U.S. patent application number 10/057844 was filed with the patent office on 2004-03-18 for compositions of tocol-soluble therapeutics.
This patent application is currently assigned to Sonus Pharmaceuticals, Inc.. Invention is credited to Constantinides, Panayiotis P., Lambert, Karel J., Nienstedt, Andrew M., Tustian, Alexander K..
Application Number | 20040053993 10/057844 |
Document ID | / |
Family ID | 22558224 |
Filed Date | 2004-03-18 |
United States Patent
Application |
20040053993 |
Kind Code |
A1 |
Constantinides, Panayiotis P. ;
et al. |
March 18, 2004 |
Compositions of tocol-soluble therapeutics
Abstract
Tocol-based compositions of charged amphiphilic and water
soluble pharmaceutically active compounds or their charged
precursors are prepared by forming a tocol-soluble ion pair with an
oppositely charged ion-pair forming compound capable of forming a
tocol-soluble ion-pair with the active compound. Also disclosed are
novel compounds tocopherolsuccinate-aspartate and
tocopherolsuccinate-glutamate, which are useful as ion-pair forming
compounds.
Inventors: |
Constantinides, Panayiotis P.;
(Gurnee, IL) ; Lambert, Karel J.; (Woodinville,
WA) ; Tustian, Alexander K.; (Bothell, WA) ;
Nienstedt, Andrew M.; (Seattle, WA) |
Correspondence
Address: |
CHRISTENSEN, O'CONNOR, JOHNSON, KINDNESS, PLLC
1420 FIFTH AVENUE
SUITE 2800
SEATTLE
WA
98101-2347
US
|
Assignee: |
Sonus Pharmaceuticals, Inc.
|
Family ID: |
22558224 |
Appl. No.: |
10/057844 |
Filed: |
January 25, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10057844 |
Jan 25, 2002 |
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09671753 |
Sep 27, 2000 |
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6479540 |
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60156128 |
Sep 27, 1999 |
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Current U.S.
Class: |
514/458 ;
514/557 |
Current CPC
Class: |
A61K 9/1075 20130101;
A61P 25/06 20180101; A61P 9/06 20180101; A61P 25/24 20180101; A61P
43/00 20180101; A61P 9/08 20180101; A61P 37/06 20180101; A61P 29/00
20180101; A61P 37/08 20180101; Y10S 514/938 20130101; A61P 31/04
20180101; A61P 39/02 20180101; A61K 47/22 20130101; A61P 25/04
20180101; A61P 31/12 20180101; A61P 5/38 20180101; Y10S 514/937
20130101; A61P 9/00 20180101; Y10S 977/907 20130101; A61P 25/18
20180101; A61P 25/22 20180101; A61P 25/20 20180101; A61K 9/0019
20130101; A61P 5/02 20180101; A61P 31/10 20180101 |
Class at
Publication: |
514/458 ;
514/557 |
International
Class: |
A61K 031/355; A61K
031/19 |
Claims
We claim:
1. A pharmaceutical composition comprising a tocol as a solvent,
and a tocol soluble ion pair comprised of a charged
pharmaceutically active compound or a charged precursor of a
pharmaceutically active compound, and a compound of opposite charge
capable of forming a tocol-soluble ion pair with the
pharmaceutically active compound or precursor.
2. A composition according to claim 1 wherein the tocol is a
tocopherol or tocotrienol.
3. A composition according to claim 1 wherein the tocol is a
tocopherol.
4. A composition according to claim 3 wherein the tocopherol is
.alpha.-tocopherol.
5. A composition according to claim 3 wherein the tocopherol is
.beta.-, .gamma.- or .delta.-tocopherol.
6. A composition according to claim 1 wherein the tocol is a
tocotrienol.
7. A composition according according to claim 1, wherein the tocol
is selected from 6-hydroxy, 2,5,7,8-tetramethylchroman-2-carboxylic
acid and its desmethyl analogs.
8. A composition according to claim 1 wherein the pharmaceutically
active compound or precursor is selected from pharmaceutically
active bases, acids, and natural and synthetic polyelectrolytes,
and precursors thereof.
9. A composition according to claim 8 wherein the pharmaceutically
active compound or precursor is selected from pharmaceutically
active carboxylic acids, polycarboxylic acids, amines, polyamines,
peptides, polypeptides, proteins, nucleotides, polynucleotides,
saccharides, polysaccharides and charged polyelectrolytes, and
precursors thereof.
10. A composition according to claim 9 wherein the pharmaceutically
active compound or precursor is selected from pharmaceutically
active amines, peptides and polypeptides, and precursors
thereof.
11. A composition according to claim 10 wherein the
pharmaceutically active compound is a macrolide antibiotic or a
precursor thereof.
12. A composition according to claim 11 wherein the macrolide
antibiotic is erythromycin or clarithromycin or a precursor
thereof.
13. A composition according to claim 11 wherein the
pharmaceutically active compound or precursor is an anti-arrhythmic
drug or a precursor thereof.
14. A composition according to claim 13 wherein the anti-arrhythmic
drug is amiodarone or a precursor thereof.
15. A composition according to claim 10 wherein the
pharmaceutically active compound or precursor is an anthracycline
antibiotic or a precursor thereof.
16. A composition according to claim 15 wherein the anthracycline
antibiotic is doxorubicin, daunorubicin, epirubicin or a derivative
thereof, or a precursor thereof.
17. A composition according to claim 10 wherein the
pharmaceutically active agent or precursor is mitomycin, bleomycin
or an analog thereof, or a precursor thereof.
18. A composition according to claim 10 wherein the
pharmaceutically active compound or precursor is vincristine,
vinblastine, a nitrogen mustard, nitrosourea, an analog thereof, or
a precursor thereof.
19. A composition according to claim 10 wherein the
pharmaceutically active compound or precursor is camptothecin, an
analog thereof or a precursor thereof.
20. A composition according to claim 19 wherein the
pharmaceutically active compound is camptothecin, topotecan,
irenotecan, a derivative thereof, or a precursor thereof.
21. A composition according to claim 10 wherein the
pharmaceutically active compound or precursor is a quinolone
antibiotic or a precursor thereof.
22. A composition according to claim 21 wherein the quinolone
antibiotic is ciprofloxacin, clinafloxacin, levofloxacin,
moxifloxacin or a precursor thereof.
23. A composition according to claim 10 wherein the
pharmaceutically active compound or precursor is a biogenic amine
or a precursor thereof.
24. A composition according to claim 23 wherein the biogenic amine
is histamine, serotonin, epinephrine, an analog thereof, or a
precursor thereof.
25. A composition according to claim 1 in wherein the ion pair
forming compound is selected from tocol derivatives,
C.sub.2-C.sub.25 fatty acids , alkyl phosphates, lipids,
phospholipids, retinoids, benzoquinones and esters of Vitamin A, D
and K.
26. A composition according to claim 25 wherein the ion pair
forming compound is a tocol derivative.
27. A composition according to claim 26 wherein the ion pair
forming compound is a charged ester of .alpha.-tocopherol.
28. A composition according to claim 27 wherein the charged ester
is selected from tocopherol acetate, phosphate, succinate,
aspartate, and glutamate and mixtures thereof.
29. A composition according to claim 26 in which the ion pair
forming compound is selected from amines of tocopherols and
derivatives thereof.
30. A composition according to claim 29 wherein the ion pair
forming compound is tocopheramine.
31. A composition according to claim 1 wherein the ion pair forming
compound is selected from C.sub.2-C.sub.25 carboxylic acids,
C.sub.2-C.sub.25 amines and mixtures thereof.
32. A composition according to claim 31 wherein the ion pair
forming compound is selected from acetic, propionic, butyric,
valeric, valproic, caprylic, caproic, lauric, myristic, palmitic,
oleic, palmitoleic, stearic, linoleic, linolenic, arachidic and
arachidonic acids, and mixtures thereof.
33. A composition according to claim 31 wherein the ion pair
forming compound is stearylamine.
34. A composition according to claim 25 wherein the ion pair
forming compound is selected from charged lipids, phospholipids,
sphingolipids and mixtures thereof.
35. A composition according to claim 34 wherein the ion pair
forming compound is a cholesterol analog or a mixture of
cholesterol analogs.
36. A composition according to claim 35 wherein the ion pair
forming compound is selected from cholesterol sulfate, cholesterol
hemisuccinate, cholesterol succinate and mixtures thereof.
37. A composition according to claim 34 wherein the ion pair
forming compound is a phospholipid or a mixture of
phospholipids.
38. A composition according to claim 37 wherein the ion pair
forming compound is selected from phosphatidic acid,
phosphatidylserine, phosphatidylinositol, phosphatidylglycerol and
diphosphatidylglycerol, and mixtures thereof.
39. A composition according to claim 34 wherein the ion pair
forming compound is a sphingolipid or mixture of sphingolipids.
40. A composition according to claim 39 wherein the ion pair
forming compound is selected from sphingosine, phosphatide analogs
of sphingosine, and mixtures thereof.
41. A composition according to claim 39 wherein the ion pair
forming compound is sphingomyelin.
42. A composition according to claim 1 wherein the pharmaceutically
active compound is cationic and the ion pair forming compound is
anionic.
43. A composition according to claim 42 wherein the ion pair
forming compound is a succinate or phosphate derivative of a
tocopherol.
44. A composition according to claim 42 wherein the
pharmaceutically active compound is selected from erythromycin,
clarithromycin, amiodarone, doxorubicin and cationic analogs
thereof.
45. A composition according to claim 43 wherein the ion pair
forming compound is selected from tocopherol succinate, tocopherol
phosphate and mixtures thereof.
46. A composition according to claim 1 wherein the pharmaceutically
active compound is anionic and the ion pair forming compound is
cationic.
47. A composition according to claim 46 wherein the
pharmaceutically active compound is a peptide, peptide mimetic,
polypeptide, nucleotide or polynucleotide.
48. A composition according to claim 46 wherein the ion pair
forming compound is tocopheramine, stearylamine, or
sphingomyelin.
49. A composition according claim 1 in the form of a multiphase
system.
50. A biphasic composition according to claim 49.
51. A composition according to claim 49 in the form of an emulsion
or microemulsion.
52. A composition according to claim 49 comprising micelles, mixed
micelles, reverse micelles, liposomes, niosomes and mixtures
thereof.
53. A composition according to claim 49 comprising an oil-in-water
or water-in-oil emulsion or microemulsion.
54. A composition according to claim 49 comprising an
oil-in-water-in oil or water-in-oil-in-water emulsion or
microemulsion.
55. A composition according to claim 49 further comprising one or
more surfactants, one or more co-solvents and one or more aqueous
phases.
56. A composition according to claim 1 in the form of a
self-emulsifying drug delivery system.
57. A process for solubilizing in an oil phase a charged
pharmaceutically active compound or a charged precursor thereof
comprising combining the pharmaceutically active compound or
precursor with an oppositely charged compound capable of forming a
tocol-soluble ion pair with the pharmaceutically active compound or
precursor, and with a tocol as a solvent for the ion pair.
58. A process according to claim 57 in which the oil phase is an
oil phase of a multiphase system.
59. Tocopherolsuccinate-aspartate.
60. Tocopherolsuccinate-glutamate.
61. A compositon according to claim 1 wherein the ion pair forming
compound is tocopherolsuccinate-aspartate.
62. A composition according to claim 1 wherein the ion pair forming
compound is tocopherolsuccinate-glutamate.
63. Pharmaceutical use of compositions of claim 1 by administration
to an animal or human.
Description
BACKGROUND AND PRIOR ART
[0001] The invention is directed to compositions having an oil
phase that contains pharmaceutically active ingredients that are
charged amphiphilic or water soluble. The compositions generally
comprise tocol-soluble ion pairs in a tocol-based oil of a
multiphasic system or a precursor of such a system. The
compositions of the invention can be in the form of an emulsion,
liquid crystalline gel, self-emulsifying drug delivery system, or a
liposomal or niosomal dispersion for oral or parenteral
administration, which term is meant to include, for instance,
intravenous, subcutaneous, intraperitoneal, intramuscular,
pulmonary, intranasal, and topical administration such as
transdermal and ocular. Emulsions or microemulsions and
self-emulsifying drug delivery systems are the preferred form of
the compositions of the present invention.
[0002] Emulsions, and emulsification as a composition and method of
administration of pharmaceuticals, have a long history in the
medical arts. A recent advance was the use of .alpha.-tocopherol or
other tocopherols, tocotrienols or derivatives thereof as a solvent
to dissolve certain drugs at high enough concentrations to be
therapeutically useful. TPGS (.alpha.-tocopherol polyethyleneglycol
1000 succinate) for administration of a therapeutic was claimed by
Biogal (U.S. Pat. No. 5,583,105) following disclosure in trade
publications of the utility of TPGS as a bioavailability enhancer
for drug delivery (Sokol, et al. The Lancet 338:212-215, 1991).
Vitamin E and tocopherol acetates and succinates, including TPGS,
were recently found useful in pharmaceutical formulations as
solubilizers and co-solvents for the administration of medicaments
(Dumex WO/95,31217 and Liposome Company, U.S. Pat. No. 5,041,278).
Other patents disclose that tocopherols are excellent solvents for
the peptide cyclosporin (Klokkers WO 95/11039), and for certain
steroids (Peat, U.S. Pat. No. 4,439,432). Stillman (U.S. Pat. No.
4,551,332), and Hermes Pharma (EP 019817) described composition in
which steroids and antibiotics, or ubiquinones, respectively, were
co-solubilized in Vitamin E as pharmaceutical formulations.
[0003] Subsequent disclosures by Sonus Pharmaceuticals (WO
98/30205); Sherman (WO 97/22358; WO 98/30204) and Danbiosyst (WO
97/03651; WO 99/04787) expanded this new appreciation of
tocopherols and tocotrienols as a solvent for delivery of
hydrophobic medicaments, particularly when combined with TPGS,
phospholipids, and certain co-solvents and emulsifiers.
[0004] The benefits of emulsions are several. In general,
emulsification can lead to reduced toxicity when compared to
aqueous solutions of the drug. Extreme conditions of pH or ionic
strength are required to solubilize some drugs in aqueous
solutions. Also, sustained release has been observed from emulsions
formed as a blood pool or intra-tissue depot, from which the active
agent is progressively released with desirable increased efficacy
or duration of treatment. In other cases, a high plasma peak
concentration (Cmax) can be obtained without undue risk to the
patient. Finally, the stability of selected drugs in the oil phase
may be improved when compared to aqueous solutions of the same
drug. Emulsions in tocopherols, tocotrienols or derivatives thereof
have the added advantage that the emulsion itself may be
therapeutic for certain conditions.
[0005] However, only selected lipophilic active agents are highly
soluble in tocopherols and tocotrienols. Furthermore, lipophilic
agents that are charged tend to remain associated with the water or
plasma, where they may be subject to degradation, even while
residing in part in the oil phase. Finally, some water-soluble
agents or amphiphilic agents that could benefit from the advantages
of a tocopherol or tocotrienol formulation are not readily soluble
in these oils.
[0006] It would thus be desirable to provide pharmaceutical
compositions in which a charged amphiphilic or water soluble active
agent is partitioned into the tocol oil phase of a multiphasic
system.
[0007] One approach to improve the oil solubility of such
ingredients is to covalently modify the active agent so as to
render it more lipophilic. Fatty acid- or lipid-drug conjugates
have been disclosed as a means of rendering water-soluble drugs
more lipophilic, more readily absorbable through various mucosal
membranes, such as the intestinal, corneal and dermal, and for
targeting of drugs (NexStar U.S. Pat. Nos. 6,024,977; 5,827,819;
5,543,389; 5,543,390; 5,840,674; 5,543,391; 5,256,641;
5,149,794).
[0008] Another solution has been to use liposomes, reverse
emulsions or water/oil/water multiple emulsions, in which the drug
may be contained in an aqueous phase dispersed in the oil matrix
or, in the case of liposomes, enclosed within a lipid bilayer.
These formulations are particularly valuable for water-loving drugs
and macromolecules but may not provide the advantages of
solubilizing the drug directly in the oil. In addition there are
physical stability considerations of such systems.
SUMMARY OF THE INVENTION
[0009] The invention comprises a pharmaceutical composition
comprising a tocol as a solvent and a tocol-soluble ion pair of two
oppositely charged compounds, one of the said compounds being a
charged pharmaceutically active agent or a charged precursor of the
active agent and the other being an oppositely charged compound
capable of forming a tocol-soluble ion pair with the
pharmaceutically active compound. In cases of multiply charged
pharmaceutically active compounds or precursors of charged
pharmaceutically active compounds at least one charge on the active
agent is available for ion-pairing. The invention also relates to
processes for preparing such compositions.
DETAILED DESCRIPTION OF THE INVENTION
[0010] The present invention is directed to formulations or
compositions of those drugs which are amphiphilic or water soluble
by virtue of having a substituent ionic charge, for example a
cation formed from a secondary amine (a base), or an anion formed
by dissociation of a carboxyl, phosphate or sulfate (an acid).
These drugs may be rendered tocol-soluble by the formation of an
ion-pair between the drug and an oppositely charged molecule. The
active agent of the composition must be more soluble in the tocol
oil in the form of an ion pair than without it. Thus, formation of
the ion-pair results in substantial improvement in the solubility
of the active agent in the tocol oil.
[0011] To better aid in understanding the invention, the following
definitions are offered:
[0012] Tocopherols: tocopherols are a family of natural and
synthetic compounds. d-.alpha.-tocopherol, also known as Vitamin E,
is the most familiar member of this class of compounds and has the
following chemical structure (Scheme I): 1
[0013] The molecule contains three structural elements, a chroman
head with a phenolic alcohol and a phytyl tail. Not all tocopherols
have three methyl groups on the chroman head. The simplest member
of this group, 6-hydroxy-2-methyl-2-phytylchroman contains no
methyl groups on the chroman ring, and is sometimes simply referred
to as "tocol". However, the terms "tocols" and "tocol" is used
herein to represent a broader class of compounds. Other members of
the tocopherol class include .alpha.-, .beta.-, .gamma.-, and
.delta.-tocopherols and Trolox.RTM. (6-hydroxy,
2,5,7,8-tetramethylchroman-2-carboxylic acid) and its desmethyl
analogs. In addition to their use as a primary solvent, some
tocopherols and their derivatives are useful as a therapeutic
agents.
[0014] Tocotrienols: tocotrienols have structures related to the
tocopherols but possess a 3,7,11 triene "tail". The structure of
d-.alpha.-tocotrienol is shown in Scheme II. 2
[0015] Again, as is the case for the tocopherols, not all
tocotrienols have three methyl groups on the chroman head. There
are four major tocotrienols, .alpha.-, .beta.-, .gamma.-, and
.delta.-tocotrienols.
[0016] Tocols: "Tocols" is used herein in a broad sense to indicate
the family of tocopherols and tocotrienols and derivatives thereof,
including those common derivatives esterified at the 6-hydroxyl on
the chroman ring. This use of the term "tocols" is appropriate
since all tocopherols and tocotrienols are fundamentally
derivatives of the simplest tocopherol,
6-hydroxy-2-methyl-2-phytylchroman (sometimes referred to as
"tocol").
[0017] Tocol-Soluble: Refers to the property of certain molecules
characterized as being soluble directly, or with the aid of a
co-solvent, in a tocol. As an operative definition, the most useful
way to determine tocol solubility is to dissolve the compound of
interest in a tocol or to use a co-solvent such as ethanol.
[0018] Amphiphilic: A molecule that is both oil and water
soluble.
[0019] Lipophilic: Literally, fat-loving, referring to the property
of certain molecules characterized as soluble in triglyceride oils,
hydrocarbons or waxes.
[0020] Ion Pair: A neutral pair formed between two oppositely
charged compounds.
[0021] Tocol-Soluble Ion Pair: An ion pair formed between two
oppositely charged compounds and which is soluble in tocols.
[0022] Biocompatible: Capable of performing functions within or
upon a living organism in a manner that does not terminate or
excessively disable the life of the organism, i.e. without undue
toxicity or harmful physiological or pharmacological effects.
[0023] Multiphase System: As used herein, this term refers to a
system where one or more phases is (are) dispersed throughout
another phase, which is usually referred to as the continuous phase
or vehicle, or a precursor thereof. Emulsions, microemulsions and
other nanoparticulates, including liposomes and niosomes, are
examples of multiphase systems.
[0024] Liposome: A lipid bilayer vesicle formed spontaneously upon
dispersion of lipids/phospholipids in water. "Liposome" is also
defined as a vesicular structure consisting of hydrated
bilayers.
[0025] Niosome: In analogy to a liposome, a niosome is a nonionic
surfactant vesicle. Classes of commonly used non-ionic surfactants
include polyglycerol alkylethers, glucosyl dialkylethers, crown
ethers and polyoxyethylene alkyl ethers and esters.
[0026] Micelle: Organized aggregates of one or more surfactants in
solution.
[0027] Emulsion: A colloidal dispersion of two immiscible liquids,
such as oil and water, in the form of droplets. The internal phase
is also termed the dispersed phase and the external phase is termed
the continuous phase. The mean diameter of the dispersed phase, in
general, is between about 0.1 and about 5.0 microns, as is commonly
measured by particle sizing methods. Emulsions in which the
dispersed phase and continuous phase have different refractive
indexes are typically optically opaque. Emulsions possess a finite
or limited stability over time, and can be stabilized by the
incorporation of amphiphilic excipients known as surfactants and by
viscosity modifiers.
[0028] Microemulsion: A thermodynamically stable, isotropically
clear dispersion of two immiscible liquids, stabilized by an
interfacial film of surfactant molecules. Microemulsions have a
mean droplet diameter of less than about 200 nm, in general between
about 10-100 nm and are typically self-assembling.
[0029] Tocol microemulsion: A thermodynamically stable, translucent
or clear dispersion of a tocol oil in water, stabilized by an
interfacial film of surfactant molecules. Tocol microemulsions have
a mean droplet diameter of less than about 200 nm, in general
between about 50 and about 100 nm, and typically are not
self-assembling, but require heat or increased shear to assemble
due to the high viscosity of the tocol oil.
[0030] A highly preferred form of the invention for drug delivery
is a "tocol microemulsion". These vehicles for drug delivery are
translucent and isotropic, of small mean droplet diameter,
preferably less than about 150 nm, even more preferably less than
about 100 nm, and most preferably from about 30 to 90 nm. They
possess high drug solubilization capacity (a relative measure for
each individual drug), and most characteristically have extended or
indefinite stability on storage by virtue of their thermodynamic
stability, which is preferably greater than 1 year, even more
preferably greater than two years or more. The microemulsions of
the current invention have a surfactant to oil ratio of about 1:1
to 1:5, preferably from about 1:1 to 1:2 and are frequently
formulated with one or more co-solvents or co-surfactants to
improve processing. Unlike vegetable oil microemulsions, which form
spontaneously, tocol microemulsions are formed by homogenization in
a high-shear device because of the extremely high viscosity of
these excipients. However, once formed, they are essentially
transparent or translucent, and highly stable. They preferably
exhibit no particle size growth over a typical pharmaceutical shelf
life of one year or more.
[0031] Self-Emulsifying Drug Delivery Systems (SEDDS):
[0032] In the absence of an aqueous phase, mixtures of oil(s) and
non-ionic surfactant(s) form clear and isotropic solutions that are
known as self-emulsifying drug delivery systems (SEDDS). They have
successfully been used to improve lipophilic drug dissolution and
oral absorption. Such systems are essentially precursors of
emulsion-type multiphasic systems.
[0033] Active Agent: A compound or precursor thereof, natural or
synthetic, with an established therapeutic/pharmacological activity
in animals and humans. Relevant to this invention are compounds
that are relatively soluble in tocols and compounds that are
relatively insoluble in tocols.
[0034] Polyelectrolyte: A natural or synthetic molecule with
multiple ionizable groups. A polyelectrolyte can have multiple
anions, multiple cations or a combination of both. Examples include
peptides, polypeptides, proteins, saccharides and polysaccharides,
polynucleotides and nucleic acids.
[0035] Pharmaceutically active ingredients that may be employed in
the compositions of this invention are those that are charged
amphiphilic or water soluble. These include, for instance,
therapeutic amines or bases, acids and zwitterions. Preferred
classes of compounds include carboxylic acids, polycarboxylic
acids, amines, polyamines, peptides, polypeptides, proteins,
nucleosides, nucleotides, polynucleotides, saccharides,
polysaccharides, polymers, and other charged polyelectrolytes. Most
preferred are amines, peptides and polypeptides.
[0036] Some examples of preferred active ingredients for use in
this invention are macrolide antibiotics such as clarithromycin and
erythromycin, anthracycline antibiotics such as doxorubicin and
daunorubicin, camptothecin and its analogs (such as camptothecin,
topotecan, irenotecan and derivatives thereof), quinolone
antibiotics such as ciprofloxacin, clinafloxacin, levofloxacin and
moxifloxacin, amiodarone and its analogs, angiotensin-converting
enzyme (ACE) inhibitors such as enalapril, enalaprilat, linosopril
and their analogs, biogenic amines such as histamine, serotonin,
tryptophane, epinephrine and analogs or derivatives thereof, the
antineoplastics mitomycin and bleomycin and their analogs, and
vincristine, nitrogen mustards, and nitrosourea and their analogs.
Other chemotherapeutic agents may be used, as may antibiotics
(antiviral, antibacterial, antihelminthic, antiplasmodial, or
antimycotic), analgesics and local anesthetics, antidepressants
anxietolytics, anti-psychotics, sedatives, hypnotics, hormones,
steroids, cytomedines or cytokines, anti-histamines,
anti-allergics, steroids, vaccine adjuvants and epitopes,
immunosuppressive agents, vascular tonics, coronary drugs,
vasodilators, anti-arrhythmics such as amiodarone, calcium
antagonists, cardiac glycosides, antidotes, non-steroidal
anti-inflammatory drugs, oligonucleotides, oligopeptides,
anti-emetics, motion sickness drugs, and migraine therapeutics.
[0037] Specific examples of active ingredients that may be used in
the compositions of this invention include dihydroergotamines,
epinephrine, adenosine, hydralazine, pipamazine, pyridoxine,
prednimustine, propanolol, phenobarbital, arniodarone, miconazole,
secobarbital, trimethoprim sulfamethoxazole, cytarabine,
amphotericin B, diltiazem, verapamil, diazoxide, ketorolac,
pentobarbital, phenyltoin, esmolol, capsaicins, oxytetracycline,
chlorodiazepoxide, dimenhydrinate, benzodiazepines such as
diazepam, fenoldopam, nitrazepam, flurazepam, lorazepam, estazolam,
flunitrazepam, triazolam, alprazolam, midazolam, ternazepam,
lermetazeparn, brotizolam, clobazam, oxazepam, clonazepam,
thiethylperazine, nicardipine, haloperiodol, tobramycin,
ciprofloxacin, clinafloxacin, levofloxacin, moxifloxacin,
fluoxetine, metronidazole, doxepin, doxycycline, chloramphenicol,
acyclovir, idoxuridine, dynorphine, tromantadine, tranylcypromine,
meconazole, nystatin, metronidazole, tinidazol, diclofenac,
piroxicam, morphine, Selegiline, lidocaine, buprenorphine,
buspirone, metoclopramide, granisetron, tropisetron, ondansetron,
chonemorphine, cinnarizine, ceftriaxone, eprosartan, ganciclovir,
betamethasone acetate, methylprednisolone acetate, prednisolone,
sumatriptan, hydrocortisones, ibuprofen, methocarbamol,
resveratrol, retinoids, carotenoids, tamoxifen, decarbazine,
lonidamine, piroxantrone, chloroquine, streptomycin, kanamycin,
gentamycin, dehydrostreptomycin, amikacin, chloropromazine,
imipramin, suramin, perhexilene, methotrexate, sulmazol, leupeptin,
methylamine, colchicine, pyridoxine, acetaminophen, desipramine,
biperiden, dibenzepine, alprenolol, opipramol, propranolol,
chlorpheniramine, clonixin, desipramine, n-acetyldesipramine,
imipramine, chlomipramine, amitryptyline, sertraline, perazine,
thioridazine, carbamazepine, promazine, amantadine, memantine,
isoproterenol, methadone, lignocaine, pentacaine, nalorphine,
trimetazidine, morphine-6-O-.beta.-d-glucuronide, sulmazol, and
phenothiazine.
[0038] Compositions of this invention containing tocol-soluble ion
pairs are useful to formulate and deliver biogenic amines or their
amino acid or peptide precursors. Biogenic amines are those cell
signaling or transmitter molecules produced by the body which
contain a free amine. In some cases the precursor is also
efficacious, for example the amino acid tryptophane which is
metabolized into serotonin, an active cell signaling and
neurotransmitter molecule. Cytomedines comprise a broader class of
ligands that interact with cellular receptors to evoke a biological
response.
[0039] Benefits have also been reported for the administration of
tocotrienols or tocopherols for therapy of cardiovascular disease.
Compositions of this invention including active agents such as
amiodarone, persantine or adenosine in tocol-based emulsions may be
useful for bolus or IV drip infusion as a vascular tonic in the
treatment of myocardial infarction or for oral administration.
[0040] Where it is desirable to shift the partition coefficient so
that more of the drug is contained in an oil phase, for example for
slow release, the teachings of the present invention offer a useful
solution. By delivering the active compound in the form of an
emulsion, the release time of the active compound in the blood or
tissue can be extended. Reducing the peak concentration (C.sub.max)
for the free amine can minimize or modulate systemic or
non-specific toxic or adverse events.
[0041] Other lipophilic active ingredients can be included in the
compositions of this invention, so as to provide additional or
complementary effects to the active ingredient present as part of
the tocol-soluble ion pair. For instance if the active ingredient
of the ion pair is a chemotherapeutic or oncolytic agent, the
composition may contain other chemotherapeutics that are soluble or
that can be solubilized in tocols, such as qmonafide, illudin S,
6-hydroxymethylacylfulvene, bryostatin 1, 26-succinylbryostatin 1,
palmitoyl rhizoxin, penclomedine, interferon-alpha, angiogenesis
inhibitor compounds, cisplatin hydrophobic complexes such as
2-hydrazino-4,5-dihydro-1H-imidazole with platinum chloride and
5-hydrazino-3,4-dihydro-2H-pyrrole with platinum chloride, vitamin
A, vitamin E and its derivatives, particularly tocopherol
succinate, vinblastine, 5-fluorouracil, methotrexate, edatrexate,
muramyl tripeptide, muramyl dipeptide, lipopolysaccharides,
9-.beta.-d-arabinofuranosyladenine ("vidarabine") and its 2-fluoro
derivative.
[0042] Other useful therapeutic agents for inclusion in the
tocol-soluble ion pairs of this invention may be selected on the
basis of their amphiphilicity and charge as a function of pH, by
their partition coefficient in buffer:octanol, or by their tocol
solubility. As an operative definition, preferred candidates are
those for which tocol solubility can be shown experimentally to
increase in the presence of an ion pair forming compound by
measuring drug solubility in the tocol oil with and without the
ion-pair. For screening, we have prepared the free base of a drug
with an amine functionality and dissolved the free base and vitamin
E succinate directly in tocopherol with heat. In other cases we
have used ethanol or another volatile co-solvent to initially
dissolve the active agent and its ion pair in a tocol, and then
evaporated the ethanol. Ion pairs that are not soluble in the tocol
of choice readily precipitate or crystallize by these methods.
Limits of solubility may also be established by preparing a series
of samples containing increasing amounts of the compound in a
constant molar mass of tocol. After direct dissolution, or after
evaporation of residual ethanol or other volatile solvent used as a
co-solvent, the critical limit of solubility (S.sub.c) of the
compound in the tocol of choice can be determined with
accuracy.
[0043] Relatively non-volatile co-solvents such as PEG-400, benzyl
benzoate, benzyl alcohol, glycerol, glycerol-, propylene glycol-
and polyethylene glycol-based esters (oils) that are commercially
available under different trade names such as Capmul.RTM. MCM
(glyceryl mono-/di-caprylate/caprate), Captex.RTM. 355
(caprylic/capric triglycerides from coconut oil), Captex.RTM. 200
(propylene glycol dicaplylate/dicaprate), Labrafil.RTM. M1944
(primarily oleic acid polyglycolyzed glycerides from apricot kernel
oil), Labrasol.RTM. (caprylate/caprate polyglycolyzed glycerides
from coconut oil), Myvacet.RTM. (distilled acetylated
monoglycerides), Lauroglycol.RTM. (propylene glycol
mono-/di-laurate), propylene essential lipids (as in U.S. Pat. No.
5,716,928) such as allspice berry, fennel, amber essence, anise
seed, arnica, balsam of Peru, basil, bay leaf, parsley, peanut,
benzoin gum, bergamot, rosewood, cajeput, marigold, camphor,
caraway, cardamon, carrot, cedarwood, celery, chamomile, cinnamon,
citronella, palm oils, sage, clove, coriander, cumin, cypress,
eucalyptus, aloe, fennel, fir, frankincense, garlic, geranium,
rose, ginger, lime, grapefruit, orange, hyssop, jasmine, jojoba,
juniper, lavender, lemon, lemongrass, marjoram, mugwort,
watercress, mullen, myrrh, bigarde neroli, nutmeg, bitter orange,
oregano, patchouly, pennyroyal, primrose, retinols, papaya, pepper,
peppermint, poppyseed, petitegrain, pine, poke root, rosehip,
rosemary, sandalwood, sassafras, spearmint, spikenard, hemlock,
tangerine, tea tree, thyme, vanilla, banana, coconut, vetivert,
wintergreen, witch hazel, ylang ylang extract, or synthetic
analogs, also .beta.-carotene, carotenoids, quinones, menadiones,
lycopene, crown ethers, tributyrin, 1-methyl-2-pyrrolidinone,
dimethylsulfoxide, polyvinylalcohol, polyvinylpyrrolidinone,
phenol, cholesterol, astaxanthins, phospholipids, polyoxyethylated
phospholipids, secondary tocols, Amifat.RTM. P30 (glyceryl
monopyroglutamate monooleate), surfactants such as Cremophor.RTM.
EL (polyoxyethylated castor oil), Poloxamer 407.RTM., also lnown as
Pluronic.RTM. F-127 (polyoxyethylene/polyoxypropylene copolymer),
lecithin, bile acids, palmitoyl camitine, fatty acids,
Transcutol.RTM. (diethylene glycol monoethyl ether) and mixtures
thereof, can be used in the compositions of this invention.
[0044] For use in forming ion pairs with cationic drugs, the
preferred method is to select one or more charged derivatives of a
tocol from the list: vitamin E succinate (VESA), vitamin E
phosphate, and other charged tocopherol esters, amino acid
derivatives such as tocopherol aspartate and glutamate, and other
tocopherol ester or amide derivatives such as those disclosed
herein or by Senju Pharmaceuticals (U.S. Pat. No. 5,606,080 or PCT
WO 99/22818). For example, tocopherol succinate as the free acid
(anionic) can be used to complex clarithromycin or amiodarone as
the free base (cationic) to form a tocol-soluble neutral ion pair.
In an oil phase of low dielectric constant, these ion pairs are
highly stable once formed. Other tocol-soluble ion pair forming
compounds include C.sub.2-C.sub.25 tocol-soluble carboxylic acids
(preferably the fatty acids) such as acetic, propionic, butyric,
valeric, valproic, caprylic, caproic, lauric, myristic, palmitic,
oleic, palmitoleic, stearic, linoleic, linolenic, arachidic and
arachidonic acid; and include C.sub.2-C.sub.25 acyl amines such as
stearylamine, alkyl phosphates such as decyl and hexadecyl
phosphate, other charged lipids such as cholesterol analogs,
particularly cholesterol esters such as cholesterol sulfate and
cholesterol hemisuccinate and succinate, bile acids, phospholipids
such as phosphatidic acid, phosphatidylserine, phosphatidylglycerol
and diphosphatidylglycerol (cardiolipin), phosphatidylinositol,
sphingolipids such as sphingomyelin, cationic lipids such as,
N-[1-(2,3-dioleoyloxy]-N, N,N-trimethylammonium chloride (DOTMA),
N-L-arginylphosphatidyl-ethanolamine, and
1,2-Diacetyl-3-dimethyl-and trimethyl-ammonium propane, retinoids,
vitamin A, D or K esters, and charged biosurfactants such as the
Amisoft.RTM. line of glutamates available from Ajinomoto (Tokyo,
Japan) and ascorbyl palmitate.
[0045] In the case of anionic drugs, a preferred composition
contains tocopheramine. Other positively charged ion pair
candidates include stearylamine and sphingomyelin.
[0046] In the case of zwitterionic drugs, more ingenuity is
required, but it is well within the scope of this invention to use
multiply charged species so as to neutralize the polarity of the
target molecule. For example, esterified fatty acids such as
glutamyl stearate can be used to pair with drugs containing both an
anionic and cationic functional group.
[0047] The compositions of the current invention may be emulsions,
microemulsions, self-emulsifying systems, liposomal and niosomal
dispersions, gels or liquid crystalline mesophases or their
precursors. The preferred forms of the invention are oil-in-water
emulsions, microemulsions and self-emulsifying drug delivery
systems for oral or parenteral administration of an active agent.
Examples of multiphasic systems having two or more phases include
oil-in-water and water-in-oil emulsions and microemulsions, and
multiple emulsions of the oil-in-water-in-oil and
water-in-oil-in-water structure.
[0048] Therapeutic applications of the formulations envisaged here
include the delivery of drugs effective in the treatment of cancer,
pain, infections, atherosclerosis, kidney disease, for suppression
of rejection of transplanted organs, and for other medical
arts.
[0049] Specific embodiments of this invention are described herein.
However, variations and modifications of these embodiments can be
effected without further inventive step, within the teachings and
scope of the invention as described herein.
EXAMPLES
Example 1
[0050] Tocol-Soluble Ion Pair Formulation of Clarithromycin for
Intravenous Administration.
[0051] Clarithromycin is a macrolide antibiotic widely prescribed
for a variety of bacterial infections. Other important members of
this class of drugs include azithromycin and erythromycin.
Macrolide antibiotics are primarily given orally, although
intravenous dosing is indicated in some cases. Macrolides are known
for causing venous irritation/pain on injection, so they are
generally given in dilute (2 mg/mL) solutions by slow infusion
(total daily doses can be in gram quantities).
[0052] Clarithromycin free base is poorly water soluble but can be
solubilized in water as a water-soluble salt, for example the
lactobionate or glucoheptonate, solutions of which display the
aforementioned venous irritation. The relative lipophilicity of
clarithromycin has led various investigators to propose a variety
of lipid dispersed systems, such as liposomes, mixed micelles, and
oil-in-water (o/w) emulsions which might shield the drug from
contact with sensitive tissues at the injection site. To date,
however, none of these has advanced as far as clinical
development.
[0053] In particular, the amino group can be exploited through
lipophilic ion pairing to capture the drug in the oil phase of an
o/w emulsion. Lovell et al; (1994), Less-painful intravenous
administration of clarithromycin, Int. J. Pharmaceutics 109: 45-57,
developed a triglyceride emulsion using fatty acids as lipidic
counterions, which displayed roughly a two-fold reduction in pain
response in the animal models chosen.
[0054] Clarithromycin was obtained as the free base from Wockhardt
(Delhi, India). Vitamin E Succinate (VESA) was obtained from
Eastman (Freeport Tenn.). Capmul.RTM. MCM was obtained from Abitec
(Janesville Wis.); Poloxamer.RTM. 407 (Pluronic.RTM. F-127) from
BASF (Parsippany N.J.); PEG-400 from Spectrum Chemicals (Gardenia
Calif.), and d-.delta.-tocopherol from Sigma Chemicals (St Louis
Mo.). An oil phase consisting of d-.delta.-tocopherol and Capmul
MCM was prepared using 2 parts of .delta.-tocopherol. Surfactant
and clarithromycin were then added as shown in the table below. Dry
ethanol was used to dissolve the components at 70.degree. C. and
the ethanol was then removed under vacuum. A clear amber oil
resulted, but upon cooling, oblong, "casket-lid" crystals of
clanithromycin were observed. A tocol-soluble ion pair of this
compound was then produced by addition of a stoichiometric
equivalent of Vitamin E succinate (VESA) as the free acid. On
re-dissolution in ethanol and cooling no crystals formed. The
clarithromycin was now sufficiently soluble in the tocopherol oil
to allow subsequent preparation of the emulsion. The oil was then
re-heated to 45.degree. C. and degassed immediately prior to
emulsification as described below.
1 Weight in Final Component Oil Phase Percent (%)
d-.delta.-tocopherol 2.53 gm 5.0% Capmul MCM 1.28 gm 2.5% Poloxamer
407 2.98 gm 3.0% Clarithromycin 0.53 gm 0.5% Vitamin E Succinate
0.45 gm 0.9%
[0055] The aqueous phase, consisting of 40 mL of 5 mM citrate TEA
buffer, pH 6.8, was brought to 45.degree. C. before addition to the
oil phase. Upon addition, the resultant mixture was mixed
vigorously to loosen any adherent oll on the walls of the flask.
This suspension was then placed in a vessel and processed in a C5
homogenizer (Avestin, Ottawa Calif.) for 3 min with continuous
recycling. Processing conditions were 45.degree. C. feed
temperature, 20 kpsi processing pressure and 120 mL/min flow rate.
A heat exchanger set at 22.degree. C. was placed at the exit port
to remove excess heat generated in the homogenizer. The temperature
in the feed vessel was measured at 44.degree. C. during steady
state homogenization. Following processing, the emulsion was
collected and cooled to room temperature. It was then terminally
sterilized by filtration through a 0.2 .mu.m filter and had a mean
droplet diameter of less than 52 nm when measured on a Nicomp 370
photon correlation spectrophotometer (Particle Sizing Systems,
Santa Barbara Calif.).
[0056] Similar emulsions can be made for other lipophilic drugs
that exist as a free base, for example doxorubicin or erythromycin.
Optionally, other oils as discussed earlier in the specification
and preferably Lauroglycol.RTM. may be used in place of Capmul MCM
in the formulation. Miglyol 812 (caprylic/capric triglycerides) and
like oils may also be used.
Example 2
[0057] Stability of Clarithromycin Formulation
[0058] The physical and chemical stability of the formulation of
Example 1 at 4.degree. C. was followed for 6 months. No detectable
physical change in the microemulsion incorporating a tocol-soluble
ion-pair could be detected by gross examination or by measuring
emulsion droplet size using standard particle sizing methods.
Likewise, no detectable degradation of clarithromycin could be
detected by HPLC. In contrast, a solution of the lactobionate salt
had degraded by about 50% over the same time period. Thus, the
microemulsion when stored at 4.degree. C. remained stable for at
least 6 months.
Example 3
[0059] Amiodarone as a Tocol-Soluble Ion Pair Compound
[0060] Amiodarone is a Class III anti-arrhythmic for care of
patients suffering or at risk of heart attack. Since 1977, it has
been administered as an aqueous solution of the HCl salt in 10%
Tween 80 and 2% benzyl alcohol under the tradename Cordarone.RTM.
IV.
[0061] Amiodarone was purchased as the HCl salt (Sigma Chemicals,
St Louis Mo.). The free base was prepared by dissolving the drug in
chloroform and washing the organic phase with saturated sodium
bicarbonate. The drug in the organic phase was then recovered as a
pale yellow oil. An emulsion containing 12 mg/mL amiodarone as the
free base was then formulated as follows:
2 Weight in Final Percent Component Oil Phase (%) d,1-a-tocopherol
1.0 gm 2.0% TPGS 1.6 gm 3.2% Poloxamer 407 0.25 gm 0.5% Amiodarone
(free base) 0.6 gm 1.2% Vitamin E Succinate 0.5 gm 1.0% PEG-400 3.0
gm 6.0% Buffer to pH 5.0 qs to 50 mL
[0062] The formulation uses a molar equivalent of amiodarone as the
free base and Vitamin E succinate as the free acid to form the
tocol-soluble ion pair in the tocol oil before processing.
Following homogenization at 47.degree. C. for 5 min, a translucent
microemulsion was obtained with a mean particle size of 71 nm.
Other anions that are therapeutic for heart disease, for example
the free fatty acids linolenate, eicosapentaenoate or
docosahexaenoate from castor oil, were also useful as tocol-soluble
ion pairs with amiodarone and can be used in the form of an oral
drug supplement for maintenance therapy.
[0063] Mice were then dosed with emulsified amiodarone versus the
commercially available amiodarone solution (Cordarone IV, Wyeth
Laboratories). Before use, Cordarone was diluted 1:5 with 5%
dextrose in water for injection. Animals receiving the commercial
solution at 100 mg/kg lost coordination, mobility, and experienced
prolonged respiratory disturbance. At an equivalent dose, the
emulsion was tolerated much better than the commercially available
solution.
Example 4
[0064] Effect of Formulation on Amiodarone Blood Pool Levels
[0065] Amiodarone as the free base was formulated in an emulsion
(A) with tocopherol phosphate and was compared with amiodarone HCl
with Tween 80 and benzyl alcohol as a free solution (B). The
comparison involved injection of mice with equal amounts of the
drug in a bolus volume, and then sacrificing the mice at T=6 hr to
determine the blood levels of drug by HPLC. The data demonstrate
that blood levels of emulsified drug fall more slowly than those of
free or solubilized drug, suggesting that the emulsion composition
is present as a blood pool and may have improved therapeutic
effect.
3 Treatment (n = 6) Blood Level (.mu.g/mL) A 4.79 .+-. 1.37 B 1.35
.+-. 0.41
[0066] Significant levels of drug metabolites in the animals
treated with solubilized amiodarone HCl were detected, but low
levels in animals treated with emulsion. This suggests that hepatic
uptake in the case of the soluble form of drug is a principal cause
of the low blood levels, and that the liver is responsible for the
rapid clearance from blood followed by the appearance of
metabolites in blood. Because hepatotoxicity is a major concern
with this drug, the results presented in this invention suggest a
benefit from the use of an emulsified formulation of
amiodarone.
Example 5
[0067] Relative Release Rates for Amiodarone HCl Versus Amiodarone
Tocol-Soluble Ion Pair in a Diffusion Chamber Model
[0068] Amiodarone HCl and a tocol emulsion containing amiodarone
and tocopherol phosphate as a tocol-soluble binary ion pair,
prepared as mentioned above, were dialyzed against 20% glycerol, 3%
Poloxamer 407 at pH 7.4 and 37.degree. C.
[0069] The rate of free or complexed drug exiting the dialysis
chamber provides an indirect estimate of the "sustained release"
properties of the emulsion and the stfrength of the ion pair
species. Rates of dialysis were linear with concentration for
Amiodarone HCl, whereas diffusion for the amiodarone:tocopherol
phosphate ion pair was negligible at the highest concentration
tested. Given the low dielectric constant of the oil phase, this
suggests the formation of a stable ion pair in the tocol
emulsion.
Example 6
[0070] Tocotrienol Formulation for Vitamin E Succinate
Co-Therapy
[0071] Given the potential therapeutic effect of Vitamin E succinic
acid (VESA) in conjunction with xenotocols for the treatment of
breast cancer and other cancers, there is a special need for
multiphasic formulations that contain VESA in a tocotrienol oil.
Here "vehicle" is taken in its customary meaning among
pharmaceutical formulators to indicate the agent that carries the
drug, the base formulation and excipients, particularly the oil
phase thereof, without consideration of the active drug itself.
[0072] VESA and d-.gamma.-tocotrienol were obtained from Eastman
and the tocotrienol was further purified by vacuum distillation at
about 30 milliTorr and 210.degree. C. A final emulsion of 20 mg/mL
VESA in 50 mg/mL of d-.gamma.-tocotrienol and 12.5 mg/mL Capmul MCM
as an oil phase was prepared using 30 mg/mL Poloxamer 407 as
surfactant. PEG-400 was added to a final concentration of 5% before
emulsification. Emulsification is performed as described in
Examples 1 or 4, but may be more rapidly completed by increasing
the temperature of emulsification to 70.degree. C. or higher.
Optionally, tocopheramine as the free base may be used to emulsify
this oil mixture at lower temperature.
Example 7
[0073] Erythromycin Emulsion Compositions.
[0074] Erythromycin (free base) solubility in .alpha.-tocopherol
and medium-chain triglycerides (MCT) was determined to be
approximately 10% and 4% w/w, respectively. Examples of emulsions
incorporating erythromycin that were successfully prepared are
shown in the table below.
[0075] Emulsions were prepared as described above. Emulsions A, B,
C, and D were homogenized on the C5 to achieve microemulsions that
were translucent and readily filter-sterilizable through a 0.2
.mu.m membrane. The mean particle diameters of formulations A, B,
and D were 47 nm, 48 nm, and 81 nm, Emulsion E was processed with
the Virtis Handishear to produce a particle size of approximately
1.7 .mu.m, and emulsion F was formed by simple stirring. All
emulsions and microemulsions showed no sign of any crystallization
or drug precipitation when examined visually and with a light
microscope.
4 Erythromycin emulsion examples Component A B C D E F Component
Function (Weight %) Erythromycin Active 0.5 0.5 1.0 1.3 2.5 2.0
Vitamin E Ion pair 0.5 1.0 1.0 1.8 11.5 Succinate forming Compound
.alpha.-Tocopherol Oil/Solvent 8.0 8.0 8.0 7.1 MCT Oil/Solvent 25.0
3.5 TPGS Surfactant 5.0 5.0 5.0 4.5 5.0 3.5 Poloxamer 407
Surfactant 1.0 1.0 1.0 0.9 Water Aqueous q.s. q.s. q.s. q.s. q.s.
q.s. Phase
Example 8
[0076] Conversion of Doxorubicin HCL to Free Base
[0077] Doxorubicin HCl in 8:1 CHCl.sub.3:MeOH produced a drug
suspension upon stirring under a stream of gaseous NH.sub.3. The
resulting suspension was subsequently filtered to remove the
insoluble material leaving behind a red solvent solution. It was
subsequently dried down to a solid free base with an approximate
recovery of 90% based on HPLC without any evidence of drug
degradation.
Example 9
[0078] Tocol-Soluble Doxorubicin Ion Pair Formation and Emulsion
Composition
[0079] Vitamin E phosphate is supplied commercially as the sodium
salt, so extraction into chloroform with acidic water was necessary
to get the free acid, which was used to make an ion pair with
doxorubicin free base at 2:1 molar ratio, which was soluble in
vitamin E. This oil phase, when combined with the surfactant
Tagat.RTM. TO (PEG-25 glyceryl trioleate), was readily emulsified
at 60.degree. C. with water by hand mixing to make a crude emulsion
of the composition shown below with no evidence of drug
precipitation. A fine emulsion can be prepared using high pressure
homogenization to reduce particle size.
5 Component mg/mL Doxorubicin (free base) 0.3 Vitamin E Phosphate
0.6 Vitamin E 23.0 Tagat TO 23.8 Water qs
Example 10
[0080] Alternative Doxorubicin Ion-Pairs and Emulsion
Compositions
[0081] Using procedures analogous to those of Examples 8 and 9
ion-pairs of doxorubicin with vitamin E succinate, oleic acid,
decyl and hexadecyl phosphates can be formned and incorporated in
.alpha.-tocopherol emulsions. In addition to vitamin E and TPGS,
poloxamers, polysorbates, lecithin, triglycerides, propylene glycol
and polyethylene glycol can be included. Emulsion and drug
stability can be controlled by optimizing the surfactant:ion
pair:oil phase ratio.
Example 11
[0082] Tocopherolsuccinate-Aspartate
[0083] Tocopherolsuccinate-aspartate is a novel compound that can
be used to form ion pairs with cationic pharmaceutically active
compounds used in this invnetion. Synthesis of the
tocopherolsuccinate aspartate conjugate was carried out via the use
of mixed anhydride chemistry. D-.alpha.-tocopherol succinate was
activated by adding 1.2 equivalents of isobutylchloroformate (IBCF)
and 1.4 equivalents of N-methylmorpholine (NMM) in a
tetrahydrofuran (THF) medium at -5.degree. C. To insure complete
conversion to the mixed anhydride the reaction was stirred for 1
hour allowing the mixture to slowly warm to room temperature. The
mixed anhydride was filtered to remove the N-methylmorpholine
hydrochloride salt (NMM>HCl). The resulting filtrate was added
drop-wise over 45 minutes to a -5.degree. C. solution of 1.0
equivalence of L-aspartic acid dibenzyl ester p-toluenesulfonate
salt and 1.5 equivalence of triethylamine (TEA) in THF solution
over 1 hour. The reaction was allowed to continue for an additional
1 hr at -5.degree. C., then warm to room temperature and was
stirred for an additional 15 hours before isolating the
product.
[0084] Once the reaction was complete, the THF was removed in a
vacuo to yield a crude yellow sticky solid. The product was
dissolved in dichloromethane (DCM) and washed with 2.times.0.1 N
HCl, 1.times.Sat. NaHCO.sub.3, and 1.times.Sat. NaCl. The resulting
organic mixture was dried over MgSO.sub.4 and removed in a vacuo to
yield an off white solid.
[0085] The tocopherolsuccinate-aspartate dibenzyl ester was
deprotected by hydrogenation to yield the free diacid product.
Total yield=72%. Purity=95%+ by HPLC analysis. FT-IR: [N--H
(amide), C.dbd.O (ester), C.dbd.O (amide), and C--O (ether)
stretch] are 3336, 1736, 1645, 1153 cm.sup.-1, respectively. The
structure of tocopherolsuccinate-aspartate was confirmed by
LC-MS.
Example 12
[0086] Tocopherolsuccinate-Glutamate
[0087] Using the methodologies of Example 11, the novel compound
tocopherolsuccinate-glutamate can readily be synthesized and
characterized.
* * * * *