U.S. patent application number 10/796411 was filed with the patent office on 2004-11-04 for controlled release metformin compositions.
Invention is credited to Chen, Chih-Ming, Cheng, Xiu-Xiu, Chou, Joseph, Jan, Steve.
Application Number | 20040219209 10/796411 |
Document ID | / |
Family ID | 33311185 |
Filed Date | 2004-11-04 |
United States Patent
Application |
20040219209 |
Kind Code |
A1 |
Chen, Chih-Ming ; et
al. |
November 4, 2004 |
Controlled release metformin compositions
Abstract
A composition for treating patients having non-insulin-dependent
diabetes mellitus (NIDDM) by administering a controlled release
oral solid dosage form containing preferably a biguanide drug such
as metformin, on a once-a-day basis. The dosage form provides a
mean time to maximum plasma concentration (T.sub.max) of the drug
which occurs at 5.5 to 7.5 hours after oral administration on a
once-a-day basis to human patients. Preferably, the dose of drug is
administered at dinnertime to a patient in the fed state.
Inventors: |
Chen, Chih-Ming; (US)
; Cheng, Xiu-Xiu; (US) ; Jan, Steve;
(US) ; Chou, Joseph; (US) |
Correspondence
Address: |
DAVIDSON, DAVIDSON & KAPPEL, LLC
14th Floor
485 Seventh Avenue
New York
NY
10018
US
|
Family ID: |
33311185 |
Appl. No.: |
10/796411 |
Filed: |
March 9, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10796411 |
Mar 9, 2004 |
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09705630 |
Nov 3, 2000 |
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Current U.S.
Class: |
424/468 ;
514/635 |
Current CPC
Class: |
A61K 31/155 20130101;
A61K 9/2027 20130101; A61K 9/0004 20130101 |
Class at
Publication: |
424/468 ;
514/635 |
International
Class: |
A61K 031/155; A61K
009/22 |
Claims
What is claimed is:
1. A controlled release oral dosage form for the reduction of serum
glucose levels in human patients with NIDDM, comprising an
effective dose of at least one suitable antihyperglycemic drug or a
pharmaceutically acceptable salt thereof and a controlled-release
carrier, said dosage form being suitable for providing once-a-day
oral administration of the agent or pharmaceutically acceptable
salt thereof, wherein the dosage form provides a mean time to
maximum plasma concentration (T.sub.max) of the agent from 5.5 to
7.5 hours after the administration.
2. The controlled release dosage form of claim 1 wherein said at
least one antihyperglycemic drug is a biguanide.
3. The controlled release dosage form of claim 2 wherein said
biguanide is metformin or a pharmaceutically acceptable salt
thereof.
4. The controlled release oral dosage form of claim 1, which
provides a mean time to maximum plasma concentration (T.sub.max) of
the drug from 6.0 to 7.0 hours after the administration of the
dose.
5. The controlled release oral dosage form of claim 1, which
provides a mean time to maximum plasma concentration (T.sub.max) of
the drug from 5.5 to 7.0 hours after the administration of the
dose, when the dose is administered at dinner time.
6. The controlled release oral dosage form of claim 1, which
provides a mean time to maximum plasma concentration (T.sub.max) of
the drug from about 6.0 to 7.5 hours after the administration of
the dose, when the dose is administered at breakfast.
7. The controlled release oral dosage form of claim 1, which
exhibits the following dissolution profiles when tested in a USP
type 2 apparatus at 75 rpm in 900 ml of simulated intestinal fluid
(pH 7.5 phosphate buffer) and at 37 C: 0-30% of the drug is
released after 2 hours; 10-45% of the drug is released after 4
hours; 30-90% of drug is released after 8 hours; not less than 50%
of the drug is released after 12 hours; not less than 60% of the
drug is released after 16 hours; and not less than 70% of the drug
is released after 20 hours.
8. The controlled release oral dosage form of claim 1, which
exhibits the following dissolution profiles when tested in a USP
type 2 apparatus at 75 rpm in 900 ml of simulated intestinal fluid
(pH 7.5 phosphate buffer) and at 37 C: 0-25% of the drug is
released after 2 hours; 20-40% of the drug is released after 4
hours; 45-90% of the drug is released after 8 hours; not less than
60% of the drug is released after 12 hours; not less than 70% of
the drug is released after 16 hours; and not less than 80% of the
drug is released after 20 hours.
9. The controlled release oral dosage form of claim 1, which
provides a width at 50% of the height of a mean plasma
concentration/time curve of the drug from about 4.5 to about 13
hours.
10. The controlled release oral dosage form of claim 1, which
provides a width at 50% of the height of a mean plasma
concentration/time curve of the drug from about 5.5 to about 10
hours.
11. The controlled release oral dosage form of claim 3, which
provides a mean maximum plasma concentration (C.sub.max) of
metformin which is more than about 7 times the mean plasma level of
said metformin at about 24 hours after the administration.
12. The controlled release oral dosage form of claim 3, which
provides a mean maximum plasma concentration (C.sub.max) of
metformin which is from about 7 times to about 14 times the plasma
level of said metformin at about 24 hours after administration.
13. The controlled release oral dosage form of claim 3 which
provides a mean maximum plasma concentration (C.sub.max) of
metformin which is from about 8 times to about 12 times the plasma
level of said metformin at about 24 hours after administration.
14. The controlled release oral dosage form of claim 3 which
provides a mean maximum plasma concentration (C.sub.max) of
metformin from about 1500 ng/ml to about 3000 ng/ml, based on
administration of a 2000 mg once-a-day dose of metformin.
15. The controlled release oral dosage form of claim 3, which
provides a mean maximum plasma concentration (C.sub.max) of
metformin from about 1700 ng/ml to about 2000 ng/ml, based on
administration of a 2000 mg once-a-day dose of metformin.
16. The controlled release oral dosage form of claim 3 which
provides a mean AUC.sub.0-24hr of at least 80% of the mean
AUC.sub.0-24 provided by administration of an immediate release
reference standard twice a day, wherein the daily dose of the
reference standard is substantially equal to the once-a-day dose of
metformin administered in the controlled release oral dosage
form.
17. The controlled release oral dosage form of claim 3 which
provides a mean AUC.sub.0-24hr of at least 90% of the mean
AUC.sub.0-24 provided by administration of an immediate release
reference standard twice a day, wherein the daily dose of the
reference standard is substantially equal to the once-a-day dose of
metformin administered in the controlled release oral dosage
form.
18. The controlled release oral dosage form of claim 3 which
provides a mean AUC.sub.0-24hr from about 17200 ng.hr/ml to about
33900 ng.hr/ml, based on administration of a 2000 mg once-a-day
dose of metformin.
19. The controlled release oral dosage form of claim 3 which
provides a mean AUC.sub.0-24hr from about 17200 ng.hr/ml to about
26500 ng.hr/ml, based on administration of a 2000 mg once-a-day
dose of metformin.
20. The controlled release oral dosage form of claim 3 which
provides a mean AUC.sub.0-24hr from about 19800 ng.hr/ml to about
33900 ng.hr/ml, based on administration of a 2000 mg once-a-day
dose of metformin.
21. The controlled release oral dosage form of claim 3 which
provides a mean plasma concentration-time profiles of metformin
substantially as set forth in FIG. 1, based on administration of a
1700 mg once-a-day dose of metformin.
22. The controlled release oral dosage form of claim 3 which
provides a mean plasma concentration-time profiles of metformin
substantially as set forth in FIG. 2, based on administration of a
2000 mg once-a-day dose of metformin.
23. The controlled release oral dosage form of claim 3 which
provides a mean plasma concentration-time profiles of metformin
substantially as set forth in FIG. 4, based on administration of a
2000 mg once-a-day dose of metformin at dinner.
24. The controlled release oral dosage form of claim 3 which
provides a mean plasma concentration-time profiles of metformin
substantially as set forth in FIG. 6, based on administration of a
2000 mg once-a-day dose of metformin at breakfast.
25. The controlled release oral dosage form of claim 3 which
provides a mean plasma glucose concentration-time profiles
substantially as set forth in FIG. 5, based on administration of a
2000 mg once-a-day dose of metformin at dinner.
26. The controlled release oral dosage form of claim 9, which
provides a mean time to maximum plasma concentration (T.sub.max) of
metformin from 6.0 to 7.0 hours after the administration.
27. The controlled release oral dosage form of claim 9, which
provides a mean time to maximum plasma concentration (T.sub.max) of
metformin from 5.5 to 7.0 hours after administration at dinner
time.
28. The controlled release oral dosage form of claim 9, which
provides a mean time to maximum plasma concentration (T.sub.max) of
metformin from 6.0 to 7.5 hours after administration at
breakfast.
29. The controlled release dosage form of claim 1, wherein the
metformin is provided by at least one controlled-release tablet,
said tablet comprising: (a) a core comprising: (i) the metformin or
a pharmaceutically acceptable salt; (ii) optionally a binding
agent; and (iii) optionally an absorption enhancer; (b) a membrane
coating surrounding the core; and (c) at least one passageway in
the membrane.
30. The controlled release oral dosage form of claim 29, wherein
said membrane is a semipermeable membrane.
31. A controlled release oral dosage form for the reduction of
serum glucose levels in human patients with NIDDM, comprising at
least one biguanide or pharmaceutically acceptable salt thereof and
a controlled release carrier wherein a single administration of
said dosage form provides a higher mean fluctuation index in the
plasma than a substantially equal dose of an immediate release
composition administered as two equal divided doses, one divided
dose at the start of the dosing interval and the other divided dose
administered 12 hours later.
32. The controlled release oral dosage form of claim 31 wherein the
mean fluctuation index of the dosage form is from about 1 to about
4.
33. The controlled release oral dosage form of claim 32 wherein the
mean fluctuation index of the dosage form is from about 2 to about
3.
34. The controlled release oral dosage form of claim 33 wherein the
mean fluctuation index of the dosage form is about 2.5.
35. The controlled release oral dosage form of claim 31 wherein the
ratio of the mean fluctuation index between the dosage form and the
immediate release composition is about 3:1.
36. The controlled release oral dosage form of claim 35 wherein the
ratio of the mean fluctuation index between the dosage form and the
immediate release composition is about 2:1.
37. The controlled release oral dosage form of claim 36 wherein the
ratio of the mean fluctuation index between the dosage form and the
immediate release composition is about 1.5:1.
38. The controlled release oral dosage form of claim 31 wherein
said dosage form comprises metformin or a pharmaceutically
acceptable salt thereof.
39. The controlled release oral dosage form of claim 31 wherein
said dosage form maintains bioavailability from at least about 80%
of the immediate release composition.
40. The controlled release oral dosage form of claim 31 wherein the
substantially equal dose of the dosage form and the immediate
release composition comprises from about 500 mg to about 2500 mg
metformin or pharmaceutically acceptable salt thereof.
41. The controlled release oral dosage form of claim 40 wherein the
substantially equal dose of the dosage form and the immediate
release composition comprises from about 1000 mg to about 2000 mg
metformin or pharmaceutically acceptable salt thereof.
42. The controlled release oral dosage form of claim 40 wherein the
substantially equal dose of the dosage form and the immediate
release composition comprises from about 850 mg to about 1700 mg
metformin or pharmaceutically acceptable salt thereof.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to controlled release unit
dose formulations containing an antihyperglycemic drug. More
specifically, the present invention relates to an oral dosage form
comprising a biguanide such as metformin or buformin or a
pharmaceutically acceptable salt thereof such as metformin
hydrochloride or the metformin salts described in U.S. Pat. Nos.
3,957,853 and 4,080,472 which are incorporated herein by
reference.
[0002] In the prior art, many techniques have been used to provide
controlled and extended-release pharmaceutical dosage forms in
order to maintain therapeutic serum levels of medicaments and to
minimize the effects of missed doses of drugs caused by a lack of
patient compliance.
[0003] In the prior art are extended release tablets which have an
osmotically active drug core surrounded by a semipermeable
membrane. These tablets function by allowing a fluid such as
gastric or intestinal fluid to permeate the coating membrane and
dissolve the active ingredient so it can be released through a
passageway in the coating membrane or if the active ingredient is
insoluble in the permeating fluid, pushed through the passageway by
an expanding agent such as a hydrogel. Some representative examples
of these osmotic tablet systems can be found in U.S. Pat. Nos.
3,845,770, 3,916,899, 4,034,758, 4,077,407 and 4,783,337. U.S. Pat.
No. 3,952,741 teaches an osmotic device wherein the active agent is
released from a core surrounded by a semipermeable membrane only
after sufficient pressure has developed within the membrane to
burst or rupture the membrane at a weak portion of the
membrane.
[0004] The basic osmotic device described in the above cited
patents have been refined over time in an effort to provide greater
control of the release of the active ingredient. For example U.S.
Pat. Nos. 4,777,049 and 4,851,229 describe an osmotic dosage form
comprising a semipermeable wall surrounding a core. The core
contains an active ingredient and a modulating agent wherein the
modulating agent causes the active ingredient to be released
through a passageway in the semipermeable membrane in a pulsed
manner. Further refinements have included modifications to the
semipermeable membrane surrounding the active core such as varying
the proportions of the components that form the membrane; i.e.,
U.S. Pat. Nos. 5,178,867, 4,587,117 and 4,522,625 or increasing the
number of coatings surrounding the active core; i.e., U.S. Pat.
Nos. 5,650,170 and 4,892,739.
[0005] Although vast amounts of research has been performed on
controlled or sustained release compositions and in particular on
osmotic dosage forms, very little research has been performed in
the area of controlled or sustained release compositions that
employ antihyperglycemic drugs.
[0006] Metformin is an oral antihyperglycemic drug used in the
management of non-insulin-dependent diabetes mellitus (NIDDM). It
is not chemically or pharmacologically related to oral
sulfonylureas. Metformin improves glucose tolerance in NIDDM
patients by lowering both basal and postprandial plasma glucose.
Metformin hydrochloride is currently marketed as GLUCOPHAGE.RTM.
tablets by Bristol-Myers Squibb Co. Each GLUCOPHAGE.RTM. tablet
contains 500, 850 or 1000 mg of metformin hydrochloride. There is
no fixed dosage regimen for the management of hyperglycemia in
diabetes mellitus with GLUCOPHAGE.RTM.. Dosage of GLUCOPHAGE.RTM.
is individualized on the basis of both effectiveness and tolerance,
while not exceeding the maximum recommended dose of 2550 mg per
day.
[0007] Metformin has been widely prescribed for lowering blood
glucose in patients with NIDDM. However, being a short acting drug,
metformin requires twice-daily (b.i.d.) or three-times-a-day
(t.i.d.) dosing. Adverse events associated with metformin use are
often gastrointestinal in nature (e.g., anorexia, nausea, vomiting
and occasionally diarrhea, etc.). These adverse events may be
partially avoided by either reducing the initial and/or maintenance
dose or using an extended-release dosage form. Another clear
advantage of an extended release dosage form is a reduction in the
frequency of administration. All of these findings suggest that an
extended-release dosage form of metformin may improve the quality
of therapy in patients with NIDDM and the safety profile relative
to a conventional dosage form.
[0008] The limited work on controlled or sustained release
formulations that employ antihyperglycemic drugs such as metformin
hydrochloride includes the combination of the antihyperglycemic
drug and an expanding or gelling agent to control the release of
the drug from the dosage form. This research is exemplified by the
teachings of WO 96/08243 and by the GLUCOPHAGE.RTM. metformin HCl
product.
[0009] It is reported in the 50.sup.th Edition of the Physicians'
Desk Reference, copyright 1996, p. 753, that food decreases the
extent and slightly delays the absorption of metformin delivered by
the GLUCOPHAGE.RTM. dosage form. This decrease is shown by
approximately a 40% lower peak concentration, a 25% lower
bioavailability and a 35-minute prolongation of time to peak plasma
concentration following administration of a single GLUCOPHAGE.RTM.
tablet containing 850 mg of metformin HCl with food compared to the
similar tablet administered under fasting conditions.
[0010] A controlled release metformin dosage form is also described
in WO 99/47128. This reference describes a controlled release
delivery system for metformin which includes an inner solid
particulate phase formed of substantially uniform granules
containing metformin and one or more hydrophilic polymers, one or
more hydrophobic polymers and one or more hydrophobic materials,
and an outer continuous phase in which the above granules are
embedded and dispersed throughout. The outer continuous phase
includes one or more hydrophilic polymers, one or more hydrophobic
polymers and one or more hydrophobic materials.
[0011] Our own WO 99/47125 discloses controlled release metformin
formulations providing a Tmax from 8 to 12 hours.
OBJECTS AND SUMMARY OF THE INVENTION
[0012] It is an object of the present invention to provide a
controlled or sustained release of an antihyperglycemic drug which
provides effective control of blood glucose levels in humans.
[0013] It is a further object of the present invention to provide a
method of treating human patients with non-insulin-dependent
diabetes mellitus (NIDDM) on a once-a-day basis with an
antihyperglycemic drug which provides effective control of blood
glucose levels in humans.
[0014] It is a further object of the present invention to provide
formulations for treating human patients with non-insulin-dependent
diabetes mellitus (NIDDM) which provides advantages over the
state-of-the-art, and which may be administered on a once-a-day
basis by itself or together with other antidiabetic agents, and
methods thereof.
[0015] It is a further object of the present invention to provide a
controlled or sustained release formulation of an antihyperglycemic
drug wherein the bioavailability of the drug is not decreased by
the presence of food.
[0016] It is a further object of the present invention to provide a
controlled or sustained release formulation of an antihyperglycemic
drug that does not employ an expanding polymer.
[0017] It is also a further object of the present invention to
provide a controlled or sustained release formulation of an
antihyperglycemic drug that can provide continuous and
non-pulsating therapeutic levels of the drug to an animal or human
in need of such treatment over a twelve hour to twenty-four hour
period.
[0018] It is an additional object of other embodiments of the
present invention to provide a controlled or sustained release
formulation for an antihyperglycemic drug that obtains peak plasma
levels from 5.5 to 7.5 hours after administration under various
conditions. Alternatively, the time to peak plasma levels are from
6.0 to 7.0, from 5.5 to 7.0 or from 6.0 to 7.5.
[0019] It is also an object of this invention to provide a
controlled or sustained release pharmaceutical formulation having a
homogeneous core wherein the core component may be made using
ordinary tablet compression techniques.
[0020] In accordance with the above-mentioned objects and others,
the present invention provides a controlled release oral dosage
form comprising an antihyperglycemic drug, preferably a biguanide
(e.g., metformin or a pharmaceutically acceptable salt thereof)
that is suitable for providing once-a-day administration of the
drug, wherein the dosage form provides a mean time to maximum
plasma concentration (T.sub.max) of the drug from 5.5 to 7.5 hours
after administration. The dosage form comprises the drug and a
membrane. In certain preferred embodiments, the dosage form
comprises a tablet.
[0021] In preferred embodiments, the controlled release oral dosage
form of the present invention is a tablet comprising:
[0022] (a) a core comprising:
[0023] (i) the antihyperglycemic drug;
[0024] (ii) optionally a binding agent; and
[0025] (iii) optionally an absorption enhancer;
[0026] (b) a membrane coating surrounding the core; and
[0027] (c) at least one passageway in the membrane.
[0028] When the drug is metformin or a pharmaceutically acceptable
salt thereof and is administered on a once-a-day basis, the daily
dose may vary, e.g., from about 500 mg to about 2500 mg. Such daily
dose may be contained in one controlled release dosage form of the
invention, or may be contained in more than one such dosage form.
For example, a controlled-release metformin dosage form may be
formulated to contain about 1000 mg of the drug, and two of said
dosage form may be administered together to provide once-a-day
metformin therapy. The daily dose of the drug (i.e. metformin or
pharmaceutically acceptable salt thereof) may range from about 500
mg to about 2500 mg, from about 1000 mg to about 2500 mg, or from
about 2000 mg to about 2500 mg, depending on the clinical needs of
the patient.
[0029] In certain preferred embodiments, the controlled release
solid oral dosage form of the present invention provides a width at
50% of the height of a mean plasma concentration/time curve of the
drug (e.g., of metformin) from about 4.5 to about 13 hours, more
preferably from about 5.5 to about 10 hours, more preferably from
about 6 to about 8 hours.
[0030] In certain embodiments, the controlled release oral dosage
form of the present invention provides a mean maximum plasma
concentration (C.sub.max) of the antihyperglycemic drug which is
more than about seven times the mean plasma level of said drug at
about 24 hours after administration. In preferred embodiments, the
controlled release oral dosage form of the present invention
provides a mean maximum plasma concentration (C.sub.max) of the
drug which is from about 7 times to about 14 times the plasma level
of the drug at about 24 hours after the administration, more
preferably from about 8 times to about 12 times the plasma level of
the drug at about 24 hours after administration.
[0031] In certain embodiments of the present invention, when the
drug is metformin or a pharmaceutically acceptable salt thereof,
the controlled release oral dosage form provides a mean maximum
plasma concentration (C.sub.max) of the drug that is about 1500
ng/ml to about 3000 ng/ml, based on administration of a 2000 mg
once-a-day dose of metformin, more preferably about 1700 ng/ml to
about 2000 ng/ml, based on administration of a 2000 mg once-a-day
dose of metformin.
[0032] In certain embodiments of the present invention, when the
drug is metformin or a pharmaceutically acceptable salt thereof,
the controlled release dosage form provides a mean AUC.sub.0-24hr
that is about 17200 ng.hr/ml to about 33900 ng.hr/ml, based on
administration of a 2000 mg once-a-day dose of metformin;
preferably about 17200 ng.hr/ml to about 26500 ng.hr/ml, based on
administration of a 2000 mg once-a-day dose of metformin; more
preferably about 19800 ng.hr/ml to about 33900 ng.hr/ml, based on
administration of a 2000 mg once-a-day dose of metformin.
[0033] In certain embodiments of the invention, the administration
of the antihyperglycemic drug, e.g., at least one metformin dosage
form provides a mean AUC.sub.0-24hr from at least 80%, preferably
at least 90% of the mean AUC.sub.0-24 provided by administration of
the reference standard (GLUCOPHAGE) twice a day, wherein the daily
dose of the reference standard is equal to the once-a day dose of
metformin administered in the controlled release oral dosage form
of the present invention.
[0034] In certain embodiments of the present invention, the
controlled release dosage form exhibits the following dissolution
profiles of the antihyperglycemic drug (e.g., metformin) when
tested in a USP type 2 apparatus at 75 rpm in 900 ml of simulated
intestinal gastric fluid (pH 7.5 phosphate buffer) at 37.degree.
C.: 0-30% of the drug released after 2 hours; 10-45% of the drug
released after 4 hours; 30-90% of the drug released after 8 hours;
not less than 50% of the drug released after 12 hours; not less
than 60% of the drug released after 16 hours; and not less than 70%
of the drug released after 20 hours.
[0035] In certain preferred embodiments, the controlled release
solid oral dosage form exhibits the following dissolution profiles
when tested in USP type 2 apparatus at 75 rpm in 900 ml of
simulated intestinal gastric fluid (pH 7.5 phosphate buffer) at
37.degree. C.: 0-25% of the drug (e.g., metformin or a
pharmaceutically acceptable salt thereof) released after 2 hours;
20-40% of the drug released after 4 hours; 45-90% of the drug
released after 8 hours; not less than 60% of the drug released
after 12 hours; not less than 70% of the drug released after 16
hours; and not less than 80% of the drug released after 20
hours.
[0036] With respect to embodiments of the present invention where
the antihyperglycemic drug is metformin, it has been found that
drugs such as metformin provide substantially linear
pharmacokinetics up to a level of about 2 grams per day. Therefore,
it is contemplated for purposes of the present invention that a
given plasma level (e.g., C.sub.max) of metformin per specified
dose will be directly proportional to other doses of metformin.
Such proportional doses and plasma levels are contemplated to be
within the scope of the invention and to be within the scope of the
appended claims.
[0037] The dosage form of the present invention can provide
therapeutic levels of the antihyperglycemic drug for twelve to
twenty-four hour periods and does not exhibit a decrease in
bioavailability if taken with food. In fact, a slight increase in
the bioavailability of the antihyperglycemic drug is observed when
the controlled release dosage form of the present invention is
administered with food. In a preferred embodiment, the dosage form
can be administered once-a-day, ideally with or after a meal,
preferably with or after the evening meal, and provides therapeutic
levels of the drug throughout the day with peak plasma levels being
obtained between 5.5 to 7.5 hours after administration.
[0038] The present invention is also directed to a method of
lowering blood glucose levels in human patients needing treatment
for non-insulin-dependent diabetes mellitus (NIDDM), comprising
orally administering to human patients on a once-a-day basis a dose
of a drug comprising a biguanide (e.g., metformin or a
pharmaceutically acceptable salt thereof), said drug being
contained in at least one solid oral controlled release dosage form
of the present invention. When the drug is metformin, the daily
dose of the drug may be from about 500 mg to about 2500 mg, from
about 1000 mg to about 2500 mg, or from about 2000 mg to about 2500
mg, depending on the clinical needs of the patient.
[0039] The controlled release dosage form of the present invention
provides a delayed T.sub.max, as compared to the T.sub.max provided
by GLUCOPHAGE. The delayed T.sub.max occurs from 5.5 to 7.5 hours
after administration. If the drug (e.g., metformin) is administered
at dinner time, the T.sub.max would occur during the time when
gluconeogenesis is usually at its highest (e.g., around 2
a.m.).
[0040] The present invention also includes a method of treating
patients with NIDDM comprising orally administering to human
patients on a once-a-day basis a dose of a drug comprising a
biguanide (e.g., metformin or a pharmaceutically acceptable salt
thereof), contained in at least one oral controlled release dosage
form of the present invention. When the drug is metformin, the
daily dose of the drug may be from about 500 mg to about 2500 mg,
from about 1000 mg to about 2500 mg, or from about 2000 mg to about
2500 mg, depending on the clinical needs of the patient. In certain
embodiments, the method of treatment according to the present
invention involves once-per-day metformin monotherapy as an adjunct
to diet to lower blood glucose in patients with NIDDM whose
hyperglycemia may not be satisfactorily managed on diet alone. In
certain other embodiments, the once-a-day metformin therapy of the
present invention may be used concomitantly with a sulfonylurea,
e.g., when diet and monotherapy with a sulfonylurea alone do not
result in adequate glycemic control. In certain other embodiments,
the once-a-day metformin therapy of the present invention may be
used concomitantly with a glitazone, e.g., when diet and
monotherapy with a glitazone alone do not result in adequate
glycemic control.
[0041] The present invention is further directed to a method of
controlling the serum glucose concentration in human patients with
NIDDM, comprising administering to patients having NIDDM on a
once-a-day basis, preferably at dinner time, an effective dose of a
biguanide (e.g., metformin) contained in at least one oral
controlled release dosage form of the present invention.
[0042] The present invention further includes a controlled-release
dosage form of a drug comprising a biguanide (e.g., metformin)
suitable for once-a-day administration to human patients with
NIDDM, the dosage form comprising an effective amount of the drug
to control blood glucose levels for up to about 24 hours and an
effective amount of a controlled-release carrier to provide
controlled release of the drug with a mean time to maximum plasma
concentration (T.sub.max) of the drug from 5.5 to 7.5 hours after
administration and a width at 50% of the height of a mean plasma
concentration/time curve of the drug from about 6 to about 13
hours. In preferred embodiments, the administration of the
controlled-release dosage form occurs at fed state, more preferably
at dinner time.
[0043] In certain preferred embodiments, the controlled-release
dose of the drug (e.g., metformin or a pharmaceutically acceptable
salt thereof) according to the present invention is provided by one
or more of a controlled-release tablet comprising
[0044] (a) a core comprising:
[0045] (i) the antihyperglycemic drug (e.g., metformin or a
pharmaceutically acceptable salt thereof);
[0046] (ii) optionally a binding agent; and
[0047] (iii) optionally an absorption enhancer;
[0048] (b) a membrane coating surrounding the core; and
[0049] (c) at least one passageway in the membrane.
[0050] In certain preferred embodiments, the mean time to maximum
plasma concentration of the drug is reached from 6.5 to 7.5 hours
after administration at dinner time.
[0051] In certain embodiments of the invention when the drug is a
biguanide (e.g. metformin or a pharmaceutically acceptable salt
thereof), the controlled release dosage form provides upon single
administration, a higher mean fluctuation index in the plasma than
an equivalent dose of an immediate release composition administered
as two equal divided doses, one divided dose at the start of the
dosing interval and the other divided dose administered 12 hours
later, preferably maintaining bioavailability from at least 80%
preferably from at least 90% of the immediate release
composition.
[0052] In certain embodiments of the present invention, the mean
fluctuation index of the dosage form is from about 1 to about 4,
preferably about 2 to about 3, more preferably about 2.5.
[0053] In certain embodiments of the invention which exhibit a
higher mean fluctuation index in the plasma than an equivalent dose
of an immediate release composition administered as two equal
divided doses, the ratio of the mean fluctuation index between the
dosage form and the immediate release composition is about 3:1,
preferably about 2:1, more preferably 1.5:1.
[0054] When the drug is metformin or a pharmaceutically acceptable
salt thereof, the doses of drug which exhibit the above disclosed
mean fluctuation indexes can be any effective dose administered to
a patient with NIDDM for the reduction of serum glucose levels. For
example, the dose can from about 500 mg to about 2500 mg, from
about 1000 mg to about 2000 mg or from about 850 mg to about 1700
mg metformin or pharmaceutically acceptable salt thereof.
[0055] The drugs which may used in conjunction with the present
invention include those drugs which are useful for the treatment of
non-insulin-dependent diabetes mellitus (NDDM), including but not
limited to biguinides such as metformin or buformin or
pharmaceutically acceptable salts thereof. When the drug used in
the present invention is metformin, it is preferred that the
metformin be present in a salt form, preferably as metformin
hydrochloride.
[0056] The term "metformin" as it is used herein means metformin
base or any pharmaceutically acceptable salt e.g., metformin
hydrochloride.
[0057] The term "dosage form" as it is used herein means at least
one unit dosage form of the present invention (e.g. the daily dose
of the antihyperglycemic agent can be contained in 2 unit dosage
forms of the present invention for single once-a-day
administration).
[0058] The term "morning" as it is used herein with respect to the
dosing of the controlled release formulations of the invention
means that the controlled release formulation is orally
administered early in the day after the patient has awakened from
overnight sleep, generally between about 6 a.m. and 11 a.m.
(regardless of whether breakfast is eaten at that time, unless so
specified herein).
[0059] The term "dinnertime" or "at dinner" as it is used herein
with respect to the dosing of the controlled release formulations
of the invention means that the controlled release formulation is
orally administered at a time when dinner is normally eaten
(regardless of whether a meal is actually eaten at that time,
unless so specified herein), generally between about 4 p.m. and 8
p.m.
[0060] The term "bedtime" as it is used herein with respect to the
dosing of the controlled release formulations of the invention
means that the controlled release formulation is orally
administered before the patient goes to bed in the evening,
generally between about 8 p.m. and 12 p.m.
[0061] The term "therapeutically effective reduction" when used
herein is meant to signify that blood glucose levels are reduced by
approximately the same amount as an immediate release reference
standard (e.g., GLUCOPHAGE.RTM.) or more, when the controlled
release dosage form is orally administered to a human patient on a
once-a-day basis.
[0062] The term "sustained release" and "controlled release" are
used interchangeably in this application and are defined for
purposes of the present invention as the release of the drug from
the dosage form at such a rate that when a once-a-day dose of the
drug is administered in the sustained release or controlled-release
form, blood (e.g., plasma) concentrations (levels) of the drug are
maintained within the therapeutic range but below toxic levels over
a period of time from about 12 to about 24 hours. When the drug
used in the present invention is metformin (preferably metformin
hydrochloride) the controlled release solid oral dosage form
containing such drug is also referred to as "Metformin XT."
[0063] The term "C.sub.max" is the highest plasma concentration of
the drug attained within the dosing interval, i.e., about 24
hours.
[0064] The term "C.sub.min" is the minimum plasma concentration of
the drug attained within the dosing interval, i.e. about 24
hours.
[0065] The term "C.sub.avg" as used herein, means the plasma
concentration of the drug within the dosing interval, i.e. about
24-hours, and is calculated as AUC/dosing interval.
[0066] The term "T.sub.max" is the time period which elapses after
administration of the dosage form at which the plasma concentration
of the drug attains the highest plasma concentration of drug
attained within the dosing interval (i.e., about 24 hours).
[0067] The term "AUC" as used herein, means area under the plasma
concentration-time curve, as calculated by the trapezoidal rule
over the complete 24-hour interval.
[0068] The term "steady state" means that the blood plasma
concentration curve for a given drug does not substantially
fluctuate after repeated doses to dose of the formulation.
[0069] The term "single dose" means that the human patient has
received a single dose of the drug formulation and the drug plasma
concentration has not achieved steady state.
[0070] The term "multiple dose" means that the human patient has
received at least two doses of the drug formulation in accordance
with the dosing interval for that formulation (e.g., on a
once-a-day basis). Patients who have received multiple doses of the
controlled release formulations of the invention may or may not
have attained steady state drug plasma levels, as the term multiple
dose is defined herein.
[0071] The term "a patient" means that the discussion (or claim) is
directed to the pharmacokinetic parameters of an individual patient
and/or the mean pharmacokinetic values obtained from a population
of patients, unless further specified.
[0072] The term "mean", when preceding a pharmacokinetic value
(e.g. mean T.sub.max) represents the arithmetic mean value of the
pharmacokinetic value taken from a population of patients unless
otherwise specified (e.g. geometric mean).
[0073] The term "Degree of Fluctuation" is expressed as
(C.sub.max-C.sub.min)/C.sub.avg.
BRIEF DESCRIPTION OF THE DRAWINGS
[0074] FIG. 1 is a graph showing the relative bioavailability of
the metformin XT formulation of Example 2 to GLUCOPHAGE.RTM. for
Clinical Study 2.
[0075] FIG. 2 is a graph showing the relative bioavailability of
the metformin XT formulation of Example 1 (500 mg) to
GLUCOPHAGE.RTM. for Clinical Study 3.
[0076] FIG. 3 is a graph showing the difference in plasma
concentration-time profiles of metformin in eight healthy
volunteers between Day 1 and Day 14 dosing following oral
administration of the metformin XT formulation of Example 1;
4.times.500 mg q.d. for 14 days for Clinical Study 4.
[0077] FIG. 4 is a graph showing the mean plasma profiles and
values of pharmacokinetic parameters of the metformin XT
formulation of Example 3 for Clinical Study 5.
[0078] FIG. 5 is a graph showing the mean plasma glucose
concentration time profiles after 4 weeks of treatment with the
metformin XT formulation of Example 3 and GLUCOPHAGE.RTM. for
Clinical Study 5.
[0079] FIG. 6 is a graph showing the dissolution profile of a 500
mg controlled release metformin formulation of Example 1 of the
present invention.
[0080] FIG. 7 is a graph showing the dissolution profile of a 850
mg controlled release metformin formulation of Example 2 of the
present invention.
[0081] FIG. 8 is a graph showing the dissolution profile of a 1000
mg controlled release metformin formulation of Example 3 of the
present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0082] The term antihyperglycemic drugs as used in this
specification refers to drugs that are useful in controlling or
managing noninsulin-dependent diabetes mellitus (NIDDM).
Preferably, the antihyperglycemic drug is a biguanide such as
metformin or buformin or a pharmaceutically acceptable salt thereof
such as metformin hydrochloride.
[0083] It has surprisingly been found that when biguanides such as
metformin are administered orally in a controlled release dosage
form suitable for once-a-day dosing in the "fed" state, preferably
at dinner, the bioavailability is improved as compared to the
administration of the controlled release dosage form in the
"fasted" state. This is in contrast to GLUCOPHAGE.RTM., which
exhibits opposite characteristics. In accordance with the methods
and dosage forms of the present invention, it has been determined
that the patients suffering from NIDDM achieve improved results
(e.g., lowered blood glucose levels) than GLUCOPHAGE.RTM.
administered according to accepted protocols, e.g., on a
twice-a-day basis.
[0084] The methods and dosage forms of the invention provide the
further advantage in that when dosed at dinnertime, the controlled
release formulations of the invention provide a T.sub.max (from 5.5
to 7.5 hours) after oral administration (which T.sub.max is delayed
relative to the reference standard, GLUCOPHAGE.RTM.), such that the
level of drug is greatest at the time when human patients are
manufacturing glucose at highest levels. Gluconeogenesis is well
known to those skilled in the art to be greatest at night. Thus, in
accordance with the invention, the T.sub.max of the drug occurs for
example between 11:30 p.m. and 1:30 a.m., based on a dose
administered at 6:00 p.m. Likewise, such administration of the
dosage form provides lower drug levels during the day (e.g. the
afternoon) when gluconeogenesis is lower than at night. Also, the
invention preferably provides the added benefit of lowering insulin
levels. Insulin is considered a risk factor in NIDDM, in and of
itself, for cardiovascular disease.
[0085] In comparison to a twice-daily dose of the reference
standard (GLUCOPHAGE.RTM.), the plasma levels of metformin are
preferably lower in the afternoon. This is an advantage
particularly in patients who are under concomitant therapy with one
or more additional antidiabetic agents, such as for example, a
sulfonylurea. It is known in the art that to date approximately 60%
of patients being treated with metformin are also being treated
with at least one additional antidiabetic agent (such as a
sulfonylurea). Sulfonylureas can possibly cause hypoglycemia,
whereas metformin cannot, so there is a benefit to having lower
metformin levels in the blood during the afternoon due to the
potential for the patient to have hypoglycemia.
[0086] Accordingly, the present invention also includes a method of
treating human patients with NIDDM comprising administering on a
once-a-day basis a therapeutically effective dose of metformin in a
controlled-release oral dosage form ("Metformin XT"), in
combination with administering an effective amount of a
sulfonylurea. In preferred embodiments, metformin is provided by a
controlled release dosage form comprising metformin or a
pharmaceutically acceptable salt thereof, the dosage form being
useful for providing a once-a-day oral administration of the drug,
wherein the dosage form provides a mean time to maximum plasma
concentration (T.sub.max) of metformin from 5.5 to 7.5 hours after
administration.
[0087] In certain embodiments, the combination therapy may be
provided as follows. If patients do not respond to four weeks of
the maximum dose of Metformin XT (2500 mg/day) monotherapy, a
sulfonylurea may be gradually added while maintaining the maximum
dose of Metformin XT, even if prior primary or secondary failure to
a sulfonylurea has occurred. Examples of the sulfonylurea include
glyburide (glibenclamid), chloropropamide, tolbutamide, glipizide,
acetohexamide and tolazamide. Although Metformin XT is preferably
administered on once-a-day basis, the sulfonylurea may be
administered in a different dosage form and at a different
frequency.
[0088] With concomitant Metformin XT and sulfonylurea therapy, the
desired control of blood glucose may be obtained by adjusting the
dose of each drug.
[0089] In certain embodiments, the foregoing objectives are met by
a controlled release dosage form comprising:
[0090] (a) a core comprising:
[0091] (i) an antihyperglycemic drug;
[0092] (ii) optionally a binding agent; and
[0093] (iii) optionally an absorption enhancer;
[0094] (b) a membrane coating surrounding the core; and
[0095] (c) at least one passageway in the membrane.
[0096] The binding agent may be any conventionally known
pharmaceutically acceptable binder such as polyvinyl pyrrolidone,
hydroxypropyl cellulose, hydroxyethyl cellulose, ethylcellulose,
polymethacrylate, waxes and the like. Mixtures of the
aforementioned binding agents may also be used. The preferred
binding agents are water soluble such as polyvinyl pyrrolidone
having a weight average molecular weight of 25,000 to 3,000,000.
The binding agent comprises approximately about 0 to about 40% of
the total weight of the core and preferably about 3% to about 15%
of the total weight of the core.
[0097] The core may optionally comprise an absorption enhancer. The
absorption enhancer can be any type of absorption enhancer commonly
known in the art such as a fatty acid, a surfactant, a chelating
agent, a bile salt or mixtures thereof. Examples of some preferred
absorption enhancers are fatty acids such as capric acid, oleic
acid and their monoglycerides, surfactants such as sodium lauryl
sulfate, sodium taurocholate and polysorbate 80, chelating agents
such as citric acid, phytic acid, ethylenediamine tetraacetic acid
(EDTA) and ethylene glycol-big (B-aminoethyl ether
-N,N,N,N-tetraacetic acid (EGTA). The core comprises approximately
0 to about 20% of the absorption enhancer based on the total weight
of the core and most preferably about 2% to about 10% of the total
weight of the core.
[0098] In this embodiment, the core which comprises the
antihyperglycemic drug, the binder which preferably is a
pharmaceutically acceptable water soluble polymer and the
absorption enhancer is preferably formed by wet granulating the
core ingredients and compressing the granules with the addition of
a lubricant into a tablet on a rotary press. The core may also be
formed by dry granulating the core ingredients and compressing the
granules with the addition of a lubricant into tablets or by direct
compression.
[0099] Other commonly known excipients may also be included into
the core such as lubricants, pigments or dyes.
[0100] The homogeneous core is coated with a membrane, preferably a
polymeric membrane to form the controlled release tablet of the
invention. The membrane can be a semipermeable membrane by being
permeable to the passage of external fluid such as water and
biological fluids and being impermeable to the passage of the
antihyperglycemic drug in the core. Materials that are useful in
forming the membrane are cellulose esters, cellulose diesters,
cellulose triesters, cellulose ethers, cellulose ester-ether,
cellulose acylate, cellulose diacylate, cellulose triacylate,
cellulose acetate, cellulose diacetate, cellulose triacetate,
cellulose acetate propionate, and cellulose acetate butyrate. Other
suitable polymers are described in U.S. Pat. Nos. 3,845,770,
3,916,899, 4,008,719, 4,036,228 and 411,210 which are incorporated
herein by reference. The most preferred membrane material is
cellulose acetate comprising an acetyl content of 39.3 to 40.3%,
commercially available from Eastman Fine Chemicals.
[0101] In an alternative embodiment, the membrane can be formed
from the above-described polymers and a flux enhancing agent. The
flux enhancing agent increases the volume of fluid imbibed into the
core to enable the dosage form to dispense substantially all of the
antihyperglycemic drug through the passageway and/or the porous
membrane. The flux enhancing agent can be a water soluble material
or an enteric material. Some examples of the preferred materials
that are useful as flux enhancers are sodium chloride, potassium
chloride, sucrose, sorbitol, mannitol, polyethylene glycol (PEG),
propylene glycol, hydroxypropyl cellulose, hydroxypropyl
methycellulose, hydroxyprophy methycellulose phthalate, cellulose
acetate phthalate, polyvinyl alcohols, methacrylic acid copolymers
and mixtures thereof. The preferred flux enhancer is PEG 400.
[0102] The flux enhancer may also be a drug that is water soluble
such as metformin or its pharmaceutically acceptable salts or a
drug that is soluble under intestinal conditions. If the flux
enhancer is a drug, the present dosage form has the added advantage
of providing an immediate release of the drug which is selected as
the flux enhancer.
[0103] The flux enhancing agent comprises approximately 0 to about
40% of the total weight of the coating, most preferably about 2% to
about 20% of the total weight of the coating. The flux enhancing
agent dissolves or leaches from the membrane to form paths in the
membrane for the fluid to enter the core and dissolve the active
ingredient.
[0104] In alternate embodiments, the membrane may also be formed
with commonly known excipients such as a plasticizer. Some commonly
known plasticizers include adipate, azelate, enzoate, citrate,
stearate, isoebucate, sebacate, triethyl citrate, tri-n-butyl
citrate, acetyl tri-n-butyl citrate, citric acid esters, and those
described in the Encyclopedia of Polymer Science and Technology,
Vol. 10 (1969), published by John Wiley & Sons. The preferred
plasticizers are triacetin, acetylated monoglyceride, grape seed
oil, olive oil, sesame oil, acetyltributylcitrate,
acetyltriethylcitrate, glycerin sorbitol, diethyloxalate,
diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate,
dioctylphthalate, dibutylsebacate, triethylcitrate,
tributylcitrate, glyceroltributyrate, and the like. Depending on
the particular plasticizer, amounts of from 0 to about 25%, and
preferably about 2% to about 15% of the plasticizer can be used
based upon the total weight of the coating.
[0105] As used herein the term passageway includes an aperture,
orifice, bore, hole, weakened area or an erodible element such as a
gelatin plug that erodes to form an osmotic passageway for the
release of the antihyperglycemic drug from the dosage form. A
detailed description of the passageway can be found in United
States Patent Nos. such as U.S. Pat. Nos. 3,845,770, 3,916,899,
4,034,758, 4,063,064, 4,077,407, 4,088,864, 4,783,337 and 5,071,607
(the disclosures of which are hereby incorporated by
reference).
[0106] In certain embodiments, the passageway is formed by laser
drilling. In other embodiments, the passageway is formed by making
an indentation onto the core prior to the membrane coating to form
a weakened area of the membrane at the point of the indentation. In
preferred embodiments of the invention, the dosage form contains
two passageways in order provide the desired pharmacokinetic
parameters of the formulation.
[0107] Generally, the membrane coating around the core will
comprise from about 1% to about 7%, preferably about 1.5% to about
3%, based on the total weight of the core and coating.
[0108] The term "membrane" means a membrane that is permeable to
both aqueous solutions or bodily fluids and to the active drug or
pharmaceutical ingredient (e.g. the formulations of Examples 1-3).
Thus, the membrane is porous to drug and, in a preferred
embodiment, drug is released through the hole or passageway and
through the porous membrane in solution or in vivo. The term
"membrane" also generically encompasses the term "semipermeable
membrane" as heretofore defined.
[0109] In an alternative embodiment, the dosage form of the present
invention may also comprise an effective amount of the
antihyperglycemic drug that is available for immediate release. The
effective amount of antihyperglycemic drug for immediate release
may be coated onto the membrane of the dosage form or it may be
incorporated into the membrane.
[0110] In certain preferred embodiments of the invention where the
dosage form is prepared in accordance with the above, the dosage
form will have the following composition:
1 INGREDIENT Preferred Most Preferred CORE: Drug 50-98% 75-95%
Binder 0-40% 3-15% Absorption Enhancer 0-20% 2-10% COATING:
Membrane Polymer 50-99% 75-95% Flux Enhancer 0-40% 2-20%
Plasticizer 0-25% or 0-30% 2-15%
[0111] The dosage forms prepared according to certain embodiments
of the present invention preferably exhibit the following
dissolution profile when tested in a USP type 2 apparatus at 75
rpms in 900 ml of simulated intestinal fluid (pH 7.5 phosphate
buffer) and at 37.degree. C.:
2 Time (Hours) Preferred Most Preferred 2 0-30% 0-15% or 0-25% 4
10-45% 20-40% 8 30-90% 45-90% 12 NTL 50% NTL 60% 16 NTL 60% NTL 70%
20 NTL 70% NTL 80% NTL = Not less than
[0112] In the preparation of the tablets of the invention, various
conventional well known solvents may be used to prepare the
granules and apply the external coating to the tablets of the
invention. In addition, various diluents, excipients, lubricants,
dyes, pigments, dispersants, etc. which are disclosed in
Remington's Pharmaceutical Sciences, 1995 Edition may be used to
optimize the formulations of the invention.
[0113] Other controlled release technologies known to those skilled
in the art can be used in order to achieve the controlled release
formulations of the present invention, i.e., formulations which
provide a mean T.sub.max of the drug and/or other pharmacokinetic
parameters described herein when orally administered to human
patients. Such formulations can be manufactured as a controlled
oral formulation in a suitable tablet or multiparticulate
formulation known to those skilled in the art. In either case, the
controlled release dosage form may optionally include a controlled
release carrier which is incorporated into a matrix along with the
drug, or which is applied as a controlled release coating.
[0114] An oral dosage form according to the invention may be
provided as, for example, granules, spheroids, beads, pellets
(hereinafter collectively referred to as "multiparticulates")
and/or particles. An amount of the multiparticulates which is
effective to provide the desired dose of drug over time may be
placed in a capsule or may be incorporated in any other suitable
oral form.
[0115] In certain preferred embodiments, the tablet core or
multiparticulates containing the drug are coated with a hydrophobic
material selected from (i) an alkylcellulose and (ii) a polymeric
glycol. The coating may be applied in the form of an organic or
aqueous solution or dispersion. The coating may be applied to
obtain a weight gain from about 2 to about 25% of the substrate in
order to obtain a desired sustained release profile. The sustained
release coatings of the present invention may also include an exit
means comprising at least one passageway, orifice, or the like as
previously disclosed.
DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS
[0116] The following examples illustrate various aspects of the
present invention. They are not to be construed to limit the claims
in any manner whatsoever.
EXAMPLE 1
[0117] A controlled release tablet containing 500 mg of metformin
HCl and having the following formula is prepared as follows:
[0118] I. Core
3 Ingredients Amount (mg/tab) Metformin HCl 500.0 Povidone.sup.3,
USP 36.0 Sodium Lauryl Sulfate 25.8 Magnesium Stearate 2.8
.sup.3approximate molecular weight = 1,000,000; dynamic viscosity
(10% w/v solution at 20.degree. C.) = 300-700 m Pa s.
[0119] (a) Granulation
[0120] The metformin HCl and sodium lauryl sulfate are delumped by
passing them through a 40 mesh screen and collecting them in a
clean, polyethylene-lined container. The povidone, K-90-F is
dissolved in purified water. The delumped metformin HCl and sodium
lauryl sulfate are then added to a top-spray fluidized bed
granulator and granulated by spraying with the binding solution of
povidone under the following conditions: inlet air temperature of
50-70.degree. C.; atomization air pressure of 1-3 bars; and spray
rate of 10-100 ml/min.
[0121] Once the binding solution is depleted, the granules are
dried in the granulator until the loss on drying is less than 2%.
The dried granules are passed through a Comil equipped with the
equivalent of an 18 mesh screen.
[0122] (b) Tableting
[0123] The magnesium stearate is passed through a 40 mesh stainless
steel screen and blended with the metformin HCl granules for
approximately five (5) minutes. After blending, the granules are
compressed on a rotary press fitted with {fraction (15/32)}" round
standard concave punches.
[0124] (c) Seal Coating (Optional)
[0125] The core tablet is seal coated with an Opadry material or
other suitable water-soluble material by first dissolving the
Opadry material, preferably Opadry Clear (YS-1-7006), in purified
water. The Opadry solution is then sprayed onto the core tablet
using a pan coater under the following conditions: exhaust air
temperature of 38-42.degree. C.; atomization pressure of 28-40 psi;
and spray rate of 10-15 ml/min. The Opadry Clear of the coating
constitutes about 11.5 mg/tablet.
[0126] II. Sustained Release Coating
4 Amount Ingredients (mg/tablet) Cellulose Acetate (398-10).sup.2
21.5 Triacetin 1.3 PEG 400 2.5 .sup.2acetyl content 39.3-40.3%
[0127] The cellulose acetate is dissolved in acetone while stirring
with a homogenizer. The polyethylene glycol 400 and triacetin are
added to the cellulose acetate solution and stirred until a clear
solution is obtained. The tablet is coated by spraying the clear
coating solution onto the seal coated tablets in a fluidized bed
coater employing the following conditions: product temperature of
16-22.degree. C.; atomization pressure of approximately three bars;
and spray rate of 120-150 ml/min.
[0128] (d) Laser Drilling
[0129] The coated tablets were laser drilled two holes (one hole on
each side of the tablet).
EXAMPLE 2
[0130] A controlled release tablet containing 850 mg of metformin
HCl and having the following formula is prepared as follows:
[0131] I. Core
5 Ingredients Amount (mg/tab) Metformin HCl 850.0 Povidone.sup.3,
USP 61.1 Sodium Lauryl Sulfate 43.9 Magnesium Stearate 4.8
.sup.3approximate molecular weight = 1,000,000; dynamic viscosity
(10% w/v solution at 20.degree. C.) = 300-700 m Pa s.
[0132] (a) Granulation
[0133] The metformin HCl and sodium lauryl sulfate are delumped by
passing them through a 40 mesh screen and collecting them in a
clean, polyethylene-lined container. The povidone, K-90-F is
dissolved in purified water. The delumped metformin HCl and sodium
lauryl sulfate are then added to a top-spray fluidized bed
granulator and granulated by spraying with the binding solution of
povidone under the following conditions: inlet air temperature of
50-70.degree. C.; atomization air pressure of 1-3 bars; and spray
rate of 10-100 ml/min.
[0134] Once the binding solution is depleted, the granules are
dried in the granulator until the loss on drying is less than 2%.
The dried granules are passed through a Comil equipped with the
equivalent of an 18 mesh screen.
[0135] (b) Tableting
[0136] The magnesium stearate is passed through a 40 mesh stainless
steel screen and blended with the metformin HCl granules for
approximately five (5) minutes. After blending, the granules are
compressed on a rotary press fitted with {fraction (15/32)}" round
standard concave punches.
[0137] (c) Seal Coating (Optional)
[0138] The core tablet is seal coated with an Opadry material or
other suitable water-soluble material by first dissolving the
Opadry material, preferably Opadry Clear (YS-1-7006), in purified
water. The Opadry solution is then sprayed onto the core tablet
using a pan coater under the following conditions: exhaust air
temperature of 38-42.degree. C.; atomization pressure of 28-40 psi;
and spray rate of 10-15 ml/min. The Opadry Clear of the coating
constitutes about 11.5 mg/tablet.
[0139] II. Sustained Release Coating
6 Amount Ingredients (mg/tablet) Cellulose Acetate (398-10).sup.2
24.0 Triacetin 1.4 PEG 400 2.8 .sup.2acetyl content 39.3-40.3%
[0140] The cellulose acetate is dissolved in acetone while stirring
with a homogenizer. The polyethylene glycol 400 and triacetin are
added to the cellulose acetate solution and stirred until a clear
solution is obtained. The tablet is coated by spraying the clear
coating solution onto the seal coated tablets in a fluidized bed
coater employing the following conditions: product temperature of
16-22.degree. C.; atomization pressure of approximately three bars;
and spray rate of 120-150 ml/min.
[0141] (d) Laser Drilling
[0142] The coated tablets were laser drilled two holes (one hole on
each side of the tablet).
EXAMPLE 3
[0143] A controlled release tablet containing 1000 mg of metformin
HCl and having the following formula is prepared as follows:
[0144] I. Core
7 Amount Ingredients (mg/tablet) Metformin HCl 1000.0
Povidone.sup.3, USP 71.9 Sodium Lauryl Sulfate 51.7 Magnesium
Stearate 5.6 .sup.3approximate molecular weight = 1,000,000;
dynamic viscosity (10% w/v solution at 20.degree. C.) = 300-700 m
Pa s.
[0145] (a) Granulation
[0146] The metformin HCl and sodium lauryl-sulfate are delumped by
passing them through a 40 mesh screen and collecting them in a
clean, polyethylene-lined container. The povidone, K-90-F is
dissolved in purified water. The delumped metformin HCl and sodium
lauryl sulfate are then added to a fluidized bed granulator and
granulated by spraying with the binding solution of povidone under
the following conditions: inlet air temperature of 50-70.degree.
C.; atomization air pressure of 1-3 bars; and spray rate of 10-100
ml/min.
[0147] Once the binding solution is depleted, the granules are
dried in the granulator until the loss on drying is less than 2%.
The dried granules are passed through a Comil equipped with a
screen equivalent to 18 mesh.
[0148] (b) Tableting
[0149] The magnesium stearate is passed through a 40 mesh stainless
steel screen and blended with the metformin HCl granules for
approximately five (5) minutes. After blending, the granules are
compressed on a rotary press fitted with 1/2" round standard
concave punches.
[0150] (c) Seal Coating (Optional)
[0151] The core tablet is seal coated with an Opadry material or
other suitable water-soluble material by first dissolving the
Opadry material, preferably Opadry Clear (YS-1-7003), in purified
water. The Opadry solution is then sprayed onto the core tablet
using a pan coater under the following conditions: exhaust air
temperature of 38-42.degree. C.; atomization pressure of 28-40 psi;
and spray rate of 10-15 ml/min. The core tablet is coated with the
sealing solution until the tablet is coated with 23.0 mg/tablet of
the Opadry material.
[0152] II. Sustained Release Coating
8 Amount Ingredients (mg/tablet) Cellulose Acetate (398-10).sup.2
19.0 Triacetin 1.1 PEG 400 2.2 .sup.2acetyl content 39.3-40.3%
[0153] The cellulose acetate is dissolved in acetone while stirring
with a homogenizer. The polyethylene glycol 400 and triacetin are
added to the cellulose acetate solution and stirred until a clear
solution is obtained. The tablet is coated by spraying the clear
coating solution onto the seal coated tablets in a fluidized bed
coater employing the following conditions: product temperature of
16-22.degree. C.; atomization pressure of approximately three bars;
and spray rate of 120-150 ml/min.
[0154] (d) Laser Drilling
[0155] The coated tablets were laser drilled two holes (one hole on
each side of the tablet).
[0156] (e) Color Coating (Optional)
[0157] Subsequent to the sustained release coating, the laser
drilled tablet is coated with a color coating using Opadry White
(24 mg/tablet) and waxed with Candelilla wax powder (0.4
mg/tablet).
Clinical Studies
Study 1
[0158] In study 1, a total of twelve (12) healthy subjects (six
males, six females) were randomized to receive either a single oral
dose of metformin XT, 850 mg, prepared in accordance with Example 2
or b.i.d. doses of GLUCOPHAGE in assigned study periods which
consisted of one of the following groups: Group A-metformin XT
(2.times.850 mg tablets) taken at approximately 8:00 a.m.,
immediately following breakfast, Group B-metformin XT (2.times.850
mg tablets) taken at approximately 6:00 p.m., immediately following
dinner; and Group C-GLUCOPHAGE (1.times.850 mg tablet) taken at
approximately 8:00 a.m., immediately following breakfast, and at
approximately 6:00 p.m., immediately following dinner. Each drug
administration was separated by a washout period of seven days. In
this study, one male subject was removed from the study prior to
Period II due to non-treatment-related mononucleosis. Thus, 11
(five males and six females) subjects completed the study.
[0159] For metformin XT, plasma samples were obtained from subjects
at 0 (predose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, and 24 hour(s)
after dosing. For GLUCOPHAGE, plasma samples were obtained from
subjects at 0 (predose), 1, 2, 3, 4, 5, 6, 8, 10, 11, 12, 13, 14,
15, 16, 18, 20, 22, and 24 hour(s) after the first dose in the
morning. Plasma concentrations of metformin were determined using a
validated HPLC method. The lower quantitation limit of this method
is 10 ng/ml. Mean plasma concentration-time profiles are shown in
FIG. 1 and mean values of pharmacokinetic parameters of metformin
obtained from this study are presented in Table 1.
9TABLE 1 Mean (.+-.SD, n = 11) values of pharmacokinetic parameters
of metformin (Example 2) in 11 healthy subjects (metformin XT, 2
.times. 850 mg q.d. or GLUCOPHAGE, 1 .times. 850 mg b.i.d.)
Geometric Mean AUC.sub.0-.infin. C.sub.max t.sub.1/2 Ratio*
Treatment (ng-hr/ml) (ng/ml) T.sub.max (hr.) T.sub.lag (hr) (hr)
AUC.sub.0-.infin. C.sub.max Metformin XT 18156 2045 6 0.18 4.4 1.00
1.36 after breakfast (4183) (567) (2) (0.40) (0.7) Metformin XT
18277 1929 7 0.09 3.6 1.02 1.32 after dinner (2961) (333) (2)
(0.30) (0.8) GLUCOPHAGE 18050 1457 5 0 3.5 -- -- (3502) (217) (3)
(0) (0.9) *Ratio = Metformin XT/GLUCOPHAGE
[0160] As shown in FIG. 1 and Table 1, when metformin XT was
administered immediately after either breakfast or dinner, the
relative bioavailability of metformin XT formulation to GLUCOPHAGE
is approximately 100%.
[0161] The results of study 1 were used to calculate the
approximate degree of fluctuation (C.sub.max-C.sub.min/C.sub.avg)
of the formulations.
[0162] The C.sub.max was directly obtained from the study (see
Table 1). The C.sub.avg was obtained by dividing the AUC value by
the dosing interval, i.e. 24 hours. The value for C.sub.min was
extrapolated from FIG. 1.
[0163] The results are set forth in Table 2 below:
10TABLE 2 Mean (.+-.SD, n = 12) values of pharmacokinetic
parameters of metformin XT in 12 healthy subjects (metformin XT, 2
.times. 850 mg q.d. and GLUCOPHAGE, 850 mg b.i.d.) C.sub.avg
AUC.sub.0-.infin. C.sub.max C.sub.min (ng/ Degree of Treatment
(ng-hr/ml) (ng/ml) (ng/ml) ml) Fluctuation Metformin XT 18156 2045
143 756 2..51 after breakfast (4183) (567) Metformin XT 18277 1929
107 761 2.39 after dinner (2961) (333) GLUCOPHAGE 18050 1457 214
752 1.65 (3502) (217) (at 24 hours) 393 752 1.41 (between
doses)
[0164] As shown in FIG. 1 and Table 2, a single administration of
the metformin XT formulation provides a higher mean fluctuation
index in the plasma than a substantially equal dose of Glucophage
administered as two equal divided doses, one divided dose at the
start of the dosing interval and the other divided dose
administered 12 hours later.
Study 2
[0165] The study design of Study 2 is the same as Study 1 except
for the formulation and the dose (4.times.500 mg q.d., total dose
2000 mg, for metformin XT prepared according to Example 1 and
2.times.500 mg b.i.d., total dose 2000 mg, for GLUCOPHAGE in the
second study). In this study, 12 healthy volunteers (five males and
seven females) were randomized to receive treatments and completed
the study. Mean plasma concentration-time profiles and mean values
of pharmacokinetic parameters of metformin obtained from this study
are presented in FIG. 2 and Table 3.
[0166] As shown in FIG. 2 and Table 3, when the metformin XT
formulation (500 mg) was administered immediately after dinner, the
relative bioavailability of this formulation to GLUCOPHAGE is
approximately 100%, while the mean C.sub.max value is about the
same. The relative bioavailability of metformin XT, however, is
approximately 80% when administered immediately after breakfast. A
prolonged profile, together with later T.sub.max and similar
C.sub.max of metformin following administration of metformin XT
immediately after dinner compared to GLUCOPHAGE indicated that
metformin was released in vivo in a sustained fashion (FIG. 2).
11TABLE 3 Mean (.+-.SD, n = 12) values of pharmacokinetic
parameters of metformin of Example 1 in 12 healthy subjects
(metformin XT, 4 .times. 500 mg q.d. or GLUCOPHAGE, 2 .times. 500
mg b.i.d.) Geometric Mean AUC.sub.0-.infin. C.sub.max T.sub.lag
t.sub.1/2 Ratio* Treatment (ng-hr/ml) (ng/ml) T.sub.max (hr) (hr)
(hr) AUC.sub.0-.infin. C.sub.max Metformin XT 17322 2127 5 0 6.1
0.80 1.15 after breakfast (4984) (545) (1) (0) (1.8) Metformin XT
20335 2053 7 0.08 3.9 0.96 1.12 after dinner (4360) (447) (2)
(0.29) (0.6) GLUCOPHAGE 21181 1815 4 0 3.6 -- -- (4486) (302) (3)
(0) (0.8) *Ratio = Metformin XT/GLUCOPHAGE
[0167] The results of study 2 were used to calculate the
approximate degree of fluctuation of the formulations in accordance
with the calculations used in study 1 (using FIG. 2 to obtain the
extrapolated value for C.sub.min)
[0168] The results are set forth in Table 4 below:
12TABLE 4 Mean (.+-.SD, n = 12) values of pharmacokinetic
parameters of metformin XT in 12 healthy subjects (metformin XT, 4
.times. 500 mg q.d. and GLUCOPHAGE, 2 .times. 500 mg b.i.d.)
C.sub.avg AUC.sub.0-.infin. C.sub.max C.sub.min (ng/ Degree of
Treatment (ng-hr/ml) (ng/ml) (ng/ml) ml) Fluctuation Metformin XT
17322 2127 143 721 2.9 after breakfast (4984) (545) Metformin XT
20335 2053 143 847 2.25 after dinner (4360) (447) GLUCOPHAGE 21181
1815 214 882 1.8 (4486) (302) (at 24 hours) 357 882 1.65 (between
doses)
[0169] As shown in FIG. 2 and Table 4, a single administration of
the metformin XT formulation provides a higher mean fluctuation
index in the plasma than an equivalent dose of Glucophage
administered as two equal divided doses, one divided dose at the
start of the dosing interval and the other divided dose
administered 12 hours later.
Study 3
[0170] In Study 3, a multiple-dose, open-label, one-period study
was conducted to evaluate the short-term tolerability and
steady-state pharmacokinetics of the 500 mg metformin XT
formulation used in Study 2. In this study, eight healthy
volunteers (four males and four females) were randomized to receive
2000 mg of metformin XT (4.times.500 mg tablets) at approximately
6:00 p.m., immediately following dinner, for 14 days.
[0171] Blood samples were obtained from each subject at 0
(predose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16 and 24 hour(s)
following the first dose on Day 1 and at 0 (predose), 1, 2, 3, 4,
5, 6, 8, 10, 12, 14, 16, 24, 38 and 48 hour(s) following the last
dose on Day 14. Blood samples were also drawn from each subject
immediately prior to dosing on Days 10-13. Urine samples were
collected from each subject at the following time intervals: six
hours prior to the first dose; 0-6, 6-12 and 12-24 hours after the
first dose; and 0-6, 6-12, 12-24 and 24-48 hours after the last
dose.
[0172] Mean plasma profiles and values of pharmacokinetic
parameters of metformin are presented in Table 5 below:
13TABLE 5 Mean Pharmacokinetic Parameters (Example 1) C.sub.max
T.sub.max AUC.sub.0-24hr(ng.multidot.hr/ml) Day 1 Mean 2435 6.9
22590 SD 630 1.9 3626 Day 14 Mean 2288 6.9 24136 SD 736 2.5
7996
[0173] Following oral administration of metformin XT, 4.times.500
mg q.d., for 0.14 days, there was little or no difference in plasma
concentration-time profiles of metformin in eight healthy
volunteers between Day 1 and Day 14 dosing (FIG. 3). On average,
trough plasma concentrations of metformin were nearly constant,
ranging from 188.8 to 205.1 ng/ml on Days 10-14, indicating that
the steady state of metformin was attained rapidly. The mean
accumulation ratio was 1.01, indicating that the once-daily dose
regimen of metformin XT results in no accumulation.
[0174] Following oral administration of a single dose (4.times.500
mg) of metformin XT, approximately 31% of the dose was excreted in
the urine within the first 24 hours. On average, the renal
clearance of metformin was 366 ml/min. A slightly higher renal
clearance (454 ml/min) was found after multiple-dose administration
of 4.times.500 mg q.d. of metformin XT.
[0175] Gastrointestinal symptoms (diarrhea, nausea, vomiting,
abdominal bloating, flatulence and anorexia) are the most common
adverse reactions to GLUCOPHAGE. In controlled trials, GLUCOPHAGE
was started at low, nontherapeutic doses and gradually titrated to
higher doses. In spite of this gradual titration, GLUCOPHAGE was
discontinued due to gastrointestinal reactions in approximately 4%
of patients. In contrast, in the multiple-dose study, metformin XT
begun at a therapeutic initial dose of 2000 mg once daily with
dinner was well tolerated by all healthy volunteers. Diarrhea and
nausea were the most common gastrointestinal reactions probably or
possibly related to metformin XT. These reactions, however, were
either mild or moderate. This suggests that it may be possible to
initiate metformin XT treatment with effective doses rather than
using the slow titration from non-therapeutic doses required for
GLUCOPHAGE.
Study 4
[0176] Study 4 was a study designed to evaluate the safety,
tolerability, pharmacokinetics and pharmacodynamics of metformin XT
compared to GLUCOPHAGE after multiple-dose treatment in patients
with NIDDM. Metformin XT tablets prepared according to Example 3
were used in this study. This study had a single-center,
randomized, two-way crossover design. A total of 24 NIDDM patients
who were on a stable dose of GLUCOPHAGE, between 1000 and 2550
mg/day, for at least 12 weeks were selected for the study. A
Pretreatment Period of at least 3 weeks preceded randomization to
study treatment. At the start of the Pretreatment Period, all
patients stopped taking any other hypoglycemic agents besides
GLUCOPHAGE, and the GLUCOPHAGE dose was adjusted to 1000 mg b.i.d.
(with breakfast and with dinner).
[0177] Following the pretreatment period, patients began Treatment
Period I, which lasted 4 weeks. During Period I, a total of 12
patients were randomized to receive two 1000-mg metformin XT
tablets q.d. (immediately after dinner), at approximately 6:00
p.m., and 12 were randomized to receive one 1000-mg GLUCOPHAGE
tablet b.i.d. (immediately after breakfast and immediately after
dinner). Immediately following Period I, each patient was switched
to the alternate medication for 4 weeks in Period II. There was no
washout between treatment periods.
[0178] Plasma metformin concentrations were determined over a
24-hour period at the end of Treatment Periods I and II as follows:
immediately prior to dosing and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14,
15, 16, 17, 18, 19, 20, 22, and 24 hours after the evening dose.
One subject withdrew from the study for personal reasons after two
weeks of treatment in Treatment. Period I, thus pharmacokinetic
data were obtained from 23 patients.
[0179] Mean plasma profiles and values of pharmacokinetic
parameters of metformin are presented in FIG. 4 and Table 6. As
shown in FIG. 4 and Table 6, when metformin XT was administered
immediately after dinner, the bioavailability of metformin XT
relative to GLUCOPHAGE at steady state is close to 100%. Although
the dose of metformin XT was twice as large as the dose of
GLUCOPHAGE at dinner, the mean C.sub.max value was only 32%
higher.
14TABLE 6 Mean (.+-.SD) values of pharmacokinetic parameters of
metformin of Example 3 in 23 NIDDM patients (metformin XT, 2
.times. 1000 mg q.d. with dinner or GLUCOPHAGE, 1 .times. 1000 mg
b.i.d.) Geometric Mean AUC.sub.0-24hr C.sub.max T.sub.max Ratio*
Treatment (ng .multidot. hr/ml) (ng/ml) (hr) T.sub.lag (hr)
t.sub.1/2 (hr) AUC.sub.0-24hr C.sub.max Metformin XT 26818 2849 6 0
5.4 0.96 1.32 after dinner (7052) (797) (2) (0) GLUCOPHAGE 27367
2131 14 0 4.4 -- -- (5759) (489) (6) (0) *Ratio = Metformin
XT/GLUCOPHAGE
[0180] When the metformin XT was administered immediately after
dinner, the bioavailability of metformin XT relative to GLUCOPHAGE
at steady state was close to 100%. However, when metformin XT was
administered immediately after breakfast, the corresponding
relative bioavailability of metformin XT was approximately 80%. The
safety profile of metformin XT, 2000 mg given once daily either
after dinner or after breakfast was comparable to that of an equal
dose of GLUCOPHAGE given b.i.d. The efficacy profile of metformin
XT, 2000 mg given once daily after dinner was similar to that of an
equal dose of GLUCOPHAGE given b.i.d. The efficacy of metformin XT,
2000 mg given once daily after breakfast, however, appeared to be
comparable to or slightly less than that of GLUCOPHAGE given
b.i.d.
[0181] While certain preferred and alternative embodiments of the
invention have been set forth for purposes of disclosing the
invention, modifications to the disclosed embodiments may occur to
those who are skilled in the art. Accordingly, the appended claims
are intended to cover all embodiments of the invention and
modifications thereof which do not depart from the spirit and scope
of the invention.
* * * * *