U.S. patent application number 10/741177 was filed with the patent office on 2004-09-30 for ingestible formulations for transient, noninvasive reduction of gastric volume.
Invention is credited to Burnett, Daniel R., Edelman, Peter G..
Application Number | 20040192582 10/741177 |
Document ID | / |
Family ID | 32685301 |
Filed Date | 2004-09-30 |
United States Patent
Application |
20040192582 |
Kind Code |
A1 |
Burnett, Daniel R. ; et
al. |
September 30, 2004 |
Ingestible formulations for transient, noninvasive reduction of
gastric volume
Abstract
Provided are ingestible polymeric formulations and oral dosage
forms for the reduction of gastric volume in the treatment of
overweight and obese patients. The formulation includes an
acid-sensitive, gelatin coating over a dehydrated hydrophilic
polymer. When ingested, the acid-sensitive coating is quickly
dissolved by gastric secretions and the hydrophilic polymer is
exposed to the aqueous environment of the gastric milieu. The
polymer absorbs water and expands to the point that will not allow
the polymer to pass beyond the pyloric valve, and the expanded
polymer is therefore trapped in the stomach.
Inventors: |
Burnett, Daniel R.; (Menlo
Park, CA) ; Edelman, Peter G.; (Mukilteo,
WA) |
Correspondence
Address: |
GRAY CARY WARE & FREIDENRICH LLP
153 TOWNSEND
SUITE 800
SAN FRANCISCO
CA
94107
US
|
Family ID: |
32685301 |
Appl. No.: |
10/741177 |
Filed: |
December 19, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60468131 |
May 6, 2003 |
|
|
|
60434367 |
Dec 19, 2002 |
|
|
|
Current U.S.
Class: |
424/465 ;
424/464; 514/4.8 |
Current CPC
Class: |
A61K 31/78 20130101;
A61P 3/04 20180101; A61K 9/2022 20130101; A61F 5/003 20130101; A61F
5/0036 20130101; A61K 38/16 20130101; A61K 9/4866 20130101; A61K
9/2833 20130101; A61K 31/715 20130101; A61K 38/38 20130101; A61K
9/2063 20130101; A61K 31/7088 20130101; A61K 9/0065 20130101; A61K
2800/546 20130101; A61K 9/2027 20130101; A61K 31/765 20130101; A61K
9/205 20130101 |
Class at
Publication: |
514/002 ;
424/464 |
International
Class: |
A61K 009/20; A61K
038/39 |
Claims
What is claimed is:
1. An oral dosage form useful for gastric volume reduction
comprising a polymer that (i) swells upon absorbing water from
gastric fluid to increase its size thereby promoting its gastric
retention, (ii) maintains its physical integrity in a stomach for
at least 2 hours, and (iii) is degradable by an intestinal enzyme
or exposure to an intestinal pH, wherein the dosage form is in the
form of a tablet or capsule that maintains the polymer in a packed
mass prior to its ingestion and then rapidly disintegrates in the
gastric fluid to permit the polymer to disperse in the stomach and
wherein the dosage form does not contain a drug.
2. The oral dosage form of claim 1, wherein the polymer is selected
from the group consisting of polyvinyl alcohol,
poly(ethyloxazoline), polyvinylacetate-polyvinylalcohol copolymers,
poly(2-hydroxyethylacrylate- ), poly(2-hydroxyethylmethacrylate),
polyacrylic acid, and copolymers thereof; polysaccharides, water
soluble proteins, and polynucleic acids.
3. The oral dosage form of claim 2, wherein the polysaccharides is
selected from the group consisting of carboxymethyl cellulose,
hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulo- se, chitosan, hyaluronic acid, xanthan
gum, starch, maltodextrins, corn syrup, and alginates.
4. The oral dosage form of claim 2, wherein the protein is albumin
or gelatin.
5. The oral dosage form of claim 1, wherein the polymer is
crosslinked with a crosslinker.
6. The oral dosage form of claim 5, wherein the crosslinker is a
homobifunctional crosslinker or a heterobifunctional
crosslinker.
7. The oral dosage form of claim 6, wherein the crosslinker
contains a reactive group selected from the group consisting of
glycidyl ethers, substituted and unsubstituted
N-hydroxy-succinimides, isocyanates, acids, esters, acid chlorides,
maleimides, and acrylates.
8. The oral dosage form of claim 1, wherein the polymer is cross
linked through a crosslinker which provides the polymer with a
degradation susceptibility towards an intestinal enzyme or an
intestinal pH.
9. The oral dosage form of claim 5, wherein the crosslinker is an
oligoester.
10. The oral dosage form of claim 5, wherein the crosslinker is a
diacid that forms an alpha-omega ester linkage.
11. The oral dosage form of claim 5, wherein the crosslinker is
diacid chloride.
12. The oral dosage form of claim 5, wherein the crosslinker is
selected from the group consisting of polymers and copolymers of
lactic acid, glycolic acid, trimethylene carbonate, and
caprolactone.
13. The oral dosage form of claim 1, wherein the polymer is
non-covalently cross linked.
14. The oral dosage form of claim 1, wherein the oral dosage form
contains an enteric coating.
15. The oral dosage form of claim 1, wherein the polymer degrades
faster in the intestinal than in the stomach.
16. The oral dosage form of claim 1, wherein the polymer degrades
faster in an environment with intestinal pH than in an environment
with gastric pH.
17. The oral dosage form of claim 1, wherein the intestinal enzyme
is selected from the group consisting of lipase, amylase, trypsin,
chymotrypsin, elastase, carboxypeptidase, nucleases,
aminopeptidases, disaccharidases, maltase, sucrase, and
lactase.
18. The oral dosage form of claim 1, wherein the polymer is a
biocompatible polymer.
19. The oral dosage form of claim 1 further comprises an agent
wherein the agent stabilizes the polymer in an gastric
environment.
20. The oral dosage form of claim 1 further comprises an agent
wherein the agent stabilizes the polymer in an gastric environment
and is sensitive to an intestinal pH.
21. A polymeric formulation comprising a hydrophilic polymer that
(i) swells upon absorbing water from gastric fluid to increase its
size thereby promoting its gastric retention, (ii) maintains its
physical integrity in a stomach for at least 2 hours, and (iii)
degrades faster in the intestine than in the stomach, wherein the
polymer is crosslinked through a crosslinker which provides the
polymer with a degradation susceptibility towards an intestinal
enzyme or an intestinal pH.
22. The polymeric formulation of claim 21, wherein the polymer is
selected from the group consisting of polyvinyl alcohol,
poly(ethyloxazoline), polyvinylacetate-polyvinylalcohol copolymers,
poly(2-hydroxyethylacrylate- ), poly(2-hydroxyethylmethacrylate),
polyacrylic acid, and copolymers thereof; polysaccharides, water
soluble proteins, and polynucleic acids.
23. The polymeric formulation of claim 21, wherein the
polysaccharides are selected from the group consisting of
carboxymethyl cellulose, hydroxyethylcellulose,
hydroxypropylcellulose, hydroxypropylmethylcellulo- se, chitosan,
hyaluronic acid, xanthan gum, starch, maltodextrins, corn syrup,
and alginates.
24. The polymeric formulation of claim 21, wherein the protein is
albumin or gelatin.
25. The polymeric formulation of claim 21, wherein the crosslinker
is a homobifunctional crosslinker or a heterobifunctional
crosslinker.
26. The polymeric formulation of claim 25, wherein the crosslinker
contains a reactive group selected from the group consisting of
glycidyl ethers, substituted and unsubstituted
N-hydroxy-succinimides, isocyanates, acids, esters, acid chlorides,
maleimides, and acrylates.
27. The polymeric formulation of claim 21, wherein the crosslinker
is a diacid that forms an alpha-omega ester linkage.
28. The polymeric formulation of claim 21, wherein the formulation
contains an enteric coating.
29. The polymeric formulation of claim 21, wherein the intestinal
enzyme is selected from the group consisting of lipase, amylase,
trypsin, chymotrypsin, elastase, carboxypeptidase, nucleases,
aminopeptidases, disaccharidases, maltase, sucrase, and
lactase.
30. The polymeric formulation of claim 21, wherein the polymer
degrades faster in an environment with intestinal pH than in an
environment with gastric pH.
31. The polymeric formulation of claim 21, wherein the polymer is
in a form of polymeric matrix.
32. The polymeric formulation of claim 21, wherein the polymer is
in a form of particle.
33. The polymeric formulation of claim 21, further comprises a drug
dispersed in the polymer.
34. The polymeric formulation of claim 21, wherein the formulation
is an oral dosage form.
35. The polymeric formulation of claim 21, wherein the formulation
is a tablet or capsule.
36. The polymeric formulation of claim 21, wherein the polymer is a
biocompatible polymer.
37. The polymeric formulation of claim 21 further comprises an
agent wherein the agent stabilizes the polymer in an gastric
environment.
38. The polymeric formulation of claim 21 further comprises an
agent wherein the agent stabilizes the polymer in an gastric
environment and is sensitive to an intestinal pH.
39. A method of reducing gastric volume comprising administering to
a subject in need of such treatment an oral dosage form of claim
1.
40. A method of reducing gastric volume comprising administering to
a subject in need of such treatment a polymeric formulation of
claim 21.
41. A method of reducing gastric volume comprising administering to
a subject in need of such treatment an oral dosage form of claim 1
and optionally a formulation comprising an intestinal enzyme.
42. The method of claim 41, wherein the intestinal enzyme is
selected from the group consisting of lipase, amylase, trypsin,
chymotrypsin, elastase, carboxypeptidase, nucleases,
aminopeptidases, disaccharidases, maltase, sucrase, and
lactase.
43. A method of reducing gastric volume comprising administering to
a subject in need of such treatment a polymeric formulation of
claim 21 and optionally a formulation comprising an intestinal
enzyme.
44. The method of claim 43, wherein the intestinal enzyme is
selected from the group consisting of lipase, amylase, trypsin,
chymotrypsin, elastase, carboxypeptidase, nucleases,
aminopeptidases, disaccharidases, maltase, sucrase, and
lactase.
45. A method for delivering a drug comprising administering to a
subject in need of the drug the polymeric formulation of claim 21,
wherein the formulation further contains the drug dispersed in the
polymer.
46. The method of claim 45, wherein the drug is an antibiotic.
Description
CROSS REFERENCE TO RELATED APPLICATION(S)
[0001] This application claims the benefit of priority under 35
U.S.C. .sctn. 119(e) of U.S. Serial No. 60/468,131 filed May 6,
2003, and U.S. Serial No. 60/434,367 filed Dec. 19, 2002, the
entire contents of which are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The invention relates generally to polymeric formulations,
especially polymers useful for weight loss methods and devices.
BACKGROUND OF THE INVENTION
[0003] Obesity is a condition of epidemic proportions in the United
States. Recent government studies have indicated that up to 40% of
Americans are obese, and of those, almost 20% are morbidly obese.
In and of itself, however, obesity is not the problem. The
difficulty with obesity arises with the multiple conditions,
including cardiovascular disease, diabetes, and obstructive sleep
apnea, that occur with this ubiquitous problem. There have been
many attempts to treat obesity, most of which either have serious
side effects or are ineffective.
[0004] For example, various diets, supplements, and pharmaceuticals
have been developed in an attempt to treat obesity. Typically,
these types of treatment have not provided any significant benefit.
Indeed, some weight loss pharmaceuticals have been associated with
many serious life-threatening conditions. To date, there are no
commercially available supplements or drugs on the market that have
been found to have significant success in weight reduction.
[0005] Recognizing this, the medical industry has turned to more
extreme measures, the best example of which is the Roux-En-Y
gastric bypass. More effective, but also potentially lethal, this
major surgery with 1-2% mortality, 6 month recovery period and a
price tag of tens of thousands of dollars, is still increasing in
its popularity due to the inefficacy of other treatments. Gastric
reduction, or simply removing a large segment of the stomach, is
similar to gastric bypass in its potentially lethal
combinations.
[0006] Progress was made, however, with the introduction of
intragastric balloons, as described in U.S. Pat. Nos. 4,739,758;
5,234,454; 4,485,805; and 4,899,747. These balloons, designed to be
placed surgically or endoscopically, are constructed of silicone
and inflated once positioned in the stomach, thereby reducing
effective gastric volume. These balloons were found to be effective
in increasing the sensation of fullness in the patient and reducing
weight by reducing intake.
[0007] Unfortunately, these intragastric balloons still required an
invasive procedure and also generated ulcers and other
complications due to having the inflexible silicone surface in
contact with the stomach wall in the same orientation for months.
Also, these devices require further invasive surgery or endoscopic
procedures to reduce or increase the balloon volume in the common
event that the balloon was filled too much or too little.
[0008] A further advancement was proposed by Ratjen in German
Patent No. NDN-050003290517 in which a compressed cellulose
derivative was utilized. This compressed cellulose derivative was
coated with gelatin and was designed to be expanded once ingested
into the stomach. The difficulty with this derivation is that
cellulose is broken down at roughly equivalent rates in the stomach
and small bowel. Thus, any partially digested masses of cellulose
that have been passed from the stomach will remain intact in the
intestine and cause a possible small bowel obstruction. This risk
outweighs the possible benefit, in many cases making the therapy
undesirable.
[0009] A similar difficulty is likely to be associated with the
therapy described in U.S. Pat. Nos. 5,750,585 and 6,271,278. The
polymers described therein do not exhibit differential degradation
rates in the stomach and the intestine, thereby placing patients at
risk for a small bowel obstruction. Therefore, there is a need in
the industry to develop more methods and devices, especially
noninvasive methods and devices useful for weight loss and/or
weight management.
SUMMARY OF THE INVENTION
[0010] The present invention is based, in part, on the discovery
that certain polymers can be modified so that they have a higher
degradation rate in an intestine like environment than in a gastric
like environment, whose enzymatic and pH make up is different from
each other. Accordingly the present invention provides polymeric
formulations capable of being retained in a stomach for a certain
period of time and being rapidly degraded upon entering into an
intestine. The polymeric formulations provided by the present
invention can be used for various applications including delivery
of therapeutics, e.g., in a stomach over a period of time, and
reduction of gastric volume in the treatment of overweight and
obese patients.
[0011] In one embodiment of the invention, there are provided oral
dosage forms useful for gastric volume reduction. Such oral dosage
forms, include, for example, a polymer that (i) swells upon
absorbing water from gastric fluid to increase its size thereby
promoting its gastric retention, (ii) maintains its physical
integrity in a stomach for about 4 hours to 30 hours, and (iii) is
degradable by an intestinal enzyme or exposure to an intestinal pH,
e.g., 8.0, wherein the dosage form is in the form of a tablet or
capsule that maintains the polymer in a packed mass prior to its
ingestion and then rapidly disintegrates in the gastric fluid to
permit the polymer to disperse in the stomach and wherein the
dosage form does not contain a drug.
[0012] In another embodiment, there are provided polymeric
formulations including a hydrophilic polymer that (i) swells upon
absorbing water from gastric fluid to increase its size thereby
promoting its gastric retention, (ii) maintains its physical
integrity in a stomach for at least 2 hours, e.g., from 2 to 30
hours, and (iii) degrades faster in an intestine than a stomach,
wherein the polymer is cross linked through a linker which provides
the polymer with a sensitivity towards an intestinal enzyme.
[0013] In still further embodiments, there are provided methods for
reducing gastric volume in a subject. Such methods can be
performed, for example, by administering to a subject in need
thereof an oral dosage form described herein. In an alternative
embodiment, such methods can be performed by administering to a
subject in need thereof a polymeric formulation described
herein.
[0014] In yet another embodiment, there are provided methods for
delivering a drug. Such methods can be performed, for example, by
administering to a subject in need of the drug a polymeric
formulation described herein, wherein the formulation further
contains the drug dispersed in the polymer.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 shows a cross-sectional view of an oral dosage form
in tablet form.
[0016] FIG. 2 shows cross-sectional views of the stomach
illustrating the ingestion of the polymeric formulation of the
invention and its subsequent expansion in the stomach.
[0017] FIG. 3 shows cross-sectional views of the stomach
illustrating the ingestion of multiple tablets of the polymeric
formulation of the invention and subsequent expansion in the
stomach.
[0018] FIG. 4 shows cross-sectional views of the stomach
illustrating the presence of multiple tablets polymeric
formulations of the invention in various stages of degradation with
one tablet sufficiently degraded to pass the pyloric valve and be
rapidly degraded in the small intestine milieu.
[0019] FIG. 5 shows cross-sectional views of the stomach
illustrating the presence of a hydrated polymer and the ingestion
of a depolymerizer.
DETAILED DESCRIPTION OF THE INVENTION
[0020] The present invention provides polymeric formulations
capable of being retained in a gastric like environment for a
certain period of time and being rapidly degraded upon entering
into an intestine like environment. Specifically the present
invention provides oral dosage forms and polymeric formulations
useful for reduction of gastric volume in the stomach or delivering
therapeutics to a subject, e.g., human.
[0021] The polymers utilized in the oral dosage forms and
formulations of the invention are capable of being degraded
differentially in an intestine like environment as compared to a
gastric like environment. For example, the polymers of the present
invention degrades faster in an environment with an enzymatic
and/or pH make up characteristic of the intestine than that of the
stomach. Usually such differential degradation is based on pH
sensitivity of an entity or an entity's sensitivity to one or more
intestinal specific substances, such as, bile, lipases, and other
intestinal enzymes or entities and the like.
[0022] Sensitivity to intestinal enzymes or pH can be obtained by
any suitable means available to one skilled in the art, e.g.,
chemical modification. For example, sensitivity to intestinal
enzymes, e.g., lipases can be achieved through chemical
modification of either natural entities, e.g., alginate, cellulose,
and the like or modification of artificially synthesized entities,
e.g., an acrylate. By acquiring one or more lipase-sensitive, fatty
acid-like polymerizable groups and/or crosslinking groups, an
entity can have optimal differential degradation characteristics in
which degradation occurs much more rapidly in the intestine as
compared to the gastric environment. Alternatively, differential
degradation can be accomplished via incorporation of components
that are selectively degraded in the intestine, e.g., fats, and
need not be limited to proteins and polymers.
[0023] The oral dosage form or polymeric formulation of the present
invention usually can include an acid-sensitive, gelatin coating
over a dehydrated hydrophilic polymer. When ingested, the
acid-sensitive coating is quickly dissolved by gastric secretions
and the hydrophilic polymer is exposed to the aqueous environment
of the gastric milieu. The polymer absorbs water and expands to the
point that will not allow the polymer to pass beyond the pyloric
valve, and the expanded polymer is therefore trapped in the
stomach. The expanded polymer remains in the stomach until acids
and proteases or other enzymes in the stomach reduce its volume
such that it is able to pass the pyloric valve into the
intestine.
[0024] Although the polymeric formulation of the present invention
is designed to be somewhat resistant to degradation by gastric
secretions, it remains highly susceptible to the environment of the
intestine, e.g., intestinal enzymes or pH. Thus, while the
polymeric formulation of the present invention can remain in the
stomach for many hours or even days, once it has passed into the
intestine, it is rapidly degraded, thereby reducing the risk of
small bowel obstruction. Since the polymer of the present invention
degrades much more rapidly in an intestinal environment than in the
stomach, the potential risk of small bowel obstruction is
significantly reduced or virtually eliminated.
[0025] In addition, the formulations and dosage forms of the
invention are designed to expand to a diameter that is sufficient
to prevent passage beyond the pyloric valve, but will not cause
small bowel obstruction or rupture, e.g., a diameter no greater
than about 6 cm or so. Due to this size restriction, use of the
present invention entails ingestion of multiple tablets until the
subject begins to feel a sensation of fullness. The present
invention avoids the complications of excessive gastric distension
that is common after intragastric balloon placement. Once the oral
dosage forms and polymeric formulations described herein pass
beyond the pyloric valve and are degraded in the intestine, the
subject simply ingests additional tablets.
[0026] According to one feature of the present invention, it
provides oral dosage forms of polymers useful for gastric volume
reduction. The oral dosage form of the present invention includes a
polymer that (i) swells upon absorbing water from gastric fluid to
increase its size thereby promoting its gastric retention, (ii)
maintains its physical integrity in the stomach for a period of
time and (iii) is degradable by an intestinal enzyme or exposure to
an intestinal pH. The dosage form of the present invention can be
in the form of a tablet or capsule, e.g., maintains the polymer in
a packed mass prior to its ingestion and then rapidly disintegrates
in the gastric fluid to permit the polymer to disperse in the
stomach. In one embodiment, the dosage form of the present
invention does not contain a drug. In another embodiment, the oral
dosage form of the present invention maintains its physical
integrity for at least 2 hours, 4 hours, or 6 hours. In yet another
embodiment, the oral dosage form of the present invention maintains
its physical integrity from about 4 hours to 30 hours, 6 hours to
24 hours, or 8 hours to 16 hours.
[0027] As used herein, the phrase "gastric volume reduction" means
1) any temporary reduction of available gastric volume, e.g., any
temporary reduction of gastric volume available to an ingested
subject, 2) any temporary reduction of gastric capability with
respect to content intake, or 3) any temporary sensation of gastric
fulfillment or fullness.
[0028] As used herein, the phrase "physical integrity", when used
with reference to the polymers described herein, means that the
polymers do not significantly or appreciably dissolve, erode or
otherwise decompose or degrade, e.g., the polymer chains remain
substantially intact, and, if the polymers are crosslinked, that
the crosslinks remain substantially intact, thereby providing a
three-dimensional polymeric network.
[0029] Polymers contemplated for use in the practice of the
invention are typically water-soluble polymers or co-polymers,
e.g., polymers or copolymers capable of swelling upon contacting
with water. Such polymers include, for example, polyvinyl alcohol,
poly(ethyloxazoline), poly(2-hydroxy ethylacrylate), poly(2-hydroxy
ethylmethacrylate), polyacrylic acid, polysaccharides, proteins,
polynucleic acids, and the like. In one embodiment, the polymers of
the present invention is polyvinylacetate-polyvinylalcohol
copolymers, poly(2-hydroxyethyl acrylate) and copolymers,
poly(ethyloxazoline) and copolymers, or
poly(2-hydroxyethylmethacrylate) and copolymers.
[0030] As used herein, the term "polysaccharides" includes
polysaccharides, polysaccharoses, sugars, and the like. Exemplary
polysaccharides include starch, sodium starch glycolate, alginic
acid, cellulose, carboxymethylcellulose, hydroxyethylcellulose,
hydropropylcellulose, hydroxypropylmethylcellulose, ethylcellulose,
carageenan, chitosan, chondroitin sulfate, heparin, hyaluronic
acid, pectinic acid, chitosan, hyaluronic acid, xanthan gum,
starch, maltodextrins, corn syrup, alginates, and the like.
Proteins contemplated for use include, but are not limited to,
water soluble proteins, e.g., albumin, gelatin, and the like.
[0031] According to one embodiment of the present invention, the
oral dosage form or polymeric formulation of the present invention
includes a polymer that is biocompatible and/or pH sensitive, e.g.,
sensitive to intestinal pH. Such oral dosage form or polymeric
formulation typically includes a dehydrated combination of a
biocompatible polymer, e.g., an alginate and a
solubilizer/stabilization agent, e.g., xanthan gum, propylene
glycol alginate, and the like (to allow for maintenance of a firm
solid polymer within the gastric environment) covered with an
acid-sensitive coating (e.g., a gelatin). Alginate itself
precipitates to a certain degree in the acidic environment of the
stomach and so likely requires an additional component in order to
prevent precipitation. In one embodiment, the additional component
is propylene glycol alginate. In another embodiment, the
solubilizer/stabilization agent is sensitive to intestinal pH. For
example, propylene glycol alginate forms a solid in the stomach but
becomes viscous at intestinal pH. Typically, about half of the
polymer of alginate with propylene glycol alginate is degraded
after 3 to 4 hours at intestinal pH.
[0032] According to another embodiment of the present invention,
the polymers described herein are crosslinked. Crosslinking can be
achieved either through a covalent crosslinker or non-covalent
crosslinker. Typical the covalent crosslinker of the present
invention includes, for example, homobifunctional crosslinkers with
reactive molecules of diglycidyl ethers, substituted and
unsubstituted diN-hydroxy succinimides (NHS), diisocyanates,
diacids, diesters, diacid chlorides, dimaleimides, diacrylates, and
the like. Heterobifunctional crosslinkers can also be utilized.
Heterobifunctional crosslinkers usually include molecules that
contain different functional groups to accomplish the crosslinking,
for example, combining NHS and maleimide, an acid and ester,
etc.
[0033] Non-covalent crosslinkers, e.g., based on ionic, hydrogen
bonding and other intramolecular associations are also contemplated
for use in the practice of the invention. The non-covalent
crosslinkers of the present invention include chitosan/polyacrylic
acid, polyacrylic acid/polyethylene glycol (at low pH), polyacrylic
acid copolymers and hydroxyl containing polymers, polymers
containing carboxylic acid pendant groups, pluronics (ethylene
oxide-propylene oxide-ethylene oxide (EO-PO-EO) triblock
copolymers), metal crosslinked polymers, ionomers, and the like.
For example, the non-covalent crosslinkers of the present invention
can be based on hydrophobic associations. Such non-covalent
crosslinkers can be any suitable system that demonstrates lower
critical association temperatures including, without any
limitation, pluronics (triblock copolymers of ethylene oxide and
propylene oxide structured as EO-PO-EO), which can form gels at
elevated temperatures such as body temperature and convert to a
soluble form at a lower temperature such as room temperature.
[0034] In one embodiment, the crosslinker of the present invention
contains one or more hydrolysable groups. In another embodiment,
the crosslinker of the present invention is susceptible to
hydrolysis, e.g., either by chemical means or by biological means
such as enzyme catalyzed hydrolysis. In yet another embodiment, the
crosslinker of the present invention is a polymer or copolymer of
lactic acid, glycolic acid, trimethylene carbonate, caprolactone,
or any other hydrolysable esters.
[0035] In still another embodiment, the crosslinker of the present
invention includes a linker between the crosslinking
functionalities that renders the ultimate crosslinked polymer a
degradation susceptibility towards an intestinal enzyme, e.g.,
susceptibility to degradation by an intestinal enzyme. These types
of crosslinkers typically include basic sensitive groups or
C.sub.12-C.sub.22 aliphatic unsaturated hydrocarbon linkers, since
an intestinal enzyme such as a lipase recognizes fatty acid type
structures. In some embodiments, these linkers include diacids that
form alpha-omega ester linkages between polymer chains, thereby
crosslinking the polymer chains. In addition, oligoesters having
alternating PEG spacers can be utilized. Indeed, PEG chains or
other hydrophilic spacers can be incorporated into the crosslinkers
of the present invention to control hydrophilicity and swelling of
the polymers provided by the present invention.
[0036] According to another embodiment of the present invention,
the polymer used in the present invention can be any polymer that
degrades faster in an environment with an intestinal pH, e.g., pH
8. In one embodiment, the polymer of the present invention can be
crosslinked hydrogel formulations that are held together by
physical crosslinks between acid groups and ether oxygens. Examples
of acid containing polymers include carboxymethylcellulose,
agarose, polyacrylic acid and copolymers, etc. Polymers containing
ether oxygens include, for example, any PEGs (branched or linear),
any PEG copolymers including, without any limitation, pluronics,
polysaccharides, starches, etc.
[0037] In another embodiment, the polymer of the present invention
includes any polymer containing pendant acid groups or chemically
hydrolysable groups. For example, polymers containing one or more
pendant acid groups, e.g., carboxymethylcellulose, agarose,
polyacrylic acid and copolymers etc. and/or chemically hydrolysable
groups, e.g., anhydrides, ketals, acetals, and esters can be
covalently crosslinked. In general, as the pH increases in an
environment the hydrolyzability of the ester groups in these
polymers can increase due to their increased accessibility caused
by the polymeric swelling.
[0038] With specific reference now to the figures, FIG. 1 shows a
cross-sectional view of an oral dosage form of the invention in
tablet form. Specifically, FIG. 1 shows the ingestible compound 1
including a dissolvable coating 2 surrounding the desiccated
polymeric formulation 3. In FIG. 2A and 2B, the tablet is shown
functioning in the stomach. In FIG. 2A, the ingestible tablet 1 of
FIG. 1 is shown passing the lower esophageal sphincter 5 into the
stomach. In FIG. 2B, the tablet 1 is shown after its coating 2 has
dissolved and the tablet 1 has expanded to its hydrated form 4. The
expanded polymer 4 cannot pass either the lower esophageal
sphincter 5 or the pyloric sphincter 6 resulting in its retention
in the stomach.
[0039] In FIG. 3A-B, multiple tablets are shown functioning in the
stomach. In FIG. 3A, the ingestible tablets 1 of FIG. 1 are shown
passing the lower esophageal sphincter 5 into the stomach. In FIG.
3B, the tablets 1 are shown after their coatings 2 have dissolved
and the tablets 1 have expanded to their hydrated forms 4. The
expanded polymers 4 cannot pass either the lower esophageal
sphincter 5 or the pyloric sphincter 6 resulting in its retention
in the stomach. Obese patients can take as many tablets 1 as are
required to produce a sensation of fullness.
[0040] In FIG. 4A, multiple polymeric masses 4 are shown in the
stomach in various stages of degradation. One of the masses 10 has
degraded sufficiently to pass the pyloric sphincter 6. In FIG. 4B,
the polymeric masses 4 are shown in the stomach again with the
smallest mass being rapidly degraded in the small intestine to its
polymeric precursors 7 after passing the pyloric sphincter 6.
[0041] In FIG. 5A-B, the polymer is shown being de-polymerized
after its placement in the stomach. In FIG. 5A, the hydrated
polymer 4, which cannot pass either the lower esophageal sphincter
5 or the pyloric sphincter 6, is shown in the stomach as
de-polymerizer 8 is introduced. The de-polymerizer 8 is shown in
tablet form, but may also be in liquid form. In FIG. 5B the
de-polymerizer has acted on the polymer 4 resulting in
de-polymerization to the polymeric precursors 7. In the case of the
alginates and other pH-sensitive groups, the de-polymerizer 8 is a
compound which simply raise the pH. In the case of lipid-modified
polymers (e.g., acrylates, alginates, cellulose, and the like), the
de-polymerizer 8 is a commercially available pharmaceutical grade
lipase.
[0042] The oral dosage forms and polymeric formulations described
herein typically achieve 90% of equilibrium swelling in about 6-18
hours, and typically have completely disappeared from the gut in
about 3-10 days. The dosage forms and formulations typically
contain an enteric coating so that expansion occurs only in the
stomach, and not in the esophagus. Invention oral dosage forms and
polymeric formulations typically exhibit swelling resulting in a
size increase of about 200%-1000%.
[0043] The present invention allows for the safe, controlled
distension of the stomach in a noninvasive and completely
reversible manner. The oral dosage forms described herein usually
include an enterically coated polymeric formulation that is small
enough to be swallowed in its pre-gastric state. Once the polymeric
formulation reaches the stomach, the coating is dissolved by
gastric secretions and the polymer is hydrated resulting in
significant swelling, enough so that the resulting hydrated polymer
cannot pass the pyloric valve and remains in the stomach.
[0044] The oral dosage forms are designed such that the obese
patient can simply continue to ingest additional dosage forms until
a sensation of fullness is achieved. The polymer then degrades over
time and/or is de-polymerized by ingestion of a specific substance,
e.g., a de-polymerizer including, without any limitation, an agent
that is capable of raising the pH in the stomach or an intestinal
enzyme or derivatives thereof.
[0045] Examples of intestinal enzymes include amylase, which
hydrolyzes starch into a mixture of maltose and glucose; lipase,
which hydrolyzes ingested fats into a mixture of fatty acids and
monoglycerides (and its action maybe enhanced by the detergent
effect of bile); trypsin, which cleaves peptide bonds on the
C-terminal side of arginines and lysines; chymotrypsin, which cuts
on the C-terminal side of tyrosine, phenylalanine, and tryptophan
residues (the same bonds as pepsin, whose action ceases when the
NaHCO.sub.3 raises the pH of the intestinal contents); elastase,
which cuts peptide bonds next to small, uncharged side chains such
as those of alanine and serine; carboxypeptidase, which removes,
one by one, the amino acids at the C-terminal of peptides;
nucleases, which hydrolyze ingested nucleic acids (RNA and DNA)
into their component nucleotides; aminopeptidases, which attack the
amino terminal (N-terminal) of peptides producing amino acids;
disaccharidases, which convert disaccharides into their
monosaccharide subunits; maltase which hydrolyzes maltose into
glucose, sucrase, which hydrolyzes sucrose (common table sugar)
into glucose and fructose; and lactase which hydrolyzes lactose
(milk sugar) into glucose and galactose.
[0046] The invention is desirable since the oral dosage forms are
not metabolically active and do not contain significant calories.
Indeed, once the polymer has been de-polymerized and/or degraded,
it simply passes through the gastrointestinal tract and is
excreted.
[0047] A further advantage provided by the invention is the
temporary nature of the gastric volume reduction. With current
treatments that result in reduction of gastric volume, including
gastric bypass, gastric reduction, and intragastric balloons, a
significant difficulty exists: adaptation of the stomach to its
distended state. By allowing the stomach volume to be temporarily
reduced and then returned to its original volume before being
reduced again, the present invention reduces the occurrence of
stomach distension.
[0048] In addition to use in weight loss, the oral dosage forms and
polymeric formulations described herein are useful as safe,
effective drug delivery systems. The dosage forms and formulations
described herein allow for a longer residence time of a drug in the
stomach without the risk of small bowel obstruction. Drugs that are
taken orally on an hourly basis could instead be ingested on a
daily basis using the oral dosage forms and polymeric formulations
described herein. The inner core of the oral dosage forms and
polymeric formulations described herein would not contain any drug
as this would cause a large bolus of drug release with passage and
rapid dissolution into the intestine, but the outer layers can be
infused with the drug as they must be dissolved prior to any
intestinal passage.
[0049] In one embodiment, the polymeric formulation provided by the
present invention is useful for delivering drugs that, as a solid,
are irritating to the gastrointestinal tract such as the mucosal
surface or efficacious when administered in a sustained manner. For
example, various antibiotics, especially antibiotics useful for
eradicating Helicobacter pylori from the submucosal tissue of the
gastrointestinal tract can be delivered by the polymeric
formulations of the present invention.
[0050] The invention provides methods for reducing gastric volume
in a subject in need thereof. The methods include administering to
the subject an effective amount of the oral dosage forms described
herein. The dosage forms can be administered orally in the form of
tablets, capsules, solutions, emulsions or suspensions. The
compositions may be prepared in conventional forms, for example,
capsules, tablets. Pharmaceutical formulations containing compounds
of this invention can be prepared by conventional techniques, e.g.,
as described in Remington's Pharmaceutical Sciences, 1985.
[0051] In one embodiment, the polymers of the present invention is
formed into a packed mass for ingestion, e.g., encapsulated as a
"hard-filled capsule" or a "soft-filled capsule" using any suitable
encapsulating procedures and materials. The encapsulating material
should be highly soluble so that the polymer particles can be
rapidly dispersed in the stomach after the capsule is ingested. In
another embodiment, the polymer of the present invention is
formulated with a soluble binder and compressed into a tablet or
pill.
[0052] The pharmaceutical carrier or diluent employed may be a
conventional solid or liquid carrier. Examples of solid carriers
are lactose, sucrose, talc, gelatin, agar, pectin, acacia,
magnesium stearate, stearic acid, or lower alkyl ethers of
cellulose. Examples of liquid carriers are syrup, peanut oil, olive
oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene
or water. The carrier or diluent may include any sustained release
material known in the art, such as glyceryl monostearate or
distearate, alone or mixed with a wax.
[0053] If a solid carrier is used for oral administration, the
preparation may be tabletted or placed in a hard gelatin capsule in
powder or pellet form. The amount of solid carrier will vary
widely, but will usually be from about 25 mg to about 1 gm. If a
liquid carrier is used, the preparation may be in the form of a
syrup, emulsion, soft gelatin capsule, or sterile injectable liquid
such as an aqueous or non-aqueous liquid suspension or
solution.
[0054] Tablets are prepared by mixing the active ingredient with
pharmaceutically inert, inorganic or organic carrier, diluents,
and/or excipients. Examples of such excipients which can be used
for tablets are lactose, maize starch or derivatives thereof, talc,
stearic acid or salts thereof. Examples of suitable excipients for
gelatin capsules are vegetable oils, waxes, fats, semisolid, and
liquid polyols.
[0055] The pharmaceutical products can additionally contain any of
a variety of added components, such as, for example, preservatives,
solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,
colorants, flavorings, buffers, coating agents, antioxidants,
diluents, and the like.
[0056] Although the invention has been described with reference to
the above examples, it will be understood that modifications and
variations are encompassed within the spirit and scope of the
invention. Accordingly, the invention is limited only by the
following claims.
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