U.S. patent application number 09/874622 was filed with the patent office on 2001-11-01 for self-emulsifying systems containing anticancer medicament.
Invention is credited to Liu, Rong Ron, Wang, Zheng.
Application Number | 20010036962 09/874622 |
Document ID | / |
Family ID | 23329750 |
Filed Date | 2001-11-01 |
United States Patent
Application |
20010036962 |
Kind Code |
A1 |
Liu, Rong Ron ; et
al. |
November 1, 2001 |
Self-emulsifying systems containing anticancer medicament
Abstract
The present invention relates to a stabilized self-emulsifying
system, comprising a therapeutically effective amount of
o-(chloroacetylcarbamoyl- )fumigillol, a pharmaceutically
acceptable carrier and a stabilizing component, wherein the
pharmaceutically acceptable carrier comprises an oily constituent
and at least one surfactant. The stabilizing component comprises
from about 1% to about 15% water relative to the weight of the
self-emulsifying system, an acid, an adsorbent, or a
complex-forming agent.
Inventors: |
Liu, Rong Ron; (Gurnee,
IL) ; Wang, Zheng; (Westboro, MA) |
Correspondence
Address: |
Steven F. Weinstock
Abbott Laboratories
Dept. 377/AP6D-2
100 Abbott Park Road
Abbott Park
IL
60064-6050
US
|
Family ID: |
23329750 |
Appl. No.: |
09/874622 |
Filed: |
June 5, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09874622 |
Jun 5, 2001 |
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09339595 |
Jun 24, 1999 |
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60090452 |
Jun 24, 1998 |
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Current U.S.
Class: |
514/475 |
Current CPC
Class: |
A61K 9/1075 20130101;
Y10S 514/941 20130101; Y10S 514/943 20130101; A61P 35/04 20180101;
Y10S 514/938 20130101; A61K 31/336 20130101; Y10S 514/937 20130101;
A61P 35/00 20180101; A61K 9/4858 20130101 |
Class at
Publication: |
514/475 |
International
Class: |
A61K 031/336 |
Claims
What is claimed is:
1. A stabilized self-emulsifying system, comprising a
therapeutically effective amount of
o-(chloroacetylcarbamoyl)fumigillol, a pharmaceutically acceptable
carrier and a stabilizing component, wherein the pharmaceutically
acceptable carrier comprises an oily constituent and at least one
surfactant and the stabilizing component comprises from about 1% to
about 15% water relative to the weight of the stabilized
self-emulsifying system.
2. The stabilized self-emulsifying system according to claim 1,
wherein the stabilizing component comprises from about 2% to about
10% water.
3. The stabilized self-emulsifying system according to claim 2,
wherein the stabilizing component comprises from about 7.0% to
about 7.5% water.
4. A stabilized self-emulsifying system, comprising a
therapeutically effective amount of
o-(chloroacetylcarbamoyl)fumigillol, a pharmaceutically acceptable
carrier and a stabilizing component, wherein the pharmaceutically
acceptable carrier comprises an oily constituent and at least one
surfactant and the stabilizing component comprises an acid.
5. The stabilized self-emulsifying system according to claim 4,
wherein the acid is an organic or an inorganic acid.
6. The stabilized self-emulsifying system according to claim 5,
wherein the organic acid is selected from the group consisting of
aliphatic carboxylic acids, aromatic carboxylic acids, and sulfonic
acids.
7. The stabilized self-emulsifying system according to claim 6,
wherein the organic acid is selected from the group consisting of
aminobenzoic acid, benzoic acid, acetylsalicylic acid, salicylic
acid, formic acid, acetic acid, propionic acid, butyric acid,
valeric acid, caproic acid, enanthic acid, caprylic acid,
pelargonic acid, capric acid, lauric acid, myristic acid, palmitic
acid, stearic acid, glycolic acid, lactic acid, malic acid, citric
acid, methanesulfonic acid, 2-propanesulfonic acid,
trifluoromethanesulfonic acid, benzenesulfonic acid, and
p-toluenesulfonic acid.
8. The stabilized self-emulsifying system according to claim 7,
wherein the acid is citric acid.
9. The stabilized self-emulsifying system according to claim 5,
wherein the inorganic acid is selected from the group consisting of
orthophosphoric acid, polyphosphoric acid, pyrophosphoric acid, and
hydrochloric acid.
10. The stabilized self-emulsifying system according to claim 4,
wherein the stabilizing component comprises from about 0.005% to
about 5.0% acid.
11. The stabilized self-emulsifying system according to claim 10,
wherein the stabilizing component comprises from about 0.05% to
about 1.0% acid.
12. A stable drug system comprising a therapeutically effective
amount of o-(chloroacetylcarbamoyl)fumigillol, a pharmaceutically
acceptable carrier and a stabilizing component, wherein the
pharmaceutically acceptable carrier comprises an oily constituent
and at least one surfactant and the stabilizing component is an
adsorbent or complex-forming agent.
13. The stabilized self-emulsifying system according to claim 12,
wherein the stabilizing component is selected from the group
consisting of gelatin, active charcoal, and silica gel.
14. The stabilized self-emulsifying system according to claim 12,
wherein the stabilizing component is a chelate or salt of
ethylenediaminetetraace- tic acid.
15. The stabilized self-emulsifying system according to claim 13,
wherein the stabilizing component is gelatin.
16. The stabilized self-emulsifying system according to claim 12,
wherein the stabilizing component comprises from about 0.01% to
about 15% of the adsorbent or complex-forming agent.
17. The stabilized self-emulsifying system according to claim 16,
wherein the stabilizing component comprises from about 0.05% to
about 10% of the adsorbent or complex-forming agent.
18. The stabilized self-emulsifying system according to claim 1,
wherein the oily component is a non-surface active oil.
19. The stabilized self-emulsifying system according to claim 1,
wherein the oily component is selected from Captex 100, Captex 300,
Captex 355, Miglyol 810, Miglyol 812, Miglyol 818, Miglyol 829, and
Dynacerin 660.
20. The stabilized self-emulsifying system according to claim 1,
wherein the self-emulsifying system is suitable for oral, enteral,
parenteral, and intravenous administration.
21. The stabilized self-emulsifying system according to claim 4,
wherein the self-emulsifying system is suitable for oral, enteral,
parenteral, and intravenous administration.
22. The stabilized self-emulsifying system according to claim 12,
wherein the self-emulsifying system is suitable for oral, enteral,
parenteral, and intravenous administration.
23. A pharmaceutical composition comprising a therapeutically
active amount of o-(chloroacetylcarbamoyl)fumigillol, an oily
constituent, at least one surfactant, and stabilizing component,
wherein the stabilizing component is selected from about 1 to about
15 weight percent water; from about 0.005 to about 5.0 weight
percent acid; and 0.05 to about 15 weight percent of an adsorbent
or complex-forming agent.
24. The composition according to claim 23, comprising from 40 to 60
weight percent of the oily component; from 20 to 40 weight percent
surfactant; from 4 to 20 weight percent co-surfactant, and from 2
to about 12 weight percent water.
25. The composition according to claim 24, wherein the composition
comprises from about 7.0 to about 7.5 weight percent water.
26. The composition according to claim 23, comprising from 40 to 60
weight percent of the oily component; from 20 to 40 weight percent
surfactant; from 4 to 20 weight percent co-surfactant; and from
0.005 to about 5.0 weight percent acid.
27. The composition according to claim 26, wherein the composition
comprises from about 0.05 to about 1.0 weight percent acid.
28. The composition according to claim 23, comprising from 40 to 60
weight percent of the oily component; from 20 to 40 weight percent
surfactant; from 4 to 20 weight percent co-surfactant; and from
0.05 to about 15 weight percent.
29. The composition according to claim 28, wherein the composition
comprises from about 0.05 to about 10 weight percent of the
adsorbent or complex-forming agent.
30. A method of suppressing cell proliferation and
neovascularization comprising administering the self-emulsifying
system of claim 1.
31. A method of suppressing cell proliferation and
neovascularization comprising administering the stabilized
self-emulsifying system of claim 4.
32. A method of suppressing cell proliferation and
neovascularization comprising administering the stabilized
self-emulsifying system of claim 10.
Description
TECHNICAL FIELD
[0001] The present invention relates to a stabilized
self-emulsifying system comprising anticancer medicament. The
claimed invention is suitable for formulation of angiogenesis
inhibitor o-(chloroacetylcarbamoyl)fumagillol.
BACKGROUND OF THE INVENTION
[0002] Fumagillins are a class of compounds naturally secreted from
aspergillus fumigatus fungus. Synthetic analogues of fumagillins
provide a class of angiogenesis inhibitors that exhibit potent
anti-angiogenic activity and low systemic toxicity. A synthetic
derivative of fumagillin having a formula (I): 1
[0003] has been described in European Patent No. 0 359 036 and
European Patent No. 0 357 061 as having inhibitory effect of
suppressing the proliferation of endothelial cells and inhibiting
neovascularization. The compounds having angiogenesis inhibiting
activity have use in treating tumors in cancerous conditions.
(Cancer Medicine, 3d. edition, Lea & Febiger, Philadelphia
(1993)).
[0004] Developing stable formulations for delivering effective
amounts of medicament to target organs presents unique challenges
in obtaining a suitable formulation for the medicament.
Characterized by their lipophilic properties and low water
solubility, these drugs typically result in formulations producing
low oral bioavailability. European Patent No. 0 602 586 discloses a
pharmaceutical composition comprising a fumagillol derivative and a
fatty acid ester of glycerin or polyglycerin. Typical formulations
are less effective for delivery of the medicament to the angiogenic
tumors due to low oral bioavailability of the medicament in the
formulation.
[0005] Recent developments in drug formulation have resulted in
self-emulsifying drug systems (SES) being used as vehicles for
orally administering lipophilic medicaments. (Charman,
Pharmaceutical Research, 39(1): 87-93 (1992)). Self-emulsifying
systems are generally recognized to be mixtures of oil and
surfactant which, upon exposure to aqueous media, form isotropic
dispersions stabilized by an interfacial film of surfactant
molecules.
[0006] Several self-emulsifying systems containing active drug in
mixtures of oil and surfactant, which emulsify and form dispersions
under gentle agitation, have been described using various
components and for numerous uses.
[0007] European Patent No. 0 517 412 describes an oil-based
self-emulsifying formulation containing benzodiazepine compounds
useful for treating pain, panic, or anxiety.
[0008] The self-emulsifying systems described in Shah, Intl. J. of
Pharm., 106:15-23 (1994) contain polyglycolized glyceride oils with
varying fatty acid and polyethylene glycol.
[0009] Pouton, et al., Intl. J. of Pharm., 27:335-348 (1985),
discloses self-emulsifying systems containing Miglyol 812 or
Miglyol 840 oils in combination with Tween 85 surfactant.
[0010] Pharmaceutical formulations wherein the composition is in
the form of a self-emulsifying system have particularly
advantageous properties with respect to the above fumagillol
derivative. Formulations of fumagillin anticancer agents in typical
self-emulsifying systems rapidly degrade if formulated without a
suitable stabilizing component. Therefore, there continues to be a
need to provide effective methods of formulating fumagillin
anticancer agents to ensure more effective bioavailability and
wider availability of the desired medicaments.
SUMMARY OF THE INVENTION
[0011] The present invention relates to a stabilized
self-emulsifying system, comprising a therapeutically effective
amount of o-(chloroacetylcarbarnoyl)fumigillol, a pharmaceutically
acceptable carrier, and a stabilizing component, wherein the
pharmaceutically acceptable carrier comprises an oily constituent
and at least one surfactant. In one aspect of the invention, the
stabilizing component of the self-emulsifying system comprises from
about 1% to about 15% water relative to the weight of the
formulation. Another aspect of the invention relates to a
self-emulsifying system comprising a therapeutically effective
amount of o-(chloroacetylcarbamoyl)fumigillol and a
pharmaceutically acceptable carrier stabilized by an acid. Yet
another aspect of the present invention relates to a stable system
for active medicament, comprising a self-emulsifying system
comprising medicament, a pharmaceutically acceptable carrier, and a
stabilizing component, wherein the stabilizing component is an
adsorbent or complex-forming agent.
DETAILED DESCRIPTION OF THE INVENTION
[0012] The present invention relates to a stabilized
self-emulsifying system for medicaments having anticancer activity.
The invention particularly relates to a self-emulsifying system
having a stabilizing component to prevent degradation of the active
medicament in the formulation. Formulations of the present
invention exhibit improved bioavailablity of lipophilic compounds
useful against cancer conditions.
[0013] "Self-emulsifying system" as used herein refers to a
physically and chemically stable oily solutions, suspensions, or
semisolids which, upon contact in an aqueous medium, form a fine
dispersion of oil in aqueous medium wherein the dispersion is
stabilized by an interfacial film of surfactant molecules. The
aqueous medium can be water or the aqueous physiological fluids of
the gastrointestinal system.
[0014] The term "emulsion" as used herein refers to a liquid-liquid
dispersion wherein the dispersion droplets are stabilized by an
interfacial film of surfactant molecules. "Emulsion" as defined
herein refers to all such dispersions whether formed by a mixture
of nonhomogenous liquids and/or solutions or by introducing a
self-emulsifying system as defined above into an aqueous
medium.
[0015] The term "stabilizing component" as used herein refers to
the useful components of the self-emulsifying system that provide
chemical and/or physical stability to a self-emulsifying system as
defined above. The stabilizing component provides useful materials
for stabilizing a formulation described as the self-emulsifying
system independent of its contact with an aqueous environment or
medium.
[0016] Medicaments useful in the compositions of the present
invention are a class of compounds naturally secreted from
aspergillus fumigatus fungus named fumagillins, derivatives, and
synthetic analogues thereof. In particular, the medicaments useful
in the compositions of the present invention have a formula: 2
[0017] which have been described as having anti-angiogenic activity
in the European Patent No. 0 359 036. The medicaments and
pharmaceutical formulations containing the medicaments are useful
for the treatment of cancer conditions characterized by
proliferation of endothelial cells and neovascularization. In
particular, the useful medicament is (3R, 4S, 5S,
6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxasp-
iro[2,5]-oct-6yl(chloroacetylcarbamoyl)carbamate or
o-(chloroacetylcarbamoyl)fumagillol. The drug typically degrades by
hydrolysis under aqueous conditions. The pharmaceutical
compositions described herein provide suitable formulations of
o-(chloroacetylcarbamoy- l)fumigillol in an aqueous environment,
such as the stomache of a mammal ingesting the composition,
demonstrating an improved oral formulation. Benefits of the claimed
formulations include, but are not limited to, the improved
solubility of the medicament in solution as well as improved oral
bioavailability of the active agent over formulations reported in
the scientific literature.
[0018] The medicaments useful in the compositions of the present
invention include not only those specifically named above, but also
where appropriate the pharmaceutically acceptable salts, esters,
amides and prodrugs thereof.
[0019] "Pharmaceutically acceptable salts, esters, amides and
prodrugs" as used herein means those carboxylate salts, amino acid
addition salts, esters, amides and prodrugs of a compound which
are, within the scope of sound medical judgment, suitable for use
in contact with the tissues of humans and lower animals with undue
toxicity, irritation, allergic response and the like, commensurate
with a reasonable benefit/risk ratio and effective for their
intended use. A preferred therapeutic agent is sparingly soluble in
water and has solubility in water of less than 5 mg/mL.
[0020] The term "pharmaceutically acceptable carrier" refers to a
non-toxic solid, semisolid or liquid filler, diluent, encapsulating
material or formulation auxiliary of any type. In relation to the
present invention, the pharmaceutically acceptable carrier
comprises the combination of solvents, surfactants, optional
co-surfactants, and stabilizing agents used in the formulation.
[0021] Oily components suitable for the process are selected from
the group consisting of alcohols, propylene glycol, polyethylene
glycol, propylene glycol esters, medium chain mono-, di-, or
triglycerides, long chain fatty acids, naturally occurring oils,
and a mixture thereof. The oily components suitable for the solvent
system include commercially available oils as well as naturally
occurring oils. The oils can be characterized as non-surface active
oils, which typically have no hydrophile lipophile balance value.
Commercially available excipients comprising medium chain
triglycerides include, but are not limited to, Captex 100, Captex
300, Captex 355, Miglyol 810, Miglyol 812, Miglyol 818, Miglyol
829, and Dynacerin 660. Propylene glycol ester compositions that
are commercially available encompass Captex 200 and Miglyol 840,
and the like. The commercial product, Capmul MCM, discloses one of
many medium chain mixtures comprising monoglycerides and
diglycerides. Suitable naturally occurring oils are seed oils.
Exemplary natural oils include oleic acid, castor oil, safflower
seed oil, soybean oil, olive oil, sunflower seed oil, and peanut
oil. The active medicament generally has greater solubility in
commercially available excipients, and therefore, commercially
available excipients are preferred over naturally occurring oils as
the suitable oil.
[0022] Preferably, the oily component comprises medium chain
triglycerides or propylene glycol esters. Equivalent compositions
whether commercially prepared or prepared according to methods
known to those having skill in the art are also suitable for the
invention. The most preferred oily component is Captex 200, Miglyol
840, Miglyol 812 or an equivalent composition.
[0023] Generally, the surfactants are selected from a group of
compounds having a hydrophile lipophile balance (HLB) of less than
or equal to 7. Suitable surfactants are selected from a group
consisting of propylene glycols, glyceryl fatty acids, glyceryl
fatty acid esters, polyethylene glycol esters, glyceryl glycol
esters, polyglycolyzed glycerides and polyoxyethyl steryl ethers.
Propylene glycol esters or partial esters form the composition of
commercial products, such as Lauroglycol FCC, which contains
propylene glycol laureate. The commercially available excipient
Maisine 35-1 comprises long chain fatty acids, for example glyceryl
linoleate. Products, such as Acconon E, which comprise
polyoxyethylene stearyl ethers are also suitable for the
formulation of the invention. Mixtures of the above named
surfactants and compounds are also suitable for the invention.
Labrafil M 1944 CS is one example of a suitable surfactant wherein
the composition contains a mixture of glyceryl glycol esters and
polyethylene glycol esters. These surfactants, mixtures, and other
equivalent compositions having an HLB less than or equal to 7 can
be used for the formulation of the invention.
[0024] Certain surfactants show acceptable compatibility despite
having an HLB greater than 7. Generally, acceptable surfactants
having an HLB greater than 7 are used in combination with other
surfactant as co-surfactants. Suitable co-surfactants are selected
from the group consisting of glyceryl glycol esters, polyethylene
glycol esters, polyglycolyzed glycerides, polyoxyethylene glycerol
esters, and a mixture thereof. Commercially available
co-surfactants based on an oleate or laureate ester of a
polyalcohol copolymerized with ethylene oxide are also useful in
the invention. Labrasol is a commercially available excipient based
on glyceryl glycol esters and polyethylene glycol esters. Gelucire
44/14 comprises polyglycolyzed glycerides. Tween 80 (polysorbate
80) exemplifies a polyoxyethylene sorbitan monooleate suitable as
the co-surfactant. Tween 80 and Labrasol are the preferred
co-surfactants.
[0025] In one aspect, the present invention relates to a stabilized
self-emulsifying system comprising the medicament, a
pharmaceutically acceptable carrier and a stabilizing component,
wherein the stabilizing component is water. In another aspect of
the invention, the stabilized self-emulsifying system comprises the
medicament, the pharmaceutically acceptable carrier, and a
stabilizing component, wherein the stabilizing component comprises
an acid. In yet another aspect, the present invention relates to a
stabilized self-emulsifying system comprising the medicament, the
pharmaceutically acceptable carrier, and a stabilizing component,
wherein the stabilizing component comprises an adsorbent or
complex-forming agent.
[0026] Surprisingly, adding a small amount of water to the
oil-based formulation stabilizes the self-emulsifying system. The
stabilizing component in the present aspect of the invention
comprises from about 1% to about 15% water relative to the weight
of the self-emulsifying system. The relative amount of water is
critical to the stability of the self-emulsifying system in this
aspect of the invention. Presence of excess water causes
degradation of the active medicament in the formulation. Moreover,
formulations having less than 1% water are unsatisfactory due to
instability of the medicament. Chemical stability of the medicament
in the self-emulsifying system is accomplished from about 1% to
about 15% water. Preferably, the self-emulsifying system contains
from about 2% to about 12% water relative to the weight of the
formulation. Most preferably, the formulation contains from about
7.0% to about 7.5% water.
[0027] The presence of water in the self-emulsifying system will
form reverse micelles with surfactants, for example Tween 80 or
Capmul MCM. The core of the micelle consists of an aqueous or
hydrophilic micro-phase. Hydrophilic impurities will be solubilized
or partitioned into the reversed micelles in formulation, thereby
minimizing the degradation of the
o-(chloroacetylcarbamoyl)fumigillol. The formation of reversed
micelles in the self-emulsifying system protects the drug from
degradation or stabilizes the drug in the macroscopically
homogeneous SES solution.
[0028] Another stabilizing component useful in the stabilized
self-emulsifying system is an acid. Suitable acids for the
formulation comprise organic acids as well as inorganic acids and
derivatives thereof. Organic acids suitable for the formulation are
selected from the group consisting of aliphatic carboxylic acids,
aromatic carboxylic acids, and sulfonic acids. Suitable aliphatic
carboxylic acids comprise C.sub.1-C .sub.16 carboxylic acids,
including hydroxycarboxylic acids. Exemplary aliphatic carboxylic
acids include, but are not limited to, formic acid, acetic acid,
propionic acid, butyric acid, valeric acid, caproic acid, enanthic
acid, caprylic acid, pelargonic acid, capric acid, lauric acid,
myristic acid, palmitic acid, stearic acid, and the like, or a
mixture thereof. Hydroxycarboxylic acids are selected from the
group consisting of citric acid, glycolic acid, lactic acid, malic
acid, and the like, or a mixture thereof. Aromatic organic acids
suitable for the formulation are selected from the group comprising
benzoic acids and derivatives thereof. Suitable aromatic carboxylic
acids and derivatives thereof include, but are not limited to,
aminobenzoic acid, benzoic acid, acetylsalicylic acid, salicylic
acid, and the like, or a mixture thereof. Additional organic acids
include suitable sulfonic acids, such as alkanesulfonic and
arenesulfonic acids, which are selected from the group consisting
of methanesulfonic acid, 2-propane-sulfonic acid,
trifluoromethanesulfonic acid, benzenesulfonic acid,
p-toluenesulfonic acid, and the like, or a mixture thereof.
Inorganic acids suitable for the invention are selected from the
group consisting of orthophosphoric acid, polyphosphoric acid,
pyrophosphoric acid, hydrochloric acid and the like, or a mixture
thereof. Preferably, the acid used is an organic acid. The
preferred organic acid is hydroxycarboxylic acid. Citric acid is
the most preferred acid.
[0029] Preferably, the acid will comprise between about 0.005% to
about 5.0% weight relative to the self-emulsifying system. It is
preferred that the acid comprises from about 0.05% to about 1.0%
weight of the stabilized self-emulsifying system.
[0030] Suitable adsorbents or complex forming agents are selected
from the group consisting of gelatin, active charcoal, silica gel,
and chelating agents. The pharmaceutically acceptable carrier
having the medicament can be filled, mixed, adsorbed, filtered or
otherwise combined, contacted, or reacted with the adsorbent or
complex forming agent. Exemplary chelating agents are chelates
and/or salts of ethylenediaminetetraacetic acid (EDTA). Preferably,
the adsorbent is a gelatin, which can be shaped as a capsule,
shell, pod, caplet or any other suitable form for containing a
liquid self-emulsifying system. The gelatin form can be a hard or
soft gelatin capsule.
[0031] The adsorbent or complex-forming agent typically comprises
from about 0.05% to 15% weight adsorbent or complex-forming agent
relative to the weight of the medicament. Preferably, the adsorbent
or complex-forming agent comprises from about 0.05 to about 10
weight percent of the total formulation. The exact amount of
adsorbent or complex-forming agent can be determined by one having
ordinary skill in the art considering the active agent, excipients,
and the nature of the stabilizing component in the self-emulsifying
system and the amount of material necessary to stabilize the
medicament.
[0032] The stabilized self-emulsifying systems of the present
invention form emulsions upon gentle agitation in an aqueous
environment. Droplet sizes of the emulsion preferably have a
diameter of less than 25 microns. The preferred droplet sizes are
less than 5 microns in diameter. Typically, smaller droplets in the
formed emulsion more effectively deliver the active medicament.
Droplet size in the formed emulsion can be determined using a
Sympatec Helos (H0687) laser diffraction particle sizer. The
dispersing system is stirred at a rate of 40 r.p.m. and 0.1 mL of
sample is added to 4 mL of water. The sample is shaken for 10
minutes and measured for a measuring time of 10 seconds.
[0033] A preferred mixture having the proper ratio of components is
described below in Table 1.
1TABLE 1 Emulsion Component Preferred Proportions Oil components
between 20% and 90%, preferably 40% to 60% by weight of the total
Surfactant between 5% and 50%, preferably 20% to 40% by weight of
the total Co-surfactants between 0 and 40%, preferably 4% to 20% by
weight of the total Stabilizing agent at least one of the following
in the indicated proportions: preferably 1-15%, and more preferably
2-12%, water by weight of the total; preferably 0.005-5.0%, and
more preferably 0.05-1.0%, acid by weight of the total, and
preferably more than 0.05-15%, and more preferably 0.05-10%,
adsorbent or complex- forming agent relative to the weight of the
medicament
[0034] A pharmaceutical composition in accordance with the
invention comprises a therapeutically active amount of
o-(chloroacetylcarbamoyl)fum- igillol, an oily constituent, at
least one surfactant, and stabilizing component, wherein the
stabilizing component is selected from about 1 to about 15 weight
percent water; from about 0.005 to about 5.0 weight percent acid;
and from about 0.05 to about 15 weight percent of an adsorbent or
complex-forming agent.
[0035] A preferred composition of the invention comprises from 40
to about 60 weight percent of the oily component; from 20 to about
40 weight percent surfactant; from about 4 to about 20 weight
percent co-surfactant, and from 1 to about 15 weight percent water.
A more preferred composition comprises from about 2 to about 12
weight percent water. The most preferred composition comprises from
about 7.0 to about 7.5 weight percent water.
[0036] Another preferred composition of the invention comprises
from 40 to about 60 weight percent of the oily component; from 20
to about 40 weight percent surfactant; from about 4 to about 20
weight percent co-surfactant; and from about 0.05 to about 5.0
weight percent acid. A more preferred composition comprises from
about 0.05 to about 1.0 weight percent acid.
[0037] Yet another preferred composition of the invention comprises
from 40 to about 60 weight percent of the oily component; from 20
to about 40 weight percent surfactant; from about 4 to about 20
weight percent co-surfactant; and from about 0.05 to about 15
weight percent adsorbent or complex-forming agent. A more preferred
composition comprises from about 0.05 to about 10 weight percent
adsorbent or complex-forming agent.
[0038] The compositions of the present invention can comprise
additives conventionally used for preparing formulations. Examples
of the additives include those used for oral liquid systems and
injectable preparations, such as preservatives, antioxidants, and
thickening agents. Exemplary preservatives include, but are not
limited to, benzylalcohol, ethylalcohol, benzalkonium chloride,
phenol, chlorobutanol, and the like. The antioxidants for the
invention provide oxygen or peroxide inhibiting agents for the
formulation and include, but are not limited to, butylated
hydroxytoluene, butylhydroxyanisole, propyl gallate, ascorbic acid
palmitate, .alpha.-tocopherol, and the like. Thickening agents,
such as lecithin, hydroxypropylcellulose, aluminum stearate, and
the like, may improve the texture of the formulation.
[0039] The pharmaceutical formulations of the present invention
optionally can be molded into solid, semisolid or liquid
preparations. For such preparations, the composition of the present
invention is molded into powder composition as it is or after
mixing it with added vehicles, such as glucose, mannitol, starch,
microcrystalline cellulose, and the like; thickening agents, such
as natural gums, cellulose derivatives, acrylic acid polymers, and
the like; and other additives or excipients used in solid or
semisolid preparations. For the liquid preparations, oily or
aqueous preparations of emulsions formed from the self-emulsifying
systems of the invention are prepared according to almost the same
manner as that in the above injectable preparations.
[0040] To prepare suppositories, the composition of the present
invention can be molded into oily or aqueous solid, semisolid or
liquid suppositories by methods known in the art.
[0041] In another aspect of the invention, the present invention
relates to a method of suppressing cell proliferation and
neovascularization comprising administering a formulation having
the above stabilized self-emulsifying system. The stabilized
self-emulsifying system suitable for an intended mode of
administration, such as topical, parenteral, or oral, e.g. in the
form of capsule fillings. The term "parenteral" as used herein
refers to modes of administration, which include intravenous,
intramuscular, intraperitoneal, intracisternal, subcutaneous and
intraarticular injection and infusion.
[0042] The compositions and methods of the present invention will
be better understood in connection with the following Examples. The
Examples are intended as illustrations of and not a limitation upon
the scope of the invention.
EXAMPLES
Example 1
Preparation of the Stabilized SES formulation
Example 1a
[0043] Captex 200 (propylene glycol dicaprylate/dicaprate; ABITEC
Co.), Capmul MCM (medium chain mono and diglyceride; ABITECH Co.),
Tween 80 (polysorbate 80; Sigma) were added in a container and
mixed well with a magnetic stir bar. The
o-(chloroacetylcarbamoyl)fumagillol (EP 0 359 036; Takeda Chemical
Industries., Ltd., Tokyo, Japan) was added with stirring until the
drug completely dissolved to form a clear, yellowish solution. The
final formulations were gently agitated to blend the ingredients.
To a base formulation of Captex 200, Capmul MCM, and Tween 80 was
added o-(chloroacetylcarbamoyl)fumigillol until the drug was
completely dissolved. Water was added to the formulation to obtain
a composition having final concentrations of 66.5% Captex 200, 19%
Capmul MCM, 9.5% Tween 80, 7.5% water, and 5% medicament wt./wt.
based on the total weight of the formulation.
Example 1b
[0044] To a base formulation of Labrasol, Miglyol 812, and
Lauroglycol FCC was added o-(chloroacetylcarbamoyl)fumigillol until
the drug was completely dissolved to obtain a composition having
final concentrations of 20% Labrasol, 20% Miglyol 812, 50%
Lauroglycol FCC, and 10% medicament wt./wt. based on the total
weight of the formulation. The solution was filled into a 200 mg
airfill softgell capsule.
Example 1c
[0045] To a base formulation of Miglyol 840, Lauroglycol FCC and
Tween 80 was added o-(chloroacetylcarbamoyl)fumigillol until the
drug was completely dissolved to obtain a composition having final
concentrations of 42.5% of Miglyol 840, 42.5% of Lauroglycol FCC,
5% of Tween 80, and 10% of the medicament wt./wt. based on the
total weight of the formulation. The solution was filled into a 50
mg airfill softgell capsule shell.
Example 2
Stability of Stabilized SES Formulations Containing Water
[0046] A determination of the effect of water on the stability of
several SES formulations prepared in accordance with the invention
were conducted as follows: Captex 200 (propylene glycol
dicaprylate/dicaprate; ABITEC Co.), Capmul MCM (medium chain mono
and diglyceride; ABITECH Co.), Tween 80 (polysorbate 80; Sigma)
were added in a container and mixed well with a magnetic stir bar.
The o-(chloroacetylcarbamoyl) fumagillol (EP 0 359 036; Takeda
Chemical Industries., Ltd., Tokyo, Japan) was added with stirring
until the drug completely dissolved to form a clear, yellowish
solution to prepare a base formulation having final concentrations
of 66.5% Captex 200, 19% Capmul MCM, 9.5% Tween 80, and 5%
medicament wt./wt. based on the total weight of the formulation.
Water was combined in the amounts shown in Table 2 based on the
weight of the base formulation. The final formulations were gently
agitated to blend the ingredients before the initial stability
determination was taken.
[0047] Results of these tests are shown below in Table 2. The data
obtained showed that water produced a good stabilizing quality in
the self-emulsifying systems, with the best results obtained at
7.5%.
2 TABLE 2 Amount of Water (% wt./wt.) k (per day) t 0.5 (day) Corr.
r. 0 0.351 1.976 0.9795 2.5 0.082 8.413 0.9940 5 0.025 27.709
0.9969 7.5 0.019 36.130 0.9950
Example 3
Stability of Stabilized SES Formulations in Acid
[0048] To illustrate the effect of citric acid on the stability of
the SES, several formulations were prepared as follows: Citric acid
was added to Labrasol (glyceryl and polyethylene glycol esters;
Gettefosse) and stirred using a magnetic stir bar at 50.degree. C.
until the citric acid dissolved. To the cooled solution, Miglyol
812 (caprylic acid/capric acid triglyceride; Huls America) and
Laurolglycol FCC (Gettefosse) were added and mixed well. The
o-(chloroacetylcarbamoyl)fumagillol was added with stirring until
the drug completely dissolved to produce a final formulation
containing concentrations of 20% Labrasol, 20% Miglyol 812, 50%
Lauroglycol FCC, and 10% medicament wt./wt based on the total
weight of the formulation. The final formulations were gently
agitated to blend the ingredients. The formulations were stored at
80.degree. C. for 24 hours before determining the percentage of
medicament remaining.
[0049] The results of these studies, shown below in Table 3,
demonstrate the stabilizing effect of citric acid on the
formulations of the present invention. The percentages of
medicament remaining in the respective citric acid formulations at
80.degree. C. are indicated below.
3 TABLE 3 % Citric Acid 0 .2 .4 .6 1.0 % Medicament 77.6 93.7 96.1
92.4 90.5 Remaining
Example 4
Stability of Stabilized SES Formulations in Gelatin
[0050] The effect of gelatin on the stability of several SES
formulations prepared in accordance with the invention was
determined by studies conducted as follows: Tween 80, Miglyol 840
and Laurolglycol FCC were combined at room temperature and mixed
well. The o-(chloroacetylcarbamoyl- )fumagillol was added with
stirring until the drug completely dissolved to produce a final
formulation containing concentrations of 5% Tween 80, 42.5% Miglyol
840, 42.5% Laurolglycol FCC, and 10% medicament wt./wt. based of
the total weight of the formulation. The final formulations were
gently agitated before the initial stability determination was
taken.
[0051] To prepare the formulation with gelatin, an opening was
formed in the tip of a gelatin capsule and the preparation was
injected into the capsule using a Hamilton gastight teflon glass
syringe. Sealing the opening with heat and pinching contained the
formulation in the capsule.
[0052] The amounts of medicament remaining in the prepared
formulation and in the filled capsule were measured. Measurements
were taken under separate reaction condition at 50.degree. C. and
80.degree. C., respectively. Results of these tests shown below in
Table 4 describe the percentage of medicament remaining in the
formulation with and without gelatin relative to each set of
reaction conditions. The data obtained showed that the gelatin
produced a good stabilizing effect on self-emulsifying drug
formulations.
4 TABLE 4 Reaction Conditions Prototype 50.degree. C., 15 days
80.degree. C., 5 days Formulation 80.52% 14.52% without Gelatin
Formulation with 90.14% 52.47% Gelatin
Example 5
Stability of Stabilized SES Formulations in Gelatin
[0053] Measurements were also taken under separate reaction
conditions in a related study of the formulation stability. The
formulation with gelatin was prepared as described above in Example
4. Results of the storage stability for the formulation with
gelatin is shown below in Table 5. The results illustrate the
percentage of medicament remaining in the formulation per time
interval, described in months (M), relative to each set of storage
conditions. The data obtained showed that the gelatin produced a
long-term stabilizing effect on self-emulsifying drug
formulations.
5 TABLE 5 Stability Data % Medicament Storage Conditions Interval
Remaining Initial 0 100% 5.degree. C. 1 M 99.5% 3 M 99.0%
25.degree. C./60RH.dagger. 1 M 99.0% 2 M 98.5% 3 M 97.0% .dagger.RH
denotes relative humidity.
Example 6
Bioavailability of the Stabilized SES Formulation
[0054] A control group of 5 mice and 3 subject groups of athymic
mice with 50 mice per group were treated in the study. The control
group was bled before treatment and the plasma from the mice was
prepared by mixing 0.1 volumes of 2% sulfuric acid in water. Each
of the subject groups, 1, 2, and 3, was treated with a single dose
of 50 mg/kg body weight of o-(chloroacetylcarbamoyl)fumagillol (the
medicament) administered subcutaneously (in gum arabic solution),
orally in gum arabic (2% ethanol/5% gum arabic/93% saline), or
orally in a self-emulsifying system, respectively. A
self-emulsifying system (10 g) was prepared by combining medicament
(0.5 mg) in Captex 200 (6.5 g), Capmul CMC (1.9 g), and Tween 80
(0.95 g). The dosing volume for all mice was 0.1 mL per 10 grams of
body weight. Plasma samples were collected at pre-treatment
(control group only) and at the following time intervals: 15 min.,
30 min., 60 min., 90 min., 120 min., 150 min., 3 hrs., 4 hrs., 6
hrs., and 8 hrs. after treatment. At the designated time intervals,
5 mice in each subject group were sacrificed and bled using heparin
as an anti-coagulant. Plasma samples taken from the subject group
mice were treated in the same manner as indicated for the
pretreatment group.
[0055] Compilation of the results determining the bioavailability
of the o-(chloroacetylcarbamoyl)fumagillol are shown in Table 6
below. Subcutaneous administration in gum arabic solution provides
a standard for comparing gum arabic and the SES oral dosage forms.
Samples were measured for plasma concentration of the medicament
(A), an active metabolite (B), and an inactive metabolite (C).
6TABLE 6 Relative C.sub.max T.sub.max AUC.sub.0-8 hrs.
Bioavailability Dosage Form (ng/mL) (hr) (ng .multidot. hr/mL) (%)
Subcutaneous A: 70.41 A: 0.4 A: 30.09 N/A B: 218.86 B: 0.3 B:
116.62 C: 536.36 C: 0.3 C: 329.14 Oral Solution A: 1.06 A: 3.1 A:
1.11 A: 3.7% (Gum Arabic) B: 14.61 B: 0.3 B: 6.93 B: 5.9% C: 148.71
C: 0.25 C: 106.46 C: 32.3% Oral SES A: 5.54 A: 1.4 A: 5.40 A: 17.9%
Formulation B: 11.41 B: 1.3 B: 20.57 B: 17.6% C: 51.70 C: 2.3 C:
171.90 C: 52.2%
Example 7
Comparison of Stabilized SES Bioavailability with Oil
Formulations
[0056] A 50 mg oral dose of o-(chloroacetylcarbamoyl)fumagillol
dissolved in a glyceride solution was compared with an SES prepared
as described in Example 4. Each dose was orally administered to dog
subjects treated in the study. Blood samples were collected at 0,
0.25, 0.5, 1, 1.5, 2, 3, 4, 6, and 9 hours after the dosing.
Bioavailability of the drug was assessed by evaluating the plasma
level of an o-(chloroacetylcarbamoyl)fumagillol inactive
metabolite.
[0057] Results of the comparative study illustrate that, for MII, a
metabolite of TNP-470 which was used as one the criteria for
bioavailability assessment, the SES formulation provides nearly 2.5
times the absolute oral bioavailability (F) of a known oily
solution. Summary of the study is shown below in Table 7.
7 TABLE 7 C.sub.max T.sub.max AUC F Formulation (ng/mL) (hr) (ng
.multidot. hr/mL) (%) SES 1111.2 1.0 2541.3 66.7 SD.dagger-dbl.
153.9 0.5 752.0 7.6 Glyceride Solution 486.3 0.5 1069.5 26.9 SD
91.9 0.3 494.6 9.3 .dagger-dbl.SD denotes the standard deviation of
each measurement relative to the mean values.
Example 8
Droplet Size Comparison of Stabilized SES with Oil Formulations
[0058] The effect of gelatin on the stability of several SES
formulations prepared in accordance with the invention was
determined by studies conducted as follows: Tween 80, Captex 200
and Capmul MCM were combined at room temperature and mixed well.
The o-(chloroacetylcarbamoyl)fumagill- ol was added with stirring
until the drug completely dissolved to produce a final formulation
containing concentrations of 9.5% Tween 80, 66.5% Captex 200, 19%
Capmul MCM, and 5% medicament wt./wt. (I).
[0059] To the mixture of Tween 80, Captex 200 and Capmul MCM was
added 7% wt./wt. water. The o-(chloroacetylcarbamoyl)fumigillol was
added with stirring until the drug completely dissolved to product
a final formulation containing concentrations of 8.8% Tween 80,
61.6% Captex 200, 17.6% Capmul MCM, and % medicament wt./wt.
(II).
[0060] The final formulations were gently agitated before the
self-emulsifying ability for the SES formulations were taken.
[0061] The tip an airfill softgell capsule shell was snipped off
and an agitated solution of formula (I) (0.8 mL) was filled into
the capsule. The neck of the capsule shell was heated using a heat
gun and then immediately sealed by pinching the opening with
forceps.
[0062] Self-emulsifying formulations I, II and III were agitated
and added into a 10 mL test tube containing 4 mL of water as the
dispersant. The samples were analyzed for particle size using a
laser light scattering particle sizer (HELOS BF, Sympatec GmbH) at
a stirring rate of 40 r.p.m.
[0063] The mean droplet sizes of the O/W emulsions generated by
formulations I and II were 1.48 .mu.m and 1.60 .mu.m, respectively.
No significant difference in the size was observed between
formulations I and II.
[0064] It is understood that the foregoing detailed description and
accompanying examples are merely illustrative and are not to be
taken as limitations upon the scope of the invention, which is
defined solely by the appended claims and their equivalents.
Various changes and modifications to the disclosed embodiments will
be apparent to those skilled in the art. Such changes and
modifications, including without limitation those relating to the
substituents, means or preparation and/or methods of use of the
invention, may be made without departing from the spirit and scope
thereof.
* * * * *