US 2014.0005219A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0005219 A1 Foster et al. (43) Pub. Date: Jan. 2, 2014

(54) INTRATHECAL HYDROMORPHONE (60) Provisional application No. 61/607,774, filed on Mar. SOLUTIONS HAVING IMPROVED 7, 2012. STABILITY Publication Classification (71) Applicant: Mallinckrodt LLC, Hazelwood, MO (51) Int. Cl. (US) A613 L/485 (2006.01) (72) Inventors: John J. Foster, St. Paul, MN (US); (52) U.S. Cl. Thomas R. Prentice, St. Paul, MN (US) CPC ...... A6 IK3I/485 (2013.01) USPC ...... S14/282 (21) Appl. No.: 14/019,828 (57) ABSTRACT The present disclosure relates generally to a pharmaceutical (22) Filed: Sep. 6, 2013 Solution comprising hydromorphone or a pharmaceutically acceptable salt thereofthat is substantially free of buffer and optionally one or more other additives. The pharmaceutically Related U.S. Application Data acceptable salt may be hydromorphone hydrochloride. Also (63) Continuation-in-part of application No. 13/787,042, disclosed are methods for the manufacture and use of the filed on Mar. 6, 2013. Solution.

Patent Application Publication Jan. 2, 2014 Sheet 2 of 2 US 2014/0005219 A1

FIG. 2 US 2014/0005219 A1 Jan. 2, 2014

INTRATHECAL HYDROMORPHONE with relative levels of some liver enzymes being the main SOLUTIONS HAVING IMPROVED cause; the normal human range appears to be from 8:1 to a STABILITY little under 4:1. It is not uncommon, for example, for the 8-mg tablet to have an effect similar to 30 mg of morphine sulfate or CROSS REFERENCE TO RELATED a similar morphine preparation. APPLICATIONS 0007. The currently available hydromorphone hydrochlo 0001. This application is a continuation-in-part of prior ride solutions all contain buffer. The buffer is often added to U.S. patent application Ser. No. 13/787,042, filed Mar. 6, a composition to regulate the pH and/or aid in the stability of the compound in solution. The addition of buffer can lead to 2013, which claims the benefit of priority of U.S. Provisional potential complications. Such as toxicity or other side effects, Application No. 61/607,774, filed Mar. 7, 2012. allergic responses and/or granuloma formation. Further, the BACKGROUND OF THE DISCLOSURE use of less or no buffer would decrease the costs of producing the pharmaceutical composition and reduce manufacturing 0002 The present disclosure relates generally to a sterile complexity. Currently available hydromorphone hydrochlo Solution of hydromorphone and/or one or more pharmaceu ride Solutions also have not been approved for intrathecal use. tically acceptable salts thereof that is substantially free of Accordingly, there is a need for a hydromorphone hydrochlo buffer and optionally one or more other additives. For ride solution that does not contain buffer, and is suitable for example, in one aspect, the present disclosure relates to a intrathecal use. Surprisingly, it has been found that hydro sterile hydromorphone hydrochloride solution that is sub morphone hydrochloride, as well as other hydromorphone stantially free of buffer and other additives. salts, in water do not require buffering agents to maintain 0003 Hydromorphone hydrochloride is a narcotic analge stability over time. sic, and one of its principle uses is the relief of pain. It is a 0008. Additionally, there has been increasing interest semi-synthetic L-opioid agonist. There is no intrinsic limit to recently in the regulation of the cerebrospinal fluid (CSF) pH. the analgesic effect of hydromorphone hydrochloride; like Part of this interest stems from the fact that the extracellular morphine, adequate doses will relieve even the most severe fluid (ECF) pH in the brain serves as an important regulator of pain. Hydromorphone is the generic (USAN) name (USP pulmonary ventilation and a major determinant of cerebral Dictionary of USAN and International Drug Names 2003) for blood flow. Furthermore, since the CSF pH has been shown to 4.5-O-epoxy-3-hydroxy-17-methyl morphinan-6-one, a be subject to a considerable degree of homeostatic control in derivative of morphine. Its structural formula is: a variety of conditions which change the acid-base status of blood, many attempts have been made to unravel the physi ological mechanisms which are responsible for this control. Finally, since the acid-base metabolism of the cerebral com N partments (including the ECF) may influence cerebral func tion to a significant degree, the CSF pH and the mechanisms which regulate it have become of concern to neurologists and neurosurgeons. CSF normally has a pH near 7.3. Since intrathecal delivery of hydromorphone hydrochloride is direct injection into the CSF, and it is desirable to keep the pH of the resulting CSF hydromorphone solution mixture as close to 7.3 as possible, injection of a hydromorphone hydro chloride formulation with a pH near 7.3 is appealing. Advan 0004 Presently, intrathecal hydromorphone hydrochlo tageously, the pH of the formulation without buffer is closer ride is commercially available for injection in 10 mg/ml solu to the natural physiological pH of CSF than the formulation tions in a preservative-free formula containing 0.2% sodium containing buffer (5.0 vs. 4.1). citrate and 0.2% of a citric acid solution. BRIEF DESCRIPTION OF THE DISCLOSURE 0005 Hydromorphone is used in medicine as an alterna tive to morphine and diacetylmorphine for analgesia and as a 0009. In one aspect, the present disclosure is directed to a second- or third-line narcotic antitussive (cough suppressant) sterile pharmaceutical Solution comprising hydromorphone, for cases of dry, painful, paroxysmal coughing resulting from a pharmaceutically acceptable salt(s) thereof, or combina continuing bronchial irritation after influenza and other ail tions thereof, wherein the solution is substantially free of ments, inhalation of fungus and other causes, and is generally buffer and optionally one or more other additives. In one regarded to be the strongest of the latter class of drugs, and particular embodiment, the solution comprises hydromor was developed shortly after another powerful antitussive, phone hydrochloride. heroin, was removed from clinical use for this purpose in 0010. Another aspect of the present disclosure is a sterile most of the world and in many countries banned outright. pharmaceutical Solution consisting essentially of hydromor 0006. The hydrogenation of morphine resulting in the for phone and/or a pharmaceutically acceptable salt(s) thereof mation of hydromorphone results in a drug with higher lipid and water. In one particular embodiment, the pharmaceuti solubility and ability to cross the blood-brain barrier and cally acceptable salt is hydromorphone hydrochloride. therefore more rapid and complete central nervous system 0011 Yet another aspect of the present disclosure is a penetration, with the result that hydromorphone is somewhat sterile pharmaceutical Solution consisting of hydromorphone faster-acting and about eight times stronger than morphine and/or a pharmaceutically acceptable salt(s) thereof (e.g., and about three times stronger than heroin on a milligram hydromorphone hydrochloride) and water. basis. The effective morphine to hydromorphone conversion 0012. A further aspect of the disclosure provides a method ratio can vary from patient to patient by a significant amount for manufacturing a pharmaceutical Solution, the method US 2014/0005219 A1 Jan. 2, 2014 comprising (i) combining hydromorphone, a pharmaceuti a hydromorphone solution containing buffer, thus provide an cally acceptable salt(s) thereof, or combinations thereof with unexpected advantage over hydromorphone solutions con sterile water in the absence of buffers and/or other additives, taining buffers. and (ii) dissolving the hydromorphone and/or the pharmaceu 0020. Additionally, since hydromorphone solutions of the tically acceptable salt(s) thereof to form the solution. In one present disclosure are intended for intrathecal administration, particular embodiment, the pharmaceutically acceptable salt it is also desirable for the pH of the solutions to be sufficiently is hydromorphone hydrochloride. In this or other embodi high to prevent corrosion of delivery pumps used during ments, the method may further comprise (iii) Sparging the intrathecal administration. Accordingly, the solutions of the sterile water with an inert gas prior to combining with the present disclosure have a pH above about 3, and more par hydromorphone and/or the pharmaceutically acceptable salt ticularly have a pH from about 3 to about 7, or from about 3.5 (s) thereof, and/or (iv) sparging the resulting solution after the to about 7. For instance. Some embodiments may have a pH hydromorphone, and/or the pharmaceutically acceptable salt from about 3.5 to about 5.5, or from about 3.7 to about 5.3, or (s) thereof, is dissolved in the sterile water. from about 3.9 to about 5.1, or from about 4.2 to about 5, 0013 Yet another aspect of the present disclosure is a while other embodiments may have a pH from about 3 to method of treating pain in a subject, the method comprising about 5, or from about 4 to about 5, or from about 4.5 to about administering intrathecally a sterile, pharmaceutical Solution 5. Advantageously, buffers are not needed to maintain the pH comprising hydromorphone, a pharmaceutically acceptable of the hydromorphone solutions of the present disclosure salt(s) thereof, or combinations thereof, wherein the solution within this range, even over extended periods of storage. is substantially free of buffer and optionally one or more other 0021. As further demonstrated in the examples, solutions additives. of the present disclosure also advantageously maintain their 0014. Other aspects of the disclosure are described in stability, and have low levels of impurities (also referred to more detail below. herein as “side products”), over extended periods of storage. Buffer or other stability-enhancing additives are thus not BRIEF DESCRIPTION OF THE DRAWINGS necessary to maintain stability of the hydromorphone solu 0015 FIG. 1 is an illustration of a syringe containing a tions. hydromorphone solution according to an exemplary embodi 0022. Because hydromorphone solutions of the present ment. disclosure are substantially free of buffer and optionally one or more other additives, the risk of potential complications, 0016 FIG. 2 is an illustration of the syringe as used with such as toxicity or other side effects, allergic responses and/or an infusion system. granuloma formation, is lowered in comparison to hydromor DETAILED DESCRIPTION OF THE phone compositions comprising buffer and/or other addi tives. Further, the use of less or no buffer or other additives DISCLOSURE decreases the costs of producing the hydromorphone solu 0017. The present disclosure provides sterile solutions of tions, and thus reduces manufacturing complexity. hydromorphone, and/or one or more pharmaceutically acceptable salts thereof, that are suitable for intrathecal injec Hydromorphone Solutions tion. Advantageously, the hydromorphone solutions of the present disclosure are substantially free of buffer and option 0023 The present disclosure provides sterile solutions of ally one or more other additives, yet have a pH closer to the hydromorphone and/or a pharmaceutically acceptable salt(s) physiological pH of cerebrospinal fluid than formulations thereof. The drug hydromorphone, as depicted above, is com containing buffer. Also disclosed are methods for the manu prised of 4.5-O-epoxy-3-hydroxy-17-methyl morphinan-6- facture of such hydromorphone solutions, as well as methods one, and possesses analgesic properties. As used herein, the for the use thereof. term "hydromorphone solution' is intended to encompass Solutions containing hydromorphone, one or more pharma Overview ceutically acceptable salts of hydromorphone, or combina tions thereof. Suitable hydromorphone salts include any 0018. The present disclosure is based on the finding that water Soluble salt of hydromorphone, including those hydromorphone and/or one or more pharmaceutically accept selected from the group consisting of a hydromorphone Sul able salts thereof can beformulated as an intrathecal solution, fate, hydromorphone hydrochloride, hydromorphone sodium without the need for buffers or other additives to maintain chloride, hydromorphone trifluoracetate, hydromorphone stability of the solution and/or pH of the solution within a thiosemicarbazone hydrochloride, hydromorphone pen desired range. tafluoropropionate, hydromorphone p-nitrophenyl-hydro 0019. As demonstrated in the examples, hydromorphone Zone, hydromorphone hydrazine, hydromorphone hydrobro solutions formulated without buffers or other additives have a mide, hydromorphone mucate, hydromorphone pH higher than that of hydromorphone solutions containing methylbromide, hydromorphone oleate, hydromorphone buffer, and exhibit little if any change (e.g., decrease) in pH n-oxide, hydromorphone acetate, hydromorphone phosphate overextended periods of storage. Since intrathecal delivery of dibasic, hydromorphone phosphate monobasic, hydromor hydromorphone and its salts is via direct injection into the phone inorganic salt, hydromorphone organic salt, hydromor CSF, and it is desirable to keep the pH of the resulting CSF phone acetate trihydrate, hydromorphone bis(heptafluorobu hydromorphone solution mixture as close to the physiologi tyrate), hydromorphone bis(methylcarbamate), cal pH of the CSF (i.e., about 7.3) as possible, injection of a hydromorphone (bis-pentafluoropropionate), hydromor hydromorphone solution with a pH near 7.3 is appealing. The phone bis(pyridine-3-carboxylate), hydromorphone bis(trif hydromorphone solutions of the present disclosure, which luoroacetate), hydromorphone bitartrate, hydromorphone have a pH closer to the natural physiological pH of CSF than chlorohydrate, and hydromorphone Sulfate pentahydrate. US 2014/0005219 A1 Jan. 2, 2014

Preferably, the hydromorphone solutions of the present dis the present disclosure preferably meet USP standards for closure comprise hydromorphone hydrochloride. quality (e.g., USP <1>, injections). 0024. In one embodiment, the solution of the present dis 0028 Hydromorphone solutions of the present disclosure closure comprises, consists essentially of, or consists of may have a viscosity similar to that of water at room tempera hydromorphone and/or one or more pharmaceutically accept ture (e.g., about 20° C.). For instance, a given Solution may able salt(s) of hydromorphone, and sterile water, wherein the have a Viscosity of about 2 centipoise (cps) or less (e.g., a pharmaceutically acceptable salt(s) is other than hydromor Viscosity of about 1 cps) at room temperature. phone hydrochloride. For instance, in one embodiment, the 0029. As previously noted, in view of various consider Solution comprises, consists essentially of, or consists of ations (e.g., pump corrosion, pH of CSF, etc.), hydromor hydromorphone and/or one or more pharmaceutically accept phone solutions of the present disclosure have a pH of at least able salt(s) of hydromorphone, and water, wherein the phar about 3. Typically, the pH of the solution is from about 3 to maceutically acceptable salt(s) is selected from the group about 7, or from about 3.5 to about 7, or from about 3 to about consisting of a hydromorphone Sulfate, hydromorphone 5.5, or from about 3.5 to about 5.5, or from about 3.7 to about Sodium chloride, hydromorphone trifluoracetate, hydromor 5.3, or from about 3.9 to about 5.1, or from about 4.2 to about phone thiosemicarbazone hydrochloride, hydromorphone 5, or from about 3 to about 5, or from about 4 to about 5, or pentafluoropropionate, hydromorphone p-nitrophenyl-hy from about 4.5 to about 5. droZone, hydromorphone hydrazine, hydromorphone hydro 0030. It has been discovered that the hydromorphone solu bromide, hydromorphone mucate, hydromorphone methyl tions of the present disclosure only exhibit little if any change bromide, hydromorphone oleate, hydromorphone n-oxide, in pH (e.g., a small decrease in pH), even over extended hydromorphone acetate, hydromorphone phosphate dibasic, periods of storage. For example, the pH of the solutions will hydromorphone phosphate monobasic, hydromorphone inor typically remain within the range of from about 3 to about 7. ganic salt, hydromorphone organic salt, hydromorphone and or within the range of from about 3.5 to about 5.5, or from acetate trihydrate, hydromorphone bis(heptafluorobutyrate), about 3.7 to about 5.3, or from about 3.9 to about 5.1, or from hydromorphone bis(methylcarbamate), hydromorphone about 4 to about 5, or from about 4.5 to about 5, for at least (bis-pentafluoropropionate), hydromorphone bis(pyridine-3- about 1 month, at least about 2 months, at least about 3 carboxylate), hydromorphone bis(trifluoroacetate), hydro months, at least about 6 months, at least about 1 year, or at morphone bitartrate, hydromorphone chlorohydrate, hydro least about 2 years. Preferably, the pH of the solutions will morphone sulfate pentahydrate, and combinations thereof. remain within these ranges when stored at about 25°C. and 0025 Solutions of the present disclosure may include about 60% relative humidity (RH), about 30° C. and about hydromorphone and/or one or more pharmaceutically accept 65% RH, or about 40° C. and about 75% RH over these time able salts thereof, wherein the total concentration of hydro periods. In some exemplary embodiments, the hydromor morphone and/or pharmaceutically acceptable salt(s) thereof phone solutions have a pH of at least about 3, and more is about 1 mg/ml or more, including, for example, about 1 preferably at least about 4 or at least about 4.5, when stored mg/ml, about 2 mg/ml, about 5 mg/ml, about 10 mg/ml, about for at least about 1 month, and preferably for at least about 2 15 mg/ml, about 20 mg/ml, or about 25 mg/ml. Typically, the months, at least about 3 months, at least about 6 months, at hydromorphone solutions comprise hydromorphone and/or least about 1 year, or at least about 2 years at about 25°C. and one or more pharmaceutically acceptable salts thereof in a about 60% RH, about 30° C. and about 65% RH, or about 40° total concentration (i.e., concentration of any hydromor C. and about 75% RH. In some embodiments, the hydromor phone and pharmaceutically acceptable salt(s) thereof in the phone solutions have a pH of at least about 4.5 when stored solution) of from about 1 mg/ml to about 25 mg/ml, or from for about 3 months at (i) about 25°C. and about 60% RH., (ii) about 2 mg/ml to about 25 mg/ml, or from about 2 mg/ml to about 30° C. and about 65% RH, or (iii) about 40° C. and about 20 mg/ml, or from about 2 mg/ml to about 15 mg/ml, or about 75% RH. from about 2 mg/ml to about 10 mg/ml, or from about 2 mg/ml to about 5 mg/ml, or from about 5 mg/ml to about 25 Buffers and Other Additives mg/ml, or from about 5 mg/ml to about 20 mg/ml, or from 0031. The hydromorphone solutions of the present disclo about 5 mg/ml to about 15 mg/ml, or from about 5 mg/ml to sure are substantially free of buffers and optionally one or about 10 mg/ml, or from about 10 mg/ml to about 15 mg/ml. more other additives, as further described and detailed herein In some particular embodiments, the total concentration of below. hydromorphone and pharmaceutically acceptable salt(s) 0032. It has now been discovered that buffers and other thereof is about 2 mg/ml, about 5 mg/ml, about 10 mg/ml, or additives are not needed to maintain the pH and/or stability of about 15 mg/ml, with a concentration of about 10 mg/ml the hydromorphone solutions of the present disclosure. As being preferred. inclusion of buffers and other additives to a composition can 0026. Hydromorphone solutions of the present disclosure lead to potential complications. Such as toxicity or other side are aqueous solutions, i.e., the hydromorphone and/or phar effects, allergic responses and/or granuloma formation, the maceutically acceptable salt(s) thereof is dissolved in water, hydromorphone solutions of the present disclosure have an and preferably, sterile water for injection (WFI). As used unexpected advantage over hydromorphone solutions con herein, the term “water” or “sterile water does not encom taining such additives. Further, the exclusion of buffer or pass bacteriostatic water (i.e., water comprising benzyl alco other additives from the solutions would decrease the costs of holas a bacteriostatic preservative). Indeed, in Some embodi producing the hydromorphone solutions, and reduce manu ments, nothing other than the hydromorphone and/or facturing complexity. pharmaceutically acceptable salt(s) thereof and water is used 0033. As used herein, “buffer refers to a substance used to to form the resulting hydromorphone solution. resist change in pH over time or upon dilution or addition of 0027. The hydromorphone and/or pharmaceutically acid or alkali. A buffer may be, for example, an ionic com acceptable salt(s) thereof and water included in solutions of pound (e.g., a salt or weak acid or base) that is added to a US 2014/0005219 A1 Jan. 2, 2014

Solution to resist changes in its acidity or alkalinity, and thus and its ethoxymethyl and fluoroethoxymethyl homologues, stabilize the pH of the solution. A "buffer may also refer to spiradoline, tifluadom, deltorphin, ethoxymetopon, leu-en an agent which aids in maintaining stability of a compound in kephalin, met-enkephalin, mitragyna speciosa (kratom), solution. Buffers may include, by way of example and with mitragynine, mitragynine-pseudoindoxyl. N-phenethyl-14 out limitation, phosphates such as potassium metaphosphate, norbuprenorphine, norclozapine, 7-spiroindanyloxymor potassium phosphate; acetates, such as monobasic sodium phone, naloxone, and the like. acetate; citrates, such as sodium citrate, sodium citrate anhy 0037. The API which may be excluded from, or not added drous and dehydrate, and citric acid; salts of inorganic or to, the Solutions of the disclosure may also include other organic acids; salts of inorganic or organic bases; and others analgesics or anesthetics, such as bupivacaine, lidocaine, known to those of ordinary skill in the art. The solutions of the clonidine, baclofen, fentanyl citrate, Sufentanil citrate, flupir present disclosure are substantially free of buffer, and prefer itine, ketamine, acetaminophen, ibuprofen, fluriprofen, keto ably are completely free of buffer. profen, Voltaren, phenacetin, Salicylamide, or pharmaceuti 0034. As used herein, “other additives' generally refers to cally acceptable salts thereof. and includes any other additives, components or agents that 0038. The API which may be excluded from, or not added may be added to the solutions of the present disclosure, to, the solutions of the disclosure may also include omega including those that have been known to be included in phar conopeptides; antibodies; glycoproteins: doxapram or salts maceutical compositions or solutions—such as hydromor thereof anti-inflammatories (e.g., naproxen and indometha phone solutions. Additives that may optionally be excluded cin); antihistamines (e.g., chlorpheniramine maleate, phenin from, or not added to, the Solutions of the disclosure may damine tartrate, pyrilamine maleate, doxylamine Succinate, include, without limitation: an active pharmaceutical ingre phenyltoloxamine citrate, diphenhydramine hydrochloride, dient (API) other than hydromorphone orpharmaceutically promethazine, brompheniramine maleate, dexbromphe acceptable salts of hydromorphone; acids; pH adjusters; pre niramine maleate, clemastine fumarate and triprolidine); servatives; polymeric materials; emulsifiers; lubricants; anti antitussives; expectorants; decongestants; antibiotics (e.g., oxidants; Suspending agents; excipients (other than water); amebicides, broad and medium spectrum, final medications, diluents; oils; Surfactants; saline; solvents; metal salts; min monobactams and viral agents, such as erythromycin, peni erals; vitamins; sterilizers; and stabilizers. The solutions of cillin and cephalosporins and their derivatives); bronchodila the present disclosure are optionally substantially free of one tors; cardiovascular preparations; central nervous system or more of such additives, or may be completely free of one or drugs; immunomodulators; immunosuppressives; thyroid more of Such additives. In certain embodiments, the solutions preparations; steroids and hormones (e.g., norepinephrine; are substantially free of all such additives, or may be com ACTH, anabolics, androgen and estrogen combinations, pletely free of all such additives. androgens, corticoids and analgesics, estrogens, glucocorti 0035. Thus, in one aspect, hydromorphone solutions of the coid, gonadotropin, gonadotropin releasing, human growth disclosure are substantially free (or completely free) of buffer hormone, hypocalcemic, menotropins, parathyroid, progest and are also substantially free (or completely free) of one or erone, progestogen, progestogen and estrogen combinations, more of the following other additives: an API other than Somatostatin-like compounds, urofollitropin, vasopressin, hydromorphone or pharmaceutically acceptable salts of and others); and the like. hydromorphone; acids; pH adjusters; preservatives; poly 0039. The “other additives” which may be excluded from, meric materials; emulsifiers; lubricants; antioxidants; Sus or not added to, hydromorphone solutions of the disclosure pending agents; excipients (other than water); diluents; oils; may be an acid. Acids include carboxylic acid and salts Surfactants; Saline; solvents; metal salts; minerals; vitamins; thereof. The term “carboxylic acid refers to any suitable sterilizers; stabilizers, or any combination of these additives. carboxylic acid, usually a monocarboxylic acid, dicarboxylic 0036. The API which may be excluded from, or not added acid, or tricarboxylic acid, more usually a monocarboxylic to, the solutions of the disclosure may include opioids and acid or dicarboxylic acid, normally a monocarboxylic acid. salts, prodrugs, esters, derivatives, or analogs thereof (other The carboxylic acid may be a “low molecular weight car than hydromorphone and its pharmaceutically acceptable boxylic acid', i.e., a carboxylic acid having less than 8 carbon salts). In general, opioids and opioid derivatives are active in atoms. Examples of carboxylic acids include acetic acid, binding to the opioid receptor and may include an opioid lactic acid and salts thereof. receptor agonist or antagonist, and may include both natural 0040. The “other additives” which may be excluded from, and synthetic compounds. Examples of opioids or opioid or not added to, hydromorphone solutions of the disclosure derivatives include, but are not limited to, morphine (and may be a pH adjuster. As used herein, “pH adjuster refers to structurally related analogs and derivatives), alvimopan, ben a Substance used to increase or decrease pH upon addition to Zomorphans, buprenorphine, codeine, 6-desomorphine, a composition. Such adjusters include, for example, acids or dihydromorphine, dihydromorphinone, dihydrocodeine, alkali. Specific examples include, but are not limited to, dihydrocodeinone, 3,6-diacetylmorphine, 6-methylene-di hydrochloric acid solutions, sodium hydroxide, Sulfates, etc. hydromorphine, diphenoxylate, drotebanol, eseroline, etor 0041. The “other additives” which may be excluded from, phine, etonitazine, fentanyl, fentanyl congeners (e.g., Sufen or not added to, hydromorphone solutions of the disclosure tanil, alfentanil, lofentanil, carfentanil, remifentanil, may be a preservative. Preservatives are well known, and trefentanil, and mirfentanil), hydrocodone, levophenacyl generally include compounds for inhibiting or preventing morphan, methadone, oxymorphone, C.-Oxymorphamine, microbial activity, including growth. Non-limiting examples nicomorphine, pethidine, picenadol, tapentadole, thebaine, of preservatives include mercury-containing Substances Such trimebutane, asimadoline, butorphanol, bremazocine, cycla as merfen and thiomersal; stabilized chlorine dioxide; and Zocine, dextromethorphan, dynorphin, enadoline, ketaZo quaternary ammonium compounds such as benzalkonium cine, nalbuphine, nalfurafine, norbuprenorphine, oxycodone, chloride, cetyltrimethylammonium bromide and cetylpyri pentazocine, Salvinorin A, 2-methoxymethyl salvinorin B dinium chloride; and the like. Other examples of preserva US 2014/0005219 A1 Jan. 2, 2014

tives include benzethonium chloride, benzyl alcohol, chlo may be an oil. Non-limiting examples of oils include simple robutanol, phenol, phenylethyl alcohol, phenylmercuric lipids, derived lipids, complex lipids that are derived from nitrate, thimerosal, and others known to those of ordinary natural vegetable oil and fat, animal oil and fat, and mineral skill in the art. oil, or a mixture of those. The oil may be soybean oil, olive oil, 0042. The “other additives” which may be excluded from, sesame oil, castor oil, corn oil, peanut oil, safflower oil, grape or not added to, hydromorphone solutions of the disclosure seed oil, eucalyptus oil, medium-chain fatty acid ester, or may be a polymeric material. Non-limiting examples of poly low-chain fatty acid ester. Animal oils andfat include, but are meric materials include polysulfated glucosoglycans, glu not limited to, cod-liver oil, Seal oil, Sardine oil, docosahexi cosaminoglycans, mucopolysaccharides (e.g., chondroitins, aenoic acid, and eicosapentaenoic acid. Mineral oils include, Such as chondroitin Sulfate; and hyaluronic acid and its salts but are not limited to, liquid paraffins. Such as Sodium hyaluronate), cellulose derivatives (e.g., car 0047. The “other additives” which may be excluded from, boxymethylcellulose sodium, hydroxyethyl cellulose, or not added to, hydromorphone solutions of the disclosure hydroxypropyl cellulose, etc.), and derivatives thereof and may be a stabilizer. Stabilizers include substances that act to mixtures thereof. The term “polymeric material' includes prevent oxidation, for example, by controlling or trapping individual polymeric materials, such as those listed above, those Substances (e.g., metals) that may cause oxidation. combinations of two or more different polymeric materials, Examples of stabilizers include metal-sequestering agents, and polymeric matrices, such as described in WO 97/1 1681. such as ethylenediamine tetraacetic acid (EDTA). 0043. The “other additives” which may be excluded from, 0048. The “other additives” which may be excluded from, or not added to, hydromorphone solutions of the disclosure or not added to, hydromorphone solutions of the disclosure may be a lubricant. Lubricants include, but are not limited to may be a metal salt (e.g. potassium chloride, Sodium chloride, fatty esters, glyceryl monooleate, glyceryl monostearate, and lithium carbonate); mineral (e.g., iron, chromium, wax, carnauba wax, beeswax, Vitamin E Succinate, and the molybdenum and potassium); or vitamin (e.g., water-soluble like, and combinations thereof. vitamins such as B complex, vitamin C, vitamin B12 and folic 0044) The “other additives” which may be excluded from, acid and Veterinary formulations); Sterilizer (e.g., benzyl or not added to, hydromorphone solutions of the disclosure alcohol); and the like. In one embodiment, the hydromor may be an antioxidant. The term “antioxidant refers to an phone solutions of the present disclosure are substantially agent that inhibits oxidation and thus is used to prevent the free of sodium chloride. deterioration of compositions by oxidation due to the pres ence of oxygen free radicals or free metals in the composition. 0049. The “other additives” which may be excluded from, Such compounds include, by way of example and without or not added to, hydromorphone solutions of the disclosure limitation, ascorbic acid (Vitamin C), ascorbyl palmitate, may be an emulsifier, excipient, diluent, solvent, or Suspend butylated hydroxyanisole (BHA), butylated hydroxytoluene ing agent. Emulsifiers, excipients, diluents, solvents, and Sus (BHT), hypophosphorous acid, monothioglycerol, Sodium pending agents are well known to those skilled in the art. ascorbate, Sodium formaldehyde Sulfoxylate, sodium met Specific examples include bacteriostatic water, but not water abisulfite, sodium bisulfate, vitamin E and its derivatives, or sterile water, as defined herein. propyl gallate and others known to those of ordinary skill in the art. Sterilization and Stability 0045. The “other additives” which may be excluded from, or not added to, hydromorphone solutions of the disclosure 0050. The hydromorphone solutions of the present disclo may be a Surfactant. Surfactants include Soaps, synthetic Sure are advantageously sterile and Suitable for intrathecal detergents, and wetting agents. Surfactants may be cationic injection. While there are no absolute FDA standards for Surfactants, anionic Surfactants, non-ionic Surfactants, or sterilization processes, pharmaceutical Solutions are most amphoteric Surfactants. Examples of Surfactants include commonly sterilized using a heating regimen at about 121°C. Polysorbate 80; sorbitan monooleate; sodium lauryl sulfate with an F of about 30 minutes. While this may be an effective (sodium dodecylsulfate); Soaps such as fatty acid alkali metal method for thermally stable compounds, this practice is coun salts, ammonium salts, and triethanolamine salts; cationic terproductive for some heat-labile active pharmaceutical detergents such as dimethyl dialkyl ammonium halides, alkyl ingredients (API's). In these cases, the resulting Solution may pyridinium halides, and alkylamine acetates; anionic deter be sterile, but it is often plagued with an unacceptable gents such as alkyl, aryl and olefin Sulfonates, alkyl, olefin, increase in degradation products brought on by the excessive ether and monoglyceride Sulfates, and SulfoSuccinates; non use of heat in the Sterilization process. Furthermore, compo ionic detergents such as fatty amine oxides, fatty acid alkano sitions containing heat-labile API's are often not terminally lamides, and poly(oxyethylene)-block-poly(oxypropylene) sterilized to avoid this degradation. Therefore, it is desirable copolymers; and amphoteric detergents, for example, alkyl to find and implement a sterilization method that utilizes less B-aminopropionates and 2-alkylimidazoline quaternary harsh conditions in order to prevent this thermal degradation ammonium salts; wetting agents such as, glycerin, proteins, from taking place, while continuing to meet Sterility stan and peptides; water miscible solvents such as glycols; and dards. mixtures thereof. Examples of Surfactants also include phos 0051 Indeed, during the terminal sterilization process, pholipids (e.g., egg-yolk lecithin or soybean lecithin, phos heat-labile hydromorphone undergoes transformations to phatidylinocytol, phosphatidyl ethanolamine, phosphati undesirable side products such as hydromorphone N-oxide dylserine, sphingomyeline, phosphatidylcholine), (HNO), 6-3-tetrahydrooripavine (THO), dihydromorphine polyethylene glycol, polyoxyalkylene copolymer, and Sorbi (DHM), and pseudo-hydromorphone (PHM). This obviously tan fatty acid ester. reduces the amount of hydromorphone in Solution, and thus 0046. The “other additives” which may be excluded from, the overall efficacy of the solution. Additionally, the degra or not added to, hydromorphone solutions of the disclosure dation products may have undesirable side effects, including US 2014/0005219 A1 Jan. 2, 2014 toxicity. The amount of side products found in commercially 0058 Preferably, the hydromorphone solutions of the available non-terminally sterilized hydromorphone solutions present disclosure contain less than about 1%, or less than is shown in the table below. about 0.5%, or less than about 0.15%, or less than about 0.05% of pseudo-hydromorphone, as a percent of the active peak (% area) as determined using HPLC. Preferably, the Solutions are Substantially free of pseudo-hydromorphone, Hydromorphone Hydrochloride (Commercial) and more preferably are free of detectable levels of pseudo Ong inL hydromorphone. % HNO % THO %DHM % PHM 0059 Preferably, the hydromorphone solutions of the present disclosure contain less than about 0.2%, or less than

than about 1% of pseudo-hydromorphone, less than about 0074 According to another embodiment, a solution of 0.2% of hydromorphone N-oxide, less than about 0.2% of intrathecal hydromorphone hydrochloride is substantially dihydromorphone, less than about 0.2% of 6-f-tetrahydroori free of dihydromorphone. pavine, less than about 0.2% of unknown impurities, less than 0075 According to another embodiment, a solution of about 1% of total impurities, as a percent of the active peak (% intrathecal hydromorphone hydrochloride is substantially area) as determined using HPLC, or any combination thereof. free of 6-3-tetrahydrooripavine. In other preferred embodiments, the hydromorphone solu 0076 According to one embodiment, the solution tions of the present disclosure are stable and contain less than described herein is not terminally sterilized. about 1% or less than about 0.15% of pseudo-hydromor 0077 According to another embodiment, the solution phone, less than about 0.05% of hydromorphone N-oxide, described herein is free, or substantially free, of particulates. less than about 0.05% of dihydromorphone, less than about 0078. According to yet another embodiment, the solution 0.05% of 6-3-tetrahydrooripavine, as a percent of the active described herein is stable at 25°C. and 60% relative humidity peak (% area) as determined using HPLC, or any combination for at least 1 month. thereof. In other embodiments, the hydromorphone solutions 0079 According to yet another embodiment, the solution are stable and are substantially free of pseudo-hydromor described herein is stable at 30°C. and 65% relative humidity phone, hydromorphone N-oxide, dihydromorphone, 6-3-tet for at least 1 month. rahydrooripavine, or any combination thereof. 0080 According to a further embodiment, the solution 0067 Preferably, the hydromorphone solutions will meet described herein is stable at 40°C. and 75% relative humidity one or more of the above-listed impurity levels after storage at for at least 1 month. about 25° C. and about 60% RH, at about 30° C. and about I0081. According to yet another embodiment, the solution 65% RH, or at about 40° C. and about 75% RH for at least 1 described herein is stable at 25°C. and 60% relative humidity month, at least about 2 months, at least about 3 months, at for at least 3 months. least about 6 months, at least about 1 year, or at least about 2 I0082. According to yet another embodiment, the solution years. described herein is stable at 30°C. and 65% relative humidity for at least 3 months. 0068. The hydromorphone solutions of the present disclo I0083. According to a further embodiment, the solution sure also have low levels of particulates. Particulates may described herein is stable at 40°C. and 75% relative humidity include undissolved hydromorphone or pharmaceutically for at least 3 months. acceptable salts thereof, or other particulate matter. The I0084. According to yet another embodiment, the solution amount of particulates present in the hydromorphone solu described herein is stable at 25°C. and 60% relative humidity tions may be determined using any suitable method known to for at least 6 months. those skilled in the art including, for example, the Light I0085. According to yet another embodiment, the solution Obscuration Particle Count Test described in USP 788. The described herein is stable at 30°C. and 65% relative humidity hydromorphone solutions preferably meet the USP limits for for at least 6 months. particulate levels for 10 um or greater and 25 um or greater I0086 According to a further embodiment, the solution sized particulates, which is 6000 and 600, respectively. Pref described herein is stable at 40°C. and 75% relative humidity erably, the hydromorphone solutions will meet these limits for at least 6 months. after storage at about 25° C. and about 60% RH, at about 30° I0087. According to yet another embodiment, the solution C. and about 65% RH, or at about 40° C. and about 75% RH described herein is stable at 25°C. and 60% relative humidity for at least about 1 month, at least about 2 months, at least for at least 1 year. about 3 months, at least about 6 months, at least about 1 year, I0088 According to yet another embodiment, the solution or at least about 2 years. described herein is stable at 30°C. and 65% relative humidity 0069. In some embodiments, the hydromorphone solu for at least 1 year. tions may contain about 1300 or less, about 1000 or less, I0089. According to a further embodiment, the solution about 750 or less, about 600 or less, about 400 or less or about described herein is stable at 40°C. and 75% relative humidity 200 or less of 10 nm or greater sized particulates, and/or may for at least 1 year. comprise about 40 or less, about 20 or less, or about 10 or less 0090 According to yet another embodiment, the solution of 25 um or greater sized particulates, or combinations described herein is stable at 25°C. and 60% relative humidity thereof. Preferably, the hydromorphone solutions are free of for at least 2 years. particulates, and in particular, are free of undissolved hydro 0091. According to yet another embodiment, the solution morphone or pharmaceutically acceptable salt. described herein is stable at 30°C. and 65% relative humidity 0070. In an embodiment, a solution of intrathecal hydro for at least 2 years. morphone hydrochloride contains less than 1.0% pseudo 0092. According to a further embodiment, the solution hydromorphone. described herein is stable at 40°C. and 75% relative humidity 0071. According to a further embodiment, a solution of for at least 2 years. intrathecal hydromorphone hydrochloride contains less than 0093. Disclosed herein is a pharmaceutical solution com 0.1% pseudo-hydromorphone. prising a sterile, intrathecal, aqueous hydromorphone hydro chloride Solution, wherein said composition is Substantially 0072. In an embodiment, a solution of intrathecal hydro free of buffer. morphone hydrochloride contains less than 0.2% hydromor 0094. According to another embodiment, the solution phone N-oxide. described herein is suitable for intrathecal delivery. 0073. According to another embodiment, a solution of 0.095 Disclosed herein is a pharmaceutical composition intrathecal hydromorphone hydrochloride is substantially consisting of a sterile, aqueous solution of hydromorphone free of hydromorphone N-oxide. hydrochloride. US 2014/0005219 A1 Jan. 2, 2014

0096. In an embodiment, the concentration of the hydro ticularly, oxygen may increase the degree of degradation of morphone hydrochloride solution is 10.0 mg/mL. the hydromorphone and/or pharmaceutically acceptable salt 0097. In an embodiment, the concentration of the hydro (s) thereof and thus increase impurity levels in the solution. morphone hydrochloride solution is 2.0 mg/mL. Thus, in Some embodiments, some or all of the oxygen 0098 Disclosed herein in an embodiment is a sterile phar present in the water may be removed by sparging the water maceutical solution comprising hydromorphone and/or a with an inert gas, Such as argon or nitrogen. The water may be pharmaceutically acceptable salt(s) thereof, wherein the Solu sparged at any point during the manufacturing process, tion is substantially free of buffer and optionally one or more including prior to combination with the hydromorphone and/ other additives. In one particular embodiment, the solution or pharmaceutically acceptable salt(s) thereof, after the comprises hydromorphone hydrochloride. hydromorphone and/or pharmaceutically acceptable salt(s) 0099. In some embodiments, the hydromorphone compo thereof has dissolved, after the concentration of the hydro sitions consist essentially of hydromorphone and/or one or morphone and/or pharmaceutically acceptable salt(s) thereof more pharmaceutically acceptable salts thereof and water. in the solution has been adjusted by further additions, or any Thus, also provided is a sterile pharmaceutical solution con combination thereof. In order to reduce the presence of sisting essentially of hydromorphone and/or one or more unwanted oxygen, the hydromorphone solution may option pharmaceutically acceptable salts thereof and water. In Such ally be held under a blanket of inert gas, such as argon or an embodiment, the solution may contain impurities inher nitrogen, during the manufacturing process and prior to ently formed as a result of degradation of the hydromorphone inserting the solution into a container. Additionally, an inert or salt thereof, but does not contain impurities, buffers, or gas may be added or injected into the headspace of the con other substances or additives that have been affirmatively tainer, to further purge oxygen therefrom. added to or included in the composition. In one particular 0103) Following manufacture, the hydromorphone solu embodiment, the pharmaceutically acceptable salt is hydro tion may be aseptically inserted into a container, such as an morphone hydrochloride. ampoule, vial, or Syringe. Optionally, the solution is asepti 0100 Also disclosed herein in an embodiment is a sterile cally filtered prior to aseptically filling the container. In some pharmaceutical Solution comprising hydromorphone and/or embodiments, the solution may be aseptically filtered using, one or more pharmaceutically acceptable salts thereof, for example, a 0.2 um sterile filter. wherein the solution is substantially free (or completely free) 0104. In some embodiments, the containers may be col of buffer and also substantially free (or completely free) of ored. Without wishing to be bound to any particular theory, it one or more (e.g., any combination) of the following: API is believed exposure to light may cause or accelerate degra other than hydromorphone or pharmaceutically acceptable dation of the hydromorphone and/or pharmaceutically salt(s) of hydromorphone; acids; pH adjusters; preservatives; acceptable salt(s) thereof, and thus formation of impurities polymeric materials; emulsifiers; lubricants; antioxidants; and discoloration of the solution. Use of colored containers Suspending agents; excipients (other than water); diluents; may help reduce exposure of the solution to light, thus oils; Surfactants; Saline; Solvents; metal salts; minerals; Vita decreasing the amount of impurity formation. Thus in some mins; sterilizers; and stabilizers. embodiments, the container is a colored container, such as an amber container. Method of Manufacture and Storage 0105. In order to reduce or eliminate interactions between 0101 Also provided are methods for manufacturing the container and the hydromorphone solution, in some hydromorphone solutions disclosed herein. The solutions embodiments, the container may be treated prior to filling to may be prepared by combining the desired amount of hydro render the interior surface of the containerinert. For instance, morphone and/or pharmaceutically acceptable salt(s) thereof containers, and in particular glass containers, may be dealka with sterile water, in the absence of buffers and optionally one lized in order to prevent or reduce the diffusion or exchange of or more other additives, and dissolving the hydromorphone ions between the Solution and the glass, which may lead to and/or pharmaceutically acceptable salt(s) thereof to form a alterations in the pH of the solution over time. Any suitable hydromorphone solution of the present disclosure. This dis container treatment known in the art may be used. In one Solving of the hydromorphone and/or pharmaceutically particular embodiment, the containers are treated with a Sul acceptable salt(s) thereof may occur simply as a result of the fate. Such as ammonium sulfate, prior to sterilization of the combining or may be facilitated by mixing or stirring the container and aseptic filling. hydromorphone and/or pharmaceutically acceptable salt(s) 0106. In one embodiment, the container is a vial. The vial thereof and water using any suitable technique. Upon can be made of glass or plastic. It may be closed off at the top completion of the dissolving, the solution is preferably by a stopper with crimp top. Flip offtops may also be used for homogenous, and there is little or no undissolved hydromor optional tamper proof and/or color coding. Color coding may phone or pharmaceutically acceptable salts thereof detected be done by concentration and/or vial size, thereby reducing (using methods generally known in the art) or present in the practitioner error and increasing safety to the recipient. Types solution. Optionally, additional sterile water, and/or hydro of stoppers that may be used include rubber and plastic. The morphone and/or pharmaceutically acceptable salt(s) thereof, size of the vial may be, for example, 20 ml or 40 ml. In one may be added and dissolved into the solution as desired, in embodiment, the vial is an amber vial. order to alter the concentration of the hydromorphone and/or 0107. In other embodiments, the container is a syringe. pharmaceutically acceptable salt(s) thereof in the final Solu Any syringe known in the art as Suitable for intrathecal injec tion to the desired level. tion may be used. One exemplary syringe is set forth in FIG. 0102. It has been discovered that oxygen, including oxy 1. gen inherently present in the water (i.e., dissolved in the 0.108 Referring to FIG. 1, the syringe 10 comprises a water) used to prepare the hydromorphone solutions, may barrel 14, a plunger 11 with attached gasket 12, and a leer impact the stability and pH of the final solution. More par lock tip 13. The barrel 14 may be made of glass or plastic US 2014/0005219 A1 Jan. 2, 2014

having two open ends. The Syringe 10 may be of varying or diseases. The disclosure thus further provides methods of sizes, for example, may have sizes of 5 ml, 20 ml, or 40 ml. treating pain in a Subject, comprising administering intrath One end of the barrel 14 is closed off by a plunger 11 that ecally a hydromorphone solution of the disclosure to a subject forces the hydromorphone solution (not shown) to the other in need of pain relief or prevention. The solutions are admin end of the barrel 14 when dispensing. A gasket 12 is attached istered intrathecally using any known technique (e.g., using a to the plunger 11 for sealing the solution in the barrel 14. The drug delivery device, Such as an infusion system, or injecting gasket 12 may be made of a rubbery elastic material. Such as by hand directly into the intrathecal space). The hydromor natural rubber or synthetic rubber. The dispensing end of the phone solutions are desirably suitable for use with an intrath barrel 14 is closed off by a leur-lock tip 13. The leur-lock tip ecal infusion system. The solutions of the present disclosure 13 mates with the infusion system for dispensing the solution. are suitable for use with any intrathecal delivery system 0109 The syringe may be aseptically filled with a hydro known in the art. Suitable intrathecal drug delivery systems morphone solution of the present disclosure to form a pre are commercially available, and include the Medtronic Syn filled syringe, which may be used to fill and refill infusion chroMedR Infusion System, the SynchroMedR II Program systems for intrathecal delivery of the hydromorphone solu mable Pump, the Johnson and Johnson Codman(R) division tion. The pre-filled syringe may be formed by aseptically pumps, and InSet(R) technologies pumps. filling the barrel of the syringe with the hydromorphone solu 0114. One exemplary intrathecal drug delivery system is tion of the present disclosure. The filled syringe is then asep illustrated in FIG. 2, which displays a syringe 10 filled with a tically sealed (e.g., capped) using any suitable technique hydromorphone solution of the present disclosure (not known in the art, to form a pre-filled Syringe containing sterile shown) as used with a pump delivery system. The delivery hydromorphone solution therein. In certain aspects, the pre system includes a catheter 23 for connecting the Syringe to the filled Syringe may be subsequently inserted into an outer pump 21. The hydromorphone solution may be dispensed packaging material (e.g., box, sealed tray, etc.) and sold as a from the syringe 10, through the catheter 23, into the pump packaged pre-filled Syringe. 21. The pump 21 then pumps the hydromorphone solution 0110 Thus, also provided is a pre-filled syringe compris through a second catheter 22 to a desired location in the body. ing a hydromorphone solution of the present disclosure that is 0115 The methods of the present disclosure can be used to ready for immediate injection of the hydromorphone solution treat a variety of different types of pain. The causes of the pain into the intrathecal space or delivery to an infusion system. may be identifiable or unidentifiable. Where identifiable, the Since the Syringe already contains the hydromorphone solu origin of pain may be, for example, of malignant, non-malig tion, the process of drawing up and filtering the composition nant, infectious, non-infectious, or autoimmune origin. Of into a syringe prior to administering the Solution or filling or particular interest is the management of pain associated with refilling the infusion system is eliminated. Eliminating this disorders, diseases, or conditions that require long-term process makes filling and refilling the infusion system safer therapy, e.g., chronic and/or persistent diseases or conditions and easier, since a practitioner does not have to draw up and for which therapy involves treatment over a period of several filter the solution while administering the therapy to the days (e.g., about 3 days to 10 days), to several weeks (e.g., patient, and also avoids the potential of contamination of the about 3 or 4 weeks to 6 weeks), to several months or years, up Solution with, for example, glass particles from an ampoule, to including the remaining lifetime of the Subject. Subjects bacteria, and the like. A practitioner merely opens the outer who are not presently suffering from a disease or condition, packaging to gain access to the pre-filled Syringe, which is but who are susceptible to such may also benefit from pro ready for use. phylactic pain management using the devices and methods of 0111. The containers and/or packaging may optionally be the disclosure, e.g., prior to traumatic Surgery. Pain amenable labeled and/or color-coded to allow for easy identification of to therapy according to the disclosure may involve prolonged the size of the container (e.g., the volume of solution within episodes of pain alternating with pain-free intervals, or Sub the container) and/or the concentration of the hydromorphone stantially unremitting pain that varies in severity. Solution in the container. The containers may optionally be 0116. In general, pain can be somatogenic, neurogenic, or packaged with instructions for use. psychogenic. Somatogenic pain can be muscular or skeletal 0112 AS discussed above, the presence of oxygen may (i.e., osteoarthritis, lumbosacral back pain, posttraumatic, lead to oxidation of the hydromorphone or salt thereof, insta myofascial), visceral (i.e., chronic pancreatitis, ulcer, irri bility of the Solution, and unwanted changes in pH. In order to table bowel), ischemic (i.e., arteriosclerosis obliterans), or reduce the chances of oxidation of the hydromorphone solu related to the progression of cancer (e.g., malignant or non tions, a blanket of inert gas, such as argon or nitrogen, may be malignant). Neurogenic pain can be due to posttraumatic and laid across the containers before they are sealed to displace postoperative neuralgia, can be related to neuropathies (i.e., any oxygen present. Oxidation of the hydromorphone solu diabetes, toxicity, etc.), and can be related to nerve entrap tions in Syringes may also be minimized by the lack of head ment, facial neuralgia, perineal neuralgia, postamputation, space in the Syringes, which limits the presence of any gasses, thalamic, causalgia, and reflex sympathetic dystrophy. including oxygen, within the Syringe. Thus, in another 0117 Specific examples of conditions, diseases, disor embodiment, the hydromorphone solution is stored under an ders, and origins of pain amenable to management according inert atmosphere (e.g., nitrogen, argon) within the container. to the present disclosure include, but are not necessarily lim In one particular embodiment, the hydromorphone solution is ited to, cancer pain (e.g., metastatic or non-metastatic can stored under an intert atmosphere within a vial. cer), chronic inflammatory disease pain, neuropathic pain, post-operative pain, iatrogenic pain (e.g., pain following Method of Use invasive procedures or high dose radiation therapy, e.g., 0113. The hydromorphone solutions of the present disclo involving scar tissue formation resulting in a debilitating Sure can be used to facilitate management of pain that is compromise of freedom of motion and Substantial chronic associated with any of a wide variety of disorders, conditions, pain), complex regional pain syndromes, failed-back pain US 2014/0005219 A1 Jan. 2, 2014

(chronic back pain), Soft tissue pain, joints and bone pain, a value as variable within a margin of error. When no particu central pain, injury (e.g., debilitating injuries, e.g., paraple lar margin of error, such as a standard deviation to a mean gia, quadriplegia, etc., as well as non-debilitating injury (e.g., value given in a chart or table of data, is recited, the term to back, neck, spine, joints, legs, arms, hands, feet, etc.), “about’ should be understood to mean that range which arthritic pain (e.g., rheumatoid arthritis, osteoarthritis, would encompass the recited value and the range which arthritic symptoms of unknown etiology, etc.), hereditary would be included by rounding up or down to that figure as disease (e.g., sickle cell anemia), infectious disease and well, taking into account significant figures. resulting syndromes (e.g., Lyme disease, AIDS, etc.), chronic 0.124. The term “sterile, as used herein in reference to the headaches (e.g., migraines), causalgia, hyperesthesia, Sym claimed Solutions, means the Solution meets or exceeds the pathetic dystrophy, phantom limb syndrome, denervation, standards for sterility set forth in the United States Pharma and the like. Pain can be associated with any portion(s) of the copeia (USP). In certain particular embodiments, a sterile body, e.g., the musculoskeletal system, visceral organs, skin, solution of the present disclosure is free from all detectable nervous system, etc. live bacteria or other microorganisms and their spores. The 0118 Pain associated with any type of malignant or non sterility of the compositions of the present disclosure may be malignant cancer is amenable to alleviation according to the tested using any Suitable technique known in the art. disclosure. Specific examples of cancers that can be associ 0.125. The term “particulate as used herein, is meant to ated with pain (due to the nature of the cancer itselfortherapy describe undissolved particles, other than gas bubbles, unin to treat the cancer) include, but are not necessarily limited to tentionally present in the drug solution. lung cancer, bladder cancer, melanoma, bone cancer, multiple 0.126 The term “intrathecal,” as used herein, means intro myeloma, brain cancer, non-Hodgkin’s lymphoma, breast duced into or occurring in the space under the arachnoid cancer, oral cancers, cervical cancer, ovarian cancer, colon membrane which covers the brain and spinal cord. Intrathecal cancer, rectal cancer, pancreatic cancer, dysplastic nevi, drug delivery is designed to manage chronic pain and/or endocrine cancer, prostate cancer, head and neck cancers, spasticity. Such as intractable cancer pain, by delivering pain sarcoma, Hodgkin’s disease, skin cancer, kidney cancer, medication directly to the intrathecal space. Intrathecal drug stomach cancer, leukemia, testicular cancer, liver cancer, delivery typically uses an implantable infusion system to uterine cancer, and aplastic anemia. Certain types of neuro deliver pain medication directly to the intrathecal space via a pathic pain can also be amenable to treatment according to the Surgically implanted infusion pump and catheter, but also disclosure. refers to direct injection of the drug into the intrathecal space 0119 Chronic back pain, which is also amenable to man using a Syringe (e.g., injected by hand). agement using the methods of the disclosure, is another broad 0127. The term “stable' as used herein in reference to the category of pain that can be alleviated by application of the disclosed solutions means retaining Substantially the same methods of the disclosure. Chronic back pain is generally due properties and characteristics throughout its period of storage to one or more of the following six causes: (i) stress on and use that it possessed at the time of its manufacture. Such intervertebral facetjoints, caused by slippage, arthritis, wedg that the solution or composition provides substantially the ing, or Scoliosis; (ii) radiculopathy, the mechanical compres same therapeutic benefit to the patient over the period of time sion of the nerve root due to bulging discs or tumors; (iii) that the solution is stored and delivered, such as for about 1 tendonitis or tendon sprain; (iv) muscle spasm or muscle month, about 3 months, about 6 months, about 1 year, or about sprain; (v) ischemia, a local insufficiency in circulatory flow: 2 years. For example, in particular embodiments, the solu and (vi) neuropathy, damage to nervous tissue of metabolic tions or compositions disclosed herein are stable if they con etiology or arising from cord tumors or central nervous sys tain within 3% of the amount of hydromorphone hydrochlo tem disease. ride as claimed on the label (% LC) after about 12 weeks, as 0120. The hydromorphone solutions may be administered determined by HPLC assay. at any dosage regimen Suitable for treating the pain. The I0128. The term “active pharmaceutical ingredient’ or Solution may be administered continuously and/or at intervals API. as used herein, means any substance that may be used over a pre-selected administration period ranging from sev in a pharmaceutical product, and which is intended to furnish, eral hours, one to several weeks, one to several months, up to alone or in combination with another Substance, pharmaco one or more years. In one embodiment, the Solution is admin logical activity or to otherwise have direct effect in the diag istered in an amount Sufficient so as to provide a dose of nosis, cure, mitigation, treatment or prevention of disease, or hydromorphone and/or pharmaceutically acceptable salt(s) to have direct effect in restoring, correcting, or modifying thereof of from about 0.5 mg/day to about 4 mg/day. When physiological functions in human beings or other mammals. administered using an infusion system, the solution may be I0129. The term “substantially free of, when used in con administered at any suitable infusion rate, including at an nection with the solutions of the present disclosure, means the infusion rate of from about 0.05 ml/day to about 0.4 ml/day, indicated substance (e.g., a buffer or an “other additive') has including from about 0.05 ml/day to about 0.1 ml/day. not been affirmatively added to the solution during manufac 0121. In one aspect, disclosed herein is a method of treat ture of the solution. ing pain by administration of a sterile aqueous solution of 0.130. As used herein, “other additives' generally refers to hydromorphone hydrochloride, wherein said solution is sub and includes any other additives, components or agents that stantially free of buffer or other additives. may be affirmatively added to the solutions of the present disclosure, including those that have been known to be DEFINITIONS included in pharmaceutical compositions or solutions—such 0122. As used herein, the terms below have the meanings as hydromorphone solutions. Additives that may optionally indicated. be excluded from, and thus not added to, the solutions of the 0123. The term “about,” as used herein, is intended to disclosure may include, without limitation: an active pharma qualify the numerical values which it modifies, denoting Such ceutical ingredient (API) other than hydromorphone or US 2014/0005219 A1 Jan. 2, 2014 pharmaceutically acceptable salt(s) of hydromorphone; Example 4 acids; pH adjusters; preservatives; polymeric materials; emulsifiers; lubricants; antioxidants; Suspending agents; Preparation of 10.0 Mg/mL Hydromorphone excipients (other than water); diluents; oils; Surfactants; Hydrochloride Solution with 0.03% Citrate Buffer saline; solvents; metal salts; minerals; vitamins; sterilizers; (0.139. To 1 L of WFI is added 6.06 g citrate buffer, and the and stabilizers; and any combination thereof. mixture is stirred for 10+2 minutes. To the resulting solution 0131 “Subject' when used in connection with the meth is added 200.0 g hydromorphone hydrochloride and 2 LWFI. ods of treatment disclosed herein refers to a human or other The mixture is then stirred for 45 minutes. The resulting mammal. solution is diluted to 20 L with WFI and stirred for at least an 0132 “Treatment as in “treatment of pain' is used herein additional 10 minutes. to encompass both a decrease in pain severity and/or intensity to provide partial or complete relief of pain and/or pain Symp Example 5 toms. The effect may be prophylactic in terms of completely or partially preventing or reducing the severity of pain. Preparation of 10.0 mg/mL hydromorphone 0133. The term “pain management is used here to gener hydrochloride solution with 0% citrate buffer ally describe regression, Suppression, or mitigation of pain, including acute and chronic pain, so as to make the Subject 0140. To 3 L of WFI is added 200.0 g hydromorphone more comfortable as determined by subjective criteria, objec hydrochloride. The mixture is stirred for 45 minutes. The tive criteria, or both. In general, pain is assessed subjectively resulting solution is diluted to 20 L with WFI and stirred for by patient report, with the health professional taking into at least an additional 10 minutes. consideration the patient’s age, cultural background, environ ment, and other psychological background factors known to Example 6 alter a person's Subjective reaction to pain. 0134. The term “aqueous” as used herein in reference to Impurity Profile of Hydromorphone Hydrochloride the hydromorphone solutions means the Solutions contain Solutions with Varying Amounts of Buffer Water. 0.141. The impurity profile of the compositions produced 0135 Certain embodiments disclosed herein may be illus in Examples 1-5, showing the amount of each impurity, as trated by the following non-limiting examples. well as the percent of the label claim (% LC) of the API, as determined by HPLC assay. Example 1 Preparation of 10.0 Mg/mL Hydromorphone Hydrochloride Solution with 0.2% Citrate Buffer Buffer-containing Solutions 0136. To 1 L of water for injection (WFI) is added 40.4g citrate buffer, and the mixture is stirred for 10+2 minutes. To the resulting solution is added 200.0 g hydromorphone hydro chloride and 2 L WFI. The mixture is then Stirred for 45 minutes. The resulting solution is diluted to 20 L with WFI and stirred for at least an additional 10 minutes. Example 2 Preparation of 10.0 Mg/mL Hydromorphone Hydrochloride Solution with 0.1% Citrate Buffer Impurity Profile of Hydromorphone Hydrochloride 0137 To 1 L of WFI is added 20.2 g citrate buffer, and the Solution with 0% Buffer Over Time mixture is stirred for 10+2 minutes. To the resulting solution 0142. The impurity profile of the composition prepared in is added 200.0 g hydromorphone hydrochloride and 2 LWFI. Example 5 over time, showing the amount of each impurity, The mixture is then stirred for 45 minutes. The resulting as well as the percent of the label claim (% LC) of the hydro solution is diluted to 20 L with WFI and stirred for at least an morphone HCl, as determined by HPLC assay. additional 10 minutes. Example 3 Preparation of 10.0 Mg/mL Hydromorphone Hydrochloride Solution with 0.05% Citrate Buffer 0.138. To 1 L of WFI is added 10.1 g citrate buffer, and the mixture is stirred for 10+2 minutes. To the resulting solution is added 200.0 g hydromorphone hydrochloride and 2 LWFI. The mixture is then stirred for 45 minutes. The resulting solution is diluted to 20 L with WFI and stirred for at least an additional 10 minutes. US 2014/0005219 A1 Jan. 2, 2014 12

0143. The data shows that compositions containing buffer additional 10 minutes. The Solutions were again sparged with have the same levels of impurities as the composition without nitrogen, and filtered into a holding tank. A nitrogen blanket buffer. This indicates that the buffer is not an essential part of was maintained during the hold period prior to container the composition from an impurity standpoint. Further, addi filling. tional data shows that the buffer-free composition maintains its low levels of impurities over time, indicating that buffer is 0147 The solutions were used to fill amber 20 cc glass not essential to the long-term stability of the composition. vials. A 20 cc rubber vial stopper (available from West) and 0144. The formulation without buffer has a small pH flip top aluminum crimp (available from West) were used as change (only 0.5 pH units) over the time period tested. This the container closure system. The filled containers were either indicates that the buffer is not necessary to keep the pH stable terminally sterilized (TS) or withheld from terminal steriliza over time. This pH data, coupled with the impurity data, tion (non-terminally sterilized, NTS). The containers sub shows that the small change in pH that is observed does not jected to terminal sterilization were sterilized for 20 minutes have a detrimental effect on the purity of the formulation. at 121° C. or greater. A summary of the manufacture of Further, the absence of the buffer gives the formulation a pH solutions A-E is set forth in Table 1 below: closer to the patient’s natural physiological pH of the cere brospinal fluid than the formulation containing the buffer (5.0 TABLE 1 vs. 4.1). pH prior to Total Example 8 % citrate HMHCI vials Sterilization Solution buffer addition Final pH filled parameters Effect of Terminal Sterilization on Impurity Formation A. O.20% 3.75 3.77 18O TS, NTS B None S.48 4.8O 60 TS, NTS 0145 The effect of terminal sterilization on the formation C O.O.3% 4.09 3.83 60 TS, NTS of impurities was evaluated for hydromorphone HCl solu D O.05% 4.10 3.95 60 TS, NTS tions containing varying amounts of citrate buffer. E O.10% 4.17 4.03 60 TS, NTS 0146 Five batches (400 L each) of hydromorphone HCl Solutions (Solutions A-E) having a concentration of hydro HMHC1 = hydromorphone HCl; morphone HCl of 10 mg/ml were prepared using varying TS = terminally sterilized; amounts of citrate buffer and WFI (obtained from Steriles NTS = non-terminally sterilized South). WFI was added to a compounding tank and mixing was started. The WFI was sparged with nitrogen to remove 0148 125 commercially available samples of hydromor dissolved oxygen present in the WFI. For solutions contain phone HCl (10 mg/ml) were also purchased from Best Value ing citrate buffer, citrate buffer was added to the tank in an Drugs (Farmville, N.C.). amount sufficient to obtain the desired final concentration of buffer, and the resulting mixture was stirred for 10+2 minutes. 014.9 The commercially available sample and solutions Hydromorphone HC1 was added to the resulting mixture (or A-E were tested at day 0 (i.e., the day solutions A-E were to WFI if no citrate buffer was used), and the mixture was prepared) for stability (% LC) and impurities using high stirred until the hydromorphone HCl was dissolved and the performance liquid chromatography (HPLC). The percent mixture was homogenous. Once dissolved and homogenous, age of unknown impurities that eluted from the HPLC column the mixture was again sparged with nitrogen. The resulting at a relative retention time (RRT) of 0.56 and 0.80 (relative to solutions were diluted with WFI to obtain a concentration of the hydromorphone HCl peak elution time) was also mea hydromorphone HCl of 10 mg/ml, and stirred for at least an sured. The results are set forth in Table 2 below.

TS or Citrate Solution NTS Buffer pH

Commercial — Yes 4.1 A. NTS O.2% 4.1 A. TS O.2% 4.1 B NTS O% S.O B TS O% S.O C NTS O.03% 4.2 C TS O.03% 4.2 D NTS O.05% 4.1 D TS O.05% 4.2 E NTS O.10% 4.1 E TS O.10% 4.1

LC = label claim; HNO = hydromorphone N-oxide; DHM = dihydromorphine; THO = 6-3-tetrahydrooripavine; RRT = relative retention time; PHM= pseudo-hydromorphone *The sterilization method for the commercial samples was unknown at day 0. The commercial samples contained 0.2% sodium citrate and 0.2% citric acid. US 2014/0005219 A1 Jan. 2, 2014 13

0150. As can be seen from Table 2, the pH of the solutions Example 9 at day 0 ranged from 4.1 to 5.0. Solution B, which contained no citrate buffer, had the highest pH (i.e., pH 5.0), further Effect of Terminal Sterilization and Storage demonstrating that the absence of buffer gives the Solution a Conditions on Stability and Impurity Formation pH closer to the natural physiological pH of cerebrospinal 0151. The effect of terminal sterilization and storage con fluid than the Solutions containing buffer (e.g. compositions A ditions on solution stability and the formation of impurities and C-E and the commercial composition). The assay values was evaluated for hydromorphone HCl Solutions containing for percent label claim (% LC) of hydromorphone HCl ranged varying amounts of citrate buffer. from 99.0% to 100.8%, which are all comparable and within 0152 Terminally sterilized samples of solutions A-E from normal analytical variance. The levels of the known impurity Example 8 were stored either upright or inverted at 25°C., 30° pseudo-hydromorphone (PHM), unknown impurities at 0.80 C. or 40°C., and tested for stability (% LC) and impurities 3, RRT, and total impurities were higher in the terminally ster 7, 14, 28, 56, and 84 days after manufacture. The commer ilized products when compared to the non-terminally steril cially available composition from Example 8 was also tested. ized products. These results suggest that terminal sterilization The results were compared to those obtained for a non-termi of the hydromorphone HCl solutions adversely impacts sta nally sterilized sample of Solution B (containing no citrate bility of the solutions. buffer). The results are set forth in Tables 3-8 below. TABLE 3 Day 3 Storage O.S6 O.80 Total TS or Citrate U or Temp LC HNO DHM THO RRT RRT PHM Impurity Solution NTS Buffer (°C.) pH (%) (%) (%) (%) (%) (%) (%) (%) Commercial — Yes U 25 4.O. 99.4 Commercial — Yes 25 na. 97.5 A. TS O.2% U 25 na 98.8 A. TS O.2% 25 nia 99.5 B TS O.0% U C TS O.O.3% U D TS O.05% U E TS O.10% U Commercial — Yes U Commercial — Yes 30 na 98.9 A. TS O.2% U 30 na. 96.6 A. TS O.2% 30 nia 99.5 B TS O.0% U C TS O.O.3% U D TS O.05% U E TS O.10% U Commercial — Yes U Commercial — Yes 40 nia 99.9 A. TS O.2% U 40 nia 99.3 A. TS O.2% 40 nia 99.4 B TS O.0% U C TS O.O.3% U D TS O.05% U E TS O.10% U B NTS O.0% I = inverted; U = upright

Day 7 Storage O.S6 O.80 Total TS or Citrate U or Temp LC HNO DHM THO RRT RRT PHM Impurity Solution NTS Buffer (°C.) pH (%) (%) (%) (%) (%) (%) (%) (%) Commercial — Yes U Commercial — Yes A. TS O.2% U A. TS O.2% B TS O.0% U C TS O.O.3% U D TS O.05% U E TS O.10% U Commercial — Yes U Commercial — Yes A. TS O.2% U A. TS O.2% B TS O.0% U

US 2014/0005219 A1 Jan. 2, 2014 16

TABLE 8-continued Day 84 Storage TS or Citrate U or Temp LC HNO DEHM Solution NTS Buffer (°C.) pH (%) (%) (%) C TS O.O.3% U 25 4.0 99.7

0153. The appearance for all samples over the tested time 0156. Upon close review of the impurity data for day 3, an period was clear, colorless, and without visible particulate unidentified peak at RRT 0.80 was found that was greater than matter. All pH values tested were within the expected speci other impurity peaks and exceeded the ICH threshold for fication of 3.5 to 5.5. As can be seen from Tables 3-8, both the 7,7-dihydroxy-hydromorphone for all of the terminally ster terminally sterilized samples and the non-terminally steril ilized samples for compositions A-E. All of the terminally ized samples of solution B (containing no citrate buffer) had sterilized samples had higher impurity levels at RRT 0.80 a higher pH than solutions A and C-E and the commercial when compared to the commercial compositions as well as composition at each day and storage condition tested, further the non-terminally sterilized sample of solution B that was demonstrating that the absence of buffer gives the Solution a tested at this time point. Although this unknown peak was pH closer to the natural physiological pH of cerebrospinal present in both the terminally sterilized and non-terminally fluid than the solutions containing buffer (e.g. solutions A and sterilized solution B samples, as well as the commercial com C-E and the commercial compositions). position samples, there was a significant difference in the 0154 The level of known impurities (and in particular level of the impurity in the different samples; i.e., the uniden PHM), unknown impurities at 0.80 RRT, and total impurities tified impurity level was about 0.07%, <0.05%, or 0.21% for for terminally sterilized solutions A-E were higher at each the 0.80 RRT peak for the commercial sample, the non day tested as compared to the non-terminally sterilized terminally sterilized sample of solution B, and the terminally sample of Solution B (containing no citrate buffer), demon sterilized sample of solution B, respectively. Thus, to further strating that terminal sterilization of the hydromorphone HCl evaluate the effects of terminal sterilization on the product Solutions adversely impacts stability of the solutions. impurity profile, the commercial composition was terminally 0155 As compared to the commercial composition, ter sterilized using the same protocolas for Solutions A-E (i.e., 20 minally sterilized samples of solutions A-E all had lower minutes at 121.1° C.). The unknown impurity was found to be levels of known impurities, and in particular PHM, at all days 0.17% at 0.80 RRT for the terminally sterilized commercial and storage conditions tested, with the exception of the ter composition. Thus, the terminally sterilized sample of the minally sterilized samples of solution B at day 3, 25° C. commercial composition and of solution Bboth had around a storage; and at day 28, 25° C. storage, both of which had 0.2% level of the 0.80 RRT impurity, while the non-termi similar levels of PHM as the corresponding commercial nally sterilized commercial composition and non-terminally samples. Similarly, the levels of total impurities were less for Sterilized solution B had around a 0.05% level of the 0.80 terminally sterilized solutions A and C-E, as compared to the RRT impurity. This suggests that the commercial composi commercial compositions, at all days and time periods tested, with the exception of terminally sterilized samples of solution tion was aseptically filled rather than terminally sterilized. Cat day 3, 30° C.; day 7, 30° C.; day 28, 25° C. and 30° C.: 0157 According to ICH guidelines, for the designed dos day 56, 40°C.; and day 84, 40°C., all of which had compa age of hydromorphone HCl intrathecal injection, the qualify rable levels of total impurities, as compared to the corre ing threshold for unknown impurities is 0.20%. To control the sponding commercial composition. In contrast, the level of levels of the 0.80RRT impurity to lower than the qualification unknown impurities at 0.80 RRT was higher for terminally threshold, it is preferable that the solutions of the present sterilized solutions A-E, as compared to the commercial com disclosure be aseptically processed and not terminally steril position. ized. US 2014/0005219 A1 Jan. 2, 2014 17

Example 10 TABLE 9-continued Particulate Profile of Terminally Sterilized Particulate Data Hydromorphone Hydrochloride Solutions Under TS or Storage Time Varying Storage Conditions Over Time Solution NTS Conditions Tested 10 m 25 Im Commercial NTS 30° C.65% RH Week 8 900 O 0158 Solution A and the commercial composition from Commercial NTS 40° C.;75% RH Week 8 6SO O Example 8 were stored inverted under varying storage con 0159. The amount of particulates having a size of 10um or ditions and evaluated over 8 weeks for particulate formation greater and 25um or greater that were present in each Solution to determine whether the container (vial) closure system (i.e., was determined using the Light Obscuration Particle Count amberglass 20 cc vials with rubber 20cc vial stoppers and flip Test described in USP 788. top aluminum crimp) used in Example 8 to prepare the vials (0160. As can be seen from Table 9, solution A had from containing hydromorphone HCl affected solution quality. 180 to 1450 particulates 10 um or greater in size and from 10 Particulates levels were also tested at day 0 for the commer to 60 particulates 25um or greater in size over the course of cial composition and both the terminally sterilized and non the 8 week experiment, while the commercial composition had from 190 to 1310 particulates 10um or greater in size, and terminally sterilized samples of solution A. The results are set from 0 to 40 particulates 25um or greater in size. The USP forth in Table 8. limits for this testing for 10um and 25um sized particulates is 6000 and 600, respectively. Thus, the container closure TABLE 9 system used to prepare the vials in Example 8 did not adversely impact the levels of particulates in the product. Particulate Data Example 11 TS or Storage Time Solution NTS Conditions Tested 10 m 25 m Composition Profile of Hydromorphone Hydrochloride Solution with 0% Buffer Under A. TS na Day 0 430 2O Varying Storage Conditions Over Time A. NTS na Day 0 320 2O A. TS 25° C.60% RH. Day 3 450 2O 0.161 The impurity profile and stability of 10 mg/mL A. TS 30° C.65% RH. Day 3 550 10 hydromorphone HCl solutions stored understandard storage A. TS 40° C.75% RH. Day 3 290 10 conditions (20° C./60% RH) or accelerated storage condi A. TS 25° C.60% RH. Day 7 910 2O A. TS 30° C.65% RH. Day 7 790 2O tions (40°C./75% RH) was determined at various time points A. TS 40° C.75% RH. Day 7 930 30 up to 36 months (standard storage) or 6 months (accelerated A. TS 25° C.f60% RH Week 2 600 30 storage). A. TS 30° C.f65% RH Week 2 430 60 0162. A hydromorphone HCl solution containing 0% A. TS 40° C.;75% RH Week 2 18O 2O buffer was prepared and filtered as described in Example 8. A. TS 25° C.f60% RH Week 4 400 10 A. TS 30° C.f65% RH Week 4 660 10 The solution was used to fill round amber 20 mL vials (avail A. TS 40° C.;75% RH Week 4 610 60 able from The Glass Group, Inc., DSM Material No.311398). A. TS 25° C.f60% RH Week 8 960 2O A 20 mm barrier faced stopper (available from West, DSM A. TS 30° C.f65% RH Week 8 1140 40 Material No. 006262) and 20 mm flip-offseal (available from A. TS 40° C.;75% RH Week 8 1450 50 Commercial NTS na Day 0 860 10 West, DSM Material No. 005786) were used as the container Commercial NTS 25° C.60% RH. Day 3 1310 2O closure system. The container closure system complied with Commercial NTS 30° C.65% RH. Day 3 800 O USP 661 monograph requirements. The filled containers Commercial NTS 40° C.75% RH. Day 3 1OOO 10 were not terminally sterilized. Commercial NTS 25° C.60% RH. Day 7 730 10 0163 The appearance of the solutions was visually Commercial NTS 30° C.65% RH. Day 7 610 O Commercial NTS 40° C.75% RH. Day 7 500 O inspected to Verify that the solutions were clear, colorless, and Commercial NTS 25° C.f60% RH Week 2 440 O essentially free of visible contaminants. The percent label Commercial NTS 30° C.f65% RH Week 2 440 O claim, level of related substances and impurities, level of Commercial NTS 40° C.;75% RH Week 2 300 O Commercial NTS 25° C.f60% RH Week 4 410 10 particulate matter, level of bacterial endotoxins, and sterility Commercial NTS 30° C.f65% RH Week 4 190 O were assessed to determine if the solutions complied with Commercial NTS 40° C.;75% RH Week 4 460 O USP or European Pharmacopoeia (EP) standards at the time Commercial NTS 25° C.f60% RH Week 8 920 40 periods tested. pH was also tested. The results are set forth in Tables 10 and 11 below: TABLE 10 Stability at 25 C.60% RH Time Period (Months

Attribute Specification/Requirement O 3 6 9 12 18 24 36

Appearance Clear, colorless, and X X X X X X X X essentially free of visible contaminants Label claim 98.0%-101.0% on dried basis X X X X X X X X (USP) US 2014/0005219 A1 Jan. 2, 2014 18

TABLE 10-continued Stability at 25 C.60% RH Time Period (Months

Attribute Specification/Requirement O 3 6 9 12 18 24 36 Related Substances. Total Impurities: NMT 0.5% X X X X X X X Impurities (EP) pH 3.S.-S.O X X X X X X X X Particulate Matter 10 m: 6000 X NT NT NT X NT X X 25 Im:600 (USP 788) Bacterial Endotoxin NMT 0.7 EU/g (USP 85) X NT NT NT X NT (EU/g) Sterility Total aerobic microbial count X NT NT NT X NT Total combined molds and yeasts count (USP) X = requirements met; NT = not tested; NMT = not more than Particulate matter was evaluated using the method described in USP 788, General Method entitled “Determi nation of Particulate Matter by Electronic Particle Counting System”.

TABLE 11 TABLE 12 Stability at 40 C.75% RH Stability Data at 25 C. Time Period Time Period (days Months Attribute O 3 7 14 28 S6 84 Attribute Specification/Requirements 1 3 6 pH S.O 45 4.6 4.5 4.5 4.6 4.3 Appearance Clear, colorless, and essentially X X X Label claim (%) 99.0 99.0 99.0 100.0 100.2 98.9 99.7 free of visible contaminants HNO (%)

TABLE 14-continued TABLE 15-continued Stability Data at 40 C. Storage % Unknown % Total % 7,7 Dihydroxy Time Period (days Conditions PHM Impurities RRT Impurities Hydromorphone Attribute O 3 7 14 28 S6 84 30° C.65% RH

DHM (%)

TABLE 1.5 1 month 0.4 O.26 O.81 0.7 3 month 0.4 O46 O.81 1 % O.O7 O.87 Storage % Unknown % Total % 7.7 Dihydroxy- 6 month 0.6 O.O6 O.14 1.6 O.6 Conditions PHM Impurities RRT Impurities Hydromorphone 9. 9. Lot 1 O.OS 0.55 30° C.65% RH Initial 0.2 O.O7 O.81 O.3 O.2 O.O7 O.81 O.3 2 month 0.2 O.19 O.81 O.S O.2 O.O6 O.81 O.3 O.O6 O.87 25 C.60% RH Lot 4 2 month 0.3 O.14 O.81 0.4 O.OO O.87 Initial 0.2 O.O6 O.81 O.3 3 month 0.3 O.2O O.81 O.6 O.2 O.O6 O.81 O.3 6 month 0.3 g 8. 0.7 O.3 O.2 O.OS O.81 O.3 Oil 25 C.60% RH 40° C.;75% RH 0. 1 month 0.4 O.26 O.81 0.7 2 month 0.3 0.13, 0.05 0.81, 0.87 O.S 3 month 0.5 O46 O.81 1.1 3 month 0.2 0.20, 0.06 0.81, 0.87 O.S O.O7 O.87 6 month 0.3 0.7 0s. 0.7 6 month 0.7 O.O6 O.14 1.7 O.6 40° C.;75% RH O.22 O.32 O.11 O.S1 1 month 0.4 0.27 O.81 0.7 O.O6 O.85 3 month 0.5 O49 O.81 1.1 O.OS O.88 O.O7 O.87 US 2014/0005219 A1 Jan. 2, 2014 20

TABLE 15-continued 2. The solution of claim 1, wherein the solution is substan tially free of one or more other additive selected from the group consisting of an active pharmaceutical ingredient other Storage % Unknown % Total % 7.7 Dihydroxy than hydromorphone or a pharmaceutically acceptable salt Conditions PHM Impurities RRT Impurities Hydromorphone thereof, an acid, a pH adjuster, a preservative, a polymeric 6 month 0.6 O.OS O.14 1.6 O.6 material, an emulsifier, a lubricant, an antioxidant, a suspend O.22 O.32 O.13 O.S ing agent, an excipient other than water, a diluent, an oil, a 30° C.65% RH Surfactant, saline, a solvent, a metal salt, a mineral, a vitamin, a sterilizer, a stabilizer, and combinations thereof. 2 month 0.3 O.19 O.8 O.S 3. The solution of claim 1, wherein the solution comprises O.OS O.87 hydromorphone hydrochloride. Lot 5 4. The solution of claim 1, wherein the pH of the solution is from about 3 to about 7. Initial O.2 O.OO O.8 O.2 5. The solution of claim 4, wherein the pH of the solution O.1 O.OO O.8 O.1 O.1 O.OO O.8 O.1 is from about 4 to about 5 after storage for at least 3 months. 25 C.60% RH 6. The solution of claim 5, wherein the storage conditions are selected from the group consisting of about 25° C. and 3 month 0.2 O.11 O.8 O.3 about 60% relative humidity, about 30° C. and about 65% O.OO O.87 6 month 0.2 ND ND 0.4 O.2 relative humidity, and about 40° C. and about 75% relative 40° C.;75% RH humidity. 7. The solution of claim 1, wherein the solution is stable at 1 month 0.3 O16 O.81 O.S about 25° C. and about 60% relative humidity for at least 3 2 month months. 3 month 0.4 O.31 O.81 O.8 O.O6 O.87 8. The solution of claim 1, wherein the solution is stable at 6 month 0.6 O.08 O.14 1.2 0.4 about 30° C. and about 65% relative humidity for at least 3 O.12 O.32 months. 30° C.65% RH 9. The solution of claim 1, wherein the solution is stable at 2 month 0.2 O.11 O.81 O.3 about 40° C. and about 75% relative humidity for at least 3 O.OO O.87 months. 10. The solution of claim 1, wherein the solution comprises Lot 6 less than about 1.0% of pseudo-hydromorphone, less than Initial O.2 O.OO O.81 O.2 about 0.1% of hydromorphone N-oxide, less than about O.1 O.OO O.81 O.1 0.15% of dihydromorphone, and less than about 0.1% of O.1 O.OO O.81 O.1 6-3-tetrahydrooripavine. 25 C.60% RH 11. The solution of claim 10, wherein the solution com 3 month 0.2 O.11 O.81 O.3 prises less than about 0.15% of pseudo-hydromorphone, less O.OO O.87 than about 0.05% of hydromorphone N-oxide, less than about 6 month 0.3 ND ND 0.4 O.2 0.05% of dihydromorphone, and less than about 0.05% of 40° C.;75% RH 6-3-tetrahydrooripavine after storage for at least 3 months. 1 month 0.4 O.18 O.81 O.S 12. The solution of claim 11, wherein the solution is stored 3 month 0.4 O.31 O.81 O.8 at about 25°C. and about 60% relative humidity, at about 30° O.OS O.87 6 month 0.6 O.08 O.14 1.2 0.4 C. and about 65% relative humidity, or at about 40° C. and O.13 O.32 about 75% relative humidity. 30° C.65% RH 13. A sterile pharmaceutical solution consisting essentially of hydromorphone, a pharmaceutically acceptable salt 2 month 0.2 O.12 O.81 O.3 O.OO O.87 thereof, or combinations thereof, and water. 14. The solution of claim 13, wherein the solution consists PHM= pseudohydromorphone; essentially of hydromorphone hydrochloride and water. RRT is the RRT at which the unknown impurities were determined. 15. The solution of claim 13, wherein the solution consists 0171 As can be seen from Table 15, there was not a of hydromorphone, a pharmaceutically acceptable salt significant increase in impurity levels, even after 6 months of thereof, or combinations thereof, and water storage under accelerated Storage conditions (i.e., 40° C. 16. The solution of claim 13, wherein the pH of the solution 75% RH), indicating that the solutions should be stable after is from about 4 to about 5 after storage for at least 3 months. 2 years of storage under recommended storage conditions, even without buffer. 17. The solution of claim 13, wherein the solution is stable 0172 From the foregoing description, one skilled in the art for at least about 3 months. can easily ascertain the essential characteristics of this dis 18. The solution of claim 17, wherein the solution is stored closure, and without departing from the spirit and scope at about 25°C. and about 60% relative humidity, at about 30° thereof, can make various changes and modifications of the C. and about 65% relative humidity, or at about 40° C. and disclosure to adapt it to various usages and conditions. about 75% relative humidity for at least 3 months. What is claimed is: 19. The solution of claim 17, wherein the solution contains 1. A sterile pharmaceutical solution comprising hydromor less than about 0.15% of pseudo-hydromorphone, less than phone, a pharmaceutically acceptable salt thereof, or combi about 0.05% of hydromorphone N-oxide, less than about nations thereof, wherein the solution is substantially free of 0.05% of dihydromorphone, and less than about 0.05% of buffer. 6-3-tetrahydrooripavine after storage for at least 3 months. US 2014/0005219 A1 Jan. 2, 2014

20. A method for manufacturing a pharmaceutical solution, 25. The method of claim 23, further comprising aseptically the method comprising combining hydromorphone, a phar filtering the solution. maceutically acceptable salt thereof, or combinations thereof 26. The method of claim 25, further comprising aseptically in the absence of buffers with sterile water, and dissolving the filling a container selected from the group consisting of an hydromorphone, the pharmaceutically acceptable salt ampoule, a vial, and a syringe with the filtered solution. thereof, or combinations thereof to form the solution. 21. The method of claim 20, wherein the pharmaceutically 27. A method of treating pain in a subject, the method acceptable salt is hydromorphone hydrochloride. comprising administering intrathecally a sterile pharmaceu 22. The method of claim 20, wherein the hydromorphone, tical Solution comprising hydromorphone, a pharmaceuti the pharmaceutically acceptable Salt thereof, or combinations cally acceptable salt thereof, or combinations thereof, thereof is combined with the sterile water in the absence of wherein the solution is substantially free of buffer. one or more additive selected from the group consisting of an 28. The method of claim 27, wherein the solution is sub active pharmaceutical ingredient other than hydromorphone stantially free of one or more other additive selected from the or a pharmaceutically acceptable salt thereof, an acid, a pH group consisting of an active pharmaceutical ingredient other adjuster, a preservative, a polymeric material, an emulsifier, a than hydromorphone or a pharmaceutically acceptable salt lubricant, an antioxidant, a Suspending agent, an excipient thereof, an acid, a pH adjuster, a preservative, a polymeric other than water, a diluent, an oil, a surfactant, Saline, a material, an emulsifier, a lubricant, an antioxidant, a suspend Solvent, a metal salt, a mineral, a vitamin, a sterilizer, a ing agent, an excipient other than water, a diluent, an oil, a stabilizer, and combinations thereof. Surfactant, saline, a solvent, a metal salt, a mineral, a vitamin, 23. The method of claim 20, further comprising sparging a sterilizer, a stabilizer, and combinations thereof. the sterile water with an inert gas. 29. The method of claim 27, wherein the pharmaceutically 24. The method of claim 23, wherein the sterile water is acceptable salt is hydromorphone hydrochloride. sparged with the inert gas prior to combining with the hydro morphone or pharmaceutically acceptable salt thereof, after 30. The method of claim 27, wherein the solution consists dissolving the hydromorphone or pharmaceutically accept essentially of hydromorphone hydrochloride and water. able salt thereof, or combinations thereof. k k k k k