PAMAM dendrimer based formulation of haloperidol for brain targeting via intranasal delivery

Yogesh K Katare (Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada)
Ritesh P Daya (Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada)
Christal Sookram (Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada)
Roger Luckham (Department of Chemistry, McMaster University, Hamilton, ON, Canada)
Jayant Bhandari (Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada)
Abhay S Chauhan (School of Pharmacy, Concordia University, Wisconsin, WI USA)
Ram K Mishra (Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada)


Delivery of therapeutics across blood brain barrier is a challenging task as most small organic molecules have inadequate aqueous solubility, limited bioavailability or poor permeation across blood brain barrier (1). Intranasal drug delivery has been reported to target drugs to the brain via olfactory nerve pathway and trigeminal nerve pathways. Water insoluble drugs needs to be formulated into drug delivery systems like nanoparticles for efficient brain targeting (2). Dendrimers have been reported to improve the delivery of water-soluble radiolabeled siRNA complexes incorporated into in situ forming mucoadhesive gels (3). In the present investigation, we studied the effect of Polyamidoamine (PAMAM) dendrimer entrapment of, haloperidol, a water insoluble drug, and its targeted delivery to the brain when administered intranasally.

Materials and Methods

Dendrimer based formulation of haloperidol (D-HP) was prepared and characterized for drug content, particle size, zeta potential and in vitro release profile of haloperidol. The control haloperidol formulation (HP-A) consisted of 1 mg/ml solution of haloperidol in 0.2 % acetic acid in water. Effect of formulation on the binding of haloperidol to dopamine D2 receptors in bovine striatal membranes was determined by competitive receptor binding assay. For in vivo evaluation of the formulation, D-HP was delivered via intranasal (IN), oral and intraperitoneal (IP) routes to Sprague Dawley rats. Doses administered were equivalent to 0.3 mg/Kg body weight of haloperidol through IN and oral routes and 2 mg/Kg body weight through the IP route. Behavioral responses (catalepsy and motor suppression) and tissue distribution in brain and plasma of rats following these modalities of administrations and following the IP administration of a similar dose of control haloperidol (HP-A) were evaluated according to the procedures reported previously (4-6). For estimation of haloperidol concentration in brain tissue and plasma, animals were sacrificed one hour after administration and assessed with HPLC-MS .


More than a 100 fold improvement in the aqueous solubility was achieved by using 1 % w/v dendrimer along with 20% v/v ethanol and 2% v/v Tween-20 in the D-HP formulation; leading to final solubility of 1.2 mg/ml. The average size of the dendrimer was 15.10±5.4 nm and mean zeta potential was 10.7±1.75 mV, these values were not significantly different from those observed with the blank dendrimer formulation prepared without haloperidol (D-Veh). Binding to dopamine D2 receptors of haloperidol was unaffected by formulation into the dendrimers. IN administration of the formulation D-HP led to significant motor suppression and cataleptic responses in rats, while the oral administration of equal dose of the same formulation did not produce these effects. The magnitudes of behavioral effects observed following intranasal administration of D-HP were similar to those obtained following the IP administration of 6.7 fold higher doses of formulation D-HP or HP-A (Fig 1). Formulation D-HP, when administered intraperitoneally at dose 2 mg/Kg body weight, produced significantly higher plasma and brain tissue concentrations then those obtained following the administration of similar dose of HP-A or following the IN administration of 0.3 mg/Kg of haloperidol. Percent of administered haloperidol present in the olfactory bulb and cerebellum following IP administration of D-HP were significantly higher than those obtained following the IP administration of equivalent dose of HP-A, but not from those obtained following IN administration of the D-HP. Mean value of the percent of administered doses present in striatum were highest in the rats administered with D-HP by the IN route, which were significantly higher than those obtained following IP administration of HP-A. Oral administration of D-HP, where the dose was equivalent to that administered to the IN group, did not result in a detectable quantity of haloperidol in both brain tissues and plasma. Ratio of percent of dose present in each gram of straitum to the percent of dose present in plasma was highest following intranasal administration.

Discussion and Conclusion

Dendrimer based formulations of water insoluble drugs provides a means for their targeting to the brain via intranasal delivery. Lack of behavioral responses as well as non-detectable levels of haloperidol in the tissue and plasma of rats, which were administered an equal dose by oral administration rule out the possibility that intranasally administered haloperidol is reaching brain through ingestion and subsequent absorption into systemic circulation. The absence of detectable concentrations in haloperidol following IN administration also suggest that haloperidol is not being absorbed into systemic circulation following oral administration. Improved delivery of haloperidol to straitum following intranasal administration of D-HP corraborates with earlier report, where intranasal delivery of haloperidol encapsulated into PLGA nanoparticles has shown better targeting of haloperidol to striartum as compared to the IP administration of HP-A (4). A high ratio of percentage dose in the striatum to plasma achieved following intranasal administration of the dendrimer based formulation demonstrates that dendimer based solubilization is a compelling strategy for the targeted delivery of hydrophobic drugs to the brain.

Figure 1: Effect of administration of D-HP through IP, IN, oral routes, HP-A through IP route and D-Veh through IP route on locomotion scores (A and B) during two hours post administration and catalepsy in adult rats (n=3) at 30 minutes (C and D) and 60 minutes (E and F) post-administration.

Figure 2: Distribution of haloperidol in olfactory bulb, striatum, cerebellum and plasma of rats (n=3) at 60 minutes following administration of formulation D-HP through IP, IN, oral route and following HP-A through IP route. Percent of total dose administered present in 1 g of tissue, has been plot


Ontario Mental Health Foundation (OMHF), Canadian Institutes of Health Research (CIHR) and the Collaborative Health Research Program (CHRP –CIHR and NSERC).


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