Intra-articular analgesic viscosupplementation based on chitosan and poly-cyclodextrin hydrogel for maxillofacial surgery – CHITOGEL
Intra-articular analgesic viscosupplementation based on chitosan and polycyclodextrin hydrogel for maxillofacial surgery
There is no satisfactory therapy to resolve the problem of temporomandibular dysfunction, so we propose the preparation and characterization of a viscoelastic hydrogel based on chitosan and cyclodextrin polymers with prolonged release of an active principle, for injection at the level of the temporomandibular joint and an anti-inflammatory and lubricating action
Develop a hydrogel based on chitosan and cyclodextrin polymers for maxillofacial surgery
The objective was to develop a viscoelastic hydrogel based on chitosan (CHT) and cyclodextrin polymers (PCD) with sustained release of an active ingredient, in order to develop an injectable medical device for active viscosupplementation and to ensure, 1) lubrication of the temporomandibular joint (mechanical effect) and 2) anti-inflammatory and pain relief activity. Initially, the hydrogel without active ingredient (AP), a hydrogel with optimal viscoelastic and lubricating properties, is prepared for its use in injectable therapy in the treatment of temporomandibular joint (TMJ) dysfunction. Afterwards, the hydrogel is prepared with an active ingredient (AP), for its use in injectable therapy for drug delivery in the treatment of TMJ dysfunctions. Two formulation approaches were targeted. The first part by the use of naproxen (NaNX) to form an inclusion complex with soluble (PCDs) and insoluble (PCDi) PCD and control its release using CHT/PCDs/PCDi hydrogels. In a second part, the use of a Chitosan-Rosmarinic Acid conjugate (CHT:RA) will be evaluated in order to add an adjuvant pharmacological property to the CHT which is part of the hydrogel formulation.
The preparation of the hydrogel was based on patent WO2017001808 (2017), which describes the process for manufacturing a hydrogel and a porous alveolar material based on chitosan (positively charged) and negatively charges polyelectrolytes (such as PCD) of controlled particle size
To qualitatively evaluate the formation of the hydrogel, two types of test were carried out: the inverted pot test, and the cohesion test. Concerning the inverted pot test, a precise quantity of hydrogel was injected into a vial and then it was inverted. The resistance to flow over time was then evaluated. A reference product based on hyaluronic acid (HA) marketed under the name Ostenil ® was used as a control and tested at the same time.
To characterize the viscoelastic properties of the hydrogels, a rheological evaluation (Anton Paar Rheometer, MCR 301) was carried out.
The inclusion of NaNX in the formulation was carried out in the 2nd part, with and without wet granulation, and a rheological evaluation was also carried out in order to study the impact of the addition of NaNX on the formation of hydrogels.
The formulations resulting in a hydrogel are (CHT:PCDs:PCDi): 1.5:1.5:0, 1.5:0.75:0.75, 2:1:0, and 2:0.5:0.5.
Regarding the inverted vial test (Figure 1), the reference product (RP), Ostenil®, showed lower resistance to flow (less than 8 seconds) compared to the CHT:PCD:PCDi formulations (10 minutes and 2 hours).
On the other hand, hydrogel formation was observed in all CHT:PCD:PCDi formulations; however, varying cohesion was noted among them.
The 2:1:0 formulation exhibited higher resistance to flow (>2 hours) compared to the 1.5:1.5:0 formulation (2 hours). However, once PCDi was added (1.5:0.75:0.75 and 2:0.5:0.5), a decrease in flow resistance was observed (10 minutes and 2 hours, respectively), indicating lower cohesion.
The hydrogels were then injected using an 18G needle into a buffer solution at pH 7.4 to test hydrogel cohesion in a medium mimicking physiological pH.
Figure 2 shows photos of the hydrogels after injection into PBS.
A cord-like structure was observed in all samples; however, stronger cohesion was seen for the 2:1:0 and 2:0.5:0.5 hydrogels over 24 hours.
In particular, the 2:0.5:0.5 formulation showed higher stability. In contrast, the 1.5:1.5:0 and 1.5:0.75:0.75 formulations showed lower cohesion over 24 hours.
The 1.5:1.5:0 formulation lost its structure by shrinking after 1 hour, while the 1.5:0.75:0.75 formulation partially lost its cord-like structure and formed a mass.
The commercial product (Ostenil®), being a hyaluronic acid (HA)-based solution, does not form a cohesive product after injection.
In conclusion, the cohesion of the CHT/PCD hydrogels from different formulations was confirmed.
Stronger cohesion was observed for the 2:1:0 and 2:0.5:0.5 hydrogels.
Although a decrease in flow resistance was observed for the 2:0.5:0.5 formulation compared to 2:1:0, the addition of PCDi appears to improve the structural stability of the formulation.
In rheology, the study of Tan δ allows us to demonstrate that hydrogel formation is more optimal when using CHT/PCDs (without PCDi), specifically in the 2:1:0 and 1.5:1.5:0 formulations.
Add an active ingredient and repeat all tests to study the impact of the active ingredient on the properties of the hydrogel, as well as the release of the active ingrédient.
Temporomandibular dysfunctions are myoarthropathies of the manducatory apparatus, responsible in most cases of chronic pain without satisfactory treatment. Lately, methods of administering active ingredients via hydrogels have attracted a lot of attention. UMET and U1008 laboratories have developed a patented hydrogel based on chitosan (CHT) and cyclodextrin polymer (PCD) for the release of active ingredients. The objective of this project is to evaluate and optimize the hydrogel to meet the specifications: viscoelastic properties; release of nonsteroidal anti-inflammatory drugs (NSAIDs) over 3 weeks; therapeutic efficacy in vivo. The base of the hydrogel will be maintained by adding hyaluronic acid. A rheological screening will be carried out to find the ideal formation. Naproxen release studies and in vivo studies with winstar rats will be performed.
Project coordination
Maria-Jose GARCIA FERNANDEZ (U 1008 - ADDS - Systèmes avancés de délivrance de principes actifs - Advanced Drug Delivery Systems)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Partnership
U1008 U 1008 - ADDS - Systèmes avancés de délivrance de principes actifs - Advanced Drug Delivery Systems
Help of the ANR 267,423 euros
Beginning and duration of the scientific project:
September 2021
- 42 Months
