U.S. patent application number 11/805225 was filed with the patent office on 2008-11-27 for salts of physiologically active and psychoactive alkaloids and amines simultaneously exhibiting bioavailability and abuse resistance.
Invention is credited to Vicki Haynes Audia, David William Bristol, Clifford Riley King, Joseph Pike Mitchener, JR..
Application Number | 20080293695 11/805225 |
Document ID | / |
Family ID | 40072979 |
Filed Date | 2008-11-27 |
United States Patent
Application |
20080293695 |
Kind Code |
A1 |
Bristol; David William ; et
al. |
November 27, 2008 |
Salts of physiologically active and psychoactive alkaloids and
amines simultaneously exhibiting bioavailability and abuse
resistance
Abstract
Drug substances comprising a pharmaceutically acceptable organic
acid addition salt 6f amine containing pharmaceutically active
compounds useful for the treatment of a therapeutic ailment
administration and exhibiting prophylactic properties when employed
in non-therapeutic administration.
Inventors: |
Bristol; David William;
(Mills River, NC) ; King; Clifford Riley;
(Hendersonville, NC) ; Mitchener, JR.; Joseph Pike;
(Flat Rock, NC) ; Audia; Vicki Haynes; (Mills
River, NC) |
Correspondence
Address: |
NEXSEN PRUET, LLC
P.O. BOX 10648
GREENVILLE
SC
29603
US
|
Family ID: |
40072979 |
Appl. No.: |
11/805225 |
Filed: |
May 22, 2007 |
Current U.S.
Class: |
514/217 ;
514/532; 514/555; 514/567; 514/568; 540/587; 560/8; 562/405;
562/433 |
Current CPC
Class: |
A61K 31/55 20130101;
A61K 31/195 20130101; A61K 31/235 20130101; A61P 25/30 20180101;
A61K 31/192 20130101; A61K 31/205 20130101 |
Class at
Publication: |
514/217 ;
514/532; 514/555; 514/567; 514/568; 540/587; 560/8; 562/405;
562/433 |
International
Class: |
A61K 31/55 20060101
A61K031/55; A61K 31/192 20060101 A61K031/192; A61K 31/195 20060101
A61K031/195; A61P 25/30 20060101 A61P025/30; C07C 65/00 20060101
C07C065/00; C07D 223/14 20060101 C07D223/14; C07C 69/76 20060101
C07C069/76; C07C 229/02 20060101 C07C229/02; A61K 31/205 20060101
A61K031/205; A61K 31/235 20060101 A61K031/235 |
Claims
1. A drug substance comprising a pharmaceutically acceptable
organic acid addition salt of an amine containing pharmaceutically
active compound useful for the treatment of an ailment by
therapeutic administration and exhibiting anti-abuse properties
when employed in non-therapeutic administration.
2. The drug substance of claim 1 wherein said therapeutic
administration is selected from gastrointestinal tract
bio-availability; gastrointestinal tract permeability;
gastrointestinal tract dissolution; gastrointestinal tract efficacy
and pH dependent release in a gastrointestinal tract.
3. The drug substance of claim 1 wherein said non-therapeutic
administration is selected from mucosal membrane
bio-unavailability; non-permeability in mucosal membranes;
essentially no dissolution in the mucosal membranes; non-efficacy
for mucosal membranes and non-release properties when delivered to
mucosal membranes.
4. The drug substance of claim 3 wherein said mucosal membranes are
selected from ocular, nasal, pulmonary, buccal, sublinqual,
gingival, rectal, and vaginal mucosa.
5. The drug substance of claim 4 wherein said mucosal membranes
have a pH in a range of about 4 to about 9.
6. The drug substance of claim 1 wherein said non-therapeutic
administration occurs at a pH of 4-9 and said therapeutic ailment
administration is at a pH of below 4 or above 9.
7. The drug substance of claim 1 wherein said pharmaceutically
active compound comprises a material selected from acetaminophen,
caffeine, acetorphine, acetylmethadol, allylprodine,
alphacetylmethadol, bufotenine, dextromoramide, diethyltryptamine,
etorphine, heroin, ibogaine, ketobemidone, lysergic acid
diethylamide, mescaline, methaqualone,
3,4-methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine,
N-ethyl-1-phenylcyclohexylamine, peyote,
1-(1-phenylcyclohexyl)pyrrolidine, psilocybin, psilocin,
1-{1-(2-thienyl)-cyclohexyl}-piperidine, alphaprodine, anileridine,
cocaine, dextropropoxyphene, diphenoxylate, ethylmorphine,
glutethimide, hydrocodone, hydromorphone, levo-alphaacetylmethadol,
levorphanol, meperidine, methadone, morphine, opium, oxycodone,
oxymorphone, poppy straw, thebaine, amphetamine, methamphetamine,
methylphenidate, phencyclidine, codeine, benzphetamine, ketamine,
alprazolam, chlorodiazepoxide, clorazepate, diethylpropion,
fenfluramine, flurazepam, halazepam, lorazepam, mazindol,
mebutamate, midazolam, oxazepam, pemoline, pentazocine,
phentermine, prazepam, quazepam, temazepam, triazolam, zolpidem,
and buprenorphine.
8. The drug substance of claim 1 wherein said amine containing
pharmaceutically active material is selected from the group
consisting of opiates, morphinoids, amphetamines, compounds
containing a piperidine or substituted piperidine sub-structure
within a molecule, benzodiazapines, benzazepines, tropinoids and
compounds containing a phenethyl amine or substituted
phenethylamine sub-structure within a molecule.
9. The drug substance of claim 1 wherein said organic acid addition
salt is selected from: ##STR00010## wherein R.sup.1-R.sup.4 are
independently selected from H, alkyl of 1-6 carbons, adjacent
groups may be taken together to form a cyclic alkyl, cyclic
alkyl-aryl, or cyclic aryl moiety; R.sup.5 is selected from H, or
an alkali earth cation; R.sup.6 and R.sup.7 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.
10. The drug substance of claim 9 wherein said organic acid
addition salt is selected from the group consisting of:
##STR00011## wherein R.sup.5, R.sup.6 and R.sup.7 remain as defined
for Structure A; ##STR00012## wherein X, R.sup.5, R.sup.6 and
R.sup.7 remain as defined above for Structure A; ##STR00013##
wherein X, R.sup.1, R.sup.2, R.sup.5, R.sup.6 and R.sup.7 remain as
defined above for Structure A; ##STR00014## wherein X, R.sup.1,
R.sup.4, R.sup.5, R.sup.6 and R.sup.7 remain as defined above for
Structure A; ##STR00015## wherein X, R.sup.1, R.sup.5, R.sup.6 and
R.sup.7 are independently defined as above for Structure A; and
##STR00016## wherein X, R.sup.5, R.sup.6 and R.sup.7 are
independently defined as above for Structure A.
11. The drug substance of claim 10 wherein for Structure D X is O;
R.sup.1 and R.sup.2 are hydrogen.
12. The drug substance of claim 10 wherein for Structure E X is O,
R.sup.1 and R.sup.4 are hydrogen.
13. The drug substance of claim 10 wherein for Structure F at least
one X is O and at least one R.sup.1 is hydrogen.
14. The drug substance of claim 10 wherein for Structure G X is O
and R.sup.5 is hydrogen.
15. The drug substance of claim 10 wherein said organic acid
comprises a material selected from the group consisting of pamoic
acid, disodium pamoate, di-ammonium pamoate, di-potassium pamoate,
lower molecular weight di-alkyl amine pamoate, lower molecular
weight di-aryl amine pamoate, lower molecular weight di-alkyl
esters of pamoic acid, lower molecular weight di-aryl esters of
pamoic acid, lower molecular weight di-alkylacyl O-esters of pamoic
acid and lower molecular weight di-arylacyl O-esters of pamoic
acid.
16. The drug substance of claim 10 wherein the organic acid
comprises a material selected from the group consisting of ortho
isomers of hydroxy naphthoic acid, sodium hydroxy naphthoic acid,
ammonium hydroxy naphthoate, potassium hydroxy naphthoate, lower
molecular weight alkyl amine salts of hydroxy naphthoic acid, lower
molecular weight aryl amine salts of hydroxy naphthoic acid, lower
molecular weight alkyl esters of hydroxy naphthoic acid, lower
molecular weight aryl esters of hydroxy naphthoic acid, lower
molecular weight alkylacyl O-esters of hydroxyl naphthoic acid and
lower molecular weight arylacyl O-esters of hydroxyl naphthoic
acid.
17. The drug substance of claim 10 wherein the organic acid is
selected from the group consisting of salicylic acid, sodium
salicylate, ammonium salicylate, potassium salicylate, lower
molecular weight alkyl amine salts of salicylic acid, lower
molecular weight aryl amine salts of salicylic acid, lower
molecular weight alkyl esters of salicylic acid, lower molecular
weight aryl esters of salicylic acid, lower molecular weight
alkylacyl O-esters of salicylic acid and lower molecular weight
arylacyl O-esters of salicylic acid.
18. The drug substance of claim 10 wherein said organic acid salt
comprises an acid selected from pamoic acid or a synthetic
equivalent thereof; salicylic acid or a synthetic equivalent
thereof and hydroxy naphthoic acid or a synthetic equivalent
thereof.
19. The drug substance of claim 1 in a form selected from the group
consisting of a tablet, a capsule, a caplet, and an oral
suspension.
20. The drug substance of claim 1 wherein said pharmaceutically
acceptable organic acid addition salt of an amine containing
pharmaceutically active compound has a phase transition temperature
of at least 100.degree. C.
21. The drug substance of claim 1 wherein said pharmaceutically
active organic acid addition salt is bio-unavailable when exposed
to mucosal membranes and exhibits recovery from aqueous solution at
about pH 4.5 of at least 85 weight percent.
22. The drug substance of claim 1 wherein said pharmaceutically
active orgainc acid addition salt is bio-unavailable when exposed
to mucosal membranes and exhibits recovery from aqueous solution at
about pH 7.0 of at least 85 weight percent.
23. The drug substance of claim 1 wherein said pharmaceutically
active organic acid addition salt comprises a mixture of physical
forms.
24. The drug substance of claim 23 wherein said mixture of physical
forms comprises an amorphous material and at least one
polymorph.
25. The drug substance of claim 1 designed for immediate release in
the gastrointestinal tract and for essentially non-release in the
mucosal membranes.
26. The drug substance of claim 1 wherein said pharmaceutically
active organic acid addition salt of an amine containing
pharmaceutically active compound is selected from the group
consisting of phentermine pamoate, ephedrine pamoate,
pseudophedrine pamoate, benzphetamine pamoate, imipramine pamoate,
phentermine xinafoate, ephedrine xinafoate, pseudophedrine
xinafoate, benzphetamine xinafoate, imipramine xinafoate,
phentermine salicylate, ephedrine salicylate, pseudophedrine
salicylate, benzphetamine salicylate and imipramine salicylate.
27. The drug substance of claim 1 administered for at least one
purpose selected from pain management, anti-convulsant,
anti-depressant, analgesic, anesthetic, anxiolytic, psychotropic,
hallucinogenic, hypnotic, anorexic, cough, cold and sinus.
28. The drug substance of claim 1 administered by one method
delivery presentation selected from solid oral delivery, parenteral
delivery, transdermal delivery and inhalation delivery.
29. A drug substance as a pharmaceutically acceptable organic acid
addition salt of an amine containing pharmaceutically active
compound exhibiting at least two dissolution profiles one of which
provides for drug efficacy when administered in a formulated oral
dosage and one which does not provide drug efficacy when
administered as a non-oral dosage.
30. The drug substance of claim 29 wherein said pharmaceutically
active compound comprises a material selected from acetaminophen,
caffeine, acetorphine, acetylmethadol, allylprodine,
alphacetylmethadol, bufotenine, dextromoramide, diethyltryptamine,
etorphine, heroin, ibogaine, ketobemidone, lysergic acid
diethylamide, mescaline, methaqualone,
3,4-methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine,
N-ethyl-1-phenylcyclohexylamine, peyote,
1-(1-phenylcyclohexyl)pyrrolidine, psilocybin, psilocin,
1-{1-(2-thienyl)-cyclohexyl}-piperidine, alphaprodine, anileridine,
cocaine, dextropropoxyphene, diphenoxylate, ethylmorphine,
glutethimide, hydrocodone, hydromorphone, levo-alphaacetylmethadol,
levorphanol, meperidine, methadone, morphine, opium, oxycodone,
oxymorphone, poppy straw, thebaine, amphetamine, methamphetamine,
methylphenidate, phencyclidine, codeine, benzphetamine, ketamine,
alprazolam, chlorodiazepoxide, clorazepate, diethylpropion,
fenfluramine, flurazepam, halazepam, lorazepam, mazindol,
mebutamate, midazolam, oxazepam, pemoline, pentazocine,
phentermine, prazepam, quazepam, temazepam, triazolam, zolpidem,
and buprenorphine.
31. The drug substance of claim 29 wherein said amine containing
pharmaceutically active material is selected from the group
consisting of opiates, morphinoids, amphetamines, compounds
containing a piperidine or substituted piperidine sub-structure
within a molecule, benzodiazapines, benzazepines, tropinoids and
compounds containing a phenethyl amine or substituted
phenethylamine sub-structure within a molecule.
32. The drug substance of claim 29 wherein said organic acid
addition salt is selected from: ##STR00017## wherein
R.sup.1-R.sup.4 are independently selected from H, alkyl of 1-6
carbons, adjacent groups may be taken together to form a cyclic
alkyl, cyclic alkyl-aryl or cyclic aryl moiety; R.sup.5 is selected
from H, or an alkali earth cation; R.sup.6 and R.sup.7 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.
33. The drug substance of claim 32 wherein said organic acid
addition salt is selected from the group consisting of:
##STR00018## wherein R.sup.5, R.sup.6 and R.sup.7 remain as defined
for Structure A; ##STR00019## wherein X, R.sup.5, R.sup.6 and
R.sup.7 remain as defined above for Structure A; ##STR00020##
wherein X, R.sup.1, R.sup.2.sub.9 R.sup.5, R.sup.6 and R.sup.7
remain as defined above for Structure A; ##STR00021## wherein X,
R.sup.1, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 remain as defined
above for Structure A; ##STR00022## wherein X, R.sup.1, R R.sup.6
and R.sup.7 are independently defined as above for Structure A; and
##STR00023## wherein X, R.sup.5, R.sup.6 and R.sup.7 are
independently defined as above for Structure A.
34. The drug substance of claim 33 wherein for Structure D X is O;
R.sup.1 and R.sup.2 are hydrogen.
35. The drug substance of claim 33 wherein for Structure E X is O,
R.sup.1 and R.sup.4 are hydrogen.
36. The drug substance of claim 33 wherein for Structure F at least
one X is O and at least one R.sup.1 is hydrogen.
37. The drug substance of claim 33 wherein for Structure G X is O
and R.sup.5 is hydrogen.
38. The drug substance of claim 33 wherein said organic acid
comprises a material selected from the group consisting of pamoic
acid, disodium pamoate, di-ammonium pamoate, di-potassium pamoate,
lower molecular weight di-alkyl amine pamoate, lower molecular
weight di-aryl amine pamoate, lower molecular weight di-alkyl
esters of pamoic acid, lower molecular weight di-aryl esters of
pamoic acid, lower molecular weight di-alkylacyl O-esters of pamoic
acid and lower molecular weight di-arylacyl O-esters of pamoic
acid.
39. The drug substance of claim 33 wherein the organic acid
comprises a material selected from the group consisting of ortho
isomers of hydroxy naphthoic acid, sodium hydroxy naphthoic acid,
ammonium hydroxy naphthoate, potassium hydroxy naphthoate, lower
molecular weight alkyl amine salts of hydroxy naphthoic acid, lower
molecular weight aryl amine salts of hydroxy naphthoic acid, lower
molecular weight alkyl esters of hydroxy naphthoic acid, lower
molecular weight aryl esters of hydroxy naphthoic acid, lower
molecular weight alkylacyl O-esters of hydroxyl naphthoic acid and
lower molecular weight arylacyl O-esters of hydroxyl naphthoic
acid.
40. The drug substance of claim 33 wherein the organic acid is
selected from the group consisting of salicylic acid, sodium
salicylate, ammonium salicylate, potassium salicylate, lower
molecular weight alkyl amine salts of salicylic acid, lower
molecular weight aryl amine salts of salicylic acid, lower
molecular weight alkyl esters of salicylic acid, lower molecular
weight aryl esters of salicylic acid, lower molecular weight
alkylacyl O-esters of salicylic acid and lower molecular weight
arylacyl O-esters of salicylic acid.
41. The drug substance of claim 33 wherein said organic acid salt
comprises an acid selected from pamoic acid or a synthetic
equivalent thereof; salicylic acid or a synthetic equivalent
thereof and hydroxy naphthoic acid or a synthetic equivalent
thereof.
42. The drug substance of claim 29 in a form selected from the
group consisting of a tablet, a capsule, a caplet, and an oral
suspension.
43. The drug substance of claim 29 wherein said pharmaceutically
acceptable organic acid addition salt of an amine containing
pharmaceutically active compound has a phase transition temperature
of at least 100.degree. C.
44. The drug substance of claim 29 wherein said pharmaceutically
active organic acid addition salt is bio-unavailable when exposed
to mucosal membranes and exhibits recovery from aqueous solution at
about pH 4.5 of at least 85 weight percent.
45. The drug substance of claim 29 wherein said pharmaceutically
active organic acid addition salt is bio-unavailable when exposed
to mucosal membranes and exhibits recovery from aqueous solution at
about pH 7.0 of at least 85 weight percent.
46. The drug substance of claim 29 wherein said pharmaceutically
active organic acid addition salt comprises a mixture of physical
forms.
47. The drug substance of claim 46 wherein said mixture of physical
forms comprises an amorphous material and at least one
polymorph.
48. The drug substance of claim 29 designed for immediate release
in the gastrointestinal tract and for essentially non-release in
the mucosal membranes.
49. The drug substance of claim 29 wherein said pharmaceutically
active organic acid addition salt of an amine containing
pharmaceutically active compound is selected from the group
consisting of phentermine pamoate, ephedrine pamoate,
pseudophedrine pamoate, benzphetamine pamoate, imipramine pamoate,
phentermine xinafoate, ephedrine xinafoate, pseudophedrine
xinafoate, benzphetamine xinafoate, imipramine xinafoate,
phentermine salicylate, ephedrine salicylate, pseudophedrine
salicylate, benzphetamine salicylate and imipramine salicylate.
50. The drug substance of claim 29 administered for at least one
purpose selected from anti-convulsant, anti-depressant, analgesic,
anesthetic, anxiolytic, psychotropic, hallucinogenic, hypnotic,
anorexic, cough, cold and sinus.
51. The drug substance of claim 29 administered by one method
delivery presentation selected from solid oral delivery, parenteral
delivery, transdermal delivery and inhalation delivery.
52. A drug substance comprising an organic acid addition salt of an
amine containing pharmaceutically active compound used to treat a
combination of two or more therapeutic ailments, at least one of
which is drug abuse.
53. The drug substance of claim 52 wherein said pharmaceutically
active compound comprises a material selected from acetaminophen,
caffeine, acetorphine, acetylmethadol, allylprodine,
alphacetylmethadol, bufotenine, dextromoramide, diethyltryptamine,
etorphine, heroin, ibogaine, ketobemidone, lysergic acid
diethylamide, mescaline, methaqualone,
3,4-methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine,
N-ethyl-1-phenylcyclohexylamine, peyote,
1-(1-phenylcyclohexyl)pyrrolidine, psilocybin, psilocin,
1-{1-(2-thienyl)-cyclohexyl}-piperidine, alphaprodine, anileridine,
cocaine, dextropropoxyphene, diphenoxylate, ethylmorphine,
glutethimide, hydrocodone, hydromorphone, levo-alphaacetylmethadol,
levorphanol, meperidine, methadone, morphine, opium, oxycodone,
oxymorphone, poppy straw, thebaine, amphetamine, methamphetamine,
methylphenidate, phencyclidine, codeine, benzphetamine, ketamine,
alprazolam, chlorodiazepoxide, clorazepate, diethylpropion,
fenfluramine, flurazepam, halazepam, lorazepam, mazindol,
mebutamate, midazolam, oxazepam, pemoline, pentazocine,
phentermine, prazepam, quazepam, temazepam, triazolam, zolpidem,
and buprenorphine.
54. The drug substance of claim 52 wherein said amine containing
pharmaceutically active material is selected from the group
consisting of opiates, morphinoids, amphetamines, compounds
containing a piperidine or substituted piperidine sub-structure
within a molecule, benzodiazapines, benzazepines, tropinoids and
compounds containing a phenethyl amine or substituted
phenethylamine sub-structure within a molecule.
55. The drug substance of claim 46 wherein said organic acid
addition salt is selected from: ##STR00024## wherein
R.sup.1-R.sup.4 are independently selected from H, alkyl of 1-6
carbons, adjacent groups may be taken together to form a cyclic
alkyl, cyclic alkyl-aryl or cyclic aryl moiety; R.sup.5 is selected
from H, or an alkali earth cation; R.sup.6 and R.sup.7 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.
56. The drug substance of claim 55 wherein said organic acid
addition salt is selected from the group consisting of:
##STR00025## wherein R.sup.5, R.sup.6 and R.sup.7 remain as defined
for Structure A; ##STR00026## wherein X, R.sup.5, R.sup.6 and
R.sup.7 remain as defined above for Structure A; ##STR00027##
wherein X, R.sup.1, R.sup.2, R.sup.5, R.sup.6 and R.sup.7 remain as
defined above for Structure A; ##STR00028## wherein X, R.sup.1,
R.sup.4, R.sup.5, R.sup.6 and R.sup.7 remain as defined above for
Structure A; ##STR00029## wherein X, R.sup.1, R.sup.5, R.sup.6 and
R.sup.7 are independently defined as above for Structure A; and
##STR00030## wherein X, R.sup.5, R.sup.6 and R.sup.7 are
independently defined as above for Structure A.
57. The drug substance of claim 56 wherein for Structure D X is O;
R.sup.1 and R.sup.2 are hydrogen.
58. The drug substance of claim 56 wherein for Structure E X is O,
R.sup.1 and R.sup.4 are hydrogen.
59. The drug substance of claim 56 wherein for Structure F at least
one X is O and at least one R.sup.1 is hydrogen.
60. The drug substance of claim 56 wherein for Structure G X is O
and R.sup.5 is hydrogen.
61. The drug substance of claim 56 wherein said organic acid
comprises a material selected from the group consisting of pamoic
acid, disodium pamoate, di-ammonium pamoate, di-potassium pamoate,
lower molecular weight di-alkyl amine pamoate, lower molecular
weight di-aryl amine pamoate, lower molecular weight di-alkyl
esters of pamoic acid, lower molecular weight di-aryl esters of
pamoic acid, lower molecular weight di-alkylacyl O-esters of pamoic
acid and lower molecular weight di-arylacyl O-esters of pamoic
acid.
62. The drug substance of claim 56 wherein the organic acid
comprises a material selected from the group consisting of ortho
isomers of hydroxy naphthoic acid, sodium hydroxy naphthoic acid,
ammonium hydroxy naphthoate, potassium hydroxy naphthoate, lower
molecular weight alkyl amine salts of hydroxy naphthoic acid, lower
molecular weight aryl amine salts of hydroxy naphthoic acid, lower
molecular weight alkyl esters of hydroxy naphthoic acid, lower
molecular weight aryl esters of hydroxy naphthoic acid, lower
molecular weight alkylacyl O-esters of hydroxyl naphthoic acid and
lower molecular weight arylacyl O-esters of hydroxyl naphthoic
acid.
63. The drug substance of claim 56 wherein the organic acid is
selected from the group consisting of salicylic acid, sodium
salicylate, ammonium salicylate, potassium salicylate, lower
molecular weight alky amine salts of salicylic acid, lower
molecular weight aryl amine salts of salicylic acid, lower
molecular weight alkyl esters of salicylic acid, lower molecular
weight aryl esters of salicylic acid, lower molecular weight
alkylacyl O-esters of salicylic acid and lower molecular weight
arylacyl O-esters of salicylic acid.
64. The drug substance of claim 56 wherein said organic acid salt
comprises an acid selected from pamoic acid or a synthetic
equivalent thereof; salicylic acid or a synthetic equivalent
thereof and hydroxy naphthoic acid or a synthetic equivalent
thereof.
65. The drug substance of claim 52 in a form selected from the
group consisting of a tablet, a capsule, a caplet, and an oral
suspension.
66. The drug substance of claim 52 wherein said pharmaceutically
acceptable organic acid addition salt of an amine containing
pharmaceutically active compound has a phase transition temperature
of at least 100.degree. C.
67. The drug substance of claim 52 wherein said pharmaceutically
active organic acid addition salt is bio-unavailable when exposed
to mucosal membranes and exhibits recovery from aqueous solution at
about pH 4.5 of at least 85 weight percent.
68. The drug substance of claim 52 wherein said pharmaceutically
active organic acid addition salt is bio-unavailable when exposed
to mucosal membranes and exhibits recovery from aqueous solution at
about pH 7.0 of at least 85 weight percent.
69. The drug substance of claim 52 wherein said pharmaceutically
active organic acid salt comprises a mixture of physical forms.
70. The drug substance of claim 69 wherein said mixture of physical
forms comprises an amorphous material and at least one
polymorph.
71. The drug substance of claim 69 designed for immediate release
in the gastrointestinal tract and for essentially non-release in
the mucosal membranes.
72. The drug substance of claim 52 wherein said pharmaceutically
active organic acid addition salt of an amine containing
pharmaceutically active compound is selected from the group
consisting of phentermine pamoate, ephedrine pamoate,
pseudophedrine pamoate, benzphetamine pamoate, imipramine pamoate,
phentermine xinafoate, ephedrine xinafoate, pseudophedrine
xinafoate, benzphetamine xinafoate, imipramine xinafoate,
phentermine salicylate, ephedrine salicylate, pseudophedrine
salicylate, benzphetamine salicylate and imipramine salicylate.
73. The drug substance of claim 52 administered for at least one
purpose selected from pain management, anti-convulsant,
anti-depressant, analgesic, anesthetic, anxiolytic, psychotropic,
hallucinogenic, hypnotic, anorexic, cough, cold and sinus.
74. The drug substance of claim 52 administered by one method
delivery presentation selected from solid oral delivery, parenteral
delivery, transdermal delivery and inhalation delivery.
75-288. (canceled)
289. An organic acid addition salt of amine-containing
pharmaceutically active compounds wherein the organic acid
comprises a compound of Formula A: ##STR00031## wherein
R.sup.1-R.sup.4 are independently selected from H, alkyl of 1-6
carbons, adjacent groups may be taken together to form a cyclic
alkyl, cyclic alkyl-aryl or cyclic aryl moiety; R.sup.5 is selected
from H, or an alkali earth cation; R.sup.6 is 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.
290-309. (canceled)
310. Organic acid addition salts of amine containing
pharmaceutically active compounds selected for their targeted
release characteristic in the gastro intestinal tract and
bio-unavailability in mucosal membranes, and formulated into a drug
product wherein said amine containing pharmaceutically active
compounds can not be directly isolated.
311-336. (canceled)
337. A tamper resistant oral dosage drug product comprising an
organic acid salt of an amine-containing pharmaceutically active
compound formulated wherein said organic acid and said
amine-containing pharmaceutically active compound can not be
directly isolated.
338-381. (canceled)
382. A pharmaceutically active compound comprising the organic acid
addition salt of an amine-containing pharmaceutically active
material wherein said compound is essentially bio-unavailable when
exposed to mucosal membranes and exhibits recovery from aqueous
solution at pH 4.5 of at least 85 weight percent.
383-403. (canceled)
404. A pharmaceutically active compound comprising the organic acid
addition salt of an amine-containing pharmaceutically active
material wherein said compound is essentially bio-unavailable when
exposed to human mucosal membranes and exhibits recovery from
aqueous solution at pH 7.0 of at least 85 weight percent.
405-427. (canceled)
428. A pharmaceutically active compound comprising an organic acid
addition salt of an amine-containing pharmaceutically active
compound wherein said compound is essentially bio-unavailable when
exposed to mucosal membranes unless processed by the steps of: a)
dissolution in an aqueous solution of pH greater than 8; b)
extraction of the active pharmaceutical ingredient into a water
immiscible solvent; c) separation of the aqueous layer from the
solvent; d) washing of the solvent layer with an aqueous solution
of pH greater than 8; and e) drying the solvent layer to remove
traces of water.
429-455. (canceled)
456. A pharmaceutically active compound comprising an organic acid
addition salt of an amine-containing pharmaceutically active
compound wherein said compound is essentially bio-unavailable when
exposed to mucosal membranes unless processed by the steps of: a.
dissolution in an aqueous solution of pH greater than about 1; b.
filtration of the precipitated organic acid; c. adjustment of the
filtrate to a pH of about 8; d. addition of a water immiscible
solvent in which the pharmaceutically active compound is soluble;
e. separation of the aqueous layer from the solvent; f. washing of
the solvent layer with an aqueous solution of pH greater than 8;
and g. drying the solvent layer to remove traces of water.
457-507. (canceled)
508. A drug substance comprising a pharmaceutically acceptable
organic acid addition salt of an amine containing pharmaceutically
active compound useful for the treatment of a therapeutic ailment
administration and exhibiting anti-abuse properties when employed
in non-therapeutic administration wherein said pharmaceutically
active compound comprises a material selected from acetaminophen,
caffeine, acetorphine, acetylmethadol, allylprodine,
alphacetylmethadol, bufotenine, dextromoramide, diethyltryptamine,
etorphine, heroin, ibogaine, ketobemidone, lysergic acid
diethylamide, mescaline, methaqualone,
3,4-methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine,
N-ethyl-1-phenylcyclohexylamine, peyote,
1-(1-phenylcyclohexyl)pyrrolidine, psilocybin, psilocin, 1
-{1-(2-thienyl)-cyclohexyl}-piperidine, alphaprodine, anileridine,
cocaine, dextropropoxyphene, diphenoxylate, ethylmorphine,
glutethimide, hydrocodone, hydromorphone, levo-alphaacetylmethadol,
levorphanol, meperidine, methadone, morphine, opium, oxycodone,
oxymorphone, poppy straw, thebaine, amphetamine, methamphetamine,
methylphenidate, phencyclidine, codeine, benzphetamine, ketamine,
alprazolam, chlorodiazepoxide, clorazepate, diethylpropion,
fenfluramine, flurazepam, halazepam, lorazepam, mazindol,
mebutamate, midazolam, oxazepam, pemoline, pentazocine,
phentermine, prazepam, quazepam, temazepam, triazolam, zolpidem,
and buprenorphine and wherein said organic acid addition salt
comprises a material selected from the group consisting of pamoic
acid, disodium pamoate, di-ammonium pamoate, di-potassium pamoate,
lower molecular weight di-alkyl amine pamoate, lower molecular
weight di-aryl amine pamoate, lower molecular weight di-alkyl
esters of pamoic acid, lower molecular weight di-aryl esters of
pamoic acid, lower molecular weight di-alkylacyl O-esters of pamoic
acid and lower molecular weight di-arylacyl O-esters of pamoic
acid.
509. The drug substance of claim 1 comprising oxycodone
pamoate.
510. A drug substance comprising a pharmaceutically acceptable
organic acid addition salt of an amine containing pharmaceutically
active compound useful for the treatment of an ailment by
therapeutic administration and exhibiting anti-abuse properties
when employed in non-therapeutic administration; wherein said
non-therapeutic administration is selected from mucosal membrane
bio-unavailability, non-permeability in mucosal membranes,
essentially no dissolution in the mucosal membranes, non-efficacy
for mucosal membranes and non-release properties when delivered to
mucosal membranes; wherein said pharmaceutically active compound
comprises a material selected from acetaminophen, caffeine,
acetorphine, acetylmethadol, allylprodine, alphacetylmethadol,
bufotenine, dextromoramide, diethyltryptamine, etorphine, heroin,
ibogaine, ketobemidone, lysergic acid diethylamide, mescaline,
methaqualone, 3,4-methylenedioxyamphetamine,
3,4-methylenedioxymethamphetamine, N-ethyl-1-phenylcyclohexylamine,
peyote, 1-(1-phenylcyclohexyl)pyrrolidine, psilocybin, psilocin,
1-{1-(2-thienyl)-cyclohexyl}-piperidine, alphaprodine, anileridine,
cocaine, dextropropoxyphene, diphenoxylate, ethylmorphine,
glutethimide, hydrocodone, hydromorphone, levo-alphaacetylmethadol,
levorphanol, meperidine, methadone, morphine, opium, oxycodone,
oxymorphone, poppy straw, thebaine, amphetamine, methamphetamine,
methylphenidate, phencyclidine, codeine, benzphetamine, ketamine,
alprazolam, chlorodiazepoxide, clorazepate, diethylpropion,
fenfluramine, flurazepam, halazepam, lorazepam, mazindol,
mebutamate, midazolam, oxazepam, pemoline, pentazocine,
phentermine, prazepam, quazepam, temazepam, triazolam, zolpidem,
imipramine and buprenorphine; and wherein said organic acid
comprises a material selected from the group consisting of pamoic
acid, disodium pamoate, di-ammonium pamoate, di-potassium pamoate,
lower molecular weight di-alkyl amine pamoate, lower molecular
weight di-aryl amine pamoate, lower molecular weight di-alkyl
esters of pamoic acid, lower molecular weight di-aryl esters of
pamoic acid, lower molecular weight di-alkylacyl O-esters of pamoic
acid and lower molecular weight di-arylacyl O-esters of pamoic
acid.
511. The drug substance of claim 510 wherein said pharmaceutically
active compound is oxycodone.
512. The drug substance of claim 511 wherein said organic acid is
pamoic acid.
513. A drug substance comprising a pharmaceutically acceptable
organic acid addition salt of an amine containing pharmaceutically
active compound useful for the treatment of an ailment by
therapeutic administration and exhibiting anti-abuse properties
when employed in non-therapeutic administration; wherein said
non-therapeutic administration is selected from mucosal membrane
bio-unavailability, non-permeability in mucosal membranes,
essentially no dissolution in the mucosal membranes, non-efficacy
for mucosal membranes and non-release properties when delivered to
mucosal membranes; wherein said pharmaceutically active compound
comprises a material selected from acetaminophen, caffeine,
acetorphine, acetylmethadol, allylprodine, alphacetylmethadol,
bufotenine, dextromoramide, diethyltryptamine, etorphine, heroin,
ibogaine, ketobemidone, lysergic acid diethylamide, mescaline,
methaqualone, 3,4-methylenedioxyamphetamine,
3,4-methylenedioxymethamphetamine, N-ethyl-1-phenylcyclohexylamine,
peyote, 1-(1-phenylcyclohexyl)pyrrolidine, psilocybin, psilocin,
1-{1-(2-thienyl)-cyclohexyl}-piperidine, alphaprodine, anileridine,
cocaine, dextropropoxyphene, diphenoxylate, ethylmorphine,
glutethimide, hydrocodone, hydromorphone, levo-alphaacetylmethadol,
levorphanol, meperidine, methadone, morphine, opium, oxymorphone,
poppy straw, thebaine, amphetamine, methamphetamine,
methylphenidate, phencyclidine, codeine, benzphetamine, ketamine,
alprazolam, chlorodiazepoxide, clorazepate, diethylpropion,
fenfluramine, flurazepam, halazepam, lorazepam, mazindol,
mebutamate, midazolam, oxazepam, pemoline, pentazocine,
phentermine, prazepam, quazepam, temazepam, triazolam, zolpidem,
imipramine and buprenorphine; and wherein said organic acid
comprises a material selected from the group consisting of pamoic
acid, disodium pamoate, di-ammonium pamoate, di-potassium pamoate,
lower molecular weight di-alkyl amine pamoate, lower molecular
weight di-aryl amine pamoate, lower molecular weight di-alkyl
esters of pamoic acid, lower molecular weight di-aryl esters of
pamoic acid, lower molecular weight di-alkylacyl O-esters of pamoic
acid and lower molecular weight di-arylacyl O-esters of pamoic
acid.
514. A drug substance comprising a pharmaceutically acceptable
organic acid addition salt of an amine containing pharmaceutically
active compound useful for the treatment of an ailment by
therapeutic administration and exhibiting anti-abuse properties
when employed in non-therapeutic administration; wherein said
non-therapeutic administration is selected from mucosal membrane
bio-unavailability, non-permeability in mucosal membranes,
essentially no dissolution in the mucosal membranes, non-efficacy
for mucosal membranes and non-release properties when delivered to
mucosal membranes; wherein said pharmaceutically active compound
comprises a material selected from acetaminophen, caffeine,
acetorphine, acetylmethadol, allylprodine, alphacetylmethadol,
bufotenine, dextromoramide, diethyltryptamine, etorphine, heroin,
ibogaine, ketobemidone, lysergic acid diethylamide, mescaline,
methaqualone, 3,4-methylenedioxyamphetamine,
3,4-methylenedioxymethamphetamine, N-ethyl-1-phenylcyclohexylamine,
peyote, 1-(1-phenylcyclohexyl)pyrrolidine, psilocybin, psilocin,
1-{1-(2-thienyl)-cyclohexyl}-piperidine, alphaprodine, anileridine,
cocaine, dextropropoxyphene, diphenoxylate, ethylmorphine,
glutethimide, hydrocodone, hydromorphone, levo-alphaacetylmethadol,
levorphanol, meperidine, methadone, morphine, opium, oxycodone,
oxymorphone, poppy straw, thebaine, amphetamine, methamphetamine,
methylphenidate, phencyclidine, codeine, benzphetamine, ketamine,
alprazolam, chlorodiazepoxide, clorazepate, diethylpropion,
fenfluramine, flurazepam, halazepam, lorazepam, mazindol,
mebutamate, midazolam, oxazepam, pemoline, pentazocine,
phentermine, prazepam, quazepam, temazepam, triazolam, zolpidem,
imipramine and buprenorphine; and wherein said organic acid
comprises a material selected from the group consisting of disodium
pamoate, di-ammonium pamoate, di-potassium pamoate, lower molecular
weight di-alkyl amine pamoate, lower molecular weight di-aryl amine
pamoate, lower molecular weight di-alkyl esters of pamoic acid,
lower molecular weight di-aryl esters of pamoic acid, lower
molecular weight di-alkylacyl O-esters of pamoic acid and lower
molecular weight di-arylacyl O-esters of pamoic acid.
515. The drug substance of claim 1 further comprising at least one
additional anti-abuse formulation selected from incorporation of an
antagonist, incorporation of a prodrug; a coating and a matrix.
Description
CROSS-REFERENCE TO COPENDING APPLICATIONS
[0001] The present application is related to co-pending U.S. patent
application Ser. No. 11/595,379 filed Nov. 10, 2006.
BACKGROUND OF THE INVENTION
[0002] The present application is related to pharmaceutically
acceptable salts of alkaloids or amine containing compounds,
particularly those exhibiting physiological and/or psychological
activity in humans and simultaneously designed for targeted release
in a controlled pH range so as to eliminate or reduce the
compound's physiological or psychological response when used in, or
for, medically non-sanctioned, and/or illegitimate purposes. The
invention embodies a platform technology for incorporating a
targeted release mechanism within an organic-acid addition salt of
amine-containing pharmaceutically active compounds. More
specifically, many final dose drug products are formulated with
active pharmaceutical ingredients (drug substances) that provide
pain relief, mood alteration or modification, sense of euphoria,
analgesia, sedation, or in addition, affect a psychotropic
response. These drug products most often have the highest
probability of abuse. As discussed herein, abuse means human use of
physiologically or psychologically active compounds for purposes
than otherwise intended or legally prescribed. As an example, the
drug product Oxycontin.RTM. contains the drug substance oxycodone
hydrochloride. The U.S. Drug Enforcement Agency (DEA) recognizes
Oxycontin.RTM. as being implicated in a huge number of drug abuse
cases resulting in a substantial societal impact. Beyond the human
suffering emanating from drug abuse, the financial costs to society
are a well-known burden shared by all citizens. The method of
abuse, once the drug product is obtained (usually by illegal
means), is to remove any coating on the tablet (often by lemon
juice or saliva) followed by grinding the remaining portion into a
powder. The powder is then inhaled into the nasal passageway (i.e.
sniffed or "snorted") to impart the "high" to the abuser.
Alternatively, the powder can be extracted or melted and the drug
abuse performed by intravenous injection. Additional routes of
administration for abusive purposes include the muscosal surfaces
(ocular, nasal, pulmonary, buccal, sublinqual, gingival, rectal and
vaginal mucosa).
[0003] Of significant seriousness with detrimental consequences to
society is the illicit production of methamphetamine ("meth").
Frequently, laboratories illegally producing meth are ill-equipped
for the required synthetic transformations and as a consequence,
introduce significant health risks to the laboratory operators.
Serious conflagrations and fires have resulted from poorly operated
laboratories and these incidents resulted in burn victims which in
turn are overwhelming the resources of citizen-funded burn centers.
Further, law enforcement is often exposed to hazardous chemical
situations and local environmental damage occurs because of the
lack of containment of toxic and/or hazardous chemicals. Key raw
materials used to produce "meth" include ephedrine and
pseudoephedrine which are most often found as the active ingredient
in legitimate, useful cough and cold, and allergy medicines.
Pseudoephedrine or ephedrine is easily extracted from these
medicines by preferentially dissolving the active ingredient
pseudoephedrine hydrochloride or ephedrine hydrochloride into, for
example, isopropyl ("rubbing") alcohol followed by isolation and
recovery by evaporation of the solvent. These beneficial products
are now receiving more scrutiny and market restriction because of
their illicit use to manufacture methamphetamine, "meth".
[0004] In a report dated July 2005 from the National Center on
Addiction and Substance Abuse (CASA) at Columbia University and
entitled "Under the Counter: The Diversion and Abuse of Controlled
Prescription Drugs in the US", a recommendation was extolled for
the FDA to require controlled drug manufacturers to take measures,
where possible, to minimize the abuse potential of the drugs they
manufacture. The suggested route for accomplishing this task was to
formulate or reformulate the drug products to retain the desired
therapeutic effect while preventing abuse. Also contained within
the report are the disturbing data representing severe societal
repercussions that in the period 1992 to 2003, drug abuse cases
increased seven times faster than the increase in the US
population.
[0005] Prior to the CASA report, the pharmaceutical industry
recognized the severity of the drug abuse problem and innovative
techniques to mitigate or control non-medical uses of drug
substances and products have been published. Essentially, three
mechanisms have been reported which minimize the potential for drug
abuse: 1) encase within the drug product's formulation an
antagonist to the drug substance, 2) chemically modify the drug
substance to yield a prodrug, and 3) employ formulation techniques
to yield products resistant to drug abuse.
[0006] The combination product wherein the drug substance prone to
abuse is simultaneously delivered with an antagonist which is
activated only under special circumstances typically employed by
abusers (crushing, chewing, or dissolving) has received significant
attention. Successful clinical trials were announced by the company
Alpharma and reported in FDAnews Drug Pipeline Alert.TM. (Volume 4,
No. 193, Oct. 3, 2006). The capsule formulation consists of an
extended-release opioid with a sequestered core of naltrexone, an
opioid antagonist. The sequestering subunit enabling this
technology is described by Boehm in United States Patent
Application Publication US 2004/01341552 A1, and is totally
incorporated herein by reference.
[0007] Similarly, Elite Pharmaceuticals is reportedly initiating a
Phase II clinical trial of its abuse resistant pain drug also
employing the antagonist naltrexone hydrochloride. The report found
in FDAnews Drug Pipeline Alert.TM. (Volume 4, No. 179, Sep. 13,
2006) states the previous Phase 1 trial confirmed the technical
approach such that when the drug product was taken as intended, no
antagonist was measured in the blood stream. However, if the drug
product was crushed, the antagonist was released into the blood
stream and the euphoria normally experience by oxycodone
hydrochloride abusers was reduced.
[0008] Alternatives to the preceding agonist/antagonist approach
include the preparation of prodrugs that exhibit their therapeutic
value only when used for their intended purpose. Buchwald, et al.
in United States Patent Application Publication (US 2004/0058946
A1), the disclosure of which is totally incorporated herein by
reference, identifies modified oxycodone derivatives (prodrug) such
that its physiological activity is only observed after the prodrug
is converted to the drug in the mammalian gastrointestinal tract.
Mickle, et al. in United States Patent Application Publication (US
2005/0266070 A1), the disclosure of which is totally incorporated
herein by reference, identifies hydrocodone conjugates that release
the drug substance following oral administration yet are resistant
to intravenous or intranasal abuse.
[0009] Similarly, U.S. Pat. No. 7,105,486 B2 (Mickle et al.) the
disclosure of which is totally incorporated herein by reference,
describes the covalent attachment of L-lysine to the drug
substance, amphetamine, to provide compounds and compositions
exhibiting abuse-resistant properties and useful for the treatment
of disorders including attention deficit hyperactivity disorder
(ADHD), attention deficit disorder (ADD), narcolepsy and
obesity.
[0010] In regard to formulation techniques, Vaghefi, et al. in
United States Patent Application Publication (US 2006/0104909 A1),
the disclosure of which is totally incorporated herein by
reference, describes the creation of a matrix of discrete particles
within which an active ingredient susceptible to abuse is
distributed. The particles are coated with a water insoluble
coating material creating the matrix from which the active
ingredient is difficult to separate. The methodology provides a
controlled release pharmaceutical composition having a reduced
potential for abuse.
[0011] Another formulation technique is described in Unites States
Patent Application Publication US 2006/0051298 A1, (Groenewoud),
the disclosure of which is totally incorporated herein by
reference. The abuse resistant pharmaceutical dosage consists of an
active ingredient and at least one gel forming granule, and said
granule possesses an outer brittle coating. Should the outer
coating be crushed (for the purpose of abusing the drug), the
subsequent exposure to an aqueous media creates a gel and inhibits
extraction of the active ingredient.
[0012] Yet another formulation technique, but from the perspective
of utilizing an agonist, is described in U.S. Pat. No. 4,622,244
(Lapka et al.), the disclosure of which is totally incorporated
herein by reference. In Lapka et al. the inventors recommend the
exposure of the drug substance, naltrexone pamoate, and a
bioabsorbable polymer material to humidity before a
microencapsulation process occurs. The equilibration in a humid
environment of a hydrophobic drug and other materials impacts
important effects on the nature of the microcapsule thus
formed.
[0013] Similarly, in U.S. Pat. No. 6,203,813 B1 (Gooberman), the
disclosure of which is totally incorporated herein by reference,
the authors make reference to the controlled release of an opiate
antagonist implant of naltrexone pamoate in a linear poly(ortho)
ester.
[0014] The three mechanistic approaches presented above
(antagonist, prodrug and formulation) attempt to address abuse
potential by impacting the route of administration, or to
differentiate the physiological environment in which the drug
fulfills its intended purpose versus the drug's misuse. The release
of the antagonist by illicit mechanical or physical manipulations
effectively "neutralizes" the attempted abuse by the perpetrator.
Alternatively, addiction could be treated by the implant of a
slow-release of an antagonist as in Gooberman. A fundamental
disadvantage to this combination drug/anti-drug technology is the
presence of two drug substances in a product formulation for which
an equivalent pharmacokinetic profile must fit potential users (or
abusers) of the drug. There is also the added cost of the
additional antagonist. As a technology, the antagonist approach
does not offer a platform methodology to the many controlled
substances having medicinal benefit. While the opioids as a class
may have readily available antagonists (e.g naltrexone and
naloxone), other controlled substances may not have effective
antagonists. From a marketing and patient perspective, many
perceived problems may arise particularly if the reliability or the
intended effect of the drug is questioned.
[0015] In regard to the prodrug approach (for which not all abused
drugs are susceptible to this approach), elegant chemistry is
employed as an anti-abuse technology. In this case, release of the
drug substance is controlled by physiological, enzymatic cleavage
of the covalently bound protecting group attached to the drug
substance. Theoretically, the drug is only released when the
prodrug is in the intended environment for its absorption.
Unfortunately, drug abusers and those illicitly supplying drugs for
abuse understand free-basing techniques which are directly
applicable to liberating a drug from its prodrug analog. Further
the physiological aspects of the prodrug may alter the drug's
anticipated pharmacokinetic profile and sufficient concentrations
may not be available in certain patient populations to achieve the
legitimate therapeutic effect.
[0016] The third mechanism employed for providing abuse-resistant
drug products is through formulation techniques. Sophisticated
manufacturing techniques are employed to produce products whose
anti-abuse mechanism relies on forming a matrix from which the drug
substance cannot easily be extracted. As with all formulated
products, content uniformity becomes a dominating factor at the
commercial scale. In the formulation process during commercial
scale product manufacture, the assurance that each individual dose
is identical is of critical importance. The matrix technology has
inherent limitations for achieving content uniformity from a
chemical assay perspective. In addition, the anti-abuse property
must be maintained for every single dosage presentation and
performance (anti-abuse) uniformity is likely challenged. Here too,
encasing the drug in a matrix inherently alters the drug's
pharmacokinetic profile and sufficient concentration may not be
obtainable to achieve the desired therapeutic effect.
[0017] Historically, the preparation of mineral acid salts of basic
drugs has been the preferred choice for imparting immediate release
characteristics to drug substances. A drug substance's dissolution
profile can influence its absorption characteristics, and in the
case of a drug with a potential for abuse by snorting into the
nasal cavity, rapid dissolution in nasal fluid would be required.
Other factors influencing the absorption of the drug include the
physiological pH encountered, the drug substance's morphology, the
particle size and the particle size distribution. Typically, the
nasal cavity pH is about 4.5 which provides for the rapid
dissolution and absorption of highly soluble, mineral acid salts of
drug substances.
[0018] U.S. Pat. No. 5,232,919 (Scheffler, et al.), the disclosure
of which is totally incorporated herein by reference, discloses
azelastine embonate and pharmaceutical formulations/compositions
which contain it; the embonate salt to eliminate the bitter taste
of azelastine alone. The term embonate is a synonym for
pamoate.
[0019] French Patent 1,461,407 (Saias, et al.), the disclosure of
which is totally incorporated herein by reference, discloses a
process for the preparation of amine pamoates where the amine
component includes piperazine, promethazine, papaverine,
pholocodine, codeine, noracotine and chlorpheniramine.
[0020] The United Kingdom Patent Specification No. 295,656,
(Carpmaels & Ransford, agents for applicants) the disclosure of
which is totally incorporated herein by reference, discloses a
process for the manufacture of difficulty soluble salts of organic
bases and alkaloids. The disclosure further indicates the process
for manufacture provides sparingly soluble and tasteless salts of
organic nitrogenous basic compounds including alkaloids.
[0021] U.S. Pat. No. 3,502,661 (Kasubick, et al.), the disclosure
of which is totally incorporated herein by reference, discloses a
process for the preparation of variously substituted pyridinium and
imidazolines along with their acid addition salts. Some examples
indicate pamoate salts were prepared for select organic bases.
[0022] U.S. Pat. No. 2,925,417 (Elslager, et al.), the disclosure
of which is totally incorporated herein by reference, discloses
quinolinium salts of pamoic acid and a process for their
manufacture.
[0023] U.S. Pat. No. 5,776,885 (Orsolini, et al.), the disclosure
of which is totally incorporated herein by reference, discloses a
pharmaceutical composition for the sustained and controlled release
of water insoluble polypeptides whereby the therapeutically active
peptide is in the form of its pamoate, tannate or stearate
salt.
[0024] U.S. Pat. No. 5,445,832 (Orsolini, et al.), the disclosure
of which is totally incorporated herein by reference, discloses a
process for the preparation of microspheres made of a biodegradable
polymeric material whereby a water soluble peptide or peptide salt
is converted into a corresponding water-insoluble peptide salt
selected from pamoates, stearates or palmitates of the said
peptide.
[0025] U.S. Pat. No. 5,439,688 (Orsolini, et al.), the disclosure
of which is totally incorporated herein by reference, discloses a
process for preparing a pharmaceutical composition in the form of
microparticles designed for the controlled release of a drug that
includes a biodegradable polymer and where the active ingredient
can be selected from a group of possible salts, one being a
pamoate.
[0026] U.S. Pat. No. 5,271,946 (Hettche) the disclosure of which is
totally incorporated herein by reference, discloses a controlled
release azelastine containing pharmaceutical composition whereby
azelastine is incorporated into the formulation as its pamoate or
other pharmaceutically active salt.
[0027] U.S. Pat. No. 5,225,205 (Orsolini, et al.), the disclosure
of which is totally incorporated herein by reference, discloses a
pharmaceutical composition in the form of micropoarticles; the
formulation consisting of a peptide as its pamoate, tannate,
stearate or palmitate salt; the formulation to provide a controlled
release, pharmaceutical composition for the prolonged release of a
medicamentous substance.
[0028] In spite of the long history of research directed at
prohibiting the illicit use of pharmaceutical compounds the problem
remains. There has yet to be a suitable solution which is widely
applicable, easily implemented and applicable to a wide range of
active pharmaceutical ingredients. The present invention provides a
platform technology to address this long standing problem.
SUMMARY OF THE INVENTION
[0029] It is an object of the present invention to provide a method
for supplying a pharmaceutical formulation which is bio-available
by an oral administration route but is bio-unavailable when illicit
or abuse-intended routes of administration are attempted.
[0030] It is another object of the present invention to provide a
method for supplying a pharmaceutical formulation which prohibits
or impedes de-formulation to a degree sufficient to alter the
manner in which the active pharmaceutical ingredient can be
absorbed physiologically beyond its intended, legal, absorption
route.
[0031] It is another object of the present invention to provide a
pharmaceutical composition possessing anti-abuse characteristics
attributable to targeted release properties.
[0032] It is another object of the present invention to provide
drug substances and drug products having orthogonal dual property
combinations wherein a binary differentiation is observed between
the intended, or legal, and the abusive, illegal/illilcit, use of
the drug substance or product. The patient receives the intended
dosage when used properly, but the desired effect is not obtained
if not used properly.
[0033] It is another object of the present invention to provide a
method for supplying a pharmaceutical formulation where the active
pharmaceutical ingredient is resistant to direct extraction
techniques either into an aqueous solution or into an organic
solvent.
[0034] It is another object of the present invention to inhibit
and/or prevent de-formulation of a drug product by increasing the
technical difficulty of isolating the active pharmaceutical
ingredient from its carrier matrix such as excipients, binders and
the like. This feature of the invention further decreases the
economic viability of isolating the API for illicit purposes.
[0035] It is another object of the present invention to provide
drug products employing the pharmaceutical salt methodology
described herein whereby the potential for abuse of either the drug
substance and/or the drug product is eliminated or greatly reduced
when abuse is attempted via the mucosal surfaces or by injection or
by illicit de-formulation to allow use via the muscosal surfaces or
by injection.
[0036] These and other advantages, as will be realized are provided
in a drug substance with a pharmaceutically acceptable organic acid
addition salt of an amine containing pharmaceutically active
compound useful for the treatment of a therapeutic ailment
administration and exhibiting prophylactic properties when employed
in non-therapeutic administration.
[0037] Yet another embodiment is provided in a drug substance as a
pharmaceutically acceptable organic acid addition salt of an amine
containing pharmaceutically active compound exhibiting at least two
dissolution profiles one of which provides for drug efficacy when
administered in a formulated oral dosage and one which does not
provide drug efficacy when administered as a non-oral dosage.
[0038] Yet another embodiment is provided in a drug substance with
an organic acid addition salt of an amine containing
pharmaceutically active compound used to treat a combination of two
or more therapeutic ailments, at least one of which is drug
abuse.
[0039] Yet another embodiment is provided in the prescribing of a
drug product containing at least one drug substance as an organic
acid addition salt of an amine containing API to a patient by a
defined method of administration wherein the drug substance is a
prophylactic in a different method of administration.
[0040] Yet another embodiment is provided in the prescribing of a
drug product containing at least one drug substance comprising an
organic acid addition salt of an amine containing active
pharmaceutical ingredient to a patient for the purpose of treating
an ailment by a specific administration mechanism wherein the drug
product is rendered ineffective by a different administration
mechanism.
[0041] Yet another embodiment is provided in prescribing a drug
product containing at least one drug substance as an organic acid
addition salt of an amine containing Drug Enforcement
Administration controlled substance to a patient for the purpose of
treating a legitimate ailment of the patient wherein the patient
has a history of drug abuse meaning they have been clinically
diagnosed as having drug abuse propensity.
[0042] Yet another embodiment is provided in prescribing a drug
product containing at least one drug substance as an organic acid
addition salt of an amine containing DEA controlled substance to a
patient for the purpose of treating a legitimate ailment while
simultaneously interrupting the potential for mental and physical
addiction through the patient inadvertently or deliberately using
the drug substance for other than the intended purpose.
[0043] Yet another embodiment is provided in a process for
preparing organic acid addition salts of amine containing
pharmaceutically active compounds comprising the steps of:
[0044] dissolving of an amine containing pharmaceutically active
compound in a suitable solvent;
[0045] preparing a solution of an organic acid of Structure A
##STR00001##
wherein R.sup.1-R.sup.4 are independently selected from H, alkyl of
1-6 carbons, adjacent groups may be taken together to form a cyclic
alkyl or cyclic aryl moiety;
[0046] R.sup.5 is selected from H, or an alkali earth cation;
[0047] R.sup.6 is 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,
[0048] combining the solutions of amine containing pharmaceutically
active compound, and the organic acid to form the reaction mixture
wherein said organic acid has at least one mole of organic acid per
mole of amine containing pharmaceutically active compound;
[0049] allowing said reaction mixture to react;
[0050] isolating said organic acid salt of amine containing
pharmaceutically active compound by filtration, centrifugation or
concentration, and
[0051] drying the isolated or purified material to remove reaction
solvent.
[0052] Yet another embodiment is provided in a process for
preparing the organic acid addition salts of amine-containing
pharmaceutically active compound exhibiting targeted release
properties comprising the steps of: combining a pH adjusted
solution of said amine-containing pharmaceutically active compound
with an organic acid having at least one aromatic ring and
possessing carboxyl and hydroxyl functionality in an ortho
relationship or their synthetic equivalent to form a reaction
solution; cooling and precipitating solids from said reaction
solution; collecting said precipitated solid; and drying said
solids.
[0053] Yet another embodiment is provided in a process for
preparing a pharmaceutically acceptable drug product exhibiting
drug abuse prevention properties comprising the steps of:
[0054] selecting an organic acid addition salt of an amine
containing active pharmaceutical ingredient,
[0055] combining the organic acid salt with excipients and
processing aids to yield a mixture;
[0056] mixing the combined ingredients to provide blend
uniformity;
[0057] sieving, screening or milling the mixture to obtain a
uniform consistency; and
[0058] adding ingredients to the mixture for desired proportions of
each ingredient to yield a final formulated mix.
[0059] Yet another embodiment is provided in an organic acid
addition salt of amine-containing pharmaceutically active compounds
wherein the organic acid comprises a compound of Formula A:
##STR00002##
wherein R.sup.1-R.sup.4 are independently selected from H, alkyl of
1-6 carbons, adjacent groups may be taken together to form a cyclic
alkyl or cyclic aryl moiety;
[0060] R.sup.5 is selected from H, or an alkali earth cation;
[0061] R.sup.6 is 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.
[0062] Yet another embodiment is provided in organic acid addition
salts of amine-containing pharmaceutically active compounds
selected for their targeted release characteristic in the gastro
intestinal tract and bio-unavailability in mucosal membranes, and
formulated into a drug product wherein the amine-containing
pharmaceutically active compounds can not be directly isolated.
[0063] Yet another embodiment is provided in a tamper resistant
oral dosage drug product comprising an organic acid salt of an
amine-containing pharmaceutically active compound formulated
wherein said organic acid and said amine-containing
pharmaceutically active compound can not be directly isolated.
[0064] Yet another embodiment is provided in a method of
administering an amine-containing pharmaceutically active compound
formulation comprising:
[0065] preparing an organic acid salt of said compound;
[0066] preparing an oral dose formulation comprising said organic
acid salt;
[0067] wherein upon oral digestion said compound forms a
bio-available amine-containing pharmaceutically active compound;
and
[0068] wherein upon use for administration via a mucosal membrane
said amine-containing pharmaceutically active compound is
ineffective.
[0069] Yet another embodiment is provided in a pharmaceutically
active compound comprising the organic acid addition salt of an
amine-containing pharmaceutically active material wherein the
compound is essentially bio-unavailable when exposed to mucosal
membranes and exhibits recovery from aqueous solution at pH 4.5 of
at least 85 weight percent.
[0070] Yet another embodiment is provided in a pharmaceutically
active compound comprising the organic acid addition salt of an
amine-containing pharmaceutically active material wherein the
compound is essentially bio-unavailable when exposed to human
mucosal membranes and exhibits recovery from aqueous solution at pH
7.0 of at least 85 weight percent.
[0071] Yet another embodiment is provided in a pharmaceutically
active compound comprising an organic acid addition salt of an
amine-containing pharmaceutically active material wherein the
compound is essentially bio-unavailable when exposed to mucosal
membranes unless processed by the steps of:
[0072] dissolution in an aqueous solution of pH greater than 8;
[0073] extraction of the active pharmaceutical ingredient into a
water immiscible solvent; separation of the aqueous layer from the
solvent;
[0074] washing of the solvent layer with an aqueous solution of pH
greater than 8; and
[0075] drying the solvent layer to remove traces of water.
[0076] Yet another embodiment is provided in a pharmaceutically
active compound comprising an organic acid addition salt of an
amine-containing pharmaceutically active material wherein the
compound is essentially bio-unavailable when exposed to mucosal
membranes unless processed by the steps of:
[0077] dissolution in an aqueous solution of pH greater than about
1;
[0078] filtration of the precipitated organic acid;
[0079] adjustment of the filtrate to a pH of about 8;
[0080] addition of a water immiscible solvent in which the
pharmaceutically active compound is soluble;
[0081] separation of the aqueous layer from the solvent;
[0082] washing of the solvent layer with an aqueous solution of pH
greater than 8; and
[0083] drying the solvent layer to remove traces of water.
[0084] Yet another embodiment is provided in the use of a drug
product containing at least one drug substance as an organic acid
addition salt of an amine containing DEA controlled substance
wherein oral administration of the drug substance provides an
efficacious dosage and non-oral administration does not provide an
efficacious dosage.
BRIEF DESCRIPTION OF DRAWINGS
[0085] FIG. 1 is an DSC thermogram of phentermine pamoate.
[0086] FIG. 2 is an DSC thermogram of ephedrine pamoate.
[0087] FIG. 3 is an DSC thermogram of pseudoephedrine pamoate.
[0088] FIG. 4 is an FTIR spectrum phentermine pamoate.
[0089] FIG. 5 is an FTIR spectrum of ephedrine pamoate.
[0090] FIG. 6 is an FTIR spectrum of pseudoephedrine pamoate.
[0091] FIG. 7 is an PXRD diffractogram of phentermine pamoate.
[0092] FIG. 8 is an PXRD diffractogram of ephedrine pamoate.
[0093] FIG. 9 is an PXRD diffractogram of pseudoephedrine
pamaote.
[0094] FIG. 10 is an DSC thermogram of benzphetamine pamoate.
[0095] FIG. 11 is an FTIR spectrum benzphetamine pamoate.
[0096] FIG. 12 is an PXRD diffractogram of benzphetamine
pamoate.
[0097] FIG. 13 is an DSC thermogram of imipramine xinafoate.
[0098] FIG. 14 is an FTIR spectrum of imipramine xinafoate.
[0099] FIG. 15 is an .sup.1H NMR spectrum of imipramine
xinafoate.
[0100] FIG. 16 is an DSC thermogram of imipramine salicylate.
[0101] FIG. 17 is an FTIR spectrum of imipramine salicylate.
[0102] FIG. 18 is an .sup.1H NMR spectrum of imipramine
salicylate.
[0103] FIG. 19 is a graphical presentation of the dissolution
profile comparison of imipramine pamoate vs. imipramine
hydrochloride under simulated gastric conditions.
[0104] FIG. 20 is a graphical presentation of the dissolution
profile comparison of imipramine xinafoate vs. imipramine
hydrochloride under simulated gastric conditions.
[0105] FIG. 21 is a graphical presentation of the dissolution
profile comparison of imipramine salicylate vs. imipramine
hydrochloride under simulated gastric conditions.
[0106] FIG. 22 is a graphical presentation of the dissolution
profile comparison of ephedrine pamoate vs. ephedrine hydrochloride
under simulated gastric conditions.
[0107] FIG. 23 is a graphical presentation of the dissolution
profile comparison of pseudoephedrine pamoate vs pseudoephedrine
hydrochloride under simulated gastric conditions.
[0108] FIG. 24 is a graphical presentation of the dissolution
profile comparison of benzphetamine pamoate vs. benzphetamine
hydrochloride under simulated gastric conditions.
[0109] FIG. 25 is a graphical presentation of the dissolution
profile comparison of phentermine pamoate vs. phentermine
hydrochloride under simulated gastric conditions.
[0110] FIG. 26 is a graphical presentation of the release profile
of imipramine hydrochloride vs. imipramine pamoate under gastric
conditions compared to release under mucosal conditions.
[0111] FIG. 27 is a graphical presentation of the release profile
of imipramine hydrochloride vs. imipramine xinafoate under gastric
conditions compared to release under mucosal conditions.
[0112] FIG. 28 is a graphical presentation of the release profile
of imipramine hydrochloride vs. imipramine salicylate under gastric
conditions compared to release under mucosal conditions.
[0113] FIG. 29 is a graphical presentation of the release profile
of ephedrine hydrochloride vs. ephedrine pamoate under gastric
conditions compared to release under mucosal conditions.
[0114] FIG. 30 is a graphical presentation of the release profile
of pseudoephedrine hydrochloride vs. pseudoephedrine pamoate under
gastric conditions compared to release under mucosal
conditions.
[0115] FIG. 31 is a graphical presentation of the release profile
of benzphetamine hydrochloride vs. benzphetamine pamoate under
gastric conditions compared to release under mucosal
conditions.
[0116] FIG. 32 is a graphical presentation of the release profile
of phentermine hydrochloride vs. phentermine pamoate under gastric
conditions compared to release under mucosal conditions.
DETAILED DESCRIPTION
[0117] The invention disclosed herein provides an entirely new
mechanism for providing abuse resistant drug substances and drug
products whereby the method of inhalation, smoking, intravenous
injection, and mucosal surface abuse is eliminated or reduced by
forming an organic acid addition salt of the active ingredient
having release properties incompatible with the normal
administration routes for drug abuse and employing a targeted
release mechanism. This platform technology is widely applicable to
amine containing alkaloid drug substances including but not limited
to those drug substances categorized by the DEA as Controlled
Substances. To elaborate on the invention's mode of action, but
without relying on any particular theory or principle, drugs that
are abused require that the active ingredient be bio-available in
the mucosal membranes and particularly the ocular, nasal,
pulmonary, buccal, sublinqual, gingival, rectal or vaginal mucosa.
In effect, a drug must first be released and have sufficient
permeability in its biological environment for it to be
bio-available. Therefore, by altering the dissolution profile to
restrict, limit, reduce or eliminate release of the drug substance
at physiological pH the potential for abuse is decreased. Simply
stated, the drug cannot be abused without involved and technically
sophisticated chemical transformations and isolation prior to the
behavioral act of drug abuse. Simultaneously, the invention as
described serves valuable and beneficial purposes in society by
preventing drug abuse yet the invention retains the medicinal
properties of the drug product when used for the intended purpose.
The following discussion illustrates the design features for
producing commercial drug substances and products. The benefits of
the present invention are those described above and can be
practiced while retaining the complex requirements reviewed
below.
[0118] Independent of the route of administration, it is axiomatic
that a drug substance must be bio-available in its intended
physiological environment in order for it to elicit the desired
pharmaceutical effect. Indeed, the number of pharmaceutical
products based on insoluble amine salts is very limited and not
surprisingly, the pharmaceutical literature describing the
absorption benefits of otherwise insoluble amine salts is
essentially non-existent. Basically, the literature teaches that
higher solubility in general implies better bio-availability. While
entirely speculative, the use of insoluble salts was probably
avoided because practitioners of the art incorrectly correlated
poor API aqueous solubility with poor bio-availability. Indeed, the
commercial success of mineral acid salts of amine-containing APIs
suggests a negative teaching away from insoluble salts. An
unexpected observation and correct correlation pertaining to the
current invention is that selective, or engineered API aqueous
release properties inhibits illicit use, or drug abuse, of the API
and its associated products while retaining the bio-availability
when employed for its intended purpose. And indeed, these features
can be provided by employing a host of organic acids.
[0119] The actual basis for the invention is more complex than an
insolubility feature of an API pamoate salt (or associated family
of organic acid salts). As mentioned in the introduction and as
will be shown in the experimental section and associated figures,
the dissolution behavior of these organic acid salts of
amine-containing APIs provide the unanticipated observation that
these compounds can be employed in targeted release applications,
and in particular to address drug abuse. As performed according to
test procedures recognized by the United States Food and Drug
Administration and documented within the United States Pharmacopeia
(USP), dissolution properties are established as a function of
time, temperature, concentration and pH. In particular, one test
established the saturation solubility of the drug substance and is
performed over a pH range to correlate with the physiological pH
ranges the drug may encounter during use. For instance, the test
employs a pH of about 1 to represent simulated gastric fluid. At
the other end of the range, a pH of about 7.4 is employed to
represent blood pH. Intermediate pH's are also tested to evaluate
the drug's dissolution properties over the entire range.
[0120] The present invention is applicable to a variety of drug
delivery presentations including solid oral dose, parenteral dosage
forms (depo-type products) and by devices and formulations suitable
for transdermal delivery and nasal/inhalation administration. It is
responsibly acknowledged that many factors may influence the
overall pharmacokinetic profile of a drug product, for instance,
the particle size distribution of the drug substance may markedly
influence drug substance bioavailability. Hence, the optimum
practice of this invention when employed for a specific drug
product must account for the multitude of additional factors. The
benefit of the current invention is a means to provide a dominating
or controlling factor to prevent abuse while achieving efficacious
and therapeutic patient dosages to which refinements, adjustments
or modifications can be asserted to yield an optimal response.
[0121] The three alternate mechanistic approaches presented
earlier, (antagonist, prodrug and formulation, attempt to address
abuse potential by impacting the route of administration, or to
differentiate the physiological environment in which the drug
fulfills its intended purpose versus the drug's misuse. Each of
these routes was shown to possess inherent limitations for
mitigating drug abuse. For the purposes of additional clarity and
completeness, the mineral acid salts, which are typically abused,
do not exhibit a suitable means to prevent abuse. The dissolution
properties of the mineral acid salts of the physiologically active
and/or controlled substance amines consistently exhibit high
dissolution rates and substantial achievable release rates
(85-100%) over the entire physiological pH range.
[0122] In contrast, it is relevant to the present invention to note
the importance of pH in controlling the release of a drug substance
from its product formulation to achieve absorption and
consequently, the medicinal effect. The pH of the gastrointestinal
tract essentially remains highly acidic with the exception of the
lower colon which reaches pH 8; vaginal pH is typically around 5.8
and the nasal cavity is approximately pH 4.5. More generally, each
of the mucosal surfaces, particularly ocular, nasal, pulmonary,
buccal, sublingual, gingival, rectal and vaginal are receptive to
drug absorption if release can occur. A dominating feature of the
present invention is the severely retarded release of the
controlled substance, particularly amine-containing pamoate salt
(or related salt family) in the pH range of about 4 to 9 which
encompasses the physiological pH of the mucosa. These release
properties were an unexpected finding recognized and observed after
performing dissolution tests over a wide pH range on several
unrelated compounds. The release properties and saturation
solubility profiles are a means to evaluate a reasonable dosage
application to the mucosa. The non-release of the drug in the 4 to
9 pH range negates absorption and prevents the physical act of
abuse. For the amine-containing hydrochloride salts, an abuse
mechanism remains operative since these salts do not exhibit the
discriminating "on/off" switch of the present invention.
[0123] An experimental refinement of the dissolution tests was
performed on several compounds to better represent the
physiological conditions encountered during abuse attempts and to
account for the saturation solubility factor. Further, control
experiments were included in the experimental design to compare the
organic acid addition salts of the current invention with the
hydrochloride salts of identical amine-containing controlled
substances. In some cases, model compounds were used to demonstrate
the principles of the invention instead of using compounds legally
designated as controlled substances. Side-by-side dissolution
experiments on hydrochloride salts versus those of the present
invention were conducted at three different pH conditions: a) a pH
of about 1 to simulate gastric conditions, b) pH of about 4.5 to
simulate mucosal surface pH, and c) a pH of about 7 to evaluate a
potential pH range of mucosal surfaces and blood pH for purposes of
simulating injection. In addition, the experimentation was designed
to demonstrate the equivalence of the organic acid addition salts
to the mineral acid salts if used by their intended route of oral
administration route and hence the concentration effects were
included in the study. For oral administration of a dosage form,
the United States Pharmacopeia (USP) recommends the immediate
release testing procedure on a unit dosage to be performed on a
simulated stomach "solution" volume of 900 mL. For the mucosal
membranes, the available mucous fluid may be better approximated at
10 mL. Hence, dissolution tests were conducted at different
concentrations at the different pH levels. Besides temperature, pH
and concentration, the time factor was also evaluated under the
presumption that an individual abusing a drug will want to obtain
their anticipated physiological response within an hour.
[0124] It was observed that the organic acid addition salts under
simulated mucosal conditions were not released whereas the
hydrochloride salts released rapidly (refer to FIGS. 26-32).
Therefore, recovery studies from the simulated mucosal environments
were more appropriate for demonstrating the inability of the
organic acid salt to release the active ingredient and thereby
prevent a physiological response. Therefore, the abuse mechanism
was inoperative. For simulated gastric ingestion, the organic acid
addition salts exhibited a release property during dissolution
testing essentially equivalent to the hydrochloride salts'
dissolution properties in that both presentations were essentially
immediately available (refer to FIGS. 16 through 25). To summarize
the trends, the organic acid addition salts were highly available
for absorption at gastric pH. Secondly, the organic acid addition
salts exhibit a low release rate under mucosal conditions. And
lastly, the organic acid addition salts exhibit a low level of
release under the mucosal conditions (see FIGS. 26-32). These
definitive examples support the present invention's duality of
providing an abuse controlling mechanism and yet retaining the
desired medicinal benefit of the drug substance when used in the
intended manner.
[0125] For confirming tests and to demonstrate general
applicability of the targeted release properties of the
amine-containing organic acid addition salts, a model compound was
selected to challenge the hypothesis. Imipramine was chosen as a
representative amine-containing compound for study comparison of
its hydrochloride and organic acid addition salts, namely pamoate,
xinafoate and salicylate salts. The selection of imipramine was
based on practical considerations since working with controlled
substances has legal and moral responsibilities and imipramine
fulfilled the structural features associated with many
amine-containing controlled substances. These structural features
often include: at least one nitrogen; at least one aromatic ring;
ideally the multi-ring/fused ring/heterocyclic sub-structures
observed in many controlled substances; lipophilicity as the free
base; the salts exhibit sufficient stability for the duration of
the test regimens so as to minimize interference and potentially
incorrect conclusions attributed to degradation products or
impurities and the various salts employed in the tests could be
readily synthesized and characterized. Clearly, the controlled
substance designation to an amine-containing compound having
physiological activity is a legal assignment/assessment and has
little to no relevance to chemical structure or physical behavior.
Hence, the scope of the invention is well supported by the
selection of controlled and non-controlled substances exhibiting
structural variation to evaluate the novel and unexpected
observations disclosed herein.
[0126] Also disclosed herein are processes for the preparation of
drug substances and DEA controlled drug substances (APIs) using
organic acid addition salts of the active pharmaceutical ingredient
(API) which are optionally formulated with other non-therapeutic
materials to aid in delivery, stability, efficacy, targeted release
and to engineer a pharmacokinetic profile of the organic acid
addition salts as compared to other salt forms, including inorganic
(mineral) acid salt forms. The present invention provides for
release of the API for its intended purpose and prevents
availability of the drug substance for typical routes of abuse. The
present invention describes a method for evaluating, and
formulations for, the organic acid addition salts of appropriate
APIs to provide an efficacious and therapeutic dosage to animals
and humans.
[0127] The present invention practically and financially thwarts
efforts to convert drug substances to their corresponding mineral
acid salt(s). This severely restricts, limits, reduces or
eliminates the efforts of purposeful de-formulation of commercially
available drug products into a form suitable for physiological
absorption in a manner different than intended by the original
commercial formulation. The drug substance cannot be easily
modified for alternate routes of administration without numerous,
involved and technically sophisticated chemical transformations and
isolations. Simultaneously, many of these drug products prone to
abuse serve valuable and beneficial purposes in society and the
invention retains the properties of the drug product (and in some
cases enhances them) when used for the intended purpose. The
benefits of the present invention are those described above and can
be practiced while retaining the complex requirements reviewed
below.
[0128] A drug formulation which is selected for the prevention of
drug abuse is specifically a drug which is bio-unavailable or not
isolable if efforts to alter the intended or established route of
administration are undertaken. In a preferred embodiment the drug
formulation is not released under aqueous conditions at a pH of
about 4 to about 9 and generates a solid of an organic acid at pH
below about 4. At pH above about 9, the organic acid (as its
inorganic salt) and the amine containing active pharmaceutical
ingredient (as its free base) are sufficiently soluble as to
prevent separation of the components and thus inhibiting direct
isolation of the API (as its free base) without additional
processing.
[0129] In the present invention a drug product can be prescribed
and administered in a manner wherein proper administration provides
a therapeutic effect and the function of the API is realized. With
a different manner of administration, in other words, a
non-therapeutic administration the API does not enter the
bloodstream in an amount sufficient to be active. To be effective
the API must be bio-available. For the purposes of the present
invention, one method of establishing a compound's bio-availability
is by determining the percentage of weight API recovered from an
aqueous solution at a pH representative of the method of
administration described herein. For the purposes of the present
invention a compound is considered to be effective when at least 85
wt % of the compound is recovered from an aqueous solution at a pH
representative of the method of administration. If, for example, 85
weight percent or more of a drug compound is recovered from a
solution at a pH of 4-9, pH 7 for example, the material is
considered to be bio-unavailable at a mucosal membrane and is
considered non-permeable at the mucosal membrane and the compound
exhibits prophylactic properties. If, for example, less than 85
weight percent of a drug compound is recovered from a solution at a
pH of less than 4, pH 1 for example, the material is considered to
be bio-available under oral administration and is considered
permeable in, for example, the gastrointestinal tract due to the
release of the API at the pH of the gastrointestinal tract.
[0130] A particularly preferred embodiment and method of
administering the amine-containing pharmaceutically active compound
is by oral dose. The oral dose is prepared by first preparing an
organic acid salt of the active compound. The organic salt is then
formulated into a carrier matrix to provide an oral dose drug
product. The carrier matrix is composed of ingredients (excipients)
optionally selected from the group, but not limited to binders,
fillers, flow enhancers, surfactants, disintegrants, buffers, and
the like, typically employed in the art and found in the "Handbook
of Pharmaceutical Excipients", Rowe, Sheskey and Owen (Editors),
Fifth Edition, 2006, Pharmaceutical Press (publishers). When the
oral dose is ingested the organic salt dissociates under
physiological conditions. The organic acid portion of the
amine-containing organic acid addition salt forms the insoluble
(organic) acid while the active compound is liberated and becomes
bio-available. Efforts to directly isolate the active compound from
the oral dose would be thwarted as described herein.
[0131] A common technique for de-formulating drug products,
particularly for illicit use, is to isolate the active ingredient
by organic phase extraction and separation from an aqueous
environment. An example of such illicit activity is extraction of
highly soluble ephedrine hydrochloride or pseudoephedrine
hydrochloride with isopropanol, which is more commonly known as
rubbing alcohol. In an embodiment of the present invention, both
pseudoephedrine pamoate and ephedrine pamoate and their related
family of salts are insoluble in isopropanol and other organic
solvents such as acetone and toluene.
[0132] In an embodiment of the present invention, the controlled
substance is an amine-containing organic salt which does not
release in the pH window of about 4 to about 9. At a pH of less
than about 4, the subject organic salts become protonated with the
concomitant precipitation of organic acid. At pH greater than about
9, the addition salt is soluble yet it is quite difficult to
distinguish between the organic acid component and the active amine
by organic solvent extraction.
[0133] The organic acids of the present invention are those forming
salts with amine-containing active pharmaceutical ingredients which
do not release in an aqueous solution within a pH window of about 4
to about 9 and which interfere with the direct isolation of the API
outside of the central pH window.
[0134] The organic acid is defined by the following Structures A
through G wherein Structure A represents the general family of
Markush compounds embodied within the invention. Structure B
represents the subset of salicylic acid and its derivatives
conceived as a component of this invention. Structures C, D and E
are regio-isomeric variations on Compound A wherein two adjacent
substituents on Compound A form a fused aryl ring (i.e.
R.sup.1+R.sup.2; R.sup.2+R.sup.3; and R.sup.3+R.sup.4). Structures
F and G represent a further sub-category of dimer-like compounds
derived from Structure A. In Structure F, dimerization has occurred
through R.sup.4 of two Structure A compounds with both possessing
fused-aryl ring systems formed via R.sup.2+R.sup.3. In Structure G,
dimerization has again occurred through R.sup.4 of two Structure A
compounds however both Structure A residues possess fused-aryl ring
systems formed via R.sup.1+R.sup.2.
##STR00003##
[0135] Wherein R.sup.1-R.sup.4 are independently selected from H,
alkyl of 1-6 carbons, adjacent groups may be taken together to form
a cyclic alkyl or cyclic aryl moiety; R.sup.5 represents H, alkyl,
alkylacyl or arylacyl; R.sup.6 and R.sup.7 are independently
selected from H, alkyl of 1-6 carbons, aryl of 6-12 carbons,
alkylacyl or arylacyl analogues sufficient to satisfy the valence
of X (e.g. to provide a mixed anhydride or carbamate); X is
selected from nitrogen, oxygen or sulfur, and when X.dbd.O,
R.sup.6+R.sup.7 may represent an alkali earth cation, ammonium or
together form a heterocyclic moiety;
[0136] Particularly preferred organic acids include Structures B
through E.
##STR00004##
wherein R.sup.5, R.sup.6 and R.sup.7 remain as defined above for
Structure A;
##STR00005##
wherein X, R.sup.5, R.sup.6 and R.sup.7 remain as defined above for
Structure A and more preferably X is O;
##STR00006##
wherein X, R.sup.1, R.sup.2, R.sup.5, R.sup.6 and R.sup.7 remain as
defined above for Structure A and more preferably X is O; R.sup.1
and R.sup.2 are hydrogen;
##STR00007##
wherein X, R.sup.1, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 remain as
defined above for Structure A and more preferably X is O, R.sup.1
and R.sup.4 are hydrogen;
##STR00008##
wherein X, R.sup.1, R.sup.5, R.sup.6 and R.sup.7 are independently
defined as above for Structure A and more preferably at least one X
is O and at least one R.sup.1 is hydrogen; and
##STR00009##
wherein X, R.sup.5, R.sup.6 and R.sup.7 are independently defined
as above for Structure A and more preferably X is O and R.sup.5 is
hydrogen.
[0137] Pamoic acid, or a synthetic equivalent of pamoic acid, is
the preferred embodiment. Pamoic acid has a formula corresponding
to Structure F wherein X is O; R.sup.5, R.sup.6and R.sup.7 are
hydrogen.
[0138] A synthetic equivalent of pamoic acid is a material that
provides the structural moiety independent of its particular salt,
ester, or amide form and that upon pH adjustment yields pamoate
functionality suitable for reaction, optionally with one or two
equivalents of an amine-containing active pharmaceutical ingredient
to form a pamoate salt. Examples of synthetic equivalents of pamoic
acid capable of manipulation to produce pamoate salts include but
are not limited to, disodium pamoate, di-ammonium pamoate,
di-potassium pamoate, lower molecular weight di-alkyl and/or
di-aryl amine pamoate, lower molecular weight di-alkyl and/or
di-aryl esters of pamoic acid, and lower molecular weight
di-alkylacyl and/or di-arylacyl O-esters of pamoic acid, i.e. those
alkylacyl and arylacyl esters formed using the hydroxyl moiety of
pamoic acid and not the carboxylic acid functional group. The
descriptor phrase "lower molecular weight" used above means the
indicated moiety has a molecular mass contribution within the
pamoate derivative of less than about 200 amu.
[0139] For clarity, the use of lower molecular weight di-alkyl or
di-aryl amine pamoate allows for the exchange of higher molecular
weight amines, or drug free bases, to be exchanged for the lower
molecular weight amine component during the salt formation
reaction. Similarly, the use of lower molecular weight di-alkylacyl
and/or di-arylacyl pamoates allow for their conversion through
ester hydrolysis to the pamoic/pamoate moiety followed by reaction
with the desired drug free base.
[0140] In a preferred embodiment of the invention, at least one
equivalent of the amine containing drug substance is reacted per
mole of disodium pamoate to yield the drug substance pamoic acid
salt. Preferably, 2:1, 1:1, or mixtures thereof, equivalents of
amine per mole pamoic acid moiety or related organic acids are
prepared. Typically, an aqueous acidic solution of the amine
containing drug substance is combined with a basic solution of
pamoic acid or disodium pamoate. The acid/base reaction ensues and
the insoluble organic acid salt precipitates from the aqueous
solution. Optionally, the salt can be purified, dried and milled to
obtain a drug substance ready for formulation into the desired
delivery format. The drug product formulated with the drug
substances then possesses the targeted delivery characteristics of
the drug substance and the potential for abuse of either the drug
substance and/or drug product is eliminated or greatly reduced when
abuse is attempted via the mucosal surfaces or by injection.
[0141] Another feature of the invention is the preparation of
pamoate salts for legitimate active pharmaceutical ingredients
wherein the active pharmaceutical ingredient is otherwise used as a
synthetic raw material in the illegal or illicit production of
dangerous drugs. More specifically, the invention encompasses the
preparation and composition of pseudoephedrine pamoate and
ephedrine pamoate. The insolubility of these compounds in organic
solvents thwarts attempts to extract pseudoephedrine and/or
ephedrine from drug products. These compounds when subjected to the
illicit activities of methamphetamine production, a first step of
which is to attempt extraction of the pseudoepehdrine pamoate or
ephdedrine pamoate from tablets or capsules usually with an alcohol
solvent, results in an intractable residue of insoluble excipients
and pseudoephedrine pamoate or ephedrine pamoate. Here too, the
pamoate salts are for illustration and a broader family of organic
acid salts (vide supra) may be employed for practicing the
invention.
[0142] For the purposes of the present invention an API of a drug
product is not directly isolable if it can not be isolated by
solubilizing the drug product to form a solubilized drug substance
and filtering the solubilized drug substance without further
chemical processing.
[0143] Another feature of the invention addresses a significant
commercial and long-felt need to return the availability of
traditional over-the-counter (OTC) drug products to the
unrestricted aisles and shelves of drug stores and pharmacies.
Historically, products containing pseudoephedrine and/or ephedrine
were readily available to the general public and served to provide
relief for cold, cough, decongestion, and allergy symptoms.
Commerce has been severely impeded for these products due to
governmental controls placed on their sale and distribution in an
attempt to mitigate diversion for the production of
methamphetamine. When intended for the preparation of
methamphetamine, pseudoephedrine or ephedrine must be obtained in
reasonably pure form prior to the chemical reduction step of
benzylic hydroxyl removal. This chemical reduction step provides a
second active pharmaceutical ingredient, methamphetamine, usually
intended for illicit use or for the behavioral act of drug
abuse.
[0144] Isolation of pseudoephedrine or ephedrine from drug products
formulated with the insoluble organic acid additional salts of the
present invention such as pseudoephedrine pamoate or ephedrine
pamoate require tedious and costly mult-step isolation techniques
comprising the steps of: [0145] a) suspension of the drug product
in an aqueous medium; [0146] b) careful pH adjustment [0147] c)
filtration of the insoluble excipients and the pamoic acid moiety
[0148] d) extraction of the active ingredient into a water
immiscible solvent; [0149] e) washing the water immiscible solvent
containing the active ingredient [0150] f) drying the solvent;
[0151] g) optionally evaporating the solvent to obtain the active
ingredient, or [0152] h) optionally precipitating the active
ingredient by forming its mineral acid salt, followed by, [0153] i)
isolating the active ingredient as its mineral acid salt by
filtration, and [0154] j) drying the mineral acid salt, wherein the
excipients may include starch, talc, lactose or another sugar or
sugar derivatives, magnesium stearate, gelatin, colorants, dyes,
flow enhancers, anti-statics, preservatives, compression aids,
buffers and the like. The presence of these inert ingredients or
formulation additives severely complicates and impedes the
isolation of purified pseudoephedrine or ephedrine employing the
processing steps listed above.
[0155] An "alkaloid" is an amine nitrogen containing natural
product, or synthetically modified or derivatized natural product,
or wholly synthesized analog of a natural product, or an amine
containing compound that exhibits biological activity in animals or
humans. The amine nitrogen can be present as a primary, secondary,
tertiary or quaternary amine moiety and a given compound may
contain more than one type of amine functionality. Examples of
these materials are the US Drug Enforcement Agency's (DEA) Form 225
of Schedule I through V controlled substances, generally divided
between narcotic and non-narcotic materials. There are also other
compounds applicable to the present invention not found on the DEA
list or which may be added to it in the future. Further, the
compounds applicable to the present invention may arise from plant
or animal origin, or may be totally obtained through human effort
of design and synthesis. A reference to compound classes
(pharmocophores) applicable to the invention are found within
Strategies for Organic Drug Synthesis, by Daniel Lednicer,
published by John Wiley and Sons, Inc. .COPYRGT.1998, Chapters 7
through 13 inclusive and individually, Chapter's 13 and 15. Classes
of compounds subject to this invention include but are not limited
to opiates, morphinoids, tropinoids, amphetamines, compounds
containing a piperidine or substituted piperidine sub-structure
within the molecule, benzodiazepines, benzazepines, and compounds
containing a phenethyl amine or substituted phenethylamine
sub-structure within the molecule. The common characteristic to
each compound is the presence of an amine nitrogen whereby the
amine nitrogen is either a primary, secondary or tertiary amine
group and is capable of forming a salt with an inorganic or organic
acid, or combinations thereof. Within the description of the
invention, the term alkaloid or amine may be used interchangeably
to identify a compound possessing, or suspected of possessing,
biological activity in humans or animals, in its free base
(non-salt form) or in a salt form. The differentiating factor
defining the invention is the alkaloid's ability to form an organic
acid salt that will retain the expected biological activity when
used as intended for legitimate therapeutic purposes, but is not
readily accessible for abuse by inhalation (smoking), mucosal
application, nasal absorption (snorting) or by intravenous
injection (shooting).
[0156] A "drug substance" is a molecular entity or compound, also
known as an active pharmaceutical ingredient (API) that exhibits
biological activity for the purpose of providing human or animal
medication to treat disease, pain or any medically diagnosed
condition. It is possible for a drug substance to be used in
combination with one or more different drug substances to
ultimately impart a biological response in humans or animals. A
drug substance is typically formulated with other, non-biologically
active compounds to provide a means of predictable and quantitative
dosage delivery, or perhaps to impart acceptable stability features
to the drug product. What is meant by a drug product is a
formulation, mixture or admixture of the drug substance with
combinations of excipients, processing aids, buffers and perhaps
other inert ingredients that allow delivery of the drug substance
by the selected delivery mechanism to the patient at a predictable
dosage (the carrier matrix). Various delivery mechanisms include
solid oral dosage, for example, pills, tablets, or capsules.
Additional delivery systems can include solution or suspension
injection dosage forms (including depo drug products), transdermal
patches, and nasal or inhalation devices. The dosage is the actual
concentration delivered to the patient, and depending upon many
factors and the actual delivery system selected, the dosage may be
available for essentially immediate release, release over time, or
manipulated by additional means for stimulated release such as for
example, by irradiation. Immediate release is defined as a drug
substance wherein under simulated gastric conditions at least 85%
is released within 1 hour.
[0157] It is a well-known chemical principle that an acid and a
base will react to form a salt. It is sometimes possible to predict
the physical and chemical properties of these compounds in
generalized concepts such as which way a melting point will change
compared to the un-reacted acid or base. Dissolution and
dissociation rates of drug salts and their associated achievable
solution concentrations are substantially less predictable when
attempting to correlate this experimental data to some anticipated
bio-availability of the drug. For instance, at a given pH, an
observed dissolution rate and the associated solution concentration
of the drug may be dissociation controlled (i.e. ionization) rather
than governed strictly by solubility parameters. Indeed, different
salts of the same amine-containing active ingredient are likely to
display diverging mechanisms of bio-availability as a function of
pH. As such, an evaluation of amine-containing active ingredients
and their different salts would help elucidate their
bio-availability mechanisms. This approach could be incorporated
into a broader design feature to address drug abuse.
[0158] For instance, by manipulating the bio-availability mechanism
of a particular API by incorporating functional properties into the
API's salt, a design feature is introduced. This feature can also
extend to eliminating the ability to simply extract the active
ingredient from a finished dosage form and abuse the drug by
injection. For illustration, the attempted separation of the active
ingredient as the free base from orally administered pharmaceutical
product with the intent for injection abuse would require
filtrations, toxic solvent removal and multiple extraction
procedures including careful pH adjustments to separate the amine
free base from the pamoic acid component. Without an involved and
technically sophisticated separation, followed by purification, the
administration of the drug for the behavioral act of abuse is
physically, practically and financially precluded.
[0159] Classes of compounds subject to this invention include but
are not limited to opiates, morphinoids, tropinoids, amphetamines,
compounds containing a pyrrolidine, piperidine or a substituted
sub-structure of either or both pyrrolidine and piperidine within
the molecule, benzodiazepines, benzazepines, and compounds
containing a phenethyl amine or substituted phenethylamine
sub-structure within the molecule.
[0160] The opiates, or those compounds isolated from opium, or
analogous to the principle isolate, morphine, generally serve as
narcotic analgesics. Similarly, cocaine, a representative
tropinoid, was isolated from coca leaves, and as a class of
compounds exhibit anesthetic qualities. Various amphetamines impact
processes of the central nervous system and are often employed as
stimulants and appetite suppressants (anorexics). The piperidines
and pyrrolidines are often employed as useful psychotropic drugs.
The benzodiazepines have been employed as antianxiety agents
(anxiolytics), as hypnotics and occasionally as muscle relaxants.
Clearly, many synthetic and semi-synthetic compounds of each of
these classes have been prepared and have shown utility in a broad
range of therapeutic ailment administration.
[0161] A table of controlled substances is readily available on the
United States Drug Enforcement Agency's website at www.DEA.gov. As
representative examples, amines from that table which are
applicable to the present invention, but without restricting the
scope of the invention, include acetorphine, acetylmethadol,
allylprodine, alphacetylmethadol, bufotenine, dextromoramide,
diethyltryptamine, etorphine, heroin, ibogaine, ketobemidone,
lysergic acid diethylamide, mescaline, methaqualone,
3,4-methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine,
N-ethyl-1-phenylcyclohexylamine, peyote,
1-(1-phenylcyclohexyl)pyrrolidine, psilocybin, psilocin,
1-{1-(2-thienyl)-cyclohexyl}-piperidine, alphaprodine, anileridine,
cocaine, dextropropoxyphene, diphenoxylate, ethylmorphine,
glutethimide, hydrocodone, hydromorphone, levo-alphaaceytlmethadol,
levorphanol, meperidine, methadone, morphine, opium oxycodone,
oxymorphone, poppy straw, thebaine, amphetamine, methamphetamine,
methylphenidate, phencyclidine, codeine, benzphetamine, ketamine,
alprazolam, chlorodiazepoxide, clorazepate, diethylpropion,
fenfluramine, flurazepam, halazepam, lorazepam, mazindol,
mebutamate, midazolam, oxazepam, pemoline, pentazocine, phentermine
prazepam, quazepam, temazepam, triazolam, zolpidem, and
buprenorphine. Other amines that receive considerable legal
attention are potential and known precursors to methamphetamine,
specifically, ephedrine and pseudoephedrine.
[0162] The Merck Manual of Diagnosis and Therapy, 18.sup.th
Edition, published by the Merck Research Laboratories (2006) is an
excellent source for cross-referencing the cited drug substances,
their derivatives, the various classifications and categories of
drug substances, and how these compounds are employed for
beneficial medical purposes. It is a legal distinction to classify
some drugs substances as "controlled substances" as per the DEA's
requirements versus the medical benefits available through
administration of a specific drug. Within the context of this
invention, the legal distinction does not limit, or impose
limitations upon the invention. The invention provides a chemical
solution to the societal need for beneficial medications while
preventing the aberrant human behavior or intention to incorrectly
administer, participate in substance use disorder or to
deliberately abuse these drugs. Most controlled substances fall
within the following therapeutic categories: anorexics,
anxiolytics, analgesics, anesthetics, antihypertensives,
anticonvulsants, sedatives, hypnotics and hallucinogens. Of special
interest are ephedrine (a bronchodilator) and pseudoephedrine (a
decongestant), both of which can serve as suitable precursors to
methamphetamine.
[0163] The Merck Manual indicates the following opioids have
analgesic properties: codeine, hydrocodone, propoxyphene, fentanyl,
hydromorphone, levorphanol, meperidine, methadone, morphine,
oxycodone, oxymorphone, buprenorphine, butorphanol, nalbuphine, and
pentazocine. The Manual further lists classes of non-opioid
analgesics also applicable to the present invention and include:
indoles, naphthylalkanones, oxicam, para-aminophenol derivatives,
fenamates, pyrazaoles, pyrrolo-pyrrolo derivatives, and selective
COX-2 inhibitors. Dextromoramide, pentazocine, buprenorphine,
alphaprodine phencyclidine, ketobemidone, heroin, allylprodine,
acetylmethadol, and anileridine also exhibit analgesic
properties.
[0164] The Merck Manual also describes several anesthetic compounds
to which the current invention is applicable. These compounds
include but are not limited to lidocaine, bupivacaine, tetracaine
and epinephrine.
[0165] Antipsychotic compounds are prone to abuse or deliberate
mis-administration. Classes of these compounds listed in the Merck
Manual include: phenothiazines, piperidines, piperazines,
dibenzoxazepines, dihydroindolones, thioxanthenes, butyrophenones,
diphenylbutylpiperidines, dibenzodiazepines, benzisoxzoles,
theinobenzodiazepines, dibenzothiazepines,
benzisothiazolylpiperazine, and dihydrocarostyrils.
[0166] Obesity is often treated with anorexics such as
benzphetamine, and similar phenethylamine derivatives, for example,
phentermine. Other therapeutic agents for treating obesity include
sibutramine, mazindol, diethylpropion and fenfluramine.
[0167] With regard to psychiatric disorders, the Merck Manual
discusses drug use and the potential for subsequent dependence of:
amphetamines, anxiolytics and sedatives (hypnotics), cocaine, gamma
hydroxybutyrates, hallucinogens, ketamine, marijuana,
methylenedioxymethamphetamine, and opioids. Most interestingly, the
Merck Manual states, "Drug abuse is definable only in terms of
societal disapproval". The phrase, "substance use disorder" is
applied concerning children and adolescents using controlled
substances whereas, experimental or recreational use of drugs,
while usually illegal, are the terms used for adult use of
controlled substances. The amphetamines include amphetamine and
methamphetamine. The Manual states, "Methamphetamine is the chief
type of amphetamine abuse in North America". Unfortunately, the
cough, cold and sinus medications pseudoephedrine and ephedrine
have received close commercial scrutiny because of the ability to
convert these compounds to methamphetamine. Anxiolytics include the
barbiturates and benzodiazepines. The latter category includes drug
substances such as alprazolam, lorazepam and triazolam. Other
anxiolytics include halazepam, oxazepam, prazepam, diazepam,
chlorazepate and chlordiazepoxide. Cocaine can cause euphoric
excitement or schizophrenic like symptoms whereas ketamine exhibits
anesthetic properties. Methylenedioxymethamphetamine produces a
feeling of excitement, disinhibition and accentuates physical
sensation.
[0168] The Merck Manual reports that learning and developmental
disorders are often treated with the controlled substances,
methylphenidate or dextroamphetamine.
[0169] Compounds included within the sedative or hypnotic
therapeutic category include but are not limited to: quazepam,
temazepam, triazolam, zolpidem, glutethimide and flurazepam.
[0170] Compounds included within the hallucinogenic category inclue
N-ethyl-1-phenylcyclohexylamine, peyote,
1-(1-phenylcyclohexyl)pyrrolidine, psilocybin, psilocin, mescaline,
1-[1-(2-thienyl)-cyclohexyl]piperidine, bufotenine, ibogaine, and
lysergic acid diethylamide.
[0171] With respect to a specific list of controlled substances,
the list is maintained by the DEA and as a legal action occurring
through due process of law, compounds may be added to or deleted
from the list. In context of this invention, the compounds of
interest may be categorized and/or classified according to a number
of names as the preceding discussion indicates. Specific compounds
will fall within a general class and to that particular class, new
derivatives may be synthesized yielding similar therapeutic
indications and consequently, the potential for abuse.
Additionally, dosage levels of a particular compound may also
impact its therapeutic indication. By way of example, midazolam has
a therapeutic indication as an anesthetic, anticonvulsant, sedative
and hypnotic.
[0172] The basic physical and chemical properties of these
amines/alkaloids are consistent with amines which receive
considerably less attention and which are typically not prone to
abuse. It is well understood that the pKa values of the conjugate
acid for each amine confirms their ability to produce organic acid
addition salts. For comparative purposes between amines, a higher
pKa (amine conjugate acid) indicates a lower basicity strength for
the amine. Consequently, and by way of example without limiting the
scope, the controlled substances listed, demonstrate the
fundamental requirement (amine basicity) for producing an organic
acid addition salt and indeed, amines having a conjugate acid pKa
greater than approximately 1.5 are receptive to pamoate salt
formation.
[0173] Interestingly, pamoate salts have been shown to exhibit
polymorphism as described in co-pending U.S. patent application
Ser. No. 11/595,379 filed Nov. 10, 2006 titled "Physical States of
a Pharmaceutical Drug Substance", the disclosure of which is
totally incorporated herein by reference. This property of a
compound is its ability to solidify in different crystal
structures, habits or lattices to yield polymorphs. Indeed, for a
drug substance that exhibits polymorphism, different situations may
exist: the material may solidify and be isolated from the reaction
as 1) an amorphous solid; 2) a single polymorph may be obtained, or
3) a mixture of polymorphs and 4) combinations of the previous
three possibilities. Therefore it is important, when polymorphism
is suspected, to deliberately attempt to prepare, isolate and
characterize the different polymorphs by techniques sufficient to
differentiate between amorphous material and individual polymorphs
or their mixtures. Often differential scanning calorimetry (DSC)
can be employed to identify or monitor the creation of polymorphs.
Indeed, when a salt candidate's stability profile can be correlated
to a specific polymorph, appropriate synthetic process development
activities can define the controlling conditions necessary to yield
the single, desired polymorph or some other defined ratio of
polymorphs exhibiting an acceptable stability profile.
[0174] API salts and their polymorphs often exhibit different
dissolution characteristics. For instance the rate of dissolution
is pH dependent, and therefore yields a different pharmacokinetic
profile and/or therapeutic efficacy. Sometimes, a given drug
product formulation expertise or technology can dominate any
biological effects the API salt and/or polymorph present.
Conversely, drug product formulation and the resulting mechanical
properties of a tablet, capsule or bead can be dominated by the
physical behavior of the API salt and/or its particular crystal
structure. It is not unusual that difficult trade-offs must be made
between the ease of manufacture of the drug product and the
pharmacokinetics desired.
[0175] Drug product formulation can impact the pharmacokinetics of
an API salt candidate (and potential polymorph) by a host of
technologies, including but not limited to, preparing formulated
beads, different sized beads, coated beads, combinations of various
bead technologies, formulated matrix systems, addition of
hydrophobic layers to tablets, capsules or beads (for example, as a
control mechanism to limit the dissolution rate of hydrophilic
gelatin capsules), coated tablets and capsules, capsules filled
with beads, and different mixtures of beads with different
coatings. These formulation techniques make available a wide range
of drug product properties including, but not limited to, slow
release, controlled release, and extended release drug
pharmacokinetics. These activities are dependent upon the API salt
selected (and potential polymorph issues) because of the salt's
dissolution profile at the pH where drug release is to occur (for
liberation of the API from its salt form). In fact, different API
salts and formulation techniques can be selected based on where the
desired release is to occur in the gastrointestinal tract and the
formulator can use the API salt's pKa, solubility, melting point,
shape and particle size as primary factors to utilize, moderate or
overcome localized insolubility through the use of formulation
techniques.
Experimental
Experimental Methods
Differential Scanning Calorimetry
[0176] Samples were evaluated using a Differential Scanning
Calorimeter from TA Instruments (DSC 2010). Prior to analysis of
samples, a single-point calibration of the TA Instruments DSC 2010
Differential Scanning Calorimeter (DSC 2010) with the element
indium as calibration standard (156.6.+-.0.25.degree. C.) was
completed.
Infrared Spectroscopy
[0177] IR Spectra were obtained in a KBr disc using a Perkin Elmer
Spectrum BX Fourier Transform Infrared Spectrophotometer.
Powder X-Ray Diffraction (PXRD)
[0178] Powder X-Ray diffraction patterns were acquired on a Scintag
XDS2000 powder diffractometer using a copper source and a germanium
detector.
High Pressure Liquid Chromatography (HPLC)
[0179] HPLC analyses were performed on a Waters 2695 HPLC system
equipped with a Waters 2996 photo diode array detector.
Dissolution
[0180] Dissolution testing was performed using a Distek Dissolution
System 2100 consisting of six 1000 mL dissolution vessels with
covers containing sampling ports, six stainless steel paddles and
spindles, RPM control unit, and a Distek TCS0200C Water Bath,
Temperature Controller Unit.
EXAMPLES
Example 1
Preparation of Phentermine Pamoate
[0181] Phentermine HCl (37.3 g) was suspended in USP H.sub.2O
(700.0 g) and stirred to achieve a solution (0.05 g/g) and a pH
5.3. The solution was transferred to a metered addition funnel. A
solution of disodium pamoate (45.0 g) was prepared by dissolving in
USP water (902.0 g) to give a clear solution at a pH 10.4. The
solution was adjusted to about pH 9.4 with 0.2N HCl and clarified
by solution filtration. At 20.degree. C., the Phentermine HCl
solution was added to the stirred disodium pamoate solution at a
controlled rate over about 2.5 hours and the addition funnel rinsed
with USP H.sub.2O (20.0 g) into the reaction mixture. The mixture
was stirred for 1 h then warmed to 70.degree. C. where more
precipitation was observed. The mixture was heated from about
70.degree. C. to 95.degree. C. over about 1 h then cooled. Solids
were collected by filtration and washed with USP H.sub.2O
(3.times.200 g) and dried on a vacuum Buchner for about 3 h. The
solids collected (83.5 g) were transferred to a drying oven
(50-55.degree. C., vacuum/N.sub.2 sweep) and dried about 48 h to
give Phentermine Pamoate (64.7 g, 94.2%). The pamoate was
characterized by DSC (FIG. 1), FTIR (FIG. 4) and PXRD (FIG. 7).
Example 2
Preparation of Ephedrine Pamoate
[0182] Ephedrine Hydrochloride (6.1 g) was stirred in USP water
(45.0 g) to yield a solution pH of about 4.9. In a separate flask a
disodium pamoate (6.5 g) solution was prepared using USP water
(54.0 g) to yield a solution pH of about 9.5. The ephedrine HCl
solution was transferred to a metered addition funnel and added to
the disodium pamoate solution over approximately 1 h. When about
one-half of the addition was completed, the solution became opaque.
USP water (2.6 g) was used to rinse in the residue from the
addition funnel. The opaque mixture was heated from about
26.degree. C. to near 80.degree. C. The reaction was stirred at
about 80.degree. C. for approximately 4.5 h. A thick residue
settled in the reaction vessel as the solution cooled. The solution
was decanted and the residue transferred to drying dishes. The
residue was dried at about 100.degree. C. under vacuum (nitrogen
sweep) for about 5.5 h. Drying was continued for about 66 h, the
solid ground with a mortar and pestle to give a dense powder (4.2
g, 39%). and a DSC analysis indicated a clear melt (T.sub.max
243.4.degree. C., T.sub.onset 227.7.degree. C., and heat of fusion
142.2 J/g).
Example 3
Alternate Preparation of Ephedrine Pamoate
[0183] Ephedrine Hydrochloride (7.1 g) was stirred in methanol
(62.6 g). Disodium pamoate (8.0 g) was stirred in USP water (71.0
g) and adjusted to about pH 9.5. The methanolic ephedrine
hydrochloride solution was added to the disodium pamoate solution
over a period of about 1.75 h. The reaction solution was heated to
about 60.degree. C. for around 4.5 h then cooled. The reactor was
equipped with a distillation head and aqueous methanol was removed
by heating. The opaque mixture was cooled and a residue settled to
the bottom of the reaction vessel. The solution was carefully
decanted and the residue was transferred to a drying dish. The
material was placed in a vacuum drying oven (103.degree. C.) for 24
h with a nitrogen sweep. Ephedrine Pamoate was obtained as a solid,
8.4 g (66.6%) 2:1 ephedrine pamoate (by HPLC assay) and
characterized by DSC (FIG. 2), FTIR (FIG. 5) and PXRD (FIG. 8).
Example 4
Preparation of Pseudoephedrine Pamoate
[0184] Disodium pamoate (10.4 g) was dissolved in USP water (73.5
g) and filtered to clarify. The filtrate was returned to a rinsed
reactor employing a water rinse (15 g). The solution of disodium
pamoate exhibited a pH of about 9.5. Pseudoephedrine HCl (9.3 g) in
USP water (53.1 g) was prepared and exhibited a pH of about 6.3.
The pseudoephedrine HCl solution was added to the disodium pamoate
solution. As the addition continued, the oily mixture became
opaque. After complete addition (.about.1 h), the residue in the
addition funnel was rinsed into the reaction vessel with USP water
(5.0 g). The mixture was heated at about 84.degree. C. for
approximately 3.25 h. The mixture was then cooled overnight and
solids were collected by filtration. The filter cake was washed
with USP water (3.times.30 g) and dried in a vacuum oven
(98-102.degree. C.) for about 5.2 h with a nitrogen sweep. After
cooling, the finely powdered 2:1 (by HPLC) pseudoephedrine pamoate
solids (15.9 g, 87%) was characterized by DSC (FIG. 3), FTIR (FIG.
6) and PXRD (FIG. 9).
Example 5
Preparation of Benzphetamine Pamoate
[0185] To a solution containing disodium pamoate (19.1 g) in water
(218.0 g) was added as needed dilute HCl or NaOH solution to adjust
the solution to about pH 9.4. To a second solution of benzphetamine
HCl (24.3 g) in water (211.0 g) was added dilute HCl or NaOH
solution to adjust the solution to about pH 4.5. The benzphetamine
HCl solution was added to the disodium pamoate solution over a
period of about 3 h. The mixture was stirred and held at about
53.degree. C. for at least 18 h. The mixture was cooled to below
25.degree. C. and the solids were collected by filtration. The
solid cake was washed with USP purified water. The wet cake was
dried at 70.degree. C. under reduced pressure to yield a solid
(30.0 g). The 2:1 benzphetamine pamoate by HPLC assay was
characterized by DSC (FIG. 10), FTIR (FIG. 11) and PXRD (FIG.
12).
Example 6
Solubility Recovery Comparison of Selected Amine Salts
[0186] A comparison of pseudoephedrine as its pamoate salt and as
it hydrochloride was performed at 37.degree. C. Each salt was
tested for its solubility recovery at pH 4.5 and pH 7.0. For
comparison equivalency, the amount of pamoate salt was adjusted to
account for the molecular weight difference between the pamoate and
the hydrochloride such that equal amounts of pseudoephedrine were
compared at each pH condition.
[0187] A flask containing USP H.sub.2O (10.0 mL at pH 4.5 having
used HCl to adjust) was warmed to 37.degree. C..+-.2.degree. C. in
a water bath. Pseudoephedrine HCl (1.0 g) was added to the solution
at 37.degree. C..+-.2.degree. C. A visual observation indicated the
immediate dissolution of about 2/3 of the bulk solids. Magnetic
stirring was initiated and a solution was observed. The solution
was stirred for 31 min then filtered. No solids were collected and
flask was rinsed to the filter with USP H.sub.2O (pH 4.5)
(2.times.5.0 g). Pseudoephedrine HCl was completely soluble at pH
4.5.
[0188] In a second flask containing USP H.sub.2O (10.0 mL at pH 4.5
having used HCl to adjust) was warmed to 37.degree. C..+-.2.degree.
C. in a water bath. Pseudoephedrine pamoate (1.8 g) was added to
the solution. The pamoate salt, as a solid, floated on top of the
water and did not wet. Magnetic stirring was initiated and some
solids were pulled below the surface and stirred. Approximately
1/2-2/3 of the solids remained above the water surface and the
thermometer was used to push the remaining solids below the water
surface. A bi-phasic mixture was observed which was stirred for 32
min and then filtered to collect the solids. The flask contents
were rinsed to the filter with USP H.sub.2O (pH 4.5) (3.times.5.0
g). The solids were dried under vacuum then transferred to a drying
pan and into a vacuum oven (80.+-.2.degree. C.) under N.sub.2.
After 19.75 h, the solids were removed to cool and weighed yielding
a mass recovery of peudoephedrine pamoate (1.76 g) (98%).
[0189] Pseudoephedrine pamoate was insoluble at pH 4.5.
[0190] A similar set of experiments was conducted whereby a flask
containing USP H.sub.2O (10.0 mL at pH 7.0 having used HCl and NaOH
to adjust) was warmed to 37.degree. C..+-.2.degree. C. in a water
bath. Pseudoephedrine HCl (1.02 g) was added to the solution at
37.degree. C..+-.2.degree. C. A visual observation indicated the
immediate dissolution of about 2/3 of the bulk solids. Magnetic
stirring was initiated and a solution was observed. The solution
was stirred for 31 min then filtered. No solids were collected and
flask was rinsed to the filter with USP H.sub.2O (pH 7.0)
(2.times.5.0 g). Pseudoephedrine HCl was completely soluble at pH
7.0.
[0191] In a second flask containing USP H.sub.2O (10.0 mL at pH 7.0
having used HCl and NaOH to adjust) was warmed to 37.degree.
C..+-.2.degree. C. in a water bath. Pseudoephedrine pamoate (1.80
g) was added to the solution. The solid pseudoephedrine pamoate
floated on top of the water and did not wet. Magnetic stirring was
initiated and some solids were pulled below the surface and
stirred. Approximately 1/2-2/3 of the solids remained above the
water surface and the thermometer was used to push the remaining
solids below the water surface. A bi-phasic mixture was observed.
The mixture was stirred for 31 min and then vacuum filtered to
collect the solids. The flask contents were rinsed to the filter
with USP H.sub.2O (pH 7.0) (3.times.5 g). The solids were dried
under vacuum then transferred to a drying pan and into a vacuum
oven (80.+-.2.degree. C.) under N.sub.2. After 14.75 h, the solids
were removed to cool and weighed to yield a mass recovery of
pseudoephedrine pamoate (1.76 g) (98%). Pseudoephedrine pamoate was
insoluble at pH 7.0.
[0192] In a similar fashion, the recovery solubility comparisons
were performed on benzphetamine, ephedrine, phentermine and
imipramine as their hydrochloride and pamoate salts at the two pH
conditions of 4.5 and 7.0 at 37.degree. C. Imipramine xinafoate and
salicylate were also tested under these conditions. The results
from each of these comparative studies are summarized in the table
below. It was consistently observed that the hydrochloride salt
yielded a complete solution whereas the pamoate, xinafoate and
salicylate within experimental error of handling and recovery
manipulations, demonstrated insolubility at pH 4.5 and 7.0.
TABLE-US-00001 Drug pH % Recovery Phentermine Pamoate 4.5 98.4
Phentermine HCl 4.5 0 Phentermine Pamoate 7.0 97.3 Phentermine HCl
7.0 0 Ephedrine Pamoate 4.5 94.4 Ephedrine HCl 4.5 0 Ephedrine
Pamoate 7.0 94.4 Ephedrine HCl 7.0 0 Pseudoephedrine Pamoate 4.5
98.9 Pseudoephedrine HCl 4.5 0 Pseudoephedrine Pamoate 7.0 97.8
Pseudoephedrine HCl 7.0 0 Benzphetamine Pamoate 4.5 91.1
Benzphetamine HCl 4.5 0 Benzphetamine Pamoate 7.0 92.7
Benzphetamine HCl 7.0 0 Imipramine HCl 4.5 0 Imipramine Xinaforate
4.5 97.0 Imipramine Salicylate 4.5 104 Imipramine HCl 7.0 0
Imipramine Xinafoate 7.0 97.0 Imipramine Salicylate 7.0 104
Example 7
Preparation of Imipramine Xinafoate
[0193] To a solution containing 7.7 g of 3-hydroxy-2-napthoic acid
in 75.0 g of USP water was added as necessary dilute HCl or NaOH
solution to adjust the solution to about pH 9.4. To a second
solution of 13.6 g of imipramine HCl in 100.0 g of USP water was
added as necessary dilute HCl or NaOH solution to adjust the
solution to about pH 4.5. The imipramine HCl solution was added to
the 3-hydroxy-2-napthoic sodium salt solution over a period of
about 2 h. The mixture was stirred and held at around 50.degree. C.
for at least 18 h. The mixture was cooled to below 25.degree. C.
and the solids were collected by filtration. The solid cake was
washed with USP water (2.times.100 g). The solid cake was dried at
105.degree. C. under vacuum to yield a powder (12.7 g) and
characterized by DSC (FIG. 13), FTIR (FIG. 14) and .sup.1H NMR
(FIG. 15).
Example 8
Preparation of Imipramine Salicylate
[0194] Sodium Salicylate (16.4 g) in USP water (118.0 g) was
stirred at 20.degree. C. in a 1 L reactor. After 15 min, the
solution was checked and exhibited pH 6.23. In a Imipramine HCl
(31.7 g) in USP water (320.0 g) was stirred at 22.degree. C. in a
500 mL reactor until a solution was observed (>20 min). The
Imipramine HCl solution was checked and exhibited a pH 4.54. The
Imipramine HCl solution was added via metered addition funnel to
the sodium salicylate solution at 20.degree. C. over 1.75 h. The
reactor and addition funnel was rinsed to the reaction with USP
water (20.0 g). The reaction mixture was heated from about
20.degree. C. to about 50.degree. C. for 1.2 h. The mixture was
heated to about 62.degree. C. for 17 h. Solids were collected by
filtration of the mixture at 50.degree. C. Residue was rinsed from
the reactor to the filter with USP water (4.times.110.0 g). After
drying on the filter for 1 h, solids were dried at about 65.degree.
C. to about 78.degree. C. for approximately a day. Imipramine
salicylate, mp 141-143.6.degree. C. (39.8 g, 95.1%).
Recrystallization of imipramine salicylate from a solution of
ethanol-water (98/2) provided solid, mp 142.2-144.2.degree. C. The
DSC thermogram (FIG. 16), FTIR analysis (FIG. 17) and .sup.1H NMR
spectra (FIG. 18) were consistent with the expected structure.
Example 9
Dissolution Testing Procedure
[0195] Dissolution testing was performed according to the FDA's
Guidance for Industry document entitled, "Waiver of In Vivo
Bioavailability and Bioequivalence Studies for Immediate-Release
Solid Oral Dosage Forms Based on a Biopharmaceutics Classification
System and following the recommendations under section III C
tiltled "Determining Drug Product Dissolution Characteristics and
Dissolution Profile Similarity". A comparison dissolution test was
performed for each active ingredient's hydrochloride salt versus
its pamoate salt with concentrations adjusted for molecular weight
differences. This adjustment provided an equal concentration of
active ingredient (calculated as the free base) for both the
hydrochloride and pamoate salts. A similar calculation and charge
adjustment was performed in the case of xinafoate and salicylate
salt comparisons to the corresponding hydrochloride salt.
[0196] The Distek Dissolution System was arranged in an Apparatus
II configuration as per United States Pharmacopeia dissolution
testing procedure USP <711> employing paddles and a 50 RPM
spindle speed. The water bath temperature was set and controlled at
37.+-.1.degree. C.
[0197] The dissolution tests on drug hydrochlorides and the drug
pamoates, xinafoate, and salicylate were performed as separate
experimental sets. Each experimental set was subjected to simulated
gastric conditions by employing a standardized (and traceable)
buffered 0.1 N HCl solution supplied by VWR.
[0198] Each test sample was filled into a clear gelatin capsule
(Capsuline Size "2"). The pharmaceutical grade gelatin capsules are
derived from bovine raw materials from BSE-free countries. The
gelatin is 100% HIDE gelatin. A wire (.about.1.7-2.0 g) was coiled
around each capsule to assure the capsule did not float in the test
medium. The amount of each API filled into an individual capsule
was determined based on the highest unit dose available for a
commercialized drug product. By way of example, the highest dose
commercialized drug product containing the active pharmaceutical
ingredient phentermine hydrochloride contains 37.5 mg of the active
ingredient as its hydrochloride. The following table summarizes the
amount of each active ingredient loaded into a capsule. The amounts
of the active ingredient for the pamoates, xinafoate and salicylate
salts have been adjusted for their higher molecular weight
contribution and for the actual stoichiometry within the salt. For
instance, the pamoates herein exist as a 2:1 complex of
amine-containing active ingredient to pamoate moiety.
TABLE-US-00002 MW (Active as Free Drug Salt g/mol Weight (mg) Base)
(mg) Drug Hydrochloride Ephedrine Hydrochloride 201.69 47.6 39.4
Pseudoephedrine 201.69 60.6 49.6 Hydrochloride Phentermine
Hydrochloride 185.70 37.5 30.1 Benzphetamine 275.86 50.3 40.3
Hydrochloride Imipramine Hydrochloride 316.88 150.7 133.1 Drug Salt
(Pamoate, Xinafoate, Salicylate)* Ephedrine Pamoate 717.98 85.4
39.2 Pseudoephedrine Pamoate 717.98 107.0 49.2 Phentermine Pamoate
658.80 66.5 30.8 Benzphetamine Pamoate 866.32 78.5 43.3 Imipramine
Xinafoate 468.16 221.0 132.1 Imipramine Salicylate 419.30 198.0
132.2 Imipramine Pamoate 949.18 225.0 132.7 *All Pamoate Salts are
2:1, Xinafoate Salt is 1:1, Salicylate Salt is 1:1, and
Hydrochloride Salts are 1:1
[0199] Prior to use, the 0.1 N HCl solution was warmed to
38-42.degree. C. with adequate stirring and then degassed for 30
minutes with helium passed through a sparge stone attached to Tygon
tubing. The degassed buffered solution was dispensed into each of
five dissolution vessels (900 mL/vessel) using a volumetric flask.
The vessels were immersed in the constant temperature bath and
allowed to reach thermal equilibrium (37.+-.1.degree. C.). A single
capsule (with wire weighting) and containing a specified drug salt
was then added to each vessel, the paddles and spindles lowered
into the solution and agitation initiated at 50 RPM. The covers
with sampling ports were then placed on each vessel. Sampling was
performed at regular time intervals on each vessel using a sampling
syringe dedicated to each vessel. At each sampling time point about
10 mL of solution was removed from the vessel and filled into a
test vial for HPLC analysis.
Example 10
Dissolution Monitoring by HPLC
[0200] Drug dissolution assays at specified time intervals were
determined by a high pressure liquid chromatography (HPLC) method
employing a Waters Atlantis column (dC18, 5 micron, 4.6.times.150
mm), or equivalent. The HPLC system was a Waters 2695 HPLC system
equipped with a Waters 2996 photo diode array detector (detection
wavelength: 265 nm extracted; 215 nm extracted). The eluant
consisted of mobile phase A (0.1% TFA in water) and mobile phase B
(acetonitrile). The gradient elution conditions were as tabulated
below.
Gradient Elution Table
TABLE-US-00003 [0201] Time min % A % B 1 80 20 2 6.00 80 20 3 10.00
52 48 4 25.00 52 48 5 25.10 80 20 6 33.00 80 20
[0202] The drug hydrochlorides were employed as reference
comparisons for the dissolution of the corresponding organic acid
addition salt of the drug. Reference standards are available from
the United States Pharmacopeia; imipramine hydrochloride employed
as reference standard was used "as is" and was available from
Sigma-Aldrich Catalog #10899. Proceeding, 30-45 mg of the drug
hydrochloride reference standard was accurately weighed into a 100
mL volumetric flask and diluted to volume with a previously
prepared sample diluant consisting of a filtered 8:2
water:acetonitrile solution. Samples of the dissolution trial
solutions were obtained at timed intervals and diluted prior to
analysis to obtain targeted concentrations of approximately 45
micro grams/mL-75 micro grams/mL of active pharmaceutical
ingredient (API). The prepared samples were then filtered through a
0.45 micron filter directly into an HPLC vial, labeled and loaded
for injection into the HPLC system.
[0203] HPLC data collection was performed and concentrations
determined for each dissolution time interval for each drug
substance tested. Concentration assays were determined as a
weight/weight percent based on the assay obtained from the
reference standard. The data was plotted as a function of percent
unit dose released versus the sampling interval time (FIGS. 19
through 25) wherein the per cent unit dose released corresponds to
a mass assay of the active species found by HPLC analysis of each
dissolution time point divided by the available mass initially
delivered to the test solution in the capsule. Pairs of data sets
were plotted to assess the behavior of the hydrochloride salts
versus the organic acid addition salts of the present invention
under simulated gastric conditions. Similarly, the dissolution data
from HPLC analyses was plotted along with the mass recovery data
for each amine salt obtained at pH 4.5 and 7.0 (Example 6). Here
also, data set pairs were plotted to assess the behavior of the
hydrochloride salts versus the associated organic acid addition
salts over a pH range encompassing gastric and mucosal conditions
(FIGS. 26-32).
Example 11
Solubility Evaluation of the Pseudoephedrine Pamoate
[0204] The solubility of pseudoephedrine pamoate was evaluated in
each of isopropanol, acetone and toluene. About 0.5 grams of the
salt was added to approximately 5.0 grams of each solvent. The
samples were stirred at room temperature for about 15 minutes,
filtered and dried to determine a mass percent recovery of the
salt. The filtrates appeared clear and without color with the
exception of the acetone filtrate exhibiting some color. The mass
recoveries for the salt from each solvent were: 97% (isopropanol);
92% (acetone); 99% (toluene). Similar results were obtained for the
solubility evaluation of ephedrine pamoate.
[0205] The invention may be embodied in other specific forms
without departing from the spirit or essential characteristics
thereof. The present embodiments are therefore to be considered in
all respects as illustrative and not restrictive, the scope of the
invention being indicated by the appended claims rather than by the
foregoing description, and all changes which come within the
meaning and range of equivalency of the claims are therefore
intended to be embraced therein.
* * * * *
References