(12) Patent Application Publication (10) Pub. No.: US 2014/0005219 A1 Foster Et Al

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.

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