U.S. patent application number 12/926463 was filed with the patent office on 2011-08-04 for extended release composition containing tramadol.
This patent application is currently assigned to GALEPHAR PHARMACEUTICAL RESEARCH, INC.. Invention is credited to Arthur M. Deboeck, Antonio Sereno, Francis Vanderbist.
Application Number | 20110189269 12/926463 |
Document ID | / |
Family ID | 33550841 |
Filed Date | 2011-08-04 |
United States Patent
Application |
20110189269 |
Kind Code |
A1 |
Deboeck; Arthur M. ; et
al. |
August 4, 2011 |
Extended release composition containing tramadol
Abstract
The present invention relates to a once daily extended release
pharmaceutical preparation of Tramadol or its acceptable
pharmaceutical salts. The preparation provides, effective blood
concentration for a period of about 24 hours with reduced peak
concentrations. It is characterized that effective Tramadol levels
appear within the first hours after administration, the time to
maximal Tramadol content T.sub.max is at least 10 hours and the
peak Tramadol concentration is less than three times the
concentration obtained after 24 hours of said administration.
Inventors: |
Deboeck; Arthur M.; (Gurabo,
PR) ; Vanderbist; Francis; (Meise, BE) ;
Sereno; Antonio; (Melsbroeck, BE) |
Assignee: |
GALEPHAR PHARMACEUTICAL RESEARCH,
INC.
Juncos
PR
|
Family ID: |
33550841 |
Appl. No.: |
12/926463 |
Filed: |
November 18, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10119939 |
Apr 11, 2002 |
7858118 |
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12926463 |
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60282858 |
Apr 11, 2001 |
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Current U.S.
Class: |
424/451 ;
424/490; 514/646; 564/443 |
Current CPC
Class: |
A61P 29/00 20180101;
A61K 31/135 20130101; A61K 31/137 20130101; A61K 9/5084
20130101 |
Class at
Publication: |
424/451 ;
564/443; 514/646; 424/490 |
International
Class: |
A61K 31/137 20060101
A61K031/137; C07C 217/74 20060101 C07C217/74; A61K 9/16 20060101
A61K009/16; A61K 9/48 20060101 A61K009/48; A61P 29/00 20060101
A61P029/00 |
Claims
1. Oral Tramadol pharmaceutical composition suitable for once daily
administration comprising an effective amount of Tramadol or its
pharmaceutically acceptable salts providing in vivo, a time of
Tramadol peak plasma concentration (T.sub.max) greater than 10
hours and a peak Tramadol plasma concentrations (C.sub.max) which
are less than three times the plasma concentration obtained 24
hours after administration (C.sub.24h) of a single dose of such
composition.
2. Compositions of claim 1 wherein said pharmaceutical composition
provides after repeated once daily administration in vivo, a time
of Tramadol peak plasma concentration (T.sub.max) greater than 10
hours and a peak Tramadol plasma concentrations (C.sub.max) which
are not more than three times the plasma concentration obtained 24
hours of administration (C.sub.24h).
3. Composition of claim 1 wherein said pharmaceutical composition
provides, after single administration in vivo, o-demethyl Tramadol
peak plasma concentrations (C.sub.max) which are not more than
twice the plasma concentration obtained 24 hours after
administration (C.sub.24h).
4. Composition of claim 1 wherein said pharmaceutical composition
provides, after repeated once daily administrations, o-demethyl
Tramadol peak plasma concentrations (C.sub.max) which are not more
than twice the plasma concentration obtained 24 hours after
administration (C.sub.24h).
5. Composition of claim 1 wherein said pharmaceutical composition
provides, after single administration in vivo, a time of o-demethyl
Tramadol peak plasma concentration (T.sub.max) greater than 10
hours.
6. Composition of claim 1 wherein said pharmaceutical, composition
provides, after repeated once daily administrations in vivo, a time
of o-demethyl Tramadol peak plasma concentrations (T.sub.max)
greater than 10 hours.
7. Composition of claim 1 wherein said pharmaceutical composition
exhibit an in vitro dissolution biphasic profile.
8. Composition of claim 1 wherein said pharmaceutical composition
comprises individual containing Tramadol units from which Tramadol
is released at different rates.
9. Composition of claim 10 wherein said pharmaceutical composition
comprises at least one individual unit from which about 80% of
Tramadol is released within about 6 hours.
10. Composition of claim 10 wherein said pharmaceutical composition
comprises at least one individual unit from which about 80% of
Tramadol is released within 1 hour.
11. Composition of claim 1 wherein said pharmaceutical composition
comprises sustained released beads covered by layers containing
Tramadol from which the Tramadol is released at a different rate
than from the sustained release beads.
12. Composition of claim 13 wherein said pharmaceutical composition
comprises layers containing Tramadol from which at least 80% of
Tramadol is released within about 6 hours.
13. Composition of claim 13 wherein said pharmaceutical composition
comprises layers containing Tramadol from which at least 80% of
Tramadol is released within about 1 hour.
14. Composition of claim 10 wherein said pharmaceutical composition
is characterized in vivo, by a rapid rise of Tramadol plasma
concentration.
15. Composition of claim 16 wherein said rapid Tramadol plasma
concentration rise occurs within about 0.5 to 3 hours after
administration.
16. Composition of claim 16 wherein said rapid Tramadol plasma is
less than the peak concentration (C.sub.max) measured between
successive administration.
17. Composition of claim 1 wherein pharmaceutical composition
comprises multiple Tramadol containing units contained in a
capsule.
18. Composition of claim 1 wherein said pharmaceutical composition
comprises multiple Tramadol containing units compressed in a
tablet.
19. Composition of claim 1 wherein said pharmaceutical composition
provides similar pharmaceutical profile when such composition is
administered orally with or without food.
20. Composition of claim 1 wherein said pharmaceutical composition
provides effective pain control in humans during a period of about
24 hours after administration.
21. Composition of claim 1, wherein said pharmaceutical composition
provides effective pain control in humans, starting at about 1 to 2
hours after administration and lasting for about 24 hours after
administration.
22. Composition of claim 1, which exhibits a biphasic absorption
profile in vivo under fed and fasted administration conditions.
23. Composition of claim 1, wherein a first C.sub.max obtained from
said fast release tablet is less than a second C.sub.max obtained
from said slow release beads.
24. A method of managing post-surgery pain control, which comprises
the step of administering the composition of claim 1, to a patient
in need thereof.
25. The method of claim 24, wherein said managing is effected under
fed and fasted administration conditions.
26. The method of claim 24, wherein said administering is once
daily.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to a once daily extended
release oral Tramadol pharmaceutical preparation which provides
effective blood concentration for a period of about 24 hours with
reduced peak Tramadol plasma concentrations. The formulation of the
present invention provides peak. Tramadol plasma concentration s
that are less than twice the plasma concentration measured 24 hours
after administration, while providing for effective Tramadol plasma
concentration about 1 to 2 hours after administration.
[0002] Tramadol is a centrally acting synthetic analgesic compound
that is not derived from natural sources nor is it chemically
related to opiates. Although its mode of action is not completely
understood, at least two complementary mechanisms appear
applicable: Binding to .mu.-opioid receptors and inhibition of
reuptake of nor epinephrine and serotonin. Tramadol opioid activity
derives from low affinity binding the parent compound to
.mu.-opioid receptors and higher affinity binding of the M1
metabolite. In animal models, M1 is up to 6 times more potent than
Tramadol in producing analgesia and 200 times more potent in
.mu.-opioid binding. The contribution to human analgesia of
Tramadol relative to M1 is unknown.
[0003] Tramadol-induced antinociception is only partially
antagonized by the opiate antagonist naloxone in animal test. In
addition, Tramadol inhibits reuptake of nor-epinephrine and
serotonin in-vitro after oral administration of immediate release
dosage form the onset of analgesia is evident within 1 hour after
administration and reaches a peak in .apprxeq.2 to 3 hours. Peak
plasma concentrations are reached about 2 hours after
administration, which correlates closely with the time to peak pain
relief.
[0004] Tramadol immediate release is rapidly and almost completely
absorbed after oral administration. The mean absolute
bioavailability of 100 mg oral dose is .apprxeq.75%. Administration
with food does not significantly affect its rate or extent of
absorption; therefore, it can be administered without regard to
meals. The mean peak plasma concentration is 308.+-.78 ng/ml and
occurs at .apprxeq.2 hours after a single 100 mg oral dose in
healthy subjects. At this dose, the mean peak plasma concentration
of the active mono-O-desmethyl metabolite (racemic 1) is 55.+-.20
ng/ml and occurs .apprxeq.3 hours post-dose. The separate [+]- and
[-]-enantiomers of Tramadol generally follow a parallel time course
in plasma after a single 100 mg oral dose. Following a 100 mg dose,
the maximum plasma concentrations of the [-]-enantiomers are
some-what lower than those of the [+]-enatiomer (148.+-.33 vs.
168.+-.36 ng/ml, respectively). The [-]-M1 enantiomer (35.+-.10 vs.
26.+-.13 ng/ml, respectively). Steady state is achieved after 2
days of a 100 mg four times daily dosing regimen (maximum plasma
concentration was 592.+-.177 ng/ml). The plasma half-life of
Tramadol, following single and multiple dosing, was 6 and 7 hours,
respectively. The most common adverse reaction is nausea, vertigo,
constipation and headaches and is correlated to the patients plasma
Tramadol concentrations.
[0005] Tramadol is used for the management of moderate to
moderately severe pain such as pain following surgical procedures
(orthopedic, gynecological, cesarean section) and pain following
dental surgery (extraction of impacted molars).
[0006] Tramadol ability to control pain is directly related to its
concentration in the patient's plasma stream. The minimum effective
therapeutical Tramadol plasma level is around 100 ng/ml. Due to
Tramadol plasma elimination short half-live to maintain the minimum
effective plasma levels requires generally the oral administration
of 50 to 100 mg every 4 to 6 hours of immediate release
Pharmaceutical compositions. This administration schedule of the
drug makes it difficult for the patient to control pain, specially
during night time, since pain will reappear every 4 to 6 hours.
[0007] On the other hand, if patient in an attempt to control pain
for a longer period of time should take higher doses of immediate
release Tramadol than peak plasma levels will increase dramatically
and very serious side effects due to high blood levels will appear
immediately.
[0008] Another difficulty encountered by the man skilled in the art
for the production of a once daily Tramadol formulation arises from
Tramadol extremely high solubility in water and body fluids. The
prior art teaching related to Tramadol compositions that may be
useful for once daily administration are basically related to
maintain effective therapeutically plasma concentrations between
administration. Since It is known that the therapeutically
effective Tramadol plasma levels are close to the unwanted adverse
reaction plasma levels, once a day Tramadol compositions to be
useful to treat effectively patients in need must not only provide
for minimum effective therapeutic plasma levels but also must
provide for the control of toxic levels. Any once a day Tramadol
formulation which should not comply with both requirements would be
useless.
[0009] U.S. Pat. No. 5,601,842 discloses a tablet containing
Tramadol and a matrixing agent with a viscosity between 3,000 and
150,000 mPa in a 2% aqueous solution at 20.degree. C. U.S. Pat. No.
5,811,126 discloses a controlled release pharmaceutical composition
containing Tramadol and comprising sodium alginate, C.sub.2 to
C.sub.50, edible hydrocarbon derivative with melting point range
from 25.degree. C. to 90.degree. C. and divalent salt to cross link
the alginate. In vivo performance from these formulations is not
available.
[0010] U.S. Pat. Nos. 5,639,476 (12h) and 5,580,578 discloses
controlled release dosage form containing a substrate containing
Tramadol, said substrate being coated with a plasticized aqueous
dispersion of ammonio-methacrylate copolymer having low content of
quaterny ammonium groups and a permeability enhancing pore former
said coating being cured for about 24 to about 60 hours to
stabilize said formulation.
[0011] U.S. Pat. No. 5,955,104 discloses a delayed release Tramadol
formulation consisting of pellets in a water soluble capsule or in
a tablet compressed from said pellets, each pellet having (a) a
substantially inert core; (b) an active ingredient layer containing
(i) Tramadol particles in mixture with a binder for adhering said
Tramadol particles over said inert core, and optionally (iii) a
pharmaceutically acceptable, inner adjuvant; and (c) a delay
coating for retarding the release of Tramadol consisting
principally of mixtures of Ethylcellulose and shellac.
[0012] U.S. Pat. Nos. 5,645,858, 5,474,786 and 5,395,626 discloses
multilayered controlled release pharmaceutical dosages forms for
water soluble drugs comprising a plurality of coated beads and
which comprises a core and seven or eight different coatings.
[0013] U.S. Pat. No. 5,849,240 describes a process for the
manufacture of particles by the "melt-pelletization" process.
Tramadol is one of the examples but in vivo performances of such
formulation is not available.
[0014] U.S. Pat. No. 5,968,551 (continuation of U.S. Pat. No.
5,273,760) describes sustained release oral analgesic form for once
a day administration comprising a unit dose comprising a plurality
of pharmaceutical acceptable matrices comprising ananalgesically
effective amount of Tramadol and hydrophobic material each of said
matrices having a diameter of about 0.1 to 3 mm bioavailability and
therapeutical effect for about 24 hours or more after oral
administration to a human patient (no control of side effect). It
also discloses (claim 33) a method of treating patients for
moderate to severe pain with a once daily oral administration of a
unit dose consisting of a plurality of inert pharmaceutical
acceptable beads control with an analgesically effective amount of
an opioid analgesically effective amount of analgesic said beads
having a diameter of 0.1 to 3 mm and having effective blood levels
for about 24 hours (against side effects) with a peak of said
opioid in vivo for about 3 to about 10 hours after
administration.
[0015] U.S. Pat. No. 5,965,163 describes a solid dosage form
comprising a plurality of particles including Tramadol in a matrix,
the matrix including a mixture of hydrophobic and hydrophilic
fusible carriers having melting point from 35.degree. C. to
150.degree. C., which are produced by the method of "melt
pelletization".
[0016] U.S. Pat. No. 5,591,452 discloses a once daily Tramadol
preparation constituted of Tramadol incorporate into a controlled
release matrix constituted of one or more hydrophilic or
hydrophobic polymers which provides a T.sub.max of about 3 to about
6 hours.
[0017] U.S. Pat. No. 5,958,482 describes a sustained release
pharmaceutical formulation comprising an extruded blend of
Tramadol, and one or more hydrophobic fusible carriers having a
melting point from about 30.degree. to about 200.degree. C.,
providing a sustained-release of said therapeutically active agent
for a time period of from about 8 to about 24 hours. With a peak
plasma for about 2 to 8 hours.
[0018] U.S. Pat. No. 5,891,471 discloses Tramadol pharmaceutical
particles for once a day administration which provides a time to
peak plasma level of Tramadol in about 2 to about 6 hours after
administration, produced by a process of "melt-pelletization".
[0019] U.S. Pat. Nos. 5,072,360 and 5,478,577 discloses a method of
treating pain in humans comprising orally administering of a once a
day basis an oral sustained release dosage form of an opioid
analgesic which upon single dose and multiple doses administration
provides a time to maximum plasma concentration (T.sub.max) of said
opioid in about 2 to 10 hours and a maximum plasma concentration
(C.sub.max) which is more than twice the plasma level of said
opioid at about 24 hours after administration of the dosage form,
and which, dosage form provides effective treatment of pain for
about 24 hours or more after administration to the patient.
[0020] An orally administrable Tramadol formulation for once a day
administration, which would provide effective Tramadol plasma
concentrations without Tramadol plasma peaks would be highly
desirable.
[0021] A pharmaceutical oral dosage formulation of Tramadol a)
providing rapidly effective plasma concentration and b) able to
maintain such effective plasma concentration for a long period of
time while simultaneously avoiding peak Tramadol blood
concentrations would be highly desirable to provide an immediate
and extended duration of analgesia without low incidence of adverse
effects to patients in pain.
[0022] The Tramadol (or salt) once daily composition of the present
invention permit the rapid obtention of Tramadol effective plasma
concentration, within one or two hours which are maintained for a
period of about 24 hours while providing for peak Tramadol blood
concentration which are less than three times the concentration
obtained twenty four hours after administration.
OBJECT AND SUMMARY OF THE INVENTION
[0023] It is an object of the present invention to provide a once a
day oral pharmaceutical preparation of Tramadol or its
pharmaceutical acceptable salts.
[0024] It is another object of the present invention to provide a
once a day Tremadol pharmaceutical preparation which is able to
provide effective Tramadol plasma concentration for a period of
about 24 hours.
[0025] It is another object of the present invention to provide a
once daily oral Tramadol preparation which provides effective
plasma concentrations within about 1 to 2 hours after single
administration of an effective amount of Tramadol for said
formulation.
[0026] It is another object of the present invention to provide a
once a day Tramadol pharmaceutical preparation which effectively
reduces the excessive Tramadol plasma concentration.
[0027] It is another object of the present invention to provide a
Tramadol once a day oral pharmaceutical preparation which after
single dose administration to humans provides Tramadol peak plasma
concentration (C.sub.max) less than three times the plasma
concentration obtained 24 hours (C.sub.24h) after said
formulation.
[0028] It is another object of the present invention to provide a
Tramadol once a day oral pharmaceutical preparation which after
multiple doses administration to humans provides Tramadol peak
plasma concentration (C.sub.max), which are less than three times
the plasma concentration obtained 24 hours (C.sub.24h) after said
multiple administrations.
BRIEF DESCRIPTION OF THE DRAWINGS
[0029] FIG. 1 illustrates Tramadol and O-desmethyl Tramadol mean
blood concentration obtained after single administration to 8
volunteers of one capsule of example 5 (200 mg) data in Table 1 and
2.
[0030] FIG. 2 illustrates Tramadol and O-desmethyl Tramadol mean
blood concentration obtained after multiple, 7 consecutive, once a
day administration to 8 volunteers of one capsule of the product of
example 5 containing 200 mg of Tramadol (data in Table 3 and
4).
[0031] It is another object of the present invention to provide a
Tramadol once a day oral pharmaceutical preparation which after
single and/or multiple doses administration to humans provides
Tramadol peak concentrations not less than 10 hours (T.sub.max)
after said administration.
[0032] It is another object of the present invention to provide a
once daily oral Tramadol pharmaceutical preparation from which the
Tramadol rapid rise maximum plasma concentration is lower that the
peak concentration of the formulation.
[0033] It is another object of the present invention to provide a
once a day Tramadol pharmaceutical preparation which is able to
control effectively pain during a period of about 24 hours.
[0034] It is another object of the present invention to provide a
once a day Tramadol preparation which reduces pain within 1 to 2
hours after single administration of an effective amount of
Tramadol.
[0035] It is another object of the present invention to provide a
once daily oral Tramadol pharmaceutical preparation which
effectively reduces the unwanted Tramadol side effects due to
excessive Tramadol plasma concentration.
[0036] It is another object of the present invention to provide a
once daily oral Tramadol pharmaceutical preparation which comprise
controlled release beads and a tablet into a hard gelatine and/or
hydroxypropylmethycellulose capsule.
[0037] It is another object of the present invention to provide a
once daily oral Tramadol preparation from which the plasma Tramadol
concentration are not affected when the formulation is taken with
or without food.
[0038] It is another object of the present invention to provide a
tablet containing Tramadol controlled release beads and a fast
release portion of Tramadol constituted by granules, beads or
powder which releases the Tramadol in such a manner that the fast
releasing Tramadol portion peak plasma concentration is less than
the peak concentration obtained from the Tramadol released from the
coated beads.
[0039] The present invention relate to a novel Tramadol
pharmaceutical preparations that provide effective Tramadol plasma
concentrations one or two hours after administration and which will
be maintained for 24 hours while simultaneously avoiding excessive
Tramadol plasma concentrations which are the origin of the unwanted
side effects.
[0040] More particularly the present invention is related to the
discovery, contrary to the teaching of U.S. Pat. Nos. 5,672,360 and
5,478,577 that in order to control pain for about 24 hours, it is
necessary that the peak of opioid analgesics concentration
(C.sub.max) is more than twice the concentration obtained 24 hours
after administration. In other words, what is disclosed in these
patents is the need for large fluctuations of opioid analgesic
blood concentrations between successive administration.
[0041] More particularly the present invention is related to the
discovery that in order to provide for Tramadol peak plasma
concentrations that are less than three times the plasma
concentration obtained 24 hours after administration it is
necessary that the pharmaceutical composition has an in vitro
release profile that is not of the first order but rather
multiphasic.
[0042] More particularly, the present invention relates to a once
daily oral pharmaceutical composition comprising a unit dose with
at least two Tramadol containing portions who release the Tramadol
at different rates. The unit dose may be per example a hard
gelatine and/or hydroxypropylmethylcellulose capsule for oral
administration.
[0043] More particularly, the present invention relate to a unit
dose that contains a Tramadol portion who liberate slowly the
Tramadol and a Tramadol containing portions that liberates the
Tramadol in a faster manner. The unit dose may be a hard capsule
and/or a tablet.
[0044] In certain preferred embodiments the unit dose comprises a
hard gelatine and/or hydroxypropylcellulose capsule containing slow
release beads and a fast releasing Tramadol tablet.
[0045] In accordance with the present invention any
pharmaceutically acceptable salt of Tramadol may be used. In the
preferred embodiment the hydrochloride salt of Tramadol may be
used.
[0046] In another preferred embodiment the unit dose comprises hard
gelatine and/or hydroxypropylmethylcellulose capsule containing a
slow release tablet and fast releasing beads.
[0047] In another preferred embodiment, the unit dose comprises
hard gelatine and/or hydroxypropylmethylcellulose capsule
containing slow release beads covered by layers of fast release
Tramadol.
[0048] Bead which are spheroids containing Tramadol or any of its
salts may be produced by any conventional known method such as
layering the Tramadol in solution with water over a neutral core,
or layering over a core, the Tramadol in mixture with other
pharmaceutical acceptable excipients such as a binders,
polymers.
[0049] The preferred method for the manufacture of beads in the
present invention is the method of extrusion-spheronization. This
method comprises mixing the Tramadol or its salts with a
spheronizing agent such as microcrystalline cellulose and
optionally other pharmaceutical excipients with water. The blend
obtained is thereafter extruded trough an extruder and the
extrudate is thereafter rounded with the help of a spheronizer.
[0050] In a preferred embodiment beads are produced without any
binder and comprises a mixture of Tramadol hydrochloride,
microcrystalline cellulose and sucrose stearate.
[0051] Sustained release bead, are obtained by coating beads,
previously manufactured, with a porous membrane from which the
Tramadol is liberated slowly. The microporous membrane comprises
mixtures of water-soluble and/or water dispersible polymers and/or
copolymers and may also include pharmaceutically acceptable
adjuvants such as plastifying agents, pigments, fillers, wetting
agents, lubricants and anti-foam agents.
[0052] Among the water-soluble and/or dispersible RIM forming
polymers or copolymers constituting the microporous membrane, may
be mentioned particularly polyacrylates and polymethacrylates of
the Eudragit type, such as Eudrgit E30D, L30D, RS30 D NE30D of Rohm
Pharma (USA), ethylcelluoses, such as Ethocels of DOW, USA and such
as AquaCoat of FMC, USA, Hydroxypropyl cellulose and
hydroxypropylmethylcellulose and their derivatives.
[0053] The polymers or copolymers may be associated into the
microporous membrane with at least one adjutant as exemplified by
the following: Plastifying agents, such as triacetin,
dibutylphthalate, dibutylsebacate, citric acid esters,
polyethyleneglycols, polypropyleneglycols and polyvinylpyrrolidone;
Pigments such as iron oxides and titanium oxide; fillers, such as
lactose and sucrose; Wetting agents, such as surfactive agents of
the Span and Tween types, namely partial esters of fatty acids
(lauric, palmitic, stearic and oleic acids) and anhydrides of
hexitols derived from sorbitol possibly containing polyoxyethylenic
chains, preferably surfactive agents of the Tween type, namely
Tween 80, as well as polyethyleneglycols; lubricants, such as
magnesium stearate and talc; antifoaming agents, such as silicone
oil.
[0054] In addition to the polymer or copolymer, the microporous
membrane contains preferably, talc and/or magnesium stearate as a
lubricant, polyvinylpyrrolidone as a plastifying agent, titanium
dioxide as a pigment, Tween 80 as an emulsifier, and silicone oil
as an antifoaming agent.
[0055] Generally, the thickness of the microporous membrane is
expressed by the percentage of the dry coating applied onto the
uncoated beads.
[0056] The weight of the microporous membrane may be 2 to 55%,
preferably, 10 to 40%, of the weight of said microganules. These
beads may contain the Tramadol or its salt in an amount of 20 to
95% by weight, preferably 30 to 85% by weight. The microporous
membrane may contain 5 to 95% and, preferably, 30 to 50% of
polymers, polymer mixture or copolymers.
[0057] The microporous membrane for use in the present invention
may be applied by coating in equipment such as fluid bed coaters,
pan coaters or any suitable coating equipment.
[0058] The tablet of the present invention which will be included
in the unit dose may be of the fast and/or as sustained release
type. In the preferred embodiment fast release tablets are used.
The tablets useful for the present invention shall be of such size
that it may be incorporated into the capsule. Tablets having a
diameter comprise between 3 and 5 mm are suitable for the present
invention. The amount of Tramadol or its salts included into the
tablet shall be such that the tablet peak plasma concentration is
less than the peak concentration of the beads included in the unit
dose. The unit dose Tramadol ratio between the fast release and the
sustained release beads is comprised between 1 and 50%, preferably
between 5% and 40% and more preferably between 10 and 30%.
[0059] The fast release tablets useful for the present invention
comprises Tramadol or its salt in mixture with pharmaceutical
tabletting agents. The tablets may be produced using conventional
tabletting technics.
[0060] Sustained release tablets useful for the present invention
comprises Tramadol or its salts in combination with retarding agent
such as cellulose derivatives, acrylic polymers.
[0061] In another embodiment for use in the present invention the
sustained release beads coated with the microporous membrane may be
covered by layers of a fast release Tramadol. For that purpose,
Tramadol or its salts in solution and/or suspension in a solvent is
applied onto the coated beads. Adjuvants such as plastifying
agents, pigments, fillers, wetting agents lubricants and antifoam
agents may also been included. The overcoated Tramadol containing
layer may also contain polymer and a copolymers or mixtures thereof
to control the release of the fast releasing Tramadol layer.
[0062] The following examples illustrate various aspects of the
present invention. They are not meant to be constituted to limit
the claims in any matter whatsoever.
EXAMPLE 1
Uncoated Beads
TABLE-US-00001 [0063] Tramadol Hcl 31.8 kg Microcrystalline
Cellulose (Avicel pH101) 21.0 kg Sucrose Stearate (Crosdeta F160)
2.17 kg Purified Water 7.24 kg
[0064] In a planetary mixer collette of 160 liter capacity
introduce the Tramadol Hcl, microcrystalline cellulose and the
sucrose stearate, blend at speed 2 for about 15 min. Slowly add the
purified water and continue mixing for an additional 15 minutes at
speed 2 after all water is added. Extrude the blend through a Fuji
Paudal extruder equipped with a 1 mm screen. Spheronize the
extrudate during about 2 minutes and dry the beads in an oven at
50.degree. C. for about 12 hours. The dried beads axe screened
though sieves of 1.4 and 0.7 mm. The yields of uncoated beads
comprised between 0.7 and 1.4 mm was 44.0 kg (81%).
EXAMPLE 2
Coated Beads
[0065] 2a. Pre Coating
TABLE-US-00002 Hydroxypropylmethylcelllose 1.35 kg Talc 5.40 kg
Purified Water 18.0 kg 45 kg of sieved beads from Example 1 were
placed in an fluidized bed coater (Aeromatic).
[0066] The beads were pre coated with 8.25 kg of the coating
suspension. 2b. Sustained Release Coating
TABLE-US-00003 [0066] Polyacrylate (30%) Eudragit NE30D 36.7 kg
Hydroxypropylmethylcelllose 1.08 kg Talc 1.08 kg Polysorbate 80
0.216 kg Simethicone 0.540 kg Magnesium Stearate 0.216 kg Purified
Water 18.0 kg
[0067] Immediately after the pre coating, 47.8 kg of the sustained
release coating was applied onto the pre coated beads. Upon
completion of the coating, the coated beads were placed onto trays
in a drying oven for about 16 hours at 50.degree. C. Upon cooling
the coated beads were stored in containers for further use.
EXAMPLE 3
Tramadol Fast Release Tablet--30 mg
TABLE-US-00004 [0068] Tramadol Hcl 3.00 kg Lactose 2.63 kg Avicel
pH102 1.13 kg Povidone 0.150 kg Starch 0.525 kg Magnesium Stearate
0.075 kg
[0069] Introduce a collette planetary mixer with a 20 liter bowl,
all ingredients, except the magnesium stearate, are blend for 15
minutes at speed 2. Add the magnesium stearate and blend for about
1 minute at speed 1. The blend is compressed using dip cup punches
of 5 mm diameter to produce 94,000 tablets of 75 mg containing 30
mg of Tramadol Hcl per tablet. The tablets at Example 3 were tested
for release of Tramadol using USP Apparatus 1 (Paddles) in 900 mL
of a buffer at pH 6.9 at 37.degree. C. and at 50 rotations per
minute.
TABLE-US-00005 Tramadol Time [h] Hcl Dissolved [%] 0.25 74.5 0.50
98.6 0.75 101.8
EXAMPLE 4
Fast Release Tablet--15 mg
TABLE-US-00006 [0070] Tramadol Hcl 1.50 kg Manitol 3.00 kg Povidone
XL 1.73 kg Povidone 0.20 kg Corn Starch 1.00 kg Magnesium Stearate
0.075 kg
[0071] Following the same manufacturing procedure as, in Example 4
to produce the blend, 92,000 tablets weighing 75 mg and containing
15 mg of Tramadol. Hcl per tablet where produced.
EXAMPLE 5
Tramadol Unit Dose
[0072] Hard gelatine capsule size #0 where filled with 386.7 mg of
beads from Example 2 mid one tablet from Example 3 to provide a
composition containing 200 mg of Tramadol Hcl per capsule.
[0073] A dissoluution test was performed on this composition using
USP Apparatus 1 (paddle) at 100 revolution per minute in 900 mL of
water at 37.degree. C.
TABLE-US-00007 Tramadol percent Time [hours] dissolved [%] 1 18 2
20 4 24 6 32 8 56 12 67 16 82 22 92
[0074] As may be seen the dissolution profile is not of the first
order type but of the biphasic type.
Single Dose Administration
[0075] A single dose of 200 mg of Tramadol Hcl from Example 5 was
administered to 8 healthy volunteers and blood concentrations were
measured up to 36 hours after administration.
[0076] Tramadol HO and its metabolite, 0-Desmethyl Tramadol, blood
concentrations were measured by LC/MS method. The results are
summarized in Tables 1 and 2.
Multiple Dose Study
[0077] 200 mg of the composition of example 5 was given once daily
during seven days to 8 healthy volunteers. On day 7 the blood
concentration were measured during a period of about 35 hours.
Tramadol and its metabolite o-demethyl Tramadol blood
concentrations were determined using LC/MS analytical method. The
results are in Tables 3 and 4.
TABLE-US-00008 TABLE 1 Tramadol plasma levels [mg/ml] obtained from
8 healthy volunteers after single administration of Hcl from
Example 5 (200 mg). Subject 0 h 0.5 0.75 1 1.5 2 4 6 8 10 1 0 1.068
57.47 61.168 72.609 69.002 45.398 57.97 81.206 84.703 2 0 0.734
26.894 79.184 104.18 100.95 100.42 163.46 234.15 304.35 3 0 0.805
42.483 84.899 87.138 92.105 87.27 108.6 127.35 171.3 4 0 1.135
24.201 134.42 111.62 116.53 78.643 75.297 96.719 134.16 5 0 0.384
10.726 48.862 100.12 74.449 84.476 100.88 101.3 152.23 6 0 2.123
3.873 16.958 81.877 67.261 72.954 74.083 78.184 102.07 7 0 0.09
0.969 19.501 71.931 101.62 124.62 148.51 148.23 197.66 8 0 10.165
23.992 56.001 104.14 103.35 120.33 126.33 135.05 167 MEAN 0 2.1
23.8 62.8 91.7 90.7 89.1 106.9 122.8 161.7 SD 0 3.3286 19.228
36.134 15.356 15.273 25.98 37.456 53.644 71.302 Subject 12 14 24 36
AUC Cmax Tmax Cmax/C24 1 109.06 99.172 72.374 25.313 2378.8 109.06
12 1.51 2 327.05 346.38 201.32 75.774 722.13 348.38 14 1.72 3
236.23 197.5 169.47 96.063 5288.5 235.23 12 1.38 4 145.45 138.37
88.483 42.285 3372.7 145.45 12 1.64 5 144.74 159.64 140.87 67.89
4182.7 159.64 14 1.13 6 92.148 100.05 70.298 36.974 2587.4 102.07
10 1.45 7 240.27 280.23 201.99 118.39 6503.5 280.23 14 1.39 8
196.78 180.56 168.7 62.092 4994.2 186.78 12 1.11 MEAN 185.2 187.7
139.2 64.3 4563.8 195.73 12.5 1.42 SD 78.771 86.709 55.257 31.311
1786.9 85.917 1.4142 0.217
TABLE-US-00009 TABLE 2 O-demethyl Tramadol plasma levels
[mg/ml]obtained from 8 healthy volunteers after single
administration of 200 mg of Tramadol from Example 5. subjects 0 0.5
0.75 1 1.5 2 4 6 8 10 12 14 24 36 AUC Cmax Tmax Cmax/C24 1 0 0.1
22.3 27.3 33.8 30.4 25.8 26.8 31.1 44.2 43.1 46.8 44.1 19.6 1290.8
45.8 14 1.04 2 0 0.0 1.8 2.1 5.3 5.7 5.7 8.1 12.1 16.4 13.0 19.5
16.1 6.8 480.57 19.6 14 1.21 3 0 0.0 4.3 7.4 9.6 11.7 11.1 14.4
18.1 27.9 34.2 28.7 23.9 17.9 777.5 34.2 12 1.43 4 0 0.0 4.5 22.7
33.5 29.6 25.7 23.6 27.5 41.6 38.0 38.8 36.6 22.1 1121.1 41.6 10
1.17 5 0 0.0 0.9 5.0 8.8 8.1 9.4 12.5 12.7 21.3 21.9 20.8 28.2 13.1
685.55 28.2 24 1.00 6 0 2.2 0.4 6.4 21.5 24.9 38.2 26.7 25.7 31.3
30.9 25.6 37.7 17.6 1022.6 37.7 24 1.00 7 0 0.0 0.0 1.5 8.3 5.3 7.0
9.5 12.1 16.5 18.5 23.8 23.7 18.0 652.47 23.8 14 1.00 8 0 3.0 6.8
11.3 16.8 19.2 22.8 33.4 35.1 69.0 43.8 42.5 53.4 25.1 1479.6 69.0
10 1.29 MEAN 0 0.7 5.0 10.5 16.8 18.8 18.0 19.4 24.4 33.8 31.0 30.4
32.8 17.4 936.3 37.6 15.3 1.14 SD 0 1.20 7.32 9.56 11.65 10.55
11.15 9.38 14.56 17.48 10.46 10.04 12.23 5.85 350.02 15.5 5.7
0.160
TABLE-US-00010 TABLE 3 tramadol levels multiple doses tramadol
plasme concentrations [mg/ml] obtatined after 7 consecutive
administrations of 200 mg of tramadol HCl from Example 5 to 8
healthy volunteers time [hours] after the seventh administration
subject -24 0 1 1.5 2 4 6 8 10 1 162.2 187.9 230.5 139.1 271.7 210
209.0 285.5 340.6 2 128.8 99.5 165.7 172.3 158.1 128 103.4 117.9
161.7 3 87.4 84.1 104.9 168.8 162.8 181 157.0 180.9 200.2 4 49.9
82.8 170.4 130.2 135.7 114 110.4 103.6 132.0 5 104.1 125.9 195.1
191.5 179.0 204 242.4 289.0 358.4 6 183.2 135.0 207.7 199.5 185.3
150 189.6 183.1 176.4 7 187.7 193.6 238.4 244.4 224.0 178 198.0
227.9 259.8 8 81.7 103.1 140.6 150.8 155.3 125 138.9 131.7 155.0
984.9 1288 mean 120.6 124.0 181.7 186.8 183.7 158.2 185.5 180.0
221.5 SD 47.8171 46.92 45.392 40.089 44.284 36.342 48.046 65.676
67.524 time [hours] after the seventh administration subject 12 15
24 36 AUC 0-38 Cmax Tmax Cmax/C24 1 315.0 308.6 143.7 48.8 7198.9
340.5 10 2.4 2 177.7 181.7 110.8 32.9 4226.1 177.7 12 1.5 3 226.4
174.8 131.0 41.3 4997.6 226.4 12 1.7 4 152.0 131.2 84.6 23.2 3509.2
170.4 1 2.0 5 322.3 287.3 181.4 37.6 7121.6 358.4 10 2.2 6 198.0
209.3 147.0 45.9 5437.7 209.3 15 1.4 7 309.7 281.7 190.3 78.3
7213.0 309.7 12 1.5 8 163.7 183.2 113.3 38.0 4331.6 163.7 12 1.4
mean 232.8 211.9 135.3 43.2 5504.5 244.3 10.5 1.8 SD 72.13 65.15
32.914 15.2362 1498.6 79.3 4.1 0.4 indicates data missing or
illegible when filed
TABLE-US-00011 TABLE 4 O-desmethyl tramadol levels multiple doses
)-desmethyl tramadol blood concentrations obtained after 7
consecutive administrations of 200 mg of tramadol HCl from example
5 to 8 healthy volunteers time [hours] after the seventh
administration subject -24 0 1 1.5 2 4 6 8 10 1 53.8 36.1 54.3 50.3
44.8 44.1 38.4 46.1 53.9 2 98.1 38.5 43.9 43.4 41.6 34.9 30.6 32.9
39.0 3 71.9 38.6 49.8 65.0 58.5 52.9 70.9 69.0 117.1 4 28.0 32.4
54.8 40.5 49.5 47.1 41.3 40.8 47.2 5 10.1 11.0 14.5 14.4 14.5 13.8
16.7 18.7 22.8 6 9.2 8.4 11.4 10.8 10.0 9.1 7.9 7.5 7.5 7 30.9 84.1
39.6 58.9 68.2 72.2 52.5 79.0 74.3 8 34.2 33.7 41.5 42.0 43.9 41.5
38.6 40.8 43.2 mean 40.7 32.5 38.7 40.4 41.1 39.4 37.1 41.8 50.6 SD
26.3685 17.333 16.548 19.056 19.8 20.499 19.896 23.744 33.422 time
[hours] after the seventh administration subject 12 15.2 24 36 AUC
0-38 Cmax Tmax Cmax/C24 1 58.4 43.8 29.4 10.4 1279.3 56.4 10 1.9 2
45.8 55.0 40.0 17.4 1359.5 55.0 15 1.4 3 72.6 84.5 90.4 21.6 2808.7
117.1 10 1.3 4 49.5 53.6 31.2 12.8 1341.7 54.6 1 1.7 5 23.8 23.6
15.3 4.2 583.2 23.8 12 1.6 6 9.5 11.5 9.2 2.7 300.5 11.5 15 1.2 7
86.6 78.4 54.8 34.8 2207.8 88.5 12 1.6 8 44.0 42.3 33.8 13.8 1252.8
44.6 12 1.3 mean 48.9 50.3 38.1 14.7 1387.6 56.4 10.9 1.5 SD 25.06
28.98 26.269 19.2549 757.5 33.7 4.4 0.2 indicates data missing or
illegible when filed
EXAMPLE 6
Coated Beads
[0078] 30 kg of beads from Example 1 were coated firs with 5.5 kg
of the precoating suspension of Example 2 followed by 36 kg of the
sustained release coating of Example 2.
EXAMPLE 7
30 mg Tablets
TABLE-US-00012 [0079] Tramadol Hcl 6.00 kg Lactose 0.72 kg
Microcrystalline Cellulose 1.20 kg Povidone 0.18 kg Starch 0.56 kg
Sodium Starch Glycolate 0.24 kg Magnesium Stearate 0.09 kg Purified
Water 1.00 kg
[0080] Tablets containing 30 mg Tramadol were prepared as per
method described in Example 3--using a 160 L planetary blend. The
tablets weight was 75 mg.
EXAMPLE 8
200 mg Capsules
[0081] Hard gelatin capsules Size #0 were filled with one tablet of
Example 7 and 341 mg of beads from Example 6 treated with 0.5% of
Talc.
[0082] A dissolution test was performed on this drug composition
using USE apparatus 12 at 100 rpm in 900 mL of water at 37.degree.
C.
TABLE-US-00013 Time Tramadol Percent [h] Dissolved 1 28 7 50 24
100
EXAMPLE 9
300 mg Capsules
[0083] Hard gelatin capsules Size #00 were filled with one tablet
of Example 7 and 568 mg of beads from Example 6 treated with 0.5%
of Talc.
[0084] A dissolution test was performed on this drug composition
using the same equipment and parameters as for Example 8.
TABLE-US-00014 Time Tramadol Percent [h] Dissolved 1 21 8 48 24
95
[0085] As shown by the dissolution results of pharmaceutical
preparations of examples 8 and 9, the Tramadol release profile is
diphasic.
[0086] A Single Dose pharmaceutical study was undertaken with
formulations of Examples 8 and 9.
[0087] Single Tramadol ER capsules, containing 200 mg and 300 mg
were administered in cross over to twenty healthy subjects without
food. Blood was monitor and plasma analyzed for Tramadol content up
to 72 hours.
[0088] Results are summarized in Table 5.
TABLE-US-00015 TABLE 5 Tramadol and o-desmethyl-tramadol plasma
concentration after single dose administered to 20 healthy
volunteers of 200 mg (Example 8) and 300 mg (Example 9) of Tramadol
formulation. O-demethyl- Tramadol Tramadol Plasma Level Plasma
Level Time [mg/ml] [mg/ml] [h] 200 mg 300 mg 200 mg 300 mg 0 0.0
0.0 0.0 0.0 0.5 19.20 20.4 5.5 6.5 1 123.7 121.6 23.2 24.2 1.5
158.9 156.7 32.0 32.3 2 168.1 159.9 35.5 35.1 2.5 165.0 160.6 37.2
36.2 3 152.3 156.1 35.0 36.8 3.5 147.9 150.0 35.7 36.3 4 144.5
152.2 35.3 38.2 5 160.7 180.9 38.7 43.2 6 175.2 228.0 39.9 50.1 8
228.1 320.8 51.8 69.6 10 271.6 385.8 62.4 86.4 11 275.6 384.3 64.1
89.7 12 273.9 387.8 64.7 89.7 13 267.2 386.3 64.9 93.1 14 255.7
384.9 63.4 95.0 15 251.1 364.0 64.9 90.8 16 232.0 344.0 61.7 88.8
17 216.7 318.0 59.8 83.9 18 198.7 302.2 56.1 81.4 20 177.4 269.7
52.6 73.1 24 126.9 201.0 40.2 57.5 36 46.6 78.6 15.8 24.5 48 18.5
33.0 6.4 10.6 72 2.6 4.4 0.8 1.5 Ratio C.sub.max/ 2.2 1.9 1.6 1.7
C.sub.24 T.sub.max[h] 11 12 13-15 14
* * * * *