Polysubunit opioid prodrugs resistant to overdose and abuse
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-031/485
A61K-047/55
A61K-047/61
A61K-047/64
출원번호
US-0683356
(2017-08-22)
등록번호
US-10251878
(2019-04-09)
발명자
/ 주소
Jenkins, Thomas E.
출원인 / 주소
Elysium Therapeutics, Inc.
대리인 / 주소
Wilson Sonsini Goodrich & Rosati
인용정보
피인용 횟수 :
0인용 특허 :
61
초록▼
The invention provides compositions and methods for the treatment or prevention of pain. The invention provides constructs whereby hydrolysis of the construct by a specified gastrointestinal enzyme directly, or indirectly, releases an opioid when taken orally as prescribed. The gastrointestinal enzy
The invention provides compositions and methods for the treatment or prevention of pain. The invention provides constructs whereby hydrolysis of the construct by a specified gastrointestinal enzyme directly, or indirectly, releases an opioid when taken orally as prescribed. The gastrointestinal enzyme mediated release of opioid from constructs of the invention is designed to be attenuated in vivo via a saturation or inhibition mechanism when overdoses are ingested. The invention further provides constructs that are highly resistant to oral overdose, chemical tampering, and abuse via non-oral routes of administration.
대표청구항▼
1. A composition comprising at least one GI enzyme-labile opioid releasing subunit that releases an opioid agonist upon the action of a GI enzyme, wherein the at least one GI enzyme-labile opioid agonist releasing subunit is covalently linked to at least one non-opioid agonist releasing GI enzyme su
1. A composition comprising at least one GI enzyme-labile opioid releasing subunit that releases an opioid agonist upon the action of a GI enzyme, wherein the at least one GI enzyme-labile opioid agonist releasing subunit is covalently linked to at least one non-opioid agonist releasing GI enzyme subunit that attenuates the activity of said GI enzyme, wherein the composition has the formula: or a salt thereof, wherein: each S1 is independently a non-opioid releasing GI enzyme subunit or GI enzyme inhibitor;each S2 is independently an opioid agonist releasing GI enzyme substrate subunit;each S3 is independently an opioid antagonist releasing moiety;each Z is independently a linking moiety;each s and q is independently an integer from 1 to 10; andt is an integer from 0 to 10. 2. The composition of claim 1, or a salt thereof, wherein the at least one non-opioid releasing GI enzyme subunit is an inverse-substrate. 3. The composition of claim 1, or a salt thereof, wherein the GI enzyme is trypsin. 4. The composition of claim 1, or a salt thereof, wherein the GI enzyme is chymotrypsin. 5. The composition of claim 1, or a salt thereof, wherein the GI enzyme-labile opioid releasing subunit releases the opioid agonist in the presence of the GI enzyme. 6. The composition of claim 1, or a salt thereof, wherein the opioid agonist is selected from the group consisting of morphine, hydromorphone, hydrocodone, oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone, dihydrocodeine, tramadol, tapentadol, buprenorphine, and pharmaceutically acceptable salts, prodrugs, and mixtures thereof. 7. The composition of claim 6, or a salt thereof, wherein the opioid agonist is oxycodone. 8. The composition of claim 6, or a salt thereof, wherein the opioid agonist is hydrocodone. 9. The composition of claim 6, or a salt thereof, wherein the opioid agonist is morphine. 10. The composition of claim 1, or a salt thereof, wherein the non-opioid agonist releasing subunit saturates or inhibits the GI enzyme. 11. The composition of claim 10, or a salt thereof, wherein the non-opioid agonist releasing subunit reduces the expected systemic exposures of delivered opioid agonist when doses of the opioid agonist greater than the prescribed dose are orally administered. 12. The composition of claim 1, or a salt thereof, wherein the S1 subunit is selected from the group consisting of: wherein: Y is amidine, guanidine, benzylamine, alkyl substituted amidine, alkyl substituted guanidine, alkyl substituted benzylamine, benzylamidine, benzylguanidine, alkyl substituted benzylamidine, or alkyl substituted benzylguanidine;Z is a linking moiety;each Ko is independently hydrogen or methyl;A is an amino acid side chain;r is an integer from 0-10;m is an integer from 1-10;p is an integer from 1-10;n is an integer from 0-10;each R is alkyl, alkylene, alkynyl, aryl, substituted alkyl, substituted alkylene, substituted alkynyl, or substituted aryl;each R′ is independently alkyl, aryl, substituted alkyl, substituted aryl, acyl, substituted acyl, or polyethylene glycol containing acyl, aryl, or alkyl; andeach R″ is independently hydrogen, methyl, alkyl, or aryl. 13. The composition of claim 12, or a salt thereof, wherein at least one of Z and Ko comprises an electron donating or electron withdrawing group. 14. The composition of claim 13, or a salt thereof, wherein the electron donating group is alkyl, substituted alkyl, —OH, 13 OR, —NH2, —NR2, —SH, —SR, or —NHC(O)R. 15. The composition of claim 13, or a salt thereof, wherein the electron withdrawing group is: —C(O)OH, —C(O)OR, —C(O)NH2, —C(O)NR2, —NO2, —NR3+, —C(O)CF3, halogen, —CCl3, cyano, —SO3H, —SO3R, —CHO, —COR, —C(NH)NH2, or —NHC(NH)NH2. 16. The composition of claim 1, or a salt thereof, wherein the S3—Z— subunit is selected from the group consisting of: wherein: R is cyclopropylmethyl or allyl;R′ is hydrogen, methyl, alkyl, aryl, substituted alkyl, or substituted aryl; andZ is a linking moiety. 17. The composition of claim 1, or a salt thereof, wherein the opioid antagonist is naltrexone. 18. The composition of claim 1, or a salt thereof, wherein the opioid antagonist is naloxone. 19. The composition of claim 1, or a salt thereof, wherein S2 has a structure selected from the group consisting of: wherein: D is an opioid agonist;each R1 and R2 is independently R or R′, and R3 is R″; and/or R1 and R2 are joined to form an optionally substituted spirocyclic ring; and/orR3 is joined with R1 or R2 to form an optionally substituted heterocyclic ring;each R is independently hydrogen, methyl, or alkyl;each R′ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, a natural or unnatural amino acid side chain, an amino acid side-chain mimic, —Z—(S2)n, or —Z—(Sx)n, wherein each x is independently 1 or 3 (thereby designating each Sx as a S1 or S3 subunit), and n is an integer from 1-10;each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl, polyethylene glycol containing acyl, polyethylene glycol containing alkyl, a natural or unnatural amino acid, an amino acid mimic, —Z—(S2)n, or —Z—(Sx)n, wherein each x is independently 1 or 3 (thereby designating each Sx as a S1 or S3 subunit), and n is an integer from 1-10;R4 is hydrogen, methyl, —C(═NR10)—NR102,wherein each R10 is independently hydrogen or methyl, or a group of formula: A2 is an amino acid side chain or an amino acid side-chain mimic that is recognized by the GI enzyme;n is an integer from 1 to 10; andr is independently at each occurrence an integer from 1 to 6. 20. The composition of claim 1, or a salt thereof, wherein Z is: wherein: each F is independently: wherein:each R is independently hydrogen, lower alkyl, aryl, or arylalkyl;X is carbon or nitrogen; andL is a linear, branched, or multivalent scaffold comprised of alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, polyalkylene glycol, polypeptide, polyamide, polycarbamate, polyurea, polycarbonate, or a combination thereof. 21. The composition of claim 20, or a salt thereof, wherein the moiety F forms a substituted ester, amide, amine, carbamate, ether, alkylane, arene, or urea; and L is a linear, branched, or a multivalent scaffold comprised of alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, polyalkylene glycol, polypeptide, or polyamide. 22. The composition of claim 19, or a salt thereof, wherein D is a morphone. 23. The composition of claim 19, or a salt thereof, wherein D is a codone. 24. The composition of claim 19, or a salt thereof, wherein D is morphine. 25. The composition of claim 1, or a salt thereof, having the formula: 26. A composition, or salt thereof, comprising at least one GI enzyme-labile opioid agonist releasing subunit (S2) that releases an opioid agonist upon the action of a GI enzyme, at least one GI enzyme inhibitor subunit (S1) that inhibits the GI enzyme, and optionally one or more opioid antagonist releasing moieties (S3); wherein all S1, S2, and S3 present are independently covalently linked via the independently selected linker Z, wherein the composition has the formula: or a salt thereof, wherein:each S1 is independently a GI enzyme inhibitor subunit;each S2 is independently a GI enzyme-labile opioid agonist releasing subunit; each S3 isan opioid antagonist releasing moiety;each Z is independently a linking moiety;each q is independently at each occurrence an integer from 1 to 10;s and u are independently integers from 1 to 10; andt is an integer from 0 to 10. 27. The composition of claim 26, wherein the composition has the formula: or a salt thereof, wherein q of (S1)q is 1, q of (S3)q is 1, s is 2, and t is 1. 28. The composition of claim 26, or a salt thereof, wherein the GI enzyme is trypsin. 29. The composition of claim 26, or a salt thereof, wherein the GI enzyme is chymotrypsin. 30. The composition of claim 26, or a salt thereof, wherein the GI enzyme-labile opioid releasing subunit releases the opioid agonist in the presence of the GI enzyme. 31. The composition of claim 26, or a salt thereof, wherein the opioid agonist is selected from the group consisting of morphine, hydromorphone, hydrocodone, oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone, dihydrocodeine, tramadol, tapentadol, buprenorphine, and pharmaceutically acceptable salts, prodrugs, and mixtures thereof. 32. The composition of claim 31, or a salt thereof, wherein the opioid agonist is oxycodone. 33. The composition of claim 31, or a salt thereof, wherein the opioid agonist is hydrocodone. 34. The composition of claim 31, or a salt thereof, wherein the opioid agonist is morphine. 35. The composition of claim 26, or a salt thereof, wherein the S1 subunit is selected from the group consisting of: wherein:Y is amidine, guanidine, benzylamine, alkyl substituted amidine, alkyl substituted guanidine, alkyl substituted benzylamine, benzylamidine, benzylguanidine, alkyl substituted benzylamidine, or alkyl substituted benzylguanidine;Z is a linking moiety;each Ko is independently hydrogen or methyl;A is an amino acid side chain;r is an integer from 0-10;m is an integer from 1-10;p is an integer from 1-10;n is an integer from 0-10;each R is alkyl, alkylene, alkynyl, aryl, substituted alkyl, substituted alkylene, substituted alkynyl, or substituted aryl;each R′ is independently alkyl, aryl, substituted alkyl, substituted aryl, acyl, substituted acyl, or polyethylene glycol containing acyl, aryl, or alkyl; andeach R″ is independently hydrogen, methyl, alkyl, or aryl. 36. The composition of claim 35, or a salt thereof, wherein at least one of Z and Ko comprises an electron donating or electron withdrawing group. 37. The composition of claim 36, or a salt thereof, wherein the electron donating group is alkyl, substituted alkyl, —OH, —OR, —NH2, —NR2, —SH, —SR, or —NHC(O)R. 38. The composition of claim 36, or a salt thereof, wherein the electron withdrawing group is: —C(O)OH, —C(O)OR, —C(O)NH2, —C(O)NR2, —NO2, —NR3+, —C(O)CF3, halogen, —CCl3, cyano, —SO3H, —SO3R, —CHO, —COR, —C(NH)NH2, or —NHC(NH)NH2. 39. The composition of claim 26, or a salt thereof, wherein the S2 subunit has the structure: wherein: D is an opioid agonist;each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl, polyethylene glycol containing acyl, a polyethylene glycol containing moiety, a natural or unnatural amino acid, an amino acid mimic, or a linking moiety (Z); andA2 is an amino acid side chain or an amino acid side-chain mimic that is recognized by the GI enzyme. 40. The composition of claim 26, or a salt thereof, wherein the S2 subunit has the structure: wherein: D is an opioid agonist;each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl, polyethylene glycol containing acyl, a polyethylene glycol containing moiety, a natural or unnatural amino acid, an amino acid mimic, or a linking moiety (Z); andA2 is an amino acid side chain or an amino acid side-chain mimic that is recognized by the GI enzyme. 41. The composition of claim 26, or a salt thereof, wherein the S2 subunit has the structure: wherein: D is an opioid agonist;each R1, R2 and R3 is independently R′; and/or R2 and R3 are joined to form an optionally substituted spirocyclic ring; and/orR2 or R3 is joined with le to form an optionally substituted heterocyclic ring; and/orR2 or R3 is joined with R′ to form an optionally substituted ring; and/orR′ is joined with a geminal R′ to form an optionally substituted spirocyclic ring;each R′ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl , polyethylene glycol, a polyethylene glycol containing moiety, a linking moiety Z, —Z—(S2)n, or —Z—(Sx)n, wherein each x is independently 1 or 3 (thereby designating each Sx as a S1 or S3 subunit), and n is an integer from 1-10;each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl, polyethylene glycol containing acyl, polyethylene glycol containing alkyl, a natural or unnatural amino acid, an amino acid mimic, —Z—(S2)n, or —Z—(Sx)n, wherein each x is independently 1 or 3 (thereby designating each Sx as a S1 or S3 subunit), and n is an integer from 1-10; andeach A2 is independently an amino acid side chain or an amino acid side-chain mimic that is recognized by the GI enzyme. 42. The composition of claim 39, or a salt thereof, wherein A2 is: wherein: R is each independently hydrogen or methyl; R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol containing acyl, polyethylene glycol containing alkyl, a natural or unnatural amino acid, an amino acid mimic, —Z—(S2)n, or —Z—(Sx)n, wherein each x is independently 1 or 3 (thereby designating each Sx as a S1 or S3 subunit), and n is an integer from 1-10;r is each independently at each occurrence an integer from 1 to 6;n is an integer from 0 to 10;R′″ is hydrogen, methyl, —C(═NR10)—NR102, wherein R10 is each independently hydrogen or methyl, or wherein A2 is a natural or unnatural amino acid side chain, or an amino acid side-chain mimic, and A2 is recognized by a digestive enzyme that directs the regiospecific hydrolysis of the S2 subunit prior to the release of the appended opioid agonist from the S2 subunit; and R″ is as defined above. 43. The composition of claim 26, or a salt thereof, wherein the S2 subunit has the structure: wherein D is an opioid agonist;each R′ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, a natural or unnatural amino acid side chain, an amino acid side-chain mimic, polyethylene glycol, a polyethylene glycol containing moiety, or a linking moiety Z;each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol containing acyl, a polyethylene glycol containing moiety, a natural or unnatural amino acid side chain, an amino acid side-chain mimic, or a linking moiety Z; andeach A2 is independently an amino acid side chain or an amino acid side-chain mimic that is recognized by the GI enzyme. 44. The composition of claim 41, or a salt thereof, wherein A2 is: wherein: R is each independently hydrogen or methyl; r is each independently at each occurrence an integer from 1 to 6; n is an integer from 0 to 10; andR′″ is hydrogen, methyl, —C(═NR10)—NR102, wherein R10 is each independently hydrogen or methyl, or wherein A2 is a natural or unnatural amino acid side chain, or an amino acid side-chain mimic, and A2 is recognized by a digestive enzyme that directs the regiospecific hydrolysis of the S2 subunit prior to the release of the appended opioid agonist from the S2 subunit. 45. The composition of claim 26, or a salt thereof, wherein the S3—Z— subunit is selected from the group consisting of: wherein: R is cyclopropylmethyl or allyl;R′ is hydrogen, methyl, alkyl, aryl, substituted alkyl, or substituted aryl; andZ is a linking moiety. 46. The composition of claim 26, or a salt thereof, wherein the opioid antagonist is naltrexone. 47. The composition of claim 26, or a salt thereof, wherein the opioid antagonist is naloxone. 48. The composition of claim 26, or a salt thereof, wherein S2 has a structure selected from the group consisting of: wherein:D is an opioid agonist;each R1 and R2 is independently R or R′, and R3 is R″; and/or R1 and R2 are joined to form an optionally substituted spirocyclic ring; and/orR3 is joined with R1 or R2 to form an optionally substituted heterocyclic ring;each R is independently hydrogen, methyl, or alkyl;each R′ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, a natural or unnatural amino acid side chain, an amino acid side-chain mimic, —Z—(S2)n, or —Z—(Sx)n, wherein each x is independently 1 or 3 (thereby designating each Sx as a S1 or S3 subunit), and n is an integer from 1-10;each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl, polyethylene glycol containing acyl, polyethylene glycol containing alkyl, a natural or unnatural amino acid, an amino acid mimic, —Z—(S2)n, or —Z—(Sx)n, wherein each x is independently 1 or 3 (thereby designating each Sx as a S1 or S3 subunit), and n is an integer from 1-10;R4 is hydrogen, methyl, —C(═NR10)—NR102, wherein each R10 is independently hydrogen or methyl, or a group of formula: A2 is an amino acid side chain or an amino acid side-chain mimic that is recognized by the GI enzyme;n is an integer from 1 to 10; andr is independently at each occurrence an integer from 1 to 6. 49. The composition of claim 26, or a salt thereof, wherein Z is: wherein:each F is independently: each R is independently hydrogen, lower alkyl, aryl, or arylalkyl;X is carbon or nitrogen; andL is a linear, branched, or multivalent scaffold comprised of alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, polyalkylene glycol, polypeptide, polyamide, polycarbamate, polyurea, polycarbonate, or a combination thereof. 50. The composition of claim 49, or a salt thereof, wherein the moiety F forms a substituted ester, amide, amine, carbamate, ether, alkylane, arene, or urea; and L is a linear, branched, or a multivalent scaffold comprised of alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, polyalkylene glycol, polypeptide, or polyamide. 51. The composition of claim 41, or a salt thereof, wherein D is a morphone. 52. The composition of claim 41, or a salt thereof, wherein D is a codone. 53. The composition of claim 41, or a salt thereof, wherein D is morphine.
Jenkins, Thomas E.; Husfeld, Craig O.; Seroogy, Julie D.; Wray, Jonathan W., Compositions comprising enzyme-cleavable opioid prodrugs and inhibitors thereof.
Zhao, Robert Yongxin; Miller, Michael Louis; Widdison, Wayne Charles; Chari, Ravi V. J., Cytotoxic agents bearing a reactive polyethylene glycol moiety, cytotoxic conjugates comprising polyethylene glycol linking groups, and methods of making and using the same.
Urquhart John (Palo Alto CA) Theeuwes Felix (Los Altos CA), Delivery system comprising means for shielding a multiplicity of reservoirs in selected environment of use.
Ayer Atul D. (Palo Alto CA) Swanson David R. (Palo Alto CA) Kuczynski Anthony L. (Palo Alto CA), Dosage form for treating cardiovascular diseases comprising isradipine.
Noakes Timothy J. (Hampshire GB2) Hewitt Nevil E. (Surrey GB2) Grocott Arend L. (Hampshire GB2) Franks Philip C. W. (Hampshire GB2), Electrostatic spraying apparatus.
Ehrenberg Scott G. (Fishkill NY) Serpico Joseph (Troy NY) Wnek Gary E. (Latham NY) Rider Jeffrey N. (Troy NY), Fuel cell incorporating novel ion-conducting membrane.
Cantrell Buddy E. (Fountaintown IN) Zimmerman Dennis M. (Mooresville IN), Intermediates of peripherally selective N-carbonyl-3,4,4-trisubstituted piperidine opioid antagonists.
Grosswald Ralph R. (Fairfield IA) Anderson Jeffory B. (Springville UT) Andrew Clair S. (Provo UT), Method for the manufacture of pharmaceutical cellulose capsules.
Armer Thomas Alex ; Evans Bryce Burwick ; Mohsen Nahed Mohsen ; Pavkov Richard Matthew ; Sudhalkar Atul M., Methods and apparatus for delivering aerosolized medication.
Harris J. Milton ; Veronese Francesco Maria,ITX ; Caliceti Paolo,ITX ; Schiavon Oddone,ITX, Multiarmed, monofunctional, polymer for coupling to molecules and surfaces.
Mickle, Travis C., Polar hydrophilic prodrugs and non-standard amino acid conjugates of amphetamine and other stimulants and processes for making and using the same.
Frank Scott A. (Lebanon IN) Prather Douglas E. (Brownsburg IN) Ward Jeffrey A. (Indianapolis IN) Werner John A. (Indianapolis IN), Preparation of 3,4,4-trisubstituted-piperidinyl-N-alkylcarboxylates and intermediates.
Nabil Farah FR; Philippe Barthelemy FR; Joseph Joachim FR, Process for the manufacture of pharmaceutical composition with modified release of active principle comprising the matrix.
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