Development of Mucoadhesive Microemulsion of Clozapine for Nose to Brain Delivery: Design, Optimization, in Vitro and in Vivo Evaluation.
Year: 2020
Type: preprint
Abstract: The mental and behavioural disorders are chronic, severe and disabling brain disorders affecting about 6-7% of Indian population. The economic burden of schizophrenia is also very high. Clozapine is the prototype of atypical antipsychotic drug used to treat patients with schizophrenia who are unresponsive or intolerant to typical antipsychotics. It is more effective in treating the positive and negative symptoms of schizophrenia than older antipsychotics. Clozapine also reduces suicidal behavior in patients with schizophrenia.
The conventional dosage forms (oral and intravenous) of clozapine are unable to reach the brain in sufficient concentration for its therapeutic action due to blood brain barrier, degradation in GI harsh environment and extensive hepatic first pass metabolism (oral bioavailability of clozapine is <27%). Many (69-82%) patients discontinue the conventional medication due to its invasiveness and intolerable side effects.
In the present research work, the intranasal microemulsions of Clozapine (CZP) were developed and their brain targeting efficiency was evaluated. This approach is non-invasive; drug absorption is rapid and bypasses the Blood Brain Barrier (BBB). Also avoids the hepatic metabolism and gastric degradation. This method could be of potential benefit due to unique connection between the nose and the brain through olfactory nerve pathway and trigeminal nerve endings.
The main objective behind the research was to formulate the microemulsions of Clozapine and evaluate pharmacokinetics parameters in plasma, brain and pharmacodynamic activity in comparison to oral route in rat model. The microemulsions of Clozapine were developed using oleic acid (oil), Labrasol (surfactant) and Transcutol P (co-surfactant) and water. All the formulations were prepared by water titration method and the microemulsions were optimized using 3 level Box Behnken statistical design. The prepared microemulsions were evaluated for globule size, Zeta potential, PDI, pH, viscosity and ex vivo drug permeation studies on excised porcine nasal mucosa. The optimized microemulsion (ME18) was composed of oil (Oleic acid), Smix (Labrasol: Transcutol P; 3:1) and water in the ratio of 5:60:65 showed the globule size of 85.071 nm, zeta potential -32.008 mV and flux 720.24μg/cm2/h. The flux of microemulsion containing 0.5% chitosan (MME) as permeation enhancer and mucoadhesive agent was significantly high (984.28μg/cm2/h).The enhancement ratio(ER) of MME was 6.15 folds to drug solution and 1.36 folds to ME18. The pharmacokinetic and pharmacodynamic evaluation of optimized microemulsion ME18 and MME was investigated using male Wistar rats and compared to CZP drug solution orally and nasally. The DTE (Drug targeting efficiency) and %DTP (Direct nose to brain transport) were found to be 3.73 and 78.45% for MME and 2.85 and 71.78% for ME18 which were significantly high (p<0.0001) compared to drug solution administered orally (DTE-0.80) and nasally (1.19 & 32.54%). Antipsychotic effect of optimized MME and ME18 was evaluated in (+)-MK801 induced rat model by assessing locomotor activity. The motor activity was induced by using (+)-MK801 and the locomotion counts were determined by photoactometer and compared to treated groups. The results showed that the significant recovery was found in ME18, MME treated groups compared to drug solution (orally and nasally). From the results, it is clear evident that the intranasal route is far superior to oral route for delivery of clozapine to the brain and ME & MME showed significantly high action than nasal solution and oral solution. Thus, the intranasal MME of clozapine may be clinically useful for treating schizophrenia.
Source: SSRN Electronic Journal
Institution: Kakatiya University
Language: English
Subfield: Pharmaceutical Science
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3133553993