen mechanical allodynia. These findings demonstrate that in-situ gelling hydrogels are not suitable vehicles for highly lipophilic drugs such as CBD, while cationic CBD-NLC dispersions are promising formulations for the nasal administration of CBD.
... 6-9%) owing to its low aqueous solubility and its susceptibility to ready clearance during first pass metabolism; therefore, it is up to the formulation science community to devise new routes for orally administering cannabinoids to both increase and ensure reproducibility of blood plasma concentrations (Elgart et al., 2012). Protocols such as self-emulsifying drug delivery systems have been applied in the past to increase solubility and reduce first pass metabolism of lipophilic bioactives such as cannabinoids in the context of pharmaceutical preparations (Cherniakov et al., 2017). ...
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div>This study describes the design, optimization, and stress-testing of a novel phytocannabinoid nanoemulsion generated using high-pressure homogenization. QNaturale®, a plant-derived commercial emulsifier containing quillaja saponin, was used to stabilize the lipid phase droplets in water. Optimization studies revealed that after 10 homogenization cycles at a pressure of 30,000 psi in the presence of 10 wt% QNaturale® (1.5 wt% quillaja saponin), average nanoemulsion droplet diameters were ca. 120 nm and average droplet surface zeta-potentials were ca. -30 mV for a lipid phase comprising 16.6 wt% CBD-enriched cannabis extract and 83.4 wt% carrier (soybean) oil. The optimized nanoemulsion proved to be stable to droplet agglomeration and phase separation upon storage under ambient conditions for 6 weeks, as well as under a variety of physical stressors such as heat, cold, dilution, and carbonation. pH values under 2 and moderately high salt concentrations (> 100 mM), however, destabilized 0the CD<sub>CBD</sub> nanoemulsion, eventually leading to phase separation. Cannabis potency, determined by HPLC, was detrimentally affected by any changes in the nanoemulsion phase stability. Quillaja saponin stabilized cannabidiol (CBD)-enriched nanoemulsions are stable, robust systems even at low emulsifier concentrations, and are therefore significant from both a scientific as well as a commercial perspective.</div
... Each clinical batch was prepared at the beginning of each study cycle. SNEDDS formulation was prepared as previously described [19,23]. Briefly, ethanol and soy lecithin were placed in a clean glass vial. ...
Article
Recent advances in the research of medicinal cannabis has placed the non-intoxicating cannabinoid cannabidiol (CBD) at the front of many investigations. The reasons behind this popularity is the compound’s therapeutic properties, alongside a safe profile of administration lacking addictive properties such as euphoric state of mind and characterized with a wide dosing range. Oral administration of CBD is challenging due to poor solubility in the gastro-intestinal system and susceptibility to extensive first pass metabolism. As a result, the practice in clinic and investigational trials is to administer cannabinoids in edible oils or oil-based solutions. Nonetheless, reported pharmacokinetics of cannabinoids and CBD in particular are not uniform among research groups and are affected by the vehicle of administration. The purpose of the work presented here is to investigate oral absorption processes of synthetic CBD when given in different oral formulations in healthy volunteers. The study design was a three way, blind, cross-over single administration study of 12 healthy male volunteers. CBD was administered in powder form, dissolved in sesame oil and in self-nano-emulsifying drug delivery system (SNEDDS). Administration of CBD in lipid-based vehicles resulted in a significant increase in Cmax and AUC of CBD, as compared to powder form. Overall plasma exposure of CBD did not differ between sesame oil vehicle and the SNEDDS formulation. However, administration of CBD in pure oil resulted in two absorption behaviors of early and delayed absorption among subjects, as opposed to SNEDDS platform that resulted in a uniform early absorption profile. Results of this trial demonstrate the importance of solubilization process of lipophilic drugs such as CBD and demonstrated the ability of the nano formulation to achieve a reliable, predictable PK profile of the drug. These findings offer a standardized oral formulation for the delivery of cannabinoids and contribute data for the growing field of cannabinoid PK.
... This procedure favours the solubility and oral bioavailability of the liposoluble drugs [88]. Absorption enhancers such as piperine can be incorporated in the PNL, thus increasing the oral bioavailability of CBD, according to in vivo evaluations in a rat model [89]. ...
Chapter
The use and study of medicinal cannabis is growing in accordance with the changes in the laws of many countries, along with the technological advances that allowed expanding the knowledge about its multiple pharmacological properties. Exhaustive studies on the pharmacological effects of the different Cannabis sativa constituents are of great importance due to the high impact that this ancient plant has on biological systems. Besides, the pharmaceutical form used for their administration is one of the relevant factors determining the absorption of phytocannabinoids by the human body, the physiological effects and their behaviour in relation to the nature of the analysed organic matrices, either for medicinal or legal purposes. This chapter summarizes the activity of phytocannabinoids on their specific receptors in mammals and the processes that they undergo in the body. The traditional and novel pharmaceutical formulations and the analytical methodologies to evaluate the organic matrices exposed to cannabis are also reviewed.
... Some formulation technologies including solid 2 solubilization of several poorly soluble bioactive compounds including vanillin, reserpine, sinapic acid and apigenin has been very well reported in the literature [24][25][26][27]. Some formulation technologies including solid dosage forms [28,29], emulsion/self-emulsifying formulations [30][31][32], nanomedicine-based drug delivery systems [33][34][35][36] and solid dispersion technology [37] have been studied in order to enhance solubility and bioactivity/bioavailability of PPN. The solubility of PPN in pure solvents including pure water, pure propylene glycol (PG), pure polyethylene glycol-400 (PEG-400) and pure THP at ambient temperature was reported elsewhere [1,30,31]. ...
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The solubility values and thermodynamic parameters of a natural phytomedicine/nutrient piperine (PPN) in Transcutol-HP (THP) + water combinations were determined. The mole fraction solubilities (x e) of PPN in THP + water combinations were recorded at T = 298.2-318.2 K and p = 0.1 MPa by the shake flask method. Hansen solubility parameters (HSPs) of PPN, pure THP, pure water and THP + water mixtures free of PPN were also computed. The x e values of PPN were correlated well with "Apelblat, Van't Hoff, Yalkowsky-Roseman, Jouyban-Acree and Jouyban-Acree-Van't Hoff" models with root mean square deviations of < 2.0%. The maximum and minimum x e value of PPN was found in pure THP (9.10 × 10 −2 at T = 318.2 K) and pure water (1.03 × 10 −5 at T = 298.2 K), respectively. In addition, HSP of PPN was observed more closed with that of pure THP. The thermodynamic parameters of PPN were obtained using the activity coefficient model. The results showed an endothermic dissolution of PPN at m = 0.6-1.0 in comparison to other THP + water combinations studied. In addition, PPN dissolution was recorded as entropy-driven at m = 0.8-1.0 compared with other THP + water mixtures evaluated.
... The bioavailability of delta-9-tetrahydrocannabinol and cannabidiol was enhanced by co-encapsulation with the piperine, although other enhancers, e.g., curcumin and resveratrol were also tried. The piperine based SNEDDS, termed as pronano-lipo-spheres, exhibited 6 x, and 9.3 x up-scaled AUC values for cannabidiol, and delta-9-tetrahydrocannabinol, respectively, when equated with the pure, non-SNEDDS formulated API solutions in rat models [283]. An extension of the study involving healthy volunteers was also conducted [284]. ...
Article
The self-generating nano-emulsifying drug delivery system (SNEDDS) is among the most effective approaches to enhance the oral bioavailability of a therapeutic agent, especially of a hydrophobic or poorly-water soluble drug. The methodology for SNEDDS preparation has been established on a number of therapeutic agents from several pharmacological classes. The requisite studies have validated the concept, and detailed experimentations in pharmaceutical, pharmacokinetics, and pharmacodynamics evaluations have corroborated the feasibility of SNEDDS formulation in providing higher levels of drug uploading, transport, dissolution, and intestinal permeation together with enhanced bioavailability at the site, and enhanced therapeutic effectiveness of the drug administered through oral route. The anti-cancer and anti-diabetic drugs having solubility issues, poor absorption, unwanted toxicity, and low bioavailability at the site of action have been dealt-with by the SNEDDS technology. The present review encompasses the SNEDDS technology applications primarily in these segments of drugs, and natural bioactive agents as well as synthetic agents for several bioactivities. It analyses the SNEDDS formulation approaches both in liquid and solid-SNEDDS based formulations, the absorption differences, bioavailability, and overall therapeutic effectiveness of these SNEDDS based products in comparison to the free drug behavior and other forms of drug delivery modalities as well as administration routes.
... CBD absorption increases three times with a high-fat meal and six times with new oral delivery system for lipophilic active compounds (61,62). Its high estimated volume of distribution (18,800-30,959 L) indicates accumulation of CBD in body fat (63). ...
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Cannabis sativa L. contains more than 100 phytocannabinoids that can interact with cannabinoid receptors CB1 and CB2. None of the cannabinoid receptor ligands is entirely CB1- or CB2-specific. The effects of cannabinoids therefore differ not just because of different potency at cannabinoid receptors but also because they can interact with other non-CB1 and non-CB2 targets, such as TRPV1, GPR55, and GPR119. The most studied phytocannabinoid is Δ9-tetrahydrocannabinol (THC). THC is a partial agonist at both cannabinoid receptors, but its psychotomimetic effect is produced primarily via activation of the CB1 receptor, which is strongly expressed in the central nervous system, with the noteworthy exception of the brain stem. Although acute cognitive and other effects of THC are well known, the risk of irreversible neuropsychological effects of THC needs further research to elucidate the association. Unlike THC, phytocannabinoid cannabidiol (CBD) does not appear to have psychotomimetic effects but may interact with some of the effects of THC if taken concomitantly. CBD administered orally has recently undergone well-controlled clinical trials to assess its safety in the treatment of paediatric epilepsy syndromes. Their findings point to increased transaminase levels as a safety issue that calls for postmarketing surveillance for liver toxicity. The aim of this review is to summarise what is known about acute and chronic toxicological effects of both compounds and address the gaps in knowledge about the safety of exogenous cannabinoids that are still open.
... Available data show that oral administration of CBD-piperine-PNL leads to a 6-fold increase in AUC when compared to a free CBD solution. Pharmacokinetic experiments of THC-piperine-PNL showed a similar behaviour with a 9.3-fold increase in the AUC when compared to the free THC solution [113]. ...
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Cannabis has been used in pain management since 2900 BC. In the 20th century, synthetic cannabinoids began to emerge, thus opening the way for improved efficacy. The search for new forms of synthetic cannabinoids continues and, as such, the aim of this review is to provide a comprehensive tool for the research and development of this promising class of drugs. Methods for the in vitro assessment of cytotoxic, mutagenic or developmental effects are presented, followed by the main in vivo pain models used in cannabis research and the results yielded by different types of administration (systemic versus intrathecal versus inhalation). Animal models designed for assessing side-effects and long-term uses are also discussed. In the second part of this review, pharmacokinetic and pharmacodynamic studies of synthetic cannabinoid biodistribution, together with liquid chromatography–mass spectrometric identification of synthetic cannabinoids in biological fluids from rodents to humans are presented. Last, but not least, different strategies for improving the solubility and physicochemical stability of synthetic cannabinoids and their potential impact on pain management are discussed. In conclusion, synthetic cannabinoids are one of the most promising classes of drugs in pain medicine, and preclinical research should focus on identifying new and improved alternatives for a better clinical and preclinical outcome.
... Oral capsules with piperine pronanolipospheres also increased AUC and C max . This is also demonstrated in animal studies; co-administration of lipids with oral CBD increased systemic availability by almost 3-fold in rats (Zgair et al., 2016) and a pro-nanoliposphere formulation increased oral bioavailability by about 6-fold (Cherniakov et al., 2017b). As CBD is a highly lipophilic molecule, it is logical that CBD may dissolve in the fat content of food, increasing its solubility, and absorption and therefore bioavailability as demonstrated by numerous pharmacological drugs (Winter et al., 2013). ...
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Background: Cannabidiol is being pursued as a therapeutic treatment for multiple conditions, usually by oral delivery. Animal studies suggest oral bioavailability is low, but literature in humans is not sufficient. The aim of this review was to collate published data in this area. Methods: A systematic search of PubMed and EMBASE (including MEDLINE) was conducted to retrieve all articles reporting pharmacokinetic data of CBD in humans. Results: Of 792 articles retireved, 24 included pharmacokinetic parameters in humans. The half-life of cannabidiol was reported between 1.4 and 10.9 h after oromucosal spray, 2–5 days after chronic oral administration, 24 h after i.v., and 31 h after smoking. Bioavailability following smoking was 31% however no other studies attempted to report the absolute bioavailability of CBD following other routes in humans, despite i.v formulations being available. The area-under-the-curve and Cmax increase in dose-dependent manners and are reached quicker following smoking/inhalation compared to oral/oromucosal routes. Cmax is increased during fed states and in lipid formulations. Tmax is reached between 0 and 4 h. Conclusions: This review highlights the paucity in data and some discrepancy in the pharmacokinetics of cannabidiol, despite its widespread use in humans. Analysis and understanding of properties such as bioavailability and half-life is critical to future therapeutic success, and robust data from a variety of formulations is required.
... Also, bioavailability following oral administration of CBD to dogs was low due to the first pass effect [24]. Extremely poor oral bioavailability of CBD in in vivo studies might be due to its poor water solubility, or metabolism to other metabolites such as 7-OH CBD via CYP3A4 and CYP2C19 enzymes, or glucuronidation, resulting in clearance [25,26]. Therefore, understanding CBD bioaccessibility and absorption following oral administration is very important to comprehend the challenges in dose dependent administration and provide insight for formulation and drug delivery to increase oral bioavailability of CBD and other cannabinoid species in humans. ...
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Cannabidiol (CBD) is a hydrophobic non-psychoactive compound with therapeutic characteristics. Animal and human studies have shown its poor oral bioavailability in vivo, and the impact of consuming lipid-soluble CBD with and without food on gut bioaccessibility has not been explored. The purpose of this research was to study the bioaccessibility of CBD after a three-phase upper digestion experiment with and without food, and to test lipase activity with different substrate concentrations. Our results showed that lipase enzyme activity and fatty acid absorption increased in the presence of bile salts, which may also contribute to an increase in CBD bioaccessibility. The food matrix used was a mixture of olive oil and baby food. Overall, the fed-state digestion revealed significantly higher micellarization efficiency for CBD (14.15 ± 0.6% for 10 mg and 22.67 ± 2.1% for 100 mg CBD ingested) than the fasted state digestion of CBD (0.65 ± 0.7% for 10 mg and 0.14 ± 0.1% for 100 mg CBD ingested). The increase in bioaccessibility of CBD with food could be explained by the fact that micelle formation from hydrolyzed lipids aid in bioaccessibility of hydrophobic molecules. In conclusion, the bioaccessibility of CBD depends on the food matrix and the presence of lipase and bile salts.
... Similar formulation approaches have been investigated by other researchers but using selfnano-emulsifying drug delivery systems (SNEDDS) focusing on increasing CBD overall oral bioavailability, where they predominantly used a high proportion of surfactant with LCT to reduce the particle size at the nanoscale following self-emulsification of formulations [128,201,337]. Even though oral administration of SNEDDS was shown to substantially improve the bioavailability of CBD in comparison to CBD powder, equivalent drug absorption was observed when compared to sesame oil-based or other natural oils formulations. ...
Article
Lipid-based formulations play a significant role in oral delivery of lipophilic drugs. Previous studies have shown that natural sesame oil promotes the intestinal lymphatic transport and oral bioavailability of highly lipophilic drug cannabidiol (CBD). However, both lymphatic transport and systemic bioavailability were also associated with considerable variability. The first aim of this thesis was to test the hypothesis that pre-digested lipid formulations (oleic acid, linoleic acid, oleic acid with 2-oleoylglycerol, oleic acid with 2-oleoylglycerol and oleic acid with glycerol) could reduce variability and increase the extent of the intestinal lymphatic transport and oral bioavailability of CBD. In vivo studies in rats showed that pre-digested or purified triglyceride did not improve the lymphatic transport and bioavailability of CBD in comparison to sesame oil. Moreover, the results suggest that both the absorption of lipids and the absorption of co-administered CBD were more efficient following administration of natural sesame oil vehicle compared with pre-digested lipids or purified trioleate. However, this natural oil-based formulation also leads to considerable variability in absorption of CBD [1]. Therefore, the second approach in this thesis was to test the performance of lipid-based formulations with the addition of medium-chain triglyceride (MCT) or surfactants to the sesame oil vehicle in vitro and in vivo using CBD as a model drug. The in vitro lipolysis has shown that addition of the MCT leads to a higher distribution of CBD into the micellar phase. Further addition of surfactants to MCT-containing formulations did not improve distribution of the drug into the micellar phase. In vivo, formulations containing MCT led to lower or similar concentrations of CBD in serum, lymph and mesenteric lymph nodes (MLN), but with reduced variability. MCT improves the emulsification and micellar solubilisation of CBD, but surfactants did not facilitate further the rate and extent of lipolysis. Even though addition of MCT reduces the variability, the in vivo performance for the extent of both lymphatic transport and systemic bioavailability remains superior with a pure natural oil vehicle [2]. These results lead to the hypothesis that differences in composition of vegetable oils lead to differences in promotion of intestinal lymphatic transport of lipophilic drugs. Therefore, the differences in composition of sesame, sunflower, peanut, soybean, olive and coconut oils and their corresponding role as vehicles in promoting CBD lymphatic targeting and bioavailability were investigated in this thesis. The comparative analysis suggested that the fatty acids profile of vegetable oils is overall similar to the fatty acids profile in the corresponding chylomicrons in rat lymph. However, arachidonic acid (C20:4), was introduced to chylomicrons from endogenous nondietary sources in all cases. Overall, fatty acid composition of natural vegetable oils vehicles affected the intestinal lymphatic transport and bioavailability of CBD following oral administration in this work. Olive oil led to the highest concentration of CBD in the lymphatic system and systemic circulation and low variability in comparison to other natural vegetable oils following oral administration in rats. The natural rapeseed oil bodies also used as lipid-based vehicles to facilitate CBD oral bioavailability and lymphatic transport in this thesis. The oral bioavailability of CBD was 1.7-fold higher in oil bodies-based formulation than rapeseed oil-based formulation in rats. This finding indicates that oil bodies could potentially to improve lipophilic drug systemic exposure and lymphatic targeting in comparison to simple oils, and their other pharmaceutical properties as a drug delivery carrier needs to be further investigated. Overall in this thesis, olive oil and oil bodies are preferred lipid vehicles for improving intestinal lymphatic transport and bioavailability of co-administered CBD following oral administration.
... Cherniakov et al. reported that piperine enhanced the adsorption of THC and CBD on single dose administration [109]. ...
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Nowadays cardiovascular diseases (CVDs) are the major causes for the reduction of the quality of life. The endocannabinoid system is an attractive therapeutic target for the treatment of cardiovascular disorders due to its involvement in vasomotor control, cardiac contractility, blood pressure and vascular inflammation. Alteration in cannabinoid signalling can be often related to cardiotoxicity, circulatory shock, hypertension, and atherosclerosis. Plants have been the major sources of medicines until modern eras in which researchers are experiencing a rediscovery of natural compounds as novel therapeutics. One of the most versatile plant is Cannabis sativa L., containing phytocannabinoids that may play a role in the treatment of CVDs. The aim of this review is to collect and investigate several less studied plants rich in cannabinoid-like active compounds able to interact with cannabinoid system; these plants may play a pivotal role in the treatment of disorders related to the cardiovascular system.
... 6-9%) owing to its low aqueous solubility and its susceptibility to ready clearance during first pass metabolism; therefore, it is up to the formulation science community to devise new routes for orally administering cannabinoids to both increase and ensure reproducibility of blood plasma concentrations (Elgart et al. 2012). Protocols such as self-emulsifying drug delivery systems have been applied in the past to increase solubility and reduce first pass metabolism of lipophilic bioactives such as cannabinoids in the context of pharmaceutical preparations (Cherniakov et al. 2017). ...
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Background This study describes the design, optimization, and stress-testing of a novel phytocannabinoid nanoemulsion generated using high-pressure homogenization. $\text {QNaturale}^{\circledR }$ QNaturale Ⓡ , a plant-derived commercial emulsifier containing quillaja saponin, was used to stabilize the lipid phase droplets in water. Stress-testing was performed on this nanoemulsion in order to evaluate its chemical and colloidal stability under the influence of different environmental factors, encompassing both physical and chemical stressors. Methods Extensive optimization studies were conducted to arrive at an ideal nanoemulsion formulation. A coarse emulsion containing 16.6 wt% CBD-enriched cannabis distillate and 83.4 wt% carrier (soybean) oil dispersed in 10 wt% $\text {QNaturale}^{\circledR }$ QNaturale Ⓡ (1.5 wt% quillaja saponin) solution after 10 homogenization cycles at a pressure of 30,000 psi produced a stable nanoemulsion. This nanoemulsion was then subjected to the stress studies. Results The optimized nanoemulsion had an average droplet diameter of ca. 120 nm and average droplet surface ζ potentials of ca. -30 mV. It was imaged and characterized by a variety of protocols. It proved to be stable to droplet agglomeration and phase separation upon storage under ambient conditions for 6 weeks, as well as under a variety of physical stressors such as heat, cold, dilution, and carbonation. pH values ≤2 and moderately high salt concentrations (> 100 mM), however, destabilized the nanoemulsion, eventually leading to phase separation. Cannabis potency, determined by HPLC, was detrimentally affected by any changes in the nanoemulsion phase stability. Conclusions Quillaja saponin stabilized cannabidiol(CBD)-enriched nanoemulsions are stable, robust systems even at low emulsifier concentrations, and are therefore significant from both a scientific as well as a commercial perspective.
... In this context, it has been proposed in the therapy of cancer, epilepsy, pain, inflammation, and autism spectrum disorder with promising clinical results [1,2,6,7]. The development of CBD formulations is challenging because it is highly lipophilic (partition coefficient-log P-of 6.3) [8]; CBD is classified into Class II of the Biopharmaceutics Classification System (BCS) [9,10]. Oral CBD is often administered in oil or alcoholic formulations [11], and undergoes limited intestinal absorption and substantial hepatic first-pass, which results in a very low oral bioavailability (<20%) [12]. ...
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Ocular drug delivery is challenging due to the very short drug residence time and low permeability. In this work, we produce and characterize mucoadhesive mixed polymeric micelles (PMs) made of chitosan (CS) and poly(vinyl alcohol) backbones graft-hydrophobized with short poly(methyl methacrylate) blocks and use them to encapsulate cannabidiol (CBD), an anti-inflammatory cannabinoid. CBD-loaded mixed PMs are physically stabilized by ionotropic crosslinking of the CS domains with sodium tripolyphoshate and spray-drying. These mixed PMs display CBD loading capacity of 20% w/w and sizes of 100–200 nm, and spherical morphology (cryogenic-transmission electron microscopy). The good compatibility of the unloaded and CBD-loaded PMs is assessed in a human corneal epithelial cell line. Then, we confirm the permeability of CBD-free PMs and nanoencapsulated CBD in human corneal epithelial cell monolayers under liquid–liquid and air–liquid conditions. Overall, our results highlight the potential of these polymeric nanocarriers for ocular drug delivery.
... Preclinical and early clinical phase studies demonstrate the potential of cannabidiol (CBD) in cancer, stroke, anxiety, and pain [1][2][3][4][5][6][7][8], and a purified form of CBD (98%, Epidiolex ® ) is already licensed to treat sei-zures associated with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis [9]. Around 65 molecular targets for CBD have been identified [10,11] with different targets responsible for different therapeutic effects of CBD. ...
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Introduction: Cannabidiol (CBD) can be isolated from Cannabis sativa L. or synthetically produced. The aim of this study was to compare the in vitro effects of purified natural and synthetic CBD to establish any pharmacological differences or superiority between sources. Methods: Six purified samples of CBD were obtained, 4 of these were natural and 2 synthetic. The anticancer effects of CBD were assessed in a human ovarian cancer cell line (SKOV-3 cells). The neuroprotective effects of CBD were assessed in human pericytes in a model of stroke (oxygen glucose deprivation [OGD]). The ability of CBD to restore inflammation-induced intestinal permeability was assessed in differentiated human Caco-2 cells (a model of enterocytes). Results: (1) In proliferating and confluent SKOV-3 cells, all CBD samples similarly reduced resazurin metabolism as a marker of cell viability in a concentration-dependent manner (p < 0.001). (2) In pericytes exposed to OGD, all CBD samples similarly reduced cellular damage (measured by lactate dehydrogenase) at 24 h by 31-48% and reduced inflammation (measured by IL-6 secretion) by 30-53%. Attenuation of IL-6 was inhibited by 5HT1A receptor antagonism for all CBD sources. (3) In differentiated Caco-2 cells exposed to inflammation (TNFα and IFNγ, 10 ng/mL for 24 h), each CBD sample increased the speed of recovery of epithelial permeability compared to control (p < 0.05-0.001), which was inhibited by a CB1 receptor antagonist. Conclusion: Our results suggest that there is no pharmacological difference in vitro in the antiproliferative, anti-inflammatory, or permeability effects of purified natural versus synthetic CBD. The purity and reliability of CBD samples, as well as the ultimate pharmaceutical preparation, should all be considered above the starting source of CBD in the development of new CBD medicines.
... Regarding cannabidiol, this lipophilic phytocannabinoid is poorly water soluble and subjected to extensive first-pass metabolism in the gastrointestinal tract, leading to a limited oral bioavailability of ∼9% (73). However, natural substances, such as polyphenols, that can interfere with phase I and/or II enzymes and/or with enteric P-glycoprotein enhance its plasma levels in rats ∼6-fold (73). Finally, among the three compounds tested in our investigation, cannabidiol is the only ingredient that has been studied in dogs, where its detected oral bioavailability ranged from 13 to 19% of the administered dose (74,75). ...
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Canine atopic dermatitis (AD) is a multifactorial allergic disease associated with immune and abnormal skin barrier dysfunction and it is one of the primary causes of pruritus. Using a novel in vitro model of AD, here we tried to revert the alteration of transcriptional regulation of AD canine key genes testing a nutraceutical mixture containing flavonoids, stilbene, and cannabinoids, which are already well-known for their applications within dermatology diseases. The nutraceutical mixture induced in inflamed cells a significant downregulation (p < 0.05) of the gene expression of ccl2, ccl17, and tslp in keratinocytes and of ccl2, ccl17, and il31ra in monocytes. Consistent with the observed alterations of tslp, ccl2, ccl17, and il31ra messenger RNA (mRNA) levels, a significant increase (p < 0.05) of DNA methylation at specific CpG sites on the gene regulatory regions was found. These results lay the foundation for the use of these natural bioactives in veterinary medicine and provide a model for deeper understanding of their mechanisms of action, with potential translation to human research.
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This study aimed to determine if orally administered cannabidiol (CBD) lessens the cortical over-release of glutamate induced by a severe traumatic brain injury (TBI) and facilitates functional recovery. The short-term experiment focused on identifying the optimal oral pretreatment of CBD. Male Wistar rats were pretreated with oral administration of CBD (50, 100, or 200 mg/kg) daily for 7 days. Then, extracellular glutamate concentration was estimated by cortical microdialysis before and immediately after a severe TBI. The long-term experiment focused on evaluating the effect of the optimal treatment of CBD (pre- vs. pre- and post-TBI) 30 days after trauma. Sensorimotor function, body weight, and mortality rate were evaluated. In the short term, TBI induced a high release of glutamate (738% ± 173%; p < 0.001 vs. basal). Oral pretreatment with CBD at all doses tested reduced glutamate concentration but with higher potency at when animals received 100 mg/kg (222 ± 33%, p < 0.01 vs. TBI), an effect associated with a lower mortality rate (22%, p < 0.001 vs. TBI). In the long-term experiment, the TBI group showed a high glutamate concentration (149% p < 0.01 vs. SHAM). In contrast, animals receiving the optimal treatment of CBD (pre- and pre/post-TBI) showed glutamate concentrations like the SHAM group (p > 0.05). This effect was associated with high sensorimotor function improvement. CBD pretreatment, but not pre-/post-treatment, induced a higher body weight gain (39% ± 2.7%, p < 0.01 vs. TBI) and lower mortality rate (22%, p < 0.01 vs. TBI). These results support that orally administered CBD reduces short- and long-term TBI-induced excitotoxicity and facilitated functional recovery. Indeed, pretreatment with CBD was sufficient to lessen the adverse sequelae of TBI.
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Cannabidiol (CBD) has poor water solubility and is subjected to extensive first-pass metabolism. These absorption obstacles are responsible for low and variable oral bioavailability of CBD. This study endeavored to improve CBD bioavailability by intramuscular (IM) injection of CBD nanocrystals (CBD-NC). The nanocrystals were prepared by antisolvent precipitation method and were characterized in terms of the particle size, polydispersity index (PDI), zeta potential, morphology, and crystalline status. CBD-NC displayed a particle size of 141.7±1.5 nm, a PDI of 0.18±0.01, and a zeta potential of -25.73 mV. CBD-NC freeze-dried powder using bovine serum albumin (BSA) as cryoprotectant had good redispersibility, and the average particle size was 139.1±1.4 nm after reconstitution. Moreover, these freeze-dried powders were characterized for drug loading and pH and were evaluated for in vitro dissolution and in vivo studies in a rat model. The in vivo results showed that AUC0-24 h and Cmax of CBD by IM injection of CBD nanocrystals increased significantly compared with that of oral (P.O) administration of CBD nanocrystals and CBD oil solution. This underlines the nano-sized CBD could be suggested as a practical and simple nanosystem for IM delivery with improved bioavailability. More importantly, these results pave the way for future development of CBD-NC retentive dosage forms. Graphical abstract.
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In this study, the solubility, molecular interactions and mixing thermodynamic properties of a poorly water soluble bioactive compound piperine in twelve different pure solvents namely “water, methanol, ethanol, isopropyl alcohol (IPA), ethylene glycol (EG), propylene glycol (PG), 1-butanol, 2-butanol, ethyl acetate (EA), dimethyl sulfoxide (DMSO), polyethylene glycol-400 (PEG-400) and 2-(2-ethoxyethoxy) ethanol [Transcutol®]” were evaluated. The solubility of piperine was determined at temperatures “T = 298.2 K to 318.2 K” and pressure “p = 0.1 MPa”. The experimental solubility values of piperine were determined using a static equilibrium method by high-performance liquid chromatography at 254 nm. The solubility data of piperine obtained in this study was regressed using “van't Hoff and Apelblat models” with root mean square deviation values of < 5.0%. The solubilities of piperine in mole fraction were obtained maximum in Transcutol (9.17 × 10− 2) followed by PEG-400 (7.88 × 10− 2), DMSO (3.59 × 10− 3), 2-butanol (2.25 × 10− 2), 1-butanol (2.20 × 10− 2), IPA (1.82 × 10− 2), EA (1.54 × 10− 2), PG (1.47 × 10− 2), ethanol (1.34 × 10− 2), methanol (7.91 × 10− 3), EG (6.70 × 10− 3) and water (1.52 × 10− 5) at “T = 318.2 K”. Based on the results of activity coefficient, the solute-solvent interaction was seen maximum in piperine-Transcutol and piperine-PEG-400 in comparison with other solute-solvent combination studied. Mixing thermodynamic properties of piperine were determined by activity coefficient model and results indicated spontaneous and entropy-driven dissolution of piperine in most of the pure solvents studied.
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A new amphiphilic derivative–methoxy(polyethoxy)ethyl stearate has been synthesized with the goal of creating therefrom systems for delivery and enhancement of bioavailability of piperine. The aggregation and solubilizing properties of ω-methylpoly(oxyethylene) stearate have been studied by means of a set of physicochemical methods.
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Introduction: Oral administration of cannabinoids is a convenient route of administration in many cases. To enhance the poor and variable bioavailability of cannabinoids, selected strategies utilizing proper delivery systems have been designed. Low solubility in the GI aqueous media is the first and most critical barrier. Thereafter, cannabinoids can reach the systemic blood circulation via the portal vein that is associated with significant hepatic first pass metabolism (FPM) or bypass it via lymphatic absorption. Areas covered: The solubility obstacle of cannabinoids is mainly addressed with lipid-based formulations such as self-nanoemulsifying drug delivery systems (SNEDDS). Certain lipids are used to overcome the solubility issue. Surfactants and other additives in the formulation have additional impact on several barriers, including dictating the degree of lymphatic bioavailability and hepatic FPM. Gastro-retentive formulation is also plausible. Expert opinion: Comparison of the role of the same SNEDDS formulation, cyclosporine vs. cannabinoids, when used to elevate the oral bioavailability of different compounds, is presented. It illustrates some similarities and major mechanistic differences obtained by the same SNEDDS. Thus, the different influence over the absorption pathway illuminates the importance of understanding the absorption mechanism and its barriers to properly select appropriate strategies to achieve enhanced oral bioavailability.
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Cannabis is one of the most widely used illicit drugs during pregnancy and lactation. With the recent legalization of cannabis in many countries, health professionals are increasingly exposed to pregnant and breastfeeding women who are consuming cannabis on a regular basis as a solution for depression, anxiety, nausea, and pain. Cannabis consumption during pregnancy can induce negative birth outcomes such as reduced birth weight and increased risk of prematurity and admission to the neonatal intensive care unit. Yet, limited information is available regarding the pharmacokinetics of cannabis in the fetus and newborn exposed during pregnancy and lactation. Indeed, the official recommendations regarding the use of cannabis during these two critical development periods lack robust pharmacokinetics data and make it difficult for health professionals to guide their patients. Many clinical studies are currently evaluating the effects of cannabis on the brain development and base their groups mostly on questionnaires. These studies should be associated with pharmacokinetics studies to assess correlations between the infant brain development and the exposure to cannabis during pregnancy and breastfeeding. Our project aims to review the available data on the pharmacokinetics of cannabinoids in adults, neonates, and animals. If the available literature is abundant in adult humans and animals, there is still a lack of published data on the exposure of pregnant and lactating women and neonates. However, some of the published information causes concerns on the exposure and the potential effects of cannabis on fetuses and neonates. The safety of cannabis use for non-medical purpose during pregnancy and breastfeeding needs to be further characterized with proper pharmacokinetic studies in humans feasible in regions where cannabis has been legalized. Given the available data, significant transfer occurs to the fetus and the breastfed newborn with a theoretical risk of accumulation of products known to be biologically active.
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Nature has been used as therapeutic resources in the treatment of diseases for many years. However, some natural compounds have poor water solubility. Therefore, physicochemical strategies and technologies are necessary for development of systems for carrying these substances. The self-emulsifying drug delivery systems (SEDDS) have been used as carriers of hydrophobic compounds in order to increase the solubility and absorption, improving their bioavailability. SEDDS are constituted with a mixture of oils and surfactants which, when come into contact with an aqueous medium under mild agitation, can form emulsions. In the last years, a wide variety of self-emulsifying formulations containing bioactive compounds from natural origin has been developed. This review provides a comprehensive overview of the main excipients and natural bioactive compounds composing SEDDS. In addition, applications, new technologies and innovation are reviewed as well. Examples of self-emulsifying formulations administered in different sites are also considered for a better understanding of the use of this strategy to modify the delivery of compounds from natural origin.
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Cannabidiol (CBD) exhibits significant efficacy in mental and inflammatory diseases. Several studies have recently reported on the rapid antidepressant-like effects of CBD, suggesting that CBD is a potential anti-depressant or anti-stress drug. However, CBD is mainly administered orally or by inhalation with poor bioavailability, resulting in high costs. We aim to explore the efficacy of long-term periodic administration of CBD in chronic mild stress (CMS) via two routes and its pharmacokinetics. We treated ICR mice with CBD administered orally and intravenously and then determined the kinetic constants. A single bolus intravenous injection of CBD resulted in a half-life of 3.9 h, mean residence time of 3.3 h, and oral bioavailability of about 8.6%. The antidepressant-like effects of periodically administered CBD on the chronic mild stress mouse model are evaluated. Results demonstrated that such treatment at a high dose of 100 mg/kg CBD (p.o.) or a low dose of 10 mg/kg CBD (i.v.), elicited significant antidepressant-like behavioral effects in forced swim test, following increased mRNA expression of brain-derived neurotrophic factor (BDNF) and synaptophysin in the prefrontal cortex and the hippocampus. Our findings are expected to provide a reference for the development of intravenous antidepressant formulations of CBD.
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The aim of this research was to investigate the effect of the lipid component in self-emulsifying drug delivery systems on the oral absorption of major cannabinoids Δ9-tetrahydrocannabinol (THC) and Cannabidiol (CBD). The investigated lipids were either long chain triglycerides (LCT) or medium chain triglycerides (MCT) with different composition, fatty acid chain length, degree of saturation and their absorption pathway to the systemic circulation. Formulations were developed with the purpose of creating thermodynamically stable oil-in-water nano emulsions/suspensions with particle size of 50 nm or less which carry the lipophilic drug and increase water solubility. Following a methodic screening of suitable excipients in-vitro, leading formulations based on sesame oil or MYGLIOL 812®N (Type I LCT/MCT SNEDDS) and cocoa butter or tricaprin (Type II LCT/MCT SNEDDS) were investigated in the freely moving rat model. Results in rat model demonstrated that the effect of each type of lipid on bioavailability of cannabinoids is not straightforwardly anticipated. The differences in the effect of LCT and MCT on absorption was not substantial for Type I formulations, however, more prominent for Type II formulations. This unpredictable behavior in-vivo demonstrates the importance of investigating each vehicle pre-clinically, following the in-vitro development.
Article
The piperine is an alkaloid naturally found mostly in black pepper with a myriad of pharmacological attributes. The most far reaching indication of piperine is its use as an absorption enhancer, with supportive data regarding piperine's ability to inhibit first pass effect mechanisms. However, alongside these findings, the role of piperine as an absorption enhancer is undermined with publications stating an effect of a metabolic inducer. The aim of this commentary is to investigate the effect of repeated administration of piperine on oral absorption of cannabidiol (CBD), compared to single dose administration. The effect of piperine on absorption was determined pre-clinically in the freely moving rat model. Repeated administration of piperine, dissolved in a lipid-based formulation did not differ from acute piperine demonstration in its effect on CBD absorption, with a 2.5-fold increase in oral bioavailability in comparison to control group without piperine.
Article
Lipid-based delivery systems have been vastly investigated as a pharmaceutical method to enhance the oral absorption of lipophilic drugs. However, these vehicles affect not only drug bioavailability, but may also have an impact on gastric emptying, drug disposition, lymphatic absorption and are affected by lipid digestion mechanisms. The work presented here compared pharmacokinetic (PK) behavior of the non-intoxicating cannabinoid cannabidiol (CBD) in sesame oil vs. a self-emulsifying drug delivery system (SNEDDS). This investigation was conducted with a unique tool termed the “absorption cocktail approach”. In this concept, selected molecules: metoprolol, THC and ibuprofen were co-administered with CBD in SNEDDS and sesame oil. This method was used to shed light on the complex absorption process of poorly soluble drugs in-vivo, specifically assessing absorption kinetics of CBD. It was found that the concentration vs. time curve following CBD-sesame oil oral administration showed extended input of the drug with delayed Tmax compared to CBD-SNEDDS. Using the “cocktail” approach, a unique finding was observed when the less lipophilic compounds (metoprolol and ibuprofen) exited the stomach much earlier than the lipophilic cannabinoids in sesame oil, proving differential absorption kinetics. Findings of the absorption cocktail approach reflected the physiological process of the GI e.g gastric retention, stomach content separation, lipid digestion, drug precipitation and more, demonstrating its utility. Nonetheless, the search for more compounds as suitable molecule probes is underway.
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Cannabis is an excellent natural source of fiber and various bioactive cannabinoids. So far, at least 120 cannabinoids have been identified, and more novel cannabinoids are gradually being unveiled by detailed cannabis studies. However, cannabinoids in both natural and isolated forms are especially vulnerable to oxygen, heat, and light. Therefore, a diversity of cannabinoids is associated with their chemical instability to a large extent. The research status of structural conversion of cannabinoids is introduced. On the other hand, the use of drug-type cannabis and the phytocannabinoids thereof has been rapidly popularized and plays an indispensable role in both medical therapy and daily recreation. The recent legalization of edible cannabis further extends its application into the food industry. The varieties of legal edible cannabis products in the current commercial market are relatively monotonous due to rigorous restrictions under the framework of Cannabis Regulations and infancy of novel developments. Meanwhile, patents/studies related to the safety and quality assurance systems of cannabis edibles are still rare and need to be developed. Furthermore, along with cannabinoids, many phytochemicals such as flavonoids, lignans, terpenoids, and polysaccharides exist in the cannabis matrix, and these may exhibit prebiotic/probiotic properties and improve the composition of the gut microbiome. During metabolism and excretion, the bioactive phytochemicals of cannabis, mostly the cannabinoids, may be structurally modified during enterohepatic detoxification and gut fermentation. However, the potential adverse effects of both acute and chronic exposure to cannabinoids and their vulnerable groups have been clearly recognized. Therefore, a comprehensive understanding of the chemistry, metabolism, toxicity, commercialization, and regulations regarding cannabinoid edibles is reviewed and updated in this contribution.
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Background“Using active chemicals as excipients” refers to a preparation strategy. It makes use of the drugs owning the special physical and chemical properties as the roles of excipients to assist the preparation forming or achieve some specific drug delivery function, especially in the compound preparation.Area CoveredThis paper proposed the concept of “using active chemicals as excipients”, expounded the advantages and potentials of “medicine as excipient’s use”, and analyzed the research status of “using active chemicals as excipients” from the aspects of chemical compound preparations and traditional Chinese medicine preparations. We classified the excipient function of drugs in formulations, and expounded the functional principles and characteristics of drugs as excipients from drug physical properties and drug dispersing forms in preparation.Expert OpinionThis preparation strategy has the advantages of reducing the amount of excipients, improving drugs compliance and reducing production costs. It is an important development direction of modern pharmaceutical preparation research and production. In a word, “using active chemicals as excipients” is a potential preparation strategy, which should be paid attention to and be implemented in the process of preparation research and development.
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Self-emulsifying drug-delivery systems (SEDDS) have been extensively shown to increase oral absorption of solvation-limited compounds. However, there has been little clinical and commercial use of these formulations, in large part because the demonstrated advantages of SEDDS have been outweighed by our inability to precisely predict drug absorption from SEDDS using current in vitro assays. To overcome this limitation and increase the biological relevancy of in vitro assays, an absorption function can be incorporated using biomimetic membranes. However, the effects that SEDDS have on the integrity of a biomimetic membrane are not known. In this study, a quartz crystal microbalance with dissipation monitoring and total internal reflection fluorescence microscopy were employed as complementary methods to in vitro lipolysis-permeation assays to characterize the interaction of various actively digested SEDDS with a liquescent artificial membrane comprising lecithin in dodecane (LiDo). Observations from surface analysis showed that interactions between the digesting SEDDS and LiDo membrane coincided with inflection points in the digestion profiles. Importantly, no indications of membrane damage could be observed, which was supported by flux profiles of the lipophilic model drug felodipine (FEL) and impermeable marker Lucifer yellow on the basal side of the membrane. There was a correlation between the digestion kinetics of the SEDDS and the flux of FEL, but no clear correlation between solubilization and absorption profiles. Membrane interactions were dependent on the composition of lipids within each SEDDS, with the more digestible lipids leading to more pronounced interactions, but in all cases, the integrity of the membrane was maintained. These insights demonstrate that LiDo membranes are compatible with in vitro lipolysis assays for improving predictions of drug absorption from lipid-based formulations.
Article
Industrial hemp is an important economic crop. The ethanol extract of its leaf is also known as cannabidiol full-spectrum oil (CFSO) and has a lot of health benefits. But its applications in many fields are limited owing to the poor thermal stability and low aqueous solubility. In this study, 2, 6-di-O-methyl-β-cyclodextrin (DM-β-CD) was used to prepare inclusion complex (IC) of CFSO to enhance its thermal stability and water solubility. Phase solubility study indicated that CFSO formed ICs with DM-β-CD at a 1:1 stoichiometric ratio. The complexation rate of CFSO/DM-β-CD IC was 91.5%. The results of SEM, FT-IR, DSC, PXRD, NMR, and molecular docking revealed that the bioactive components of CFSO were embedded into DM-β-CD cavities. After complexation, the aqueous solubility of CFSO in CFSO/DM-β-CD IC was increased from 0.046 to 12.4 μg/mL. The DPPH and ABTS EC50 values of CFSO/DM-β-CD IC were 130.5 and 12.0 μg/mL respectively, which indicated that the antioxidant ability of CFSO/DM-β-CD IC was stronger than that of CFSO. The MICs of CFSO/DM-β-CD IC were around 6.25-12.5 μg/mL for Escherichia coli and 12.5-25 μg/mL for Bacillus subtilis. The data showed that the antibacterial activity of CFSO was nearly not influenced by complexation. The thermal stability of CFSO was also improved after inclusion. The findings could promote the use of CFSO and the development of the industrial hemp industry.
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Apomorphine (APO), a potent treatment for Parkinson's disease, is only administered parenterally either as intermittent injections or as an infusion. This is due to extensive hepatic “first pass” metabolism. Prolonged delivery through buccal mucosa may be potential substitute for parenteral infusions. To investigate this concept of buccal mucosal delivery, permeability ex vivo studies were performed through excised porcine buccal mucosa by utilizing Ussing diffusion chamber. Permeability rates were assessed for APO from simulated saliva medium at pH 7.4 as well as with utilization of different permeability modifying methods. Lowering the pH to 5.9 decreased permeability rate six-fold, while addition of ethanol : propylene glycol solution elevated it four-fold. Addition of nano-scale lipospheres to the donor compartment delayed the accumulation of APO at the receiver side, prolongating the lag-time from one to approx. three hours. These findings were strengthened by results obtained with co-administration of permeability markers (standards) atenolol and metoprolol. Simulation of the obtained permeability rates to in vivo setup in human showed therapeutically relevant plasma levels when using the outcomes of the current study. These findings verify the novel concept of APO prolonged release buccal administration as a noninvasive substitute for parenteral infusions in treating Parkinson's disease.
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The endocannabinoid system (ECS) is a widespread cell signaling network that maintains homeostasis in response to endogenous and exogenous stressors. This has made the ECS an attractive therapeutic target for various disease states. The ECS is a well-known target of exogenous phytocannabinoids derived from cannabis plants, the most well characterized being Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). However, the therapeutic efficacy of cannabis products comes with a risk of toxicity and high abuse potential due to the psychoactivity of THC. CBD, on the other hand, is reported to have beneficial medicinal properties including analgesic, neuroprotective, anxiolytic, anticonvulsant, and antipsychotic activities, while apparently lacking the toxicity of THC. Nevertheless, not only is the currently available scientific data concerning CBD’s efficacy insufficient, there is also ambiguity surrounding its regulatory status and safety in humans that brings inherent risks to manufacturers. There is a demand for alternative compounds combining similar effects with a robust safety profile and regulatory approval. Palmitoylethanolamide (PEA) is an endocannabinoid-like lipid mediator, primarily known for its anti-inflammatory, analgesic and neuroprotective properties. It appears to have a multi-modal mechanism of action, by primarily activating the nuclear receptor PPAR-α while also potentially working through the ECS, thus targeting similar pathways as CBD. With proven efficacy in several therapeutic areas, its safety and tolerability profile and the development of formulations that maximize its bioavailability, PEA is a promising alternative to CBD.
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This narrative review represents an output from the International Association for the Study of Pain's global task force on the use of cannabis, cannabinoids, and cannabis-based medicines (CBM) for pain management, informed by our companion systematic review and meta-analysis of preclinical studies in this area. Our aims in this review are: 1) to describe the value of studying cannabinoids and endogenous cannabinoid (endocannabinoid) system modulators in preclinical/animal models of pain; 2) to discuss both pain-related efficacy and additional pain-relevant effects (adverse and beneficial) of cannabinoids and endocannabinoid system modulators as they pertain to animal models of pathological or injury-related persistent pain; and 3) to identify important directions for future research. In service of these goals, this review a) provides an overview of the endocannabinoid system and the pharmacology of cannabinoids and endocannabinoid system modulators, with specific relevance to animal models of pathological or injury-related persistent pain; b) describes pharmacokinetics of cannabinoids in rodents and humans; and c) highlights differences and discrepancies between preclinical and clinical studies in this area. Preclinical (rodent) models have advanced our understanding of the underlying sites and mechanisms of action of cannabinoids and the endocannabinoid system in suppressing nociceptive signaling and behaviors. We conclude that substantial evidence from animal models supports the contention that cannabinoids and endocannabinoid system modulators hold considerable promise for analgesic drug development, although the challenge of translating this knowledge into clinically useful medicines is not to be underestimated.
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The number of lipophilic drug candidates in pharmaceutical discovery pipelines has increased in recent years. These drugs often possess physicochemical properties that result in poor oral bioavailability, and their clinical potential may be limited without adequate formulation strategies. Cannabidiol (CBD) is an excellent example of a highly lipophilic compound with poor oral bioavailability, due to low water solubility and extensive first-pass metabolism. An approach that may overcome these limitations is formulation of the drug in self-nanoemulsifying drug delivery systems (SNEDDS). Herein, CBD-SNEDDS formulations were prepared and evaluated in vitro. Promising formulations (F2, F4) were administered to healthy female Sprague-Dawley rats via oral gavage (20 mg/kg CBD). Resulting pharmacokinetic parameters of CBD were compared to those following administration of CBD in two oil-based formulations: a medium-chain triglyceride oil vehicle (MCT-CBD), and a sesame oil-based formulation similar in composition to an FDA-approved formulation of CBD, Epidiolex® (SO-CBD). Compared to MCT-CBD, administration of the SNEDDS formulations led to more rapid absorption of CBD (median Tmax values: 0.5 h (F2), 1 h (F4), 6 h (MCT-CBD)). Administration of F2 and F4 formulations also improved the systemic exposure to CBD by 2.2 and 2.8-fold compared to MCT-CBD; however, no improvement was found compared to SO-CBD.
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Modified starches can form hydrophobic conglomerates, which induce enzymatic degradation resistance. They have been used for compounds encapsulation because they prevent degradation by environmental and physiological factors. This study aimed to evaluate enzymatically acylated rice starch as a wall material for encapsulation and release and to evaluate the effect on the antioxidant activity of phenolic compounds of gulupa seeds (Passiflora edulis. f. edulis). Two entrapment methodologies (emulsion and aspersion) were evaluated. The capsules were characterized by their trapping efficiency, size, zeta potential, release parameters, and maintenance of the antioxidant activity in vitro. Trapping percentages greater than 40 and 90% were observed by emulsion and aspersion, respectively. The systems exhibited active release parameters in response to basic pH, showing a significant statistical differential behavior in the material, depending on the compound. The antioxidant activity was maintained for 8 months. The potential of the modified rice starch for the encapsulation was evaluated.
Article
The psychoactive and non-psychoactive constituents of cannabis, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), have synergistic analgesic efficacy in animal models of neuropathic pain when injected systemically. However, the relevance of this preclinical synergy to clinical neuropathic pain studies is unclear because many of the latter use oral administration. We therefore examined the oral effectiveness of these phytocannabinoids and their interactions in a mouse chronic constriction injury (CCI) model of neuropathic pain. THC produced a dose-dependent reduction in mechanical and cold allodynia, but also induced side-effects with similar potency. CBD also reduced allodynia, albeit with lower potency than THC, but did not produce cannabinoid-like side-effects at any dose tested. Combination THC:CBD produced a dose-dependent reduction in allodynia, however, it displayed little to no synergy. Combination THC:CBD produced substantial, synergistic side-effects which increased with the proportion of CBD. These findings demonstrate that oral THC and CBD, alone and in combination, have analgesic efficacy in an animal neuropathic pain model. Unlike prior systemic injection studies, combination THC:CBD lacks analgesic synergy when delivered orally. Furthermore, both THC and combination THC:CBD display a relatively poor therapeutic window when delivered orally. This suggests that CBD provides a safer, albeit lower efficacy, oral treatment for nerve injury induced neuropathic pain than THC-containing preparations. This article is part of the special issue on ‘Cannabinoids’.
Chapter
Over the past few years, considerable attention has focused on cannabidiol (CBD) and Δ⁹-tetrahydrocannabinol (THC), the two major constituents of Cannabis sativa, mainly due to the promising potential medical uses they have shown. However, more information on the fate of these cannabinoids in human subjects is still needed and there is limited research on the pharmacokinetic drug-drug interactions that can occur in the clinical setting and their prevalence. As the use of cannabinoids is substantially increasing for many indications and they are not the first-line therapy in any treatment, health care professionals must be aware of drug-drug interactions during their use as serious adverse events can happen related with toxic or ineffective outcomes. The present chapter overview summarizes our current knowledge on the pharmacokinetics and metabolic fate of CBD and THC in humans and discusses relevant drug-drug interactions, giving a plausible explanation to facilitate further research in the area.
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The cannabis plant has been widely researched for many therapeutic indications and found to be effective in many chronic conditions such as epilepsy, neuropathic or chronic pain and more. However, biased opinion against compounds of the plant, regulatory as well as compounding challenges have led to very few approved medicinal products. Those formulations which are approved are dosed several times a day, creating an unmet need for controlled release (CR) formulations of cannabinoids. Conventional CR formulations rely on prolonged absorption including the colon. The purpose of this work is to investigate regional absorption of major cannabinoids THC and CBD from the colon and develop a suitable CR formulation. As hypothesized by researchers, THC and CBD have poor absorption from the colon compared to small intestine, suggesting that these compounds have a narrow absorption window. The suggested formulation examined in-vitro was a floating gastro retentive tablet based on egg albumin matrix, gas generating agents and surfactants. In-vivo investigation of CBD containing formulation in the freely moving rat model proved a prolonged absorption phase with a substantial increase in bioavailability compared to CBD solution. The findings of this paper answer a crucial question regarding potential application of CR dosage forms for cannabinoids and shed light on the regional intestinal absorption of these compounds. Ultimately, these results cement the way for future development of cannabinoid gastro retentive dosage forms.
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Lipidic formulations (LFs) are increasingly utilized for the delivery of drugs that belong to class II of the Biopharmaceutics Classification System (BCS). The current work proposes, for the first time, the combination of in vitro lipolysis and microsomal metabolism studies for the quantitative prediction of human oral bioavailability of BCS II drugs administered in LFs. Marinol® and Neoral® were selected as model LFs and their observed oral bioavailabilities (Fobserved) obtained from published clinical studies in humans. Two separate lipolysis buffers, differing in the level of surfactant concentrations, were used for digestion of the LFs. The predicted fraction absorbed (Fabs) was calculated by measuring the drug concentration in the micellar phase after completion of the lipolysis process. To determine first-pass metabolism (Fg∙Fh), drug depletion studies with human microsomes were performed. Clearance values were determined by applying the “in vitro half-life approach”. The estimated Fabs and Fg∙Fh values were combined for the calculation of the predicted oral bioavailability (Fpredicted). Results showed that there was a strong correlation between Fobserved and Fpredicted values only when Fabs was calculated using a buffer with surfactant concentrations closer to physiological conditions. The general accuracy of the predicted values suggests that the novel in vitro lipolysis/metabolism approach could quantitatively predict the oral bioavailability of lipophilic drugs administered in LFs.
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There has been an escalating interest in the medicinal use of Cannabis sativa in recent years. Cannabis is often administered orally with fat-containing foods, or in lipid-based pharmaceutical preparations. However, the impact of lipids on the exposure of patients to cannabis components has not been explored. Therefore, the aim of this study is to elucidate the effect of oral co-administration of lipids on the exposure to two main active cannabinoids, ∆9-tetrahydrocannabinol (THC) and cannabidiol (CBD). In this study, oral co-administration of lipids enhanced the systemic exposure of rats to THC and CBD by 2.5-fold and 3-fold, respectively, compared to lipid-free formulations. In vitro lipolysis was conducted to explore the effect of lipids on the intestinal solubilisation of cannabinoids. More than 30% of THC and CBD were distributed into micellar fraction following lipolysis, suggesting that at least one-third of the administered dose will be available for absorption following co-administration with lipids. Both cannabinoids showed very high affinity for artificial CM-like particles, as well as for rat and human CM, suggesting high potential for intestinal lymphatic transport. Moreover, comparable affinity of cannabinoids for rat and human CM suggests that similar increased exposure effects may be expected in humans. In conclusion, co-administration of dietary lipids or pharmaceutical lipid excipients has the potential to substantially increase the exposure to orally administered cannabis and cannabis-based medicines. The increase in patient exposure to cannabinoids is of high clinical importance as it could affect the therapeutic effect, but also toxicity, of orally administered cannabis or cannabis-based medicines.
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Chronic neuropathic pain is often refractory to standard pharmacological treatments. Although growing evidence supports the use of inhaled cannabis for neuropathic pain, the lack of standard inhaled dosing plays a major obstacle in cannabis becoming a “main stream” pharmacological treatment for neuropathic pain. The objective of this study was to explore the pharmacokinetics, safety, tolerability, efficacy, and ease of use of a novel portable thermal-metered-dose inhaler (tMDI) for cannabis in a cohort of eight patients suffering from chronic neuropathic pain and on a stable analgesic regimen including medicinal cannabis. In a single-dose, open-label study, patients inhaled a single 15.1 ± 0.1 mg dose of cannabis using the Syqe Inhaler device. Blood samples for Δ9-tetrahydrocannabinol (THC) and 11-hydroxy-Δ9-THC were taken at baseline and up to 120 minutes. Pain intensity (0–10 VAS), adverse events, and satisfaction score were monitored following the inhalation. A uniform pharmacokinetic profile was exhibited across all participants (Δ9-THC plasma Cmax ± SD was 38 ± 10 ng/mL, Tmax ± SD was 3 ± 1 minutes, AUC0→infinity ± SD was 607 ± 200 ng·min/mL). Higher plasma Cmax increase per mg Δ9-THC administered (12.3 ng/mL/mg THC) and lower interindividual variability of Cmax (25.3%), compared with reported alternative modes of THC delivery, were measured. A significant 45% reduction in pain intensity was noted 20 minutes post inhalation (P = .001), turning back to baseline within 90 minutes. Tolerable, lightheadedness, lasting 15–30 minutes and requiring no intervention, was the only reported adverse event. This trial suggests the potential use of the Syqe Inhaler device as a smokeless delivery system of medicinal cannabis, producing a Δ9-THC pharmacokinetic profile with low interindividual variation of Cmax, achieving pharmaceutical standards for inhaled drugs.
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Recently, the use of herbal medicines has been increased all over the world due to their therapeutic effects and fewer adverse effects as compared to the modern medicines. However, many herbal drugs and herbal extracts despite of their impressive in-vitro findings demonstrates less or negligible in-vivo activity due to their poor lipid solubility or improper molecular size, resulting in poor absorption and hence poor bioavailability. Nowadays with the advancement in the technology, novel drug delivery systems open the door towards the development of enhancing bioavailability of herbal drug delivery systems. For last one decade many novel carriers such as liposomes, microspheres, nanoparticles, transferosomes, ethosomes, lipid based systems etc. have been reported for successful modified delivery of various herbal drugs. Many herbal compounds including quercetin, genistein, naringin, sinomenine, piperine, glycyrrhizin and nitrile glycoside have demonstrated capability to enhance the bioavailability. The objective of this review is to summarize various available novel drug delivery technologies which have been developed for delivery of drugs (herbal), and to achieve better therapeutic response. An attempt has also been made to compile a profile on bioavailability enhancers of herbal origin with the mechanism of action (wherever reported) and studies on improvement in drug bioavailability, exhibited particularly by natural compounds.
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1. Urine from a dystonic patient treated with cannabidiol (CBD) was examined by g.l.c.-mass spectrometry for CBD metabolites. Metabolites were identified as their trimethylsilyl (TMS), [2H9]TMS, and methyl ester/TMS derivatives and as the TMS derivatives of the product of lithium aluminium deuteride reduction. 2. Thirty-three metabolites were identified in addition to unmetabolized CBD, and a further four metabolites were partially characterized. 3. The major metabolic route was hydroxylation and oxidation at C-7 followed by further hydroxylation in the pentyl and propenyl groups to give 1"-, 2"-, 3"-, 4"- and 10-hydroxy derivatives of CBD-7-oic acid. Other metabolites, mainly acids, were formed by beta-oxidation and related biotransformations from the pentyl side-chain and these were also hydroxylated at C-6 or C-7. The major oxidized metabolite was CBD-7-oic acid containing a hydroxyethyl side-chain. 4. Two 8,9-dihydroxy compounds, presumably derived from the corresponding epoxide were identified. 5. Also present were several cyclized cannabinoids including delta-6- and delta-1-tetrahydrocannabinol and cannabinol. 6. This is the first metabolic study of CBD in humans; most observed metabolic routes were typical of those found for CBD and related cannabinoids in other species.
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A biopharmaceutics drug classification scheme for correlating in vitro drug product dissolution and in vivo bioavailability is proposed based on recognizing that drug dissolution and gastrointestinal permeability are the fundamental parameters controlling rate and extent of drug absorption. This analysis uses a transport model and human permeability results for estimating in vivo drug absorption to illustrate the primary importance of solubility and permeability on drug absorption. The fundamental parameters which define oral drug absorption in humans resulting from this analysis are discussed and used as a basis for this classification scheme. These Biopharmaceutic Drug Classes are defined as: Case 1. High solubility-high permeability drugs, Case 2. Low solubility-high permeability drugs, Case 3. High solubility-low permeability drugs, and Case 4. Low solubility-low permeability drugs. Based on this classification scheme, suggestions are made for setting standards for in vitro drug dissolution testing methodology which will correlate with the in vivo process. This methodology must be based on the physiological and physical chemical properties controlling drug absorption. This analysis points out conditions under which no in vitro-in vivo correlation may be expected e.g. rapidly dissolving low permeability drugs. Furthermore, it is suggested for example that for very rapidly dissolving high solubility drugs, e.g. 85% dissolution in less than 15 minutes, a simple one point dissolution test, is all that may be needed to insure bioavailability. For slowly dissolving drugs a dissolution profile is required with multiple time points in systems which would include low pH, physiological pH, and surfactants and the in vitro conditions should mimic the in vivo processes.(ABSTRACT TRUNCATED AT 250 WORDS)
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Dietary constituents (e.g., in grapefruit juice; NaCl) and phytochemicals (e.g., St. John's wort) are important agents modifying drug metabolism and transport and thereby contribute to interindividual variability in drug disposition. Most of these drug-food interactions are due to induction or inhibition of P-glycoprotein and/or CYP3A4. Preliminary data indicate that piperine, a major component of black pepper, inhibits drug-metabolizing enzymes in rodents and increases plasma concentrations of several drugs, including P-glycoprotein substrates (phenytoin and rifampin) in humans. However, there are no direct data whether piperine is an inhibitor of human P-glycoprotein and/or CYP3A4. We therefore investigated the influence of piperine on P-glycoprotein-mediated, polarized transport of digoxin and cyclosporine in monolayers of Caco-2 cells. Moreover, by using human liver microsomes we determined the effect of piperine on CYP3A4-mediated formation of the verapamil metabolites D-617 and norverapamil. Piperine inhibited digoxin and cyclosporine A transport in Caco-2 cells with IC(50) values of 15.5 and 74.1 microM, respectively. CYP3A4-catalyzed formation of D-617 and norverapamil was inhibited in a mixed fashion, with K(i) values of 36 +/- 8 (liver 1)/49 +/- 6 (liver 2) and 44 +/- 10 (liver 1)/77 +/- 10 microM (liver 2), respectively. In summary, we showed that piperine inhibits both the drug transporter P-glycoprotein and the major drug-metabolizing enzyme CYP3A4. Because both proteins are expressed in enterocytes and hepatocytes and contribute to a major extent to first-pass elimination of many drugs, our data indicate that dietary piperine could affect plasma concentrations of P-glycoprotein and CYP3A4 substrates in humans, in particular if these drugs are administered orally.
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Cyclosporin is a first line immunosuppressive drug used to prevent transplant rejection and to treat autoimmune diseases. It is a hydrophobic cyclic peptide built from nonmammalian amino acids with low oral bioavailability. The aim of this study was to develop an oral delivery system for cyclosporin A (CyA) and investigate the effect of composition and particle size of the CyA lipid nanoparticles (lipospheres) on the oral bioavailability of this drug. Dispersible concentrated oil formulations that upon mixing in water spontaneously form a nanodispersion were developed. The concentrated oil formulations were clear solutions composed of the drug, a solid triglyceride, a water miscible organic solvent, and a mixture of surfactants and emulsifiers. The activity of the formulated cyclosporin was determined in vitro following the effect on the proliferation of T cells. The oral bioavailability was determined on humans following the cyclosporin blood levels after oral intake of formulated cyclosporin. Cyclosporin dispersion systems resulting in particle size of 25 to 400 nm were prepared from acceptable pharmceutical components. The composition of the surfactants and emulsifiers, the lipid core component, and the amount and type of the water miscible organic solvent N-methylpyrrolidone (NMP) and alcohols had a strong effect on the particle size of the dispersions. All formulations were reproducible and stable at room temperature for at least 6 months, with full activity of cyclosporin retained. Human oral bioavaiability study indicated a correlation between the AUC and C(max) and the particle size of the dispersion. A C(max) of approximately 1300 ng/mL was found after 2 h of oral intake of four capsules, each loaded with 50 mg cyclosporin.
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(-)-Epigallocatechin-3-gallate (EGCG), from green tea (Camellia sinensis), has demonstrated chemopreventive activity in animal models of carcinogenesis. Previously, we reported the bioavailability of EGCG in rats (1.6%) and mice (26.5%). Here, we report that cotreatment with a second dietary component, piperine (from black pepper), enhanced the bioavailability of EGCG in mice. Intragastric coadministration of 163.8 micromol/kg EGCG and 70.2 micromol/kg piperine to male CF-1 mice increased the plasma C(max) and area under the curve (AUC) by 1.3-fold compared to mice treated with EGCG only. Piperine appeared to increase EGCG bioavailability by inhibiting glucuronidation and gastrointestinal transit. Piperine (100 micromol/L) inhibited EGCG glucuronidation in mouse small intestine (by 40%) but not in hepatic microsomes. Piperine (20 micromol/L) also inhibited production of EGCG-3"-glucuronide in human HT-29 colon adenocarcinoma cells. Small intestinal EGCG levels in CF-1 mice following treatment with EGCG alone had a C(max) = 37.50 +/- 22.50 nmol/g at 60 min that then decreased to 5.14 +/- 1.65 nmol/g at 90 min; however, cotreatment with piperine resulted in a C(max) = 31.60 +/- 15.08 nmol/g at 90 min, and levels were maintained above 20 nmol/g until 180 min. This resulted in a significant increase in the small intestine EGCG AUC (4621.80 +/- 1958.72 vs. 1686.50 +/- 757.07 (nmol/g.min)). EGCG appearance in the colon and the feces of piperine-cotreated mice was slower than in mice treated with EGCG alone. The present study demonstrates the modulation of the EGCG bioavailablity by a second dietary component and illustrates a mechanism for interactions between dietary chemicals.
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Curcuma species (Zingiberaceae) are used as both food and medicine in Asia. Ten sesquiterpenes (1-10) and two curcuminoids (11 and 12) were isolated from the rhizomes of Curcuma aromatica Salisb. and identified. The compounds were evaluated for their ability to inhibit cytochrome P450 (CYP). Among them, the sesquiterpene (4S,5S)-(+)-germacrone-4,5-epoxide (7) inhibited certain subtypes of CYP more potently than or at levels comparable to the curcuminoids curcumin (11) and demethoxycurcumin (12); 7 (IC(50) = 1.0 ± 0.2 μM) > 12 (IC(50) = 7.0 ± 1.7 μM) > 11 (IC(50) = 14.9 ± 1.4 μM) for CYP3A4 inhibition; 12 (IC(50) = 1.4 ± 0.2 μM) > 11 (IC(50) = 6.0 ± 1.4 μM) > 7 (IC(50) = 7.6 ± 2.5 μM) for CYP2C9 inhibition; and 7 (IC(50) = 33.2 ± 3.6 μM) = 12 (IC(50) = 34.0 ± 14.2 μM) > 11 (IC(50) > 100 μM) for CYP1A2 inhibition. These results suggest the possibility that Curcuma aromatica Salisb. may cause food-drug interactions via cytochrome P450 inhibition by sesquiterpene 7 and curcuminoids 11 and 12.
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The present study aimed to investigate the effect of piperine, a major component of black pepper, on the oral exposure of fexofenadine in rats. Pharmacokinetic parameters of fexofenadine were determined in rats following an oral (10 mg/kg) or intravenous (5 mg/kg) administration of fexofenadine in the presence and absence of piperine (10 or 20 mg/kg, given orally). Compared to the control group given fexofenadine alone, the combined use of piperine increased the oral exposure (AUC) of fexofenadine by 180% to 190% while there was no significant change in C(max) and T(1/2) of fexofenadine in rats. The bioavailability of fexofenadine was increased by approximately 2-folds via the concomitant use of piperine. Furthermore, T(max) tends to be increased which might be attributed to the delayed gastric emptying in the presence of piperine. In contrast, piperine did not alter the intravenous pharmacokinetics of fexofenadine, implying that piperine may increase mainly the gastrointestinal absorption of fexofenadine rather than reducing hepatic extraction. In conclusion, piperine significantly enhanced the oral exposure of fexofenadine in rats likely by the inhibition of P-glycoprotein-mediated cellular efflux during the intestinal absorption, suggesting that the combined use of piperine or piperine-containing diet with fexofenadine may require close monitoring for potential drug-diet interactions.
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Curcumin (diferuloylmethane) is a commonly used spice and nutritional supplement that has demonstrated potential anti-tumor and anti-inflammatory activity. There is limited information regarding curcumin metabolism and the potential for drug-drug interactions. The objective of this study was to characterize the hepatic metabolism of synthetic curcumin used in the liposomal curcumin formulation. High-throughput cytochrome P450 (CYP450) metabolism inhibition assays were conducted in vitro evaluating CYP450 3A4, 2C8, 2C9, and 2D6. An ex vivo model of cryopreserved human hepatocytes was used to evaluate the CYP450 metabolism induction potential of curcumin for CYP P450 3A4, 2C8/2C9, and 2D6. In the in vitro CYP450 inhibition studies, curcumin at any concentration did not inhibit CYP450 3A4 or CYP450 2D6 activity. At a curcumin concentration of 58.3 microM, 10.5% and 22.5% inhibition of CYP450 2C9 and CYP450 2C8 activity, respectively, was observed. In the ex vivo hepatocyte inductions studies, minimal to no induction of CYP450 3A4, CYP450 2C8/2C9 or CYP450 2D6 was observed. Rifampicin did not induce the metabolism of curcumin and curcumin did not induce its own metabolism. There is low potential for CYP450 mediated drug interactions at physiologic serum concentrations of liposomal curcumin. Based on preliminary data, liposomal curcumin will not interact with other chemotherapy agents that are metabolized and/or eliminated via the primary drug metabolizing CYP450 pathways.
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The present study aimed to assess the effect of resveratrol on the bioavailability of nicardipine in rats. Nicardipine was administered orally (12 mg kg(-1)) or intravenously (4 mg kg(-1)) with or without oral administration of resveratrol (0.5, 2.5 or 10 mg kg(-1)). The oral administration of 2.5 or 10 mg kg(-1) of resveratrol significantly increased both the area under the plasma concentration-time curve (AUC) (P < 0.01, 111-126%) and the peak plasma concentration (Cmax) (P < 0.01, 105-121%), and significantly decreased the total body clearance (CL/F) (P < 0.01, 52.8-55.8%) of orally administered nicardipine. In contrast, resveratrol did not significantly change the pharmacokinetic parameters of i.v. nicardipine. Resveratrol significantly reduced rhodamine123 efflux via P-gp in MCF-7/ADR cells overexpressing P-gp. Resveratrol also inhibits CYP3A4, suggesting that the enhanced oral bioavailability of nicardipine by resveratrol may result from decreased P-gp-mediated efflux or inhibition of intestinal CYP3A4 metabolism. Based on these results, nicardipine dosage should be adjusted when given with supplements containing resveratrol.
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