US20150359790A1 - Stability of hydromorphone hydrochloride solutions - Google Patents
Stability of hydromorphone hydrochloride solutions Download PDFInfo
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- US20150359790A1 US20150359790A1 US14/834,536 US201514834536A US2015359790A1 US 20150359790 A1 US20150359790 A1 US 20150359790A1 US 201514834536 A US201514834536 A US 201514834536A US 2015359790 A1 US2015359790 A1 US 2015359790A1
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- Prior art keywords
- hydromorphone
- pharmaceutical composition
- solution
- composition
- hydromorphone hydrochloride
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- DYUTXEVRMPFGTH-UHFFFAOYSA-N 4-(2,5-dimethylphenyl)-5-methyl-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2C(=CC=C(C)C=2)C)=C1C DYUTXEVRMPFGTH-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 229960002738 hydromorphone hydrochloride Drugs 0.000 title claims abstract description 39
- 239000000203 mixture Substances 0.000 claims description 38
- WVLOADHCBXTIJK-YNHQPCIGSA-N hydromorphone Chemical compound O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O WVLOADHCBXTIJK-YNHQPCIGSA-N 0.000 claims description 27
- 229960001410 hydromorphone Drugs 0.000 claims description 26
- 238000007913 intrathecal administration Methods 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- SDOMGTNHSREGJN-MSLLCSOGSA-N (4r,4ar,7ar,12bs)-10-[(4r,4ar,7ar,12bs)-9-hydroxy-3-methyl-7-oxo-1,2,4,4a,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-10-yl]-9-hydroxy-3-methyl-1,2,4,4a,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one Chemical group C([C@H]12)CC(=O)[C@@H]3OC4=C(O)C(C=5C=C6C7=C(C=5O)O[C@@H]5[C@]77CCN([C@H](C6)[C@@H]7CCC5=O)C)=CC5=C4[C@]13CCN(C)[C@@H]2C5 SDOMGTNHSREGJN-MSLLCSOGSA-N 0.000 claims description 10
- 239000007857 degradation product Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- XDOZFXQPRPKZLY-FQFYJRTASA-N (4r,4ar,7ar,12bs)-9-hydroxy-3-methyl-3-oxido-1,2,4,4a,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-3-ium-7-one Chemical group O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CC[N+](C)([O-])[C@@H]3CC5=CC=C4O XDOZFXQPRPKZLY-FQFYJRTASA-N 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 208000002193 Pain Diseases 0.000 claims description 5
- 238000012865 aseptic processing Methods 0.000 claims description 4
- 230000036407 pain Effects 0.000 claims description 4
- 239000000872 buffer Substances 0.000 abstract description 23
- 239000000243 solution Substances 0.000 description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 239000008215 water for injection Substances 0.000 description 15
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 13
- 239000012535 impurity Substances 0.000 description 11
- 239000007979 citrate buffer Substances 0.000 description 9
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 8
- 238000009472 formulation Methods 0.000 description 7
- 230000001954 sterilising effect Effects 0.000 description 7
- 238000004659 sterilization and disinfection Methods 0.000 description 7
- 229960005181 morphine Drugs 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000008186 active pharmaceutical agent Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 238000010268 HPLC based assay Methods 0.000 description 3
- GVGLGOZIDCSQPN-PVHGPHFFSA-N Heroin Chemical compound O([C@H]1[C@H](C=C[C@H]23)OC(C)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4OC(C)=O GVGLGOZIDCSQPN-PVHGPHFFSA-N 0.000 description 3
- 229940124584 antitussives Drugs 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229960002069 diamorphine Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 210000003722 extracellular fluid Anatomy 0.000 description 3
- 230000036512 infertility Effects 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 230000000954 anitussive effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 229940124583 pain medication Drugs 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 206010006438 Bronchial irritation Diseases 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 208000008238 Muscle Spasticity Diseases 0.000 description 1
- WVLOADHCBXTIJK-LSXBATHSSA-N [H][C@@]12OC3=C(O)C=CC4=C3[C@@]13CCN(C)C(C4)[C@]3([H])CCC2=O Chemical compound [H][C@@]12OC3=C(O)C=CC4=C3[C@@]13CCN(C)C(C4)[C@]3([H])CCC2=O WVLOADHCBXTIJK-LSXBATHSSA-N 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- 210000000576 arachnoid Anatomy 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 229940099212 dilaudid Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000003284 homeostatic effect Effects 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- -1 morphine Chemical compound 0.000 description 1
- 229960004715 morphine sulfate Drugs 0.000 description 1
- GRVOTVYEFDAHCL-RTSZDRIGSA-N morphine sulfate pentahydrate Chemical compound O.O.O.O.O.OS(O)(=O)=O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O GRVOTVYEFDAHCL-RTSZDRIGSA-N 0.000 description 1
- 239000002756 mu opiate receptor agonist Substances 0.000 description 1
- 239000004084 narcotic analgesic agent Substances 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- 230000001314 paroxysmal effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000003186 pharmaceutical solution Substances 0.000 description 1
- 230000008288 physiological mechanism Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 208000018198 spasticity Diseases 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
Classifications
-
- 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
- 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
- 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 semi-synthetic ⁇ -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- ⁇ -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- ⁇ -tetrahydrooripavine (THO), dihydromorphone (DHM), and pseudo-hydromorphone (PHM).
- HNO hydromorphone N-oxide
- THO 6- ⁇ -tetrahydrooripavine
- HLM dihydromorphone
- PHM pseudo-hydromorphone
- This obviously reduces the amount of hydromorphone in solution, and thus the overall efficacy of the solution. Additionally, this degradation product may have undesirable side effects, including toxicity.
- the amount of side products found in commercially available hydromorphone solutions is shown in the table below.
- 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- ⁇ -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.
- 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.
- a pharmaceutical 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.
- Disclosed herein is a method of treating pain by administration of a sterile aqueous solution of hydromorphone hydrochloride, wherein said composition is substantially free of buffer.
- sterile means free from all live bacteria or other microorganisms and their spores.
- pill 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 stable 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.
- 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).
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Emergency Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Psychology (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Pain & Pain Management (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
- This application is a continuation application of U.S. patent application Ser. No. 13/787,042, filed Mar. 6, 2013, which claims the benefit of priority of U.S. provisional application 61/607,774, filed Mar. 7, 2012, the disclosures of which are hereby incorporated by reference in their entirety.
- 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 semi-synthetic μ-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-α-epoxy-3-hydroxy-17-methyl morphinan-6-one, a derivative of morphine. Its structural formula is:
- Presently, 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.
- 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.
- The currently available 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. Surprisingly, it has been found that hydromorphone hydrochloride in water does not require buffering agents to maintain it stability over time.
- Recently, there has been increasing interest in the regulation of the cerebrospinal fluid (CSF) pH. Part of this interest stems from the fact that the extracellular fluid (ECF) pH in the brain serves as an important regulator of pulmonary ventilation and a major determinant of cerebral blood flow. Furthermore, since the CSF pH has been shown to be subject to a considerable degree of homeostatic control in a variety of conditions which change the acid-base status of blood, many attempts have been made to unravel the physiological mechanisms which are responsible for this control. Finally, since the acid-base metabolism of the cerebral compartments (including the ECF) may influence cerebral function 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 hydrochloride formulation with a pH near 7.3 is appealing. Indeed, the pH of the formulation without buffer is closer to the natural physiological pH of CSF than the formulation containing buffer (5.0 vs 4.1).
- While there are no absolute FDA standards for sterilization processes, pharmaceutical solutions are most commonly sterilized using a heating regimen at 121.1.degree ° C. with an F0 of about 30 minutes. While this may be an effective method for thermally stable compounds, this practice is counterproductive for some heat-labile active pharmaceutical ingredients (APIs). In these cases, the resulting solution may be sterile, but it is often plagued with an unacceptable increase in degradation products brought on by the excessive use of heat in the sterilization process. Furthermore, compositions containing heat-labile APIs are often not terminally sterilized to avoid this degradation. Therefore, it is desirable to find and implement a sterilization method that utilizes less harsh conditions in order to prevent this thermal degradation from taking place, while continuing to meet sterility standards.
- Indeed, during the terminal sterilization process, heat-labile hydromorphone undergoes transformations to undesirable side products such as hydromorphone N-oxide (HNO), 6-β-tetrahydrooripavine (THO), dihydromorphone (DHM), and pseudo-hydromorphone (PHM). This obviously reduces the amount of hydromorphone in solution, and thus the overall efficacy of the solution. Additionally, this degradation product may have undesirable side effects, including toxicity. The amount of side products found in commercially available hydromorphone solutions is shown in the table below.
-
Hydromorphone Hydrochloride (Commercial) 10 mg/mL % NHO % THO % DHM % PHM <0.05 <0.05 <0.05 9.5 - An alternative to terminal sterilization is aseptic processing, which 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.
- Therefore, there is a clinical need for aqueous solutions of hydromorphone having fewer degradation products, preferably for concentrated solutions that are also stable in a variety of storage conditions for extended periods of time. Due to the heat-lability of the hydromorphone product, aseptic processing is herein disclosed for the reduction of impurities in the hydromorphone solution.
- Disclosed herein is a pharmaceutical composition comprising a sterile, intrathecal, aqueous hydromorphone hydrochloride solution, wherein said composition is substantially free of buffer.
- In an embodiment, a solution of intrathecal hydromorphone hydrochloride contains less than 1.0% pseudo-hydromorphone.
- According to a further aspect, a solution of intrathecal hydromorphone hydrochloride contains less than 0.1% pseudo-hydromorphone.
- In an embodiment, a solution of intrathecal hydromorphone hydrochloride contains less than 0.2% hydromorphone N-oxide.
- According to another aspect, a solution of intrathecal hydromorphone hydrochloride is substantially free of hydromorphone N-oxide.
- According to another aspect, a solution of intrathecal hydromorphone hydrochloride is substantially free of dihydromorphone.
- According to another aspect, a solution of intrathecal hydromorphone hydrochloride is substantially free of 6-β-tetrahydrooripavine.
- According to one embodiment, the solution described herein is not terminally sterilized.
- According to another aspect, the solution described herein is free of particulates.
- According to yet another aspect, the solution described herein is stable at 25° C. and 60% relative humidity for at least 1 month.
- According to yet another aspect, the solution described herein is stable at 30° C. and 65% relative humidity for at least 1 month.
- According to a further aspect, the solution described herein is stable at 40° C. and 75% relative humidity for at least 1 month.
- According to yet another aspect, the solution described herein is stable at 25° C. and 60% relative humidity for at least 3 months.
- According to yet another aspect, the solution described herein is stable at 30° C. and 65% relative humidity for at least 3 months.
- According to a further aspect, the solution described herein is stable at 40° C. and 75% relative humidity for at least 3 months.
- According to yet another aspect, the solution described herein is stable at 25° C. and 60% relative humidity for at least 6 months.
- According to yet another aspect, the solution described herein is stable at 30° C. and 65% relative humidity for at least 6 months.
- According to a further aspect, the solution described herein is stable at 40° C. and 75% relative humidity for at least 6 months.
- According to yet another aspect, the solution described herein is stable at 25° C. and 60% relative humidity for at least 1 year.
- According to yet another aspect, the solution described herein is stable at 30° C. and 65% relative humidity for at least 1 year.
- According to a further aspect, the solution described herein is stable at 40° C. and 75% relative humidity for at least 1 year.
- According to yet another aspect, the solution described herein is stable at 25° C. and 60% relative humidity for at least 2 years.
- According to yet another aspect, the solution described herein is stable at 30° C. and 65% relative humidity for at least 2 years.
- According to a further aspect, the solution described herein is stable at 40° C. and 75% relative humidity for at least 2 years.
- According to another aspect, the solution described herein is suitable for intrathecal delivery.
- Disclosed herein is a pharmaceutical composition consisting of a sterile, aqueous solution of hydromorphone hydrochloride.
- In an embodiment, the concentration of the hydromorphone hydrochloride solution is 10.0 mg/mL.
- In an embodiment, the concentration of the hydromorphone hydrochloride solution is 2.0 mg/mL.
- Disclosed herein is a method of treating pain by administration of a sterile aqueous solution of hydromorphone hydrochloride, wherein said composition is substantially free of buffer.
- As used herein, the terms below have the meanings indicated.
- The term “about,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures.
- The term “sterile,” as used herein, means free from all live bacteria or other microorganisms and their spores.
- The term “particulate,” as used herein, is meant to describe mobile undissolved particles, other than gas bubbles, unintentionally present in the drug solution.
- The term “intrathecal,” as used herein, 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.
- The term “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.
- Certain embodiments disclosed herein may be illustrated by the following non-limiting examples.
- To 1 L of water for injection (WFI) is added 40.4 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 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.
- To 1 L of WFI is added 20.2 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 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.
- 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 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.
- To 1 L of WFI is added 6.06 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 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.
- To 3 L of WFI is added 200.0 g hydromorphone hydrochloride. The mixture is stirred for 45 minutes. The resulting solution is diluted to 20 L with WFI and stirred for at least an additional 10 minutes.
- The impurity profile of Examples 1-5, showing the amount of each impurity, as well as the percent of the label claim (% LC) of the API, as determined by HPLC assay.
-
Buffer-containing Solutions %0.56 % % Buffer pH % LC % HMN % DHM % THO RRT PHM 0 5.0 99.0 <0.05 <0.05 <0.05 <0.05 <0.05 0.03 4.2 100.4 <0.05 <0.05 <0.05 <0.05 <0.05 0.05 4.1 101.1 <0.05 <0.05 <0.05 <0.05 <0.05 0.1 4.1 100.7 <0.05 <0.05 <0.05 <0.05 0.05 0.2 4.1 100.1 <0.05 <0.05 <0.05 <0.05 <0.05 - 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.
-
Time (Days) pH % LC % HMN % DHM % THO % PHM 0 5.0 99.0 <0.05 <0.05 <0.05 <0.05 3 — 97.7 <0.05 <0.05 <0.05 <0.05 7 — 99.7 <0.05 <0.05 <0.05 <0.05 14 4.6 102.4 <0.05 <0.05 <0.05 1.06 28 4.6 99.3 <0.05 <0.05 <0.05 0.07 56 4.6 99.0 <0.05 <0.05 <0.05 0.07 84 4.5 100.5 <0.05 <0.05 <0.05 0.09 - The data shows that 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 stable 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).
- From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
Claims (13)
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US14/834,536 US20150359790A1 (en) | 2012-03-07 | 2015-08-25 | Stability of hydromorphone hydrochloride solutions |
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FR2884406B1 (en) | 2005-04-14 | 2008-10-17 | Memometal Technologies Soc Par | INTRAMEDULAR OSTEOSYNTHESIS DEVICE OF TWO BONE PARTS, IN PARTICULAR HAND AND / OR FOOT |
FR2935601B1 (en) | 2008-09-09 | 2010-10-01 | Memometal Technologies | INTRAMEDULLARY IMPLANT RESORBABLE BETWEEN TWO BONE OR TWO BONE FRAGMENTS |
US9155734B2 (en) | 2012-03-07 | 2015-10-13 | Mallinckrodt Llc | Stability of hydromorphone hydrochloride solutions |
CN107028968B (en) * | 2016-02-03 | 2020-12-04 | 江苏恒瑞医药股份有限公司 | A pharmaceutical composition containing morphine glucuronide or its pharmaceutically acceptable salt |
EP3251621B1 (en) | 2016-06-03 | 2021-01-20 | Stryker European Holdings I, LLC | Intramedullary implant |
US20230301986A1 (en) * | 2022-03-23 | 2023-09-28 | Hikma Pharmaceuticals Usa Inc. | Ready-to-administer hydromorphone formulations |
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US20060235039A1 (en) * | 2005-04-18 | 2006-10-19 | Lorimer Keith R | Hydromorphone polymorphs |
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CA2233280A1 (en) | 1995-09-29 | 1997-04-03 | Peter Rothbart | Sustained release delivery system and long acting narcotic analgesics and antagonists |
EP1233966B2 (en) | 1999-11-09 | 2011-10-19 | Abbott Laboratories | Hydromorphinone and hydrocodeinone compositions and methods for their synthesis |
US8410129B2 (en) | 2002-02-15 | 2013-04-02 | Howard Brooks-Korn | Treatment for paresis/paralysis |
US20040102476A1 (en) * | 2002-11-25 | 2004-05-27 | Chan Tai Wah | High concentration formulations of opioids and opioid derivatives |
EP1689401A1 (en) | 2003-10-02 | 2006-08-16 | Elan Pharmaceuticals, Inc. | Method for reducing pain |
BRPI0503734A (en) * | 2005-08-23 | 2007-04-27 | Cristalia Prod Quimicos Farm | pharmaceutical composition in ready-to-use morphine solution for injection and unit dosage form of morphine for epidural or intrathecal administration |
US8188048B2 (en) | 2006-06-23 | 2012-05-29 | Xenome Limited | Combination therapy |
SI2341899T1 (en) * | 2008-09-24 | 2015-04-30 | Evonik Roehm Gmbh | Ph-dependent controlled release pharmaceutical opioid composition with resistance against the influence of ethanol |
JP5619780B2 (en) | 2009-02-26 | 2014-11-05 | テイコク ファーマ ユーエスエー インコーポレーテッド | Narcotic emulsion formulation for the treatment of cancer pain |
US9458536B2 (en) | 2009-07-02 | 2016-10-04 | Sio2 Medical Products, Inc. | PECVD coating methods for capped syringes, cartridges and other articles |
US8461171B2 (en) | 2010-02-09 | 2013-06-11 | QRxPharma Ltd. | Hybrid opioid compounds and compositions |
US20120270848A1 (en) | 2010-10-22 | 2012-10-25 | Galleon Pharmaceuticals, Inc. | Novel Compositions and Therapeutic Methods Using Same |
ES2444591T3 (en) | 2010-10-28 | 2014-02-25 | Acino Pharma Ag | Medication with the active substance hydromorphone with improved storage stability |
JP2014504184A (en) | 2010-12-01 | 2014-02-20 | スパイナル・モデュレーション・インコーポレイテッド | Direct delivery of drugs to the neural structure |
WO2013063289A1 (en) | 2011-10-25 | 2013-05-02 | Lycus Llc | Pharmaceutical compositions for treating pain |
CN103930595A (en) | 2011-11-11 | 2014-07-16 | Sio2医药产品公司 | Passivation, ph protective or lubricity coating for pharmaceutical package, coating process and apparatus |
US9155734B2 (en) | 2012-03-07 | 2015-10-13 | Mallinckrodt Llc | Stability of hydromorphone hydrochloride solutions |
EP2822535A1 (en) * | 2012-03-07 | 2015-01-14 | Mallinckrodt LLC | Improved stability of hydromorphone hydrochloride solutions |
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