Buccal route for fast multimodal analgesia for the treatment of moderate-to-severe acute pain: feasibility and enhancement strategies

Pain is a complex multifaced phenomenon, an “unpleasant sensory and emotional experience” as described in part by the International Association for the Study of Pain. The emotional and sensory components evoke different degrees of suffering, since pain is subjective. During the last years, pain treatment shifted to a multimodal approach in which drugs are selected not only on the basis of pain intensity, but mainly according to the different mechanisms of transmission of the pain sensation. Multimodal analgesia involves the administration of a combination of drugs which act simultaneously on multiple level of pain pathway with different mechanisms, to obtain both synergic effect and reduction of the side effects. Recently, the anti-inflammatory action of dex-ketoprofen has been combined with the double analgesic activity of tramadol, targeting both the descending inhibitory pathway of pain and the spinal cord modulation. This combination could cover a wild range of acute painful condition from moderate to severe intensity. The main limit in treating pain is the slow onset of pain-relief action associated with the oral administration. In this context the buccal drug delivery becomes a valuable alternative to provide faster and safe route of administration. The main limits of buccal administration, such short residence time, small absorption area and barrier properties of the tissue can be easily overcome with appropriate chemical or physical strategies. The aim of the work was to explore the feasibility of the buccal route for the simultaneous administration of tramadol and ketoprofen. Different classes of chemical enhancers including terpenes, fatty acids and bile salts were evaluated with pre-treatment and co-administration methods to facilitate permeation of drugs in order to reach a faster analgesic effect. The knowledge acquired on chemical enhancement has been applied for the development of in-situ thermosensitive forming hydrogel. Preliminary results showed the feasibility of the administration of tramadol and ketoprofen via buccal route. Among the chemical enhancers tested, menthol provide the highest enhancement factor for both drugs and is the best candidate for buccal application because its better organoleptic characteristics compared to fatty acids. The effect of the simultaneous presence of capric acid and menthol, belonging to different chemical classes was evaluated, but no synergic effect was evident. Poloxamer 407 thermo-reversible hydrogel has been developed and the effect of incorporation of menthol and xanthan gum was evaluated in terms of gelation, release and permeation of drugs from the hydrogel. Even if xanthan gum negatively affect release and permeation of both drugs from the gel,the inclusion of menthol 0.5% (w:w) in the formulation provide significative permeation enhancement confirming its effectiveness for buccal application.