U.S. patent application number 12/595183 was filed with the patent office on 2010-05-13 for melatonin tablet and methods of preparation and use.
This patent application is currently assigned to PHARMACEUTICAL PRODUCTIONS INC.. Invention is credited to John A. McCarty.
Application Number | 20100119601 12/595183 |
Document ID | / |
Family ID | 39864239 |
Filed Date | 2010-05-13 |
United States Patent
Application |
20100119601 |
Kind Code |
A1 |
McCarty; John A. |
May 13, 2010 |
MELATONIN TABLET AND METHODS OF PREPARATION AND USE
Abstract
The present invention provides a pharmaceutical composition for
sublingual or buccal administration of actives with low to poor
aqueous solubility, e.g. the indole hormone melatonin, which
contains a solution of the active in a pharmaceutically acceptable
solvent adsorbed or absorbed onto particles of a pharmaceutically
acceptable carrier and methods of preparing and using the
pharmaceutical composition.
Inventors: |
McCarty; John A.; (Miami
Springs, FL) |
Correspondence
Address: |
Davidson, Davidson & Kappel, LLC
485 7th Avenue, 14th Floor
New York
NY
10018
US
|
Assignee: |
PHARMACEUTICAL PRODUCTIONS
INC.
Miami Springs
FL
|
Family ID: |
39864239 |
Appl. No.: |
12/595183 |
Filed: |
April 10, 2008 |
PCT Filed: |
April 10, 2008 |
PCT NO: |
PCT/US2008/004615 |
371 Date: |
October 8, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60922921 |
Apr 11, 2007 |
|
|
|
Current U.S.
Class: |
424/464 ;
424/490; 514/171; 514/419 |
Current CPC
Class: |
A61K 9/2009 20130101;
A61K 9/143 20130101; A61K 9/2095 20130101; A61K 9/2018 20130101;
A61K 31/70 20130101; A61P 39/06 20180101; A61P 25/00 20180101; A61K
9/0056 20130101; A61P 35/00 20180101; A61K 31/4045 20130101; A61P
25/28 20180101; A61K 9/2031 20130101; A61K 9/2013 20130101; A61P
25/20 20180101; A61K 31/40 20130101 |
Class at
Publication: |
424/464 ;
424/490; 514/171; 514/419 |
International
Class: |
A61K 31/4045 20060101
A61K031/4045; A61K 9/20 20060101 A61K009/20; A61K 9/14 20060101
A61K009/14; A61K 31/56 20060101 A61K031/56; A61P 25/28 20060101
A61P025/28; A61P 35/00 20060101 A61P035/00 |
Claims
1. A solid dosage form for sublingual or buccal administration of a
hormone having low to poor aqueous solubility, said dosage form
comprising melatonin in a dissolved state, said dissolved melatonin
being associated with a pharmaceutically acceptable carrier wherein
the melatonin is in a dissolved state in the final dosage form.
2. The dosage form of claim 1 wherein the dissolve melatonin is
coated, absorbed, or adsorbed onto said carrier.
3. The dosage form of claim 1 wherein the melatonin is dissolved in
a pharmaceutically acceptable solvent selected from polyethylene
glycol, ethanol, ethyl acetate, isopropyl alcohol, triacetin,
triethyl citrate, tributyl citrate, substituted polyethylene
glycols, propylene glycol, bisabolol, glycerin, mineral oil, ethyl
oleate, oleic acid, oleyl alcohol fatty acid esters, squalane,
animal oils, vegetable oils, hydrogenated vegetable oils, isopropyl
myristate, isopropyl palmitate, glycofurol, terpenes, essential
oils, alcohols, water, polyols, silicone fluids, glycerides, or a
mixture thereof.
4. The dosage form of claim 3 in which the pharmaceutically
acceptable solvent is polyethylene glycol.
5. The dosage form of claim 3, in which the pharmaceutically
acceptable solvent is a mixture of polyethylene glycol and oleic
acid.
6. The dosage form of claim 1 in which the pharmaceutically
acceptable carrier is selected from silica, microcrystalline
cellulose, cellulose, silicified microcrystalline cellulose, clay,
talc, starch, pregelatinized starch, calcium carbonate, calcium
silicate, dicalcium phosphate, magnesium carbonate and mixtures
thereof.
7. A pharmaceutical composition as claimed in claim 6, in which the
pharmaceutically acceptable carrier is silica.
8. A pharmaceutical composition as claimed in claim 7, wherein the
silica carrier are particles ranging in size from about 3 to about
30 microns.
9. A pharmaceutical composition as claimed in claim 1, in which the
concentration of melatonin in the solvent is in the range of about
5% to about 30% w/w.
10. A pharmaceutical composition as claimed in claim 1, in which
the weight:weight ratio of carrier to solution is in the range of
about 1:0.5 to about 1:4.
11. A pharmaceutical composition as claimed in claim 1, which
further comprises a diluent.
12. A pharmaceutical composition as claimed in claim 1, which
further comprises a disintegrent.
13. A pharmaceutical composition as claimed in claim 1, which
further comprises a lubricant.
14. A pharmaceutical composition as claimed in claim 1, which
contains from about 0.01 to about 3 mg of melatonin per unit
dose.
15. A pharmaceutical composition as claimed in claim 1, which is in
the form of a tablet.
16. A process for the preparation of a pharmaceutical composition
as defined in claim 1, which comprises the steps of dissolving
melatonin in the pharmaceutically acceptable solvent to form a drug
solution, mixing the drug solution with particles of a
pharmaceutically acceptable carrier to coat, adsorb or absorb said
solution onto the carrier particles.
17. A process as claimed in claim 16, in which the drug solution is
further processed to provide a flowable powder.
18. A process as claimed in claim 16, which further comprises
adding additional excipients.
19. A process of claim 16, wherein the process further comprises
compressing the composition to form a tablet.
20. A method of providing a patient with melatonin therapy, which
comprises providing a dosage form of claim 1; and administering
said dosage form by a sublingual or buccal route to a patient in
need of said therapy.
21. A composition of claim 1 wherein the hormone is selected from
the group consisting of melatonin, estrogens, progesterone,
testosterone, and dihydroxytestosterone.
Description
[0001] This application claims priority from U.S. Provisional
Patent Application No. 60/922,921, filed on Apr. 11, 2007, through
PCT Application No. PCT/US2008/004615 filed on Apr. 10, 2008, the
disclosures of which are hereby incorporated by reference in their
entireties.
BACKGROUND OF THE INVENTION
[0002] Hormones such as the indole hormone, melatonin, are widely
distributed in both plant and animal sources. Melatonin can be
found in human milk, bananas, beets, cucumbers, and tomatoes.
Chemically, melatonin is N-acetyl-5-methoxytryptamine, a derivative
of serotonin, which in turn is derived from tryptophan. Melatonin
is a ubiquitous natural neurotransmitter-like compound produced
primarily by the pineal gland, and is involved in numerous aspects
of the biological and physiologic regulation of body functions.
[0003] See, e.g., Malhotra, S., et al., Medscape General Medicine
2004; 6(2), 46; and
www.nlm.nih.gov/medlineplus/print/druginfo/natural/patient-melatonin.html
for general discussion.
[0004] The role of endogenous melatonin in circadian rhythm
disturbances and sleep disorders is well established. Some studies
have shown that melatonin may also be effective in breast cancer,
fibrocystic breast diseases, and colon cancer. Melatonin has been
shown to modify immunity, the stress response, and certain aspects
of the aging process; some studies have demonstrated improvements
in sleep disturbances and "sundowning" in patients with Alzheimer's
disease. The antioxidant role of melatonin may be of potential use
for conditions in which oxidative stress is involved in the
pathophysiologic processes. The multiplicity of actions and variety
of biological effects of melatonin suggest the potential for a
range of clinical and wellness-enhancing uses, especially
considering that as one ages, the production of this key hormone
goes into steady decline. Indeed, for an octogenarian, the amount
produced is quite nominal.
[0005] Through melatonin release, the pineal gland maintains the
internal clock governing the natural rhythms of body function. This
apparent clock-setting property of melatonin has led to the
suggestion that it is a "chronobiotic" substance that alters and
potentially normalizes biological rhythms and adjusts the timing of
other critical processes and biomolecules (hormones,
neurotransmitters, etc.) that, in turn, exert numerous peripheral
actions. The sleep-inducing effects of melatonin have advantages
over conventional hypnotics, since melatonin, itself, is not a
hypnotic drug. Melatonin only induces a natural state of
sleepiness, and does not have the adverse side-effects of
conventional hypnotics and prescription sleeping aids.
[0006] Melatonin has previously been used pharmaceutically, and has
been prepared for oral administration (see, e.g., WO1995/003043).
These preparations include melatonin formulated with a cyclodextrin
(WO 1999/047175), and as a microemulsion (U.S. Pat. No. 5,362,745).
However, as with most oral preparations, it can take more than 30
minutes after administration for the blood plasma concentration of
melatonin to reach its peak. Goldberg, M J, Bergstrom, R F R,
Smith, B P, Simcox, E A, Thomasson, H R, Shipley, L A: Sleep
Research 1997: 26:101. This is due, in part, to the need for
gastrointestinal absorption to occur before the melatonin is
available in the bloodstream. Further, melatonin's oral
bioavailability is poor and erratic. Melatonin's absolute oral
bioavailbilty has been shown to be approximately 15% and peak
plasma concentrations can vary over 20 fold range. DeMuro R L,
Nafziger A N, Blask D E, Menhinick A M, Bertino J S: Journal of
Clinical Pharmacology 2000: 40; 781; Di W L, Kadva A, Johnston A,
Silman R: New England Journal of Medcine 1997: 336; vol. 14, 1028.
Thus, oral administration of melatonin in currently available
preparations does not provide for rapid onset of action, and its
poor and erratic GI absorption make it an unsuitable route of
administration.
[0007] Several sublingual, buccal, orally dissolving tablets and
films containing melatonin are also available commercially. For
example, transmucosal formulations are described in WO 1996/030013
and U.S. Pat. No. 5,688,520. However, in these formulations,
melatonin is compounded in its undissolved, or solid, state. For
any drug to be absorbed into the bloodstream, it must be dissolved,
i.e., in solution. Due to melatonin's poor water solubility much of
the dosage from a currently available preparation is swallowed
undissolved in the saliva, leading to poor and erratic absorption
in the GI tract. Accordingly, hormone drugs such as melatonin
having low to poor water solubility, are expected to be poorly
suited for buccal or sublingual administration.
[0008] Other routes of administration for melatonin, including
nasal and oral sprays have been considered. U.S. Pat. No.
6,007,834. However, sprays are less desirable because of inherent
compliance issues such as improper manipulation of the actuator,
swallowing of the dosage before dissolution of the drug, and the
restrictions on usage when the patient has sinus congestion or a
head cold. This again leads to erratic and poor melatonin
bioavailability. Therefore sprays are not the optimal route for
routine melatonin administration.
[0009] Accordingly, there is a need in the medical and
pharmaceutical arts to provide an oral dosage form, preferably for
sublingual or buccal administration, wherein the subject dosage
form can provide rapid and consistent delivery of a hormone having
low to poor water solubility, such as melatonin. This need is met
by the subject composition, as well as its method of preparation
and administration. The subject melatonin formulation can
advantageously be useful to administer the drug to a patient in
significantly less time and with more consistent and higher
bioavailability than previously available dosage forms. Therefore,
this invention as claimed, provides a unique composition, delivery
system and method of administration for melatonin and other
hormones having low to poor water solubility.
SUMMARY OF THE INVENTION
[0010] The present invention provides a pharmaceutical composition
for sublingual or buccal administration of a hormone, e.g.,
melatonin, having relatively low to poor solubility in water or
other aqueous solutions. The composition comprises the hormone in
association with an inactive carrier, wherein the hormone is
preferably absorbed or adsorbed onto the carrier, and thereafter
formed into a solid dosage form such as a tablet. The carrier used
in the subject composition is preferably a pharmaceutically
acceptable carrier provided as a bead, a granule, a particle, or
the like. Uniquely, the composition according to the subject
invention comprises a pharmaceutically acceptable solvent in which
the hormone is dissolved and maintained in a solubilized state in
the final solid dosage form.
[0011] For purposes of the subject invention, it would be
understood that the term "melatonin" is a specific hormone having
low to poor water solubility. Melatonin is preferably used as the
active ingredient in compositions of the invention. It would also
be understood that use of the term melatonin refers to other
hormone active ingredients having low to poor water solubility,
such as estrogens, progesterone, testosterone, and
dihydrotestosterone. Accordingly, embodiments of the subject
invention include compositions wherein an estrogen, progesterone,
testosterone, or dihydrotestosterone, or combinations thereof, are
substituted for or used with melatonin. It would also be understood
that these hormones may be in their respective derivative form.
Therefore, reference to melatonin, estrogens, progesterone,
testosterone, or dihydrotestosterone includes any salt, prodrug,
metabolite, isomer, or derivative thereof having low to poor water
or aqueous solubility.
[0012] In accordance with certain embodiments of the present
invention, the composition comprises a pharmaceutically acceptable
carrier selected from silica, microcrystalline cellulose,
cellulose, silicified microcrystalline cellulose, clay, talc,
starch, pregelatinized starch, calcium carbonate, calcium silicate,
dicalcium phosphate, magnesium carbonate and mixtures thereof.
These carriers are well known in the pharmaceutical arts as being
suitable for forming particles, such as beads, pellets and granules
using conventional methods of preparation. For purposes of the
subject invention, the term "particle" encompasses, and means, and
is used interchangeably with, "carrier," "bead," "pellet,"
"granule" or any other particle-like form as well-recognized and
accepted in the pharmaceutical arts. In a preferred embodiment, the
pharmaceutically acceptable carrier is silica, which is also called
colloidal silicon dioxide. In certain preferred embodiments, the
carrier has a particle size ranging from about 3 microns to about
30 microns.
[0013] In certain embodiments, the pharmaceutically acceptable
solvent used for dissolving the melatonin and forming the
melatonin-containing solution for associating the melatonin with
the carrier particle is selected from polyethylene glycol, ethanol,
ethyl acetate, isopropyl alcohol, triacetin, triethyl citrate,
tributyl citrate, substituted polyethylene glycols, propylene
glycol, bisabolol, glycerin, mineral oil, oleic acid, oleyl
alcohol, ethyl oleate, fatty acid esters, squalane, animal oils,
vegetable oils, hydrogenated vegetable oils, isopropyl myristate,
isopropyl palmitate, glycofurol, terpenes, essential oils,
alcohols, water, polyols, silicone fluids, and/or glycerides and
mixtures thereof.
[0014] A preferred pharmaceutically acceptable solvent is
polyethylene glycol and a mixture of polyethylene glycol and oleic
acid. It would be understood that the solution may be formed from
an aqueous or non-aqueous solvent or a mixture thereof, and may be
formed from a volatile and a non-volatile solvent, ora mixture
thereof, so long as the melatonin or other hormone having low to
poor water solubility is in solution when coated, adsorbed or
absorbed onto the carrier. In an embodiment employing a volatile
solvent, such volatile solvent is preferably removed, e.g., by
drying, after coating, adsorption, or absorption.
[0015] The concentration of active ingredient, such as melatonin,
in the solvent is preferably in the range of about 5% to about 30%
and more preferred 10% to 20%. The preferred weight:weight ratio of
carrier:solution being in the range of about 1:0.5 to about 1:4 and
more preferred 1:1 to 1:2. In certain embodiments, the
pharmaceutical composition contains from about 0.01 to about 3 mg
of melatonin per unit dose and more preferred 0.5 to 2 mg.
[0016] The pharmaceutical composition of the subject invention may
further comprise a diluent, a disintegrent, a lubricant, or other
excipient as would be readily understood in the pharmaceutical arts
for preparation of a final dosage form as desired. For example, in
order to prepare a solid dosage form such as a compressed tablet,
excipients well known in the tableting arts can be employed in a
manner consistent with such known tableting techniques and
procedures to form a compressed dosage form such as a compressed
tablet.
[0017] Preferably, the pharmaceutical composition of the subject
invention is provided as a unit dose form, and more preferably as a
solid dosage form, such as a compressed tablet, for buccal or
sublingual administration. A most preferred embodiment of the
subject invention comprises a tablet which provides rapid
administration of the API upon sublingual or buccal administration
of the composition.
[0018] The composition of the subject invention advantageously
provides the active ingredient, e.g., a hormone such as melatonin
having relatively low to poor solubility in aqueous solvents, in a
dissolved form. Being in a dissolved form, the melatonin can be
directly absorbed into the bloodstream through the oral mucosa,
without having to be dissolved by the aqueous environment provided
by saliva in the mouth or in the gastrointestinal tract. A further
advantage of the drug delivery system of the subject invention
includes enhanced oral mucosal absorption of the active provided in
the composition because less drug is swallowed as undissolved drug
released from the dosage form. Accordingly, this drug delivery
system provides for rapid onset of drug action with higher and more
consistent bioavailability.
[0019] The present invention also provides a process for the
preparation of a pharmaceutical composition as described above,
which involves dissolving a hormone having low to poor aqueous
solubility, such as melatonin, in a pharmaceutically acceptable
non-aqueous solvent to form a drug solution, mixing the solution
with particles of a pharmaceutically acceptable carrier to afford
coating, absorption or adsorption onto the particles, and then, if
desired, mixing the adsorbed or absorbed particle's with other
ingredients, e.g., the pharmaceutically acceptable excipients, to
form the final composition. In certain embodiments, the solution is
mixed with the particles to provide a flowable powder that can be
compounded or compressed into a solid dosage form or can be
combined with other or additional compressible materials to
facilitate compression of the composition into a solid, unitary
dosage form. The process can further comprise the step of
compressing the composition to form tablets.
[0020] The present invention further provides a method of providing
a patient with melatonin therapy, comprising the steps of providing
a composition in accordance with the subject invention,
administering the composition by a sublingual or buccal route to a
patient in need of treatment with melatonin.
BRIEF DESCRIPTION OF THE FIGURES
[0021] FIG. 1 shows the comparative buccal flux using a 1 mg
melatonin tablet made in accordance with Example 2 of the present
invention versus a commercially available sublingual melatonin
tablet.
[0022] FIG. 2 is a flow chart showing steps comprising the
manufacture of a sublingual tablet containing a dose of 1 mg
melatonin.
DETAILED DESCRIPTION
[0023] This invention relates to a pharmaceutical composition for
sublingual or buccal administration of a hormone having low to poor
aqueous solubility, such as melatonin. For purposes of the subject
invention, the description refers to melatonin as the active
pharmaceutical ingredient (API), or drug, but would be understood
by persons having ordinary skill in the art to include other
hormones which have low to poor water solubility in aqueous
environment or in aqueous biological fluids such as saliva or
gastrointestinal fluids. The invention further relates to a method
of manufacture for the sublingual or buccal dosage form and use of
the subject preparation for sublingual or buccal melatonin delivery
and treatment of patients in need of melatonin therapy.
[0024] This invention relates to a novel delivery system of a drug,
such as melatonin, providing a unique mechanism to enhance delivery
of the drug. This unique system is designed to deliver melatonin
through the buccal or sublingual mucosa and directly into systemic
circulation. This is unlike any of the currently marketed
sublingual or buccal products containing a hormone, such as
melatonin, because those marketed products are formulated in a
solid form, such as an emulsion or solid dispersion, so that much
of the melatonin is incompletely dissolved in the local buccal or
sublingual delivery area. Those marketed products disintegrate in
the mouth or are chewed in order to release the melatonin from the
dosage form, causing the undissolved melatonin to be swallowed and
absorbed in the gastrointestinal tract, and thereby leading to poor
and erratic bioavailability for the released drug.
[0025] Melatonin is poorly soluble in water or other aqueous
biological fluids and, when delivered in a undissolved state, as in
the currently available melatonin products, the drug remains
undissolved in saliva and must therefore be swallowed in order to
be absorbed in any substantial amount. Thus, for these products,
the onset of action, absorption and first pass metabolism are no
different than from swallowing an immediate-release oral tablet or
capsule containing undissolved melatonin. Such tablets are
considered to be immediate-release only due to the rapid
disentegration of the dosage form. These available tablets release
melaoning in an undissolved state, and drug absorption is limited
by how quickly the drug dissolves in the local delivery area.
[0026] Unlike other sublingual tablets and orally disentegrating
tablets, where melatonin must first dissolve into the saliva to be
absorbed, the subject invention advantageously provides the active
drug, e.g., a hormone such as melatonin having low to poor water or
aueous solubility, already in solution as present in the final
dosage form. In the subject invention, the hormone such as
melatonin is not provided as an emulsion or solid dispersion, but
is completely dissolved and in solution. Therefore melatonin
sublingual/buccal delivery is enhanced by this invention, because
melatonin does not have to dissolve in the saliva before being
absorbed. Further, by being formulated into a small rapidly
disintegrating tablet the area for absorption is localized around
the disentegrating tablet. Having the drug solubilized and
contained to a local delivery site keeps the drug in solution, and
thus having high thermodynamic activity which enhances transmucosal
absorption. The rapid onset of melatonin action from the delivery
system provided by the subject invention can provide for rapid drug
absorption, resulting in drug plasma pharmacokenetics more similar
to an intravenous injection, with none of the vicissitudes
associated with gastrointestinal (GI) administration, e.g., poor
absorption, erratic absorption, first pass metabolism, food and
dietary supplements effects on oral bioavailability.
[0027] A sublingual/buccal dosage form, e.g., a tablet, in
accordance with the subject invention can enhance delivery of drug
with poor aqueous solubility, such as melatonin, by sublingual or
buccal administration by providing the drug in solution, or in a
dissolved state, within a solid dosage form designed for localized
drug delivery and absorption.
[0028] The melatonin sublingual tablets as embodied in this
invention preferably range from 50 to 150 mg total tablet weight
depending on the dosage. In vitro drug dissolution testing from
rapid release formulations is substantially complete within 15
minutes and the tablet disintegrates under the tongue typically
within a few minutes, preferably less than 5 minutes, more
preferably within one to three minutes, and most preferably within
30 seconds to about two minutes. Thus onset of sleepiness from
administering this sublingual tablet occurs form about 5-25
minutes, and preferably, within about 15 minutes, providing a rapid
rise in melatonin plasma levels and reaching therapeutic levels or
maximum concentration from the dosage form within these time
periods.
[0029] A slower drug release can alternatively be formulated into
the tablet, such as the addition of a slow-release coating,
inclusion of pore-formers into the coating or core, incorporation
of a matrix formulation, or the like, as are recognized in the art,
to mimic a slow infusion using controlled release formulation
methods. Thus, because the drug's dissolution rate is not a
rate-limiting step in the delivery of drug to the patient, the
delivery and absorption of drug to the patient can be predictably
controlled by manipulation of the disintegration of the dosage
form.
[0030] Preferred pharmaceutical compositions in accordance with the
present invention can be formulated to provide a single dose of
active ingredient, e.g., melatonin, between 0.01 mg to 3 mg and,
preferably, of between 0.2 and 2.0 mg. When used in such low doses,
compositions in accordance with the invention can advantageously
provide consistent and sufficiently high peak melatonin blood
plasma concentration (C.sub.max), soon after administration to be
effective in the treatment of human disease, particularly insomnia,
or in causing drowsiness or sleep in humans. Thus, the present
invention allows for consistently effective melatonin blood plasma
concentrations to be achieved even when using lower melatonin doses
than administered in currently available products.
[0031] In an embodiment of the invention, melatonin is dissolved in
polyethylene glycol (PEG), e.g., PEG 400, PEG 200, PEG 300, PEG
600, or other suitable solvents include other molecular weight
grades of PEG, ethanol, ethyl acetate, isopropyl alcohol,
triacetin, triethyl citrate, tributyl citrate, substituted
polyethylene glycols, propylene glycol, bisabolol, glycerin,
mineral oil, ethyl oleate, oleic acid, oleyl alcohol, fatty acid
esters, squalane, animal oils, vegetable oils, hydrogenated
vegetable oils, isopropyl myristate, isopropyl palmitate,
glycofurol, terpenes, essential oils, alcohols, polyols, silicone
fluids, and/or glycerides and combinations of such solvents.
[0032] In order to convert the liquid melatonin solution into a
flowable powder suitable for use in direct compression tableting
requires the use of an adsorbent/absorbent carrier, such as silica
(ZEOPHARM 5170, AEROPERL 300, SYLOID 244FP, SYLOID 63FP, SYLOID 72
FP, SIPERNAT 160PQ, SIPERNAT 50, SIPERNAT 50S, SIPERNAT 500LS,
SIPERNAT 2200, SIDENT 8, SIDENT 9, SIDENT 10, SIDENT 22S) In
certain embodiments, the carrier according the invention may also
be microcrystalline celluloses, cellulose powder, silicified
microcrystalline celluloses (PROSOLV 50, PROSOLV 90HD), silicas,
clays, talcs, starches, pregelatinized starches, calcium
carbonates, calcium silicates, cyclodextrins, dicalcium phosphates,
and magnesium carbonates or combinations thereof.
[0033] In order to manufacture a rapidly disintegrating, directly
compressible sublingual tablet other excipients can be used. For
example, the diluent may be the water-soluble, direct compression
tableting excipient, mannitol. Other water-soluble excipient
according to the invention are one or more of the following:
sugars, polyols, saccharides, polysaccharides, dextrate, dextrins,
dextrose, fructose (ADVANTOSE FS 95), lactitol (FINLAC DC),
lactose, erythritol, maltose, maltitol, maltodextrins,
polydextroses, trehalose, mannitol (PEARLITOL 300 DC, PEARLITOL 400
DC, PEARLITOL 500 DC, MANNOGEM 2080, MANNOGEM EZ, PARTEK M200,
PARTEK M300), polyethylene glycols, isomalts, sorbitol, sucrose and
xylitol (XYLITOL 200, XYLITOL 300). A disintegrent can also be
included to formulate a rapid breaking apart of the tablet
following administration. An exemplary disintegrent is sodium
starch glycolate. An exemplary tablet lubricant is sodium stearyl
fumarate.
[0034] In an embodiment, other excipients, chosen to enhance
processability, form, function or aesthetic appeal of the
formulation can be included in a composition according to the
invention. In such an embodiment, other excipients according to the
invention is a buffering agent (such as phosphate, carbonate,
tartrate, borate, citrate, acetate, and maleate buffers), colorant,
flavoring, solvent and co-solvent, coating agent, binder, diluent,
carrier, disintegrant, glidant, lubricant, opacifying agent,
humectant, granulating agent, gelling agent, polishing agent,
suspending agent, sweetening agent, anti-adherent, preservative,
emulsifying agent, antioxidant, levigating agent, plasticizer,
surfactant, tonicity agent, viscosity agent, enteric agent and
coating, controlled-release agent and coating, wax, wetting agent,
thickening agent, suppository base, stifling agent, stabilizing
agent, solubilizing agent, sequestering agent, bioadhesive,
ointment base, oleaginous vehicle, film-forming agent, essential
oil, emollient, dissolution enhancer, dispersing agent, and/or
cryoprotectant or combinations thereof.
Example 1
[0035] In one embodiment, the invention provides a 1 mg strength
melatonin sublingual/buccal tablet having a total tablet weight of
about 100 mg, wherein the tablet comprises drug, an
absorbent/adsorbent particulate carrier, such as silica; a diluent,
such as mannitol; a disintegrent, such as sodium starch glycolate;
and a lubricant, such as sodium stearyl fumarate, to facilitate
tableting. In such an embodiment, melatonin is dissolved in PEG
400. The melatonin-in-PEG 400 solution is then processed into a
into a flowable powder suitable for use in direct compression
tableting. An exemplary formulation in accordance with the
described formulation of this embodiment is provided in Table I,
below.
TABLE-US-00001 TABLE I 1 mg Melatonin Sublingual/Buccal Tablet
Formulation INGREDIENT AMOUNT (mg/tablet) Melatonin 1.00
Polyethylene glycol 400 7.00 Silica 4.50 Mannitol 84.00 Sodium
Starch Glycolate 3.00 Sodium Stearyl Fumarate 0.50 Total Tablet
Weight 100.00
Example 2
[0036] In one embodiment, the invention provided a 1 mg strength
melatonin sublingual/buccal tablet having a total tablet weight of
about 68 mg. In this second exemplary embodiment, melatonin is
dissolved in a mixture of solvents, PEG 400 and oleic acid. In
order to convert the melatonin PEG 400/Oleic Acid solution into a
flowable powder suitable for use in direct compression tableting,
an adsorbent/absorbent particulate carrier, such as silica, can be
used as above in Example 1. A tablet diluent, such as mannitol can
be used for formulating a directly compressible tablet. Sodium
starch glycolate was used as a disintegrant, and sodium stearyl
fumarate was usd as a lubricant.
[0037] An exemplary formulation manufactured for this embodiment in
accordance with the subject invention are provided in Table II,
below.
TABLE-US-00002 TABLE II 1 mg Melatonin Sublingual/Buccal Tablet
Formulation INGREDIENT AMOUNT (mg/tablet) Melatonin 1.00
Polyethylene glycol 400 5.00 Oleic Acid 1.30 Silica 5.00 Mannitol
52.30 Sodium Starch Glycolate 2.04 Sodium Stearyl Fumarate 1.36
Total Tablet Weight 68.00
Example 3
[0038] An in vitro buccal skin flux study was conducted comparing
melatonin permeation through buccal tissue culture from two 1 mg
sublingual melatonin tablets having a formulation according to
Example 2, against a commercially available sublingual tablet which
does not include dissolved melatonin in the final dosage form. As
shown in FIG. 1, the amount of melatonin that permeated the tissue
was more than 3-fold greater after 30 minutes from a tablet of the
subject formulation compared to a commercial GNC 1 mg melatonin
sublingual tablet, as measured as percent label concentration (%
LC). This shows enhanced rate of buccal tissue permeation of the
invention as compared to a currently marketed sublingual melatonin
tablet, which suggests a faster onset of action and greater
bioavailability for the subject tablets in vivo. Therefore, it may
be concluded that the onset of sleepiness would be much faster
using a formulation in accordance with the subject invention, such
as the formulation provided in Example 2.
Example 4
[0039] A method of manufacture for a tablet according to an
embodiment of the subject invention for sublingual/buccal
administration may employ any suitable method known in the art
including, but not limited to, the addition of the melatonin
solvate to premanufactured tablets, cold compressions with inert
fillers and binders, direct tablet compression blends, direct
powder blends, wet or dry granulations, molding, lyophilization,
microencapsulation, freeze drying, spray-congealing, spray-drying,
co-melt, spheronization, triturates, troching, powder layering,
pelleting, encapsulation. An exemplary method for the manufacture
of a direct compression tablet of the formulation given in Example
1 is outlined step-wise, below and is schematically diagramed in
FIG. 2:
Embodiment 1
[0040] STEP 1: Mix melatonin and PEG 400 together to form a
solution. [0041] STEP 2: Blend the melatonin PEG 400 solution from
Step 1 with silica until homogeneous to form a silica carrier
blend. [0042] STEP 3: Add the silica carrier blend from Step 2 to
mannitol and sodium starch glycolate and mix until homogeneous to
form a further blend. [0043] STEP 4: Add sodium stearyl fumarate to
the further blend from Step 3 and blend until well lubricated to
form a lubricated blend. [0044] STEP 5: Compressing the lubricated
blend from Step 4 into 100 mg tablets using 1/4 inch round
tooling.
[0045] Method of packaging. The sublingual/buccal tablets may be
packaged in such a manner as to aid in maintaining stability.
Packaging methods and materials may include, but are not limited
to, blister packaging in a foil/foil, foil/Acrylonitrile,
foil/Polychlorotrifluoroethylene laminates for blister packaging or
glass and plastic bottles.
[0046] Method of Use: In an embodiment, a rapid onset of action
melatonin buccal/sublingual tablet formulation with consistent
bioavailability according to the invention is useful in the
treatment of in circadian rhythm disturbances and sleep disorders
is well understood. Some studies have shown that melatonin may also
be effective in breast cancer, fibrocystic breast diseases, and
colon cancer. Melatonin has been shown to modify immunity, the
stress response, and certain aspects of the aging process; some
studies have demonstrated improvements in sleep disturbances and
"sundowning" in patients with Alzheimer's disease. The antioxidant
role of melatonin may be of potential use for conditions in which
oxidative stress is involved in the pathophysiologic processes.
Since endogenous melatonin production declines with age, use of
melatonin as a hormone replacement therapy or nutritional
supplement is indicated. Accordingly, this invention is useful for
all the above mention therapies. The typically treatment regiment
starts by placing a melatonin sublingual tablet under the tongue
and leaving it undistributed until dissolved, typically within 5
minutes. This can be supplemented with additional tablets as
needed. The dosage range for this embodiment may vary from 0.01 to
3.0 mg depending on the therapeutic need.
[0047] The invention has been described with reference to various
specific and preferred embodiments and techniques. However, it
should be understood that many variations and modifications may be
made while remaining within the spirit and scope of the
invention.
* * * * *
References