U.S. patent application number 16/899353 was filed with the patent office on 2020-09-24 for pharmaceutical compositions and methods for anesthesiological applications.
The applicant listed for this patent is Melt Pharmaceuticals, Inc.. Invention is credited to Dennis Elias Saadeh.
Application Number | 20200297734 16/899353 |
Document ID | / |
Family ID | 1000004927052 |
Filed Date | 2020-09-24 |
![](/patent/app/20200297734/US20200297734A1-20200924-C00001.png)
United States Patent
Application |
20200297734 |
Kind Code |
A1 |
Saadeh; Dennis Elias |
September 24, 2020 |
PHARMACEUTICAL COMPOSITIONS AND METHODS FOR ANESTHESIOLOGICAL
APPLICATIONS
Abstract
Pharmaceutical compositions and methods for inducing conscious
sedation using such compositions are described, the compositions
including a benzodiazepine-based compound, an NMDA antagonist, and
optionally a .beta.-blocker, antiemetic, an NSAID, and/or an
antihistamine medication. Compositions may be incorporated into
vehicles for extended release. Methods for fabricating the
compositions and using them for anesthesiological applications are
also described.
Inventors: |
Saadeh; Dennis Elias;
(Brentwood, TN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Melt Pharmaceuticals, Inc. |
San Diego |
CA |
US |
|
|
Family ID: |
1000004927052 |
Appl. No.: |
16/899353 |
Filed: |
June 11, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16250450 |
Jan 17, 2019 |
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16899353 |
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15995875 |
Jun 1, 2018 |
10391102 |
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16250450 |
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15903529 |
Feb 23, 2018 |
10166240 |
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15995875 |
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15184768 |
Jun 16, 2016 |
9918993 |
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15903529 |
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15903615 |
Feb 23, 2018 |
10179136 |
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15995875 |
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15184768 |
Jun 16, 2016 |
9918993 |
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15903615 |
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62182130 |
Jun 19, 2015 |
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62182130 |
Jun 19, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/4178 20130101;
A61K 31/551 20130101; A61K 31/138 20130101; A61K 47/38 20130101;
A61K 31/135 20130101 |
International
Class: |
A61K 31/551 20060101
A61K031/551; A61K 31/135 20060101 A61K031/135; A61K 31/138 20060101
A61K031/138; A61K 31/4178 20060101 A61K031/4178; A61K 47/38
20060101 A61K047/38 |
Claims
1. A pharmaceutical composition, comprising a therapeutically
effective quantity of a pharmaceutical formulation incorporated
into a vehicle, wherein the pharmaceutical composition comprises:
(a) a therapeutically effective quantity of at least one
pharmaceutically active compound of a first class or at least one
pharmaceutically active compound of a second class; (b) a
therapeutically effective quantity of a pharmaceutically active
compound of a third class selected from the group consisting of
.beta.-blockers, antiemetic medicaments, NSAIDs, antihistamines,
.alpha.-2-adrenergic agonists, pain relievers and combinations
thereof, or pharmaceutically acceptable salts, hydrates, solvates
or N-oxides thereof; and (c) optionally, a pharmaceutically
acceptable excipient, wherein: (i) the pharmaceutically active
compound of the first class is selected from the group consisting
of midazolam, diazepam, lorazepam, flunitrazepam, alprazolam,
chlordiazepoxide, clonazepam and clorazepate, and pharmaceutically
acceptable salts, hydrates, solvates or N-oxides thereof,
optionally in combination with a non-benzodiazepine compound
selected from the group consisting of eszopiclone, ramelteon,
zolpidem, and zaleplon; and (ii) the pharmaceutically active
compound of the second class is selected from the group consisting
of ketamine, dextrorphan, etomidate, methadone, memantine,
amantadine, dextromethorphan, and pharmaceutically acceptable
salts, hydrates, solvates or N-oxides thereof; with the proviso
that the vehicle is optionally configured to provide extended
release of the pharmaceutical formulation and is selected from the
group consisting of extended release capsules ensconcing the
pharmaceutical formulation and a matrix polymer structure holding
the pharmaceutical formulation that is embedded into the matrix;
and with the further proviso that when the pharmaceutical
composition includes the pharmaceutically active compounds of the
first class, any pharmaceutically active compounds of the second
class are absent from the composition, or when the pharmaceutical
composition includes the pharmaceutically active compounds of the
second class, any pharmaceutically active compounds of the first
class are absent from the composition.
2. The pharmaceutical composition of claim 1, wherein the
antiemetic medicament is selected from the group consisting of
ondansetron, dolasetron, granisetron, palonosetron, promethazine,
imenhydrinate, and meclizine.
3. The pharmaceutical composition of claim 1, wherein the
.beta.-blocker, the .alpha.-2-adrenergic agonist or the pain
reliever is selected from the group consisting of metoprolol,
propranolol, acebutolol, nadolol, atenolol, betaxolol, esmolol,
bisoprolol fumarate, carvedilol, nebivolol, penbutolol, timolol,
sotalol, dexmedetomidine hydrochloride, and acetaminophen.
4. The pharmaceutical composition of claim 1, wherein the NSAID is
selected from the group consisting of bromfenac, ketorolac,
etodolac, sulindac, diclofenac, aceclofenac, nepafenac, tolmetin,
indomethacin, nabumetone, ketoprofen, dexketoprofen, ibuprofen,
flurbiprofen, dexibuprofen, fenoprofen, loxoprofen, oxaprozin,
naproxen, aspirin, salicylic acid, diflunisal, salsalate, mefenamic
acid, meclofenamic acid, flufenamic acid, tolfenamic acid,
meloxicam, piroxicam, ternoxicam, droxicam, lornoxicam, isoxicam,
celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib,
etoricoxib, firocoxib, nimesulide, clonixin, and licofelone.
5. The pharmaceutical composition of claim 1, wherein the
antihistamine is selected from the group consisting of hydroxyzine
pamoate, hydroxyzine hydrochloride, diphenhydramine hydrochloride,
meclizine, chlorpheniramine, clemastine, promethazine, and
prochlorperazine.
6. The pharmaceutical composition of claim 1, wherein the
pharmaceutical formulation further comprises a therapeutically
effective quantity of a receptor antagonist to benzodiazepines.
7. The pharmaceutical composition of claim 6, wherein the receptor
antagonist is flumazenil.
8. The pharmaceutical composition of claim 1, wherein the
pharmaceutically active compound of the first class is midazolam,
the pharmaceutically active compound of the second class is
ketamine and the pharmaceutically active compound of the third
class is metoprolol.
9. The pharmaceutical composition of claim 1, wherein the
pharmaceutically active compound of the first class is midazolam,
the pharmaceutically active compound of the second class is
ketamine and the pharmaceutically active compound of the third
class is ondansetron.
10. The pharmaceutical composition of claim 1, wherein the vehicle
is adapted to allow the release of the pharmaceutical formulation
in a period of time between about 12 hours and about 20 hours.
11. The pharmaceutical composition of claim 1, wherein the vehicle
comprises a polymer selected from the group consisting of esters of
cellulose, poly(lactic-co-glycolic acid), polylactic acid,
polyglycolide, dextrin, polyacetals,
poly(N-(2-hydroxypropyl)methacrylamide), polycaprolactone, and
poly-3-hydroxybutyrate.
12. The pharmaceutical composition of claim 11, wherein the esters
of cellulose are selected from the group consisting of methyl
cellulose and hydroxypropyl methyl cellulose.
13. The pharmaceutical composition of claim 1, wherein the
excipient is selected from the group consisting of gelatin, sodium
saccharin, stevioside, peppermint oil, cherry flavor, lemon oil,
raspberry flavor and combinations thereof.
14. A method for providing an extended release pharmaceutical
formulation to a patient in need thereof, the method comprising:
(a) preparing the pharmaceutical formulation of claim 1; (b)
incorporating the prepared pharmaceutical formulation into an
extended release vehicle to form an extended release formulation;
and (c) orally administering the extended release formulation to a
patient in need thereof, thereby providing the extended release
pharmaceutical formulation to the patient.
Description
CROSS REFERENCE TO RELATED APPLICATION(S)
[0001] This is a continuation-in-part patent application claiming
the benefit of priority under 35 U.S.C. .sctn. 120 to U.S. patent
application Ser. No. 16/250,450, filed Jan. 17, 2019, now pending,
which is a continuation-in-part of U.S. patent application Ser. No.
15/995,875, filed Jun. 1, 2018, now issued as U.S. Pat. No.
10,391,102, which is a continuation-in-part of U.S. patent
application Ser. No. 15/903,529, filed Feb. 23, 2018, now issued as
U.S. Pat. No. 10,166,240, which is a continuation-in-part of U.S.
patent application Ser. No. 15/184,768, filed Jun. 16, 2016, now
issued as U.S. Pat. No. 9,918,993, which in turn claims the benefit
of priority under 35 U.S.C. .sctn. 119(e) of U.S. provisional
patent application No. 62/182,130, filed Jun. 19, 2015, the entire
content of each of which is incorporated herein by reference. U.S.
patent application Ser. No. 15/995,875, filed Jun. 1, 2018, is also
a continuation-in-part claiming the benefit of priority under 35
U.S.C. .sctn. 120 to U.S. patent application Ser. No. 15/903,615,
filed Feb. 23, 2018, now issued as U.S. Pat. No. 10,179,136, which
is a continuation-in-part of Ser. No. 15/184,768, filed Jun. 16,
2016, now issued as U.S. Pat. No. 9,918,993, which claims the
benefit of priority under 35 U.S.C. .sctn. 119(e) of U.S.
provisional patent application No. 62/182,130, filed Jun. 19, 2015,
the entire content of each of which is incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] The present invention relates generally to the field of
pharmacology and more specifically to compositions having
anesthetic properties that are useful in various kinds of medical
practice, such as surgery, and to methods of preparing and using
such compositions.
BACKGROUND
[0003] The present disclosure relates to solid or liquid
pharmaceutical formulations comprising combinations of active
agents such as anesthetics, anti-emetics, blood pressure,
anti-anxiety medications and/or analgesics, and methods for using
the same for providing anesthesia by administering such
compositions orally, including such administrations as sublingual
or buccal. The formulations may also include slow release reversal
agents that would counteract the initial anesthesia effect.
[0004] It is necessary in many cases to use local anesthesia,
particularly via oral route in the course of various surgical
procedures, e.g., ophthalmic surgeries or urological interventions.
For instance, when local anesthesia is employed during or prior to
intraocular operations, the occurrences of pain, anxiety,
peri-operative stress, nausea, agitation, vomiting and the like are
less frequent, which will typically have a very beneficial effect
on the surgical experience and reducing the number of intraocular
complications such as bleeding, secretions, cardiac and/or
pulmonary complications, etc. The severity of those complications
when they do occur will also be less pronounced when local
anesthesia is used.
[0005] Traditionally, an intravenous route is used to administer
medications. Alternatives to intravenous methods and therapies have
been suggested and previously used for the treatment. In
particular, oral administration of benzodiazepines, opioid
analgesics, propofol, ketamine or etomidate utilizing the MAC
procedure (monitored anesthesia care) has been suggested and tried,
but no more than minimal to moderate improvement has been achieved
by such methods. Therefore, there remains a need for better
treatments of these disorders.
[0006] This patent specification discloses such pharmaceutical
compositions suitable for anesthesiological applications that can
achieve positive patient outcomes while free of drawbacks and
deficiencies of existing methods and formulations. Methods of
fabricating and administering the same are also discussed.
SUMMARY
[0007] According to one embodiment of the invention, there are
provided pharmaceutical compositions. The compositions include a
therapeutically effective quantity of at least one pharmaceutically
active compound of the first class comprising benzodiazepine moiety
or pharmaceutically acceptable salts, hydrates, solvates or
N-oxides thereof, a therapeutically effective quantity of at least
one pharmaceutically active compound of the second class that is an
NMDA antagonist or pharmaceutically acceptable salts, hydrates,
solvates or N-oxides thereof, and at least one pharmaceutically
acceptable excipient or carrier therefor.
[0008] According to another embodiment of the invention, the
pharmaceutical compositions described above may further include a
therapeutically effective quantity of at least one pharmaceutically
active compound of the third class that is a .beta.-blocker, a
nonsteroidal anti-inflammatory drug (NSAID), or an antiemetic
medicament, or a combination thereof, or pharmaceutically
acceptable salts, hydrates, solvates or N-oxides thereof.
[0009] According to further embodiments of the invention, in the
pharmaceutical compositions described above, the pharmaceutically
active compound of the first class may be any of midazolam,
diazepam, lorazepam, flunitrazepam, alprazolam, chlordiazepoxide,
clonazepam or clorazepate, the pharmaceutically active compound of
the second class may be any of ketamine, dextrorphan, etomidate,
methadone, memantine, amantadine or dextromethorphan and the
pharmaceutically active compound of the third class may be (if a
.beta.-blocker) any of metoprolol, propranolol, acebutolol,
nadolol, atenolol, betaxolol, esmolol, bisoprolol fumarate,
carvedilol, nebivolol, penbutolol, timolol, or sotalol or (if an
antiemetic) ondansetron, dolasetron, granisetron, palonosetron,
promethazine, imenhydrinate, or meclizine.
[0010] According to yet another embodiment of the invention, there
are provided further pharmaceutical compositions such as any
described above, wherein the compositions are formulated as a
liquid or a solid item, e.g., a troche, a lozenge, a capsule, a
pill, a cap and a bolus suitable for sublingual or oral
administration.
[0011] According to other embodiments, there are provided specific
compounds for making the compositions described above, for example,
midazolam, ketamine and ondansetron, as well as methods for using
above-mentioned composition(s) for the purposes of local anesthesia
in various applications, such as ophthalmic surgery.
[0012] According to further embodiments of the invention, the
above-mentioned methods of using the composition(s) include orally
administering to a patient in need thereof (i.e., those patients
who require conscious sedation or pre-sedation) a pharmaceutical
composition described herein as the first step of a medical or
surgical procedure, the procedure being an ophthalmic surgery
(e.g., a cataract, glaucoma, corneal, eyelid surgery, or retinal
surgery), a dental procedure (e.g., a tooth extraction, an oral
surgery, or a root canal surgery), an outpatient medical procedure
(e.g., medical imaging procedure, biopsy, bone marrow harvesting,
colonoscopy, or endoscopy), a urological procedure, a laparoscopic
procedure, obstetric and gynecological procedures, a
gastrointestinal procedure, an otolaryngological procedure, a
cosmetic surgery procedure, a dermatological procedure, a podiatric
procedure, an orthopedic procedure, an emergency medical treatment,
a psychiatric treatment, or a veterinarian procedure.
DETAILED DESCRIPTION
A. Terms and Definitions
[0013] Unless specific definitions are provided, the nomenclatures
utilized in connection with, and the laboratory procedures and
techniques of analytical chemistry, synthetic organic and inorganic
chemistry described herein, are those known in the art. Standard
chemical symbols are used interchangeably with the full names
represented by such symbols. Thus, for example, the terms
"hydrogen" and "H" are understood to have identical meaning.
Standard techniques may be used for chemical syntheses, chemical
analyses, formulating compositions and testing them. The foregoing
techniques and procedures can be generally performed according to
conventional methods well known in the art.
[0014] It is to be understood that both the foregoing general
description and the following detailed description are exemplary
and explanatory only and are not restrictive of the invention
claimed. As used herein, the use of the singular includes the
plural unless specifically stated otherwise. The section headings
used herein are for organizational purposes only and are not to be
construed as limiting the subject matter described.
[0015] As used herein, "or" means "and/or" unless stated otherwise.
Furthermore, use of the term "including" as well as other forms,
such as "includes," and "included," is not limiting.
[0016] "About" as used herein means that a number referred to as
"about" comprises the recited number plus or minus 1-10% of that
recited number. For example, "about" 100 degrees can mean 95-105
degrees or as few as 99-101 degrees depending on the context.
Whenever it appears herein, a numerical range such as "1 to 20"
refers to each integer in the given range; i.e., meaning only 1,
only 2, only 3, etc., up to and including only 20.
[0017] The term "pharmaceutical composition" is defined as a
chemical or biological compound or substance, or a mixture or
combination of two or more such compounds or substances, intended
for use in the medical diagnosis, cure, treatment, or prevention of
disease or pathology.
[0018] The terms "anesthetic," "anesthesia," "anesthesiology" and
the like refer herein to substances, compounds, processes or
procedures that induce insensitivity to pain such as a temporary
loss of sensation.
[0019] The term "conscious sedation," which for the purposes of
this application, may be used interchangeably with terms
"procedural sedation" and "analgesia" is used herein to refer to an
induced state of sedation characterized by a minimally depressed
consciousness such that the patient is able to continuously and
independently maintain a patent airway, retain protective reflexes,
and remain responsive to verbal cues and/or tactile or physical
stimulation.
[0020] Conscious sedation is typically performed/induced to
decrease the level of anxiety in a patient and to elicit an
improved degree of cooperation from the patient prior to or during
a procedure. Conscious sedation, therefore, refers to a condition
that is medically different and distinct from deep sedation which
is the next level of sedation defined as depression of
consciousness when the patient's ability to independently maintain
ventilatory function may be impaired and he or she cannot be easily
aroused; however, the patient will still purposefully respond to
repeated or painful stimulation.
[0021] Conscious sedation is also clearly distinguishable for the
purposes of the present application from the lower level of
sedation (i.e., minimal sedation when the patient is able to
maintain a normal response to verbal stimuli) as well as the
highest level of sedation (i.e., general anesthesia when there is
no response from the patient even with painful stimulus).
[0022] The term "pre-sedation" is defined for the purposes of this
application as conscious sedation that is induced some time before
a procedure, e.g., between about 5 minutes and about 1 hour
prior.
[0023] The terms "solvate" and "hydrate" are used herein to
indicate that a compound or substance is physically or chemically
associated with a solvent for "solvates" such as water (for
"hydrates").
[0024] The term "NMDA antagonist" is defined as a compound that
inhibits ("antagonizes") the action of the N-methyl-D-aspartate
receptors and is inclusive of both competitive and non-competitive
antagonists, glycine antagonists and uncompetitive channel
blockers, as these terms are understood by those having ordinary
skill in the art.
[0025] The term ".beta.-blocker" refers to a compound of any kind
that can prevent or reduce the stimulation of the adrenergic
receptors responsible for increased cardiac action.
[0026] The term "antiemetic" is defined as a drug or medicament
that treats, reduces, and/or prevents nausea and/or vomiting.
[0027] The term "non-steroid anti-inflammatory drug" or "NSAID"
refers to a class of compounds that are free of any steroid
moieties yet are capable of providing analgesic, antipyretic and/or
anti-inflammatory effects.
[0028] The term "antihistamine medicament" refers to any compound
that is capable of inhibiting or counteracting the physiological
effects of histamine.
[0029] The term "polyglycol" is defined as a polymer or oligomer
containing several ether-glycol linkages that yields one or more
glycols when these linkages are cleaved, e.g., by hydrolysis.
[0030] The term "carrier" refers to a substance that serves as a
vehicle for improving the efficiency of delivery and the
effectiveness of a pharmaceutical composition.
[0031] The term "excipient" refers to a pharmacologically inactive
substance that is formulated in combination with the
pharmacologically active ingredient of pharmaceutical composition
and is inclusive of bulking agents, fillers, diluents and products
used for facilitating drug absorption or solubility or for other
pharmacokinetic considerations.
[0032] The term "binder" refers to a substance or compound that
promotes, provides or improves cohesion, i.e., a substance that
causes the components of a mixture to cohere to form a solid item
that possesses integrity.
[0033] The term "troche" refers to a small tablet or lozenge (i.e.,
a medicated candy intended to be dissolved in the mouth), typically
in a form of a disk, a ball or rhombic in cross-section, comprising
medication and processed into a paste and dried.
[0034] The term "therapeutically effective amount" is defined as
the amount of a compound or pharmaceutical composition that will
elicit the biological or medical response of a tissue, system,
animal or human that is being sought by the researcher, medical
doctor or other clinician.
[0035] The term "pharmaceutically acceptable" when used in the
context of a carrier, diluent or excipient, refers to a substance
that is compatible with the other ingredients of the formulation
and not deleterious to the recipient thereof.
[0036] The terms "administration of a composition" or
"administering a composition" is defined to include an act of
providing a compound of the invention or pharmaceutical composition
to the subject in need of treatment.
[0037] The terms "oral administration" and "orally administering"
are broadly defined as a route of administration where a medication
is taken through the mouth including "sublingual administration"
and "buccal administration" where the medication is placed under
the tongue or between the gums and the cheek, respectively, to be
absorbed by the body, or to be administered sublingually or
buccally as a liquid.
B. Embodiments of the Invention
[0038] According to embodiments of the present invention, there are
provided pharmaceutical compositions for anesthetic purposes. The
compositions comprise, consist of or consist essentially of, a
combination of therapeutically effective quantities of at least one
pharmaceutically active compound of the first class and at least
one pharmaceutically active compound of the second class. In some
further embodiments, the compositions optionally comprise, in
addition to the above-mentioned pharmaceutically active compounds
of the first and second classes, at least pharmaceutically active
compound of the third class.
[0039] The pharmaceutically active compound of the first class that
is used in such composition comprises a benzodiazepine moiety or
pharmaceutically acceptable salts, hydrates, solvates or N-oxides
thereof. Those having ordinary skill in the art will know that
benzodiazepine moiety is a structure where a benzene ring is
condensed with diazepine ring, a seven-member heterocycle with two
nitrogen atoms which for the purposes of this specification may be
in any positions of the ring (e.g., 1,2-diazepine, 1,3-diazepine or
1,4-diazepine). An example of a compound having benzodiazepine
moiety with 1,4-diazepine structure is shown below:
##STR00001##
[0040] One particular pharmaceutically active compound of the first
class comprising a benzodiazepine moiety that can be used in
pharmaceutical compositions described and claimed herein is
midazolam. Other specific, non-limiting examples of
pharmaceutically active compounds of the first class comprising
benzodiazepine moiety that can be used include diazepam, lorazepam,
flunitrazepam, alprazolam, chlordiazepoxide, clonazepam, clobazam,
bromazepam, prazepam, oxazepam and clorazepate. Each of these is
also known under one or several trade names as shown in Table 1,
which also discloses chemical names of such compounds. Those having
ordinary skill in the art can select alternative suitable
benzodiazepine-based compound for using in the compositions, if so
desired.
TABLE-US-00001 TABLE 1 Examples of Benzodiazepine-Based Compounds
That Can Be Used in Compositions Compound Chemical Name (IUPAC)
Trade Name(s) Midazolam 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-
VERSED .RTM., DORMICUM .RTM., imidazo[1,5-a][1,4]benzodiazepine
HYPNOVEL .RTM. Diazepam 7-chloro-1-methyl-5-phenyl-3H-1,4- VALIUM
.RTM., DIASTAT .RTM. benzodiazepin-2-one Lorazepam
7-chloro-5-(2-chlorophenyl)-3-hydroxy- TEMESTA .RTM., ATIVAN .RTM.,
1,3-dihydro-2H-1,4-benzodiazepin-2-one ORFIDAL .RTM. Flunitrazepam
5-(2-fluorophenyl)-1-methyl-7-nitro-1H- ROHYPNOL .RTM., NARCOZEP
.RTM. benzo[e][1,4]diazepin-2(3H)-one and many others Alprazolam
8-chloro-1-methyl-6-phenyl-4H- XANAX .RTM.
[1,2,4]triazolo[4,3-a][1,4]benzodiazepine Chlordiazepoxide
7-chloro-2-methylamino-5-phenyl-3H-1,4- LIBRIUM .RTM.
benzodiazepine-4-oxide Clonazepam
5-(2-chlorophenyl)-7-nitro-2,3-dihydro- KLONOPIN .RTM., RIVOTRIL
.RTM. 1,4-benzodiazepin-2-one and many others Clorazepate
7-chloro-2,3-dihydro-2-oxo-5-phenyl- TRANXENE .RTM.
1H-1,4-benzodiazepine-3-carboxylic acid Bromazepam
7-bromo-5-(pyridin-2-yl)-1H- LEXOTAN .RTM., LEXOTANIL .RTM.
benzo[e][1,4]diazepin-2(3H)-one and many others Oxazepam
7-chloro-3-hydroxy-5-phenyl-2,3-dihydro- ALEPAM .RTM., SERAX .RTM.
1H-1,4-benzodiazepine-2-one and many others Clobazam
7-chloro-1-methyl-5-phenyl-1,5- URBANOL .RTM., FRISIUM .RTM.,
benzodiazepine-2,4(3H)-dione ONFI .RTM. Prazepam
7-chloro-1-(cyclopropylmethyl)-5-phenyl- LYSANXIA .RTM., CENTRAX
.RTM. 1,3-dihydro-2H-1,4-benzodiazepin-2-one and many others
[0041] The therapeutically effective quantity of the
benzodiazepine-based compound(s) in the entire pharmaceutical
composition can be between about 0.2 mass % and about 5.0 mass % of
the composition. In some embodiments, the therapeutically effective
amount of the benzodiazepine-based compound(s) can be between about
1.0 mass % and about 3.0 mass %, for example, about 2.5 mass % of
the composition.
[0042] In some applications a patient may be extra sensitive to
benzodiazepines (e.g., may become excessively drowsy). For such
patients, there are provided additional embodiments of the
composition in which benzodiazepine(s)-containing pharmaceutical
compositions described above, would additionally include a quantity
of a receptor antagonist to benzodiazepines. Such a receptor
antagonist would begin counteracting the effect of benzodiazepine
after the surgical procedure is complete, in essence providing a
slow release feature. A non-limiting example of this antagonist is
flumazenil also known under trade names such as ANEXATE.RTM.,
ROMAZICON.RTM. and others. The use of antagonists is also
envisioned as a routine practice (i.e., not just for sensitive
patients), for example, in situations when a larger than typical or
usual dosage of benzodiazepines is medically indicated, or
recommended, or necessary. In some further applications,
benzodiazepine-based compounds may be used in combination with
non-benzodiazepine based sedatives such as eszopiclone, ramelteon,
zolpidem, or zaleplon.
[0043] The pharmaceutically active compound of the second class
that is used in such compositions is an NMDA antagonist, as defined
hereinabove, or pharmaceutically acceptable salts, hydrates,
solvates or N-oxides thereof. One particular pharmaceutically
active compound of the second class that can be used in the
pharmaceutical compositions described and claimed herein is
ketamine. Other specific, non-limiting examples of NMDA antagonists
that can be used include dextrorphan, etomidate, methadone,
memantine, amantadine and dextromethorphan. Each of these is also
known under one or several trade names as shown in Table 2, which
also discloses chemical names of such compounds. Those having
ordinary skill in the art can select alternative suitable NMDA
antagonists for using in the compositions, if so desired.
TABLE-US-00002 TABLE 2 Examples of NMDA Antagonists That Can Be
Used in Compositions Compound Chemical Name (IUPAC) Trade Name(s)
Ketamine 2-(2-chlorophenyl)-2-(methylamino)cyclohexanone KETANEST
.RTM., KETASET .RTM., KETALAR .RTM. (HCl salt) Dextrorphan
17-methyl-9a,13a,14a-morphinan-3-ol None Etomidate
Ethyl-3-[(1R)-1-phenylethyl]imidazole-5-carboxylate AMIDATE .RTM.,
HYPNOMIDATE .RTM. Methadone
6-(dimethylamino)-4,4-diphenylheptan-3-one DOLOPHINE .RTM., AMIDONE
.RTM. and others Memantine 3,5-dimethyladamantan-1-amine AKATINOL
.RTM., NAMENDA .RTM. and others Amantadine Adamantan-1-amine
SYMMETREL .RTM. Dextromethorphan
(4bS,8aR,9S)-3-methoxy-11-methyl-6,7,8,8a,9,10- ROBITUSSIN .RTM.,
hexahydro-5H-9,4b-(epiminoethano)phenanthrene DELSYM .RTM. and
others
[0044] The therapeutically effective quantity of the NMDA
antagonist(s) in the entire pharmaceutical composition can be
between about 1.0 mass % and about 10.0 mass % of the composition.
In some embodiments, the therapeutically effective amount of the
NMDA antagonist(s) can be between about 4.0 mass % and about 6.0
mass %, for example, about 5.0 mass % of the composition.
Accordingly, in various embodiments, the combined quantities of
both the benzodiazepine-based compound(s) and the NMDA
antagonist(s), taken together, in the entire pharmaceutical
composition can be between about 1.2 mass % and about 15.0 mass %
of the composition, such as between about 3.0 mass % and about 12.0
mass %, for example, about 10.0 mass % of the composition.
[0045] As mentioned above, the compositions may further optionally
include at least one pharmaceutically active compound of the third
class. In such embodiments, the pharmaceutically active compound of
the third class is a .beta.-blocker, as defined hereinabove, or
pharmaceutically acceptable salts, hydrates, solvates or N-oxides
thereof, or alternatively, and .alpha.-2-adrenergic agonist or, as
another alternative, a pain reliever. In addition to, or instead
of, .beta.-blockers, the pharmaceutically active compound of the
third class may also include an antiemetic medicament, as defined
hereinabove, or pharmaceutically acceptable salts, hydrates,
solvates or N-oxides thereof.
[0046] In yet another aspect, the pharmaceutically active compound
of the third class may include one or several non-steroid
anti-inflammatory drug(s) (NSAIDs), as defined hereinabove.
NSAID(s) may be so used in addition to, or instead of,
.beta.-blocker(s), and/or antiemetic(s). In a further aspect, the
pharmaceutically active compound of the third class may also
include an antihistamine medicament, as defined hereinabove.
Non-limiting examples of specific antihistamine medicaments that
can be so used include, but are not limited to, any of hydroxyzine
pamoate, hydroxyzine hydrochloride, diphenhydramine hydrochloride,
meclizine, chlorpheniramine, clemastine, promethazine, or
prochlorperazine, or any combination thereof. Again, antihistamine
medicaments may be used in addition to, or instead of, any of the
above-mentioned compounds that may be used as the third
pharmaceutically active compound.
[0047] The therapeutically effective quantity of the third
pharmaceutically active compound(s) in the entire pharmaceutical
composition can be between about 0.1 mass % and about 5.0 mass % of
the composition. In some embodiments, the therapeutic effective
amount of the third pharmaceutically active compound(s) can be
between about 1.0 mass % and about 4.0 mass %, for example, about
2.5 mass % of the composition.
[0048] One particular .beta.-blocker that can be used as the
pharmaceutically active compound of the third class in
pharmaceutical compositions described and claimed herein is
metoprolol. Other specific, non-limiting examples of
.beta.-blockers or .alpha.-2-adrenergic agonists or pain relievers
that can be used include, propranolol, acebutolol, nadolol,
atenolol, betaxolol, esmolol, bisoprolol fumarate, carvedilol,
nebivolol, penbutolol, timolol, sotalol, dexmedetomidine
hydrochloride, and acetaminophen. Each of these is also known under
one or several trade names as shown in Table 3, which also
discloses chemical names of such compounds. Those having ordinary
skill in the art can select alternative suitable .beta.-blockers
for using in the compositions, if so desired.
TABLE-US-00003 TABLE 3 Examples of .beta.-Blockers That Can Be Used
in Compositions Compound Chemical Name (IUPAC) Trade Name(s)
Metoprolol
1-(isopropylamino)-3-[4-(2-methoxyethyl)phenoxy]propan-2-ol
LOPRESSOR .RTM., TOPROL .RTM. Propranolol
1-(1-methylethylamino)-3-(1-naphthyloxy)propan-2-ol CIPLA .RTM.,
INDERAL .RTM. and many others Acebutolol
N-{3-acetyl-4-[2-hydroxy-3-(propan-2-ylamino) SECTRAL .RTM.,
propoxy]phenyl}butanamide PRENT .RTM. Nadolol
5-{[3-(tert-butylamino)-2-hydroxypropyl]oxy}-1,2,3,4- CORGARD .RTM.
tetrahydronaphthalene-2,3-diol Atenolol
2-{4-[2-hydroxy-3-(propan-2-ylamino)propoxy] TENORMIN .RTM.
phenyl}acetamide Betaxolol
1-{4-[2-(cyclopropylmethoxy)ethyl]-phenoxy}-3- KERLONE .RTM.,
(isopropylamino)propan-2-ol BETOPTIC .RTM. and others Esmolol
3-{4-[2-hydroxy-3-(propan-2-ylamino)propoxy] BREVIBLOC .RTM.
phenyl}propanoate Bisoprolol
1-[4-[[2-(1-methylethoxy)ethoxy]methyl]phenoxy]-3[(1- ZEBETA .RTM.
fumarate methylethyl)amino]-2-propanol-2-butenedioate Carvedilol
3-(9H-carbazol-4-yloxy)-2-hydroxypropyl-2-(2- COREG .RTM.,
methoxyphenoxy)ethylamine CARVIL .RTM. and many other Nebivolol
2,2'-azanediylbis(1-(6-fluorochroman-2-yl)ethanol) NEBILET .RTM.,
BYSTOLIC .RTM. Penbutolol
1-(tert-butylamino)-3-(2-cyclopentylphenoxy)propan-2-ol LEVATOL
.RTM., LEVATOLOL .RTM. and many others Timolol
1-(tert-butylamino)-3-[(4-morpholin-4-yl-1,2,5-thiadiazol-3-
TIMOPTIC .RTM., yl)oxy]propan-2-ol BETIMOL .RTM. and many others
Sotalol N-{4-[1-hydroxy-2-(propan-2-ylamino)ethyl]phenyl} BETAPACE
.RTM. methanesulfonamide and others
[0049] One particular antiemetic that can be used as the
pharmaceutically active compound of the third class in
pharmaceutical compositions described and claimed herein is
ondansetron. Other specific, non-limiting examples of antiemetics
that can be used include dolasetron, granisetron, palonosetron,
promethazine, imenhydrinate, and meclizine. Each of these is also
known under one or several trade names as shown in Table 4, which
also discloses chemical names of such compounds. Those having
ordinary skill in the art can select alternative suitable
antiemetics for using in the compositions, if so desired.
TABLE-US-00004 TABLE 4 Examples of Antiemetics That Can Be Used in
Compositions Compound Chemical Name (IUPAC) Trade Name(s)
Ondansetron
(RS)-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-2,3- ZOFRAN
.RTM., dihydro-1H-carbazol-4(9H)-one ONDISOLV .RTM. Dolasetron
(2.alpha.,6.alpha.,8.alpha.,9.alpha..beta.)-octahydro-3-oxo-2,6-
-methano-2H-quinolizin- ANZEMET .RTM. 8-yl-1H-indole-3-carboxylate
monomethanesulfonate, monohydrate Granisetron
1-methyl-N-((1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3- KYTRIL
.RTM. yl)-1H-indazole-3-carboxamide Palonosetron
(3aS)-2-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-2,3,3a,4,5,6- ALOXI
.RTM. hexahydro-1H-benz[de]isoquinolin-1-one Promethazine
(RS)-N,N-dimethyl-1-(10H-phenothiazin-10-yl)propan-2- PHENERGAN
.RTM. amine Dimenhydrinate 2-benzhydryloxy-N,N-dimethylethanamine;
8-chloro-1,3- DRAMAMINE .RTM., dimethyl-7H-purine-2,6-dione GRAVOL
.RTM., VOMEX .RTM., many others Meclizine
(RS)-1-[(4-chlorophenyl)(phenyl)methyl]-4-(3- BONINE .RTM.,
methylbenzyl)piperazine BONAMINE .RTM., ANTIVERT .RTM., many
others
[0050] Therefore, in various embodiments, the combined quantities
of all the pharmaceutically active compounds (i.e., the
benzodiazepine-based compound(s), the NMDA antagonist(s), the
.beta.-blocker(s)), and/or the antiemetic(s) taken together, in the
entire pharmaceutical composition can be between about 1.3 mass %
and about 20.0 mass % of the composition, such as between about 3.0
mass % and about 12.0 mass %, for example, about 10.0 mass % of the
composition. Those having ordinary skill in the art will determine
the most appropriate quantities of each the pharmaceutically active
compound that are within the above-mentioned ranges and that are
most suitable for a particular patient. As a non-limiting guideline
only, the following mass ratios between the pharmaceutically active
compounds may be used (Table 5) for compositions where the
benzodiazepine-based compound is midazolam, the NMDA antagonist is
ketamine hydrochloride and the .beta.-blocker is propranolol
hydrochloride:
TABLE-US-00005 TABLE 5 Exemplary Mass Ratios between Midazolam,
Ketamine Hydrochloride and Propanolol Hydrochloride in the
Compositions Ketamine Propanolol Ratios Midazolam Hydrochloride
Hydrochloride Between about 1 2 1 and about 1 10 1 Such as between
about 1 4 1 and about 1 6 1 For example 1 5 1
[0051] In one specific embodiment, which is exemplary and
non-limiting, for the composition having midozalam as the
pharmaceutically active compound of the first class, ketamine as
the pharmaceutically active compound of the second class and
ondansetron at the third pharmaceutically active compound, the mass
midazolam:ketamine:odansetron ratio may be about 3:25:2.
[0052] The pharmaceutical compositions described herein may contain
not only pharmaceutically active components but also, in some
embodiments, may further include one or several inactive, neutral
compounds which can be pharmaceutically acceptable excipient(s) or
carrier(s), including, but not limited to, binder(s),
antioxidant(s), adjuvant(s), synergist(s) and/or preservative(s).
The mass concentration of such inactive compounds can be between
about 80 mass % and about 99 mass % of the entire pharmaceutical
composition, such as between about 85 mass % and about 95 mass %,
e.g., about 90 mass %.
[0053] Some embodiments of the invention are directed to
pharmaceutical formulations that are formulated as solid articles
suitable for sublingual or oral administration, such as troches,
lozenges, capsules, pills, caps or boluses. These solid
compositions typically comprise binder(s) and/or excipient(s). They
can be prepared by first mixing the pharmaceutically active
compounds described above with suitable binder(s) and/or
excipient(s) followed by molding or compressing the blend. Both
hard and chewable lozenges and troches are within the scope of the
invention.
[0054] Typical binder(s) that can be used for fabricating solid
articles mentioned above include, without limitation, polyglycols
as defined above, such as, e.g., polyethylene glycols (PEGs),
polyethylene oxides (POE), methoxypolyethylene glycols,
polypropylene glycols, polybutylene glycols or derivatives thereof
having a molecular weight that is sufficient to provide the
necessary hardness and time for dissolution of the troche; for
example, the acceptable molecular weight can be within the range of
between about 1,000 Daltons and about 8,000 Daltons. In some
embodiments PEG-1450 or PEG-400 can be used. Non-limiting examples
of some specific polyglycol derivatives that can be used are:
[0055] (a) PEG-laureates and dilaureates (e.g., PEG-10-, PEG-12-,
PEG-20-, PEG-32-laurates, PEG-20- and PEG-32-dilaurates,
PEG-20-glyceryl-, PEG-30-glyceryl- and PEG-40-glyceryl-laurates,
PEG-80-sorbitan laurate);
[0056] (b) PEG-oleates, dioleates and trioleates (e.g., PEG-12-,
PEG-15-, PEG-20-, PEG-32, PEG-200- and PEG-400-oleates, PEG-20- and
PEG-32-dioleates, PEG-20-trioleate, PEG-25-glyceryl trioleate,
PEG-20-glyceryl- and PEG-30-glyceryl-oleates, PEG-40-sorbitan
oleate);
[0057] (c) PEG-stearates and distearates (e.g., PEG-15-, PEG-40-,
PEG-100-stearates, PEG-32-distearate and PEG-20-glyceryl
stearate);
[0058] (d) castor, palm kernel, corn and soya oil derivatives of
PEG (e.g., PEG-35-, PEG-40- and PEG-60-castor oils, PEG-40-,
PEG-50- and PEG-60-hydrogenated castor oils, PEG-40-palm kernel
oil, PEG-60-corn oil, PEG-30-soya sterol);
[0059] (e) other PEG derivatives (e.g., PEG-24- and
PEG-30-cholesterol, PEG-25-phytosterol, PEG-6- and
PEG-8-caprate/caprylate glycerides, tocopheryl PEG-100 succinate,
PEG-15-100 octylphenol products and PEG-10-100 nonylphenol
products);
[0060] (f) other products such as polyglyceryl-10-laurate, POE-9-
and POE-23-lauryl ethers, POE-10- and POE-20-oleyl ethers,
POE-20-stearyl ether, polysorbates-20 and 80,
polyglyceryl-10-oleate, Tween 40, Tween 60, sucrose monostearate,
monolaurate and monopalmitate and various products of Poloxamer
series.
[0061] Typical excipient(s) that can be used for fabricating solid
articles mentioned above include, without limitation, gelatin,
sodium saccharin, stevioside, peppermint oil, or any natural or
artificial fruit, vegetable, flower, beverage or candy flavor.
[0062] As stated above, the compositions may optionally further
include one or several antioxidant(s). If antioxidant(s) are used,
non-limiting examples of those that can be used include
.alpha.-tocopherol acetate, acetone sodium bisulfite,
acetylcysteine, ascorbic acid, ascorbyl palmitate, butylated
hydroxyanisole, butylated hydroxytoluene, cysteine, cysteine
hydrochloride, tocopherol natural, tocopherol synthetic,
dithiothreitol, monothioglycerol, nordihydroguaiaretic acid, propyl
gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium
metabisulfite, sodium sulfite, sodium thiosulfate, thiourea and
tocopherols.
[0063] As stated above, the compositions may optionally further
include one or several adjuvant(s) or synergists(s). If adjuvant(s)
or synergists(s) are used, non-limiting examples of those that can
be used include citric acid, EDTA (ethylenediaminetetraacetate) and
salts, hydroxyquinoline sulfate, phosphoric acid and tartaric
acid.
[0064] As stated above, the compositions may optionally further
include one or several preservative(s). If preservative(s) are
used, non-limiting examples of those that can be used include
benzalkonium chloride, benzethonium chloride, benzoic acid and
salts, benzyl alcohol, boric acid and salts, cetylpyridinium
chloride, cetyltrimethyl ammonium bromide, chlorobutanol,
chlorocresol, chorhexidine gluconate or chlorhexidine acetate,
cresol, ethanol, imidazolidinyl urea, metacresol, methylparaben,
nitromersol, o-phenyl phenol, parabens, phenol, phenylmercuric
acetate/nitrate, propylparaben, sodium benzoate, sorbic acids and
salts, .beta.-phenylethyl alcohol and thimerosal.
[0065] According to certain additional embodiments, the
pharmaceutical compositions comprise, consist of or consist
essentially of, a therapeutically effective quantity of either at
least one pharmaceutically active compound of the first class or at
least one pharmaceutically active compound of the second class, but
not a combination comprising compounds of both the first class and
the second class. In such embodiments, the additional presence in
the composition of at least one pharmaceutically active compound of
the third class is required. Such compositions are defined for the
purposes of the present specification as "two-class composition"
meaning they only include two particular classes of
pharmaceutically active compound and not more.
[0066] In other words, according to these additional embodiments
the pharmaceutical compositions comprise, consist of or consist
essentially of: [0067] (a) either at least one pharmaceutically
active compound of the first class (i.e., one or more of midazolam,
diazepam, lorazepam, flunitrazepam, alprazolam, chlordiazepoxide,
clonazepam and clorazepate, and pharmaceutically acceptable salts,
hydrates, solvates or N-oxides thereof) and at least one
pharmaceutically active compound of the third class (i.e., one or
more of .beta.-blockers, antiemetic medicaments, NSAIDs,
antihistamines, .alpha.-2-adrenergic agonists, pain relievers and
combinations thereof, or pharmaceutically acceptable salts,
hydrates, solvates or N-oxides thereof); or [0068] (b) either at
least one pharmaceutically active compound of the second class
(i.e., one or more of ketamine, dextrorphan, etomidate, methadone,
memantine, amantadine, dextromethorphan, and pharmaceutically
acceptable salts, hydrates, solvates or N-oxides thereof) and at
least one pharmaceutically active compound of the third class.
[0069] The vehicle that can be used in such two-class compositions
can be the same as described herein for the three-class
compositions, and such embodiments do envision the use of in the
vehicle such polymers as esters of cellulose (e.g., methyl
cellulose or hydroxypropyl methyl cellulose),
poly(lactic-co-glycolic acid), polylactic acid, polyglycolide,
dextrin, polyacetals, poly(N-(2-hydroxypropyl)methacrylamide),
polycaprolactone, and poly-3-hydroxybutyrate. Likewise, the vehicle
can contain excipients such as gelatin, sodium saccharin,
stevioside, peppermint oil, cherry flavor, lemon oil, raspberry
flavor and combinations thereof. The use of extended release
capsules ensconcing the pharmaceutical formulation, or matrix
polymer structures is also provided for. Any two-class composition
can be also formulated as a troche, a lozenge, a capsule, a pill, a
cap, and a bolus, as discussed herein.
[0070] By using two-class compositions, some unexpected results may
be obtained. For example, ondansetron (a compound of the third
class) is a medicament having antiemetic properties. Midazolam (a
compound of the first class) is not normally considered antiemetic.
Yet, surprisingly, a two-class combination of ondansetron and
midazolam has antiemetic activity that is markedly better than that
of ondansetron alone, which may be indicative of synergy between
midazolam and ondansetron.
[0071] The pharmaceutical formulations described herein can be
administered to a subject in need of conscious sedation, procedural
sedation, analgesia and/or pre-sedation, and in general for any
kind of non-general anesthesia, by various local administrations.
More specifically, the pharmaceutical formulations described herein
may be prescribed by ordinarily skilled medical practitioners such
as physicians, as the means of conscious sedation or pre-sedation.
This is intended to be used for certain patients who experience or
expect to experience high anxiety, bouts of panic attacks,
disquietude, apprehension, angst or similar feelings of
psychological discomfort or distress prior to, or during, medical
or surgical procedures as described in more detail below. The
patients may be of any age, i.e., including children, adolescents
and adults.
[0072] For example, the formulation can be used prior to various
outpatient surgeries and medical procedures, both invasive and
non-invasive, such as an ophthalmic surgery, outpatient medical or
surgical procedures, dental procedures, urological procedures,
obstetric and gynecological procedures, gastrointestinal
procedures, otolaryngological procedures, cosmetic surgery
procedures, dermatological procedures, podiatric procedures,
orthopedic procedures, emergency medical treatments, psychiatric
treatments, and veterinarian procedures.
[0073] Specific representative examples of the procedures that are
amenable to use of the formulation include, without limitation,
cataract surgery, glaucoma surgery, corneal surgery, eyelid
surgery, retinal surgery, tooth extraction, oral surgery, root
canal surgery, medical imaging procedures (e.g., MRI or CAT
scanning, especially for patients suffering from claustrophobia),
biopsy, bone marrow harvesting, colonoscopy, endoscopy and
laparoscopy.
[0074] In one non-limiting embodiment, local administration is by
the oral route, such as sublingually or buccally, typically being
delivered to the patient in the form of a solid delivery vehicle
such as a troche, a lozenge, a capsule, a pill, a cap, and a bolus,
as mentioned above. In an additional embodiment, the pharmaceutical
composition may be formulated as a liquid item adapted for
sublingual or buccal administration (in which case it will include
all the pharmaceutically active compounds described above, but no
pharmaceutically suitable binder); such liquid formulations may be
delivered by any method to be selected by one having ordinary skill
in the art of delivery of medications, e.g., via a syringe, dropper
or pipette. Such local administration may be used instead of
intravenous administration or to complement the latter, as
appropriate.
[0075] It will be understood by those having ordinary skill in the
art that the specific dose level and frequency of dosage for any
particular patient may be varied and will depend upon many factors
including the activity of the specific compound employed, the
metabolic stability and length of action of that compound, the age,
body weight, general health, gender, diet and the severity of the
particular condition being treated.
[0076] In additional embodiments, the pharmaceutical compositions
of the present invention may be incorporated into vehicles allowing
extended release of the compositions over a period of time. To
achieve this effect, the compositions may be combined with polymers
forming such vehicles. The product will be extended release
capsules ensconcing or enveloping the pharmaceutical formulation,
or alternatively, a matrix polymer structure holding the
pharmaceutical formulation that is embedded into the matrix.
[0077] The vehicle carrying the pharmaceutical formulation may be
configured to allow the gradual release of the pharmaceutical
formulation over not less than about 12 hours, such as between
about 12 hours and about 20 hours, for example, about 16 hours. The
rate of release may be uniform throughout the entire period of
release; alternatively, those having ordinary skill in the art may
formulate the release vehicle in such a way as to allow different
rates of release at different times, for example, faster release at
the beginning of the process of release and slower at later stages,
or vice versa, or in any other way that may be necessary.
[0078] The vehicle may be manufactured from any pharmaceutically
acceptable polymer that is capable of releasing at least 95 mass %
of the pharmaceutical formulation that the vehicle incorporates
within the above-mentioned time periods, i.e., within not less than
12 hours, or 12-20 hours. In some embodiments, the vehicle may be
formulated to ensure the release of at least 97 mass % of the
pharmaceutical formulation, for example, at least 99.5 mass %.
[0079] Those having ordinary skill in the art will select the most
appropriate polymer for making the vehicle. As guidance only, some
non-limiting examples of such polymers include, but are not limited
to, esters of cellulose, e.g., methyl cellulose and hydroxypropyl
methyl cellulose. Other acceptable polymers include, but are not
limited to, poly(lactic-co-glycolic acid) (PLGA), polylactic acid,
polyglycolide, dextrin, polyacetals,
poly(N-(2-hydroxypropyl)methacrylamide), polycaprolactone, and
poly-3-hydroxybutyrate.
[0080] One particular type of product that can be used in
fabricating the vehicle carrying the pharmaceutical formulation may
be water-soluble methylcellulose and hydroxypropyl methylcellulose
polymers, such as METHOCEL.RTM. family of products, for example, a
hydroxypropyl methylcellulose product METHOCEL.RTM. E4M, 20%
METHOCEL.RTM. K4M, or 10% METHOCEL.RTM. K100 or, alternatively and
particularly useful for hot melt extrusion, another hydroxypropyl
methylcellulose product AFFINISOL.TM. HPMC (all mentioned
hydroxypropyl methylcellulose polymers are available from Dow
Chemical Co., Midland, Mich.).
[0081] While all the products that include vehicles carrying the
pharmaceutical compositions of the present invention are useful for
treating all the medical, surgical and other procedures mentioned
above, those having ordinary skill in the art may find these
systems particularly suitable and advantageous in the treatments of
depression (including major depression or treatment-resistant
depression), PTSD, alcohol or substance abuse/dependence, suicide
prevention, anxiety (including generalized anxiety disorder),
personality disorders (inclusive of borderline personality
disorder), and related psychiatric and/or psychological disorders,
syndromes, symptoms, maladies, and the like.
[0082] According to further embodiments, methods for fabricating
the above-described pharmaceutical compositions are provided. A
one-batch formulation method may be used, where the components of
the pharmaceutical formulation can be combined in single container;
the components may be added to the container simultaneously or
consecutively. Alternatively, a two- or multiple-batch method(s)
may be used if desired, where each component of the pharmaceutical
formulation can be combined in separate container followed by
combining the contents of each container.
[0083] In one exemplary, non-limiting procedure, pre-measured
quantities of each ingredient in the form of dry powder can be
mixed to form a dry blend followed by mixing it with a pre-molten
troche base. The composition can then be molded to form a
troche.
[0084] In additional embodiments, pharmaceutical kits are provided.
The kit includes a sealed container approved for the storage of
solid pharmaceutical compositions, the container containing one of
the above-described pharmaceutical compositions an instruction for
the use of the composition and the information about the
composition are to be affixed to the container or otherwise
enclosed with it.
[0085] The following examples are provided to further elucidate the
advantages and features of the present invention, but are not
intended to limit the scope of the invention. The examples are for
the illustrative purposes only. USP pharmaceutical grade products
were used in preparing the formulations described below.
Example 1. Preparing a Pharmaceutical Composition in the Form of a
Troche
[0086] A pharmaceutical composition may be prepared as described
below. The following products can be used in the amounts and
concentrations specified: [0087] (a) about 0.2 g of midazolam;
[0088] (b) about 2.0 g of ketamine hydrochloride; [0089] (c) about
0.2 g of ondansetron hydrochloride; [0090] (d) about 1 mL of lemon
oil flavoring; and [0091] (e) about 15.5 g of standard troche base
(comprising polyglycol 1450, polyglycol 400, gelatin, sodium
saccharin and steviaside).
[0092] The troche base can be melted at low heat while being
stirred; when completely molten, the heat can be turned off with
continued stirring. All the dry ingredients, pre-weighed can be
added into the molten base followed by adding the flavoring and
mixing all components together.
[0093] While any shape may be used, a half-moon shaped troche mold
can be lightly sprayed with PAM.RTM. (or a suitable oil/releasing
agent) to cover the entire surface of the mold and the mixture
prepared as explained above can then be poured into the mold and
allowed to cool and harden at room temperature. A heat gun can then
be used to smooth out the surface followed by another round of
cooling at room temperature followed by removing the so prepared
troche from the mold, placing it into a prescription vial and
labeling the vial. The troche is now ready to be administered.
Example 2. Preparing an Extended Release Pharmaceutical
Composition
[0094] An extended release pharmaceutical composition may be
prepared as described below. The following products can be used in
the amounts and concentrations specified: [0095] (a) about 3.0 g of
midazolam; [0096] (b) about 10.0 g of ketamine hydrochloride;
[0097] (c) about 21.0 g of Methocell.RTM. K100M USP grade powder;
[0098] (d) about 100 g of Methocell.RTM. E4M premium USP grade
powder; [0099] (e) about 15.0 g of microcrystalline cellulose
powder; and [0100] (f) 100 clear gelatin capsules size No. 0.
[0101] Midazolam and ketamine hydrochloride may be triturated to a
fine powdery constituency using standard mortar and pestle. Using
the principles of geometric dilution, the rest of ingredients
(i.e., the two Methocell.RTM. powders and the microcrystalline
cellulose powder) may be then mixed in with trituration in the
mortar. The use of a V-blender and a powder food coloring may be
employed to verify that the mixture is homogenous followed by
sieving through an 80 mesh sieve to ensure the evenness or the
particle sizes which can then be encapsulated in the clear gelatin
capsules (size 0).
[0102] Principles of geometric dilution that should be followed, as
mentioned above, are well known in the art, but for further
guidance may be summarized as follows. A portion of an ingredient
of a large quantity (L) is to be mixed into an ingredient of a
smaller quantity (S) in small portions. To that end, first a
portion of L is to be mixed with a portion of S, the two portions
having the same volume as a portion of S thus obtaining a mixture
Ml. Then another portion of L is to be mixed with a portion of Ml,
the two portions having the same volume. This process is to be
continued until the entire quantity of L is used up.
[0103] The entire quality of L is not to be added to the entire
quantity of S in the expectation that the uniform dispersion can be
more expeditiously obtained after brief trituration of the
mixture.
Example 3. Preparing a Two-Class Pharmaceutical Composition in the
Form of a Troche
[0104] A two-class pharmaceutical composition may be prepared as
described below. The following products can be used in the amounts
and concentrations specified: [0105] (a) about 0.3 g of midazolam;
[0106] (b) about 0.22 g of ondansetron; [0107] (c) about 0.4 g of
Stevia powder extract; [0108] (d) about 0.5 mL of artificial flavor
marshmallow; [0109] (e) about 0.5 mL of vanilla extract flavor;
[0110] (f) about 0.5 g of natural lemon flavor; and [0111] (g)
about 13.0 g of troche base.
[0112] The troche base can be heated at low heat, and once
liquified, the heat can be turned off with continued stirring. All
other components provided above can then be carefully added to the
melted troche base and mixed together to make a mixture of
ingredients.
[0113] A troche mold can then be lightly sprayed with PAM oil to
cover all the surfaces followed by pouring the mixture into the
mold, allowing it to cool, polishing, and cooling it again. It is
expected that white opaque troches will be obtained having the
smell like vanilla, marshmallow and lemon.
Example 4. Preparing a Two-Class Pharmaceutical Composition in the
Form of a Troche
[0114] A two-class pharmaceutical composition may be prepared as
described below. The following products can be used in the amounts
and concentrations specified: [0115] (a) about 2.5 g of ketamine;
[0116] (b) about 0.22 g of ondansetron; [0117] (c) about 0.4 g of
Stevia powder extract; [0118] (d) about 0.5 mL of artificial flavor
marshmallow; [0119] (e) about 0.5 mL of vanilla extract flavor;
[0120] (f) about 0.5 g of natural lemon flavor; and [0121] (g)
about 13.0 g of troche base.
[0122] The troche base can be fabricated following the procedure
described in Example 3.
[0123] Although the invention has been described with reference to
the above examples, it will be understood that modifications and
variations are encompassed within the spirit and scope of the
invention. Accordingly, the invention is limited only by the
following claims.
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