Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
1992-12-28
2001-06-12
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S423000
Reexamination Certificate
active
06245358
ABSTRACT:
The present invention relates to stable lyophilized formulations containing polymer-bound anthracycline glycosides.
Anthracycline antibiotics are among the most effective and widely used antitumour agents. The best known members of this class of compounds are Doxorubicin, Daunorubicin, Epirubicin and Idarubicin, which are used clinically to treat a variety of tumours. Several new derivatives have been synthesized for the purpose of finding an analogue with enhanced activity and/or lower toxicity, and some have already entered clinical trials.
Anthracycline antibiotics display good activity against human neoplasms, including some solid tumours. Toxic side-effects, including cardiomyopathy, the occurrence of which is related to the total dose of the drug, are associated to the administration of these with little preferential accumulation of the active drug in tumour tissue.
Numerous attempts have been made to improve therapeutic index and specificity of anthracyclines either by modifying their mode of delivery or by using a variety of drug delivery systems, such as liposomes, microspheres, antibodies, etc.
Synthetic polymers based on N-alkyl-methacrylamide, wherein the alkyl group may contain one or more hydroxy groups, have been proposed as potential drug carriers: see U.S. Pat. No. 4,062,831, U.S. Pat. No. 4,097,470 and EP-A-187547. Such polymers are soluble in aqueous media and have good biocompatibility.
The copolymerization of N-alkyl-methacrylamide, wherein the alkyl group contains one or more hydroxy groups, with p-nitrophenylesters of N-methacrylolyl oligopeptides gives a polymer containing oligopeptide side chains terminating in reactive p-nitrophenyl ester groups, which allow binding to many drugs containing a primary amino group, such as anthracycline glycosides and, optionally, targeting moieties containing a primary amino group.
The so formed polymer-anthracycline glycoside conjugates consist therefore of an inert polymeric carrier, which is a N-alkylmethacrylamide based copolymer, combined through peptide spacers with an anthracycline glycoside and, optionally, a targeting moiety. Preferably the inert polymeric carrier is N-(2-hydroxypropyl)methacrylamide (HMPA).
The oligopeptide spacers are cleaved only after internalization into cells by lysosomal thiol dependent proteinases (see, for example, Duncan R. et al. in Makromol. Chem. 184, 1997-2005, 1983). The targeting moieties optionally present within the polymer structure are able to interact with specific receptors on cell surfaces. For example, galactose interacts with receptors localized on plasma membrane of liver/cells. In this manner the drug is specifically delivered to cancer tissue, such as hepatoma.
The said polymer-anthracycline glycoside conjugates have been shown to possess antitumour activity in vivo, and decreased toxicity: for example, approximately 10-fold more doxorubicin can be administered in conjugate form without overt signs of toxicity (see, for example, Duncan R. et al. in Br. J. Cancer 57, 147-156, 1987; Duncan R. et al. in J. Controlled Release 10, 51-64, 1989; Cassidy J. et al. in Biochem. Pharmacol. 38, 875-880, 1989).
The synthesis of the above mentioned conjugates has also been described (see, for example, Rihova B. et al. in Biomaterials 10, 335-342, 1989).
Particular conjugates between the HPMA copolymer and the anthracycline glycosides are:
(i) a conjugate composed of x mol % of units of formula (A), y mol % of units of formula (B) and z mol % of units of formula (C):
and (ii) a conjugate composed of x mol % of units of formula (A) above, y mol % of units of formula (B) above, z mol % of units of formula (D) and w mol % of units of formula (C) above:
For simplicity only Doxorubicin conjugates are shown. The conjugate (i) is termed “PK1” in which x varies from 85 to 98 mol %, y varies from 1 to 10 mol % and z varies from 0 to 14 mol %. The conjugate (ii) is termed “PK2” in which x varies from 80 to 97 mol %, y varies from 1 to 10 mol %, z varies from 0 to 18 mol % and w varies from 1 to 18 mol %. In each conjugate, the anthracycline antibiotic is linked to the HPMA copolymer by a tetrapeptide sequence attached to the sugar amine of the anthracycline by a peptide bond. This linkage is resistant to acid hydrolysis, but the glycosidic bond between the sugar amine ring and the aglycone moiety is hydrolysed relatively easily, releasing the free aglycone.
The conjugates (i) and (ii) may be shown below as formulae (I) and (II):
As illustrated by Seymour L. W. et al in Biochemical Pharmacology 39, 1125-1131, 1990, following intravenous administration to mice, the pharmacokinetics of Doxorubicin were markedly altered by its conjugation to HPMA copolymer: the high initial levels of free Doxorubicin in plasma observed following administration of free drug were absent in the case of polymer Doxorubicin conjugates and the subsequently high levels of free Doxorubicin seen in other tissues were also abolished. In contrast, the circulating half-life of polymer Doxorubicin conjugates was approximately 15 times longer than that of the free drug. The initial peak level of free Doxorubicin in the heart was reduced 100-fold following administration of drug-conjugate.
As high levels of anthracyclines in cardiac tissue are known to correlate with tissue damage and cumulative, delayed-onset cardiotoxicity, the decreased cardiac levels observed following administration of HPMA copolymer—Doxorubicin conjugate are a very important issue and may account for the decreased toxicity and improved efficacy reported in the literature for the polymer-conjugated drug: for example, a recent study using rats has shown a marked reduction in the toxicity of the HPMA copolymer Doxorubicin conjugate, with no evidence for any decrease in cardiac output up to 20 weeks following administration of the drug. In this study Doxorubicin was applied at 4 mg/Kg, a dose that is usually lethal when administered to rats in unconjugated form (for details, lease refer to Yeung T. K. et al in “Proceedings of the British Association for Cancer Research Meeting”, Glasgow, UK, Apr. 10, 1989).
The significant reduction in the cardiac doxorubicin content using stable, covalent polymer—conjugated drug is thought to be related to the fact that these conjugates are stable in the bloodstream and are only cleaved intracellularly.
Similar HPMA copolymer—Daunomycin conjugates used to treat Walker Sarcoma in Wistar rats have been able to show both improvement in the therapeutic response compared with free Daunomycin and also a large increase in the amount of free Daunomycin detected in the tumour following administration of the polymer conjugated drug (see Cassidy J. et al in Biochem. Pharmacol. 38, 875-880, 1989). It has been speculated that this passive tumour targeting of the HPMA copolymer—Daunomycin conjugate may be related to the prolonged circulation of the drug in the bloodstream: in fact, certain tumours, including Walker Sarcoma, are known to have high rates of pinocytosis in vivo, and it has been suggested that extending the circulation times of antineoplastic drugs may elevate their relative concentrations in tumour cells (see, for example, Trouet A. et al in Nature New Biol. 239, 110-112, 1972, and Busch H. et al in Cancer Res. 21, 371-377, 1981).
We have now investigated the formulation of anthracycline-HPMA copolymer conjugates. We found that, although the aqueous equilibrium solubility of polymer-anthracycline glycoside conjugates is sufficiently high (>5% w/v), these polymers have got a remarkable hydrophobicity so that their dissolution rates in water were quite slow. Hence we found that, if lyophilized alone, anthracycline-HPMA copolymer conjugates formed a freeze-dried cake which dissolved very slowly. Complete dissolution took a very long time, i.e. even more than 30 minutes with continuous shaking. This is disadvantageous because of the recognized toxicity of the anthracycline glycosides family.
Moreover we found that, after reconstitution with sterile water or with sterile physiological saline or with any other aqueous phy
Adami Marco
Magrini Roberto
Maranghi Paolo
Suarato Antonino
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Pharmacia & Upjohn S.p.A.
Webman Edward J.
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