A poly(d,l-lactide-co-glycolide) microsphere depot system for delivery of haloperidol

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Abstract

Haloperidol-loaded biodegradable poly(d,l-lactide-co-glycolide) (PLG) microspheres, with theoretical mean particle sizes of about 0.8, 2 and 8 μm, have been successfully prepared by using an emulsification–solvent evaporation method. The effect of various processing parameters such as the content of polymer in dichloromethane, the content of polyvinyl alcohol in the aqueous phase, and the stirring speed of emulsification on the particle size and size distribution of microspheres has been investigated and three optimal procedures suggested. The influence of particle size on drug content and incorporation efficiency of haloperidol-loaded PLG microspheres also has been evaluated. In vitro a linear release of haloperidol from PLG microspheres over an extended period of time without a significant burst effect has been achieved; the time of 50% drug release (T50%) being around 55 days. The effect of drug content and particle size on the cumulative release of haloperidol from PLG microspheres was also studied together with the reproducibility of drug content and release profile from batch-to-batch with different particle sizes.

Introduction

Schizophrenia is the most common of the major psychoses. Drug therapy is so far the normal treatment method for schizophrenia with compounds generally classified as antipsychotics, neuroleptics and major tranquillisers [1]. Drug maintenance therapy is a very important strategy to prevent relapse, after an acute psychotic episode has resolved and the patient is free of overt psychotic symptoms [2]. Oral dosage forms (tablets, capsules and solutions) and long-acting depot injections are presently available for clinical practice. Depot formulations have several advantages over oral dosage forms: (a) less frequent administration, e.g., a patient can receive an intramuscular injection once every three or four weeks instead of ingesting capsules or tablets 1–3 times daily; (b) improved patient compliance and more predictable absorption; (c) fewer extra pyramidal side-effects and reduced medical workload. Indeed, depot therapy has allowed psychiatrists to develop the full therapeutic potential of maintenance medication [3]. So far these long-acting depot formulations of neuroleptics consist of decanoate esters of haloperidol (haloperidol decanoate), fluphenazine (fluphenazine decanoate) and flupenthixol (flupenthixol decanoate) as prodrug in oily vehicles, such as sesame oil. After deep intramuscular injection, the esters are slowly released from their oily depot and then hydrolysed from the prodrug into the original parent pharmacologically active neuroleptics [4]. These formulations have certain disadvantages. They can cause a feeling of pain during administration due to the oily nature of the formulation, which has less distribution and bigger injection resistance in the muscle tissue compared to an aqueous formulation. Furthermore, the ester link of the prodrug is broken by tissue esterases to liberate the free drug, and tissue esterases can vary in the individual and with age [5]. Hence it would be beneficial to develop alternative depot delivery systems containing active neuroleptics.

Biodegradable microparticles produced from natural and synthetic polymers have been extensively investigated as drug carriers in controlled drug delivery. Natural polymers such as proteins and polysaccharides usually vary in purity because they originate from natural sources and often require cross-linking during a microencapsulation process, which can lead to denaturation of the embedded drug. Therefore, synthetic polymers are preferable for the development of commercial products. Poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and their copolymer poly(lactide-co-glycolide) (PLG) are the most widely used and studied class of synthetic biodegradable polymers because of their good histocompatibility and biodegradability [6]. They has been widely exploited for the microencapsulation of drugs, e.g., narcotic antagonists, fertility controlling agents, anticancer agents, local anaesthetics, antibiotics and vaccines, to obtain sustained or controlled release of the therapeutic agent. The biodegradation rate of these polymers will be influenced by many factors, such as particle surface area, porosity, molecular mass, molecular ratio of the lactide/glycolide, pH etc., and can vary from several days to years. The concept of microencapsulation of antipsychotics using biodegradable PLG polymer for depot controlled release is both interesting and attractive. The active neuroleptic can be loaded directly into the PLG microspheres during production. The microspheres can be suspended in an aqueous solution and then readily injected intramuscularly once every one to two months. A copolymer PLG 50:50 with an in vitro degradation rate about 50–60 days is considered to be good choice for a drug microsphere implant system designed for one to two months duration.

Haloperidol is a widely prescribed drug for the treatment of psychotic episodes. It is a good model neuroleptics for microencapsulation using the biodegradable PLG copolymer because of its lipophilic property and very low daily effective dose range (by intramuscular administration: 2–10 mg of haloperidol every 4–8 h or 50–100 mg of haloperidol as decanoate ester every four weeks) 2, 7, 8. A small mean particle size of microspheres will be favourable for an aqueous suspension injection in order to achieve easy administration and syringeability by injection. In this report, an emulsification–solvent evaporation method has been used to prepare haloperidol-loaded PLG microspheres of theoretical particle sizes of 0.8, 2 and 8 μm. The following factors were studied: (a) the reproducibility of the particle size distribution; (b) the incorporation of haloperidol into the PLG microspheres; (c) the burst effect and release of haloperidol in vitro from the haloperidol-loaded PLG microspheres.

Section snippets

Materials

PLG (lactide–glycolide ratio: 50:50; inherent viscosity: 0.50–0.65 dl/g) was supplied by Medisorb, USA. Haloperidol, sodium dodecyl sulfate (SDS), phosphate buffered saline (PBS) tablets, and polyvinyl alcohol (PVA) (Mr 30 000–70 000, cold water soluble) were supplied by Sigma, Poole, UK. Dichloromethane (DCM) was obtained from Fisons, Lougborough, UK. All materials were used as supplied.

Preparation of haloperidol-loaded PLG microspheres

Haloperidol-loaded PLG microspheres were prepared using an emulsification–solvent evaporation method. A

Optimal procedures

The emulsification–solvent evaporation method is the most common technique used for preparation of PLG microspheres. Although the method is conceptually simple, many factors have been shown to influence the final characteristics of resultant PLG microspheres 10, 11. The optimal processing parameters, the mean particle size and size distribution of haloperidol-loaded PLG microspheres are summarised in Table 1 and Fig. 1a–b. Incorporation of haloperidol in/onto PLG microspheres had little effect

Conclusions

This work has confirmed that haloperidol-loaded microspheres with three theoretical mean particle sizes of 0.8, 2 and 8 μm can be prepared successfully using the emulsification–solvent evaporation method by adjusting various processing parameters. The in vitro controlled release of haloperidol over four to nine weeks (without a significant burst effect) from drug-loaded PLG microspheres of three different particle sizes, indicates the possibility of providing a long-acting depot formulation for

Acknowledgements

We thank Ms. Catherine Otori of the Department of Pharmaceutical Sciences, The University of Nottingham for help with the GC–MS assay of the residual DCM in PLG microspheres.

References (17)

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