U.S. patent application number 09/282233 was filed with the patent office on 2001-08-30 for extending the duration of drug release within the stomach during the fed mode.
Invention is credited to LOUIE-HELM, JENNY, MARKEY, MICHELINE, SHELL, JOHN W..
Application Number | 20010018070 09/282233 |
Document ID | / |
Family ID | 25355537 |
Filed Date | 2001-08-30 |
United States Patent
Application |
20010018070 |
Kind Code |
A1 |
SHELL, JOHN W. ; et
al. |
August 30, 2001 |
EXTENDING THE DURATION OF DRUG RELEASE WITHIN THE STOMACH DURING
THE FED MODE
Abstract
Drugs are formulated as unit oral dosage forms by incorporating
them into polymeric matrices comprised of hydrophilic polymers that
swell upon imbibition of water to a size that is large enough to
promote retention of the dosage form in the stomach during the fed
mode. The oral formulation is designed for gastric retention and
controlled delivery of an incorporated drug into the gastric
cavity, and thus administered, the drug is released from the matrix
into the gastric fluid by solution diffusion. The swollen polymeric
matrix, having achieved sufficient size, remains in the gastric
cavity for several hours if administered while the patient is in
the fed mode, and remains intact long enough for substantially all
of the drug to be released before substantial dissolution of the
matrix occurs. The swelling matrix lowers the accessibility of the
gastric fluid to the drug and thereby reduces the drug release
rate. This process, together with diffusion retardation by
selection of specific polymers, polymer molecular weights, and
other variables, results in a sustained and controlled delivery
rate of the drug to the gastric cavity.
Inventors: |
SHELL, JOHN W.;
(HILLSBOROUGH, CA) ; LOUIE-HELM, JENNY; (UNION
CITY, CA) ; MARKEY, MICHELINE; (SANTA CRUZ,
CA) |
Correspondence
Address: |
M HENRY HEINES
TOWNSEND TOWNSEND & CREW
TWO EMBARCADERO CENTER
8TH FLOOR
SAN FRANCISCO
CA
941113834
|
Family ID: |
25355537 |
Appl. No.: |
09/282233 |
Filed: |
March 29, 1999 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
09282233 |
Mar 29, 1999 |
|
|
|
08870509 |
Jun 6, 1997 |
|
|
|
08870509 |
Jun 6, 1997 |
|
|
|
PCT/US98/11302 |
Jun 5, 1998 |
|
|
|
Current U.S.
Class: |
424/469 ;
424/464; 424/465 |
Current CPC
Class: |
A61K 9/205 20130101;
A61K 9/2013 20130101; A61K 9/2054 20130101; A61K 9/0065 20130101;
A61K 9/2031 20130101 |
Class at
Publication: |
424/469 ;
424/464; 424/465 |
International
Class: |
A61K 009/20; A61K
009/26; A61K 009/14 |
Claims
What is claimed is:
1. A controlled-release oral drug dosage form for releasing a drug
whose solubility in water is greater than one part by weight of
said drug in ten parts by weight of water, said dosage form
comprising a solid polymeric matrix with said drug dispersed
therein at a weight ratio of drug to polymer of from about 15:85 to
about 80:20, said polymeric matrix being one that swells upon
imbibition of water thereby attaining a size large enough to
promote retention in the stomach during said fed mode, that
releases said drug into gastric fluid by the dissolution and
diffusion of said drug out of said matrix by said gastric fluid,
that upon immersion in gastric fluid retains at least about 40% of
said drug one hour after such immersion and releases substantially
all of said drug within about eight hours after such immersion, and
that remains substantially intact until all of said drug is
released.
2. A dosage form of claim 1 in which the solubility of said drug in
water is greater than one part by weight of said drug in five parts
by weight of water.
3. A dosage form of claim 1 in which said drug is a member selected
from the group consisting of metformin hydrochloride, vancomycin
hydrochloride, captopril, erythromycin lactobionate, ranitidine
hydrochloride, sertraline hydrochloride, tramadol and ticlopidine
hydrochloride.
4. A dosage form of claim 1 in which said drug is metformin
hydrochloride.
5. A dosage form of claim 1 in which said drug is sertraline
hydrochloride.
6. A dosage form of claim 1 in which said drug is captopril.
7. A dosage form of claim 1 in which said drug is vancomycin
hydrochloride.
8. A dosage form of claim 1 in which said polymeric matrix is
formed of a polymer selected from the group consisting of
poly(ethylene oxide), cellulose, alkyl-substituted celluloses,
crosslinked polyacrylic acids, and xanthan gum.
9. A dosage form of claim 8 in which said alkyl-substituted
celluloses are members selected from the group consisting of
hydroxymethyl-cellulose, hydroxyethyl-cellulose,
hydroxypropyl-cellulose, hydroxypropylmethyl-cell- ulose, and
carboxymethyl-cellulose.
10. A dosage form of claim 1 in which said polymeric matrix is
formed of poly(ethylene oxide) at a molecular weight of at least
about 4,000,000.
11. A dosage form of claim 1 in which said polymeric matrix is
formed of poly(ethylene oxide) at a molecular weight in the range
of about 4,500,000 to about 10,000,000.
12. A dosage form of claim 1 in which said polymeric matrix is
formed of poly(ethylene oxide) at a molecular weight in the range
of about 5,000,000 to about 8,000,000.
13. A dosage form of claim 1 in which said polymeric matrix upon
immersion in gastric fluid retains at least about 50% of said drug
one hour after such immersion.
14. A dosage form of claim 1 in which said polymeric matrix upon
immersion in gastric fluid retains at least about 60% of said drug
one hour after such immersion.
15. A dosage form of claim 1 in which said polymeric matrix upon
immersion in gastric fluid retains at least about 80% of said drug
one hour after such immersion.
16. A dosage form of claim 1 further comprising a member selected
from the group consisting of glyceryl monostearate and sodium
myristate, formulated with said drug to further retard the release
of said drug to said gastric fluid.
17. A dosage form of claim 1 in which said polymeric matrix
consists of two cylindrical tablets, each measuring about 9 mm to
about 12 mm in length and about 6.5 mm to about 7 mm in
diameter.
18. A dosage form of claim 1 in which said polymeric matrix
consists of a single elongated tablet measuring about 18 mm to
about 22 mm in length, about 6.5 mm to about 7.8 mm in width, and
about 6.2 to 7.5 mm in height.
19. A method of administering to a subject a drug that is
therapeutic to said subject when absorbed in the stomach but also
capable of altering intestinal flora in a manner detrimental to the
health of said subject, said method comprising orally administering
to said subject a dosage form of said drug while said subject is in
a fed mode, said dosage form comprising a solid polymeric matrix
with said drug dispersed therein at a weight ratio of drug to
polymer of from about 0.01:99.99 to about 80:20, said polymeric
matrix being one that: (a) swells upon imbibition of gastric fluid
to a size large enough to promote retention in the stomach during
said fed mode, (b) releases said drug into gastric fluid by the
dissolving of said drug by said gastric fluid and either erosion of
said matrix or diffusion of said dissolved drug out of said matrix,
(c) retains at least about 40% of said drug one hour after such
immersion in gastric fluid, (d) releases substantially all of said
drug within about ten hours after such immersion, and (e) remains
substantially intact until all of said drug is released, thereby
extending the release rate of said drug with time during said fed
mode while releasing substantially all of said drug within said
stomach and substantially avoiding contact of said drug with said
intestinal flora.
20. A method in accordance with claim 19 in which said drug is a
member selected from the group consisting of amoxicillin,
cefuroxime axetil, cefaclor, clindamycin, clarithromycin,
azithromycin, ceftazidine, and ciprofloxacin.
21. A method in accordance with claim 19 in which said drug is a
highly soluble drug selected from the group consisting of
amoxicillin, cefuroxime axetil, cefaclor, and clindamycin.
22. A method of treating a subject suffering from infections
selected from the group consisting of pneumonia, sinus bacterial
infections, topical bacterial infections and staphylococcus
infections, by administering to said subject a drug which is a
member selected from the group consisting of amoxicillin,
cefuroxime axetil, cefaclor, clindamycin, clarithromycin,
azithromycin, and ceftazidine, without substantially causing side
effects resulting from the alteration of the intestinal flora of
said subject, said method comprising orally administering to said
subject a dosage form of said drug while said subject is in a fed
mode, said dosage form comprising a solid polymeric matrix with
said drug dispersed therein at a weight ratio of drug to polymer of
from about 0.01:99.99 to about 80:20, said polymeric matrix being
one that: (a) swells upon imbibition of gastric fluid to a size
large enough to promote retention in the stomach during said fed
mode, (b) releases said drug into gastric fluid by the dissolving
of said drug by said gastric fluid and either erosion of said
matrix or diffusion of said dissolved drug out of said matrix, (c)
retains at least about 40% of said drug one hour after such
immersion in gastric fluid, (d) releases substantially all of said
drug within about ten hours after such immersion, and (e) remains
substantially intact until all of said drug is released, thereby
extending the release rate of said drug with time during said fed
mode while releasing substantially all of said drug within said
stomach and substantially avoiding contact of said drug with said
intestinal flora.
23. A method in accordance with claim 22 in which said drug is a
highly soluble drug selected from the group consisting of
amoxicillin, cefuroxime axetil, cefaclor, and clindamycin.
24. A method of administering to a subject a drug that is
therapeutic to said subject when absorbed in the stomach but also
degradable by colonic bacterial enzymes residing in lower
gastrointestinal tract enterocytes, said method comprising orally
administering to said subject a dosage form of said drug while said
subject is in a fed mode, said dosage form comprising a solid
polymeric matrix with said drug dispersed therein at a weight ratio
of drug to polymer of from about 0.01:99.99 to about 80:20, said
polymeric matrix being one that: (a) swells upon imbibition of
gastric fluid to a size large enough to promote retention in the
stomach during said fed mode, (b) releases said drug into gastric
fluid by the dissolving of said drug by said gastric fluid and
either erosion of said matrix or diffusion of said dissolved drug
out of said matrix, (c) retains at least about 40% of said drug one
hour after such immersion in gastric fluid, (d) releases
substantially all of said drug within about ten hours after such
immersion, and (e) remains substantially intact until all of said
drug is released, thereby extending the release rate of said drug
with time during said fed mode while releasing substantially all of
said drug within said stomach and substantially avoiding contact of
said drug with said intestinal enzymes and said drug
transporters.
25. A method in accordance with claim 24 in which said drug is a
member selected from the group consisting of cyclosporine, digoxin,
and doxifluridine.
26. A method in accordance with claim 24 in which said drug is
doxifluridine.
27. A method of treating a subject undergoing an organ transplant
to suppress an immune response to said transplant, by administering
cyclosporine to said subject without substantial degradation of
said cyclosporine by colonic bacterial enzymes residing in
enterocytes of the lower gastrointestinal tract, said method
comprising orally administering to said subject a dosage form of
said cyclosporine while said subject is in a fed mode, said dosage
form comprising a solid polymeric matrix with said cyclosporine
dispersed therein at a weight ratio of cyclosporine to polymer of
from about 0.01:99.99 to about 80:20, said polymeric matrix being
one that: (a) swells upon imbibition of gastric fluid to a size
large enough to promote retention in the stomach during said fed
mode, (b) releases said drug into gastric fluid by the dissolving
of said drug by said gastric fluid and either erosion of said
matrix or diffusion of said dissolved drug out of said matrix, (c)
retains at least about 40% of said cyclosporine one hour after such
immersion in gastric fluid, (d) releases substantially all of said
cyclosporine within about ten hours after such immersion, and (e)
remains substantially intact until all of said cyclosporine is
released, thereby extending the release rate of said cyclosporine
with time during said fed mode while releasing substantially all of
said cyclosporine within said stomach and substantially avoiding
contact of said cyclosporine with said colonic bacterial
enzymes.
28. A method of treating a subject for heart disease by
administering digoxin to said subject without substantial
degradation of said digoxin by colonic bacterial enzymes residing
in enterocytes of the lower gastrointestinal tract, said method
comprising orally administering to said subject a dosage form of
said digoxin while said subject is in a fed mode, said dosage form
comprising a solid polymeric matrix with said digoxin dispersed
therein at a weight ratio of digoxin to polymer of from about
0.01:99.99 to about 80:20, said polymeric matrix being one that:
(a) swells upon imbibition of gastric fluid to a size large enough
to promote retention in the stomach during said fed mode, (b)
releases said drug into gastric fluid by the dissolving of said
drug by said gastric fluid and either erosion of said matrix or
diffusion of said dissolved drug out of said matrix, (c) retains at
least about 40% of said digoxin one hour after such immersion in
gastric fluid, (d) releases substantially all of said digoxin
within about ten hours after such immersion, and (e) remains
substantially intact until all of said digoxin is released, thereby
extending the release rate of said digoxin with time during said
fed mode while releasing substantially all of said digoxin within
said stomach and substantially avoiding contact of said digoxin
with said colonic bacterial enzymes.
29. A method of treating a subject suffering from a condition
selected from the group consisting of ovarian cancer, colorectal
cancer, gastric cancer, renal cancer, and breast cancer, by
administering doxifluridine to said subject without substantial
degradation of said doxifluridine by intestinal enzymes or
substantial inactivation of said doxifluridine by drug transporters
residing in enterocytes of the lower gastrointestinal tract, said
method comprising orally administering to said subject a dosage
form of said doxifluridine while said subject is in a fed mode,
said dosage form comprising a solid polymeric matrix with said
doxifluridine dispersed therein at a weight ratio of doxifluridine
to polymer of from about 0.01:99.99 to about 80:20, said polymeric
matrix being one that: (a) swells upon imbibition of gastric fluid
to a size large enough to promote retention in the stomach during
said fed mode, (b) releases said drug into gastric fluid by the
dissolving of said drug by said gastric fluid and either erosion of
said matrix or diffusion of said dissolved drug out of said matrix,
(c) retains at least about 40% of said doxifluridine one hour after
such immersion in gastric fluid, (d) releases substantially all of
said doxifluridine within about ten hours after such immersion, and
(e) remains substantially intact until all of said doxifluridine is
released, thereby extending the release rate of said doxifluridine
with time during said fed mode while releasing substantially all of
said doxifluridine within said stomach and substantially avoiding
contact of said doxifluridine with said enzymes.
30. A method of administering to a subject a drug that is
therapeutic to said subject when absorbed in the stomach but also
susceptible to inactivation by drug transporters residing in lower
gastrointestinal tract enterocytes, said method comprising orally
administering to said subject a dosage form of said drug while said
subject is in a fed mode, said dosage form comprising a solid
polymeric matrix with said drug dispersed therein at a weight ratio
of drug to polymer of from about 0.01:99.99 to about 80:20, said
polymeric matrix being one that: (a) swells upon imbibition of
gastric fluid to a size large enough to promote retention in the
stomach during said fed mode, (b) releases said drug into gastric
fluid by the dissolving of said drug by said gastric fluid and
either erosion of said matrix or diffusion of said dissolved drug
out of said matrix, (c) retains at least about 40% of said drug one
hour after such immersion in gastric fluid, (d) releases
substantially all of said drug within about ten hours after such
immersion, and (e) remains substantially intact until all of said
drug is released, thereby extending the release rate of said drug
with time during said fed mode while releasing substantially all of
said drug within said stomach and substantially avoiding contact of
said drug with said drug transporters.
31. A method in accordance with claim 30 in which said drug is a
member selected from the group consisting of cyclosporine and
paclitaxel.
32. A method of treating a subject undergoing an organ transplant
to suppress an immune response to said transplant, by administering
cyclosporine to said subject without substantial inactivation of
said cyclosporine by p-glycoprotein in the lower gastrointestinal
tract, said method comprising orally administering to said subject
a dosage form of said cyclosporine while said subject is in a fed
mode, said dosage form comprising a solid polymeric matrix with
said cyclosporine dispersed therein at a weight ratio of
cyclosporine to polymer of from about 0.01:99.99 to about 80:20,
said polymeric matrix being one that: (a) swells upon imbibition of
gastric fluid to a size large enough to promote retention in the
stomach during said fed mode, (b) releases said drug into gastric
fluid by the dissolving of said drug by said gastric fluid and
either erosion of said matrix or diffusion of said dissolved drug
out of said matrix, (c) retains at least about 40% of said
cyclosporine one hour after such immersion in gastric fluid, (d)
releases substantially all of said cyclosporine within about ten
hours after such immersion, and (e) remains substantially intact
until all of said cyclosporine is released, thereby extending the
release rate of said cyclosporine with time during said fed mode
while releasing substantially all of said cyclosporine within said
stomach and substantially avoiding inactivation of said
cyclosporine by p-glycoprotein in said lower gastrointestinal
tract.
33. A method of treating a subject suffering from cancer by
administering paclitaxel to said subject without substantial
inactivation of said paclitaxel by p-glycoprotein in the lower
gastrointestinal tract, said method comprising orally administering
to said subject a dosage form of said paclitaxel while said subject
is in a fed mode, said dosage form comprising a solid polymeric
matrix with said paclitaxel dispersed therein at a weight ratio of
paclitaxel to polymer of from about 0.01:99.99 to about 80:20, said
polymeric matrix being one that: (a) swells upon imbibition of
gastric fluid to a size large enough to promote retention in the
stomach during said fed mode, (b) releases said drug into gastric
fluid by the dissolving of said drug by said gastric fluid and
either erosion of said matrix or diffusion of said dissolved drug
out of said matrix, (c) retains at least about 40% of said
paclitaxel one hour after such immersion in gastric fluid, (d)
releases substantially all of said paclitaxel within about ten
hours after such immersion, and (e) remains substantially intact
until all of said paclitaxel is released, thereby extending the
release rate of said paclitaxel with time during said fed mode
while releasing substantially all of said paclitaxel within said
stomach and substantially avoiding inactivation of said paclitaxel
by p-glycoprotein in said lower gastrointestinal tract.
34. A method of administering to a subject a drug that is
therapeutic to said subject when absorbed in the stomach and whose
bioavailability is substantially greater in an acidic environment
than an alkaline environment, said method comprising orally
administering to said subject a dosage form of said drug while said
subject is in a fed mode, said dosage form comprising a solid
polymeric matrix with said drug dispersed therein at a weight ratio
of drug to polymer of from about 0.01:99.99 to about 80:20, said
polymeric matrix being one that: (a) swells upon imbibition of
gastric fluid to a size large enough to promote retention in the
stomach during said fed mode, (b) releases said drug into gastric
fluid by the dissolving of said drug by said gastric fluid and
either erosion of said matrix or diffusion of said dissolved drug
out of said matrix, (c) retains at least about 40% of said drug one
hour after such immersion in gastric fluid, (d) releases
substantially all of said drug within about ten hours after such
immersion, and (e) remains substantially intact until all of said
drug is released, thereby extending the release rate of said drug
with time during said fed mode while releasing substantially all of
said drug within said stomach where said drug is maintained in an
acidic environment.
35. A method in accordance with claim 34 in which said drug is a
member selected from the group consisting of esters of ampicillin,
iron salts, digoxin, and ketoconazole.
36. A method in accordance with claim 34 in which said drug is a
member selected from the group consisting of esters of
ampicillin.
37. A method of treating a subject suffering from a bacterial
infection by administering an ester of ampicillin to said subject
while maintaining maximum bioavailability of said ester of
ampicillin, said method comprising orally administering to said
subject a dosage form of said ester of ampicillin while said
subject is in a fed mode, said dosage form comprising a solid
polymeric matrix with said ester of ampicillin dispersed therein at
a weight ratio of said ester of ampicillin to polymer of from about
0.01:99.99 to about 80:20, said polymeric matrix being one that:
(a) swells upon imbibition of gastric fluid to a size large enough
to promote retention in the stomach during said fed mode, (b)
releases said drug into gastric fluid by the dissolving of said
drug by said gastric fluid and either erosion of said matrix or
diffusion of said dissolved drug out of said matrix, (c) retains at
least about 40% of said ester of ampicillin one hour after such
immersion in gastric fluid, (d) releases substantially all of said
ester of ampicillin within about ten hours after such immersion,
and (e) remains substantially intact until all of said ester of
ampicillin is released, thereby extending the release rate of said
ester of ampicillin with time during said fed mode while releasing
substantially all of said ester of ampicillin within said stomach
and maintaining said ester of ampicillin in the acidic environment
of said stomach during said release.
38. A method of treating a subject suffering from anemia by
administering iron salts to said subject while maintaining maximum
bioavailability of said iron salts, said method comprising orally
administering to said subject a dosage form of said iron salts
while said subject is in a fed mode, said dosage form comprising a
solid polymeric matrix with said iron salts dispersed therein at a
weight ratio of iron salts to polymer of from about 0.01:99.99 to
about 80:20, said polymeric matrix being one that: (a) swells upon
imbibition of gastric fluid to a size large enough to promote
retention in the stomach during said fed mode, (b) releases said
drug into gastric fluid by the dissolving of said drug by said
gastric fluid and either erosion of said matrix or diffusion of
said dissolved drug out of said matrix, (c) retains at least about
40% of said iron salts one hour after such immersion in gastric
fluid, (d) releases substantially all of said iron salts within
about ten hours after such immersion, and (e) remains substantially
intact until all of said iron salts is released, thereby extending
the release rate of said iron salts with time during said fed mode
while releasing substantially all of said iron salts within said
stomach where said iron salts are maintained in an acidic
environment.
39. A method of treating a subject suffering from a systemic fungal
infection by administering ketoconazole to said subject while
maintaining maximum bioavailability of said ketoconazole, said
method comprising orally administering to said subject a dosage
form of said ketoconazole while said subject is in a fed mode, said
dosage form comprising a solid polymeric matrix with said
ketoconazole dispersed therein at a weight ratio of ketoconazole to
polymer of from about 0.01:99.99 to about 80:20, said polymeric
matrix being one that: (a) swells upon imbibition of gastric fluid
to a size large enough to promote retention in the stomach during
said fed mode, (b) releases said drug into gastric fluid by the
dissolving of said drug by said gastric fluid and either erosion of
said matrix or diffusion of said dissolved drug out of said matrix,
(c) retains at least about 40% of said ketoconazole one hour after
such immersion in gastric fluid, (d) releases substantially all of
said ketoconazole within about ten hours after such immersion, and
(e) remains substantially intact until all of said ketoconazole is
released, thereby extending the release rate of said ketoconazole
with time during said fed mode while releasing substantially all of
said ketoconazole within said stomach where said ketoconazole is
maintained in an acidic environment.
40. A method of administering to a subject a drug that is
therapeutic to said subject when absorbed in the stomach but also
degradable in an alkaline environment, said method comprising
orally administering to said subject a dosage form of said drug
while said subject is in a fed mode, said dosage form comprising a
solid polymeric matrix in which said drug is dispersed at a weight
ratio of drug to polymer of from about 0.01:99.99 to about 80:20,
said polymeric matrix being one that: (a) swells upon imbibition of
gastric fluid to a size large enough to promote retention in the
stomach during said fed mode, (b) releases said drug into gastric
fluid by the dissolving of said drug by said gastric fluid and
either erosion of said matrix or diffusion of said dissolved drug
out of said matrix, (c) retains at least about 40% of said drug one
hour after such immersion in gastric fluid, (d) releases
substantially all of said drug within about ten hours after such
immersion, and (e) remains substantially intact until all of said
drug is released, thereby extending the release rate of said drug
with time during said fed mode while releasing substantially all of
said drug within said stomach where said drug is maintained in an
acidic environment.
41. A method in accordance with claim 40 in which said drug is
nelfinar mesylate.
42. A method of treating a subject infected with human
immunodeficiency virus by administering nelfinar mesylate to said
subject without substantial degradation of said nelfinar mesylate
by intestinal flora or substantial inactivation of said nelfinar
mesylate by drug transporters residing in enterocytes of the lower
gastrointestinal tract, said method comprising orally administering
to said subject a dosage form of said nelfinar mesylate while said
subject is in a fed mode, said dosage form comprising a solid
polymeric matrix with said nelfinar mesylate dispersed therein at a
weight ratio of nelfinar mesylate to polymer of from about
0.01:99.99 to about 80:20, said polymeric matrix being one that:
(a) swells upon imbibition of gastric fluid to a size large enough
to promote retention in the stomach during said fed mode, (b)
releases said nelfinar mesylate into gastric fluid by the
dissolving of said nelfinar mesylate by said gastric fluid and
either erosion of said matrix or diffusion of said dissolved
nelfinar mesylate out of said matrix, (c) retains at least about
40% of said nelfinar mesylate one hour after such immersion in
gastric fluid, (d) releases substantially all of said nelfinar
mesylate within about ten hours after such immersion, and (e)
remains substantially intact until all of said nelfinar mesylate is
released, thereby extending the release rate of said nelfinar
mesylate with time during said fed mode while releasing
substantially all of said nelfinar mesylate within said stomach
where said nelfinar mesylate is maintained in an acidic
environment.
43. A method of administering to a subject a drug that is
therapeutic to said subject when absorbed in the stomach where said
drug has at least one ionized group in the pH range 5 through 8,
said method comprising orally administering to said subject a
dosage form of said drug while said subject is in a fed mode, said
dosage form comprising a solid polymeric matrix with said drug
dispersed therein at a weight ratio of drug to polymer of from
about 0.01:99.99 to about 80:20, said polymeric matrix being one
that: (a) swells upon imbibition of gastric fluid to a size large
enough to promote retention in the stomach during said fed mode,
(b) releases said drug into gastric fluid by the dissolving of said
drug by said gastric fluid and either erosion of said matrix or
diffusion of said dissolved drug out of said matrix, (c) retains at
least about 40% of said drug one hour after such immersion in
gastric fluid, (d) releases substantially all of said drug within
about ten hours after such immersion, and (e) remains substantially
intact until all of said drug is released, thereby extending the
release rate of said drug with time during said fed mode while
releasing substantially all of said drug within said stomach where
said drug is maintained in an acidic environment.
44. A method of administering to a subject a drug that is
therapeutic to said subject when absorbed in the stomach but also
degradable in an acidic environment, said method comprising orally
administering to said subject a dosage form of said drug while said
subject is in a fed mode, said dosage form comprising a solid
polymeric matrix with said drug dispersed therein at a weight ratio
of drug to polymer of from about 0.01:99.99 to about 80:20, said
polymeric matrix being one that: (a) swells upon imbibition of
gastric fluid to a size large enough to promote retention in the
stomach during said fed mode, (b) releases said drug into gastric
fluid by the dissolving of said drug by said gastric fluid and
either erosion of said matrix or diffusion of said dissolved drug
out of said matrix, (c) protects any unreleased drug in said matrix
from said gastric fluid, (d) retains at least about 40% of said
drug one hour after such immersion in gastric fluid, (e) releases
substantially all of said drug within about ten hours after such
immersion, and (f) remains substantially intact until all of said
drug is released, thereby extending the release rate of said drug
with time during said fed mode while releasing substantially all of
said drug within said stomach where said drug is maintained in an
acidic environment.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation-in-part of co-pending
application Ser. No. 08/870,509, filed Jun. 6, 1997, the entire
contents of which are hereby incorporated herein by reference.
[0002] This invention is in the general field of pharmacology, and
relates in particular to formulations for drugs that benefit from a
prolonged time of controlled release in the stomach and upper
gastrointestinal (GI) tract, and from an enhanced opportunity of
absorption in the stomach and upper GI tract rather than the lower
portions of the GI tract. One goal in this invention is to release
highly soluble drugs in a controlled manner over an extended period
of time. Another goal is to extend the time of delivery into the
stomach of drugs that are preferentially absorbed high in the GI
tract, for purposes of achieving a greater and more prolonged
therapeutic effect and thus reducing the frequency of
administration required; a more efficient use of the drugs; and a
more effective treatment of local stomach disorders. Another goal
is to minimize both lower-tract inactivation of the drug and drug
effects on the lower intestinal flora by confining the delivery and
absorption of the drug to the upper GI tract.
BACKGROUND OF THE INVENTION
[0003] Drugs that are administered in the form of conventional
tablets or capsules become available to body fluids at a rate that
is initially very high, followed by a rapid decline. For many
drugs, this delivery pattern results in a transient overdose,
followed by a long period of underdosing. This is a pattern of
limited clinical usefulness. The delivery pattern was improved in
the 1970's with the introduction of a variety of controlled
delivery systems. By providing relatively constant, controlled drug
delivery, these systems avoided the overdose and the underdose
effects. These improvements provided effective medication with
reduced side effects, and achieved these results with reduced
dosing frequency.
[0004] Many of these controlled delivery systems utilize
hydrophilic, polymeric matrices that provide useful levels of
control to the delivery of sparingly soluble drugs. For soluble
drugs, however, and particularly for highly soluble drugs, such
matrices do not provide adequate control over the drug release
rate, instead resulting in a release that approximates first-order
kinetics. That is, the rate of release is an inverse function of
the square root of the elapsed time. With this pattern of release,
most of the drug in the matrix is often released within the first
hour in an aqueous medium.
[0005] One method of prolonging the release of a highly
water-soluble drug is disclosed in International Patent Application
Publication No. WO 96/26718, published Sep. 6, 1996 (applicant:
Temple University; inventor: Kim). The method of this publication
is the incorporation of the drug into a polymeric matrix to form a
tablet that is administered orally. The polymer is water-swellable
yet erodible in gastric fluids, and the polymer and the proportion
of drug to polymer are chosen such that:
[0006] (i) the rate at which the polymer swells is equal to the
rate at which the polymer erodes, so that the swelling of the
polymer is continuously held in check by the erosion, and
zero-order release kinetics (constant delivery rate) of the drug
from the matrix are maintained;
[0007] (ii) the release of drug from the matrix is sustained over
the full erosion period of the polymer, the tablet therefore
reaching complete solution at the same time that the last of the
drug is released; and
[0008] (iii) release of the drug from the matrix will be extended
over a period of 24 hours.
[0009] A key disclosure in WO 96/26718 is that to achieve the
release of drug in this manner requires the use of a low molecular
weight polymer. If, by contrast, a high molecular weight polymer is
used and the swelling rate substantially exceeds the erosion rate,
the lack of erosion will prolong even further the delivery of the
drug residing close to the center of the tablet and even prevent it
from being released. Thus, there is no disclosure in WO 96/26718
that a drug of high water solubility can be released from a high
molecular weight polymer in a period of time substantially less
than 24 hours, or that any advantage can be obtained by the use of
a polymer that does not erode as quickly as it swells. This failure
is particularly significant since even swollen tablets will not
remain in the stomach beyond the duration of the fed mode, which
typically lasts for only 4 to 6 hours.
[0010] For drugs of any level of solubility, the retention of the
drug in a tablet or other dosage form beyond the duration of the
fed mode raises a number of problems that detract from the
therapeutic efficacy of the drug. These problems arise from the
tendency of the tablet when the patient is no longer in the fed
mode to pass from the stomach into the small intestine, and over a
period of 2-4 hours to pass through the small intestine, thus
reaching the colon with the drug still in the tablet. This loss of
effectiveness occurs with drugs that provide their maximum benefit
with minimum side effects when absorbed in the stomach and upper GI
tract rather than the colon. The reasons are either favorable
conditions in the stomach, unfavorable conditions in the colon, or
both.
[0011] For example, most orally administered antibiotics have a
potential of altering the normal flora of the gastrointestinal
tract, and particularly the flora of the colon. One result of these
alterations is the overgrowth of the organism Clostridium
difficile, which is a serious adverse event since this organism
releases dangerous toxins. These toxins can cause pseudomembranous
colitis, a condition that has been reported as a side effect of the
use of many antibiotics. In its milder forms, pseudomembranous
colitis can cause mild nausea and diarrhea while in its stronger
forms, it can be life-threatening or fatal. Examples of highly
soluble antibiotics that pose this type of threat are amoxicillin,
cefuroxime axetil, and clindamycin. Cefuroxime axetil (i.e., the
axetil ester of cefuroxime), for example, becomes active when
hydrolyzed to free cefuroxime, but when this occurs prior to
absorption, it can be detrimental to essential bacterial flora.
Hydrolysis to the active form typically occurs in the tissues into
which the ester has been absorbed, but if the ester reaches the
lower intestine, enzymes in the lower intestine cause the
hydrolysis to occur in the intestine itself, which not only renders
the drug unabsorbable but also converts the drug to the active form
where its activity alters the flora. Examples of sparingly soluble
antibiotics that pose the same type of threat are clarithromycin,
azithromycin, ceftazidine, ciprofloxacin, and cefaclor.
[0012] A goal of the present invention is to avoid this type of
alteration of the lower intestinal flora by delivering antibiotics,
regardless of their level of solubility, in a manner that confines
their delivery to the stomach and upper small intestine. Slow,
continuous delivery from a gastric retentive system assures that
both drug delivery and drug absorption are confined to the upper GI
tract. More efficient delivery of antibiotics will also avoid
transient overdosing which is a major cause of overgrowth of
Clostridium difficile.
[0013] Another example is the class of drugs that are susceptible
to degradation by exposure to gastric fluid, either by enzymes or
low solution pH. The swellable hydrophilic matrix of the present
invention protects the yet undelivered drug during the 4 to 6 hour
delivery period during which the drug is continuously released
while the dosage form is retained in the stomach. One example of
such a drug is topiramate, a drug that is used for the treatment of
epilepsy. Topiramate is absorbed preferentially high in the GI
tract and is hydrolyzed by the acidic environment of the stomach.
The dosage form and delivery system of the present invention will
confine the delivery of the drug to the stomach and duodenum. As
the drug diffuses out of the swollen matrix, it is susceptible to
the acidic environment, but the undelivered drug is protected from
degradation by the polymer matrix.
[0014] Another example is the class of drugs that are known to have
an absorption window high in the GI tract, but are incompletely
absorbed or have a wide absorption range, intrapatient as well as
interpatient. One example of such a drug is cyclosporine, a drug of
low solubility that is used as an immunosuppressant to reduce organ
rejection in transplant surgery. In addition to this problem,
cyclosporine is in general only incompletely absorbed (on the
average around 30%), and the degree of absorption is highly
variable from one patient to the next (ranging from about 5% to
about 89%). The variability can be attributed in part to
differences among the various disease states existing in the
patients to whom the drug is administered, and differences in the
length of time between the transplant surgery and the
administration of the drug. The variability can also however be
attributed to the poor aqueous solubility of the drug and to
variations in the gastric emptying, variations in the length of
time required for intestinal transit between the stomach and the
colon, variations in mesenteric and hepatic blood flow, variations
in lymph flow, variations in intestinal secretion and fluid volume,
variations in bile secretion and flow, and variations in epithelial
cell turnover. All of these variations are addressed by the dosage
form and delivery system of the present invention, which by
confining drug delivery to the stomach reduces these differences
and maximizes the absorption of the cyclosporine.
[0015] Another example is the class of drugs that are susceptible
to degradation by intestinal enzymes. The degradation occurs before
the drug can be absorbed through the intestinal wall, leaving only
a fraction of the administered dose available for the intended
therapeutic action.
[0016] An example of a highly soluble drug that is susceptible to
degradation by intestinal enzymes is the pro-drug doxifluridine
(5'-deoxy-5-fluouridine (dFUR)). The activity of doxifluridine
depends on its activation to 5-fluorouracil by pyrimidine
nucleoside phosphorylases. These enzymes are found in tumors as
well as in normal tissues, with their highest activity being in the
small intestine. The activity of these enzymes in tumor cells is
more than twice that of normal tissues. When doxifluridine is
administered orally, it can be converted to 5-fluorouracil in the
intestine before it reaches the tumors. 5-Fluorouracil is much more
toxic than doxifluridine and causes intestinal toxicity (nausea and
diarrhea) and severe damage to the intestinal villi. A goal of the
present invention is to confine the absorption of doxifluridine to
the stomach and upper GI tract, thereby avoiding or reducing its
conversion to 5-fluorouracil and the attendant toxicity risk. A
similar result is sought for other drugs with similar
susceptibilities, such as cyclosporine and digoxin.
[0017] Another class of drugs whose effectiveness suffers when the
drugs are not fully absorbed high in the GI tract are those that
are susceptible to inactivation by drug transporters that reside in
lower gastrointestinal tract enterocytes. The inactivation occurs
before the drug penetrates the intestinal wall, here again leaving
only a fraction of the administered dose available for the intended
therapeutic action. One example of a drug transporter is the
p-glycoprotein efflux system, in which a p-glycoprotein acts as an
absorption barrier to certain drugs that are substrates for the
p-glycoprotein. The barrier acts by attaching to these drugs and
transporting them drug back into the lumen, e.g., the stomach,
duodenum, jejunum/ileum or colon, from which they were absorbed, or
preventing them from being absorbed at all. This restriction of the
drug to the interior of the GI tract is effectively an inactivation
of the drug if the drug must pass out of the GI tract into the
bloodstream to be effective. The p-glycoprotein efflux system is
useful in many respects, such as preventing toxic compounds from
entering the brain. It interferes however in some cases with the
efficacy of certain drugs that would otherwise be absorbed. The
p-glycoprotein concentration is lowest in the stomach and increases
in concentration down the GI tract to the colon where the
p-glycoprotein is most prevalent. The dosage form of the present
invention will release the drug over an extended period into the
upper GI tract where p-glycoprotein is lowest.
[0018] Cyclosporine is an example of a drug of low solubility that
is susceptible to inactivation by the p-glycoprotein efflux system,
in addition to its susceptibility to degradation by colonic
bacterial enzymes. Other examples of drugs of low solubility that
are susceptible to the p-glycoprotein efflux system are the
anti-cancer drug paclitaxel, ciprofloxacin, and the HIV protease
inhibitors saquinavir, ritonavir, and nelfinavir. All of these
drugs will benefit through preserved activity by the present
invention.
[0019] A still further class of drugs that suffer in effectiveness
when not fully absorbed before reaching the colon are drugs that
require an acidic environment for effective bioavailability. For
certain drugs, the pH at a given site within the GI tract is an
essential determinant of the bioavailability of the drug, since the
solubility of the drug varies with pH. The stomach has a low pH and
hence an acidic environment, while the small intestine has a higher
pH and hence an alkaline environment. Higher bioavailability is
achieved in some cases by higher solubility, which with some drugs
occurs in a more acidic environment, and in other cases by keeping
the drugs in a non-ionized state that is necessary for absorption,
which with some drugs also occurs in a more acidic environment.
Acidic drugs that have a low pK, for example, are in the neutral
form that is required for absorption and are therefore
preferentially absorbed in the stomach. Examples of highly soluble
drugs that achieve their highest bioavailability at a low pH are
esters of ampicillin. Examples of low solubility drugs that behave
similarly are iron salts, digoxin, ketoconazole, fluconazole,
griseofulvin, itraconazole, and micoconazole. A further goal of the
present invention is therefore to maximize the bioavailability of
drugs of these types by confining them to the acidic environment of
the stomach while controlling their release rate to achieve an
extended release profile. The invention thus improves the
efficiency of iron salts in the treatment of the various forms of
anemia, the efficiency of digoxin in the treatment of the heart
disease, and the efficiency of ketoconazole in the treatment of
systemic fungal infections such as candidiasis, canduria,
blastomycosis, coccidiomycosis, histoplasmosis, chronomycosis, and
pacococcidiomycosis.
[0020] The invention also improves the efficiency of drugs that
have at least one ionized group in the pH range of 5 through 8.
Since this is the pH range encountered in the small intestine and
the region of the colonic junction and ionized drugs are less
absorbable than neutral drugs, this invention improves the
absorption of these drugs by retaining them in the stomach
environment. The invention also improves the efficiency of drugs
that are degradable in an acidic environment such as that of the
stomach by protecting them from the acidic environment until they
are released from the dosage form, thereby reducing the duration of
their exposure to the acidic environment.
[0021] A still further example of drugs that lose their efficacy
upon reaching the lower portions of the GI tract are drugs that are
soluble in an acidic environment but insoluble in an alkaline
environment. The HIV protease inhibitor nelfinavir mesylate is one
example of such a drug. Portions of the drug that are undissolved
cannot be absorbed. Portions that are dissolved but not yet
absorbed when they pass from the stomach into the small intestine
may undergo precipitation and loss of their therapeutic benefit.
This is confirmed by the fact that the presence of food in the GI
tract substantially increases the extent of absorption of oral
nelfinavir. Peak plasma concentration and area under the plasma
concentration-time curve of nelfinavir are two-fold to three-fold
greater when doses are administered with or following a meal. This
is presumably due, at least in part, to enhanced retention of the
drug in the stomach. A further goal of the present invention is
therefore to provide a means of administering these drugs that will
maximize their therapeutic effectiveness by extended, controlled
release into the stomach.
SUMMARY OF THE INVENTION
[0022] It has now been discovered that drugs that are highly
soluble in water can be administered orally in a manner that will
prolong their delivery time to spread their release rate more
evenly throughout the duration of the fed mode and beyond or not as
desired. This significantly reduces, and often avoids, the problems
of transient overdosing caused by the initial spike in
concentration entering the blood stream immediately after
administration and the subsequent underdosing, and instead controls
the dosage to safer and more effective levels over an extended
period of time.
[0023] It has further been discovered that for drugs of high,
intermediate or low solubility, the problems arising from the
release of the drugs in the lower GI tract, i.e., from the failure
to absorb these drugs into the blood stream prior to reaching the
lower GI tract, can be mitigated as well. For all drugs regardless
of solubility, therefore, this invention corrects problems such as
the overgrowth of detrimental intestinal flora by drugs that are
toxic to normal intestinal flora, protection of undelivered
acid-labile drugs in the dosage form, chemical degradation of drugs
by intestinal enzymes, loss of bioavailability of the drugs due to
their leaving the acidic environment of the stomach, and chemical
degradation of the drugs due to the alkaline environment of the
intestinal tract. By mitigating these problems, this invention thus
further improves the efficiency of the use of these drugs.
[0024] Each of the beneficial effects enumerated above is achieved
by using a formulation in which the drug is dispersed in a
polymeric matrix that is water-swellable rather than merely
hydrophilic, that has an erosion rate that is substantially slower
than its swelling rate, and that releases the drug primarily by
diffusion. It has further been found that the rate of diffusion of
the drug out of the matrix can be slowed by increasing the drug
particle size, by the choice of polymer used in the matrix, and/or
by the choice of molecular weight of the polymer. The matrix is a
relatively high molecular weight polymer that swells upon
ingestion, preferably to a size that is at least about twice its
unswelled volume, and that promotes gastric retention during the
fed mode. Upon swelling, the matrix may also convert over a
prolonged period of time from a glassy polymer to a polymer that is
rubbery in consistency, or from a crystalline polymer to a rubbery
one. The penetrating fluid then causes release of the drug in a
gradual and prolonged manner by the process of solution diffusion,
i.e., dissolution of the drug in the penetrating fluid and
diffusion of the dissolved drug back out of the matrix. The matrix
itself is solid prior to administration and, once administered,
remains undissolved in (i.e., is not eroded by) the gastric fluid
for a period of time sufficient to permit the majority of the drug
to be released by the solution diffusion process during the fed
mode. The rate-limiting factor in the release of the drug is
therefore controlled diffusion of the drug from the matrix rather
than erosion, dissolving or chemical decomposition of the
matrix.
[0025] For highly soluble drugs, the swelling of the polymeric
matrix thus achieves two objectives--(i) the tablet swells to a
size large enough to cause it to be retained in the stomach during
the fed mode, and (ii) it retards the rate of diffusion of the
highly soluble drug long enough to provide multi-hour, controlled
delivery of the drug into the stomach. For drugs that are either
sparingly soluble, of limited solubility, or of high solubility,
and that experience any of the specific problems enumerated above
upon reaching the lower GI tract prior to absorption into the
bloodstream, the swelling of the polymeric matrix (i) renders the
matrix sufficiently large to cause retention in the stomach during
the fed mode, and (ii) localizes the release of the drug to the
stomach and small intestine so that the drug will have its full
effect without colonic degradation, inactivation, or loss of
bioavailability.
[0026] In either of these aspects, the invention provides an
effective means of using these drugs to treat local stomach
disorders as well as a wide variety of disease conditions. For
example, use of this invention provides more effective eradication
of ulcer-causing bacteria in the gastric mucosa with soluble
antibiotics. The invention also provides enhanced absorption of
soluble drugs that are absorbed mostly in the stomach or high in
the gastrointestinal tract, such as metformin hydrochloride or
ciprofloxacin. The invention is also useful in providing a
multi-hour flow of a drug past the upper part of the small
intestine (the most efficient absorption site for many agents).
[0027] Details of these and other features of the invention will be
apparent from the description that follows.
BRIEF DESCRIPTION OF THE DRAWINGS
[0028] FIG. 1 is a plot showing the release rate of metformin
hydrochloride from three different compositions of the drug in
poly(ethylene oxide) matrices.
[0029] FIG. 2 is a plot showing the release rate of captopril from
a poly(ethylene oxide) matrix, in accordance with this invention,
both with and without glyceryl monostearate as a solubility
modifier.
[0030] FIG. 3 is a plot showing the release rate of captopril from
hydroxyethyl cellulose, in which the pellet size was varied.
[0031] FIG. 4 is a plot showing the release rate of metformin
hydrochloride from various polymeric matrices.
[0032] FIG. 5 is a plot showing the release rate of metformin
hydrochloride from a single capsule-shaped tablet.
[0033] FIG. 6 is a plot showing the release rate of captopril from
various polymeric matrices.
[0034] FIG. 7 is a plot showing further release rate studies of
metformin hydrochloride from two different polymeric matrices.
[0035] FIG. 8 is a plot showing the release rate of vancomycin
hydrochloride from different polymeric matrices.
[0036] FIG. 9 is a plot showing the release rate of metformin
hydrochloride from a single capsule-shaped tablet.
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
[0037] In aspects of this invention that are directed to highly
soluble drugs, the drugs thus addressed are those that are
characterized by the United States Pharmacopeia XXII as at least
"freely soluble" in water, i. e., drugs whose solubility is greater
than one part of the drug in about ten parts of water. Drugs of
particular interest are those whose solubility is greater than one
part in about five parts of water, and drugs of even greater
interest are those whose solubility is greater than one part in
about three parts of water. The parts referred to in this paragraph
and throughout this specification are parts by weight.
[0038] The term "drug" is used herein to denote any chemical
compound, complex or composition that is suitable for oral
administration and that has a beneficial biological effect,
preferably a therapeutic effect in the treatment of a disease or
abnormal physiological condition. Examples of drugs of high
solubility to which this invention is applicable are metformin
hydrochloride, vancomycin hydrochloride, captopril, erythromycin
lactobionate, ranitidine hydrochloride, sertraline hydrochloride,
ticlopidine hydrochloride, amoxicillin, cefuroxime axetil,
cefaclor, clindamycin, doxifluridine, tramadol, fluoxitine
hydrochloride, ciprofloxacin, gancyclovir, bupropion, lisinopril,
and esters of ampicillin. Examples of drugs of low solubility to
which this invention is applicable are cefaclor, ciprofloxacin,
saguinavir, ritonavir, nelfinavir, clarithromycin, azithromycin,
ceftazidine, cyclosporin, digoxin, paclitaxel, iron salts,
topiramate, and ketoconazole. Other drugs suitable for use and
meeting the solubility criteria described above will be apparent to
those skilled in the art. Drugs of particular interest are
metformin hydrochloride and sertraline hydrochloride. The drug
loadings (weight percent of drug relative to total of drug and
polymer) in most of these cases will be about 80% or less.
[0039] The invention is also of use with drugs that have been
formulated to include additives that impart a small degree of
hydrophobic character, to further retard the release rate of the
drug into the gastric fluid. One example of such a release rate
retardant is glyceryl monostearate. Other examples are fatty acids
and salts of fatty acids, one example of which is sodium myristate.
The quantities of these additives when present can vary; and in
most cases, the weight ratio of additive to drug will range from
about 1:20 to about 1:1, and preferably from about 1:8 to about
1:2.
[0040] The water-swellable polymer forming the matrix in accordance
with this invention is any polymer that is non-toxic, that swells
in a dimensionally unrestricted manner upon imbibition of water,
and that provides for sustained release of an incorporated drug.
Examples of polymers suitable for use in this invention are
cellulose polymers and their derivatives (such as for example,
hydroxyethylcellulose, hydroxypropylcellulose,
carboxymethylcellulose, and microcrystalline cellulose,
polysaccharides and their derivatives, polyalkylene oxides,
polyethylene glycols, chitosan, poly(vinyl alcohol), xanthan gum,
maleic anhydride copolymers, poly(vinyl pyrrolidone), starch and
starch-based polymers, poly (2-ethyl-2-oxazoline),
poly(ethyleneimine), polyurethane hydrogels, and crosslinked
polyacrylic acids and their derivatives. Further examples are
copolymers of the polymers listed in the preceding sentence,
including block copolymers and grafted polymers. Specific examples
of copolymers are PLURONIC.RTM. and TECTONIC.RTM., which are
polyethylene oxide-polypropylene oxide block copolymers available
from BASF Corporation, Chemicals Div., Wyandotte, Mich., USA.
[0041] The terms "cellulose" and "cellulosic" are used herein to
denote a linear polymer of anhydroglucose. Preferred cellulosic
polymers are alkyl-substituted cellulosic polymers that ultimately
dissolve in the gastrointestinal (GI) tract in a predictably
delayed manner. Preferred alkyl-substituted cellulose derivatives
are those substituted with alkyl groups of 1 to 3 carbon atoms
each. Examples are methylcellulose, hydroxymethyl-cellulose,
hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, and carboxymethylcellulose. In terms
of their viscosities, one class of preferred alkyl-substituted
celluloses includes those whose viscosity is within the range of
about 100 to about 110,000 centipoise as a 2% aqueous solution at
20.degree. C. Another class includes those whose viscosity is
within the range of about 1,000 to about 4,000 centipoise as a 1%
aqueous solution at 20.degree. C. Particularly preferred
alkyl-substituted celluloses are hydroxyethylcellulose and
hydroxypropylmethylcellulose. A presently preferred
hydroxyethylcellulose is NATRASOL.RTM. 250HX NF (National
Formulary), available from Aqualon Company, Wilmington, Del.,
USA.
[0042] Polyalkylene oxides of greatest utility in this invention
are those having the properties described above for
alkyl-substituted cellulose polymers. A particularly preferred
polyalkylene oxide is poly(ethylene oxide), which term is used
herein to denote a linear polymer of unsubstituted ethylene oxide.
Poly(ethylene oxide) polymers having molecular weights of about
4,000,000 and higher are preferred. More preferred are those with
molecular weights within the range of about 4,500,000 to about
10,000,000, and even more preferred are polymers with molecular
weights within the range of about 5,000,000 to about 8,000,000.
Preferred poly(ethylene oxide)s are those with a weight-average
molecular weight within the range of about 1.times.10.sup.5 to
about 1.times.10.sup.7, and preferably within the range of about
9.times.10.sup.5 to about 8.times.10.sup.6. Poly(ethylene oxide)s
are often characterized by their viscosity in solution. For
purposes of this invention, a preferred viscosity range is about 50
to about 2,000,000 centipoise for a 2% aqueous solution at
20.degree. C. Two presently preferred poly(ethylene oxide)s are
POLYOX.RTM. NF, grade WSR Coagulant, molecular weight 5 million,
and grade WSR 303, molecular weight 7 million, both products of
Union Carbide Chemicals and Plastics Company Inc. of Danbury,
Conn., USA.
[0043] Polysaccharide gums, both natural and modified
(semi-synthetic) can be used. Examples are dextran, xanthan gum,
gellan gum, welan gum and rhamsan gum. Xanthan gum is
preferred.
[0044] Crosslinked polyacrylic acids of greatest utility are those
whose properties are the same as those described above for
alkyl-substituted cellulose and polyalkylene oxide polymers.
Preferred crosslinked polyacrylic acids are those with a viscosity
ranging from about 4,000 to about 40,000 centipoise for a 1%
aqueous solution at 25.degree. C. Three presently preferred
examples are CARBOPOL.RTM. NF grades 971P, 974P and 934P
(BFGoodrich Co., Specialty Polymers and Chemicals Div., Cleveland,
Ohio, USA). Further examples are polymers known as WATER LOCK.RTM.,
which are starch/acrylates/acrylamide copolymers available from
Grain Processing Corporation, Muscatine, Iowa, USA.
[0045] The hydrophilicity and water swellability of these polymers
cause the drug-containing matrices to swell in size in the gastric
cavity due to ingress of water in order to achieve a size that will
be retained in the stomach when introduced during the fed mode.
These qualities also cause the matrices to become slippery, which
provides resistance to peristalsis and further promotes their
retention in the stomach. The release rate of a drug from the
matrix is primarily dependent upon the rate of water imbibition and
the rate at which the drug dissolves and diffuses from the swollen
polymer, which in turn is related to the solubility and dissolution
rate of the drug, the drug particle size and the drug concentration
in the matrix. Also, because these polymers dissolve very slowly in
gastric fluid, the matrix maintains its physical integrity over at
least a substantial period of time, in many cases at least 90% and
preferably over 100% of the dosing period. The particles will then
slowly dissolve or decompose. Complete dissolution or decomposition
may not occur until 24 hours or more after the intended dosing
period ceases, although in most cases, complete dissolution or
decomposition will occur within 10 to 24 hours after the dosing
period.
[0046] The amount of polymer relative to the drug can vary,
depending on the drug release rate desired and on the polymer, its
molecular weight, and excipients that may be present in the
formulation. The amount of polymer will be sufficient however to
retain at least about 40% of the drug within the matrix one hour
after ingestion (or immersion in the gastric fluid). Preferably,
the amount of polymer is such that at least 50% of the drug remains
in the matrix one hour after ingestion. More preferably, at least
60%, and most preferably at least 80%, of the drug remains in the
matrix one hour after ingestion. In all cases, however, the drug
will be substantially all released from the matrix within about ten
hours, and preferably within about eight hours, after ingestion,
and the polymeric matrix will remain substantially intact until all
of the drug is released. The term "substantially intact" is used
herein to denote a polymeric matrix in which the polymer portion
substantially retains its size and shape without deterioration due
to becoming solubilized in the gastric fluid or due to breakage
into fragments or small particles.
[0047] The water-swellable polymers can be used individually or in
combination. Certain combinations will often provide a more
controlled release of the drug than their components when used
individually. Examples are cellulose-based polymers combined with
gums, such as hydroxyethyl cellulose or hydroxypropyl cellulose
combined with xanthan gum. Another example is poly(ethylene oxide)
combined with xanthan gum.
[0048] The benefits of this invention will be achieved over a wide
range of drug loadings, with the weight ratio of drug to polymer
ranging in general from 0.01:99.99 to about 80:20. Preferred
loadings (expressed in terms of the weight percent of drug relative
to total of drug and polymer) are those within the range of 15% to
80%, more preferably within the range of 30% to 80%, and most
preferably in certain cases within the range of about 30% to 70%.
For certain applications, however, the benefits will be obtained
with drug loadings within the range of 0.01% to 80%, and preferably
15% to 80%.
[0049] The formulations of this invention may assume the form of
particles, tablets, or particles retained in capsules. A preferred
formulation consists of particles consolidated into a packed mass
for ingestion, even though the packed mass will separate into
individual particles after ingestion. Conventional methods can be
used for consolidating the particles in this manner. For example,
the particles can be placed in gelatin capsules known in the art as
"hard-filled" capsules and "soft-elastic" capsules. The
compositions of these capsules and procedures for filling them are
known among those skilled in drug formulations and manufacture. The
encapsulating material should be highly soluble so that the
particles are freed and rapidly dispersed in the stomach after the
capsule is ingested.
[0050] In certain embodiments of this invention, the formulation
contains an additional amount of the drug applied as a quickly
dissolving coating on the outside of the particle or tablet. This
coating is referred to as a "loading dose" and it is included for
immediate release into the recipient's bloodstream upon ingestion
of the formulation without first undergoing the diffusion process
that the remainder of the drug in the formulation must pass before
it is released. The "loading dose" is high enough to quickly raise
the blood concentration of the drug but not high enough to produce
the transient overdosing that is characteristic of highly soluble
drugs that are not formulated in accordance with this
invention.
[0051] One presently preferred dosage form is a size 0 gelatin
capsule containing either two or three pellets of drug-impregnated
polymer. For two-pellet capsules, the pellets are cylindrically
shaped, 6.6 or 6.7 mm (or more generally, 6.5 to 7 mm) in diameter
and 9.5 or 10.25 mm (or more generally, 9 to 12 mm) in length. For
three-pellet capsules, the pellets are again cylindrically shaped,
6.6 mm in diameter and 7 mm in length. For a size 00 gelatin
capsule with two pellets, the pellets are cylindrical, 7.5 mm in
diameter and 11.25 mm in length. For a size 00 gelatin capsule with
three pellets, the pellets are cylindrical, 7.5 mm in diameter and
7.5 mm in length. Another presently preferred dosage form is a
single, elongated tablet, with dimensions 18 to 22 mm in length,
6.5 to 10 mm in width, and 5 to 7.5 mm in height. Still another
presently preferred dosage form is a single, elongated tablet, with
dimensions 18 to 22 mm in length, 6.5 to 7.8 mm in width, and 6.2
to 7.5 mm in height. A preferred set of dimensions is 20 mm in
length, 6.7 mm in width, and 6.4 mm in height. These are merely
examples; the shapes and sizes can be varied considerably.
[0052] The particulate drug/polymer mixture or drug-impregnated
polymer matrix can be prepared by various conventional mixing,
comminution and fabrication techniques readily apparent to those
skilled in the chemistry of drug formulations. Examples of such
techniques are as follows:
[0053] (1) Direct compression, using appropriate punches and dies,
such as those available from Elizabeth Carbide Die Company, Inc.,
McKeesport, Pa., USA; the punches and dies are fitted to a suitable
rotary tableting press, such as the Elizabeth-Hata single-sided
Hata Auto Press machine, with either 15, 18 or 22 stations, and
available from Elizabeth-Hata International, Inc., North
Huntington, Pa., USA;
[0054] (2) Injection or compression molding using suitable molds
fitted to a compression unit, such as those available from
Cincinnati Milacron, Plastics Machinery Division, Batavia, Ohio,
USA.;
[0055] (3) Granulation followed by compression; and
[0056] (4) Extrusion in the form of a paste, into a mold or to an
extrudate to be cut into lengths.
[0057] When particles are made by direct compression, the addition
of lubricants may be helpful and sometimes important to promote
powder flow and to prevent capping of the particle (breaking off of
a portion of the particle) when the pressure is relieved. Useful
lubricants are magnesium stearate (in a concentration of from 0.25%
to 3% by weight, preferably less than 1% by weight, in the powder
mix), and hydrogenated vegetable oil (preferably hydrogenated and
refined triglycerides of stearic and palmitic acids at about 1% to
5% by weight, most preferably about 2% by weight. Additional
excipients may be added to enhance powder flowability and reduce
adherence.
[0058] The term "dosage form" denotes any form of the formulation
that contains an amount sufficient to achieve a therapeutic effect
with a single administration. When the formulation is a tablet or
capsule, the dosage form is usually one such tablet or capsule. The
frequency of administration that will provide the most effective
results in an efficient manner without overdosing will vary with
the characteristics of the particular drug, including both its
pharmacological characteristics and its physical characteristics
such as solubility, and with the characteristics of the swellable
matrix such as its permeability, and the relative amounts of the
drug and polymer. In most cases, the dosage form will be such that
effective results will be achieved with administration no more
frequently than once every eight hours or more, preferably once
every twelve hours or more, and even more preferably once every
twenty-four hours or more.
[0059] As indicated above, the dosage forms of the present
invention find their greatest utility when administered to a
subject who is in the digestive state (also referred to as the
postprandial or "fed" mode). The postprandial mode is
distinguishable from the interdigestive (or "fasting" ) mode by
their distinct patterns of gastroduodenal motor activity, which
determine the gastric retention or gastric transit time of the
stomach contents.
[0060] In the interdigestive mode, the fasted stomach exhibits a
cyclic activity called the interdigestive migrating motor complex
(IMMC). The cyclic activity occurs in four phases:
[0061] Phase I is the most quiescent, lasts 45 to 60 minutes, and
develops few or no contractions.
[0062] Phase II is marked by the incidence of irregular
intermittent sweeping contractions that gradually increase in
magnitude.
[0063] Phase III, which lasts 5 to 15 minutes, is marked by the
appearance of intense bursts of peristaltic waves involving both
the stomach and the small bowel.
[0064] Phase IV is a transition period of decreasing activity which
lasts until the next cycle begins.
[0065] The total cycle time is approximately 90 minutes, and thus,
powerful peristaltic waves sweep out the contents of the stomach
every 90 minutes during the interdigestive mode. The IMMC may
function as an intestinal housekeeper, sweeping swallowed saliva,
gastric secretions, and debris to the small intestine and colon,
preparing the upper tract for the next meal while preventing
bacterial overgrowth. Pancreatic exocrine secretion of pancreatic
peptide and motilin also cycle in synchrony with these motor
patterns.
[0066] The postprandial or fed mode is induced by food ingestion,
and begins with a rapid and profound change in the motor pattern of
the upper GI tract, the change solubility, and with the
characteristics of the swellable matrix such as its permeability,
and the relative amounts of the drug and polymer. In most cases,
the dosage form will be such that effective results will be
achieved with administration no more frequently than once every
eight hours or more, preferably once every twelve hours or more,
and even more preferably once every twenty-four hours or more.
[0067] As indicated above, the dosage forms of the present
invention find their greatest utility when administered to a
subject who is in the digestive state (also referred to as the
postprandial or "fed" mode). The postprandial mode is
distinguishable from the interdigestive (or "fasting" ) mode by
their distinct patterns of gastroduodenal motor activity, which
determine the gastric retention or gastric transit time of the
stomach contents.
[0068] In the interdigestive mode, the fasted stomach exhibits a
cyclic activity called the interdigestive migrating motor complex
(IMMC). The cyclic activity occurs in four phases:
[0069] Phase I is the most quiescent, lasts 45 to 60 minutes, and
develops few or no contractions.
[0070] Phase II is marked by the incidence of irregular
intermittent sweeping contractions that gradually increase in
magnitude.
[0071] Phase III, which lasts 5 to 15 minutes, is marked by the
appearance of intense bursts of peristaltic waves involving both
the stomach and the small bowel.
[0072] Phase IV is a transition period of decreasing activity which
lasts until the next cycle begins.
[0073] The total cycle time is approximately 90 minutes, and thus,
powerful peristaltic waves sweep out the contents of the stomach
every 90 minutes during the interdigestive mode. The IMMC may
function as an intestinal housekeeper, sweeping swallowed saliva,
gastric secretions, and debris to the small intestine and colon,
preparing the upper tract for the next meal while preventing
bacterial overgrowth. Pancreatic exocrine secretion of pancreatic
peptide and motilin also cycle in synchrony with these motor
patterns.
[0074] The postprandial or fed mode is induced by food ingestion,
and begins with a rapid and profound change in the motor pattern of
the upper GI tract, the change occurring over a period of 30
seconds to one minute. The stomach generates 3-4 continuous and
regular contractions per minute, similar to those of the
interdigestive mode but of about half the amplitude. The change
occurs almost simultaneously at all sites of the GI tract, before
the stomach contents have reached the distal small intestine.
Liquids and small particles flow continuously from the stomach into
the intestine. Contractions of the stomach result in a sieving
process that allows liquids and small particles to pass through a
partially open pylorus. Indigestible particles greater than the
size of the pylorus are retropelled and retained in the stomach.
Particles exceeding about 1 cm in size are thus retained in the
stomach for approximately 4 to 6 hours. The dosage form of the
present invention is designed to achieve the minimal size through
swelling following ingestion during the fed mode.
[0075] The following examples are offered for purposes of
illustration, and are not intended to limit the invention in any
manner.
EXAMPLE 1
[0076] This example illustrates the controlled-release behavior of
metformin hydrochloride, a highly soluble drug (whose solubility is
approximately 30%), from a polymeric matrix consisting of
poly(ethylene oxide). Three different dose levels were
prepared--systems designed to release 90% of their drug contents at
approximately 3 hours, 6 hours, and 8 hours, respectively.
[0077] Drug and polymer, with 0.5% magnesium stearate as a
tableting lubricant, were compressed into pellets measuring 7.2 mm
diameter.times.8.8 mm length and weighing 390 mg for samples
designed for 3-hour and 6-hour release, and 7.4 mm
diameter.times.8.5 mm length and weighing 380 mg for samples
designed for 8-hour release, and two pellets of a given type were
incorporated into a single gelatin capsule. Thus, three different
types of gelatin capsule were prepared as follows:
1 t.sub.90% .congruent. 3 hours metformin hydrochloride 250.00 mg
POLYOX .RTM. 1105, 138.67 molecular weight 900,000 magnesium
stearate 1.95 Total 390.62 mg t.sub.90% .congruent. 6 hours
metformin hydrochloride 250.00 mg POLYOX .RTM. Coagulant, 138.67
molecular weight 5,000,000 magnesium stearate 1.95 Total 390.62 mg
t.sub.90% .congruent. 8 hours metformin hydrochloride 125.00 mg
POLYOX .RTM. 303, 266.11 molecular weight 7,000,000 magnesium
stearate 1.97 Total 393.08 mg
[0078] Release rate tests on each of these three formulations were
performed in modified artificial gastric fluid by the following
procedure.
[0079] Dissolution was performed in a USP Apparatus 2, modified to
include a stainless steel cone (7/8 inch in height and 7/8 inch in
diameter at the base) at the bottom of each vessel, placed directly
beneath the paddle shaft to eliminate the "dead zone" effect. A
paddle speed of 60 rpm and a bath temperature of 37.4.degree. C.
were used. The gelatin capsule was opened and the individual
pellets and empty gelatin capsule were dropped into the dissolution
vessel containing 900 mL of modified simulated gastric fluid (7 mL
of hydrochloric acid and 2 g of sodium chloride in 100 mL of
deionized water; the enzyme pepsin was omitted). Once the pellets
had settled to the bottom of the vessel, the paddle rotation was
initiated. Samples 5 mL in size were taken at specified time
points, and the sample volumes were not replaced. The samples were
diluted as necessary for quantitative analysis by HPLC.
[0080] The results are shown in FIG. 1, where the filled diamonds
represent the t.sub.90%.congruent.3 formulation, the x's represent
the t.sub.90%.congruent.6 formulation, and the open circles
represent the t.sub.90%.congruent.8 formulation. The curves show
that the t.sub.90% value of the first formulation was fairly close
to 3.5 hours, the t.sub.90% value of the second formulation was
fairly close to 6.0 hours, and t.sub.90% value of the third
formulation was fairly close to 7.5 hours.
EXAMPLE 2
[0081] This example illustrates the controlled-release behavior of
captopril from a polymeric matrix consisting of poly(ethylene
oxide), both with and without glyceryl monostearate (8% by weight).
The formulations used were as follows:
2 1. Captopril 92.50 mg Poly(ethylene oxide) (POLYOX .RTM. 301),
407.50 molecular weight 4,000,000 Total 500.00 mg 2. Captopril 92.5
mg glyceryl monostearate 15.0 Poly(ethylene oxide) (POLYOX .RTM.
301), 392.5 molecular weight 4,000,000 Total 500.0 mg
[0082] Each formulation was compressed into a tablet measuring 6.0
mm diameter.times.6.7 mm length and weighing 180 mg. Release rate
tests on each of the two tablets were performed in modified
simulated gastric fluid by the procedure of Example 1, except that
the paddle rotation speed was 30 rpm and the tablets were dropped
directly into the dissolution vessel.
[0083] The results are shown in FIG. 2, where the filled squares
represent Formulation No. 1 consisting of captopril and
poly(ethylene oxide) only, and the open circles represent
Formulation No. 2 which further contained glyceryl
monostearate.
EXAMPLE 3
[0084] This example illustrates the controlled-release behavior of
captopril from a polymeric matrix of hydroxyethyl cellulose with
the inclusion of glyceryl monostearate, but at varying pellet
sizes. The formulation contained 19% captopril (all percents by
weight) and 4.8% glyceryl monostearate in hydroxyethyl cellulose of
molecular weight within the range of 1,000,000 to 1,500,000. The
pellet sizes and weights were (a) 3.3 mm diameter.times.3.5 mm
length at 35 mg (referred to herein as 3-mm tablets), (b) 4.3 mm
diameter.times.4.9 mm length at 75 mg (referred to herein as 4-mm
tablets), and (c) 6.3 mm diameter.times.6.5 mm length at 187 mg
(referred to herein as 6-mm tablets).
[0085] Release rate tests on each of the three tablet sizes
(fifteen of the 3-mm tablets, seven of the 4-mm tablets, and three
of the 6-mm tablets) were performed using the procedures of Example
1, except that a weighted watchglass was used in place of the
stainless steel cone, and analyses of the samples were performed by
UV/Vis. The results are shown in FIG. 3, where the filled squares
represent the 3-mm pellets, the filled triangles the 4-mm pellets,
and the filled circles the 6-mm pellets. This demonstrates the
variation of pellet size as a further means of varying the release
pattern, the larger pellets having less surface area.
EXAMPLE 4
[0086] This example further illustrates the controlled release of
metformin hydrochloride, using a higher drug loading, and various
polymers and combinations of polymers. The procedures used were the
same as those described above, and the formulations together with
the symbols used in FIG. 4 where the results are plotted, were as
follows (all percentages are by weight):
[0087] Filled circles: 79.6% metformin HCl; 20% poly(ethylene
oxide) (POLYOX.RTM. 303, molecular weight 7,000,000); 0.4%
magnesium stearate. Pellet dimensions 6.04 mm diameter.times.9.48
mm length; containing approximately 478 mg metformin HCl.
[0088] Filled squares: 79.6% metformin HCl; 20% xanthan gum
(KELTROL.RTM. F, Kelco, Div. of Merck & Co., Inc., San Diego,
Calif., USA); 0.4% magnesium stearate. Pellet dimensions 6.06 mm
diameter.times.9.40 mm length; containing approximately 483 mg
metformin HCl.
[0089] Plus signs: 79.6% metformin HCl; 20% hydroxypropylmethyl
cellulose (BENECEL.RTM. 824, Aqualon Co., Wilmington, Del., USA),
viscosity (2%, 20.degree. C.) 11,000 to 15,000 cps; 0.4% magnesium
stearate. Pellet dimensions 6.06 mm diameter.times.9.49 mm length;
containing approximately 480 mg metformin HCl.
[0090] Open diamonds: 79.6% metformin HCl; 5% hydroxyethyl
cellulose (250HX, molecular weight 1,000,000); 15% poly(ethylene
oxide (POLYOX.RTM. 303, molecular weight 7,000,000); 0.4% magnesium
stearate. Pellet dimensions 6.06 mm diameter.times.9.60 mm length;
containing approximately 480 mg metformin HCl.
[0091] x's: 79.6% metformin HCl, 18.05% xanthan gum (KELTROL.RTM.
F); 1.99% WATER LOCKS D-223 (starch graft
poly(2-propenamide-co-2-propenoic acid)), mixed sodium and aluminum
salts, Grain Processing Corporation, Muscatine, Iowa, USA); 0.4%
magnesium stearate. Pellet dimensions were 6.06 mm
diameter.times.9.24 mm length; containing approximately 476 mg
metformin HCl total.
EXAMPLE 5
[0092] This example further illustrates the controlled release of
metformin hydrochloride from a single capsule-shaped tablet. The
procedures used were the same as those described above, and the
resulting curve is plotted in FIG. 5. The formulation was as
follows (all percentages are by weight): 64% metformin HCl; 35.5%
poly(ethylene oxide) (POLYOX.RTM. 303, molecular weight 7,000,000);
0.5% magnesium stearate; plus an additional 2% OPADRY.RTM. Clear
coating (hydroxypropyl methylcellulose, Colorcon, West Point, Pa.,
USA). The tablet dimensions were 6.48 mm diameter.times.7.20 mm
height.times.19.21 mm length, and contained approximately 506 mg
metformin HCl per tablet.
EXAMPLE 6
[0093] This example further illustrates the controlled release of
captopril, using various polymers and combinations of polymers. The
procedures used were the same as those described above, and the
formulations together with the symbols used in FIG. 6 where the
results are plotted, were as follows (all percentages are by
weight):
[0094] Plus signs: 80% captopril; 20% hydroxypropylmethyl cellulose
(BENECEL.RTM. 824, viscosity (2%, 20.degree. C.) 11,000 to 15,000
cps). Pellet dimensions: 6.03 mm diameter.times.9.25 mm length, 2
pellets weighing 293 mg each, containing approximately 469 mg
captopril total.
[0095] Filled diamonds: 80% captopril; 20% xanthan gum
(KELTROL.RTM. F). Pellet dimensions: 6.04 mm diameter.times.9.18 mm
length, 2 pellets weighing 299 mg each, containing approximately
478 mg captopril total.
[0096] Filled triangles: 80% captopril; 20% hydroxyethyl cellulose
(250HX, molecular weight 1,000,000). Pellet dimensions: 6.03 mm
diameter.times.9.53 mm length, 2 pellets weighing 299 mg each,
containing approximately 478 mg captopril total.
[0097] Open circles: 80% captopril; 20% poly(ethylene oxide)
(POLYOX.RTM.) 303, molecular weight 7,000,000). Pellet dimensions:
6.04 mm diameter.times.9.59 mm length, 2 pellets weighing 301 mg
each, containing approximately 482 mg captopril total.
[0098] Filled squares: 80% captopril; 20% carboxymethyl cellulose
(12M31P, molecular weight 250,000). Pellet dimensions: 6.04 mm
diameter.times.9.18 mm length, 2 pellets weighing 299 mg each,
containing approximately 478 mg captopril total.
[0099] Open triangles: 79.93% captopril; 10.03% hydroxyethyl
cellulose (250HX, molecular weight 1,000,000); 10.04% xanthan gum
(KELTROL.RTM. F). Pellet dimensions: 6.04 mm diameter.times.9.26 mm
length, 2 pellets weighing 296 mg each, containing approximately
473 mg captopril total.
[0100] x's: 79.96% captopril; 10.03% hydroxyethyl cellulose (250HX,
molecular weight 1,000,000); 10.01% poly(ethylene oxide)
(POLYOX.RTM. 303, molecular weight 7,000,000). Pellet dimensions:
6.04 mm diameter.times.9.41 mm length, 2 pellets weighing 297 mg
each, containing approximately 475 mg captopril total.
[0101] Dashes: 80% captopril; 10% hydroxyethyl cellulose (250HX,
molecular weight 1,000,000); 10% hydroxypropylmethyl cellulose
(BENECEL.RTM. 824, viscosity (2%, 20.degree. C.) 11,000 to 15,000
cps). Pellet dimensions: 6.04 mm diameter.times.9.41 mm length, 2
pellets weighing 298 mg each, containing approximately 477 mg
captopril total.
[0102] Open diamonds: 79.96% captopril; 18.05% xanthan gum
(KELTROL.RTM. F); 1.99% WATERLOCK.RTM. D-223. Pellet dimensions:
6.04 mm diameter.times.9.16 mm length, 2 pellets weighing 297 mg
each, containing approximately 475 mg captopril total.
EXAMPLE 7
[0103] This example presents further data on metformin
hydrochloride formulations, illustrating the effect of lower drug
loadings than those used in the preceding examples. The procedures
used were the same as those described above, and the formulations
together with the symbols used in FIG. 7 where the results are
plotted, were as follows (all percentages are by weight):
[0104] Filled squares: 32.5% metformin HCl; 67% poly(ethylene
oxide) (POLYOX.RTM. 303, molecular weight 7,000,000); 0.5%
magnesium stearate. Pellet dimensions 6.62 mm diameter.times.10.40
mm length, 2 pellets weighing 400 mg each, containing approximately
260 mg metformin HCl total.
[0105] Open circles: 32.5% metformin HCl; 67% xanthan gum
(KELTROL.RTM. F); 0.5% magnesium stearate. Pellet dimensions 6.65
mm diameter.times.9.28 mm length; 2 pellets weighing 401 mg each,
containing approximately 261 mg metformin HCl total.
EXAMPLE 8
[0106] This example illustrates the sustained release of vancomycin
hydrochloride from various polymers. The procedures used were the
same as those described above, and the formulations together with
the symbols used in FIG. 8 where the results are plotted, were as
follows (all percentages are by weight):
[0107] Open squares: 31.5% vancomycin hydrochloride; 68%
poly(ethylene oxide) (POLYOX.RTM. 303, molecular weight 7,000,000);
0.5% magnesium stearate. Pellet dimensions: 6.59 mm
diameter.times.10.23 mm length, 2 pellets weighing 403 mg each,
containing approximately 254 mg vancomycin hydrochloride total.
[0108] Open triangles: 31.5% vancomycin hydrochloride; 68%
poly(ethylene oxide) (POLYOX.RTM. 301, molecular weight 4,000,000);
0.5% magnesium stearate. Pellet dimensions: 6.59 mm
diameter.times.10.28 mm length, 2 pellets weighing 402 mg each,
containing approximately 253 mg vancomycin hydrochloride total.
[0109] x's: 31.5% vancomycin hydrochloride; 68% hydroxypropyl
methylcellulose (BENECEL(T 824, viscosity 11,000-15,000 cps (2%
solution at 20.degree. C.)); 0.5% magnesium stearate. Pellet
dimensions: 6.59 mm diameter.times.10.10 mm length, 2 pellets
weighing 405 mg each, containing approximately 255 mg vancomycin
hydrochloride total.
[0110] Open circles: 31.5% vancomycin hydrochloride; 68% xanthan
gum (KELTROL.RTM. F); 0.5% magnesium stearate. Pellet dimensions:
6.62 mm diameter.times.9.77 mm length, 2 pellets weighing 401 mg
each, containing approximately 253 mg vancomycin hydrochloride
total.
[0111] Filled squares: 62.5% vancomycin hydrochloride; 37%
poly(ethylene oxide) (POLYOX.RTM. 303, molecular weight 7,000,000);
0.5% magnesium stearate. Pellet dimensions: 6.60 mm
diameter.times.10.01 mm length, 2 pellets weighing 409 mg each,
containing approximately 511 mg vancomycin hydrochloride total.
[0112] In the prior art, vancomycin and its salts are administered
by injection, due to poor absorption when administered orally. By
providing for all or at least a portion of the total administered
amount to be delivered by controlled delivery in the gastric
retentive system of this invention, that portion so delivered is
directed to the proximal portion of the small intestine, the most
efficient site for absorption of this drug, resulting in an
enhanced absorption from the oral dosage form of the invention.
EXAMPLE 9
[0113] This example illustrates the difference between subjects in
the fed mode and subjects not in the fed mode in terms of the
gastric retention of tablets of various sizes administered orally.
Both Beagle dogs and human subjects were used.
[0114] Barium-containing tablets for oral administration were
prepared from the following ingredients:
[0115] 25% Barium Sulfate
[0116] 30% PolyOx 303 (average molecular weight 7,000,000)
[0117] 44.5% Hydroxypropylcellulose
[0118] 0.5% Magnesium Stearate
[0119] For tests on Beagle dogs, 400-mg tablets measuring 5.8 mm
diameter.times.5.1 mm height.times.15.4 mm length were prepared in
a tablet press at 2,500 psi pressure, and 800-mg tablets measuring
7.9 mm diameter.times.5.6 mm height.times.19.1 mm length were
prepared in a tablet press at 5,000 psi. Four beagle dogs were
used, and the location of the tablets in the GI tract was followed
using fluoroscopy. Two studies were initiated with the dogs. In the
first study, each dog received two tablets (one 400-mg and one
800-mg) with a small amount of water after a 16-hour fast. In the
second study, each dog received two tablets (one 400-mg and one
800-mg) thirty minutes after ingesting 50 grams of a standard meal.
The location of the tablets (in or out of the stomach) was
monitored every 30 minutes with the fluoroscope.
[0120] The fluoroscopy revealed that tablets that were administered
while the dogs were in the fasted condition were emptied from the
dogs' stomachs within 90 minutes: in two of the dogs, the stomachs
contained no barium tablets at 30 minutes, in a third this was true
at 60 minutes, and in the fourth at 90 minutes. Tablets that were
administered while the dogs were in the fed state remained in the
dogs' stomach for between 4 and 5 hours.
[0121] Human tests were performed on ten normal adults of both
sexes, each taking part in two trials, the first after fasting and
the second after a bacon and egg breakfast of approximately 1,500
calories. The tablets used in the tests had the same composition as
those used for the Beagle dogs and measured either 4 mm.times.4 mm
or 6 mm.times.6 mm. The subjects were X-rayed at 30 minutes and at
1, 2, 4, 6, 8, 10, and approximately 12 hours after ingesting the
tablets. In some subjects, visualization was achieved by ultrasound
rather than X-rays.
[0122] Imaging revealed that in the fasted trials, the tablets left
the stomach in 30 minutes to one hour after administration. In the
fed trials, the tablets demonstrated multiple-hour retention in the
stomach in all subjects, 80% of the contents of all tablets being
retained at 4 hours. Five of the ten subjects retained the tablets
for 6 hours or more, and four of these five retained them for ten
hours or more.
EXAMPLE 10
[0123] This example further illustrates the controlled release of
metformin hydrochloride from a single capsule-shaped tablet. The
procedures used were the same as those described above, and the
resulting curve is plotted in FIG. 9. The formulation was as
follows (all percentages are by weight): 48.5% metformin HCl; 49%
poly(ethylene oxide) (POLYOX.RTM. 303, molecular weight 7,000,000);
0.5% magnesium stearate; plus an additional 2% OPADRY.RTM. Clear
coating (hydroxypropyl methylcellulose, Colorcon, West Point, Pa.,
USA). The tablet dimensions were 9.66 mm diameter.times.6.95 mm
height.times.19.24 mm length, and contained approximately 506 mg
metformin HCl per tablet.
[0124] The foregoing is offered primarily for purposes of
illustration. It will be readily apparent to those skilled in the
art that the components, additives, proportions, methods of
formulation, and other parameters of the invention can be modified
further or substituted in various ways without departing from the
spirit and scope of the invention.
* * * * *