Polymeric Based Mucoadhesive Film for CannabidiolControl Release

doi:10.21203/rs.3.rs-2951037/v1

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Polymeric Based Mucoadhesive Film for CannabidiolControl Release

https://doi.org/10.21203/rs.3.rs-2951037/v1

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published 05 Jan, 2024

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Cannabidiol is a non-psychoactive cannabinoid isolated from the cannabis plant. Instead of intoxicating effects, Cannabidiol is known for its antioxidant, anti-inflammatory, and anti-anxiety effects. Being antagonist to CB1 and CB2 cannabinoid receptors, Cannabidiol binds to CB receptors through negative allosteric modulation; reduce binding affinity of endocannabinoids to corresponding receptors decreasing activities without adverse agonist effects. Cannabidiol could be administered via several routes, for example, oral, sublingual, nebulizing, and transdermal. However, due to its low water solubility and first-pass metabolism, Cannabidiol showed low bioavailability in several administrations, including the most common, oral delivery. Mucoadhesive drug delivery is one solution to increase drug retention time at oral absorption sites, buccal and sublingual, in which the drug could be absorbed directly into the bloodstream without passing through the digestive tract and its first-pass metabolism. Among several biocompatible mucoadhesive polymers, hydroxypropyl methylcellulose (HPMC) was found to be a suitable matrix that could be formulated into a thin film with up to 20% cannabidiol content. To prolong the retention and disintegration time, polyvinyl alcohol (PVA) was added as a backing layer due to its softness and flexibility. The bilayer film showed excellent mechanical properties with tensile strength of 8.54 N/mm² and elongation of 30 %. The addition of a PVA backing layer not only improves mechanical properties but also prolongs up to 90 minutes of film disintegration time. HPMC-PVA film shows the controlled release of cannabidiol over a 6-hour period. The results indicate that HPMC-PVA bilayer is a suitable polymer matrix for cannabidiol delivery because it provides mucoadhesive properties in oral administration and controls release for higher cannabidiol absorption.

Cannabidiol

Mucoadhesive

Hydroxypropyl methylcellulose

Drug control release

PVA

Cannabidiol (CBD) is one of the main constituents extracted from Cannabis sativa. CBD is a non-psychoactive compound which has proved to have promising benefits in pharmaceutical field. Evidence indicates that CBD has antioxidant, antibacterial, and anti-inflammatory effects. (Hazekamp, 2010) CBD also has well-established usage in neurological medication because it possesses neuroprotective properties. (Schröder, 2017) CBD structure belongs to the group of cannabinoids that have been investigated to have very low solubility in water. Being a hydrophobic drug, the bioavailability of CBD is reported to be highest at 31% via smoking and vaping. (Ujváry and Hanuš, 2016) The value could even be as low as 8.6% for oral-administered drugs. (Xu, 2019) Since pure CBD intake proved to be inefficient, several formulations of CBD have been investigated to improve drug absorption.

Since the beginning of the 1980s, the idea of mucoadhesion has garnered considerable attention in the pharmaceutical field. Mucoadhesion generally refers to the state in which the surface is held to the mucous substrate in the body by interfacial forces. As the percentage of absorption increases, the therapeutic effects of the medicine are enhanced by the action of intimate touch. Numerous routes of mucoadhesive drug administration, including oral, nasal, intestinal, and rectal, have been examined due to the numerous benefits. (Boddupalli, 2010) The medicine in the mucoadhesive platform was absorbed through the mucosal layer, which typically has a high blood flow, resulting in quick absorption and high bioavailability. Oral administration is the most common and convenient mode of administration for medicines. This oral medication administration method is by far the most used in the pharmaceutical business, due mostly to its simplicity and noninvasiveness. (Viswanathan, 2017) Oral mucoadhesive medication delivery method comprises two distinct components. One was designed to promote intestinal medication absorption by increasing the residence time in the gastrointestinal mucus. (Bernkop-Schnürch, 2005) However, an oral mucoadhesive platform could be created exclusively for oral mucosa attachment, primarily separating buccal and sublingual delivery. (Gilhotra, 2014) Since the chemical enters the bloodstream directly through the mucosa, it avoids gastrointestinal degradation and first-pass hepatic metabolism, unlike the previously stated design. Mucoadhesive film is the most desirable since it provides greater flexibility and comfort than tablet form and greater retention than gel form. (Gilhotra, 2014) In general, the mucoadhesive film formulation was produced by the film casting method. This standard production approach affords the opportunity to design cost-effective medication delivery systems.

The purpose of this project is to develop CBD-containing mucoadhesive films that have adequate physical qualities and provide sustained CBD release over time. In order to determine the qualities of the films as biological materials, their cytotoxicity against the NCTC 929 cell line was also analyzed.

2.1 Materials

PVA (Mw 89,000–98,000, hydrolysis degree, 99%), PVP, HPMC, Chitosan, and PAA were purchased from Sigma Aldrich (USA). Cannabidiol (CBD, hemp-derived, 99%) was purchased from Extract Labs (USA). Absolute ethanol (99%) was purchased from RCI Labscan Ltd. (Thailand). All the chemicals were of analytical reagent grade and used without further purification.

2.2 CBD and Mucoadhesive Polymers Compatibility

Five different mucoadhesive polymers; PVP, PVA, HPMC, Chitosan, and PAA were formulated into thin film using suitable solvents; 2% w/w CBD to polymer was set as formulating condition. Up to 50% v/v of ethanol AR grade was added to the solvent system to dissolve CBD in polymer solution. The solution was stirred overnight for homogeneity and casted onto petri dish before drying at 50°C for 24 h. The film was observed in terms of physical properties and CBD compatibility.

2.3 HPMC Based Mucoadhesive Film Formulation

Mucoadhesive polymer HPMC was dissolved in 15% EtOH - DI water solvent system at concentration of 1%w/v. CBD solution was prepared and added to the polymer solution. CBD-HPMC solution was stirred overnight at 100 rpm to achieve bubble less viscous. The drug-polymer solution was then casted on to 9 mm diameter petri dish and dried in an oven at 50°C for 24 h. PVA solution was prepared at a concentration of 2% w/v in DI water, 180°C for 6 h to form clear homogeneous solution. After HPMC solution dried, PVA solution was casted onto the dried film and dried in oven under similar conditions. The film was then removed from the petri dish and stored in desiccator for at least 48 h before further characterizations.

2.4 Thickness Uniformity

The thickness of each film formulation was measured using Mitutoyo digital dial gauge stand. 5 spots across the 3 x 8 cm cut films were measured and recorded in triplicates. (Corners and Center).

2.5 Scanning Electron Microscope (SEM)

The morphology of CBD and films were observed by Scanning Electron Microscopy (SEM; JEOL JSM-6610LV, Oxford X-Max 50) at 500- and 5000-times magnification.

2.6 Mechanical Properties

The mechanical properties of the films were characterized by Universal Testing Machine (UTM; Lloyd, LRX, Tensile mode) with 500 N load cell. The films were cut into 1 x 8 cm for 5 cm gauge length measurement at the speed of 5 mm/s under pull until break condition by investigating maximum load and elongation at break of the films.

2.7 Disintegration and Dissolution

The 1.5 cm diameter circle films were obtained using a sample cutter. PBS was used as a testing medium. The characterizations were performed using shaking incubator at constant speed of 150 rpm, 37°C. Films were placed into 10 ml of PBS fluid. The time in which the film matrix disintegrated (Alopaeus, 2020), and complete dissolution was achieved was recorded.

2.8 Ex Vivo Retention Time

Pork cheek was cut into 2 x 2 cm with 0.5 cm thickness. A few droplets of PBS were added to wet the pork cheek for film attachment. The pork cheek was put into 20 mL of PBS, stirring conditions at 150 rpm, 38°C were maintained. The times which film was detached from the pork cheek were recorded.

2.9 Mucoadhesive Properties

The adhesiveness of each sample was investigated at room temperature using the Texture Analyzer (TA.XT plus) in adhesive mode. The pork cheek bulge was cut into square shape (1x1 cm) and attached to the upper part of the P/6 probe type. The pork cheek bulge attached to the probe was lowered to the surface of each sample and maintained for 30 s under 0.981 N. After 30 s, the pork cheek bulge was moved upwards at 5 mm/s.

2.10 In Vitro Drug Release Study

Total immersion method was used in investigating CBD release profile over the period of 240 min. Releasing medium PBS was incubated at 37°C with continuous stirring. 1 mL of solution was extracted for CBD determination under specified periods, 1 mL of incubated PBS was then added to maintain to total volume of releasing medium. The concentration of CBD at specified time was calculated and the drug released profile was constructed in term of CBD accumulation percentage.

2.11 Indirect Cytotoxicity Evaluation

Biocompatibility of CBD loaded HPMC film formulations were determined using L929 mouse fibroblast cells (NCTC 929 clone cells (17th passage)). The cells were cultured in Dulbecco’s Modified Eagle’s Medium (DMEM) with 10% Fetal Bovine Serum (FBS) and 1% Antibiotic-Antimycotic agent. Approximately 8,000 cells were seeded in 1 well of a 96 well-plate (Tissue-Culture, Polystyrene) and incubated at 37°C, in a humidified atmosphere, at a temperature of 37°C (95% air, 5% CO₂). After film samples were rendered sterile by UV radiation, Serum free medium (SFM; 1% Antibiotic-Antimycotic agent in DMEM) was employed for sample immersion in order to prepare the extraction media. The SFM medium was subsequently substituted with five doses of extraction medium (0.50, 5.00, 25.00, and 50 mg/mL). The cell immersed in replaced medium was incubated for 24 h before determining the viability via 3-(4,5-dimethylthaiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. The incubating medium was removed, cell samples were washed with PBS, then MTT solution (0.5 mg/mL) was added for 3 h incubation. After that, MTT solution was replaced by DMSO to dissolve formazan crystal. Formazan solution was retrieved and measured the content at 570 nm absorption using Microplate Reader to determine cell vitality rate.

3.1 CBD and Mucoadhesive Polymers Compatibility

CBD loaded film formulations from 5 mucoadhesive polymers were obtained. As mentioned, amount of CBD loaded in the polymers was set at 2%w/w for initial investigation. Optimal conditions in dissolving CBD in polymer solution were summarized in Table 1.

Table 1

Formulation conditions and results from different types of mucoadhesive polymers
Mucoadhesive polymers	Solvent system	EtOH in solvent system (%v/v)	Results
PVP	DI water	50	CBD crystal
PVA	DI water (heat)	10	CBD crystal
HPMC	DI water	10	Clear film
Chitosan	0.1 M acetic acid	5	precipitation
PAA	DI water(heat)	20	CBD crystal

PVP is soluble in ethanol, which allowed addition of EtOH up to 50% in solvent system. CBD-PVP solution was recorded as only clear drug loaded polymer solution. CBD-loaded PVA, HPMC, and PAA were observed as white, turbid, viscous solutions (indicating low water solubility of CBD) that were visually homogenous. Chitosan requires specific dissolving conditions in acid; therefore, the addition of CBD-EtOH solution to the solvent decreases chitosan solubility, resulting in the precipitation of polymer. The films were fabricated via solvent casting method with drying conditions of 50°C and 24 h. When they were dried, CBD crystal was visible on PVP, PVA, and PAA films that indicate low compatibility between polymer and loaded drug. The smooth and transparent nature of the HPMC film containing CBD indicates the strong compatibility between CBD and HPMC.

3.2 HPMC Based Mucoadhesive Film Formulation

By using solvent casting method under same drying condition as previous experiment section, CBD loaded HPMC film formulations were obtained. PVA was introduced as backing layer to formulate HPMC-PVA bilayer film. The purpose of backing layer is to prolong the retention time of the mucoadhesive film on the drug absorption site (Satishbabu and Srinivasan, 2008). The CBD loading capacity of HPMC was examined, and films containing up to 20% w/w CBD-HPMC could be obtained. In Table 2, the composition of film formulations cast onto 9 mm petri dishes is summarized and labeled. Noted that the EtOH concentration in DI water was fixed at 15% v/v, the HPMC concentration in DI water was fixed at 1% w/v, and the PVA solution concentration is 2% w/v. The films were kept in a desiccator for 48 hours before their physical and mechanical properties were characterized. The optimal conditions were then selected for fabrication of CBD loaded HPMC bilayer films for further pharmaceutical applications analysis.

Table 2

Composition of film formulations
Film formulations	HPMC (g)	PVA (g)	CBD/HPMC (% w/w)	Description
A1	0.2	0	0	Pure HPMC
A2	0	0.2	0	Pure PVA
A3	0.2	0.05	0	Bilayer
A4	0.2	0.1	0
A5	0.2	0.2	0
A6	0.2	0.25	0
A7	0.2	0	20	CBD loaded HPMC
A8	0	0.2	2	CBD loaded PVA

3.3 Thickness Uniformity

Sample uniformity is crucially important in product fabrication (Alopaeus, 2020). Thickness of A1 - A7 cut films (3 x 8 cm) (4 corners and center) was measured and recorded in triplicate. The data was shown with standard deviation in Table 3.

Table 3

Thickness of films
Film	A1	A2	A3	A4	A5	A6	A7	A8
Thickness (mm)	0.026	0.021	0.031	0.039	0.048	0.055	0.026	0.025
SD (mm)	0.001	0.001	0.005	0.003	0.002	0.008	0.002	0.010

The low overall thickness variation of films suggests that the solvent casting procedure was appropriate for film production. A3 and A6 films exhibited a lesser degree of consistency, with thickness deviations of about 15%, and were therefore deemed unsuitable for film formation. CBD-loaded HPMC film (A7) had the same thickness as pure HPMC film (A1), indicating that the thickness of the film was not altered by the addition of CBD.

3.4 Scanning Electron Microscope (SEM)

SEM micrograph of CBD and 4 film formulations, HPMC, PVA, CBD loaded HPMC, and CBD loaded PVA at 500 times magnification (Fig. 1.) were investigated to confirm CBD compatibility with HPMC mucoadhesive polymer. Both pure HPMC and PVA films exhibited a smooth film surface. CBD-loaded HPMC film also maintains a flat surface without CBD crystals or powder, indicating great component compatibility. Crystalline CBD was detected in CBD-loaded PVA film, indicating poor CBD dispersion in the PVA matrix.

3.5 Mechanical Properties

Two crucial parameters, tensile strength, and elongation at break, were the focus of the investigation into the mechanical properties of the film. The tensile strength of the films represents structural integrity for application-specific purposes (e.g., withstand oral cavity stress). Elongation at break or maximum strain is a value perceived as flexibility and responsible for the level of film of comfort. (Nair, 2013).

From Fig. 2. were illustrated that HPMC pure film (A1) has high tensile strength with relatively low elongation of 16.5 N/mm² and 17% respectively. PVA film (A2) showed low tensile property of 9.6 N/mm² with extensively high elongation at break of 100%. Because of this, PVA was widely employed as a biological material with a high degree of flexibility and comfort. The addition of a PVA backing layer to HPMC films increases their elongation (A4, A5, and A6). It is possible that the uneven distribution of PVA on the HPMC surface of the A3 film resulted in nonuniform thickness and diminished mechanical characteristics. A7 exhibited greater tensile strength but lower elongation than A1; nonetheless, the difference was insignificant as the value deviation was close to zero, allowing us to conclude that CBD loading into HPMC film had a minimal effect.

3.6 Disintegration and Dissolution

A1-A6 film solubility was examined, and the time required for the film to lose its integrity and dissolve fully was noted in Table 4. It is crucial to note that PVA film is not soluble in water at low temperatures, resulting in no change to its integrity even after 24 hours. HPMC film dissolves swiftly in PBS, requiring only 5 minutes to observe ripping. Complete dissolution needed a longer period of time. PVA backing layer acts as a protective layer against PBS, resulting in longer disintegration and dissolution times for bilayer films.

Table 4

Disintegration and dissolution time
Films	A1	A2	A3	A4	A5	A6
Disintegration time (min)	5	-	10	15	20	20
Dissolution time (min)	60	-	60	90	90	90

3.7 Ex Vivo Retention Time

Fresh pork cheek was used as model material of human buccal to investigate the effect of PVA backing layer in prolonging the retention time. A1 – A6 films were cut as circle sample (diameter = 1.5 cm) and used in triplicate. Time required for films to detach were shown in Table 5. Due to high water solubility, HPMC film rapidly dissolve within 15 min, the film was not detached but disintegrated on the pork cheek. PVA was formerly recognized as a sort of mucoadhesive polymer; however, due to its limited water solubility (at low temperature), PVA films had relatively low adhesiveness and were included to improve the mechanical properties of the films (Vecchi, 2021). Nevertheless, this “non-sticking” property was desirable as PVA was fabricated as backing layer and ideally aid for unidirectional release of the loaded drug (Govindasamy, 2013). A3 film retention time increased to 30 min which is significant but inferior compares to other formulations. A5 and A6 showed optimum retention time of 180 min which significantly improve contact period of the film on mucus membrane. Despite its uniform thickness and improved overall mechanical qualities, the retention duration of A4 is significantly lower than that of A5 and A6. This circumstance was concluded to be related to water permeability of PVA film (Byron and Dalby, 1987). Due to this reason, A5 and A6 with thicker PVA layer can significantly extend the retention time of HPMC film. A5 was concluded to be optimal condition to be used for CBD loaded HPMC-PVA bilayer mucoadhesive film.

Table 5

Retention time of films on Pork cheek.
Films	A1	A2	A3	A4	A5	A6
Retention time (min)	15	< 1	30	90	180	180

3.8 Mucoadhesive Properties

By using texture analyzer, force of adhesion of HPMC film, PVA film, and the bilayer film was measured and recorded, as illustrated in Fig. 3. The maximum force (N) of each film was determined and the work of adhesion (N*mm) was calculated by finding area under the curve of Force-distance plot. The measured maximum force of adhesion of HPMC, PVA, and bilayer films were 3.03 ± 0.29 N, 0.41 ± 0.02 N, and 3.37 ± 0.27 N, respectively. Both HPMC and bilayer film force of adhesion far exceed average force applied in oral cavity in which the average is below 0.5 N (Valentim, 2014). The data obtained corresponded to the result from Ex vivo retention time evaluation. HPMC showed high value of work of adhesion at 4.43 ± 0.24 N*mm. PVA exhibit negligible interaction to mucous surface with only 0.32 ± 0.09 N*mm work of adhesion. Bilayer film showed similar adhesiveness of its pure film with the value of 4.39 ± 0.27 N*mm.

3.9 In Vitro Drug Release Study

Drug release profile of CBD loaded HPMC film formulation was investigated in 2 CBD loaded content 10 and 20% w/w of both pure and bilayer HPMC films, respectively. The data were calculated and expressed in CBD accumulation percentage over the period of 6 h, as illustrated in Fig. 4. Over 70% of CBD was released in 30-minute intervals from HPMC films without a supporting layer, exhibiting burst release behavior. Gradual release of CBD was observed from bilayer film. R² values of 10 and 20%w/w CBD loaded films were 0.9584 and 0.9539, respectively.

3.10 Indirect Cytotoxicity Evaluation

For fabricated material to be used in medical applications, cytotoxicity of the samples was evaluated via MTT assay. Generally, more than 70% cell viability are accepted for material to be called biocompatible. (Potaś, 2021).

From Fig. 5. at low extract medium concentration, bilayer film exbibit high biocompatibility with over 90% at 0.5 mg/mL, and over 70% viability at 5 mg/mL. In contrast, CBD-loaded HPMC films exhibited substantial toxicity at all doses, indicating that CBD dosages were excessive for medical applications. Fabrication of bilayer films significantly lessens cytotoxicity of the drug loaded films by preventing “burst” release of CBD. However, at high concentration, bilayer film also resulted in high cytotoxicity value, which is predictable as % drug loaded is very high compare to general formulations (Salehi and Boddohi, 2017), (Muzib and Kumari, 2011).

In this study, CBD loaded HPMC film formulations were successfully prepared via solvent casting method. Film formulations, A1 – A8, were characterized in terms of physical, mechanical, before finalizing the fabricating formulations. Maximum CBD loading capacity was confirmed to be at 20%w/w CBD to HPMC. A5 condition determined to be highly uniformed in thickness with high tensile strength of 8.54 N/mm² and flexible with 30% elongation at break. Moreover, retention time of the film was prolonged to 180 min compared to 15 min contact of pure HPMC film. Thus, this condition was set to produce 10 and 20%w/w CBD/HPMC bilayer films. HPMC/PVA bilayer films have significantly higher potential as biomedical material. PVA backing layer evidently responsible for controlled release behavior. The maximum force of adhesion of the bilayer films was measured to be 3.37 N which far exceeds average force in oral cavity. Work of mucoadhesion was calculated to be 4.39 N/mm². Results from MTT assay of more 70% cell viability confirmed the potential of CBD loaded HPMC-PVA bilayer film in biomedical applications.

Acknowledgements

This work was conducted with the support of (1) The Ratchadaphiseksomphot Fund for Postdoctoral Fellowship 2562, Chulalongkorn University, (2) Herbal Extracts-infused Advanced Wound Dressing Research Unit, Rachadaphiseksomphot Endowment Fund, Chulalongkorn University, (3) Fundamental Fund 2565: FF65, Chulalongkorn University, and (4) the 90^th Anniversary of Chulalongkorn University Scholarship Batch 50: GCUGR1125643049M No. 2–15.

Funding

The funding was provided by1) The Ratchadaphiseksomphot Fund for Postdoctoral Fellowship 2562, 2) Herbal Extracts-infused Advanced Wound Dressing Research Unit, Rachadaphiseksomphot Endowment Fund, Chulalongkorn University, 3) Fundamental Fund 2565: FF65, Chulalongkorn University, and 4) the 90^th Anniversary of Chulalongkorn University Scholarship Batch 50: GCUGR1125643049M No. 2–15.

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No competing interests reported.

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18 May, 2023
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18 May, 2023

You are reading this latest preprint version

Polymeric Based Mucoadhesive Film for CannabidiolControl Release

Status:

Journal Publication

Version 1

Abstract

Figures

1. Introduction

2. Materials and methods

2.1 Materials

2.2 CBD and Mucoadhesive Polymers Compatibility

2.3 HPMC Based Mucoadhesive Film Formulation

2.4 Thickness Uniformity

2.5 Scanning Electron Microscope (SEM)

2.6 Mechanical Properties

2.7 Disintegration and Dissolution

2.8 Ex Vivo Retention Time

2.9 Mucoadhesive Properties

2.10 In Vitro Drug Release Study

2.11 Indirect Cytotoxicity Evaluation

3. Result and discussion

3.1 CBD and Mucoadhesive Polymers Compatibility

3.2 HPMC Based Mucoadhesive Film Formulation

3.3 Thickness Uniformity

3.4 Scanning Electron Microscope (SEM)

3.5 Mechanical Properties

3.6 Disintegration and Dissolution

3.7 Ex Vivo Retention Time

3.8 Mucoadhesive Properties

3.9 In Vitro Drug Release Study

3.10 Indirect Cytotoxicity Evaluation

4. Conclusions

Declarations

Acknowledgements

References

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1