How Biodegradable Polymers Can be Effective Drug Delivery Systems for Cannabinoids? Prospectives and Challenges

Abstract

Graphical Abstract

Introduction

Cannabinoids are obtained from plants belonging to the genus Cannabis, Cannabaceae family. Cannabis, particularly Cannabis sativa, has been known for its therapeutic and psychotomimetic applications for over 6000 years. Every Cannabis sativa plant produces active compounds, but the levels and proportions of these compounds vary among different varieties. These variations cannot be attributed solely to genetic makeup, as environmental factors such as climate and growing conditions may also influence them. Therefore, it is more accurate to refer to these variables as chemical varieties or chemovars, instead of strains.¹ The main active components present in Cannabis sativa comprise ∆⁹-tetrahydrocannabinol ((6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol) (THC) and cannabidiol (2-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol) (CBD).²

The mechanism of action of cannabinoids is dependent on their interaction with two cannabinoid receptors known as CB1 and CB2, which are found throughout the central and peripheral nervous systems. They are present in axons, dendrites, and cell bodies, and they influence neuronal, glial, and microglial activity.³ When these receptors are activated, they inhibit adenylyl cyclase production causing hyperpolarization of neurons, which stops the transmission of electric impulses. CB1 and CB2 receptors are highly concentrated in the hippocampal formation and olfactory bulb, where they impact memory, cognition, smell, and pain perception.⁴ Additionally, CB1 receptors can be found in the dorsal horn of the spinal cord and on afferent A-β and A-ẟ fibers, suggesting their potential as analgesics for nerve damage.⁵ CB2 receptors, on the other hand, are unique as their presence is not solely limited to the nervous system and can be found on immune cells, macrophages, and solid tumor tissues, indicating their potential anti-cancer activity.^6–8 Furthermore, the activation of CB1 receptors in the brain via THC is responsible for the mind-altering effects of Cannabis sativa, whereas CBD has no psychoactive effects.⁹

Medicinal Cannabis refers to the use of Cannabis or cannabinoids with an intention to treat a disease or alleviate some of its symptoms. There are several ways, in which cannabinoids can be administered to a patient.¹⁰ Smoking is the most widespread form of Cannabis consumption, yet it is not accepted for therapeutic purposes, due to health hazards evoked by pyrolytic by-products.² Cannabinoids can be administered orally, sublingually, and topically, they can be vaporized and inhaled or even mixed into food.^10–12 For instance, CBD inhalation and intranasal administration provides a rapid rise of the drug’s concentration in the plasma, thus reaching the brain faster. On the other hand, transdermal route of CBD administration delivers the drug systemically in a slower manner, gradually over time.¹³ Prescribed cannabinoids include the oromucosal spray nabiximols (Cannabis-based extract with CBD:THC in a 1:1 ratio) and capsules with the synthetic analogue of THC – dronabinol or nabilone.^10–12

Cannabinoids’ beneficial features have given them a new therapeutic meaning in the treatment of a wide range of conditions. These include multiple sclerosis (MS), epilepsy, post-traumatic stress disorder (PTSD), anxiety, cancer, and, most critically, chronic pain.¹⁴ Furthermore, Cannabis sativa-based products have gained significant popularity and attention in the areas of cosmetology and dermatology. CBD, in particular, has caught the attention of scientists due to its multiple therapeutic characteristics, including anti-inflammatory and antioxidant properties. Furthermore, CBD has a noteworthy therapeutic potential in the treatment of skin disorders such as atopic dermatitis, pruritus, psoriasis, and acne.¹⁵

Despite the various healing benefits that cannabinoids offer, their effectiveness in therapy is significantly limited due to their physical and chemical properties, such as their low solubility in water and instability. Studies performed by Fairbairn et al in 1976 and Pacifici et al in 2018 demonstrated that cannabinoids can undergo degradation when exposed to heat, light, or long-term storage, which can affect their potency.^16,17 According to the study conducted by Drooge et al, THC undergoes rapid degradation within a few hours of exposure to air, and this process is accelerated at higher temperatures.¹⁸ The Biopharmaceutics Classification System (BCS) classifies cannabinoids such as THC and CBD as drugs with high lipophilicity (logP of around 6.3 and 6.97 respectively) and low water solubility (12.6 and 28.0 mg/L respectively). Additionally, the pK_a values of THC and CBD are 9.29 and 10.6, respectively.^19–21

The inconsistent and unreliable absorption patterns observed with cannabinoids can be attributed to their physicochemical properties. When taken orally, THC-based medications have a lower bioavailability rate (between 6% and 10%) due to their instability in the acidic environment of the stomach. Additionally, they are heavily metabolized by the CYP450 enzymes in the liver (specifically, CYP3A4 and CYP2C9) into an equally potent metabolite called 11-OH THC, which is then further metabolized into the inactive THC-COOH form.²² According to the reports, the absorption of THC is limited by the excretion of P-glycoprotein (P-gp) from the enterocytes.²³ Like THC, CBD also exhibits low oral bioavailability in humans, typically falling in the range of 9% to 13%. This is owing to its low solubility in water and extensive initial metabolism by CYP enzymes (specifically, CYP3A4 and CYP2C19) into a 7-OH metabolite, which results in the loss of roughly 75% of the drug that enters systemic circulation.^24,25 The inhalation of cannabinoids through smoking has been found to have the highest bioavailability, ranging from 2% to 56%. The reason for this is that smoking enables swift and effective delivery of drugs to the brain via the lungs and bloodstream. Likewise, the use of smoking for medicinal purposes cannot be endorsed because it poses health risks from the combustion by-products produced.² Given the limitations of cannabinoids, innovative drug delivery strategies that protect these compounds from oxidation, while increasing their potency and bioavailability, are required.²⁶

What Do We Know About Clinically Important Cannabinoids?

In recent years, the scientific community has exhibited a growing interest in investigating Cannabis’ possible therapeutic applications. Many researchers have presented encouraging results from preclinical and clinical studies, indicating that cannabinoids have the potential to treat a wide range of conditions, including pain, cancer, neurological, and psychiatric illnesses. Considering cannabinoids’ pharmacological targets are not only limited to CB1 and CB2 receptors, their physiological activities and potential therapeutic applications are still being investigated and expanded.²⁷

In the subsequent sections of this review, the therapeutic potential of cannabinoids in the treatment of various disorders will be addressed.

What are Drug Delivery Systems?

The term “drug delivery systems” (DDSs) refers to a wide range of carriers designed to improve the selectivity of action and the pharmacodynamic and pharmacokinetic properties of the drug. The vast majority of drugs currently in use are low molecular weight compounds. They are distinguished by rapid metabolism and excretion from the human body, as well as low selectivity of pharmacodynamic properties, necessitating the search for formulations capable of overcoming the aforementioned challenges.¹⁷⁰ Furthermore, DDSs allow the modification of drug properties by increasing solubility, preventing the drug from being transformed into an inactive form, resulting in a beneficial modification of pharmacokinetics and biodistribution parameters.¹⁷¹ The matrix material used as a carrier for the active substance must meet a number of criteria, including nontoxicity, biocompatibility, non-immunogenicity, and lack of accumulation in the body.¹⁷⁰ Furthermore, the size, surface character, drug bonding type, and presence of functional groups on the surface all play important roles in DDSs action.¹⁷²

Due to the type of connection between the polymer carrier and the active substance, two types of DDSs may be distinguished; namely those obtained by the physical incorporation/absorption of the drug and the systems obtained by conjugation of the drug to the carrier. The concept of the drug-polymer carrier conjugates was proposed by Helmut Ringsdorf in 1975. The Ringsdorf’s model included a framework made of a biocompatible polymer combined with a solubility-modifying group, a labelling element (antibody or another tropic group) ensuring transport to the target site of action, and a drug (Figure 2).¹⁷³

The type of bonding between the polymer carrier and the drug is a critical parameter for the controlled drug release characteristic, as it determines conjugates’ susceptibility to hydrolytic and enzymatic degradation.¹⁷⁴

It is worthwhile to mention the DDSs obtained through physical incorporation/adsorption carriers such as micelles, NPs and liposomes. Polymeric micelles (PMs) (Figure 3) are spherical, colloidal nanosystems that spontaneously form in aqueous solutions when the critical micelle concentration (CMC) of amphiphilic block copolymers is exceeded.¹⁷⁵ In PMs, the hydrophilic part of the copolymer faces outwards, while the lipophilic (hydrophobic) part forms the core. Conversely, in reverse micelles, the lipophilic part is directed outwards, while the hydrophilic component faces the core.¹⁷⁶

PMs are a promising group of carriers, particularly in the field of oncology. In preclinical studies, PMs demonstrated significant potential as a vehicle for lipophilic drugs and small molecules in cancer treatment, as well as in tumor imaging.¹⁷⁸ The physicochemical properties of PMs primarily depend on the type of used polymer together with the sizes of their hydrophilic and lipophilic blocks. In PMs, the drug can be bonded to the core via electrostatic interactions with a lipophilic drug molecule or it can be covalently bonded to the polymer chains. The perfect PM should possess an excellent drug loading capacity, precise control over drug release, and exhibit biocompatibility and stability.¹⁴

One of the most prominent DDSs are NPs. Similarly to the PMs, these are also spherical, colloidal structures with at least one dimension below 100 nm.¹⁷⁹ Due to the mechanism of drug encapsulation, two types of carriers among NPs may be distinguished – nanospheres and nanocapsules. Nanospheres are matrix structures, in which the active substance is evenly dispersed (Figure 4A), while nanocapsules are systems, in which the active substance is enclosed in a polymeric shell (Figure 4B).¹⁸⁰

Various physical interactions such as absorption, adsorption, as well as chemical bonding including covalent, ionic and van der Waals forces, are employed to associate the active substance with NPs.¹⁸²

Polymeric NPs have the ability to regulate drug release, protect the drug from adverse conditions, control bioavailability, and improve therapeutic efficacy, making them promising carriers for a variety of drugs.¹⁸³ Furthermore, surface modification of NPs enables precise drug targeting to specific sites, while avoiding interactions with blood morphotic elements. This modification can be achieved by attaching monoclonal antibodies, antigens or other ligands capable of influencing specific receptors.¹⁸⁴

One of the most popular methods of surface functionalization of NPs is PEGylation. PEGylation was first described in 1977 when Abuchowski et al described the covalent association of polyethylene glycol (PEG) with bovine serum albumin. This combination reduced the immunogenicity of the protein and established the basis for enzyme therapy, which is often associated with severe side effects.¹⁸⁵ Furthermore, Abuchowski and colleagues found that while using bovine liver catalase covalently bound to PEG, the obtained complexes had a longer residence time in the blood (without a significant reduction in enzyme activity) than self-administered catalase.¹⁸⁶

Until now, many active substances and carriers modified with PEG have been described in the literature, including proteins, peptides, enzymes, antibodies, and NPs. PEGylation improves the drug solubility and protects them from enzymatic degradation and antibody recognition. Furthermore, it reduces renal elimination and extends the drugs’ residence time in the body.¹⁸⁷

Last but not least, liposomes are considered very promising carriers for pharmaceutical purposes. Due to their exceptional characteristics that encompass prolonging the half-life of the active substance, exerting control over drug release kinetics, safeguarding the encapsulated molecules against physiological degradation as well as demonstrating excellent biocompatibility.^188,189 Additionally, liposomes express the capability of selective transport to the target site via active and/or passive targeting strategies, thereby diminishing systemic side effects, enhancing the maximal tolerated dose and in consequence augmenting the therapeutic advantages.¹⁹⁰

Liposomes, initially identified by a British researcher Alec D. Bangham in the 1960s at the University of Cambridge, are comprised of one or multiple lipid bilayers that encapsulate the hydrophilic core (Figure 5). Originally constituted solely of natural lipids, liposomes nowadays encompass a combination of natural or/and synthetic lipids and surfactants.¹⁹¹ The lipophilic (hydrophobic) coating may be neutral in nature or contain modifying elements in the structure, ensuring specific targeting.¹⁹² The functionalization of liposomes can occur as a result of PEGylation, attachment of antibodies, peptides or aptamers.¹⁹³

Despite various aforementioned benefits that liposomes offer as DDSs, they also possess three crucial drawbacks – instability, high potential of accumulation in the spleen and liver, and finally slow drug release.¹⁹⁴ Numerous techniques can be applied to enhance the stability of liposomes including modification of liposomal membrane, implementation of protective coating and utilization of surfactants. Furthermore, with the use of biodegradable polymers as surface coatings for liposomes it is possible to achieve enhanced delivery and release of the drugs, decreased oxygen exposure, thereby higher stability, and consequently, prolonged circulation time.¹⁹⁵

Recently, the primary application of polymers has been directed to the development of highly advanced DDSs, where polymers serve as carriers for various active substances. Biodegradable polymers, in particular, are highly appealing for the DDSs advancement due to their ability to decompose naturally within the human body. This distinguishing feature eliminates the need for their removal or any additional procedures once they have been introduced. Furthermore, biodegradable polymers provide the opportunity to create novel DDSs with highly specialized properties (physical, chemical, and biological) through simple structural or preparation method modifications.¹⁹⁶ At this point, it is worthwhile to start addressing the most common biodegradable polymers used in the development of the DDSs.

What is the Role of Biodegradable Polymers in the Development of Drug Delivery Systems?

Polymers are commonly divided into three categories: synthetic, semi-synthetic and natural (also known as biopolymers). Biopolymers can be further classified into those of plant and animal origin. Notable examples of biopolymers derived from plants include cellulose (which serves as the fundamental building block of plant cell walls) and alginic acid (a gelling agent found in species of red algae such as Gelidium amansii). Biopolymers originating from animals include inter alia chitosan, which acts as the primary component of Invertebrate bone tissue.¹⁹⁷ All quoted biopolymers belong to the group of polysaccharides, which is one of the most widespread groups of natural polymers. Due to the fact that they expose noteworthy physicochemical and physiological properties, such as biodegradability and biocompatibility and, thus can be utilized in the development of novel DDSs, they are worthwhile meticulous characterization.¹⁹⁸

Cellulose is a natural polymer found abundantly in nature and is composed of repeating glucose units. It is the most prevalent organic material and polysaccharide on Earth. Cellulose is commonly found in the form of microfibrils in wood and plant cell walls, algae tissues, and the epidermal cell membranes of tunicates.¹⁹⁹ Bacteria can also produce cellulose in the form of nanofiber networks. Cellulosic materials exhibit a hierarchical structure that spans from the nanoscale to macroscopic dimensions, including fibril aggregates, fibrils, nanocrystallites, and nanoscale-disordered domains.²⁰⁰ Cellulose has a complex multi-level structure consisting of bundles or aggregates of superfine fibrils. Each superfine fibril contains multiple cellulose chains. The fibril itself is comprised of both large crystalline domains and small disordered, amorphous domains. The cross-sectional dimension of the fibril ranges from 2 to 20 nm, depending on the synthesis source. Within a cellulose fibril, a single cellulose chain passes through numerous crystalline and disordered domains, connected by strong β(1-4)-glycosidic bonds. The crystalline domain of a cellulose fibril exhibits an impressive alignment of cellulose chains.²⁰¹

Due to its physical and mechanical properties, cellulose and its derivatives have garnered significant attention for biomedical applications as biocompatible polymers. Cellulose naturally demonstrates functionality, flexibility, and high specific strength due to its hierarchical structure. Additionally, it offers advantages such as low density, affordability, and biodegradability. These cellulose-based materials allow for the manipulation of porosity and interconnectivity, which are desirable in various biomedical applications. However, cellulose has some disadvantages for biomedical applications, such as moisture sensitivity, insolubility in water and common solvents, and low resistance to microbial attack. Nonetheless, this compound can be chemically modified by substituting its native hydroxyl groups with other functional groups like acids, chlorides, and oxides. This modification addresses the less desirable properties of cellulose or creates new desired characteristics.²⁰²

Another natural polymer widely used in biomedical applications is an alginate. This compound belongs to the heteropolysaccharides and is composed of 1,4 linked β-D-mannuronic acid (M residue) and 1.4 linked α-L-guluronic acid (G residue). It naturally occurs in the cell walls of Phaeophyceae sp., providing resilience and elasticity.²⁰³ Alginate possesses the unique property of forming hydrogel, which makes it an excellent thickener, stabilizer, emulsifier and gelling agent.²⁰⁴ Depending on the content of G and M residues in the alginate molecule, obtained hydrogel may be respectively stiffer (at higher content of G residues) or softer.²⁰⁵ Generally, alginate is considered to be non-toxic, non-immunogenic and biocompatible, however, molecules with a higher content of M residues may cause an immune response.²⁰⁶

One of the first biomedical applications of alginate involved dressing materials, which prevent wound drying by providing a moist environment, resulting in faster healing. At the same time, alginate dressings improve patient comfort by reducing pain during dressing changes.²⁰⁷ In recent years alginate has gained importance in the scientific community due to its capability to appear in different forms. Through easy modifications, it can form microspheres, microcapsules, hydrogels, fibers and foams. This versatile characteristic expands the potential biomedical applications of alginate in fields like drug delivery and tissue engineering.²⁰⁸ To achieve specific desired properties and functions such as cell compatibility, gelation capability and appropriate mechanical strength, various chemical and physical modifications can be applied.²⁰⁹

The final natural polymer worth mentioning is chitosan (CS). CS is a plentiful biopolymer sourced from natural chitin, which is widely found in the exoskeletons of arthropods, insects, crustacean shells and fungal cell walls.¹⁹⁸ In terms of its structure, CS is a polysaccharide that contains native amine groups, which possess a positive charge. It is composed of D-glucosamine and N-acetyl-D-glucosamine, that are randomly distributed in the chain via β-(1→4) linkages. The presence of D-glucosamine is responsible for conferring its cationic nature at physiological pH.²¹⁰

CS belongs to the group of biodegradable and biocompatible polymers. In the human body, it can be degraded by endogenous enzymes, such as chitosanases and lysozymes, into smaller molecules such as oligosaccharides and monosaccharides, which can be further absorbed by the organism. Moreover, CS demonstrates antibacterial properties, as well as mucoadhesion, film formation capacity and lack of toxicity.^211,212 Regardless of its exceptional biological and physicochemical features, its use in biomedical applications is highly limited due to poor solubility and weak mechanical properties.²¹⁰ Nevertheless, several strategies have been devised in order to overcome these limitations by modifying the CS structure. The presence of free amino and hydroxyl groups has been exploited to create diverse CS derivatives, which exhibited enhanced water solubility.^213,214 Consequently, CS has found widespread application in numerous pharmaceutical purposes, including controlled drug delivery, tissue engineering and creating novel cosmetic commodities.²¹⁰

Furthermore, CS has gained significant attention as a coating material for NPs, liposomes and other DDSs. The main advantages of CS-coating include improvement of physicochemical stability, controlled drug release, increased mucoadhesion, increased cellular uptake and improvement of antimicrobial features.²¹²

To summarize, the main advantages of natural polymers are their biocompatibility, lack of toxic effects, safety, low cost, and widespread availability. Unfortunately, natural polymers are also characterized by extremely high volatility, the possibility of heavy metal contamination, and microbiological contamination.²¹⁵

As a result, synthetic biodegradable polyesters are a unique class of polymers that exhibit no cytotoxic, immunologic, systemic, cardiogenic, or teratogenic effects when used in vivo. Their characteristics are intricately linked to their chemical composition, morphology, and an average molecular weight (M_n). By judiciously choosing these parameters, it is possible to create a drug carrier based on biodegradable polyester with distinct structural, microstructural and physicochemical properties. This group comprises polymers such as polylactide (PLA), poly(ε-caprolactone) (PCL), polyglycolide (PGA) or lactide (LA), ε-caprolactone (ε-CL) and glycolide copolymers.^216,217

The most widely used biodegradable polyesters are poly(lactic acid) and PLA. These polymers are composed of the same repeating units, however, they are obtained through different chemical reactions. Poly(lactic acid) is synthesized via direct polycondensation of lactic acid, while PLA is obtained through the Ring-Opening Polymerization (ROP) of a cyclic dimer of lactic acid (so-called lactide).²¹⁸

Currently, PLA has gained popularity in the production of biomedical materials and disposable goods such as food packaging. PLA consists of two enantiomeric polymers, poly(D-lactide) (PDLA) and poly(L-lactide) (PLLA), which can form stereocomplex crystals.²¹⁹

PLLA belongs to the group of compounds that have been approved by the FDA.²²⁰ Its use in biomedical applications has risen due to its biocompatibility and biodegradability. Both in vitro and in vivo, PLLA undergoes hydrolytic degradation, which results in the formation of lactic acid and its short oligomers as by-products. The degradation products of PLLA can later be integrated into Krebs’s cycle and be eliminated as carbon dioxide and water.²²¹

Another biodegradable polymer worth mentioning is PCL, which is a semi-crystalline, linear aliphatic polyester obtained by ROP of ε-CL. PCL possesses a low melting point (T_m = 59–64°C) and glass transition temperature (T_g around −60°C), which both contribute to its favorable plastic properties.²²²

Compared to other aliphatic polyesters, PCL exhibits relatively higher elasticity, with Young’s modulus of 0.4–0.6 GPa (more than two times lower than that of PLA).^222,223 As a result, PCL has inferior mechanical properties, which is why it is very often modified by copolymerization with other monomers. PCL is a stable polyester that takes approximately 2 to 4 years to degrade, making it one of the slowest degrading biodegradable polyesters. Its resistance to hydrolytic degradation can be attributed to the presence of repetitive CH₂ groups within structural units, which delays the degradation process unless exposed to long-term conditions favoring hydrolysis.²²⁴ In the human body, PCL is hydrolyzed to 6-hydroxycaproic acid, which can be further metabolized through the citric acid cycle and eliminated. Due to its properties, PCL has been used in the design of various DDSs and medical products such as sutures, subcutaneous contraceptive implants, dressings and materials for filling root canal cavities in dentistry.²²⁵

Last but not least, PGA is another important biodegradable polymer obtained also by ROP. It is a thermoplastic, semi-crystalline polyester characterized by a low glass transition temperature (Tg ~ 40°C) and a relatively high melting point (T_m ~ 230°C).²²² PGA exhibits good mechanical properties, also it is both biodegradable and biocompatible. Its hydrolytic degradation occurs within 6 weeks. Unfortunately, due to its high price, PGA has been a material less frequently used than PLA and PCL. Furthermore, its highly crystalline structure makes it very poorly soluble in popular organic solvents.²²⁶ Nevertheless, PGA still remains one of the most promising biodegradable polyesters, therefore being a point of interest for many researchers involved in the design of innovative DDSs.¹⁹⁶

In order to obtain biodegradable materials with specific structural, amphiphilic, mechanical or physicochemical properties, copolymers prove to be useful. By varying the molar ratios of the monomers used, it is possible to obtain a copolymer carrier with the desired specification utile for biomedical applications.²²⁷

One of the most important biodegradable copolymers, which has been approved both by the FDA and the European Medicines Agency (EMA), is poly(lactide-co-glycolide) (PLGA).²²⁸ In an aqueous environment, PLGA is degraded by the hydrolysis of ester bonds, resulting in the formation of lactic and glycolic acids, which can later be incorporated into Krebs’s cycle. This fact makes PLGA both a biocompatible and non-toxic copolymer.¹²⁷ Furthermore, the properties of PLGA are closely related to the ratio of lactide to glycolide units in the copolymer chain, its M_n and chain microstructure. All these factors can affect the degradation profile of PLGA, thus its potential for use in the development of DDSs.²²⁹

Another biodegradable copolymer worth mentioning is poly(lactide-co-ε-caprolactone) (PLACL). PLACL combines the mechanical properties of PCL with the rapid degradation of PLA.¹²⁷ These factors make PLACL widely used in the design of membranes and scaffolds, which have found application in regenerative medicine.²³⁰ Furthermore, the unique features of PLACL make it an excellent material in the development of DDSs, such as sirolimus loaded polymer films,²³¹ doxorubicin and ciprofloxacin pH-responsive fiber scaffolds²³² and protein loaded nanocapsules for oral delivery.²³³

Last but not least, poly(glycolide-co-ε-caprolactone) (PGACL) is a material that is stable in mechanically dynamic environments and induces proper intercellular activities. Furthermore, PGACL is a significantly more flexible polymer than PLGA, making it a suitable material for the development of scaffolds for blood vessels and other smooth muscle tissues.²³⁴

To sum up, biodegradable polymers are an emerging group of materials used in the design of novel DDSs. By providing biodegradability, biocompatibility and lack of toxic side effects combined with the possibility of achieving controlled release of the drugs, they offer an interesting opportunity for the versatile administration routes of cannabinoids.

How to Unravel Cannabinoids’ Therapeutical Potential with the Use of Biodegradable Polymeric Carriers?

Since cannabinoids exhibit high therapeutic potential in the treatment of various disorders, they have become a point of interest for many researchers. Unfortunately, their use in classical pharmaceutical forms is limited by their physicochemical properties, rapid degradation, and reduced bioavailability. For that reason, many scientists have attempted to create DDSs that would overcome the aforementioned difficulties.

The current review presents latest information gathered from an extensive literature investigation on biodegradable polymers as carriers for cannabinoids delivery. The data was compiled using keywords and advanced search techniques, as well as databases such as PubMed, Web of Science, Scopus, and Google Scholar.

In the table below (Table 1), the details of innovative biodegradable polymer-based DDSs for cannabinoid delivery have been collected. Importantly, both in vitro and in vivo data, as well as additional studies performed by the authors, were summarized. Furthermore, the most interesting examples were acknowledged and investigated, with a particular emphasis on the results obtained from in vitro and in vivo studies.

Poor oral bioavailability is a result of the low aqueous solubility of CBD when administered orally. Recently, Shreiber‐Livne et al conducted a study, in which the researchers managed to encapsulate CBD within NPs of a highly hydrophobic PEG-b-PCL block copolymer. Furthermore, the pharmacokinetic properties of CBD were investigated in male Sprague Dawley rats administered with the formulation orally. When compared to the free form of CBD, the use of CBD-loaded NPs resulted in a ~20-fold increase of C_max. Furthermore, the use of loaded NPs reduced the time to achieve C_max (T_max) from 4 to 0.3 hours and increased the AUC of oral bioavailability by 14 times. This data emphasizes the nanotechnology strategy’s ability to enhance CBD’s oral performance with minimal systemic side effects.²³⁹

Muresan et al examined the anti-nociceptive effects of two distinct CBD formulations with an emphasis on intrathecal delivery of the CBD. Two formulations were used: triblock star co-polymer 3-arm PEG₁₀₁₄-(LA)₁₀₀ NPs and an oil-in-water nanoemulsion (NE). The researchers observed that both of the CBD formulations maintained in the spinal cord and reached high concentrations in the brain within 10 minutes of intrathecal treatment during pharmacokinetics investigations on adult male Sprague Dawley rats. While the polymeric NPs established their T_max at 30 minutes, the CBD NE reached its C_max in the brain in 120 minutes. In comparison to blank formulations, the two CBD formulations discussed above demonstrated immediate anti-nociceptive effects. This study reveals the potential advantages of CBD encapsulation in a variety of cannabinoid applications once again.²³⁸

Researchers have focused on the anti-tumorigenic properties of CBD in bladder cancer in a different study carried out by Chen et al. Using an emulsion solvent evaporation approach, researchers have developed two nano-sized CBD carriers: PLGA NPs and PLGA CS-coated NPs. The obtained PLGA NPs and PLGA-CS coated NPs were spherical in shape, had an average size of 192.90 ± 2.41 nm and 287.20 ± 0.90 nm, zeta potential (ζ) of −6.27 ± 0.93 mV and 3.37 ± 0.16 mV, and entrapment efficiency (EE) of 70.3 ± 0.7% and 78.5 ± 0.8% respectively. Furthermore, researchers have performed in vitro drug release studies in two different pH media – pH 5.0, which represented liposome and pH 6.5, which mimicked urine and tumor microenvironment. In both media, PLGA NPs showed an initial burst release within 15 h, followed by a sustained release lasting up to 110 h. The drug release kinetics in the case of PLGA-CS coated NPs showed a sustained pattern, with each release profile pointing to a slow release of the drug. During cytotoxicity studies of CBD PLGA NPs, evaluated in the human urothelial bladder cancer cell line (T24) and human uroepithelial cell line (SV-HUC-1), researchers established that both of the formulations can successfully inhibit the proliferation of T24 cells, at the same time causing no adverse impact on SV-HUC-1 cells. Moreover, the CS coating allowed the PLGA NPs to adhere to the bladder wall, creating a new and effective long-term treatment for uro-oncology.²³⁵

The research conducted by Monou et al exemplified the potential of cannabinoids in antimicrobial and wound-healing formulations. Scientists have developed NPs encapsulated CBD and cannabigerol (CBG) using Pluronic-F127 (PF127). NPs showed a high value of EE and were uniformly sized, with a diameter of less than 200 nm. The obtained NPs were additionally added to 3D printed films containing sodium alginate. In vitro release studies have shown a prolonged release of both, CBD and CBG, whereas CBG NPs loaded films exhibited zero-order kinetics. Further, aneuploid immortal keratocyte cell lines (HaCaT) were subjected to an in vitro cell scratch assay using various concentrations of cannabinoid-loaded NPs. In the first 6 hours, the percentage of wound area decreased for both cannabinoids and all concentrations applied. Nonetheless, following that, the wound areas for all concentrations were larger than the initial measurements. The results show that CBD and CBG NPs do not have significant wound healing capabilities in vitro, but they do have a brief impact on the healing process. To verify the potential wound-healing properties of CBD and CBG, more investigations are necessary.²⁴⁰ In addition, the antibacterial efficacy against three common pathogens (E. coli, S. aureus, and a Bacillus spp.) of the CBG and CBD formulations (5 mg/mL) was assessed using the agar diffusion method with filter paper discs. It is worth noting that both formulations exhibited inhibition of S. aureus and Bacillus spp. strains, suggesting that the two cannabinoid formulations were released into the medium. However, there was no inhibition observed on E. coli. Moreover, it was observed that CBG exhibited a slightly stronger antibacterial effect against S. aureus, while CBD demonstrated a better impact on the tested Bacillus spp. strains. The authors concluded that additional specialized research is necessary to elucidate the differences in antibacterial activity between these two cannabinoids.²⁴⁰

In continuity, Fraguas-Sánchez and coauthors established CBD-loaded PLGA NPs using the emulsion solvent evaporation technique for intraperitoneal application in the treatment of ovarian cancer.²²² The products obtained had an average particle size of 236 ± 12 nm and ζ value of −16.6 ± 1.2 mV. The biodegradable NPs delivered high CBD concentrations in a controlled manner for more than 96h during the in vitro release study and exhibited stability for at least three months of storage. Furthermore, obtained NPs were assessed in the in vitro cell culture experiments with the use of an epithelial ovarian cancer cell line (SKOV-3). The encapsulated form of CBD maintained its ability to prevent the growth of ovarian cancer cells and had a lower IC₅₀ compared to the solution form. During Western Blot analysis both CBD in its solution form as well as CBD NPs triggered the activation of poly(ADP-ribose) polymerase (PARP), indicating the initiation of cell apoptosis. In an experimental model using SKOV-3-derived tumors in the chorioallantoic membrane (CAM) of fertilized chicken eggs, there was an insignificantly higher level of inhibition of tumor growth observed with CBD NPs compared to CBD solution.²³⁷

An interesting study was described by Kamali et al, which investigated the potential of CBD-loaded PLGA microspheres incorporated into gelatin/nano-hydroxyapatite scaffolds in the treatment of critical-sized bone defects. The obtained microspheres were spherical, with an average size of 11.6 ± 1.3 μm and EE of 70.1 ± 4.5%. The in vitro release characteristics showed that both PLGA microspheres and scaffold incorporated with PLGA microspheres could continuously release the drug for 25 days. In in vivo studies, gross views of the harvested radial bones from adult male Wistar rats were evaluated after 4- and 12-weeks post-surgery and the macroscopical score was assessed based on newly formed tissues at the 12^th-week post-surgery. The researchers discovered that bone defects treated with a gelatin/nano-hydroxyapatite scaffold but not with CBD were replaced by fibrous and cartilaginous-like tissue. The defects treated with CBD-PLGA-gelatin/nano-hydroxyapatite scaffolds were completely filled with bone-like tissue, just like the autograph. The migration of bone marrow mesenchymal stem cells towards the injury site, as well as their differentiation into osteoblasts, was observed. This suggests that the created scaffold is biocompatible and capable of promoting the formation of new bone tissue.^242,243

Furthermore, Demisli et al focused their research on the transdermal CBD delivery in the form of NE-filled CS-hydrogel.²⁴⁸ The goal of that study was to develop a new method of delivering lipophilic bioactive substances through the skin that would minimise the irritation caused by the burst release on the surface. A lab-controlled permeation test was performed to determine how effectively CBD penetrates the skin from hydrogels containing NEs. As a substitute for human skin, the test used the intact porcine ear skin. While compared to the NEs alone, the hydrogels loaded with NEs showed a higher rate of CBD penetration and permeation coefficient. This suggests that the NE-filled hydrogels improve transdermal absorption. These findings were expected because CS is widely recognised as a penetration enhancer. It interacts with the stratum corneum in a variety of ways, including modifying the protein structure of the stratum corneum and acting as a moisturising agent to increase the water content of the stratum corneum. These systems have the potential to be excellent options for transdermal delivery of highly lipophilic bioactive compounds. More research is needed in the future to investigate their ability to encapsulate both lipophilic and hydrophilic bioactive substances at the same time, with the goal of achieving synergistic effects and improving biological outcomes.²⁴⁸

Naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (CB13) shows significant therapeutic promise as an analgesic for chronic pain conditions that have limited response to traditional medications. Nonetheless, its use in humans is hampered by the occurrence of mild-to-moderate dose-dependent adverse effects, as well as its pharmacokinetic properties. As a result, using an appropriate carrier system for CB13 oral administration appears to be an appealing approach to fostering the development of a valuable treatment option.²⁵⁰

Durán-Lobato and colleagues produced CS- and PEG-modified polymeric PLGA NPs and lipid NPs (LNPs). They subsequently carried out a comparative evaluation of these carriers under the same experimental conditions to determine their suitability for oral administration of CB13. When compared to LNPs, polymeric PLGA NPs had significantly longer release profiles. PEG-coated formulations had limited uptake in GI model cells and strongly inhibited uptake by monocytes. CS-coated NPs, on the other hand, showed the highest uptake in GI model cells and minimal uptake in THP1 cells. The coated PLGA NPs had slightly reduced GI tract uptake and more significant phagocytic uptake than the LNPs, which was likely due to the larger particle size of the formulations investigated in this study. Although more research is needed to understand how these carriers interact with biological entities, this study provides a comparative understanding of how PLGA NPs and LNPs perform under identical experimental conditions. Finally, this knowledge will help in determining which formulation is best suited for oral delivery of cannabinoids.²⁵⁰

In recent years, Δ⁹-THC has gained recognition for its therapeutic potential in treating different medical conditions.^258,259 However, the main barrier of using cannabinoids, such as THC, for medicinal purposes is determining a safe and efficient method of administration. The currently used soft gelatin capsules administered orally have limitations due to the significant first-pass metabolism of THC and the difficulty for patients experiencing severe nausea to retain the capsules in the stomach for an adequate amount of time for absorption and effectiveness. Using the nasal mucosa to deliver drugs into the body systemically is an efficient way to avoid the initial breakdown of drugs in the liver. Furthermore, the nasal mucosa is advantageous for drug absorption due to its large epithelial surface area created by numerous microvilli. Al-Ghananeem et al investigated the feasibility of administering dissolved Δ⁹-THC via the intranasal route. They were additionally interested to find out how the use of a CS-based nasal bioadhesive gel affected THC bioavailability. This formulation strategy was designed to reduce drug clearance by the mucociliary system. The researchers used conscious rabbits to administer the THC formulations via the nasal route and compare them to intravenous administration. After being administered nasally, the THC nasal solution showed a C_max of 20 ± 3 ng/mL at 20 minutes. Interestingly, the THC loaded in the CS gel formulation exhibited a similar profile initially and later reached a higher C_max of 31 ± 4 ng/mL (reached at 45 minutes). The researchers additionally examined into the absolute bioavailability of THC after nasal administration, comparing the concentration of THC in blood plasma after nasal administration to that after intravenous injection. THC nasal solution and gel formulations showed absolute bioavailability values of 13.3 ± 7.8% and 15.4 ± 6.5%, respectively. Based on the findings of this study, it appears that both solubilized THC administered intranasally and THC in a mucoadhesive CS gel formulation could be promising methods for delivering THC throughout the body. However, more research is needed to fully assess the clinical effectiveness and safety of this intranasal delivery system.²⁵³

However, Villate and colleagues conducted a study, in which they obtained full-spectrum Cannabis extract CS-coated alginate microcapsules using the vibration microencapsulation nozzle technique. This was carried out in order to produce an edible pharmaceutical-grade product. The synthesized microcapsules predominantly contained cannabinoids of the ∆⁹-THC-type and CBD-type. These microcapsules had an average size of 460 ± 260 μm and an average sphericity of 0.5 ± 0.3. According to the in vitro GI release experiment, the rapid release of cannabinoids in the intestinal phase results in a moderate to high bioaccessibility (57–77%) of medically significant compounds. When compared to alternative methods and materials for encapsulation, the vibration microencapsulation nozzle technique stands out for its use of natural materials that are readily available in abundance, resulting in a low cost of the process. Furthermore, this technique does not rely on expensive technology, involves any potentially hazardous steps, or produces any harmful waste that could have an impact on health or the environment. Furthermore, it does not necessitate the use or manufacture of any organic solvents. The performed study opens the door to the development of numerous new formulations based on full-spectrum Cannabis extracts. Allowing the creation of formulations with specific desired properties, any Cannabis extract can be encapsulated using a customizable synthesis pathway.²⁵⁶

Lastly, Uziel et al pursued the idea of full spectrum Cannabis extract administration. An extended-release formulation, in the form of polymeric microdepots, that had been created through melt printing, was developed for a full-spectrum extract rich in CBD. Once microdepots were injected subcutaneously into mice, they allowed for the continuous release of the enclosed extract for two weeks. Mice were given a single injection of microdepots containing Cannabis extract or a Cannabis extract solution with the same dosage to determine how effectively the formulation functioned within a living organism. Microdepots were extracted from the tissue beneath the skin at various time intervals throughout the experiment to determine the amount of cannabinoids released. Blood samples were also analysed to obtain pharmacokinetics profiles of cannabinoid levels in the serum. This prolonged administration results in a higher concentration of various significant and minor cannabinoids in the bloodstream, surpassing the effects of injecting regular Cannabis extract. In terms of seizure prevention, the microdepots reduced the occurrence of tonic-clonic seizures by 40%, increased the survival rate by 50%, and delayed the onset of the first tonic-clonic seizure by 170% one week after administration. These findings suggest that a long-term delivery system that includes the entire Cannabis spectrum has the potential to offer a novel method of Cannabis administration and treatment.²⁵⁷

Future Prospectives

As the interest in biodegradable polymers is thriving, they become utilized towards increasingly sophisticated issues. The discovery of biodegradable polymer-based DDSs opens new opportunities for clinical application of drugs, whose poor physicochemical, pharmacodynamic, or pharmacokinetic characteristics limit their administration routes and deployment in applied medicine.

One of the promising substances, which have caught the attention of researchers around the world are cannabinoids. With ample amount of new research, that indicate effectiveness of cannabinoids in various conditions, there emerges the need for a proper way of their administration. Cannabinoids exhibit poor bioavailability, low water solubility and significant instability, which is why it is troublesome to properly study their effectiveness in treatment of different conditions. With the use of polymeric drug vehicles, not only are the cannabinoids’ pharmacokinetic properties improved, but also the controlled release of the drug may be achieved.

The current review gathered and described both the cannabinoids individually and the DDSs that encapsulate them. The main objective was to underline how the biodegradable DDSs promote the controlled drug release and augment the drug’s bioavailability. With a big heterogeneity of the polymers that constitute the matrix of the carriers, the administration perspective broadens.

Even though there has been extensive research in that area, the use of biodegradable carriers with cannabinoids still encounters several uncertainties and concerns. More clinical trials need to be performed to properly study every aspect of medical cannabinoid therapies in vivo, although thus far observed results emphasize the future optimism in the development of that field.

As a last note, it should be acknowledged that scientists could explore the use of biodegradable polymeric DDSs containing cannabinoids for combined therapy (delivering cannabinoids at the same time or combining with other treatments). Additionally, these systems could also deliver cannabinoids or their analogues alongside other compounds. This approach would make better use of the flexibility of the suggested systems and their ability to overcome limitations in drug availability, ultimately improving the overall effectiveness of the treatment. Furthermore, with the use of biodegradable polymers a targeted therapy towards different specific disorders may be achieved.

The analysis of the literature allows to believe that in the coming years there will be a further increase in interest in new cannabinoid delivery systems. Intensification of work in this area will probably lead to the commercialization of the new type DDSs.

References