U.S. patent application number 15/403784 was filed with the patent office on 2017-05-04 for carbidopa/levodopa gastroretentive drug delivery.
The applicant listed for this patent is INTEC PHARMA LTD.. Invention is credited to Giora Carni, David Kirmayer, Elena Kluev, Eytan Moor, Nadav Navon.
Application Number | 20170119664 15/403784 |
Document ID | / |
Family ID | 41376643 |
Filed Date | 2017-05-04 |
United States Patent
Application |
20170119664 |
Kind Code |
A1 |
Navon; Nadav ; et
al. |
May 4, 2017 |
CARBIDOPA/LEVODOPA GASTRORETENTIVE DRUG DELIVERY
Abstract
A gastroretentive drug formulation for the sustained release of
an active agent in the gastrointestinal tract comprises internal
layer or compartment comprising an active agent and one or more
pharmaceutical excipients, of which at least one is a polymer and
two membranes forming together an envelope around the inner
membrane, each membrane comprising at least one polymeric
combination of an enteric polymer which is not soluble in gastric
juice, and an hydrophilic swelling polymer, and at least one
plasticizer.
Inventors: |
Navon; Nadav; (Rehovot,
IL) ; Moor; Eytan; (Jerusalem, IL) ; Kirmayer;
David; (Maale Adumim, IL) ; Kluev; Elena;
(Jerusalem, IL) ; Carni; Giora; (Tel Aviv,
IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
INTEC PHARMA LTD. |
Jerusalem |
|
IL |
|
|
Family ID: |
41376643 |
Appl. No.: |
15/403784 |
Filed: |
January 11, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14995611 |
Jan 14, 2016 |
9554991 |
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15403784 |
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14715077 |
May 18, 2015 |
9259387 |
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14995611 |
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14322436 |
Jul 2, 2014 |
9072663 |
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14715077 |
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12937955 |
Jan 31, 2011 |
8771730 |
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PCT/IB2009/005691 |
Apr 17, 2009 |
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14322436 |
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61120051 |
Dec 4, 2008 |
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61046261 |
Apr 18, 2008 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0065 20130101;
A61K 45/06 20130101; A61P 31/02 20180101; A61P 35/00 20180101; A61K
31/195 20130101; A61P 1/00 20180101; A61K 9/282 20130101; A61K
9/4891 20130101; A61K 9/2873 20130101; A61K 9/48 20130101; A61K
9/2866 20130101; A61K 9/7007 20130101; A61K 9/4866 20130101; A61P
3/00 20180101; A61K 9/4875 20130101; A61K 31/198 20130101; A61K
9/2846 20130101; A61K 2300/00 20130101; A61K 9/4808 20130101; A61K
9/2886 20130101; A61K 31/198 20130101; A61P 3/04 20180101; A61P
25/16 20180101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 9/28 20060101 A61K009/28; A61K 9/48 20060101
A61K009/48; A61K 31/198 20060101 A61K031/198 |
Claims
1. A degradable, multi-layered gastroretentive drug formulation for
the sustained release of an active agent in the stomach and
gastrointestinal tract of a patient, comprising: an internal layer
comprising an active agent and a degradable polymer composition
which is not instantly soluble in gastric fluid, the internal layer
including a first side and an opposing second side; and at least
one membrane covering the internal layer, the membrane comprising
at least one polymeric combination of a hydrophilic polymer and a
polymer, insoluble in gastric media, the membranes being hydratable
at a rate greater than the internal layer; the membrane being
directly secured to and covering both sides of the internal layer
and having a predetermined length greater than 20 mm in a planar
orientation, the membrane and internal layer being arranged in an
accordion folded orientation sufficiently compact to be placed
within a capsule dissolvable within the stomach; the membrane and
internal layer developing sufficient mechanical force to unfold
from the initial accordion folded orientation to a length of at
least 20 mm within 30 minutes of being exposed to gastric medium,
the membrane permitting passage of gastric media from the
environment to the internal layer and permitting passage of the
active agent from the internal layer through the membrane to the
environment.
2. The gastroretentive drug formulation of claim 1, wherein the
membrane and internal layer unfold to a length of at least 20 mm
within 15 minutes of being exposed to gastric fluid.
3. The gastroretentive drug formulation of claim 1, wherein the
internal layer has a mechanical strength described with Young's
modulus ranging from about 0.5 to 15 Kgf/mm/.sup.2 and stress of
about 0.03 to about 0.6 Kgf/mm.sup.2 after 1 hour in simulated
gastric fluid.
4. The gastroretentive drug formulation of claim 1, wherein the
membrane includes two separate membranes, each membrane being
directly joined together along an outer periphery of the membranes,
the entire internal layer being located completely between the
membranes, the membranes being secured to the internal layer along
a portion of at least one surface of the internal layer.
5. The gastroretentive drug formulation of claim 4, wherein the
membranes are joined together with ultrasonic welding.
6. The gastroretentive drug formulation of claim 5, wherein the
membranes are joined together with the internal layer with
ultrasonic welding along a region adjacent the outer periphery of
the internal layer.
7. The gastroretentive drug formulation of claim 6, wherein a
central portion of the surface of the internal layer is essentially
free from ultrasonic welds.
8. The gastroretentive drug formulation of claim 4, wherein the
internal layer and membranes are free of an additional adhesive
member.
9. The gastroretentive drug formulation of claim 1, wherein the
multi-layered gastroretentive drug formulation for the sustained
release of an active agent in the gastrointestinal tract comprises:
an internal layer comprising an active agent and a degradable
polymer composition which is not instantly soluble in gastric
fluid, the internal layer including a first side and an opposing
second side, a first and second membrane coveting the internal
layer, the membrane including at least one polymeric combination of
a hydrophilic polymer and a polymer, insoluble in gastric media,
the membranes being hydratable at a rate greater than the internal
layer, the first and second membrane having a width and length,
greater than a width and length of the internal layer, the first
and second membranes being ultrasonically welded or otherwise
affixed or attached directly together about the periphery of the
first and second membranes, the first membrane being attached to a
first side of the internal layer, the second membrane being
attached to the second side of the internal layer, the internal
layer and first and second membranes having a predetermined length
greater than 20 mm in a planar orientation, the membrane and
internal layer being arranged in an accordion folded orientation
sufficient to be placed within a capsule dissolvable within the
stomach, the ultrasonic welds having sufficient mechanical strength
to remain intact upon being exposed to gastric medium.
10. The gastroretentive drug formulation of claim 11, wherein the
internal layer and first and second outer layers include a central
region that is substantially free of ultrasonic welds.
11. The gastroretentive drug formulation of claim 12, wherein the
ultrasonic welds between the membrane and internal layer do not
penetrate entirely through the internal layer.
12. The gastroretentive drug formulation of claim 11, wherein the
ultrasonic weld pattern between the membranes and internal layer is
not continuous.
13. The gastroretentive drug formulation of claim 12, wherein the
ultrasonic welds on the periphery of the membranes form a skirt
region that surrounds but does not capture the internal layer.
14. The gastroretentive drug formulation of claim 13, wherein the
internal layer and first and second outer layers include a central
region that is substantially free of ultrasonic welds.
15. The gastroretentive drug formulation of claim 11, wherein the
ultrasonically welded internal layer and membranes have a
mechanical strength, described with Young's modulus from about 0.05
to 0.4 Kgf/mm.sup.2 after 1 hour in simulated gastric fluid.
16. The gastroretentive drug formulation of claim 15, wherein the
membrane and. internal layer unfold to a length of at least 20 mm
within 15 minutes of being exposed to gastric fluid.
17. The gastroretentive drug formulation of claim 16, wherein the
length of the membrane in the planar orientation is at least 30
mm.
18. A biodegradable, multi-layered gastroretentive drug formulation
for the sustained release of an active agent in the
gastrointestinal tract, comprising: an internal layer comprising an
active agent and a degradable hydrophilic polymer and a degradable
enteric polymer which is substantially insoluble at pH less than
5.5, and a plasticizer, at least one membrane covering the internal
layer, the membrane including at least one polymeric combination of
a hydrophilic polymer and a polymer, insoluble in gastric media,
and at least one plasticizer, the membrane swelling in the presence
of gastric medium one of the materials in each of the internal
layer and membrane being capable of being ultrasonically welded
together, the membrane being directly secured to and covering both
sides of the internal layer and having a predetermined length
greater than 20 mm in a planar orientation, the membrane and
internal layer being arranged in an accordion folded orientation
sufficient to be placed within a capsule dissolvable within the
stomach, the membrane permitting passage of gastric fluid from the
stomach to the internal layer and permitting passage of gastric
fluid and the active agent from the internal layer through the
membrane to the stomach, the membrane and internal layer develop
sufficient mechanical force to unfold from the accordion folded
orientation to a length of at least 20 mm within 30 minutes of
being exposed to gastric fluid.
19. The gastroretentive drug formulation of claim 18, wherein the
enteric polymer in the internal layer is selected from the group
consisting of cellulose acetate phthalate, hypromelose phthalate,
hydroxy-propyl methylcellulose acetate succinate, polyvinyl acetate
phthalate and methylmethacrylate-methacrylic acid copolymers.
20. The gastroretentive drug formulation of claim 18, wherein the
polymeric combination in the outer membranes comprises gelatin.
21. The gastroretentive drug formulation of claim 18, wherein the
enteric polymer in the membrane is selected from the group
consisting of one or more type of polymethacrylate USP.
22. The gastroretentive drug formulation of claim 18, wherein the
membranes comprise propylene glycol as a plasticizer.
23. The gastroretentive drug formulation of claim 22, wherein the
amount of gelatin in the membrane is an amount of between about 20%
and about 45% of the total outer membrane composition.
24. The gastroretentive drug formulation of claim 18, wherein the
internal layer has a mechanical strength described with Young's
modulus of from about 0.5 to about 15 Kgf/mm.sup.2 find stress of
from about 0.03 to about 0.6 Kgf/mm.sup.2 after 1 hour in simulated
gastric fluid.
25. The gastroretentive drug formulation of claim 18, wherein the
outer membrane swells at a rate faster than the inner membrane
causing the accordion folded membrane and internal layer to unfold
in gastric medium.
26. The gastroretentive drug formulation, of claim 25, wherein the
outer membrane that swells at a rate faster than the inner membrane
thus causing the accordion folded membrane and internal layer to
unfold in gastric medium is lightly affixed or attached to the said
inner membrane to exert the force resulting in unfolding.
27. The gastroretentive drug formulation of claim 1, wherein the
gastroretentive drug formulation is fully degradable within 3 hours
in simulated intestinal fluid.
28. The gastroretentive drug formulation of claim 1, wherein the
gastroretentive drug formulation provides gastric retention of an
active agent for up to 24 hours under low or medium calorie diet to
humans.
29. The gastroretentive drug formulation of claim 1, wherein the
active agent is a drug for the local treatment of the
gastrointestinal tract, such as drugs for the treatment of local
infections, obesity and GI pathologies.
30. The gastroretentive drug formulation of claim 1, wherein at
least one additional layer is affixed to the outer membrane on one
or two sides of the gastroretentive drug formulation, and where
this layer comprises a drug or a combination of drugs, together
with one or more additives selected from the group consisting of
water soluble polymers, a plasticizer, a solubilizing agent
intended for immediate release of the drug in the stomach, a
disintegrant and a glidant.
31. The gastroretentive drug formulation of claim 29, wherein the
active agent comprises a drug selected from the group consisting of
levodopa and carbidopa.
32. The gastroretentive drug formulation of claim 31, where the
formulation contains 250 mg of levodopa and 50 mg of carbidopa.
33. The gastroretentive drug formulation of claim 32, wherein 70 mg
of the levodopa and 25 mg carbidopa are formulated as an immediate
release component, whereas the rest of the carbidopa and the
levodopa are released in a controlled manner over 8-10 hours.
34. The gastroretentive drug formulation of claim 31, where the
formulation contains 375 mg of levodopa and 50 mg of carbidopa.
35. The gastroretentive drug formulation of claim 34, wherein 100
mg of the levodopa and 25 mg carbidopa are formulated as ail
immediate release component, and wherein the rest of the carbidopa
and the levodopa are released in a controlled manner over 8-10
hours.
36. The gastroretentive drug formulation of claim 1, wherein the
inner compartment comprises one layer intended as backbone to
increase the mechanical strength of the formulation, and to this
layer are attached on one or two sides additional layer or layers
containing the active ingredient or ingredients and an inactive
ingredient and intended for the controlled release of the drug and
wherein these layers are covered by and contained between two
layers of outer membrane as described previously in these
claims.
37. A biodegradable, multi-layered gastroretentive drug formulation
for the sustained release of an active agent in the
gastrointestinal tract, comprising: an internal layer comprising an
active agent and a degradable hydrophilic polymer which is not
instantly soluble in gastric fluid and a degradable enteric polymer
which is substantially insoluble at pH less than 5.5, and a
plasticizer, the internal layer including a first side and an
opposing second side, a first and second membrane covering the
internal layer, the membranes including at least one polymeric
combination of a hydratable swelling polymer and an enteric
polymer, and at least one plasticizer, the membrane swelling in the
presence of gastric fluid, one of the materials in each of the
internal layer and membranes being capable of being ultrasonically
welded together, the membranes being directly secured to and
covering both sides of the internal, layer and having a
predetermined length, greater than 20 mm in a planar orientation,
the membranes and internal layer being arranged in an accordion
folded orientation sufficient to be placed within a capsule
dissolvable within the stomach, the membranes and internal layer
developing sufficient mechanical force to unfold from the accordion
folded orientation to a length of at least 20 mm within 30 minutes
of being exposed to gastric fluid, the first and second membranes
having a width and length greater than a width and length of the
internal layer, the first and second membranes being ultrasonically
welded directly together about the periphery of the first and
second membranes, the first membrane being ultrasonically welded to
a first side of the internal layer, the second membrane being
ultrasonically welded to the second side of the internal layer, the
membrane permitting passage of gastric fluid from the stomach to
the internal layer and permitting passage of gastric fluid and the
active agent from the internal layer through the membrane to the
stomach, the internal layer and first and second membranes having a
predetermined length greater than 20 mm in a planar orientation,
the membrane and internal layer being arranged in an accordion
folded orientation sufficient to be placed within a capsule
dissolvable within the stomach, the ultrasonic welds having
sufficient mechanical strength to remain intact upon being exposed
to gastric medium.
38. A gastroretentive drug formulation for the sustained release of
an active agent in the gastrointestinal tract comprising: i.) an
internal layer or compartment comprising an active agent, and one
or more pharmaceutical excipients, of which at least one is a
polymer; i.i.) two membranes forming together an envelope around
the inner membrane, each membrane comprising at least one polymeric
combination of an hydrophilic polymer and a polymer, insoluble in
gastric media, and at least one plasticizer; and iii.) optionally
an additional layer covering each outer membrane comprising a
powder or a film that prevents adherence of the outer membrane onto
itself when folded inside the capsule.
39. The gastroretentive drug formulation of claim 38 further
including one or two layers comprising the active agent and a
soluble polymer that provides for the immediate release of the
active agent and being attached to the outside of one outer
membrane or two outer membranes or part of the outer membrane.
40. The gastroretentive drug formulation of claim 38 wherein, the
internal layer and membranes effectively unfold from an accordion
folded orientation and are stable in acidic pH for up to 24 hours
and completely biodegrade after 3 hours in simulated intestinal
fluid.
41. The gastroretentive drug formulation of claim 39, wherein,, the
polymer in the internal layer is selected from the group consisting
of a degradable hydrophilic polymer which is not instantly soluble
in gastric fluid and a degradable enteric polymer which is
substantially insoluble at pH less than 5.5.
42. The gastroretentive drug formulation of claim 41, wherein the
enteric polymer in the internal layer is polymethacrylate
copolymer.
43. The gastroretentive drug formulation of claim 41, wherein the
enteric polymer is at least one of cellulose acetate phthalate,
hypromelose phthalate, hydroxypropyl methylcellulose acetate
succinate, polyvinyl acetate phthalate or cellulose acetate
trimellitate.
44. The gastroretentive drug formulation of claim 38, wherein the
active agent and the polymer are uniformly distributed in the
internal layer.
45. The gastroretentive drug formulation of claim 38, wherein the
polymeric combination in the outer membranes comprises gelatin and
cellulose acetate succinate.
46. The gastroretentive drug formulation of claim 38, wherein the
enteric polymer in the membranes is polymethacrylate copolymer USP
type A.
47. The gastroretentive drug formulation of claim 38, wherein the
enteric polymer in the membranes is polymethacrylate copolymer USP
type C.
48. The gastroretentive drug formulation of claim 38, wherein, the
plasticizer in the outer membranes is propylene glycol.
49. The gastroretentive drug formulation of claim 38, wherein the
internal layer or compartment, the membranes and the optional
additional layers or the immediate release layers are joined by
applying ultrasonic welding.
50. The gastroretentive drug formulation of claim 38, wherein, the
internal layer provides at least 50% of the mechanical strength of
the welded internal layer and membranes when wetted with gastric
medium.
51. The gastroretentive drug formulation of claim 38, wherein the
GRDF reaches its eventual maximum strength within less than two
hours in simulated gastric fluid.
52. The gastroretentive drug formulation of claim 38, wherein, the
internal layer has a planar-accordion geometry that unfolds to at
least 50% of its original length within 30 minutes in simulated
gastric fluid.
53. The gastroretentive drug formulation of claim 38, wherein the
internal layer and membranes are fully degradable within 3 hours in
simulated intestinal fluid.
54. The gastroretentive drug formulation of claim 38, wherein the
GRDF comprises an internal layer that provides gastric retention
for up to 24 hours under low or medium calorie diet.
55. The gastroretentive drug formulation of claim 38 is designed
for oral administration and are compacted or folded into a standard
size capsule which is easily swallowed.
56. The gastroretentive drug formulation of claim 38, wherein the
active ingredient or ingredients are incorporated in the internal
layer as one or more of solid solutions, powders, grains, spheres,
particles, microparticles, nanoparticles, multiparticulates, or
microcapsules.
57. The gastroretentive drug formulation of claim 38, wherein the
active agent has a narrow window of absorption in the
gastrointestinal tract, the active agent being one or more of a
therapeutic nucleic acid sequence, a therapeutic protein or
peptide, a peptidomimetic drug, a nucleoside analogue, an aminoacid
analogue, an antibiotic, a therapeutic ion, a vitamin, a
bronchodilator, an anti-gout agent, an anti-hypertensive agent, a
diuretic agent, an anti-hyperlipidemic agent, an ACE inhibitor, a
CNS active agent, an anti-tumor agent, an histamine (H2) blocker, a
bismuth salt or a synthetic prostaglandin.
58. The gastroretentive drug formulation of claim 57, wherein the
active agent is levodopa.
59. The gastroretentive drug formulation of claim 57, wherein the
active agent is a drug for the local treatment in the
gastrointestinal tract, or for the treatment of local infections,
gastrointestinal diseases and symptoms, metabolic disorders, local
cancers or cancer-related diseases.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims priority to U.S. Provisional
Patent Applications Nos. 61/046,261, filed on Apr. 18, 2008, and
61/120,051, filed Dec. 4, 2008, and which are incorporated herein
by reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention is related to multi-layered,
biodegradable gastroretentive drug formulations for the controlled
release of active pharmaceutical agents with a narrow absorption
window in the upper gastrointestinal tract, that act locally in the
gastrointestinal tract, or that possess other rationales for
gastric retentive administration. Further, the invention describes
multi-layered, biodegradable gastroretentive drug formulations for
the immediate release and sustained release of such active agents.
The gastroretentive drug formulations of the invention may be
administered orally to a mammal for the systemic or local treatment
of a pathologic condition or deficiency.
BACKGROUND OF THE INVENTION
[0003] Administration of some drugs, such as amino and nucleic acid
analogs, peptides peptidomimetic drugs, various antibiotics,
various anti-viral drugs, and some others, to a mammal, results in
delivery to gastrointestinal tract and absorption of these drugs
only in specific regions of the gastrointestinal tract, like the
stomach, duodenum and small intestine, such that only drugs
delivered to proximity of these regions are absorbed. This
phenomenon is frequently referred to as "narrow absorption window"
(NAW). Various other drugs' action sites are located in specific
regions of the gastrointestinal tract. In addition, various other
drugs, such as water-insoluble drugs, possess pharmaceutical
rationales for gastric retentive administration. Moreover, the
transit time through every region of gastrointestinal tract is a
highly variable value.
[0004] Despite the advances in sustained release technology for
many drugs, controlled release of drugs having a relatively narrow
absorption window in the gastrointestinal tract remains a
challenge. A need exists to extend the gastric residence time for
these drugs, so that the drug is released into the proximity of its
site of absorption (or action) for an extended period, or reaches
other sites of the GI tract in a uniform manner. Examples of
delivery systems capable of increasing the residence time of a drug
are floating low-density dosage forms, such as so-called
hydrodynamically-balanced delivery systems, effervescent systems
comprising gas-generating materials Also other delivery systems,
such as high-density dosage forms and bioadhesive or mucoadhesive
formulations that slow upper GI transit by adhering to the
intestinal mucosa have been attempted (Hwang, S J. et al., Critical
Reviews in Therapeutic Drug Carrier Systems, 15 (3): 243-84 (1998);
Desai, S. and Bolton, S., Pharmac. Res. 10 (9): 1321-25 (1993);
Whitehead, L., et al., European J. Pharm. Sci., 4 (1): S182 (1996);
Iannuccelli, V. et al., Intern. J. Pharmac. 174: 55-62 (1998);
Jimenez-Castellanos, N R. et al., Drug Develop. Industr. Pharmacy
19: 143 (1993); Moes, A J. Crit. Rev. Ther. Drug Carrier Syst. 10
(2): 143-195 (1993)).
[0005] Controlled-release (CR) drug formulations present the
advantage of delivering the drug of interest over a prolonged time
intervals and eliminating the inconvenience of repetitive daily
dosages with concomitant side effects. However, conventional CR
drug delivery systems are seldom suitable for drugs with a
relatively narrow absorption window in the gastrointestinal tract,
since their residence time in or above the absorption window is
shorter than the release time span that could be deemed beneficial.
Thus, there is a need in the art for controlled-release drug
formulations that provide sustained release of drugs having a
relatively narrow absorption window in the gastrointestinal tract.
Similarly, it is deemed beneficial in certain instances to
establish therapeutic blood levels quickly and sustain them over
longer periods, the subject known in the art as "the loading dose",
and there is a need in the art for a combined drug formulation
comprising an immediate release component and a sustained release
component suitable for delivery of narrow-absorption window
substances. U.S. Pat. No. 6,685,962 B2, incorporated herein by
reference, provides pharmaceutical gastroretentive drug delivery
systems for the controlled release of an active agent in the
gastrointestinal tract.
[0006] The present invention satisfies the need in the art for
formulations that provide sustained release or combined immediate
release and sustained release of drugs with a narrow absorption
window in the gastrointestinal tract, or other rationales for a
gastroretentive administration, by providing gastroretentive drug
formulations that are also completely biodegradable, and with a
relatively high loading capacity.
SUMMARY OF THE INVENTION
[0007] Further to these objects, the invention provides
biodegradable, multi-layered gastroretentive drug formulations for
the sustained release of an active agent in the gastrointestinal
tract. In another aspect, the invention provides biodegradable,
multi-layered gastroretentive drug formulations for combined
immediate release and sustained release of an active agent in the
gastrointestinal tract.
[0008] In one embodiment, a biodegradable, multi-layered
gastroretentive drug formulation for the sustained release of an
active agent in the stomach and gastrointestinal tract of a
patient, includes an internal layer containing an active agent and
a degradable polymer which is not instantly soluble in gastric
fluid. The internal layer includes a first side and an opposing
second side. At least one membrane is covering the internal layer.
The membrane comprises at least one polymeric combination of a
hydrophilic polymer and a polymer, insoluble in gastric media, the
membrane being hydratable in the gastric media. The membrane is
directly secured to and covers both sides of the internal layer and
has a predetermined length greater than 20 mm in a planar
orientation, the membrane and internal layer being arranged in an
accordion folded orientation sufficiently compact to be placed
within a capsule dissolvable within the stomach of a patient and
simulated gastric media. The membrane and internal layer unfold
from the accordion folded orientation to a length of at least 20 mm
within 30 minutes of being exposed to gastric media. The membrane
permits passage of gastric media from the environment to the
internal layer and permits passage of the active agent from the
internal layer through the membrane to the environment.
[0009] In another embodiment, a biodegradable, multi-layered
gastroretentive drug formulation for the sustained release of an
active agent in the gastrointestinal tract, includes an internal
layer comprising an active agent and a degradable polymer which is
not instantly soluble in gastric fluid. A first and second
membranes cover the internal layer, the membranes including at
least one polymeric combination of a hydrophilic polymer and a
polymer, insoluble in gastric media and the membranes being
hydratable. The first and second membranes are having a width and
length greater than a width and length of the internal layer. The
first and second membranes are being ultrasonically welded or
otherwise affixed or attached directly together about the periphery
of the first and second membranes. The first membrane is being
ultrasonically welded to a first side of the internal layer, the
second membrane is being ultrasonically welded to the second side
of the internal layer. The ultrasonically welded internal layer and
first and second membranes have a predetermined length greater than
20 mm in a planar orientation, the membrane and internal layer
being arranged in an accordion folded orientation sufficiently
compact to be placed within a capsule dissolvable within the
stomach or simulated gastric media. The ultrasonic welds having
sufficient mechanical strength and stability to remain intact when
being exposed to gastric fluid.
[0010] In still another embodiment, a biodegradable, multi-layered
gastroretentive drug formulation for the sustained release of an
active agent in the gastrointestinal tract is disclosed, including
an internal layer comprising an active agent and a degradable
hydrophilic polymer which is not instantly soluble in gastric fluid
and a degradable enteric polymer which is substantially insoluble
at pH less than 5.5, and optionally a plasticizer. At least one
membrane covers the internal layer, the membrane includes at least
one polymeric combination of a hydrophilic polymer and a polymer,
insoluble in gastric media, and at least one plasticizer. The
membranes swell in the presence of gastric fluid. At least one of
the materials in each of the internal layer and membranes are being
capable of being ultrasonically welded together. The membrane is
directly secured to and covers both sides of the internal layer and
has a predetermined length greater than 20 mm in a planar
orientation. The membrane and internal layer are being arranged in
an accordion folded orientation sufficiently compact to be placed
within a capsule dissolvable within the stomach or in simulated
gastric media. The membrane permits passage of gastric media from
the environment to the internal layer and permits passage of the
active agent from the internal layer through the membrane to the
environment. The membrane and internal layer unfold from the
accordion folded orientation to a length of at least 20 mm within
30 minutes of being exposed to gastric fluid.
[0011] In still another embodiment a biodegradable, multi-layered
gastroretentive drug formulation for the sustained release of an
active agent in the gastrointestinal tract includes an internal
layer comprising an active agent and a degradable hydrophilic
polymer which is not instantly soluble in gastric fluid and a
degradable enteric polymer which is substantially insoluble at pH
less than 5.5, and a plasticizer. First and second membranes cover
the internal layer, the membranes include at least one polymeric
combination of a hydrophilic polymer and a polymer, insoluble in
gastric media, and at least one plasticizer. The membranes swell in
the presence of gastric fluid. At least one of the materials in
each of the internal layer and membranes are being capable of being
ultrasonically welded together.
[0012] The membranes being directly secured to and covering both
sides of the internal layer and having a predetermined length
greater than 20 mm in a planar orientation, the membranes and
internal layer being arranged in an accordion folded orientation
sufficiently compact to be placed within a capsule dissolvable
within the stomach. The membranes and internal layer unfold from
the accordion folded orientation to a length of at least 2.0 mm
within 30 minutes of being exposed to gastric fluid. The first and
second membranes have a width and length greater than a width and
length of the internal layer. The first and second membranes are
ultrasonically welded or otherwise affixed or attached directly
together about a periphery of the first and second membranes. The
first membrane is ultrasonically welded to a first side of the
internal layer. The second membrane is ultrasonically welded to the
second side of the internal layer. The membrane permits passage of
gastric media from the environment to the internal layer and
permits passage of the active agent from the internal layer through
the membrane to the environment. The ultrasonically welded internal
layer and first and second membranes have a predetermined length
greater than 20 mm in a planar orientation. The membrane and
internal layer being arranged in an accordion folded orientation
sufficient to be placed within a capsule dissolvable within the
stomach. The ultrasonic welds having sufficient mechanical strength
and stability to remain intact when being exposed to gastric
fluid.
[0013] In one embodiment, the gastroretentive drug formulations are
for the sustained release of an active agent in the
gastrointestinal tract and comprise: i.) an internal layer or
compartment comprising the active agent and one or more
pharmaceutical excipients, of which at least one is a polymer; ii.)
two membranes forming together an envelope around the inner
membrane, each comprising at least one polymeric combination of a
polymer which is not soluble in gastric juice, and a hydrophilic
swelling polymer, and at least one plasticizer; and iii.)
optionally an additional layer covering each outer membrane
comprising a powder or a film that prevents adherence of the outer
membrane onto itself when folded inside the capsule.
[0014] In a different embodiment, the gastroretentive drug
formulations are for the immediate release and the sustained
release of an active agent in the gastrointestinal tract and
comprise: i.) an internal layer or compartment comprising the
active agent and a polymer; ii.) two membranes forming together an
envelope around the inner membrane, each comprising at least one
polymeric combination of a polymer which is not soluble in gastric
juice, and a hydrophilic swelling polymer, and at least one
plasticizer; and iii.) one or two layers comprising the active
agent and a soluble polymer that provides for the immediate release
of the active agent and is attached to the outside of one outer
membrane or both outer membranes or part of an outer membrane.
Optionally an additional layer may be covering each immediate
release membrane comprising a powder or a film that prevents
adherence of the outer membrane or IR membrane onto itself when
folded inside the capsule. In some embodiments, the
immediate-release membranes possess surface properties that prevent
adherence onto itself when folded inside the capsule.
[0015] In preferred embodiments, the gastroretentive drug
formulations effectively unfold and retain their mechanical
integrity in acidic pH for up to 24 hours and completely biodegrade
after 3 hours in simulated intestinal fluid.
[0016] In one aspect, the polymer in the internal layer is a
degradable polymer which is not instantly soluble in gastric fluid,
in another aspect, the polymer is a degradable enteric polymer
which is substantially insoluble at pH less than 5.5. The invention
also contemplates mixtures of polymers as described above.
[0017] In one embodiment the enteric polymer in the internal layer
is polymethacrylate copolymer. In different embodiments, the
enteric polymer is cellulose acetate phthalate, or
hydroxypropylmethyl cellulose phthalate, or hydroxy-propyl methyl
cellulose acetate succinate. In a preferred embodiment, the active
agent and the polymer are substantially uniformly distributed in
the internal layer.
[0018] In another embodiment, the polymeric combination of the
outer membranes comprises gelatin and hydroxypropyl methyl
cellulose acetate succinate as enteric polymer. In one embodiment,
the enteric polymer in the outer membranes is polymethacrylate
copolymer type A. In a different embodiment, the enteric polymer in
the outer membranes is polymethacrylate copolymer type C. In a
further embodiment, the plasticizer in the outer membranes is
propylene glycol.
[0019] In a preferred embodiment, the internal layer or
compartment, the outer membranes and the optional additional layers
or the immediate release layers are sealed by applying ultrasonic
welding.
[0020] In an additional embodiment, the internal layer provides at
least 50% of the mechanical strength of the whole GRDF when wetted
with gastric fluid. In a preferred embodiment, the gastroretentive
drug formulation reaches its maximum strength within one hour in
simulated gastric fluid. In yet another preferred embodiment, the
internal layer has a planar-accordion geometry that unfolds to at
least 50% of its original length within 30 minutes in gastric
media.
[0021] In one aspect, the gastroretentive drug formulation is fully
degradable within 3 hours in simulated intestinal fluid. In an
additional aspect, the gastroretentive drug formulation provides
gastric retention for up to 24 hours under low or medium calorie
diet. In yet another aspect, the gastroretentive drug formulation
moves in the stomach during gastric retention.
[0022] The gastroretentive drug formulations are designed for oral
administration and are compacted or folded into a standard size
capsule which is easily swallowed. The active ingredient or
ingredients is/are incorporated in the gastroretentive drug
formulations as dissolved matter in composition of the formulation,
powders, grains, spheres, particles, microparticles, nanoparticles,
multiparticulates, tablets or microcapsules.
[0023] In one aspect, the active agent has a narrow window of
absorption in the gastrointestinal tract. The active agent can be a
therapeutic nucleic acid sequence, a therapeutic protein or
peptide, amino acid analogs, a peptidomimetic drug, a nucleoside
analogue, an antibiotic, a therapeutic ion, a vitamin, a
bronchodilator, an anti-gout agent, an anti-hypertensive agent, a
diuretic agent, an anti-hyperlipidemic agent, an ACE inhibitor, an
anti-tumor agent, an histamine (H2) blocker, a bismuth salt or a
synthetic prostaglandin. In one aspect, the active agent is
levodopa and levodopa/carbidopa mixture. Preferred antibiotic agent
is selected from a beta-lactam group, and from fluoroquinolone
group.
[0024] In another aspect the active agent is a drug for the local
treatment in the gastrointestinal tract, such as various drugs for
the treatment of local infections, or drugs for the treatment of
various gastrointestinal diseases and symptoms, or drugs for the
treatment of metabolic disorders, such as obesity, diabetes,
hyper-cholesterol, or for the treatment of local cancers or for the
treatment of cancer related diseases. In preferred aspects the
drugs comprise serotonergic compounds and another enteric
neuromodulators, poorly absorbed substances, poorly absorbed
antibiotics and compounds, acting in the liver as primary
pharmacological site.
[0025] The foregoing general description and following brief
description of the drawings and the detailed description are
exemplary and explanatory and are intended to provide further
explanation of the invention as claimed. Other objects, advantages,
and novel features will be readily apparent to those skilled in the
art from the following detailed description of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] FIG. 1 shows one embodiment of the GRDF design showing the
planar dimensions of the whole GRDF and of the internal layer.
[0027] FIGS. 2A and 2B show the placement of a single immediate
release layer on top of the outer membrane in a cross section view
(A). As shown in (B), the immediate release layer covers the entire
surface of the GRDF.
[0028] FIG. 3 shows the physical dimensions of the GRDF
formulations shown in Example 11.
[0029] FIG. 4 shows a GRDF folded inside capsule prior to placing
the capsule cap. Visible are the folds and their fold geometry.
[0030] FIG. 5 provides results indicating the mechanical properties
of GRDFs and films cut into a dog bone shape. The photographs
marked 1, 2 and 3 show the stages of mechanical testing of a GRDF
after immersion in SGF. The figure in the top right corner shows
the results as expressed in a load-to-displacement graph, where the
stages of the test correspond to the stages shown in photographs 1,
2 and 3, respectively.
[0031] FIGS. 6A and 6B show the design of the anvil (A) and horn
(B) of the ultrasound welding machine used for attaching the GRDF
layers together.
[0032] FIGS. 7A and 7B show a drawing of the ultrasound welding on
the GRDF (A). The perimeter line of the internal layer is shown
with an arrow and the extent of welding in a cross section of the
GRDF is provided (B).
[0033] FIG. 8 shows a welded GRDF.
[0034] FIG. 9 shows the dissolution profile of a combined immediate
release and controlled release carbidopa/levodopa GRDF.
[0035] FIGS. 10 and 11 show the measurements from the unfolding of
a placebo GRDF device in acetate buffer and SGF.
[0036] FIG. 12 shows the mean dose-adjusted Carbidopa
concentrations for single dose GRDF CD/LD 75/300 mg gastric
retentive, IR+CR; single dose Sinemet.RTM. IR 100/25 mg; and single
dose Sinemet CR.RTM. 25/100 mg, as described in Example 7.
[0037] FIG. 13 shows the Levodopa Least-Squares Mean Concentrations
in blood samples versus time in subjects treated with GRDF CD/LD
75/300 mg; GRDF CD/LD 50/200 mg; and Sinemet.RTM. TR CD/LD 50/200
mg, as described in Example 10.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0038] "Gastroretentive dosage form" as used herein refers to
dosage forms with delayed gastric emptying as compared to food (or
retention in the stomach beyond the retention of food).
[0039] "Simulated gastric fluid" and "Gastric medium", and
"Simulated intestinal fluid" and "Intestinal medium", as used
interchangeably herein refer to media, occurring in stomach and in
intestines, correspondingly, or to the solutions that are used to
mimic their chemical and/or enzymatic environment in vitro. One
such media is described in Example 2.
[0040] The term "degradable" as used herein is intended as capable
of being chemically and/or physically reduced, dissolved or broken
down in the body of a patient and within a relevant time
period.
[0041] The phrase "polymer which is not instantly soluble in
gastric fluid" as used herein means that the polymer will gradually
dissolve in the GI tract during its residence therein.
[0042] The term "inert" as used herein refers to components in the
internal layer or compartment, outer membranes, optional layers
and/or the immediate release layers that do not react with the
active ingredient or affect its properties under normal conditions,
or cause any biological effect upon administration to a
subject.
[0043] The phrase "prolonged period" as used herein intends a
period of delivery that lasts for several hours to about 24 hours,
usually above 5 hours, and often between about 5 and 15 hours.
[0044] The terms "swellable" and "swelling" mean, with respect to a
polymer, that the polymer is capable of imbibing fluid and
expanding when in contact with fluid present in the environment of
use.
[0045] The terms "active agent" and "drug" are used interchangeably
herein and refer to an active pharmaceutical ingredient (API),
compound, composition of matter or mixture thereof which provides a
therapeutic or prophylactic effect.
[0046] A "patient" as referenced herein is a human or non-human
mammal who may need to receive the gastroretentive drug
formulations of the present invention.
[0047] "Treating" or "treatment", are used herein to refer to
obtaining a desired pharmacological and physiological effect. The
effect may be prophylactic in terms of preventing or partially
preventing a disease, symptom or pathological condition and/or may
be therapeutic in terms of a partial or complete cure of a disease,
condition, symptom or adverse effect attributed to a pathological
condition. Thus, "treatment" covers any treatment of a disease in a
mammal, particularly a human, and includes: (a) preventing a
pathological condition from occurring in an individual which may be
predisposed to develop a pathological condition but has not yet
been diagnosed as having it, i.e., causing the clinical symptoms of
a pathological condition not to develop in a subject that may be
predisposed to develop the condition but does not yet experience or
display symptoms of the condition; (b) inhibiting, i.e., arresting
or reducing the development of the pathological condition or its
clinical symptoms; or (c) relieving symptoms associating with the
pathological condition.
[0048] In the current embodiments, the gastroretentive drug
delivery system includes an internal layer and an outer layer. The
outer layer is formed from two films which are slightly larger than
the internal layer and which are sealed or welded together around
their perimeter and completely envelope the internal layer. Along
with welding which connects the outer layers together, the outer
portion of the internal layer is also welded to the outer
layers.
[0049] Alternatively, in the current embodiments, the
gastroretentive drug delivery system includes an internal layer and
an outer layer, whereas the outer layer is formed from two
membranes which are equal in size with the internal layer and which
are sealed or welded together around their perimeter and the outer
portion of the inner layer. Optionally the gastroretentive delivery
system comprises an additional layer which is either larger or
equal in size to the inner/outer membranes assembly, and envelops
the assembly to prevent adhesion of the membranes onto themselves;
the said layer can be formed with one or more membranes,
ultrasonically welded or otherwise attached or affixed onto the
assembly, and can optionally comprise an API. The ultrasonically
welded or otherwise attached internal layer and outer layers are
folded in an accordion arrangement and placed within a capsule. In
some embodiments, the capsules are made from gelatin or
hypromelose. The layers are shaped in essentially oval polygonal
form such that they maximize the amount of space within the capsule
that is filled. Once the gelatin or hypromelose capsule dissolves
within the gastric medium, the internal layer and outer layers
expand from the accordion folded orientation to a more planar
orientation.
[0050] The gastroretentive drug formulations of the present
invention markedly improve absorption and bioavailability of
suitable active agents, and, in particular, ameliorate the
absorption and bioavailability of drugs having a narrow window of
absorption in the gastrointestinal tract, due to its ability to
withstand peristalsis and mechanical contractility of the stomach,
and consequently, release the drug in a controlled manner onto its
absorption sites and without premature transit into non-absorbing
regions of the GI tract. The inventors discovered that the
gastroretentive drug formulation provides gastric retention of
active agents having a narrow window of absorption for up to 24
hours under low or medium, calorie diet, unlike other formulations
in the art, that require high calorie and high fat diet for proper
functioning. In addition, administration of these formulations to a
mammal can improve the pharmacokinetic and pharmacodynamic
properties of active agents having a narrow window of absorption.
Since the gastroretentive drug formulations are fully degradable,
they provide a means to administer the proper dose of the drug
without generating non-degradable residues that would not be
eliminated after drug release.
[0051] The gastroretentive drug formulations are stable, fully
degradable and provide efficient delivery of various drugs in the
gastrointestinal tract due to the combination of an internal layer
having planar-accordion geometry where all components are fully
biodegradable. The combination of swelling outer membrane layers
with a substantially non-swelling internal layer having planar
accordion geometry causes the internal layer to undergo an
unfolding process once the formulation reaches the stomach, thus
extending gastric residence time and preventing the dosage form
from being evacuated until substantial or complete release.
Sustained-Release Gastroretentive Drug Formulations
[0052] In accordance with the first embodiment of the invention, a
stable, degradable, multi-layered gastroretentive drug formulation
for the sustained release of an active agent in the
gastrointestinal tract is provided. The gastroretentive drug
formulation comprises: i.) an internal layer or compartment
comprising the active agent, one or more polymers and one or more
modifying agents such as plasticizers and/or solubilizers and/or
fillers; ii.) two outer membranes, each comprising at least one
polymeric combination of hydrophilic polymer and a polymer
insoluble in gastric media, and at least one plasticizer; and iii.)
optionally an additional layer covering each outer membrane and
comprising a powder or a film that prevents adherence of the outer
membranes to itself.
[0053] In accordance with another embodiment of the invention,
degradable, multi-layered gastroretentive drug formulation for the
sustained release of an active agent can be combined with one or
more immediate release layers covering the outer membranes and
comprising the active agent and a polymer and optionally other
excipients, known in the art, that provides for the immediate
release of the active agent to form degradable, multi-layered
gastroretentive drug formulation for combined immediate-release and
sustained-release of the active agent. Optionally an additional
layer covering each outer membrane and comprising a powder or a
film that prevents adherence of the outer membranes to itself is
included. Additional disclosure regarding the immediate and
controlled release formulations are provided below.
Internal Layer
[0054] The internal layer or compartment in the gastroretentive
drug formulations comprise the active agent and a polymer
substantially uniformly distributed throughout the internal layer.
The polymer can be a degradable hydrophilic polymer which is not
instantly soluble in gastric fluid, a degradable enteric polymer
which is substantially insoluble at pH less than 5.5, a hydrophobic
polymer or mixtures thereof. It can further comprise acceptable
pharmaceutical additives, such as plasticizers, humectants, fillers
and others.
[0055] Examples of degradable hydrophilic polymers which are not
instantly soluble in gastric fluid suitable for the invention are
hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl
pyrrolidone, polyethylene oxide and methyl cellulose. Preferably,
the enteric polymer is a polymethacrylate copolymers, cellulose
acetate phthalate, hypromelose acetate succinate or hypromellose
phthalate. These polymers are combined with active agent, such as
Levodopa and/or Carbidopa. Exemplary ranges for active agents and
polymers are provided the table below.
TABLE-US-00001 Range In Inner Component Layer Carbidopa 5-17%
Levodopa 40-65% Eudragit L100 10-35% Poloxamer 407 7-19% PEG 400
4-14%
[0056] Preferably, the internal layer has planar accordion
geometry. This feature, together with the presence of polymers as
described above in the internal layer or compartment provides the
internal layer with substantial mechanical strength. Preferably,
the internal layer has a mechanical strength with Young's modulus
of from about 0.5 to 15 Kgf/mm.sup.2. Preferably, the range could
be from about 3.0 to about 10.0 Kgf/mm.sup.2 or from about 3.0 to
about 6.0 Kgf/mm.sup.2. The stress may range from about 0.03 to
about 0.6 Kgf/mm.sup.2 after 1 hour in simulated gastric fluid,
such that the gastroretentive drug formulation reaches its maximum
strength within one hour in simulated gastric fluid. Alternatively
the range for stress may be from about 0.05 to about 0.4 Kgf/mm or
about 0.1 to about 0.4 Kgf/mm.
[0057] The components of the internal layer may be altered based on
the characteristics of the active ingredients being delivered. For
example, some ingredients may be more soluble in certain polymers
than others and may require a reformulation of the internal layer.
In some instances, the active ingredient may require a formulation
of the internal layer that does not allow effective welding between
the outer and internal layer. In such situations, the internal
layer may be composed of the two or more portions, where each
portion has definite function. In one instance, the central region
(welding free) can be formulated as separate film to hold the
active ingredient and be placed into the central portion and over
the inner film comprising as additional portion that will support
this central portion. This additional portion can then be welded to
the outer layer. In another instance, whereas the internal layer
cannot be formulated to develop the necessary mechanical strength
in the gastric medium, at least one additional layer, optionally
comprising no drug, could be used as a scaffold, whereupon the
formulated drug reservoir film could be laid and welded or
otherwise attached or affixed, onto one or both sides of said
backbone, and the assembly could be welded to the outer membranes
and other components of the delivery system.
Outer Membranes
[0058] Each of the outer membranes in the gastroretentive drug
formulations comprises at least one polymeric combination of a
hydrophilic polymer and a polymer, insoluble in gastric media, and
at least one plasticizer.
[0059] Examples of suitable ingredients for the invention include
gelatin, hydroxypropylcellulose, hydroxypropyl methycellulose,
pectin, polyethylene oxide, starch, and zein. Preferably, the
hydrophilic polymer is gelatin. The amount of gelatin in each of
the outer membranes is between about 20 and about 45% of the total
outer membrane composition, and preferably between about 25 and
about 35% of the total outer membrane composition.
[0060] Examples of enteric polymers that can be used in the outer
membranes include hypromellose phthalate, hypromellose acetate
succinate and polymethacrylate co-polymers. Preferably, the enteric
polymer is polymethacrylate copolymer type A or polymethacrylate
copolymer type C.
[0061] Plasticizers suitable tor the invention include various
polyethylene glycols, glycerin, triethylcitrate. Preferably, the
plasiticizer is propylene glycol.
[0062] The outer membranes swell in the presence of gastric fluid
and are fully degradable within two hours in simulated intestinal
fluid. The combination of swelling outer membrane layers with a
non-swelling internal layer having planar accordion geometry causes
the internal layer to undergo an unfolding process once the
formulation reaches the stomach, thus extending gastric residence
time and preventing the drug-containing dosage form from being
evacuated until complete release. In one embodiment the internal
layer has a swelling rate less than the swelling rate of the
membrane.
[0063] The membrane permits passage of gastric medium from the
environment to the internal layer and permits passage of the active
agent from the internal layer through the membrane to the
environment.
[0064] In some instances the kinetics of such transport can be
unacceptably low. Therefore in some embodiments the outer membranes
can be perforated with one or more orifices to facilitate the mass
transfer processes through the membrane. In preferred embodiments
the orifices are uniformly distributed over the area hereabout the
formulated drug layer.
[0065] In a preferred embodiment, the outer layer does not contain
any active ingredient. In other embodiments, the outer layer
comprises one or more active ingredients.
Optional Additional Layer
[0066] The gastroretentive drug formulations of the invention may
further comprise an optional additional layer covering each outer
membrane and comprising a powder or a film. In some instances it
may be found that the outer layers stick together in the capsule
and do not unfold properly upon dissolving of the capsule. In such
situations, this optional layer prevents adherence of the outer
membranes to themselves and allows for the proper opening of the
GRDF. In preferred embodiments, the optional layer comprises at
least one powder, and optionally at least one polymer. In other
embodiments the preferred polymers are rapidly-dissolving film
formers, which can be selected from but not limited to soluble
cellulose derivatives, i.e. methyl cellulose, hydroxypropyl
cellulose, hydroxyethyl cellulose, hypromelose; various grades of
povidone; polyvinyl alcohol and its derivatives, i.e. Kollicoat IR;
soluble gums and others. The films may further comprise
surface-active agents, plasticizers and humectants.
The Immediate Release Layers
[0067] The invention further contemplates gastroretentive drug
formulations for combined immediate-release and controlled release
of an active agent in the gastrointestinal tract. These
formulations comprise an internal layer or compartment and at least
two outer membranes as described above, and additionally comprise
one or more immediate release layers covering the outer membranes
and comprising the active agent and a soluble polymer that provides
for the immediate release of the active agent. Examples of soluble
polymers that can be used in the immediate release which can be
selected from soluble cellulose derivatives, i.e. methyl cellulose,
hydroxypropvl cellulose, hydroxyethyl cellulose, hypromelose;
various grades of povidone; polyvinyl alcohol and its derivatives,
i.e. Kollicoat IR; soluble gums and others. The films may further
comprise surface-active agents, plasticizers and humectants, such
as PEGs, different grades of polysorbates and sodium lauryl
sulfate, for example.
[0068] The relative amounts of the polymers may be adjusted based
on the solubility on the active ingredient.
[0069] While the internal layer and outer layer are generally
welded together, the immediate release layer will not generally
require such a strong connection with the rest of the GRDF device.
Rather the immediate release formulation will quickly dissolve in
order to deliver the drug of interest. The immediate release layer
may be affixed to the outside of the GRDF using a compatible
solvent, ultrasonic welding, or other means.
[0070] The ability to add an additional immediate release layer is
particularly helpful in the development of GRDFs. By combining the
immediate and controlled release nature of the current invention,
one can alter the drug release profile for the drug of interest.
Consequently, patients may receive both an immediate bolus of the
drug as well as a prolonged delivery of the active agent with the
purpose of establishing therapeutic levels of the drug quickly and
maintaining these levels for prolonged period of time, up to 24
hour.
[0071] Of further note is the ability to deliver multiple drugs in
the current GRDF. The current embodiments are not limited to the
delivery of a single active pharmaceutical agent. Rather, multiple
drugs may be formulated and delivered simultaneously. By combining
the immediate and controlled release layers, multiple drugs may be
simultaneously delivered with specific profiles. For example, a
combined release formulation for levodopa/carbidopa is provided in
the Examples.
[0072] All components of the internal layer or compartment, the
outer membranes, the optional layers and/or the immediate release
layers are pharmaceutically acceptable and inert.
[0073] As an additional method of delivering the immediate release
of the drug, a coating may be applied to the capsule comprising the
drug. Upon entry into the stomach, the coating will immediately
allow release of the drug and enhance the release profile of the
drug. Methods for applying coating to a capsule are well known to
those of skill in the art.
Ultrasonic Welding
[0074] The internal layer or compartment, the outer membranes, the
optional layers and/or the immediate release layers may be attached
to each other by many means. Preferably, they are sealed by
applying ultrasonic welding. One example of a device suitable for
these purposes is the Dynamic 745 ultrasonic welder from Rinco
Ultrasonics, but other devices may be employed. The welding
effectively seals the internal layer within the outer layer by
welding the outer layers together and also welding the perimeter of
the internal layer to the outer layer. It can also efficiently
attach the layers to one another without sealing a whole envelope,
meaning that there is no need for same-material welding, should the
formulations be compatible.
[0075] Different patterns and times may be used for the welding
based on the needs of those skilled in the art. Although the
periphery of the layers can be welded together, the current
embodiments do not weld the central portion of the GRDF device so
as to minimize any heating or effects on the majority of the
internal layer which holds the active pharmaceutical agent for
controlled release. In some situations it may be necessary to weld
more of the internal layer based on the composition of the
GRDF.
The GRDF Capabilities
[0076] The gastroretentive drug formulations are designed for oral
administration and are compacted or folded into a standard size
capsule which is easily swallowed. The active ingredient or
ingredients is/are incorporated in the accordion pill as powders,
grains, spheres, particles, microparticles, nanoparticles,
multiparticulates, solid solutions, tablets or microcapsules.
Active agents that may be delivered with the gastroretentive drug
formulations include active agents which act on the peripheral
nerves, adrenergic receptors, cholinergic receptors, the skeletal
muscles, the cardiovascular system, smooth muscles, the blood
circulatory system, synoptic sites, neuroeffector junctional sites,
endocrine and hormone systems, the immunological system, the
reproductive system, the skeletal system, the digestion system, the
histamine system and the central nervous system. Especially
preferred are active agents used in the treatment of
gastrointestinal diseases, including, but not limited to, duodenal
ulcers, gastric ulcers, Zollinger-Ellison syndrome,
gastroesophageal reflux disease, erosive esophagitis, gastritis,
gastric carcinoma and spasticity. Other indications such as cancer,
infections, and metabolic disorders are also envisioned in addition
to other conditions known by those of skill in the art which may be
addressed through gastroretentive device delivery.
[0077] Suitable active agents include, for example, proteins,
enzymes, enzyme inhibitors, hormones, polynucleotides,
nucleoproteins, polysaccharides, glycoproteins, lipoproteins,
peptides, polypeptides, steroids, hypnotics and sedatives, psychic
energizers, tranquilizers, anticonvulsants, antidepressants, muscle
relaxants, antiparkinson agents, analgesics, immunosuppressants,
anti-inflammatories, antihistamines, local anesthetics, muscle
contractants, antimicrobials, antimalarials, antivirals,
antibiotics, bronchodilators, anti-gout agents, antiobesity agents,
antidiabetic agents, anti-hyper-cholesterol agents, hormonal agents
including contraceptives, sympathomimetics, anti-hypertensive
agents, diuretics, lipid regulating agents, ACE inhibitors, bismuth
salts, synthetic prostaglandins, antiandrogenic agents,
antiparasitics, neoplastics, antineoplastics, antihyperglycemics,
hypoglycemics, nutritional agents and supplements, growth
supplements, fats, ophthalmics, antienteritis agents, electrolytes
and diagnostic agents.
[0078] Preferably, the active agent has a narrow window of
absorption in the gastrointestinal tract. Antiviral, antifungal and
antibiotic agents, including sulfonamides, quinolones, penicillins,
cephalosporins, aminoglycosides, and tetracyclines, are
representative classes of active agents that have a narrow window
of absorption in the gastrointestinal tract. Specific examples of
drugs include, but are not limited to, cimetidine, ranitidine,
famotidine, nizatidine, zolentine, metronidazole, imidazole,
amoxicillin, clarithromycin, minocycline, tetracycline,
somatostatin analogues, including levodopa and carbidopa.
[0079] In addition, active agent that act locally are, for example,
drugs for the treatment of local infections, or drugs for the
treatment of various gastrointestinal diseases and symptoms, or
dings for the treatment of metabolic disorders, for the treatment
of local cancers or for the treatment of cancer related diseases.
More specifically, the agents relevant in this aspect are these
that have to be administered in the inflamed bowel, as occurs
during inflammatory bowel diseases, such as metronidazole,
vancomycin, budesonide and others, whose efficacy is impaired by
unusually rapid emptying of the inflamed tissue. These materials
can be poorly absorbed systemically, such as vancomycin, or could
be incorporated into a targeted delivery system, such as for
budesonide.
[0080] Other drugs that may be formulated according to the
invention include drugs for the treatment of Parkinson's Disease.
Parkinson's Disease (PD), one of the most common neurodegenerative
diseases of the elderly, is a slowly progressive clinical syndrome
characterized by resting tremor, slowness of movement, muscular
rigidity, and gait instability. PD may also be accompanied by
difficulty in swallowing, loss of olfactory sense, difficulty in
speech, depression and dementia. The pathogenesis of PD involves
degeneration of dopaminergic neurons in the substantia nigra pars
compacta and a consequent depletion of the neurotransmitter
dopamine in the basal ganglia. Since dopamine cannot cross the
blood-brain barrier, Levodopa (LD) (which is enzymatically
decarboxylated by the enzyme L-amino dopa decarboxylase in the CNS
to dopamine), is used therapeutically to replenish the brain's
diminished dopamine reservoir. LD is considered the most effective
therapeutic drug for the treatment of Parkinson's disease.
Decarboxylation reaction can also occur at some rate peripherally,
even before levodopa reaches the brain. Therefore Levodopa is
generally co-administered with an effective L-amino dopa
decarboxylase inhibitor such as Carbidopa. The inhibition of
Levodopa decarboxylation in the periphery reduces peripheral
dopamine formation and decreases the side effects attributed to
dopamine (i.e. orthostatic hypotension, nausea and vomiting), while
simultaneously increasing the bioavailability of Levodopa to the
CNS. Carbidopa/Levodopa is commercially available as a combination
products, both as immediate-release (e.g. Sinemet.RTM., Merck &
Co., Inc.) or controlled-release (e.g. Sinemet-CR.RTM., Merck &
Co., Inc.) tablets.
[0081] The plasma half-life of LD is about 50 minutes, without
Carbidopa (CD). When CD and LD are administered together, the
half-life of LD is increased to about 1.5 hours. At steady state,
the bioavailability of LD from Sinemet.RTM. tablets is
approximately 99% relative to the concomitant administration of
Carbidopa and LD.
[0082] Although LD is the most effective treatment for Parkinson's
disease (PD), there are problems with its long term use. Early PD
patients fair well with LD with a sustained response to each LD
dose. Over time, however, the duration of the response after each
dose declines, resulting in "wearing off", where the medication
does not work until the next dose reaches therapeutic levels. As
the disease progresses the patient suffers from longer OFF periods
when the LD is not working. In addition, a disabling side effect of
LD treatment is the occurrence of dyskinesias, usually as a peak
dose effect. Both of these phenomena, wearing off and dyskinesias,
are believed to be caused by the pulsatile stimulation of striatal
dopamine receptors and the large difference between peak to trough
levels of dopamine. It is beneficial, therefore, to provide
continuous, rather then pulsatile, dopaminergic stimulation by
either increasing the frequency of dosing or by treatment with a
controlled release product. The current available controlled
release LD treatment, Sinemet CR.RTM., has shown decreased
bioavailability and efficacy, since LD is absorbed mainly in the
upper intestines and a slow release product that has passed the
area of absorption will not be effective.
[0083] The GRDF formulations of the invention maintain controlled
release of LD, that is retained at or above the area of absorption,
the upper intestines, with minimal peak/trough variations, and thus
provide the most beneficial treatment in terms of efficacy and
safety profiles.
[0084] The gastroretentive dosage forms of this invention can
conveniently release active agents in a sustained profile or in a
combined immediate and sustained profile over a prolonged period,
while maintaining high drug bioavailability for an extended period
of time.
[0085] The detailed description of the present invention is further
illustrated by the following examples, which are illustrative only
and are not to be construed as limiting the scope of the invention.
Variations and equivalents of these examples will be apparent to
those skilled in the art in light of the present disclosure, the
drawings and the claims herein.
Gastric Retention Under Low and Medium Calorie Diet
[0086] The gastroretentive drug formulations maintain their
physical integrity over a prolonged period of time, such that the
active agent is retained in the stomach for up to 24 hours under
low or medium calorie diet. The use of a low and medium calorie
diet is advantageous because it follows normal dietary habits of
the patients and does not demand an excessive meal with each
instance of dosing of the GRDF. Although the GRDF may be retained
in the stomach for extended periods of time all of the GRDF
components are degradable and undergo complete degradation once
they reach the intestine.
[0087] The invention is further represented by the following
examples. The examples are representative only and are not intended
to limit the invention to the particular embodiments described
therein.
EXAMPLES
Example 1
Ultrasonic Welding of GRDF
[0088] In order to weld the layers of the GRDF, the Dynamic 745
ultrasonic welder from Rinco Ultrasonics was used with the
following parameters:
TABLE-US-00002 Parameters of ultrasonic welding Trigger 275 N Rise
of force Trigger 380 N/s Melting time 650 ms Rise of force Trigger
600 N/s Amplitude 9 Solidification force 600 N Holding time 600
ms
[0089] FIGS. 6A, 6B, 7A and 7B show the design of the anvil and
horn of the ultrasonic welding machine used for attaching the GRDF
layers together. In addition, a cross sectional view of the extent
of the welded area is provided. FIG. 8 shows an enlarged photograph
of a portion of a GRDF with the ultrasonic welding of the outer
layers to each other forming an envelope around the internal layer.
The welding between the peripheral portion of the internal layer
with the outer layer is also visible.
Example 2
Unfolding of GRDF
[0090] The following data show that the GRDF of the current
invention unfold within a short period of time and would not be
quickly passed through the stomach before deployment and release of
the active ingredients. The below experiments were conducted with a
placebo GRDFs first loaded into capsules and then placed in either
SGF pH 1.2 or acetate buffer (USF) pH 4.1 in a USP Apparatus 2, 50
rpm. GRDFs were visually inspected after 15 minutes. In addition,
the lengths of the accordion laminates along its longest dimension
were measured after 30, 60 and 120 minutes in the medium.
Completely flat devices have a length of 45 mm. See FIGS. 10 and 11
for the results. The devices are unfolded by 30 minutes. Visual
inspection at 15 minutes indicated that the pills were dissolved
and the devices had opened to about the same size as seen at 30
minutes.
Example 3
Mechanical Properties of GRDF
[0091] The mechanical properties of the GRDFs and their films wets
tested. See FIG. 5 for results. Intact GRDFs, as well as specimens
which were cut into a dog bone shape were tested in order to
determine their mechanical properties. Values for the strain, load,
stress, and Young's modulus are provided.
Example 4
Degradabiiity of GRDF
[0092] The following results show the complete biodegradability of
the GRDF of the current invention once it is passed into an
environment similar to the intestinal tract. Four GRDF devices were
placed in simulated intestinal fluid (USP SIF) and monitored every
hour for three hours. The devices were not first loaded in a pill,
but were placed directly into SIF. After three hours the devices
dissolved.
Example 5
Carbidopa-Levodopa GRDF Formulation
[0093] A GRDF was manufactured using the following components for
the internal layer, outer layers, and an immediate release
layer.
TABLE-US-00003 Amount/GRDF (mg) Internal Outer (sum of Immediate
Component layer two films) Release Layer Total Carbidopa 45.0 30.0
75.0 Levodopa 200.0 100.0 300.0 Eudragit S100 53.2 53.2 Eudragit
L100 100.0 26.6 126.6 Eudragit L100-55 26.6 26.6 Fish Gelatin 106.5
106.5 Propylene glycol 106.5 106.5 KOH 6.7 6.7 Poloxamer 407 65.0
65.0 PEG 400 40.0 8.3 48.3 Methylcellulose 4.7 4.7 Povidone 90 18.4
18.4 Total 450 326.1 161.4 937.5
Example 6
Cartoidopa-Levodopa GRDF Release Profiles
[0094] In order to illustrate the ability of the GRDF to provide
both immediate release and controlled release of active
ingredients, the release profile for the above (Example 5)
Carbidopa/Levodopa GRDF was determined. Carbidopa and Levodopa are
present in total amounts of 75 and 300 mg, respectively.
Specifically, there are 30 mg Carbidopa in the immediate release
layer and 45 mg in the internal layer which are provided to the
patient as a controlled release. For Levodopa, 100 mg are in the
immediate release layer and 200 mg in the internal layer.
[0095] Experiments were conducted in an acetate buffer (LISP) pH
4.1 in a USP Apparatus 2, 50 rpm. As shown in FIG. 9, immediate
release for both drugs occurred within 1 hour and extended release
was seen for 8 hours.
[0096] These experiments illustrate the ability to effectively
deliver a single or multiple drugs at the same time using the
current GRDF. If delivered simultaneously, the drugs may be
concentrated in the immediate release and controlled release layers
to provide the desired profiles and release characteristics in one
system.
Example 7
Carbidopa/Levodopa GRDF Pharmacokinetic Profiles Compared to
Immediate Release Sinemet.RTM. and Controlled Release Sinemet
CR.RTM. Pharmacokinetic Profiles in Healthy Subjects
The Study
[0097] A three-way crossover study was performed in healthy
subjects to assess the pharmacokinetics of two single GRDF
Levodopa/Carbidopa (LD/CD) dose formulations. A single dose of GRDF
LD/CD containing Levodopa 300 mg and Carbidopa 75 mg (formulation
in Example 5) administered to healthy male subjects after a light
meal were compared with Sinemet.RTM. containing Levodopa 100 mg and
Carbidopa 25 mg and Sinemet CR.RTM. containing Levodopa 200 mg and
Carbidopa 50 mg.
Pharmacokinetics of Levodopa
[0098] The plasma half-life of Levodopa is about 50 minutes,
without Carbidopa. When Carbidopa and Levodopa are administered
together, the half-life of Levodopa is increased to about 1.5
hours. At steady state, the bioavailability of Carbidopa from
Sinemet.RTM. tablets is approximately 99% relative to the
concomitant administration of Carbidopa and Levodopa.
[0099] Carbidopa inhibits decarboxylation of peripheral Levodopa.
It does not cross the blood-brain barrier and does not affect the
metabolism of Levodopa within the central nervous system.
[0100] Carbidopa reduces the amount of Levodopa required to produce
a given response by about 75 percent and, when administered with
Levodopa, increases both plasma levels and the plasma half-life of
Levodopa, and decreases plasma and urinary dopamine and
homovanillic acid.
[0101] In clinical pharmacologic studies, simultaneous
administration of Carbidopa and Levodopa produced greater urinary
excretion of Levodopa in proportion to the excretion of dopamine
than administration of the two drugs at separate times.
[0102] Patients treated with Levodopa therapy for Parkinson's
Disease may develop motor fluctuations characterized by end-of-dose
failure, peak dose dyskinesia, and akinesia. The advanced form of
motor fluctuations (`on-off` phenomenon) is characterized by
unpredictable swings from mobility to immobility. Although the
causes of the motor fluctuations are not completely understood, in
some patients they may be attenuated by treatment regimens that
produce steady plasma levels of Levodopa.
[0103] A current formulation of Levodopa/Carbidopa (Sinemet
CR.RTM.) provides controlled-release of ingredients over a 4- to
6-hour period. However, the sustained-release product of this
combination is less systemically bio available (70 to 75%) than the
immediate-release product (99%), and may require increased daily
doses to achieve the same level of symptomatic relief. Typical
starting doses of LD/CD are Levodopa 100 mg and Carbidopa 25 mg 3
or 4 times a day for a total of 300-400 mg Levodopa daily.
[0104] For the purpose of this study, the GRDF CD/LD 75/300 mg was
planned for a 600 mg total daily dose of Levodopa.
[0105] Since gastric retention can be achieved by eating a high
fat, high calorie meal (food retention), true gastric retention was
assessed in healthy subjects that were administered a low calorie
breakfast.
The Products
A. Reference Product
TABLE-US-00004 [0106] Product Sinemet .RTM. Dose Administered
25/100 (1 tablet) Active Ingredient Carbidopa/Levodopa, immediate
release Dosage Form Tablet Strength 100 mg/25 mg Manufacturer MERCK
& CO., INC
B. Reference Product
TABLE-US-00005 [0107] Product Sinemet CR .RTM. Dose Administered
50/200 (1 tablet) Active Ingredient Carbidopa/Levodopa, controlled
release Dosage Form Tablet Strength 25/100 mg Manufacturer MERCK
& CO., INC
C. Reference Product
TABLE-US-00006 [0108] Product GRDF CD/LD Dose Administered 75/300
mg Active Ingredient Carbidopa/Levodopa, controlled release Dosage
Form capsule Strength 75/300 mg
The Treatment
[0109] The single-center, open-label single-dose, three way
crossover, pharmacokinetic study was performed in 24 healthy male
subjects between 18 and 55 years of age. Adult healthy subjects
participated in 3 study days with at least 1 week washout period
between days.
[0110] All oral formulations were swallowed whole with 240 ml water
alter a light breakfast. Standardized meals were given to all
subjects throughout the study days.
[0111] Venous blood samples was drawn before dosing and then at
frequent intervals to match the pharmacokinetic behavior of the
drug. Levodopa plasma levels were analyzed.
[0112] The results of the study are shown in the Tables below and
in FIG. 12:
Levodopa Results
TABLE-US-00007 [0113] Sinemet 90% 90% GRDF IR Ra- CV CI CI Signif-
Lsmean Lsmean tio % Lo Hi icant LnAUC 5164 1218 4.238 11.58 4.008
4.482 ** LnCmax 1400 624 2.243 20.42 2.034 2.474 ** LnMRT 4.45 2.69
1.656 16.12 1.533 1.790 ** LnAUC_DA 5164 3655 1.413 1.336 1.494 **
LnCmax_DA 1400 1873 0.748 0.678 0.825 ** Tmax 2.65 1.40 1.896 **
Sinemet 90% 90% GRDF CR Ra- CV CI CI Signif- Lsmean Lsmean tio % Lo
Hi icant LnAUC 5164 3104 1.664 11.58 1.573 1.761 ** LnCmax 1400
1043 1.343 20.42 1.217 1.481 ** LnMRT 4.45 3.54 1.259 16.12 1.165
1.360 ** LnAUC_DA 5164 4655 1.109 1.049 1.173 ** LnCmax_DA 1400
1565 0.895 0.812 0.987 ** Tmax 2.65 2.17 1.221 ** 90% 90% CR IR Ra-
CV CI CI Signif- Lsmean Lsmean tio % Lo Hi icant LnAUC 3104 1218
2.547 11.58 2.409 2.694 ** LnCmax 1043 624 1.671 20.42 1.515 1.843
** LnMRT 3.54 2.69 1.316 16.12 1.218 1.422 ** LnAUC_DA 4655 3655
1.274 1.204 1.347 ** LnCmax_DA 1565 1873 0.836 0.758 0.922 ** Tmax
2.17 1.40 1.552 ** For log-transformed data (Ln) the LSmeans are
geometric mean ratios are geometric mean ratios. AUC = AUC 0-t MRT
= Mean Residence Time (hours) _DA = Indicates Parameter Was
Dose-Adjusted to 300 mg CV % = Estimated Within-Subject Coefficient
of Variation ** = p < 0.05, blank entry indicates p > 0.05
(adjusted for multiple pairwise comparisons)
[0114] The results show that the GRDF LD/CD, compared to the
reference products, extended retention time in the stomach and
controlled release of the active ingredients over a 5-hour period.
GRDF LD/CD provided prolonged release of the active ingredients at
a site above their absorption window and improved bioavailability
with fewer variations in plasma levels, thus providing steady
plasma levels of Levodopa and Carbodopa.
[0115] It is known that patients treated with Levodopa therapy for
Parkinson's Disease may develop motor fluctuations characterized by
end-of-dose failure, peak dose dyskinesia, and akinesia. These
symptoms may be attenuated by treatment regimens that produce
steady plasma levels of Levodopa. By providing a quick rise, yet
steady level of Levodopa and Carbodopa, the GRDF LD/CD satisfy the
need for a combination of immediate release and controlled release
mechanism of LD/CD that provide steady plasma levels of Levodopa
and Carbodopa, thus resulting in fewer doses per day and better
patient response and compliance.
Example 8
Effect of GRDF Formulations on Gastric Retention in Healthy
Subjects and in Parkinson Patients
[0116] To determine the effect of GRDF formulations on gastric
retention clinical trials were performed with various placebo GRDFs
using MRI. The drug reservoir layer of the GRDF for these studies
does not contain an active ingredient. Instead, the drug reservoir
contains iron oxide food coloring (sicovit black e172) that can be
visualized in a magnetic resonance imaging (MRI).
[0117] Results of these MRI studies showed that in healthy
volunteers the GRDF formulations were retained in the stomach for
7-13 hours and for 7-24 hours in Parkinson patients.
Example 9
Carbidopa-Levodopa GRDF Formulation
[0118] Three additional GRDF formulations were manufactured.
TABLE-US-00008 [0118] mg per GRDF Levodopa 200.0 Carbidopa 50.0 KOH
6.0 Propylene glycol 94.2 Gelatin (Fish) 94.2 Eudragit L100-55 23.5
Eudragit L100 184.4 Eudragit S100 47.1 PEG 400 13.1 Tween 80 11.8
Povidone (Kollidon) 90F 13.7 Lutrol F127 (Poloxamer 407) 89.3 Total
827.3 Levodopa 300.0 Carbidopa 75.0 KOH 6.0 Propylene glycol 94.2
Gelatin (Fish) 94.2 Eudragit L100-55 23.5 Eudragit L100 83.9
Eudragit S100 47.1 PEG 400 43.5 Tween 80 14.7 Povidone (Kollidon)
90F 14.7 Lutrol F127 (Poloxamer 30.3 407) HPMCP 55 32.4 HPMCP 55 S
32.4 Total 827.0 Levodopa 300.0 Carbidopa 75.0 KOH 6.0 Propylene
glycol 94.2 Gelatin (Fish) 94.2 Eudragit L100-55 23.5 Eudragit L100
93.7 Eudragit S100 47.1 PEG 400 43.4 Tween 80 14.7 Povidone
(Kollidon) 90F 14.7 Lutrol F127 (Poloxamer 30.2 407) HPMCP 55 32.4
HPMCP 55 S 32.4 Total 836.8
Example 18
Carbidopa/Levodopa GRDF Immediate and Controlled Release Profiles
Compared to Immediate Release Sinemet.RTM. and Controlled Release
Sinemet CR.RTM. Pharmacokinetic Profiles in Healthy Subjects
The Objectives of the Study
[0119] The aim of this study was to evaluate the GRDF CD/LD optimal
profile, by comparing the pharmacokinetic profiles of Levodopa and
Carbidopa, following oral administration of a single-dose of the
three different controlled-release GRDF CD/LD formulations (Example
9) with differing ranges of release profiles, with the
pharmacokinetic profiles of a single-dose of the reference
formulation, Sinemet.RTM. 50/200 mg given as two 25/100 mg IR
tablets. An additional objective was to monitor subjects for
adverse events during the study period and to compare the safety of
the test formulations with the reference formulation.
Study Design
[0120] The study was designed as a single center, randomized,
single-dose, open label, four-way, four-treatment, comparative
crossover study. The study included four identical dosing periods,
with each period including a Carbidopa pre-treatment day and a
study-drug dosing day, during which a single dose of either one of
the test formulations or reference drug was administered after a
light-medium breakfast. Administration was followed by
pharmacokinetic blood sampling and adverse event monitoring for the
next 24 hours. A single dose of GRDF CD/LD with Levodopa either 200
or 300 mg and Carbidopa either 50 or 75 mg was administered to
twenty four (24) healthy male subjects aged 18-55 (inclusive) after
a light meal. The GRDF CD/LD was planned for a bid dosing schedule
for a total daily dose of 400-600 mg per day of Levodopa. The GRDF
CD/LD was formulated to release its two active ingredients as a
combination of immediate release and controlled release mechanisms
to provide quick yet steady levels of Levodopa. This study tested
the pharmacokinetics of the gastric retentive controlled release
GRDF CD/LD after a low-medium calorie breakfast with a low protein
content since protein competes with Levodopa absorption.
The Products
TABLE-US-00009 [0121] Test Product GRDF CD/LD Doses Administered
75/300 mg, or 50/200 mg Active Ingredient Carbidopa/Levodopa, IR +
CR Dosage Form capsule
[0122] The 75/300 rug dose was tested in two formulations (a and
b), the 50/200 mg dose was in one formulation.
TABLE-US-00010 Reference Product Sinemet .RTM..RTM. tablet
(Carbidopa/Levodopa 25/100 mg) Dose Administered 50 mg carbidopa
and 200 mg levodopa (2 tablets of 25/100 mg) Active Ingredient
Carbidopa/Levodopa immediate release Dosage Form Tablet
Manufacturer MERCK & CO., INC Carbidopa Pretreatment Lodosyn
.RTM. Dose Administered 50 mg (2 tablet) 3 times on Day (-1) Active
Ingredient Carbidopa Dosage Form Tablet Manufacturer MERCK &
CO., INC
[0123] The subjects were randomly assigned to a unique treatment
sequence.
Study Procedures
[0124] The study drugs were swallowed whole with 240 ml of water at
room temperature. Each subject was exposed to a washout period of
at least 7 days between treatments.
[0125] For measurement of Carbidopa and Levodopa plasma levels, for
each of the study periods, 17 serial blood samples were collected
per subject. The pharmacokinetic data of Levodopa were
evaluated.
Levodopa Results
[0126] The Levodopa results of 21 volunteers are shown in FIG. 13
in the Tables below:
TABLE-US-00011 Least-Squares Means (N = 21) GRDF GRDF GRDF CD/LD
CD/LD CD/LD Sinemet .RTM. 75/300 A 75/300 B 50/200 (2 .times. 100
mg) AUC 0-t 5291 5216 3732 3886 AUC 0-inf 5650 5545 3828 3945 Cmax
1240 1076 1116 1424 Tmax 2.60 2.74 2.51 1.38 MRT 0-t 5.56 6.64 4.14
2.80 MRT 0-inf 5.96 7.20 4.35 2.97 Ratios of Least Squares Means
GRDF GRDF GRDF 300A/ 300B/ GRDF 300A/GRDF GRDF GRDF GRDF 300B/ 300B
200 mg 300A/Sinemet .RTM. 200 mg Sinemet .RTM. AUC 1.014 1.418
1.362 1.398 1.342 0-inf Cmax 1.019 1.476 1.432 1.449 1.406 Tmax
1.153 1.111 0.871 0.964 0.756 MRT 0.673 1.690 1.801 2.509 2.674 0-t
MRT 0.837 1.342 1.989 1.602 2.376 0-inf AUC 0.828 1.370 2.010 1.654
2.427 0-t 90% Confidence Intervals on Least-Squares Geometric Mean
Ratios GRDF GRDF GRDF 300A/ 300A/ GRDF 300B/ GRDF GRDF GRDF 300A/
GRDF 300B/ 300B 200 mg Sinemet .RTM. 200 mg Sinemet .RTM. AUC 0-t
90% CI Low 0.968 1.353 1.294 1.330 1.271 90% CI Hi 1.070 1.495
1.429 1.470 1.405 AUC 0-inf 90% CI Low 0.931 1.348 1.303 1.344
1.298 90% CI Hi 1.100 1.577 1.520 1.545 1.489 Cmax 90% CI Low 1.029
0.965 0.751 0.829 0.646 90% CI Hi 1.314 1.232 0.959 1.059 0.824
[0127] The results indicate that gastroretentive controlled-release
delivery of levodopa yields true controlled-release behavior Both
gastroretentive formulations have shown comparable bioavailability,
slightly inferior to lower-doses CRDFs, and to the
immediate-release formulation, as expected. The mean residence
times are increased in gastroretentive controlled-release products
in comparison with immediate-release formulation, two-fold and
higher. The lack of proportionality of Cmax in correlation to the
dose is evident, and consistent with true controlled-release
behavior.
Example 11
Carbidopa-Levodopa GRDF Formulation
[0128] Two additional GRDF formulations was manufactured using the
following components for the internal layer, outer layers, and an
immediate release layer.
TABLE-US-00012 Outer (sum of Immediate Component Internal layer two
films) Release Layer Total Accordion pill Carbidopa/Levodopa 50/250
mg Amount/GRDF (mg) Carbidopa 25.0 25.0 50.0 Levodopa 180.0 70.0
250.0 Eudragit S100 47.1 47.1 Eudragit L100 61.0 23.5 84.5 Eudragit
L100-55 23.5 23.5 Fish Gelatin 94.2 94.2 Propylene glycol 94.2 94.2
KOH 6.0 6.0 Poloxamer 407 32.0 32.0 PEG 400 30.0 3.1 33.1 Tween 80
11.8 11.8 Povidone 90 13.7 13.7 Total 328.0 288.5 123.6 740.1
Accordion pill Carbidopa/Levodopa 50/375 mg Amount/GRDF (mg)
Carbidopa 25.0 25.0 50.0 Levodopa 275.0 100.0 375.0 Eudragit S100
47.1 47.1 Eudragit L100 80.8 23.5 104.3 Eudragit L100-55 23.5 23.5
Fish Gelatin 94.2 94.2 Propylene glycol 94.2 94.2 KOH 6.0 6.0
Poloxamer 407 45.1 45.1 PEG 400 40.4 3.9 44.3 Tween 80 14.7 14.7
Povidone 90 14.7 14.7 Total 466.3 288.5 158.3 913.1
Example 12
Carbidopa-Levodopa GRDF Release Profiles
[0129] In order to illustrate the ability of the GRDF to provide
both immediate release and controlled release of active
ingredients, the release profile for the above two
Carbidopa/Levodopa GRDF was determined. Carbidopa and Levodopa are
present in total amounts of 50 and 250 or 50 and 375 mg,
respectively (Example 11). Specifically, there are 25 mg Carbidopa
in the immediate release layer and 25 mg in the internal layer
which are provided to the patient as a controlled release. For
Levodopa, 70 or 100 mg are in the immediate release layer and 180
or 275 mg in the internal layer.
[0130] Experiments were conducted in an acetate buffer (USP) pH 4.1
in a USP Apparatus 2, 50 rpm. Immediate release for both drugs
occurred within 1 hour and extended release was seen for 12 hours
for the 250 mg Levodopa formulation and 16 hours for the 375 mg
Levodopa formulation.
* * * * *