The Journal of International Medical Research 1990; 18 (suppl 1): 35 - 41

Pharmaceutical Manipulation of Leuprorelin Acetate to Improve Clinical Performance H. Toguchi Research and Development Division, Takeda Chemical Industries Ltd, Osaka, Japan

Leuprorelin acetate, a highly potent luteinizing hormone releasing hormone agonist, was originally launched in the USA to be administered once daily by self-injection for the treatment of metastatic prostatic cancer. A once-monthly intramuscularly or subcutaneously injectable depot form of leuprorelin acetate has, subsequently, been developed. Biodegradable copolynn-Iactlc acid/glycolic acid) was chosen as the release-controlling polymer and the microcapsules containing leuprorelin acetate were prepared by an in-water drying method. Results of studies in rats showed that a copolymer with a molecular weight of 14 000 and a lactic acid/glycolic acid ratio of 75/25 had the most satisfactory releasing properties. Microcapsules givenoncemonthly reduced serum testosterone levels in rats, dogs and man. In clinical studies, the depot preparation effectively reduced the dose ofleuprorelin acetate required to up to one-eighth of that needed when injected daily. A sophisticated manufacturing system has now been developed and a very reliable controlled-release product is now available that has many advantages. L'acetate de leuproreline, un tres puissant agoniste des hormones Iutelnisantes, a ete lance it I'origine aux Etats-Unis en vue d'etre administre une fois par jour par injection dans Ie traitement du cancer prostatique metastatique, L'acetate de leuproreline sous presentation retard, injectable par voie sous-cutanee ou intramusculaire une fois par mois, a ainsi ete developpe. Le copolymere biodegradable (acide Iactlque-m/acide glycellque-m) a ete choisi comme polymere de con-

Address for correspondence: Dr H. Toguchi, Research and Development Division, Takeda Chemical Industries Ltd, 27 Doshomachi 2-Chome, HigashiKu, Osaka, Japan.

© Copyright 1990 by Cambridge Medical Publications Ltd

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H. Toguchi

trole de liberation et les microgelules contenant I'acetate de leuproreline ont ete preparees par la methode de sechage dans I'eau. Les resultats de I'etude chez les rats ont mis en evidence qu'un copolymere d'un poids moleculaire de 14000 et d'un rapport acide lactique/acide glycolique de 75/25 presentait les proprietes de liberation les plus satisfaisantes. Les microcapsules administrees une fois par mois ont diminue les taux seriques de la testosterone chez Ie rat, Ie chien et I'homme. Dans les etudes c1iniques, la preparation retard a diminue conslderablement la dose d'acetate de leuproreline requise d'un huitieme de ce qui etait necessaire lors d'une injection journaliere. Un systeme de fabrication sophistique a maintenant ete developpe et un produit de liberation controlee tres fiable et presentant de nombreux avantages est maintenant disponible. IIleuprorelin acetato, un agonista del LHRH di elevata potenza estato lanciato, originariamente, negli USA, in preparato per auto-iniezione da somministrare una volta al giorno, per ll trattamento del cancro alia prostata metastatico. Successivamente, estata messa a punto una forma 'rltardo' di leuprorelin acetato, iniettabile per via sottocutanea od intramuscolare, una volta al mese. Un copolimero biodegradabile (nt-acldo lattico/acido glicolico) e stato scelto come polimero di controllo del rilascio e Ie microcapsule contenenti il leuprorelin acetato sono state preparate con un metodo di essiccamento in acqua. I risultati degli studi condotti sui ratti hanno evidenziato che un copoIimero con un peso molecolare di 14000 ed un rapporto acido lattico/ acido glicolico pari a 75/25 presenta Ie piiI soddisfacenti proprieta di rilascio. Le microcapsule somministrate una volta al mese hanno ridotto i livelli serichi di testosterone nei ratti, nei cani e negli uomini. Negli studi c1inicicondotti, la preparazione 'rttardo' ha efficacemente ridotto la dose dl leuprorelin acetato necessaria fino ad un ottavo di quella necessaria in caso di somministrazione giornsliera. Oggi, e, stato realizzato un sofisticato impianto produttivo ed edisponibile un prodotto nella formulazione 'ritardo', estremamente affidabile e dai molteplici vantaggi. KEY WORDS: Leuprorelin acetate; controlled release; microcapsule; biodegradable polymer; luteinizing hormone releasing hormone agonist; serum testosterone; prostatic cancer.

INTRODUCTION

T

he suppression of serum testosterone concentration to the castration level by daily administration of leuprorelin acetate has proved effective in treating metastatic prostatic cancer' and a once-daily injectable form ofleuprorelin acetate for selfadministration was made available commercially in the USA in 1985. Administra-

tion of this drug daily for the rest of a patient's life, however, would place a considerable burden on the patient; thus the aim was to develop a once-monthly depot to increase patient compliance. A depot form would enable luteinizing hormone releasing hormone receptors to be exposed constantly to leuprorelin acetate, thus greatly enhancing the efficacy of the drug.

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Improved performance leuprorelin acetate

H

{

~

~H O-CH ~C-O-CHz- ~C-O-CHz-C~} OH

O-~H-C-O-~H-C

CH 3

CH 3

2-

x

I

Copoly(DL-lactic acid/glycolic acid)

y

Hp

oII HO-CH-C-OH I

oII

+ HO-CHz- C-OH

Biodegradation products

CH 3 Lactic acid

Glycolic acid

Fig. 1. Structure and biodegradation products of copolymt-lactlc acid/glycolic acid). PREPARATION OF THE MICROCAPSULES

Copoly(DL-lactic acid/glycolicacid) (PLGA), which is used in absorbable surgical sutures, slowly decomposes non-enzymatically in the body to yield lactic acid and glycolic acid (Fig. 1), which are both readily metabolized by the body; from a safety standpoint, therefore, this copolymer would be an ideal release-controlling material. Another feature of PLGA is that it can be synthesized without a catalyst, thus avoiding the possibility of a potentially toxic compound being present in the depot preparation. To find the copolymer with the optimal depot properties PLGA plates with varying molecular weights and lactic acid/glycolic acid ratios were implanted in rats and the disappearance patterns were determined. For a once-monthly depot, a polymer with a molecular weight of 14000 and a lactic acid/glycolic acid ratio of 75/25 met the requirements most effectively.' Microcapsules containing leuprorelin acetate were prepared by an in-water drying method, which involved emulsifying an aqueous solution of leuprorelin acetate in a methylene chloride solution of PLGA. The emulsion was then dispersed in a 5% aqueous solution of poly(vinyl alcohol) to form

a water/oil/water emulsion. The methylene chloride was subsequently evaporated off by bubbling air through the emulsion, leading to the drug being encapsulated. The wet microcapsules were collected by centrifugation, freeze dried and then vacuum dried to remove any residual organic solvent. The selection of the optimal processing temperature and the optimal viscosity of each solution was essential to obtain wellshaped microcapsules and to entrap efficiently the water-soluble drug.' ANIMAL EXPERIMENTS

Microcapsules of 20 urn diameter were easily injected either subcutaneously or intramuscularly into rats using a suspending vehicle and a conventional syringe with a 23 gauge needle. The leuprorelin acetate remaining in the microcapsules at the excised injection site was measured at intervals for up to 4 weeks;" leuprorelin acetate was released at a constant rate over this period (Fig. 2). Intramuscular injection of microcapsules containing 13.5 - 1350 ~g leuprorelin acetate suppressed serum testosterone levels in rats (Fig. 3a), the effect being maintained for 6 weeks. Leuprorelin acetate also dose dependently reduced genital organ 37

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H. Toguchi

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