U.S. patent application number 13/491432 was filed with the patent office on 2013-04-11 for sustained release pharmaceutical compositions for highly water soluble drugs.
This patent application is currently assigned to Farnam Companies, Inc.. The applicant listed for this patent is David L. Bledsoe, Andrew Xian Chen. Invention is credited to David L. Bledsoe, Andrew Xian Chen.
Application Number | 20130089608 13/491432 |
Document ID | / |
Family ID | 37116041 |
Filed Date | 2013-04-11 |
United States Patent
Application |
20130089608 |
Kind Code |
A1 |
Chen; Andrew Xian ; et
al. |
April 11, 2013 |
Sustained Release Pharmaceutical Compositions for Highly Water
Soluble Drugs
Abstract
The present invention provides pharmaceutical compositions for
controlled release of pharmaceutically active agents, especially
those with a high water solubility, high dose, and/or short
half-life. In addition, the present application provides methods
for preparing and using such pharmaceutical compositions.
Inventors: |
Chen; Andrew Xian; (San
Diego, CA) ; Bledsoe; David L.; (Phoenix,
AZ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Chen; Andrew Xian
Bledsoe; David L. |
San Diego
Phoenix |
CA
AZ |
US
US |
|
|
Assignee: |
Farnam Companies, Inc.
Phoenix
AZ
|
Family ID: |
37116041 |
Appl. No.: |
13/491432 |
Filed: |
June 7, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11482502 |
Jul 7, 2006 |
8221792 |
|
|
13491432 |
|
|
|
|
60697912 |
Jul 7, 2005 |
|
|
|
Current U.S.
Class: |
424/465 ;
514/646 |
Current CPC
Class: |
A61K 31/135 20130101;
A61P 43/00 20180101; A61K 31/165 20130101; A61K 31/195 20130101;
A61K 9/2054 20130101; A61K 31/737 20130101; A61K 31/7008 20130101;
A61P 29/00 20180101; A61K 9/14 20130101; A61K 9/2077 20130101; A61K
45/06 20130101; A61K 9/205 20130101; A61K 9/2866 20130101 |
Class at
Publication: |
424/465 ;
514/646 |
International
Class: |
A61K 9/20 20060101
A61K009/20 |
Claims
1. A sustained release pharmaceutical tablet, said tablet
comprising: tramadol micronized at a dose selected from the group
consisting of 90 mg, 180 mg, 300 mg and 600 mg; a matrix comprising
hydroxypropylmethyl cellulose (HMPC) and the micronized tramadol
dispersed in the matrix; microcrystalline cellulose; and a tablet
lubricant.
2. The pharmaceutical tablet of claim 1, wherein the
pharmaceutically active agent contributes greater than 15% of the
total weight of the pharmaceutical composition.
3. The pharmaceutical tablet of claim 1, wherein the
pharmaceutically active agent contributes greater than 50% of the
total weight of the pharmaceutical composition.
4. The pharmaceutical tablet of claim 1, wherein the
pharmaceutically active agent is present in an amount of about 50%
to about 80% by weight.
5. The pharmaceutical tablet of claim 1, wherein the hydrophilic
polymer is present in an amount of about 15% to about 50% by
weight.
6. The pharmaceutical tablet of claim 1, wherein the HPMC is a high
molecular weight HPMC in an amount of about 20% to about 30% by
weight of the tablet.
7. The pharmaceutical tablet of claim 1, wherein the tableting
lubricant is present in an amount of about 1% to about 3% by weight
of the tablet.
8. The pharmaceutical tablet of claim 7, wherein the tablet
lubricant is magnesium stearate.
9. The pharmaceutical tablet of claim 1, further comprising a
coating on the tablet.
10. The pharmaceutical tablet of claim 9, wherein said coating is a
release-controlling layer.
11. The pharmaceutical tablet of claim 9, wherein said coating
constitutes about 1% to about 5% by weight of the tablet.
12. The pharmaceutical tablet of claim 9, wherein said tablet is
coated with a layer of film containing ethyl cellulose.
13. The pharmaceutical tablet of claim 9, wherein the tramadol dose
is 90 mg.
14. The pharmaceutical tablet of claim 9, wherein the tramadol dose
is 180 mg.
15. The pharmaceutical tablet of claim 9, wherein the tramadol dose
is 300 mg.
16. The pharmaceutical tablet of claim 9, wherein the tramadol dose
is 600 mg.
17. A method for reducing pain in an animal, said method
comprising: administering a tramadol micronized tablet at a dose
selected from the group consisting of 90 mg, 180 mg, 300 mg and 600
mg or a fragment thereof, said tablet comprising a matrix
comprising hydroxypropylmethyl cellulose (HMPC) and the micronized
tramadol dispersed in the matrix; microcrystalline cellulose; and a
tablet lubricant, to reduce pain in the animal.
18. The method of claim 17, wherein the tramadol dose is 180
mg.
19. The method of claim 17, wherein the tramadol dose is 300
mg.
20. The method of claim 17, wherein the tramadol dose is 600 mg.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 11/482,502, filed on Jul. 7, 2006, which claims the benefit
under 35 USC 119(e) of U.S. Provisional Application No. 60/697,912,
filed on Jul. 7, 2005. Each patent application identified above is
incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The invention relates to compositions, which provide
sustained release (SR), extended release (ER), or controlled
release of highly water-soluble pharmaceutically active agents,
including those, which are categorized as highly water-soluble,
with a short metabolic half-life, and therapeutically efficacious
at a high daily dose.
[0004] 2. Description of the Related Art
[0005] It is difficult to provide a sustained release oral dosage
form for drugs of a high-solubility, a short half-life, and a high
dose. A drug of a high water-solubility can dissolve in water or
gastrointestinal milieu readily and tends to release from its
dosage form in a burst and thus is absorbed quickly, leading to a
sharp increase in the drug blood concentration. Compared to less
soluble drugs, it is often difficult to sequester a highly water
soluble drug in the dosage form (such as a tablet) and retard the
drug release, especially when the drug dose is high.
[0006] If the drug of a high water-solubility is also of a short
half-life (i.e., quickly metabolized in the body thereby losing its
activity), the drug would remain in the blood for only a short
time, resulting in a short duration of action. For such a drug, a
multiple daily dosing regimen (three, four or more times a day) is
necessary to maintain a steady drug concentration in the blood
above its effective concentration level. A multiple daily dosing is
inconvenient and reduces the patient compliance significantly. A
sustained release dosage form, which allows for a reduced dosing
frequency such as once a day, is thus much desired.
[0007] If the drug of a high water-solubility and a short half-life
is also a high dose drug (e.g., those that require a daily dose
exceeding 500 mg), it becomes even more challenging to develop
sustained release oral dosage forms. For short half-life drugs, to
provide a once-a-day tablet, it requires not only that a large
amount of drug be incorporated in a dosage unit to provide the
daily dose, but also that the dosage units be small in size to
allow for ease of swallowing by the human or non-human subject. The
requirement for smaller sizes would leave little space in the
dosage unit for other ingredients needed to control the release of
the drug. The size of the dosage unit becomes even more critical
with highly water-soluble drugs since even a larger amount of
inactive ingredients (e.g., more than 50% of the total weight) is
usually needed to provide the sustained release property, according
to the conventional SR methods.
[0008] Typically, a tablet of a total weight about 1-1.5 g is
considered as the largest tablet that can be readily swallowed by a
normal adult patient without discomfort, the same limitation
applies to veterinary patients such as dogs. So it is important for
an SR composition to have not only high drug content (e.g., more
than 50% of the total weight) but also a reasonable size.
[0009] In summary, the combined features of a high-solubility,
short half-life and high dose poses a great challenge in developing
an easy-to-swallow and once-a-day or twice-a-day dosage form for
many drugs in the category of high-solubility, short half-life and
high dose.
[0010] Tablets are by far the most popular dosage form for oral
administration. Generally, sustained release tablets have been
prepared in a number of ways including matrix tablets, coated
tablets and combination thereof. In a matrix tablet, the drug is
usually mixed with a gelling material, which upon contact with
water can form a thick layer of gel that slows down the diffusion
of the drug while undergoing slow erosion. Both diffusion and
erosion contribute to drug release. A coating can provide both a
barrier limiting the erosion and drug release from its core.
[0011] Matrix tablets are probably the most important sustained
release form in which the sustain-release components are commonly
selected from hydrogel polymers such as cellulose polymer or other
synthetic water-soluble polymers such as polyethylene oxides
(polyox) or methacrylate polymers (carbomers). Non-ionic cellulose
ethers, and more frequently, hydroxypropyl methylcellulose (HPMC,
hypromellose) have been widely used for applications in oral SR
systems.
[0012] Matrix tablets are of particular interest for veterinarian
applications because the patients (e.g., dogs, cats, horses, etc.)
are likely to chew the tablets. Therefore, a preferable tablet form
must be able to withstand some degree of pulverization without
losing its sustained-release property. In comparison with a coated
sustained release tablet (i.e., sustained release controlled by
only or primarily through a layer of coating), matrix tablets are
advantageous because an SR coating of a coated sustained release
tablet, which is the primary barrier, may be destroyed easily by
animal chewing, and the bulk of the drug content is thus at risk of
being released as a burst, which could be toxic in more serious
cases.
SUMMARY OF THE INVENTION
[0013] The present invention provides pharmaceutical compositions
for controlled release of pharmaceutically active agents and
methods for preparing and using such pharmaceutical compositions.
The pharmaceutical compositions may have one or more of the
following characteristics: (1) providing sustained plasma levels of
pharmaceutical active agents, including those of a high water
solubility, short half life, and/or high dose; (2) capable of high
drug loading (e.g., Containing drug content in an amount of about
or greater than 50% of the total weight of the pharmaceutical
composition); (3) suitable for both human and veterinary uses; and
(4) capable of being in a once-a-day or twice-a-day dosage
form.
[0014] In one aspect, the present invention provides a
pharmaceutical composition comprising (i) a pharmaceutically active
agent having a high water solubility, a high daily dose, and a
short half-life, and (ii) a matrix that comprises a hydrophilic
polymer, wherein the pharmaceutically active agent is micronized
and dispersed in the matrix.
[0015] In certain embodiments, the pharmaceutically active agent
contributes about or greater than 15%, 20%, 30%, 40%, 50%, or 60%
of the total weight of the pharmaceutical composition.
[0016] In certain embodiments, the pharmaceutically active agent
has a water solubility of at least about 10 mg/ml, such as at least
about 100 mg/ml or about 200 mg/ml.
[0017] In certain embodiments, the pharmaceutically active agent is
therapeutically effective for a human (e.g., an adult human
patient) or non-human subject (e.g., a dog, a cat, a horse, a pig,
etc.) at a daily dose of at least about 90 mg, such as at least
about 100 mg, 300 mg, or 500 mg.
[0018] In certain embodiments, the pharmaceutically active agent is
therapeutically effective for a human (e.g., an adult human
patient) or non-human subject (e.g., a dog, a cat, a horse, a pig,
etc.) at a daily dose of at least about 5 mg/kg of the body weight
of the subject, such as at least about 7.5, 10, 12, 14, 16, 18, 20,
25, 30, 35, 40, or 50 mg/kg of the body weight of the subject.
[0019] In certain embodiments, the pharmaceutically active agent
has a half-life, in an immediate release form, of about or less
than 10 hours, such as about or less than 8, 6, or 4 hours in a
human (e.g., an adult human patient) or non-human subject (e.g., a
dog, cat, house, pig, etc.).
[0020] In certain embodiments, the pharmaceutically active agent
has a water solubility of about or greater than 100 mg/ml, is
therapeutically effective at a daily dose of at least about 90 mg
(e.g., at least about 100, 150, 200, 250, 300, 350, 400, 450, or
500 mg), and has a half-life, in an immediate release form, of
about or less than 8 hours in a human (e.g., an adult human
patient) or non-human subject (e.g., a dog, cat, house, pig,
etc.).
[0021] In certain embodiments, the pharmaceutically active agent is
tramadol, glucosamine, chondroitin, metformin, gabapentin, vitamin
C, vitamin B1, vitamin B2, an amino acid, or a pharmaceutically
acceptable salt thereof.
[0022] In certain embodiments, the pharmaceutically active agent is
present the pharmaceutical composition in an amount of about 50% to
about 80%, such as about 55% to about 75%, and about 60% to about
70%, by weight.
[0023] In certain embodiments, the pharmaceutical composition
further comprises a second pharmaceutically active agent. In
certain embodiments, the second pharmaceutically active agent is
also of a high water solubility, high dose, and/or short
half-life.
[0024] In certain embodiments, the pharmaceutically active agent is
tramadol, glucosamine, or a pharmaceutically acceptable salt
thereof, and the second pharmaceutically active agent is
chondroitin, a non-steroidal anti-inflammatory drug (NSAID), or a
pharmaceutically acceptable salt thereof.
[0025] In certain embodiments, the pharmaceutically active agent is
tramadol, and the second pharmaceutically active agent is
acetaminophen, carprofen, aspirin, or glucosamine.
[0026] In certain embodiments, the pharmaceutically active agent is
micronized to, or selected from, a size range with an upper size
limit of about or less than 210 micron (70 mesh) and a lower limit
of about or greater than 63 micron (230 mesh), such as an upper
limit of about or less than 177 micron (80 mesh) and a lower limit
of about or greater than 74 micron (200 mesh), an upper limit of
about or less than 149 micron (100 mesh) and a lower limit of about
or greater than 74 micron (200 mesh), and an upper limit of about
or less than 125 micron (120 mesh) and a lower limit of about or
greater than 74 micron 200 (mesh).
[0027] In certain embodiments, the hydrophilic polymer is
hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose,
methylcellulose, carboxymethylcellulose, polyethylene oxide),
alginate, pectin, guar gum, chitosan, carrageenan, starch, dextrin,
tragacanth, xanthan gum, povidone, carbomer, or a salt thereof. In
certain embodiments, the hydrophilic polymer is present in an
amount of about 15% to about 50%, such as about 20% to about 40%
and about 20% to about 30%, by weight.
[0028] In certain embodiments, the pharmaceutical composition, upon
oral administration to a human or non-human patient in need
thereof, provides controlled release for at least about 8, 10, 12,
14, 16, 18, 20, 24, 36, 48, 72, 96, 120, 144, or 168 hours.
[0029] In certain embodiments, the pharmaceutical composition is
suitable for administration to a patient in need thereof no more
than twice a day or no more than once a day. In certain
embodiments, the pharmaceutical composition is suitable for
administration to a patient in need thereof no more than once per
day, per two, three, four, five, six, or seven days.
[0030] In certain embodiments, the pharmaceutical composition has
an in vitro dissolution rate from about 5% to about 40% of the
pharmaceutically active agent released after 2 hours, from about
15% to about 55% of the pharmaceutically active agent released
after 4 hours, from about 40% to about 80% of the pharmaceutically
active agent released after 8 hours, from about 60% to about 95% of
the pharmaceutically active agent released after 12 hours, and from
about 70% to about 100% of the pharmaceutically active agent
released after 18 hours, by weight.
[0031] In certain embodiments, the pharmaceutical composition, upon
oral administration to a human or non-human patient in need
thereof, has an in vitro dissolution rate from about 10% to about
30% of the pharmaceutically active agent released after 2 hours,
from about 25% to about 45% of the pharmaceutically active agent
released after 4 hours, from about 50% to about 70% of the
pharmaceutically active agent released after 8 hours, from about
70% to about 90% of the pharmaceutically active agent released
after 12 hours, and from about 80% to about 100% of the
pharmaceutically active agent released after 18 hours, by
weight.
[0032] In certain embodiments, the pharmaceutical composition is in
the form of an orally deliverable tablet. In certain embodiments,
the tablet comprises a coating (e.g., a release controlling layer
or a coating that does not control the release of the drug from the
tablet). In certain embodiments, the coating layer constitutes
about 1% to about 5% (e.g., about 1% to about 2%) by weight of the
tablet. In certain embodiments, the tablet further comprises a
tableting binder, a filler, and/or a lubricating agent.
[0033] In certain embodiments, the tablet maintains its in vitro
sustained release property even after broken into two or more
pieces. In certain embodiments, the tablet maintains its in vivo
sustained release property even after being breaking into two or
more pieces.
[0034] In certain embodiments, the pharmaceutical composition is in
the form of a fragmented or crushed matrix tablet. In certain
embodiments, the composition in the form of a fragmented or crushed
matrix tablet, upon oral administration, provides controlled
release for at least about 8, 10, 12, 14, 16, 18, 20, 24, 36, 48,
72, 96, 120, 144, or 168 hours.
[0035] In certain embodiments, the composition, upon oral
administration to a patient in need thereof, provides a plasma
concentration at or above a therapeutically effective concentration
for a period of time that is at least about 100%, 150%, 200%, or
250% longer than an immediate release formulation containing the
same amount of the pharmaceutically active agent.
[0036] In certain embodiments, the composition, upon oral
administration to a patient in need thereof, provides an Area Under
the Curve (AUC) (0 to infinity) (plasma concentration versus time)
at least about 50%, 100%, 150%, 200%, or 250% higher than the AUC
(0 to infinity) provided by an immediate release formulation
containing the same amount of the pharmaceutically active
agent.
[0037] In certain embodiments, the pharmaceutically active agent is
tramadol, and upon oral administration in a dog, the pharmaceutical
composition provides an AUC (0 to infinity) (plasma concentration
versus time) of tramadol about or greater than 2, 4, or 6 .mu.g
hr/mL. In certain embodiments, such a pharmaceutical composition,
upon oral administration in a dog, further provides a C.sub.max
(maximum concentration) of tramadol of about or less than 10
.mu.g/mL.
[0038] In certain embodiments, the pharmaceutically active agent is
tramadol, and upon oral administration in a dog, the pharmaceutical
composition provides an AUC (0 to infinity) (plasma concentration
versus time) of the active metabolite of tramadol, M1
(O-desmethyltramadol), about or greater than 0.2, 0.4, 0.6, 0.8,
1.0, or 1.2 .mu.g hr/mL. In certain embodiments, such a
pharmaceutical composition, upon oral administration in a dog,
further provides a C.sub.max of M1 of about or less than 2
.mu.g/mL.
[0039] In another aspect, the present invention provides a
pharmaceutical composition in the form of an orally deliverable
tablet comprising tramadol hydrochloride having an upper size limit
of about or less than 125 micron (120 mesh) and a lower size limit
of about or greater than 74 micron (200 mesh) in an amount of about
75 mg to about 1000 mg (e.g., about 90, 100, 180, 200, 300, 400,
500, 600, 700, 800, 900, or 1000 mg), dispersed in a matrix
comprising (a) HPMC of a high molecular weight in an amount of
about 20% to about 30% by weight of the tablet, (b) a
microcrystalline cellulose having a particle size of about or less
than 210 micron, in an amount of about 10% to about 20% by weight
of the tablet, and (c) a tableting lubricant in an amount of about
1% to about 3% by weight of the tablet.
[0040] In another aspect, the present invention provides a
pharmaceutical composition in the form of an orally deliverable
tablet comprising tramadol hydrochloride having an upper size limit
of about or less than 125 micron (120 mesh) and a lower size limit
of about or greater than 74 micron (200 mesh) in an amount of about
150 mg to about 500 mg (e.g., about 150, 200, 250, 300, 350, 400,
450, or 500 mg), dispersed in a matrix comprising (a) HPMC of a
high molecular weight in an amount of about 20% to about 40% by
weight of the tablet, (b) a microcrystalline cellulose having a
particle size of about or less than 210 micron, in an amount of
about 10% to about 30% by weight of the tablet, and (c) a tableting
lubricant in an amount of about 1% to about 3% by weight of the
tablet.
[0041] In another aspect, the present invention provides a
pharmaceutical composition in the form of an orally deliverable
tablet comprising glucosamine hydrochloride having an upper size
limit of about or less than 125 micron (120 mesh) and a lower size
limit of about or greater than 74 micron (200 mesh) in an amount of
about 500 mg to about 1000 mg (e.g., about 500, 600, 700, 800, 900,
or 1000 mg), and chondroitin sulfate having an upper size limit of
about or less than 210 micron (70 mesh), in an amount of about 300
mg to about 1000 mg, dispersed in a matrix comprising (a) HPMC of a
high molecular weight in an amount of about 20% to about 30% by
weight of the tablet, (b) a binder having a particle size of about
or less than 210 micron, in an amount of about 2% to about 20% by
weight of the tablet, and (c) a tableting lubricant in an amount of
about 1% to about 3% by weight of the tablet.
[0042] In another aspect, the present invention provides a
pharmaceutical composition in the form of an orally deliverable
tablet comprising glucosamine hydrochloride having an upper size
limit of about or less than 125 micron (120 mesh) and a lower size
limit of about or greater than 74 micron (200 mesh) in an amount of
about 500 mg to about 1500 mg (e.g., about 500, 600, 700, 800, 900,
1000, 1100, 1200, 1300, 1400, or 1500 mg), dispersed in a matrix
comprising (a) HPMC of a high molecular weight in an amount of
about 20% to about 30% by weight of the tablet, (b) a binder having
a particle size of about or less than 210 micron, in an amount of
about 2% to about 20% by weight of the tablet, and (c) a tableting
lubricant in an amount of about 1% to about 3% by weight of the
tablet.
[0043] In another aspect, the present invention provides a
pharmaceutical composition in the form of an orally deliverable
tablet comprising gabapentin having an upper size limit of about or
less than 125 micron (120 mesh) and a lower size limit of about or
greater than 74 micron (200 mesh) in an amount of about 300 to
about 1500 mg (e.g., about 300, 400, 500, 600, 700, 800, 900, 1000,
1100, 1200, 1300, 1400, or 1500 mg), dispersed in a matrix
comprising (a) HPMC of a high molecular weight in an amount of
about 20% to about 30% by weight of the tablet, (b) a binder having
a particle size of about or less than 210 micron, in an amount of
about 2% to about 20% by weight of the tablet, and (c) a tableting
lubricant in an amount of about 1% to about 3% by weight of the
tablet.
[0044] In another embodiment, the present invention provides a
pharmaceutical composition in the form of an orally deliverable
tablet comprising acetaminophen having an upper size limit of about
or less than 125 micron (120 mesh) and a lower size limit of about
or greater than 74 micron (200 mesh) in an amount of about 300 mg
to about 1500 mg (e.g., about 300, 400, 500, 600, 700, 800, 900,
1000, 1100, 1200, 1300, 1400, or 1500 mg), dispersed in a matrix
comprising (a) HPMC of a high molecular weight in an amount of
about 20% to about 30% by weight of the tablet, (b) a binder having
a particle size of about or less than 210 micron, in an amount of
about 2% to about 20% by weight of the tablet, and (c) a tableting
lubricant in an amount of about 1% to about 3% by weight of the
tablet.
[0045] In another aspect, the present invention provides a
pharmaceutical composition in the form of an orally deliverable
tablet comprising metformin hydrochloride having an upper size
limit of about or less than 125 micron (120 mesh) and a lower size
limit of about or greater than 74 micron (200 mesh) in an amount of
about 300 to about 1500 mg (e.g., about 300, 400, 500, 600; 700,
800, 900, 1000, 1100, 1200, 1300, 1400, or 1500 mg), dispersed in a
matrix comprising (a) HPMC of a high molecular weight in an amount
of about 20% to about 30% by weight of the tablet, (b) a binder
having a particle size of about or less than 210 micron, in an
amount of about 2% to about 20% by weight of the tablet, and (c) a
tableting lubricant in an amount of about 1% to about 3% by weight
of the tablet.
[0046] In certain embodiments, the above-described tablet is
optionally coated with a layer of film using a coating composition
comprising an aqueous. dispersion containing ethyl cellulose, oleic
acid, ammonium hydroxide and water and a solution containing
polyethylene glycol.
[0047] In certain embodiments, the tablets described herein are
processed by a direct compression method.
[0048] In certain embodiments, the pharmaceutical compositions
(e.g., intact, fragmented, or crushed matrix tablets) described
herein are adapted for delivery to humans (e.g., adult human
patients) or veterinary subjects (e.g., dogs, cats, horse, pigs,
etc.).
[0049] In another aspect, the present invention provides a process
for preparing a sustained-release pharmaceutical composition in a
form of an orally deliverable tablet wherein the process comprising
(a) micronizing a pharmaceutically active agent, (b) selecting the
pharmaceutically active agent having an upper size limit of about
or less than 125 micron (120 mesh) and a lower size limit of about
or greater than 74 micron (200 mesh), (c) dry blending the
pharmaceutically active agent from step (b) with a hydrophilic
polymer and a binder, (d) admixing the mixture of step (c) with a
lubricant, a glidant, or both, (e) compressing the mixture of step
(d) into tablets (e.g., those of hardness of about 10 to about 20
kp), and (f) optionally coating the tablets (e.g., using a spray
pan coater or a fluid bed processor).
[0050] These and other embodiments of the invention will become
apparent from the detailed description below.
BRIEF DESCRIPTION OF THE DRAWINGS
[0051] FIG. 1 is a graph depicting the in vitro release of tramadol
hydrochloride from (a) an uncoated matrix SR tablet (1 lot), with
(b) a coated matrix SR tablet (2 lots) prepared according to
Example 1 of the present application using a micronized tramadol
HCl drug substance. The SR tablets released their entire drug
content in about 12-16 hours from the uncoated tablets and in about
18-24 hours from the coated tablets.
[0052] FIG. 2 is a graph that compares the in vitro release rate of
tramadol hydrochloride from a coated matrix tablet composition
prepared according to Example 1 of the present application using
(a) "micronized" particles of tramadol HCl (Dai-Ichi Karkaria, Ltd.
lot TDL/M/03/04004), with (b) a "coarse" tramadol HCl substance
(Degussa, lot 0041194237). The tablets made with the "coarse"
particles failed to meet the dissolution specification, i.e.,
coated tablets to release 80-100% of tramadol in about 18-24
hours.
[0053] FIGS. 3A and 3B are graphs that depict the in vivo release
rate in dogs of tramadol hydrochloride from a SR tramadol HCl
matrix tablet prepared according to Example 3 of the present
application using fine particles of tramadol HCl. FIG. 3A: uncoated
600 mg tablets (administered as 1/2 tablets broken along a score).
FIG. 3B: coated 600 mg tablets (administered as 1/2 tablets broken
along a score)
[0054] FIG. 4 is a graph that shows the in vitro release of
glucosamine hydrochloride from a matrix tablet prepared according
to Example 6.
[0055] FIG. 5 is a graph that shows in vitro release of tramadol
from ULTRAM.RTM. ER 300 mg and a tramadol HCl ER matrix tablet
prepared according to Example 3 of the present invention. Both
tablets were cut into four sections about equal size to simulate
tablet fractions after being chewed by animal patients.
[0056] FIG. 6 is a graph that shows blood concentrations of
tramadol HCl in Beagle dogs administered with either crushed or
intact SR matrix tablets containing 300 mg tramadol HCl at a dose
of approximate 15 mg/kg.
[0057] FIG. 7 is a graph that shows blood concentrations of
tramadol HCl M1 metabolite in Beagle dogs administered with either
crushed or intact SR matrix tablets containing 300 mg tramadol HCl
at a dose of approximate 15 mg/kg.
[0058] FIG. 8 is a graph that shows in vitro dissolution of SR
matrix tablets containing 90 mg, 180 mg, 300 mg, or 600 mg tramadol
HCl.
[0059] FIG. 9 is a graph that shows plasma concentrations of
tramadol and its active metabolite M1 in dogs administered at 30
mg/kg as single ER matrix tablets containing 300 mg tramadol HCl.
The dogs were fed immediately before dosing.
[0060] FIG. 10 is a graph that shows plasma concentrations of
tramadol and its metabolite M1 in dogs administered at 30 mg/kg as
single ER matrix tablets containing 300 mg tramadol HCl. The dogs
were fasted for 12 hours, dosed, and fasted for another 4
hours.
[0061] FIG. 11 is a graph that shows plasma concentrations of
tramadol and its metabolite M1 in dogs administered at 30 mg/kg as
single ER matrix tablets containing 300 mg tramadol HCl. The dogs
were fasted for 12 hours, dosed, and fasted for another 12
hours.
[0062] FIG. 12 is a graph that shows plasma concentrations of
tramadol and its metabolite M1 in male and female dogs administered
at approximately 18 mg/kg as single ER matrix tablets containing
180 mg tramadol HCl. The dogs were fasted for 12 hours and fed
within 30 minutes for dosing.
[0063] FIG. 13 is a graph that shows plasma concentrations of
tramadol and its metabolite M1 in cats treated at 30 mg/kg via
administration of halves of ER matrix tablets containing 300 mg
tramadol HCl.
[0064] FIG. 14 is a graph that shows plasma concentrations of
glucosamine in fasted Beagle dogs received 1600 mg of an SR
formulation of glucosamine as an uncoated matrix tablet.
DETAILED DESCRIPTION OF THE INVENTION
[0065] The present invention provides pharmaceutical compositions
for controlled release of pharmaceutically active agents,
especially those with a high water solubility, high dose, and/or
short half-life. In addition, the present application provides
methods for preparing and using such pharmaceutical
compositions.
[0066] In one aspect, the present invention provides a
pharmaceutical composition comprising (i) a pharmaceutically active
agent having a high water solubility, a high daily dose, and a
short half-life, and (ii) a matrix that comprises a hydrophilic
polymer, wherein the pharmaceutically active agent is micronized
and dispersed in the matrix.
[0067] In certain embodiments, the pharmaceutical composition of
the present invention is in the form of an orally deliverable
tablet (i.e., an orally deliverable matrix tablet). In certain
other embodiments, the pharmaceutical composition of the present
invention is in the form of a fragmented or crushed matrix
tablet.
[0068] "Matrix tablets" refers to tablet dosage forms in which a
drug is substantially homogenously dispersed in a polymer in
association with conventional excipients. This admixture is
typically compressed under pressure to produce a tablet. The drug
is released from the tablet by diffusion and erosion. Matrix tablet
systems are described in detail in The Handbook of Pharmaceutical
Controlled Release Technology, D. L. Wise (ed.), Marcel Dekker,
Inc., New York (2000) and Treatise on Controlled Drug Delivery:
Fundamentals, Optimization, and Applications, A. Kydonieus (ed.),
Marcel Dekker, Inc., New York, (1992).
[0069] The term "matrix" refers to the combination of the
components of a matrix tablet other than the drug or the coating.
It comprises primarily one or more polymers and may comprise other
excipients.
[0070] The term "pharmaceutically active agents" (used
interchangeably with "drugs") refers to compounds or compositions,
including plant extracts, herbal powders, minerals, or naturally
occurring ingredients, that have beneficial pharmaceutical,
nutritional, therapeutic, or cosmetic effects.
[0071] A pharmaceutically active agent of a "high water
solubility," or that is "highly soluble" or "highly water soluble,"
refers to a pharmaceutically active agent (in its free base, free
acid or salt form) having solubility in water in excess of about 10
mg/ml at room temperature (20-25.degree.). In certain embodiments,
the pharmaceutically active agent of the present invention has a
water solubility of about or greater than 20, 30, 40, 50, 60, 70,
80, 90, 100, 120, 140, 160, 180, 200, or 250 mg/mL at room
temperature.
[0072] A pharmaceutically active agent of a high daily dose refers
to a pharmaceutically active agent that is orally administered at a
dose of about or greater than 75 mg to a human (e.g., an adult
human patient) or non-human subject (e.g., a dog, cat, house, pig,
etc.). In certain embodiments, the pharmaceutically active agent of
the present invention has a daily dose about or greater than 90,
100, 200, 250, 300, 350, 400, 450, or 500 mg for a human (e.g., an
adult human patient) or non-human subject (e.g., a dog, cat, house,
pig, etc.). Exemplary pharmaceutically active agents of a high dose
include tramadol (100 mg/dose or more), acyclovir (200 mg/dose),
acetaminophen (300 mg/dose), metformin (500 mg/dose), gabapentin
(100-800 mg/dose), glucosamine (500 mg/dose), etc.
[0073] In certain embodiments, the pharmaceutically active agent is
therapeutically effective for a human (e.g., an adult human
patient) or non-human subject (e.g., a dog, a cat, a horse, a pig,
etc.) at a daily dose of at least about 5 mg/kg of the body weight
of the subject, such as at least about 7.5, 10, 12, 14, 16, 18, 20,
25, 30, 35, 40, or 50 mg/kg of the body weight of the subject.
[0074] The term "half-life" of a pharmaceutically active agent
refers to the time in which the plasma concentration of the
pharmaceutically active agent in a human (e.g., an adult human
patient) or non-human subject (e.g., a dog, cat, horse, pig, etc.)
to which the pharmaceutically active agent is administered is
reduced by half when the pharmaceutically active agent is
administered in an immediate release form.
[0075] A pharmaceutically active agent of a "short half-life"
refers to a pharmaceutically active agent that has a half-life
about or less than 10 hours. In certain embodiments, the
pharmaceutically active agent of the present invention has a
half-life of about or less than about 9, 8, 7, 6, 5, 4, 3, or 2
hours in a human (e.g., an adult human patient) or non-human
subject (e.g., a dog, cat, horse, pig, etc.). In general, a
pharmaceutically active agent of a short half-life is required to
be taken more than twice a day in its immediate release forms to
maintain the efficacious blood concentration level through the
day.
[0076] A pharmaceutically active agent of a high water solubility,
a high daily dose and a short half-life refers to a drug that meets
all three requirements for being of (1) a high water solubility,
(2) high daily dose, and (3) short half-life. In certain
embodiments, the pharmaceutically active agent of the present
invention has a water solubility of about or greater than 100
mg/ml, is therapeutically effective at a daily dose of about or
greater than 90 mg (e.g., about or greater than 100, 150, 200, 250,
300, 350, 400, 450, or 500 mg), and has a half-life, in an
immediate release form, of about or less than 8 hours in a human
(e.g., an adult human patient) or non-human subject (e.g., a dog,
cat, horse, pig, etc.).
[0077] Examples of drugs of high water solubility, short half-life,
and high dose include, but not limited to: verapamil HCl, potassium
chloride, cefdnir, propafenone HCl, hydroxyurea, hydrocodone
bitartrate, delavirdine mesylate, nelfinavir meslyate, pentosan
polysulfate sodium, tocainide HCl, quetiapine fumarate,
fexofenadine HCl, carafate, rifampin, moxifloxacin HCl,
praziquantel, ciprofloxacin, phosphate sodium potassium,
methenamine mandelate, sotalol HCl, cefprozil, cefadroxil,
metformin HCl, irbesartan, nefazodone HCl, gatifloxacin,
didanosine, modafinil, efavirenz, metaxalone, amantadine HCl,
morphine sulfate, mefenamic acid, diltiazem HCl, sevelamer HCl,
albendazole, amoxicilline, clavulanate potassium, lithium
carbonate, lamivudine, sumatriptan succinate, nabumetone,
zidovudine, cimetidine, chlorpromazine HCl, valacyclovir HCl,
bupropion HCl, ranitidine, abacavir sulfate, acyclovir,
aminobenzoate potassium, pyridostigmine bromide, potassium
chloride, isosorbide mononitrate, nicin, demeclocycline HCl,
cefixime, naproxen sodium, tetratcycline HCl, cefuroxime axetil,
propoxyphene napsylate, pyrazinamide, flecainide acetate,
simethicone, mebendazole, methdopa, chlorathiazide, indinavir,
penicillamine, meyyrosine, losartan potassium, thiobendazole,
norfloxacin, hydroxyurea, procainamide, entacapone, valsartan,
terbinafine HCl, metaprolol tartrate, ofloxacin, levofloxacin,
chlorzoxazone, tolmetin sodium, tramadol HCl, bepridil HCl,
phenyloin sodium, atorvastatin calcium, gabapentine, celecoxib,
fluconazole, doxepine HCl, trovafloxacin mesylate, azithromycin,
sertraline HCl, rifabutin, cefpodoxime proxetil, mesalamine,
etidronate disodium, nitrofurantoin, choline magnesium
trisalicylate, theophylline, nizatidine, pancreatin, quinidine
sulfate, methocarbamol, mycophenolate mefetil, ganciclovir,
saquinavir mesylate, tolcapne, ticlopidine HCl, valganciclovir HCl,
capecitabine, orlistat, colsevelam HCl, irbesartan, succimer,
meperidine HCl, hydroxychloroquine sulfate, guaifenesine,
eprosartan mesylate, aminodarone HCl, felbamate, pseudoephedrine
sulfate, carisoprodol, venlafaxine, propanolol HCl, etodolac,
acebutolol, chondrotin, pyruvate, water soluble vitamins, creatine,
Isoflavone, betaine HCl, psyllium, pantothenic Acid, zinc chloride,
zinc gluconate, zinc sulfate, hytoestrogen, pycnogenol,
proanthocyanidin, suntheanine, methylsulfonyl-methane, L-glutamine,
colostrums, biotin, acetyl-L-carnitine, inositol, L-tyrosine,
s-adenosyl methionine, bromelain, 2-dimethylaminoethanol, chromium
picolinate, and combinations thereof.
[0078] Additional examples of drugs of a high water solubility,
short half-life, and high dose include, but not limited to, amino
acids, sugars, carbohydrates, proteins, saccharides, phospholipids,
ginkgo biloba, standardized St. John's Wort, standardized
Echinacea, yeasts, enzymes, bacteria, and combinations thereof.
[0079] In certain embodiments, the pharmaceutically active agents
useful in the present invention is tramadol HCl, acyclovir,
glucosamine, chondroitin, acetaminophen, metformin, gabapentin,
vitamin C, vitamin B's, amino acids, or a pharmaceutically
acceptable salt thereof.
[0080] A "pharmaceutically acceptable salt" of a pharmaceutically
active agent refers to a salt of the pharmaceutically active agent,
within the scope of sound medical judgment, suitable for use in
contact with the tissues of humans and lower animals without undue
toxicity, irritation, allergic response, and the like, and
effective for the intended use of the pharmaceutically active
agent.
[0081] In certain embodiments, the pharmaceutical compositions of
the present invention further comprise one or more other
pharmaceutically active agents. In certain embodiments, the other
pharmaceutically active agents may also be of a high water
solubility, high dose, and/or short half-life. For example, in
certain embodiments, the pharmaceutical compositions of the present
invention comprise glucosamine hydrochloride and chondroitin
sulfate, tramadol hydrochloride and glucosamine hydrochloride, or
tramadol hydrochloride and acetaminophen. In certain other
embodiments, the other pharmaceutically active agents may not be of
high water solubility, high dose and/or short half-life.
[0082] In certain embodiments, the other pharmaceutically active
agent may have a same or similar pharmaceutical effect as the
pharmaceutically active agent of a high water solubility, high
dose, and/or short half-life in a pharmaceutical composition. For
instance, a pharmaceutical composition of the present invention may
comprise tramadol and another analgesic agent. In certain
embodiments, the other pharmaceutically active agent may have a
pharmaceutical effect different from the pharmaceutically active
agent of a high water solubility, high dose, and/or short half-life
in a pharmaceutical composition. For instance, a pharmaceutical
composition of the present invention may comprise tramadol and an
antibacterial compound.
[0083] In the embodiments where a pharmaceutical composition
comprises two or more drugs that produce an additive pharmaceutical
effect, the amount of each drug is generally lower than that used
for each drug in monotherapy (i.e., when the drugs are given
alone). For example, in one embodiment, the dose of each drug in
the composition may be from 0.1 to 0.75 of the dose used in
monotherapy, such as from 0.25 to 0.75 of the dose used in
monotherapy. In another embodiment, the dose of one drug is one
quarter of its normal dose used in monotherapy, and the dose of the
other drug is three quarters of its normal dose used in
monotherapy. In another embodiment, the dose of each drug is
approximately one half of its normal dose when used in
monotherapy.
[0084] In the embodiments where a pharmaceutical composition
comprises two or more drugs that produce a synergistic
pharmaceutical effect, the combined dose of the drugs is lower than
that if the two drugs produce only an additive pharmaceutical
effect. For example, in one embodiment, the dose of one drug is one
quarter of its normal dose used in monotherapy, and the dose of the
other drug is also quarter of its normal dose used in
monotherapy.
[0085] In the embodiments where a pharmaceutical composition
comprises two or more drugs that produce different pharmaceutical
effects, the amount of each drug should be sufficient to produce
the intended effect of the drug. In most of embodiments, the dose
of each drug is similar to that used in monotherapy. In certain
other embodiments, the dose of each drug may be higher or lower
than that used in monotherapy.
[0086] The weight ratio of a drug of a high water solubility, short
half-life, and/or high dose to another drug in a pharmaceutical
composition of the present invention depend on both drugs and their
dosages used in monotherapy. In certain embodiments, the weight
ratio of a drug of high water solubility, short half-life, and/or
high dose to another drug in a pharmaceutical composition is from
about 1:1000 to 1000:1, such as 1:100 to 100:1, 1:50 to 50:1, 1:10
to 10:1, 1:5 to 5:1, 1:2 to 2:1, 1:1 to 1:10, 1:1 to 1:50, 1:1 to
1:100, 100:1 to 1:1, 50:1 to 1:1, or 10:1 to 1:1.
[0087] In certain embodiments, the pharmaceutical composition
comprises tramadol and another analgesic agent. For example, in
certain embodiments, the pharmaceutical composition comprises
tramadol and an opioid analgesic. In certain other embodiments, the
pharmaceutical composition comprises tramadol and a non-steroidal
anti-inflammatory drug (NSAID).
[0088] Exemplary opioid analgesics that may be included in
tramadol-containing pharmaceutical compositions include, but are
not limited to, alfentanil, alphaprodine, anileridine, apomorphine,
betaprodine, buprenorphine, butorphanol, carfentanil, codeine,
codeinone, cyclorphan, cylcazocine, dextromethorphan,
dextropropoxyphene, diamorphine (heroin), dihydrocodeine,
diphenoxylate, ethoheptazine, etorphine, fentanyl, hydrocodone,
hydromorphone, isomethadone, levallorphan, levorphanol, loperamide,
meperidine, methadone, metopon, morphine, morphinone, nalbuphine,
normorphine, N-(2-phenylethyl)-normorphine, oxycodone, oxymorphone,
pentazocine, pethidine (meperidine), phenazocine, piminodine,
propoxyphene, racemorphan, remifentanil, and sufentanil.
[0089] Exemplary NSAIDs that may be included in tramadol-containing
pharmaceutical compositions include, but are not limited to,
aspirin, carprofen, deracoxib, etodolac, firocoxib, celecoxib,
diclofenac, diflunisal, fluriprofen, ibuprofen, indomethacin,
ketoprofen, kietorolac, mefenamic acid, meloxicam, naproxen,
piroxicam, rofecoxib, sulindac, and valdecoxib.
[0090] In certain embodiments, the pharmaceutical compositions of
the present invention comprise both tramadol and acetaminophen. In
a certain embodiment, the weight ratio of tramadol to acetaminophen
in the composition is from about 1:10 to about 1:5.
[0091] In certain embodiments, the pharmaceutical compositions of
the present invention comprise both tramadol and diclofenac. In a
certain embodiment, the weight ratio of tramadol to diclofenac is
about 1:4 to 4:1, such as 1:2 to 3:1, and 1:1 to 2.5:1.
[0092] In certain embodiments, the pharmaceutical compositions of
the present invention comprise both tramadol and aspirin. In a
certain embodiment, the weight ratio of tramadol to aspirin is
about 1:4 and 4:1, such as between 1:2 and 2:1. In certain
embodiments, the pharmaceutical compositions of the present
invention comprise both tramadol and carprofen. In a certain
embodiment, the weight ratio of tramadol to carprofen is about 3:1
to 10:1.
[0093] In certain embodiments, the pharmaceutical compositions of
the present invention comprise both tramadol and flupirtine. In a
certain embodiment, the weight ratio of tramadol to flupirtine is
about 1:1 to 1:5.
[0094] In certain embodiments, the pharmaceutical compositions of
the present invention comprise both tramadol and codeine or
oxycodone. In a certain embodiment, the weight ratio of tramadol to
codeine or oxycodone is about 1:20 to about 20:1, such as about 1:2
to about 2:1 and about 1:1 to 2:1.
[0095] In certain embodiments, the pharmaceutical compositions of
the present invention comprise both tramadol and a NSAID, wherein
the weight ratio of tramadol to the NSAID is about 1:1 to about
1:200, from about 1:2 to about 1:200, and about 1:2 to about
1:20.
[0096] In certain embodiments, the pharmaceutical compositions of
the present invention comprise both tramadol and a calcium channel
antagonist (e.g., nimodipine, nicardipine, nifedipine, diltiazem,
verapamil, gallopamil, flunarizine, and cinnarizine). In a certain
embodiment, the weight ration of tramadol to the calcium channel
antagonist is about 200:1 to about 5:1.
[0097] In certain embodiments, the tramadol-containing
pharmaceutical compositions of the present invention further
comprise ketoprofen, cyproheptadine (serotonin antagonist),
prozosin (.alpha.-1-adrenoceptor antagonist), clonidine
(.alpha.-2-adrenoceptor agonist), clomipramine (selective inhibitor
of serotonin neuronal uptake), or xylamine (selective irreversible
inhibitor of norepinepherine uptake).
[0098] In certain embodiments, the pharmaceutical compositions of
the present invention comprise glucosamine and an analgesic, such
as a NSAID. Exemplary NSAIDs include, but are not limited to,
aspirin; phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine,
dipyrone and apazone; indomethacin; sulindac; fenamates such as
mefenamic, meclofenamic, flufenamic, tolfenamic and etofenamice
acids; aryl acetic acid and propionic acid compounds such as
2-(p-isobutylphenyl)propionic acid (ibuprofen);
alphamethyl-4-(2-thienylc-arbonyl)benzene acetic acid (suprofen);
4,5-diphenyl-2-oxazole propionic acid (oxprozin);
rac-6-chloro-alphamethyl-carbazole-2-acetic acid (carprofen);
2-(3-phenyloxyphenyl)-propionic acid, particularly the calcium salt
dihydrate thereof (fenoprofen and fenoprofen calcium);
2-(6-methoxy-2-naphthyl)propionic acid (naproxen);
4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-.alpha.-methylbenzene acetic
acid (indoprofen); 2-(3-benzoylphenyl)propionic acid (ketoprofen);
and 2-(2-fluoro-4-biphenylyl)propionic acid (flurbiprofen) and
1-5-(4-methylbenzoyl)-1H-pyrrole-2-acetic acid (tolmetin).
Additional exemplary NSAIDs are compounds within the class
including sodium
5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate dihydrate
(zomepirac sodium);
4-hydroxy-2-methyl-N-(2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1-di-
oxide (piroxicam); 2',4'-difluoro-4-hydroxy-3-biphen-ylcarboxylic
acid (diflunisal) or
1-isopropyl-7-methyl-4-phenyl-2(1H)-quinozolinone (proquazone), and
Cox-2 inhibitors such as rofecoxib and celecoxib.
[0099] In certain embodiments, the weight ratio of glucosamine to
the analgesic in the above pharmaceutical compositions is from
about 1:10 to about 100:1, such as from about 1:1 to about 20:1,
and about 1:2 to about 10:1.
[0100] In certain embodiments, the glucosamine-containing
pharmaceutical compositions of the present invention further
comprise ibuprofen, diclofenac, tramadol, or acetaminophen. In
certain embodiments, the weight ratio of glucosamine to ibuprofen,
diclofenac, tramadol, or acetaminophen is from about 1:10 to about
100:1, such as from about 1:1 to about 20:1, and about 1:2 to about
10:1.
[0101] In certain embodiments, the pharmaceutical composition of
the present invention comprises glucosamine (e.g., glucosamine
hydrochloride and glucosamine sulfate), hydrolyzed collagen, and a
bioflavanol (e.g., proanthocyanidin, leucocyanidin, pcynogenol, and
those extracted from grape seeds, pine bark or turmeric root).
[0102] It is generally difficult to provide a sustained release
oral dosage form for drugs of a high-solubility, short half-life,
and high dose. Highly water-soluble drug substances are difficult
to sequester in a solid dosage form and often released quickly in a
burst in the gastrointestinal tract, leading to sharp increases and
subsequent decreases in plasma level concentrations. A relatively
large amount of release controlling ingredients is needed to slow
down or sustain the release of a highly water-soluble drug.
[0103] When such a highly water-soluble drug substance is also
metabolized quickly in vivo, it would require multiple dosing to
maintain the drug in blood at a concentration above its effective
concentration level. To prepare a once-a-day dosage form, a total
amount of drug required for the daily dose, along with the required
inactive ingredients needed for fabricating the once-a-day dosage
form, would become too much for a patient to swallow.
[0104] For example, tramadol, having the structure set forth below
and the systematic (IUPAC) name of
rac-(1R,2R)-2-(dimethylaminomethyl)-1-(3-methoxyphenyl)-cyclohexanol,
is a centrally acting analgesic and has a short half-life (5.6-7.0
hours in human and 0.8-1.7 hours in dogs). It is available as a
hydrochloric acid salt, which is highly water soluble. The current
human tablet formulation (ULTRAM.RTM. by Ortho-McNeil) is dosed at
a high frequency, i.e., 50-100 mg every six hours or 4 times a day.
It is estimated that a once-a-day tablet would require 400-500 mg
of tramadol be formulated in a tablet with a total weight less than
1000 mg, such as less than 800 mg for ease of swallowing.
##STR00001##
[0105] In a veterinary application, it was reported by KuKanich
& Papich (J. Vet. Pharmacol. Therap. 27, 239-46, 2004) that 5
mg/kg dose at every 6 hours (i.e., 4 times a day) was predicated to
achieve a plasma concentrations of tramadol and its active
metabolite M1 consistent with analgesia in humans. It is estimated
that a dose of 15 mg/kg or more would be needed for once-a-day
sustained-release tablets, which translates to a dose of 150, 300,
and 450 mg for a dog of body weight of 10, 20 and 30 kg,
respectively.
[0106] Furthermore, when such a highly water-soluble and fast
metabolizing drug substance also happens to be a high dose drug,
i.e., requires a high dose to be therapeutically effective, it
would make a once-a-day dosage form even more difficult using
conventional formulation techniques. With the current art known to
those in the field of pharmaceutical sciences, to achieve such
dosing, one almost always ends up with a very large tablet or
capsule (i.e., too big to swallow) or a large quantity of tablets
or capsules (i.e., too many to swallow). The reason is that the
current sustained release techniques require a relatively large
amount of inactive ingredients, e.g., more than 50% of the total
dosage weight, to provide the appropriate sustained release for the
active drug. The large amount of inactive ingredients inevitably
increases the total size (weight) of the tablet or capsule to a
level that is too big to swallow.
[0107] This invention, in certain embodiments, discloses a new
composition and method of preparing the composition (e.g., a matrix
tablet) in which the inactive ingredients are reduced to less than
about 50%, such as to less than about 45%, 40%, 35%, or 30% of the
total weight of the composition. By reducing the amount of inactive
ingredients used, the pharmaceutical composition (e.g., the matrix
tablet) of this invention is capable of delivering, in a once-a-day
or twice-a-day dosage form (e.g., a once-a-day or twice-a-day
tablet), a drug of a high water solubility, short half-life and
high dose, wherein the amount of the drug in each dosage form can
be more than about 500 mg, such as more than about 600, 700, 800,
900, 1000, 1100, or 1200 mg, while the total tablet weight is kept
at about 1000 to 1500 mg or less and the size of the dosage form
appropriate for swallowing by a normal human or non-human
subject.
[0108] One approach used in the present invention to minimizing the
amount of inactive ingredients while maintaining sustained release
of drugs in a pharmaceutical composition is to select drug
particles from a specific particle size range as described in
detailed below.
[0109] Particle size of the drug substance (raw material) is
customarily defined by an upper limit of particle size (e.g.,
90-95% of drug particles is less than 210 micrometer). It is also
common to see that a bulk of drug substance powder is specified by
its ability to pass a sieve of certain size (mesh) (e.g., 90-95% of
drug particles pass a 70-mesh sieve). Common drug particle sizes
and useful sieve types are listed in the table below:
TABLE-US-00001 Sieve Designation Nominal Sieve Opening Mesh Inches
mm Microns No. 40 0.0165 0.420 420 No. 45 0.0139 0.354 354 No. 50
0.0117 0.297 297 No. 60 0.0098 0.250 250 No. 70 0.0083 0.210 210
No. 80 0.0070 0.177 177 No. 100 0.0059 0.149 149 No. 120 0.0049
0.125 125 No. 140 0.0041 0.105 105 No. 170 0.0035 0.088 88 No. 200
0.0029 0.074 74 No. 230 0.0025 0.063 63 No. 270 0.0021 0.053 53 No.
325 0.0017 0.044 44 No. 400 0.0015 0.037 37
[0110] The particle size of the drug substance to be used in the
pharmaceutical composition (e.g., the matrix tablet) of this
invention is considerably smaller than conventional particle size
and is in a range having an upper size limit of about or less than
210 micron (70 mesh) and a lower limit of about or greater than 63
micron (230 mesh), such as an upper limit of about or less than 177
micron (80 mesh) and a lower limit of about or greater than 74
micron (200 mesh), an upper limit of about or less than 149 micron
(100 mesh) and a lower limit of about or greater than 74 micron
(200 mesh), and an upper limit of about or less than 125 micron
(120 mesh) and a lower limit of about or greater than 74 micron
(200 mesh).
[0111] An "upper size limit" or an "upper limit" of a drug
substance refers to a size that greater than 95% by weight drug
substance particles are under.
[0112] A "lower size limit" or a "lower limit" of a drug substance
refers to a size that greater than 95% by weight drug substance
particles are above.
[0113] Drug substance particles in the above-noted size ranges
(e.g., a range having an upper size limit of about or less than 210
micron (70 mesh) and a lower limit of about or greater than 63
micron (230 mesh)) are regarded as "fine particles" or "micronized
particles", as most commercially available drug substances are
provided in a particle size range above the most typical size
ranges for this invention. The inventors of this application have
found that drug particles with size greater than the aforementioned
preferable upper size limit would fail to produce the desired
sustained release property, while drug particles with size smaller
than the aforementioned preferable lower size limit would have poor
compressibility (unable to form a tablet by compression) and poor
flow property (cannot be processed by an automated tablet press),
resulting in tablets of much greater size (less dense tablet).
[0114] Micronizing drug substance particles to minimize the amount
of inactive ingredients while maintaining sustained release of
drugs of a high water solubility, high dose, and/or short half-life
in a pharmaceutical composition is contrary to what is known in the
art. The use of fine or micronized drug particles has generally
been used for the opposite purpose, i.e., for a fast (not
sustained) release of water-insoluble (instead of highly soluble)
drugs. Micronization of a drug substance reduces its particle size
thereby increasing the surface area of the solid particles, and
allows for a better contact with or exposure to the surrounding
liquid. A tablet containing a micronized drug substance is
generally intended to increase the drug dissolution into the
surrounding liquid such as gastrointestinal milieu or saliva. In
addition, micronization of a drug substance has been applied almost
exclusively to water-insoluble drug substances to improve their
dissolution and solubility properties, leading to improved
absorption and shorter onset of action. A number of drug products
containing micronized water-insoluble drug substances have been
marketed in the US. Tablets or capsules having the micronized drug
substances are claimed to have faster action and better drug
absorption than the unmicronized form. Examples include micronized
fenofibrate (TRICOR.RTM. by Abbott labs), glyburide (MICRONASE.RTM.
by Pfizer), tadalafil (CIALIS.RTM. by Eli Lilly), progesterone
(progesterone micronized USP), griseofulvin (griseofulvin
micronized, USP), etc., all of which are water-insoluble drugs.
[0115] In certain embodiments, the present invention provides
pharmaceutical compositions that comprise a pharmaceutically active
agent of a high water solubility, high daily dose, and/or short
half-life that is micronized and dispersed in a matrix comprising a
hydrophilic polymer, and contribute about or greater than 15%, 20%,
30%, 40%, 50%, or 60% of the total weight of the pharmaceutical
composition.
[0116] The hydrophilic polymers useful to form a matrix in the
pharmaceutical compositions of the present invention include, but
are not limited to, polyvinylpyrrolidine, hydroxypropylcellulose,
hydroxypropylmethyl cellulose, methyl cellulose, vinyl acetate
copolymers, polysaccharides (such as alignate, chitosan, xanthum
gum, pectin, guan gum, starch, dextrin, etc.), polyethylene oxide,
methacrylic acid copolymers (carbomers), maleic anhydride/methyl
vinyl ether copolymers, carboxymethylcellulose sodium, and
derivatives and mixtures of the above-listed polymers.
[0117] In certain embodiments, the polymer is selected from
hydroxypropyl cellulose, hydroxypropylmethyl cellulose (HPMC),
carboxymethylcellulose sodium polyethylene oxide, methyl cellulose
and methacrylic acid copolymers (carbomers), and derivatives and
mixtures of the above-noted polymers. In certain embodiments, the
polymer is hydroxypropylmethyl cellulose. In certain other
embodiments, the polymer is hydroxypropylmethyl cellulose with a
high viscosity ranging from about 4,000 mPa s to about 10,000 mPa s
(measured as a 2% aqueous solution). In certain other embodiments,
the high viscosity polymer is hydroxypropylmethyl cellulose,
commercially available under the tradename, METHOCEL K100M Premium
CR, from The Dow Chemical Company. METHOCEL K100M Premium CR EP is
hypromellose 2208 that meets the requirements of the United States
Pharmacopoeia XXV and European Pharmacopoeia 4th edition and is
certified as Kosher. It meets apparent viscosity specification of
16922-19267 mPas (nominal value 18243 mPas) by rotation or
80000-120000 cP (nominal value 100000 cP) by the Ubbelhode
method.
[0118] In certain embodiments, the polymer is HPMC of a high
molecular weight. Molecular weight of a HPMC is proportional to its
viscosity and is typically represented by its viscosity in a 2%
aqueous solution. An "HPMC of a high molecular weight" is defined
as a HPMC polymer with a nominal viscosity in mPas ranging from
about 4000 to 10,000, as measured in a 2% aqueous solution.
[0119] The amount of the polymer in the dosage form generally
varies from about 10% to about 50% by weight of the composition
(e.g., a matrix tablet). In certain embodiments, the amount of
polymers varies from about 15% to about 50%, about 15% to about
40%, about 15% to about 30%, about 15% to about 25%, about 20% to
about 50%, about 20% to about 40%, about 20% to about 30%, about
25% to about 50%, or about 25% to about 40%, by weight of the
composition (e.g., a matrix tablet).
[0120] The pharmaceutical composition of the invention also
typically includes pharmaceutically acceptable excipients. As is
well known to those skilled in the art, pharmaceutical excipients
are routinely incorporated into solid dosage forms. This is done to
ease the manufacturing process as well as to improve the
performance of the dosage form. Common excipients include binders,
diluents or bulking agents, lubricants, etc. Such excipients are
routinely used in the dosage forms of this invention. Binders may
be incorporated into the formulation to improve the compressibility
of the bulk powder blend and thus hardness and friability of the
resultant tablets. Examples of suitable binders include povidone,
polyvinylpyrrolidone, xanthan gum, cellulose gums such as
carboxymethylcellulose, methyl cellulose,
hydroxypropylmethylcellulose, hydroxycellulose, gelatin, starch,
and pregelatinized starch.
[0121] Diluents, or fillers, may be added in the compositions of
the present invention to increase the mass of an individual dose to
a size suitable for tablet compression. Suitable diluents include
powdered sugar, calcium phosphate, calcium sulfate,
microcrystalline cellulose, lactose, mannitol, kaolin, sodium
chloride, dry starch, sorbitol, etc. In certain embodiments, the
diluent or filler is selected from microcrystalline cellulose and
lactose. In certain embodiments, the diluent or filler is
microcrystalline cellulose, commercially available under the
tradename AVICEL, from The FMC Biopolymer Company.
[0122] Lubricants may also be incorporated into the composition of
the present invention for a variety of reasons. They reduce
friction between the powder and die wall during compression and
ejection. This prevents the powder from sticking to the tablet
punches and facilitates its ejection from the tablet punches, etc.
Examples of suitable lubricants include talc, stearic acid,
vegetable oil, calcium stearate, zinc stearate, magnesium stearate,
etc.
[0123] Glidants may also be incorporated into the compositions of
the present invention. A glidant improves the flow characteristics
of the powder. Examples of suitable glidants include talc, silicon
dioxide, and cornstarch.
[0124] Other excipients that may be incorporated into the
compositions of the present invention include preservatives,
antioxidants, or any other excipient commonly used in the
pharmaceutical industry. The amount of excipients used in the
formulation will correspond to that typically used in a matrix
system. The total amount of excipients, fillers and extenders, etc.
varies from about 2% to about 20% by weight of the dosage form.
[0125] In certain embodiments, the pharmaceutical compositions of
the present invention provide sustained release for the
pharmaceutically active agents in the composition.
[0126] The term "sustained release" refers release of a drug from
its dosage form (e.g., tablet) at such a rate that its blood levels
are maintained within the therapeutic range (i.e., at or above
minimum effective concentration (MEC)) but below toxic levels over
an extended period of time (e.g., about 8, 10, 12, 14, 16, 18, 20,
22, 24 hours or greater). The term "sustained release" may be used
interchangeably with "slow-release," "controlled release," or
"extended release." The sustained release property of a dosage form
is typically measured by an in vitro dissolution method and
confirmed by an in vivo blood concentration-time profile (i.e., a
pharmacokinetic profile).
[0127] The MEC of a pharmaceutically active agent of interest in a
human or non-human patient may be determined using appropriate
techniques known in the art (see, e.g., Grond et al., British
Journal of Clinical Pharmacology 48: 254-7, 1999; and Lehmann et
al., Clinical Journal of Pain 6: 212-20, 1990 for determining the
MEC of tramadol in humans).
[0128] A desired specification for an in vitro dissolution is that
the dosage form releases 90-100% of its drug content in a linear
(O-order) or nearly linear fashion in about 18-24 hours for a
once-a-day, or 10-12 hours for a twice-a-day dosage form. A desired
pharmacokinetic profile is thus a blood concentration level of the
drug maintained at or above its efficacy level and below its
toxicity level for about 18-24 hours for a once-a-day, or 10-12
hours for a twice-a-day dosage form.
[0129] In certain embodiments, the pharmaceutical compositions of
the present invention release about 90% to 100% of their
pharmaceutically active agents in a linear or near linear fashion
for at least about 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,
20, 21, 22, 23, or 24 hours in an in vitro dissolution analysis as
described herein. A pharmaceutically active agent is released in a
"nearly linear" fashion for a specified period of time if the
release rate of the agent does not change more than 20% during any
hour within the specified period of time.
[0130] In certain embodiments, the pharmaceutical compositions of
the present invention, upon oral administration to a human or
non-human patient in need thereof, has an in vitro dissolution rate
measured by the Ph. Eur. Paddle method at 100 rpm in 900 ml 0.1 N
hydrochloric acid at 37.degree. C. and using UV detection at 270 nm
or by the method as described in Example 2 or 11 from about 5% to
about 40% of the pharmaceutically active agent released after 2
hours, from about 15% to about 55% of the pharmaceutically active
agent released after 4 hours, from about 40% to about 80% of the
pharmaceutically active agent released after 8 hours, from about
60% to about 95% of the pharmaceutically active agent released
after 12 hours, and from about 70% to about 100% of the
pharmaceutically active agent released after 18 hours by
weight.
[0131] In certain embodiments, the pharmaceutical compositions of
the present invention, upon oral administration to a human or
non-human patient in need thereof, has an in vitro dissolution rate
measured by one of the methods described above from about 10% to
about 30% of the pharmaceutically active agent released after 2
hours, from about 25% to about 45% of the pharmaceutically active
agent released after 4 hours, from about 50% to about 70% of the
pharmaceutically active agent released after 8 hours, from about
70% to about 90% of the pharmaceutically active agent released
after 12 hours, and from about 80% to about 100% of the
pharmaceutically active agent released after 18 hours by
weight.
[0132] In some of the above-noted embodiments related to in vitro
dissolution rate, the pharmaceutical compositions are in the form
of a matrix tablet and may be orally administered to a patient in
need thereof as either an intact or crushed tablet.
[0133] In certain embodiments, the pharmaceutical compositions
(e.g., matrix tablets) of the present invention, upon oral
administration to a human or non-human patient in need thereof,
provides sustained release of the pharmaceutically active agents in
the compositions for at least about 8, 9, 10, 11, 12, 13, 14, 15,
16, 17, 18, 19, 20, 21, 22, 23, 24, 36, 48, 72, 96, 120, 144, or
168 hours.
[0134] In certain embodiments, the pharmaceutical compositions are
in the form of matrix tablets suitable for one-a-day or twice-a-day
administration to a human or non-human patient. In certain other
embodiments, the pharmaceutical compositions are in the form of
matrix tablets suitable for administration to a human or non-human
patient no more than once per two, three, four, five, six, or seven
days. In certain embodiments, the patient is a cat, the
pharmaceutical compositions are in the form of matrix tablets
containing tramadol and suitable for administration for oral
administration once per three days or once per week.
[0135] In certain embodiments, the pharmaceutical compositions of
the present invention, upon oral administration to a human or
non-human patient in need thereof, produce a pharmacokinetic
profile with a T.sub.max of about 1 to 18 hours, such as about 1 to
16, 1 to 14, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 2 to 16, 2 to 14, 2
to 12, 2 to 10, 2 to 8, 2 to 6, 4 to 16, 4 to 14, 4 to 12, 4 to 10,
4 to 8, or 4 to 6 hours.
[0136] The term "T.sub.max" refers to the time for the plasma
concentration of a pharmaceutically active agent to reach its
maximum value after a pharmaceutical composition comprising the
pharmaceutically active agent is administered to a patient.
[0137] In certain embodiments, the pharmaceutical compositions of
the present invention, upon oral administration to a human or
non-human patient in need thereof, produce a pharmacokinetic
profile with a W.sub.50 value in the range of about 6 to 18 hours,
such as about 8 to 16, 8 to 14, 8 to 12, or 8 to 10 hours.
[0138] The term "W.sub.50" refers to the width of a pharmacokinetic
profile at 50% C.sub.max, that is, the duration over which the
plasma concentrations are equal to or greater than 50% of the peak
plasma concentration (i.e., C.sub.max). In certain embodiments, the
pharmaceutical compositions of the present invention, upon oral
administration to a human or non-human patient in need thereof,
produce an Area Under the Curve (AUC) (0 to infinity) (plasma
concentration versus time) of the pharmaceutically active agent at
least about 50%, 100%, 150%, 200%, or 250% higher than the AUC (0
to infinity) provided by an immediate release formulation
containing the same amount of the pharmaceutically active
agent.
[0139] The term "Area Under the Curve (AUC)" refers to a parameter
determined from the graphical presentation of an actual or
theoretical plasma profile (concentration verse time) that
represents the area under the curve of such a profile. The term
"AUC (0 to infinity)" refers to the total area under the curve of a
plasma concentration versus time profile from the time of
administration to infinity. AUC may be measured or determined by
appropriate methods known in the art. One exemplary method is
described in KuKanich & Papich (J. Vet. Pharmacol. Therap. 27,
239-46, 2004).
[0140] An "immediate release formulation" (or "immediate release
form", or the like) of a drug refers to a formulation that releases
at least 80% of the drug within one hour measured by an in vitro
dissolution method, such as those described herein.
[0141] In certain embodiments, the pharmaceutical compositions of
the present invention comprise tramadol, and upon oral
administration in a dog, provide an AUC (0 to infinity) (plasma
concentration versus time) of tramadol about or greater than 2, 4,
or 6 .mu.g hr/mL. In certain embodiments, such pharmaceutical
compositions, upon oral administration in a dog, further provide a
C.sub.max of tradamol about or less than 10 .mu.g/mL.
[0142] In certain embodiments, the pharmaceutical compositions of
the present invention comprise tramadol, and upon oral
administration in a dog, provide an AUC (0 to infinity) (plasma
concentration versus time) of the active metabolite of tramadol, M1
(O-desmethyltramadol), about or greater than 0.2, 0.4, 0.6, 0.8,
1.0, or 1.2 .mu.g hr/mL. In certain embodiments, such
pharmaceutical compositions, upon oral administration in a dog,
further provide a C.sub.max of M1 about or less than 2
.mu.g/mL.
[0143] In certain embodiments, the composition of the present
invention, upon oral administration to a patient in need thereof,
provides a plasma concentration at or above a therapeutically
effective concentration for a period of time that is at least about
100%, 150%, 200%, or 250% longer than an immediate release
formulation containing the same amount of the pharmaceutically
active agent.
[0144] The pharmaceutical compositions (e.g., matrix tablets) are
generally prepared using standard techniques well known in the art.
In certain embodiments, they may be prepared by (a) micronizing a
drug of a high water solubility, short half-life and high dose, as
needed, (b) selecting drug particles having an upper size limit of
about or less than 210 micron (70 mesh) and a lower limit of about
or greater than 63 micron (230 mesh), such as an upper size limit
of about or less than 125 micron (120 mesh) and a lower size limit
of about or greater than 74 micron (200 mesh), (c) optionally
passing a hydrophilic polymer and excipients through a 70 mesh
sieve, (d) dry blending the drug with the hydrophilic polymer, a
diluent, a binder, and/or one or more other excipients to
uniformity, (e) optionally lubricating the powder blend with a
lubricant/glidant, (f) compressing the resulting mixture into
tablets (e.g., those of hardness of about 10 to 20 kp using, for
example, a conventional tablet press), and (g) optionally coating
the tablets, for example, using a spray coater or a fluid bed
coater.
[0145] In certain embodiments, a matrix tablet of this invention
may be prepared by: (a) Micronizing a drug of a high water
solubility, short half-life and high dose using a FITZMILL.RTM.
Comminutor by Fitzpatrick Corp. (Elmhurst, Ill.). The FITZMILL.RTM.
Comminutor can be configured for comminution to a specific particle
range, or fine grinding applications. The micronizing step is
applied to only coarse drug substances with particle size exceeding
the upper limit of the desired size range, i.e., 210 micron (70
mesh). Most commercially available drug substances are regarded
"coarse" for this invention and thus require size reduction. For
drug substances with a fine particle size to begin with, this step
may not be necessary.
[0146] (b) Sieving the micronized or unmicronized drug substance
and selecting the fraction with an upper size limit of about or
less than 210 micron (70 mesh) and a lower limit of about or
greater than 63 micron (230 mesh), such as an upper limit of about
or less than 177 micron (80 mesh) and a lower limit of about or
greater than 74 micron (200 mesh), an upper limit of about or less
than 149 micron (100 mesh) and a lower limit of about or greater
than 74 micron (200 mesh), and an upper limit of about or less than
125 micron (120 mesh) and a lower limit of about or greater than 74
micron (200 mesh). The sieving can be done using conventional
standard sieves and sieving equipment, such as a Russel Model 16300
Portable Sieve.
[0147] (c) Additionally, passing the hydrophilic polymer and all
excipients individually or combined through a 70 mesh sieve.
[0148] (d) Combining and dry blending a mixture of the sieved drug
substance from about 50 weight percent to about 80 weight percent,
a hydrophilic polymer from about 10 weight percent to about 40
weight percent, and an excipient(s) (filler and/or binder) from
about 2 weight percent to about 20 weight percent, to obtain a
uniform powder blend. The dry blending can be done using a
conventional powder blender such as a Patterson-Kelly V-blender. A
typical blending time is about 15 to 30 minutes.
[0149] (e) Adding to the powder blend produced in step (d) a
lubricant and/or glidant of about 1 weight percent to about 3
weight percent and blending for 1-5 minutes, preferable about 2
minutes.
[0150] (f) Compressing the powder blend from step (e) into tablets
with hardness of about 10 to 20 kp using a conventional tablet
press such as a Colton rotary press. The tablet weight may vary
from about 400 to 2000 mg. Any tablet shape that is easy swallowed
is desired. A score or certain trademark feature may also be added
to the tablet.
[0151] (g) Optionally, spray coating the tablets with film
coatings, release-controlling coatings or enteric coating for the
purpose of taste masking, easing swallow ability, extended release
or acid protection, etc. The coating may be colored with a
pharmaceutically accepted dye. The process may be accomplished
using a conventional spray coater (e.g., a VECTOR HI-COATER) or a
fluidized bed processor (e.g., a GLATT MODEL GPCG-5 COATER).
[0152] In certain embodiments, the tablets are processed by a
direct compression method. Direct compression is a simplest process
of making tablets where all tablet components are dry mixed to form
a uniform blend and then directly compressed into tablets. It
requires the tablet component blend to possess adequate flow
property and compressibility. Direct compression eliminates other
processing steps such as granulation, which is required for a
tablet component blend that does not have suitable flow or
compression property.
[0153] The coating liquid generally comprises film forming polymers
such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
cellulose esters or ethers (such as cellulose acetate or
ethylcellulose), an acrylic polymer or a mixture of polymers. The
coating solution is generally an aqueous solution or an organic
solvent further comprising propylene glycol, sorbitan monoleate,
sorbic acid, fillers such as titanium dioxide, a pharmaceutically
acceptable dye.
[0154] An exemplary coating system for taste masking, easing
swallow ability, and/or extended release comprises an aqueous
dispersion of ethyl cellulose, oleic acid, ammonium hydroxide and
water (under the tradename of Surelease E-7-19010 by Colorcon) and
a polyethylene glycol aqueous solution (under the tradename Opadry
II by Colorcon). An exemplary coating system is a mixture of about
20-50% Surelease E-7-19010), about 0.5-5% Opadry, and water.
[0155] In certain embodiments, the matrix tablets of the present
invention comprise a coating layer that controls the release of the
drug in the matrix tablets (referred to as a "release controlling
coating," "release controlling layer," or "release controlling
coating layer"). A coating controls the release of a drug in a
matrix tablet if the release of the drug over time in the matrix
tablet with the coating is statistically significantly different
from that in the matrix tablet without the coating. In certain
embodiments, the coating prolongs the release of the drug in the
matrix tablet. For example, the coating may increase the time the
effective plasma concentration of the drug in a patient after
administered with the matrix tablet for about 1, 2, 3, 4, or 5
hours.
[0156] In certain other embodiments, the matrix tablets of the
present invention comprise a coating layer that does not control
the release of the drug in the matrix tablets. Such a coating may
have one or more other properties, such as taste masking or
facilitating swallow.
[0157] In certain embodiments, the matrix tablet of the present
invention is of an oval shape with a single score perpendicular to
the long axis of the tablet. Such a design facilitates the
fragmentation of the matrix tablets and minimizes the disruption of
the integrity of the resulting tablet fragments.
[0158] An exemplary matrix tablet composition for the extended
release of the drug of a high-solubility, short half-life and high
dose comprises: from about 55 weight percent to about 75 weight
percent of a micronized tramadol HCl; from about 20 weight percent
to about 25 weight percent of hydroxypropyl methylcellulose
(METHOCEL.TM. K100M Premium CR); from about 2 weight percent to
about 20 weight percent of microcrystalline cellulose (AVICEL
PH102); from about 0.5 weight percent to about 2 weight percent. of
magnesium stearate, USP; and from about 1 weight percent to about 3
weight percent of a film coating comprising Surelease E-7-19010 and
Opadry II.
[0159] Another exemplary matrix composition in a form of an orally
deliverable SR tablet comprising tramadol hydrochloride having an
upper size limit of about or less than 125 micron (120 mesh) and a
lower size limit of about or greater than 74 micron (200 mesh) in
an amount of about 75, 90, 100, 180, 200, 300, 400, 500, 600, 700,
800, 900, or 1000 mg, dispersed in a matrix comprising: (a) HPMC of
a high molecular weight (e.g., METHOCEL.TM. K100M by Dow Chemical)
in an amount of about 20% to about 30% by weight of the tablet, (b)
a microcrystalline cellulose having a particle size of not greater
than 210 micron, in an amount of about 10% to about 20% by weight
of the tablet, (c) a tableting lubricant in an amount of about 1%
to about 3% by weight of the tablet, and (d) optionally a film
coating (e.g., a film coating comprising Surelease E-7-19010 and
Opadry II) of about 1 weight percent to about 3 weight percent of
the tablet. In this exemplary matrix composition, the tramadol
hydrochloride may contribute about 44% to about 69% of the total
weight of the tablet.
[0160] In another aspect, the present invention provides a
pharmaceutical composition in the form of an orally deliverable
tablet comprising tramadol hydrochloride having an upper size limit
of about or less than 125 micron (120 mesh) and a lower size limit
of about or greater than 74 micron (200 mesh) in an amount of about
150 mg to about 500 mg (e.g., about 150, 200, 250, 300, 350, 400,
450, or 500 mg), dispersed in a matrix comprising (a) HPMC of a
high molecular weight (e.g., METHOCEL.TM. K100M by Dow Chemical) in
an amount of about 20% to about 40% by weight of the tablet, (b) a
microcrystalline cellulose having a particle size of about or less
than 210 micron, in an amount of about 10% to about 30% by weight
of the tablet, (c) a tableting lubricant in an amount of about 1%
to about 3% by weight of the tablet, and (d) optionally a film
coating (e.g., a film coating comprising Surelease E-7-19010 and
Opadry II) of about 1 weight percent to about 3 weight percent of
the tablet. In this exemplary matrix composition, the tramadol
hydrochloride may contribute about 27% to about 69% of the total
weight of the tablet.
[0161] Another exemplary matrix composition in a form of an orally
deliverable SR tablet comprises glucosamine HCl or another salt
such as N-butyryl glucosamine having an upper size limit of about
or less than 125 micron (120 mesh) and a lower size limit of about
or greater than 74 micron (200 mesh) in an amount of about 100,
200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300,
1400, or 1500 mg, dispersed in a matrix comprising: (a) HPMC of a
high molecular weight (e.g., METHOCEL.TM. K100M by Dow Chemical) in
an amount of about 20% to about 30% by weight of the tablet, (b) a
binder having a particle size of about or less than 210 micron, in
an amount of about 2% to about 20% by weight of the tablet, (c) a
tableting lubricant in an amount of about 1% to about 3% by weight
of the tablet, and (d) optionally a film coating (e.g., a film
coating comprising Surelease E-7-19010 and Opadry II) of about 1
weight percent to about 3 weight percent of the tablet. In this
exemplary matrix composition, glucosamine HCl or another salt such
as N-butyryl glucosamine may contribute about 50% to about 77% of
the total weight of the matrix composition.
[0162] Yet another exemplary matrix composition in a form of an
orally deliverable SR tablet comprises glucosamine HCl having an
upper size limit of about or less than 125 micron (120 mesh) and a
lower size limit of about or greater than 74 micron (200 mesh) in
an amount of about 100, 200, 300, 400, 500, 600, 700, 800, 900,
1000, 1100, 1200, 1300, 1400 or 1500 mg, and chondroitin sulfate
having an upper size limit of about or less than 125 micron (120
mesh) and a lower size limit of about or greater than 74 micron
(200 mesh) in an amount of about 100, 200, 300, 400, 500, 600, 700,
800, 900, 1000, 1100, 1200, 1300, 1400 or 1500 mg, dispersed in a
matrix comprising: (a) HPMC of a high molecular weight (e.g.,
METHOCEL.TM. K100M by Dow Chemical) in an amount of about 20% to
about 30% by weight of the tablet, (b) a binder having a particle
size of about or less than 210 micron, in an amount of about 2% to
about 20% by weight of the tablet, (c) a tableting lubricant in an
amount of about 1% to about 3% by weight of the tablet, and (d)
optionally a film coating (e.g., a film coating comprising
Surelease E-7-19010 and Opadry II) of about 1 weight percent to
about 3 weight percent of the tablet. In this exemplary matrix
composition, glucosamine HCl and chondroitin sulfate together may
contribute about 50% to about 77% of the total weight of the matrix
composition.
[0163] Yet another exemplary matrix composition in a form of an
orally deliverable SR tablet comprises gabapentin having an upper
size limit of about or less than 125 micron (120 mesh) and a lower
size limit of about or greater than 74 micron (200 mesh) in an
amount of about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000,
1100, 1200, 1300, 1400 or 1500 mg, dispersed in a matrix
comprising: (a) HPMC of a high molecular weight (e.g., METHOCEL.TM.
K100M by Dow Chemical) in an amount of about 20% to about 30% by
weight of the tablet, (b) a binder having a particle size of about
or less than 210 micron, in an amount of about 2% to about 20% by
weight of the tablet, (c) a tableting lubricant in an amount of
about 1% to about 3% by weight of the tablet, and (d) optionally a
film coating (e.g., a film coating comprising Surelease E-7-19010
and Opadry II) of about 1 weight percent to about 3 weight percent
of the tablet. In this exemplary matrix composition, gabapentin may
contribute about 50% to about 77% of the total weight of the matrix
composition.
[0164] A further exemplary matrix composition in a form of an
orally deliverable SR tablet comprises metformin hydrochloride
having an upper size limit of about or less than 125 micron (120
mesh) and a lower size limit of about or greater than 74 micron
(200 mesh) in an amount of about 100, 200, 300, 400, 500, 600, 700,
800, 900, 1000, 1100, 1200, 1300, 1400 or 1500 mg, dispersed in a
matrix comprising: (a) HPMC of a high molecular weight (e.g.,
METHOCEL.TM. K100M by Dow Chemical) in an amount of about 20% to
about 30% by weight of the tablet, (b) a binder having a particle
size of about or less than 210 micron, in an amount of about 2% to
about 20% by weight of the tablet, (c) a tableting lubricant in an
amount of about 1% to about 3% by weight of the tablet, and (d)
optionally a film coating (e.g., a film coating comprising
Surelease E-7-19010 and Opadry II) of about 1 weight percent to
about 3 weight percent of the tablet. In this exemplary matrix
composition, metformin hydrochloride may contribute about 44% to
about 77% of the total weight of the matrix composition.
[0165] A further exemplary matrix composition in a form of an
orally deliverable SR tablet comprises acetaminophen having an
upper size limit of about or less than 125 micron (120 mesh) and a
lower size limit of about or greater than 74 micron (200 mesh) in
an amount of about 100, 200, 300, 400, 500, 600, 700, 800, 900,
1000, 1100, 1200, 1300, 1400 or 1500 mg, dispersed in a matrix
comprising: (a) HPMC of a high molecular weight (e.g., METHOCEL.TM.
K100M by Dow Chemical) in an amount of about 20% to about 30% by
weight of the tablet, (b) a microcrystalline cellulose having a
particle size of about or less than 210 micron, in an, amount of
about 10% to about 20% by weight of the tablet, (c) a tableting
lubricant in an amount of about 1% to about 3% by weight of the
tablet, and optionally (d) a film coating (e.g., a film coating
comprising Surelease E-7-19010 and Opadry II) of about 1 weight
percent to about 3 weight percent of the tablet. In this exemplary
matrix composition, acetaminophen may contribute about 44% to about
69% of the total weight of the matrix composition.
[0166] In one aspect, the present invention provides methods for
using the pharmaceutical compositions described herein. Such
pharmaceutical compositions may be used for treating or preventing
(i.e., reducing the risk of) diseases or disorders that the
pharmaceutically active agents in the compositions are suitable for
treating or preventing.
[0167] In certain embodiments, the present invention provides a
method for reducing pain comprising administering orally to a
patient in need thereof a pharmaceutical composition as described
herein that comprises an effective amount of tramadol, tramadol HCl
or another pharmaceutically acceptable salt
[0168] In certain embodiments, the present invention provides a
method for reducing joint discomfort or increasing joint
flexibility comprising administering orally to a patient in need
thereof a pharmaceutical composition as described herein that
comprises an effective amount of glucosamine, glucosamine HCl or
another pharmaceutically acceptable salt.
[0169] In certain embodiments, the present invention provides a
method for reducing joint discomfort or increasing joint
flexibility comprising administering orally to a patient in need
thereof a pharmaceutical composition as described herein that
comprises an effective amount of glucosamine HCl and chondroitin
sulfate.
[0170] In certain embodiments, the present invention provides a
method for reducing pain or fever that comprises administering
orally to a patient in need thereof a pharmaceutical composition as
described herein comprising an effective amount of
acetaminophen.
[0171] In certain embodiments, the present invention provides a
method for treating or preventing (i.e., reducing the risk of)
seizure or reducing neuropathic pain that comprises administering
orally to a patient in need thereof a pharmaceutical composition as
described herein comprising an effective amount of gabapentin.
[0172] In certain embodiments, the present invention provides a
method for lowering blood sugar level comprising administering
orally to a patient in need thereof a pharmaceutical composition as
described herein that comprises an effective amount of metformin
hydrochloride.
[0173] Patients in need of treatment or prevention of a disease or
disorder include both human patients (e.g., adult human patients)
and non-human patients (e.g., dogs, cats, horses, and other pets or
farm animals). As described above, the matrix tablets of the
present invention are especially suitable for animal use because
such tablets, unlike other tablets in which controlled release of
drugs depend on their intact coating, provide controlled release of
drugs even after being chewed, fragmented or crushed.
[0174] An "effective amount" refers to the amount of a
pharmaceutically active agent effective in treating or preventing a
disease or disorder. Such amount may be determined by appropriate
methods known in the art. For instance, a sufficient amount of an
analgesic or analgesics (such as tramadol and acetaminophen) in a
pharmaceutical composition of the present invention may be
determined using various methods for measuring analgesia, such as
those described in U.S. Patent Application Publication No.
20050089558, Collier et al., Br. J. Pharmacol. 32: 295, 1968;
D'Amour et al., J. Pharmacol. Exp. Ther. 72: 74, 1941; and
Hargreaves et al., Pain 32: 77, 1988.
[0175] To exemplify the results achieved using the sustained
release compositions of the present invention, the following
examples are provided without any intent to limit the scope of the
instant invention to the discussion therein. All parts and
percentages are by weight unless otherwise indicated.
EXAMPLES
Example 1
Composition and Method for Preparing Tramadol SR Matrix Tablets
[0176] Herein below, describes components, composition,
manufacturing process, test and specification of a tramadol HCl
sustained release tablets prepared by the methods disclosed in this
invention. Tramadol HCl is "freely soluble" in water according to
the USP definition. Due to its short half-life, an SR tablet of
tramadol is desired for pain management including pains associated
with osteoarthritis in dogs and humans.
Components and Composition
[0177] The tramadol sustained release tablets presented in this
example are coated matrix tablets of this invention. The components
and compositions of the uncoated tablet and the coating are listed
separately in the tables below:
Uncoated Matrix Tablet
TABLE-US-00002 [0178] % Mg per Brand and Component w/w tablet
Manufacturer Tramadol HCl, micronized* 60.0 600 DAI-ICHI KARKARIA
Hydroxypropyl 22.4 224 Methocel K100M Methylcellulose, USP Prem CR
by Dow Chemical Microcrystalline Cellulose, NF 15.6 156 Avicel
PH-102 by FMC BioPolymer Magnesium Stearate, NF 2.0 20 Witco
Corporation Total 100 1000 *The particle size of this material is
rated at 120 mesh, i.e., 90% of the tramadol HCl drug substance can
pass through a 120 mesh sieve (121 micron).
Coating Dispersion
TABLE-US-00003 [0179] Component % w/w Grade Brand and Manufacturer
An aqueous dispersion 34.0 NF Surelease E-7-19010 containing ethyl
cellulose, by Colorcon oleic acid, ammonium hydroxide and water A
solution containing 1.5 NF Opadry II by Colcrcon polyethylene
glycol DI Water 64.5 E-Pure by Bamstead Coating weight 2% of the
weight of an uncoated tablet
The characteristics of the tablets in this example are described as
follows: [0180] Each tablet contains 600 mg tramadol HCl. [0181]
Average uncoated tablet weight is 1000 mg and average coating
weight is 20 mg per tablet. [0182] The tablets are in an oval shape
with a bisecting score on one side. [0183] The uncoated tablets are
monolithic and non-disintegrating. [0184] The in vitro release of
tramadol is insensitive to pH of the dissolution medium due to lack
of ionizable and soluble excipients in the formulation, and
insensitive to speed of agitation because of the non-disintegrating
and slow erosion nature of the tablets. [0185] The tablets are
coated to further control the drug release (FIG. 1) and to improve
taste and ease of swallow of the tablets. The coating is intended
(1) to suppress the initial burst release of the uncoated tablets,
(2) to provide an improved zero-order release, (3) to extend the
release to about 20-24 hours (from the 12-16 hr of the uncoated
tablets), (4) for taste masking (tramadol HCl tastes very salty and
somewhat bitter), (5) to serve as a protective layer, and finally
(6) for easy swallow. [0186] The uncoated tablets are likely to be
twice-a-day tablets, while the coated tablets may be for once-a-day
use. [0187] The uncoated tablets are produced by a direct
compression method using a rotary tablet press. [0188] The tablets
are spray coated in a pan coater.
Manufacturing Process
[0189] The tablets of this example may be manufactured following
the general steps as listed below:
Micronizing
[0190] 1. Charge a coarse tramadol HCl drug substance into a
FitzMill Model DAS06 Comminutor. Grind the powder for 10-60 minutes
to reduce particle size. [0191] 2. Collect the product and pass
through a 120 mesh sieve. Collect the fraction that passes through
the 120 mesh sieve. [0192] 3. Determine the % of extra-fine
particles (i.e., <74 micron) present in the collected fraction,
if the wt % extra-fine particle exceeds 10% of the total weight,
sieve the fraction through a 200 mesh sieve to remove the
extra-fine particles.
Tableting
[0192] [0193] 1. Weigh out HPMC (METHOCEL K100M Premium CR),
microcrystalline cellulose (AVICEL PH102) and tramadol HCl
(micronized), transfer into a V-blender, mix for 2-10 minutes.
[0194] 2. Pass the mixture through a 70-mesh sieve. [0195] 3.
Charge the mixture into the V-blender again and mix for 20 minutes
to form a uniform powder mixture. [0196] 4. Add magnesium stearate,
mix for 0.5-2 minutes. [0197] 5. Compress into oval shaped tablets
of appropriate weight and hardness (10-20 kp). [0198] 6. Vacuum
dedust the tablets. [0199] 7. Store the tablets in appropriated
container for coating process.
Coating
[0199] [0200] 1. Mix Opadry II and Surelease dispersion to form the
final coating dispersion. [0201] 2. Charge an appropriate number of
tablets into a coating pan and start coating using the following
approximate conditions: [0202] Pan rotation: 10-50 RPM [0203]
Liquid spray rate: 5-30 mL/min [0204] Dry air temperature:
40-70.degree. C. [0205] 3. The final weight gain is 2.0.+-.0.2%
based on the average uncoated tablet weight.
Specification
[0206] The tablets of this example may be tested against the
following quality specifications:
TABLE-US-00004 Test Method Specification Appearance Visual A white
or off-while and oval shape tablet without any chip, defeat, or
layers In vitro USP dissolution Meet the requirement dissolution
apparatus II Identification HPLC Conforms to standard Uniformity of
HPLC Meet the requirement dosage units Assay HPLC 90 to 110% label
claim
Example 2
Effects of Drug Particle Size on In Vitro Dissolution Rate of
Tramadol SR Matrix Tablets
[0207] This example exhibits the significant effect of drug
particle size on in vitro dissolution rate from the tablets
prepared according to this invention. In addition, this example
shows that fine or micronized drug substance particles, in the size
specification defined in this disclosure, are required to provide
the sustained or extended release of a drug of high-solubility,
short half-life and high dose.
[0208] Multiple lots of tramadol hydrochloride drug substances of
varying particle size (Table below) were used to prepare the matrix
tablets using the method described in Example 1.
TABLE-US-00005 Particle size Upper of tramadol Manufacture and
particle HCl lot number size limit* Note "Coarse" Degussa, lot
>400 micron This lot was difficult 0041194237 to process - extra
compression forces were needed to obtain tablets that meet the
hardness specification, but it failed to meet the dissolution
specification "Micronized" Dai-Ichi 210 micron This lot was
processed Karkaria, Ltd. lot to form tablets that TDL/M/03/04004
meet the hardness and dissolution specifications, using the method
disclosed in this application A fine Dai-Ichi 125 micron This lot
was processed particle Karkaraia Ltd., to form tablets that
fraction lot DKM04030 meet the hardness and collected dissolution
by sieving specifications, using a coarse the method disclosed
starting in this application material through a 120 mesh sieve
"Extra-fine" Chemagis, lot 80 micron This lot was very fluffy
3TRMDNOF505 and had a poor flow property and could not processed to
form tablets of the target size or hardness, using the method
disclosed in this application *Upper particle size limit: a value
by which 95% of the particles are below in size.
[0209] An in vitro dissolution test was carried for the tablets
prepared according to this invention using a standard UPS
dissolution apparatus II (Paddle). The method is detailed as
follow: [0210] APPARATUS: USP dissolution apparatus II (Paddle)
[0211] Medium: USP Simulated gastric fluid (without enzymes) [0212]
Medium volume: 1000 mL [0213] Temperature: 37.degree. C. [0214]
Stir: 50 RPM [0215] Sample volume: 1 mL (without replenishment with
fresh medium). Each sample was filtered through a 10-micron filter
prior to filling into HPLC vial. [0216] Sampling time: 0.25, 0.5,
0.75, 1, 2, 3, 6, 12, 18 and 24 hours [0217] Tablet sinker: A metal
wire sinker with an approximate diameter of 0.8 mm and 1 g weight
was used to coil around each tablet and to hold a tablet to the
bottom of the vessel to prevent floating or movement during the
stirring. [0218] Sample analysis: HPLC [0219] Date normalization:
After 24 hours, the remaining tablet mass (a soft gel) was
homogenized in the medium using a mechanical mixer to form a
uniform dispersion, which was then filtered through the 10-micron
filter and analyzed by HPLC as the "100% release" sample. The in
vitro release (%) values in all previous samples (0.25-24 hr) were
normalized based on the "100% release" using the following
equation:
[0219] % release=100*(tramadol conc. in a previous
sample)/(tramadol conc. in the "100% release sample")
[0220] The concentration of tramadol in the medium samples were
analyzed using a reversed phase HPLC method with the following
conditions: [0221] System: An HPLC system capable of performing
binary gradient elution and UV detection [0222] Column: Luna C18
5.mu., 4.6.times.250 mm, by Phenomenex Part #00G-4041-E0 [0223]
Mobile Phase A: 0.1% v/v trifluoroacetic acid in water, 0.8 micron
filtered [0224] Mobile Phase B: 0.1% v/v trifluoroacetic acid in
acetonitrile, 0.8 micron filtered [0225] Column temp: 40.degree. C.
[0226] Injection: 5 .mu.L [0227] UV Detection: 270 nm [0228] Run
time: 5 min [0229] Elution: Isocratic at 65% (v/v) Mobile Phase A
and 35% (v/v) Mobile Phase B
[0230] The in vitro dissolution results from these tablets are
depicted in FIG. 2. It is apparent that only the tablets made with
micronized particles of tramadol hydrochloride drug substances in
the specified particle size range were able to provide the
sustained release characteristics desired specification (i.e.,
coated tablets to release about 80-100% in about 18-24 hours).
Tablets prepared with coarse drug particles exhibited a
significantly fast dissolution rate and failed to meet the
sustained release requirement set forth for these tablets. The
extra-fine tramadol hydrochloride did not flow and compress
properly using the method described in this application. The
tablets formed were very soft and fragile and could not be coated
due to a very high friability.
Example 3
In Vivo Pharmacokinetic Analysis of Coated and Uncoated Tramadol SR
Matrix Tablets
[0231] The tramadol HCl SR tablets prepared according to Example 1
(i.e., 600 mg tablets) were administered orally to fasted beagle
dogs of an approximate body weight of 10 kg. In Group No. 1 (6
dogs, n=6), each 600 mg uncoated SR tramadol HCl tablet was broken
at the scored line and a half tablet (containing 300 mg tramadol
HCl) was given to each dog. In Group No. 2 (6 dogs, n=6), each 600
mg coated SR tramadol HCl tablet was broken at the scored line and
a half tablet (containing 300 mg tramadol HCl) was given to each
dog. Blood samples were taken at 20 m, 40 m, 60 m, 1.5 h, 2 h, 2.5
h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, 14 h, 16 h, 18 h, 20 h, 22 h, 24
h and 36 h and analyzed by high performance liquid chromatography
(HPLC) for concentration of tramadol and its active metabolite M1
(O-desmethyl-tramadol). The blood concentration profiles are shown
in FIGS. 3A and 3B.
[0232] The pharmacokinetic parameters determined are listed in the
table below:
TABLE-US-00006 Dog_Number Paramaeter Units 206 207 209 215 222 224
Mean Std. Dev. Group 1: M1 Pharmacokinetics Rsq 0.884 0.911 0.9534
0.971 0.9423 0.9338 0.933 0.031 Lambda_z 1/hr 0.1664 0.1638 0.0804
0.1379 0.0954 0.141 0.131 0.036 Half-life hr 4.1649 4.2308 8.6257
5.0249 7.2687 4.9146 5.705 1.823 Tmax hr 1 1 1 0.67 1 1.5 1.028
0.266 Cmax ug/mL 0.3597 0.3843 0.3512 0.3363 0.4052 0.351 0.365
0.025 Tlast hr 24 24 24 24 24 16 22.667 3.266 Clast ug/mL 0.0048
0.0083 0.0129 0.0221 0.0167 0.009 0.012 0.006 AUC(0_to_Clast) hr *
ug/mL 1.8493 2.2478 1.4644 2.1028 2.2874 1.0944 1.841 0.476
AUC(0_to_infinity) hr * ug/mL 1.8854 2.3048 1.6382 2.1874 2.5262
1.1667 1.951 0.496 AUC_(%_extrap.) % 1.9161 2.4719 10.6114 3.8689
9.4497 6.1947 5.752 3.647 Vz_F_pred mL/kg 95608.76 79448.84
227882.5 99425.41 124535.8 182318.7 134869.996 58101.243 Cl_F_pred
mL/hr/kg 15911.74 13016.27 18312.25 13714.9 11875.72 25713.82
16424.116 5094.453 AUMC hr * hr * 11.7827 17.1373 15.5268 17.06
25.4013 5.8624 15.462 6.478 ug/mL MRT hr 6.2495 7.4355 9.4777
7.7992 10.0553 5.0248 7.674 1.900 Group 1: Tramadol
Pharmacokinetics Rsq 0.9907 0.9495 0.9991 0.9891 1 0.9842 0.985
0.019 Lambda_z 1/hr 0.8741 0.7017 0.6628 0.5343 1.3173 0.4448 0.756
0.312 Half-life hr 0.793 0.9878 1.0458 1.2974 0.5262 1.5584 1.035
0.364 Tmax hr 2 2 1.5 4 8 1.5 3.167 2.543 Cmax ug/mL 1.8593 0.8259
1.2633 2.7365 1.3706 1.56 1.603 0.652 Tlast hr 22 20 20 24 24 16
21.000 3.033 Clast ug/mL 0.0019 0.0044 0.0069 0.0131 0.0018 0.0107
0.006 0.005 AUC(0_to_Clast) hr * ug/mL 13.1733 4.9998 9.2125
18.5038 15.7447 3.7965 10.905 5.909 AUC(0_to_infinity) hr * ug/mL
13.1757 5.0074 9.2232 18.505 15.746 3.8009 10.910 5.906
AUC_(%_extrap.) % 0.0182 0.1523 0.1161 0.0066 0.0086 0.1159 0.070
0.065 Vz_F_pred mL/kg 2604.899 8537.772 4907.703 3034.495 1446.345
17745.94 6379.526 6095.786 Cl_F_pred mL/hr/kg 2276.914 5991.128
3252.674 1621.186 1905.244 7892.812 3823.326 2549.728 AUMC hr * hr
* 85.1731 30.6714 57.3122 116.3354 123.615 11.0943 70.700 45.665
ug/mL MRT hr 6.4644 6.1252 6.2139 6.2867 7.8506 2.9188 5.977 1.629
Dog_Number Paramaeter Units 204 205 208 211 221 223 Mean Std. Dev.
Group 2: M1 Pharmacokinetics Rsq 1 0.9808 0.9851 0.8214 0.8433
0.9373 0.928 0.077 Lambda_z 1/hr 0.1353 0.3977 0.206 0.0588 0.1216
0.218 0.190 0.118 Half-life hr 5.1215 1.7428 3.3651 11.7918 5.6979
3.1789 5.150 3.552 Tmax hr 1 3 1 3 1 3 2.000 1.095 Cmax ug/ml
0.1632 0.1565 0.2174 0.2943 0.1477 0.1608 0.190 0.057 Tlast hr 36
22 18 36 22 18 25.333 8.454 Clast ug/mL 0.0074 0.0017 0.0328 0.0148
0.026 0.0093 0.015 0.012 AUC(0_to_Clast) hr * ug/mL 1.591 1.2023
1.7833 2.3962 1.4456 1.3324 1.625 0.428 AUC(0_to_infinity) hr *
ug/mL 1.6456 1.2074 1.9379 2.6115 1.6477 1.3889 1.740 0.495
AUC_(%_extrap.) % 3.3185 0.425 7.978 8.2452 12.266 4.0697 6.050
4.247 Vz_F_pred mL/kg 134699.6 62473.13 75157.07 195427.9 149670.3
99056.85 119414.158 50085.061 Cl_F_pred mL/hr/kg 18230.26 24846.88
15480.72 11487.72 18207.25 21599.28 18308.684 4650.063 AUMC hr * hr
* 22.1431 8.5922 16.2483 34.518 20.0062 10.1029 18.602 9.442 ug/mL
MRT hr 13.4558 7.1163 8.3845 13.2178 12.1419 7.2738 10.265 2.994
Group 2: Tramadol Pharmacokinetics Rsq 0.8808 0.9736 0.9874 0.9501
0.8909 0.9989 0.947 0.050 Lambda_z 1/hr 0.0945 0.494 0.4987 0.3692
0.3841 0.4376 0.380 0.150 Half-life hr 7.3337 1.4031 1.39 1.8775
1.8046 1.5838 2.565 2.345 Tmax hr 6 6 6 3 10 8 6.500 2.345 Cmax
ug/mL 0.5968 2.1666 2.936 2.9567 0.5351 1.8789 1.845 1.077 Tlast hr
24 18 18 36 22 16 22.333 7.312 Clast ug/mL 0.0926 0.0291 0.0819
0.0113 0.0593 0.0828 0.060 0.033 AUC(0_to_Clast) hr * ug/mL 7.6339
12.7417 22.9313 17.2425 4.456 13.2268 13.039 6.611
AUC(0_to_infinity) hr * ug/mL 8.5754 12.7988 23.1066 17.243 4.5881
13.4111 13.287 6.484 AUC_(%_extrap.) % 10.9798 0.446 0.7586 0.0027
2.8794 1.3744 2.740 4.158 Vz_F_pred mL/kg 37013.8 4744.666 2603.641
4712.522 17022.98 5111.353 11868.160 13358.955 Cl_F_pred mL/hr/kg
3498.366 2343.972 1298.329 1739.838 6538.703 2236.951 2942.693
1910.361 AUMC hr * hr * 114.4944 92.5742 180.2629 125.5943 58.4876
103.4698 112.481 40.406 ug/mL MRT Hr 13.3514 7.233 7.8014 7.2838
12.7478 7.7152 9.355 2.877
[0233] As shown in FIGS. 3A and 3B, both the uncoated (Group No. 1,
FIG. 3A) and coated (Group No. 2, FIG. 3B) tablets exhibited
sustained blood concentration profiles for tramadol and M1.
Example 4
In Vivo Gastric Retention Study of Tramadol SR Matrix Tablets
[0234] In another in vivo study, the coated tramadol SR tablets
prepared according to Example 1 were administered orally to beagle
dogs of an approximate body weight of 10 kg. Three (3) hours after
the dosing, the dogs were humanely sacrificed and gastric and
intestinal contents were recovered. A non-disintegrated, deformed
and swollen tablet mass was found in the small intestine region.
This indicates that the tablets stayed in the dog stomach for
maximal three hours whereas the observed sustained release of
tramadol lasted for 12-16 hours, suggesting that the prolonged
blood concentration profile of tramadol was not caused by gastric
retention of the tablet. It is concluded that matrix SR tablets
disclosed in this invention are not gastric retention tablets.
Example 5
Stability Analysis of Tramadol SR Matrix Tablets
[0235] Coated tramadol HCl SR tablets prepared according to Example
1 were packaged in plastic screw cap bottle (high density
polyethylene) without desiccant and stored at 25.degree. C./60%
relative humidity. Tablet samples were removed at designated time
points and analyzed by HPLC for tramadol stability. The amounts of
tramadol HCl in a tablet (strength) are listed below:
TABLE-US-00007 Initial 7 months 18 months Avg. strength 614.9 628.7
637.3 (mg tramadol HCL/tablet, n = 6) % label claim 102.5 104.8
104.5
[0236] The above stability data suggests that the tramadol HCl SR
tablets prepared according to the composition and method disclosed
in the invention are stable and suitable for commercialization.
Example 6
Composition, Method of Preparation, and In Vitro Dissolution Study
of Glucosamine SR Matrix Tablets
[0237] Glucosamine is an amino sugar and has been used extensively
for joint health. It has been shown in clinical trials for decades
to be effective at easing the joint discomfort and largely
increasing flexibility. Some studies even indicate that glucosamine
may help rebuild cartilage--something traditional NSAID pain
relievers are unable to do.
[0238] Glucosamine is normally available as a hydrochloride salt,
which is extremely soluble in water (dissolves in water in any
proportion). Glucosamine is also a high dose drug with unit dose up
to 1000-1500 mg. Due to its fast metabolism (short half life),
glucosamine in a conventional tablet form (i.e., non-sustained
release or immediate-release tablet) is required for 3-6 times
daily dosing. Thus, glucosamine HCl is a perfect example of a drug
with a high solubility, high dose and short half-life, which makes
it a good candidate for the matrix SR tablet composition and method
of preparation disclosed in this invention. Almost all currently
available commercial products of glucosamine are of the
immediate-release formulation.
[0239] Other than inconvenience of the 3-6 times daily dosing, the
immediate-release glucosamine formulations deliver a burst of
glucosamine that spikes almost immediately after administration. A
complicating factor to consider is an associated insulin spike
(glucosamine is structurally similar to glucose, which triggers
insulin release), and possibly wasted glucosamine with a very high
dose released in a short time, since the oral bioavailability
(amount of drug absorbed) of many highly water soluble drugs does
not correlate linearly with the dose given (such as gabapentin),
i.e., the larger the dose of a highly water soluble drug is given,
the greater percent of the drug is not absorbed and thus more drug
gets wasted.
[0240] Therefore, a glucosamine SR tablet is expected to have the
following advantages:
[0241] (1) Convenience in dosing, i.e., twice-a-day or
once-a-day.
[0242] (2) Less complication associated with insulin spike, which
is particularly important in diabetes patients.
[0243] (3) Reduce the total daily dose by improving
bioavailability.
[0244] Glucosamine SR matrix tablets were prepared using the
compositions and methods disclosed in this application. SR matrix
tablets containing only glucosamine HCl and glucosamine HCl in
combination with chondroitin sulfate, which is another common agent
used for joint health, were prepared with the following composition
using a method similar to that described in Example 1.
TABLE-US-00008 Component % w/w Mg per tablet Glucosamine
Glucosamine HCl, micronized 60 600 ONLY HPMC (Methocel K100M 22.4
224 Premium CR) Microcrystalline cellulose 15.6 156 (AVICEL PH 102)
Magnesium stearate, USP 2 20 Total 1000 Glucosamine- Glucosamine
HCl, micronized 40 400 chondroitin Chondroitin sulfate, micronized
30 300 Combination Manganese 0.5 5 Vitamin C 2 20 HPMC (Methocel
K100M 23 230 Premium CR) Microcrystalline cellulose 2.5 25 (AVICEL
PH 102) Magnesium stearate, USP 2 20 Total 100 1000
[0245] The in vitro release profiles of glucosamine from the SR
matrix tablets are shown in FIG. 4. The uncoated tablets provided a
sustained release of glucosamine for about 12 hours and the coated
for about 18 hours. The SR matrix tablet composition and method of
making disclosed in the application can be applied to glucosamine
HCl and chondroitin sulfate--two drugs of a highly water
solubility, high dose and short half-life.
Example 7
Composition and Method of Acetaminophen SR Matrix Tablets
[0246] Acetaminophen is another drug of high water solubility, high
dose and short half-life. It is commonly available under a trade
name of TYLENOL.RTM.. For pain control or fever reduction,
TYLENOL.RTM. is taken orally every 4 hours (6 times a day).
Acetaminophen SR matrix tablets can be prepared using the
compositions and methods of disclosed in this application. For
example, acetaminophen SR matrix tablets with the following
composition may be prepared using a method similar to that
described in Example 1.
TABLE-US-00009 Component % w/w Mg per tablet Mg per tablet
Acetaminophen, micronized 60 600 900 HPMC (Methocel K100M 22.4 224
335 Premium CR) Microcrystalline cellulose 15.6 156 234 (AVICEL PH
102) Magnesium stearate, USP 2 20 30 Total 100 1000 1500
Example 8
Composition and Method of Preparing Gabapentin SR Matrix
Tablets
[0247] Gabapentin is indicated for seizure control and has been
used for neuropathic pain. It is freely soluble in water. The
current immediate release tablets (NEURONTIN.RTM.) are given orally
to an adult patient at 900-1800 mg/day in three divided doses,
i.e., three times a day and 300-600 mg each time. Because of the
high dose requirement, the NEURONTIN.RTM. 800 mg tablet is regarded
as one of the largest prescription tablets available. With an
elimination half-life of about 5-7 hours, gabapentin makes another
good candidate drug for SR delivery using the matrix SR tablet
composition and method of making disclosed in this application.
[0248] Gabapentin SR matrix tablets can be prepared using the
compositions and methods disclosed in this application. For
example, gabapentin SR matrix tablets with the following
composition may be prepared using a method similar to that
described in Example 1.
TABLE-US-00010 Component % w/w Mg per tablet Gabapentin, micronized
60 900 HPMC (Methocel K100M Premium CR) 22.4 335 Microcrystalline
cellulose (AVICEL PH 102) 15.6 234 Magnesium stearate, USP 2 30
Total 100 1500
[0249] The gabapentin SR tablets in this example may be taken
once-a-day while providing the efficacious blood concentration
level for its indications.
Example 9
Comparative In Vitro Dissolution Studies Between ULTRAM.RTM.
Tablets and Tramadol SR Matrix Tablets
[0250] Coated ER tablets containing 300 mg tramadol HCl were
prepared using a method similar to that described in Example 1. The
components and their concentrations of these tablets are shown in
the tables below:
Uncoated Matrix Tablet
TABLE-US-00011 [0251] % Mg per Component w/w tablet Tramadol HCl,
micronized* 43.0 300 Hydroxypropyl Methylcellulose, USP 33.0 230
Microcrystalline Cellulose, NF 23.0 160 Magnesium Stearate, NF 1.0
7 Total 100 697
Coating Dispersion
TABLE-US-00012 [0252] Function Component Mg/tablet Barrier
Surelease E-7-19010 suspension 47.4 Coating (Solids content 25.0%
w/w) Solution Opadry II Clear Y-19-7483 2.1 Purified Water USP to
dilute -- Yellow Opadry II Yellow 85F92077 13.9 Film Purified Water
USP to dilute -- Coating Camauba Wax NF 0.10
[0253] In vitro dissolution of the SR tablets containing 300 mg
tramadol HCl (intact tablets and tablets cut into four pieces) was
compared to that of ULTRAM.RTM.ER 300 mg tablets (intact tablets
and tablets cut into four pieces, respectively) using the method
described in U.S. Pat. No. 6,254,887 (i.e., the Ph. Eur. Paddle
Method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37.degree.
C. and using UV detection at 270 nm). The results are shown in FIG.
5 and the table below.
TABLE-US-00013 Time Avg dissolution Tablet (hr) (%, n = 4 tablets)*
Std Dev Ultram .RTM. ER 300 mg 0 0.0 0.0 tablet cut into 4 0.25
79.4 6.2 fragments about the 0.5 98.3 8.3 same size 1 103.8 6.0 2
101.9 5.0 4 99.1 3.3 8 96.3 1.6 12 97.1 2.1 16 95.3 4.0 24 98.7 4.5
Tramadol ER 300 mg 0 0 0.0 tablet prepared 0.25 13.0 3.5 according
to 0.5 20.7 4.0 Example 1 cut into 1 31.1 4.6 4 fragments about 2
52.3 7.0 the same size 4 65.8 5.6 8 87.0 3.9 12 91.5 3.2 16 95.47
2.55 24 97.86 1.76 *Using the method as described in the Claim 1 of
U.S. Pat. No. 6,254,887
[0254] ULTRAM.RTM. ER tablets exhibited sustained release property
only when the tablets were intact. When ULTRAM.RTM. ER tablets were
cut into four pieces, they lost the sustained release property and
essentially became an immediate release formulation that released
an entire day's dose in one quick release (burst). Such a burst
would cause significant safety concerns to non-human patients such
as cats, dogs, or horses who likely chew the tablets. Therefore,
ULTRAM.RTM. ER tablets or other sustained release technology that
depend on a coating as the drug release barrier are deemed
unsuitable for animal use. In comparison, the matrix tablets
prepared according to this invention maintained the in vitro
sustained release property even when the tablets have been cut into
four pieces.
Example 10
In Vivo Pharmacokinetic Studies of Intact v. Crushed Tramadol SR
Matrix Tablets
[0255] Coated sustained release tablets containing 300 mg tramadol
HCl were prepared using a method similar to that described in
Example 1. The components and their concentrations of these tablets
are shown in the tables in Example 9. They were administered orally
to dogs at 15.+-.2 mg/kg as halves of 300 mg tablets or as crushed
halves of 300 mg tablets. The dogs were fed twice daily and not
fasted prior to administration of the tablets. Blood samples were
taken at various time points and analyzed by high performance
liquid chromatography for plasma tramadol concentrations.
[0256] The results shown that both crushed and intact tablets
exhibited sustained blood tramadol concentration profiles (FIG. 6)
and sustained blood concentration profiles of the active metabolite
of tramadol, M1 (FIG. 7). It is thus concluded that such tablets
are of particular use for veterinarian applications where intact
tablets are likely to be chewed upon by animal patients.
Example 11
In Vitro Dissolution Studies of Tramadol SR Matrix Tablets of
Various Dosages
[0257] Coated tablets containing 90 mg, 180 mg, 300 mg, or 600 mg
tramadol HCl were prepared using a method described in Example 1 or
a method similar to that described in Example 1. The components and
their concentrations of the tablets containing 300 mg tramadol HCl
are shown in the tables in Example 9. The components and their
concentrations of the tablets containing 90 mg, 180 mg, and 600 mg
tramadol HCl are shown in the tables below.
Tablets Containing 90 mg Tramadol HCl
[0258] Uncoated Matrix Tablet
TABLE-US-00014 Component % w/w Mg per tablet Tramadol HCl,
micronized* 20 1083 Hydroxypropyl Methylcellulose, USP 46.4 209.7
Microcrystalline Cellulose, NF 32.4 145.8 Magnesium Stearate, NF 1
4.5 Total 100 450
[0259] Coating Dispersion
TABLE-US-00015 Function Component Mg/tablet Barrier Surelease
E-7-19010 suspension 30.6 Coating (Solids content 25.0% w/w)
Solution Opadry II Clear Y-19-7483 1.35 Purified Water USP to
dilute -- Yellow Opadry II Yellow 85F92077 9.0 Film Purified Water
USP to dilute -- Coating Carnauba Wax NF 0.2
Tablets Containing 180 mg Tramadol HCl
[0260] Uncoated Matrix Tablet
TABLE-US-00016 Component % w/w Mg per tablet Tramadol HCl,
micronized* 31.3 180 Hydroxypropyl Methylcellulose, USP 40 230
Microcrystalline Cellulose, NF 27.8 160 Magnesium Stearate, NF 1
5.8 Total 100 575.8
[0261] Coating Dispersion
TABLE-US-00017 Function Component Mg/tablet Barrier Surelease
E-7-19010 suspension 43.1 Coating (Solids content 25.0% w/w)
Solution Opadry II Clear Y-19-7483 1.9 Purified Water USP to dilute
-- Yellow Opadry II Yellow 85F92077 13.8 Film Purified Water USP to
dilute -- Coating Carnauba Wax NF 0.2
Tablets Containing 600 mg Tramadol HCl
[0262] Uncoated Matrix Tablet
TABLE-US-00018 Component % w/w Mg per tablet Tramadol HCl,
micronized* 43 300 Hydroxypropyl Methylcellulose, USP 33 230
Microcrystalline Cellulose, NF 23 160 Magnesium Stearate, NF 1 7
Total 100 697
[0263] Coating Dispersion
TABLE-US-00019 Function Component Mg/tablet Barrier Surelease
E-7-19010 suspension 47.4 Coating (Solids content 25.0% w/w)
Solution Opadry II Clear Y-19-7483 2.1 Purified Water USP to dilute
-- Yellow Opadry II Yellow 85F92077 13.9 Film Purified Water USP to
dilute -- Coating Camauba Wax NF 0.1
[0264] The in vitro dissolution study was performed using the
rotating basket method USP Apparatus 1 (USP <711>). The
results from these tablets show that all the coated tablets
exhibited sustained release characteristics for about 18 hours
(FIG. 8).
Example 12
In Vivo Pharmacokinetic Studies of Tramadol SR Matrix Tables
Administered to Dogs Under Various Feeding and Dosing
Conditions
[0265] In one study, SR tablets containing 300 mg tramadol HCl were
prepared using a method similar to that described in Example 1. The
components and their concentrations of the tablets are shown in the
tables in Example 9. The tablets were administered at 30 mg/kg as
single 300 mg tablets to dogs under various feeding and dose
conditions. Blood samples were taken at various time points and
analyzed by high performance liquid chromatography for plasma
tramadol and its metabolite (M1) concentrations. Group No. 1 were
dogs fed immediately before dosing, Group No. 2 dogs fasted 12
hours, dosed, and fasted another 4 hours, and Group No. 3 dogs
fasted 12 hours, dosed, and fasted another 12 hours. The
pharmacokinetic profiles of tramadol and M1 in various groups of
dogs are shown in FIG. 9 (Group No. 1), FIG. 10 (Group No. 2), and
FIG. 11 (Group No. 3).
[0266] In another study, ER tablets containing 180 mg tramadol HCl
were prepared using a method similar to that described in Example
1. The components and their concentrations of the tablets are as
shown in Example 11. The tablets were administered at 18 mg/kg as
single 180 mg tablets to male and female dogs that were fasted 12
hours and fed within 30 minutes for dosing. Blood samples were
taken at various time points and analyzed by high performance
liquid chromatography for plasma tramadol and its metabolite (M1)
concentrations. The pharmacokinetic profiles of tramadol and M1 are
shown in FIG. 12.
[0267] The results of both studies shown that both tramadol and its
active metabolite, M1, were present for an extended period of time
in dog blood under various feeding and dosing conditions.
Example 13
In Vivo Pharmacokinetic Study of Tramadol Matrix Tablets
Administered in Cats
[0268] Coated ER tablets containing 300 mg tramadol HCl were
prepared using a method similar to that described in Example 1. The
components and their concentrations are shown in the tables in
Example 9. The tablets were administered at 30 mg/kg as halves of
single 300 mg tablets to cats that were fasted prior to
administration and offered food no less than 1 hour after dosing.
Blood samples were taken at various time points and analyzed by
high performance liquid chromatography for plasma tramadol and its
metabolite (M1) concentrations. The resulting pharmacokinetic
profiles (FIG. 13) show that both tramadol and M1 were present for
an extended period of time in cat blood.
Example 14
In Vivo Pharmacokinetic Study of Glucosamine SR Matrix Tablets
[0269] Four uncoated matrix tablets prepared in a manner similar to
that cited in Example 1 were administered to fasted beagle dogs at
a glucosamine dose of 1600 mg/dog. Each tablet contains 400 mg
glucosamin hydrochloride, 200 mg chondroitin sulfate, 20 mg
Ester-C.TM. (vitamin C), 5 mg manganese sulfate, 230 mg HPMC, 135
mg microcrystalline cellulose, and 10 mg magnesium stearate. Blood
samples were taken and analyzed by high performance liquid
chromatography coupled with a mass spectrometer (LC-MS) for
concentration of glucosamine.
[0270] The resulting pharmacokinetic profile of glucosamine shows
that glucosamine was present for an extended period of time in
plasma (FIG. 14).
[0271] All of the above U.S. patents, U.S. patent application
publications, U.S. patent applications, foreign patents, foreign
patent applications and non-patent publications referred to in this
specification, are incorporated herein by reference, in their
entirety.
[0272] From the foregoing it will be appreciated that, although
specific embodiments of the invention have been described herein
for purposes of illustration, various modifications may be made
without deviating from the spirit and scope of the invention.
Accordingly, the invention is not limited except as by the appended
claims.
* * * * *