WO2013134362A1 - Improved stability of hydromorphone hydrochloride solutions - Google Patents
Improved stability of hydromorphone hydrochloride solutions Download PDFInfo
- Publication number
- WO2013134362A1 WO2013134362A1 PCT/US2013/029328 US2013029328W WO2013134362A1 WO 2013134362 A1 WO2013134362 A1 WO 2013134362A1 US 2013029328 W US2013029328 W US 2013029328W WO 2013134362 A1 WO2013134362 A1 WO 2013134362A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition
- hydromorphone
- recited
- hydromorphone hydrochloride
- solution
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0085—Brain, e.g. brain implants; Spinal cord
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
Definitions
- the present invention relates generally to a sterile hydromorphone hydrochloride solution that is substantially free of buffer.
- Hydromorphone hydrochloride (sold as Dilaudid, Laudicon, Hydromorphan) is a narcotic analgesic, and one of its principle uses is the relief of pain. It is a semisynthetic ⁇ -opioid agonist. There is no intrinsic limit to the analgesic effect of hydromorphone hydrochloride; like morphine, adequate doses will relieve even the most severe pain. Hydromorphone is the generic (USAN) name (USP Dictionary of USAN and International Drug Names 2003) for 4,5-a-epoxy-3-hydroxy-17-methyl morphinan-6-one, a derivative of morphine. Its structural formula is:
- intrathecal hydromorphone hydrochloride is commercially available for injection in 10 mg/ml solutions in a preservative-free formula containing 0.2% sodium citrate and 0.2% of a citric acid solution.
- Hydromorphone is used in medicine as an alternative to morphine and diacetylmorphine for analgesia and as a second- or third-line narcotic antitussive (cough suppressant) for cases of dry, painful, paroxysmal coughing resulting from continuing bronchial irritation after influenza and other ailments, inhalation of fungus and other causes, and is generally regarded to be the strongest of the latter class of drugs, and was developed shortly after another powerful antitussive, heroin, was removed from clinical use for this purpose in most of the world and in many countries banned outright.
- cough suppressant narcotic antitussive
- the hydrogenation of morphine resulting in the formation of hydromorphone results in a drug with higher lipid solubility and ability to cross the blood-brain barrier and therefore more rapid and complete central nervous system penetration, with the result that hydromorphone is somewhat faster-acting and about eight times stronger than morphine and about three times stronger than heroin on a milligram basis.
- the effective morphine to hydromorphone conversion ratio can vary from patient to patient by a significant amount with relative levels of some liver enzymes being the main cause; the normal human range appears to be from 8:1 to a 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 a similar morphine preparation.
- hydromorphone hydrochloride solutions all contain buffer.
- the buffer is often added to a composition to regulate the pH and/or aid in the stability of the compound in solution.
- the addition of buffer can lead to potential complications such as toxicity, side effects and allergic responses. Further, the use of less or no buffer would decrease the costs of producing the pharmaceutical composition. Accordingly, there is a need for a hydromorphone hydrochloride solution that does not contain buffer.
- hydromorphone hydrochloride in water does not require buffering agents to maintain it stability over time.
- CSF cerebrospinal fluid
- ECF extracellular fluid
- heat-labile hydromorphone undergoes transformations to undesirable side products such as hydromorphone N- oxide (HNO), 6-p-tetrahydrooripavine (THO), dihydromorphone (DHM), and pseudo- hydromorphone (PHM).
- HNO hydromorphone N- oxide
- THO 6-p-tetrahydrooripavine
- HLM dihydromorphone
- PHM pseudo- hydromorphone
- aseptic processing is the process by which a sterile (aseptic) product is packaged in a sterile container in a way which maintains sterility. This avoids the harsh conditions of terminal sterilization without sacrificing sterility of the resulting solution. It was hypothesized that aseptic processing may lead to a solution with fewer degradation products, as the hydromorphone would not be subjected to the rigors of the terminal sterilization process.
- composition comprising a sterile, intrathecal, aqueous hydromorphone hydrochloride solution, wherein said composition is substantially free of buffer.
- a solution of intrathecal hydromorphone hydrochloride contains less than 1.0% pseudo-hydromorphone.
- a solution of intrathecal hydromorphone hydrochloride contains less than 0.1% pseudo-hydromorphone.
- a solution of intrathecal hydromorphone hydrochloride contains less than 0.2% hydromorphone N-oxide.
- a solution of intrathecal hydromorphone hydrochloride is substantially free of hydromorphone N-oxide.
- a solution of intrathecal hydromorphone hydrochloride is substantially free of dihydromorphone.
- a solution of intrathecal hydromorphone hydrochloride is substantially free of 6-p-tetrahydrooripavine.
- the solution described herein is not terminally sterilized.
- the solution described herein is free of particulates.
- the solution described herein is stable at 25°C and 60% relative humidity for at least 1 month.
- the solution described herein is stable at 30°C and 65% relative humidity for at least 1 month.
- the solution described herein is stable at 40°C and 75% relative humidity for at least 1 month.
- the solution described herein is stable at 25°C and 60% relative humidity for at least 3 months. [0025] According to yet another aspect, the solution described herein is stable at 30°C and 65% relative humidity for at least 3 months.
- the solution described herein is stable at 40 °C and 75% relative humidity for at least 3 months.
- the solution described herein is stable at 25°C and 60% relative humidity for at least 6 months.
- the solution described herein is stable at 30°C and 65% relative humidity for at least 6 months.
- the solution described herein is stable at 40°C and 75% relative humidity for at least 6 months.
- the solution described herein is stable at 25 °C and 60% relative humidity for at least 1 year.
- the solution described herein is stable at 30°C and 65% relative humidity for at least 1 year.
- the solution described herein is stable at 40°C and 75% relative humidity for at least 1 year.
- the solution described herein is stable at 25 °C and 60% relative humidity for at least 2 years.
- the solution described herein is stable at 30°C and 65% relative humidity for at least 2 years.
- the solution described herein is stable at 40°C and 75% relative humidity for at least 2 years.
- the solution described herein is suitable for intrathecal delivery.
- composition consisting of a sterile, aqueous solution of hydromorphone hydrochloride.
- the concentration of the hydromorphone hydrochloride solution is 10.0 mg mL.
- the concentration of the hydromorphone hydrochloride solution is 2.0 mg/mL.
- composition comprising a sterile aqueous solution of hydromorphone hydrochloride, wherein said composition is substantially free of buffer.
- composition comprising a sterile aqueous solution of hydromorphone hydrochloride for use in human therapy, wherein said composition is substantially free of buffer.
- composition comprising a sterile aqueous solution of hydromorphone hydrochloride for use in treating pain, wherein said composition is substantially free of buffer.
- composition comprising a sterile aqueous solution of hydromorphone hydrochloride for use in treating pain, wherein said composition is substantially free of buffer.
- composition comprising a sterile aqueous solution of hydromorphone hydrochloride for the manufacture of a medicament to treat pain, wherein said composition is substantially free of buffer.
- sterile means free from all live bacteria or other microorganisms and their spores.
- pill as used herein, is meant to describe mobile undissolved particles, other than gas bubbles, unintentionally present in the drug solution.
- Intrathecal means introduced into or occurring in the space under the arachnoid membrane which covers the brain and spinal cord.
- Intrathecal drug delivery is designed to manage chronic pain and/or spasticity, such as intractable cancer pain, by delivering pain medication directly to the intrathecal space.
- Intrathecal drug delivery uses an implantable infusion system to deliver pain medication directly to the intrathecal space via a surgically implanted infusion pump and catheter.
- stable as used herein in reference to claimed compositions means retaining substantially the same properties and characteristics throughout its period of storage and use that it possessed at the time of its manufacture, such that the composition provides substantially the same therapeutic benefit to the patient over the period of time that the composition is stored and delivered, such as for 1 month, 3 months, 6 months, 1 year, or 2 years.
- the compositions disclosed herein are stable if they contain within 3% of the amount of hydromorphone hydrochloride as claimed on the label (%LC) after 12 weeks, as determined by HPLC assay.
- Example 5 The impurity profile of Example 5 over time, showing the amount of each impurity, as well as the percent of the label claim (%LC) of the API, as determined by HPLC assay.
- compositions containing buffer have the same levels of impurities as the composition without buffer. This indicates that the buffer is not an essential part of the composition from an impurity standpoint. Further, additional data shows that the buffer-free composition maintains its low levels of impurities over time, indicating that buffer is not essential to the long-term stability of the composition.
- the formulation without buffer has a small pH change (only 0.5 pH units) over the time period tested. This indicates that the buffer is not necessary to keep the pH stabile over time. This pH data, coupled with the impurity data, shows that the small change in pH that is observed does not have a detrimental effect on the purity of the formulation. Further, the absence of the buffer gives the formulation a pH closer to the patient's natural physiological pH of the cerebrospinal fluid than the formulation containing the buffer (5.0 vs. 4.1).
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA2865815A CA2865815C (en) | 2012-03-07 | 2013-03-06 | Improved stability of hydromorphone hydrochloride solutions |
KR1020147028030A KR101710244B1 (en) | 2012-03-07 | 2013-03-06 | Improved stability of hydromorphone hydrochloride solutions |
EP13713600.8A EP2822535A1 (en) | 2012-03-07 | 2013-03-06 | Improved stability of hydromorphone hydrochloride solutions |
JP2014561072A JP6074442B2 (en) | 2012-03-07 | 2013-03-06 | Improved stability of hydromorphone hydrochloride solution |
MX2014010622A MX361779B (en) | 2012-03-07 | 2013-03-06 | Improved stability of hydromorphone hydrochloride solutions. |
CN201380021041.2A CN104244925B (en) | 2012-03-07 | 2013-03-06 | The stability of the raising of dihydromorphinone hydrochloride solution |
IL234452A IL234452B (en) | 2012-03-07 | 2014-09-03 | Improved stability of hydromorphone hydrochloride solutions |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201261607774P | 2012-03-07 | 2012-03-07 | |
US61/607,774 | 2012-03-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2013134362A1 true WO2013134362A1 (en) | 2013-09-12 |
Family
ID=48045027
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2013/029328 WO2013134362A1 (en) | 2012-03-07 | 2013-03-06 | Improved stability of hydromorphone hydrochloride solutions |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP2822535A1 (en) |
JP (1) | JP6074442B2 (en) |
KR (1) | KR101710244B1 (en) |
CN (1) | CN104244925B (en) |
CA (1) | CA2865815C (en) |
IL (1) | IL234452B (en) |
MX (1) | MX361779B (en) |
WO (1) | WO2013134362A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10905685B2 (en) | 2012-03-07 | 2021-02-02 | Piramal Critical Care, Inc. | Intrathecal hydromorphone solutions having improved stability |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997011681A1 (en) * | 1995-09-29 | 1997-04-03 | Lam Pharmaceuticals Inc. | Sustained release delivery system and long acting narcotic analgesics and antagonists |
US20040102476A1 (en) * | 2002-11-25 | 2004-05-27 | Chan Tai Wah | High concentration formulations of opioids and opioid derivatives |
US20100216842A1 (en) * | 2009-02-26 | 2010-08-26 | Kiichiro Nabeta | Narcotic Emulsion Formulations for Treatment of Cancer Pain |
EP2446882A1 (en) * | 2010-10-28 | 2012-05-02 | Acino Pharma AG | Medicament with improved storage stability containing the active ingredient hydromorphone |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011019954A2 (en) * | 2009-08-13 | 2011-02-17 | Yehuda Ivri | Intracochlear drug delivery to the central nervous system |
-
2013
- 2013-03-06 WO PCT/US2013/029328 patent/WO2013134362A1/en active Application Filing
- 2013-03-06 KR KR1020147028030A patent/KR101710244B1/en active IP Right Grant
- 2013-03-06 CN CN201380021041.2A patent/CN104244925B/en not_active Expired - Fee Related
- 2013-03-06 MX MX2014010622A patent/MX361779B/en active IP Right Grant
- 2013-03-06 EP EP13713600.8A patent/EP2822535A1/en not_active Withdrawn
- 2013-03-06 JP JP2014561072A patent/JP6074442B2/en not_active Expired - Fee Related
- 2013-03-06 CA CA2865815A patent/CA2865815C/en not_active Expired - Fee Related
-
2014
- 2014-09-03 IL IL234452A patent/IL234452B/en not_active IP Right Cessation
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997011681A1 (en) * | 1995-09-29 | 1997-04-03 | Lam Pharmaceuticals Inc. | Sustained release delivery system and long acting narcotic analgesics and antagonists |
US20040102476A1 (en) * | 2002-11-25 | 2004-05-27 | Chan Tai Wah | High concentration formulations of opioids and opioid derivatives |
US20100216842A1 (en) * | 2009-02-26 | 2010-08-26 | Kiichiro Nabeta | Narcotic Emulsion Formulations for Treatment of Cancer Pain |
EP2446882A1 (en) * | 2010-10-28 | 2012-05-02 | Acino Pharma AG | Medicament with improved storage stability containing the active ingredient hydromorphone |
Non-Patent Citations (1)
Title |
---|
See also references of EP2822535A1 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10905685B2 (en) | 2012-03-07 | 2021-02-02 | Piramal Critical Care, Inc. | Intrathecal hydromorphone solutions having improved stability |
Also Published As
Publication number | Publication date |
---|---|
EP2822535A1 (en) | 2015-01-14 |
JP2015509541A (en) | 2015-03-30 |
IL234452B (en) | 2020-01-30 |
MX361779B (en) | 2018-12-17 |
KR101710244B1 (en) | 2017-02-24 |
JP6074442B2 (en) | 2017-02-01 |
CA2865815A1 (en) | 2013-09-12 |
CN104244925B (en) | 2017-03-29 |
MX2014010622A (en) | 2014-11-14 |
CN104244925A (en) | 2014-12-24 |
KR20140132765A (en) | 2014-11-18 |
CA2865815C (en) | 2017-06-13 |
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