U.S. patent application number 11/551815 was filed with the patent office on 2007-05-03 for orally administrable gallium compositions and methods of use.
Invention is credited to Lawrence R. Bernstein.
Application Number | 20070098815 11/551815 |
Document ID | / |
Family ID | 38459473 |
Filed Date | 2007-05-03 |
United States Patent
Application |
20070098815 |
Kind Code |
A1 |
Bernstein; Lawrence R. |
May 3, 2007 |
Orally Administrable Gallium Compositions and Methods of Use
Abstract
Provided are pharmaceutical gallium compositions that are
particularly useful for oral administration. The pharmaceutical
compositions include solid, liquid, and paste formulations, which
have high oral gallium bioavailability and are suitable for human
and veterinary applications. The compositions comprise
pharmaceutically acceptable gallium compounds, such as gallium
maltolate, gallium 8-quinolinolonate, or gallium nitrate, together
with certain viscosity-increasing agents, such as water-soluble
forms of methylcellulose or carboxymethylcellulose.
Inventors: |
Bernstein; Lawrence R.;
(Menlo Park, CA) |
Correspondence
Address: |
MINTZ, LEVIN, COHN, FERRIS, GLOVSKY AND POPEO, P.C
1400 PAGE MILL ROAD
PALO ALTO
CA
94304-1124
US
|
Family ID: |
38459473 |
Appl. No.: |
11/551815 |
Filed: |
October 23, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60730696 |
Oct 27, 2005 |
|
|
|
Current U.S.
Class: |
424/617 ;
424/195.18; 514/184; 514/185; 514/187; 514/492; 514/57 |
Current CPC
Class: |
A61K 31/717 20130101;
A61K 9/2054 20130101; A23L 33/16 20160801; A61K 33/244 20190101;
A61K 9/4866 20130101; A61K 33/242 20190101; A61K 9/4858 20130101;
A61K 31/28 20130101; A61K 47/38 20130101; A61K 31/555 20130101;
A61K 33/243 20190101; Y02A 50/30 20180101; A61K 45/06 20130101;
A61K 9/0095 20130101; A23K 20/20 20160501; A61P 31/04 20180101;
A61K 9/2013 20130101; A61K 33/24 20130101; A23V 2002/00 20130101;
A61K 31/28 20130101; A61K 2300/00 20130101; A61K 31/717 20130101;
A61K 2300/00 20130101; A61K 33/24 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
424/617 ;
424/195.18; 514/185; 514/184; 514/492; 514/187; 514/057 |
International
Class: |
A61K 36/483 20060101
A61K036/483; A61K 31/555 20060101 A61K031/555; A61K 31/717 20060101
A61K031/717; A61K 31/28 20060101 A61K031/28; A61K 33/24 20060101
A61K033/24 |
Claims
1. A pharmaceutical composition comprising a pharmaceutically
acceptable gallium compound and a pharmaceutically acceptable
viscosity-increasing agent.
2. The pharmaceutical composition of claim 1, wherein the
viscosity-increasing agent is selected from the group consisting of
viscosity-increasing forms of methylcellulose,
carboxymethylcellulose, hydroxypropyl methylcellulose, and other
cellulose derivatives, including their pharmaceutically acceptable
salts, esters, hydrates, and solvates.
3. The pharmaceutical composition of claim 2, wherein the
viscosity-increasing agent is methylcellulose or
carboxymethylcellulose.
4. The pharmaceutical composition of claim 3, wherein the
viscosity-increasing agent is carboxymethylcellulose.
5. The pharmaceutical composition of claim 1, wherein the
viscosity-increasing agent is selected from the group consisting of
viscosity-increasing forms of polyethylene glycol, Carbopols,
povidones, gum Arabic, and xanthum gum.
6. The pharmaceutical composition of claim 1, wherein the gallium
compound is selected from the group consisting of gallium nitrate,
gallium sulfate, gallium chloride, gallium citrate, gallium
acetate, gallium tartrate, gallium gluconate, gallium palmitate,
gallium succinate, gallium maltolate, gallium ethyl maltolate,
gallium pyridinones, gallium 8-quinolinolate, gallium
protoporphyrin IX, gallium pyridoxal isonicotinoyl hydrazone, and
bis(2-acetylpyridine 4N-dimethylthiosemicarbazone) gallium(III),
gallium(III) tetrachloride.
7. The pharmaceutical composition of claim 6, wherein the gallium
compound is gallium maltolate.
8. The pharmaceutical composition of claim 1, comprising a solid
state mixture of the gallium compound and the viscosity-increasing
agent.
9. The pharmaceutical composition of claim 8, wherein the weight
ratio of the gallium compound to the viscosity-increasing agent is
approximately 0.1 to 1000.
10. The pharmaceutical composition of claim 9, wherein the weight
ratio of the gallium compound to the viscosity-increasing agent is
approximately 1 to 250.
11. The pharmaceutical composition of claim 8, wherein the weight
ratio of the gallium compound to the viscosity-increasing agent is
approximately 10 to 100.
12. The pharmaceutical composition of claim 1, comprising a
drinkable liquid suitable for oral administration.
13. The pharmaceutical composition of claim 12, comprising a
solution, an emulsion, a gel, a sol, a suspension, or a mixture of
any of the foregoing.
14. The pharmaceutical composition of claim 13, wherein the weight
ratio of the gallium compound to the viscosity-increasing agent is
approximately 0.1 to 1000.
15. The pharmaceutical composition of claim 14, wherein the weight
ratio of the gallium compound to the viscosity-increasing agent is
approximately 1 to 500.
16. The pharmaceutical composition of claim 15, wherein the weight
ratio of the gallium compound to the viscosity-increasing agent is
approximately 20 to 200.
17. The pharmaceutical composition of claim 1, comprising a viscous
liquid or paste.
18. The pharmaceutical composition of claim 17, comprising a
solution, an emulsion, a gel, a sol, a suspension, or a mixture of
any of the foregoing.
19. The pharmaceutical composition of claim 18, wherein the weight
ratio of the gallium compound to the viscosity-increasing agent is
approximately 0.1 to 1000.
20. The pharmaceutical composition of claim 19, wherein the weight
ratio of the gallium compound to the viscosity-increasing agent is
approximately 1 to 500.
21. The pharmaceutical composition of claim 20, wherein the weight
ratio of the gallium compound to the viscosity-increasing agent is
approximately 50 to 250.
22. The pharmaceutical composition of claim 1 adapted for oral
administration.
23. The pharmaceutical composition of claim 1, further comprising
means to prevent or inhibit dissociation of the gallium compound in
the acidic environment of the stomach.
24. The pharmaceutical composition of claim 23, wherein the means
to prevent or inhibit dissociation of the gallium compound is
selected from the group consisting of an enteric coating, a buffer,
and excess ligand.
25. The pharmaceutical composition of claim 23, wherein the means
to prevent or inhibit dissociation of the gallium compound is
encapsulation in liposomes.
26. The pharmaceutical composition of claim 1, further comprising
one or more additional active agents.
27. The pharmaceutical composition of claim 1, in unit dosage
form.
28. The pharmaceutical composition of claim 1, further comprising
animal feed.
29. The pharmaceutical composition of claim 28, wherein the animal
feed is horse feed.
30. A solid composition derived from the evaporation of liquid from
any of the compositions of claims 12 through 21.
31. A pharmaceutical formulation comprising gallium maltolate,
carboxymethylcellulose, benzyl alcohol, water, and simple
syrup.
32. The pharmaceutical composition of claim 31, comprising 1 to 20%
w/v gallium maltolate, 10 to 30% v/v simple syrup, 0.1 to 4% v/v
benzyl alcohol, 0.5 to 2.5% w/v carboxymethylcellulose, and a
balance of water.
33. A method of treating or preventing a gallium-responsive disease
or disorder in a human or veterinary patient, comprising
administering an effective amount of the pharmaceutical composition
of claim 1.
34. The method of claim 33, wherein the patient is human.
35. The method of claim 33, wherein the patient is a horse or other
equid.
36. The method of claim 33, wherein the patient is a bovine animal.
Description
CROSS REFERENCE TO RELATED PATENT APPLICATIONS
[0001] This application claims priority under 35 U.S.C. .sctn.
119(e) to U.S. Provisional Application No. 60/730,696, filed on
Oct. 27, 2005, which is incorporated by reference in its entirety
herein.
TECHNICAL FIELD
[0002] This invention relates generally to pharmaceutical
compositions comprising gallium. More specifically, this invention
relates to the preparation and use of orally administrable gallium
pharmaceutical compositions comprising a pharmaceutically
acceptable gallium compound, such as for example, gallium
maltolate, gallium 8-quinolinolonate, or gallium nitrate, and a
viscosity-increasing agent, such as for example, methylcellulose or
carboxymethylcellulose.
BACKGROUND OF THE INVENTION
[0003] Gallium is used therapeutically and diagnostically in the
management and treatment of cancer, infectious disease,
inflammatory disease, bone disease, autoimmune disease, and other
diseases and disorders. The administration of gallium orally, as
compared to administration intravenously or by injection, provides
advantages to the patient in terms of convenience, cost, safety,
and possibly efficacy.
[0004] Most gallium compounds are poorly absorbed when taken
orally. A few compounds, including gallium maltolate and gallium
8-quinolinolate, have oral gallium bioavailabilities significantly
higher than those of other gallium compounds. Gallium
bioavailabilities from these compounds may not, however, always be
consistent, and, because the gallium compounds may be acid labile,
protection from stomach acid may be needed in some cases.
SUMMARY OF THE INVENTION
[0005] With the present invention, the inventor has unexpectedly
and surprisingly found that the combination of a pharmaceutically
acceptable gallium compound, such as for example, gallium
maltolate, with a viscosity-increasing agent, such as for example,
methylcellulose or carboxymethylcellulose, can increase the oral
bioavailability of gallium.
[0006] In a first embodiment of the invention, there is provided a
pharmaceutical composition comprising a pharmaceutically acceptable
gallium compound and a pharmaceutically acceptable
viscosity-increasing agent.
[0007] In another embodiment of the invention, there is provided a
pharmaceutical composition comprising a pharmaceutically acceptable
gallium compound in the solid state, preferably gallium maltolate,
mixed with a viscosity-increasing agent, preferably methylcellulose
or carboxymethylcellulose, in the solid state.
[0008] In a further embodiment of the invention, there is provided
a the pharmaceutical composition comprising a drinkable liquid
suitable for oral administration (which may be a solution, an
emulsion, a gel, a sol, a suspension, or a mixture of these)
comprising water with dissolved and/or suspended gallium compound,
preferably gallium maltolate, and dissolved and/or suspended
viscosity-increasing agent, preferably methylcellulose or
carboxymethylcellulose.
[0009] In another embodiment of the invention, the pharmaceutical
composition of the invention comprises a viscous liquid or paste
(which may be a solution, an emulsion, a gel, a sol, a suspension,
or a mixture of these) comprising water with dissolved and/or
suspended gallium compound, preferably gallium maltolate, and
dissolved and/or suspended viscosity-increasing agent, preferably
methylcellulose or carboxymethylcellulose.
[0010] The solid obtained by evaporation of any of the preceding
liquid or partially liquid formulations of the invention is a
pharmaceutical composition comprised by an additional embodiment of
the invention.
[0011] In another embodiment of the invention, the pharmaceutical
composition of the invention comprises animal feed to which has
been added any of the preceding liquid, partially liquid, viscous
liquid, paste, solid, or other formulations of the invention.
[0012] In a further embodiment of the invention, there is provided
a method of treating or preventing a gallium-responsive disease or
disorder in a human or veterinary patient, comprising administering
a therapeutically effective amount of the gallium pharmaceutical
compositions of the present invention.
[0013] In each of the foregoing embodiments, the pharmaceutical
composition is preferably adapted for oral administration. In each
embodiment, the pharmaceutical compositions may further comprise
one or more additional active agents.
[0014] The viscosity-increasing agent of each embodiment may be
selected from the group consisting of viscosity-increasing forms of
methylcellulose, carboxymethylcellulose, hydroxypropyl
methylcellulose, and other cellulose derivatives, including their
pharmaceutically acceptable salts, esters, hydrates, and solvates,
or from the group consisting of viscosity-increasing forms of
polyethylene glycol, Carbopols, povidones, gum Arabic, and xanthum
gum.
[0015] The gallium compound of each embodiment may be selected from
the group consisting of gallium nitrate, gallium sulfate, gallium
chloride, gallium citrate, gallium acetate, gallium tartrate,
gallium gluconate, gallium palmitate, gallium succinate, gallium
maltolate, gallium ethyl maltolate, gallium pyridinones, gallium
8-quinolinolate, gallium protoporphyrin IX, gallium pyridoxal
isonicotinoyl hydrazone, and bis(2-acetylpyridine
4N-dimethylthiosemicarbazone) gallium(III), gallium(III)
tetrachloride.
[0016] When the pharmaceutical composition is a solid state mixture
of the gallium compound and the viscosity-increasing agent, the
weight ratio of the gallium compound to the viscosity-increasing
agent is approximately 0.1 to 1000, with a preferred weight ratio
of the gallium compound to the viscosity-increasing agent of
approximately 1 to 250, and a more preferred weight ratio of the
gallium compound to the viscosity-increasing agent of approximately
10 to 100.
[0017] When the pharmaceutical composition is a drinkable liquid
suitable for oral administration, such as a drinkable solution, an
emulsion, a gel, a sol, a suspension, or a mixture of any of the
foregoing, the weight ratio of the gallium compound to the
viscosity-increasing agent is approximately 0.1 to 1000, with a
preferred weight ration of the gallium compound to the
viscosity-increasing agent of 1 to 500, and a more preferred weight
ratio of the gallium compound to the viscosity-increasing agent of
approximately 20 to 200.
[0018] When the pharmaceutical composition is a viscous liquid or
paste, such as an emulsion, a gel, a sol, a suspension, or a
mixture of any of the foregoing, the weight ratio of the gallium
compound to the viscosity-increasing agent is approximately 0.1 to
1000, with a preferred weight ratio of the gallium compound to the
viscosity-increasing agent of approximately 1 to 500, and a more
preferred weight ratio of the gallium compound to the
viscosity-increasing agent is approximately 50 to 250. A preferred
viscous liquid or paste formulation of the invention comprises 1 to
20% w/v gallium maltolate, 10 to 30% v/v simple syrup, 0.1 to 4%
v/v benzyl alcohol, 0.5 to 2.5% w/v carboxymethylcellulose, and a
balance of water.
[0019] The pharmaceutical composition of each embodiment may
further comprise means to prevent or inhibit dissociation of the
gallium compound in the acidic environment of the stomach. Such
means may be selected from the group consisting of an enteric
coating, a buffer, and excess ligand, or means wherein the gallium
compound is encapsulated in liposomes.
[0020] The pharmaceutical compositions of each embodiment may be in
a unit dosage form or in divided or multiple dosage forms.
[0021] Additional aspects, advantages and features of the invention
will be set forth, in part, in the description that follows, and,
in part, will become apparent to those skilled in the art upon
examination of the following, or may be learned by practice of the
invention.
BRIEF DESCRIPTION OF THE DRAWING
[0022] FIG. 1 shows serum gallium concentrations in two foals
following the administration to each of 20 mg/Kg gallium maltolate
in a single dose, either by intragastric administration of an
aqueous formulation without a viscosity-increasing agent, or by
oral administration of a viscous liquid/paste formulation
containing carboxymethylcellulose.
DETAILED DESCRIPTION OF THE INVENTION
[0023] The following definitions are presented to assist one of
ordinary skill in the art to which the invention pertains to
interpret the description of the invention and the appended claim
and are not meant to limit the scope of the invention and appended
claims.
[0024] As used in the specification and the appended claims, the
singular forms "a," "an," and "the" include plural referents unless
the context clearly dictates otherwise. Thus, for example,
reference to "a viscosity-increasing agent" encompasses a
combination or mixture of different viscosity-increasing agents as
well as a single viscosity-increasing agent.
[0025] The terms "optional" or "optionally" as used herein mean
that the subsequently described circumstance may or may not occur,
so that the description includes instances where the circumstance
occurs and instances where it does not.
[0026] The terms "oral administration" and "oral ingestion" refer
to all conventional forms for the oral delivery of a pharmaceutical
composition and that result in the deposition of the pharmaceutical
composition into the gastrointestinal tract (including the gastro
portion of the gastrointestinal tract, i.e., the stomach) via the
esophagus. Accordingly, oral administration and oral ingestion
include, by way of example, actual ingestion of a solid, gel,
semisolid, or liquid pharmaceutical composition, oral gavage,
nasogastric intubation, and the like.
[0027] The term "inhibit dissociation" as used herein means that at
least 20%, preferably at least 50%, and more preferably at least
80%, of the complex is not dissociated under acidic conditions
(e.g., about pH 2-4) for a period of at least 1 hr and preferably
at least 3 hours.
[0028] The terms "active agent," "drug," and "pharmacologically
active agent" are used interchangeably herein to refer to a
chemical material or compound which, when administered to an
organism (human or animal, generally human) induces a desired
pharmacologic effect.
[0029] The terms "to treat" and "treatment" as used herein
encompass the usual meanings of these terms plus the usual meanings
of the terms "to prevent" and "prevention." Thus, for example,
"treatment" of a gallium responsive disease, as the term
"treatment" is used herein, encompasses both prevention of a
gallium responsive disease in a predisposed individual and
treatment of a gallium responsive disease in an individual who has
such a disease.
[0030] "Viscosity-increasing forms" of compounds are those forms
that are water soluble and that increase the viscosity of aqueous
solutions in which they are dissolved such that a 1% w/v solution
will have a viscosity of at least 10 centipose (cps), and
preferably at least 50 cps, and more preferably at least 150 cps,
but less than about 30,000 cps, and preferably less than about
10,000 cps. Forms of compounds that are insoluble or nearly
insoluble (i.e., solubility less than about 0.01% w/v) in water,
such as, for example, cross-linked forms carboxymethylcellulose
(e.g., croscarmellose) and povidone (e.g., crospovidone), are not
viscosity-increasing agents of this invention.
[0031] The term "patient" is meant to include a human or a
veterinary patient. Within the context of the present invention,
veterinary patients are intended to include both mammalian and
non-mammalian veterinary patients, the latter including such
veterinary patients as for example, lizards and birds.
[0032] Set forth below is a description of what are currently
believed to be the preferred embodiments and best examples of the
claimed invention. Any alternates or modifications in function,
purpose, or structure are intended to be covered by the claims of
this application.
[0033] As previously noted, the present invention relates to
pharmaceutical compositions comprising gallium compounds in
combination with certain viscosity-increasing agents. The gallium
compositions of the invention have the advantages of retaining high
oral gallium bioavailability when exposed to acidic conditions of
the stomach, and of retaining high oral gallium bioavailability
when administered as a liquid (e.g., Example 6 and FIG. 1).
[0034] Pharmaceutically acceptable gallium compounds that may be
used to prepare the pharmaceutical compositions of the present
invention include, without limitation, inorganic gallium salts,
such as gallium nitrate, gallium sulfate, and gallium chloride;
organic gallium salts and esters, such as gallium citrate, gallium
acetate, gallium tartrate, gallium gluconate, gallium palmitate,
and gallium succinate; gallium coordination complexes, including
gallium hydroxypyrones, such as gallium maltolate and gallium ethyl
maltolate, gallium pyridinones, and gallium 8-quinolinolate;
gallium porphyrins, such as gallium protoporphyrin IX (PPIX);
gallium pyridoxal isonicotinoyl hydrazone; bis(2-acetylpyridine
4N-dimethylthiosemicarbazone) gallium(III), gallium(III)
tetrachloride; and any other pharmaceutically acceptable gallium
compounds, salts, organic salts or esters, inorganic compounds,
chelates, coordination compounds, and organometallic compounds.
Neutral and non-neutral compounds are included, as are salts and
esters of the compounds.
[0035] Preferred pharmaceutically acceptable gallium compounds from
the foregoing list include gallium maltolate, gallium
8-quinolinolate, gallium nitrate, gallium chloride, and gallium
sulfate. The more preferred gallium compounds are gallium
maltolate, gallium 8-quinolinolate, and gallium nitrate, with
gallium maltolate being most preferred. The gallium compound may be
neutral or non-neutral.
[0036] Viscosity-increasing agents the may be used to prepare the
pharmaceutical compositions of the present invention include,
without limitation, pharmaceutically acceptable
viscosity-increasing forms of, without limitation, methylcellulose,
carboxymethylcellulose, hydroxypropyl methylcellulose, and other
cellulose derivatives (including their pharmaceutically acceptable
salts, esters, hydrates, and solvates), cellulose, polyethylene
glycol, Carbopols, povidones, gum Arabic, and xanthum gum, with
methylcellulose and carboxymethylcellulose being preferred.
[0037] The ability of certain viscosity-increasing agents, in
particular methylcellulose or carboxymethylcellulose, to enhance
the oral bioavailability of a metal, such as gallium, is unexpected
and surprising because cellulose and its derivatives may bind to
metals, and might even be expected to form insoluble metal
complexes that could decrease oral bioavailability. Without
limiting the invention to any particular theory or hypothesis, it
is possible that certain viscosity-increasing agents, particularly
methylcellulose or carboxymethylcellulose, bind or complex with
gallium or a gallium compound in a way that helps protect the
gallium or gallium compound from hydrolysis or other degradation in
stomach acid. Because these viscosity-increasing agents may also be
soluble in the mucus layer of the stomach, further protection from
stomach acid may be afforded through transient sequestration in the
mucus layer. Once past the stomach, in the duodenum (where most
metal absorption is thought to occur), the higher pH and otherwise
changed chemical environment allows the gallium or gallium compound
to be released and absorbed.
[0038] While the viscosity-increasing agents described herein are
described within the context of pharmaceutical compositions
containing gallium, it is to be understood that the
viscosity-increasing agents described herein may be combined with
other pharmaceutically acceptable metal compounds to increase the
absorption of other metals (such as, for example, iron, cobalt,
zinc, copper, indium, manganese, antimony, arsenic, gold, platinum,
ruthenium, and lanthanides).
[0039] The pharmaceutical compositions of the present invention may
be in any acceptable state, such as for example, solid, semisolid,
gel, sol, and liquid compositions, as well as mixtures of any of
the foregoing. Solid dosage forms include without limitation,
tablets, capsules, caplets, lozenges, troches, chewing gums, and
beads. Liquid dosage forms include without limitation, liquid
solutions, emulsions, suspensions, or combinations thereof. Other
dosage forms contemplated under the invention include without
limitation, pastes, ointments, creams, aerosols, dusts, shampoos,
and powders. Solid or liquid dosage forms wherein the gallium
compounds are present in liposomes are also contemplated under the
present invention as is animal feed that has been prepared to
contain the gallium compositions of the present invention.
[0040] While the pharmaceutical compositions of the present
invention are preferably formulated in unit dose forms, it is to be
understood that they may also be formulated in divided or multiple
dose forms.
[0041] The pharmaceutical compositions of the invention may
comprise one or more pharmaceutically acceptable excipients
appropriate to the pharmaceutical form and the intended mode of
administration. Such excipients include, without limitation,
pharmaceutically acceptable carriers, vehicles, propellants,
disintegrants, diluents, dilutants, preservatives, pH adjusters,
surface-active substances, emulsifiers, stabilizers, preservatives,
coating agents, enteric coatings, buffers, absorption enhancers,
solubility modifiers, flavorings, fillers, solvents, gel-forming
agents, tablet excipients, antioxidants, dispersants, antifoams,
flavor corrigents, solubilizers, colorants, color enhancers, dyes,
pigments, permeation promoters, permeation enhancers, complexing
agents, absorbents, adsorbents, acidulents, anticaking agents,
sequestrants, conditioners, controlled release agents, emollients,
emulsifiers, encapsulants, flow aids, fragrances, perfumes,
hardeners, stiffeners, humectants, lubricants, moisturizers, odor
masking agents, opacifiers, plasticizers solvents, spreading
agents, sweeteners, UV absorbers, and viscosity modifiers.
[0042] Although the compositions of the invention are designed
primarily for oral administration, other modes of administration
are possible. Such other modes of administration include, without
limitation, topical, transdermal, rectal, buccal, sublingual,
vaginal, transurethral, intravenous, intramuscular, intra-arterial,
intralesional, topical ocular, intraocular, otic, nasal, and
inhaled. For these various modes of administration, the
compositions are prepared with suitable vehicles, excipients,
carriers, and/or devices (such as patches, implants, and pumps)
appropriate to the particular mode of administration, as are well
known in the art.
[0043] In one embodiment of the invention, a pharmaceutical
composition comprises a pharmaceutically acceptable gallium
compound in the solid state, preferably gallium maltolate, mixed
with a viscosity-increasing agent, preferably methylcellulose or
carboxymethylcellulose, in the solid state. Within this embodiment,
the weight ratio of the gallium compound to the
viscosity-increasing agent is approximately 0.1 to 1000, preferably
from approximately 1 to 250, and most preferably from approximately
10 to 100. Examples 1 and 2 describe the preparation of solid state
dosage forms of the present invention.
[0044] Other pharmaceutically acceptable and chemically compatible
components that may be used in the preparation of the solid state
dosage forms, including without limitation preservatives,
flavorings, colorants, buffering agents, disintegrants, lubricants,
binders, coatings (including enteric coatings), and other
excipients and active agents. Other pharmaceutically acceptable
oral agents that may enhance bioavailability may also be included,
such as, for example, carboxylic acids such as citric acid or
succinic acid, carboxylates such as sodium citrate or sodium
succinate, ascorbic acid, or ascorbates such as sodium
ascorbate.
[0045] In another embodiment of the invention, the pharmaceutical
composition of the invention comprises a drinkable liquid suitable
for oral administration (which may be a solution, an emulsion, a
gel, a sol, a suspension, or a mixture of these) comprising water
with dissolved and/or suspended gallium compound, preferably
gallium maltolate, and dissolved and/or suspended
viscosity-increasing agent, preferably methylcellulose or
carboxymethylcellulose. Within this embodiment, the weight ratio of
the gallium compound to the viscosity-increasing agent is
approximately 0.01 to 1000, preferably from approximately 1 to 500,
and most preferably from approximately 50 to 250. Example 3
describes the preparation of a liquid state dosage form of the
present invention.
[0046] Other pharmaceutically acceptable and chemically compatible
components that may be used in the preparation of the liquid state
dosage forms include without limitation preservatives, flavorings,
colorants, desensitizing agents, pH-adjusting agents, buffering
agents, and other excipients and active agents. Preferred
preservatives include benzyl alcohol, ascorbic acid, methyl
paraben, butyl paraben, and propyl paraben, with benzyl alcohol
being particularly preferred. Optionally, the pH can be adjusted to
approximately 6-7.5; preferred pH-adjusting agents include HCl and
Na.sub.2CO.sub.3. Other pharmaceutically acceptable oral agents
that may enhance bioavailability may also be included, such as, for
example, carboxylic acids such as citric acid or succinic acid,
carboxylates such as sodium citrate or sodium succinate, ascorbic
acid, or ascorbates such as sodium ascorbate.
[0047] In a further embodiment of the present invention, the
pharmaceutical composition of the invention comprises a viscous
liquid or paste (which may be a solution, an emulsion, a gel, a
sol, a suspension, or a mixture of these) comprising water with
dissolved and/or suspended gallium compound, preferably gallium
maltolate, and dissolved and/or suspended viscosity-increasing
agent, preferably methylcellulose or carboxymethylcellulose. Within
this embodiment, the weight ratio of the gallium compound to the
viscosity-increasing agent is approximately 0.01 to 1000,
preferably from approximately 1 to 500, and most preferably from
approximately 20 to 200. Example 4 describes a viscous liquid/paste
dosage form of the present invention.
[0048] Other pharmaceutically acceptable and chemically compatible
components may also be present, including preservatives,
flavorings, colorants, desensitizing agents, pH-adjusting agents,
and other excipients and active agents. Optionally, the pH can be
adjusted to approximately 6-7.5; preferred pH-adjusting agents
include HCl and Na.sub.2CO.sub.3. Preferred preservatives include
benzyl alcohol, ascorbic acid, methyl paraben, butyl paraben, and
propyl paraben, with benzyl alcohol being particularly preferred.
Other pharmaceutically acceptable oral agents that may enhance
bioavailability may also be included, such as, for example,
carboxylic acids such as citric acid or succinic acid, carboxylates
such as sodium citrate or sodium succinate, ascorbic acid, or
ascorbates such as sodium ascorbate.
[0049] The viscous liquid or paste dosage forms described above are
particularly suitable for oral administration to many mammals,
particularly large mammals such as, for example, horses and other
equids, bovine animals such as cattle, sheep, goats, cats, and
dogs. For this purpose, the viscous liquid or paste may be put into
a syringe and squirted into the back of the mouth, or otherwise
administered to the mouth, from where it is swallowed.
[0050] In yet another embodiment of the present invention, the
solid pharmaceutical composition of the present invention is
obtained by evaporation of any of the preceding liquid or partially
liquid formulations. The solid obtained by evaporation of a liquid
comprising gallium maltolate and methylcellulose or
carboxymethylcellulose (such as the liquid formulation of Example
3) is a preferred pharmaceutical composition of the invention.
Within this embodiment, the weight ratio of the gallium compound to
the viscosity-increasing agent is approximately 0.01 to 1000,
preferably from approximately 1 to 500, more preferably from
approximately 10 to 250, and most preferably from approximately 20
to 200.
[0051] Evaporation may be accomplished by drying methods well known
in the art (e.g., Remington: The Science and Practice of Pharmacy,
20.sup.th Edition, Gennaro, A. R., Ed., Lippincott, Williams and
Wilkins, 2000). Such methods include, without limitation, drying at
room temperature or at elevated temperatures of up to about
90.degree. C. in air or in a partial vacuum, on exposed trays with
or without shaking, in ovens or vacuum ovens, in rotary
evaporators, and so on.
[0052] In still another embodiment of the present invention, the
pharmaceutical composition of the invention comprises animal feed
to which has been added any of the preceding liquid, partially
liquid, viscous liquid, paste, solid, or other formulations of the
invention. Example 5 describes the preparation of animal feed
containing the gallium compositions of the present invention.
[0053] Any of the pharmaceutical compositions described above may
further include means to prevent or inhibit dissociation of the
gallium compound in the acidic environment of the stomach. Such
means are well known in the art, and are recited in standard
pharmaceutical manufacturing textbooks (e.g., Remington: The
Science and Practice of Pharmacy, 20.sup.th Edition, Gennaro, A.
R., Ed., Lippincott, Williams and Wilkins, 2000). These means
include, without limitation, the use of enteric coatings, buffers,
gels such as hydrogels, excess ligand (such as excess maltol in the
case of gallium maltolate), and encapsulation within liposomes.
Methods to inhibit or prevent dissociation that are described in
U.S. Pat. No. 5,574,027 to Bernstein, which is incorporated herein,
are among those contemplated under the present invention.
[0054] It is to be understood that the pharmaceutical compositions
of the present invention may include one or more active agents in
addition to the gallium compositions.
[0055] In another embodiment of the invention, there is provided a
method of treating a human or veterinary patient for a
gallium-responsive disease or disorder through the administration
of a therapeutically effective amount of a gallium-containing
pharmaceutical composition of the present invention.
[0056] Gallium-responsive diseases and disorders contemplated under
the present invention include without limitation, cancer, including
breast cancer, prostate cancer, liver cancer, cancers of the bone,
lymphomas, leukemias, multiple myeloma, cancers of the brain,
cancers of the throat, pancreatic cancer, neck cancers, gastric
cancers, intestinal cancers, colon cancers, rectal cancers,
testicular cancers, bladder cancers, ovarian cancers, cervical
cancers, uterine cancers, skin cancers, melanoma, ocular cancers,
mouth cancers, tongue cancers, metastatic cancers, and other
cancers; conditions of excessive bone resorption and/or disorders
of calcium homeostasis, including osteoporosis, Paget's disease,
metastatic bone disease, hyperparathyroidism, hypercalcemia,
osteonecrosis, laminitis, and navicular disorders; inflammatory
and/or autoimmune disorders, including rheumatoid arthritis,
inflammatory arthritis, psoriasis and related dermatoses, multiple
sclerosis, lupus erythematosus, Sjogren's syndrome, uveitis,
asthma, Type 1 diabetes, Graves' disease, autoimmune Addison's
disease, Hashimoto's thyroiditis, central nervous system
vasculitis, spondylitis, inflammatory bowel disease, Crohn's
disease, colitis, celiac disease, myasthenia gravis, inflammatory
myopathies, scleroderma, alopecia areata, and septicemia;
infectious diseases, including intracellular pathogenic diseases
such as tuberculosis, Johne's disease, leprosy, listeriosis,
brucellosis, typhoid fever, legionnaire's disease, Rhodococcus
infections (including those caused by Rhodococcus equi), plague,
typhus, chlamydia, leishmaniasis, trypanosomiasis, and malaria;
Pseudomonas infections; biofilm-forming infections; neuropathies
including painful peripheral neuropathies; adverse conditions of
the liver, including hepatitis, hepatomegaly, and cirrhosis;
splenomegaly; and other conditions that are now known, or are
discovered in the future, to be responsive to gallium.
[0057] When the gallium-containing pharmaceutical compositions are
used in such a treatment method, the compositions are administered
in a therapeutically effective amount to treat the
gallium-responsive disease or disorder. When administered
systemically, such effective amounts generally result in maximal
plasma gallium concentrations of about 10 to 8,000 ng/mL,
preferably about 100 to 3,000 ng/mL, and most preferably about 500
to 1,500 ng/mL. As an example, a liquid pharmaceutical composition
comprising 10% w/v gallium maltolate, 30% w/v sucrose, 1% v/v
benzyl alcohol, and 0.8% w/v carboxymethylcellulose in de-ionized,
sterile water (as described in Example 3) may be administered
orally at a gallium maltolate dose of about 0.1 to 100 mg per
kilogram body weight per day (0.1 to 100 mg/Kg/day), preferably
about 4 to 60 mg/Kg/day, and more preferably about 6 to 40
mg/Kg/day, preferably administered once per day.
[0058] It is to be understood that while the invention has been
described in conjunction with the preferred specific embodiments
thereof, that the foregoing description as well as the examples
that follow are intended to illustrate and not limit the scope of
the invention. Other aspects, advantages and modifications within
the scope of the invention will be apparent to those skilled in the
art to which the invention pertains.
[0059] All patents and publications mentioned herein are
incorporated by reference in their entireties.
EXPERIMENTAL
[0060] The following examples are put forth so as to provide those
of ordinary skill in the art with a complete disclosure and
description of how to make and use the compositions of the
invention. The examples are intended as non-limiting examples of
the invention. While efforts have been made to ensure accuracy with
respect to variables such as amounts, temperature, etc.,
experimental error and deviations should be taken into account.
Unless indicated otherwise, parts are parts by weight, temperature
is degrees centigrade, and pressure is at or near atmospheric. All
components were obtained commercially unless otherwise
indicated.
[0061] The practice of the present invention will employ, unless
otherwise indicated, conventional techniques of pharmaceutical
formulation, medicinal chemistry and the like, which are within the
skill of the art. Such techniques are explained fully in the
literature. Preparation of various types of pharmaceutical
formulations are described, for example, in REMrNGTON: THE SCIENCE
AND PRACTICE OF PHARMACY, 20.sup.th edition (Lippincott Williams
& Wilkins, 2000) and Ansel et al., PHARMACEUTICAL DOSAGE FORMS
AND DRUG DELIVERY SYSTEMS, 6.sup.th Ed. (Media, PA: Williams &
Wilkins, 1995).
EXAMPLE 1
Solid Oral Dosage Forms
[0062] The following ingredients in wt % are used to prepare the
solid oral dosage forms of the present invention, which includes
capsules, tablets, or caplets:
[0063] 66.67 wt % Gallium maltolate powder; and
[0064] 33.33 wt % Carboxymethylcellulose powder.
[0065] For the preparation of a single dosage unit, such as a
single tablet, caplet, or capsule, the following amounts of the
ingredients are used:
[0066] 500 mg Gallium maltolate powder; and
[0067] 250 mg Carboxymethylcellulose powder.
[0068] A recommended carboxymethylcellulose for use in the
formulation of the solid oral dosage forms described herein is
AQUALON.RTM. sodium carboxymethylcellulose gum, grade 7H3SF, X
grind (fine), viscosity of 1% solution approximately 1,000-2,800
cps (Hercules, Inc., Wilmington, Del.).
EXAMPLE 2
Solid Oral Dosage Forms with Sodium Citrate
[0069] The following ingredients in wt % are used to prepare sodium
citrate-containing solid oral dosage forms of the present
invention, which includes capsules, tablets, or caplets:
[0070] 62.5 wt % Gallium maltolate powder;
[0071] 18.75 wt % Carboxymethylcellulose powder; and
[0072] 18.75 wt % Sodium citrate powder.
[0073] For the preparation of a single dosage unit, such as a
single tablet, caplet, or capsule, the following amounts of the
ingredients are used:
[0074] 500 mg Gallium maltolate powder;
[0075] 150 mg Carboxymethylcellulose powder; and
[0076] 150 mg Sodium citrate powder.
[0077] A recommended carboxymethylcellulose for use in the
formulation of the solid oral dosage forms described herein is
AQUALON.RTM. sodium carboxymethylcellulose gum, grade 7H3SF, X
grind (fine), viscosity of 1% solution approximately 1,000-2,800
cps (Hercules, Inc., Wilmington, Del.).
EXAMPLE 3
Liquid Oral Dosage Forms
[0078] The following ingredients in w/v and/or v/v are dissolved
and/or suspended in de-ionized sterile water to prepare the liquid
oral dosage forms of the present invention:
[0079] 10% w/v Gallium maltolate;
[0080] 30% w/v Sucrose;
[0081] 1% v/v Benzyl alcohol; and
[0082] 0.8% w/v Carboxymethylcellulose.
[0083] For the preparation of one liter of the liquid oral dosage
form of the present invention, the following amounts of the
ingredients are used:
[0084] 990 mL Water (de-ionized, sterile);
[0085] 100 g Gallium maltolate;
[0086] 300 g Sucrose;
[0087] 10 mL Benzyl alcohol; and
[0088] 8 g Carboxymethylcellulose.
[0089] A recommended carboxymethylcellulose for use in the
formulation of the liquid oral dosage form described herein is
AQUALON.RTM. sodium carboxymethylcellulose gum, grade 7M2F, X grind
(fine), viscosity of 2% solution approximately 150-200 cps
(Hercules, Inc., Wilmington, Del.).
[0090] At room temperature, add the gallium maltolate to the water
with moderately vigorous stirring. Continue stirring for about 30
minutes. With moderate stirring, add the sucrose to the water,
allowing it to dissolve completely over a period of a few minutes.
With continued stirring, add the benzyl alcohol, and then gradually
add the carboxymethylcellulose over a period of several minutes.
Continue moderate stirring for 10 minutes.
EXAMPLE 4
Viscous Liquid/Paste Dosage Forms
[0091] The following ingredients in w/v and/or v/v were dissolved
and/or suspended in de-ionized sterile water to prepare the viscous
liquid/paste dosage forms of the present invention:
[0092] 10% w/v Gallium maltolate;
[0093] 20% v/v Simple syrup (67 wt % sucrose in water);
[0094] 1% v/v Benzyl alcohol; and
[0095] 1.5% w/v Carboxymethylcellulose.
[0096] For the preparation of one liter of the viscous liquid/paste
dosage form of the present invention, the following amounts of the
ingredients were used:
[0097] 100 grams Gallium maltolate;
[0098] 200 mL Simple syrup (400 g sucrose in 200 mL water);
[0099] 10 mL Benzyl alcohol;
[0100] 15 g Carboxymethylcellulose; and
[0101] 790 mL Water (de-ionized, sterile).
[0102] The carboxymethylcellulose used in the formulation of the
viscous liquid/paste dosage form described herein was AQUALON.RTM.
sodium carboxymethylcellulose gum, grade 7H4F, X grind (fine),
viscosity of 1% solution approximately 3,000-6,000 cps (Hercules,
Inc., Wilmington, Del.).
[0103] At room temperature, gallium maltolate was added to the
water with moderately vigorous stirring, which continued for about
30 minutes. With continued stirring, the benzyl alcohol was added
to the solution and then the carboxymethylcellulose was gradually
added to the solution over a period of several minutes. After about
10 minutes of stirring, the simple syrup was gradually added to the
formulation under continued moderate to slow stirring over a period
of a few minutes after which the stirring continued for an
additional five minutes.
[0104] To make the simple syrup, 400 mL of water was brought to a
boil and then with continued stirring, 800 g sucrose was added to
the boiling water. After the sugar had entirely dissolved, the heat
was reduced and the solution was left to simmer for about five
minutes with continuous stirring, and water was added with
continued stirring to bring the total weight to 1200 g. The
solution was then removed from the heat and allowed to cool
gradually to room temperature.
EXAMPLE 5
Preparation of Medicated Animal Feed
[0105] Animal feed in a form suitable for administration to a
particular animal (e.g., hay or other fodder, pellets, chews,
kibbles, crumbles, liquids, pastes, etc.) is prepared by adding
gallium maltolate to the animal feed in an amount such that the
animal receives a daily dose of the gallium maltolate in one day's
consumption of feed. For example, for typical horse feed, e.g. hay
or prepared pellets, the amount of gallium maltolate to be put into
the feed will vary depending on the size of the animal, but will
generally be in an amount of about 0.01 to 10 g per Kg of feed,
preferably 0.1 to 6 g, and more preferably 1 to 4 g per Kg of
feed.
[0106] For the preparation of typical horse feed with a
concentration of gallium maltolate at 2 g per Kg of feed, the
following procedure may be followed: One liter of the liquid
composition of Example 3 is added to 50 Kg of solid horse feed
(e.g., hay or other fodder, pellets, etc.). The liquid is
thoroughly mixed with the solid feed for five minutes, and is
allowed to soak into the feed. The feed is then dried in air while
spread on a tray, in this case at 40.degree. C. for six hours. The
feed is then administered to the horse in a conventional manner.
Example of typical horse feed that may be used in the preparation
described herein is LMF California Complete horse feed (LMF Feeds
Inc., Weiser, Id.)
EXAMPLE 6
Evaluation of Viscous Liquid/Paste Formulation in Foals
[0107] A viscous liquid/paste formulation of the invention was
investigated for gallium bioavailability in two healthy foals, each
foal about six months old and about 175 Kg in weight. For
comparison, each foal was first administered gallium maltolate (20
mg/Kg of body weight) in a formulation consisting only of gallium
maltolate and water. The formulation was administered
intragastrically, via a nasogastric tube. Blood samples were taken
from the foals just prior to dosing (0 hours), and at 1, 2, 4, 6,
and 8 hours post-dosing, and the serum was separated by coagulation
and centrifugation. After a washout period of seven days, the same
two foals were each administered the same dose of gallium maltolate
(20 mg/Kg of body weight), but this time using the viscous
liquid/paste formulation of Example 4, containing
carboxymethylcellulose. This viscous liquid/paste formulation was
administered by squirting it from a syringe into the back of the
mouth, from where it was swallowed. Blood samples were again taken
from the foals just prior to dosing (0 hours), and at 1, 2, 4, 6,
and 8 hours post-dosing, and the serum was separated by coagulation
and centrifugation. Gallium concentrations in all the serum samples
were measured by inductively coupled plasma/mass spectrometry
(ICP-MS).
[0108] The results of the experiment, presented in FIG. 1, show
that serum levels of gallium were significantly higher when the
oral viscous liquid/paste formulation of Example 4 was administered
than when the intragastric aqueous formulation was administered.
For foal 1, the maximum serum gallium concentrations (C.sub.max)
were 1.68 .mu.g/mL for the aqueous formulation and 3.03 .mu.g/mL
for the viscous liquid/paste formulation (an 80% increase); for
foal 2, C.sub.max was 1.93 .mu.g/mL for the aqueous formulation and
4.00 .mu.g/mL for the viscous liquid/paste formulation (a 107%
increase).
* * * * *