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Pharmaceutics
Special Issues
Therapeutic Cannabinoid Formulation Development and Delivery Systems
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Therapeutic Cannabinoid Formulation Development and Delivery Systems

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Biopharmaceutics".

Deadline for manuscript submissions: closed (20 September 2023) | Viewed by 21591

Special Issue Editor

Dr. Chulhun Park

E-Mail Website
Guest Editor
College of Pharmacy, Jeju National University, Jeju 63243, Republic of Korea
Interests: patient-centered drug development; fattigation platform; cannabinoid formulation development; solubilization; controlled release; improved bioavailability
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Therapeutic cannabinoids have been exclusively investigated for specific diseases such as chronic pain, cancer, epilepsy, or demystifying novel mechanisms of action related to the human endocannabinoid system. However, strict regulation and biased opinions against cannabis-derived compounds have hampered the research and development of medical cannabis.

Healthcare providers and pharmaceutical scientists are recently beginning to pay great attention to medical cannabis and its potential. The emerging advances in medical cannabis have led to the establishment of a department in the United States Food and Drug Administration (US FDA). Highly standardized medical cannabis is managed by addressing issues related to the extraction and formulation development process.

This Special Issue covers advanced cannabinoid delivery systems and the continual process development for the extraction and formulation of cannabinoids. Based on the therapeutic effects of cannabinoids, the future perspectives of medical cannabis could be provided considering the applicability to other indications.

Dr. Chulhun Park
Guest Editor

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Keywords

  • therapeutic cannabinoid
  • phytocannabinoids
  • cannabidiol
  • Δ9-tetrahydrocannabinol
  • cannabinoid delivery systems
  • lipid-based drug delivery
  • bioavailability

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Published Papers (7 papers)

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Research

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21 pages, 6058 KiB  
Article
Investigation of Cannabinoid Acid/Cyclodextrin Inclusion Complex for Improving Physicochemical and Biological Performance
by Chulhun Park, Jieyu Zuo, Myung-Chul Gil, Raimar Löbenberg and Beom-Jin Lee
Pharmaceutics 2023, 15(11), 2533; https://doi.org/10.3390/pharmaceutics15112533 - 26 Oct 2023
Cited by 3 | Viewed by 1879
Abstract
This study aimed to investigate the enhancement of cannabinoid acid solubility and stability through the formation of a cannabinoid acid/cyclodextrin (CD) inclusion complex. Two cannabinoid acids, tetrahydro-cannabinolic acid (THCA) and cannabidiolic acid (CBDA), were selected as a model drug along with five types [...] Read more.
This study aimed to investigate the enhancement of cannabinoid acid solubility and stability through the formation of a cannabinoid acid/cyclodextrin (CD) inclusion complex. Two cannabinoid acids, tetrahydro-cannabinolic acid (THCA) and cannabidiolic acid (CBDA), were selected as a model drug along with five types of CD: α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD), hydroxypropyl-β-cyclodextrin (HP-β-CD), and methylated-β-cyclodextrin (M-β-CD). Phase solubility studies were conducted using various types of CD to determine the complex stoichiometry. The preparation methods of the CD inclusion complex were optimized by adjusting the loading pH solution and the drying processes (spray-drying, freeze-drying, spray-freeze-drying). The drying process of the cannabinoid acid/M-β-CD inclusion complex was further optimized through the spray-freeze-drying method. These CD complexes were characterized using solubility determination, differential scanning calorimetry (DSC), field-emission scanning electron microscopy (FE-SEM), X-ray diffraction (XRD), and 1H NMR spectroscopy. DSC, XRD, and FE-SEM studies confirmed the non-crystalline state of the cannabinoid acid/CD inclusion complex. The permeation of THCA or CBDA from the M-β-CD spray-freeze-dried inclusion complex was highly improved compared to those of cannabis ethanolic extracts under simulated physiological conditions. The stability of the cannabinoid acid/M-β-CD inclusion complex was maintained for 7 days in a simulated physiological condition. Furthermore, the minimum inhibitory concentration of cannabinoid acid/M-β-CD inclusion complex had superior anti-cancer activity in MCF-7 breast cancer cell lines compared to cannabinoid acid alone. The improved physicochemical and biological performances indicated that these CD inclusion complexes could provide a promising option for loading lipophilic cannabinoids in cannabis-derived drug products. Full article
(This article belongs to the Special Issue Therapeutic Cannabinoid Formulation Development and Delivery Systems)
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16 pages, 2748 KiB  
Article
Chitosan-Coated Alginate Microcapsules of a Full-Spectrum Cannabis Extract: Characterization, Long-Term Stability and In Vitro Bioaccessibility
by Aitor Villate, Markel San Nicolas, Maitane Olivares, Oier Aizpurua-Olaizola and Aresatz Usobiaga
Pharmaceutics 2023, 15(3), 859; https://doi.org/10.3390/pharmaceutics15030859 - 7 Mar 2023
Cited by 6 | Viewed by 2658
Abstract
Cannabinoids present in Cannabis sativa are increasingly used in medicine due to their therapeutic potential. Moreover, the synergistic interaction between different cannabinoids and other plant constituents has led to the development of full-spectrum formulations for therapeutic treatments. In this work, the microencapsulation of [...] Read more.
Cannabinoids present in Cannabis sativa are increasingly used in medicine due to their therapeutic potential. Moreover, the synergistic interaction between different cannabinoids and other plant constituents has led to the development of full-spectrum formulations for therapeutic treatments. In this work, the microencapsulation of a full-spectrum extract via vibration microencapsulation nozzle technique using chitosan-coated alginate is proposed to obtain an edible pharmaceutical-grade product. The suitability of microcapsules was assessed by their physicochemical characterization, long-term stability in three different storage conditions and in vitro gastrointestinal release. The synthetized microcapsules contained mainly ∆9-tetrahydrocannabinol (THC)-type and cannabinol (CBN)-type cannabinoids and had a mean size of 460 ± 260 µm and a mean sphericity of 0.5 ± 0.3. The stability assays revealed that capsules should be stored only at 4 °C in darkness to maintain their cannabinoid profile. In addition, based on the in vitro experiments, a fast intestinal release of cannabinoids ensures a medium–high bioaccessibility (57–77%) of therapeutically relevant compounds. The full characterization of microcapsules indicates that they could be used for the design of further full-spectrum cannabis oral formulations. Full article
(This article belongs to the Special Issue Therapeutic Cannabinoid Formulation Development and Delivery Systems)
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17 pages, 3453 KiB  
Article
In Vitro Release, Mucosal Permeation and Deposition of Cannabidiol from Liquisolid Systems: The Influence of Liquid Vehicles
by Peera Tabboon, Thaned Pongjanyakul, Ekapol Limpongsa and Napaphak Jaipakdee
Pharmaceutics 2022, 14(9), 1787; https://doi.org/10.3390/pharmaceutics14091787 - 26 Aug 2022
Cited by 15 | Viewed by 2963
Abstract
This work investigated the influence of liquid vehicles on the release, mucosal permeation and deposition of cannabidiol (CBD) from liquisolid systems. Various vehicles, including EtOH, nonvolatile low- and semi-polar solvents, and liquid surfactants, were investigated. The CBD solution was converted into free-flowing powder [...] Read more.
This work investigated the influence of liquid vehicles on the release, mucosal permeation and deposition of cannabidiol (CBD) from liquisolid systems. Various vehicles, including EtOH, nonvolatile low- and semi-polar solvents, and liquid surfactants, were investigated. The CBD solution was converted into free-flowing powder using carrier (microcrystalline cellulose) and coating materials (colloidal silica). A physical mixture of the CBD and carrier–coating materials was prepared as a control. The non-crystalline state of CBD in the liquisolid systems was confirmed using XRD, FTIR and SEM studies. The CBD liquisolid powder prepared with volatile and nonvolatile solvents had a better CBD release performance than the CBD formed as the surfactant-based and control powders. The liquisolid systems provided the CBD permeation flux through porcine esophageal mucosa ranging from 0.68 ± 0.11 to 13.68 ± 0.74 µg·cm−2·h−1, with the CBD deposition levels of 0.74 ± 0.04 to 2.62 ± 0.30 μg/mg for the dry mucosa. Diethylene glycol monoethyl ether showed significant CBD permeation enhancement (2.1 folds) without an increase in mucosal deposition, while the surfactants retarded the permeation (6.7–9.0 folds) and deposition (1.5–3.2 folds) significantly. In conclusion, besides the drug release, liquid vehicles significantly influence mucosal permeation and deposition, either enhanced or suppressed, in liquisolid systems. Special attention must be paid to the selection and screening of suitable liquid vehicles for liquisolid systems designed for transmucosal applications. Full article
(This article belongs to the Special Issue Therapeutic Cannabinoid Formulation Development and Delivery Systems)
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19 pages, 1847 KiB  
Article
Mucosal Delivery of Cannabidiol: Influence of Vehicles and Enhancers
by Peera Tabboon, Thaned Pongjanyakul, Ekapol Limpongsa and Napaphak Jaipakdee
Pharmaceutics 2022, 14(8), 1687; https://doi.org/10.3390/pharmaceutics14081687 - 13 Aug 2022
Cited by 6 | Viewed by 2575
Abstract
In this study, the mucosal permeation and deposition of cannabidiol (CBD) with neat and binary vehicles were investigated. Permeation experiments were performed using static diffusion cells coupled with fresh porcine esophageal mucosa. The CBD–vehicle solutions were applied at a fixed dose (~5 mg/cm [...] Read more.
In this study, the mucosal permeation and deposition of cannabidiol (CBD) with neat and binary vehicles were investigated. Permeation experiments were performed using static diffusion cells coupled with fresh porcine esophageal mucosa. The CBD–vehicle solutions were applied at a fixed dose (~5 mg/cm2), and the corresponding permeation parameters were calculated. In neat vehicles, the permeation flux (Jss) ranged from 0.89 ± 0.15 to 179.81 ± 23.46 µg·cm−2·h−1, while the CBD deposition ranged from 11.5 ± 1.8 to 538.3 ± 105.3 μg·cm−2. Propylene glycol (PG) and diethylene glycol monoethyl ether (DEGEE) yielded the highest permeability (Ps) and CBD deposition, while medium-chain triglycerides (MCT) yielded the lowest Ps and deposition. This was due to the difference in apparent partition coefficient (K), which is related to the solubility of CBD in the vehicle. The PG:DEGEE binary vehicle boosted Jss (1.5–1.6 fold) and deposition (2.0–2.7 folds) significantly, compared to neat DEGEE. The combination of DEGEE with MCT dramatically enhanced Jss (11–44 fold) and deposition (1.6–4.7 fold). The addition of lipophilic enhancers, laurocapram, and oleic acid, to PG:DEGEE and DEGEE:MCT vehicles significantly reduced Jss (0.3–0.7 fold) and deposition (0.4–0.8 fold) while nerolidol had no effect. These permeation reductions were found to be related to modification of the K and/or diffusivity values. This study provides useful basic information for the development of CBD formulations intended for transmucosal delivery. Full article
(This article belongs to the Special Issue Therapeutic Cannabinoid Formulation Development and Delivery Systems)
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18 pages, 1149 KiB  
Article
Cannabidiol Reduces Short- and Long-Term High Glutamate Release after Severe Traumatic Brain Injury and Improves Functional Recovery
by Cindy Santiago-Castañeda, Saúl Huerta de la Cruz, Christopher Martínez-Aguirre, Sandra Adela Orozco-Suárez and Luisa Rocha
Pharmaceutics 2022, 14(8), 1609; https://doi.org/10.3390/pharmaceutics14081609 - 2 Aug 2022
Cited by 13 | Viewed by 3002
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Therapeutic Cannabinoid Formulation Development and Delivery Systems)
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Review

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29 pages, 3619 KiB  
Review
Cannabinoid-Based Ocular Therapies and Formulations
by Sofia M. Saraiva, Lucía Martín-Banderas and Matilde Durán-Lobato
Pharmaceutics 2023, 15(4), 1077; https://doi.org/10.3390/pharmaceutics15041077 - 27 Mar 2023
Cited by 4 | Viewed by 3073
Abstract
The interest in the pharmacological applications of cannabinoids is largely increasing in a wide range of medical areas. Recently, research on its potential role in eye conditions, many of which are chronic and/or disabling and in need of new alternative treatments, has intensified. [...] Read more.
The interest in the pharmacological applications of cannabinoids is largely increasing in a wide range of medical areas. Recently, research on its potential role in eye conditions, many of which are chronic and/or disabling and in need of new alternative treatments, has intensified. However, due to cannabinoids’ unfavorable physicochemical properties and adverse systemic effects, along with ocular biological barriers to local drug administration, drug delivery systems are needed. Hence, this review focused on the following: (i) identifying eye disease conditions potentially subject to treatment with cannabinoids and their pharmacological role, with emphasis on glaucoma, uveitis, diabetic retinopathy, keratitis and the prevention of Pseudomonas aeruginosa infections; (ii) reviewing the physicochemical properties of formulations that must be controlled and/or optimized for successful ocular administration; (iii) analyzing works evaluating cannabinoid-based formulations for ocular administration, with emphasis on results and limitations; and (iv) identifying alternative cannabinoid-based formulations that could potentially be useful for ocular administration strategies. Finally, an overview of the current advances and limitations in the field, the technological challenges to overcome and the prospective further developments, is provided. Full article
(This article belongs to the Special Issue Therapeutic Cannabinoid Formulation Development and Delivery Systems)
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Other

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14 pages, 674 KiB  
Systematic Review
Adverse Effects of Oral Cannabidiol: An Updated Systematic Review of Randomized Controlled Trials (2020–2022)
by José Diogo R. Souza, Julia Cozar Pacheco, Giordano Novak Rossi, Bruno O. de-Paulo, Antonio W. Zuardi, Francisco S. Guimarães, Jaime E. C. Hallak, José Alexandre Crippa and Rafael G. Dos Santos
Pharmaceutics 2022, 14(12), 2598; https://doi.org/10.3390/pharmaceutics14122598 - 25 Nov 2022
Cited by 29 | Viewed by 4444
Abstract
(1) Background: With the massive demand for the use and commercialization of medicinal cannabidiol (CBD) products, new randomized clinical trials (RCTs) are being published worldwide, with a constant need for safety and efficacy evaluation. (2) Methods: We performed an update on a systematic [...] Read more.
(1) Background: With the massive demand for the use and commercialization of medicinal cannabidiol (CBD) products, new randomized clinical trials (RCTs) are being published worldwide, with a constant need for safety and efficacy evaluation. (2) Methods: We performed an update on a systematic review published in 2020 that focused on analyzing the serious adverse effects (SAEs) of CBD in RCTs and its possible association with drug interactions. We also updated the report of the most prevalent CBD adverse effects (AEs). We systematically searched EMBASE, MEDLINE/PubMed, and Web of Science without language restriction for RCTs that reported adverse effects after repeated oral CBD administration for at least one week in healthy volunteers or clinical samples published from January 2019 to May 2022. The included studies were assessed for methodological quality by the Quality Assessment of Controlled Intervention Studies tool. The present review is registered on PROSPERO, number CRD42022334399. (3) Results: Twelve studies involving 745 randomized subjects analyzed were included (range 1.1–56.8 y). A total of 454 participants used CBD in the trials. The most common AEs of CBD were mild or moderate and included gastrointestinal symptoms (59.5%), somnolence (16.7%), loss of appetite (16.5%), and hypertransaminasemia (ALT/AST) (12.8%). Serious adverse effects include mainly hypertransaminasemia with serum levels elevations greater than three times the upper limit of the normal (6.4%), seizures (1.3%), and rash (1.1%). All SAEs reported in the studies were observed on CBD as an add-on therapy to anticonvulsant medications, including clobazam and valproate. (4) Conclusion: Recent RCTs involving oral CBD administration for at least a week suggest that CBD has a good safety and tolerability profile, confirming previous data. However, it can potentially interact with other drugs and its use should be monitored, especially at the beginning of treatment. Full article
(This article belongs to the Special Issue Therapeutic Cannabinoid Formulation Development and Delivery Systems)
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