US 2003.0114430A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0114430 A1 MacLeod et al. (43) Pub. Date: Jun. 19, 2003 (54) STABILIZED INJECTABLE SUSPENSION OF Publication Classification A STEROIDAL DRUG (51) Int. Cl." ......................... A61K 31156; A61K 31/57; (76) Inventors: Steven K. MacLeod, Portage, MI (US); A61K 9/14 Lloyd E. Fox, Richland, MI (US); Neal (52) U.S. Cl. ........................... 514/177; 514/182; 424/489 S. Adams, Kalamazoo, MI (US); David J. Salvat, Marcellus, MI (US) Correspondence Address: (57) ABSTRACT PHARMACIA CORPORATION 800 NORTH LINDBERGH BLVD. A parenterally deliverable composition is provided, com MAIL ZONE 04E prising an aqueous medium having dispersed therein, in ST. LOUIS, MO 63167 (US) Solid particulate form, a Steroidal drug in a therapeutically effective amount. The aqueous medium comprises one or (21) Appl. No.: 10/225,320 more wetting and/or Suspending agents in an amount effec tive to provide controlled flocculation of the drug, at least (22) Filed: Aug. 21, 2002 one of the wetting and/or Suspending agents being Suscep Related U.S. Application Data tible to oxidative degradation. The composition further comprises, as a component thereof or as an adjunct thereto, (63) Continuation-in-part of application No. 09/571,395, means for protecting the Oxidative degradation Susceptible filed on May 15, 2000, now Pat. No. 6,495,534. agent from oxidative degradation. Patent Application Publication Jun. 19, 2003 US 2003/0114430 A1 Fig. 1 US 2003/0114430 A1 Jun. 19, 2003 STABILIZED INJECTABLE SUSPENSION OFA thickening of the formulation and/or poor resuspendability STEROIDAL DRUG of a Solid deposit, and, especially in unbuffered or weakly buffered formulations, can be accompanied or mediated by 0001. This application is a continuation-in-part of U.S. a drift in pH with time, usually a downward drift. Excessive application Ser. No. 09/571,395, filed on May 15, 2000. drift in pH of an injectable formulation is undesirable not only for its impact on physical Stability of the formulation FIELD OF THE INVENTION but also because of the risk of carrying the formulation 0002 The present invention relates to pharmaceutical outside a biocompatible pH range. compositions in the form of aqueous Suspensions, more 0008. It would be of benefit in the art to provide an particularly to Such compositions Suitable for parenteral aqueous Suspension formulation of a Steroidal drug exhib administration, for example by intramuscular, Subcutaneous iting enhanced shelf life. In particular, where shelf life is or intradermal injection. The invention relates especially to limited by drug particles forming a deposit that is difficult to parenterally deliverable aqueous Suspensions containing as resuspend, there would be great advantage in enhancing active agent in particulate form a steroidal compound or Salt Stability. Where the formulation is packaged in a unit-dose thereof. container Such as a vial or pre-filled Syringe, it is particularly important to be able to resuspend Substantially all of a drug BACKGROUND OF THE INVENTION deposit so that the full dose can be administered. It would 0003) A well-known approach to stabilizing an aqueous also be of benefit to improve the pH stability of Such a Suspension formulation of a drug is by the principle of formulation. controlled flocculation. According to Such an approach, an aqueous medium or vehicle for the drug is provided that SUMMARY OF THE INVENTION permits aggregation of particles of the drug to form a floc. A desirable floc is one that tends to settle but is readily 0009. There is now provided a parenterally deliverable resuspended with slight agitation and remains in uniform composition comprising an aqueous medium having dis Suspension during a period of time long enough to permit persed therein, in Solid particulate form, a Steroidal drug in a therapeutically effective amount. The aqueous medium administration, for example parenterally, to a Subject. Con comprises one or more wetting and/or Suspending agents in trolled flocculation of a hydrophobic drug Such as a Steroid an amount effective to provide controlled flocculation of the generally requires presence in the aqueous medium of one or drug, at least one of the wetting and/or Suspending agents more wetting agents and one or more Suspending agents. being Susceptible to oxidative degradation. The composition 0004 U.S. Pat. No. 3,457,348 to Nash & Haeger, incor further comprises, as a component thereof or as an adjunct porated herein by reference, discloses that polyoxyethylene thereto, means for protecting the oxidative degradation nonionic Surfactants, for example polyoxyethylene Sorbitan Susceptible agent (hereinafter the “Susceptible agent') from monooleate, are Suitable wetting agents for this purpose. A oxidative degradation. formulation of Sulfadiazine comprising polyoxyethylene 0010 Non-limiting examples of means for protecting the sorbitan monooleate and polyethylene glycol (PEG) of Susceptible agent from Oxidative degradation include pres molecular weight 4000 is specifically described therein. ence of an antioxidant or oxygen Scavenger in the compo 0005 Polysorbates such as polysorbate 80 (polyoxyeth Sition, presence of a chelating agent in the composition, and ylene (20) Sorbitan monooleate) and PEGs of molecular provision of an oxygen-depleted atmosphere in headspace weight from about 1000 to about 20,000 such as PEG 3350 overlying the composition in a Sealed vessel. are known wetting and Suspending agents for use in inject able aqueous injection formulations of Steroidal drugs. For 0011. It has surprisingly been found that by providing example, Depo-Provera(E) contraceptive injection of Phar means for protecting the Susceptible agent from oxidative macia & Upjohn is an aqueous Suspension formulation of degradation, the composition exhibits significantly the Steroidal drug medroxyprogesterone acetate containing: improved physical Stability during Storage, as manifested for example by a significantly reduced tendency of the drug to form deposits that are difficult to resuspend. It has also been observed that significant improvement in pH stability of the medroxyprogesterone acetate 150 mg composition can result from provision of Such protecting PEG 3350 28.9 mg polysorbate 80 2.41 mg CS. sodium chloride 8.68 mg methylparaben 1.37 mg 0012. By “oxidative degradation” is meant chemical propylparaben 0.15 mg change in a wetting and/or Suspending agent arising from water for injection q.S. to 1 ml reaction with oxygen or other oxidizing agent. It will be understood that the present invention applies to composi tions as defined above whether or not the drug itself is 0006) See Physicians' Desk Reference, 56th ed. (2002), Susceptible to oxidative degradation; in a particular embodi pp. 2798-2801. ment, however, the drug is one that exhibits Substantial chemical Stability in presence of oxygen. 0007. It has been found that where an aqueous suspension of a Steroidal drug includes, for provision of Stability 0013 Many wetting and/or suspending agents useful in through controlled flocculation, compounds Such as polySor preparing parenterally deliverable Suspensions have been bates and/or PEGs having polyoxyethylene chains, the SuS found to be Susceptible to oxidative degradation in an pension tends to show a decline in Such Stability with time. aqueous medium. Examples of Such agents are those com This decline in Stability can be manifested, for example, in prising polyoxyethylene chains, for example polyethylene US 2003/0114430 A1 Jun. 19, 2003 glycols and polyoxyethylene Surfactants Such as polySor tane, epristeride, equilenin, equilin, ergosterol, estradiol, bates. In presence of oxygen, the wetting and/or Suspending C-estradiol, estramustine, estriol, estrone, ethinyl estradiol, properties of these agents are gradually lost as degradation ethisterone, ethyleStrenol, ethynodiol, etonogeStrel, exemes occurs. It is believed, without being bound by theory, that tane, fluazacort, flucloronide, fludrocortisone, flumethasone, this loSS of wetting and/or Suspending properties due to flunisolide, fluocinolone, fluocinonide, fluocortin, fluocor oxidative degradation causes, or at least contributes Substan tolone, fluorometholone, fluoxymesterone, fluperolone, flu tially to, physical instability of a Suspension composition prednidene, fluprednisolone, flurandrenolide, flurogestone, lacking means for restricting exposure to oxygen. Compo fluticasone, formebolone, formeStane, formocortal, Sitions of the present invention typically exhibit significantly gestodene, gestonorone, gestrinone, halcinonide, halobeta reduced oxidative degradation of one or more wetting and/or Sol, halometasone, halopredone, hydrocortamate, hydrocor Suspending agents and thereby, it is believed, significantly tisone, hydroxydione, 17O-hydroxyprogesterone, lotepred enhanced physical Stability as illustrated herein. nol, lynestrenol, maZipredone, medrogestone, medroxyprogesterone, medrySone, megestrol, melengestrol, 0.014. In a particularly preferred embodiment of the mepitioStane, meprednisone, meStanolone, mesterolone, invention, the Susceptible agent is a polySorbate Surfactant, meStranol, methandriol, methandrostenolone, methenolone, for example polysorbate 80. The invention is illustrated methylprednisolone, 17-methyltestosterone, methyl herein with particular reference to compositions wherein the trienolone, mifepristone, mometasone, moxestrol, nan Steroidal drug is medroxyprogesterone acetate.