Note: Descriptions are shown in the official language in which they were submitted.
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CORRESPONDING PRIOR US NATIONAL APPLICATION FILED UNDER
35 USC 111(a): Serial No. 11/731,294 filed March 31, 2007
HALIDE-FREE GLUCOSAMINE-ACIDIC DRUG COMPLEXES
Field of the Invention
The invention relates to halide-free glucosamine complexes of acidic drugs and
to
methods for preparing such complexes.
Backg.round of the Invention
Glucosamine is a well-known amino monosaccharide found in chitin,
glycoproteins and glycosaminoglycans. Glucosamine is widely used for the
treatment of
rheumatic fever, arthritic and arthosic complaints, in the acute as well as
chronic forms,
as well as in the treatment of pathological conditions originating from
metabolic
disorders of the osteo-articular tissue. Although products in the marketplace
are labeled
as, or referred to as, "glucosamine", they are misnomers since such products
consist of
glucosamine hydrochloride or as unreacted mixtures of glucosamine
hydrochloride and a
complex such as potassium or sodium sulfate.
One drawback of many therapeutic drugs is their relative insolubility in the
body
after they have been administered to a patient. It would be most desirable if
more
soluble versions of therapeutic drugs could be made available.
It has now been found that complexes of halide-free glucosamine and acidic
drugs
are more soluble than the drugs themselves. An added benefit is that
glucosamine itself
is formed in the body (typically in the form of glucosamine phosphate) and
therefore no
"foreign" ingredients will be introduced in the body when the complexes of the
invention
are administered to patients in need of such drugs.
Salts or mixtures of "glucosamine" or "glucosamine sulfate" and a therapeutic
drug such as aspirin, ibuprofen, ketoprofen, etc. are known in the prior art,
e.g., see U.S.
Patent Publication 2002/0058642 Al; U.S. Patent 6,608,041 B2; U.S. Patent
6,291,527
B1; U.S. Patent 5,604,206; and U.S. Patent 3,008,874. However, the
"glucosamine" or
"glucosamine sulfate" employed in such compositions are misnomers, inasmuch as
such
materials are actually glucosamine hydrochloride or mixed complexes of
glucosamine
hydrochloride and an alkali or alkaline earth metal sulfate.
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In contradistinction thereto, the glucosamine employed in preparing the
complexes of the invention is halide-free (i.e., the glucosamine has a purity
of at least
about 99 wt.% and a maximum halide content of about 0.01 wt.%) and as a
result, the
complexes of the invention will contain neither a halide nor any extraneous
anions nor
any extraneous cations (e.g., sodium, potassium, calcium, etc.).
Details of the Invention
The starting materials for preparing the complexes of the invention are halide-
free
glucosamine and a therapeutic drug having a pKa of less than 7. Such drugs
will contain
at least one acid functionality, e.g., a carbonyl moiety, a carboxyl moiety
and/or a
sulfoxide moiety.
Glucosamine, extracted from shellfish or prepared by a fermentation process,
is
only available in the form of its hydrochloride salt. If the glucosamine
hydrochloride salt
is neutralized with a base, e.g., NaOH, KOH, etc. in order to release the
glucosamine, the
resultant product will always contain a salt, i.e., NaCI or KCI, respectively,
and it is not
possible to separate the glucosamine from the salt since both the glucosamine
and the salt
are fiilly soluble in water.
Free glucosamine be prepared by the method recited in Chem. Ber., volume 75,
page 1274. Such method involves the treatment of glucosamine hydrochloride
with an
ethanolic solution of a tertiary base such as triethylamine. Triethylamine
hydrochloride
is filtered off and the free glucosamine is then recovered from the reaction
mixture.
However, triethylamine is a toxic material even in small quantities and the
yield of the
free glucosamine is quite low. Moreover, the free glucosamine still contains
residual
chloride.
A method for producing halide-free glucosamine with a very high degree of
purity
has now been discovered. Such method may be summarized as follows::
(a) a glucosamine halide complex (e.g., glucosamine hydrochloride, glucosamine
hydroiodide, etc.) is reacted with a lithium base in the presence of a Cl - C4
alcohol to thereby generate a C, - C4 alcohol solution of a lithium halide and
insoluble halide-free glucosamine; and
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(b) the insoluble halide-free glucosamine is separated from the Cl - C4
alcohol
solution of the lithium halide complex.
For maximum yields, the reaction should be carried out at a temperature of
about
15 to about 35 C; conveniently, the reaction may be carried out at ambient
temperatures.
The Cl - C4 alcohol may be, e.g., methanol, ethanol (preferably anhydrous),
isopropanol,
etc; the preferred alcohol comprises methanol. The lithium base may be
anhydrous
lithium hydroxide, lithium hydroxide monohydrate, lithium methoxide, lithium
ethoxide
or lithium isopropoxide. The prefeffed lithium base comprises anhydrous
lithium
hydroxide. It has been found that the presence of water in the reaction
mixture reduces
the yield of the halide-free glucosamine. Accordingly, it is preferred that
the reaction be
carried out under anhydrous conditions. In general, the lithium base is
employed in an
amount of about 1.0 to about 1.2 moles per mole of halide present in the
glucosamine
halide complex. Excess lithium base is unnecessarily wasteful and will reduce
the yield
of the halide-free glucosamine. Typically, the alcohol is employed in an
amount of about
1 to about 10 parts, preferably 3 to 6 parts, per part of lithium base.
After allowing the reaction to proceed (preferably with stirring) for about 5
minutes to about 2 hours, the solid halide-free glucosamine is filtered off
from the
resultant alcohol solution of the lithium halide and washed with additional
alcohol. The
halide-free glucosamine may then be dried under vacuum at a temperature of
about 15 to
about 30 C. The yield typically ranges from about 85 to about 90 %. The halide-
free
glucosamine is quite pure. It will have a purity level of greater than about
99 wt.% and
the halide content will be about 0.01 wt.% or less, e.g., 100 ppm or less and
very often,
the halide content will be less than 50 ppm and as low as 25 ppm. Based upon
the
residual halide content of the halide-free glucosamine, the lithium residue in
the
glucosamine will generally be about 20 ppm or less and very often, the lithium
residue
content will be less than 10 ppm
The halide-free glucosamine is quite hygroscopic and will decompose over a
period of time if subjected to ambient temperature and/or to the atmosphere.
Accordingly, it should be refrigerated in a closed container or preferably
promptly used
after recovery for conversion to the complexes of the invention as described
below.
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The halide-free glucosamine may be readily converted to the glucosamine-acidic
drug complex of the invention by reacting the glucosamine with a therapeutic
drug
having at least one acidic functionality, i.e. a therapeutic drug having a
pI{e of less than 7.
The molar ratio of the halide-free glucosamine to the acidic drug in the
complex is not
critical and may be in the range of about I mole of glucosamine per mole of
the drug up
to about 15 moles of the glucosamine per mole of the drug. If the selected
drug has more
than one acidic functionality, the molar ratio of the glucosamine to the
selected drug
should be adjusted such that there will be about 1 to about 15 moles of
glucosamine
employed per acidic functionality in the selected drug.
Typically, the reaction mixture will comprise the halide-free glucosamine,
about 5
to about 30 parts, preferably 15 to 20 parts, of water (preferably purified
water) per part
of the glucosamine and the selected drug. Although lesser amounts of water may
be
employed, the resultant solutions may become too viscous to be properly
agitated,
particularly if the glucosamine-therapeutic drug complex is not isolated from
the reaction
mixture, but is stabilized by the addition of a polymer to the reaction
mixture, as
described below. On the other hand, excessive amounts of water may lead to
reduced
yields if a water-miscible solvent is used to recover the complex and if
freeze-drying is
used to recover the complex, the freeze-drying process becomes more time-
consuming
and expensive because of the large amount of water to be removed from the
reaction
mixture.
The selected acidic drug is slowly added to the aqueous solution of the halide-
free
glucosamine while the aqueous solution is agitated, e.g. over a period of a
few minutes,
and the reaction mixture is further agitated for 5 to 120 minutes. The
reaction is typically
conducted at a temperature of about 15 to about 40 C. Thereafter, the
glucosamine-
acidic drug complex of the invention may be recovered from the reaction
mixture by
freeze-drying or by adding a water-miscible solvent such as acetone to the
reaction
mixture such that the complex will precipitate from the reaction mixture and
the complex
is then recovered by conventional filtration methods. The complex may then be
dried by
conventional methods, e.g., a stream of nitrogen, a vacuum oven at 30-50 C for
a period
of I to 10 hours, etc. It is preferred that the recovery of the halide-free
glucosamine-
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acidic drug complex of the invention be carried out by a fieeze-drying process
as
described in greater detail below.
Some of the halide-free glucosamine-acidic drug complexes of the invention may
decompose over a period of time if they are exposed to ambient temperatures or
the
5 atmosphere. Therefore, it is preferred that the complex not be recovered
from the
reaction mixture as is, but converted to a stabilized form prior to recovery.
Conversion of
the complex to its stabilized form may be desirable even for those complexes
that do not
decompose upon exposure to ambient temperatures and/or the atmosphere, since
the
pharmaceutica.lly acceptable polymers employed in stabilizing, i.e., coating,
the
complexes of the invention may provide extended-release properties when the
complexes
are administered to warm-blooded vertebrates in need of treatment.
Stabilization of the halide-free glucosamine-acidic drug complex is readily
accomplished by adding a suitable pharmaceutically acceptable polymer to the
reaction
mixture prior to recovery of the complex. The pharmaceutically acceptable
polymer may
be a water-soluble, water-dispersible and/or or a water-swellable homopolymer
and/or
copolymer. Preferably, the pharmaceutically acceptable polymer will be water-
soluble.
In general, the polymer will be employed in an amount of about 2 to about 70,
preferably
to 50, parts by weight of the polymer per part of the complex in the reaction
mixture.
Nonlimiting examples of commercially available pharmaceutically acceptable
20 homopolymers and copolymers suitable for stabilizing the halide-free
glucosamine-
therapeutic drug complexes of the invention include the following: carboxypoly-
methylene homopolymers and copolymers, i.e., vinyl polymers having active
carboxyl
groups such as high molecular weight homopolymers of acrylic acid crosslinked
with
allyisucrose or allylpentaerythritol and copolymers of acrylic acid modified
by long chain
(CIo - C30) alkyl acrylates and crosslinked with allylpentaerythritol - such
polymers are
commercially available and are marketed as Carbopol polymers; polyethylene
glycol
homopolymers and copolymers (e.g., polyethylene-co-lactic acid copolymers),
particularly polyethylene glycol polymers having molecular weights in the
range of about
2,000 to about 20,000, preferably 4,000 to 18,000; polypropylene glycol
homopolymers
and copolymers, especially polypropylene glycol homopolymers having molecular
weights of about 800 to about 18,000; ethylcellulose; povidone homopolymers,
i.e.,
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synthetic water-soluble homopolymers of N-vinyl-pyrrolidone, especially those
having a
molecular weight of about 2,500 to about 10,000; copovidone, i.e. synthetic
random
copolymers of N-vinylpyrrolidone and vinyl acetate in a 60:40 ratio;
polyacrylic acid
homopolymers and copolymers; polyacrylamide homopolymers and copolymers;
polysaccharides; etc.
The choice of particular homopolymers and/or copolymers for coating, i.e.,
stabilizing, the complex, is not critical so long as the polymers are
pharmaceutically
acceptable, have the capability of coating, i.e., stabilizing, the complex
without any
adverse chemical reaction occurring between the selected polymer and the
complex and
the resultant coated complexes are stable, i.e., they will not undergo
decomposition when
exposed to ambient temperatures and/or the atmosphere.
If the complex is to be recovered from the reaction mixture in a stabilized
form,
the desired pharmaceutically acceptable polymer is added, preferably in
increments, with
stirring, to the aqueous halide-free glucosamine solutlon preferably prior to
the addition
of the acidic drug. This step will generally take about 5 to about 15 minutes
and is
preferably conducted at a temperature of about 15 to about 40 C. After all
increments of
the selected polymer have been added, stirring is continued for an additional
5 to 120
minutes. Thereafter, the acidic drug is slowly added to the reaction mixture,
while
maintaining the reaction mixture at a temperature of about 15 to 40 C.
The last step is the recovery of the polymer-coated, i.e., stabilized, complex
from
the reaction mixture. The stabilized complex may be recovered from the
reaction mixture
by freeze-drying or by adding a water-miscible solvent, e.g., acetone, to the
reaction
mixture to cause the stabilized complex to precipitate out from the reaction
mixture. The
precipitate is then recovered by conventional filtration methods and it may be
dried as
described below. Of course, the choice of stabilizing polymer and water-
miscible solvent
should be such that the polymer will not dissolve in, or otherwise react with,
the solvent.
The complex of the invention is preferably recovered by removal of water from
the reaction mixture by freeze-drying, a well-known technique for removing
water from
compositions. Although freeze-drying is a time-consuming process, (a reaction
mixture
containing one liter of water will typically require 30-36 hours to remove
about 97% of
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the water), it is preferred since the formation of decomposition products
resulting from
heating the reaction mixture or adding solvents to the reaction mixture can be
avoided.
The freeze-drying process will generally be carried out at a reduced pressure
and
reduced temperature, e.g., a pressure of not greater than 500 milliTorre,
preferably 300 to
100 milliTorre and at a temperature of about -60 to about -20 C, preferably -
50 to -40 C.
The endpoint of the completion of the freeze-drying process may be determined
by
condensing and measuring the quantity of water removed during the freeze-
drying
process. The time required for completion of the freeze-drying process will
vary
depending on factors such as pressure, temperature, quantity of reaction
mixture to be
free-dried, level of water to be tolerated in the stabilized halide-free
glucosamine-drug
complex, the thickness and surface area of the reaction mixture in the trays
of the freeze-
drying equipment, etc.
If the stabilized complex is to be recovered by precipitation from the
reaction
mixture by addition of a water-miscible solvent such as acetone to the
reaction mixture,
generally about 2 to about 10 parts of solvent per part of reaction mixture
will be
required.
After the stabilized complex has been recovered from the reaction mixture, it
may
be dried by conventional techniques, e.g., a stream of nitrogen, vacuum oven
at a
temperature of about 30 to about 50 C for I to 10 hours or more, etc.
It should also be noted that the stabilization of the complexes of the
invention
may provide an additional advantage to warm-blooded vertebrates to whom such
complexes are administered. The stabilized, i.e., polymer-coated, versions of
the
complexes may provide extended release properties, i.e., the glucosamine-
therapeutic
drug complex may be released within the vertebrate over an extended period of
time,
thereby possibly resulting in a reduction of the frequency and the amount of
the dosage
that would otherwise be required to be administered to the vertebrate.
The therapeutic drug that is to be complexed with the halide-free glucosamine
may be any therapeutic drug that exhibits an acidic pKB, i.e., a plCe of less
than 7Ø Such
drugs will contain one or more acidic functionalities such as a carbonyl
moiety, a
carboxyl moiety, a sulfoxide moiety, etc. The list of therapeutic drugs that
fit such
definition is quite voluminous. Suitable therapeutic drugs containing at least
one acidic
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functionality may be found in one or more of the following nonlimiting,
representative
classes of drugs: a- and R-Adrenergic Agonists; Narcotic and Non-Narcotic
Analgesics;
Anorexics; Antiallergics; Antianginals; Antiarrhythmics; Antiasthmatics;
Antibiotics;
Anti-coagulants; Anticonvulsants; Antidepressants; Antidiabetics;
Antihistaminics;
Antihypertensives; Nonsteroidal Anti-Inflammatories; Antimigraines;
Antineoplastics;
Antiparkinsonians; Antipsychotics; Antipyretics; Antispasmodics;
Antithrombotics;
Antiulceratives; Anxiolytics; Decongestants; Diuretics; Hepatoprotectants;
Sedatives; and
Vasodilators.
Not every possible therapeutic drug within the foregoing-listed classes will
be
suitable for preparing a complex with the halide-free glucosamine. Only those
therapeutic drugs that are sufficiently acidic in nature to form such a
complex with the
halide-free glucosamine are suitable. As mentioned above, such therapeutic
drugs will
have a pKa of less than 7.0 and will contain at least one acid functionality,
e.g. a carbonyl
moiety, a carboxyl moiety, a sulfoxide moiety, etc.
Particularly suitable specific drugs within the foregoing classes include:
acetaminophen, acetazolamide, ampicillin, ampiroxicam, aspirin, bromfenac,
carprofen,
celecoxib, cetirizine, chlorothiazide, chlorpropamide, ciprofloxacin,
diazepam,
diclofenac, ethacrynic acid, flufenamic acid, furosemide, ibuprofen,
indomethacin,
indoprofen, ketoprofen, levodopa, meclofenamic acid, methotrexate, methyldopa,
naproxen, orazamide, penicillamine, pentobarbital, phenobarbital, phenytoin,
piroxicam,
propylthiouracil, protoprophyrin IX, rofecoxib, salicyclic acid, sulfadiazine,
sulfapyridine, sulindac, theophylline, thioctic acid, timonacic, tiopronin,
tolbutamide,
tolfenamic acid, warfarin, tolmetin, zaltoprofen, and mixtures thereof. and
the like.
The following nonlimiting examples shall serve to illustrate the preferred
embodiments of the invention. Unless otherwise indicated, all parts and
percentages are
on a weight basis.
EXAMPLE 1
A reaction vessel was equipped with a stirrer and a nitrogen blanket. To the.
reaction vessel were added 4.1 g (0.02 mole) of ibuprofen and 200 cc of
pharmaceutical
grade methanol. The mixture was stirred to obtain a solution and thereafter,
3.58 g(0.02
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mole) of halide-free glucosamine were added to the reaction mixture. The
reaction
mixture was then stirred for 1 hour at 25-30 C, resulting in a clear solution.
The
methanol was stripped off from the reaction mixture using a rotary evaporator
at a
temperature of 50 C. The resultant glucosamine-ibuprofen complex weighed 7 g.
EXAMPLE 2
A reaction vessel was set up with a stirrer and a warm water bath. Into the
reaction vessel were added 1.79 g (0.01 mole) of halide-free glucosamine and
the mixture
was stirred at 25-35 C to obtain, a clear solution. Thereafter, 3.57 g (0.01
mole) of
indomethacin were added and the reaction mixture was stirred for 1 hour at 35-
45 C. The
reaction mixture was then freeze-dried at a pressure of about 200 milliTorre
and a
temperature of about -45 C. 3.8 g of a light yellow powder consisting of the
glucosamine-indomethacin complex were obtained.
EXAMPLE 3
Example 2 was repeated using 8.6 g (0.05 mole) of halide-free glucosamine, 150
cc of purified water and 7.54 g (0.05 mole) of acetaminophen. 15 g of a white
powder
consisting of the glucosamine-acetarninophen complex were obtained.
EXAMPLE 4
Example 2 was repeated using 9.0 g (slight excess above 0.05 mole) of halide-
free
glucosamine, 150 cc of purified water and 9 g (0.05 mole) of acetylsalicyclic
acid. 17.4 g
of a white solid consisting of the glucosamine-acetylsalicyclic acid complex
were
obtained.
EXAMPLE 5
Example 2 was repeated using 1.79 g (0.01 mole) of halide-free glucosamine,
100
cc of purified water and 2.3 g (0.01 mole) of naproxen. 3.8 g of a white
product
consisting of the glucosamine-naproxen complex were obtained.
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EXAMPLE 6
Example 2 was repeated using 1.79 g(0.01 mole) of halide-free glucosamine, 100
cc of purified water and 2.96 g (0.01 mole) of diclofenac. 4.0 g of an off-
white powder
consisting of the glucosamine-diclofenac complex were obtained.
5
EXAMPLE 7
Example 2 was repeated using 1.79 g (0.01 mole) of halide-free glucosamine, 50
cc of purified water and 0.28 g (0.01 mole) of diazepam. 0.43 g of a white
solid
consisting of the glucosamine-diazepam complex was obtained.
EXAMPLE 8
Example 1 was repeated using 3.6 g (0.02 mole) of halide-free glucosamine, 300
cc of pharmaceutical grade methanol and 5.04 g (0.02 mole) of phenytoin. 8 g
(92%
yield) of a white solid consisting of the glucosamine-phenytoin complex were
obtained
