Opioid salts and formulations exhibiting anti-abuse and anti-dose dumping properties
Inventors
King, Clifford Riley • D'Ambrosio, Stephen G. • Bristol, David W. • English, Michael L.
Assignees
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Publication Number
US-8211905-B1
Publication Date
2012-07-03
Expiration Date
Abstract
A drug substance with a pharmaceutically acceptable organic acid addition salt of an opioid wherein said organic acid is selected from Structure A: wherein R1-R4 are independently selected from H, alkyl or substituted alkyl of 1-6 carbons, adjacent groups may be taken together to form a cyclic alkyl, cyclic alkyl-aryl, or cyclic aryl moiety; R5 is selected from H, or an alkali earth cation; R6 and R7 are independently selected from H, alkyl of 1-6 carbons, an alkali earth cation, and aryl of 6 to 12 carbons, in a number sufficient to complete the valence bonding of X, and wherein X is selected from nitrogen, oxygen or sulfur; and wherein the drug substance has a morphology selected from amorphous and crystalline.
Core Innovation
The patent describes opioid organic-acid addition salts, including hydrocodone pamoate and pamoate-based forms, as drug substances and drug products that suppress alcohol/acid-induced dose dumping compared with corresponding mineral-acid salts such as hydrochlorides. It further includes opioid organic acid addition salts formed with an organic acid, especially pamoate and xinafoate, made from amine-containing opioids such as hydrocodone and oxycodone.
The document addresses dose dumping, including dissolution and release behavior in an acidic medium and in the presence of ethanol, and describes drug substances and drug products whose dissolution and release are retarded so that dose dumping is inhibited. It also reports unexpected behavior for amorphous and polymorphic salt forms, including polymorphic forms described as acetone solvates, while maintaining essentially identical dissolution rates.
Related salt systems using other organic-acid moieties, including xinafoate and pamoate/xinafoate combinations and cross-salt combinations with BON acid or pamoic acid, are described as inhibiting dose dumping while modulating dissolution and pH behavior within the physiological pH range about 4-9. The invention also states that adding excess organic acid component synergistically reduces dose dumping and describes tamper-resistant/tamper-proof behavior.
Claims Coverage
The provided claim set covers hydrocodone pamoate in amorphous and polymorphic forms, with claim identity anchored to specific characterization outputs. Across the independent claims, the main inventive features are the solid form identity, the organic acid salt, and characterization by DSC thermogram, FTIR, or X-ray diffraction diffractogram.
Polymorphic hydrocodone pamoate characterized by DSC thermogram of FIG. 13
A drug substance that is polymorphic hydrocodone pamoate and is characterized by a differential scanning calorimetry thermogram of FIG. 13.
Polymorphic hydrocodone pamoate characterized by FTIR of FIG. 14
A drug substance that is polymorphic hydrocodone pamoate and is characterized by an FTIR of FIG. 14.
Polymorphic hydrocodone pamoate characterized by X-ray diffraction diffractogram of FIG. 15
A drug substance that is polymorphic hydrocodone pamoate and is characterized by an X-ray diffraction diffractogram of FIG. 15.
Amorphous hydrocodone pamoate characterized by DSC thermogram of FIG. 10
A drug substance that is amorphous hydrocodone pamoate characterized by a differential scanning calorimetry thermogram of FIG. 10.
Amorphous hydrocodone pamoate characterized by FTIR of FIG. 11
A drug substance that is amorphous hydrocodone pamoate characterized by an FTIR of FIG. 11.
Amorphous hydrocodone pamoate characterized by X-ray diffraction diffractogram of FIG. 12
A drug substance that is amorphous hydrocodone pamoate characterized by an X-ray diffraction diffractogram of FIG. 12.
Polymorphic hydrocodone pamoate drug product characterized by DSC thermogram of FIG. 13
A drug product comprising a drug substance where the drug substance is polymorphic hydrocodone pamoate characterized by a differential scanning calorimetry thermogram of FIG. 13.
Polymorphic hydrocodone pamoate drug product characterized by FTIR of FIG. 14
A drug product comprising a drug substance where the drug substance is polymorphic hydrocodone pamoate characterized by an FTIR of FIG. 14.
Polymorphic hydrocodone pamoate drug product characterized by X-ray diffraction diffractogram of FIG. 15
A drug product comprising a drug substance where the drug substance is polymorphic hydrocodone pamoate characterized by an X-ray diffraction diffractogram of FIG. 15.
Amorphous hydrocodone pamoate drug product characterized by DSC thermogram of FIG. 10
A drug product comprising a drug substance where the drug substance is amorphous hydrocodone pamoate characterized by a differential scanning calorimetry thermogram of FIG. 10.
Amorphous hydrocodone pamoate drug product characterized by FTIR of FIG. 11
A drug product comprising a drug substance where the drug substance is amorphous hydrocodone pamoate characterized by an FTIR of FIG. 11.
Amorphous hydrocodone pamoate drug product characterized by X-ray diffraction diffractogram of FIG. 12
A drug product comprising a drug substance where the drug substance is amorphous hydrocodone pamoate characterized by an X-ray diffraction diffractogram of FIG. 12.
The claim coverage is directed to hydrocodone pamoate salts in amorphous or polymorphic form, with independent claims defined by DSC thermogram, FTIR, or X-ray diffraction diffractogram characterization.
Stated Advantages
Anti-abuse and anti-dose dumping performance.
Retarded dissolution and release to inhibit dose dumping, including limited wt% released at 30 min in 0.1 N HCl with and without ethanol.
Formulations inhibit dose dumping even in the presence of ethanol.
Amorphous and polymorphic salt forms show unexpectedly low/high phase transitions while maintaining essentially identical dissolution rates.
Tamper-resistant/tamper-proof behavior.
Adding excess organic acid component synergistically reduces dose dumping.
Markedly attenuated dose dumping compared with mineral-acid salts such as hydrochloride salts.
Suppression of release in the physiological pH range about 4-9.
Improved coating/granulation compatibility.
Higher molecular weight.
Robust formulations.
Documented Applications
Drug substances and drug products formulated as opioid organic acid addition salts for anti-abuse and anti-dose dumping performance.
Use in dissolution/dose-dumping contexts including acidic medium 0.1 N HCl and conditions with ethanol.
Formulations with tamper-resistant/tamper-proof behavior.
Controlled/extended-release abuse-deterrent dosage forms for opioid drug products.
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