U.S. patent application number 10/696370 was filed with the patent office on 2004-05-06 for antidepressant dosage form.
Invention is credited to Bhatti, Gurdish Kaur, Edgren, David Emil, Hatamkhani, Zahedeh, Wong, Patrick S.L..
Application Number | 20040086570 10/696370 |
Document ID | / |
Family ID | 22082852 |
Filed Date | 2004-05-06 |
United States Patent
Application |
20040086570 |
Kind Code |
A1 |
Edgren, David Emil ; et
al. |
May 6, 2004 |
Antidepressant dosage form
Abstract
The invention pertains to a dosage form 10 and to administering
an antidepressant medicament 16 for an extended period of time in a
rate-known dose.
Inventors: |
Edgren, David Emil; (El
Granada, CA) ; Bhatti, Gurdish Kaur; (Fremont,
CA) ; Hatamkhani, Zahedeh; (Fremont, CA) ;
Wong, Patrick S.L.; (Palo Alto, CA) |
Correspondence
Address: |
PHILIP S. JOHNSON
JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
22082852 |
Appl. No.: |
10/696370 |
Filed: |
October 28, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10696370 |
Oct 28, 2003 |
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08442292 |
May 16, 1995 |
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08442292 |
May 16, 1995 |
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08068480 |
May 27, 1993 |
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6440457 |
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Current U.S.
Class: |
424/486 ;
514/649 |
Current CPC
Class: |
A61P 25/26 20180101;
A61P 25/24 20180101; Y10S 514/964 20130101; A61K 31/135 20130101;
Y10S 514/96 20130101; A61K 9/0004 20130101 |
Class at
Publication: |
424/486 ;
514/649 |
International
Class: |
A61K 009/14; A61K
031/137 |
Claims
We claim:
1. A therapeutic composition comprising 0.5 mg to 750 mg of a drug
of the formula: 5wherein the dotted line represents an unsaturation
or a cycloalkenyl group; R.sub.1 is a member selected from the
group consisting of hydrogen and alkyl of 1 to 6 carbon atoms;
R.sub.2 is a member selected from the group consisting of hydrogen
and alkyl of 1 to 6 carbon atoms; R.sub.4 is a member selected from
the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms,
formyl, and alkanoyl of 2 to 7 carbon atoms; R.sub.5 and R.sub.6
are independently a member selected from the group consisting of
hydrogen, hydroxyl, an alkyl of 1 to 6 carbon atoms, an alkoxy of 1
to 6 carbon atoms, alkanoyloxy of 2 to 7 carbon atoms, nitro,
alkylmercapto of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6
carbon atoms in which each alkyl group comprises 1 to 6 carbon
atoms, alkanamide of 2 to 7 carbon atoms, halo, and trifluoroethyl,
R.sub.7 is a member selected from the group consisting of hydrogen
and alkyl of 1 to 6 carbons, and n is one of the integers 0, 1, 2,
3, and 4, and a pharmaceutically acceptable addition salt; and
wherein the drug of the formula is blended with a poly(alkylene
oxide) polymer.
2. A therapeutic composition comprising 0.5 mg to 750 mg of a drug
of the formula; 6wherein the dotted line represents an unsaturation
or a cycloalkenyl group; R.sub.1 is a member selected from the
group consisting of hydrogen and alkyl of 1 to 6 carbon atoms;
R.sub.2 is a member selected from the group consisting of hydrogen
and alkyl of 1 to 6 carbon atoms; R.sub.4 is a member selected from
the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms,
formyl, and alkanoyl of 2 to 7 carbon atoms; R.sub.5 and R.sub.6
are independently a member selected from the group consisting of
hydrogen, hydroxyl, an alkyl of 1 to 6 carbon atoms, an alkoxy of 1
to 6 carbon atoms, alkanoyloxy of 2 to 7 carbon atoms, nitro,
alkylmercapto of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6
carbon atoms in which each alkyl group comprises 1 to 6 carbon
atoms, alkanamido of 2 to 7 carbon atoms, halo, and trifluoroethyl;
R.sub.7 is a member selected from the group consisting of hydrogen
and alkyl of 1 to 6 carbons and n is one of the integers 0, 1, 2,
3, 4, and a pharmaceutically acceptable addition salt; and wherein
the drug of the formula is blended with a cellulose polymer.
3. A therapeutic composition comprising 0.5 mg to 750 mg of a drug
of the formula: 7wherein the dotted line represents an unsaturation
or a cycloalkenyl group; R.sub.1 is a member selected from the
group consisting of hydrogen and alkyl of 1 to 6 carbon atoms;
R.sub.2 is a member selected from the group consisting of hydrogen
and alkyl of 1 to 6 carbon atoms; R.sub.4 is a member selected from
the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms,
formyl, and alkanoyl of 2 to 7 carbon atoms; R.sub.5 and R.sub.6
are independently a member selected from the group consisting of
hydrogen, hydroxyl, an alkyl of 1 to 6 carbon atoms, an alkoxy of 1
to 6 carbon atoms, alkanoyloxy of 2 to 7 carbon atoms, nitro,
alkylmercapto of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6
carbon atoms in which each alkyl group comprises 1 to 6 carbon
atoms, alkanamido of 2 to 7 carbon atoms, halo, and trifluoroethyl,
R.sub.7 is a member selected from the group consisting of hydrogen
and alkyl of 1 to 6 carbons, and n is one of the integers 0, 1, 2,
3, and 4; and a pharmaceutically acceptable addition salt; and
wherein the drug of the formula is blended with a maltodextrin
polymer.
4. A method for administering a drug to the gastrointestinal tract
of an animal, wherein the method comprises: (a) admitting orally
into the animal a dosage form comprising a drug of the formula:
8which drug possesses antidepressant therapy and the dosage form
comprises a member selected from the group consisting of a
sustained-release dosage form and a controlled-release dosage form;
and, (b) administering the drug from the dosage form over an
extended period of time in a therapeutically responsive dose to
produce the antidepressant therapy.
5. A dosage form for administering a drug to an environment of use,
wherein the dosage form comprises a drug of the formula: 9which
dosage form comprises a member selected from the group consisting
of a sustained-release dosage form and a controlled release dosage
form, and wherein said dosage form comprises means for storing the
drug and means for releasing the drug over an extended period of
time.
6. A dosage form for the oral delivery of a drug to an environment
of use, wherein the dosage form comprises: (a) a wall comprising at
least in part a composition permeable to the passage of fluid,
which wall surrounds: (b) a compartment; (c) a drug composition in
the compartment comprising a drug of the formula: 10wherein the
dotted line represents a member selected from the group consisting
of an unsaturation and cycloalkenyl group; R.sub.1 is a member
selected from the group consisting of hydrogen and alkyl of 1 to 6
carbon atoms; R.sub.2 is a member selected from the group
consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R.sub.4 is
a member selected from the group consisting of hydrogen, alkyl of 1
to 6 carbon atoms, formyl, and alkanoyl of 2 to 7 carbon atoms;
R.sub.5 and R.sub.6 are independently a member selected from the
group consisting of hydrogen, hydroxyl and alkyl of 1 to 6 carbon
atoms, alkoxy of 1 to 6 carbon atoms, alknaoyloxy of 2 to 7 carbon
atoms, nitro, alkylmercapto of 1 to 6 carbon atoms, amino,
alkylamino of 1 to 6 carbon atoms, alkanamido of 2 to 7 carbon
atoms, halo and trifluoroethyl; R.sub.7 is a member selected from
the group consisting of hydrogen and alkyl of 1 to 6 carbons; an n
is 0 to 4; and (d) a displacement in the compartment comprising a
composition comprising an osmotically active compound; and, (e) an
exit passageway in the dosage form for delivering the drug
composition from the dosage form.
7. A dosage form for the oral delivery of the drug to an
environment of use according to claim 6, wherein the drug is
1-[2-(dimethylamino)-1(4-me- thoxeyphenyl)ethyl]-cyclohexanol.
Description
FIELD OF THE INVENTION
[0001] This invention pertains to a controlled-release dosage form
comprising a compound of the following structural formula: 1
[0002] useful for antidepressant therapy. The invention concerns
also a method useful for antidepressant therapy by administering
the controlled-release dosage form comprising the compound of the
formula.
BACKGROUND OF THE INVENTION
[0003] The primary goal of drug administration is to provide a
therapeutic dose of drug in the body to achieve a desired blood
concentration, and then maintain the desired drug blood
concentration. The prior art, in attempts to obtain the desired
therapeutic effect, often used different dosage forms or programs.
One dosage program consists of a single dosing of the drug from a
conventional capsule or tablet that produced a rapid rise followed
by an immediate decline of the drug blood level versus time. The
single dosing does not maintain the drug within a therapeutic range
for an extended period of time, but exhibits of a short duration of
action due to the inability of the conventional dosage form to
provide drug delivery over time.
[0004] Another prior art dosing program used to obtain and to
achieve drug blood levels consists in administering the drug
repetitively using conventional dosage forms at various dosing
intervals, as in multiple-dose therapy. In administering a drug
according to the multiple-dose therapy, the drug blood level
reached and the time required to reach that level depends on the
dose and the dosing interval. There are, however, several potential
problems inherent in multiple dose therapy. For example, if the
dosing interval is not appropriate for the biological half-life of
the drug, large peaks and valleys may result in the drug blood
levels. Also, the drug blood level may not be within the
therapeutic range at sufficiently early times, an important
consideration for many disease states. And too, patient
noncompliance with the multiple dosing regimen can result in a
failure of this approach, especially as a drug in circulation
surges to a high each time the drug is administered followed by a
decline in drug concentration in the blood and in body
compartments. Thus, a graph of drug in circulation following a
dosage program of several doses, has an appearance of a series of
peaks, which may surpass the toxic threshold. Then, each time the
blood levels decreases into valleys, below a critical level needed
to achieve a desired therapeutic effect, that effect may not be
obtainable in the blood and body. Conventional dosage forms and
their mode of operation are discussed in Remington's Pharmaceutical
Sciences, 18th Edition, pages 1676 to 1686, (1990), Mack Publishing
Co.; The Pharmacological Basis of Therapeutics, 7th Edition, page 7
(1985) published by MacMillian Publishing Co., and in U.S. Pat.
Nos. 3,598,122 and 3,598,123 both issued to Zaffaroni.
[0005] A critical need exists for a controlled-rate dosage form for
administering the drug of the formula: 2
[0006] which drug is presently administered in conventional dosage
forms including tablets, capsules, elixirs and suspensions. These
conventional dosage forms produce the peaks and valleys drug
pattern presented above and they do not provide for controlled-rate
therapy over an extended period of time. The drug of the formula is
dosed twice or thrice a day now because of its elimination
half-life of three to five hours. This pattern of dosing indicates
the need for a controlled-release dosage form that can administer
the drug at a controlled rate over an extended time to provide
constant therapy and thereby eliminate the need for multiple
dosing. The drugs of the structural formula are known in U.S. Pat.
Nos. 4,535,186; 4,611,078; and 4,761,501 all issued to Husbands,
Yardley and Muth.
[0007] The prior art provided controlled-release dosage forms that
can continuously over time administer a drug for controlled-rate
therapy. For example, in U.S. Pat. No. 4,327,725 issued to Cortese
and Theeuwes and in U.S. Pat. Nos. 4,612,008; 4,765,989; and
4,783,337 issued to Wong, Barclay, Deters, and Theeuwes. The dosage
forms disclosed in these patents provide a drug at a constant rate
for effecting a therapeutic range for preferred therapy. The dosage
forms of the patents provide a therapeutic range and avoids
delivering the drug in excess in a toxic range with its
accompanying side-effects. The dosage forms of the patents in
providing a controlled dose in a therapeutic range also avoids
delivering the drug in an ineffective dose in an ineffective
range.
[0008] The dosage forms presented immediately above operate
successfully for their intended use and they can deliver many drugs
indicated for good therapy. The drugs of the above structural
formula, however, possess properties such as a high solubility of
570 mg per ml at a body temperature of 37.degree. C. that can lead
to a premature release of the drug from the dosage form. During
operation of the dosage forms, the convection motion of the imbibed
fluid, and the hydrostatic pressure of the,imbibed fluid coupled
with the high solubility can result in the premature release of the
drugs of the formula.
[0009] It is immediately apparent in the light of the above
presentation that an urgent need exists for a dosage form endowed
with controlled-release delivery for delivering the drugs embraced
by the structural formula. The need exists for the dosage form for
delivering the drug at a controlled dose in a therapeutic range
while simultaneously providing the intended therapy. It will be
appreciated by those versed in the dispensing art, that such a
dosage form that can administer the drug in a controlled-rate dose
over time, would, represent an advancement and a valuable
contribution to the art.
OBJECTS OF THE INVENTION
[0010] Accordingly, in view of the above presentation, it is an
immediate object of this invention to provide a dosage from that
possesses controlled-release delivery for providing a dosage form
for administering a drug of the structural formula.
[0011] Another object of the present invention is to provide a
dosage form for administering the drug of the formula in a
controlled-rate dose in a therapeutic range over a prolonged period
of time.
[0012] Another object of the present invention is to provide a
dosage form that can deliver the drug of the formula
essentially-free of a premature release from the dosage form.
[0013] Another object of the present invention is to provide a drug
delivery controlled-release system that can deliver a drug for
maintaining constant drug levels in the blood thereby functioning
as a prolonged release system.
[0014] Another object of the present invention is to provide drug
delivery sustained-release system that provides slow release of the
drug over an extended period of time optionally in a therapeutic
range.
[0015] Another object of the present invention is to provide a
dosage form that substantially reduces and/or substantially
eliminates the unwanted influences of a gastrointestinal
environment of use and still provides controlled drug
administration.
[0016] Another object of the present invention is to provide an
improvement in a dosage form for administering a drug embraced by
the structural formula and its pharmaceutically acceptable salt,
wherein the improvement comprises delivering the drug in a
controlled-release rate from the dosage form for improved and known
therapy.
[0017] Another object of the invention is to provide a once-a-day
controlled-release dosage form to deliver the drug of the
structural formula orally to a patent in need of therapy.
[0018] Another object of the invention is to provide a method for
administering a drug of the formula by orally administering the
drug in a controlled rate dose per unit dose over an extended time
to an animal in need of therapy.
[0019] Another object of the present invention is to provide a
method for administering a drug of the formula in a therapeutic
range while simultaneously substantially-avoiding a toxic range and
an infective range.
[0020] Another object of the present invention is to provide a
therapeutic composition comprising a drug of the structural formula
blended with a drug-composition forming polymer.
[0021] Another object of the invention is to provide a therapeutic
composition comprising a member selected from the group consisting
of venlafaxine and its pharmaceutically acceptable additional salt
and a pharmaceutically acceptable polymer carrier for venlafaxine
and its acceptable salts.
[0022] Other objects, feature, and advantages of the invention will
more apparent to those versed in the dispensing arts from the
following detailed specification, taken in conjunction with the
drawings and the accompanying claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] In the drawing figures, which are not drawn to scale, but
are set forth to illustrate various embodiments of the invention,
the drawing figures are as follows:
[0024] Drawing FIG. 1 is a general view of a dosage form provided
by the invention, which dosage form is designed and shaped for oral
administration, and for a drug delivery in a controlled-rate dose
in the gastrointestinal tract;
[0025] Drawing FIG. 2 is an opened view of the dosage form of
drawing FIG. 1 for depicting the structure of the dosage form and
the composition member contained inside the dosage form; and
[0026] Drawing FIG. 3 is a view of a dosage form that depicts an
external, instant-release of drug of the structural formula coated
on the exterior surface of the dosage form.
[0027] In the drawing figures, and in the specification, like parts
in related figures are identified by like numbers. The terms
appearing earlier in the specification and in the description of
the drawing figures, as well as embodiments thereof, are further
described elsewhere in the disclosure.
DETAILED DESCRIPTION OF THE DRAWINGS
[0028] Turning now to the drawing figures in detail, which drawing
figures are examples of dosage forms provided by this invention,
and which examples are not to be construed as limiting, one example
of a dosage form is seen in drawing FIG. 1. In drawing FIG. 1, a
dosage form 10 is seen comprising a body member 11, which body 11
comprises wall 12, that surrounds and forms an internal area, not
seen in drawing FIG. 1. Dosage form 10 comprises at least one exit
port 13 for connecting the exterior with the interior of dosage
form 10.
[0029] The dosage form 10 of drawing FIG. 1 illustrates a
controlled-release dosage form manufactured as an osmotic dosage
form that delivers a drug by osmotic action over an extended period
of time. The dosage form comprising controlled-release properties
embraced by this invention are successful at maintaining
substantially constant drug levels in the blood or in a tissue. The
dosage forms within the mode and manner of this invention comprises
also sustained-release dosage forms. The sustained-release dosage
forms releases the drug and provide drug levels in the blood or
target tissue within a therapeutic range over an extended period of
time. The invention embraces additionally prolonged release dosage
forms. The prolonged release dosage form denotes extended duration
of drug delivery action over that achieved by conventional drug
delivery.
[0030] In drawing FIG. 2, dosage form 10 of FIG. 1 is seen in
opened section. In drawing FIG. 2, dosage form 10 comprises a body
11, a wall 12 that surrounds and defines an internal compartment
14. In drawing FIG. 2, internal compartment 14 communicates through
an exit passageway 13 with the exterior of dosage form 10.
[0031] Wall 12 of dosage form 10 comprises totally or in at least a
part of a composition that is permeable to the passage of an
exterior fluid present in an environment of use, such as aqueous
and biological fluids. Wall 12 is formed of nontoxic ingredients,
is substantially impermeable to the passage of a drug and other
ingredients present in compartment 14. Wall 12 comprises a
composition that is substantially inert, that is, wall 12 maintains
its physical and chemical integrity during the drug dispensing life
of a drug from dosage form 10. The phrase, "maintaining its
physical and chemical integrity," means wall 12 does not lose its
structure and it does not change during the dispensing life of
dosage form 10, except for possible leaching of one or more exit 13
passageway formed during operation of dosage form 10 or for
leaching a water-soluble flux enhancers blended into wall 12. Wall
12 comprises a material that does not adversely affect an animal, a
human or any other components comprising the dosage form.
Representative materials for forming wall 12, are in one
embodiment, a cellulose ester polymer, a cellulose ether polymer
and a cellulose esterether polymer. These cellulosic polymers have
a degree of substitution. D.S., on the anhydroglucose unit, from
greater than 0 up to 3 inclusive. By degree of substitution is
meant the average number of hydroxyl groups originally present on
the anhydroglucose unit comprising the cellulose polymer that are
replaced by a substituting group. Representative materials include
a member selected from the group consisting of cellulose acylate,
cellulose diacylate, cellulose triacylate, cellulose acetate,
cellulose diacetate, cellulose triacetate, mono-, di- and
tricellulose alkanylates, mono-,di-, and tricellulose aroylates,
and the like. Exemplary polymers include cellulose acetate having a
D.S. up to 1 and an acetyl content up to 21%; cellulose acetate
having a D.S. of 1 to 2 and an acetyl content of 21 to 35 %;
cellulose acetate having a D.S. of 2 to 3 and an acetyl content of
35 to 44.8%, and the like. More specific cellulosic polymers
include cellulose propionate having a D.S. of 1.8 and a propyl
content of 39.2 to 45% and a hydroxyl content of 2.8 to 5.4%;
cellulose acetate butyrate having a D.S. of 1.8, an acetyl content
of 13 to 15% and a butyryl content of 34 to 39%; cellulose acetate
butyrate having an acetyl content of 2 to 29%, a butyryl content of
17 to 53% and a hydroxyl content of 0.5 to 4.7; cellulose
triacylates having a D.S. of 2.9 to 3 such as cellulose
trivalerate, cellulose trilaurate, cellulose tripolmitate,
cellulose trisuccinate, and cellulose trioctanoate; cellulose
diacylates having a D.S. of 2.2 to 2.6 such as cellulose
disuccinate, cellulose dipalmitate, cellulose dioctanoate,
cellulose dipentanoate, co-esters of cellulose such as cellulose
acetate butyrate and cellulose acetate propionate, and the
like.
[0032] Additional polymers include ethyl cellulose of various
degree of etherification with ethoxy content of from 40% to 55%,
acetaldehyde dimethyl cellulose acetate, cellulose acetate ethyl
carbamate, cellulose acetate methyl carbamate, cellulose acetate
diethyl aminoacetate, semipermeable polyamides; semipermeable
polyurethanes; semipermeable sulfonated polystyrenes; semipermeable
cross-linked selective polymers formed by the coprecipitation of a
polyanion and a polycation as disclosed in U.S. Pat Nos. 3,173,876,
3,276,586, 3,541,005; 3,541,006, and 3,546,142; semipermeable
polymers as disclosed by Loeb and Sourirajan in U.S. Pat. No.
3,133,132; semipermeable lightly cross-linked polystyrene
derivatives, semipermeable cross-linked poly(sodium styrene
sulfonate); semipermeable cross-linked poly(vinylbenzyltrimethyl
ammonium chloride); semipermeable polymers exhibiting a fluid
permeability of 2.5.times.10.sup.-8 to
2.5.times.10.sup.-4(cm.sup.2/hr.atm) expressed per atmosphere of
hydrostatic or osmotic pressure difference across the semipermeable
wall. The polymers are known to the art in U.S. Pat. Nos.
3,845,770; 3,916,899; and 4,160,020; and in Handbook of Common
Polymers by Scott, J. R. and Roff, W. J., 1971 published by CRC
Press, Cleveland, Ohio.
[0033] Compartment 14 comprises a drug composition, identified as
drug layer 15 which contains drug 16, identified by dots. Drug 16
comprises a drug of the following structural formula: 3
[0034] wherein the dotted line represents optional unsaturation or
a cycloalkenyl moiety; R.sub.1 is a member selected from the group
consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R.sub.2 is
a member selected from the group consisting of hydrogen and alkyl
of 1 to 6 carbon atoms; R.sub.4 is a member selected from the group
consisting of hydrogen, alkyl of 1 to 6 carbon atoms, formyl, and
alkanoyl of 2 to 7 carbon atoms; R.sub.5 and R.sub.6 are
independently a member selected from the group consisting of
hydrogen, hydroxyl, an alkyl of 1 to 6 carbon atoms, an alkoxy of 1
to 6 carbon atoms, alkanoyloxy of 2 to 7 carbon atoms, nitro,
alkylmercapto of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6
carbon atoms in which each alkyl group comprises 1 to 6 carbon
atoms, alkanamido of 2 to 7 carbon atoms, halo, and trifluoroethyl,
R.sub.7 is a member selected from the group consisting of hydrogen
and alkyl of 1 to 6 carbons, and n is one of the integers 0, 1, 2,
3, and 4. The formula embraces also the pharmaceutically acceptable
addition salts including a member selected from the group
consisting of inorganic, organic, hydrochloric, hydrobromic,
gluconic, fumaric, maleric, sulfonic, succinic, sulfuric,
phosphoric, tartaric, acetic, proponic, citric, oxalic and similar
pharmaceutically acceptable addition salts. The compounds are known
in U.S. Pat. Nos. 4,535,186; 4,611,078; 4,761,501; and
5,190,765.
[0035] The drugs of the structural formula are represented by the
drug 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol of
the structural formula: 4
[0036] The drug embraced by the formula possesses antidepressant
properties. The drug in vitro prevents the neuronal uptake of
seroton in, morepinephrine, and dopamine and it does not inhibit
monoamine oxidase. The drug antagonizes reserpine-induced
hypothermia and potentiates the effects of levodopa, and reduces
histamine-induced corticotropin release and induces cyclicadenosine
monophosphate subsensitivity after both acute and chronic
administration. The drug possesses excellent antidepressant
activity in humans. The therapeutic amount of drug 16 in dosage
form 10 is 0.5 mg to 750 mg, with individual dosage forms
comprising 2, 5, 10, 25, 40, 50, 75, 100, 150, 250, 300, 500, and
600 mg of drug 16 for administering in a single dose or in more
then one dose over an extended period of 24 hours. The therapeutic
properties of the drug embraced by the structural formula are
reported in Current Therapeutic Research, Vol. 42, No. 5, pages 901
to 909 (1987).
[0037] Composition 15 comprising drug 16 may comprise a drug
dispensing carrier and composition formulating member consisting of
a member selected from the group consisting of 0 wt % to 25 wt % of
a hydroxypropylalkylcellulose where alkyl consists of 1 to 7
carbons selected from the group consisting of methyl, ethyl,
isopropyl, butyl, pentyl, and hexyl which cellulose member
comprises a 9,000 to 1,250,000 molecular weight and is exemplified
by hydroxypropylmethylcelluose, hydroxypropylethylcellulose,
hydroxypropylisopropylcellulose, hydroxypropylbutylcellulose and
hydroxypropylhexylcellulose represented by dashes 17; a member
selected from the group consisting of 0 wt % to 20 wt %
hydroxylalkylcellulose where alkyl is 1 to 6 carbons including
methyl, ethyl, propyl, butyl, pentyl, and hexyl which cellulose
member comprises a 7,500 to 750,000 molecular weight and is
exemplified by hydroxymethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose, hydroxyisopropylcellulose and
hydroxybutylcellulose as represented by slanted line 18; a member
selected from the group consisting of 0 wt % to 35 wt % of a
vinyl-polymer having a 3,500 to 750,000 molecular weight
represented by poly-n-vinylamide, poly-n-vinlycetamide,
poly-n-vinylethylacetamide, poly-n-vinylmethylpropionamide,
poly-n-vinyl ethylpropionamide, poly-n-vinylmethylisobutyramide,
poly-n-vinyl-2-pyrrolidone, poly-n-vinypiperidone also known as
polyvinylpyrrolidone and as poly-n-vinylpyrroledone,
poly-n-vinylcaprolactam, poly-n-vinyl-5-methyl-2-pyrrolidone and
poly-n-vinyl-3-methyl-2-pyrrolidone, and poly-n-vinylpyrrolidone
copolymer with a member selected from the group consisting of vinyl
acetate, vinyl alcohol, vinyl chloride, vinyl fluoride, vinyl
butyrate, vinyl laurate and vinyl stearate represented by small
circles 19; and 0 wt %, where wt % is weight percent, 35 wt % of a
maltodextrin polymer composition comprising the formula
(C.sub.6H.sub.12O.sub.5).sub.n H.sub.2O wherein n is 3 to 7,500 and
the maltodextrin polymer comprises a 500 to 1,250,000 number
average molecular weight represented by a small square 20; as
member selected from the group consisting of 0 wt % to 40 wt % of
poly(etheylen oxide) having a molecular weight of 100,000 to
600,000 grams per mole, represented by half-circles 20a.
Composition 15 optionally comprises from 0 to 4.5 wt % of a
lubricant represented by magnesium stearate, calcium stearate or
stearic acid. The total weight of all ingredients in composition 15
is equal to 100 wt %, weight percent.
[0038] Compartment 14 comprises a displacement composition or push
layer 21. Displacement composition 21 comprises a polymer member
selected from the group consisting of a polymer possessing a
repeating molecular unit (--0--CH.sub.2CH.sub.2--).sub.n wherein n
is a positive whole number of 50,000 to 300,000 as represented by a
poly(alkylene oxide) comprising poly(ethylene oxide) seen as wavy
line 22; a maltodextrin polymer of the formula
(C.sub.6H.sub.12O.sub.5).sub.n H.sub.2O wherein n is 50 to 62,000
and comprises a 9,000 to 10,000,000 molecular weight and
represented by triangle 23; a carboxymethylcellulose polymer
comprising a 10,000 to 5,000,000 molecular weight represented by
alkali carboxymethylcellulose, sodium carboxymethylcellulose and
potassium carboxymethylcellulose, ammonium carboxymethylcellulose,
sodium carboxymethyl-2-hydroxyethylcellu- lose, sodium
carboxymethyl-methylcellulose, alkali carboxymethyl-hydroxypr-
opyl-methylcellulose, alkali
carboxymethyl-2-hydroxyethylmethylcellulose, alkali
carboxymethyl-2-hydroxybutylmethylcellulose, alkali
carboxymethyl-2-hydroxyethyl-ethylcellulose and alkali
carboxymethyl-2-hydroxypropylcellulose, where alkali is sodium and
potassium and seen in drawing FIG. 2 as hexagonal 23a. The polymers
in push layer 21 provide unforeseen operating advantages as the
polymer maintains its chemical composition during operation as it
imbibes an external aqueous fluid including biological fluid while
simultaneously pushing the drug from the dosage form
essentially-free of substantially mixing the drug composition with
the push composition. The displacement composition 21 comprises
optionally from 4 to 35 wt % of an osmotically active compound,
also known as osmagent and represented by vertical line 24.
Representative of osmotically effective compounds comprises salts,
oxides, esters that exhibit imbibition properties, carbohydrates
and acids including a member selected from the group consisting of
magnesium sulfate, magnesium chloride, sodium chloride, lithium
chloride, potassium chloride, potassium sulfate, sodium sulfate,
sodium sulfite, lithium sulfate, ammonium chloride, potassium
lactate, mannitol, urea, magnesium succinate, tartaric acid,
raffinose, sorbitol, sucrose, fructose, and glucose. Displacement
layer 21 optionally comprises 0.5 wt % to 30 wt % of a cellulose
polymer 25 represented by the letter v. Representative of cellulose
polymer 25 comprise a member selected from the group consisting of
hydroxypropylcellulose, hydroxypropylmethylcellulose,
hydroxypropylethylcellulose, hydroxypropylisopropylcellulose,
hydroxypropylbutylcellulose, hydroxypropylpentylcellulose, and
hydroxypropylhexylcellulose comprising a 9,000 to 225,000 molecular
weight. The displacement composition optionally comprises 0 wt % to
5 wt % of lubricant stearic acid and, magnesium stearate, calcium
oleate, oleic acid, and caprylic acid. The polymers are known in
U.S. Pat Nos. 3,845,770; and 4,160,020; in Handbook of Common
Polymers by Scott, J. R., and Roff, W. J., published by CRC Press,
Cleveland, Ohio.
[0039] Dosage form 10, a seen in drawing FIG. 3 depicts another
preferred manufacture provided by the invention. Dosage form 10, in
drawing FIG. 3, comprises an external coat on a the exterior
surface of dosage form 10. Coat 26 is a therapeutic composition
comprising 10 mg to 150 mg of drug 16, represented by dots 16.
Exterior coat 26 provides instant drug 16 for instant therapy. Drug
16 is blended with an aqueous-soluble composition comprising a
carrier methylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, and blends of hydroxypropylcellulose
and hydroxypropylmethylcellulose. Coat 26 optionally comprises
polyethylene glycol or acetylated triglycerides. Coat 26 provides
instant therapy as coat 26 dissolves or undergoes dissolution in
the presence of a biological fluid and concurrently therewith
delivers drug 16 to a drug receiving patient. Coat 26 provides
instant therapy and it essentially overcomes the time required for
the drug to be delivered from the dosage form.
[0040] Dosage form 10, as provided by this invention, and as seen
in the above drawing figures can be manufactured for administering
drug 16 by the oral route, and in another embodiment, dosage form
10 comprising exterior and interior drug 16 can be sized and shaped
for administering drug 16 by the sublingual and buccal routes. The
sublingual and buccal routes can be used for quicker therapy and
they can be used when a smaller dose of drug 16 is needed for
therapy. The buccal and sublingual routes can be used as a by-pass
of the first pass of hepatic metabolism of drug 16. The sublingual
or buccal routes can be used for administering the first dose of
drug, followed by permitting dosage form 10 to enter the
gastrointestinal tract for subsequent drug delivery.
[0041] Dosage form 10, when manufactured as an osmotic,
controlled-release dosage form, comprises at least one passageway
13, or more than one passageway 13. The expression "at least one
passageway" includes aperture, orifice, bore, pore, porous element
through which the drug can be pumped, diffuse, travel or migrate,
hollow fiber, capillary tube, porous overlay, porous insert,
microporous member, porous composition, and the like. The
expression also includes a material that erodes or is leached from
wall 12 in the fluid environment of use to produce at least one
passageway in dosage form 10. Representative material suitable for
forming at least one passageway, or a multiplicity of passageways,
includes an erodible poly(glycolic) acid or poly(lactic) acid
member in the wall; a gelatinous filament; poly(vinyl alcohol);
leachable materials such as fluid removable pore forming
polysaccharides, salts, or oxides, and the like. A passageway or a
plurality of passageways can be formed by leaching a material such
as sorbitol, sucrose, lactose, fructose, or the like, from the wall
to provide an osmotic dimensioned pore-passageway. The passageway
can have any shape such as round, triangular, square, elliptical,
and the like, for assisting in the metered release of drug from
dosage form 10. Dosage form 10 can be constructed with one or
passageways in spaced apart relation on one or more than a single
surface of a dosage form. Passageways and equipment for forming
passages are disclosed in U.S. Pat. Nos. 3,845,770 and 3,916,899 by
Theeuwes and Higuchi; in U.S. Pat No. 4,063,064 by Saunders et al;
and in U.S. Pat. No. 4,088,864 by Theeuwes et al. Osmotic
passageways comprising controlled-drug releasing dimension, sized,
shaped and adapted as a drug releasing pore formed by aqueous
leaching to provide a drug-releasing pore of controlled osmotic
release rate are disclosed in U.S. Pat. No. 4,200,098 by Ayer and
Theeuwes; and in U.S. Pat. No. 4,285,987 by Ayer and Theeuwes.
[0042] Wall 12 of osmotic dosage form 10 can be formed in one
technique using the air suspension procedure. This procedure
consists in suspending and tumbling the compressed drug-push core
laminate in a current of air and wall forming composition until a
wall is applied to the drug-push compartment. The air suspension
procedure is well-suited for independently forming the wall. The
air suspension procedure is described in U.S. Pat. No. 2,799,241;
J. Am. Pharm. Assoc., Volume 48, pages 451 to 454, (1959); and
ibid, Volume 49, pages 82 to 84, (196). Osmotic dosage forms can
also be coated with a wall forming composition in a Wurster.RTM.
air suspension coater, using methylene dichloride-methanol
cosolvent, 80:20, wt:wt, an ethanol-water, or acetone-water
cosolvent, 95:5 wt:wt using 2.5 to 4% solids. The Aeromatic.RTM.
air suspension coater using a methylene dichloride-methanol
cosolvent, 80:20 wt:wt, also can be used for applying the wall.
Other wall forming techniques such as pan coating system, where
wall forming compositions are deposited by successive spraying of
the composition on the drug-push compartment, accompanied by
tumbling in a rotating pan. Finally, the wall coated compartments
are dried in a forced air over at 30.degree. C. to 50.degree. C.
for up to a week to free dosage form 10 of solvent. Generally, the
walls formed by these techniques have a thickness of 2 to 30 mils
with a presently preferred thickness of 4 to 10 mils.
[0043] Dosage form 10 of the invention is manufactured by standard
manufacturing techniques. For example, in one manufacture the
beneficial drug and other ingredients comprising the drug layer
facing the exit means are blended and pressed into a solid layer.
The drug and other ingredients can be blended with a solvent and
mixed into a solid or semisolid formed by conventional methods such
a ball-milling, calendering, stirring or rollmilling and then
pressed into a preselected shape. The layer possesses dimensions
that correspond to the internal dimensions of the area the layer is
to occupy in the dosage form and it also possesses dimensions
corresponding to the second layer for forming a contacting
arrangement therewith. Next, the push layer, is placed in contact
with the drug layer. The push layer is manufactured using
techniques for providing the drug layer. The layering of the drug
layer and the push layer can be fabricated by conventional
press-layering techniques. Finally, the two layer compartment
forming members are surrounded and coated with an outer wall. A
passageway is laser, leached, or mechanically drilled through the
wall to contact the drug layer, with the dosage form optically
oriented automatically by the laser equipment for forming the
passageway on the preselected surface when a laser is used for
forming the passageway.
[0044] In another manufacture, the dosage form is manufactured by
the wet granulation technique. In the wet granulation technique,
for example, the drug and the ingredients comprising the drug layer
are blended using an organic solvent, such as isopropyl
alcohol-ethylene dichloride 80:20 v:v (volume:volume) as the
granulation fluid. Other granulating fluid such as denatured
alcohol 100% can be used for this purpose. The ingredients forming
the drug layer are individually passed through a 40 mesh screen and
then thoroughly blended in a mixer. Next, other ingredients
comprising the drug layer are dissolved in a portion of the
granulation fluid, such as the cosolvent described above. Then the
latter prepared wet blend is slowly added to the drug blend with
continual mixing in the blender. The granulating fluid is added
until a wet blend is produced, which wet mass then is forced
through a 20 mesh screen onto oven trays. The blend is dried for 18
to 24 hours at 30.degree. C. to 50.degree. C. The dry granules are
sized then with a 20 mesh screen. Next, a lubricant is passed
through an 80 mesh screen and added to the dry screen granule
blend. The granulation is put into milling jars and mixed on a jar
mill for 1 to 15 minutes. The push layer is made by the same wet
granulation techniques. The compositions are pressed into their
individual layers in a Manesty .RTM. press-layer press.
[0045] Another manufacturing process that can be used for providing
the compartment-forming composition layers comprises blending the
powered ingredients for each layer independently in a fluid bed
granulator. After the powered ingredients are dry blended in the
granulator, a granulating fluid, for example,
poly(vinyl-pyrrolidone) in water, or in denatured alcohol, or in
95:5 ethyl alcohol water, or in blends of ethanol and water is
sprayed onto the powders. Optionally, the ingredients can be
dissolved or suspended in the granulating fluid. The coated powders
are then dried in a granulator. This process granulates all the
ingredients present therein while adding the granulating fluid.
After the granules are dried, a lubricant such as stearic acid or
magnesium stearate is added to the granulator. The granules for
each separate layer are pressed then in the manner described
above.
[0046] The dosage form of the invention is manufactured in another
manufacture by mixing a drug with composition forming ingredients
and pressing the composition into a solid lamina possessing
dimensions that correspond to the internal dimensions of the
compartment. In another manufacture the drug and other drug
composition-forming ingredients and a solvent are mixed into a
solid, or a semisolid, by conventional methods such as ballmilling,
calendering, stirring or rollmilling, and then pressed into a
preselected layer forming shape. Next, a layer of a composition
comprising an osmopolymer and an optional osmagent are placed in
contact with the layer comprising the drug. The layering of the
first layer comprising the drug and the second layer comprising the
osmopolymer and optional osmagent composition can be accomplished
by using a conventional layer press technique. The wall can be
applied by molding, spraying or dipping the pressed bilayer's
shapes into wall forming materials. Another and presently preferred
technique that can be used for applying the wall is the air
suspension coating procedure. The procedure consists in suspending
and tumbling the two layers in current of air until the wall
forming composition surrounds the layers. The air suspension
procedure is described in U.S. Pat. No. 2,799,241; J. Am. Pharm.
Assoc., Vol. 48 pp 451-454 (1979); and, ibid, Vol. 49, pp 82-84
(1960). Other standard manufacturing procedures are described in
Modern Plastics Encyclopedia, Vol 46, pp 62-70 (1969); and in
Pharmaceutical Science, by Remington, 14th Ed., pp 1626-1678
(1970), published by Mack Publishing Co., Easton, Pa.
[0047] Exemplary solvents suitable for manufacturing the wall, the
laminates and laminae include inert inorganic and organic solvents
final laminated wall. The solvents broadly include members selected
for the group consisting of aqueous solvents, alcohols, ketones,
esters, ethers, aliphatic hydrocarbons, halogenated solvents,
cyclaliphatics, aromatics, heterocyclic solvents and mixtures
thereof. Typical solvents include acetone, diacetone, alcohol,
methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl
acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl
isobutyl ketone, methyl propyl ketone, n-hexane, n-heptaene
ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate,
methylene dichloride, ethylene dichloride, propylene dichloride,
carbon tetrachloride, chloroform, nitroethane, nitropropane,
tetrachoroethan, ethyl ether, isopropyl ether, cyclohexane,
cyclooctane, benzene, toluene, naphtha, tetrahydrofuran, diglyme,
aqueous and nonaqueous mixtures thereof, such as acetone and water,
acetone and methanol, acetone and ethyl alcohol, methylene
dichloride and methanol, and ethylene dichloride and methanol.
DETAILED DISCLOSURE OF EXAMPLES OF THE INVENTION
[0048] The following examples are merely illustrative of the
present invention and they should not be considered as limiting
thscope of the invention in any way as these examples and other
equivalents thereof will become apparent to those versed in the art
in the light of the present disclosure, the drawings and
accompanying claims.
EXAMPLE 1
[0049] A dosage form adapted for delivering a drug in a therapeutic
range is manufactured as follows: first a displacement or push
layer is prepared by blending and passing through a stainless steel
sizing screen having a mesh opening of 420 microns 587.5 grams of
sodium carboxymethylcellulose having a degree of polymerization of
approximately 3,200 and a degree of substitution of 0.7
carboxymethyl groups per anhydroglucose unit, 300 grams of powdered
sodium chloride, 50 grams of hydroxypropylcellulose having a
molecular weight of approximately 60,000 grams per mole, and 50
grams of hydroxypropylmethylcellulose having an average methoxyl
content of 29 weight percent and an average hydroxypropyl content
of 10 weight percent and an average molecular weight of
approximately 11,300 grams per mole. Next 10 grams of red ferric
oxide were passed through a sizing screen having openings of
approximately 250 microns. The resulting powders were mixed in a
planetary mixer to a uniform blend. The resulting blend was wet
granulated by adding with stirring anhydrous ethyl alcohol until, a
cohesive mass was formed. This mass was passed through a sizing
screen having openings of approximately 840 microns, forming coated
displacement particles, which were an dried overnight at ambient
temperature and humidity. The dried particles were then passed
again through the 840 micron sizing screen. Next 2.5 grams of
magnesium stearate, which had been previously sized through a mesh
having 180 micron openings, were tumble mixed into the coated
particles.
[0050] A composition comprising a drug of the structural formula
was prepared as follows: first, a drug composition was prepared by
passing 840 grams of venlafaxine hydrochloride, 100 grams of
hydroxypropylcellulose having a molecular weight of approximately
60,000 grams per mole, and 50 grams of polyvinylpyrrolidone having
a molecular weight of approximately 40,000 grams per mole, were
passed through a sizing having openings of approximately 420
microns, and mixed in a planetary mixer to yield a uniform blend.
Then, anhydrous ethyl alcohol was added to the mixture with
stirring to produce a cohesive damp mass. The resulting damp mass
was sized through a sieve having an opening of 840 microns,
producing coated venlafaxine drug, which was air dried overnight.
The resulting dried coated venlafaxine drug was passed again
through the sizing screen having an 840 micron opening. Next, 10
grams of magnesium stearate, sized to 180 microns, was tumble mixed
into the blend.
[0051] Next, the displacement-push composition and the drug
composition were formed into a bilayer core as follows: first, 87
mg of the drug composition was placed in a {fraction (9/32)} inch
round die cavity and lightly tamped with a standard concave round
tooling to form a slightly cohesive layer. Then, 70 mg of push
composition was added to die and the and the resulting fill was
compressed with a final force of 2 tons, thereby forming a two
layer cores.
[0052] The bilayer cores were placed next in a coating pan having a
12 inch diameter and they were coated with a wall-forming solution.
The wall-forming solution was prepared by dissolving 380 grams of
cellulose acetate having an acetyl content of 39.8 weight percent
in 7,220 grams of acetone. In a separate mixing vessel, 20 grams of
polyethylene glycol having a molecular weight of approximately
3,350 grams per mole were dissolved in approximately 380 grams of
purified water. The two solutions were mixed to form the
wall-coating solution which was spray coated onto the cores until
about 20 mg of wall composition was deposited on the surfaces of
the bilayer core.
[0053] A delivery exit port was formed across the wall by drilling
an exit port, centered on the face of the dosage form on the drug
composition side of the dosage form. The resulting dosage form was
placed in simulated physiological fluid at 37.degree. C., and the
dosage form delivered a dose of 73 mg of venlafaxine hydrochloride
at a controlled, zero rate over an extended duration of 15
hours.
EXAMPLE 2
[0054] The procedure of Example 1 was followed with the
manufacturing procedures as set forth, except that the drug
composition comprises 890 grams of venlafaxine hydrochloride, 100
grams of hydroxypropylcellulose, and 10 grams of magnesium
stearate. The resulting dosage form released in simulated
intestinal fluid 77 mg of venlafaxine hydrochloride at a zero-order
rate over an extended duration of 16 hours.
EXAMPLE 3
[0055] The procedure of Example 1 was followed with all
manufacturing steps as described, except that the drug composition
consists of 650.0 grams of venlafaxine hydrochloride, 240.0 grams
of maltodextrin having an average molecular weight of approximately
1800 grams per mole and an average degree of polymerization of
11.1, 80.0 grams of hydroxypropyl cellulose, 20.0 grams of
polyvinyl pyrrolidone, and 10.0 grams of magnesium stearate. The
resulting dosage form was tested in artificial intestinal fluid,
the dosage form delivered a dose of 57 mg of venlafaxine
hydrochloride at zero order rate over a period of 15 hours.
EXAMPLE 4
[0056] The procedure of Example 1 was repeated with the manufacture
as previously set-forth, except that the drug composition consists
of 840.0 grams of venlafaxine hydrochloride, 150.0 grams of
polyethylene oxide having an average molecular weight of
approximately 100,000 grams per mole, and 10.0 grams of magnesium
stearate. The wall weight weighed approximately 25 mg. The
resulting dosage forms were tested in simulated intestinal fluid,
and they released a dose of 73 mg of venlafaxine hydrochloride at
controlled rate over an extended period of 20 hours.
EXAMPLE 5
[0057] The compositions were manufactured as in Example 1. The
process of manufacture was the same except that the push layer
manufactured was prepared in a fluid bed aqueous-based granulation
process. This was accomplished by sizing the sodium carboxymethyl
cellulose, the sodium chloride, the hydroxypropyl cellulose, and
red ferric oxide through a screen having openings of 420 microns.
The resulting powders were charged into a fluid bed granulation
column and binder solution consisting of the hydroxypropyl
methylcellulose at a 5 percent solids concentration in water was
sprayed on, thereby forming the granules for the push layer.
EXAMPLE 6
[0058] The compositions and processes followed in this example were
the same as in Example 1 except the push consisted of 740.0 grams
polyethylene oxide with an average molecular weight of
approximately 5 million grams per mole, 200.0 grams of sodium
chloride, 50.0 grams of hydroxypropyl methyl cellulose having
average molecular weight of approximately 11,300 per mole, 5.0
grams of red ferric oxide, and 5.0 grams of magnesium stearate.
DESCRIPTION OF METHOD OF PERFORMING THE INVENTION
[0059] Additional embodiments of the invention pertains to a method
for delivering a drug embraced by the structural formula of this
invention for its intended therapy. One embodiment pertains to a
method for delivering a drug of the formula by administering a
dosage form comprising 0.5 mg to 750 mg of the drug from a dosage
form selected from sustained-release and controlled-release dosage
forms in a therapeutically responsive dose over an extended period
of time. Another embodiment of the invention pertains to a method
for delivering a drug of the formula disclosed in this invention,
to the gastrointestinal tract of a human in need of this therapy,
wherein the method comprises the steps of: (A) admitting orally
into the gastrointestinal tract of the human a dosage form
comprising: (1) a non-toxic wall composition comprising means for
imbibing an external aqueous fluid through the wall into the dosage
form, which wall surrounds and defines; (2) an internal
compartment; (3) a drug composition comprising a drug of the
formula in the compartment comprising a dosage unit amount of said
drug; (4) a push composition in the compartment for pushing the
drug composition from the compartment; (5) at least one exit means
in the wall for delivering the drug from the dosage form; (B)
imbibing fluid through the wall into the compartment thereby
causing the composition to form a deliverable dosage form and
concomitantly causing the push composition to expand and push the
drug composition through the exit means from the dosage form; and
(C) deliver the therapeutic drug in a therapeutically effective
amount at a controlled rate over an extended period of time to the
patient in need of said therapy. The method also comprising
dispensing a dose amount of said drug from an instant release
exterior dosage amount of drug to the patient for providing instant
anti-depressant therapy.
[0060] Inasmuch as the foregoing specification comprises preferred
embodiments of the invention, it is understood that variations and
modifications may be made herein, in accordance with the inventive
principles disclosed, without departing from the scope of the
invention.
* * * * *