U.S. patent application number 14/283298 was filed with the patent office on 2014-10-02 for intravenous formulation with water-soluble cocrystals of acetylsalicylic acid and theanine.
This patent application is currently assigned to THEAPRIN PHARMACEUTICALS INC.. The applicant listed for this patent is THEAPRIN PHARMACEUTICALS INC.. Invention is credited to Harry G. Brittain, Philip V. Felice.
Application Number | 20140296189 14/283298 |
Document ID | / |
Family ID | 43050309 |
Filed Date | 2014-10-02 |
United States Patent
Application |
20140296189 |
Kind Code |
A1 |
Brittain; Harry G. ; et
al. |
October 2, 2014 |
INTRAVENOUS FORMULATION WITH WATER-SOLUBLE COCRYSTALS OF
ACETYLSALICYLIC ACID AND THEANINE
Abstract
A method of reducing niacin flushing in a subject using a
water-soluble cocrystal composition which contains a quantity of
acetylsalicylic acid and a quantity of a theanine enantiomer.
Inventors: |
Brittain; Harry G.;
(Milford, NJ) ; Felice; Philip V.; (Smithtown,
NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
THEAPRIN PHARMACEUTICALS INC. |
Hauppauge |
NY |
US |
|
|
Assignee: |
THEAPRIN PHARMACEUTICALS
INC.
Hauppauge
NY
|
Family ID: |
43050309 |
Appl. No.: |
14/283298 |
Filed: |
May 21, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14262281 |
Apr 25, 2014 |
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14283298 |
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14188841 |
Feb 25, 2014 |
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14262281 |
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14169291 |
Jan 31, 2014 |
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14188841 |
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13967027 |
Aug 14, 2013 |
8685948 |
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14169291 |
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13617508 |
Sep 14, 2012 |
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13967027 |
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13440693 |
Apr 5, 2012 |
8304404 |
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13617508 |
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12437735 |
May 8, 2009 |
8173625 |
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13440693 |
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Current U.S.
Class: |
514/162 |
Current CPC
Class: |
A61K 31/60 20130101;
C07C 231/22 20130101; A61K 9/14 20130101; C07C 67/52 20130101; A61K
31/60 20130101; C07C 231/22 20130101; C07B 2200/13 20130101; A61K
45/06 20130101; A61K 31/198 20130101; A61K 31/198 20130101; A61K
9/0019 20130101; C07C 67/52 20130101; A61P 9/00 20180101; A61K
2300/00 20130101; A61K 31/616 20130101; C07C 69/157 20130101; A61K
2300/00 20130101; A61P 35/00 20180101; A61P 29/00 20180101; C07C
237/06 20130101 |
Class at
Publication: |
514/162 |
International
Class: |
A61K 9/14 20060101
A61K009/14; A61K 31/198 20060101 A61K031/198; A61K 31/616 20060101
A61K031/616 |
Claims
1. A method of reducing niacin flushing in a subject by
administering to the subject an effective amount of a water-soluble
composition comprising: a cocrystal composition containing a
quantity of acetylsalicylic acid and a quantity of a theanine
enantiomer selected from the group consisting of L-theanine,
D-theanine, and DL-theanine.
2. The method of claim 1, wherein said quantity of acetylsalicylic
acid comprises about 50% by weight of said mixture.
3. The method of claim 1, wherein said mixture has an aqueous
solubility of at least about 9.0 mg/mL.
4. The method of claim 1, wherein said mixture has an aqueous
solubility of at least about 9.4 mg/mL.
5. The method of claim 1, wherein said mixture further comprises a
sugar alcohol.
6. The method of claim 5, wherein said sugar alcohol has an
L-configuration.
7. The method of claim 1, wherein said water soluble composition is
combined with an agent for reduction of niacin flushing prior to
administration.
8. The method of claim 1, wherein said reduction is achieved by an
administration means selected from the group consisting of
intravenous route, intramuscular route, intradermal route,
subcutaneous route, intraperitoneal route, intraarticular route,
sublingual route, subconjunctival route, and intravitreal
route.
9. A method of reducing niacin flushing in a subject by
administering to the subject an effective amount of a water-soluble
composition comprising a cocrystal composition containing a
quantity of acetylsalicylic acid and a quantity of L-Theanine, the
composition made by a process comprising the steps of: providing a
quantity of acetylsalicylic acid; adding a quantity of L-Theanine
to said quantity of acetylsalicylic acid to form a mixture
comprising said quantity of acetylsalicylic acid and said
L-Theanine; wetting said mixture; and grinding said mixture for a
length of time sufficient to produce a dried crystalline mass.
10. The method of claim 9, wherein said reduction is achieved by an
administration means selected from the group consisting of
intravenous route, intramuscular route, intradermal route,
subcutaneous route, intraperitoneal route, intraarticular route,
sublingual route, subconjunctival route, and intravitreal
route.
11. A method of reducing niacin flushing in a subject by
administering to the subject an effective amount of a water-soluble
composition comprising a cocrystal composition containing a
quantity of acetylsalicylic acid and a quantity of L-Theanine, the
composition made by a process comprising the steps of: providing a
quantity of acetylsalicylic acid; adding a quantity of L-Theanine
to said quantity of acetylsalicylic acid to form a mixture
comprising said quantity of acetylsalicylic acid and said quantity
of L-Theanine; dissolving said mixture in a quantity of a solvent
to form a solution; and drying said solution for a length of time
sufficient to produce a dried crystalline mass of an
aspirin-theanine cocrystal composition.
12. The method of claim 11, wherein said reduction is achieved by
an administration means selected from the group consisting of
intravenous route, intramuscular route, intradermal route,
subcutaneous route, intraperitoneal route, intraarticular route,
sublingual route, subconjunctival route, and intravitreal
route.
13. A method of reducing niacin flushing in a subject by
administering to the subject an effective amount of a water-soluble
aspirin-theanine cocrystal composition, the composition made by a
method comprising the steps of: providing a quantity of
acetylsalicylic acid; adding a quantity of a theanine enantiomer
selected from the group consisting of L-theanine, D-theanine, and
DL-theanine to said quantity of acetylsalicylic acid to form a
mixture comprising said quantity of acetylsalicylic acid and said
enantiomer of theanine; wetting said mixture; and grinding said
mixture for a length of time sufficient to produce a dried
crystalline mass.
14. The method of claim 13, wherein said reduction is achieved by
an administration means selected from the group consisting of
intravenous route, intramuscular route, intradermal route,
subcutaneous route, intraperitoneal route, intraarticular route,
sublingual route, subconjunctival route, and intravitreal
route.
15. A method of reducing niacin flushing in a subject by
administering to the subject an effective amount of a water-soluble
aspirin-theanine cocrystal composition, the composition made by a
method comprising the steps of: providing a quantity of
acetylsalicylic acid; adding a quantity of a theanine enantiomer
selected from the group consisting of L-theanine, D-theanine, and
DL-theanine to said quantity of acetylsalicylic acid to form a
mixture comprising said quantity of acetylsalicylic acid and said
quantity of a theanine enantiomer; dissolving said mixture in a
quantity of a solvent to form a solution; and drying said solution
for a length of time sufficient to produce a dried crystalline mass
of an aspirin-theanine cocrystal composition.
16. The method of claim 15, wherein said reduction is achieved by
an administration means selected from the group consisting of
intravenous route, intramuscular route, intradermal route,
subcutaneous route, intraperitoneal route, intraarticular route,
sublingual route, subconjunctival route, and intravitreal route.
Description
[0001] This application is a continuation of U.S. application Ser.
No. 14/262,281, filed Apr. 25, 2014, and now U.S. Pat. No. ______,
which is a continuation of U.S. application Ser. No. 14/188,841,
filed Feb. 25, 2014, and now U.S. Pat. No. ______, which is a
continuation of U.S. application Ser. No. 14/169,291, filed Jan.
31, 2014 and now U.S. Pat. No. ______, which is a continuation of
U.S. application Ser. No. 13/967,027, filed Aug. 14, 2013 and now
U.S. Pat. No. 8,685,948, which is a continuation of U.S.
application Ser. No. 13/617,508, filed Sep. 14, 2012 and now
abandoned, which is a divisional of U.S. application Ser. No.
13/440,693, filed Apr. 5, 2012 and now U.S. Pat. No. 8,304,404,
which is a divisional of U.S. application Ser. No. 12/437,735 filed
May 8, 2009 and now U.S. Pat. No. 8,173,625, which are all
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to a novel method of
administering acetylsalicylic acid, more specifically to a novel
intravenous formulation, using a water-soluble cocrystal product of
acetylsalicylic acid and theanine that has a neutral pH and
provides enhanced stability and bioactivity as compared to
previously known water-soluble formulations of aspirin.
BACKGROUND OF THE INVENTION
[0003] Coronary artery disease is the leading cause of mortality in
developed countries. In the United States, a heart attack occurs
approximately every 20 seconds. Aspirin inhibition of
cyclooxygenase has been shown to be beneficial in patients
presenting with acute coronary syndrome and acute myocardial
infarction. Researchers found that the median platelet inhibition
times for chewed baby aspirin 324 mg, soluble aspirin
(alka-seltzer) 325 mg, and whole compressed non-enteric coated
aspirin 324 mg, were 7.5 minutes, 7.5 minutes, and 10.0 minutes,
respectively. Schwertner, et al, "Effects of different aspirin
formulations on platelet aggregation times and on plasma salicylate
concentration." Thromb Res. 2006; 118(4): 529-34. Epub 2005 Nov.
18. Within 7.5 minutes, though, an individual could be dead from
one of a number of potentially fatal arrhythmias such as
ventricular tachycardia, ventricular fibrillation or complete heart
block. Early administration of a novel intravenous aspirin
formulation could start benefiting the patient in a matter of
seconds, whereas the full benefit of traditional aspirin may not
take effect until major sequelae, complications or death has
occurred. In a person presenting with an acute myocardial
infarction, intravenous aspirin is the preferred route for early
platelet aggregation inhibition. According to the American Heart
Association's 2007 National STEMI Statistics, 75% of the nation's
acute care hospitals are not capable of performing life-saving PCI
(Percutaneous Coronary Intervention) for STEMI (ST elevation
myocardial infarction) patients. As such, there is a clear unmet
need for a novel intravenous aspirin with improved pharmacokinetics
and pharmacodynamics in patients presenting with acute myocardial
infarction.
[0004] Aspirin inhibits prostanoid biosynthesis, in particular that
of thromboxane A2 and prostaglandins PGE2 and PGI2. Aspirin
irreversibly inhibits platelet cyclooxygenase 1 (COX-1) through
acetylation of the amino acid serine at position 529, thereby
preventing arachidonic acid access to the COX-1 catalytic site
through steric hindrance. By inhibiting COX-1, the platelet is
unable to synthesize prostaglandin H2, which would otherwise be
converted to thromboxane A2, which causes platelet aggregation, an
early step in the coagulation cascade.
[0005] Control of the inflammatory process is regulated by a
cascade of biomolecular mechanisms. These mechanisms occur via two
pathways: the cyclooxygenase pathway, which results in the
formation of prostaglandins, and the lipoxygenase pathway, which
results in the formation of leukotrienes. Non-steroid
anti-inflammatory drugs (NSAID), like aspirin, function via the
cyclooxygenase pathway. There are three major human lipoxygenases.
They differ in the position of the double bond on the arachidonic
acid molecule. These human lipoxygenases include the 5-, 12-, and
15-lipoxygenases, which respectively catalyze the insertion of
oxygen at the C-5, C-12 and C-15 positions of arachidonic acid. The
resulting leukotrienes and lipoxins provide signaling molecules
associated with a variety of human diseases such as asthma,
atherosclerosis, psoriasis and inflammatory bowel disease.
Leukotrienes and lipoxins, have been implicated as critical
signaling molecules in a variety of cancers. 15-HLO has been shown
to be a key biological agent in colorectal cancers, while 12-HLO is
involved in pancreatic, breast and prostate cancers. 5-HLO is
up-regulated in prostate cancer and its inhibition abolishes all
cell proliferation, inducing apoptosis.
[0006] Tylenol accounts for most drug overdoses in the United
States and other Western countries. The hepatotoxicity of Tylenol
(acetaminophen), statins (cholesterol lowering drugs),
antiretrovirals (taken for HIV and AIDS), and alcohol are well
known. Researchers at Yale University have now provided new insight
into the mechanism by which acetaminophen causes liver damage in
mice and determined that aspirin provides substantial protection
from these toxic effects of acetaminophen. Wajahat Z Mehal;
Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9
and the Nalp3 Inflammasome; Journal of Clinical Investigation; Jan.
26, 2009.
[0007] Currently, intravenous aspirin is not approved for use in
the United States. The poor solubility of aspirin in water and its
rapid hydrolysis in the plasma to salicylic acid and acetic acid
have limited its intravenous use.
[0008] Attempts have been made in the past to produce an aspirin
product having an acceptable solubility, but none have proven to be
totally satisfactory.
[0009] For example, the introduction of Bayer aspirin, as well as
Disprin (distributed in the United Kingdom), into water results in
the formation of a cloudy suspension indicative of incomplete
dissolution in water. Aspro Clear (distributed in Australia and New
Zealand and marketed throughout Europe) imparts a non-cloudy, snow
globe effect in water for more than three minutes after the tablets
have effervesced.
[0010] It is well-known that lysine acetylsalicylate (sold as,
e.g., Aspegic and Aspisol) is suitable for intravenous
administration. The suitability of lysine for intravenous
administration is due to the formation of a salt of acetylsalicylic
acid with a basic amino acid, with the salt form exhibiting
improved solubility. Lysine acetylsalicylate, however, is not
approved by the FDA for use in the United States. See e.g., FDA
Reports 2006-2008: Aspegic Side-Effect Report #5076936-8 (after
drug was administered, patient developed cardio-respiratory arrest
and ventricular fibrillation and died); FDA Reports 2006-2008:
Aspegic Side Effect Report #5379074-X (after drug was administered,
patient experienced angina pectoris and recovered).
[0011] U.S. Pat. Nos. 5,665,388 and 5,723,453 to Phykitt, disclose
an essentially sodium-free, soluble alkaline aspirin compound. The
formulations disclosed in these references, however, suffer from a
number of disadvantages. One disadvantage is that the use of
bicarbonates, as disclosed therein, causes gas to be formed when
ingested by patients. Another disadvantage is that the relatively
high pH of the compositions disclosed therein (i.e., greater than
8.0) leads to rapid hydrolysis and instability of the drug
substance and, therefore, a shortened shelf-life.
[0012] Many of the formulations disclosed in U.S. Pat. Nos.
5,157,030 and 5,776,431 to Galat are formed as two separate
compositions (mixture "A" and mixture "B"), which is
disadvantageous from manufacturing, packaging and use standpoints.
Furthermore, the formulations in these references are blended and
then directly added to water. There is no indication that the
blended product is stable. Further, compositions formulated in
accordance with the Galat patents take up to two to three minutes
to substantially completely dissolve in water.
[0013] Compositions formulated in accordance with the methods
disclosed in Patent Application Publication No. 2006/0292225 to
Felix take up to 15-30 seconds to completely dissolve in water with
stirring.
[0014] Theanine, like aspirin, is known to have salutary effects.
It is found in ordinary tea leaves from Camellia sinensis and the
mushroom Xerocomus badius, but is otherwise rare in nature.
Preliminary research, suggests that L-theanine promotes alpha wave
generation in the brain. Thereby, an awake, alert and relaxed
physical and mental condition is achieved, which demonstrates
theanine's effectiveness in stress management. L-theanine does not
cause drowsiness or impair a person's motor skills. It has been
shown to work antagonistically against the negative side effects of
caffeine, to increase dopamine and serotonin concentrations in the
brain, to be effective in reducing the hypertension and disturbance
of sleep often associated with the use of caffeine, and to diminish
symptoms of premenstrual syndrome. Laboratory studies indicate that
theanine produces these effects by increasing the level of GABA
(gamma-aminobutyric acid), an important inhibitory neurotransmitter
in the brain.
[0015] It has been reported that theanine supports the immune
system and may reduce plasma total cholesterol, cholesterol ester
and very-low-density lipoprotein cholesterol.
[0016] Studies on the effects of theanine on alcohol metabolism and
hepatic toxicity have shown that theanine is effective against
alcoholic liver injury.
[0017] Theanine also has the potential to protect neurons from
excesses of glutamate. Glutamate is an essential brain chemical
that may be released in excess amounts with some disease conditions
(e.g., amyotrophic lateral sclerosis and cerebrovascular dementia)
and with brain injuries, as occurs with strokes or physical
injuries. Theanine may protect against this damage by blocking
glutamine entrance to cells due to the similarity in the
stereochemical structures of theanine and glutamine.
[0018] A direct metabolite of amino acids glutamine and glutamic
acid, theanine is made different by its ethyl-N alkylation of
glutamine's nitrogen. The amino acid scaffolds glutamine and its
metabolite glutamic acid provide the general, alpha amino acid core
structure responsible for theanine's transport, while ethyl-N
alkylation of glutamine provides both its transport and
pharmacological properties. The similarity of glutamine's and
glutamic acid's structure with theanine allows theanine to be
substrate and product competitors for all physiological glutamine
and glutamic acid reactions, providing their charges are similar.
Therefore, wherever glutamine or glutamic acid is a metabolite,
theanine can activate, inhibit or add to target activity. This is
why its effects are so far-reaching. It is a glutamine mimetic with
pharmacological activity. Glutamine is a significant consumer of
ATP for nitrogen incorporation, which may explain some of the
anti-cancer and anti-HIV activity of theanine. If N-fixation is
inhibited, cell or viral structure growth is also inhibited.
[0019] The amino acids glutamine and glutamic acid have common
molecular elements with theanine. Some examples of common molecular
elements are pI (isoelectric point), polarity, hydropathy index,
and elements that support their role as metabolite targets for
theanine. The overlapping molecular properties allow theanine to
function as a glutamine or glutamic acid analogue. These properties
relate to the electrostatic profile of theanine under physiological
conditions and its overall structural geometry, which includes
atoms common to the related core amino acids glutamine and glutamic
acid. The coincident array of atoms and the relative electrostatic
structure of glutamine and glutamic acid allow them to serve as
targets for theanine. The targets also include the enzymes,
proteins, receptors or other macromolecules they effectively bind.
In the case of glutamic acid, the atoms that make up the isosteric
structure up to the C5 or gamma carboxyl are in the same array as
theanine. In the case of glutamine, the isosteric and isoelectronic
atoms of glutamine are equal to theanine's where hydrogen has been
replaced by ethyl (--C.sub.2H.sub.5) on the carboxamide nitrogen of
glutamine.
[0020] Glutathione is the liver's first-line defense against drugs
and chemicals. It is used by cancer cells against drugs and
chemicals. Cancer cells use glutathione to detoxify doxorubicin and
escort the drug out of cells. Theanine is able to interfere with
this process due to its structural similarity to glutamate.
Glutamic acid, or glutamate, is one of the components of
glutathione, the drug detoxifier. Because it looks like glutamic
acid, cancer cells take up and mistakenly use the theanine to
create glutathione. But the glutathione they create with theanine
does not detoxify like natural glutathione. Instead, this
theanine-based glutathione appears to block the ability of cancer
cells to detoxify.
[0021] Further, in addition to enhancing doxorubicin's
cancer-killing effects without harming healthy tissue, theanine
also keeps doxorubicin out of healthy tissue. This is a major added
benefit, since one of the drawbacks of the use of doxorubicin is
its toxicity to the heart. The potential of theanine as an adjunct
to cancer chemotherapy was proposed by researcher Yasuyuki Sadzuka,
who confirmed that theanine, a major amino acid in green tea,
enhances the antitumor activity of doxorubicin (DOX) without an
increase in DOX-induced side effects. He postulated that the action
of theanine is due to decreases in glutamate uptake via inhibition
of the glutamate transporter and reduction of glutathione and DOX
export from the cell. Theanine enhances the antitumor activity not
only of DOX but also of cisplatin and irinotecan (CPT-11). In
essence, Sadzuka found that theanine could block the export of
doxorubicin (Adriamycin) from cancer cells by blocking the
glutamate and glutathione transporter mechanisms; the elevated
level of the drug within cancer cells strongly inhibits the tumor.
Sadzuka Y, et al., "The effects of theanine, as a novel biochemical
modulator, on the antitumor activity of adriamycin," Cancer Letters
1996; 105(2): 203-209; Sadzuka Y, et al., "Modulation of cancer
chemotherapy by green tea," Clinical Cancer Research 1998; 4(1):
153-156; Sadzuka Y, et al., "Efficacies of tea components on
doxorubicin induced antitumor activity and reversal of multidrug
resistance," Toxicology Letters 2000; 114 (1-3): 155-162; Sadzuka
Y, et al., "Improvement of idarubicin induced antitumor activity
and bone marrow suppression by theanine, a component of tea,"
Cancer Letters 2000; 158(2): 119-24; Sadzuka Y, et al.,
"Enhancement of the activity of doxorubicin by inhibition of
glutamate transporter," Toxicology Letters 2001; 123(2-3):159-67;
Sadzuka Y, et al., "Effect of dihydrokainate on the antitumor
activity of doxorubicin," Cancer Letters 2002; 179(2): 157-163.
[0022] Therapeutic compounds, such as aspirin, are most stable in a
crystalline form, but can display poor aqueous solubilities and
slow dissolution rates. These properties impart the tendency to
reduce the bioavailability of the active pharmaceutical ingredient
(API), thereby slowing absorption.
[0023] A cocrystal is a multiple-component crystal, in which two or
more molecules associate (but do not bond) on the molecular level
in solid crystalline form under ambient conditions. They are
attractive to the pharmaceutical industry because they offer
opportunities to modify the chemical and/or physical properties of
an API without the need to make or break covalent bonds. In
pharmaceutical cocrystals, the molecular structure of the API is
not changed. This has important implications for streamlined
regulatory approval of new forms. By their very nature, APIs,
molecules that contain exterior hydrogen-bonding moieties, are
predisposed to formation of cocrystals. Pharmaceutical cocrystals
will afford forms of APIs with improved physical properties such as
solubility, stability, hygroscopicity, and dissolution rate.
Physical properties are not just dependent upon molecular
structure. They are also critically dependent upon supramolecular
chemistry and its influence upon crystal structure. The application
of the concepts of supramolecular synthesis and crystal engineering
to the development of pharmaceutical cocrystals offers many
opportunities related to drug development and delivery.
[0024] Thus, a water-soluble aspirin-theanine cocrystal composition
which has enhanced stability and bioactivity as compared to
previously-known, water-soluble analgesic compositions, and which
delivers the salutary effects of both aspirin and theanine, is
needed.
[0025] The present invention satisfies these and other medical
needs and overcomes deficiencies found in the prior art.
SUMMARY OF THE INVENTION
[0026] Accordingly, it is an object of the present invention to
provide a water-soluble aspirin-theanine cocrystal composition
having a crystalline structure and which has enhanced stability and
bioactivity, as compared to previously-known, water-soluble
analgesic compositions.
[0027] A further object of the present invention is to provide a
water-soluble aspirin-theanine cocrystal composition having the
above characteristics and which is rapidly water-soluble.
[0028] Yet a further object of the present invention is to provide
a water-soluble aspirin-theanine cocrystal composition having the
above characteristics and which may be used in the relatively large
dosages that are required for anti-inflammatory treatment.
[0029] It is an object of the present invention to provide a method
of administering a water-soluble aspirin-theanine cocrystal
composition intravenously in humans that has a neutral pH, provides
enhanced stability and bioactivity, and is suitable for treatment
of various diseases and medical conditions.
[0030] Still another object of the present invention is to provide
aqueous aspirin-theanine cocrystal formulations suitable for
intravenous administration having the above characteristics and
which allow for rapid delivery of acetylsalicylic acid to the
bloodstream.
[0031] Yet a further object of the present invention is to provide
aqueous aspirin-theanine cocrystal formulations suitable for
intravenous administration having the above characteristics and
which may be used for extended periods of time without causing the
gastrointestinal upset and/or erosions, bleeding, or perforation of
the gastrointestinal tract which may occur with conventional oral
aspirin.
[0032] Another object of the present invention is to provide
aqueous aspirin-theanine cocrystal formulations suitable for
intravenous administration having the above characteristics and
which allow for delivery of therapeutic quantities of theanine to
the bloodstream.
[0033] These and other objects of the present invention are
achieved in accordance with one embodiment of the present invention
by provision of a water-soluble aspirin-theanine cocrystal
composition which includes a quantity of acetylsalicylic acid and a
quantity of a theanine enantiomer associated with the quantity of
acetylsalicylic acid, the cocrystal composition being formed by
physically combining the quantity of acetylsalicylic acid and the
quantity of a theanine enantiomer into a mixture and wetting the
mixture with a quantity of a wetting agent and grinding the
combination for a length of time sufficient to produce a
dried-crystalline mass. In some embodiments, the wetting agent
employed is methanol.
[0034] Formulations according to embodiments of the present
invention protect aspirin from hydrolysis, with the bulk active
ingredient being a well-defined, free-flowing crystalline solid
which has enhanced stability and bioactivity. The solid has a
solubility in water of about 10 mg/mL, and yields a clear aspirin
solution shortly after being mixed.
[0035] Compositions according to embodiments of the present
invention are very soluble in water, requiring about less than one
part water per part solute, especially when compared to traditional
aspirin, which is only very slightly soluble, requiring about 1,000
to 10,000 parts water per part solute.
[0036] In accordance with an embodiment of the present invention, a
method of creating a water-soluble aspirin-theanine cocrystal
composition includes the steps of (i) providing a quantity of
acetylsalicylic acid; adding a quantity of a theanine enantiomer to
the quantity of acetylsalicylic acid to form a mixture comprising
the quantity of acetylsalicylic acid and the enantiomer of
theanine; (ii) wetting the mixture; and (iii) grinding the mixture
for a length of time sufficient to produce a dried crystalline
mass. In certain of these embodiments, methanol is employed in the
step of wetting the mixture. In certain of these embodiments, the
dried crystalline mass has an aqueous solubility of at least about
9.0 mg/mL.
[0037] In some embodiments of the present invention the quantity of
acetylsalicylic acid falls within the range of about 5% to 95% by
weight of the mixture of the quantity of acetylsalicylic acid and
the quantity of a theanine enantiomer. In other embodiments, the
quantity of acetylsalicylic acid falls within the range of about
15% to 85% by weight of the mixture of the quantity of
acetylsalicylic acid and the quantity of a theanine enantiomer. In
further embodiments, the quantity of acetylsalicylic acid is about
50% by weight of the mixture of the quantity of acetylsalicylic
acid and the quantity of a theanine enantiomer.
[0038] In some of these embodiments, the theanine enantiomer is the
L-form. In other embodiments, the theanine enantiomer is the
D-form. In further embodiments, the theanine enantiomer is the
DL-form.
[0039] In some of these embodiments, the resultant aspirin-theanine
cocrystal composition is dissolved in a solvent to form an
aspirin-theanine cocrystal solution. In certain of these
embodiments, the solvent is water. In certain of these embodiments,
the resultant aspirin-theanine cocrystal solution has a pH that is
physiologic. In certain of these embodiments, the resultant
aspirin-theanine cocrystal solution has a pH in the range of about
7.35 to about 7.45. In certain of these embodiments, the resultant
aspirin-theanine cocrystal solution has a pH which is about
7.4.
[0040] In accordance with another embodiment of the present
invention, a method of creating a water-soluble aspirin-theanine
cocrystal composition includes the steps of: (i) providing a
quantity of acetylsalicylic acid; (ii) adding a quantity of an
enantiomer of theanine to said quantity of acetylsalicylic acid to
form a mixture comprising said quantity of acetylsalicylic acid and
said enantiomer of theanine; (iii) dissolving said combination in a
quantity of a solvent to form a solution; and (iv) drying said
solution for a length of time sufficient to produce a dried
crystalline mass. In certain of these embodiments, the dried
crystalline mass has an aqueous solubility of at least about 9.4
mg/mL. In certain of these embodiments, water is employed as the
solvent. In certain of these embodiments, the drying step is
performed by means of a rotary evaporation process.
[0041] In certain of these embodiments, the theanine enantiomer is
the L-form. In some of these embodiments the theanine enantiomer is
the D-form. In further of these embodiments, the theanine
enantiomer is the DL-form.
[0042] In some embodiments of the present invention, the theanine
enantiomer further comprises a carbohydrate functional group
thereon. In these embodiments, the carbohydrate functional group
may be of the L-configuration or the D-configuration. In these
embodiments, the carbohydrates employed may be monosaccharides,
disaccharides, trisaccharides, oligosaccharides or
polysaccharides.
[0043] In some embodiments of the present invention, the theanine
enantiomer further comprises an amino acid functional group
thereon. In certain of these embodiments, the amino acid functional
group is a dipeptide.
[0044] The various features of novelty which characterize the
invention are pointed out with particularity in the claims annexed
to and forming a part of this disclosure. For a better
understanding of the invention, its operating advantages and
specific objects attained by its uses, reference is made to the
accompanying figures and descriptive matter in which a preferred
embodiment of the invention is illustrated.
BRIEF DESCRIPTION OF THE DRAWINGS
[0045] In the drawings:
[0046] FIG. 1 depicts photomicrographs taken at two magnifications
of the crystalline cocrystal product formed by acetylsalicylic acid
and L-theanine according to embodiments of the present
invention;
[0047] FIG. 2 is a differential scanning calorimetry thermogram of
the cocrystal formed by acetylsalicylic acid and L-theanine
according to embodiments of the present invention;
[0048] FIG. 3 is an x-ray powder diffraction pattern of the
cocrystal formed by acetylsalicylic acid and L-theanine according
to embodiments of the present invention;
[0049] FIG. 4 is an infrared absorption spectrum of the cocrystal
formed by acetylsalicylic acid and L-theanine according to
embodiments of the present invention;
[0050] FIG. 5 is a Raman spectrum of the cocrystal formed by
acetylsalicylic acid and L-theanine according to embodiments of the
present invention;
[0051] FIG. 6 depicts photomicrographs taken at two magnifications
of the crystalline cocrystal product formed by acetylsalicylic acid
and D-theanine;
[0052] FIG. 7 is a differential scanning calorimetry thermogram of
the cocrystal formed by acetylsalicylic acid and D-theanine
according to embodiments of the present invention;
[0053] FIG. 8 is an x-ray powder diffraction pattern of the
cocrystal formed by acetylsalicylic acid and D-theanine according
to embodiments of the present invention;
[0054] FIG. 9 is an infrared absorption spectrum of the cocrystal
formed by acetylsalicylic acid and D-theanine according to
embodiments of the present invention;
[0055] FIG. 10 is a Raman spectrum of the cocrystal formed by
acetylsalicylic acid and D-theanine according to embodiments of the
present invention;
[0056] FIG. 11 depicts photomicrographs taken at two magnifications
of the crystalline cocrystal product formed by acetylsalicylic acid
and DL-theanine;
[0057] FIG. 12 is a differential scanning calorimetry thermogram of
the cocrystal formed by acetylsalicylic acid and DL-theanine
according to embodiments of the present invention;
[0058] FIG. 13 is an x-ray powder diffraction pattern of the
cocrystal formed by acetylsalicylic acid and DL-theanine according
to embodiments of the present invention;
[0059] FIG. 14 is an infrared absorption spectrum of the cocrystal
formed by acetylsalicylic acid and DL-theanine according to
embodiments of the present invention; and
[0060] FIG. 15 is a Raman spectrum of the cocrystal formed by
acetylsalicylic acid and DL-theanine according to embodiments of
the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0061] The present invention satisfies needs left unresolved by the
prior art by providing a method for synthesizing a soluble
cocrystal formed by acetylsalicylic acid and L-theanine which is
readily administrable to individuals through a variety of
media.
[0062] Embodiments of the present invention employ L-theanine, a
rare amino acid. L-theanine is a water-soluble, white crystalline
powder, having a Chemical Abstracts Service (CAS) Registry Number
of 3081-61-6 and a GRAS classification (GRAS Notice Number: GRN
000209). L-theanine has the empirical formula
C.sub.7H.sub.14N.sub.2O.sub.3, a molecular weight of 174.20, and
the systematic name of 2-Amino-4-(ethylcarbamoyl)butyric acid.
Being 5-N-ethyl glutamine, theanine differs from glutamine by the
CH2-CH3 (ethyl) group (replacing hydrogen). N-Ethyl confers on
theanine its active properties.
[0063] Embodiments of the present invention include cocrystals of
acetylsalicylic acid with theanine (5-N-ethyl-glutamine). Further,
the theanine contained in compositions according to embodiments of
the present invention may be of any of L-form, D-form, DL-form.
[0064] Embodiments of the present invention may include the amino
acid scaffolds glutamine and/or glutamic acid.
[0065] Non-limiting examples of enantiomers utilized in embodiments
according to the present invention may include a D-enantiomer of
Theanine, D-Glu(NHEt)-OH, 2R enantiomer; an L-enantiomer of
Theanine, L-Glu(NHEt)-OH, 2R enantiomer; a DL enantiomer of
Theanine, DL-Glu(NHEt)-OH enantiomer; a D-enantiomer of Theanine,
D-Gln(Et)-OH, 2R enantiomer; an L-enantiomer of theanine,
L-Gln(Et)-OH, 2R enantiomer; and a DL-enantiomer of theanine,
DL-Gln(Et)-OH, 2R enantiomer. The purity percentages of the
D-enantiomers of theanine, D-Glu(NHEt)-OH, 2R enantiomer and
D-Gln(Et)-OH, 2R enantiomer; the L enantiomers of theanine,
L-Glu(NHEt)-OH, 2R enantiomer and L-Gln(Et)-OH, 2R enantiomer; and
the DL-enantiomers of theanine, DL-Glu(NHEt)-OH, 2R enantiomer and
DL-Gln(Et)-OH, 2R enantiomer in compositions according to
embodiments of the present invention is 99+%; 99+% 2R enantiomer.
The D-enantiomer at 99+%; 99+% ee % (2R) is where the first measure
is the overall chemical purity (hplc) and where the second measure
is ee % (2R) known as the "percent enantiomeric excess." The % ee
is the measure of chiral purity equal to [% R-%S/%R]*100 defined by
the ratios of their diasteriomeric derivatives. Purity percentages
may range from 90% to 99.99% in any D or L configuration of any
theanine or any enantiomer thereof.
[0066] Embodiments of the present invention may include cocrystal
compositions of acetylsalicylic acid and alpha variants of
L-theanine, acetylsalicylic acid and alpha variants of D-theanine,
and acetylsalicylic acid and alpha variants of DL-theanine.
[0067] Non-limiting examples of alpha variants used in embodiments
according to the present invention may include L-northeanine,
D-northeanine, DL-northeanine, L-homotheanine, D-homotheanine,
DL-homotheanine L-bishomotheanine, D-bishomotheanine, and
DL-bishomotheanine, i.e., the respective C-1, C+1, and C+2
homologous analogues of theanine.
[0068] According to embodiments of the present invention the L-,
D-, DL-alpha amino acids of theanine and their side-chain carbon
homologues (nor, homo, and bishomologues) may have a functional
R-group, where R1 may contain linear, cyclic, or branched alkyl
groups and derivatives thereof; linear, cyclic, or branched alkenyl
groups and derivatives thereof; and aromatic radicals and
derivatives thereof. In embodiments of the present invention, the
aromatic radicals may be aryl radicals.
[0069] According to the embodiments of the present invention the
single enantiomers (S and R) and racemic forms (S, R-mixture) of
the beta amino acids of theanine may have a functional R-group,
where R1 may contain linear, cyclic, or branched alkyl groups and
derivatives thereof; linear, cyclic, or branched alkenyl groups and
derivatives thereof; and aromatic radicals and derivatives thereof.
In embodiments of the present invention, the aromatic radicals may
be aryl radicals.
[0070] Embodiments of the present invention may include cocrystal
compositions of acetylsalicylic acid and the enantiomers, L- and
D-isomers, D, L-racemic mixture, S- and R-isomers, S, R-racemic
mixtures, all rotamers, tautomers, salt forms, and hydrates of the
alpha and beta amino acids of theanine in which the N-substituted
functional R1-group [C4 or gamma-CH2-C(O)--NR1] may contain linear,
cyclic, or branched alkyl groups and derivatives thereof; linear,
cyclic, or branched alkenyl groups and derivatives thereof; and
aromatic radicals and derivatives thereof making up all the
analogue forms of theanine. In embodiments of the present
invention, the aromatic radicals may be aryl radicals.
[0071] An aqueous solution is a solution in which water is the
dissolving medium or solvent, and which is essentially free of
colloidal solids. Dissolved crystals form true solutions and are
capable of passing through a semi-permeable membrane as in
dialysis, whereas colloids are unable to pass through a
semi-permeable membrane. The compositions according to embodiments
of the present invention form a true solution when dissolved in
water, are able to pass through a semi-permeable membrane, and can
be used in dialysis. Examples of aqueous solutions that may be used
in embodiments of the present invention include pure water, and the
following: D5W, D10W, D50, D5 0.3% NS, D5 0.45% NS, 0.45% NS, D5
0.9% NS, 0.9% NS, 3% NaCl, D5RL, LR, NaHCO.sub.3, and Xylitol
solutions.
[0072] Solutions formed by dissolving acetylsalicylic acid-theanine
cocrystal compositions according to embodiments of the present
invention in water do not contain colloidal particles, and hence,
do not exhibit the strong Tyndall effect characteristic of
colloidal dispersions.
[0073] It should be understood that the term "suitable," as it is
used herein, generally refers to the fact that the solution can be
administered intravenously to humans, without causing unfavorable
side effects.
[0074] The effective amount of acetylsalicylic acid administered to
a patient (i.e., the amount that will have a salutary effect with
regards to a disease or condition being treated) will be influenced
by gender, age, weight, body fluid status, severity of the disease
or condition being treated, liver enzyme function, and renal
excretion of salicylate which, in turn, is dependent upon urine pH,
and protein binding of salicylates, which is
concentration-dependent.
[0075] The term "carbohydrate," as it is used herein, generally
refers to simple organic compounds that are aldehydes or ketones
substituted with multiple hydroxyl groups, of the general formula
(CH.sub.2O).sub.n, where n is any number of three or greater.
[0076] Monosaccharides, disaccharides, trisaccharides,
oligosaccharides, polysaccharides, dipeptides, and combinations of
these may be used with the acetylsalicylic acid-theanine cocrystal
compositions according to embodiments of the present invention, in
particular, with those cocrystals formed according to the steps
applied in Examples 1-8 below.
[0077] Compositions according to embodiments of the present
invention may contain the trisaccharide theanderose
(G6-.alpha.-glucosyl sucrose), a substance found specifically in
honey.
[0078] Non-limiting examples of other natural sugars that may be
used in embodiments of the present invention include abequose,
allose, allulose, altrose, apiose, arabinose, beet
oligosaccharides, bifurcose, deoxyribose, dextrose (D-glucose),
erlose, erythrose, erythrulose, fructose (levulose), fucose,
fuculose, galactose, gentiobiose, gentiotriose, gentiotetraose,
etc., gulose, hamamelose, inulobiose, inulotriose, inulotetraose,
isomaltose, isomaltotriose, isomaltotetraose, isomaltopentaose,
isomaltulose (palatinose), kestose, kojibiose, lactose, lactulose,
laminaribiose, lyxose, mannose, maltose, maltotriose,
maltotetraose, etc., maltulose, meletzitose, melibiose, methose,
nigerose, nystose, panose, paratose, primeverose, psicose,
raffinose, rhamnose, ribose, ribulose, rutinose, sorbinose,
sorbose, soybean oligosaccharides, stachyose, sucrose, tagatose,
talose, theanderose, threose, trehalose, turanose, xylobiose,
xylotriose, etc., xylose, or xylulose, all of which may be used
with acetylsalicylic acid in compositions according to embodiments
of the present invention. The carbohydrates used in embodiments of
the present invention may be of their respective D- or
L-configurations.
[0079] In certain embodiments, non-limiting examples of sugar
alcohols that may be used include allitol, arabitol, erythritol,
galactitol, glycerol, glycol, iditol, inositol, isomalt, lactitol,
maltotetraol, maltotriol, mannitol, ribitol, sorbitol, talitol,
threitol, and xylitol. The sugar alcohols used in embodiments
according to the present invention may be of their respective the
D- or L-configurations. These sugar alcohols have the benefits of
having low glycemic indices. Mannitol, for example, has been used
to treat increased intracranial pressure. The following
crystalloids may be used in formulations according to embodiments
of the present invention: D5W, D10W, D50, D5 0.3% NS, D5 0.45% NS,
0.45% NS, D5 0.9% NS, 0.9% NS, 3% NaCl, D5RL, LR, NaHCO.sub.3, and
Xylitol solutions.
[0080] Formulations according to embodiments of the present
invention may be fully dissolved in an aqueous solution and
administered via the parenteral route. The following infusion
fluids may be used in formulations according to embodiments of the
present invention: D5W, D10W, D50, D5 0.3% NS, D5 0.45% NS, 0.45%
NS, D5 0.9% NS, 0.9% NS, 3% NaCl, D5RL, LR, NaHCO3, and Xylitol
solutions.
[0081] Next, the present invention will be described in further
detail by means of examples, without intending to limit the scope
of the present invention to these examples alone. The following are
exemplary formulations of water-soluble acetylsalicylic acid
compositions in accordance with the present invention.
Example 1
[0082] A cocrystal product of the present invention was prepared by
weighing 352 mg of acetylsalicylic acid and 340 mg of L-theanine,
and transferring the solids to an agate mortar. The solids were
wetted with 500 .mu.L of methanol, and hand-ground with a pestle
until a dried crystalline mass was obtained. This product was
characterized using differential scanning calorimetry ("DSC;" see
FIG. 2), x-ray powder diffraction ("XRP D;" see FIG. 3),
Fourier-transform infrared spectroscopy with attenuated total
reflectance sampling ("FTIR-ATR;" see FIG. 4), and Raman
spectroscopy with diffuse reflectance sampling ("RAM-DR;" see FIG.
5). In addition, 117 mg of the cocrystal product was found to
dissolve in 13 mL of water, making the aqueous solubility
approximately 9 mg/mL.
Example 2
[0083] The aqueous solution formed in Example 1 was poured in an
evaporating dish, and allowed to dry completely. The DSC thermogram
of the solid product is reflected in FIG. 2, the XRPD pattern is
reflected in FIG. 3, the FTIR-ATR spectrum is reflected in FIG. 4,
and the RAM-DR spectrum is reflected in FIG. 5.
Example 3
[0084] 1.721 g of acetylsalicylic acid and 1.667 g of L-theanine
were weighed and transferred into a large glass mortar. The solids
were wetted with 20 mL of methanol, and hand-ground with a pestle
until a dried crystalline mass was obtained. The DSC thermogram of
the solid product is reflected in FIG. 2, the XRPD pattern is
reflected in FIG. 3, the FTIR-ATR spectrum is reflected in FIG. 4,
and the RAM-DR spectrum is reflected in FIG. 5. 752 mg of the
cocrystal product was found to dissolve in 80 mL of water, making
the aqueous solubility 9.4 mg/mL.
[0085] Aliquots of the aqueous solution were separately diluted in
1:1 v/v ratios with (a) pH 7.4 tromethamine buffer, (b) 0.9% saline
solution, (c) 7.5% sodium bicarbonate solution, (d) 5% dextrose for
injection, and (e) 50% dextrose for injection. The solutions were
observed to remain physically unchanged over a six-day period,
indicating compatibility of the cocrystal product with each of the
infusion solutions.
Example 4
[0086] 435 mg of acetylsalicylic acid and 424 mg of L-theanine were
weighed into a 200 mL round-bottomed flask, and dissolved in 100 mL
of water. The resulting clear solution was then dried using
rotatory evaporation until a dried crystalline mass was obtained.
The DSC thermogram of this solid product is reflected in FIG. 2,
the XRPD pattern is reflected in FIG. 3, the FTIR-ATR spectrum is
reflected in FIG. 4, and the RAM-DR spectrum is reflected in FIG.
5. 752 mg of the cocrystal product was found to dissolve in 80 mL
of water, making the aqueous solubility 9.4 mg/mL.
Example 5
[0087] A cocrystal product of the present invention was prepared by
weighing 353 mg of acetylsalicylic acid and 341 mg of D-theanine,
and transferring the solids to an agate mortar. The solids were
wetted with 500 .mu.L of methanol, and hand ground with a pestle
until a dried crystalline mass was obtained. Representative
photomicrographs of the cocrystal product are shown in FIG. 6 This
product was characterized using differential scanning calorimetry
(DSC; see FIG. 7), x-ray powder diffraction (XRPD; see FIG. 8),
Fourier-transform infrared spectroscopy with attenuated total
reflectance sampling (FTIR-ATR; see FIG. 9), and Raman spectroscopy
with diffuse reflectance sampling (RAM-DR; see FIG. 10). In
addition, 68 mg of the cocrystal product was found to dissolve in
7.5 mL of water, making the aqueous solubility approximately 9
mg/mL.
Example 6
[0088] 363 mg of acetylsalicylic acid and 354 mg of D-theanine were
weighed into a 150 mL beaker, and dissolved in 100 mL of water. The
resulting clear solution was then dried using rotatory evaporation
until a dried crystalline mass was obtained. The DSC thermogram of
this solid product is reflected in FIG. 7, the XRPD pattern is
reflected in FIG. 8, the FTIR-ATR spectrum is reflected in FIG. 9,
and the RAM-DR spectrum is reflected in FIG. 10.
Example 7
[0089] A cocrystal product of the present invention was prepared by
weighing 368 mg of acetylsalicylic acid, 179 mg of L-theanine, and
178 mg of D-theanine, and transferring the solids to an agate
mortar. The solids were wetted with 500 .mu.L of methanol, and hand
ground with a pestle until a dried crystalline mass was obtained.
Representative photomicrographs of the cocrystal product are shown
in FIG. 11. This product was characterized using differential
scanning calorimetry (DSC; see FIG. 12), x-ray powder diffraction
(XRPD; see FIG. 13), Fourier-transform infrared spectroscopy with
attenuated total reflectance sampling (FTIR-ATR; see FIG. 14), and
Raman spectroscopy with diffuse reflectance sampling (RAM-DR; see
FIG. 15). In addition, 67 mg of the cocrystal product was found to
dissolve in 9.5 mL of water, making the aqueous solubility
approximately 7 mg/mL.
Example 8
[0090] 358 mg of acetylsalicylic acid, 175 mg of L-theanine, and
174 mg of D-theanine were weighed into a 150-mL beaker, and
dissolved in 100 mL of water. The resulting clear solution was then
dried using rotatory evaporation until a dried crystalline mass was
obtained. The DSC thermogram of this solid product is reflected in
FIG. 12, the XRPD pattern is reflected in FIG. 13, the FTIR-ATR
spectrum is reflected in FIG. 14, and the RAM-DR spectrum is
reflected in FIG. 15.
[0091] The Tyndall effect is observed when particles of a solid are
dispersed in water but not dissolved. Such an effect is strongly
observed in dispersions of Bayer aspirin, Disprin, and Aspro Clear.
No such strong effect is observed in water, or when cocrystal
compositions according to embodiments of the present invention are
dissolved in water. Colloids are particles which range in size from
1-1000 nm, and a Tyndall effect is created when a laser beam is
scattered by its passage through a colloidal dispersion of
non-dissolved particles. For such dispersions, the illumination of
a visible path through the colloidal dispersion is observable. A
true solution, such as water or a composition according to
embodiments of the present invention dissolved in water, does not
contain colloidal particles, and hence does not exhibit a strong
Tyndall effect characteristic of colloidal dispersions. These
findings, detailed below, as well as the preceding examples,
demonstrate that compositions according to embodiments of the
present invention dissolve to form true solutions in water, and do
not merely disperse to form a colloidal dispersion.
Tyndall Experiment 1
Comparison of Aspirin:(L)-Theanine Cocrystal Product with
Disprin
[0092] 300 mg of the aspirin:(L)-theanine cocrystal product was
dissolved in 150 ml of water in one beaker and a 325 mg tablet of
Disprin was dispersed in 150 ml of water in another beaker. A 514
nm laser beam was first passed through the aspirin:(L)-theanine
cocrystal solution and then through the Disprin dispersion. A
strong Tyndall effect was observed in the aqueous dispersion of
Disprin, but was not observed with the composition according to the
present invention dissolved in water.
[0093] An investigation regarding the degree of insoluble substance
remaining after performance of the Tyndall effect experiment was
carried out. The dispersions in the beakers were stirred to collect
any undissolved solid in the center. An accumulation of undissolved
solid formed at the bottom of the Disprin beaker, but not in the
beaker containing aspirin (L)-theanine cocrystal product which
displayed a crystal-clear solution.
Tyndall Experiment 2
Comparison of Aspirin:(L)-Theanine Cocrystal Product with Aspro
Clear
[0094] 300 mg of the aspirin:(L)-theanine cocrystal product was
dissolved in 150 ml of water in one beaker and a 300 mg tablet of
Aspro Clear was dispersed in 150 ml water in another beaker. A 514
nm laser beam was first passed through the aspirin:(L)-theanine
cocrystal solution and then through the Aspro Clear dispersion. A
strong Tyndall effect was observed in the aqueous dispersion of
Aspro Clear, but was not observed with the composition according to
the present invention dissolved in water.
[0095] An investigation regarding the degree of insoluble substance
remaining after performance of the Tyndall effect experiment was
carried out. The dispersions in the beakers were stirred to collect
any undissolved solid in the center. An accumulation of undissolved
solid formed at the bottom of the Aspro Clear beaker, but not in
the beaker containing aspirin:(L)-theanine cocrystal product which
exhibited a crystal-clear solution.
Tyndall Effect Experiment 3
Comparison of Aspirin:(L)-Theanine Cocrystal Product with Bayer
Aspirin
[0096] 300 mg of the aspirin:(L)-theanine cocrystal product was
dissolved in 150 ml of water in one beaker and a 325 mg tablet of
Bayer aspirin was dispersed in 150 ml of water in another beaker. A
514 nm laser beam was first passed through the aspirin:(L)-theanine
cocrystal solution and then through the Bayer aspirin dispersion. A
strong Tyndall effect was observed in the aqueous dispersion of
Bayer aspirin, but was not observed with the composition according
to the present invention dissolved in water.
[0097] An investigation regarding the degree of insoluble substance
remaining after performance of the Tyndall effect experiment was
carried out. The dispersions in the beakers were stirred to collect
any undissolved solid in the center. An accumulation of undissolved
solid formed at the bottom of the Bayer aspirin beaker, but not in
the beaker containing aspirin:(L)-theanine cocrystal product which
displayed a crystal-clear solution.
Tyndall Effect Experiment 4
Comparison of Aspirin:(L)-Theanine Cocrystal Product with Water
[0098] 300 mg of the aspirin:(L)-theanine cocrystal product was
dissolved in 150 ml of water in one beaker and 150 ml of water
alone was place in another beaker. A 514 nm laser beam was first
passed through the aspirin:(L)-theanine cocrystal solution and then
through the water. A strong Tyndall effect was not observed with
water, nor was it observed with the composition according to the
present invention dissolved in water. Both water and the
aspirin:(L)-theanine cocrystal product exhibited crystal-clear
solutions and were indistinguishable from one other.
[0099] An investigation regarding the degree of insoluble substance
remaining after performance of the Tyndall effect experiment was
carried out. The dispersion in the beaker containing the dissolved
aspirin:(L)-theanine cocrystal product was stirred to collect any
undissolved solid in the center. No undissolved solids were
observed at the bottom of the beaker with the aspirin:(L)-theanine
cocrystal product. Both water and the aspirin:(L)-theanine
cocrystal product produced crystal-clear solutions and were
indistinguishable from one other.
Tyndall Effect Experiment 5
Comparison of Aspirin:(D)-Theanine Cocrystal Product with
Dispirin
[0100] 300 mg of the aspirin:(D)-theanine cocrystal product was
dissolved in 150 ml of water in one beaker and a 325 mg tablet of
Disprin was dispersed in 150 ml of water in another beaker. A 514
nm laser beam was first passed through the aspirin:(D)-theanine
cocrystal solution and then through the Disprin dispersion. A
strong Tyndall effect was observed in the aqueous dispersion of
Disprin, but was not observed with the composition according to the
present invention dissolved in water.
[0101] An investigation regarding the degree of insoluble substance
remaining after performance of the Tyndall effect experiment was
carried out. The dispersions in the beakers were stirred to collect
any undissolved solid in the center. An accumulation of undissolved
solid formed at the bottom of the Disprin beaker, but not in the
beaker containing aspirin (D)-theanine cocrystal product which
displayed a crystal-clear solution.
Tyndall Effect Experiment 6
Comparison of Aspirin:(D)-Theanine Cocrystal Product with Aspro
Clear
[0102] 300 mg of the aspirin:(D)-theanine cocrystal product was
dissolved in 150 ml of water in one beaker and a 300 mg tablet of
Aspro Clear was dispersed in 150 ml water in another beaker. A 514
nm laser beam was first passed through the aspirin:(D)-theanine
cocrystal solution and then through the Aspro Clear dispersion. A
strong Tyndall effect was observed in the aqueous dispersion of
Aspro Clear, but was not observed with the composition according to
the present invention dissolved in water.
[0103] An investigation regarding the degree of insoluble substance
remaining after performance of the Tyndall effect experiment was
carried out. The dispersions in the beakers were stirred to collect
any undissolved solid in the center. An accumulation of undissolved
solid formed at the bottom of the Aspro Clear beaker, but not in
the beaker containing aspirin:(D)-theanine cocrystal product which
displayed a crystal-clear solution.
Tyndall Effect Experiment 7
Comparison of Aspirin:(D)-Theanine Cocrystal Product with Bayer
Aspirin
[0104] 300 mg of the aspirin:(D)-theanine cocrystal product was
dissolved in 150 ml of water in one beaker and a 325 mg tablet of
Bayer aspirin was dispersed in 150 ml of water in another beaker. A
514 nm laser beam was first passed through the aspirin:(D)-theanine
cocrystal solution and then through the Bayer aspirin dispersion. A
strong Tyndall effect was observed in the aqueous dispersion of
Bayer aspirin, but was not observed with the composition according
to the present invention dissolved in water.
[0105] An investigation regarding the degree of insoluble substance
remaining after performance of the Tyndall effect experiment was
carried out. The dispersions in the beakers were stirred to collect
any undissolved solid in the center. An accumulation of undissolved
solid formed at the bottom of the Bayer aspirin beaker, but not in
the beaker containing aspirin (D)-theanine cocrystal product which
displayed a crystal-clear solution.
Tyndall Effect Experiment 8
Comparison of Aspirin:(D)-Theanine Cocrystal Product with Water
[0106] 300 mg of the aspirin:(D)-theanine cocrystal product was
dissolved in 150 ml of water in one beaker and 150 ml of water
alone was placed in another beaker. A 514 nm laser beam was first
passed through the aspirin:(D)-theanine cocrystal solution and then
through the water. A strong Tyndall effect was not observed with
water, nor was it observed with the composition according to the
present invention dissolved in water. Both water and the
aspirin:(D)-theanine cocrystal product produced crystal-clear
solutions and were indistinguishable from one other.
[0107] An investigation regarding the degree of insoluble substance
remaining after performance of the Tyndall effect experiment was
carried out. The dispersion in the beaker containing the dissolved
aspirin:(D)-theanine cocrystal product was stirred to collect any
undissolved solid in the center. No undissolved solids were
observed at the bottom of the beaker with the aspirin:(D)-theanine
cocrystal product. Both water and the aspirin:(D)theanine cocrystal
product produced crystal-clear solutions and were indistinguishable
from one other.
Tyndall Effect Experiment 9
Comparison of Aspirin:(DL)-Theanine Cocrystal Product with
Dispirin
[0108] 300 mg of the aspirin:(DL)-theanine cocrystal product was
dissolved in 150 ml of water in one beaker and a 325 mg tablet of
Disprin was dispersed in 150 ml of water in another beaker. A 514
nm laser beam was first passed through the aspirin:(DL)-theanine
cocrystal solution and then through the Disprin dispersion. A
strong Tyndall effect was observed in the aqueous dispersion of
Disprin, but was not observed with the composition according to the
present invention dissolved in water.
[0109] An investigation regarding the degree of insoluble substance
remaining after performance of the Tyndall effect experiment was
carried out. The dispersions in the beakers were stirred to collect
any undissolved solid in the center. An accumulation of undissolved
solid formed at the bottom of the Disprin beaker, but not in the
beaker containing aspirin:(DL)-theanine cocrystal product which
displayed a crystal-clear solution.
Tyndall Effect Experiment 10
Comparison of Aspirin:(DL)-Theanine Cocrystal Product with Aspro
Clear
[0110] 300 mg of the aspirin:(DL)-theanine cocrystal product was
dissolved in 150 ml of water in one beaker and a 300 mg tablet of
Aspro Clear was dispersed in 150 ml water in another beaker. A 514
nm laser beam was first passed through the aspirin:(DL)-theanine
cocrystal solution and then through the Aspro Clear dispersion. A
strong Tyndall effect was observed in the aqueous dispersion of
Aspro Clear, but was not observed with the composition according to
the present invention dissolved in water.
[0111] An investigation regarding the degree of insoluble substance
remaining after performance of the Tyndall effect experiment was
carried out. The dispersions in the beakers were stirred to collect
any undissolved solid in the center. An accumulation of undissolved
solid formed at the bottom of the Aspro Clear beaker, but not in
the beaker containing aspirin (DL)-theanine cocrystal product which
displayed a crystal-clear solution.
Tyndall Effect Experiment 11
Comparison of Aspirin:(DL)-Theanine Cocrystal Product with Bayer
Aspirin
[0112] 300 mg of the aspirin:(DL)-theanine cocrystal product was
dissolved in 150 ml of water in one beaker and a 325 mg tablet of
Bayer aspirin was dispersed in 150 ml of water in another beaker. A
514 nm laser beam was first passed through the
aspirin:(DL)-theanine cocrystal solution and then through the Bayer
aspirin dispersion. A strong Tyndall effect was observed in the
aqueous dispersion of Bayer aspirin, but was not observed with the
composition according to the present invention dissolved in
water.
[0113] An investigation regarding the degree of insoluble substance
remaining after performance of the Tyndall effect experiment was
carried out. The dispersions in the beakers were stirred to collect
any undissolved solid in the center. An accumulation of undissolved
solid formed at the bottom of the Bayer aspirin beaker, but not in
the beaker containing aspirin (DL)-theanine cocrystal product which
displayed a crystal-clear solution.
Tyndall Effect Experiment 12
Comparison of Aspirin:(DL)-Theanine Cocrystal Product with
Water
[0114] 300 mg of the aspirin:(DL)-theanine cocrystal product was
dissolved in 150 ml of water in one beaker and 150 ml of water
alone was placed in another beaker. A 514 nm laser beam was first
passed through the aspirin:(DL)-theanine cocrystal solution and
then through the water. A strong Tyndall effect was not observed
with water, nor was it observed with the composition according to
the present invention dissolved in water. Both water and the
aspirin:(DL)-theanine cocrystal product produced crystal-clear
solutions and were indistinguishable from one other.
[0115] An investigation regarding the degree of insoluble substance
remaining after performance of the Tyndall effect experiment was
carried out. The dispersion in the beaker containing the dissolved
aspirin:(DL)-theanine cocrystal product was stirred to collect any
undissolved solid in the center. No undissolved solids were
observed at the bottom of the beaker with the aspirin:(DL)-theanine
cocrystal product. Both water and the aspirin:(DL)-theanine
cocrystal product produced crystal-clear solutions and were
indistinguishable from one other.
[0116] Derivatives prepared using compositions according to
embodiments of the present invention can be administered via
intravenous, intramuscular, intradermal, subcutaneous,
intraperitoneal, intraarticular, sublingual, subconjunctival, and
intravitreal routes, or in the form of eye drops, orally,
topically, rectally, via nasal spray, inhalation, and nanoparticle
delivery systems.
[0117] The pharmaceutical compositions according to embodiments of
the present invention may be prepared as oral solids (tablets, oral
disintegrating tablets, effervescent tablets, capsules), oral
liquids, hard or soft gelatin capsules, quick dissolve, controlled
released, modified released, syrups, suspensions, granules, wafers
(films), pellets, lozenges, powders, chewables, suppositories,
ointments, solutions, parenteral/injectable powders or granules
that are pre-mixed or reconstituted, lotions, gels, creams, foams,
and nanoemulsions.
[0118] The pharmaceutical compositions according to embodiments of
the present invention may be combined with lipooxygenase inhibitor
agents, natural lipooxygenase inhibitors, anti-hypertensive agents,
anti-hyperlipidemic agents, anti-hypertensive/anti-hyperlipidemic
agents, anti-triglyceride agents, anti-migraine agents, blood
modifier agents, especially thrombolytic agents and platelet
aggregation inhibitor agents, anti-neoplastic agents,
anti-psychotic agents, anti-anxiety agents, anti-convulsant agents,
anti-Parkinsonian agents, anti-diabetic agents, anti-inflammatory
agents such as corticosteroids, anti-pyretic agents excluding
NSAIDS (NSAIDS when combined with aspirin, negate the effects of
aspirin), anti-rheumatic agents excluding NSAIDS, agents for
treatment of symptoms associated with premenstrual syndrome
excluding NSAIDS, anti-arrhythmic agents, digitalis glycosides,
anti-anginal agents (nitrates, anti-platelet agents, beta blockers,
calcium channel blockers and ranolazine), analgesic agents,
musculoskeletal relaxants, anti-infective agents especially
antibiotics, parenteral nutritional agents, magnesium, Co-enzyme
Q.sub.10, sarcosine, amino acids, vitamins (except vitamin K), and
agents used to treat diseases associated with excess amounts of
glutamate such as, but not limited to amyotrophic lateral
sclerosis, cerebrovascular dementia, and with brain injuries, as
occurs with non-hemorrhagic strokes or physical injuries. The
pharmaceutical compositions of the invention with theanine are not
limited to these agents.
[0119] Intravenous formulations according to embodiments of the
present invention include new compounds that are combined
lipooxygenase/cyclooxygenase inhibitors for treatment of, among
other things, myocardial ischemia, myocardial infarction, cerebral
ischemia, stroke, atherosclerosis, retinal ischemia, rheumatoid
arthritis, osteoarthritis, inflammatory bowel disease, and certain
types of cancers.
[0120] Embodiments of the present invention have other potential
clinical applications including, but not limited to the following:
cardiovascular (treatment of acute coronary syndrome, treatment of
acute myocardial infarction, adjunctive therapy in
revascularization procedures: percutaneous transluminal coronary
angioplasty, coronary artery bypass grafts, carotid enarterectomy,
and stent implantation); neurologic (treatment of acute ischemic
stroke); dysphagia (from any etiology); rheumatologic (rheumatoid
arthritis, ankylosing spondylitis, spondyloarthropathies, pleurisy
and arthritis of systemic lupus erythematous, psoriatic arthritis,
fibromyalgia, Reiter's syndrome, osteoarthritis, Lyme arthritis and
gonorrhea arthritis); anti-inflammatory (epididymitis, Bornholm's
disease (coxsackie myocarditis), acute pericarditis, Dressler's
syndrome, acute rheumatic fever, Ross River fever); pain management
(marine envenomations such as from jellyfish, sea urchins, star
fish, Portuguese man-of-wars, fire corals, sea anemones, lionfish,
stonefish, and stingrays; Osgood-Schlatter disease, idiopathic
(primary) erythromelalgia, burns, acute renal colic, trigeminal
neuralgia, bone pain (osteoid osteomas, Pagets disease, sickle cell
anemia), spinal stenosis, metastatic disease, intractable
headaches, radiculopathies, and other chronic pain syndromes; as an
adjuvant to morphine for patient-controlled analgesia (PCA);
ophthalmologic (retinal ischemia and retinal occlusion); emergent
use (in ambulances, hospital emergency rooms and critical care
units, doctors' offices, air travel, in the wilderness, etc.); with
intubated patients and patients with severely compromised bowel
function, excluding Crohn's disease and ulcerative colitis; as an
anti-pyretic for high grade temperatures, excluding malignant
hyperthermia; for prevention of post-anesthetic shivering; for
closure of patent ductus arteriosus; for familial cylindromatosis;
for inhibition of angiogenesis; for inhibition of niacin flushing;
as an adjuvant to thrombolytic therapy for the treatment of
frostbite; the treatment of rare diseases (including Kawasaki
disease, Riedel thyroiditis, adult-onset Still's disease,
Kikuchi-Fujimoto disease, focal myositis, Weber-Christian disease,
and adhesive arachnoiditis); substantial protection against
hepatotoxic effects from drugs, alcohol, herbs, toxins, chemicals,
obesity-related liver disease and radiation-induced liver disease;
and for providing anti-HIV effects.
[0121] Embodiments of the present invention may be employed to
provide substantial protection against a wide variety of medical
conditions, including but not limited to, the hepatotoxic effects
from Tylenol, statins, antiretrovirals, alcohol, and other drugs,
toxins, herbs, and chemicals that are capable of inducing
hepatoxicity; obesity-related liver disease; and radiation-induced
liver disease.
[0122] Cocrystals according to embodiments of the present invention
may be used to improve one or more physical properties, such as
solubility, stability, and dissolution rate, of the active
pharmaceutical ingredient of a selected treatment or
prevention.
[0123] While specific embodiments of the invention have been shown
and described in detail to illustrate the application of the
principles of the invention, it will be understood that the
invention may be embodied otherwise without departing from such
principles.
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