Pharmaceutical Compositions with Attenuated Release of Phenolic Opioids

A pharmaceutical composition, which comprises a trypsin inhibitor and a compound of general formula (II):

• X—C(O)—NR1—(C(R2)(R3))n—NH—C(O)—CH(R4)—NH(R5) (II)
• or a pharmaceutically acceptable salt thereof, in which:
• X represents a residue of a phenolic opioid selected from the group consisting of buprenorphine, dihydroetorphine, diprenorphine, etorphine, hydromorphone, levorphanol, morphine, nalmefene, naloxone, N-methylnaloxone, naltrexone, N-methylnaltrexone, oxymorphone, oripavine, ketobemidone, dezocine, pentazocine, phenazocine, butorphanol, nalbuphine, meptazinol, O-desmethyltramadol, tapentadol, and nalorphine, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—NR1—(C(R2)(R3))n—NH—C(O)—CH(R4)—NH(R5);
• R1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
• each R2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• each R3 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• or R2 and R3 together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group, or two R2 or R3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl group;
• n represents an integer from 2 to 4;
• R4 represents —CH2CH2CH2NH(C═NH)NH2 or —CH2CH2CH2CH2NH2, the configuration of the carbon atom to which R4 is attached corresponding with that in an L-amino acid;
• and
• R5 represents a hydrogen atom, an N-acyl group, a residue of an amino acid, a dipeptide, or an N-acyl derivative of an amino acid or dipeptide.