U.S. patent application number 09/905577 was filed with the patent office on 2003-02-06 for n,n-dinitramide salts as solubilizing agents for biologically active agents.
Invention is credited to Bomberger, David C., Bottaro, Jeffrey C., Penwell, Paul E., Petrie, Mark A..
Application Number | 20030026850 09/905577 |
Document ID | / |
Family ID | 25421071 |
Filed Date | 2003-02-06 |
United States Patent
Application |
20030026850 |
Kind Code |
A1 |
Bottaro, Jeffrey C. ; et
al. |
February 6, 2003 |
N,N-dinitramide salts as solubilizing agents for biologically
active agents
Abstract
A method is provided for enhancing the solubility of an
ionizable compound in a lipophilic medium by admixing the compound
with an effective solubility-enhancing amount of an N,N-dinitramide
salt. The ionizable compound, upon ionization, gives rise to a
biologically active cationic species that ionically associates with
the N,N-dinitramide anion N(NO.sub.2).sub.2.sup.- following
admixture with the N,N-dinitramide salt. The biologically active
cationic species may be a pharmacologically active cation, in which
case the method is useful for enhancing the penetration of the
blood-brain barrier by the pharmacologically active cation. In
other embodiments, the ionizable compounds are medical imaging or
diagnostic agents, or agricultural agents such as pesticides. Salts
of biologically active cations and N,N-dinitramide ion are also
provided as novel compositions of matter.
Inventors: |
Bottaro, Jeffrey C.;
(Mountain View, CA) ; Petrie, Mark A.; (Cupertino,
CA) ; Penwell, Paul E.; (Menlo Park, CA) ;
Bomberger, David C.; (Belmont, CA) |
Correspondence
Address: |
REED & ASSOCIATES
800 MENLO AVENUE
SUITE 210
MENLO PARK
CA
94025
US
|
Family ID: |
25421071 |
Appl. No.: |
09/905577 |
Filed: |
July 13, 2001 |
Current U.S.
Class: |
424/617 ;
424/718; 514/15.7; 514/18.1; 514/18.3; 514/2.3; 514/282;
514/4.9 |
Current CPC
Class: |
A61K 47/52 20170801;
C07C 2603/32 20170501; C07D 453/04 20130101; A61K 47/02 20130101;
C07C 211/32 20130101; A01N 25/02 20130101 |
Class at
Publication: |
424/617 ;
424/718; 514/2; 514/282 |
International
Class: |
A61K 033/24; A61K
033/00; A61K 038/00 |
Claims
1. A method for increasing the solubility of an ionizable compound
in a lipophilic medium, wherein ionization of the compound results
in a biologically active cationic species in association with an
anionic counterion, the method comprising admixing the ionizable
compound with an effective solubility enhancing amount of an
N,N-dinitramide salt.
2. The method of claim 1, wherein the ionizable compound is a salt
comprised of the biologically active cationic species and an
anionic counterion.
3. The method of claim 2, wherein the biologically cationic species
is a nitrogen-containing cation containing at least one positively
charged nitrogen atom.
4. The method of claim 3, wherein the admixing is carried out under
conditions that result in replacement of the anionic counterion
with N,N-dinitramide anion.
5. The method of claim 1, wherein the ionizable compound is in
electronically neutral form prior to admixture with the
N,N-dinitramide salt, but upon admixture with the N,N-dinitramide
salt ionizes to form a biologically active cationic species
ionically associated with N,N-dinitramide anion.
6. The method of claim 1, wherein the ionizable compound becomes
protonated in an aqueous medium at physiological pH to give a
biologically active cationic species in association with hydroxide
counterions.
7. The method of claim 6, wherein the ionizable compound is a
nitrogen-containing compound containing at least one nitrogen atom
that becomes protonated and thus positively charged in an aqueous
medium at physiological pH.
8. The method of claim 1, wherein the ionizable compound is
comprised of a non-ionizable precursor modified so as to contain an
ionizable site, wherein ionization of the ionizable site results in
the biologically active cationic species.
9. The method of claim 1, wherein the N,N-dinitramide salt has the
formula M.sup.+x[N(NO.sub.2).sub.2.sup.-].sub.x wherein M is
selected so that it is displaced by the biologically active
cationic species upon admixture of the N,N-dinitramide salt with
the ionizable compound, and x is the cationic charge of M.
10. The method of claim 1, wherein the N,N-dinitramide salt has the
formula M.sup.+x[N(NO.sub.2).sub.2.sup.-].sub.x wherein M is a
cation selected from the group consisting of a metal ion and a
nitrogen-containing ion, and x is the cationic charge of M.
11. The method of claim 10, wherein M is a mono, di, or trivalent
metal cation.
12. The method of claim 11, wherein M is selected from the group
consisting of Li, Na, K, Rb, Cs, Ca, Ba, Sr, Mg, Cu, Ag, Au, Zn,
Cd, Hg, Al, Sc, Y, Ga, In, lanthanide elements (57-71), Ti, Zr, Hf,
Ge, Sn, V, Nb, Ta, Cr, Mo, W, Mn, Tc, Re, Fe, Co, Ni, Ru, Rh, Pd,
Os, Ir, and Pt.
13. The method of claim 12, wherein M is a metal cation selected
from the group consisting of Li, Na, K, Be, and Mg.
14. The method of claim 10, wherein M is a nitrogen-containing
cation.
15. The method of claim 14, wherein the nitrogen-containing cation
is an inorganic nitrogen-containing cation.
16. The method of claim 15, wherein the inorganic
nitrogen-containing cation is selected from the group consisting of
ammonium, hydrazinium, nitronium and nitrosonium.
17. The method of claim 16, wherein the inorganic
nitrogen-containing cation is ammonium.
18. The method of claim 14, wherein the nitrogen-containing cation
is an organic nitrogen-containing cation.
19. The method of claim 18, wherein the organic nitrogen-containing
cation is a cationic derivative of an organic compound having one
or more tetravalent nitrogen atoms.
20. The method of claim 19, wherein the organic nitrogen-containing
cation contains 1 to 8 carbon atoms.
21. The method of claim 20, wherein the nitrogen-containing cation
contains 1 or 2 carbon atoms.
22. The method of claim 20, wherein M has the formula
R.sub.kH.sub.mN.sub.n.sup.+q, wherein: n is an integer in the range
of 1 to 8; k is an integer in the range of 1 to 2+n; q is an
integer in the range of 1 to n; m is equal to n+2+q-k; and each R
is independent selected from the group consisting of
C.sub.1-C.sub.12 hydrocarbyl moieties.
23. The method of claim 22, wherein each R is independently
selected from the group consisting of linear and branched lower
alkyl groups.
24. The method of claim 23, wherein M is selected from the group
consisting of CH.sub.3NH.sub.3.sup.+,
(CH.sub.3).sub.2NH.sub.2.sup.+, (CH.sub.3).sub.3NH.sup.+,
(CH.sub.3).sub.4N.sup.+, C.sub.2H.sub.5NH.sub.3.sup.+,
(C.sub.2H.sub.5).sub.2NH.sub.2.sup.+, (C.sub.2H.sub.5).sub.3
NH.sup.+, (C.sub.2H.sub.5).sub.4 N.sup.+,
(C.sub.2H.sub.5)(CH.sub.3)NH.sub.2.sup.+,
(C.sub.2H.sub.5)(CH.sub.3).sub.- 2NH.sup.+,
(C.sub.2H.sub.5).sub.2(CH.sub.3).sub.2N.sup.+,
(C.sub.3H.sub.7).sub.4N.sup.+, (C.sub.4H.sub.9).sub.4N.sup.+,
CH.sub.3N.sub.2H.sub.4.sup.+, (CH.sub.3).sub.2N.sub.2H.sub.3.sup.+,
(CH.sub.3).sub.3N.sub.2H.sub.2.sup.+,
(CH.sub.3).sub.4N.sub.2H.sup.+, and
(CH.sub.3).sub.5N.sub.2.sup.+.
25. The method of claim 18, wherein the organic nitrogen-containing
cation is selected from the group consisting of guanidium,
biguanidinium, guanylurea, ethylenediaminium, piperazinediium,
monoaminoguanidinium, diaminoguanidinium, triaminoguanidinium,
tetrazolium, aminotetrazolium, amino-ammonium-furazan,
polyvinylammonium, and dicyandiamidium.
26. The method of claim 1, wherein the ionizable compound is a
pharmacologically active agent, and the biologically active
cationic species is a pharmacologically active cationic
species.
27. The method of claim 26, wherein the pharmacologically active
agent is selected from the group consisting of: sympathomimetic
amines; neuroprotective agents; neuroactive amino acids;
neuroactive peptides; neurotransmitters; muscarinic receptor
agonists and antagonists; anticholinesterases; neuromuscular
blocking agents; ganglionic stimulating drugs; agents to treat
neurodegenerative disorders; anti-epileptic agents; CNS and
respiratory stimulants; anesthetic agents; analgesic agents;
antiemetic agents; antihypertensive agents; cerebral vasodilators;
hypnotic agents and sedatives; anxiolytics and tranquilizers;
neuroleptic agents; anti-microbial agents; alpha adrenergic
receptor antagonists; and appetite suppressants.
28. The method of claim 27, wherein the pharmacologically active
agent is a sympathomimetic amine or a pharmaceutically acceptable
acid addition salt thereof.
29. The method of claim 28, wherein the sympathomimetic amine is
selected from the group consisting of albuterol, amphetamine,
benzphetamine, colterol, diethylpropion, dopamine, dobutamine,
ephedrine, epinephrine, ethylnorepinephrine, fenfluramine,
fenoldapam, hydroxyamphetamine, ibopamine, isoetharine,
isoproterenol, mephentermine, metaproterenol, metaraminol,
methoxamine, midodrine, norepinephrine, phendimetrazine,
phemnetrazine, phentennine, phenylephrine, phenylethylamine,
phenylpropanolamine, prenalterol, propylhexedrine, ritodrine,
terbutaline, terbutaline sulfate, tyramine, pharmaceutically
acceptable acid addition salts thereof, and combinations of any of
the foregoing.
30. The method of claim 27, wherein the pharmacologically active
agent is a neuroprotective agent.
31. The method of claim 30, wherein the neuroprotective agent is a
neurotrophic factor.
32. The method of claim 27, wherein the pharmacologically active
agent is a neuroactive amino acid.
33. The method of claim 27, wherein the pharmacologically active
agent is a neuroactive peptide.
34. The method of claim 27, wherein the pharmacologically active
agent is a muscarinic receptor agonist.
35. The method of claim 27, wherein the pharmacologically active
agent is a muscarinic receptor agonist.
36. The method of claim 27, wherein the pharmacologically active
agent is an anticholinesterase.
37. The method of claim 27, wherein the pharmacologically active
agent is a neuromuscular blocking agent.
38. The method of claim 27, wherein the pharmacologically active
agent is a ganglionic blocking drug.
39. The method of claim 27, wherein the pharmacologically active
agent is an agent to treat a neurodegenerative disorder.
40. The method of claim 39, wherein the neurodegenerative disorder
is Alzheimer's disease and the pharmacologically active agent is
selected from the group consisting of donezepil, physostigmine,
tacrine, pharmaceutically acceptable acid addition salts thereof,
and combinations of any of the foregoing.
41. The method of claim 39, wherein the neurodegenerative disorder
is Huntington's disease and the pharmacologically active agent is
selected from the group consisting of fluoxetine, carbamazepine,
and pharmaceutically acceptable acid addition salts and
combinations thereof.
42. The method of claim 39, wherein the neurodegenerative disorder
is Parkinson's disease and the pharmacologically active agent is
selected from the group consisting of amantadine, apomorphine,
bromocriptine, levodopa, pergolide, ropinirole, selegiline,
triexyphenidyl, atropine, scopolamine, glycopyrrolate,
pharmaceutically acceptable acid addition salts thereof, and
combinations of any of the foregoing.
43. The method of claim 39, wherein the neurodegenerative disorder
is amyotrophic lateral sclerosis (ALS) and the pharmacologically
active agent is selected from the group consisting of baclofen,
diazepam, tizanidine, dantrolene, pharmaceutically acceptable acid
addition salts thereof, and combinations of any of the
foregoing.
44. The method of claim 27, wherein the pharmacologically active
agent is an anti-epileptic agent.
45. The method of claim 27, wherein the pharmacologically active
agent is a CNS or respiratory stimulant.
46. The method of claim 27, wherein the pharmacologically active
agent is an analgesic agent.
47. The method of claim 46, wherein the analgesic agent is selected
from the group consisting of alfentanil, buprenorphine,
butorphanol, codeine, drocode, fentanyl, hydrocodone,
hydromorphone, levorphanol, meperidine, methadone, morphine,
nalbuphine, oxycodone, oxymorphone, pentazocine, propoxyphene,
sufentanil, tramadol, apazone, etodolac, difenpiramide,
indomethacine, meclofenamate, mefenamic acid, oxaprozin,
phenylbutazone, piroxicam, tolmetin, pharmaceutically acceptable
acid addition salts thereof, and combinations of any of the
foregoing.
48. The method of claim 27, wherein the pharmacologically active
agent is a cerebral vasodilator.
49. The method of claim 27, wherein the pharmacologically active
agent is a neuroleptic agent.
50. The method of claim 49, wherein the neuroleptic agent is an
antidepressant drug selected from the group consisting of tricyclic
antidepressants, serotonin reuptake inhibitors and atypical
antidepressants.
51. The method of claim 1, wherein the biologically active cationic
species is a metal cation, and the ionizable compound is a
metal-based drug, an imaging agent, a diagnostic agent, or a
mineral supplement.
52. The method of claim 51, wherein the ionizable compound is an
agriculturally active chemical compound.
53. The method of claim 52, wherein the agriculturally active
chemical compound is a pesticide.
54. The method of claim 53, wherein the pesticide is selected from
the group consisting of acaricides, avicides, bacteriocides,
fungicides, insecticides, larvicides, miticides, molluscicides,
nematocides, ovicides, predicides, pupicides, and rodenticides.
55. The method of claim 1, wherein the effective solubility
enhancing amount of an N,N-dinitramide salt is selected to provide
a molar ratio of the N,N-dinitramide salt to the ionizable compound
in the range of about 0.5z:1 to about 5z:1 wherein z is the charge
of the biologically active cationic species.
56. The method of claim 55, wherein the molar ratio of the
N,N-dinitramide salt to the ionizable compound is in the range of
about 1z:1 to about 2z:1.
57. The method of claim 56, wherein the molar ratio of the
N,N-dinitramide salt to the ionizable compound is in the range of
about 1z:1 to about 1.5z:1.
58. A salt of N,N-dinitramide anion and a biologically active
cation.
59. The salt of claim 58, wherein the biologically active cation is
selected from the group consisting of pharmacologically active
cations, positively charged imaging agents, positively charged
diagnostic agents, and cationic pesticides.
60. The salt of claim 59, wherein the biologically active cation is
a pharmacologically active cation.
61. The salt of claim 59, wherein the pharmacologically active
cation is selected from the group consisting of protonated
pharmacologically active agents, pharmacologically active
quaternary ammonium cations, and metal cations.
62. A pharmaceutical formulation comprising a salt of
N,N-dinitramide anion and a pharmacologically active cation in a
pharmaceutically acceptable carrier.
63. The formulation of claim 73, wherein the pharmacologically
active cation is selected from the group consisting of protonated
pharmacologically active agents, pharmacologically active
quaternary ammonium cations, and metal cations.
64. The formulation of claim 63, wherein the pharmacologically
active cation is present in the pharmaceutical formulation in a
therapeutically effective amount.
65. The formulation of claim 64, wherein the therapeutically
effective amount is a unit dosage.
66. The formulation of claim 64, in the form of a tablet.
67. The formulation of claim 63, wherein the pharmaceutical carrier
is a lipophilic liquid, and the formulation is in liquid form.
68. The formulation of claim 67, wherein the lipophilic liquid is
suitable for oral administration.
69. The formulation of claim 67, wherein the lipophilic liquid is
suitable for parenteral administration.
70. A pharmaceutical formulation comprising (a) a therapeutically
effective amount of an ionizable compound that upon ionization
gives a pharmacologically active cation, (b) an effective
solubility enhancing amount of an N,N-dinitramide salt, and a
pharmaceutically acceptable carrier.
71. The formulation of claim 70, wherein the pharmacologically
active cation is selected from the group consisting of protonated
pharmacologically active agents, pharmacologically active
quaternary ammonium cations, and metal cations.
72. The formulation of claim 71, wherein the pharmacologically
active cation is present in the pharmaceutical formulation in a
therapeutically effective amount.
73. The formulation of claim 72, wherein the therapeutically
effective amount is a unit dosage.
74. The formulation of claim 72, in the form of a tablet.
75. The formulation of claim 70, wherein the pharmaceutical carrier
is a lipophilic liquid, and the formulation is in liquid form.
76. The formulation of claim 75, wherein the lipophilic liquid is
suitable for oral administration.
77. The formulation of claim 75, wherein the lipophilic liquid is
suitable for parenteral administration.
78. A biologically active agent delivery system comprised of: (a)
an N,N-dinitramide salt having the formula
M.sup.+x[N(NO.sub.2).sub.2.sup.-]- .sub.x wherein M is a cation
selected from the group consisting of a metal ion and a
nitrogen-containing ion, and x is the cationic charge of M; and (b)
an ionizable compound, wherein ionization of the compound results
in a pharmacologically active cation.
79. The delivery system of claim 78, wherein the N,N-dinitramide
salt and the ionizable compound are physically segregated.
80. The delivery system of claim 78, wherein the N,N-dinitramide
salt and the ionizable compound are contained within a single
composition.
81. A method of transmitting a pharmacologically active agent
across the blood-brain barrier in a mammalian individual to achieve
a pharmacological effect in the central nervous system, comprising:
administering a therapeutically effective amount of the active
agent and an effective solubility enhancing amount of an
N,N-dinitramide salt to the individual in a manner that allows the
active agent to enter the bloodstream, wherein the active agent is
an ionizable compound that upon ionization results in a
pharmacologically active cation.
Description
TECHNICAL FIELD
[0001] This invention relates generally to methods and compositions
for increasing the solubility of biologically active agents in
lipophilic media. More particularly, the invention relates to the
use of N,N-dinitramide salts as solubilizing agents for ionizable
biologically active agents, particularly biologically active agents
that when ionized are positively charged. The invention finds
utility in a variety of fields, including pharmaceuticals and drug
delivery, medical imaging and diagnostics, agrochemical
manufacture, and dietary supplement formulation.
BACKGROUND
[0002] Many hydrophobic compounds are not only poorly soluble or
even insoluble in water, but are also insoluble or only slightly
soluble in lipophilic media. It is very difficult to manufacture
useful products with such compounds because their insolubility
limits the ability to chemically transform and/or formulate the
compounds in any sort of composition. This is particularly
problematic with hydrophobic pharmacologically active agents, which
if insoluble in both aqueous and lipophilic media have very low
oral bioavailability. Furthermore, for those drugs that are
intended to be delivered to the brain, and thus be transported
across the "blood-brain barrier" as will be described below, an
insufficient amount of the drug penetrates the blood brain barrier
and enters the central nervous system.
[0003] For treating pathologic processes inside the central nervous
system (CNS), therapeutic benefit derives from availability of the
agent inside the CNS. Undesired effects can result from effects of
the agent anywhere in the body of the treated organism. The
blood-brain barrier, regulates the exchange of materials between
the bloodstream and the CNS, and may present a formidable barrier
to drug transport into the CNS, thus affecting the effective dose
of an agent or precluding its use by systemic administration
altogether. As physical breach of the meninges is known to be
medically undesirable, the inability of a pharmacologic agent to
penetrate the blood-brain barrier can preclude its use altogether
or limit its use to only life threatening situations.
[0004] The physiological basis for the blood-brain barrier are the
brain capillaries, which are comprised of a lining of endothelial
cells (Goldstein et al. (1986) Scientific American 255:74-83
(1986); Pardridge (1986) Endocrin. Rev. 7:314-330). The endothelial
cells lining the capillaries of the blood-brain barrier are
different from those lining capillaries of other tissues.
Specifically, they form complex tight junctions, which prevent
passage of molecules and ions between cells. The blood-brain
barrier is formed by these high-resistance, tight intercellular
junctions along with the endothelial cells themselves. The
integrated structure forms a continuous wall against the passive
movement of many molecules from the blood to the brain. The
capillary endothelial cells forming the blood-brain barrier are
also different in that they have few pinocytotic vesicles, which
allow somewhat unselective transport across the capillary wall in
other tissues. Continuous gaps or channels running through the
cells, which would allow unrestrained passage of moieties, are also
absent in blood-brain barrier capillary lining.
[0005] The structure of the blood-brain barrier may be subdivided
into two components: the endothelial or capillary barrier and the
ependymalbarrier (Banks et al (1991) Pharm. Res. 8:1345-1350). The
nature of the mechanism of the penetration of substances through
the blood-brain barrier has not been fully explained, but many
regulators of brain function, such as cytokines, transferrin,
enkephalins and endorphins, are believed capable of traversing the
blood-brain barrier from the blood vessels into the brain (Raeissi
et al (1989) J. Pharm. Phy. 41:848-852; Zlokovich et al. (1989)
Peptides 10:249-254; and Zlokovich, B. (1990) J. Control. Rel.
13:185-201). However, many substances that can affect the CNS
including adenosine, .beta.-endorphin and synthetic analogs of
endogenous peptides and some excitatory and inhibitor amino acids
and trophic factors, penetrate the blood-brain barrier poorly or
not at all (Houghten et al (1980) Proc. Natl. Acad. Sci. USA
77:4588-4591; Levin et al. (1987) Biochem. Biophys. Res. Commun.
147:1226-123; Sakane et al. (1989) Int. J. Pharm. 57:77-83).
Currently, drugs with little or no blood-brain barrier penetration
can only be administered by direct CNS infusion or by implantation
of controlled-release polymers (see, e.g., U.S. Pat. No. 4,883,666
to Sabel et al.). Thus, many potentially potent drugs are not
clinically useful inside the CNS because of inability to cross the
blood-brain barrier in amounts capable of yielding therapeutic
levels in the CNS at below toxic systemic doses.
[0006] Many pharmacologic agents exert desirable therapeutic
effects inside the CNS at attainable systemic levels, but can be
employed with only limited therapeutic scope because of severe side
effects to peripheral organs and/or the peripheral nervous system.
Thus, a need generally exists to reduce the side effects of drugs
directed to the CNS by reducing side effects on peripheral organs
and tissues by increasing the action inside the blood-brain
barrier.
[0007] One approach has been to alter the permeability of the
blood-brain barrier itself. For instance, some osmotic agents
administered peripherally, as by intravenous or intramuscular
injection, result in the breach of the blood-brain barrier.
Further, some drugs acting on the CNS can alter the permeability
properties of the blood-brain barrier for other substances.
Cholinomimetic arecolines, for example, have been reported to
induce alterations of drug penetration through the blood-brain
barrier (Saija et al. (1990) J. Pharm. Pha. 42:135-138). Other
drugs that may be administered to change the blood-brain barrier
permeability are disclosed in U.S. Pat. Nos. 5,059,415 and
5,124,146 to Neuwelt. Bradykinin is one specific drug with such
effects (see U.S. Pat. No. 5,112,596 to Malfroy-Camine). Another
method involves administration of permeabilizer peptides such as
A-7 or conformational analogs thereof (see Kozarich et al.,
International Patent Publication No. WO 92/18529). Tomasz et al.
(International Patent Publication No. WO 91/16064) administer
parenteral injections of purified cell walls or cell wall fragments
of eubacteria such as Streptococcus pneumoniae to open the
blood-brain barrier, a relatively invasive method.
[0008] U.S. Pat. No. 5,260,210 to Rubin et al. discloses a method
of increasing the permeability of the blood-brain barrier by
administering an agent to reduce or inhibit intracellular cyclic
AMP concentrations or to increase cyclic GMP concentrations. One
disadvantage of wholesale alteration of blood-brain barrier
permeability is the resulting lack of selectivity. Thus, any method
of changing the permeability of the blood-brain barrier itself is
compromised by the possible entry of unwanted molecules from which
the brain is normally protected by the blood-brain barrier. Such
methods are thus impracticable due to unpredictable and
uncontrollable consequences.
[0009] Another approach has been the modification of drug molecules
themselves. The properties of the molecule, such as size and
pK.sub.a, are important to the drug's ability to penetrate the
blood-brain barrier. For example, macromolecules, including folded
proteins, do not pass the blood-brain barrier at all. One way of
modifying a molecule so as to render it capable of traversing the
blood brain barrier involves isolating the active moiety of a
macromolecule, i.e., that portion of the molecule responsible for
the biologically desirable result, and using only that active
moiety. Because size is one of the factors affecting ability of a
molecule to traverse the blood-brain barrier, reduced size is
employed to enhance the kinetics of penetration of the blood-brain
barrier, and consequently increase the likelihood that the smaller
molecule may traverse the blood-brain barrier in therapeutically
significant amounts. Other modifications to macromolecules to
enhance passage through the blood-brain barrier include glycating
proteins to enhance penetration of the blood-brain barrier, or
formation of a prodrug. U.S. Pat. No. 5,260,308 to Podusio et al.
teaches glycating proteins, while U.S. Pat. No. 4,933,324 to
Shashoua and related International Patent Publication No. WO
89/07938 disclose formation of a prodrug formed from a fatty acid
carrier and a neuroactive drug unable to pass through the
blood-brain barrier on its own. A similar system is disclosed in WO
89/07938.
[0010] One variant of the preceding approach involves linking the
desired pharmacoactive compound to a peptide that can facilitate
crossing the blood-brain barrier by transcytosis, as described in
U.S. Pat. No. 6,030,941 to Summerton et al. In transcytosis,
polarized endothelial cells of the capillary, having distinct
apical and basolateral membranes, effect traversal of the cell
forming a barrier such as the blood-brain barrier. A compound
transported by transcytosis is first taken through the apical
membrane in the inner capillary wall into a transcytotic vesicle.
Transcytotic vesicles typically have an internal pH of about 6.0.
The vesicle then transfers the compound to the basolateral membrane
of the endothelial cell, on the outer capillary wall. The compound
is then expelled from the transcytotic vesicle and across the
blood-brain barrier.
[0011] Yet another approach is the implantation of controlled
release polymers that release the active ingredient from a
matrix-system directly into the nervous tissue. However, this
approach is invasive and requires surgical intervention for
implantation directly into the brain or spinal cord (see Sabel et
al., U.S. Pat. No. 4,883,666)
[0012] To overcome these limitations, another approach has been
tried in which drug carrier systems are used including liposomes,
erythrocyte ghosts, antibody-conjugates, and monoclonal antibody
conjugates. One of the major problems in targeted drug delivery is
the rapid opsonization and uptake of such injected drug carriers by
the reticuloendothelial system (RES), especially by macrophages in
the liver and spleen. This obstacle may be partially overcome for
liposomal and other carrier systems by incorporation of "stealth"
lipids, such as phosphatidylinositol, monosialoganglioside, or
[0013] The aforementioned approaches are rather limited because
they are only effective for specific drugs in specific
circumstances. Liposomes are probably the least invasive existing
method for pharmacological agent delivery across the blood-brain
barrier. However, a number of problems are associated with
liposomal delivery. For example, liposomes often exhibit severe
stability problems and are therefore only of limited clinical
use.
[0014] Based on these considerations, a long-felt need is apparent
for new carrier systems, particularly systems that are capable of
transporting molecules that do not penetrate the blood-brain
barrier using liposomal delivery. Methods, preparations and drug
delivery systems that permit drugs to traverse are likewise needed.
Enhancing penetration of the blood-brain barrier should also,
ideally, have reduced or minimal peripheral side effects, while at
the same time allowing for full therapeutic effect in the nervous
system.
[0015] There is a specific need for a method and system for
transporting lipophilic cations across the blood-brain barrier, as
many CNS active agents and other nervous system agents are amine
drugs, the term "amine" used loosely to refer to compounds
containing a tetravalent nitrogen moiety or a nitrogen moiety
capable of being protonated. The present invention is addressed to
the aforementioned needs in the art, and provides for effective
enhancement of an ionizable (e.g., an amine) compound's
lipophilicity and hence solubility in a lipophilic medium, in turn
facilitating passage across the blood-brain barrier.
[0016] The present method is useful not only in conjunction with
delivery of CNS active agents, but also with a host of other
pharmacologically active agents, including metal-based drugs.
[0017] The invention is not, however, limited to use in drug
delivery. The invention finds utility in a host of contexts where
there is a need to increase the solubility of a biologically active
agent in a lipophilic medium. For example, the invention is useful
in conjunction with increasing the lipophilic solubility of medical
imaging and diagnostic agents, as well as the lipophilic solubility
of "non-pharmacological" nutrients such as dietary supplements,
herbal extracts, and the like. In addition, in the agricultural
field, many agricultural chemicals (or "agrochemicals"), including
insecticides, herbicides, fungicides and other pesticides, have
little or no aqueous solubility, and are only slightly soluble in
lipophilic solvents.
SUMMARY OF THE INVENTION
[0018] Accordingly, in one embodiment, the invention provides a
method for enhancing the solubility of an ionizable compound in a
lipophilic medium by admixing the ionizable compound with an
effective solubility enhancing amount of an N,N-dinitramide salt.
The ionizable compound may be in either ionized or un-ionized form
prior to admixture, and if in ionized form, in association with an
anionic counterion. The ionizable compound, upon ionization, gives
rise to a biologically active cationic species that becomes
ionically associated with the N,N-dinitramide anion following
admixture. The biologically active cationic species may be a
pharmacologically active cation.
[0019] Preferred ionizable compounds are ionizable
pharmacologically active agents, e.g., those which are centrally
acting agents such as CNS amines or other nervous system agents,
such as: sympathomimetic amines; neuroprotective and
neuroregenerative agents, including neurotrophic factors;
neuroactive amino acids and peptides; neurotransmitters; agents to
treat neurodegenerative disorders; CNS and respiratory stimulants;
and drugs that selectively modify CNS function. The ionizable
pharmacologically active agent may also be a metal-based drug or a
dietary supplement such as a vitamin, a mineral, or another
nutritional supplement.
[0020] The ionizable compounds may also be medical imaging or
diagnostic agents, or an agricultural chemical agent such as a
pesticide.
[0021] In a related embodiment, the invention provides novel salts
formed by reaction of the ionizable compounds with an
N,N-dinitramide salt, wherein the salts comprise the biologically
active cation of the ionizable compound is in association with
N,N-dinitramide anion. The salts have significantly enhanced
solubility in lipophilic media relative to that of the ionizable
compound.
[0022] In a further embodiment, methods of use are provided. One
such method is a process for enhancing the penetration of the
blood-brain barrier by a pharmacologically active agent, wherein
the method involves coadministering the active agent with an
N,N-dinitramide salt or coadministering the active agent as an
N,N-dinitramide salt.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0023] I. Definitions and Nomenclature
[0024] Before the present compounds, compositions and methods are
disclosed and described, it is to be understood that this invention
is not limited to specific biologically active agents,
N,N-dinitramide salts, dosage forms, modes of administration, or
the like, as such may vary. It is also to be understood that the
terminology used herein is for the purpose of describing particular
embodiments only and is not intended to be limiting.
[0025] It must be noted that, as used in the specification and the
appended claims, the singular forms "a," "an" and "the" include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to "a biologically active agent" in a
composition or dosage form means that one, two or more biologically
active agents can be present in the composition or dosage form,
reference to "a pharmaceutically acceptable carrier" includes a
single such carrier or a combination of different carriers, and the
like.
[0026] In this specification and in the claims which follow,
reference will be made to a number of terms which shall be defined
to have the following meanings:
[0027] As used herein, the phrase "having the formula" or "having
the structure" is not intended to be limiting and is used in the
same way that the term "comprising" is commonly used.
[0028] The term "alkyl" as used herein refers to a branched or
unbranched saturated hydrocarbon group typically although not
necessarily containing 1 to about 30 carbon atoms, such as methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl,
decyl, and the like, as well as cycloalkyl groups such as
cyclopentyl, cyclohexyl and the like. Generally, although again not
necessarily, alkyl groups herein contain 1 to about 12 carbon
atoms. The term "lower alkyl" intends an alkyl group of one to six
carbon atoms, preferably one to four carbon atoms. "Substituted
alkyl" refers to alkyl substituted with one or more substituent
groups, and the terms "heteroatom-containing alkyl" and
"heteroalkyl" refer to alkyl in which at least one carbon atom is
replaced with a heteroatom. If not otherwise indicated, the terms
"alkyl" and "lower alkyl" include linear, branched, cyclic,
unsubstituted, substituted, and/or heteroatom-containing alkyl or
lower alkyl.
[0029] The term "alkenyl" as used herein refers to a branched or
unbranched hydrocarbon group typically although not necessarily
containing 2 to about 30 carbon atoms and at least one double bond,
such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl,
octenyl, decenyl, and the like. Generally, although again not
necessarily, alkenyl groups herein contain 2 to about 12 carbon
atoms. The term "lower alkenyl" intends an alkenyl group of two to
six carbon atoms, preferably two to four carbon atoms. "Substituted
alkenyl" refers to alkenyl substituted with one or more substituent
groups, and the terms "heteroatom-containing alkenyl" and
"heteroalkenyl" refer to alkenyl in which at least one carbon atom
is replaced with a heteroatom.
[0030] The term "alkynyl" as used herein refers to a branched or
unbranched hydrocarbon group typically although not necessarily
containing 2 to about 30 carbon atoms and at least one triple bond,
such as ethynyl, n-propynyl, isopropynyl, n-butynyl, isobutynyl,
octynyl, decynyl, and the like. Generally, although again not
necessarily, alkynyl groups herein contain 2 to about 12 carbon
atoms. The term "lower alkynyl" intends an alkynyl group of two to
six carbon atoms, preferably three or four carbon atoms.
"Substituted alkynyl" refers to alkynyl substituted with one or
more substituent groups, and the terms "heteroatom-containing
alkynyl" and "heteroalkynyl" refer to alkynyl in which at least one
carbon atom is replaced with a heteroatom.
[0031] The term "aryl" as used herein, and unless otherwise
specified, refers to an aromatic substituent containing a single
aromatic ring or multiple aromatic rings that are fused together,
linked covalently, or linked to a common group such as a methylene
or ethylene moiety. The common linking group may also be a carbonyl
as in benzophenone, an oxygen atom as in diphenylether, or a
nitrogen atom as in diphenylamine. Preferred aryl groups contain
one aromatic ring or two fused or linked aromatic rings, e.g.,
phenyl, naphthyl, biphenyl, diphenylether, diphenylamine,
benzophenone, and the like. "Substituted aryl" refers to an aryl
moiety substituted with one or more substituent groups, and the
terms "heteroatom-containing aryl" and "heteroaryl" refer to aryl
in which at least one carbon atom is replaced with a
heteroatom.
[0032] The term "heteroatom-containing" as in a
"heteroatom-containing hydrocarbyl group" refers to a molecule or
molecular fragment in which one or more carbon atoms is replaced
with an atom other than carbon, e.g., nitrogen, oxygen, sulfur,
phosphorus or silicon. Similarly, the term "heteroalkyl" refers to
an alkyl substituent that is heteroatom-containing, the term
"heterocyclic" refers to a cyclic substituent that is
heteroatom-containing, the term "heteroaryl" refers to an aryl
substituent that is heteroatom-containing, and the like. When the
term "heteroatom-containing" appears prior to a list of possible
heteroatom-containing groups, it is intended that the term apply to
every member of that group. That is, the phrase
"heteroatom-containing alkyl, alkenyl and alkynyl" is to be
interpreted as "heteroatom-containing alkyl, heteroatom-containing
alkenyl and heteroatom-containing alkynyl."
[0033] "Hydrocarbyl" refers to univalent hydrocarbyl radicals
containing 1 to about 30 carbon atoms, preferably 1 to about 24
carbon atoms, most preferably 1 to about 12 carbon atoms, including
branched or unbranched, saturated or unsaturated species, such as
alkyl groups, alkenyl groups, aryl groups, and the like. The term
"lower hydrocarbyl" intends a hydrocarbyl group of one to six
carbon atoms, preferably one to four carbon atoms. The term
"hydrocarbylene" intends a divalent hydrocarbyl moiety containing 1
to about 30 carbon atoms, preferably 1 to about 24 carbon atoms,
most preferably 1 to about 12 carbon atoms, including branched or
unbranched, saturated or unsaturated species, or the like. The term
"lower hydrocarbylene" intends a hydrocarbylene group of one to six
carbon atoms, preferably one to four carbon atoms. "Substituted
hydrocarbyl" refers to hydrocarbyl substituted with one or more
substituent groups, and the terms "heteroatom-containing
hydrocarbyl" and "heterohydrocarbyl" refer to hydrocarbyl in which
at least one carbon atom is replaced with a heteroatom. Similarly,
"substituted hydrocarbylene" refers to hydrocarbylene substituted
with one or more substituent groups, and the terms
"heteroatom-containing hydrocarbylene" and "heterohydrocarbylene"
refer to hydrocarbylene in which at least one carbon atom is
replaced with a heteroatom. If not otherwise indicated,
"hydrocarbyl" indicates unsubstituted hydrocarbyl, substituted
hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted
heteroatom-containing hydrocarbyl.
[0034] By "substituted" as in "substituted hydrocarbyl,"
"substituted hydrocarbylene," "substituted alkyl," "substituted
alkenyl" and the like, as alluded to in some of the aforementioned
definitions, is meant that in the hydrocarbyl, hydrocarbylene,
alkyl, alkenyl or other moiety, at least one hydrogen atom bound to
a carbon atom is replaced with one or more substituents that are
functional groups such as hydroxyl, alkoxy, thio, amino, halo, and
the like. When the term "substituted" appears prior to a list of
possible substituted groups, it is intended that the term apply to
every member of that group. That is, the phrase "substituted alkyl,
alkenyl and alkynyl" is to be interpreted as "substituted alkyl,
substituted alkenyl and substituted alkynyl." Similarly,
"optionally substituted alkyl, alkenyl and alkynyl" is to be
interpreted as "optionally substituted alkyl, optionally
substituted alkenyl and optionally substituted alkynyl."
[0035] By the terms "effective amount" or "pharmaceutically
effective amount" of an agent as provided herein are meant a
nontoxic but sufficient amount of the agent to provide the desired
effect.
[0036] By "pharmaceutically acceptable," such as in the recitation
of a "pharmaceutically acceptable carrier," or a "pharmaceutically
acceptable acid addition salt," is meant a material that is not
biologically or otherwise undesirable, i.e., the material may be
administered to an individual along with the active agent(s)
without causing any undesirable biological effects or interacting
in a deleterious manner with any of the other components of the
pharmaceutical composition in which it is contained.
[0037] The term "ionizable compound" refers to a compound having at
least one ionizable site in its molecular structure. The term
"ionizable" does not necessarily mean "ionized," i.e., the
ionizable compounds herein may be in either ionized or un-ionized
form. Ionization of the ionizable compounds results in formation of
a biologically active (e.g., pharmacologically active) cationic
species in association with an anionic counterion.
[0038] The "solubility" of a compound refers to its solubility in
the indicated liquid determined under standard conditions, e.g., at
room temperature (typically about 25.degree. C.) and atmospheric
pressure, and neutral pH.
[0039] The term "hydrophobic" is used to refer to a compound having
an octanol:water partition coefficient (at room temperature,
generally about 23.degree. C.) of at least about 8:1, preferably at
least about 10:1, more preferably 20:1 or higher. The biologically
active agents herein are hydrophobic compounds. "Hydrophobic"
active agents are sometimes referred to herein as "water insoluble"
or "sparingly water soluble," or as having "low aqueous
solubility." The term "hydrophilic" refers to a material that is
not hydrophobic.
[0040] The term "controlled release" is intended to refer to any
drug-containing formulation in which release of the drug is not
immediate, i.e., with a "controlled release" formulation, oral
administration does not result in immediate release of the drug
into an absorption pool. The term is used interchangeably with
"nonimmediate release" as defined in Remington: The Science and
Practice ofpharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing
Company, 1995). As discussed therein, immediate and nonimmediate
release can be defined kinetically by reference to the following
equation: 1
[0041] The "absorption pool" represents a solution of the drug
administered at a particular absorption site, and k.sub.r, k.sub.a
and k.sub.e are first-order rate constants for (1) release of the
drug from the formulation, (2) absorption, and (3) elimination,
respectively. For immediate release dosage forms, the rate constant
for drug release k.sub.r is far greater than the absorption rate
constant k.sub.a. For controlled release formulations, the opposite
is true, i.e., k.sub.r<<k.sub.a, such that the rate of
release of drug from the dosage form is the rate-limiting step in
the delivery of the drug to the target area. The term "controlled
release" as used herein includes any nonimmediate release
formulation, including but not limited to sustained release,
delayed release and pulsatile release formulations.
[0042] The term "sustained release" is used in its conventional
sense to refer to a drug formulation that provides for gradual
release of a drug over an extended period of time, and that
preferably, although not necessarily, results in substantially
constant blood levels of a drug over an extended time period.
[0043] By the term "transdermal" drug delivery is meant delivery by
passage of a drug through the skin or mucosal tissue and into the
bloodstream. "Transdermal" delivery is also intended to encompass
passage through scrotal skin.
[0044] The term "topical administration" is used in its
conventional sense to mean delivery of a topical drug or
pharmacologically active agent to the skin or mucosa.
[0045] II. The N,N-dinitramide Salt
[0046] The N,N-dinitramide salts useful as solubilizers herein have
the formula M.sup.+x[N(NO.sub.2).sub.2.sup.-].sub.x wherein M is
selected so that it is displaced by the biologically active
cationic species upon admixture and/or co-administration of the
N,N-dinitramide salt with the ionizable compound, and x is the
cationic charge of M. M is a cation selected from the group
consisting of a metal ion, an inorganic nitrogen-containing cation,
and a cationic derivative of an organic compound having one or more
tetravalent nitrogen atoms.
[0047] Metallic cations: Suitable metals for the M moiety include
the alkali metals Li, Na, K, Rb, and Cs of Group 1 of the Periodic
Table of the Elements; the Group 2 alkaline earth metals Ca, Ba,
Sr, and Mg; the Group 11 metals Cu, Ag, and Au; the Group 12 metals
Zn, Cd, and Hg; the Group 3 metals Al, Sc, Y, Ga, In, and the
lanthanides (57-71); the Group 4 metals Ti, Zr, Hf, Ge, and Sn;
Group 5 metals V, Nb, and Ta; the Group 6 metals Cr, Mo, and W; the
Group 7 metals Mn, Tc, and Re; the Group 8 metals Fe, Ru and Os;
and the Group 9 metals Co, Rh and Ir; the Group 10 metals Ni, Pd
and Pt. Of the foregoing, Li, Na, K, Be, and Mg are preferred. All
references to group numbers in the Periodic Table of the Elements
are to the new IUPAC format for numbering elements and groups, as
set forth in the CRC Handbook of Chemistry and Physics, 81.sup.st
Edition, Lide, Ed., 2001.
[0048] As noted above, M may also be an inorganic
nitrogen-containing cation, including, but not necessarily limited
to, the ammonium (NH--.sub.4.sup.+), hydrazinium
(H.sub.2N-NH.sub.3.sup.+), nitronium (O.dbd.N.dbd.), and
nitrosonium (N.ident.O.sup.+) cations, although the ammonium ion is
preferred (in which case the N,N-dinitramide salt is referred to as
ammonium dinitramide).
[0049] Some cationic derivatives of organic compounds having one or
more tetravalent nitrogen atoms and have the formula
R.sub.kH.sub.mN.sub.n.sup- .+q, wherein:
[0050] n is an integer in the range of 1 to 8;
[0051] k is an integer in the range of 1 to 2+n;
[0052] q is an integer in the range of 1 to n;
[0053] m is equal to n+2+q-k; and
[0054] each R is C.sub.1-C.sub.12 hydrocarbyl, typically linear or
branched lower alkyl.
[0055] Preferred nitrogen-containing cations within the
aforementioned group contain 1 or 2 nitrogen atoms. Specific
examples of such ions include, but are not limited to,
CH.sub.3NH.sub.3.sup.+, (CH.sub.3).sub.2NH.sub.2.sup.-,
(CH.sub.3).sub.3NH.sup.+, (CH.sub.3).sub.4N.sup.+,
C.sub.2H.sub.5NH.sub.3.sup.+, (C.sub.2H.sub.5).sub.2NH.sub.2.sup.+,
(C.sub.2H.sub.5).sub.3 NH.sup.+, (C.sub.2H.sub.5).sub.4N.sup.+,
(C.sub.2H.sub.5)(CH.sub.3)NH.sub.2.sup.+,
(C.sub.2H.sub.5)(CH.sub.3).sub.2NH.sup.+,
(C.sub.2H.sub.5).sub.2(CH.sub.3- ).sub.2N.sup.+,
(C.sub.3H.sub.7).sub.4N.sup.+, (C.sub.4H.sub.9).sub.4N.sup- .+,
CH.sub.3N.sub.2H.sub.4.sup.+, (CH.sub.3).sub.2N.sub.2H.sub.3.sup.+,
(CH.sub.3).sub.3N.sub.2H.sub.2.sup.+,
(CH.sub.3).sub.4N.sub.2H.sup.+, and
(CH.sub.3).sub.5N.sub.2.sup.+.
[0056] Other cationic derivatives of organic compounds that can
serve as M.sup.+ include guanidium (a cationic derivative of
guanidine), biguanidinium (a cationic derivative of biguanidine),
the guanylurea cation H.sub.2N(NH)CNH.sub.2C(O)NH2).sup.+,
ethylenediaminium (a cationic derivative of ethylenediamine),
piperazinediium (a cationic derivative of piperazine),
monoaminoguanidinium (a cationic derivative of monoaminoguanidine),
diaminoguanidinium (a cationic derivative of diaminoguanidine),
triaminoguanidinium (a cationic derivative of triaminoguanidine),
tetrazolium (a cationic derivative of tetrazole), aminotetrazolium
(a cationic derivative of aminotetrazole), amino-ammonium-furazan
(a cationic derivative of diaminofurazan), polyvinylammonium (a
cationic derivative of polyvinylammonia), and dicyandiamidium (a
cationic derivative of dicyandiamide). See, for example, U.S. Pat.
Nos. 5,254,324 to Bottaro et al. and 6,117,255 to Blomquist.
[0057] Ammonium dinitramide, or "ADN," is a particularly preferred
solubilizing agent. ADN has the chemical formula
NH.sub.4.sup.+(N(NO.sub.- 2).sub.2.sup.-), and can be obtained from
SRI International in Menlo Park, Calif. ADN may also be readily
prepared, using the methods disclosed in the art. See, for example,
U.S. Pat. Nos. 5,198,204 and 5,254,324 to Bottaro et al. and
5,316,749 and 5,415,852 to Schmitt et al., all assigned to SRI
International.
[0058] III. The Biologically Active Agent
[0059] The ionizable compound herein is a biologically active agent
that upon ionization gives rise to a biologically active cationic
species in association with an anionic counterion. The ionizable
compound that is admixed with the N,N-dinitramide salt will,
accordingly, be a biologically active agent in one the following
forms:
[0060] (1) a salt comprised of a biologically active cationic
species (generally a nitrogen-containing cationic species that
includes at least one positively charged nitrogen atom) and an
anionic counterion; or
[0061] (2) an electronically neutral compound that:
[0062] (a) ionizes upon admixture with the N,N-dinitramide salt to
give a biologically active cationic species in ionic association
with the N,N-dinitramide anion; and/or
[0063] (b) becomes protonated in an aqueous medium at physiological
pH to give a biologically active cationic species in ionic
association with one or more hydroxide counterions.
[0064] The biologically active agent may be a pharmacologically
active agent or any other compound that has a biological, chemical
and/or physical effect on a biological system, i.e., on a living
organism. Biologically active agents herein include, by way of
example, pharmacologically active agents (e.g., prophylactic and
therapeutic pharmaceutical agents), medical imaging and diagnostic
agents, dietary supplements, and agricultural chemicals.
[0065] One group of biologically active agents of interest herein
are cationic species having the formula NR.sub.4.sup.+, in
association with a negatively charged anion. The R groups may be
the same or different, and are independently selected from
C.sub.1-30 hydrocarbyl groups, substituted C.sub.1-30 hydrocarbyl
groups, heteroatom-containing C.sub.1-30 hydrocarbyl groups, and
substituted heteroatom-containing C.sub.1-30 hydrocarbyl groups,
e.g., alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, alkaryl,
heteroaryl, and the like.
[0066] A. Pharmacologically Active Agents
[0067] In one embodiment, then, the biologically active agent is a
pharmacologically active agent, generally a hydrophobic active
agent. Preferred pharmacologically active agents are centrally
acting drugs, particularly CNS active agents and other nervous
system agents, including, but not limited to, the following:
sympathomimetic amines; neuroprotective and neuroregenerative
agents, including neurotrophic factors; neuroactive amino acids and
peptides; neurotransmitters; muscarinic receptor agonists and
antagonists; anticholinesterases; neuromuscular blocking agents;
ganglionic stimulating drugs; agents to treat neurodegenerative
disorders such as Alzheimer's disease, Huntington's disease,
Parkinson's disease, and amyotrophic lateral sclerosis (ALS);
anti-epileptic agents; CNS and respiratory stimulants; and drugs
that selectively modify CNS function, including anesthetic agents,
analgesic agents, antiemetic agents, antihypertensive agents,
cerebral vasodilators, hypnotic agents and sedatives, anxiolytics
and tranquilizers, neuroleptic agents, anti-microbial agents, alpha
adrenergic receptor antagonists, and appetite suppressants. Some
agents, as will be appreciated by those of ordinary skill in the
art, are encompassed by two or more of the aforementioned
groups.
[0068] Examples of these pharmacologically active agents are as
follows:
[0069] Sympathomimetic amines. Sympathomimetic amines, including
the catecholamines, are amine drugs that mimic the actions of drugs
that activate the sympathetic nervous system, such as epinephrine
and norepinephrine. Sympathomimetic amines thus include albuterol,
amphetamine, benzphetamine, colterol, diethylpropion, dopamine,
dopamine hydrochloride, dobutamine, ephedrine, epinephrine,
epinephrine bitartrate, ethylnorepinephrine, ethylnorepinephrine
hydrochloride, fenfluramine, fenoldapam, fenoldapam mesylate,
hydroxyamphetamine, hydroxyamphetamine hydrobromide, ibopamine,
isoetharine, isoproterenol, isoproterenol hydrochloride,
mephentermine, mephentermine sulfate, metaproterenol, metaraminol,
metaraminol bitartrate, methoxamine, methoxamine hydrochloride,
midodrine, norepinephrine, norepinephrine bitartrate,
phendimetrazine, phenmetrazine, phentermine, phenylephrine,
phenylephrine hydrochloride, phenylethylamine, phenylpropanolamine,
prenalterol, propylhexedrine, ritodrine, terbutaline, terbutaline
sulfate, and tyramine.
[0070] Neuroprotective and neuroregenerative agents. These include
excitatory amino acid antagonists and neurotrophic factors, e.g.,
brain derived neurotrophic factor, ciliary neurotrophic factor, and
nerve growth factor, neurotrophin(NT) 3 (NT3), NT4 and NT5.
[0071] Neuroactive amino acids andpeptides. The primary neuroactive
amino acids are .gamma.-aminobutyric acid (GABA), glycine,
.beta.-alanine, taurine, and glutamate, and the neuroactive
peptides include bradykinin, kallidin, des-Arg.sup.9-bradykinin,
des-Arg.sup.10-kallidin, des-Arg.sup.9-[Leu.sup.8]-bradykinin,
[D-Phe.sup.7]-bradykinin, HOE 140, neuropeptide Y, enkaphalins and
related opioid peptides such as Met.sup.5-enkaphalin,
Leu.sup.5-enkephalin, .alpha.-, .beta.- and .gamma.-endorphin,
.alpha.- and .beta.- neo-endorphin, and dynorphin.
[0072] Neurotransmitters. The primary neurotransmitters, as will be
appreciated by those of ordinary skill in the art, are GABA
(.gamma.-aminobutyric acid), glycine, glutamate, acetylcholine,
dopamine, epinephrine, 5-hydroxytryptamine, substance P, serotonin,
enkaphalins and related opioid peptides as above, and
catecholamines.
[0073] Muscarinic receptor agonists and antagonists. Muscarinic
receptor agonists include, by way of example: choline esters such
as acetylcholine, methacholine, carbachol, bethanechol
(carbamylmethylcholine), bethanechol chloride; cholinomimetic
natural alkaloids and synthetic analogs thereof, including
arecoline, pilocarpine, muscarine, McN-A-343, and oxotremorine.
Muscarinic receptor antagonists are generally belladonna alkaloids
or semisynthetic or synthetic analogs thereof, such as atropine,
scopolamine, homatropine, homatropine methylbromide, ipratropium,
methantheline, methscopolamine and tiotropium.
[0074] Anticholinesterases. As is well known, the function of
acetylcholinesterase (AChE) is to terminate the action of
acetylcholine at the junctions of various cholinergic nerve endings
with their effector organs or postsynaptic sites. See, for example,
Goodman Gilman's The Pharmacological Basis of Therapeutics,
9.sup.th Edition, Jardman et al, Eds. (1996), at Chapter 8.
Anticholinesterase agents inhibit the action of ACHE and thus
results in the accumulation of acetylcholine at cholinergic
receptor cites, stimulating cholinergic receptors throughout the
CNS and peripheral nervous system (PNS). Anticholinesterases
include, for example, ambenonium, ambenonium chloride, demecarium,
demecarium bromide, echothiophate iodide, edrophonium, edrophonium
chloride, neostigmine, neostigmine bromide, neostigmine
methylsulfate, physostigmine, physostigmine salicylate,
pyridostigmine, and pyridostigmine bromide.
[0075] Neuromuscular blocking agents and ganglionic blocking drugs.
Neuromuscular blocking agents include dicholine esters (e.g.,
succinylcholine), benzylisoquinolines (d-tubocurarine, atracurium,
doxacurium, mivacurium) and ammonio steroids (pancuronium,
pipecuronium, rocuronium, vecuronium), while the primary ganglionic
stimulating drugs are hexamethonium, trimethaphan,
mecamylamine.
[0076] Agents to treat neurodegenerative diseases. Active agents
for treating Alzheimer's disease and Huntington's disease are drugs
useful for treating dementias and/or enhancing memory and learning
processes. Donezepil, donepezil hydrochloride, physostigmine,
physostigmine salicylate, tacrine and tacrine hydrochloride are
active agents typically used for treatment of Alzheimer's Disease,
while fluoxetine and carbamazepine are used to treat Huntington's
Disease. Anti-Parkinsonism drugs useful herein include amantadine,
apomorphine, bromocriptine, levodopa (particularly a
levodopa/carbidopa combination), pergolide, ropinirole, selegiline,
trihexyphenidyl, trihexyphenidyl hydrochloride, and anticholinergic
agents. ALS is generally treated with spasmolytic (anti-spastic)
agents such as baclofen, diazepam, tizanidine, and dantrolene.
[0077] Anti-epileptic agents. Suitable anti-epileptic agents are
anti-convulsant (anti-seizure) drugs such as azetazolamide,
carbamazepine, clonazepam, clorazepate, ethosuximide, ethotoin,
felbamate, gabapentin, lamotrigine, mephenytoin, mephobarbital,
phenytoin, phenobarbital, primidone, trimethadione, vigabatrin and
the benzodiazepines. Benzodiazepines, as is well known, are useful
for a number of indications, including anxiety, insomnia, and
nausea.
[0078] CNS and respiratory stimulants. CNS and respiratory
stimulants also encompass a number of active agents useful herein.
These stimulants include, but are not limited to, the following:
xanthines such as caffeine and theophylline; amphetamines such as
amphetamine, benzphetamine hydrochloride, dextroamphetamine,
dextroamphetamine sulfate, levamphetamine, levamphetamine
hydrochloride, methamphetamine, and methamphetamine hydrochloride;
and miscellaneous stimulants such as methylphenidate,
methylphenidate hydrochloride, modafinil, pemoline, sibutramine,
and sibutramine hydrochloride.
[0079] Drugs that selectively modify CNSfunction. These include,
without limitation:
[0080] (1) anesthetic agents such as ketamine;
[0081] (2) opioid analgesics such as alfentanil, buprenorphine,
butorphanol, codeine, drocode, fentanyl, hydrocodone,
hydromorphone, levorphanol, meperidine, methadone, morphine,
nalbuphine, oxycodone, oxymorphone, pentazocine, propoxyphene,
sufentanil, and tramadol;
[0082] (3) nonopioid analgesics such as apazone, etodolac,
difenpiramide, indomethacine, meclofenamate, mefenamic acid,
oxaprozin, phenylbutazone, piroxicam, and tolmetin;
[0083] (4) antiemetics such as chlorpromazine, cisapride,
domperidone, granisetron, metoclopramide, ondansetron,
perphenazine, prochlorperazine, promethazine, thiethylperazine, and
triflupromazine;
[0084] (5) antihypertensive agents such as apraclonidine,
clonidine, guanfacine, and guanabenz;
[0085] (6) cerebral vasodilators such as vincamine, naftidrofuryl
oxalate, papaverine, and nicotinic acid;
[0086] (7) hypnotic agents and sedatives such as clomethiazole,
ethinamate, etomidate, glutethimide, meprobamate, methyprylon,
zolpidem, and barbiturates (e.g., amobarbital, apropbarbital,
butabarbital, butalbital, mephobarbital, methohexital,
pentobarbital, phenobarbital, secobarbital, thiopental);
[0087] (8) anxiolytics and tranquilizers such as benzodiazepines
(e.g., alprazolam, brotizolam, chlordiazepoxide, clobazam,
clonazepam, clorazepate, demoxepam, diazepam, estazolam,
flumazenil, flurazepam, halazepam, lorazepam, midazolam,
nitrazepam, nordazepam, oxazepam, prazepam, quazepam, temazepam,
triazolam), buspirone, chlordiazepoxyd, and droperidol;
[0088] (9) neuroleptic agents, including antidepressant drugs,
antimanic drugs, and antipsychotic agents, wherein
[0089] antidepressant drugs include (a) the tricyclic
antidepressants such as amoxapine, amitriptyline, clomipramine,
desipramine, doxepin, imipramine, maprotiline, nortryptiline,
protryptiline, and trimipramine, (b) the serotonin reuptake
inhibitors citalopram, fluoxetine, fluvoxamine, paroxetine,
sertraline, and venlafaxine, (c) monoamine oxidase inhibitors such
as phenelzine, tranylcypromine, and (-)-selegiline, and (d) other,
"atypical" antidepressants such as bupropion, nefazodone, trazodone
and venlafaxine, and
[0090] antimanic and antipsychotic agents include (a)
phenothiazines such as acetophenazine, acetophenazine maleate,
chlorpromazine, chlorpromazine hydrochloride, fluphenazine,
fluphenazine hydrochloride, fluphenazine enanthate, fluphenazine
decanoate, mesoridazine, mesoridazine besylate, perphenazine,
thioridazine, thioridazine hydrochloride, trifluoperazine, and
trifluoperazine hydrochloride, (b) thioxanthenes such as
chlorprothixene, thiothixene, and thiothixene hydrochloride, and
(c) other heterocyclic drugs such as carbamazepine, clozapine,
droperidol, haloperidol, haloperidol decanoate, loxapine succinate,
molindone, molindone hydrochloride, olanzapine, pimozide,
quetiapine, risperidone, and sertindole;
[0091] (10) anticholinergic drugs such as atropine, scopolamine and
glycopyrrolate;
[0092] (11) anti-microbial agents such as
[0093] (a) tetracycline antibiotics and related compounds
(chlortetracycline, oxytetracycline, demeclocycline, methacycline,
doxycycline, rolitetracycline),
[0094] (b) macrolide antibiotics such as erythromycin,
clarithromycin, and azithromycin,
[0095] (c) streptogramin antibiotics such as quinupristin and
dalfopristin,
[0096] (d) beta-lactam antibiotics, including penicillins (e.g.,
penicillin G, penicillin VK), antistaphylococcal penicillins (e.g.,
cloxacillin, dicloxacillin, nafcillin, and oxacillin), extended
spectrum penicillins (e.g., aminopenicillins such as ampicillin and
amoxicillin, and the antipseudomonal penicillins such as
carbenicillin), and cephalosporins (e.g., cefadroxil, cefepime,
cephalexin, cefazolin, cefoxitin, cefotetan, cefuroxime,
cefotaxime, ceftazidime, and ceftriazone), and carbapenems such as
imiprenem, meropenem and aztreonam,
[0097] (e) aminoglycoside antibiotics such as streptomycin,
gentamicin, tobramycin, amikacin, and neomycin,
[0098] (f) glycopeptide antibiotics such as vancomycin, and
teicoplanin;
[0099] (g) sulfonamide antibiotics such as sulfacetamide,
sulfabenzamide, sulfadiazine, sulfadoxine, sulfamerazine,
sulfamethazine, sulfamethizole, and sulfamethoxazole,
[0100] (h) quinolone antibiotics such as ciprofloxacin, nalidixic
acid, and ofloxacin;
[0101] (i) anti-mycobacterials such as isoniazid, rifampin,
rifabutin, ethambutol, pyrazinamide, ethionamide, aminosalicylic,
and cycloserine,
[0102] (j) systemic antifungal agents such as itraconazole,
ketoconazole, fluconazole, and amphotericin B,
[0103] (k) antiviral agents such as acyclovir, famcicylovir,
ganciclovir, idoxuridine, sorivudine, trifluridine, valacyclovir,
vidarqabine, didanosine, stavudine, zalcitabine, zidovudine,
amantadine, interferon alpha, ribavirin and rimantadine, and
[0104] (l) miscellaneous antimicrobial agents such as
chloramphenicol, spectinomycin, and polymyxin B (colistin), and
bacitracin;
[0105] (12) alpha adrenergic receptor antagonists such as
doxazosin, indoramine, phenoxybenzamine, phentolamine, prazosin,
tolazoline, terazosin, trimazosin, and yohimbine; and
[0106] (13) appetite suppressants such as amphetamine,
dextroamphetamine, dextroamphetamine sulfate, diethylpropion
hydrochloride, mazindol, methamphetamine hydrochloride,
phentermine, and phentennine hydrochloride.
[0107] For certain active agents that are commercially available in
the form of an acid addition salt, the commercially available salt
form is indicated above along with the free base form of the drug.
However, any of the foregoing active agents may be in the form of
either the free base (i.e., as an un-ionized, electronically
neutral compound) or as any pharmaceutically acceptable acid
addition salt thereof, formed with either an inorganic or an
organic acid. Suitable inorganic acids include, for example,
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
and phosphoric acid, while suitable organic acids include acetic
acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,
malic acid, malonic acid, succinic acid, maleic acid, fumaric acid,
tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic
acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic
acid, salicylic acid, and the like.
[0108] The methodology of the invention may also be used with
pharmacologically active agents other than the aforementioned
"centrally active agents," and include other nitrogenous drugs as
well as metal-based drugs, discussed infra, and nutritional
supplements, including vitamins, minerals and other dietary
supplements.
[0109] The term "vitamin" is used in the conventional sense to
refer to trace organic substances that are required in the diet,
and includes without limitation, thiamin, riboflavin, nicotinic
acid, pantothenic acid, pyridoxine, biotin, folic acid, vitamin
B.sub.12, vitamin A, vitamin D, vitamin E and vitamin K. Also
included within the term "vitamin" are the coenzymes thereof, such
as thiamine pyrophosphates (TPP), flavin mononucleotide (FMM),
flavin adenine dinucleotide (FAD), nicotinamide adenine
dinucleotide (NAD), nicotinamide adenine dinucleotide phosphate
(NADP), Coenzyme A (CoA), Coenzyme Q (CoQ), pyridoxal phosphate,
biocytin, tetrahydrofolic acid, and coenzyme B.sub.12. The term
"vitamin" also includes choline and carnitine. The term "mineral"
refers to inorganic substances that are required in the human diet,
and includes, without limitation, calcium, magnesium, iron, zinc,
selenium, copper, manganese, chromium, molybdenum, etc. The term
"dietary supplement" as used herein means a substance that has an
appreciable nutritional effect when administered in small
amounts.
[0110] B. Metal-Containing Biologically Active Agents
[0111] Metal-based drugs, as alluded to in the aforementioned
section, represent an additional class of compounds with which the
present invention is useful. The drug may be any metal-containing
drug in which the metal atom, when charged and thus in cationic
form, is biologically active. Such drugs include, by way of
example: anticancer agents, containing Al, Ga, In, Ti, Ru, Pt, Au,
or Sn (a specific example is cisplatin); antimicrobial agents,
containing Cu, Zn, Ag, Hg, or Bi (such as silver sulfadiazine);
antiarthritic agents, containing Au (such as aurothioglucose,
aurothiomalate, and auranofin), antipsychotic agents, such as
lithium; antihypertensive agents, containing Fe or Zn; antiviral
agents containing, e.g., Li, Pt, Au, W, or Cu; antiulcer drugs
containing bismuth; antacid agents containing, e.g., Al, Na, Mg or
Ca; radiosensitizing agents for cancer therapy, containing, e.g.,
Pt or Ru; metalloporphyrins and metallochlorins for photodynamic
therapy; insulin mimetics containing, e.g., Cr or V; mineral
supplements such as Ca, Mg, Fe, Zn, Se, Cu, Mn, Cr, Mo, K; contrast
agents for magnetic resonance imaging containing, e.g., Mn, Gd, Fe;
X-ray imaging agents, such as Ba-containing compounds; diagnostic
radio-imaging agents, e.g. .sup.99mTc, .sup.111In; .beta.-emitters
useful for therapy (e.g., .sup.90Y, .sup.212Bi);metalloenzyme
mimetics (Mn, Cu, Fe); and radiotherapy agents (e.g. Re, Y,
Pb).
[0112] C. Agricultural Chemicals
[0113] Other suitable biologically active agents with which the
present invention may be advantageously employed are agricultural
chemicals, e.g., compounds that can be used as agricultural
fertilizers, nutrients, plant growth accelerants, plant growth
controlling chemicals, insect growth regulators, and pesticides,
with the term "pesticides" including, but not limited to,
acaricides, avicides, bacteriocides, fungicides, insecticides,
larvicides, miticides, molluscicides, nematocides, ovicides,
predicides, pupicides, and rodenticides. Common pesticides that are
ionizable to give a biologically active cation, and may thus
benefit from the method and formulations of the invention, include
acylalanines, haloacetanilides, triazole derivatives, pyrethroids,
formamidines, and strobilurines.
[0114] Examples of specific, representative agricultural chemicals
with which the methodology of the invention may be advantageously
employed include, but are not limited to, the following:
[0115] Atrazine (2-chloro-4-ethylamino-6
isopropylamino-s-trriazine);
[0116] Simazine (2-chloro-4,6,-bis-(ethylamino)-s-triazine);
[0117] Dodine (n-dodecylguanidine acetate);
[0118] Thiram (tetramethylthiuram disulfide);
[0119] Manazon (s-(4,6-diamino-1,3,5-triazin-2-yl methyl)dimethyl
phosphorothiolthionate);
[0120] PP 675 (5-butyl-2-dimethylamino-4-hydroxy-6-methyl
pyrimidine);
[0121] PP 062 (5,6-dimethyl-2-dimethylamino-4 pyrimidinyl
dimethylcarbamate);
[0122] PP 149 (5-n-butyl-2 ethylamino-4-hydroxy-6
methylpyrimidine);
[0123] GS 14260
(4-ethylamino-2-methylthio-6-t-butyl-amino-1,3,5-triazine)- ;
[0124] Pyrazon (5-amino-4-chloro-2-phenyl-3-pylidazone);
[0125] WL 9385
(2-Azido-4-ethylamino-6-t-butylamino-s-triazine);
[0126] Ametryne
(2-methylmercapto-4-ethylamino-6-isopropyl-amino-s-triazin- e);
[0127] Prometryne( 2-methylmercapto-4,6-bisisopropyl
amino-s-triazine);
[0128] Benefin
(N-butyl-N-ethyl-2,2,2-trifluoro-2,6-dinitro-p-toluidine); and
[0129] Nitralin
(2,6-dinitro-4-methylsulfonyl-N,N-dipropyl-aniline).
[0130] IV. Pharmaceutical Compositions, Dosage Forms and Modes of
Administration
[0131] Pharmaceutical compositions and dosage forms may contain (1)
an N,N-dinitramide salt of a biologically active agent as described
in Sections IIIA and IIIB, or (2) an N,N-dinitramide anion and the
biologically active agent (wherein the active agent may be either
electronically neutral or in the form of a salt). Alternatively,
the biologically active agent and the N,N-dinitramide salt may be
in separate dosage forms. In the latter case, the active agent and
the N,N-dinitramide salt may or may not be administered at the same
time. In some cases, it may be advantageous for delivery of drugs
across the blood-brain barrier for the N,N-dinitramide salt to be
administered on the order of 30 minutes to 2 hours before
administration of the active agent.
[0132] In any of the aforementioned embodiments, the amount of the
N,N-dinitramide salt that is co-administered with the biologically
active agent should be an effective solubility enhancing amount,
i.e., an amount effective to increase the solubility of the
biologically active agent in a lipophilic medium and thereby
enhance bioavailability and transport across lipophilic membranes
and the blood-brain barrier. The effective solubility enhancing
amount of the N,N-dinitramide salt is generally selected to provide
a molar ratio of the N,N-dinitramide salt to the ionizable compound
(i.e., the biologically active agent, whether in ionized or
unionized form) in the range of about 0.5z:1 to about 5z:1 wherein
z is the charge of the biologically active cationic species.
Preferably, the amount is selected to provide a molar ratio of the
N,N-dinitramide salt to the active agent in the range of about 1z:1
to about 2z:1, and most preferably about 1z: 1 to about 1.5z: 1. Of
course, if the active agent is administered in the form of an
N,N-dinitramide salt, such that a biologically active cationic
species is associated with the dinitramide anion, the ratio of the
dinitramide anion to the biologically active cationic species will
be approximately 1z:1 wherein, again, z is the charge of the
biologically active cationic species.
[0133] The compounds may be administered orally, parenterally,
rectally, vaginally, buccally, sublingually, nasally, by
inhalation, topically, transdermally, or via an implanted reservoir
in dosage forms containing conventional non-toxic pharmaceutically
acceptable carriers and excipients. The term "parenteral" as used
herein is intended to include subcutaneous, intravenous, and
intramuscular injection. The amount of biologically active agent
administered will, of course, be dependent on the particular active
agent, the condition or disorder being treated, the severity of the
condition or disorder, the subject's weight, the mode of
administration and other pertinent factors known to the prescribing
physician.
[0134] Depending on the intended mode of administration, the
pharmaceutical compositions may be in the form of solid, semi-solid
or liquid dosage forms, such as, for example, tablets, capsules,
caplets, liquids, suspensions, emulsions, suppositories, granules,
pellets, beads, powders, or the like, preferably in unit dosage
form suitable for single administration of a precise dosage.
[0135] Oral dosage forms are preferred, and include tablets,
capsules, caplets, and nonaqueous solutions, suspensions and or
syrups, and may also comprise a plurality of granules, beads,
powders or pellets that may or may not be encapsulated. Such dosage
forms are prepared using conventional methods known to those in the
field of pharmaceutical formulation and are described in the
pertinent texts, e.g., in Remington: The Science and Practice of
Pharmacy, 20.sup.th Edition, Gennaro, A. R., Ed. (Lippincott,
Williams and Wilkins, 2000).
[0136] Tablets are the preferred oral dosage forms, and may be
manufactured using standard tablet processing procedures and
equipment. One method for forming tablets herein is by direct
compression of a powdered, crystalline or granular composition
containing the N,N-dinitramide salt, the biologically active agent,
or both, alone or in combination with diluents, binders,
lubricants, disintegrants, colorants or the like. As an alternative
to direct compression, tablets can be prepared using
wet-granulation or dry-granulation processes. Tablets may also be
molded rather than compressed, starting with a moist or otherwise
tractable material; however, compression and granulation techniques
are preferred.
[0137] In addition to the N,N-dinitramide salt of the biologically
active agent (or, in an alternative embodiment, as discussed above,
the N,N-dinitramide salt and/or the biologically active agent,),
the tablet will generally contain other materials such as binders,
diluents, lubricants, disintegrants, fillers, stabilizers,
surfactants, coloring agents, and the like. An additional active
agent may also be included if desired. Binders are used to impart
cohesive qualities to the tablet core, and thus ensure that the
core remains intact after compression and prior to coating.
Suitable binder materials include, but are not limited to, starch
(including corn starch and pregelatinized starch), gelatin, sugars
(including sucrose, glucose, dextrose and lactose), polyethylene
glycol, waxes, and natural and synthetic gums, e.g., acacia sodium
alginate, polyvinylpyrrolidone, cellulosic polymers (including
hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl
cellulose, ethyl cellulose, hydroxyethyl cellulose, and the like),
and Veegum. Diluents are typically necessary to increase bulk so
that a practical size tablet is ultimately provided. Suitable
diluents include dicalcium phosphate, calcium sulfate, lactose,
cellulose, kaolin, mannitol, sodium chloride, dry starch and
powdered sugar. Lubricants are used to facilitate manufacture of
the drug-containing core; examples of suitable lubricants include,
for example, magnesium stearate, calcium stearate, and stearic
acid. Stearates, if present, preferably represent at no more than
approximately 2 wt. % of the drug-containing core. Disintegrants
are used to facilitate disintegration of the tablet, and are
generally starches, clays, celluloses, algins, gums or crosslinked
polymers. Fillers include, for example, materials such as silicon
dioxide, titanium dioxide, alumina, talc, kaolin, powdered
cellulose and microcrystalline cellulose, as well as soluble
materials such as mannitol, urea, sucrose, lactose, dextrose,
sodium chloride and sorbitol. Stabilizers are used to inhibit or
retard drug decomposition reactions that include, by way of
example, oxidative reactions. Surfactants may be anionic, cationic,
amphoteric or nonionic surface active agents.
[0138] The dosage form may also be a capsule, in which case the
active agent-containing composition may be encapsulated in the form
of a liquid or solid (including particulates such as granules,
beads, powders or pellets). Suitable capsules may be either hard or
soft, and are generally made of gelatin, starch, or a cellulosic
material, with gelatin capsules preferred. Two-piece hard gelatin
capsules are preferably sealed, such as with gelatin bands or the
like. See, for example, Remington: The Science and Practice of
Pharmacy , Nineteenth Edition. (1995) cited supra, which describes
materials and methods for preparing encapsulated pharmaceuticals.
If the active-agent containing composition is present within the
capsule in liquid form, a lipophilic carrier is necessary to
dissolve the biologically active agent and/or the N,N-dinitramide
salt. The lipophilic carrier must be compatible with all components
of the composition, and must be suitable for ingestion.
[0139] Suitable lipophilic carriers include, but are not limited
to, the following: phospholipids such as phosphorylated diacyl
glycerides, and particularly phospholipids selected from the group
consisting of diacyl phosphatidylcholines, diacyl
phosphatidylethanolamines, diacyl phosphatidylserines, diacyl
phosphatidylinositols, diacyl phosphatidylglycerols, diacyl
phosphatidic acids, and mixtures thereof; fatty acids such as
isovaleric acid, valeric acid, caproic acid, enanthic acid,
caprylic acid, pelargonic acid, capric acid, lauric acid, myristic
acid, palmitic acid, stearic acid, arachidic acid, behenic acid,
lignoceric acid, oleic acid, linoleic acid, linolenic acid, and
arachidonic acid; lower fatty acid esters comprising esters of the
foregoing fatty acids, wherein the carboxylic acid group of the
fatty acid is replaced with an ester moiety --(CO)--OR wherein R is
a C.sub.1-C.sub.3 alkyl moiety optionally substituted with one or
two hydroxyl groups; fatty alcohols corresponding to the
aforementioned fatty acids, wherein the carboxylic acid group of
the fatty acid is replaced by a --CH.sub.2OH group; glycolipids
such as cerebroside and gangliosides; and oils, including animal
oils such as cod liver oil and, menhaden oil, and vegetable oils
such as babassu oil, castor oil, corn oil, cotton seed oil, linseed
oil, mustard oil, olive oil, palm oil, palm kernel oil, peanut oil,
poppyseed oil, rapeseed oil, safflower oil, sesame oil, soybean
oil, sunflower seed oil, tung oil or wheat germ oil.
[0140] Solid dosage forms, whether tablets, capsules, caplets, or
particulates, may, if desired, be coated so as to provide for
delayed release. For example, enteric coatings may be necessary if
it is desired to prevent drug release in the upper gastrointestinal
tract. Enterically coated dosage forms of the invention may be
manufactured using standard coating procedures and equipment. Such
procedures are known to those skilled in the art and described in
the pertinent texts, e.g., in Remington, supra. Generally, after
preparation of the solid dosage form, an enteric coating
composition is applied using a coating pan, an airless spray
technique, fluidized bed coating equipment, or the like. Enteric
coating compositions comprise a polymeric material that prevents
drug release in the acidic environment of the stomach but dissolve
sufficiently in the small intestines to gradually release the
active agent therein. Suitable enteric polymers include, but are
not limited to, cellulose butyrate phthalate, cellulose hydrogen
phthalate, cellulose proprionate phthalate, polyvinyl acetate
phthalate, cellulose acetate phthalate, cellulose acetate
trimellitate, hydroxypropyl methylcellulose phthalate,
hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose
succinate, carboxymethyl ethylcellulose, hydroxypropyl
methylcellulose acetate succinate, shellac, zein, and acrylic acid
polymers and copolymers, preferably formed from acrylic acid,
methacrylic acid, methyl acrylate, ethyl acrylate, methyl
methacrylate and/or ethyl methacrylate.
[0141] Sustained release dosage forms provide for drug release over
an extended time period, and may or may not be delayed release.
Generally, as will be appreciated by those of ordinary skill in the
art, sustained release dosage forms are formulated by dispersing a
drug within a matrix of a gradually bioerodible (hydrolyzable)
material such as an insoluble plastic, a hydrophilic polymer, or a
fatty compound, or by coating a solid, drug-containing dosage form
with such a material. Insoluble plastic matrices may be comprised
of, for example, polyvinyl chloride or polyethylene. Hydrophilic
polymers useful for providing a sustained release coating or matrix
cellulosic polymers include, without limitation: cellulosic
polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose,
hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose,
cellulose acetate, cellulose acetate phthalate, cellulose acetate
trimellitate, hydroxypropylmethyl cellulose phthalate,
hydroxypropylcellulose phthalate, cellulose hexahydrophthalate,
cellulose acetate hexahydrophthalate, and carboxymethylcellulose
sodium; acrylic acid polymers and copolymers, preferably formed
from acrylic acid, methacrylic acid, acrylic acid alkyl esters,
methacrylic acid alkyl esters, and the like, e.g. copolymers of
acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate,
methyl methacrylate and/or ethyl methacrylate, with a terpolymer of
ethyl acrylate, methyl methacrylate and trimethylammonioethyl
methacrylate chloride (sold under the tradename Eudragit RS)
preferred; vinyl polymers and copolymers such as polyvinyl
pyrrolidone, polyvinyl acetate, polyvinylacetate phthalate,
vinylacetate crotonic acid copolymer, and ethylene-vinyl acetate
copolymers; zein; and shellac, ammoniated shellac, shellac-acetyl
alcohol, and shellac n-butyl stearate. Fatty compounds for use as a
sustained release matrix material include, but are not limited to,
waxes generally (e.g., carnauba wax) and glyceryl tristearate.
[0142] Preparations according to this invention for parenteral
administration include are sterile nonaqueous solutions,
suspensions, or emulsions. Examples of nonaqueous solvents or
vehicles are propylene glycol, polyethylene glycol, vegetable oils,
such as olive oil and corn oil, gelatin, and injectable organic
esters such as ethyl oleate. Such dosage forms may also contain
adjuvants such as preserving, wetting, emulsifying, and dispersing
agents. They may be sterilized by, for example, filtration through
a bacteria-retaining filter, by incorporating sterilizing agents
into the compositions, by irradiating the compositions, or by
heating the compositions. They can also be manufactured using a
sterile injectable medium.
[0143] Although the present compositions will generally be
administered orally or parenterally, preferably using a solid oral
dosage form, other modes of administration are suitable as well.
For example, administration may be rectal or vaginal, preferably
using a suppository that contains, in addition to the active agent
and/or the N,N-dinitramide salt, excipients such cocoa butter or a
suppository wax. Compositions for nasal or sublingual
administration are also prepared with standard excipients well
known in the art. The pharmaceutical compositions of the invention
may additionally be administered by inhalation. Such compositions
may be formulated according to techniques well known in the art of
pharmaceutical formulation and may be prepared as solutions in
saline, employing benzyl alcohol or other suitable preservatives,
absorption promoters to enhance bioavailability, propellants such
as fluorocarbons or nitrogen, and/or other conventional
solubilizing or dispersing agents. Preferred formulations for
inhalation are particulate formulations administered using a dry
powder inhaler, and aerosol formulations containing a suitable
propellant and administered using a pressurized metered dose
inhaler.
[0144] Topical and transdermal administration are also suitable
delivery routes in conjunction with the methodology of the
invention. Topical formulations may be in any form suitable for
application to the body surface, and may comprise, for example, an
ointment, cream, gel, lotion, solution, paste or the like, and/or
may be prepared so as to contain liposomes, micelles, and/or
microspheres. Ointments, as is well known in the art of
pharmaceutical formulation, are semisolid preparations that are
typically based on petrolatum or other petroleum derivatives. The
specific ointment base to be used, as will be appreciated by those
skilled in the art, is one that will provide for optimum drug
delivery, and, preferably, will provide for other desired
characteristics as well, e.g., emolliency or the like. As with
other carriers or vehicles, an ointment base should be inert,
stable, nonirritating and nonsensitizing. Creams, as also well
known in the art, are viscous liquids or semisolid emulsions,
either oil-in-water or water-in-oil. Cream bases are
water-washable, and contain an oil phase, an emulsifier and an
aqueous phase. The oil phase, also called the "internal" phase, is
generally comprised of petrolatum and a fatty alcohol such as cetyl
or stearyl alcohol. The aqueous phase usually, although not
necessarily, exceeds the oil phase in volume, and generally
contains a humectant. The emulsifier in a cream formulation is
generally a nonionic, anionic, cationic or amphoteric surfactant.
Various additives, known to those skilled in the art, may be
included in the topical formulations. For example, solubilizers may
be used to solubilize certain active agents. For those drugs having
an unusually low rate of permeation through the skin or mucosal
tissue, it may be desirable to include a permeation enhancer in the
formulation.
[0145] The invention may also be used in conjunction with
administration through the skin or mucosal tissue using
conventional transdermal drug delivery systems, wherein the system
is comprised of a laminated structure (typically referred to as a
transdermal "patch") that serves as a drug delivery device to be
affixed to the skin. Transdermal drug delivery may involve passive
diffusion or it may be facilitated using electrotransport, e.g.,
iontophoresis. In a typical transdermal "patch," the drug
composition is contained in a layer, or "reservoir," underlying an
upper backing layer. The laminated structure may contain a single
reservoir, or it may contain multiple reservoirs. In one type of
patch, referred to as a "monolithic" system, the reservoir is
comprised of a polymeric matrix of a pharmaceutically acceptable
contact adhesive material that serves to affix the system to the
skin during drug delivery. Examples of suitable skin contact
adhesive materials include, but are not limited to, polyethylenes,
polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and
the like. Alternatively, the drug-containing reservoir and skin
contact adhesive are separate and distinct layers, with the
adhesive underlying the reservoir which, in this case, may be
either a polymeric matrix as described above, or it may be a liquid
or hydrogel reservoir, or may take some other form.
[0146] The invention accordingly provides a novel and highly
effective means for increasing the solubility of a hydrophobic,
cationic compound in a lipophilic medium, and for enhancing the
transport of a hydrophobic, cationic pharmacologically active agent
across the blood-brain barrier. The invention is useful with a wide
variety of biologically active agents, and administration as a
pharmacologically active agent is not accompanied by any noticeable
side effects. The invention thus represents a significant advance
in the fields of drug delivery and neuropharmacology.
[0147] It is to be understood that while the invention has been
described in conjunction with the preferred specific embodiments
thereof, the foregoing description is intended to illustrate and
not limit the scope of the invention. Other aspects, advantages and
modifications will be apparent to those skilled in the art to which
the invention pertains. Furthermore, the practice of the present
invention will employ, unless otherwise indicated, conventional
techniques of drug formulation, which are well within the skill of
the art. Such techniques are fully explained in the literature. See
Remington: The Science and Practice of Pharmacy, cited supra, as
well as Goodman & Gilman's The Pharmacological Basis of
Therapeutics, 9th Ed. (New York: McGraw-Hill, 1996).
[0148] All patents, patent applications, patent publications,
journal articles and other references cited herein are incorporated
by reference in their entireties.
[0149] The following examples are put forth so as to provide those
of ordinary skill in the art with a complete disclosure and
description of how to make and use the compounds of the invention,
and are not intended to limit the scope of what the inventors
regard as their invention. Efforts have been made to ensure
accuracy with respect to numbers (e.g., amounts, temperature, etc.)
but some errors and deviations should be accounted for. Unless
indicated otherwise, parts are parts by weight, temperature is in
.degree. C. and pressure is at or near atmospheric.
EXAMPLE 1
[0150] Protriptylene hydrochloride (100 mg) was dissolved in 100 ml
of water and extracted with 100 ml of toluene. Evaporation of the
toluene and careful vacuum drying left a residue of 8 mg of the
protriptylene hydrochloride, which had been extracted into the
toluene layer.
[0151] Execution of the above procedure with 34 mg (approximately
one molar equivalent) of ammonium dinitramide added to the water
layer resulted in the extraction of 15 mg of protriptylene
hydrochloride and dinitramide salts extracted into the toluene
layer.
EXAMPLE 2
[0152] The case of quinine sulfate required much greater volumes of
water, as 1 mmole (782 mg) required 900 ml of water to dissolve.
This 900 ml was divided into two 450-ml aliquots; the first was
extracted with 100 ml of ethyl acetate, resulting in the isolation
of 57 mg of the quinine sulfate from the ethyl acetate layer.
Addition of 124 mg (1 molar equivalent) of ammonium dinitramide to
the second aliquot, followed by extraction with 100 ml of ethyl
acetate resulted in the isolation of 121 mg of an undetermined
mixture of quinine sulfate and dinitramide from the ethyl acetate
layer. The TLC of this extract in acetone/silica gel showed the
highly fluorescent sulfate (R.sub.f=0.1) and the non-fluorescent
dinitramide ( R.sub.f=0.75) Evidently, dinitramide ion quenches the
fluorescence of protonated quinine.
* * * * *