US 2004OO39366A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0039366A1 MacLeod (43) Pub. Date: Feb. 26, 2004

(54) INJECTABLE PHARMACEUTICAL (52) U.S. Cl...... 604/416; 604/82 SUSPENSION IN A TWO-CHAMBER VIAL (76) Inventor: Steven K. MacLeod, Portage, MI (US) (57) ABSTRACT Correspondence Address: PHARMACIA CORPORATION An article of manufacture is provided comprising a vial GLOBAL PATENT DEPARTMENT having (a) a first chamber that is substantially filled with an POST OFFICE BOX 1027 injectable pharmaceutical formulation; (b) a Second cham ST. LOUIS, MO 63006 (US) ber that is Substantially empty but for a gaseous medium; (c) a Septum, impermeable to the gaseous medium, Separating (21) Appl. No.: 10/644,516 the first and Second chambers; and (d) actuating means 22) Filled: Aug. 20, 2003 effective to bring the formulation and the gaseous medium (22) File lug. ZU, into contact by breach of the Septum Such that the gaseous Related U.S. Application Data medium acts as an effective headspace for agitation of the formulation. The formulation comprises an aqueous (60) Provisional application No. 60/404.988, filed on Aug. medium, a drug in Solid particulate form in a therapeutically 21, 2002. effective amount Suspended in the medium, and one or more wetting and/or Suspending agents in an amount effective to Publication Classification provide controlled flocculation of the drug, at least one ingredient of the formulation being Susceptible to oxidative 51) Int.nt. Cl.'Cl." ...... A61B 19/00 degradatiegradation.

Patent Application Publication Feb. 26, 2004 US 2004/0039366 A1

US 2004/0039366 A1 Feb. 26, 2004

INJECTABLE PHARMACEUTICAL SUSPENSION pension tends to show a decline in Such Stability with time. IN A TWO-CHAMBER VIAL This decline in Stability can be manifested, for example, in thickening of the formulation and/or poor resuspendability 0001. This application claims priority of U.S. provisional of a Solid deposit, and, especially in unbuffered or weakly application Serial No. 60/404,988 filed on Aug. 21, 2002. buffered formulations, can be accompanied or mediated by a drift in pH with time, usually a downward drift. Excessive FIELD OF THE INVENTION drift in pH of an injectable formulation is undesirable not 0002 The present invention relates to an article of manu only for its impact on physical Stability of the formulation facture and use thereof in delivering to a Subject in need but also because of the risk of carrying the formulation thereof a pharmaceutical composition in the form of a outside a biocompatible pH range. ready-to-use aqueous Suspension, more particularly Such a 0008 Polyoxyethylene chains are susceptible, in pres Suspension Suitable for parenteral administration, for ence of oxygen over time, to oxidation of C-H groups to example by intramuscular, Subcutaneous or intradermal C-O-O-H (hydroperoxy) groups. This oxidative degra injection. The invention relates especially to Such an article dation process is known to occur, for example, in polySor and use thereof wherein the Suspension contains an ingre bates. See Donbrow et al. (1978), J. Pharm. Sci. 67, 1676 dient that is Susceptible to oxidative degradation. 1681. The hydroperoxy groups are susceptible to further degradation by a variety of mechanisms, leading to cleavage BACKGROUND OF THE INVENTION of the polyoxyethylene chains and, at least in Some situa 0003) A well-known approach to stabilizing an aqueous tions, formation of formic acid and/or other compounds as Suspension formulation of a drug, particularly a poorly degradation products with a concomitant lowering of pH. Soluble drug, is by the principle of controlled flocculation. Presence and quantitation of degradation products and/or According to Such an approach, an aqueous medium or measurement of pH can provide an indication of the degree vehicle for the drug is provided that permits aggregation of of oxidative degradation, if any, that has occurred in a particles of the drug to form a floc. A desirable floc is one Sample of a formulation. that tends to Settle but is readily resuspended with slight 0009. Oxidative degradation can also affect formulation agitation and remains in uniform Suspension during a period ingredients other than those comprising polyoxyethylene of time long enough to permit administration, for example chains, with a variety of undesirable effects, including, in parenterally, to a Subject. Controlled flocculation of a poorly addition to decline in physical Stability and pH drift, accu Soluble drug generally requires presence in the aqueous mulation of degradation products that can be toxic or medium of one or more Wetting agents and one or more otherwise deleterious if administered by injection, and, Suspending agents. where the ingredient Subject to oxidative degradation is an 0004 U.S. Pat. No. 3,457,348 to Nash & Haeger, incor active ingredient, loSS of potency. porated herein by reference, discloses that polyoxyethylene 0010) By reducing or minimizing exposure of the formu nonionic Surfactants, for example polyoxyethylene Sorbitan lation to oxygen, problems of oxidative degradation can be monooleate, are Suitable wetting agents for this purpose. A Substantially overcome. For example, if an injectable for formulation of Sulfadiazine comprising polyoxyethylene mulation is packaged in an airtight container Such as a vial sorbitan monooleate and polyethylene glycol (PEG) of having little or no headspace acting as a reservoir of gaseous molecular weight 4000 is specifically described therein. oxygen, i.e., if the container is Substantially filled with the 0005 Polysorbates such as polysorbate 80 (polyoxyeth formulation, oxidative degradation is likely to be minimized. ylene (20) Sorbitan monooleate) and PEGs of molecular This can be an acceptable way to package a formulation that weight from about 1000 to about 20,000 such as PEG 3350 does not require agitation to homogenize the formulation are known wetting and Suspending agents for use in inject prior to use, for example a formulation in the form of an able aqueous injection formulations. For example, Depo aqueous Solution. However, the lack of headspace becomes ProveraF) contraceptive injection of Pharmacia & Upjohn is a Serious problem in the case of an aqueous Suspension an aqueous Suspension formulation of the Steroidal drug formulation exhibiting controlled flocculation, because it medroxyprogesterone acetate containing: greatly impedes ability to agitate the formulation, for example by Shaking the container, to resuspend a Settled floc and provide a fine homogeneous Suspension for parenteral injection. Where the formulation is packaged in a unit-dose medroxyprogesterone acetate 150 mg container Such as a Vial, it is particularly important to be able PEG 3350 28.9 mg polysorbate 80 2.41 mg to resuspend Substantially all of a drug deposit So that the sodium chloride 8.68 mg full dose can be administered. methylparaben 1.37 mg propylparaben 0.15 mg 0011. One approach to reducing exposure of an aqueous water for injection q.S. to 1 ml Suspension formulation to oxygen yet providing a Sufficient headspace for agitation is to provide an oxygen-depleted atmosphere in the headspace, for example an atmosphere 0006) See Physicians' Desk Reference, 56th ed. (2002), enriched in nitrogen or a noble gas. This approach is not pp. 2798-2801. always convenient, and it can be difficult and expensive in 0007. It has been found that where an aqueous suspension practice to displace Substantially all of the Oxygen from of a hydrophobic drug includes, for provision of Stability headspace atmosphere. through controlled flocculation, compounds Such as polySor 0012. It would be of benefit in the art to provide an bates and/or PEGs having polyoxyethylene chains, the SuS alternative means of reducing exposure to oxygen of an US 2004/0039366 A1 Feb. 26, 2004 injectable aqueous Suspension formulation, that permits for example polysorbate 80. The invention is illustrated resuspension by agitation immediately prior to use. herein with particular reference to an article containing a formulation wherein the drug is medroxyprogesterone SUMMARY OF THE INVENTION acetate. 0013 There is now provided an article of manufacture 0019. There is further provided a method of use of an comprising a vial having at least two chambers. A first article as described above in preparing a filled Syringe for chamber of the vial is substantially filled with a parenterally parenteral injection of a drug into a Subject. The method deliverable formulation that comprises (i) an aqueous comprises a step of actuating the Vial to bring the formula medium, (ii) a drug in Solid particulate form in a therapeu tion and the gaseous medium into contact by breach of the tically effective amount Suspended in the medium, and (iii) Septum, a step of agitating the Vial to permit the formulation one or more wetting and/or Suspending agents in an amount and the gaseous medium to interact to resuspend Settled effective to provide controlled flocculation of the drug, at particulate material in the formulation to form a Substan least one ingredient of the formulation being Susceptible to tially homogeneous Suspension; and a step of withdrawing oxidative degradation. A Second chamber of the Vial is the Suspension into a Syringe. Substantially empty but for a gaseous medium, and is Separated from the first chamber by a Septum that is Sub BRIEF DESCRIPTION OF THE DRAWINGS Stantially impermeable to the gaseous medium. The Vial further comprises actuating means effective to bring the 0020 FIG. 1 is a side elevation of a two-compartment formulation and the gaseous medium into contact by breach mixing vial that is an illustrative embodiment of the inven of the Septum Such that the gaseous medium acts as an tion. effective headspace for agitation of the formulation. 0021 FIG. 2 is a central sectional view of the vial shown 0.014. In a preferred embodiment the at least one ingre in FIG. 1. dient of the formulation that is susceptible to oxidative degradation (herein Such ingredient is referred to as the DETAILED DESCRIPTION OF THE “Susceptible agent”) is a wetting and/or Suspending agent, INVENTION for example, Such an agent comprising one or more poly 0022 AS indicated above, the present invention provides oxyethylene chains. an article of manufacture comprising a vial having (a) a first 0.015. It has surprisingly been found that by protecting the chamber that is Substantially filled with an aqueous Suspen Susceptible agent from oxidative degradation, the formula Sion formulation as described herein having properties of tion exhibits significantly improved physical stability during controlled flocculation; (b) a second chamber that is sub Storage, as manifested for example by a significantly Stantially empty but for a gaseous medium; (c) a Septum, reduced tendency of the drug to form deposits that are impermeable to the gaseous medium, Separating the first and difficult to resuspend. It has also been observed that signifi Second chambers; and (d) actuating means effective to bring cant improvement in pH Stability of the formulation can the formulation and the gaseous medium into contact by result from Such protection. breach of the Septum Such that the gaseous medium acts as 0016. By “oxidative degradation” is meant chemical an effective headspace for agitation of the formulation. change in a Susceptible agent arising from reaction with 0023 The formulation in the vial as transported and oxygen or other oxidizing agent. It will be understood that Stored prior to use is not in contact with a significant the present invention applies to an article as defined above headspace Volume, thus exposure of the formulation to whether or not the drug itself is susceptible to oxidative oxygen is minimized and the Susceptible agent in the for degradation; in a particular embodiment, however, the drug mulation is thereby protected from oxidative degradation. is one that exhibits Substantial chemical Stability in presence However, immediately prior to use, the vial can be actuated of oxygen. to create a headspace permitting ready agitation for resus 0017 Many wetting and/or suspending agents useful in pension of the formulation. There is generally no need for preparing parenterally deliverable Suspensions have been the gaseous medium that becomes the headspace to be found to be Susceptible to oxidative degradation in an oxygen-depleted, as the formulation is in contact with the aqueous medium. Examples of Such agents are those com headspace for only a short period of time. A preferred prising polyoxyethylene chains, for example polyethylene gaseous medium according to this embodiment is air, but an glycols and polyoxyethylene Surfactants Such as polySor oxygen-depleted atmosphere, for example one enriched in bates. In presence of oxygen, the wetting and/or Suspending nitrogen and/or a noble gas, can, if desired, be used. properties of these agents are gradually lost as degradation 0024. An illustrative two-compartment mixing vial suit occurs. It is believed, without being bound by theory, that able for the present purpose is disclosed in U.S. Pat. No. this loSS of wetting and/or Suspending properties due to 4,258,845 to Potts, incorporated herein by reference, and is oxidative degradation causes, or at least contributes Substan shown in FIGS. 1 and 2 herein. Specific details of this tially to, physical instability of a Suspension composition illustrative vial that are not explicitly described hereinbelow lacking means for restricting exposure to oxygen. Practice of are available to the reader by reference to above-cited U.S. the present invention typically results in Significantly Pat. No. 4,258,845. reduced oxidative degradation of one or more wetting and/or 0025 The illustrative vial 11, constructed of any suitable Suspending agents and thereby, it is believed, significantly material, preferably glass, defines therein two interior com enhanced physical Stability as illustrated herein. partments, a lower compartment 13 and an upper compart 0.018. In a particularly preferred embodiment of the ment 14, which are separated by a constriction 16 in which invention, the Susceptible agent is a polySorbate Surfactant, a Substantially airtight and watertight plug 17 is engaged. US 2004/0039366 A1 Feb. 26, 2004

The plug can be made of any Suitable material, but is engaged with the protruding portion 24 of the Stopper. The preferably of butyl rubber coated with a silicone fluid to sleeve 41 has at its upper end a radially outward directed maintain an effective seal as described in U.S. Pat. No. annular flange 44 and at its lower end an annular face 42 3,464,414 to Sponnoble, incorporated herein by reference. that, prior to actuation of the Vial, is spaced upwardly a The upper compartment 14 corresponds to the “first cham substantial distance from the shoulder 27 of the stopper. ber” and the lower compartment 13 to the “second chamber” Adjacent to the lower end face 42, the sleeve 41 is connected as defined above. The plug 17 corresponds to the Septum to an annular gripping portion 32 by a fracturable connection Separating the two chambers as defined above. 43, which can be formed as a thin annular flange or a plurality of Spaced webs. The open upper end of the sleeve 0026. The vial 11 has an annular neck 18 at one end 41 is preferably covered by a manually removable seal 46 thereof, defining an opening 19 for communication between formed of a Suitable material Such as metallic foil. a free end of the neck 18 and the interior of the upper compartment 14. The neck 18 in the illustrated embodiment 0030 The gripping portion 32 surrounds the rim 21 and is of Substantially the same interior diameter as the upper has at its lower edge a plurality of Substantially uniformly compartment 14, but optionally the neck 18 can be of Spaced projections 33 extending radially inward. The inner reduced diameter. Typically the neck 18, adjacent the free Surfaces of the projections 33 define a circle having a end thereof, has a radially outward projecting annular rim diameter Somewhat less than the outside diameter of the rim 21. The upper compartment 14 is substantially filled with an 21, Such that the projections 33 resiliently Snap into position aqueous Suspension formulation as described herein, and the directly under the rim 21 to effect a Secure locking of the cap lower compartment 13 contains only a gaseous medium, for assembly on to the neck of the vial. The gripping portion 32 example air. comprises an annular plate 34 that overlies the upper end of the neck 18 of the vial. The annular plate 34 circumscribes 0027. The neck 18 is provided with a closure structure 12 a plate opening 36 of diameter Smaller than the neck opening that can be of any Suitable design, but in the illustrated 19, such that the annular plate 34 projects radially inward to embodiment comprises a resiliently flexible stopper 22 that overlap the shoulder 27 of the stopper, thereby positively is preferably fabricated from an elastomer that is impervious retaining the stopper 22 in the neck 18 of the vial. The to water and air, for example butyl rubber. The stopper 22 diameter of the opening 36 is also Smaller than the outer has a lower sealing portion 23 seated within the neck 18 of diameter of the flange 44. The gripping portion 32 can, as the vial. To improve the seal formed between the sealing illustrated, have a plurality of circumferentially spaced portion 23 of the stopper and the neck 18 of the vial, the openings 37 to help provide resiliency to the gripping periphery of the Sealing portion 23 can, if desired, be portion 32 for Snap-fitting on to the vial. provided with one to a plurality of Spaced annular ridges. The Stopper 22 also has an upper protruding portion 24 that 0031. The outer Surface of the sleeve 41 is, in the projects coaxially beyond the free end of the neck 18 of the illustrated embodiment, provided with a plurality of parallel Vial. The Stopper 22 preferably has a deep receSS 26, and Substantially uniformly spaced ramps 47 that extend typically having the shape of a cone having a blunted or axially from and converge with the sleeve 41 toward the truncated apex. The base of the receSS 26 opens into the gripping portion 32. The diameter of the circle described by upper compartment 14 and the apex of the receSS 26 is in the lower ends of the ramps 47 is approximately equal to that proximity to the upper Surface of the protruding portion 24. of the opening 36, but the upper ends 48 of the ramps A thin wall portion of the Stopper 22 between the upper describe a circle having a Somewhat greater diameter than Surface of the protruding portion 24 and the apex of the that of the opening 36. The ramps 47 function as a locking receSS 26 permits a Sharp tip of a Syringe needle to be means for retaining the Sleeve 41 in its actuated position as inserted through the thin wall into the upper compartment 14 described below. for withdrawal of the formulation therein. The protruding portion 24 is Smaller in diameter than the Sealing portion 23 0032. The cap assembly as illustrated has a lock structure and at the interface there with defines an upwardly facing 51 that coacts with the stopper 22 to prevent the stopper annular shoulder 27, which, prior to actuation of the Vial as from being slidably displaced downward relative to the described below, is substantially flush with the upper surface sleeve 41. Typically the lock structure 51 comprises a lock of the annular rim 21 of the neck portion of the vial. ring 52 projecting inward from the lower end of the sleeve 41. In croSS-Section, the lock ring 52 has a toothlike con 0028. The closure structure 12 further comprises a cap figuration Such that the inner Surface thereof tapers inwardly assembly 31 that incorporates an actuating means, prefer as it projects upwardly, and terminates in an upwardly facing ably a means for applying hydraulic pressure via the Stopper shoulder. The lock ring 52 is thereby effective in only one 22 to the liquid formulation in the upper compartment 14. direction and enables the sleeve 41 to be slidably displaced Such preSSure is transmissible by the liquid formulation to downward relative to the stopper 22. Typically the lock the plug 17 and tends to disengage the plug from the Structure 51 further comprises an undercut annular groove constriction 18 of the Vial, pushing the plug into the lower 53 formed in the stopper 22 directly above the shoulder 27 compartment 13, thereby bringing the formulation in the thereof. The groove 53 terminates in a downwardly facing upper compartment 14 into contact with the gaseous shoulder at its upper edge. medium in the lower compartment 13. The cap assembly is typically formed from a Somewhat rigid material, typically 0033) To actuate the vial, the sleeve 41 is pressed down a plastic Such as polyethylene or polypropylene. ward, for example with a thumb, thereby breaking the fracturable connection 43 and moving the lower end face 42 0029. In the illustrated embodiment the means for apply of the sleeve toward the shoulder 27 of the stopper until the ing hydraulic pressure comprises a sleeve 41 of the cap lock ring 52 engages with the groove 53. Continued depres assembly, which is Snugly disposed around and Slidingly Sion of the sleeve 41 pushes the Stopper 22 downward, US 2004/0039366 A1 Feb. 26, 2004 creating hydraulic pressure in the upper compartment 14. 0044) U.S. Pat. No. 5,385,546 to Kriesel & Thompson. Depression of the sleeve 41 can continue only until the 0045) Other than the Act-O-Vial(R) system of Pharmacia flange 44 abuts the annular plate 34, thereby preventing the Corporation, two-chamber Systems in commercial use for Stopper 22 from being pushed too far into the upper com mixing a lyophilized powder with a diluent include those partment 14. When the sleeve 41 is fully depressed, the sold under the names UnivialTM and ADD-Vantage TM of ramps 47 fixedly lock the closure structure 12 in the actuated Abbott Laboratories and PiggybackTM of SmithKline Bee State and prevent re-use of the Vial, as the closure Structure cham. cannot be disassembled from the vial without destruction or permanent damage to the closure Structure. 0046) An article of the invention comprises, in the for 0034. A mixing vial as described above is in commercial mulation that Substantially fills the first chamber of the vial, use, for example as a packaging System for Solu-CortedE) a drug in a therapeutically effective amount. Typically the hydrocortisone Sodium Succinate for injection, under the drug is one of low Solubility in water, for example having a name Act-O-Vial(R) of Pharmacia Corporation. However, solubility of less than about 10 mg/ml, illustratively less than such a vial has previously been described for use only with about 1 mg/ml or even less than about 0.1 mg/ml. a lyophilized powder formulation of a drug in the lower 0047 Solubility in water for many pharmaceutically use compartment and an aqueous diluent in the upper compart ful compounds can be readily determined from Standard ment. According to the present embodiment, the mixing vial pharmaceutical reference books, for example The Merck now contemplated differs from that known in the art at least Index, 13th ed., 2001 (published by Merck & Co., Inc., by having an aqueous Suspension formulation in the upper Rahway, N.J.); the United States Pharmacopeia, 24th ed. compartment and only a gaseous medium, typically air, in (USP24), 2000; The Extra Pharmacopoeia, 29th ed., 1989 the lower compartment. The lower compartment as pres (published by Pharmaceutical Press, London); and the Phy ently contemplated functions as a reservoir for air or other sicians Desk Reference (PDR), 2001 ed. (published by gaseous medium to provide a headspace for effective agi Medical Economics Co., Montvale, N.J.). tation following actuation of the vial, but, by virtue of its lack of contact with the upper compartment prior to actua 0048 For example, individual compounds of low solu tion, minimizes or prevents exposure to oxygen of ingredi bility include compounds categorized as “slightly Soluble', ents of the formulation that are Susceptible to oxidative “very slightly soluble”, “practically insoluble” and degradation. “insoluble” in USP 24, pp. 2254-2298; and compounds categorized as requiring 100 ml or more of water to dissolve 0035. Accordingly, in a particular embodiment, an article 1 g of the drug, as listed in USP 24, pp. 2299-2304. of manufacture of the present invention comprises an Act 0049 Illustratively, Suitable drugs of low water solubility O-Vial(F) or Substantially similar mixing vial containing, in include, without limitation, drugs from the following an upper compartment thereof, a formulation that comprises classes: abortifacients, ACE inhibitors, C- and B-adrenergic (a) an aqueous medium having dispersed therein, in Solid agonists, C- and B-adrenergic blockers, adrenocortical Sup particulate form, a Steroidal drug in a therapeutically effec preSSants, adrenocorticotropic hormones, alcohol deterrents, tive amount and (b) one or more wetting and/or Suspending aldose reductase inhibitors, aldosterone antagonists, ana agents in an amount effective to provide controlled floccu bolics, analgesics (including narcotic and non-narcotic anal lation of the drug, at least one of the wetting and/or gesics), androgens, angiotensin II receptor antagonists, anor Suspending agents being Susceptible to oxidative degrada exics, antacids, anthelninthics, antiacne agents, antiallergics, tion; and, in a lower compartment thereof, only a gaseous antialopecia agents, antiamebics, antiandrogens, antianginal medium, for example air. agents, antiarrhythmics, antiarteriosclerotics, antiarthritic/ 0036. It will be apparent to those of skill in the art that antirheumatic agents (including selective COX-2 inhibi many modifications can be made to the article of manufac tors), antiasthmatics, antibacterials, antibacterial adjuncts, ture described immediately above without taking the article anticholinergics, anticoagulants, anticonvulsants, antide outside the Scope of the present invention. For example, the preSSants, antidiabetics, antidiarrheal agents, antidiuretics, actuating means can comprise, in place of a means for antidotes to poison, antidyskinetics, antieczematics, anti applying hydraulic pressure to the contents of the upper emetics, antiestrogens, antifibrotics, antiflatulents, antifun compartment, a Substantially rigid member that, when a gals, antiglaucoma agents, antigonadotropins, antigout downward force is applied to the cap assembly or a portion agents, antihistaminics, antihyperactives, antihyperlipopro thereof, transmits the force directly to the Septum or plug teinemics, antihyperphosphatemics, antihypertensives, anti Separating the upper and lower compartments. hyperthyroid agents, antihypotensives, antihypothyroid agents, anti-inflammatories, antimalarials, antimanics, anti 0037 Other two-chamber devices that can be substituted methemoglobinemics, antimigraine agents, antimuscarinics, include those described, for example, in the patents indi antimycobacterials, antineoplastic agents and adjuncts, vidually listed below, each incorporated herein by reference. antineutropenics, antiosteoporotics, antipagetics, antiparkin 0038. Above-cited U.S. Pat. No. 3,464,414. Sonian agents, antipheochromocytoma agents, antipneu mocystis agents, antiprostatic hypertrophy agents, antipro 0039 U.S. Pat. No. 4,614,267 to Larkin. toZoals, antipruritics, antipsoriatics, antipsychotics, 0040 U.S. Pat. No. 4,871,354 to Conn et al. antipyretics, antirickettsials, antiseborrheics, antiseptics/dis infectants, antispasmodics, antisyphylitics, antithromb 0041 U.S. Pat. No. 5,335,773 to Haber et al. ocythemics, antithrombotics, antituSSives, antiulceratives, antiurolithics, antivenins, antiviral agents, anxiolytics, aro 0042 U.S. Pat. No. 5,336,180 to Kriesel & Thompson. matase inhibitors, astringents, benzodiazepine antagonists, 0043 U.S. Pat. No. 5,350,372 to Ikeda et al. bone resorption inhibitors, bradycardic agents, bradykinin US 2004/0039366 A1 Feb. 26, 2004

antagonists, bronchodilators, calcium channel blockers, cal to elicit in a Subject the required or desired therapeutic cium regulators, carbonic anhydrase inhibitors, cardiotonics, and/or prophylactic response when parenterally adminis CCK antagonists, chelating agents, cholelitholytic agents, tered to the Subject. choleretics, cholinergics, cholinesterase inhibitors, cho 0052. In one embodiment, the drug is a steroid. Steroidal linesterase reactivators, CNS Stimulants, contraceptives, drugs include without limitation those useful as abortifa debriding agents, decongestants, depigmentors, dermatitis cients, adrenocortical Suppressants, aldosterone antagonists, herpetiformis Suppressants, digestive aids, diuretics, dopam anabolics, androgens, anesthetics, antiallergics, antiandro ine receptor agonists, dopamine receptor antagonists, ecto gens, antiasthmatics, antigonadotropins, antihyperlipopro parasiticides, emetics, enkephalinase inhibitors, enzymes, teinemics, anti-inflammatories, antineoplastics, anti enzyme cofactors, estrogens, expectorants, fibrinogen recep progestins, antipruritics, antirachitics, aromatase inhibitors, tor antagonists, fluoride Supplements, gastric and pancreatic contraceptives, estrogens, glucocorticoids, mineralocorti Secretion Stimulants, gastric cytoprotectants, gastric proton coids and progestogens. Illustrative examples of Such drugs pump inhibitors, gastric Secretion inhibitors, gastroprokinet include 21-acetoxypregnenolone, alclometasone, aldoster ics, glucocorticoids, C-glucosidase inhibitors, gonad-stimu one, alfadolone, alfaxalone, algestone, allyleStrenol, amci lating principles, growth hormone inhibitors, growth hor nonide, anageStone, androisoxazole, androstane, andros mone releasing factors, growth Stimulants, hematinics, tane-3,3,113-diol-17-one, androstenediol, androstenedione, hematopoietics, hemolytics, hemostatics, heparin antago (3C.5C)-androst-16-en-3-ol, androsterone, beclomethasone, nists, hepatic enzyme inducers, hepatoprotectants, histamine betamethasone, bolandiol, bolasterone, boldenone, budes He receptor antagonists, HIV protease inhibitors, HMG CoA onide, calusterone, canrenone, chlormadinone, chloropred reductase inhibitors, immunomodulators, immunosuppres nisone, cicleSonide, clobetasol, clobetasone, clocortolone, Sants, insulin Sensitizers, ion exchange resins, keratolytics, clomestrone, cloprednol, clostebol, cloxotestosterone, lactation Stimulating hormones, laxatives/catharitics, leukot colpormon, corticosterone, cortisone, cortivaZol, cyproter riene antagonists, LH-RH agonists, lipotropics, 5-lipoxyge one, danazol, deflazacort, delmadinone, demegestone, nase inhibitors, lupus erythematoSuS Suppressants, matrix deoxycorticosterone, desogeStrel, desonide, desoximeta metalloproteinase inhibitors, mineralocorticoids, miotics, Sone, dexamethasone, dichlorisone, dienogest, diflorasone, monoamine oxidase inhibitors, mucolytics, muscle relax diflucortolone, difluprednate, dimethisterone, dromo ants, mydriatics, narcotic antagonists, neuroprotectives, Stanolone, droSpirenone, dutasteride, dydrogesterone, nootropics, ovarian hormones, oxytocics, pepsin inhibitors, epimestrol, epitioStanol, eplerenone, epoStane, epristeride, pigmentation agents, plasma Volume expanders, potassium equilenin, equilin, ergosterol, estradiol, C.-estradiol, estra channel activatorS/openers, progestogens, prolactin inhibi mustine, estriol, estrone, ethinyl estradiol, ethisterone, eth tors, prostaglandins, protease inhibitors, radio-pharmaceuti yleStrenol, ethynodiol, etonogeStrel, exemestane, fluazacort, cals, 5C.-reductase inhibitors, respiratory Stimulants, reverse flucloronide, fludrocortisone, flumethasone, flunisolide, transcriptase inhibitors, Sedatives/hypnotics, Serenics, Sero fluocinolone, fluocinonide, fluocortin, fluocortolone, fluo tonin noradrenaline reuptake inhibitors, Serotonin receptor rometholone, fluoxymesterone, fluperolone, fluprednidene, agonists, Serotonin receptor antagonists, Serotonin uptake fluprednisolone, flurandrenolide, flurogestone, fluticasone, inhibitors, Somatostatin analogs, thrombolytics, thrombox formebolone, formeStane, formocortal, gestodene, gestono ane A receptor antagonists, thyroid hormones, thyrotropic rone, geStrinone, halcinonide, halobetasol, halometasone, hormones, tocolytics, topoisomerase I and II inhibitors, halopredone, hydrocortamate, hydrocortisone, hydroxydi uricoSurics, vasomodulators including vasodilators and one, 17O-hydroxyprogesterone, loteprednol, lynestrenol, vasoconstrictors, Vasoprotectants, Xanthine oxidase inhibi maZipredone, medrogestone, medroxyprogesterone, tors, and combinations thereof medrySone, megestrol, melengestrol, mepitioStane, mepre 0050. Non-limiting illustrative examples of suitable dnisone, meStanolone, mesterolone, meStranol, methandriol, drugs of low water Solubility include acetohexamide, ace methandrostenolone, methenolone, methylprednisolone, tylsalicylic acid, alclofenac, allopurinol, atropine, benzthi 17-methyltestosterone, methyltrienolone, mifepristone, azide, carprofen, celecoxib, chlordiazepoxide, chlorprom mometasone, moxestrol, nandrolone, norbolethone, nore azine, clonidine, codeine, codeine phosphate, codeine thandrolone, norethindrone, norethynodrel, norgesterone, Sulfate, deracoxib, diacerein, diclofenac, diltiazem, norgestimate, norgestrel, norgestrienone, normethandrone, eplerenone, estradiol, etodolac, etoposide, etoricoxib, fen norvinisterone, onapristone, OSaterone, Oxabolone, OXan bufen, fenclofenac, fenprofen, fentiazac, flurbiprofen, drolone, Oxendolone, oxymesterone, Oxymetholone, griseofulvin, haloperidol, ibuprofen, indomethacin, indopro paramethasone, pentagestrone, prasterone, prednicarbate, fen, ketoprofen, lorazepam, medroxyprogesterone acetate, prednimustine, prednisolone, prednisone, prednival, pred megestrol, methoXSalen, methylprednisone, morphine, mor nylidene, pregnan-3C-ol-20-one, progesterone, promege phine Sulfate, naproxen, nicergoline, nifedipine, niflumic, Stone, quinbolone, quineStradiol, quinestrol, rimeXolone, Oxaprozin, oxazepam, oxyphenbutaZone, paclitaxel, phen Spironolactone, Stanolone, Stanozolol, Stenbolone, testoster indione, phenobarbital, piroXicam, pirprofen, prednisolone, one, tiXocortol, trenbolone, trengestone, triamcinolone, prednisone, procaine, progesterone, pyrimethamine, rofe triloStane and pharmaceutically acceptable esters, Salts, coxib, Sulfadiazine, Sulfamerazine, Sulfisoxazole, Sulindac, enantiomers, epimers and tautomers thereof. Suprofen, temazepam, tiaprofenic acid, tilomisole, tolmetic, 0053 Presently preferred steroidal drugs include closte Valdecoxib, etc. bol, eplerenone, estradiol, exemestane, medroxyprogester 0051. The amount of drug incorporated in a drug-con one, methylprednisolone, Oxabolone, testosterone and phar taining composition of the invention can be Selected accord maceutically acceptable esters and Salts thereof, for example ing to known principles of pharmacy. A therapeutically clostebol acetate, estradiol 17B-cypionate, medroxyproges and/or prophylactically effective amount of drug is specifi terone 17-acetate, methylprednisolone 21-acetate, Oxab cally contemplated, i.e., an amount of drug that is Sufficient olone cypionate and testosterone 17B-cypionate. In a par US 2004/0039366 A1 Feb. 26, 2004 ticularly preferred embodiment, the Steroidal drug is 0060 Such agents further include poloxamers (polyoxy Selected from estradiol cypionate, exemestane and medroX ethylene-polyoxypropylene copolymers), illustratively of yprogesterone acetate. More than one Steroidal drug, for grades listed in the United States Pharmacopeia Such as example a combination of estradiol cypionate and medroX poloxamers 124, 188, 237, 338 and 407. yprogesterone acetate, can be present. 0061 Such agents further include surfactants having a 0.054 What constitutes a therapeutically effective amount hydrophobic alkyl or acyl group, typically of about 8 to of the drug in the formulation depends on the drug in about 18 carbon atoms, and a hydrophilic polyoxyethylene question, the indication for which it is to be administered to chain. Preferred Such Surfactants are nonionic Surfactants, a Subject, the age and body weight of the Subject, and other illustratively including polyoxyethylene alkyl etherS Such as factors. In the case of estradiol cypionate, the drug is laureth-9, laureth-23, ceteth-10, ceteth-20, oleth-10, oleth typically present in a concentration of about 1 to about 50 20, Steareth-10, Steareth-20 and steareth-100; polyoxyethyl mg/ml, preferably about 2.5 to about 25 mg/ml. In the case ene castor oil, polyoxyethylene hydrogenated castor oil, of medroxyprogesterone acetate, the drug is typically polySorbates Such as polySorbate 20, polySorbate 40, present in a concentration of about 10 to about 400 mg/ml, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate preferably about 30 to about 300 mg/ml, and more prefer 85 and polysorbate 120; and polyoxyethylene alkyl esters, ably about 50 to about 200 mg/ml, for example about 100 for example polyoxyethylene Stearates. PolySorbates, for mg/ml or about 150 mg/ml. When both estradiol cypionate example polySorbate 80, are particularly preferred. and medroxyprogesterone are present, the concentrations of the individual drugs are typically as given above. In the case 0062 According to the present embodiment, the suscep of exemestane, the drug is typically present in a concentra tible wetting and/or Suspending agent(s), together with any tion of about 10 to about 250 mg/ml, preferably about 50 to other wetting and/or Suspending agents that can optionally be included in the formulation, are present in total and about 200 mg/ml. relative amounts providing acceptable controlled floccula 0.055 To enhance suspension stability, the drug particles tion properties as defined above. The Smaller the amount of are preferably very Small, for example having a weight mean Susceptible agent that is used to provide wetting and/or particle size Smaller than about 100 um, typically about 1 to Suspending properties consistent with controlled floccula about 100 um. It is sometimes desirable that the drug be tion, the greater is the risk of loSS of formulation Stability due micronized, i.e., reduced to an average particle Size of about to oxidative degradation. 1 to about 25 um. Optionally all or a portion of the drug can be in nanoparticulate form, i.e., having an average particle 0063. In the case of a nonionic polyoxyethylene surfac size Smaller than 1 um (1000 nm), for example about 100 to tant Such as polySorbate 80, for example, a useful concen about 900 nm, more particularly about 500 to about 900 nm. tration can be as low as about 0.5 to about 10 mg/ml, 0056. The formulation comprises one or more wetting typically about 1 to about 5 mg/ml. and/or Suspending agents in an amount effective to provide 0064. In the case of a PEG such as PEG 3350, a useful controlled flocculation of the drug, and in a preferred concentration is illustratively about 5 to about 100 mg/ml, embodiment at least one of the wetting and/or Suspending typically about 10 to about 50 mg/ml. agents is Susceptible to oxidative degradation. In one 0065. The formulation optionally further comprises an embodiment, the at least one Susceptible wetting and/or antioxidant or oxygen Scavenger. Non-limiting illustrative Suspending agent comprises a polyoxyethylene chain. examples of Suitable antioxidants include tocopherols Such 0057. It is believed, without being bound by theory, that as C-tocopherol (vitamin E), ascorbic acid (vitamin C) and the Sometimes observed gradual loSS of controlled floccu Salts and esters thereof including Sodium ascorbate and lation behavior of a composition such as the Depo-Provera(R) ascorbic acid palnitate, isoascorbic acid (erythorbic acid), formulation described above is due at least in part, in many butylated hydroxyanisole (BHA), butylated hydroxytoluene cases due primarily, to loSS of Surfactancy of the wetting (BHT), thiol derivatives including acetylcysteine, cysteine, and/or Suspending agent resulting from oxidative cleavage cystine, dithioerythritol, dithiothreitol, glutathione, of polyoxyethylene chains. methionine and thioglycerol, especially L-methionine, fima 0.058 Oxidative degradation susceptible wetting and/or ric acid and Salts thereof, hypophosphorous acid, malic acid, Suspending agents useful in formulations packaged in 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid articles of the invention include any pharmaceutically (Trolox"M), alkyl gallates, for example propyl gallate, octyl acceptable agent that comprises one or more polyoxyethyl gallate and lauryl gallate, nordihydroguaiaretic acid, and ene chains. Sodium and potassium thiosulfate, Sulfite, bisulfite and met 0059 Such agents include polyethylene glycols (PEGs), abisulfite. An especially preferred antioxidant is L-methion for example those of average molecular weight from about ine. As shown in International Patent Application No. WO 100 to about 20,000, more typically about 200 to about 01/87266, L-methionine has a pH stabilizing effect on an 10,000, most typically about 300 to about 6000. Suitable aqueous Suspension formulation of a Steroidal drug that PEGs illustratively include PEG 2000, having an average cannot be fully explained merely by its antioxidant effect. molecular weight of 1800 to 2200, PEG 3000, having an 0066 One or more free radical-scavenging antioxidants average molecular weight of 2700 to 3300, PEG 3350, are optionally present in a total amount effective to Substan having an average molecular weight of 3000 to 3700, PEG tially reduce oxidative degradation of a Susceptible agent, 4000, having an average molecular weight of 3000 to 4800, typically in a total concentration of about 0.1 to about 50 and PEG 4600, having an average molecular weight of 4400 mg/ml, preferably about 0.2 to about 20 mg/ml, and more to 4800. PEG 3350 and PEG 4000 are especially preferred. preferably about 0.5 to about 10 mg/ml. Illustratively, L-me Such PEGs act as density adjusting agents, thereby enhanc thionine can usefully be present at a concentration of about ing Suspension Stability. 1 to about 5 mg/ml. US 2004/0039366 A1 Feb. 26, 2004

0067. It is believed, without being bound by theory, that 0074. One or more tonicity adjusting agents can be antioxidants reduce oxidative degradation by inhibiting present, for example Sodium chloride, Sodium Sulfate, dex accumulation of hydroperoxides and/or free radicals, an trose, mannitol and glycerol. initial Step in the oxidative degradation proceSS. Such hydro peroxides and free radicals can accelerate the degradation 0075 One or more buffering agents can optionally be proceSS in a form of autoxidation, as described for example present, for example buffers derived from acetic, aconitic, by Donbrow et al., op. cit. By Scavenging hydroperoxides citric, glutaric, lactic, malic, Succinic, phosphoric and car and free radicals, antioxidants can Significantly slow down bonic acids. Typically Such a buffer is an alkali or alkaline the oxidative degradation of PEGs, polyoxyethylene Surfac earth metal salt of such an acid. Phosphate and citrate buffers tants and other Susceptible ingredients of a composition. Such as Sodium phosphate and Sodium citrate are preferred. 0068 The formulation optionally further comprises a 0076. In one embodiment the composition comprises a chelating agent. Again it is believed, without being bound by buffering agent and PVP. As disclosed in International Patent theory, that chelating agents inhibit hydroperoxide forma Application No. WO 01/87262, incorporated herein by tion and thereby slow down oxidative degradation. Trace reference, it has been found that PVP can enhance pH metal ion contaminants, particularly transition elements control of a composition of the invention, and can Strengthen Such as iron, are believed, under certain conditions, to the pH controlling capacity of a conventional buffering accelerate oxidation and by Sequestering Such contaminants agent. For these purposes PVP of relatively low molecular a chelating agent can provide Some degree of protection weight, for example about 2,000 to about 11,000, is pre from oxidation of an oxidative degradation Susceptible ferred. PVP K17 is especially preferred, having a molecular ingredient. weight of about 7,000 to about 11,000. Suitable amounts of PVP are typically about 1 mg/ml to about 100 mg/ml, 0069. Further degradation of hydroperoxides is believed preferably about 2 to about 50 mg/ml. to be accelerated in acid conditions, it is thus be beneficial to use a chelating agent that is capable of Sequestering metal 0077 Preferably a composition of the invention has a pH ions in media having a pH that is not Strongly acidic, of about 3 to about 7. An advantage of the invention is that particularly Such a chelating agent with Some buffering pH of the composition can often be controlled within a capacity. An illustrative example is diethylenetriaminepen narrower range than hitherto, as a result of reduced oxidative taacetic acid (DTPA) and pharmaceutically acceptable Salts degradation of certain formulation ingredients. For example, thereof, e.g., the pentaSodium Salt. Other Suitable com in a medroxyprogesterone acetate composition as described pounds of a similar nature include ethylenediaminetetraace herein, pH can typically be controlled within a range of tic acid (EDTA), nitrilotriacetic acid (NTA), ethylenedi about 3 pH units, e.g., about 4 to about 7, more preferably amine-bis(O-hydroxyphenylacetic acid) (EDDA), within a range of about 2.5 pH units, e.g., about 4.5 to about bis(aminoethyl)glycolether-N,N,N',N'-tetraacetic acid 7, and even more preferably within a range of about 2 pH (EGTA) and pharmaceutically acceptable Salts thereof. units, e.g., about 5 to about 7, Over a prolonged shelf life. Other classes of compound that can be useful as chelating 0078. A composition of the invention can be prepared by agents include polyfunctional acids Such as citric acid and a proceSS comprising a first Step of formulating a Suspension Oxalic acid, amines Such as porphyrins, phenanthrolines, of the drug in particulate form in an aqueous medium that triethanolamine, tromethamine and dimethylglyoxime, and comprises one or more wetting and/or Suspending agents, at Sulfur-containing compounds Such as 2,3-dimercaptopro least one of which is Susceptible to oxidative degradation as panol. Chelating agents can illustratively be included at defined herein. Any suitable formulation method can be used concentrations of about 0.1 to about 20 mg/ml, preferably that brings the ingredients of the composition together in a about 0.2 to about 10 mg/ml, and more preferably about 0.5 way that results in an aqueous Suspension exhibiting con to about 5 mg/ml. trolled flocculation. Such methods are well known in the art. 0070 Optionally, the formulation can comprise, in addi An antioxidant can optionally be added at any Suitable point tion to components described hereinabove, excipients Such in the formulating Step. as those mentioned below. 0079 Although it is not generally necessary to use an 0071. One or more additional wetting and/or suspending oxygen-depleted atmosphere in the Second chamber of the agents, not Susceptible to oxidative degradation as described Vial, if desired an oxygen-depleted gaseous medium can be above, can optionally be present. Such agents include poly provided in a number of ways. An especially convenient way vinylpyrrolidone (PVP), for example PVPhaving a molecu is to prepare the Vial, before insertion of the Septum or plug, lar weight of about 2,000 to about 54,000, such as PVPK12, under a blanket of a nonreactive gas Such as nitrogen or a K17, K25 and K30, and surfactants such as phospholipids noble gas (e.g., argon or helium). An oxygen-depleted (e.g., lecithin), cationic Surfactants (e.g., myristyl Y-pi gaseous medium preferably consists essentially of nitrogen colinium chloride), anionic Surfactants (e.g., Sodium lauryl and oxygen in a weight ratio not less than about 10:1, more Sulfate), etc. preferably not less than about 20:1 and still more preferably 0.072 One or more thickening or viscosity adjusting not less than about 40:1. Other gases Such as carbon dioxide, agents can optionally be present, for example cellulosic water vapor and noble gases can be present in Such a polymers (e.g., methylcellulose, carboxymethylcellulose, medium, for example at concentrations in which they occur hydroxyethylcellulose, hydroxypropylmethylcellulose), in ambient air. The gaseous medium can consist essentially gelatin and gums (e.g., acacia). of nitrogen. 0073. One or more preservatives can optionally be present, for example phenol, chlorobutanol, benzyl alcohol, EXAMPLES methyl paraben, propyl paraben, benzalkonium chloride and 0080. The following examples illustrate aspects of the cetylpyridinium chloride. present invention but are not to be construed as limitations. US 2004/0039366 A1 Feb. 26, 2004

Example 1 0089. Following centrifugation, the Supernatant was removed and assayed by HPLC (bulk solution). If traces of 0.081 Samples of commercial Depo-Provera(E) contracep Solids were present in the Supernatant, centrifugation was tive injection product of Pharmacia & Upjohn were prepared repeated before assaying. To the remaining deposit in the according to five treatments described below in a replicated vial, 1 ml of 10 mg/ml sodium chloride solution was added, experiment to Study effects of headspace conditions on followed by vortexing for 10 seconds and shaking for 1 stability of the product. The Depo-Provera(E) formulation minute. The resulting Suspension was centrifuged again for was composed of 10 minutes at 2,500 rpm, and the Supernatant discarded. Addition of Sodium chloride, Vortexing, Shaking, centrifu gation and discarding of Supernatant were repeated one more medroxyprogesterone acetate USP sterile, micronized 150 mg time. Then 0.6 ml of 50% acetonitrile was added to the vial, PEG 3350 NF 28.75 mg Vortexed to resuspend and Shaken for 1 minute, then cen polysorbate 80 NF food grade 2.39 mg trifuged for 10 minutes at 2,500 rpm. The resulting Super sodium chloride USP 8.64 mg methylparaben NF 1.36 mg natant was carefully transferred to a 2 ml Volumetric flask. propylparaben NF 0.148 mg Addition of acetonitrile, Vortexing, Shaking, centrifugation 10% sodium hydroxide solution q.s. to pH 3.5-7.0 and transfer of Supernatant were repeated two more times. 10% hydrochloric acid solution q.s. to pH 3.5-7.0 The material in the volumetric flask was diluted to 2 ml with water for injection USP q.S. to 1 ml 50% acetonitrile to provide the solution for polysorbate 80 (adsorbed on drug Surface) separation and quantitation by HPLC. 0082 In a first treatment, herein denoted “as is”, the commercial product, a Stoppered capped vial of total capac 0090. In this example, only the Supernatant (i.e., bulk ity ~3 ml containing 1.17 ml of the formulation, was used. Solution) polySorbate content was recorded. An equilibrium The headspace contained an atmosphere which was not exists between polysorbate 80 in bulk solution and adsorbed oxygen-depleted and was essentially ambient air as of the on the drug, thus bulk Solution content is a good indicator of time of filling. total polysorbate 80 content of the composition. 0.083. In a second treatment, herein denoted “refreshed”, 0091 Data showing effects of headspace condition on pH a vial as above was opened to refresh the air in the and polysorbate 80 content are shown in Tables 1 and 2 headspace; the Vial was then restoppered, recapped and respectively. Shaken. 0084. In a third treatment, herein denoted “large”, the TABLE 1. contents of one commercial product vial were transferred Effect of headspace condition on pH of Depo-Provera B samples into a rinsed and dried vial of total capacity ~8 ml to provide a large headspace. The Vial was stoppered and capped. Headspace days at SS C. 0085. In a fourth treatment, herein denoted “small', the treatment O 6 14 49 contents of three commercial product Vials were combined “as is 5.5 3.2 3.2 3.6 into a single vial of total capacity 3 ml So that the remaining “refreshed 5.5 not tested 3.0 3.3 “large 5.5 2.9 2.9 3.4 headspace was very Small, no greater than 5% of the total “small 5.5 3.9 3.9 4.2 Volume of the Vial. The Vial was restoppered and recapped. “inert 5.5 5.4 5.2 5.0 0.086. In a fifth treatment, herein denoted “inert', a com mercial product vial was opened and the headspace purged with nitrogen for approximately 1 minute before restopper 0092) ing and recapping. TABLE 2 0.087 All samples were inverted and then placed in a Fisher IsotempF) vacuum oven, Model 281 set at 85 C. Effect of headspace condition on polysorbate 80 content Samples were removed at Selected time points for measure % of theoretical) of DepO-Provera (E samples ment of pH and polysorbate 80 content. Non-removed Headspace days at 85 C. samples in the “refreshed” treatment only were opened for about 10 minutes at each time point, then restoppered, treatment O 6 14 49 recapped and Shaken before being returned to the oven. “as is 82 42 50 25 Samples were centrifuged in their vials for 10 minutes at “refreshed 82 not tested 44 7 2,500 rpm to provide a clear Supernatant for analysis. “large 82 38 39 none detected “small 82 81 82 3O 0088. Measurement of pH was by ATI Orion Expandable “inert 82 82 81 25 Ion Analyzer EA 940 with an Orion Microcombination (Catalog no. 9803BN) electrode. Polysorbate 80 was sepa rated by HPLC (HP1090 with Zorbax SB C8, 3.5m, 75x4.6 0093. The “small” and “inert” headspace treatments were mm column) and fractions of polySorbate 80 containing a representative of the effects of protecting the formulation in fatty acid ester were quantitated by HPLC (HP1090 with HP the vial from oxidative degradation. The “small' treatment Hypersil ODS, 5 mm, 250x4.6 mm column) both in the is indicative of conditions in an article of the present Supernatant (bulk Solution) and adsorbed on the drug Surface invention, wherein the formulation substantially fills the as described below. chamber in which it is packaged, with very little headspace. US 2004/0039366 A1 Feb. 26, 2004

0094. Up to the 14 days time point, significant oxidative degradation of polysorbate 80 is evident in the data for “as TABLE 3 is”, “refreshed” and “large” headspace treatments. Polysor bate 80 content declined to 50% or less of theoretical content Comparison of "good” and “bad” samples of aged (Table 2), with a concomitant reduction in pH (Table 1). Depo-Provera (R) product from the same manufacturing lot However, in the “small” and “inert' headspace treatments, no decline in polySorbate 80 content was seen up to 14 dayS. polysorbate 80 (% of theoretical) A moderate reduction in pH occurred in the “small' head Space treatment but not with the “inert' headspace. Lot Sample pH bulk solution adsorbed on drug 0.095 By the 49 days time point, degradation of polysor 1. “good 3.90 3.5 4.0 bate 80 was evident in all treatments. An anaerobic degra “bad” 3.71 1.2 3.8 dation mechanism that operates at the high temperature used 2 “good 3.68 1.3 3.5 in this study is believed to be responsible for this late effect. “bad” 3.46 1.1 3.3 It is believed that real-time aging of product under normal 3 “good 3.93 O.9 3.8 Storage conditions over a period of a year or more is “bad” 3.64 O.3 1.1 Simulated by the high temperature accelerated aging of the 4 “good 3.97 2.4 3.2 first 14 days of this Study, but that the apparent anaerobic “bad” 3.72 0.4 O.O degradation proceSS Seen following 49 days of high tem “good 4.09 4.2 5.8 perature exposure is not involved to a significant extent in “bad” 3.82 3.4 3.5 real-time aging. 6 “good 4.12 2.3 not tested “bad” 3.92 O.7 not tested 0096. The data from this study clearly indicate that 7 “good 3.49 1.5 7.7 minimizing exposure of a polySorbate 80 containing formu “bad” 3.19 1.4 5.7 lation to oxygen by Substantial elimination of a headspace during Storage, as in an article of the present invention, inhibits polySorbate 80 degradation to a very marked and useful degree. Example 3 0101. An antioxidant or a chelating agent was added to Example 2 samples of commercial Depo-Provera(E) formulation to 0097 Samples of commercial Depo-Provera(E) contracep study effects of these agents on stability of the product. The tive injection product of Pharmacia & Upjohn from different antioxidant used was TroloxCF), 6-hydroxy-2,5,7,8-tetram manufacturing lots were retrieved following up to 5 years ethylchroman-2-carboxylic acid 97% (Aldrich), and the Storage in conventional Single-chamber Vials. Settled drug chelating agent used was DTPA pentasodium salt 40% in height (SDH) was determined for several vials as an indi cator of controlled flocculation properties. SDH is the height water (J. T. Baker), diluted with water to 100 mg DTPA/ml. of Settled drug following Shaking of the vial expressed as a 0102 Under constant stirring, bulk Depo-Provera sus percentage of total product height. AS controlled flocculation pension was pipetted in an amount of 1.1 ml into each of 14 properties are lost, SDH increases, ultimately reaching vials. Into each of 4 of these vials (“set 2') had previously 100%. A sample showing good controlled flocculation been placed 1 mg of Trolox. Into each of another 4 vials (“set behavior has SDH of about 30%. 3”), after addition of the suspension, was added 10 ul of 0098) When “good” (low SDH) and “bad” (high SDH) diluted DTPA. Contents of all vials containing Depo-Prov Samples were compared as to pH, it was found that, within era plus Trolox or DTPA, and of 4 additional vials (“set 1”) any one lot, pH was always lower in the “bad” than in the containing only Depo-Provera, were adjusted to a pH of 6.3 “good' Samples. However, there was no clear correlation of to 6.9 with 0.2N hydrochloric acid or 12.5 mg/ml Sodium pH with SDH acroSS different lots, Suggesting that increase hydroxide Solution. The remaining 2 Vials containing only in SDH is not caused by pH perse but that relative lowering Depo-Provera did not have their contents pH-adjusted. of pH within a lot is merely an indicator of a degradative change causing the SDH increase. These are denoted the “control O’ vials. Half of each of the “set 1”, “set 2', “set 3' and “control O' vials were fitted with 0099 Polysorbate 80 contents in bulk solution and Helvoet StopperS and capped, and the remaining half were adsorbed to the drug Surface were measured, by the proce fitted with Dalkyo stoppers and capped. The “control O” dure described in Example 1, for “good” and “bad” samples Vials were placed in a freezer. The other vials were placed in within several lots. The “bad” samples were generally found a Fisher IsotempF) vacuum oven, Model 281, set at 85 C. to have lower amounts of polySorbate 80 remaining, both in Samples were removed from the oven or freezer after 10 bulk Solution and adsorbed to the drug Surface, than the days and resuspended by Shaking prior to measurement of “good” samples from the same lot, as shown in Table 3. pH and bulk solution polysorbate 80 content by the proce 0100. It is contemplated that substantial elimination of dures described in Example 1. headspace will minimize loss of polySorbate 80 during Storage (as demonstrated in Example 1) and will thereby 0103 Data showing effects of antioxidant (Trolox) and permit longer maintenance of controlled flocculation behav chelating agent (DTPA) on pH and polysorbate 80 content O. are shown in Table 4. US 2004/0039366 A1 Feb. 26, 2004 10

What is claimed is: TABLE 4 1. An article of manufacture comprising a vial having Effects of antioxidant and chelating agent on Depo-Provera B samples (a) a first chamber that is substantially filled with a parenterally deliverable aqueous Suspension that com polysorbate 80 prises (i) an aqueous medium; (ii) a drug in Solid pH (% of particulate form in a therapeutically effective amount treatment additive stopper initial final theoretical) Suspended in the medium; and (iii) one or more wetting control O 4.0 4.1 92 and/or Suspending agents in an amount effective to set 1 Helvoet 6.6 3.3 57 provide controlled flocculation of the drug, at least one set 2 Trolox Helvoet 6.7 3.7 82 ingredient of the formulation being Susceptible to oxi set 3 DTPA Helvoet 6.3 6.2 78 dative degradation; set 1 Daikyo 6.6 2.7 66 set 2 Trolox Daikyo 6.8 3.2 82 (b) a second chamber that is substantially empty but for a set 3 DTPA Daikyo 6.7 5.7 79 gaseous medium; (c) a septum Separating the first and Second chambers and 0104 Both the antioxidant and the chelating agent sig impermeable to the gaseous medium; and nificantly reduced polySorbate 80 degradation in this study. (d) actuating means effective to bring the aqueous Sus pension and the gaseous medium into contact by breach Example 4 of the Septum Such that the gaseous medium acts as an 0105. A parenteral aqueous suspension formulation of effective headspace for agitation of the formulation. medroxyprogesterone acetate having the following compo 2. The article of claim 1 wherein the second chamber Sition is prepared and packaged in the upper chamber of an forms a lower compartment and the first chamber forms an Act-O-Vial(R) mixing vial, Substantially filling the upper upper compartment, Said lower and upper compartments chamber: being Separated by a constriction wherein the Septum in a form of a Substantially airtight and watertight plug is engaged; Said upper compartment having an annular neck terminating in an open end; Said neck having engaged medroxyprogesterone acetate 150 mg PEG 3350 30 mg thereon a closure structure comprising (i) a resiliently flex polysorbate 80 2.5 mg ible stopper having a lower Sealing portion Seated within the sodium chloride 9 mg neck and an upper protruding portion that projects coaxially methylparaben 1.5 mg beyond the of the neck; Said Stopper having a deep receSS propylparaben 0.15 mg open at the base thereof and closed at the apex thereof Such water for injection q.S. to 1 ml that the apex of the receSS is in proximity to the upper Surface of the protruding portion, defining a thin wall portion 0106) The lower chamber of the Act-O-Vial is air-filled. of the Stopper that permits a sharp tip of a Syringe needle to The above formulation is especially suitable for intramus be inserted through the thin wall into the upper compartment cular injection. for withdrawal of the formulation therein; and (ii) a cap assembly that incorporates Said actuating means, wherein Example 5 Said actuating means is a means for applying hydraulic preSSure via the formulation in the upper compartment to the 0107 A parenteral aqueous suspension formulation of plug, Said pressure tending to disengage the plug from the medroxyprogesterone acetate having the following compo constriction, thereby pushing the plug into the lower com Sition is prepared and packaged in the upper chamber of an partment to bring the formulation into contact with the Act-O-Vial(R) mixing vial, Substantially filling the upper gaseous medium in the lower compartment. chamber: 3. The article of claim 2 wherein the means for applying hydraulic pressure comprises a sleeve of the cap assembly that is Snugly disposed around and Slidingly engaged with medroxyprogesterone acetate 104 mg the protruding portion of the Stopper; and wherein the PEG 3350 18.7 mg Sealing portion of the Stopper is of larger diameter than the polysorbate 80 1.95 mg protruding portion and defines at the interface there with an sodium chloride 5.2 mg annular shoulder; Said sleeve, adjacent to a lower end methylparaben 1.04 mg propylparaben 0.10 mg thereof, being fracturably connected to an annular gripping monobasic sodium phosphate monohydrate 0.45 mg portion of the cap assembly; Said gripping portion Surround dibasic sodium phosphate dodecahydrate 0.38 mg ing an radially outward projecting rim formed at the open L-methionine 0.98 mg end of the neck and having at the lower edge of the gripping PVP K17 PF 3.25 mg portion a plurality of Substantially uniformly Spaced projec sodium hydroxide q.s. to pH 3.5-7.0 hydrochloric acid q.s. to pH 3.5-7.0 tions extending radially inward; Said gripping portion com water for injection q.s. to 0.65 ml prising an annular plate that overlies the open end of the neck and circumscribes a plate opening of diameter Smaller than the neck opening, Such that the annular plate projects 0108). The lower chamber of the Act-O-Vial is air-filled. radially inward to overlap the Stopper shoulder and thereby The above formulation is especially suitable for subcutane positively retain the Stopper in the neck, Said sleeve having, ous injection. on an Outer Surface thereof, a plurality of parallel and US 2004/0039366 A1 Feb. 26, 2004

Substantially uniformly Spaced ramps that extend axially 18. The article of claim 17 wherein the medroxyproges from and converge with the Sleeve toward the gripping terone acetate is present in an amount of about 10 to about portion and that function as a locking means for retaining the 400 mg/ml. sleeve in an actuated position; Said Sleeve being actuatable 19. The article of claim 17 wherein the medroxyproges by depression thereof to break the fracturable connection terone acetate is present in an amount of about 30 to about and engage with the Stopper shoulder to push the Stopper 300 mg/ml. downward, thereby creating hydraulic pressure in the upper 20. The article of claim 17 wherein the medroxyproges compartment. terone acetate is present in an amount of about 50 to about 4. The article of claim 1 wherein the vial is an Act-O- 200 mg/ml. Vial(R) or substantially similar mixing vial. 21. The article of claim 17 wherein the formulation 5. The article of claim 1 wherein the gaseous medium is comprises: a. 6. The article of claim 1 wherein the at least one oxidative (a) medroxyprogesterone acetate, 100-200 mg/ml; degradation Susceptible ingredient present in the formula (b) polyethylene glycol of molecular weight 3000-4000, tion comprises a polyoxyethylene chain. 20-40 mg/ml; 7. The article of claim 1 wherein the at least one oxidative degradation Susceptible ingredient present in the formula (c) polySorbate 80, 2-4 mg/ml; tion is a polyoxyethylene Surfactant. (d) Sodium chloride, 6-12 mg/ml; and 8. The article of claim 7 wherein the polyoxyethylene (e) optionally at least one parenterally acceptable preser Surfactant is a polySorbate. vative, 0.1-5 mg/ml total. 9. The article of claim 7 wherein the polyoxyethylene 22. The article of claim 17 wherein the formulation surfactant is polysorbate 80. comprises: 10. The article of claim 9 wherein the polysorbate 80 is present in an amount of about 0.1 to about 10 mg/ml. (a) medroxyprogesterone acetate, about 150 mg/ml; 11. The article of claim 9 wherein the polysorbate 80 is present in an amount of about 1 to about 5 mg/ml. (b) polyethylene glycol of molecular weight about 3350, 12. The article of claim 1 wherein the drug present in the about 30 mg/ml; formulation is of low water solubility. (c) polysorbate 80, about 2.5 mg/ml; 13. The article of claim 1 wherein the drug present in the formulation is Selected from the group consisting of aceto (d) sodium chloride, about 9 mg/ml; hexamide, acetylsalicylic acid, alclofenac, allopurinol, atro (e) methylparaben, about 1.5 mg/ml; pine, benzthiazide, carprofen, celecoxib, chlordiazepoxide, chlorpromazine, clonidine, codeine, codeine phosphate, (f) propylparaben, about 0.15 mg/ml; and codeine Sulfate, deracoxib, diacerein, diclofenac, diltiazem, (g) water for injection, q.S. eplerenone, estradiol, etodolac, etoposide, etoricoxib, fen 23. The article of claim 17 wherein the formulation bufen, fenclofenac, fenprofen, fentiazac, flurbiprofen, comprises, in a volume of about 0.65 ml: griseofulvin, haloperidol, ibuprofen, indomethacin, indopro fen, ketoprofen, lorazepam, medroxyprogesterone acetate, (a) medroxyprogesterone acetate, about 104 mg. megestrol, methoXSalen, methylprednisone, morphine, mor (b) polyethylene glycol of molecular weight about 3350, phine Sulfate, naproxen, nicergoline, nifedipine, niflumic, about 18.7 mg; Oxaprozin, oxazepam, oxyphenbutaZone, paclitaxel, phen indione, phenobarbital, piroXicam, pirprofen, prednisolone, (c) polysorbate 80, about 1.95 mg; prednisone, procaine, progesterone, pyrimethamine, rofe (d) Sodium chloride, about 5.2 mg; coxib, Sulfadiazine, Sulfamerazine, Sulfisoxazole, Sulindac, Suprofen, temazepam, tiaprofenic acid, tilomisole, tolmetic (e) methylparaben, about 1.04 mg. and Valdecoxib. (f) propylparaben, about 0.10 mg, 14. The article of claim 1 wherein the drug present in the formulation is a Steroidal drug. (g) monobasic Sodium phosphate monohydrate, about 15. The article of claim 14 wherein the steroidal drug is 0.45 mg; Selected from the group consisting of clostebol, estradiol, (h) dibasic sodium phosphate dodecahydrate, about 0.38 exemestane, medroxyprogesterone, methylprednisolone, mg, testosterone and pharmaceutically acceptable esters and salts thereof. (i) L-methionine, about 0.98 mg; 16. The article of claim 14 wherein the steroidal drug is Selected from the group consisting of estradiol cypionate, (j) polyvinylpyrrolidone K17, about 3.25 mg; and exemestane and medroxyprogesterone acetate. (k) water for injection, q.S. 17. The article of claim 14 wherein the steroidal drug is medroxyprogesterone acetate. k k k k k