U.S. patent application number 15/451240 was filed with the patent office on 2017-06-22 for shell-and-core dosage form approaching zero-order drug release.
The applicant listed for this patent is Depomed, Inc.. Invention is credited to Bret Berner, Jenny Louie-Helm, John N. Shell.
Application Number | 20170172930 15/451240 |
Document ID | / |
Family ID | 23983134 |
Filed Date | 2017-06-22 |
United States Patent
Application |
20170172930 |
Kind Code |
A1 |
Berner; Bret ; et
al. |
June 22, 2017 |
SHELL-AND-CORE DOSAGE FORM APPROACHING ZERO-ORDER DRUG RELEASE
Abstract
Drugs are formulated as oral dosage forms for controlled release
in which the release rate limiting portion is a shell surrounding
the drug-containing core. The shell releases drug from the core by
permitting diffusion of the drug from the core. The shell also
motes gastric retention of the dosage form by swelling upon
imbibition of gastric fluid to size that is retained in the stomach
during the postprandial or fed mode.
Inventors: |
Berner; Bret; (Half Moon
Bay, CA) ; Louie-Helm; Jenny; (Fremont, CA) ;
Shell; John N.; (Lincoln, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Depomed, Inc. |
Newark |
CA |
US |
|
|
Family ID: |
23983134 |
Appl. No.: |
15/451240 |
Filed: |
March 6, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14584805 |
Dec 29, 2014 |
9597338 |
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15451240 |
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13688114 |
Nov 28, 2012 |
8945619 |
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14584805 |
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13156225 |
Jun 8, 2011 |
8329215 |
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13688114 |
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12770283 |
Apr 29, 2010 |
8043630 |
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13156225 |
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10213823 |
Aug 7, 2002 |
7736667 |
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12770283 |
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09498945 |
Feb 4, 2000 |
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10213823 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 31/00 20180101;
A61K 9/2853 20130101; A61K 9/284 20130101; A61K 9/0002 20130101;
A61K 31/525 20130101; A61K 9/2027 20130101; A61K 9/2866 20130101;
A61K 31/60 20130101; A61K 31/472 20130101; A61K 31/155 20130101;
A61P 3/10 20180101; A61P 1/00 20180101 |
International
Class: |
A61K 9/28 20060101
A61K009/28; A61K 31/472 20060101 A61K031/472; A61K 31/60 20060101
A61K031/60; A61K 31/155 20060101 A61K031/155; A61K 31/525 20060101
A61K031/525 |
Claims
1. A controlled-release oral drug dosage form for releasing a drug
into at least a portion of a region defined by the stomach and the
upper gastrointestinal tract, said dosage form comprising: (a) a
core comprising a first solid polymeric matrix with said drug
dispersed therein, and (b) a shell substantially completely
encasing said core, said shell comprising a second solid polymeric
matrix that swells upon imbibition of water to a size large enough
to promote retention in the stomach while the stomach is in a fed
mode, and said shell having a drug:polymer weight ratio that is
substantially less than that of said core, said shell having a
thickness that is at least about 0.5% of the longest linear
dimension of said dosage form, said second polymeric matrix being
of a material and thickness relative to said core such that when
said dosage form is immersed in gastric fluid, said drug is
released from said dosage form into said gastric fluid at a
controlled rate limited at least in part by diffusion of said drug
through said shell to an extent that at least about 40% of said
drug remains unreleased one hour after such immersion has begun and
substantially all of said drug is released within about twenty-four
hours after such immersion has begun.
2. A controlled-release oral drug dosage form in accordance with
claim 1, wherein said core has an outer surface and said shell has
an inner surface in full contact with said outer surface of said
core.
3. A controlled-release oral drug dosage form in accordance with
claim 1, wherein said shell thickness is from about 1% to about 60%
of the longest linear dimension of said dosage form.
4. A controlled release oral drug dosage form in accordance with
claim 1, wherein the drug:polymer weight ratio of said shell is
equal to or less than about 0.5 times the drug:polymer weight ratio
of said core.
5. A controlled release oral drug dosage form in accordance with
claim 1, wherein said shell contains substantially none of said
drug.
6. A controlled-release oral drug dosage form in accordance with
claim 1, wherein said oral drug dosage form is a tablet having a
total weight of from about 50 mg to about 5000 mg.
7. A controlled-release oral drug dosage form in accordance with
claim 1, wherein said first and second polymeric matrices are
formed of polymers independently selected from the group consisting
of poly(ethylene oxide), poly(vinyl alcohol), cellulose,
alkyl-substituted cellulose, hydroxyalkyl-substituted cellulose,
crosslinked polyacrylic acids, and xanthan gum.
8. A controlled-release oral drug dosage form in accordance with
claim 1, wherein said first and second polymeric matrices are
formed of polymers independently selected from the group consisting
of poly(ethylene oxide), hydroxypropylmethyl cellulose, and
hydroxyethyl cellulose.
9. A controlled-release oral drug dosage form in accordance with
claim 1, wherein said first and second polymeric matrices are both
poly(ethylene oxide).
10. A controlled-release oral drug dosage form in accordance with
claim 9, wherein said poly(ethylene oxide) has a molecular weight
of at least about 2,000,000.
11. A controlled-release oral drug dosage form in accordance with
claim 9, wherein said poly(ethylene oxide) of said first polymeric
matrix has a higher molecular weight than said poly(ethylene oxide)
of said second polymeric matrix.
12. A controlled-release oral drug dosage form in accordance with
claim 11, wherein the molecular weight ratio of said poly(ethylene
oxide) of said first polymeric matrix to said poly(ethylene oxide)
of said second polymeric matrix is from about 1.15:1 to about
2.5:1.
13. A controlled-release oral drug dosage form in accordance with
claim 1, wherein the amount of said drug in said core is from about
1% to about 98% by weight.
14. A controlled-release oral drug dosage form in accordance with
claim 1, wherein said second polymeric matrix is of a material and
volume relative to said core that at least about 60% of said drug
remains unreleased two hours after such immersion has begun.
15. A controlled-release oral drug dosage form in accordance with
claim 1, wherein said drug is a member selected from the group
consisting of metformin hydrochloride, vancomycin hydrochloride,
captopril, lisinopril, erythromycin lactobionate, acyclovir,
ranitidine hydrochloride, baclofen, sertraline hydrochloride,
levodopa, tramadol, and ticlopidine hydrochloride.
16. A controlled-release oral drug dosage form in accordance with
claim 1, wherein said drug is a member selected from the group
consisting of amoxicillin, cefuroxime axetil, cefaclor,
clindamycin, clarithromycin, azithromycin, ceftazidime, and
ciprofloxacin.
17. A controlled-release oral drug dosage form in accordance with
claim 1, wherein said drug is a member selected from the group
consisting of cyclosporine, digoxin, doxifluridine, and
paclitaxel.
18. A controlled-release oral drug dosage form in accordance with
claim 1, wherein
19. A controlled-release oral drug dosage form in accordance with
claim 1, wherein said drug is nelfinar mesylate.
20. A method for administering a drug to a subject comprising,
orally administering a controlled-release oral drug dosage form,
wherein the dosage form comprises: (a) a core comprising a first
solid polymeric matrix with said drug dispersed therein, and (b) a
shell substantially completely encasing said core, said shell
comprising a second solid polymeric matrix that swells upon
imbibition of water to a size large enough to promote retention in
the stomach while the stomach is in a fed mode, and said shell
having a drug:polymer weight ratio that is substantially less than
that of said core, said shell having a thickness that is at least
about 0.5% of the longest linear dimension of said dosage form,
said second polymeric matrix being of a material and thickness
relative to said core such that when said dosage form is immersed
in gastric fluid, said drug is released from said dosage form into
said gastric fluid at a controlled rate limited at least in part by
diffusion of said drug through said shell to an extent that at
least about 40% of said drug remains unreleased one hour after such
immersion has begun and substantially all of said drug is released
within about twenty-four hours after such immersion has begun.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 14/584,805, filed Dec. 29, 2014, now allowed, which is a
continuation of U.S. application Ser. No. 13/688,114, filed Nov.
28, 2012, now issued as U.S. Pat. No. 8,945,619, which is a
continuation of U.S. application Ser. No. 13/156,225, filed on Jun.
8, 2011, now issued as U.S. Pat. No. 8,329,215, which is a
continuation of U.S. application Ser. No. 12/770,283, filed Apr.
29, 2010, now issued as U.S. Pat. No. 8,043,630, which is a
continuation of U.S. application Ser. No. 10/213,823, filed Aug. 7,
2002, now issued as U.S. Pat. No. 7,736,667, which is a
continuation of U.S. application Ser. No. 09/498,945, filed Feb. 4,
2000, now abandoned, all of which are incorporated herein by
reference in their entirety.
TECHNICAL FIELD
[0002] This invention is in the general field of pharmaceuticals,
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
for absorption in the stomach and upper GI tract rather than the
lower portions of the GI tract. One goal of this invention is to
release 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, and thereby to achieve a greater and more prolonged
therapeutic effect with potentially diminished side effects. This
will reduce the frequency of administration required and achieve a
more efficient use of the drugs and a more effective treatment of
local stomach disorders. A third goal is to minimize both
lower-tract inactivation of the drug and drug effects on the lower
intestinal flora.
BACKGROUND
[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. Improved delivery patterns were first
made available in the 1970's with the introduction of a variety of
controlled delivery systems. These systems lowered the amount of
drug released immediately after dosing and extended the time period
over which drug release continued, thereby minimizing both 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 drugs. Such matrices do not provide
adequate control over the drug release rate, but instead provide a
release pattern that approximates square-root-of-time kinetics in
which the total amount of drug released is approximately
proportional to the square root of the elapsed time. With this
release pattern in an aqueous medium, much of the drug in the
matrix of many of these formulations is released into an aqueous
medium within the first hour.
[0005] The benefits of a constant release rate with regard to
prolonging therapeutic efficacy while minimizing side effects are
well established. It is well known in the art that a nearly
constant release rate that simulates zero order kinetics can be
obtained by surrounding a tablet core with a membrane or coating.
The membranes or coatings described in the art are typically 1-5%
of the weight of the tablet. Unfortunately, swelling of the tablet
can disrupt the membrane and change the kinetics considerably from
zero order, U.S. Pat. No. 4,892,742, issued Jan. 9, 1990 (assignee:
Hoffman-La Roche Inc.; inventor: Shah) discloses a tablet
consisting of: [0006] 1) a core consisting of 5-35% of a water
insoluble polymer matrix and 65-95% of a water soluble active
ingredient; and [0007] 2) a membrane coating comprising 5-10% of
the weight of the tablet and consisting of a rate-controlling
polymer.
[0008] The preferred coating material is ethyl cellulose or a
plasticized ethyl cellulose and is a typical controlled release
coating for a tablet. The lack of swelling of these membranes and
the insoluble core allow the membrane coating to remain intact
throughout the release process without breakage, thereby preventing
exposure of the core. Without swelling to a minimal size, neither
gastric retention of the tablet nor sustained delivery of the
active ingredient to the upper gastrointestinal (GI) tract would be
achieved.
[0009] U.S. Pat. No. 4,629,620, issued Dec. 16, 1986 (assignee: AB
Ferrosan; inventor: Lindahl), describes membrane-coated
sustained-release tablets where the membrane is an insoluble
polymer containing pore-forming agents. Like the tablets and
membrane coatings of the Shah patent (U.S. Pat. No. 4,892,742), the
tablets and membranes of the Lindahl patent are non-swelling and
are not retained in the upper GI tract.
[0010] U.S. Pat. No. 5,500,227, issued Mar. 19, 1996 (assignee:
Euro-Celtique, S.A.; inventor: Oshlack) discloses the use of a
controlled release tablet that consists of: [0011] 1) an immediate
release tablet core containing an insoluble drug; and [0012] 2) a
thin hydrophobic coating material.
[0013] This patent does not include any disclosure or suggestion
that either the membrane or the tablet swells, and thus the patent
does not disclose a manner of confining controlled release to the
upper GI tract.
[0014] U.S. Pat. No. 4,756,911, issued Jul. 12, 1988 (assignee:
E.R. Squibb & Sons, Inc.; inventor: Drost) discloses a
controlled release tablet for procainamide hydrochloride consisting
of: [0015] 1) a core containing about 70% (on a weight basis) of
the drug, from 5 to 15% by weight of the hydrocolloid gelling
agent, hydroxypropylmethyl cellulose, and from 0 to 8% of
non-swellable binders; and [0016] 2) a water permeable coating film
comprised of a mixture of at least one hydrophobic and one
hydrophilic polymer.
[0017] This patent teaches that the entry of water through the film
coating causes the membrane to peel off in 2 to 4 hours after
ingestion of the tablet. Drug release proceeds from the core
alone.
[0018] U.S. Pat. No. 4,891,223, issued Jan. 2, 1990 (assignee: Air
Products and Chemicals, Inc.; inventor: Ambegaonkar) discloses
compositions containing: [0019] 1) an active ingredient that is
soluble in the release medium; [0020] 2) an inner coating that is
water soluble and swellable; and [0021] 3) a second outer coating
that is water insoluble.
[0022] The second outer coating is disclosed as being able to
stretch sufficiently to remain in contact with the inner layer; but
the second outer coating still may limit the swelling of the
composition. The invention described involves controlled-release
beads rather than tablets and are far below the size that is
necessary to confine release of the active ingredient to the upper
GI tract.
[0023] The prior art also includes disclosures of multilayer
tablets designed to provide release profiles that are intermediate
between square-root-of time and zero-order. This prior art is
listed below. The multi-layered tablets disclosed in the these
patents may swell sufficiently to allow controlled delivery to the
upper GI tract, but they do not include a swelling outer layer that
fully encloses a core. The outer layers are only partial,
discontinuous coatings and thus are not subjected to the large
strains that are caused by differential swelling.
[0024] U.S. Pat. No. 5,783,212, issued Jul. 21, 1998 (assignee:
Temple University; inventor: Fassihi) discloses a three-layer
tablet, i.e., a core with a partial coating on only two sides,
described as: [0025] 1) a drug layer consisting of a swellable,
erodible polymer; and [0026] 2) two barrier layers comprising
swellable, erodible polymers that erode and swell faster than the
drug layer.
[0027] There is no disclosure or suggestion that the swelling and
erosion are matched among the three layers, nor is there any
recognition that the drug layer swells faster. There is no
disclosure of a swelling membrane or any recognition of the loss of
control over the release rate caused by a disrupted membrane.
[0028] U.S. Pat. No. 5,549,913, issued Aug. 27, 1996 (assignee:
Inverni Della Beffa, S.p.A.; inventor: Colombo), teaches the use of
a three-layer tablet where: [0029] 1) two external layers, each
covering only one side, comprised of hydrophilic swelling polymers
and at least one of which contains drug; and [0030] 2) an
interposing layer controlling the release of the drug.
[0031] In this multilayer tablet, the drug is released not through
a swelling membrane or coating, but instead through an erodible or
soluble layer.
[0032] Conte et al., in Biomaterials 17(1996):889-896, disclose
two- and three-layer tablets with barrier layers that swell or
erode. These barrier layers are described as partial coatings and
as such do not form barriers that must remain intact under the
pressure arising from cores surrounded by coatings that swell at
different rates.
[0033] Published international application WO 99/47128, published
Sep. 23, 1999 (applicant: Bristol-Myers Squibb; inventor: Timmins)
discloses a pharmaceutical tablet consisting of: [0034] 1) an inner
phase containing drug and an extended release material; and [0035]
2) an outer phase that is continuous and comprised of an extended
release material; the inner phase being dispersed throughout the
outer phase. The extended release materials described in WO
99/47128 can swell substantially to confine delivery to the upper
GI tract. The outer continuous phase is a dispersion and not a
coating or membrane. The drug release profiles resulting from this
invention consequently deviate substantially from zero-order and
actually exhibit a release profile that is proportional to the
square root of time.
[0036] 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 disclosed in WO
96/26718 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: [0037] (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; [0038] (ii) the release of drug from the matrix is
sustained over the full erosion period of the polymer, the tablet
therefore reaching complete dissolution at the same time that the
last of the drug is released; and [0039] (iii) release of the drug
from the matrix is extended over a period of 24 hours.
[0040] A key disclosure in WO 96/26718 is that to achieve the
release of drug in this manner, the polymeric matrix must be a
polymer of low molecular weight. If, by contrast, a polymer of high
molecular weight 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 is particularly significant since any tablet,
including swollen tablets, will pass from the stomach after the
termination of the fed mode, which typically lasts for only 4 to 6
hours. Moreover, this patent does not teach the use of a membrane
or coating, much less one that swells and stays in contact with the
core throughout the release of the drug.
[0041] In many cases, the passage of a drug from the stomach into
the small intestine while the drug is still in a tablet or other
dosage form raises problems that lower the therapeutic efficacy of
the drug, due to either the absence of the favorable conditions in
the stomach, the exposure to unfavorable conditions in the colon,
or both.
[0042] For example, most orally administered antibiotics are
capable 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 due to passage of the antibiotics from the
stomach through the GI tract to the small intestine. 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 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, damage to essential bacterial flora can occur.
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. Further examples are
clarithromycin, azithromycin, ceftazidime, ciprofloxacin, and
cefaclor. A goal of the present invention is to avoid
antibiotic-induced overgrowth of the lower intestinal flora by
administering antibiotics, regardless of their level of solubility,
in a manner that confines their delivery to the stomach and upper
small intestine.
[0043] A class of drugs that suffer a loss of benefit from rapid
initial release are those that are susceptible to degradation by
exposure to gastric fluid, either due to the action of gastric
enzymes or as the result of low solution pH. One example of such a
drug is topiramate, a drug that is used for the treatment of
epilepsy. Topiramate is absorbed most rapidly in the upper GI
tract, but when made available at this site, it is hydrolyzed by
the acidic environment of the stomach. Avoidance of this high rate
of hydrolysis requires a dosage form that does not expose the drug
to the acidic environment for an extended period.
[0044] A class of drugs that suffer a loss of benefit when allowed
to pass into the small intestine are those that are absorbed only
in the upper GI tract and suffer from incomplete absorption or from
wide differences in absorption, both within a single patient and
between different patients. 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 its low solubility, cyclosporine has a low
absorption rate of about 30% on average, together with wide
absorption variability ranging from as little as 5% in some
patients to as much as 98% in others. The variability is
attributable in part to differences among the various disease
states existing in the patients to whom the drug is administered,
and in part to differences in the length of time between the
transplant surgery and the administration of the drug. The
variability can also be attributed to the poor aqueous solubility
of the drug, 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.
[0045] Another class of drugs that suffer a loss of benefit when
allowed to pass into the small intestine are 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. An example of such a drug is the
pro-drug doxifluridine (5'-deoxy-S-fluouridine (dFUR)). The
activity of this pro-drug depends on its activation to
5-fluorouracil by pyrimidine nucleoside phosphorylases. These
enzymes are found in tumors as well as in normal tissues, and their
activity in tumor cells is more than twice their activity in normal
tissue. In addition, these enzymes demonstrate their highest
activity in the large intestine. When doxifluridine is administered
orally, it risks being 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. Other drugs
that can produce a similar effect upon reaching the colon are
cyclosporine and digoxin.
[0046] A further class of drugs whose effectiveness declines when
the drugs are allowed to pass into the large intestine 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,
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 duodenum,
jejunum/ileum or colon, from which they were absorbed, or by
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. Thus, while the p-glycoprotein efflux
system is useful in many respects, such as preventing toxic
compounds from entering the brain, it interferes with the efficacy
of certain drugs whose absorption is necessary in achieving the
therapeutic effect. 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. These drugs
therefore would benefit from controlled release over an extended
period into the upper GI tract where p-glycoprotein is lowest.
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 that are susceptible to the
p-glycoprotein efflux system are the anti-cancer drug paclitaxel,
ciprofloxacin, and the HIV protease inhibitors saquinavir,
ritonavir, and rielfinavir.
[0047] A still further class of drugs that suffer from loss of
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 thus creates an acidic environment, while
the small intestine has a higher pH, creating a slightly acidic to
alkaline environment. Some drugs achieve bioavailability only when
ionized by the acidic environment of the stomach. Other drugs are
more bioavailable in a non-ionized state. Acidic drugs that have a
low pK, for example, are in the neutral form in the stomach, and
those that are more bioavailable in this state are preferentially
absorbed in the stomach or upper duodenum. Examples of highly
soluble drugs that meet this description are esters of ampicillin.
Examples of low solubility drugs that behave similarly are iron
salts, digoxin, ketoconazole, fluconazole, griseofulvin,
itraconazole, and micoconazole. Iron salts are used in the
treatment of the various forms of anemia, digoxin is used in the
treatment of heart disease, and ketoconazole is used in the
treatment of systemic fungal infections such as candidiasis,
canduria, blastomycosis, coccidiomycosis, histoplasmosis,
chronomycosis, and pacococcidiornycosis. Still further drugs that
are more absorbable in the neutral form that is maintained at low
pH are those whose molecular structure contains at least one group
that becomes ionized in the pH range of 5 through 8, which is the
pH range encountered in the small intestine and the region of the
colonic junction. In addition, zwitterionic drugs may be better
absorbed in a charged form that is present in the acidic
environment of the stomach or the duodenal cap. The bioavailability
of all of these drugs can be maximized by confining them to the
acidic environment of the stomach while controlling their release
rate to achieve an extended release profile.
[0048] 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 or
neutral 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 absorption of orally
administered nelfinavir. Peak plasma concentration and area under
the plasma concentration-time curve of nelfinavir are two to three
times greater when doses are administered with or following a meal.
This is believed to be due at least in part to enhanced retention
of the drug in the stomach.
BRIEF DESCRIPTION
[0049] The present invention resides in a controlled-release dosage
form that releases a drug at a rate that approaches zero-order,
i.e., a release rate that is substantially constant over time for a
period of several hours within the early part of the release
profile of the drug, the dosage form substantially confining the
release of the drug to the upper GI tract. The dosage form is a
dual-matrix configuration, one matrix forming a core of polymeric
material in which drug is dispersed and the other matrix forming a
casing that surrounds and fully encases the core, the casing being
of polymeric material that swells upon imbibition of water (and
hence gastric fluid) to a size large enough to promote retention in
the stomach during the fed mode, the shell and core being
configured such that the drug contained in the core is released
from the dosage form by diffusion through the shell. The shell is
of sufficient thickness and strength that it is not disrupted by
the swelling and remains intact during substantially the entire
period of drug release.
[0050] This dosage form offers benefits to each of the various
types of drugs addressed above. For drugs such as amoxicillin,
cefuroxime axetil, clindamycin, and others that tend to cause
overgrowth of flora in the lower GI tract, the dosage form of this
invention confines the delivery of the drug to the stomach and
upper small intestine in a slow, continuous manner. Drugs such as
topiramate that are degraded by the gastric enzymes or by the low
gastric pH are released more slowly and are protected from the
degradation until they are released. Drugs such as cyclosporine
that are absorbed only at locations high in the GI tract and whose
absorption varies widely among individuals benefit by the dosage
form of this invention by being released with less
patient-to-patient variability and by being retained in the regions
where they are most effectively absorbed. Drugs such as
doxifluridine, cyclosporine, and digoxin that are degradable by
intestinal enzymes are delivered with less degradation by
concentrating their absorption in the stomach. Drugs that are
influenced by inactivators such as p-glycoproteins in the lower GI
tract are protected against such inactivation by concentrating
their release to the upper GI tract. Drugs that are more
bioavailable in an acidic environment are more effectively absorbed
by concentrating their release to the acidic environment of the
stomach, and drugs that tend to lose solubility in an alkaline
environment are enhanced by the acidic environment in the upper GI
tract. Other examples will be readily apparent to those
knowledgeable in the nature and characteristics of drugs.
[0051] While both the core and the shell may be water-swellable,
the water swellability of the shell is a characteristic feature of
this invention and extends to all embodiments of the invention. The
polymeric material of the shell may be erodible as well as
swellable, but when an erodible polymer is used, the polymer is one
whose erosion rate is substantially lower than the swelling rate.
As a result, drug from the core passes through the shell primarily
by diffusion in preference to release of the drug by erosion or
dissolving of the shell. A further characteristic feature of the
invention that extends to all embodiments is the inclusion of drug
in the core, but a quantity of drug may also be contained in the
shell or applied as a coating to the outside of the shell. This is
useful in dosage forms that are designed to provide an initial high
rate of drug delivery of short duration or an initial immediate
release of the drug, followed by a slow continuous rate over an
extended period of time. When drug is present in both the core and
the shell, the drug:polymer weight ratio in the shell is
substantially less than the drug:polymer weight ratio in the core.
This invention further extends to dosage forms that contain a
combination of two or more drugs in a single dosage form, where
either both drugs are present throughout the dosage form or one
drug is dispersed in the core and the other in the shell.
[0052] These and other features, characteristics, and embodiments
of the invention will be apparent from the description that
follows.
DESCRIPTION OF FIGURES
[0053] The attached FIG. 1 is a plot of the excretion rate of
metformin hydrochloride as a function of time from two dosage
forms, one of which is in accordance with this invention.
DETAILED DESCRIPTION OF THE INVENTION
[0054] Water-swellable polymers useful in the preparation of the
dosage form of this invention include polymers that are non-toxic
and, at least in the case of the shell, polymers that swell in a
dimensionally unrestricted manner upon imbibition of water and
hence of gastric fluid. The core polymer may also be a swelling
polymer, and if so, compatible polymers will be selected that will
swell together without disrupting the integrity of the shell. The
core and shell polymers may be the same or different, and if the
same, they may vary in molecular weight, crosslinking density,
copolymer ratio, or any other parameter that affects the swelling
rate, so long as any swelling occurring in the core causes
substantially no splitting of the shell. Examples of suitable
polymers are: [0055] cellulose polymers and their derivatives
including, but not limited to, hydroxymethyl cellulose,
hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, carboxymethylcellulose, and
microcrystalline cellulose [0056] polysaccharides and their
derivatives [0057] polyalkylene oxides [0058] polyethylene glycols
[0059] chitosan [0060] poly(vinyl alcohol) [0061] xanthan gum
[0062] maleic anhydride copolymers [0063] poly(vinyl pyrrolidone)
[0064] starch and starch-based polymers [0065] maltodextrins [0066]
poly (2-ethyl-2-oxazoline) [0067] poly(ethyleneimine) [0068]
polyurethane hydrogels [0069] crosslinked polyacrylic acids and
their derivatives
[0070] Further examples are copolymers of the polymers listed
above, including block copolymers and graft 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. Further examples are hydrolyzed starch polyacrylonitrile graft
copolymers, commonly known as "Super Slurper" and available from
Illinois Corn Growers Association, Bloomington Ill., USA.
[0071] The term "cellulose" is used herein to denote a linear
polymer of anhydroglucose. Preferred cellulosic polymers are
alkyl-substituted cellulosic polymers that ultimately dissolve in
the 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. In terms of their
viscosities, one class of preferred alkyl-substituted celluloses
are those whose viscosities are within the range of about 3 to
about 110,000 centipoise as a 2% aqueous solution at 25.degree. C.
Another class are those whose viscosities are within the range of
about 1,000 to about 5,000 centipoise as a 1% aqueous solution at
25.degree. C. Particularly preferred alkyl-substituted celluloses
are hydroxyethyl cellulose and hydroxypropyl methylcellulose.
Presently preferred hydroxyethyl celluloses are NATRASOL.RTM. 250HX
and 250HHX NF (National Formulary), available from Aqualon Company,
Wilmington, Del., USA.
[0072] Of the polyalkylene oxides that are useful in the dosage
forms of this invention, particularly preferred examples are
poly(ethylene oxide) and poly(propylene oxide). Poly(ethylene
oxide) is a linear polymer of unsubstantiated ethylene oxide.
Poly(ethylene oxide) polymers having viscosity-average molecular
weights of about 2,000,000 and higher are preferred. More preferred
are those with viscosity-average molecular weights within the range
of about 2,000,000 to about 10,000,000, and even more preferred are
those with viscosity-average molecular weights within the range of
about 4,000,000 to about 8,000,000. Poly(ethylene oxide)s are often
characterized by their viscosity in solution. For purposes of this
invention, a preferred viscosity range is about 500 to about
500,000 centipoise for a 2% aqueous solution at 25.degree. C. Three
presently preferred poly(ethylene oxide)s are: [0073] POLYOX.RTM.
NF, grade WSR Coagulant, molecular eight 5 million POINOX.RTM.
grade WSR 301, molecular weight 4 million [0074] POLYOX.RTM. grade
WSR 303, molecular weight 7 million [0075] POLYOX.RTM. grade WSR
N-60K, molecular weight 2 million
[0076] All four are products of Union Carbide Chemicals and
Plastics Company Inc. of Danbury, Conn., USA. In certain
embodiments of this invention, both the core matrix and the shell
matrix are poly(ethylene oxide), and the poly(ethylene oxide) used
for the core has a higher molecular weight than the poly(ethylene
oxide) used for the shell. A preferred range of the
viscosity-average molecular weight ratio (core:shell) is from about
1.15:1 to about 2.5:1. In another embodiment, the shell may have a
higher molecular weight poly(ethylene oxide) than the core. For
this embodiment the preferred range of the viscosity-average
molecular weight ratio (core:shell) is from about 0.2:1 to about
1:1.
[0077] Polysaccharide gums may be either natural and modified
(semi-synthetic). Examples are dextran, xanthan gum, gellan gum,
welan gum and rhamsan gum. Xanthan gum is preferred. Alginates
including, but not limited to, sodium and calcium alginates may
also be used.
[0078] Of the crosslinked polyacrylic acids, the preferred types
are those with a viscosity ranging from about 4,000 to about 40,000
centipoise for a 0.5% aqueous solution at 25.degree. C. Three
presently preferred examples are CARBOPOL.RTM. NF grades 9711,
9741' 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.
[0079] The rate of release of drug from the core and the linearity
of the amount released vs. time curve (i.e., the closeness of the
release profile to zero-order) will vary to some degree with the
thickness of the shell. In most cases, best results will be
achieved with a shell having a thickness that is at least about
0.5% of the longest linear dimension of the dosage form. In
preferred embodiments, the shell thickness is from about 1% to
about 60% of the longest linear dimension of the dosage form. In
further preferred embodiments, the shell thickness is from about
1.5% to about 45% of the longest linear dimension, and in the most
preferred embodiments, the shell thickness is from about 2% to
about 30% of the longest linear dimension.
[0080] The drug that is contained in the dosage form for controlled
release may be 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 an abnormal physiological condition. Examples of
high solubility drugs to which this invention is applicable are
metformin hydrochloride, vancomycin hydrochloride, captopril,
lisinopril, erythromycin lactobionate, ranitidine hydrochloride,
sertraline hydrochloride, ticlopidine hydrochloride, baclofen,
amoxicillin, cefuroxime axetil, cefaclor, clindamycin, levodopa,
doxifluridine, thiamphenicol, tramadol, fluoxitine hydrochloride,
ciprofloxacin, bupropion, and esters of ampicillin. Examples of low
solubility drugs to which this invention is applicable are
saguinavir, ritonavir, nelfinavir, clarithromycin, azithromycin,
ceftazidime, acyclovir, ganciclovir, 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.
[0081] Drugs suitable for delivery by the dosage forms of this
invention include drugs of low solubility in aqueous media, drugs
of moderate solubility, and drugs of high solubility. This
invention is of particular interest for drugs whose solubility in
water is greater than one part by weight of drug in 25 parts by
weight of water. This invention is of further interest for drugs of
solubility greater than one part by weight of drug per five parts
by weight of water.
[0082] 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.
[0083] In preferred embodiments of the invention, the drug will be
present only in the core of the dosage form and not in the shell.
In other embodiments, however, a small amount of the drug will also
be present in the shell as a means of releasing an initial amount
of the drug at a relatively high rate from the dosage form, before
the slow continuous release of drug from the core. In general, the
drug:polymer weight ratio in the shell is equal to or less than
about 0.5 times the drug:polymer weight ratio in the core. In more
preferred embodiments, the drug:polymer weight ratio in the shell
is equal to or less than about 0.25 times the drug:polymer weight
ratio in the core, and in the most preferred embodiments, the
drug:polymer weight ratio in the shell is equal to or less than
about 0.05 times the drug:polymer weight ratio in the core.
[0084] In some embodiments of this invention, particularly those in
which the drug is highly soluble in gastric fluid, the dosage form
contains an additional amount of the drug applied as a quickly
dissolving coating on the outer surface of the dosage form. This
coating is referred to as a "loading dose" and its purpose is to
provide, upon ingestion of the dosage form and without first
diffusing through a polymer matrix, immediate release into the
patient's bloodstream. An optimal "loading dose" is one that 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. When a loading dose coating is
present, the preferred amounts of drug in the coating relative to
the core are those listed in the preceding paragraph with the
coating considered as part of the shell.
[0085] A film coating may also be included on the outer surface of
the dosage form for reasons other than a loading dose. The coating
may thus serve an aesthetic function or a protective function, or
it may make the dosage form easier to swallow or to mask the taste
of the drug.
[0086] Turning to the core itself, the weight ratio of drug to
polymer in the core may vary. Optimal ratios will depend on the
drug solubility, the therapeutic dose, the desired release rate,
the polymer and its molecular weight, and the types and amounts of
any excipients that may be present in the formulation. The
drug:polymer ratio will generally be selected such that at least
about 40% of the drug initially in the core remains unreleased one
hour after immersion of the dosage form in gastric fluid and
substantially all of the drug has been released within about 24
hours after immersion. In preferred embodiments, the ratio will be
selected such that at least about 40% of the drug initially in the
core remains unreleased two hours after immersion has begun, or
more preferably such that at least about 60% of the drug initially
in the core remains unreleased two hours after immersion, and most
preferably such that at least about 70% of the drug initially in
the core remains unreleased two hours after immersion.
[0087] The drug loading may also be characterized in terms of the
weight percent of drug in the core. In preferred embodiments, the
drug constitutes from about 1% to about 98% by weight of the core.
In more preferred embodiments, the drug constitutes from about 5%
to about 95% by weight of the core, and in the most preferred
embodiments, the drug constitutes from about 50% to about 93% by
weight of the core.
[0088] The dosage forms of this invention may assume a variety of
forms, shapes and sizes, provided that the shell upon imbibing
gastric fluid swells to a size that promotes the retention of the
dosage form in the upper GI tract. Preferred dosage forms are
tablets and capsules. Tablets in accordance with this invention
consist of an inner continuous solid core which may be porous but
is a coherent mass for at least a portion of the time that the
tablet is in contact with gastric fluid, surrounded by a continuous
solid shell whose inner surface is in full contact with the outer
surface of the core and which has the attributes of the shell of
this invention as described above. Capsules in accordance with this
invention consist of a core made up of one or more particles or
tablets (of uniform or single-matrix construction) loosely retained
in an unconnected enclosure which serves as the shell and has the
attributes of the shell of this invention as described above. A
shell may also be constructed by first forming a polymer film and
then sealing the film around the core, possibly by heat shrinking.
Still further methods include overcoating or dipping of the core in
a shell-forming solution or suspension.
[0089] Tablets that include a shell as part of the tablet, i.e., a
shell that is in full contact with the outer surface of the core,
are preferred, and can be prepared by a two-stage tabletting
method. The first stage is the preparation of the core, which can
be achieved by conventional techniques, such as mixing,
comminution, and fabrication techniques readily apparent to those
skilled in the manufacture of drug formulations. Examples of such
techniques are: [0090] (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 tabletting 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.; [0091] (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.; [0092] (3)
Granulation such as, but not limited to, fluid bed or high shear
granulation or roller compaction, followed by compression; and
[0093] (4) Extrusion of a paste into a mold or to an extradite to
be cut into lengths.
[0094] The second stage of the preparation is the formation of the
shell. This can be accomplished by any of steps (I), (2), or (3)
performed directly over the core. Advanced tablet presses are
available that include pick-and-place functions that are readily
adaptable to performing the sequential operations needed to form
both the core and the shell.
[0095] When particles are made by direct compression, the addition
of lubricants may be helpful and is sometimes important to promote
powder flow and to prevent capping of the particle (the 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 about 1.degree. % or less 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, tablet hardness, and tablet friability and to reduce
adherence to the die wall.
[0096] 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, which is also referred to as
the postprandial or "fed" mode. The postprandial and interdigestive
(or "fasting") modes are distinguishable by their distinct patterns
of gastroduodenal motor activity which determine the gastric
retention or gastric transit time of the stomach contents.
[0097] 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: [0098] Phase I
is the most quiescent, lasts 45 to 60 minutes, and develops few or
no contractions. [0099] Phase II is marked by the incidence of
irregular intermittent sweeping contractions that gradually
increase in magnitude. [0100] 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.
[0101] Phase IV is a transition period of decreasing activity which
lasts until the next cycle begins.
[0102] The total cycle time of the interdigestive mode is
approximately 90 minutes and thus, powerful peristaltic waves sweep
out the contents of the stomach every 90 minutes. 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.
[0103] The postprandial or fed mode is normally 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.
[0104] The postprandial or fed mode can also be induced
pharmacologically, by the administration of pharmacological agents
that have an effect that is the same or similar to that of a meal.
These fed-mode inducing agents may be administered separately or
they may be included in the dosage form as an ingredient dispersed
in the shell, in both the shell and the core, or in an outer
immediate release coating. Examples of pharmacological fed-mode
inducing agents are disclosed in co-pending U.S. patent application
Ser. No. 09/432,881, filed Nov. 2, 1999, entitled "Pharmacological
Inducement of the Fed Mode for Enhanced Drug Administration to the
Stomach," inventors Markey, Shell, and Berner, the contents of
which are incorporated herein by reference.
[0105] The following examples are offered by way of illustration
rather than limitation.
EXAMPLES
Example 1
Compressed Core-and-Shell Tablets of Metformin Hydrochloride
[0106] This example illustrates the preparation and release rate
behavior of a tablet in accordance with the invention, with a
600-mg core and a 200-mg shell, both of polyethylene oxide) and
additionally containing metformin hydrochloride in the core only,
in a quantity amounting to 62.5% by weight of the core. The term
"compressed core-and-shell tablet" is used herein to denote a
tablet formed by first compressing the core in a tablet press from
a powdered mixture and then using a suitable tablet press to
compress another powdered mixture over the core to form the shell.
This is distinct from methods of forming a capsule.
[0107] To prepare the core, a powder blend was prepared by mixing
together metformin hydrochloride (9.374 parts by weight), POLYOX
301 (molecular weight approximately 4,000,000, 5.478 parts by
weight), and magnesium stearate (0.151 parts by weight). A 600-mg
portion of the mixture was placed on a Carver Auto C Press and
compressed at 2500 lb pressure (11,100 Newtons) with a zero-second
dwell time and pump speed set at 100%, using a modified capsule die
set measuring 0.274.times.0.725 inch (0.70.times.1.84 cm), to form
the core. The core thus formed was placed in a tablet die measuring
0.375.times.0.75 inch (0.95.times.1.90 cm), and surrounded by
POLYOX 303 powder (molecular weight approximately 7,000,000) with
between 60 and 68 mg of POLYOX 303 underneath the core and 134 to
137 mg of POLYOX 303 on the sides and on top of the core, for a
total shell weight of approximately 200 mg. The core and
surrounding polymer were then pressed at 2500 lb pressure (11,100
Newtons).
[0108] To estimate the release rate of the resulting shell-encased
tablets into gastric fluid, the tablets were placed in modified
simulated gastric fluid at pH 1.2 at 37.degree. C., and the release
of the metformin into the acid was measured as a function of time
using a modified USP Type H (paddle with cones) Dissolution
Apparatus rotating at 60 rpm. Metformin released into the solution
was detected by reverse-phase HPLC. The amounts released at
intervals of 2, 4, 6, and 8 hours are listed in Table I below and
demonstrate a release rate that approaches zero order.
TABLE-US-00001 TABLE I Metformin Hydrochloride Release Study Time
from Start of Test Amount Released (hours) (Percentage of Total in
Core) 2 20.6 4 41.7 6 58.5 8 70.7
Example 2
Compressed Core-and-Shell Tablets of Metformin Hydrochloride
[0109] This example is a further illustration of the preparation
and release rate characteristics of a metformin hydrochloride
tablet in accordance with the invention. The procedure of Example I
was repeated, using nearly identical quantities of materials,
except that the polyethylene oxide) used as the core matrix was
POLYOX Coagulant (molecular weight approximately 5,000,000) rather
than POLYOX 301 (molecular weight approximately 4,000,000). The
release rate results are listed in Table II, which shows that the
release rate again approached zero order.
TABLE-US-00002 TABLE II Metformin Hydrochloride Release Study Time
from Start of Test Amount Released (hours) (Percentage of Total in
Core) 2 17.3 4 37.4 6 55.3 8 69.5
Example 3
Compressed Core-and-Shell Tablets of Metformin Hydrochloride
[0110] This example is a further illustration of the preparation
and release rate characteristics of a metformin hydrochloride
tablet in accordance with the invention, similar to that of
Examples 1 and 2. In this example, however, metformin hydrochloride
constituted 83.3% by weight of the core (and present only in the
core, as in Examples 1 and 2), and the higher molecular weight
poly(ethylene oxide) (POLYOX 303) was used for the core while the
lower molecular weight poly(ethylene oxide) (POLYOX 301) was used
for the shell. Otherwise, the procedures were essentially the same
as those of Examples and 2, except that the die for the outer shell
measured 0.3125.times.0.75 inch (0.79.times.1.90 cm). The results
are listed in Table III, which shows that the release rate again
approached zero order.
TABLE-US-00003 TABLE III Metformin Hydrochloride Release Study Time
from Start of Test Amount Released (hours) (Percentage of Total in
Core) 2 21.5 4 45.6 6 65.4 8 78.2
Example 4
Compressed Core-and-Shell Tablets of Metformin Hydrochloride
[0111] This example is a further illustration of the preparation
and release rate characteristics of a metformin hydrochloride
tablet in accordance with the invention, the tablet in this case
being larger than those of the preceding examples, with a 700 mg
core and a 300 mg shell. The drug loading was 71.3% by weight
(present in the core only), and polymer matrices were the same as
those of Example 3. The dies in the tabletting press measured
0.274.times.0.725 inch (0.70.times.1.84 cm) for the core and
0.375.times.0.75 inch (0.95.times.1.90 cm) for the shell.
[0112] The results are listed in Table IV, which shows that the
release rate again approached zero order.
TABLE-US-00004 TABLE IV Metformin Hydrochloride Release Study Time
from Start of Test Amount Released (hours) (Percentage of Total in
Core) 2 13.2 4 31.2 6 48.3 8 61.5
Example 5
Compressed Core-and-Shell Tablets of Metformin Hydrochloride
[0113] A further metformin hydrochloride tablet may be prepared in
accordance with the invention with a 600-mg core of hydroxypropyl
cellulose and a 200-mg shell of poly(ethylene oxide), using a shell
die measuring 0.3125.times.0.75 inch (0.79.times.1.90 cm). The
metformin hydrochloride (residing only in the core) will amount to
83.3% by weight of the core. The hydroxypropyl cellulose in this
example is KLUCEL.RTM. HPC HF.
Example 6
Core-Coated Tablets of Metformin Hydrochloride
[0114] This example illustrates the preparation and release rate
characteristics of a metformin hydrochloride tablet using the same
materials as Example 5, except with a 700 mg core and a 300 mg
shell, and a drug loading (in the core only) of 71.4% by weight.
The results are listed in Table VI, which shows that the release
rate again approached zero order.
TABLE-US-00005 TABLE VI Metformin Hydrochloride Release Study Time
from Start of Test Amount Released (hours) (Percentage of Total in
Core) 2 35.5 4 61.3 6 76.0 8 84.4
Example 7
Compressed Core-and-Shell Tablets of Metformin Hydrochloride (REF.
NB 36, PP. 31; NB 34, PP. 92-95)
[0115] This example illustrates the preparation and release rate
characteristics of a metformin hydrochloride tablet similar to
those of the preceding examples, except that the shell was
constructed of a mixture of poly(ethylene oxide) (of low molecular
weight relative to the same polymer in the core) and EUDRAGIT.RTM.
L100-55 methacrylic polymers (Rohm America, Inc., Piscataway, N.J.
USA). The weight ratio of poly(ethylene oxide) to methacrylic
polymer in the shell was 1.48:1, the poly(ethylene oxide) in the
core was POLYOX 303 (molecular weight 7,000,000) and the
poly(ethylene oxide) in the shell was POLYOX 301 (molecular weight
4,000,000). The drug was present in the core only, at 83.3% by
weight of the core. The results are listed in Table VII, which
shows that the release rate again approached zero order.
TABLE-US-00006 TABLE VII Metformin Hydrochloride Release Study Time
from Start of Test Amount Released (hours) (Percentage of Total in
Core) 2 30.7 4 56.6 6 74.4 8 84.1
Example 8
Compressed Core-and-Shell Tablets of Metformin Hydrochloride
[0116] This example illustrates the preparation and release rate
characteristics of metformin hydrochloride tablets similar to those
of the preceding examples, except that three different polymers or
polymer blends were used to form the shells of the tablets: [0117]
Shell A Polymer: POLYOX 301 [0118] Shell B Polymer: blend of POLYOX
301 and EUDRAGIT L100-55, POLYOX:EUDRAGIT weight ratio 3.9:1 [0119]
Shell C Polymer: blend of POLYOX 301 and KOLLIDON 90F
(polyvinylpyrrolidone, BASF AG, Ludwigshafen, Germany),
POLYOX:KOLLIDON weight ratio 3.9:1
[0120] The core in each case was 600 mg and the shell was 200 mg,
and the drug (present only in the core) constituted 83.3% by weight
of the core. The results are listed in Table VIII, which shows that
the release rate approached zero order at early times before the
driving force was depleted.
TABLE-US-00007 TABLE VIII Metformin Hydrochloride Release Study
Amount Released Time from Start of Test (Percentage of Total in
Core) (hours) Shell A Shell B Shell C 1 15.1 11.3 15.7 2 34.0 29.3
38.9 3 55.3 45.3 54.3 4 82.8 54.5 60.1 6 93.1 61.7 63.8
Example 9
Compressed Core-and-Shell Tablets of Metformin Hydrochloride
[0121] This example illustrates the preparation and release rate
characteristics of a metformin hydrochloride tablet similar to
those of the preceding examples, except with a lower proportion of
shell to core. In particular, the core was 700 mg and the shell was
200 mg. The drug loading in the core was 71.4% by weight (with no
drug contained in the shell), the core polymer matrix was POLYOX
303, and the shell polymer matrix was POLYOX 301. The results are
listed in Table IX, which shows that the release rate approached
zero order.
TABLE-US-00008 TABLE IX Metformin hydrochloride Release Study Time
from Start of Test Amount Released (hours) (Percentage of Total in
Core) 2 20.3 4 40.2 6 56.7 8 70.8
Example 10
Compressed Core-and-Shell Tablets of Metformin Hydrochloride
[0122] This example illustrates the preparation and release rate
characteristics of metformin hydrochloride tablets similar to those
of the Example 9, except using poly(ethylene oxide) of the same
molecular weight in both the core and the shell. The core in these
tablets was 800 mg in size, the shell was 250 mg in size, and the
drug loading in the core was 79.2% by weight (with no drug in the
shell). The results are listed in Table X, which shows that the
release rate approached zero order.
TABLE-US-00009 TABLE X Metformin Hydrochloride Release Study Time
from Start of Test Amount Released (hours) (Percentage of Total in
Core) 2 15.9 4 34.6 6 50.2 8 63.9
Example 11
Compressed Core-and-Shell Tablets of Metformin Hydrochloride with
Various Polymers
[0123] This example demonstrates the release rates of metformin
hydrochloride tablets in accordance with this invention, using
various combinations of polymers for the core and shell. In each
case, the core and shell were 600 mg and 200 mg in weight,
respectively, each containing 1.0% by weight magnesium stearate,
and the drug loading in the core was 83.3% by weight (and no drug
in the shell). The apparatus used for measuring the release rate
was a USP Type 1 (10-mesh baskets) Dissolution Apparatus rotating
at 100 rpm with 900 mL of modified simulated gastric fluid (at pH
1.2), and the amount of drug released was detected by reverse-phase
HPLC. The various polymers used were as follows (all molecular
weights are viscosity average molecular weights and are
approximate): [0124] POLYOX.RTM. 301--poly(ethylene oxide),
molecular weight 4,000,000, Union Carbide Corporation, Danbury,
Conn., USA [0125] POLYOX.RTM. 303--poly(ethylene oxide), molecular
weight 7,000,000, Union Carbide Corporation, Danbury, Conn., USA
[0126] POLYOX.RTM. Coagulant--poly(ethylene oxide), molecular
weight 5,000,000, Union Carbide Corporation, Danbury, Conn., USA
[0127] NATROSOL.RTM. 250 HHX Pharm hydroxyethyl cellulose,
Brookfield viscosity of 1% solution at 25.degree. C.: 3,500-5,500
cps, Hercules, Incorporated, Aqualon Division, Wilmington, Del. USA
[0128] KLUCEL.RTM. HXF--hydroxypropyl cellulose, Brookfield
viscosity of 1% solution at 25.degree. C.: 1,500-3,000 cps,
Hercules, Incorporated, Aqualon Division, Wilmington, Del. USA
[0129] The release rate results are shown in Table XI.
TABLE-US-00010 TABLE XI Metformin Hydrochloride Release Study
Amount of Drug Released (Percentage of Total in Core) Core Polymer
Shell Polymer 2 h 4 h 6 h 8 h POLYOX 301 POLOYOX 303 30 65 87 96
POLYOX POLYOX 301 29 63 86 97 Coagulant NATROSOL NATROSOL 250 HHX
39 68 86 95 250 HHX KLUCEL HXF NATROSOL 250 HHX 29 56 74 86
Example 12
Capsules of Metformin Hydrochloride
[0130] This example illustrates the preparation and release rate
characteristics of a cylindrical capsule in which the capsule shell
serves as the shell of the invention, loosely surrounding a
compressed tablet that serves as the core containing the drug. The
drug used in this preparation was metformin hydrochloride.
[0131] The tablet was prepared by blending 3.329 parts by weight of
metformin hydrochloride, 0.630 parts by weight of POLYOX 303 and
0.039 parts by weight of magnesium stearate to from a 400-mg core.
The blend was pressed into tablet form on a Carver Auto C Press at
1500 lb pressure (6,670 Newtons) with a zero-second dwell time and
100% pump speed using a 15.35.times.5.6 mm die. To prepare the
capsule, POLYOX 301 was melted between two glass plates that had
been previously sprayed with mold release (Dry Film PTFE,
McMaster-Carr). The dry poly(ethylene oxide) film that was thus
formed was cut into rectangles and wrapped around TEFLON.RTM. bars
to form a 0.25 inch (0.64 cm) diameter cylinder. One end of each
cylinder was melt-sealed between two glass plates in a 100.degree.
C. oven. One tablet was placed inside each cylinder, and the
unsealed end of the cylinder was then melt-sealed. Another set of
capsules was prepared by wrapping each tablet in a sheet of the
POLYOX 301 film (prepared between glass plates as described above)
and pinching the ends of the wrapped film to close the capsule.
[0132] The release of the drug from the wrapped capsules (the
second set described in the preceding paragraph) into modified
simulated gastric fluid at 37.degree. C. was measured as a function
of time using an USP Type I (10 mesh baskets) Dissolution Apparatus
rotating at 100 rpm. The drug was detected by reverse phase HPLC at
2, 4, 6, and 8 hours. The results are listed in Table XII below,
showing a release rate that approaches zero order.
TABLE-US-00011 TABLE XII Metformin Hydrochloride Release Study Time
from Start of Test Amount Released (hours) (Percentage of Total in
Core) 2 0.8 4 11.7 6 32.9 8 59.1
Example 13
Compressed Core-and-Shell Tablets of Riboflavin-5'-Phosphate
[0133] This example illustrates the preparation and release rate
characteristics of a tablet in accordance with the invention, in
which the drug is riboflavin-5'-phosphate (present only in the
core). The core was prepared by compression tabletting and the
shell was formed around the core in the same manner, both as
described above in Examples 1 through 11. The core in this tablet
was 700 mg in weight, the shell was 200 mg in weight, and the drug
loading in the core was 11.1% by weight. In addition to the drug,
the core formulation contained 60.3% by weight of lactose
monohydrate, 27.6% POLYOX 303, and 1.0% magnesium stearate. The
shell was POLYOX 301 with 1.0% magnesium stearate. The detection of
released riboflavin-5'-phosphate was accomplished by UV
spectroscopy.
[0134] The release rate results are listed in Table XIII, which
shows a release profile that is faster than zero order,
TABLE-US-00012 TABLE XIII Riboflavin-5'-Phosphate Release Study
Time from Start of Test Amount Released (hours) (Percentage of
Total in Core) 2 1.3 4 2.7 6 4.8 8 8.0
Example 14
Compressed Core-and-Shell Tablets of Aspirin
[0135] This example illustrates the preparation and release rate
characteristics of a tablet in accordance with the invention by the
procedures of Examples 1-11 above, in which the drug is aspirin
(present only in the core). The core in this tablet was 400 mg in
weight, the shell was 200 mg in weight, and the aspirin loading was
81.3% by weight of the core. In addition to the aspirin, the core
formulation contained 17.7% POLYOX 303, and 1.0% magnesium
stearate. The shell was 39.268% POLYOX 301 and 59.667% EUDRAG1T
L110-55 with 1.065% magnesium stearate.
[0136] Release rate data were determined by release into 900 mL of
acetate buffer at pH 4.5, as specified in the USP method for
immediate-release aspirin, and a USP Type I Dissolution Apparatus
was used. The released aspirin was detected by reverse-phase HPLC.
The results are listed in Table XIV, showing a release rate that
approaches zero order.
TABLE-US-00013 TABLE XIV Aspirin Release Study Time from Start of
Test Amount Released (hours) (Percentage of Total in Core) 1.5 0.90
3 2.62 4.5 4.57 6 6.75
Example 15
In Vivo Comparison Study
[0137] This example presents a comparison between the release rate
characteristics of a compressed core-and-shell tablet of the
present invention in which the drug is present only in the core and
an immediate-release formulation of the same drug. The drug in each
case was metformin hydrochloride, and the two tablets were as
follows: [0138] Tablet A: Core: 600 mg, of which 78.33% by weight
was metformin hydrochloride, [0139] 15.67% by weight was POLYOX
303, 5% miscellaneous excipients present in GLUCOPHAGE.RTM.
(Bristol-Myers Squibb), and 1% by weight was magnesium stearate
[0140] Shell: 200 mg, of which 99% by weight was POLYOX 301 and 1%
by weight was magnesium stearate [0141] Tablet B: GLUCOPHAGE.RTM.,
Bristol-Myers Squibb, containing 500 mg metformin hydrochloride
with 6% miscellaneous excipients
[0142] Three healthy adult human subjects were each administered
one of each of the tablets with 100 mL water in the morning
immediately after a standard specified breakfast. A standard
specified lunch was taken by each subject. Water was drunk by each
subject at a rate of 60 mL per hour. Vital signs (blood pressure
and heart rate) and blood samples for glucose measurements were
taken prior to dosing, and at 2, 4, and 8 hours after dosing on the
first day.
[0143] All urine voids were collected from each subject for 72
hours after dosing, following emptying of the bladder prior to
dosing. Urine collections were made immediately prior to dosing and
at accumulated 0-1, 1-2, 2-4, 4-6, 6-8, 8-10, and 10-12 hours after
dosing. Subsequent urine collections were accumulated over 12-hour
periods for the next two days. The urine samples were then analyzed
for metformin hydrochloride by an HIPLC method adapted from that
described in Caine, G., Biopharm. Drug Dispos. 14 (1993): 257-263.
The results, expressed in terms of the excretion rate of metformin
hydrochloride in mg/h vs. time after dosage (in hours), are shown
in FIG. 1, where the triangle-shaped points are the data from
Tablet A (representing the present invention) and the
diamond-shaped points are the data from Tablet B. The Tablet A
curve demonstrates a clear advantage over the Tablet B curve by
virtue of the lower slope and essentially linear shape of the
Tablet A curve up through five hours (with continued delivery
through 7 hours), By avoiding an initial burst of metformin, the
present invention lessens the occurrence of gastrointestinal and
taste disturbances.
[0144] 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.
* * * * *