U.S. patent application number 17/412110 was filed with the patent office on 2022-07-14 for oral administration of ketamine.
The applicant listed for this patent is Vitalis Analgesics LLC. Invention is credited to Joseph Habboushe.
Application Number | 20220218626 17/412110 |
Document ID | / |
Family ID | 1000005809594 |
Filed Date | 2022-07-14 |
United States Patent
Application |
20220218626 |
Kind Code |
A1 |
Habboushe; Joseph |
July 14, 2022 |
ORAL ADMINISTRATION OF KETAMINE
Abstract
Disclosed are pharmaceutical compositions having a portion of
ketamine for intraoral release and another ketamine for
gastrointestinal release. The compositions can further include
aspirin. The disclosed formulations and related administration
approaches improve the bioavailability and efficacy of oral
ketamine.
Inventors: |
Habboushe; Joseph; (New
York, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Vitalis Analgesics LLC |
Wilmington |
DE |
US |
|
|
Family ID: |
1000005809594 |
Appl. No.: |
17/412110 |
Filed: |
August 25, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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63135126 |
Jan 8, 2021 |
|
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63176654 |
Apr 19, 2021 |
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63235413 |
Aug 20, 2021 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/04 20180101;
A61K 31/616 20130101; A61K 9/0053 20130101; A61K 9/0056 20130101;
A61K 31/135 20130101 |
International
Class: |
A61K 31/135 20060101
A61K031/135; A61K 9/00 20060101 A61K009/00; A61K 31/616 20060101
A61K031/616; A61P 25/04 20060101 A61P025/04 |
Claims
1. A method for administering ketamine to a subject or treating
pain in the subject, comprising administering to the subject (a) a
first composition comprising a first amount of ketamine and (b) a
second composition comprising a second amount of ketamine, wherein
the first composition disintegrates or dissolves intraorally
providing rapid release of the ketamine of the first composition,
and the second composition is ingested and released in the
gastrointestinal track of the subject.
2. The method of claim 1, wherein the first composition comprises
at least about 20% of the therapeutically effective amount of
ketamine and the second composition comprises at least about 20% of
the therapeutically effective amount of ketamine.
3. The method of claim 1, wherein the first composition further
comprises a first amount of aspirin.
4. The method of claim 3, wherein the second composition further
comprises a second amount of aspirin.
5. The method of claim 1, wherein the first composition and the
second composition are provided in the form of a tablet or
capsule.
6. The method of claim 5, wherein the second composition is
enclosed within the first composition.
7. The method of claim 6, wherein the first composition is
chewable.
8. The method of claim 7, wherein the second composition is
compressed.
9. The method of claim 8, wherein the second composition comprises
enteric coating.
10. The method of claim 1, wherein the pain is acute
musculoskeletal pain.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C. .sctn.
119(e) of United States Provisional Application Ser. No.
63/135,126, filed Jan. 8, 2021, 63/176,654, filed Apr. 19, 2021,
and 63/235,413, filed Aug. 20, 2021, the contents of which are
incorporated by reference in their entirety into the present
disclosure.
BACKGROUND
[0002] Acute Pain is one of the most frequent chief complaints and
the main reason for visiting the Emergency Department (ED). The
acute pain in the ED is largely prevalent across the country with
recent literature demonstrating that 61-91% of patients are
admitted to the ED due to a variety of acute painful syndromes.
Musculoskeletal pain (MSK) affects one out of three adults and it
is the most common source of serious long term pain and physical
disability. Furthermore, studies have demonstrated that the
frequency for analgesia for adults who received treatment for
musculoskeletal pain in the ED is between 11-29%.
[0003] To complicate the issue of MSK pain management even further,
the opioid epidemic spanning over 20 years in the USA and claiming
over 400,000 deaths from unintentional prescription opioid
overdose, has forced health care systems and hospitals across the
nation to reduce the reliance on opioid analgesics and embrace the
utility of non-opioid analgesia. Several classes of non-opioid
analgesics such as acetaminophen, NSAID's (aspirin, ibuprofen,
diclofenac) and ketamine have gained great deal of attention as
viable alternatives to opioids in management of acute MSK pain in
the ED.
[0004] Ketamine is commonly used for anesthesia. It induces a
trance-like state while providing pain relief, sedation, and memory
loss. Other uses include sedation in intensive care and treatment
of pain and depression. Heart function, breathing, and airway
reflexes generally remain functional. Common side effects include
agitation, confusion, or hallucinations as the medication wears
off. Elevated blood pressure and muscle tremors are also common.
Spasms of the larynx may occur, but relatively infrequently.
[0005] Ketamine was discovered in 1962, first tested in humans in
1964, and approved for use in the United States in 1970. It is on
the World Health Organization's List of Essential Medicines. It is
also used as a recreational drug for its hallucinogenic and
dissociative effects.
[0006] Ketamine can be absorbed by intravenous, intramuscular,
oral, and topical routes due to both its water and lipid
solubilities. In medical settings, ketamine is usually injected
intravenously or intramuscularly. Oral ketamine, however, is easily
broken down by bile acids, and hence has a low bioavailability.
Bioavailability through the oral route reaches 17 to 29%. By
contrast, bioavailability through intramuscular injection is about
93%.
[0007] The onset of action of ketamine is seconds intravenously and
1 to 5 minutes intramuscularly, but 15 to 30 minutes orally.
Moreover, maximal concentrations of ketamine are reached in 1 to 3
minutes intravenously, and 5 to 15 minutes intramuscularly, but 30
minutes orally.
[0008] There is a need to develop oral formulations for ketamine
with improved bioavailability and faster action.
SUMMARY
[0009] It has been discovered that oral administration of ketamine
achieved a remarkably higher bioavailability when the ketamine was
partially released intraorally and delivered transmucosally and
partially released through the gastrointestinal (GI) track, as
compared to intraoral or GI release alone. Further, certain desired
effects of ketamine, such as pain (acute pain, acute on chronic
pain, chronic pain) reduction, suppression of depression, reduction
of fatigue (e.g., multiple sclerosis fatigue), reduction of
suicidality, treatment of asthma/reactive airway, treatment of
cannabinoid hyperemesis syndrome exacerbations, and treatment of
Alzheimer's/dementia can be further enhanced by co-administration
with aspirin which meanwhile can reduce the undesired effects of
ketamine, including its sedation effect and addiction
potential.
[0010] In accordance with one embodiment of the present disclosure,
therefore, provided is a pharmaceutical composition comprising a
first portion comprising a first amount of ketamine, and a second
portion comprising a second amount of ketamine, wherein, upon oral
administration to a subject, the first portion disintegrates or
dissolves intraorally substantively providing rapid release of the
ketamine of the first portion, and the second portion is
substantially more difficult than the first portion to disintegrate
or dissolve intraorally but is ingestible and releasable in the
gastrointestinal track of the subject.
[0011] The pharmaceutical composition can be in the form of a
tablet or capsule. In one aspect, the second portion is enclosed
within the first portion. In one aspect, the first portion is
chewable. In another aspect, the first portion is in the form of
molded triturate.
[0012] In one aspect, the second portion is compressed. In another
aspect, the hardness of the second portion is at least about 10
kilopascal (kp). In yet another aspect, the second portion further
comprises a pharmaceutically acceptable flavoring agent not present
in the first portion.
[0013] In any of the above embodiments, the pharmaceutical
composition further comprises a third portion that comprises an
effective amount of aspirin. In still another aspect, the aspirin
is part of the first portion or the second portion. In one aspect,
the aspirin is present in both the first portion and the second
portion.
[0014] Another embodiment of the present disclosure provides a
method of administering ketamine to a subject, comprising
administering to the subject (a) a first composition comprising a
first amount of ketamine and (b) a second composition comprising a
second amount of ketamine, wherein the first composition
disintegrates or dissolves intraorally substantively providing
rapid release of the ketamine of the first portion, and the second
composition is ingested and released in the gastrointestinal track
of the subject.
[0015] In one aspect of such a method, the administration is within
30 minutes following a meal. In another aspect, the administration
is accompanied by oral administration of an acidic drink which can
assist transmucosal absorption of the first ketamine
composition.
[0016] Also provided is a method of administering ketamine to a
subject with improved bioavailability, comprising administering to
the subject a first composition comprising a first amount of
ketamine and a second composition comprising a second amount of
ketamine, wherein the first composition disintegrates or dissolves
intraorally within 10 minutes permitting rapid release of the
ketamine in the first composition, and the second composition is
ingested and released in the gastrointestinal track of the
subject.
[0017] Either of these methods can further comprise administering
to the subject an effective amount of aspirin, along with the first
composition or the second composition, or both.
[0018] Another embodiment provides a pharmaceutical composition
comprising ketamine and aspirin. In some embodiments, the
composition comprises a first portion comprising a first amount of
the aspirin, and a second portion comprising a second amount of the
aspirin, wherein, upon oral administration to a subject, the first
portion disintegrates or dissolves intraorally providing rapid
release of the aspirin of the first portion, and the second portion
is substantially more difficult than the first portion to
disintegrate or dissolve intraorally but is ingestible and
releasable in the gastrointestinal track of the subject.
[0019] Also provided is a method of administering ketamine to a
subject, comprising administering to the subject ketamine and
aspirin. In some embodiments, the aspirin is administered as (a) a
first composition comprising a first amount of aspirin and (b) a
second composition comprising a second amount of aspirin, wherein
the first composition disintegrates or dissolves intraorally
providing rapid release of the aspirin of the first portion, and
the second composition is ingested and released in the
gastrointestinal track of the subject.
[0020] In another embodiment, provided is a pharmaceutical
composition comprising ketamine and a glutamate ionotropic receptor
NMDA type subunit 2A (GRIN2A) modulator. Examples include aspirin,
nicotine, propofol, melatonin and GQ1b.
[0021] Also provided is a method of administering ketamine to a
subject, comprising administering to the subject ketamine and a
GRIN2A modulator.
[0022] Still further provided is a GRIN2A modulator for use in
enhancing the efficacy of pain relief, or reducing the side effects
of ketamine.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIG. 1 compares the pain reduction efficacies of different
treatments.
[0024] FIG. 2 compares the sedation side effects of different
treatments.
[0025] FIG. 3 compares the disassociation side effects of different
treatments.
[0026] FIG. 4 compares the moderate/severe adverse events
experienced in patients of different groups.
[0027] FIG. 5 compares the SERSDA2+ adverse events experienced in
patients of different groups.
[0028] FIG. 6 compares the pain reduction in patients of different
groups.
[0029] FIG. 7 compares the pain reduction in patients of different
groups.
[0030] FIG. 8 compares the SERSDA2+ adverse events experienced in
patients of different groups.
[0031] FIG. 9 compares the pain reduction in patients of different
groups.
[0032] FIG. 10 compares time to reach 50% pain reduction in
patients of different groups.
DETAILED DESCRIPTION
[0033] The present disclosure provides pharmaceutical compositions
for oral administration of ketamine.
A. Definitions
[0034] Unless defined otherwise, the terms used herein are intended
to have their ordinary meaning in the art.
[0035] All numerical designations, e.g., pH, temperature, time,
concentration, and weight, including ranges, are approximations
that typically may be varied (+) or (-) by increments of 0.1, 1.0,
10.0, or 100.0 as appropriate. It is to be understood, although not
always explicitly stated, that all numerical designations are
preceded by the term "about".
[0036] "About" will be understood by persons of ordinary skill in
the art and will vary to some extent on the context in which the
term is used. If there are uses of the term which are not clear to
persons of ordinary skill in the art given the context in which it
is used, "about" will mean up to plus or minus 10%, or 5%, or 2% or
1% or 0.5% of the particular term.
[0037] As used herein, the term "comprising" means any recited
elements are necessarily included and other elements may optionally
be included. "Consisting essentially of" means any recited elements
are necessarily included, elements that would materially affect the
basic and novel characteristics of the listed elements are
excluded, and other elements may optionally be included.
"Consisting of" means that all elements other than those listed are
excluded. Embodiments defined by each of these terms are within the
scope of this invention.
[0038] As used in the specification and claims, the singular form
"a", "an", and "the" includes plural references unless the context
clearly dictates otherwise.
[0039] "Administering" or "administration of" a drug to a patient
(and grammatical equivalents of this phrase) refers to direct
administration, which may be administration to a patient by a
medical professional or may be self-administration, and/or indirect
administration, which may be the act of prescribing a drug. For
example, a physician who instructs a patient to self-administer a
drug and/or provides a patient with a prescription for a drug is
administering the drug to the patient.
[0040] As used herein, "compressed" dosage form (e.g., "compressed
portion"), refers to a dosage form comprising a compressed powder.
For example, a compressed portion may be formed using a rotary
tablet press or other similar machinery known to one of skill in
the art.
[0041] As used here, "disintegrates or dissolves intraorally"
refers to that a majority of a composition or a portion of a
composition, such as a tablet or a capsule, breaks apart into
smaller particles intraorally. The majority, in one aspect, means
at least about 50%, or alternatively at about 60%, or 70%, or 80%,
or 90%, or 95%, or 98%, or 99%.
[0042] As used herein, "bilayer" compressed dosage form (e.g.,
"bilayer tablet") refers to a single compressed dosage form
comprising two layers. A bilayer compressed dosage form can be made
in a single compression step. Likewise, a "trilayer" compressed
dosage form (e.g., "trilayer tablet") refers to a single compressed
dosage form comprising three layers.
[0043] As used herein, "wet granulation" refers to a process known
in the pharmaceutical arts that involves forming granules by the
addition of a liquid, such as purified water, alcohol, or a binder
solution.
[0044] "Controlled release form" refers to a formulation in which
the aspirin is included within a matrix, which matrix can be either
insoluble, soluble, or partly soluble. Controlled release matrix
formulations of the insoluble type are also referred to as
insoluble polymer matrices, swellable matrices, or lipid matrices
depending on the components that make up the matrix. Controlled
release matrix formulations of the soluble type are also referred
to as hydrophilic colloid matrices, erodible matrices, or reservoir
systems. Controlled release formulations of the present disclosure
refer to formulations comprising an insoluble matrix, a soluble
matrix or a combination of insoluble and soluble matrices in which
the rate of release is slower than that of an uncoated non-matrix
or immediate release formulations or uncoated normal release matrix
formulations. Controlled release formulations can be coated with a
control releasing coat to further slow the release of aspirin from
the controlled release matrix formulation. Such coated controlled
release matrix formulations can exhibit modified-release,
controlled-release, sustained-release, extended-release,
prolonged-release, delayed-release, or combinations thereof, of
aspirin. Examples of controlled release forms of aspirin include
Slo-Aspirin.RTM. available from Upsher Smith Laboratories, Inc.
(Maple Grove, Minn.).
[0045] "Controlled release coat" refers to a functional coat which
can, for example, include at least one pH independent or pH
dependent (such as for example enteric or reverse enteric types)
polymer, soluble or insoluble polymer, lipids or lipidic materials,
or combinations thereof, which, when applied onto a formulation can
slow (for example, when applied to an immediate release formulation
or a normal release matrix formulation), further slow (for example
when applied to a controlled release matrix formulation), or modify
the rate of release of aspirin.
[0046] "Excipient" refers to a pharmacologically inactive substance
used with the active agents or drugs of a medication or a
formulation. Excipients are also sometimes used to bulk up
formulations that contain very potent active ingredients, to allow
for convenient and accurate dosage. In addition to their use in the
unit dose forms, excipients can be used in the manufacturing
process to aid in the handling of the active substance concerned.
Depending on the route of administration, and form of medication,
different excipients may be used. Examples of an excipient
includes, without limitation, one or more of the following: an
additive, an anti-foaming agent, a binder, a chemical stabilizer, a
coloring agent, a diluent, a disintegrating agent, an emulsifying
agent, a filler, a flavoring agents, a glidant, a lubricant, a pH
modifier, a plasticizer, a solubilizer, a swelling enhancer, a
spheronization aid, a solubility enhancer, or a suspending
agent.
[0047] "Immediate release formulation" refers to a formulation from
which the drug is released without any substantial delay and
substantially at once.
[0048] "Patient" or "subject" refers to mammals, including humans
and animals, such as simians, cattle, horses, dogs, cats, and
rodents having the need to take aspirin.
[0049] "Pharmaceutically acceptable salt" refers to
pharmaceutically acceptable salts derived from a variety of organic
and inorganic counter ions well known in the art that include, by
way of example only, sodium, potassium, calcium, magnesium,
ammonium, and tetraalkylammonium, and when the molecule contains a
basic functionality, salts of organic or inorganic acids, such as
hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate,
and oxalate. Suitable salts include those described in P. Heinrich
Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts
Properties, Selection, and Use, 2002, incorporated herein by
reference.
[0050] "Plasticizer" refers to a compound capable of plasticizing
or softening a polymer or a binder. Plasticizers can broaden the
average molecular weight of a polymer in which they are included
thereby lowering its glass transition temperature or softening
point. Plasticizers also can reduce the viscosity of a polymer. The
use of plasticizers is optional, but they can be included in a
formulation to modify the properties and characteristics of the
polymers used in the coat(s) or core of the formulation for
convenient processing during manufacture of the coat(s) and/or the
core of the formulation. Once the coat(s) and/or core has been
manufactured, certain plasticizers can function to increase the
hydrophilicity of the coat(s) and/or the core of the formulation in
the environment of use. During manufacture of the coat(s) and/or
core, the plasticizer can lower the melting temperature or glass
transition temperature (softening point temperature) of the polymer
or binder.
[0051] "Solid formulation" refers to a formulation that is neither
liquid nor gaseous. Solid formulations include tablets, powders,
microparticles, capsules, matrix forms, suppositories, sachets,
troches, patches and lozenges. Solid formulations in the form of
capsules contain a solid composition within a capsule that can be
made of gelatin or other encapsulating material. Liquid
formulations include liquid suspensions and elixirs.
[0052] "Swelling enhancer" refers to an excipient that swells
rapidly resulting in an increase in the size of the tablet. At
lower concentrations, these excipients can be used as super
disintegrants; however at higher concentrations, e.g., at
concentrations above about 5% w/w, these excipients function as
swelling enhancers and increase the size of the matrix
formulation.
[0053] "Therapeutically effective amount" refers to an amount of
the drug that, when administered to a patient, will have the
intended therapeutic effect, e.g., alleviation, amelioration,
palliation or elimination of one or more manifestations of cancer
or other hyperproliferative disease in the patient. A therapeutic
effect does not necessarily occur by administration of one dose,
and may occur only after administration of a series of doses.
Typically, cancer drugs are administered in a repeating series of
doses, and in certain instances each series may be referred to as a
"cycle" of therapy. Thus, a therapeutically effective amount may be
administered in one or more administrations.
[0054] "Treating" or "treatment of" a condition or patient refers
to taking steps to obtain beneficial or desired results, including
clinical results. For purposes of this disclosure, beneficial or
desired clinical results include, but are not limited to, in
intended treatment purpose of ketamine such as pain, anesthesia,
asthma, depression, or other beneficial results including reduction
of side effects.
B. Oral Formulations
[0055] As demonstrated in the accompanying experimental examples,
when ketamine was administered with aspirin through two different
route of administration (intraoral and oral) its efficacy was even
better than intravenously administered ketamine and was close to
orally administered MSIR (Morphine) (FIG. 1), and furthermore
significantly better than intravenously administered ketamine if
corrected for expected bioavailability of oral ketamine (oral
ketamine is about 18-20% bioavailable, while IV ketamine is about
100% bioavailable). Meanwhile, the sedation and dissociation side
effects were considerably reduced as compared to intravenously
administered ketamine (FIG. 2-3).
[0056] It is commonly known that oral ketamine has limited efficacy
and, more importantly, ketamine from any route when administered at
efficacious doses have side effects limiting outpatient use, and
thus a narrow therapeutic window outside of the monitored setting.
Accordingly, oral ketamine is not approved for outpatient use. It
was further investigated whether a simple combination of oral
aspirin and oral ketamine (oral aspirin/ketamine), or a dual route
of ketamine (dual route ketamine) would have acceptable safety
margin for outpatient use. Unexpectedly, the simple oral aspirin
and ketamine administration resulted in a 3.67-point pain reduction
(FIG. 7), close to the dual route aspirin/ketamine administration.
The dual route ketamine, likewise, reached a 2.75-point reduction
(FIG. 6) and only 25% SERSDA3+ adverse even rate (FIG. 4). Such a
safety margin is significantly improved as compared to oral
ketamine alone.
[0057] It is contemplated that such greatly improved efficacy and
reduced side effects were at least in part attributed to the dual
modes of administration of ketamine, one of which includes
intraoral administration for release in the mouth and absorption
through the mucosal membrane. The other portion of the ketamine was
released in the GI track. The partial intraoral release and partial
GI release of ketamine are contemplated to achieve a synergistic
effect in increasing the bioavailability and efficacy of ketamine.
GI-absorbed ketamine has a different metabolic profile from
intraorally absorbed ketamine which directly enters into the blood
stream. This is likely due to the first-pass metabolism of the
liver for medication absorbed through the GI track.
[0058] When administered orally, ketamine undergoes first-pass
metabolism, where it is biotransformed in the liver by CYP3A4
(major), CYP2B6 (minor), and CYP2C9 (minor) isoenzymes into
norketamine (through N-demethylation) and ultimately
dehydronorketamine. Intermediate in the biotransformation of
norketamine into dehydronorketamine is the hydroxylation of
norketamine into hydroxynorketamine by CYP2B6 and CYP2A6. As the
major metabolite of ketamine, norketamine is one-third to one-fifth
as potent as an anesthetic, and plasma levels of this metabolite
are three times higher than ketamine following oral
administration.
[0059] Ketamine given directly into the blood stream results in a
fast peak of serum ketamine concentration, which immediately begins
to drop. The immediate drop is due to the fast metabolism of
ketamine into its primary metabolite, norketamine, resulting in
high serum levels of norketamine.
[0060] Accordingly, the current data suggest that ketamine absorbed
directly into the blood stream (such as oral mucosally absorbed)
hits a peak serum concentration relatively quickly, within minutes.
Ketamine given concurrently through the GI, on the other hand, has
a serum peak concentration about 15-20 minutes later. Therefore,
when just focusing on the ketamine serum levels, a combination of
direct-absorption and GI-absorption will "smooth out" the ketamine
serum concentration over time: the direct absorption getting serum
levels high early, and the GI absorption keeping serums level high
later. This higher and wider serum level of ketamine result in a
more pronounced effect.
[0061] It is further contemplated that the greatly improved
efficacy and reduced side effects of ketamine were also attributed
to the combinatory use of ketamine with aspirin. A combination of
ketamine and aspirin is contemplated to confer multimodal
analgesia, with the contributions of aspirin and ketamine to an
opioid sparing effect. It is further contemplated that such effect
of aspirin would be observed with other modulators of glutamate
ionotropic receptor NMDA type subunit 2A (GRIN2A), such as
nicotine, propofol, melatonin, and gangliosides. Gangliosides are
sialic acid-containing glycosphingolipids, among which
tetrasialoganglioside GQ1b is an example
(alpha-N-acetylneuraminosyl-(2->8)-alpha-N-acetylneuraminosyl-(2->3-
)-beta-D-galactosyl-(1->3)-N-acetyl-beta-D-galactosaminyl-(1->4)-[al-
pha-N-acetylneuraminosyl-(2->8)-alpha-N-acetylneuraminosyl-(2->3)]-b-
eta-D-galactosyl-(1->4)-beta-D-glucosyl-(1->1')-N-(octadecanoyl)-sph-
ing-4-enine; PubChem ID: 10887808).
[0062] Oral administration of ketamine results in decreased
ketamine and increased nor-ketamine concentrations in serum.
Consequently, oral ketamine's first-pass effect from hepatic
metabolism of ketamine to nor-ketamine may help maintain analgesic
potency while simultaneously decreasing side effects when compared
to the IV form.
[0063] Aspirin is a prototype of non-steroidal anti-inflammatory
drugs (NSAIDs), and member of the family of salicylates that have
in common salicylic acid as the active agent. The pharmacological
properties of aspirin are similar to those of salicylates, but also
to the biological actions attributed to salicylate itself, and it
has other independent effects due to its reactive acetate group.
Both components, salicylate and acetate groups, are biologically
active and act independently of each other at different sites.
Aspirin is a safe and well-understood non-steroidal
anti-inflammatory drug (NSAID). It has certain and clinically
accepted analgesic properties. It is a non-selective and
irreversible NSAID that inhibits an activity of both
cyclooxygenase-1 and 2 and blocks the synthesis of prostaglandins
and thromboxanes.
[0064] An oral combination drug of aspirin (or another GRIN2A
activator such as nicotine, propofol, melatonin and GQ1b) and
ketamine (e.g., combination of two administration route) would
facilitate the shift from IV opioids to a non-IV therapy for
patients with acute MSK pain. This combination has a potential to
provide effective analgesia with reduced side effects.
[0065] It is contemplated that the synergistic effects between
intraoral ketamine and oral ketamine, and between ketamine and
aspirin, is applicable to analogs and metabolites of ketamine and
other N-methyl-D-aspartate (NMDA) receptor antagonists, and
applicable to other NSAIDs.
[0066] Example NMDA receptor antagonists include, without
limitation, ketamine, dextromethorphan, memantine, and amantadine,
as well as opioids methadone, dextropropoxyphene, and ketobemidone.
Non-limiting examples of ketamine metabolites include norketamine,
hydroxynorketamine (HNK), dehydronorketamine (DHNK), and
6-hydroxyketamine (HK).
[0067] Accordingly, one embodiment of the present disclosure
provides oral formulations of an NMDA receptor antagonist (e.g.,
ketamine or a metabolite or analog thereof) suitable/acceptable for
outpatient use. In some embodiments, provided is a pharmaceutical
composition comprising a first portion comprising a first amount of
an NMDA receptor antagonist (e.g., ketamine or a metabolite or
analog thereof), and a second portion comprising a second amount of
an NMDA receptor antagonist (e.g., ketamine or a metabolite or
analog thereof), wherein, upon oral administration to a subject,
the first portion disintegrates or dissolves intraorally providing
rapid release of the NMDA receptor antagonist of the first portion,
and the second portion is substantially more difficult than the
first portion to disintegrate or dissolve intraorally but is
ingestible and releasable in the gastrointestinal track of the
subject.
[0068] In one aspect, the NMDA receptor antagonist (e.g., ketamine
or a metabolite or analog thereof)of the first portion is at an
amount lower than the regular dose of the NMDA receptor antagonist
(e.g., 100-400 mg), such as but not limited to, from about 10 mg to
about 300 mg. In one aspect, the amount of the NMDA receptor
antagonist of the first portion is at least about 10 mg, or least
about 20 mg, 30 mg, 40 mg, 50 mg, or 100 mg. In another aspect, the
amount of the NMDA receptor antagonist of the first portion is no
more than about 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200
mg, 225 mg, 250 mg, 275 mg or 300 mg. In one aspect, the NMDA
receptor antagonist in the second portion is at an amount lower
than the regular dose of the NMDA receptor antagonist (e.g.,
100-400 mg), such as but not limited to, from about 10 mg to about
300 mg. In one aspect, the amount of the NMDA receptor antagonist
of the first portion is at least about 10 mg, or least about 20 mg,
30 mg, 40 mg, 50 mg, or 100 mg. In another aspect, the amount of
the NMDA receptor antagonist of the first portion is no more than
about 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg,
250 mg, 275 mg or 300 mg.
[0069] In one aspect, the NMDA receptor antagonist (e.g., ketamine
or a metabolite or analog thereof)of the first portion is at least
about 10%, or 20%, or 30%, or 40%, of 50%, or 60%, or 70%, or 80%,
or 90% of a therapeutically effective amount. In one aspect, the
NMDA receptor antagonist of the first portion is at most about 10%,
or 20%, or 30%, or 40%, of 50%, or 60%, or 70%, or 80%, or 90% of a
therapeutically effective amount. In one aspect, the NMDA receptor
antagonist of the second portion is at least about 10%, or 20%, or
30%, or 40%, of 50%, or 60%, or 70%, or 80%, or 90% of a
therapeutically effective amount. In one aspect, the NMDA receptor
antagonist of the second portion is at most about 10%, or 20%, or
30%, or 40%, of 50%, or 60%, or 70%, or 80%, or 90% of a
therapeutically effective amount.
[0070] In one aspect, the first portion of the NMDA receptor
antagonist (e.g., ketamine or a metabolite or analog
thereof)constitutes at least about 10% of the total NMDA receptor
antagonist in the composition. Alternatively, the first portion of
the NMDA receptor antagonist constitutes at least about 20%, or
30%, or 40%, or 50%, or 60%, or 70%, or 80%, or 90% of the total
NMDA receptor antagonist. In some aspects, however, the first
portion of the NMDA receptor antagonist can be less than about 20%,
or 30%, or 40%, or 50%, or 60%, or 70%, or 80%, or 90% of the total
NMDA receptor antagonist. In a particular aspect, the first portion
constitutes from about 40% to about 60%, or alternatively from
about 45% to about 55% of the total NMDA receptor antagonist.
[0071] In one aspect, the total amount of the NMDA receptor
antagonist (e.g., ketamine or a metabolite or analog thereof)in the
composition is less than about 50 mg, or 60 mg, or 70 mg, or 80 mg,
or 90 mg, or 100 mg, or 120 mg, or 140 mg, or 150 mg, or 160 mg, or
165 mg, or 170 mg, or 180 mg, or 190 mg, 200 mg, 210 mg, 220 mg,
230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, or 300 mg.
In another aspect, the total amount of the NMDA receptor antagonist
in the composition is greater than about 10 mg, 20 mg, or 30 mg, or
40 g, or 50 mg, or 60 mg, or 70 mg, or 80 mg, or 90 mg, or 100 mg,
or 110 mg, or 120 mg, or 130 mg, or 140 mg, or 150 mg.
[0072] It is further contemplated that the addition of aspirin (or
more generally an NSAID) can further enhance the bioavailability
and/or efficacy of the NMDA receptor antagonist (e.g., ketamine or
a metabolite or analog thereof). In one embodiment, aspirin (or
NSAID) is added to the first portion of the NMDA receptor
antagonist which disintegrates or dissolves intraorally providing
rapid release of the NMDA receptor antagonist of the first portion.
In some embodiments, the aspirin in the first portion is at least
about 40 mg. In some embodiments, the aspirin in the first portion
is at least about 80 mg, 160 mg, 240 mg or 320 mg.
[0073] In one embodiment, aspirin is added to the second portion of
the NMDA receptor antagonist which is substantially more difficult
than the first portion to disintegrate or dissolve intraorally but
is ingestible and releasable in the gastrointestinal track of the
subject. In some embodiments, the aspirin in the second portion is
at least about 40 mg. In some embodiments, the aspirin in the
second portion is at least about 80 mg, 160 mg, 240 mg or 320
mg.
[0074] Another aspect of the invention provides a process of
preparing the disclosed compositions. In some embodiments, the
process comprises forming a first portion and a second portion and
compressing the first and second portions to form a bilayer or
two-halves compressed solid oral dosage form. Preparation of each
portion is further described below.
1. First Portion of NMDA Receptor Antagonist for Intraoral
Release
[0075] Methods of preparing a composition suitable for intraoral
release are known in the art. In one aspect, the first portion
further includes a film-coating agent, an excipient, a binder, a
lubricant, or a plasticizer.
[0076] In one aspect, the first portion disintegrates or dissolves
intraorally within about 10 minutes. In other aspects, the first
portion disintegrates or dissolves intraorally within about 9
minutes, or about 8, or about 7, or about 6, or about 5, or about
4, or about 3 or about 2 minutes, or alternatively about 60
seconds, or about 50, or about 40, or about 30, or about 20, or
about 10, or about 5 seconds.
[0077] In some aspects, the first portion is chewable. In some
aspects, the first portion is in the form of molded triturate.
[0078] In one aspect, the first portion further includes an agent
that promotes the oral or buccal absorption of the NMDA receptor
antagonist. Non-limiting examples of such agents include bile acid
salts, sodium lauryl sulfate, lysalbinic acid, salicylic acid,
5-methoxy salicylic acid, 3,4-dihydroxy phenyl acetic acid (DOPAC)
and homovanillic acid and their sodium salts thereof. Other
hydroxyaryl acids, such as 1-hydroxy-2-naphthoic acid,
naphthoresorcyclic acid, ferulic acid, caffeic acid, resorcylic
acid and gentisic acid, have similar effects.
[0079] The amount of hydroxyaryl or hydroxyaralkyl acid or salt,
amide or ester derivatives thereof forms may vary over a wide
range; in general, the identity and the amount of the hydroxyaryl
or hydroxyaralkyl acids or salt, amide or ester thereof is used in
connection with the drug in order to be effective in enhancing the
absorption rate of the drug into the bloodstream.
[0080] In another aspect, the first portion further includes a
disintegrant. Non-limiting examples of disntegrants include
crospovidone, crystalline cellulose, hydroxypropylcellulose with a
low degree of substitution, croscarmellose sodium, carmellose
calcium, carboxystarch sodium, carboxymethyl starch sodium, potato
starch, wheat starch, corn starch, rice starch, partly
pregelatinized starch, and hydroxypropyl starch. One or two or more
of these can be used together. Coating with a disintegrant also
contributes to improvement of compression moldability.
2. Second Portion of NMDA Receptor Antagonist, and Optionally Third
Portion of Aspirin, for GI Release
[0081] The second and third portions of the composition can be
prepared with methods known in the art for a typical oral dosage
form suitable for GI absorption. Like the first portion, the second
portion can also include a film-coating agent, an excipient, a
binder, a lubricant, or a plasticizer.
[0082] Compared to the first portion, the second is substantially
more difficult to disintegrate or dissolve intraorally. This can be
achieved chemically or physically. For instance, the second portion
can be physically harder. In one aspect, the second portion is
compressed. In another aspect, the second portion has a hardness
that is at least about 10 kilopascal (kp), or alternatively about
11, or 12, or 13, or 14, or 15, or 20, or 25 or 30 or 40 or 50
kp.
[0083] Hardness can be assessed by means commonly used in the art,
for example, using commercially available hardness testers that are
routinely used for assessing the hardness of pharmaceutical dosage
forms.
[0084] In some aspects, the second portion further comprises a
pharmaceutically acceptable flavoring agent not present in the
first portion. The flavoring agent provides a flavor that alerts
the patients that this portion should not be chewed and needs to be
swallowed so as to increase patient compliance.
[0085] In one aspect, the NMDA receptor antagonist in the second
portion constitutes at least about 10% of the total NMDA receptor
antagonist. Alternatively, the NMDA receptor antagonist in the
second portion constitutes at least about 20%, or 30%, or 40%, or
50%, or 60%, or 70%, or 80%, or 90% of the total NMDA receptor
antagonist. In some aspects, however, the NMDA receptor antagonist
in the second portion can be less than about 20%, or 30%, or 40%,
or 50%, or 60%, or 70%, or 80%, or 90% of the total NMDA receptor
antagonist. In a particular aspect, the NMDA receptor antagonist in
second portion constitutes from about 40% to about 60%, or
alternatively from about 45% to about 55% of the total NMDA
receptor antagonist. In one aspect, the ratio of the NMDA receptor
antagonist between the first portion and the second portion is
about 1:1. Alternatively, the ratio is at least about 1:4, or 1:3,
or 1:2 or 1:1.5, or is no more than about 4:1, 3:1, 2:1 or
1.5:1.
[0086] The pharmaceutical composition of the present disclosure can
be in the form of a tablet or capsule. When in the form of a
tablet, the second portion, in one aspect, is enclosed within the
first portion or alternatively partially exposed.
[0087] When the composition is in the form of a tablet, the tablet
can include an outer portion and an inter portion, with the outer
portion containing the first portion and the inner portion
containing the second portion and optionally the third portion.
[0088] In one aspect, the outer portion is formulated to dissolve
in the oral cavity of a subject and to release the NMDA receptor
antagonist in the first portion across the oral mucosa of the
subject. In one aspect, the inner portion is harder than the outer
portion and is formulated for dissolving in stomach, intestines, or
further distal in the gastrointestinal tract of the subject.
[0089] In one aspect, the inner portion comprises a texture on the
surface that is recognizable by the tongue of a subject. In another
aspect, the outer portion comprises a water soluble sugar or sugar
substitute. In another aspect, the outer portion is surrounded by a
thin shell to allow encapsulation of liquid, powder or gel in the
outer portion.
[0090] In one aspect, the outer potion is flavored or sweetened. In
one aspect, the tablet further comprises an intermediate layer
between the outer and inner portions. In one aspect, the
intermediate layer comprises enteric coating. In one aspect, the
inner portion is formulated to absorb a biting shock and not break
a tooth. In another aspect, the tablet comprises a layer of
ketamine which breaks down in the mouth, but this layer has
particles within it that don't completely break down in the mouth
and stay full particles, such that there is partial intraoral
release and, when the particles as swallowed, partial
gastrointestinal release.
[0091] The pharmaceutical composition of the above embodiments can
further include a third portion that comprises an effective amount
of aspirin. In one aspect, the third portion is in the form of
controlled release. In another aspect, the third portion further
comprises enteric coating. In yet another aspect, the third portion
is enclosed in the first portion or the second portion.
3. Combination of NMDA Receptor Antagonist and GRIN2A Modulator
[0092] Another discovery of the present disclosure is that certain
desired effects of an NMDA receptor antagonist (e.g., ketamine or a
metabolite or analog thereof), such as pain reduction, suppression
of depression, reduction of fatigue, can be further enhanced by
co-administration with aspirin. The co-administration of aspirin,
or another GRIN2A modulator, is also associated with a reduction of
the undesired effects of the NMDA receptor antagonist, including
its sedation effect and addiction potential.
[0093] In accordance with one embodiment of the disclosure,
provided is a pharmaceutical composition comprising an NMDA
receptor antagonist (e.g., ketamine or a metabolite or analog
thereof)and a glutamate ionotropic receptor NMDA type subunit 2A
(GRIN2A) modulator. In some embodiments, the GRIN2A modulator is an
activator. Non-limiting examples include aspirin, nicotine,
propofol, melatonin and GQ1b.
[0094] In some embodiments, the NMDA receptor antagonist in the
composition is provided as two portions, with the first portion
comprising a first amount of the NMDA receptor antagonist, and a
second portion comprising a second amount of the NMDA receptor
antagonist, wherein, upon oral administration to a subject, the
first portion disintegrates or dissolves intraorally providing
rapid release of the NMDA receptor antagonist of the first portion,
and the second portion is substantially more difficult than the
first portion to disintegrate or dissolve intraorally but is
ingestible and releasable in the gastrointestinal track of the
subject.
[0095] In some embodiments, the GRIN2A modulator is formulated
together with the first portion of the NMDA receptor antagonist. In
some embodiments, the GRIN2A modulator is formulated together with
the second portion of the NMDA receptor antagonist. In some
embodiments, the GRIN2A modulator is formulated together with each
of the first portion and the second portion of the NMDA receptor
antagonist.
[0096] In another embodiment, the present disclosure provides a
pharmaceutical composition comprising an NMDA receptor antagonist
and aspirin. Either or both of the NMDA receptor antagonist and
aspirin can be formulated for both intraoral and oral
administration, as described throughout.
[0097] In some embodiments, the NMDA receptor antagonist (e.g.,
ketamine or a metabolite or analog thereof)is at an amount lower
than the regular dose of the NMDA receptor antagonist (e.g.,
100-400 mg), such as but not limited to, from about 20 mg to about
300 mg. In one aspect, the amount of the NMDA receptor antagonist
of the first portion is at least about 20 mg, or least about 30 mg,
40 mg, 50 mg, or 100 mg. In another aspect, the amount of the NMDA
receptor antagonist of the first portion is no more than about 50
mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg,
275 mg or 300 mg.
[0098] In some embodiments, the composition includes two portions
of aspirin, a first portion containing a first amount of the
aspirin, and a second portion containing a second amount of the
aspirin. Upon oral administration to a subject, the first portion
disintegrates or dissolves intraorally providing rapid release of
the aspirin of the first portion, and the second portion is
substantially more difficult than the first portion to disintegrate
or dissolve intraorally but is ingestible and releasable in the
gastrointestinal track of the subject.
4. Additional Additives to the Compositions
[0099] In yet another aspect, either or both of the first portion
and second portion further comprises excipients, lubricants, pH
adjusters, taste-masking agents, sweeteners, acidifiers,
refrigerants, foaming agents, preservatives, fluidizers,
antioxidants, colorants, stabilizers, surfactants, buffering
agents, flavors, binders or drug solubilizers. A person skilled in
the art may immediately list specific examples of these
additives.
[0100] Any excipient used for pharmaceutical preparations can be
used without limitation, but examples of excipients used in the
tablet of the present invention can include sugars such as
erythritol, mannitol, xylitol, sorbitol, lactitol, paratinit,
paratinose, maltitol, maltose, trehalose, lactose, sucrose,
glucose, olygosaccharides, fructose and maltose and the like. One
or two or more kinds of these excipients can be used.
[0101] Various embodiments of the composition may include
pharmaceutically acceptable binders (adhesives). Binders are agents
that impart cohesive properties to powdered materials through
particle-particle bonding. Examples of suitable binders include
celluloses and crosslinked polyvinyl pyrrolidone, matrix binders
(dry starch, dry sugars), film binders (polyvinyl pyrrolidone
(PVP), starch paste, celluloses, bentonite, sucrose), and chemical
binders (polymeric cellulose derivatives, such as carboxy methyl
cellulose, hydroxypropylcellulose (HPC) and
hydroxypropylmethylcellulose (HPMC); sugar syrups; corn syrup;
water soluble polysaccharides such as acacia, tragacanth, guar and
alginates; gelatin; gelatin hydrolysate; agar; sucrose; dextrose;
and non-cellulosic binders, such as polyvinyl pyrrolidone,
polyethylene glycol (PEG), vinyl pyrrolidone copolymers,
pregelatinized starch, sorbitol, glucose, microcrystalline
cellulose, such as FMC BioPolymer's Avicel.RTM. PH101 and
Avicel.RTM. PH102, and silicified microcrystalline cellulose, such
as Penwest Pharmaceutical's ProSolv SMCC.TM.). In specific
embodiments, a binder is selected from the group consisting of corn
starch, potato starch, polyvinyl pyrrolidone, hydroxypropylmethyl
cellulose, and hydroxylpropyl cellulose. A binder may be included
in any portion of the dosage form, such as the intragranular
portion and/or extragranular portion of either or both of the first
and second layers.
[0102] In some embodiments, the composition further comprises a
pharmaceutically acceptable diluent or filler. Pharmaceutically
acceptable diluents include, but are not limited to, lactose (such
as lactose monohydrate, lactose anhydrous, and DMV International's
Pharmatose.RTM. DCL21 crystalline alpha monohydrate milled
lactose), mannitol, talc, magnesium stearate, sodium chloride,
potassium chloride, citric acid, spray-dried lactose, starch,
hydrolyzed starches, directly compressible starch, microcrystalline
cellulose (such as Avicel.RTM. PH101 and Avicel.RTM. PH102),
cellulosics, sorbitol, sucrose, glucose, sucrose-based materials,
saccharides, calcium sulfate, dibasic calcium phosphate (such as
Emcompress.RTM.) and dextrose, and/or mixtures of any of the
foregoing. In specific embodiments, a diluent is selected from the
group consisting of microcrystalline cellulose, lactose, mannitol,
dicalcium phosphate, dextrose, compressible sugar, and spray-dried
lactose with microcrystalline cellulose. A diluent may be may be
included in any portion of the dosage form, such as the
intragranular portion and/or extragranular portion of either or
both of the first and second layers.
[0103] In some embodiments, the composition comprises magnesium
stearate. In specific embodiments, the magnesium stearate is
present in a range of about 0.5% to 2% w/w, based on the total
weight of the layer.
[0104] In some embodiments, the diluent is microcrystalline
cellulose or microlac (spray-dried lactose with microcrystalline
cellulose). In specific embodiments, the microcrystalline cellulose
or microlac is present in a range of about 20% to 60% w/w, based on
the total weight of the layer.
[0105] Various embodiments of the invention may include
pharmaceutically acceptable anti-adherents (anti-sticking agents,
glidants, flow promoters, lubricants) such as talc, colloidal
silicon dioxide, such as Aerosil.RTM. 200, magnesium stearate,
fumed silica (Carbosil, Aerosil), micronized silica (Syloid No. FP
244, Grace U.S.A.), polyethylene glycols, surfactants, waxes,
stearic acid, stearic acid salts, stearic acid derivatives, calcium
stearate, silica gel, starch, hydrogenated vegetable oils, sodium
benzoate, sodium acetate, leucine, PEG-4000, and magnesium lauryl
sulfate. In specific embodiments, an anti-adherents is selected
from glidants and lubricants. Suitable glidants include, but are
not limited to, colloidal silicon dioxide (Aerosil.RTM.), magnesium
trisilicate, talc, and tribasic calcium phosphate. Suitable
lubricants include, but are not limited to magnesium, aluminum,
calcium, zinc stearate, and talc. An anti-adherent may be included
in any portion of the dosage form, such as the intragranular
portion and/or extragranular portion of either or both of the first
and second layers. In specific embodiments, an anti-adherent is
included in the extragranular portion of the first layer and/or the
extragranular portion of the second layer.
[0106] In some embodiments, the glidant is talc. In specific
embodiments, talc is present in a range of about 1% to 7% w/w,
based on the total weight of each layer.
C. Therapeutic Methods
[0107] Therapeutic methods are also provided. In one aspect,
provided is a method of administering ketamine to a subject with
improved efficacy or bioavailability, comprising administering to
the subject (a) a first composition comprising a first amount of
ketamine and (b) a second composition comprising a second amount of
ketamine, wherein the first composition disintegrates or dissolves
intraorally providing rapid release of the ketamine of the first
portion, and the second composition is ingested and released in the
gastrointestinal track of the subject.
[0108] In one aspect, the ketamine of the first composition is at
an amount lower than the regular dose of ketamine (e.g., 10-400
mg), such as but not limited to, from about 10 mg to about 300 mg.
In one aspect, the amount of ketamine of the first composition is
at least about 10 mg, or least about 20 mg, 30 mg, 40 mg, 50 mg, or
100 mg. In another aspect, the amount of ketamine of the first
composition is no more than about 50 mg, 75 mg, 100 mg, 125 mg, 150
mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg or 300 mg. In one
aspect, the ketamine in the second composition is at an amount
lower than the regular dose of ketamine (e.g., 100-400 mg), such as
but not limited to, from about 10 mg to about 300 mg. In one
aspect, the amount of ketamine of the first composition is at least
about 10 mg, or least about 20 mg, 30 mg, 40 mg, 50 mg, or 100 mg.
In another aspect, the amount of ketamine of the first composition
is no more than about 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg,
200 mg, 225 mg, 250 mg, 275 mg or 300 mg.
[0109] In one aspect, the ketamine of the first composition is at
least about 10%, or 20%, or 30%, or 40%, of 50%, or 60%, or 70%, or
80%, or 90% of a therapeutically effective amount. In one aspect,
the ketamine of the first composition is at most about 10%, or 20%,
or 30%, or 40%, of 50%, or 60%, or 70%, or 80%, or 90% of a
therapeutically effective amount. In one aspect, the ketamine of
the second composition is at least about 10%, or 20%, or 30%, or
40%, of 50%, or 60%, or 70%, or 80%, or 90% of a therapeutically
effective amount. In one aspect, the ketamine of the second
composition is at most about 10%, or 20%, or 30%, or 40%, of 50%,
or 60%, or 70%, or 80%, or 90% of a therapeutically effective
amount.
[0110] In one aspect, the first composition of ketamine constitutes
at least about 10% of the total ketamine administered.
Alternatively, the first composition of ketamine constitutes at
least about 20%, or 30%, or 40%, or 50%, or 60%, or 70%, or 80%, or
90% of the total ketamine. In some aspects, however, the first
composition of ketamine can be less than about 20%, or 30%, or 40%,
or 50%, or 60%, or 70%, or 80%, or 90% of the total ketamine. In a
particular aspect, the first composition constitutes from about 40%
to about 60%, or alternatively from about 45% to about 55% of the
total ketamine.
[0111] In one aspect, the total amount of ketamine administered is
less than about 50 mg, or 60 mg, or 70 mg, or 80 mg, or 90 mg, or
100 mg, or 120 mg, or 140 mg, or 150 mg, or 160 mg, or 165 mg, or
170 mg, or 180 mg, or 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240
mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, or 300 mg. In another
aspect, the total amount of ketamine administered is greater than
about 10 mg, 20 mg, or 30 mg, or 40 g, or 50 mg, or 60 mg, or 70
mg, or 80 mg, or 90 mg, or 100 mg, or 110 mg, or 120 mg, or 130 mg,
or 140 mg, or 150 mg.
[0112] Also provided, in one embodiment, is a method for treating
acute pain in a patient, comprising orally administering an
effective amount of ketamine to the patient.
[0113] The effective amount may be at least 0.1 mg/kg, or at least
0.2 mg/kg, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75,
0.8, 0.85, 0.9, 0.95 or 1 mg/kg. In some embodiments, the effective
amount is not greater than 2 mg/kg, or not greater than 1.9 mg/kg,
1.85, 1.8, 1.75, 1.7, 1.65, 1.6, 1.55, 1.5, 1.45, 1.4, 1.35, 1.3,
1.25, 1.2, 1.15, 1.1, 1.05, 1, 0.95, 0.9, 0.85, 0.8, 0.75, 0.7,
0.65, 0.6, 0.55, or 0.5 mg/kg. In some embodiments, the effective
amount is from 0.3 mg/kg to 0.8 mg/kg, preferably from 0.4 mg/kg to
0.6 mg/kg, and more preferably 0.5 mg/kg.
[0114] Also provided, in one embodiment, is a method for treating
acute on chronic headache in a patient, comprising orally
administering an effective amount of ketamine to the patient.
[0115] The effective amount may be at least 0.1 mg/kg, or at least
0.2 mg/kg, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75,
0.8, 0.85, 0.9, 0.95 or 1 mg/kg. In some embodiments, the effective
amount is not greater than 2 mg/kg, or not greater than 1.9 mg/kg,
1.85, 1.8, 1.75, 1.7, 1.65, 1.6, 1.55, 1.5, 1.45, 1.4, 1.35, 1.3,
1.25, 1.2, 1.15, 1.1, 1.05, 1, 0.95, 0.9, 0.85, 0.8, 0.75, 0.7,
0.65, 0.6, 0.55, or 0.5 mg/kg. In some embodiments, the effective
amount is from 0.5 mg/kg to 1.5 mg/kg, preferably from 0.7 mg/kg to
1 mg/kg, and more preferably 0.85 mg/kg.
[0116] Also provided, in one embodiment, is a method for treating
depression in a patient, comprising orally administering an
effective amount of ketamine to the patient.
[0117] The effective amount may be at least 0.1 mg/kg, or at least
0.2 mg/kg, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75,
0.8, 0.85, 0.9, 0.95 or 1 mg/kg. In some embodiments, the effective
amount is not greater than 2 mg/kg, or not greater than 1.9 mg/kg,
1.85, 1.8, 1.75, 1.7, 1.65, 1.6, 1.55, 1.5, 1.45, 1.4, 1.35, 1.3,
1.25, 1.2, 1.15, 1.1, 1.05, 1, 0.95, 0.9, 0.85, 0.8, 0.75, 0.7,
0.65, 0.6, 0.55, or 0.5 mg/kg. In some embodiments, the effective
amount is from 0.75 mg/kg to 1.75 mg/kg, preferably from 1 mg/kg to
1.5 mg/kg, and more preferably 1.2 mg/kg.
[0118] Also provided, in one embodiment, is a method for treating
cannabinoid hyperemesis syndrome exacerbations in a patient,
comprising orally administering an effective amount of ketamine to
the patient.
[0119] The effective amount may be at least 0.1 mg/kg, or at least
0.2 mg/kg, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75,
0.8, 0.85, 0.9, 0.95 or 1 mg/kg. In some embodiments, the effective
amount is not greater than 2 mg/kg, or not greater than 1.9 mg/kg,
1.85, 1.8, 1.75, 1.7, 1.65, 1.6, 1.55, 1.5, 1.45, 1.4, 1.35, 1.3,
1.25, 1.2, 1.15, 1.1, 1.05, 1, 0.95, 0.9, 0.85, 0.8, 0.75, 0.7,
0.65, 0.6, 0.55, or 0.5 mg/kg. In some embodiments, the effective
amount is from 0.2 mg/kg to 1 mg/kg, preferably from 0.2 mg/kg to
0.6 mg/kg, and more preferably 0.4 mg/kg. It is further
contemplated that the addition of an GRIN2A modulator, e.g.,
aspirin, can further enhance the bioavailability and/or efficacy of
the ketamine. In accordance with one embodiment of the disclosure,
provided is a method of administering ketamine to a subject with
improved efficacy or bioavailability, or reduced side effects,
comprising administering to the subject ketamine and a glutamate
ionotropic receptor NMDA type subunit 2A (GRIN2A) modulator. In
some embodiments, the GRIN2A modulator is an activator.
Non-limiting examples include aspirin, nicotine, propofol,
melatonin and GQ1b.
[0120] In some embodiments, the ketamine is provided as two
portions or two compositions, with the first portion/composition
comprising a first amount of ketamine, and a second
portion/composition comprising a second amount of ketamine,
wherein, upon oral administration to a subject, the first
portion/composition disintegrates or dissolves intraorally
providing rapid release of the ketamine of the first portion, and
the second portion/composition is substantially more difficult than
the first portion to disintegrate or dissolve intraorally but is
ingestible and releasable in the gastrointestinal track of the
subject.
[0121] In some embodiments, the GRIN2A modulator is absorbed
intraorally. In some embodiments, the GRIN2A modulator is absorbed
in the GI track. In some embodiments, the GRIN2A modulator is
partially absorbed intraorally and partially absorbed in the GI
track.
[0122] In some embodiments, the GRIN2A modular is aspirin. In one
embodiment, aspirin is administered in a manner that disintegrates
or dissolves intraorally providing rapid release of the ketamine of
the first composition. In some embodiments, the aspirin so
administered is at least about 40 mg. In some embodiments, the
aspirin is at least about 80 mg, 160 mg, 240 mg or 320 mg.
[0123] In one embodiment, aspirin is administered such that it is
substantially more difficult than the first composition to
disintegrate or dissolve intraorally but is ingestible and
releasable in the gastrointestinal track of the subject. In some
embodiments, the aspirin so administered is at least about 40 mg.
In some embodiments, the aspirin so administered is at least about
80 mg, 160 mg, 240 mg or 320 mg.
[0124] It is also contemplated that a single composition of
ketamine can also be used to achieve the desired effect, when a
portion of the ketamine is dissolved intraorally and the remaining
is released in the GI track. Such a composition of ketamine can be
combined with aspirin, as disclosed above.
[0125] Thus, also provided is a method of administering ketamine to
a subject in need of treating a disease or condition, comprising
administering to the subject a therapeutically effective amount of
ketamine, wherein a portion of the ketamine disintegrates or
dissolves intraorally within 10 minutes permitting rapid release of
the ketamine in the portion, and the remaining ketamine is ingested
and released in the gastrointestinal track of the subject.
[0126] The disease or condition, without limitation, can be pain,
asthma, or depression. In some embodiments, the subject is need of
anesthesia.
[0127] In some aspects, the first composition or portion of the
ketamine disintegrates or dissolves intraorally within about 9
minutes, or about 8, or about 7, or about 6, or about 5, or about
4, or about 3 or about 2 minutes, or alternatively about 60
seconds, or about 50, or about 40, or about 30, or about 20, or
about 10, or about 5 seconds. In any embodiment of the above
methods, the method further comprises administering to the subject
an effective amount of aspirin.
[0128] Also provided, in one embodiment, is a method of
administering ketamine to a subject, comprising administering to
the subject ketamine and aspirin.
[0129] In some embodiments, the aspirin is administered as (a) a
first composition comprising a first amount of aspirin and (b) a
second composition comprising a second amount of aspirin, wherein
the first composition disintegrates or dissolves intraorally
providing rapid release of the aspirin of the first portion, and
the second composition is ingested and released in the
gastrointestinal track of the subject. In some embodiments, the
ketamine is administered as (a) a first composition comprising a
first amount of ketamine and (b) a second composition comprising a
second amount of ketamine, wherein the first composition
disintegrates or dissolves intraorally providing rapid release of
the ketamine of the first portion, and the second composition is
ingested and released in the gastrointestinal track of the
subject.
[0130] In some embodiments, the ketamine is at an amount lower than
the regular dose of ketamine (e.g., 10-400 mg), such as but not
limited to, from about 20 mg to about 300 mg. In one aspect, the
amount of ketamine of the first portion is at least about 20 mg, or
least about 30 mg, 40 mg, 50 mg, or 100 mg. In another aspect, the
amount of ketamine of the first portion is no more than about 50
mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg,
275 mg or 300 mg.
[0131] The administration of ketamine can be useful for treating
certain diseases or conditions, such as pain, asthma, or
depression. In some embodiments, the subject is need of
anesthesia.
EXAMPLE 1
Dual-Route Ketamine and Aspirin in Musculoskeletal Pain
Reduction
[0132] This example evaluates analgesic efficacy of dual-route
ketamine (liquid intraoral ketamine+oral ketamine) taken
simultaneously with dual-route aspirin (intraoral aspirin+oral
aspirin) for pain management of adult emergency department (ED)
patients presenting to the ED with acute musculoskeletal pain.
[0133] It is contemplated that the treatment will result in
analgesia with a change in pain score at least of 1.3 points on
numeric rating pain scale (NRS). The primary outcome of this test
is the reduction in participant's pain scores at 60 minutes post
medication administration.
[0134] Subjects: Patients 18 years of age and older presenting to
the ED with acute musculoskeletal painful conditions (traumatic and
non-traumatic) with an initial pain score of 5 or more on a
standard 11-point (0 to 10) numeric rating scale and requiring oral
analgesia as determined by the treating attending physician. Study
investigators and research assistants will perform patients'
screening and enrollment. All patients will be enrolled at various
times of the day when study investigators will be available for
patient enrollment and an ED pharmacist will be available for
medication preparation.
[0135] Eligibility Criteria: Patients 18 years of age and older
presenting to the ED with acute musculoskeletal painful conditions
(traumatic and non-traumatic) with an initial pain score of 5 on a
standard 11-point (0 to 10) numeric rating scale. Patients will be
awake, alert, oriented to person, place, and time, and will be able
to demonstrate understanding of the informed consent process and
content. Patients also will have to demonstrate ability to
verbalize the nature of any adverse effects they might experience
as well as to express their pain severity by using the NRS.
[0136] Exclusion Criteria: Patients with: altered mental status,
allergy to aspirin and ketamine, pregnant patients, unstable vital
signs (systolic blood pressure <90 or >180 mm Hg, pulse rate
<50 or >150 beats/min, and respiration rate <10 or >30
breaths/min), inability to provide consent, consumption of Aspirin
or NSAID' s within 6 hours of arrival to the ED, active PUD,
history of GI Hemorrhage, history of renal and hepatic
insufficiency, past medical history of alcohol or drug abuse, or
schizophrenia.
[0137] Design: This is a prospective observational pilot trail
evaluating analgesic efficacy and safety of dual-route ketamine in
adult patients presenting to the ED of Maimonides Medical Center
with acute musculoskeletal painful conditions. Upon meeting the
eligibility criteria, patients will be offered to participate in
the study.
[0138] Data Collection Procedures: Each patient will be approached
by a study investigator for acquisition of written informed consent
and Health Insurance Portability and Accountability Act
authorization after being evaluated by the treating emergency
physician and determined to meet study eligibility criteria. When
English is not the participant's primary language, a
language-appropriate consent form will be used and
non-investigator, hospital-employed, trained interpreters or
licensed telephone interpreter will assist in acquisition of
informed consent. Baseline pain score will be determined with an
11-point numeric rating scale (0 to 10), described to the patient
as "no pain" being 0 and "the worst pain imaginable" being 10. A
study investigator will record the patient's body weight and
baseline vital signs.
[0139] The on-duty ED pharmacist will prepare an oral dose of
ketamine by using a formulary for parenteral use. The oral dosing
regimen of ketamine is 0.5 mg/kg that will be placed in the syringe
or a medication cup and sweetener (Ora-sweet.RTM.) will be added to
offset unpleasant taste of the ketamine. The total dose for aspirin
is 325 mg as specified by the sponsor. The research associate will
deliver both medications (dual-route aspirin and dual-route
ketamine) to the patients' nurse. Study investigators will record
pain scores and adverse effects at 15, 30, 60, 90, and 120 minutes.
If patients reported a pain numeric rating scale score of 5 or
greater and requested additional pain relief, an oral immediate
release morphine tablet of 7.5 mg will be given.
[0140] All data will be recorded on data collection sheets,
including patients' sex, demographics, medical history, and vital
signs, and entered into SPSS (version 24.0; IBM Corp) by the
research manager. The statistician, who will work independently of
any data collection, will conduct statistical analyses.
[0141] Patients will be closely monitored for adverse effects
during the entire study period (up to 120 minutes) by study
investigators. Common adverse effects that are associated with oral
ketamine are felling of unreality, dizziness, nausea, vomiting, and
sedation. Common adverse effects are associated with dual-route
aspirin are nausea, dyspepsia, epigastric discomfort.
[0142] Data Analysis: Data analyses will include frequency
distributions and independent-sample t-test to assess differences
in pain scores at the various intervals. Mixed-model linear
regression will be used to compare changes in pain on numeric
rating scale across time points.
[0143] For categorical outcomes (e.g., complete resolution of
pain), X.sup.2 or Fisher's exact test will be used to compare
outcomes at 60 minutes. Based on the validation of a verbally
administered rating scale of acute pain in the ED and the
comparison of verbal and visual pain scales, this example will use
a primary outcome consisting of a minimal clinically meaningful
difference of 1.3 between three groups at the 60-minute pain
assessment.
[0144] Sample Size: Assuming a minimal clinically meaningful
difference of 1.3 in change of pain score from the baseline until
60 minutes, given a standard deviation of 3.0, with a one-side
97.5% confidence interval, this example will need 21 subjects for
this pilot trial. This example would enroll 25 patients to account
for any loss to follow-up.
[0145] Expected Outcomes: The primary outcome will include a
reduction of pain scores on numeric rating pain scale (NRS) at 60
minutes mark form the baseline. The secondary outcomes will include
a need for rescue analgesia and rates of adverse up to 90 minutes.
With respect to unique adverse effects of SDK, this example will
use Side Effect Rating Scale for Dissociative Anesthetics (SERSDA)
and Richmond Agitation Sedation Scale (RASS). SERSDA Scale includes
fatigue, dizziness, nausea, headache, feeling of unreality, changes
in hearing, mood change, general discomfort, and hallucinations
with severity of each graded by patients on a five-point scale,
with "0" representing the absence of any adverse effects and "4"
representing a severely bothersome side effect. RASS evaluates the
severity of agitation and/or sedation in accordance to the
nine-point scale with scores ranging from "-4" (deeply sedated) to
"0" (alert and calm) to "+4" (combative).
[0146] Adverse Events: Dizziness, nausea, vomiting, agitation and
or sedation, weakness or fatigue, feelings of unreality, epigastric
pain, dyspepsia.
[0147] SAE Reporting: Any serious adverse event, requiring
intervention, will be reported to the IRB within 24 hours of
discovery by the research staff. Less serious adverse events will
be reported within a week of discovery. There are known expected
outcomes and side effects to the procedures and medications being
received and these are the same risks/side effects as the standard
of care--these will be reported if they are serious and require
intervention.
[0148] Timetable: The entire study (from commencement until
recruitment of the last patient) will last 12 months. The research
team will monitor and record each patient's pain scores and adverse
events. The research team, pharmacist, and research manager will be
immediately aware and/or notified if a serious adverse event
occurs. ED team of physicians and nurses will treat the patient
appropriately, and subsequently the adverse effect report will be
filed to the IRB.
EXAMPLE 2
Comparison of Ketamine/Aspirin with Ketamine Alone
[0149] This example compares dual-route ketamine (oral+intraoral)
to oral ketamine alone plus oral aspirin alone in adult patients
presenting to the ED with acute musculoskeletal pain, in a
randomized, double-blind, clinical trial.
[0150] Oral formulations of ketamine are not commercially
available. The parenteral formulation is given as an oral solution
by using an injectable vial. The oral bioavailability of ketamine,
defined as area under plasma concentration time curve (AUC), after
a single oral dose of 0.5 mg/kg is about one fifth of the
availability after an intravenous injection. In a ketamine-naive
patient, oral administration of ketamine can start with a single
dose of 0.5 mg/kg ketamine racemic mixture or 0.25 mg/kg S-ketamine
to evaluate the effect on pain relief and the duration of
effect.
[0151] Doses can be increased in steps of 0.5 or 0.25 mg/kg
according to the efficacy and adverse effects, respectively. The
average dosing frequency of 3-4 times daily found in the clinical
studies corresponds well with the elimination half-lives of
ketamine (2-3 h) and nor-ketamine (4 h). The conversion from
parenteral to oral administration in an equipotent dose is complex
and is not solely based on a reduced bioavailability. The median
conversion rate from subcutaneous to oral ketamine used in the case
reports was 1:1.
[0152] The primary outcome of this trial is the comparative
reduction in participant's pain scores at 60 minutes
post-medication administration.
[0153] Example Arms and Interventions
TABLE-US-00001 Arms Assigned Intervention Ketamine + Aspirin 0.5
mg/kg of ketamine (oral) + 324 mg of aspirin (oral) Ketamine alone
0.5 mg/kg of ketamine (dual-route) (oral + intraoral)
[0154] Subjects: Patients 18 years of age and older presenting to
the ED with acute musculoskeletal painful conditions (traumatic and
non-traumatic) with an initial pain score of 5 or more on a
standard 11-point (0 to 10) numeric rating scale and requiring oral
analgesia as determined by the treating attending physician.
Patients' screening and enrollment will be performed by study
investigators and research assistants. All patients will be
enrolled at various times of the day when study investigators will
be available for patient enrollment and an ED pharmacist will be
available for medication preparation.
[0155] Eligibility Criteria: Patients 18 years of age and older
presenting to the ED with acute musculoskeletal painful conditions
(traumatic and non-traumatic) with an initial pain score of 5 on a
standard 11-point (0 to 10) numeric rating scale. Patients will
have to be awake, alert, and oriented to person, place, and time,
and will be able to demonstrate understanding of the informed
consent process and content. Patients also will have to demonstrate
ability to verbalize the nature of any adverse effects they might
experience as well as to express their pain severity by using the
NRS.
[0156] Exclusion Criteria: Patients with altered mental status,
allergy to aspirin and ketamine, pregnant patients, unstable vital
signs (systolic blood pressure <90 or>180 mm Hg, pulse rate
<50 or >150 beats/min, and respiration rate <10 or >30
breaths/min), inability to provide consent, consumption of Aspirin
or NSAID' s within 6 hours of arrival to the ED, active PUD,
history of GI Hemorrhage, history of renal and hepatic
insufficiency, past medical history of alcohol or drug abuse, or
schizophrenia.
[0157] Design: This is a prospective, randomized, double-blind
trial comparing analgesic efficacy and safety of the treatments in
patients presenting to the ED of Maimonides Medical Center with
acute musculoskeletal pain. Upon meeting the eligibility criteria,
patients will be randomized into one of the two study arms: 325 mg
dual-route aspirin+1 mg/kg oral ketamine, and oral ketamine alone
at 1 mg/kg.
[0158] Data Collection Procedures: Each patient will be approached
by a study investigator for acquisition of written informed consent
and Health Insurance Portability and Accountability Act
authorization after being evaluated by the treating emergency
physician and determined to meet study eligibility criteria. When
English is not the participant's primary language, a
language-appropriate consent form will be used and
non-investigator, hospital-employed, trained interpreters or
licensed telephone interpreter will assist in acquisition of
informed consent. Baseline pain score will be determined with an
11-point numeric rating scale (0 to 10), described to the patient
as "no pain" being 0 and "the worst pain imaginable" being 10. A
study investigator will record the patient's body weight and
baseline vital signs. All data will be recorded on data collection
sheets, including patients' sex, demographics, medical history, and
vital signs, and entered into SPSS (version 24.0; IBM Corp) by the
research manager. Confirmation of written consent acquisition for
all participants, and statistical analyses will be conducted by the
statistician (Michael Silver), who will work independently of any
data collection.
[0159] The on-duty ED pharmacist will prepare an oral dose of
ketamine by using an injectable form for parenteral use. The
on-duty ED pharmacist will prepare a syringe/medication cup
containing: the combo group (Combo): 325 mg and 0.5 or 1 mg/kg oral
dose ketamine; oral ketamine (OK) group: matching placebo tablets
and 0.5 or 1 mg/kg oral dose ketamine according to the
predetermined randomization list, which will be created in SPSS
(version 24; IBM Corp, Armonk, NY) with block randomization of
every 10 participants. The research associate will deliver
syringes/medication cups to the patients' nurse who will administer
medication. Study investigators will record pain scores and adverse
effects at 30, 60, 90, and 120 minutes. If patients reported a pain
numeric rating scale score of 5 or greater and requested additional
pain relief, an oral immediate release morphine tablet of 7.5 mg
will be given. Patients will be closely monitored for adverse
effects during the entire study period (up to 120 minutes) by study
investigators. Common adverse effects that are associated with OK
are felling of unreality, dizziness, nausea, vomiting, and
sedation. Common adverse effects are associated with Combo are
nausea, dyspepsia, epigastric discomfort, heartburn, dizziness.
[0160] Data Analysis: Data analyses will include frequency
distributions and independent-sample t-test to assess differences
in pain scores at the various intervals. Mixed-model linear
regression will be used to compare changes in pain numeric rating
scale across time points.
[0161] For categorical outcomes (e.g., complete resolution of
pain), a X.sup.2 or Fisher's exact test will be used to compare
outcomes at 60 minutes. Based on the validation of a verbally
administered rating scale of acute pain in the ED and the
comparison of verbal and visual pain scales, we will use a primary
outcome consisting of a minimal clinically meaningful difference of
2 between two groups at the 60-minute pain assessment.
[0162] Contemplated Outcomes: The primary outcome will include a
reduction of pain scores on numeric rating pain scale (NRS) at 60
minutes mark form the baseline. The secondary outcomes will include
a need for rescue analgesia and rates of adverse up to 120 minutes.
With respect to unique adverse effects of SDK, we will use Side
Effect Rating Scale for Dissociative Anesthetics (SERSDA) and
Richmond Agitation Sedation Scale (RASS) (ref) SERSDA Scale
includes fatigue, dizziness, nausea, headache, feeling of
unreality, changes in hearing, mood change, general discomfort, and
hallucinations with severity of each graded by patients on a
five-point scale, with "0" representing the absence of any adverse
effects and "4" representing a severely bothersome side effect.
RASS evaluates the severity of agitation and/or sedation in
accordance to the nine-point scale with scores ranging from "-4"
(deeply sedated) to "0" (alert and calm) to "+4" (combative).
[0163] SAE Reporting: Any serious adverse event, requiring
intervention, will be reported to the IRB within 24 hours of
discovery by the research staff. Less serious adverse events will
be reported within a week of discovery. There are known expected
outcomes and side effects to the procedures and medications being
received and these are the same risks/side effects as the standard
of care--these will be reported if they are serious and require
intervention.
[0164] Timetable: The entire study (from commencement until
recruitment of the last patient) will last 12 months. The research
team will monitor and record each patient's pain scores and adverse
events. The research team, pharmacist, and research manager will be
immediately aware and/or notified if a serious adverse event
occurs. The patient will be treated appropriately by ED team of
physicians and nurses, and subsequently the adverse effect report
will be filed to the IRB.
EXAMPLE 3
Management of Headache
[0165] This example compares the combination of dual-route aspirin
and dual-route ketamine to Rimegepant (Nurtec.RTM., Biohaven
Pharmaceuticals, New Haven, Conn.) for managing acute headache in
the ED in a randomized, open-label, clinical trial.
[0166] Nurtec (Rimegepant) is an orally administered small molecule
CGRP receptor antagonist with efficacy in the acute treatment of
migraine. Following oral administration of NURTEC Orally
Disintegrating Tablet, rimegepant is absorbed with the maximum
concentration at 1.5 hours. The absolute oral bioavailability of
rimegepant is approximately 64%. Rimegepant is primarily
metabolized by CYP3A4 and to a lesser extent by CYP2C9. Rimegepant
is primarily eliminated in unchanged form (.about.77% of the dose)
with no major metabolites (i.e., >10%) detected in plasma. The
most common adverse reaction are nausea (2% in patients who
received NURTEC ODT compared to 0.4% of patients who received
placebo). Hypersensitivity, including dyspnea and severe rash,
occurred in less than 1% of patients treated with NURTEC ODT.
[0167] NURTEC ODT 75 mg orally disintegrating tablets are white to
off-white, circular, debossed with the symbol, and supplied in
cartons containing a blister pack of 8 orally disintegrating
tablets. Each ODT contains 75 mg rimegepant.
[0168] This example contemplates that the administration of a
combination of dual-route aspirin and oral ketamine would provide
similar analgesic efficacy to Nurtec with respect to analgesic
efficacy at 60 min and 120 minutes in ED patients with acute
headache.
[0169] Subjects: Patients 18 years of age and older presenting to
the ED with acute headache (defined as HA lasting no more than 1
week) and an initial pain score of 5 or more on a standard 11-point
(0 to 10) numeric rating scale and requiring oral analgesia as
determined by the treating attending physician. Patients' screening
and enrollment will be performed by study investigators and
research assistants. All patients will be enrolled at various times
of the day when study investigators will be available for patient
enrollment and an ED pharmacist will be available for medication
preparation.
[0170] Eligibility Criteria: Patients 18 years of age and older
presenting to the ED with acute headache (<7 days) and an
initial pain score of 5 on a standard 11-point (0 to 10) numeric
rating scale. Patients will have to be awake, alert, and oriented
to person, place, and time, and will be able to demonstrate
understanding of the informed consent process and content. Patients
also will have to demonstrate ability to verbalize the nature of
any adverse effects they might experience as well as to express
their pain severity by using the NRS.
[0171] Exclusion Criteria: Patients with altered mental status,
allergy to aspirin/ketamine/rimegepant, pregnant patients, unstable
vital signs (systolic blood pressure <90 or >180 mm Hg, pulse
rate <50 or >150 beats/min, and respiration rate <10 or
>30 breaths/min), inability to provide consent, consumption of
Aspirin/NSAID' s within 6 hours of arrival to the ED, or
acetaminophen within 4 hours of arrival to the ED, active PUD,
history of GI Hemorrhage, history of renal and hepatic
insufficiency, past medical history of alcohol or drug abuse, or
schizophrenia, as well as clinical findings concerning for acute
intracranial process, acute infections process, or vascular
catastrophe, pregnant patients and breastfeeding patients.
[0172] Design: This is a prospective, open-label, equivalence trial
evaluating and comparing analgesic efficacy and safety of a
combination of dual-route aspirin and oral ketamine, and Nurtec in
adult patients presenting to the ED of Maimonides Medical Center
with acute headache. Upon meeting the eligibility criteria,
patients will be offered to participate in the study.
[0173] Data Collection Procedures: Each patient will be approached
by a study investigator for acquisition of written informed consent
and Health Insurance Portability and Accountability Act
authorization after being evaluated by the treating emergency
physician and determined to meet study eligibility criteria. When
English will not be the participant's primary language, a
language-appropriate consent form will be used and
non-investigator, hospital-employed, trained interpreters or
licensed telephone interpreter will assist in acquisition of
informed consent. Baseline pain score will be determined with an
11-point numeric rating scale (0 to 10), described to the patient
as "no pain" being 0 and "the worst pain imaginable" being 10. A
study investigator will record the patient's body weight and
baseline vital signs. All data will be recorded on data collection
sheets, including patients' sex, demographics, medical history, and
vital signs, and entered into SPSS (version 24.0; IBM Corp) by the
research manager. Confirmation of written consent acquisition for
all participants, and statistical analyses will be conducted by the
statistician (Michael Silver), who will work independently of any
data collection.
[0174] Study Set-up. The on-duty ED pharmacist will prepare
medications in the following fashion: the combination of dual-route
aspirin (325 mg) and oral ketamine (0.85 or 1 mg/kg) (Combo) and
Nurtec that are provided by the sponsor will be placed in the
medication cups according to a randomization list generated by the
research manager by SPSS (version 24.0; IBM Corp, Armonk, N.Y.).
The oral dose of ketamine will be prepared by using an injectable
form of ketamine at 0.85 or 1 mg/kg dose and matching (by volume)
placebo (normal saline). This weight-based dose of ketamine and
saline placebo will be placed in the syringe and sweetener will be
added to offset the bitter taste of ketamine. The Combo group will
receive the combination medication cup and oral ketamine syringe,
and Nurtec group will receive Nurtec ODT blister containing 75 mg
of rimegepant in the medication cup and oral placebo syringe.
[0175] The research associate will deliver both syringes and
medication cups to the patients' nurse who will administer
medication. Study investigators will record pain scores and adverse
effects at 30, 60, 90, and 120 minutes. If patients reported a pain
numeric rating scale score of 5 or greater and requested additional
pain relief, the rescue analgesic (s) and routes will be chosen
upon treating attending's discretion. Patients will be closely
monitored for adverse effects during the entire study period (up to
120 minutes) by study investigators. Common adverse effects that
are associated with oral ketamine are felling of unreality,
dizziness, nausea, vomiting, and sedation. Common adverse effects
that are associated with Combo are nausea, dyspepsia, epigastric
discomfort. Common adverse effect that is associated with Nurtec
include nausea.
[0176] Data Analysis: Data analyses will include frequency
distributions and independent-sample t-test to assess differences
in pain scores at the various intervals. Mixed-model linear
regression will be used to compare changes in pain numeric rating
scale across time points. For categorical outcomes (e.g., complete
resolution of pain), a X.sup.2 or Fisher's exact test will be used
to compare outcomes at 60 and 120 minutes. Based on the validation
of a verbally administered rating scale of acute pain in the ED and
the comparison of verbal and visual pain scales, we will use a
primary outcome consisting of a minimal clinically meaningful
difference of 2 points between two groups at the 60-minute and
120-minute pain assessment.
[0177] Contemplated Outcomes: The primary outcome will include a
comparative reduction of pain scores on numeric rating pain scale
(NRS) at 60 minutes from the baseline. The secondary outcomes will
include a need for rescue analgesia, rates of adverse effects, and
change in pain score up to 120 minutes.
[0178] SAE Reporting: Any serious adverse event, requiring
intervention, will be reported to the IRB within 24 hours of
discovery by the research staff. Less serious adverse events will
be reported within a week of discovery. There are known expected
outcomes and side effects to the procedures and medications being
received and these are the same risks/side effects as the standard
of care--these will be reported if they are serious and require
intervention.
EXAMPLE 4
Oral VTS-K (Combination of VTS-Aspirin and Oral Ketamine) as an
Adjunct to Oral Antidepressant Therapy in Treatment of Major
Depressive Disorder
[0179] This example tests the use of ketamine in treating
depression. It is contemplated that 486 mg of aspirin (dual-route
intraoral/oral administration) and 1.2 mg/kg ketamine (dual-route
intraoral/oral administration) as an adjunct to oral antidepressant
treatment will result in reduction of depressive symptoms based on
the change in score from baseline to day 7 after initial dose on
the Montgomery-Asberg Depression Rating Scale (MADRS).
[0180] Subjects: This is a prospective observational proof of
concept study of medically stable (based on the physical
examination, history, and vital signs) adults patients 18 years of
age and older with a diagnosis of major depressive disorder without
psychotic features according to DSM-IV-TR criteria presenting to
the psychiatric clinic for evaluation. Patients to have a score
.gtoreq.22 on the Montgomery-Asberg Depression Rating Scale (MADRS)
on day 1 before dosing. Participants ought to agree to continue
oral antidepressant therapy they were receiving prior to the
enrollment into the study.
Eligibility Criteria:
[0181] Adult patients with TRD with MADRS score >22 upon
presentation to the clinic. Participants ought to agree to
standard-of-care treatment with one or more non-investigational
antidepressants.
[0182] Participants ought to agree to continue oral antidepressant
therapy they were receiving prior to the enrollment into the study.
All participants must agree to provide and informed consent.
Exclusion Criteria:
[0183] Adult patients with recent or current suicidal ideation with
an intent to act, homicidal ideations with an intent to act,
intellectual disability, major depressive disorder with psychosis,
posttraumatic stress disorder, obsessive-compulsive disorder,
substance use disorder, antisocial personality disorder, borderline
personality disorder, or a current or past diagnosis of a psychotic
disorder altered mental status, allergy to aspirin and ketamine,
pregnant patients, unstable vital signs (systolic blood pressure
<90 or>180 mm Hg, pulse rate <50 or >150 beats/min, and
respiration rate <10 or >30 breaths/min), consumption of
Aspirin or NSAID's within 6 hours of arrival to the ED, active PUD,
history of GI Hemorrhage, and history of renal and hepatic
insufficiency.
Design:
[0184] This is a prospective observational proof of concept study
of adult patients 18 years of age and older with a diagnosis of TRD
without psychotic features according to DSM-IV-TR criteria
presenting to the psychiatric clinic for evaluation. Eligible
participants will receive 486 mg of aspirin (dual-route
intraoral/oral administration) and 1.2 mg/kg ketamine (dual-route
intraoral/oral administration) as an adjunct to oral antidepressant
treatment twice a week for 1 week (on day 1 and 4 for the week).
All participants will be observed for 4 hours in the outpatient
setting after receiving the medication and their depressive
symptoms will be assessed at 4-hour mark by MADRS Scale and QIDS-SR
scale (Quick Inventory of Depressive Symptomatology-Self Report)
and their adverse effect related to VTS=K administration will be
assessed by using the Clinician Administered Dissociative State
Scale (CADSS) and MOAA/S scale and RASS scale.
Study Set Up
[0185] The on-duty pharmacist will prepare an oral dose of ketamine
by using an injectable form for parenteral use. The on-duty ED
pharmacist will prepare a syringe/medication cup containing the
medication according to the predetermined list, which will be
created in SPSS (version 24; IBM Corp, Armonk, N.Y.). The oral
sweetener solution of 1 ml will be added to the syringe containing
ketamine. The research pharmacist will deliver syringes/medication
cup to the patients' nurse who will administer medication. Subjects
will be instructed to first suck off the outer layer of aspirin for
about 30-60 seconds and then swallow the tablet. The oral
antidepressant medication will be initiated or optimized for all
participants on day 1. Participants taking a recently initiated
antidepressant at screening could continue the antidepressant at
the same dosage during treatment with study drug. Study
investigators will record VS, and adverse effects at 30 minute, 60
minutes, 2 hours, and 4 hours. Patients will be closely monitored
for adverse effects during the entire observation period (for up to
2-4 hours) by study investigators.
Efficacy Assessments
[0186] Research associates and study investigators will assess
depressive symptom severity with the Montgomery-.ANG.sberg
Depression Rating Scale (MADRS) on day one and on day 4 and day 7
(for days 1 and 4 this will include pre-dose, 40 minutes, 120
minutes, and 240 minutes post-dose). Patients will also be screened
using the Beck Scale for Suicide Ideation and their sense of
hopelessness using the Beck Hopelessness Scale before dosing and 4
hours after dosing on day one and pre-dosing on days 4, and 7.
Safety Assessments
[0187] Vital signs will be checked before medication administration
and 1, 2, 4 hours post-drug administration during the study period.
Adverse events will be monitored throughout the study. The
Clinician-Administered Dissociative States Scale (CADSS) will be
administered before dosing and at 40 minutes, 2 hours, and 4 hours
after dosing on day 1 and day 4. In addition, a Modified Observer's
Alertness/Sedation Scale (MOAA/S) will be used to assess the level
of sedation.
[0188] Common adverse effects that are associated with oral
ketamine are felling of unreality, dizziness, nausea, vomiting,
sedation, and dissociation. Common adverse effects are associated
with VTS-Aspirin are nausea, dyspepsia, epigastric discomfort,
[0189] Data Collection Procedures: Each patient will be approached
by a study investigator for acquisition of written informed consent
and Health Insurance Portability and Accountability Act
authorization after being evaluated by the treating psychiatry
physician and determined to meet study eligibility criteria. When
English will not be the participant's primary language, a
language-appropriate consent form will be used and
non-investigator, hospital-employed, trained interpreters or
licensed telephone interpreter will assist in acquisition of
informed consent. Baseline Depression score via MADRS will be
recorded by a study investigator. All data will be recorded on data
collection sheets, including patients' sex, demographics, medical
history, and vital signs, and entered into SPSS (version 24.0; IBM
Corp) by the research manager. Confirmation of written consent
acquisition for all participants, and statistical analyses will be
conducted by the statistician who will work independently of any
data collection.
[0190] Data Analysis: Data analyses will include mixed-effect model
with repeated measures with baseline MADRS score as covariate; time
by treatment interaction as fixed effect and patient as random
effect.
Expected Outcomes:
[0191] The primary outcome will include a change in depressive
symptoms on the Montgomery-Asberg Depression Rating Scale (MADRS)
from the baseline (pre-dose day 1) and day 7.
[0192] The secondary outcomes will include: a change in depressive
symptoms on the Montgomery-Asberg Depression Rating Scale (MADRS)
from the baseline (pre-dose on day 1 and 4) and 4 hours
post-medication administration.
[0193] Rates of Side effects will be reported by using the
Clinician-Administered Dissociative States Scale (CADSS), Side
Effect Rating Scale for Dissociative Anesthetics (SERSDA), and
Modified Observer's Alertness/Sedation Scale (MOAA/S). The SERSDA
scale includes fatigue, dizziness, nausea, headache, feeling of
unreality, changes in hearing, mood change, general discomfort, and
hallucinations with severity of each graded by patients on a
five-point scale, with "0" representing the absence of any adverse
effects and "4" representing a severely bothersome side effect.
[0194] SAE Reporting: Any serious adverse event, requiring
intervention, will be reported to the IRB within 24 hours of
discovery by the research staff. Less serious adverse events will
be reported within a week of discovery. There are known expected
outcomes and side effects to the procedures and medications being
received and these are the same risks/side effects as the standard
of care--these will be reported if they are serious and require
intervention.
EXAMPLE 5
Therapeutic Effects of Dual Ketamine/Aspirin
[0195] This example presents the results from a trial as outlined
in Example 1, in comparison with data collected from similar trials
with other agents and the same testing protocol and pain
measurement scales, in the same medical center by the same research
team and same statistical methods. The testing agents and dosages
are listed in Table 1.
TABLE-US-00002 TABLE 1 Agents and Doses No. Agent Dose 1 Morphine
(IV) 0.1 mg/kg 2 Morphine Sulfate Immediate 15 mg Release (MSIR)
(oral) 3 Percocet (oral) 10 mg 4 Dual route ketamine + aspirin 0.5
mg/kg ketamine (intraoral + oral) 5 Ketamine (IV) 0.3 mg/kg 6
Nebulized ketamine Mixed dose 7 Ibuprofen (oral) Mixed dose 8
Ketorolac (IV)
[0196] The efficacy to reduce acute musculoskeletal pain by each
agent was measured as described in Example 1. The results are
presented in FIG. 1. As expected, IV morphine had the highest
efficacy, resulting in a 5.1-point reduction of acute
musculoskeletal pain. The least efficacious was oral ibuprofen (2
points). IV ketamine and intranasal (nebulized) ketamine were both
effective, achieving a reduction of about 4 points, similar to oral
morphine and Percocet.
[0197] Quite unexpectedly, the dual-route ketamine and dual-route
aspirin achieved a 3.84-point reduction of acute musculoskeletal
pain. As explained above, it has been demonstrated that the oral
bioavailability of ketamine is about 1/5 of the availability via IV
injection. Here, the measured efficacy of dual-route ketamine (0.5
mg/kg) and aspirin (3.84 points) is equivalent to that of IV
ketamine (0.3 mg/kg) (3.8 points). Therefore, these data suggest
that the dual-route ketamine (with aspirin) at 0.5 mg/kg is
equivalent to conventional oral ketamine at 1.5 mg/kg. This is a
three-fold increase of efficacy as compared to the conventional
oral ketamine.
[0198] A typical side effect of ketamine is sedation, which was
measured with a Richmond Agitation-Sedation Scale (RASS) as
described in Table 2A. The results are compared to published ones
that either used the RASS scale or a MOAA/S scale (Modified
Observer's Assessment of Alertness/Sedation) which is described in
Table 2B. The published data include those from Motov 2017 (Motov
S. et al., Ann Emerg Med. 2017 August; 70(2):177-184), Motov 2019
(Motov S. et al., Am J Emerg Med, 2019 February; 37(2):220-227),
and the drug label of Spravato.RTM. esketamine (intranasal
ketamine).
TABLE-US-00003 TABLE 2A Sedation Measurement Scores - RASS Score
Description +4 Combative +3 Very agitated +2 Agitated +1 Restless 0
Alert and calm -1 Drowsy -2 Light sedation -3 Moderate sedation -4
Deep sedation -5 Unarousable sedation
TABLE-US-00004 TABLE 2B Sedation Measurement Scores - MOAA/S Score
Description 5 Responds readily to name spoken in normal tone 4
Lethargic response to name spoken in normal tone 3 Responds only
after name is called loudly and/or repeatedly 2 Responds only after
mild prodding or shaking 1 Responds only after painful trapezius
squeeze 0 No response after painful trapezius squeeze
[0199] The results are shown in FIG. 2, along with control data
from the publications. Only 8% patients who received the dual-route
ketamine and aspirin had any sedation side effect, and only 4%
reported moderate or above sedation side effects (RASS<=-3 or
MOAA/S<=3). Such rates are considerably lower than both IV
ketamine and intranasal ketamine. Given that the dual-route
ketamine and aspirin was as efficacious as IV and intranasal
ketamine, its greatly reduced sedation side effect was truly a
surprise.
[0200] Another common side effect of ketamine is dissociation,
which was measured with a Side Effects Rating Scale of Dissociative
Anesthetics (SERSDA) scale as described in Table 3A. The results
are compared to published ones that either used the SERSDA scale or
a Clinician-Administrated Dissociative States Scale (CADSS) which
is described in Table 3B. The published data include those from
Motov 2017, Motov 2019, and the drug label of Spravato.RTM.
esketamine (intranasal ketamine).
TABLE-US-00005 TABLE 3A Dissociation Measurement Scale - SERSDA
Score Description 0 No change 1 Weak 2 Modest 3 Bothersome 4 Very
Bothersome
TABLE-US-00006 TABLE 2B Dissociation Measurement Scale - CADSS 27
questions 0-4 points each >4 increase "positive"
[0201] The results are shown in FIG. 3, along with control data
from the publications. Only 4% patients who received the dual-route
ketamine and aspirin had any dissociation side effect (SERSDA
Unreality; *CADSS >4 pt incurrence), and none (0%) reported
significant dissociation side effects (SERSDA Unreality: Bothersome
+; *CADSS >10 pt incurrence). Such rates are considerably lower
than both IV ketamine and intranasal ketamine. Given that the
dual-route ketamine and aspirin was as efficacious as IV and
intranasal ketamine, its greatly reduced dissociation side effect
was again truly a surprise.
EXAMPLE 6
[0202] This example provides the results of additional clinical
testing of various compositions of the instant disclosure, in terms
of their pain reduction efficacy and associated adverse
effects.
[0203] This new study was an extension of the study in Example 5,
at the same site, also with patients with acute musculoskeletal
pain in the ER (e.g., acute back pain, or a wrist fracture). The
tested formulations are described below.
[0204] In a first analysis, data collected from only patients
having fractures were analyzed. They were divided into an
aspirin/ketamine (Any ASA/KET) group (N=11) and a dual-route
(intraoral and oral) ketamine (Dual Route KET) group (N=4).
Primarily, the safety endpoint was examined defined as any SERSDA
scores of 3 or higher (i.e., moderately or severely "bothersome").
As shown in FIG. 4, none of the patients that received both aspirin
and ketamine (Any ASA/KET) had any moderate or severe adverse
events, while 25% of the patients receiving dual-route ketamine
(Dual Route KET) had adverse events.
[0205] The aspirin/ketamine group was further divided, into a dual
route aspirin +dual route ketamine (Dual Route A/K) arm and an oral
aspirin +oral ketamine (Oral A/K) arm. In this comparison, all
adverse events of SERSDA2+were examined. As shown in FIG. 5, the
Oral A/T arm had significantly higher (65% more) SERSDA2+ events
than the Dual Route A/K arm.
[0206] In the second analysis, also only with patients having
fractures, patients with any combination of ASA/KET (Any ASA/KET)
were compared to patients that received dual-route (intraoral and
oral) ketamine (Dual Route KET). As shown in FIG. 6, the pain
reduction efficacy of the ASA/KET combination was about 36% higher
than the Dual Route KET arm. When the ASA/KET group was divided
into two subgroups (i.e., Dual Route A/K and oral aspirin+oral
ketamine (Oral A/K)), both subgroups outperformed dual-route
ketamine (FIG. 7).
[0207] In the third analysis, patients that received oral aspirin
and oral ketamine (Oral A/K, N=25) were compared to those who
received Dual Route A/K (N=10). None of the patients experienced
SERSDA3+. The comparison of SERSDA2+0l events is shown in FIG. 8,
which shows that 65% more ASA/KET patients had adverse events than
Dual Route A/K patients.
[0208] In terms of pain reduction, Dual Route A/K patients had 42%
more pain reduction, 3.84 vs. 2.7, as shown in FIG. 9. Also, in
terms of time to onset (50% of pain reduction), the Dual Route A/K
arm experienced much quicker pain relief, 23 minutes vs. 60
minutes, as shown FIG. 10.
[0209] It will be apparent to those skilled in the art that various
modifications and variations can be made in the methods and
compositions of the present invention without departing from the
spirit or scope of the invention. Thus, it is intended that the
present invention cover the modifications and variations of this
invention provided they come within the scope of the appended
claims and their equivalents.
* * * * *