U.S. patent application number 17/327721 was filed with the patent office on 2022-09-29 for expandable multi-excipient dosage form.
This patent application is currently assigned to Aron H. Blaesi. The applicant listed for this patent is Aron H. Blaesi. Invention is credited to Aron H. Blaesi, Nannaji Saka.
Application Number | 20220304924 17/327721 |
Document ID | / |
Family ID | 1000005663471 |
Filed Date | 2022-09-29 |
United States Patent
Application |
20220304924 |
Kind Code |
A1 |
Blaesi; Aron H. ; et
al. |
September 29, 2022 |
Expandable multi-excipient dosage form
Abstract
Many drug therapies could be greatly improved by dosage forms
that reside in the stomach for prolonged time and release the drug
slowly. In this specification, therefore, an expandable,
multi-excipient dosage form for prolonged release is disclosed. The
dosage form generally comprises a three-dimensional structural
framework of solid elements. The elements comprise at least a drug,
at least a physiological fluid-absorptive excipient, and at least a
strength-enhancing excipient. Upon ingestion, the three-dimensional
structural framework expands in at least one dimension and forms an
expanded semi-solid mass that can be retained in the stomach and
release drug over prolonged time.
Inventors: |
Blaesi; Aron H.; (Cambridge,
MA) ; Saka; Nannaji; (Cambridge, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Blaesi; Aron H. |
Cambridge |
MA |
US |
|
|
Assignee: |
Blaesi; Aron H.
Cambridge
MA
|
Family ID: |
1000005663471 |
Appl. No.: |
17/327721 |
Filed: |
May 23, 2021 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
PCT/US2021/022857 |
Mar 17, 2021 |
|
|
|
17327721 |
|
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/32 20130101;
A61K 9/0065 20130101; A61K 9/70 20130101; A61K 47/38 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 9/70 20060101 A61K009/70; A61K 47/38 20060101
A61K047/38; A61K 47/32 20060101 A61K047/32 |
Claims
1. A pharmaceutical dosage form comprising: a drug-containing solid
comprising an outer surface and an internal three dimensional
structural framework of one or more structural elements, said
framework contiguous with and terminating at said outer surface;
said elements having segments spaced apart from adjoining segments,
thereby defining one or more free spaces in the drug-containing
solid; said elements further comprising at least one active
ingredient and at least two excipients; said at least two
excipients comprising at least one physiological fluid-absorptive
polymeric constituent and at least one strength-enhancing polymeric
constituent; wherein upon exposure to a physiological fluid, said
strength-enhancing excipient forms a fluid-permeable, semi-solid
network mechanically supporting said framework; and said
fluid-absorptive excipient transitions to a viscous mass or a
viscous solution expanding said framework along at least one
dimension with absorption of said physiological fluid.
2. The dosage form of claim 1, wherein one or more phases
comprising strength-enhancing excipient form a substantially
continuous or connected structure along the lengths of one or more
structural elements.
3. The dosage form of claim 1, wherein one or more free spaces are
interconnected.
4. The dosage form of claim 3, wherein upon ingestion by a human or
animal subject, physiological fluid percolates at least one
interconnected free space and diffuses into one or more said
elements, thereby expanding said framework in all dimensions and
transitioning said framework to a semi-solid mass releasing said
drug over time.
5. The dosage form of claim 1, wherein upon exposure to a
physiological fluid, said framework expands to a length between 1.3
and 4 times its length prior to exposure to said physiological
fluid.
6. The dosage form of claim 5, wherein upon prolonged exposure to a
physiological fluid, said expanded framework or semi-solid mass
maintains its length between 1.3 and 4 times the initial length for
prolonged time.
7. The dosage form of claim 1, wherein upon exposure to a
physiological fluid, said framework transitions to a semi-solid
mass, and wherein said semi-solid mass comprises a substantially
continuous or connected network of one or more strength-enhancing
excipients.
8. The dosage form of claim 1, wherein the average thickness of the
one or more structural elements is in the range of 1 .mu.m to 1.5
mm.
9. The dosage form of claim 1, wherein the three dimensional
structural framework comprises criss-crossed stacked layers of
fibers.
10. The dosage form of claim 1, wherein the solubility of a
physiological fluid in at least one absorptive excipient is greater
than 600 mg/ml.
11. The dosage form of claim 1, wherein at least one absorptive
excipient comprises hydroxypropyl methylcellulose.
12. The dosage form of claim 1, wherein at least one absorptive
excipient is selected from the group comprising hydroxypropyl
methylcellulose, hydroxyethyl cellulose, polyvinyl alcohol,
polyvinylpyrrolidone, sodium alginate, hydroxypropyl cellulose,
hydroxyethyl cellulose, methyl cellulose, hydroxypropyl methyl
ether cellulose, starch, chitosan, pectin, polymethacrylates (e.g.,
poly(methacrylic acid, ethyl acrylate) 1:1, or
butylmethacrylat-(2-dimethylaminoethyl)methacrylat-methylmathacry-
lat-copolymer), polyethylene oxide, or vinylpyrrolidone-vinyl
acetate copolymer.
13. The dosage form of claim 1, wherein the solubility of a
relevant physiological fluid in at least a strength-enhancing
excipient is no greater than 750 mg/ml under physiological
conditions.
14. The dosage form of claim 1, wherein at least a
strength-enhancing excipient comprises an elastic modulus in the
range of 0.5 MPa-100 MPa after soaking with a physiological fluid
under physiological conditions.
15. The dosage form of claim 1, wherein at least a
strength-enhancing excipient comprises a tensile strength in the
range of 0.05 MPa-200 MPa after soaking with a physiological fluid
under physiological conditions.
16. The dosage form of claim 1, wherein at least a
strength-enhancing excipient comprises a strain at fracture greater
than 0.5 after soaking with a physiological fluid under
physiological conditions.
17. The dosage form of claim 1, wherein the volume or weight
fraction of the one or more absorptive excipients in the three
dimensional structural framework of one or more elements is in the
range between 0.1 and 0.85.
18. The dosage form of claim 1, wherein the volume or weight
fraction of the one or more strength-enhancing excipients in the
three dimensional structural framework of one or more elements is
in the range between 0.15 and 0.9.
19. The dosage form of claim 1, wherein at least one
strength-enhancing excipient comprises an enteric polymer, said
enteric polymer having a solubility at least 10 times greater in a
basic solution having a pH value greater than 7 than in an acidic
solution having a a pH value no greater than 5.
20. The dosage form of claim 1, wherein at least one
strength-enhancing excipient comprises methacrylic acid-ethyl
acrylate copolymer.
21. The dosage form of claim 1, wherein at least one
strength-enhancing excipient is selected from the group comprising
hydroxypropyl methyl cellulose acetate succinate, polyvinyl
acetate, ethyl acrylate polymers (e.g., polymers including ethyl
acrylate), methacrylate polymers (e.g., polymers including
methacrylate), ethyl acrylate-methylmethacrylate copolymers,
Poly[Ethyl acrylate, methyl methacrylate, trimethylammonioethyl
methacrylate chloride], Poly[Ethyl acrylate, methyl methacrylate,
trimethylammonioethyl methacrylate chloride], and
ethylcellulose.
22. The dosage form of claim 1, wherein said at least two
excipients form a solid solution through the thickness of one or
more elements.
23. The dosage form of claim 1, wherein an element or framework
comprises a plurality of segments having substantially the same
weight fraction of physiological fluid-absorptive and/or
strength-enhancing excipient distributed within the segments.
24. The dosage form of claim 1, wherein at least one free space is
filled with matter removable by a physiological fluid under
physiological conditions.
25. The dosage form of claim 1, wherein upon immersion in a
physiological fluid the drug-containing solid transitions to a
semi-solid mass, and wherein said semi-solid mass comprises an
elastic modulus in the range of 0.005 MPa-15 MPa.
26. The dosage form of claim 1, wherein upon immersion in a
physiological fluid the drug-containing solid transitions to a
semi-solid mass, and wherein said semi-solid mass comprises a
tensile strength in the range between 0.002 MPa and 15 MPa.
27. The dosage form of claim 1, wherein eighty percent of the drug
content is released from the drug containing solid into a
physiological fluid within 1 hour to 30 days after immersion of the
drug-containing solid into said physiological fluid under
physiological conditions.
28. The dosage form of claim 1, wherein upon ingestion by a human
or animal subject, said dosage form is gastroretentive.
29. A pharmaceutical dosage form comprising: a drug-containing
solid comprising an outer surface and an internal three dimensional
structural framework of one or more thin structural elements, said
framework contiguous with and terminating at said outer surface;
said elements having segments spaced apart from adjoining segments,
thereby defining one or more interconnected free spaces through the
drug-containing solid; said elements further comprising at least
one active ingredient and at least two excipients; said at least
two excipients comprising at least one physiological
fluid-absorptive polymeric constituent and at least one
strength-enhancing polymeric constituent; whereby upon immersion in
a physiological fluid, said fluid percolates at least one
interconnected free space and diffuses into one or more said
elements, so that the framework expands in at least one dimension
and transitions to a semi-solid mass; wherein said semi-solid mass
releases drug over prolonged time.
30. A pharmaceutical dosage form comprising: a drug-containing
solid comprising an outer surface and an internal three dimensional
structural framework of one or more structural elements, said
framework contiguous with and terminating at said outer surface;
said elements having segments spaced apart from adjoining segments,
thereby defining one or more interconnected free spaces through the
drug-containing solid; said elements further comprising at least
one active ingredient and at least two excipients; said at least
two excipients comprising one or more fluid-absorptive polymeric
constituents within which the solubility of a physiological fluid
is greater than 600 mg/ml; said at least two excipients further
comprising one or more strength-enhancing polymeric constituents;
said one or more strength-enhancing polymeric constituents having
an elastic modulus in the range between 0.2 MPa and 200 MPa, and a
strain at fracture greater than 0.2 after soaking with a
physiological fluid under physiological conditions; wherein upon
exposure to a physiological fluid, said strength-enhancing
excipient forms a fluid-permeable, semi-solid network mechanically
supporting said framework; and said fluid-absorptive excipient
transitions to a viscous mass or a viscous solution expanding said
framework along at least one dimension with absorption of said
physiological fluid.
Description
CROSS-REFERENCE TO RELATED INVENTIONS
[0001] This application is a continuation of, and incorporates
herein by reference in its entirety, the International Application
No. PCT/US2021/022857 filed on Mar. 17, 2021 and titled
"Expandable, multi-excipient structured dosage form for prolonged
drug release", which claims priority to and the benefit of the U.S.
Provisional Application No. 62/991,052 filed on Mar. 17, 2020, the
U.S. Provisional Application No. 63/085,893 filed on Sep. 30, 2020,
and the U.S. Provisional Application No. 63/158,870 filed on Mar.
9, 2021. All foregoing applications are hereby incorporated by
reference in their entirety.
[0002] This application is related to, and incorporates herein by
reference in their entirety, the U.S. application Ser.
No.15/482,776 filed on Apr. 9, 2017 and titled "Fibrous dosage
form", the U.S. application Ser. No. 15/964,058 filed on Apr. 26,
2018 and titled "Method and apparatus for the manufacture of
fibrous dosage forms", the U.S. application Ser. No. 16/860,911
filed on Apr. 28, 2020 and titled "Expandable structured dosage
form for immediate drug delivery", the U.S. application Ser. No.
16/916,208 filed on Jun. 30, 2020 and titled "Dosage form
comprising structural framework of two-dimensional elements", the
International Application No. PCT/US19/19004 filed on Feb. 21, 2019
and titled "Expanding structured dosage form", and the
International Application No. PCT/US19/52030 filed on Sep. 19, 2019
and titled "Dosage form comprising structured solid-solution
framework of sparingly-soluble drug and method for manufacture
thereof".
BACKGROUND OF THE INVENTION
[0003] The prevalent oral-delivery dosage forms, the tablets and
capsules, are porous solids of compacted drug and excipient
particles. As shown schematically in FIG. 1a, the typical ingested
dosage form may fragment into its particulate constituents in the
stomach and release drug molecules. The drug particles and
molecules may then traverse along the gastrointestinal tract, and
the drug molecules may be absorbed by the blood stream. Drug that
reaches the end of the gastrointestinal tract may be excreted.
[0004] By the traditional solid dosage forms, however, many kinds
of drug cannot be optimally delivered. For example, drugs that are
soluble at very low pH, but insoluble at higher pH, may be absorbed
only in the upper gastrointestinal tract. The residence time in the
upper part is generally short, which may limit the amount of drug
absorbed and the bioavailability, and preclude prolonged drug
delivery. Consequently, the efficacy, safety, and convenience of
the drug therapy may be compromised.
[0005] Drug absorption could be extended by dosage forms that
reside in the stomach for prolonged time and release drug slowly.
Indeed, over the years several gastroretentive devices have been
proposed. The most common are the floating and the expandable
dosage forms.
[0006] The floating dosage forms are designed to float over the
gastric contents in the upper stomach, thus preventing their
passage into the small intestine. The concept, however, generally
requires that the stomach is frequently filled with food and drink,
and that the patient is in the upright posture. Because of these
impractical requirements such dosage forms may not be
preferred.
[0007] Expandable dosage forms should be smaller than the diameter
of the esophagus (.about.15 mm) to facilitate ingestion, FIG. 1b.
But in the stomach they should expand to a size greater than the
diameter of the pylorus (.about.13-20 mm) to preclude passage into
the small intestine. To date, however, a safe, ingestible dosage
form that expands rapidly and releases drug slowly into the stomach
is not available.
[0008] Accordingly, in the International Application No.
PCT/US19/19004 the present inventors (Blaesi and Saka) have
introduced fibrous dosage forms that expand rapidly due to fast
water absorption by the thin fibers. The dosage form may then form
a viscous gel from which drug molecules are released slowly.
[0009] In the prior disclosure, the non-limiting experimental
dosage forms that expanded to twice their initial length in 15
minutes released 80% of the drug in about two hours. In some cases,
however, the therapeutic benefits of the expandable,
gastroretentive dosage forms may be even greater if the drug
release time could be further prolonged.
[0010] In the present disclosure, therefore, new formulations and
dosage form microstructures are presented to stabilize and
strengthen the expanded dosage form without compromising its fast
expansion. Concepts for controlling and extending the range of the
drug release time from the stabilized, expanded dosage form are
also disclosed.
SUMMARY OF THE INVENTION
[0011] Generally, the dosage forms disclosed herein comprise a
three-dimensional structural framework of solid elements. The
elements comprise at least a drug, at least a physiological
fluid-absorptive excipient, and at least a strength-enhancing
excipient. Upon ingestion, the three-dimensional structural
framework expands in at least one dimension and forms an expanded
semi-solid mass that can be retained in the stomach and release
drug over prolonged time.
[0012] More specifically, in one aspect, the invention herein
comprises a fiber for pharmaceutical dosage form fabrication or
construction comprising at least one active ingredient and at least
two excipients forming the fiber; said at least two excipients
comprising one or more fluid-absorptive polymeric constituents and
one or more strength-enhancing polymeric constituents; wherein upon
exposure to physiological fluid, said one or more
strength-enhancing excipients form a fluid-permeable, semi-solid
network mechanically supporting the fiber; and said one or more
fluid-absorptive excipients transition to a viscous mass or a
viscous solution expanding said fiber along at least one dimension
with absorption of said physiological fluid.
[0013] In another aspect, the invention herein comprises a fiber
for pharmaceutical dosage form fabrication comprising at least one
active ingredient and at least two excipients forming the fiber;
said at least two excipients comprising one or more
fluid-absorptive polymeric constituents within which the solubility
of a physiological fluid (e.g., gastric fluid) is greater than 600
mg/ml; said at least two excipients further comprising one or more
strength-enhancing polymeric constituents; said one or more
strength-enhancing polymeric constituents having an elastic modulus
in the range between 0.2 MPa and 500 MPa and a strain at fracture
greater than 0.2 after soaking with a physiological fluid (e.g.,
gastric fluid) under physiological conditions; wherein upon
exposure to a physiological fluid, said one or more
strength-enhancing excipients form a fluid-permeable, semi-solid
network mechanically supporting the fiber; and said one or more
fluid-absorptive excipients transition to a viscous mass or a
viscous solution expanding said fiber along at least one dimension
with absorption of said physiological fluid.
[0014] In some embodiments, the solubility of physiological fluid
in the absorptive excipient is greater than 750 mg/ml.
[0015] In some embodiments, rate of penetration of
physiological/body fluid into an absorptive excipient under
physiological conditions is greater than the average thickness of
the fiber, element, or elements divided by 3600 seconds.
[0016] In some embodiments, at least one absorptive excipient
comprises hydroxypropyl methylcellulose.
[0017] In some embodiments, the molecular weight of said
hydroxypropyl methylcellulose excipient is in the range between 30
kg/mol and 1000 kg/mol (e.g., between 50 kg/mol and 300
kg/mol).
[0018] In some embodiments, at least one absorptive excipient is
selected from the group comprising hydroxypropyl methylcellulose,
hydroxyethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone,
sodium alginate, hydroxypropyl cellulose, hydroxyethyl cellulose,
methyl cellulose, hydroxypropyl methyl ether cellulose, starch,
chitosan, pectin, polymethacrylates (e.g., poly(methacrylic acid,
ethyl acrylate) 1:1, or
butylmethacrylat-(2-dimethylaminoethyl)methacrylat-methylmathacrylat-copo-
lymer), polyethylene oxide, or vinylpyrrolidone-vinyl acetate
copolymer.
[0019] In some embodiments, the molecular weight of at least one
absorptive excipient is in the range of 30 kg/mol to 100,000 kg/mol
(e.g., between 50 kg/mol and 100,000 kg/mol).
[0020] In some embodiments, the solubility of a relevant
physiological fluid in at least a strength-enhancing excipient is
no greater than 750 mg/ml (e.g., no greater than 600 mg/ml) under
physiological conditions.
[0021] In some embodiments, at least a strength-enhancing excipient
comprises an elastic modulus in the range of 0.3 MPa-150 MPa (e.g.,
0.5 MPa-100 MPa) after soaking with a physiological fluid under
physiological conditions.
[0022] In some embodiments, at least a strength-enhancing excipient
comprises a tensile strength in the range of 0.05 MPa-200 MPa
(e.g., 0.1 MPa-100 MPa) after soaking with a physiological fluid
under physiological conditions.
[0023] In some embodiments, at least a strength-enhancing excipient
comprises a strain at fracture greater than 0.3 (e.g., greater than
0.4, or greater than 0.5, or greater than 0.6) after soaking with a
physiological fluid under physiological conditions.
[0024] In some embodiments, the volume or weight fraction of the
one or more absorptive excipients in the fiber is in the range
between 0.1 and 0.85 (e.g., between 0.15 and 0.8, or between 0.15
and 0.75).
[0025] In some embodiments, the volume or weight fraction of the
one or more strength-enhancing excipients in the fiber is in the
range between 0.15 and 0.9 (e.g. 0.2-0.9, 0.25-0.9, 0.3-0.9).
[0026] In some embodiments, at least one strength-enhancing
excipient comprises an enteric polymer.
[0027] In some embodiments, at least one strength-enhancing
excipient comprises an enteric polymer, said enteric polymer having
a solubility at least 10 times greater in basic solution having a
pH value greater than 7 than in acidic solution having a pH value
no greater than 5.
[0028] In some embodiments, at least one strength-enhancing
excipient comprises methacrylic acid-ethyl acrylate copolymer.
[0029] In some embodiments, at least one strength-enhancing
excipient is selected from the group comprising hydroxypropyl
methyl cellulose acetate succinate, polyvinyl acetate, ethyl
acrylate polymers (e.g., polymers including ethyl acrylate),
methacrylate polymers (e.g., polymers including methacrylate),
ethyl acrylate-methylmethacrylate copolymers, Poly[Ethyl acrylate,
methyl methacrylate, trimethylammonioethyl methacrylate chloride],
Poly[Ethyl acrylate, methyl methacrylate, trimethylammonioethyl
methacrylate chloride], and ethylcellulose.
[0030] In some embodiments, said at least two excipients form a
solid solution through the thickness of the fiber.
[0031] In some embodiments, one or more phases comprising
strength-enhancing excipient are substantially connected or
substantially contiguous along the length of the fiber.
[0032] In some embodiments, said fiber comprises a plurality of
segments having substantially the same weight fraction of
physiological fluid-absorptive excipient distributed within the
segments.
[0033] In some embodiments, said fiber comprises a plurality of
segments having substantially the same weight fraction of
strength-enhancing excipient distributed within the segments.
[0034] In some embodiments, upon exposure to a physiological fluid
under physiological conditions, the diffusivity of absorptive
polymeric excipient through said fiber is no greater than
10.sup.-12 m.sup.2/s (e.g., no greater than 0.5.times.10.sup.-12
m.sup.2/s, or no greater than 0.2.times.10.sup.-12 m.sup.2/s).
[0035] In some embodiments, upon exposure to a physiological fluid
under physiological conditions, the diffusivity of said
physiological fluid through said fiber is greater than
0.2.times.10.sup.-12 m.sup.2/s (e.g., greater than
0.5.times.10.sup.-12 m.sup.2/s, or greater than 10.sup.-12
m.sup.2/s).
[0036] In some embodiments, upon exposure to a physiological fluid,
said fiber expands to a length between 1.3 and 4 times its length
prior to exposure to said physiological fluid.
[0037] In some embodiments, upon exposure to a physiological fluid,
said fiber expands in all dimensions.
[0038] In some embodiments, upon exposure to a physiological fluid,
said fiber transitions to a semi-solid mass.
[0039] In some embodiments, upon exposure to a physiological fluid,
said fiber transitions to a semi-solid mass, and wherein the one or
more strength-enhancing excipients form a connected network through
the semi-solid mass.
[0040] In some embodiments, said expanded fiber or semi-solid mass
maintains its length between 1.3 and 4 times the initial length for
prolonged time upon prolonged exposure to a physiological
fluid.
[0041] In some embodiments, an expanded semi-solid mass comprises
an elastic modulus in the range of 0.005 MPa-30 MPa (e.g., between
0.005 MPa-20 MPa, or 0.02 MPa-20 MPa).
[0042] In some embodiments, an expanded semi-solid mass comprises a
tensile strength in the range between 0.002 MPa and 20 MPa (e.g.,
between 0.005 MPa and 15 MPa).
[0043] In another aspect, the invention herein comprises a
pharmaceutical dosage form comprising a drug-containing solid
comprising an outer surface and an internal three dimensional
structural framework of one or more thin structural elements, said
framework contiguous with and terminating at said outer surface;
said elements having segments spaced apart from adjoining segments,
thereby defining one or more free spaces in the drug-containing
solid; said elements further comprising at least one active
ingredient and at least two excipients; said at least two
excipients comprising at least one physiological fluid-absorptive
polymeric constituent and at least one strength-enhancing polymeric
constituent; whereby upon immersion in a physiological fluid, said
fluid percolates at least one free space and diffuses into one or
more said elements, so that the framework expands in at least one
dimension and transitions to a semi-solid mass; wherein said
semi-solid mass releases the drug over prolonged time.
[0044] In some embodiments, upon exposure to a physiological fluid,
said strength-enhancing excipient forms a fluid-permeable,
semi-solid network to mechanically support said framework; and said
fluid-absorptive excipient transitions to a semi-solid or viscous
mass expanding said framework along at least one dimension with
absorption of said physiological fluid.
[0045] In a further aspect, a pharmaceutical dosage form comprises
a drug-containing solid comprising an outer surface and an internal
three dimensional structural framework of one or more thin
structural elements, said framework contiguous with and terminating
at said outer surface; said elements having segments spaced apart
from adjoining segments, thereby defining one or more
interconnected free spaces through the drug-containing solid; said
elements further comprising at least one active ingredient and at
least two excipients; said at least two excipients comprising at
least one physiological fluid-absorptive polymeric constituent and
at least one strength-enhancing polymeric constituent; wherein upon
exposure to a physiological fluid, said strength-enhancing
excipient forms a fluid-permeable, semi-solid network mechanically
supporting said framework; and said fluid-absorptive excipient
transitions to a viscous mass or a viscous solution expanding said
framework along at least one dimension with absorption of said
physiological fluid.
[0046] In a further aspect a pharmaceutical dosage form herein
comprises a drug-containing solid comprising an outer surface and
an internal three dimensional structural framework of one or more
thin structural elements, said framework contiguous with and
terminating at said outer surface; said elements having segments
spaced apart from adjoining segments, thereby defining one or more
interconnected free spaces through the drug-containing solid; said
elements further comprising at least one active ingredient and at
least two excipients; said at least two excipients comprising one
or more fluid-absorptive polymeric constituents within which the
solubility of a physiological fluid (e.g., gastric fluid) is
greater than 600 mg/ml; said at least two excipients further
comprising one or more strength-enhancing polymeric constituents;
said one or more strength-enhancing polymeric constituents having
an elastic modulus in the range between 0.1 MPa and 500 MPa and a
strain at fracture greater than 0.2 after soaking with a
physiological fluid (e.g., gastric fluid) under physiological
conditions; wherein upon exposure to a physiological fluid, said
one or more strength-enhancing excipients form a fluid-permeable,
semi-solid network mechanically supporting the fiber; and said one
or more fluid-absorptive excipients transition to a viscous mass or
a viscous solution expanding said fiber along at least one
dimension with absorption of said physiological fluid.
[0047] In some embodiments, one or more phases comprising
strength-enhancing excipient form a substantially continuous or
connected structure along the lengths of one or more structural
elements.
[0048] In some embodiments, one or more phases comprising
strength-enhancing excipient form a substantially continuous or
connected structure through the three dimensional structural
framework.
[0049] In some embodiments, upon ingestion by a human or animal
subject, physiological fluid percolates at least one free space and
diffuses into one or more said elements, thereby expanding said
framework in all dimensions and transitioning said framework to a
semi-solid mass releasing said drug over time.
[0050] In some embodiments, upon exposure to a physiological fluid,
said framework expands to a length between 1.3 and 4 times its
length prior to exposure to said physiological fluid.
[0051] In some embodiments, upon prolonged exposure to a
physiological fluid, said expanded framework or semi-solid mass
maintains its length between 1.3 and 4 times the initial length for
prolonged time.
[0052] In some embodiments, the semi-solid mass comprises a
substantially continuous or connected network of one or more
strength-enhancing excipients.
[0053] In some embodiments, the semi-solid mass comprises a
substantially continuous or connected network of strength-enhancing
excipient that extends over the length, width, and thickness of
said semi-solid mass.
[0054] In some embodiments, one or more phases comprising
strength-enhancing excipient extend along the lengths of the
structural elements.
[0055] In some embodiments, the average thickness of the one or
more structural elements is in the range of 1 .mu.m to 1.5 mm.
[0056] In some embodiments, one or more interconnected free spaces
form an open pore network that extends over a length at least equal
to the thickness of the drug-containing solid.
[0057] In some embodiments, one or more interconnected free spaces
terminate at the outer surface of the drug-containing solid.
[0058] In some embodiments, the free space is contiguous.
[0059] In some embodiments, the effective free spacing between
segments across one or more interconnected free spaces on average
is in the range of 1 .mu.m-2.5 mm.
[0060] In some embodiments, the free spacing between segments of
the one or more structural elements is precisely controlled across
the drug-containing solid.
[0061] In some embodiments, the three dimensional structural
framework comprises a single continuous structure through the
drug-containing solid.
[0062] In some embodiments, the volume fraction of structural
elements within the drug-containing solid is in the range between
0.2 and 0.98 (e.g., 0.25-0.98 or 0.3-0.98).
[0063] In some embodiments, the three dimensional structural
framework comprises criss-crossed stacked layers of fibers.
[0064] In some embodiments, the solubility of physiological fluid
in at least one absorptive excipients is greater than 700 mg/ml
(e.g., greater than 775 mg/ml, or greater than 825 mg/ml).
[0065] In some embodiments, rate of penetration of
physiological/body fluid into an absorptive excipient under
physiological conditions is greater than the average thickness of
the elements divided by 3600 seconds.
[0066] In some embodiments, at least one absorptive excipient
comprises hydroxypropyl methylcellulose.
[0067] In some embodiments, the molecular weight of said
hydroxypropyl methyl cellulose excipient is in the range between 45
kg/mol and 500 kg/mol.
[0068] In some embodiments, at least one absorptive excipient is
selected from the group comprising hydroxypropyl methylcellulose,
hydroxyethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone,
sodium alginate, hydroxypropyl cellulose, hydroxyethyl cellulose,
methyl cellulose, hydroxypropyl methyl ether cellulose, starch,
chitosan, pectin, polymethacrylates (e.g., poly(methacrylic acid,
ethyl acrylate) 1:1, or
butylmethacrylat-(2-dimethylaminoethyl)methacrylat-methylmathacrylat-copo-
lymer), polyethylene oxide, or vinylpyrrolidone-vinyl acetate
copolymer.
[0069] In some embodiments, the molecular weight of at least one
absorptive excipient is in the range of 50 kg/mol to 10,000
kg/mol.
[0070] In some embodiments, the solubility of a relevant
physiological fluid in at least a strength-enhancing excipient is
no greater than 750 mg/ml under physiological conditions.
[0071] In some embodiments, at least a strength-enhancing excipient
comprises an elastic modulus in the range of 0.5 MPa-100 MPa after
soaking with a physiological fluid under physiological
conditions.
[0072] In some embodiments at least a strength-enhancing excipient
comprises a tensile strength in the range of 0.05 MPa-100 MPa after
soaking with a physiological fluid under physiological
conditions.
[0073] In some embodiments, at least a strength-enhancing excipient
comprises a strain at fracture greater than 0.5 after soaking with
a physiological fluid under physiological conditions.
[0074] In some embodiments, the volume or weight fraction of the
one or more absorptive excipients in the fiber is in the range
between 0.15 and 0.8.
[0075] In some embodiments, the volume or weight fraction of the
one or more strength-enhancing excipients in the fiber is in the
range between 0.25 and 0.9.
[0076] In some embodiments, at least one strength-enhancing
excipient comprises an enteric polymer.
[0077] In some embodiments, at least one strength-enhancing
excipient comprises an enteric polymer, said enteric polymer having
a solubility at least 10 times greater in basic solution having a
pH value greater than 7 than in acidic solution having a a pH value
no greater than 5.
[0078] In some embodiments, at least one strength-enhancing
excipient comprises methacrylic acid-ethyl acrylate copolymer.
[0079] In some embodiments, at least one strength-enhancing
excipient is selected from the group comprising hydroxypropyl
methyl cellulose acetate succinate, polyvinyl acetate, ethyl
acrylate polymers (e.g., polymers including ethyl acrylate),
methacrylate polymers (e.g., polymers including methacrylate),
ethyl acrylate-methylmethacrylate copolymers, Poly[Ethyl acrylate,
methyl methacrylate, trimethylammonioethyl methacrylate chloride],
Poly[Ethyl acrylate, methyl methacrylate, trimethylammonioethyl
methacrylate chloride], and ethylcellulose.
[0080] In some embodiments, said at least two excipients form a
solid solution through the thickness of the fiber.
[0081] In some embodiments, one or more phases comprising
strength-enhancing excipient are substantially connected or
substantially contiguous along the length of the fiber.
[0082] In some embodiments, an element or framework comprises a
plurality of segments having substantially the same weight fraction
of physiological fluid-absorptive excipient distributed within the
segments.
[0083] In some embodiments, an element or framework comprises a
plurality of segments having substantially the same weight fraction
of strength-enhancing excipient distributed within the
segments.
[0084] In some embodiments, upon exposure to a physiological fluid
under physiological conditions, the diffusivity of absorptive
polymeric excipient through said fiber is no greater than
10.sup.-12 m.sup.2/s (e.g., no greater than 0.5.times.10.sup.-12
m.sup.2/s, or no greater than 0.2.times.10.sup.-12 m.sup.2/s).
[0085] In some embodiments, upon exposure to a physiological fluid
under physiological conditions, the diffusivity of said
physiological fluid through said fiber is greater than
0.2.times.10.sup.-12 m.sup.2/s (e.g., greater than
0.5.times.10.sup.-12 m.sup.2/s, or greater than 10.sup.-12
m.sup.2/s).
[0086] In some embodiments, at least one free space is filled with
matter removable by a physiological fluid under physiological
conditions.
[0087] In some embodiments, upon immersion in a physiological
fluid, the drug-containing solid transitions to a semi-solid mass
comprising a length in the range between 1.3 and 3.5 times its
length prior to exposure to said physiological fluid within no more
than 300 minutes of immersion in said physiological fluid.
[0088] In some embodiments, upon immersion in a physiological
fluid, the drug-containing solid transitions to a semi-solid mass
comprising a length in the range between 1.3 and 3.5 times its
length prior to exposure to said physiological fluid within no more
than 100 minutes of immersion in said physiological fluid.
[0089] In some embodiments, said expanded fiber or semi-solid mass
maintains its length between 1.3 and 4 times the initial length for
prolonged time.
[0090] In some embodiments, an expanded semi-solid mass comprises
an elastic modulus in the range of 0.002 MPa-10 MPa.
[0091] In some embodiments, an expanded semi-solid mass comprises a
tensile strength in the range between 0.001 MPa and 10 MPa.
[0092] In some embodiments, eighty percent of the drug content is
released from the drug containing solid into a physiological fluid
within 1 hour to 30 days after immersion of the drug-containing
solid into said physiological fluid under physiological
conditions.
[0093] In some embodiments, eighty percent of the drug content is
released from the drug containing solid into a physiological fluid
within 2 hours to 150 hours after immersion of the drug-containing
solid into said physiological fluid under physiological
conditions.
[0094] In some embodiments, upon ingestion by a human or animal
subject, said dosage form is gastroretentive.
[0095] Elements of embodiments described with respect to one aspect
of the invention can be applied with respect to another aspect. By
way of example but not by way of limitation, certain embodiments of
the claims described with respect to the first aspect can include
features of the claims described with respect to the second or
third aspect, and vice versa.
[0096] This invention may be better understood by reference to the
accompanying drawings, attention being called to the fact that the
drawings are primarily for illustration, and should not be regarded
as limiting.
BRIEF DESCRIPTION OF THE DRAWINGS
[0097] The objects, embodiments, features, and advantages of the
present invention are more fully understood when considered in
conjunction with the following accompanying drawings:
[0098] FIG. 1 presents schematics of the passage of dosage forms
through the gastrointestinal tract: (a) conventional dosage form,
and (b) expandable fibrous dosage form. The symbols are designated
as follows: t is the time; t.sub.0 is the time when the dosage form
enters the stomach; t.sub.1, t.sub.2, and t.sub.3 are specific
times after the dosage form entered the stomach where
t.sub.1<t.sub.2<t.sub.3; t.sub.dis is the time when the
expandable fibrous dosage form disintegrates; t.sub.tr is the
gastrointestinal transit time;
[0099] FIG. 2 shows a non-limiting example of an element for dosage
form construction or fabrication as disclosed herein, and the
expansion and microstructural evolution upon immersion in a
dissolution fluid; t.sub.1, t.sub.2, and t.sub.3 are specific times
after immersion of the element in the dissolution fluid, where
t.sub.1<t.sub.2<t.sub.3;
[0100] FIG. 3 shows a non-limiting example of a pharmaceutical
dosage form according to the invention herein and the expansion and
drug release processes upon immersion in a dissolution fluid;
[0101] FIG. 4 shows another non-limiting example of a
pharmaceutical dosage form according to the invention herein and
the expansion and drug release processes upon immersion in a
dissolution fluid;
[0102] FIG. 5 illustrates a non-limiting course of a dosage form
herein after ingestion by a human or animal subject at the
following times: (a) t=t.sub.0, (b) t=t.sub.1>t.sub.0, (c)
t=t.sub.2>t.sub.1, and (d) t.apprxeq.t.sub.dis. The times are
designated as follows: t.sub.0 is time when dosage form enters the
stomach and t.sub.dis is time when dosage form disintegrates or
fragments;
[0103] FIG. 6 shows another non-limiting example of a
pharmaceutical dosage form according to the invention herein and
the expansion and drug release processes upon immersion in a
dissolution fluid;
[0104] FIG. 7 presents non-limiting schematics of water absorption
and water concentration in the fiber: (a) initial solid fiber
comprising a solid solution of sparingly-soluble drug, absorptive
excipient (HPMC), and strength-enhancing excipient (an enteric
excipient), and (b) semi-solid or viscous fiber at time t after
immersion in acidic water. Because the solubility of acidic water
in HPMC is high but low in the enteric excipient and very small in
the drug, the HPMC-enteric excipient-drug-water solution may
separate out into three phases: (1) a highly viscous solution of
water, HPMC, and dissolved drug molecules, (2) water-plasticized
enteric excipient, and (3) drug particles;
[0105] FIG. 8 shows a non-limiting schematic microstructure of an
expanding dosage form: (a) initial structure and (b) structure at
time t after exposure to a physiological or dissolution fluid;
[0106] FIG. 9 presents non-limiting schematics of drug release by
expanded fibrous dosage forms: (a) .phi..about.0, (b)
0<.phi.<1, and (c) .phi..about.1. .phi. is the volume
fraction of fibers in the dosage form. The time increases towards
the right in the sequences of the schematics;
[0107] FIG. 10 is a non-limiting schematic illustrating drug
release from an expanded fiber containing both drug particles and
drug molecules: (a) expanded fiber at a specific time after
immersion in a stirred dissolution fluid, (b) drug concentration
versus radius, r, assuming an infinitesimally thin interfacial
region and a quasi-steady concentration profile in the
particle-depleted region. Also shown are: particle-dispersed region
(A), interfacial region (B), particle-depleted region (C) in the
fiber, and the dissolution fluid (D) outside the fiber;
[0108] FIG. 11 shows a non-limiting schematic of drug release from
an expanded, semi-solid dosage form with 2R/.lamda..about.1: (a)
dosage form at a specific time after immersion in a stirred
dissolution fluid, (b) drug concentration versus distance, x,
assuming a quasi-steady concentration profile in the
particle-depleted region. A: particle-dispersed region, B:
interfacial region, C: particle-depleted region, and D: dissolution
fluid;
[0109] FIG. 12 shows a non-limiting schematic of an expanded,
semi-solid dosage form exposed to cyclic loading;
[0110] FIG. 13 presents a non-limiting dosage form according to the
invention herein along with its microstructure;
[0111] FIG. 14 presents a non-limiting fibrous microstructure of a
dosage form herein, and a histogram of the length of fiber segments
between adjacent contacts;
[0112] FIG. 15 shows another non-limiting fibrous microstructure
herein, and a histogram of the angle between contacting fibers;
[0113] FIG. 16 presents a non-limiting example of a point contact
between elements or segments;
[0114] FIG. 17 is a non-limiting example of a line contact between
elements or segments;
[0115] FIG. 18 presents non-limiting microstructures of elements
herein prior and after exposure to a physiological fluid: (a) solid
solution of drug molecules, absorptive excipient, and
strength-enhancing excipient prior exposure to a physiological
fluid, (b) solid solution of drug molecules, absorptive excipient,
and strength-enhancing excipient after exposure to a physiological
fluid, (c) core-shell structure comprising a core of drug and
absorptive excipient, and a shell of strength-enhancing excipient
prior exposure to a physiological fluid, (d) core-shell structure
comprising a core of drug and absorptive excipient, and a shell of
strength-enhancing excipient after exposure to a physiological
fluid, (e) dispersed particles of absorptive excipient and drug in
a matrix of strength-enhancing excipient prior exposure to a
physiological fluid, (f) dispersed particles of absorptive
excipient and drug in a matrix of strength-enhancing excipient
after exposure to a physiological fluid, (g) dispersed particles of
strength-enhancing excipient in a matrix of drug and absorptive
excipient prior exposure to a physiological fluid, and (h)
dispersed particles of strength-enhancing excipient in a matrix of
drug and absorptive excipient after exposure to a physiological
fluid;
[0116] FIG. 19 shows a non-limiting example of a dosage form as
disclosed herein and its expansion and drug release after exposure
to a physiological fluid;
[0117] FIG. 20 presents scanning electron micrographs of a
non-limiting single fiber and a non-limiting fibrous dosage form
according to the invention herein;
[0118] FIG. 21 shows images of a single fiber at various times
after immersion in a dissolution fluid. The fiber transitioned from
solid to viscous and swelled both radially and axially;
[0119] FIG. 22 presents experimental results of the expansion of
single fibers after immersion in a dissolution fluid: (a)
normalized radial expansion, .DELTA.R/R.sub.0, versus time after
immersion, t, (b) normalized axial expansion, .DELTA.L/L.sub.0,
versus t, (c) .DELTA.R/R.sub.0, versus t.sup.1/2, and (d)
.DELTA.L/L.sub.0 versus t.sup.1/2;
[0120] FIG. 23 presents experimentally-derived images of the
fibrous dosage forms after immersion in a dissolution fluid. The
volume fractions of fibers in the solid dosage forms, .phi., were:
(a) .phi.=0.16, (b) .phi.=0.39, and (c) .phi.=0.56;
[0121] FIG. 24 plots experimental results of the normalized
longitudinal expansion, .DELTA.L/L.sub.0, of fibrous dosage forms
after immersion in a dissolution fluid: (a) .DELTA.L/L.sub.0 versus
time, t, after immersion, and (b) .DELTA.L/L.sub.0 versus
t.sup.1/2/R.sub.0;
[0122] FIG. 25 displays experimental results of drug release by
single fibers after immersion in a dissolution fluid: (a) fraction
of drug released, m.sub.d/M.sub.0, versus time, t, after immersion
and (b) m.sub.d/M.sub.0 versus t.sup.1/2/R.sub.0;
[0123] FIG. 26 presents experimental results of drug release by
fibrous dosage forms after immersion in a dissolution fluid: (a)
fraction of drug released, m.sub.d/M.sub.0, versus time after
immersion, t, and (b) measured data and calculated curves of
m.sub.d/M.sub.0 versus t.sup.1/2. The calculated curves were
obtained by Eq. (43) using c.sub.s=0.05 mg/ml, c.sub.d,0=37.9
mg/ml, D.sub.d=3.24.times.10.sup.-10 m.sup.2/s, R=83 .mu.m, and H=2
mm.
[0124] FIG. 27 shows a semi-log plot of t.sub.0.8 versus .phi.. The
straight line is: t.sub.0.8=0.77.times.exp(7.06.phi.);
[0125] FIG. 28 presents scanning electron micrographs of dosage
forms dip-coated with enteric excipient: (a) Low-magnification
image of top and (b) front views of the microstructure, and (c)
high-magnification image of the cross-section of a coated
fiber;
[0126] FIG. 29 shows top-view images of dosage forms after
immersion in a dissolution fluid: (a) uncoated dosage form, and (b)
enteric coated dosage form;
[0127] FIG. 30 plots the normalized radial expansion of the dosage
forms, .DELTA.R.sub.df/R.sub.df,0, versus time, t, after immersion
in the dissolution fluid;
[0128] FIG. 31 shows images of expanded, fluid-soaked dosage forms
during diametral compression: (a) uncoated and (b) coated dosage
form;
[0129] FIG. 32 presents results of the diametrial compression test
of expanded, fluid-soaked dosage forms: (a) load per unit length,
P, versus displacement, .delta., of uncoated and coated dosage
forms and (b) dP/d.delta. versus .delta.. The inset of FIG. 6a
shows a schematic of the loads applied on a homogeneous, isotropic,
linear elastic cylinder compressed by diametrically opposed flat
platen. P is the load intensity or force per unit thickness.
R.sub.df is the radius of the cylinder (or expanded dosage form).
The small arrows represent the Hertzian contact pressure
distributed over the contact width 2a;
[0130] FIG. 33 shows images of an expanded, coated dosage form
before (left) and after diametral compression (right). The
compression-tested coated dosage form had visible cracks within the
axis of symmetry;
[0131] FIG. 34 depicts the position and structure of an uncoated
dosage form after administration to a fasted dog. Dry food was
given 4-6 hours after administration; it is visible in the bottom
row images. The images were obtained by biplanar fluoroscopy. They
show the abdomen in lateral projection (cranial left, caudal
right);
[0132] FIG. 35 depicts the position and structure of a coated
dosage form after administration to a fasted dog. Dry food was
given 4-6 hours and 30 hours after administration. The images were
obtained by biplanar fluoroscopy. They show the abdomen in lateral
projection (cranial left, caudal right);
[0133] FIG. 36 Expansion of dosage form radius in vivo and
comparison with in vitro data: (a) uncoated and coated dosage forms
in vivo, and (b) in vivo/in vitro comparison of uncoated and coated
dosage forms;
[0134] FIG. 37 depicts fluoroscopic image sequences during
contraction pulsing by the stomach walls: (a) uncoated dosage form
in the stomach 2 hours after administration, and (b) coated dosage
form in the stomach 7 hours after administration;
[0135] FIG. 38 presents experimental results of the sorption of
physiological fluid by a strength-enhancing excipient herein;
[0136] FIG. 39 plots the nominal tensile stress, .sigma., versus
engineering strain, .epsilon., in thin, acidic water-soaked tensile
specimen films of Eudragit L100-55. The stress was derived as:
.sigma.=F/Wh where F is the force applied by the grips, W the width
of the thin section of the specimen film, and h its thickness. The
engineering strain, .epsilon.=.DELTA.L/L.sub.0 where .DELTA.L is
the distance travelled by the grips and L.sub.0 the initial
distance between grips.
[0137] FIG. 40 presents non-limiting schematics of
gastro-intestinal passage of drug, and drug concentration in blood
versus time. Top row: granular dosage form. Bottom row: expandable
fibrous dosage form.
DEFINITIONS
[0138] In order for the present disclosure to be more readily
understood, certain terms are first defined below. Additional
definitions for the following terms and other terms are set forth
throughout the specification.
[0139] In this application, the use of "or" means "and/or" unless
stated otherwise. As used in this application, the term "comprise"
and variations of the term, such as "comprising" and "comprises,"
are not intended to exclude other additives, components, integers
or steps. As used in this application, the terms "about" and
"approximately" are used as equivalents. Any numerals used in this
application with or without about/approximately are meant to cover
any normal fluctuations appreciated by one of ordinary skill in the
relevant art.
[0140] Moreover, in the disclosure herein, the terms "one or more
active ingredients" and "drug" are used interchangeably. As used
herein, an "active ingredient" or "active agent" or "drug" refers
to an agent whose presence or level correlates with elevated level
or activity of a target, as compared with that observed absent the
agent (or with the agent at a different level). In some
embodiments, an active ingredient is one whose presence or level
correlates with a target level or activity that is comparable to or
greater than a particular reference level or activity (e.g., that
observed under appropriate reference conditions, such as presence
of a known active agent, e.g., a positive control).
[0141] Furthermore, in the context of some embodiments herein, a
three dimensional structural framework (or network) of one or more
elements comprises a drug-containing structure (e.g., an assembly
or an assemblage or an arrangement or a skeleton or a skeletal
structure or a three-dimensional lattice structure of one or more
drug-containing elements) that extends over a length, width, and
thickness greater than 100 .mu.m. This includes, but is not limited
to drug-containing structures that extend over a length, width, and
thickness greater than 200 .mu.m, or greater than 300 .mu.m, or
greater than 500 .mu.m, or greater than 700 .mu.m, or greater than
1 mm, or greater than 1.25 mm, or greater than 1.5 mm, or greater
than 2 mm.
[0142] In other embodiments, a three dimensional structural
framework (or network) of drug-containing elements may comprise a
drug-containing structure (e.g., an assembly or an assemblage or a
skeleton or a skeletal structure of one or more elements) that
extends over a length, width, and thickness greater than the
average thickness of at least one element (or at least one segment)
in the three dimensional structural framework (or network) of
elements. This includes, but is not limited to drug-containing
structures that extend over a length, width, and thickness greater
than 1.5, or greater than 2, or greater than 2.5, or greater than
3, or greater than 3.5, or greater than 4 times the average
thickness of at least one element (or at least one segment) in the
three dimensional structural framework (or network) of
elements.
[0143] In some embodiments, a three dimensional structural
framework (or network) of drug-containing elements is continuous.
Furthermore, in some embodiments, the drug-containing elements are
bonded to each other or interpenetrating.
[0144] It may be noted that the terms "three dimensional structural
network", "three dimensional structural framework", and "three
dimensional lattice structure" are used interchangeably herein.
Also, the terms "three dimensional structural framework of
drug-containing elements", "three dimensional structural framework
of elements", "three dimensional structural framework of one or
more elements", "three dimensional structural framework of one or
more drug-containing elements", "three dimensional framework of
elements", "three dimensional structural framework of fibers",
"three dimensional framework", "structural framework", etc. are
used interchangeably herein.
[0145] In the invention herein, a "structural element" or "element"
refers to a two-dimensional element (or 2-dimensional structural
element), or a one-dimensional element (or 1-dimensional structural
element), or a zero-dimensional element (or 0-dimensional
structural element).
[0146] As used herein, a two-dimensional structural element is
referred to as having a length and width much greater than its
thickness. In the present disclosure, the length and width of a
two-dimensional structural element are greater than 2 times its
thickness. An example of such an element is a "sheet". A
one-dimensional structural element is referred to as having a
length much greater than its width or thickness. In the present
disclosure, the length of a one-dimensional structural element is
greater than 2 times its width and thickness. An example of such an
element is a "fiber". A zero-dimensional structural element is
referred to as having a length and width of the order of its
thickness. In the present disclosure, the length and width of a
zero-dimensional structural element are no greater than 2 times its
thickness. Furthermore, the thickness of a zero-dimensional element
is less than 2.5 mm. Examples of such zero-dimensional elements are
"particles" or "beads" and include polyhedra, spheroids,
ellipsoids, or clusters thereof.
[0147] Moreover, in the invention herein, a segment of a
one-dimensional element is a fraction of said element along its
length. A segment of a two-dimensional element is a fraction of
said element along its length and/or width. A segment of a
zero-dimensional element is a fraction of said element along its
length and/or width and/or thickness. The terms "segment of a
one-dimensional element", "fiber segment", "segment of a fiber",
and "segment" are used interchangeably herein. Also, the terms
"segment of a two-dimensional element" and "segment" are used
interchangeably herein. Also, the terms "segment of a
zero-dimensional element" and "segment" are used interchangeably
herein.
[0148] As used herein, the terms "fiber", "fibers", "one or more
fibers", "one or more drug-containing fibers", and "drug-containing
fibers", are used interchangeably. They are understood as the
solid, drug-containing structural elements (or building blocks)
that make up part of or the entire three dimensional structural
network (e.g., part of or the entire dosage form structure, or part
of or the entire structure of a drug-containing solid, etc.). A
fiber has a length much greater than its width and thickness. In
the present disclosure, a fiber is referred to as having a length
greater than 2 times its width and thickness (e.g., the length is
greater than 2 times the fiber width and the length is greater than
2 times the fiber thickness). This includes, but is not limited to
a fiber length greater than 3 times, or greater than 4 times, or
greater than 5 times, or greater than 6 times, or greater than 8
times, or greater than 10 times, or greater than 12 times the fiber
width and thickness. In other embodiments that are included but not
limiting in the disclosure herein, the length of a fiber may be
greater than 0.3 mm, or greater than 0.5 mm, or greater than 1 mm,
or greater than 2.5 mm.
[0149] Moreover, as used herein, the term "fiber segment" or
"segment" refers to a fraction of a fiber along the length of said
fiber.
[0150] In the invention herein, fibers (or fiber segments) may be
bonded, and thus they may serve as building blocks of "assembled
structural elements" with a geometry different from that of the
original fibers. Such assembled structural elements include
two-dimensional elements, one-dimensional elements, or
zero-dimensional elements.
[0151] In the invention herein, drug release from a solid element
(or a solid dosage form, or a solid matrix, or a drug-containing
solid) refers to the conversion of drug (e.g., one or more drug
particles, or drug molecules, or clusters thereof, etc.) that
is/are embedded in or attached to the solid element (or the solid
dosage form, or the solid matrix, or three dimensional structural
framework, or the drug-containing solid) to drug in a dissolution
medium.
[0152] A sparingly-soluble drug herein comprises an active
ingredient or drug with a solubility in physiological fluid or body
fluids (or a dissolution medium or an aqueous solution) smaller
than 1 mg/ml under physiological conditions. This includes, but is
not limited to a solubility in physiological fluid or body fluid
under physiological conditions smaller than 0.5 mg/ml, or smaller
than 0.2 mg/ml, or smaller than 0.1 mg/ml, or smaller than 0.05
mg/ml, or even smaller. It may be noted that the terms
"sparingly-soluble drug", "sparingly water-soluble drug", and
"poorly-soluble drug" are used interchangeably herein.
[0153] As used herein, the terms "dissolution medium",
"physiological fluid", "body fluid", "dissolution fluid", "medium",
"fluid", "aqueous solution", and "penetrant" are used
interchangeably. They are understood as any fluid produced by or
contained in a human body under physiological conditions, or any
fluid that resembles a fluid produced by or contained in a human
body under physiological conditions. Generally, a dissolution fluid
contains water and thus may be aqueous. Examples include, but are
not limited to: water, saliva, stomach fluid, gastrointestinal
fluid, saline, etc. at a temperature of 37.degree. C. and a pH
value adjusted to the relevant physiological condition.
[0154] In the invention herein, moreover, an "absorptive excipient"
is referred to as an excipient that is "absorptive" of gastric or a
relevant physiological fluid under physiological conditions.
Generally, said absorptive excipient is a solid, or a semi-solid,
or a viscoelastic material in the dry state at room temperature.
Upon contact with (e.g., immersion in) gastric or a relevant
physiological fluid under physiological conditions, however, said
absorptive excipient can absorb said fluid and form solutions or
mixtures with said fluid having a weight fraction of gastric or
relevant physiological fluid greater than 0.4. This includes, but
is not limited to the formation of solutions or mixtures with a
weight fraction of gastric or relevant physiological fluid greater
than 0.5, or greater than 0.6, or greater than 0.7, or greater than
0.75, or greater than 0.8, or greater than 0.85, or greater than
0.9, or greater than 0.95. In other words, the solubility of
gastric fluid or a relevant physiological fluid in the absorptive
excipient under physiological conditions generally is greater than
about 400 mg/ml. This includes, but is not limited to solubility of
gastric or relevant physiological fluid in an absorptive excipient
greater than 500 mg/ml, or greater than 600 mg/ml, or greater than
700 mg/ml, or greater than 750 mg/ml, or greater than 800 mg/ml, or
greater than 850 mg/ml, or greater than 900 mg/ml, or greater than
950 mg/ml. Preferably, absorptive excipient is mutually soluble
with a relevant physiological fluid. In the invention herein, a
"relevant physiological fluid" is understood as the relevant
physiological fluid surrounding the dosage form in the relevant
physiological application. For example, if the dosage form is a
gastroretentive dosage form, a relevant physiological fluid is
gastric fluid. Non-limiting examples of preferred absorptive,
high-molecular-weight excipients may include, but are not limited
to water-soluble polymers of large molecular weight and with
amorphous molecular structure, such as hydroxypropyl
methylcellulose with a molecular weight greater than 50 kg/mol or
hydroxypropyl methylcellulose with a molecular weight in the range
between 50 kg/mol and 300 kg/mol. The terms "physiological
fluid-absorptive excipient", "absorptive excipient",
"fluid-absorptive excipient", and "water-absorptive excipient" are
used interchangeably herein.
[0155] In the invention herein, moreover, a "strength-enhancing
excipient", too, generally is a solid, or a semi-solid, or a
viscoelastic material in the dry state at room temperature. Upon
contact with (e.g., immersion in) gastric or a relevant
physiological fluid under physiological conditions, however, said
strength-enhancing excipient is far less absorptive of said fluid,
and thus it remains a semi-solid, or viscoelastic, or highly
viscous material. Generally, the solubility of gastric or relevant
physiological fluid in strength-enhancing excipient under
physiological conditions is no greater than 800 mg/ml. This
includes, but is not limited to a solubility of gastric or a
relevant physiological fluid in strength-enhancing excipient under
physiological conditions no greater than 750 mg/ml, or no greater
than 700 mg/ml, or no greater than 650 mg/ml, or no greater than
600 mg/ml, or no greater than 550 mg/ml, or no greater than 500
mg/ml, or no greater than 450 mg/ml, or no greater than 400 mg/ml.
In the non-limiting extreme case, the relevant physiological fluid
can be insoluble or practically insoluble in the strength-enhancing
excipient.
[0156] Typically, however, a relevant physiological fluid is
sparingly-soluble in a strength-enhancing excipient. Thus, upon
immersion of said strength-enhancing excipient in said relevant
physiological fluid, the stiffness (e.g., the elastic modulus) or
the viscosity of said strength-enhancing excipient may decrease
somewhat compared with the stiffness or viscosity of the dry
strength-enhancing excipient. Similarly, upon immersion of
strength-enhancing excipient in a relevant physiological fluid, the
strain at fracture of said strength-enhancing excipient may
increase compared with the strain at fracture of the dry
strength-enhancing excipient. Because the strength-enhancing
excipient can be a semi-solid or viscoelastic or highly viscous
material even after prolonged immersion in a relevant physiological
fluid, it is also referred to herein as "stabilizing excipient",
"viscoelastic excipient", or "semi-solid excipient".
[0157] In the invention herein, moreover, a "solid solution" of at
least two constituents (e.g., at least two excipients) is referred
to as a solid having at least two constituents that are partially
or entirely dissolved (e.g., molecularly dispersed or molecularly
mixed) in each other. This includes, but is not limited to a first
constituent (e.g., a first excipient) that is dissolved or
molecularly dispersed or molecularly mixed in a second constituent
(e.g., a second excipient), or a second constituent that is
dissolved or molecularly dispersed or molecularly mixed in a first
constituent. The solid solution may have a molecular arrangement or
crystal structure that is the same or similar to that of the first
constituent, or it may have a molecular arrangement or crystal
structure that is the same or similar to that of the second
constituent, or it may have a molecular arrangement or crystal
structure that is different from that of the first constituent and
also different from that of the second constituent. Often times,
however, the at least two constituents are amorphous polymers, and
the resulting solid solution is an amorphous polymer, too. Often
times, moreover, and in preferred embodiments, the concentrations
of the at least two molecularly dispersed constituents forming the
solid solution are substantially uniform across the solid solution.
By way of example but not by way of limitation, in a solid material
a solid solution may be experimentally detected or shown by such
methods as Differential Scanning calorimetry, x-ray spectroscopy,
Fourier-transform infrared spectroscopy, Raman spectroscopy, and so
on. For further information related to solid solutions, see, e.g.,
the International Application No. PCT/US19/52030 filed on Sep. 19,
2019 and titled "Dosage form comprising structured solid-solution
framework of sparingly-soluble drug and method for manufacture
thereof" and any references therein.
[0158] Further information related to the definition,
characteristics, features, composition, analysis etc. of the
disclosed dosage forms, and the elements for fabricating or
constructing them, is provided throughout this specification.
Scope of the Invention
[0159] It is contemplated that a particular feature described
either individually or as part of an embodiment in this disclosure
can be combined with other individually described features, or
parts of other embodiments, even if the other features and
embodiments make no mention of the particular feature. Thus, the
invention herein extends to such specific combinations not already
described. Furthermore, the drawings and embodiments of the
invention herein have been presented as examples, and not as
limitations. Thus, it is to be understood that the invention herein
is not limited to these precise embodiments. Other embodiments
apparent to those of ordinary skill in the art are within the scope
of what is claimed.
[0160] By way of example but not by way of limitation, it is
contemplated that compositions, systems, devices, methods, and
processes of the claimed invention encompass variations and
adaptations developed using information from the embodiments
described herein. Adaptation and/or modification of the
compositions, systems, devices, methods, and processes described
herein may be performed by those of ordinary skill in the relevant
art.
[0161] Furthermore, where compositions, articles, and devices are
described as having, including, or comprising specific components,
or where processes and methods are described as having, including,
or comprising specific steps, it is contemplated that,
additionally, there are compositions, articles, and devices of the
present invention that consist essentially of, or consist of, the
recited components, and that there are processes and methods
according to the present invention that consist essentially of, or
consist of, the recited processing steps.
[0162] Similarly, where compositions, articles, and devices are
described as having, including, or comprising specific compounds
and/or materials, it is contemplated that, additionally, there are
compositions, articles, and devices of the present invention that
consist essentially of, or consist of, the recited compounds and/or
materials.
[0163] It should be understood that the order of steps or order for
performing certain action is immaterial so long as the invention
remains operable. Moreover, two or more steps or actions may be
conducted simultaneously.
[0164] The mention herein of any publication is not an admission
that the publication serves as prior art with respect to any of the
claims presented herein. Headers are provided for organizational
purposes and are not meant to be limiting
DETAILED DESCRIPTION OF THE INVENTION
Aspects of an Element
[0165] As shown schematically in FIG. 2a, the dosage forms 200
disclosed herein generally comprise a drug-containing solid 201
having an outer surface 202 and an internal structure 204 including
one or more elements 210. A non-limiting example of a single
element 210, such as a fiber 210, for pharmaceutical dosage form
construction or fabrication is illustrated in the insets of FIG.
2a. The fiber or element 210 includes at least one active
ingredient 220 and at least two excipients 230, 240 forming the
element or fiber 210. The at least two excipients 230, 240 comprise
one or more fluid-absorptive polymeric constituents 230 and one or
more strength-enhancing polymeric constituents 240.
[0166] Upon exposure to physiological fluid 260, such as saliva,
gastric fluid, a fluid that resembles a physiological fluid, and so
on, the one or more strength-enhancing excipients 240 form a
fluid-permeable, semi-solid network 242 to mechanically support the
element or fiber 210, FIGS. 2b-2e. Also, the one or more
fluid-absorptive excipients 230 transition to a viscous mass, or a
viscous solution 232, expanding said element or fiber 210 along at
least one dimension with absorption of said physiological fluid
260.
[0167] FIG. 2a presents a further non-limiting example of a single
element 210, such as a fiber 210, for pharmaceutical dosage form
construction or fabrication. The element or fiber 210 includes at
least one active ingredient 220 and at least two excipients 230,
240 forming the element or fiber 210. The at least two excipients
230, 240 comprise one or more fluid-absorptive polymeric
constituents 230, within which the solubility of a physiological
fluid is greater than 600 mg/ml. The at least two excipients 230,
240 further comprise one or more strength-enhancing polymeric
constituents 240. The one or more strength-enhancing polymeric
constituents 240 have an elastic modulus in the range between 0.1
MPa and 200 MPa and a strain at fracture greater than 0.5 after
soaking with said physiological fluid under physiological
conditions. Preferably, moreover, the one or more
strength-enhancing polymeric constituents 240 form one or more
phases that are substantially connected and/or substantially
contiguous along length of the element or fiber 210. Generally, a
"phase" is understood herein as a region or space within an element
or fiber 210 throughout which many or all physical properties are
substantially uniform or constant. By way of example but not by way
of limitation, a solid solution including strength-enhancing
excipient 240 comprises a "phase comprising one or more
strength-enhancing excipients".
[0168] Upon exposure to said physiological fluid 260, said fluid
260 diffuses into said element or fiber 210, thereby expanding said
element or fiber 210 in at least one dimension to a length between
1.3 and 4 times its length prior to exposure to said physiological
fluid 260, FIGS. 2b and 2c. By way of example but not by way of
limitation, the initial thickness of said element or fiber 210
(also referred to herein as the "thickness prior to exposure to
said physiological fluid"), h.sub.0, may expand to a length,
h=1.3-4 times h.sub.0, upon exposure to said physiological fluid
260.
[0169] Also, upon exposure to said physiological fluid 260, said
element or fiber 210 transitions to a semi-solid mass 212. The
semi-solid mass 212 may maintain its length between 1.3 and 4 times
the initial length for prolonged time, FIGS. 2c-2e. The term "the
semi-solid mass maintains its length between 1.3 and 4 times the
initial length for prolonged time" is referred to herein as a
semi-solid mass immersed in an unstirred or lightly stirred
dissolution fluid (e.g., acidic water), wherein said immersed
semi-solid mass maintains its length between 1.3 and 4 times the
initial length for an extended time, such as a time greater than 1
hour, or a time greater than 2 hours, or a time greater than 5
hours, or an even longer time.
[0170] Moreover, upon exposure to said physiological fluid, the one
or more strength-enhancing excipients 240 form a fluid-permeable,
semi-solid network 242 within or through the element or fiber 210
or semi-solid mass 212 to mechanically support the element or fiber
or semi-solid mass 210, 212. Also, the one or more fluid-absorptive
excipients 230 transition to a viscous mass, or a viscous solution
232, expanding said element or fiber 210 in at least one dimension
with absorption of said physiological fluid 260.
[0171] It may be noted that generally, one or more
strength-enhancing excipients form a "fluid-permeable, semi-solid
network to mechanically support the element or fiber or semi-solid
mass" within or through an element, if the mechanical strength or
stiffness (e.g., the elastic modulus, or the tensile strength,
etc.) of said element after exposure to a physiological fluid is
substantially greater than the mechanical strength or stiffness of
an element comprising fluid-absorptive excipient alone (e.g., no
strength-enhancing excipient) after exposure to said physiological
fluid. By way of example but not by way of limitation, one or more
strength-enhancing excipients form a "fluid-permeable, semi-solid
network to mechanically support the element or fiber or semi-solid
mass" within or through an element, if the tensile strength or the
elastic modulus of said element after exposure to a physiological
fluid is at least two times greater than that of a corresponding
element comprising fluid-absorptive excipient alone (e.g., no
strength-enhancing excipient) after exposure to said physiological
fluid. This includes, but is not limited to the tensile strength or
the elastic modulus of an element with one or more
strength-enhancing excipients forming a "fluid-permeable,
semi-solid network to mechanically support the element or fiber or
semi-solid mass" after exposure to a physiological fluid at least
three times greater, or at least four times greater, or at least
five times greater, or at least six times greater, or at least
seven times greater than that of a corresponding element comprising
fluid-absorptive excipient alone (e.g., no strength-enhancing
excipient) after exposure to said physiological fluid.
[0172] Additional aspects and embodiments of structural elements or
fibers according to the invention herein are described throughout
this specification. Any more aspects and embodiments of structural
elements or fibers obvious to a person of ordinary skill in the art
are all within the spirit and scope of this invention.
Aspects of the Dosage Form
[0173] FIG. 3a presents a non-limiting example of a pharmaceutical
dosage form disclosed herein. The dosage form 300 comprises a
drug-containing solid 201 having an outer surface 302 and an
internal three dimensional structural framework 304 (e.g., a
lattice structure, a network, a skeleton, etc.) of one or more
thin, structural elements 310. In the invention herein, a
structural element is understood "thin" if its thickness (e.g., its
smallest dimension) is much smaller than the length, or width, or
thickness of the dosage form. Thin, structural elements 310 are
also referred to herein as "elements" or "structural elements". The
structural elements 310 may comprise fibers, beads, sheets, or
combinations thereof.
[0174] The framework 304 is contiguous with and terminates at said
outer surface 302. In preferred embodiments, the structural
framework 304 forms a single continuous or connected structure
through the drug-containing solid 301 (e.g., in this case all
elements 310 may be bonded to at least another element 310 to form
a single continuous structure). In preferred embodiments, moreover,
the one or more thin structural elements 310 are orderly or
substantially orderly arranged.
[0175] The elements 310 further comprise segments spaced apart from
segments of adjoining elements or segments, thereby defining one or
more free spaces 315 within the drug-containing solid 301. In
preferred embodiments, the free spaces 315 are interconnected
through or across the drug-containing solid 301. In the invention
herein, a free space 315 may generally be referred to as
"interconnected through or across the drug-containing solid" if it
extends (e.g., if the free space 315 is continuous or connected)
over a length at least half the thickness of the drug-containing
solid 301. This includes, but is not limited to free space 315
extending over a length at least two-third the thickness of the
drug-containing solid 301, or free space 315 extending over a
length at least equal to the thickness of the drug-containing solid
301. A free space 315 may also be considered interconnected across
or through the drug-containing solid 301 herein if it extends over
a length at least twice the thickness of one or more elements 310.
Furthermore, in preferred embodiments one or more interconnected
free spaces 315 are connected to the outer surface 302. Thus no
walls (e.g., walls comprising the three dimensional structural
framework 304 of elements 310) must be ruptured to obtain an
interconnected free space 315 (e.g., an open channel of free space
315) from the outer surface 302 of the drug-containing solid 301 to
a point or position (or to any point) in said interconnected free
space 315. Generally, moreover, at least one of said one or more
interconnected free spaces 315 is filled with matter removable by a
physiological fluid under physiological conditions (e.g., a gas, a
solid that is highly soluble in said physiological fluid,
etc.).
[0176] A non-limiting example of a preferred internal three
dimensional structural framework 304 comprises a plurality of
criss-crossed stacked layers of fibrous elements 310. Herein
criss-crossed stacked layers of fibrous elements 310 are referred
to as plies (e.g., "layers" or "planes") of fibers 310 or fiber
segments that are stacked in a cross-ply arrangement. In cross-ply
arrangements, fibers 310 (or fiber segments) in a ply (or "layer"
or "plane") are oriented transversely or at an angle to the fibers
310 in the ply above or below. Moreover, in cross-ply structures
the free space 315 typically extends over the entire length, width,
and thickness of the drug-containing solid 301. More so, the free
space 315 is contiguous and terminates at the outer surface 302 of
the drug-containing solid 301. Further details about how
interconnected free spaces 315 are defined herein, what they may be
composed of, and how their length may be measured are provided in
FIG. 13 herein, and in section "Embodiments of the dosage
form".
[0177] In the invention herein, moreover, the structural elements
310 comprise at least an active ingredient 320, 325 (e.g., at least
a drug) and at least two excipients 330, 340 (also referred to
herein as "dual excipient"). Typically, the at least one active
ingredient 320, 325 is dispersed in at least one of said at least
two excipients 330, 340 as active ingredient molecules 320 or as
particles 325 comprising said at least one active ingredient. Thus,
the at least two excipients 330, 340 (or all excipients, or the
excipient in its totality) may form a continuous or connected
structure through one or more elements 310 (e.g., through the
thickness of one or more elements, and/or through the length of one
or more elements, and/or through the width of one or more elements)
or through the three-dimensional structural framework 304. In some
preferred embodiments, moreover, said at least two excipients 330,
340 may form a solid solution.
[0178] Said at least two excipients 330, 340 further comprise at
least a physiological fluid-absorptive polymeric constituent 340
(e.g., a water-absorptive polymeric constituent) and at least a
strength-enhancing polymeric constituent 340.
[0179] As shown schematically in the non-limiting FIG. 3b, upon
immersion of the dosage form 300 or drug-containing solid 301 in a
dissolution fluid 260 (e.g., acidic water, gastric fluid, a
relevant physiological fluid, a fluid that resembles a relevant
physiological fluid, etc.), the fluid 360 may percolate or access
interconnected free space 315, and wet the structural framework
304, 310. In the invention herein, a surface (e.g., a surface of
the three dimensional structural framework 304, 310) is "wetted by
a fluid" if said fluid contacts (e.g., is in contact with) said
surface. Moreover, a surface is generally understood herein as
"uniformly wetted" by a fluid if at least 20-70 percent of the area
of said surface is in contact (e.g., in direct contact) with said
fluid. In preferred embodiments herein, upon immersion of the
drug-containing solid 301 in a physiological fluid 360, at least
60-70 percent of the surface of the three dimensional structural
framework 304, 310 (or a coating of the three dimensional
structural framework 304, 310) is wetted by (e.g., contacted by)
said fluid at a time in the range between the time of immersion and
600 seconds after the time of immersion.
[0180] The fluid 360 may then diffuse or penetrate into the three
dimensional structural framework 304 or the elements 310 or
segments it surrounds. Moreover, as water or dissolution fluid or
physiological fluid 360 diffuses into the elements 310, and the
fluid 360 mass and volume in the elements 310 increases, they may
expand. In some embodiments, therefore, the drug-containing solid
301 or the three-dimensional structural framework 304, 310 expand
due to the penetration (e.g., the diffusion or inflow) of
physiological or body fluid 360 into the three dimensional
structural framework of elements 304, 310.
[0181] It may be noted that within or through the one or more
elements or framework 210, 304, 310, as was shown schematically in
FIGS. 2c-2e, the one or more strength-enhancing excipients 240 may
form a fluid-permeable, semi-solid network 242 to mechanically
support the elements or framework 210, 304, 310. Also, the one or
more fluid-absorptive excipients 230, 330 may transition to a
viscous mass, or a viscous solution 232, expanding said element or
framework 210, 304, 310 in at least one dimension with absorption
of said physiological fluid 260, 360.
[0182] Moreover, if the three-dimensional structural framework 304,
310 is uniformly wetted, and the composition and geometry (e.g.,
the thickness of the elements, etc.) are substantially uniform
across the three-dimensional structural framework 304, 310, the
drug-containing solid 301 or three-dimensional structural framework
304, 310 may expand uniformly and in all dimensions as shown
schematically in the non-limiting FIG. 3c. The terms "expanding in
all dimensions", "expand in all dimensions", or "expansion in all
dimensions" are understood as an increase in a length of a sample
(e.g., the length, and/or width, and/or thickness, etc. of said
sample) and an increase in volume of said sample. Thus, pure shear
deformation is not considered "expansion in all dimensions"
herein.
[0183] The expansion of the dosage form 300 or drug-containing
solid 301 can be quite substantial, as shown schematically in FIGS.
3b and 3c. Thus, in some embodiments, at least one dimension of the
drug-containing solid 301, 304 (e.g., a side length of the
drug-containing solid or framework 301, 304, the thickness of the
drug-containing solid or framework 301, 304, etc.) expands to at
least 1.3 times the initial value (e.g., the initial length or the
length prior to exposure to said physiological fluid 360) upon
immersion in said physiological fluid 360. This includes, but is
not limited to at least one dimension of the drug-containing solid
expanding to at least 1.35 times, or at least 1.4 times, or at
least 1.45 times, or at least 1.5 times, or at least 1.55 times, or
at least 1.6 times, or at least 1.65 times, or at least 1.7 times,
or at least 1.75 times, or at least 1.8 times, or at least 1.85
times, or at least 1.9 times the initial value upon immersion in or
exposure to a dissolution fluid 360.
[0184] Furthermore, in some embodiments the dosage form 300 or
drug-containing solid or framework 301, 304 expands to at least 2
times its initial volume upon immersion in or upon exposure to a
physiological fluid 360 under physiological conditions. This
includes, but is not limited to a drug-containing solid or
framework 301, 304 expanding to at least 2.5 times, or at least 3
times, or at least 3.5 times, or at least 4 times, or at least 4.5
times, or at least 5 times, or at least 5.5 times its initial
volume upon immersion in or exposure to a physiological fluid
360.
[0185] The rate of expansion generally depends on the rate at which
physiological fluid 360 is absorbed by the structural framework
304, 310 (e.g., by one or more absorptive polymeric excipients 330,
etc.), and the presence and stringency of constraints to expansion.
The absorption rate of physiological fluid 360 by the framework
304, 310 is typically increased if the specific surface area (e.g.,
the surface area to volume ratio) of the framework 304, 310 is
increased. Thus, if the elements 310 are thin, the surface area to
volume ratio is typically large, and the rate at which
physiological fluid 360 is absorbed by the framework 304, 310 can
be fast.
[0186] Constraints to expansion may, for example, originate from
non-uniformities in the physiological fluid 360 concentration
across the three dimensional structural framework 304, 310. By way
of example but not by way of limitation, a wet element or segment
may absorb physiological fluid, but expansion of said wet element
or segment may be constrained if it is connected (e.g., attached)
to a dry solid element or segment that does not expand. Thus, to
minimize constraints to expansion, uniform wetting of elements in
the structural framework can be crucial. Uniform wetting is
enabled, among others, by interconnected free spaces (e.g., by a
continuous free space through which physiological fluid may
percolate), and by a hydrophilic surface composition of the
three-dimensional structural framework of elements.
[0187] The expansion of one or more elements 310 or of the
framework 304 or of the drug-containing solid 301 may also be
constrained if the stiffness, or an elastic modulus, or a plastic
modulus of a strength-enhancing excipient 340 network within an
element or fiber 310 is too large. Thus, after exposure to a
physiological fluid 360, the stiffness, or an elastic modulus, or a
plastic modulus of one or more strength-enhancing excipients 340
should generally not be too large, so that expansion of the dosage
form (or of the drug-containing solid 301, or of the framework 304,
or of one or more elements 310) is not excessively constrained.
However, the stiffness, or an elastic modulus, or a plastic modulus
of one or more strength-enhancing excipients 340 should also be
large enough to ensure that the strength-enhancing excipient 340
network mechanically supports or stabilizes the one or more
elements or framework 304, 310 sufficiently after exposure to a
physiological fluid 360. Preferably, therefore, after soaking with
physiological fluid 360 under physiological conditions, the one or
more strength-enhancing polymeric constituents 340 have an elastic
modulus in the range between 0.1 MPa and 200 MPa.
[0188] Similarly, to ensure that semi-solid strength-enhancing
excipient network does not fracture upon expansion, and is highly
connected in an expanded element or semi-solid mass, one or more
strength enhancing polymeric constituents 340 may have a strain at
fracture greater than 0.5, or even greater.
[0189] As the fluid 360 concentration in the structural framework
or elements 304, 310 or segments increases, they may further
transition from solid to semi-solid or viscoelastic. Thus, upon
diffusion or penetration of physiological fluid 360 into the
three-dimensional structural framework, or into one or more
elements, or into one or more segments 304, 310, the
drug-containing solid 301 (or the three-dimensional structural
framework 304, or one or more elements 310, or one or more
segments) may transition from solid to a semi-solid or viscoelastic
mass 312.
[0190] Because the concentration of excipient in the semi-solid or
viscoelastic mass 312 decreases as it absorbs water or
physiological fluid, the stiffness of the semi-solid or viscous
mass 312 generally decreases as it expands. In the invention
herein, therefore, for ensuring that the stiffness and strength of
the semi-solid or viscoelastic mass 312 remains so large that the
(mechanical or geometric) integrity of the semi-solid or
viscoelastic mass 312 is substantially preserved for prolonged time
under the relevant physiological conditions, the normalized
expansion of the drug-containing solid 301 (or of the framework 304
or of the semi-solid or viscoelastic mass 312) may be limited. More
specifically, in some embodiments, a length, width, thickness,
diameter, etc. of the drug-containing solid 301 (or of the
framework of of the semi-solid or viscoelastic mass 312) may expand
to no more than 5 times the initial value (e.g., the initial length
of the drug-containing solid or framework prior to exposure to said
physiological fluid) upon immersion in a physiological fluid. This
includes, but is not limited to a length, width, thickness,
diameter, etc. of the drug-containing solid (or of the framework or
of the semi-solid or viscous mass) expanding to no more than 4.5
times, or no more than 4 times, or no more than 3.5 times, or no
more than 3, or no more than 2.5 times the initial value prior to
exposure to said physiological fluid.
[0191] Concomitant with the entrance or penetration of fluid 360
into the elements 310, drug molecules 320 may be released from the
drug-containing solid 301 or semi-solid or viscoelastic mass 312
into the physiological fluid 360. By way of example but not by way
of limitation, drug molecules may diffuse from the drug-containing
solid 301 or semi-solid or viscoelastic dosage form 312 into the
physiological fluid 360, FIGS. 3c-3f. If the amount of drug per
unit volume of the semi-solid or viscoelastic mass is far greater
than the solubility, and the semi-solid or viscoelastic mass 312 is
several millimeters thick and stabilized or preserved for prolonged
time, the drug release time can be prolonged.
[0192] As a result, upon immersion of the drug-containing solid or
dosage form in a physiological fluid, said fluid may percolate at
least an interconnected free space and diffuse into one or more
elements (e.g., fibers), so that the framework expands in at least
one dimension and transitions to a semi-solid mass. The expanded
semi-solid mass may have a length between 1.3 and 4 times the
initial length of the drug-containing solid prior to exposure to
said physiological fluid. The semi-solid mass may further release
drug over prolonged time (e.g., over a time greater than an hour,
or over a time greater than two hours, or over a time greater than
5 hours, etc.).
[0193] FIG. 4a schematically shows a further non-limiting example
of a pharmaceutical dosage form disclosed herein. The dosage form
400 comprises a drug-containing solid 401 having an outer surface
402 and an internal three dimensional structural framework 404 of
one or more thin structural elements 410. (It may be noted that in
some preferred embodiments, the framework 404 comprises
criss-crossed stacked layers of one or more fibers 410.) The
framework 404 is contiguous with and terminates at said outer
surface 402. The elements 410 have segments spaced apart from
adjoining segments, thereby defining one or more interconnected
free spaces 415 through the drug-containing solid 401. The elements
410 further comprise at least one active ingredient 420 and at
least two excipients 430, 440. The at least two excipients 430, 440
comprise one or more physiological fluid-absorptive polymeric
excipients or constituents 430 and one or more strength-enhancing
polymeric excipients or constituents 440.
[0194] Upon exposure to a physiological fluid 460, said one or more
fluid-absorptive excipients 430 transition to a viscous mass or a
viscous solution 432, FIGS. 4b-4c. Said one or more
fluid-absorptive excipients or viscous mass or viscous solution
430, 432 further expand said framework 404 along at least one
dimension with absorption of said physiological fluid 460, FIGS.
4b-4f. Also, upon exposure to a physiological fluid 460, said one
or more strength-enhancing excipients 440 form a fluid-permeable,
semi-solid network 442 to mechanically support said framework 404,
as illustrated schematically in the non-limiting FIGS. 4c-4f.
[0195] FIG. 4a also presents another non-limiting example of a
pharmaceutical dosage form disclosed herein. The dosage form 400
comprises a drug-containing solid 401 having an outer surface 402
and an internal three dimensional structural framework 404 of one
or more thin structural elements 410. (It may be noted that in some
preferred embodiments, the framework 404 comprises criss-crossed
stacked layers of one or more fibers 410.) The framework 404 is
contiguous with and terminates at said outer surface 402. The
elements 410 have segments spaced apart from adjoining segments,
thereby defining one or more interconnected free spaces 415 through
the drug-containing solid 401. The elements 410 further comprise at
least one active ingredient 420 and at least two excipients 430,
440.
[0196] The at least two excipients 430, 440 comprise one or more
fluid-absorptive polymeric constituents or excipients 430 within
which 430 the solubility of a physiological fluid is greater than
600 mg/ml. The at least two excipients 430, 440 further comprise
one or more strength-enhancing polymeric constituents or excipients
440. After soaking with said physiological fluid under
physiological conditions, the one or more strength-enhancing
polymeric constituents 440 have an elastic modulus in the range
between 0.1 MPa and 200 MPa, and a strain at fracture greater than
0.5. Preferably, moreover, the one or more strength-enhancing
polymeric constituents 440 form one or more phases that are
substantially connected and/or substantially contiguous along the
lengths of one or more structural elements 410.
[0197] As shown schematically in FIGS. 4b-4f, upon immersion in, or
upon exposure to, said physiological fluid 460, said fluid 460
percolates at least one interconnected free space 415 and diffuses
into one or more elements 410, thereby expanding said framework 404
in at least one dimension to a length between 1.3 and 4 times its
length prior to exposure to said physiological fluid 460. By way of
example but not by way of limitation, the initial thickness of said
framework 404 (also referred to herein as the "thickness prior to
exposure to said physiological fluid"), H.sub.0, may expand to a
thickness, H=1.3-4 times H.sub.0, upon exposure of said framework
404 to said physiological fluid 460. Similarly, the initial length
of said framework 404, L.sub.0, may expand to a length, L=1.3-4
times L.sub.0, upon exposure of said framework 404 to said
physiological fluid 460.
[0198] Also, upon exposure to said physiological fluid 460, said
framework 404 or drug-containing solid 401 transitions to a
semi-solid mass 412. The semi-solid mass 412 may maintain its
length between 1.3 and 4 times the initial length of said framework
404 or drug-containing solid 401 for prolonged time, FIGS. 4c-4f.
The term "the semi-solid mass maintains its length between 1.3 and
4 times the initial length for prolonged time" is referred to
herein as a semi-solid mass immersed in an unstirred or lightly
stirred dissolution fluid (e.g., acidic water), wherein said
immersed semi-solid mass maintains its length between 1.3 and 4
times the initial length for an extended time, such as a time
greater than 1 hour, or a time greater than 2 hours, or a time
greater than 5 hours, or an even longer time. Generally, also, said
semi-solid mass 412 may release said drug 420 into said
physiological fluid 460 over time (e.g., over a time greater than 1
hour, or over a time greater than 2 hours, or over a time greater
than 5 hours, etc.).
[0199] Moreover, upon exposure to said physiological fluid, the one
or more strength-enhancing excipients 440 form a fluid-permeable,
semi-solid network 442 within one or more elements 410 or
semi-solid mass 412 to mechanically support the one or more
elements 410, framework 404, or semi-solid mass 412, FIGS. 4c-4f.
Also, the one or more fluid-absorptive excipients 430 transition to
a viscous mass, or a viscous solution 432, expanding said one or
more elements 410 or framework 404 in at least one dimension with
absorption of said physiological fluid 460.
[0200] A non-limiting course of a dosage form structure after
ingestion by a human or animal subject (e.g., a dog, a pig, etc.)
is presented in FIG. 5. Initially, the dosage form 500 is solid and
has a swallowable size and geometry. Upon ingestion, the dosage
form enters the stomach, and interconnected free space 515 is
percolated by gastric fluid (and/or by saliva, oesophageal fluid,
etc.), FIG. 5a. The gastric fluid (and/or saliva, oesophageal
fluid, etc.) then diffuses into the three dimensional structural
framework and/or the elements 510 (e.g., fibers) it surrounds. As a
result, the drug-containing solid expands and a semi-solid mass 512
is formed with a size (e.g., a width, diameter, etc.) greater than
the diameter or width of the pylorus and a strength or stiffness so
large that it is substantially unfragmentable in the gastric
environment (e.g., under normal gastric conditions) for prolonged
time, FIG. 5b.
[0201] Moreover, as the drug-containing solid absorbs gastric fluid
and transitions to a semi-solid mass, drug molecules may be
released from the drug-containing solid or the semi-solid mass into
the gastric fluid over prolonged time, FIGS. 5b and 5c. Thus,
because the size and the strength or stiffness of the semi-solid
mass 512 may remain sufficiently large to prevent its passage
through the pylorus into the intestines for prolonged time, drug
release into the stomach can be prolonged and/or controlled.
Eventually, however, the stiffness or strength of the semi-solid
mass 512, 513 may be so low that it disintegrates, or deforms
excessively, or breaks up, or fragments, or dissolves, etc. in the
stomach, and passes into the intestines, FIG. 5d. It may be noted
that the terms "disintegrate" or "disintegration" are used as
equivalents to "fragment", "fragmentation", "deform", "excessive
deformation", "dissolve", "dissolution", "erode", "erosion",
"mechanically weaken", "soften", "break up", "rupture", and so
on.
[0202] Additional aspects and embodiments of structural elements or
fibers according to the invention herein are described throughout
this specification. Any more aspects and embodiments of structural
elements or fibers obvious to a person of ordinary skill in the art
are all within the spirit and scope of this invention.
Models of Expansion, Drug Release, and Disintegration of the Dosage
Form
[0203] The following examples present non-limiting ways by which
the expansion and drug release behavior of the disclosed dosage
forms may be modeled. They will enable one of skill in the art to
more readily understand the details and advantages of the
invention. The models and examples are for illustrative purposes
only, and are not meant to be limiting in any way.
(a) Dosage Form Microstructures and Formulation
[0204] The non-limiting models refer to dosage forms as shown
schematically in the non-limiting FIG. 6a. The dosage forms 600
comprise a drug-containing solid 601 having an outer surface 602
and an internal three dimensional structural framework 604
comprising a plurality of criss-crossed stacked layers of one or
more fibrous elements 610, said framework contiguous with and
terminating at (e.g., and defining) said outer surface 602. The
fibrous elements 610 have segments spaced apart from like segments
of adjoining elements, thereby defining free spaces 615, wherein a
plurality of adjacent free spaces of successive layers combine to
define one or more interconnected free spaces 615 through the
drug-containing solid 601. At least one of said one or more
interconnected free spaces 615 terminates at said outer surface 602
and is filled with matter removable by a physiological fluid under
physiological conditions. The fibrous elements 610 further comprise
at least one active ingredient 620 and at least two excipients 630,
640 through their thickness. The at least two excipients 630, 640
comprise one or more physiological fluid-absorptive polymeric
constituents 630 of molecular weight greater than 50 kg/mol and one
or more strength-enhancing constituents 640. Moreover, in the
specific non-limiting dosage forms considered in the models, said
at least two excipients 630, 640 form at least a solid solution.
Also, one or more phases comprising the one or more
strength-enhancing excipients 640 are substantially connected or
contiguous along the lengths of one or more fibers or the
structural framework. Similarly, one or more phases comprising the
one or more strength-enhancing excipients 640 are substantially
connected or contiguous through the thicknesses of one or more
fibers or the structural framework.
[0205] Furthermore, in the specific non-limiting examples herein,
the physiological fluid-absorptive polymeric excipient 630
generally comprises hydroxypropylmethylcellulose (HPMC) of
molecular weight 120 kg/mol. HPMC is mutually soluble with typical
physiological fluids. Thus, the solubility of a physiological fluid
in said absorptive excipient (e.g., HPMC) can be about 1000 mg/ml,
or greater than 750 mg/ml. The strength-enhancing excipient 640
generally comprises methacrylic acid-ethyl acrylate copolymer (also
referred to herein as "Eudragit L100-55"). The mechanical
properties of Eudragit L100-55 after exposure to a physiological
fluid are presented in Experimental example 2.7 and Table 6 of this
disclosure. Briefly, after soaking with a physiological fluid, said
strength-enhancing excipient 640 (e.g., Eudragit L100-55) comprises
an elastic modulus of about 5.7 MPa (e.g., between 0.2 MPa and 200
MPa), a tensile strength of about 1.8 MPa (e.g., between 0.2 MPa
and 200 MPa), and a strain at fracture of about 3.5 (e.g., greater
than 0.5, or between 0.5 and 20). Moreover, said strength-enhancing
excipient 640 (e.g., Eudragit L100-55) is an enteric excipient that
is sparingly soluble or practically insoluble in aqueous media with
a pH value smaller than about 5.5, but dissolves in aqueous media
with a pH value greater than about 5.5-6. The drug 620 in the
non-limiting dosage forms modeled herein generally comprises
ibuprofen.
(b) Concept of Expansion, Drug Release, and Disintegration of the
Dosage Forms
[0206] As shown schematically in the non-limiting FIG. 6b, upon
immersion of the dosage form 600 or drug-containing solid 601 in a
stirred dissolution fluid 660, such as deionized (DI) water with
0.1 M hydrochloric acid (HCl), said fluid may percolate at least
one interconnected free space 615 and wet the structural framework
604, 610. This may allow the fluid 660 to diffuse into one or more
said fibrous elements 610, and the framework 604, 610 to expand
along all dimensions and to transition to a semi-solid or
viscoelastic or viscous mass 650.
[0207] Without wishing to be bound to a particular theory,
moreover, within the elements or fibers, the solubility of the
acidic fluid may be high in absorptive excipient (e.g., HPMC,
etc.), but low in the strength-enhancing excipient (e.g., Eudragit
L100-55, etc.). Thus, as the water concentration in the fibers
increases, the excipients may separate out into at least two
phases: a highly viscous solution of water and absorptive excipient
(e.g., within polyhedral cells, cavities, etc. of the fibrous
elements) and a semi-solid network (e.g., semi-solid membranes, a
semi-solid polyhedral network of membranes, a semi-solid framework,
a semi-solid network of cell walls, a semi-solid network of fibers,
etc. within the fibrous elements) of strength-enhancing excipient,
FIG. 6c. Water molecules may readily pass through the cell walls,
or membranes, of the strength-enhancing excipient (or semi-solid
network) into the cells, but passage of absorptive excipient
molecules out of the cells may be hindered. As a result, an
internal pressure may develop in the cells due to the inward
osmotic flux of water and the cells, fibers, and dosage form may
expand. The concentration of absorptive excipient molecules and the
internal pressure in the cells, however, may decrease as they
expand. Eventually, therefore, expansion may cease and an expanded
composite semi-solid or viscoelastic or viscous mass may be formed
that may comprise a substantially stable (e.g., a substantially
constant or unchanged) geometry for prolonged time.
[0208] Moreover, as dissolution fluid (water, etc.) enters the
fibers, the fibers may supersaturate with drug and the drug
molecules may aggregate as particles until the solubility is
reached (FIGS. 6c and 6d). Also the remaining drug molecules may
diffuse out from the semi-solid dosage form or semi-solid mass or
viscous mass into the dissolution fluid. As drug molecules are
released, the drug particles in the fibers may dissolve back until
they may be depleted, FIGS. 6d-6e. If the amount of drug per unit
volume of the semi-solid or viscous mass is far greater than the
solubility, and/or the semi-solid or viscous mass is several
millimeters thick, the drug release time can be prolonged.
[0209] It may be noted, furthermore, that water-soluble components,
such as absorptive excipient, etc. may dissolve slowly from the
semi-solid or viscous mass, and the semi-solid or viscous mass may
disintegrate with time. The way by which the semi-solid or viscous
mass disintegrates may, however, depend on the conditions it is
exposed to. By way of example but not by way of limitation, in a
lightly stirred dissolution fluid the semi-solid or viscous mass
may not deform (e.g., shear) substantially, and it may also not
break up. However, if the semi-solid or viscous mass is exposed to
repeated compression or exposed to impact, etc., as it might be in
the stomach of a human or animal subject, the semi-solid or viscous
mass may deform somewhat due to the forces acting on it, and it may
eventually break up or rupture.
(c) Expansion of Single Fibers
[0210] Upon immersion of a fiber in a dissolution fluid, the
expansion rate of the fiber may be determined by the diffusive flux
of water into the interior, as shown in the non-limiting FIG. 7.
The governing diffusion equation in cylindrical coordinates may be
written as:
.differential. c w .differential. t = 1 r .times. .differential.
.differential. r ( rD w .times. .differential. c w .differential. r
) .times. 0 .ltoreq. r .ltoreq. R .function. ( t ) ( 1 .times. a )
##EQU00001##
where c.sub.w(r,t) is the concentration of water in the fiber,
D.sub.w the diffusion coefficient of water in the fiber, and R(t)
the fiber radius at time t.
[0211] Let the water concentration in the fiber at the
fluid-fiber-interface be c.sub.b. The initial and boundary
conditions, as shown in FIG. 7, may then be written as:
c.sub.w=0 t=0, 0.ltoreq.r<R.sub.0 (1b)
c.sub.w=c.sub.b t.gtoreq.0, r=R(t) (1c)
where R.sub.0 is the initial fiber radius, which increases as the
mass of water in the fiber increases.
[0212] An analytical solution of Eq. (1a) subject to the initial
condition (1b) and the moving-boundary condition (1c) may not be
available at present. However, under the highly approximate
assumptions that the diffusion coefficient of water through the
fiber is constant and the concentration of water in the fiber is
very small, the water concentration profile, as shown schematically
in the non-limiting FIG. 7, may be approximated by (see, e.g., J.
Crank, "The Mathematics of Diffusion", second edition, Oxford
University Press, 1975):
c w c b = 1 - 2 R .times. n = 1 .infin. exp .function. ( - D w
.times. .alpha. n 2 .times. t ) .times. J 0 ( r .times. .alpha. n )
.alpha. n .times. J 1 ( R .times. .alpha. n ) ( 2 )
##EQU00002##
where J.sub.0 and J.sub.1 are the Bessel functions of the first
kind of order zero and one, respectively, and the .alpha..sub.n's
are the roots of
J.sub.0(R.alpha..sub.n)=0 (3)
[0213] Integrating Eq. (2) over the fiber volume can give the ratio
of the mass of water in the fiber per unit length at time t,
M.sub.w(t), and that at infinite time, M.sub.w,.infin.. For small
times (e.g., t<<R.sub.0.sup.2/D.sub.w),
M w ( t ) M w , .infin. .apprxeq. 4 .pi. .times. ( D w .times. t R
0 2 ) 1 / 2 ( 4 ) ##EQU00003##
[0214] The mass of water per unit length of the fiber may be
written in terms of the water volume per unit length at time t,
V.sub.w(t), and the fiber volume per unit length as
t.fwdarw..infin.. Under the very approximate assumption that the
fiber expansion is small,
M.sub.w(t)=.rho..sub.wV.sub.w(t) (5a)
M.sub.w,.infin.=c.sub.bV.sub.0 (5b)
where V.sub.0 is the initial fiber volume per unit length.
[0215] From Eqs. (4) and (5) the normalized volumetric expansion of
the fiber may be expressed as:
.DELTA. .times. V .function. ( t ) V 0 .apprxeq. 4 .pi. .times. c b
.rho. w .times. ( D w .times. t R 0 2 ) 1 / 2 ( 6 )
##EQU00004##
where .DELTA.V(t)=V.sub.w.
[0216] Further assuming that the fiber expands isotropically, the
normalized radial and axial expansions may be about a third of the
volumetric expansion. Thus, for small times and small
expansions,
.DELTA. .times. R R 0 .apprxeq. .DELTA. .times. L L 0 .apprxeq. 4 3
.times. .pi. .times. c b .rho. w .times. ( D w .times. t R 0 2 ) 1
/ 2 ( 7 ) ##EQU00005##
From Eq. (7) the rate at which the normalized radius and length of
the fiber increases may increase if the boundary concentration and
diffusivity of water are increased, and the fiber radius is
decreased. Thus, for achieving rapid expansion, the diffusivity of
water in the fibers or structural elements should be large, and the
fiber radius (or element thickness) should be small.
[0217] For further information related to the diffusion of
dissolution fluid into fibers or other geometries, see, e.g., J.
Crank, "The Mathematics of Diffusion", second edition, Oxford
University Press, 1975. More models for estimating the expansion
rate of the fibers obvious to a person of ordinary skill in the art
are all within the spirit and scope of this disclosure.
(d) Expansion of Dosage Forms
[0218] Upon immersion of a fibrous dosage form in a dissolution
fluid, the dissolution fluid may percolate one or more free spaces
and diffuse into one or more fibers. As a result, the one or more
fibers may expand, as shown schematically in the non-limiting FIG.
8.
[0219] Because the dosage form may expand due to water diffusion
into the fibers, the normalized longitudinal expansion of the
dosage form, .DELTA.L/L.sub.0|.sub.DF, may be related to normalized
longitudinal and axial expansions of the single fiber,
.DELTA.L/L.sub.0|.sub.SF and .DELTA.R/R.sub.0|.sub.SF, as:
.DELTA. .times. L L 0 "\[RightBracketingBar]" DF .apprxeq. k LL
.times. .DELTA. .times. L L 0 "\[RightBracketingBar]" SF .apprxeq.
k RL .times. .DELTA. .times. R R 0 "\[RightBracketingBar]" SF ( 8 )
##EQU00006##
where k.sub.LL and k.sub.RL are constants, and
.DELTA.L/L.sub.0|.sub.SF and .DELTA.R/R.sub.0|.sub.SF,
respectively, are the normalized longitudinal and radial expansions
of the single fibers, Eq. (7). If the fibers expand isotropically,
k.sub.LL and k.sub.RL.about.1.
[0220] Thus, for some dosage forms where fiber expansion is
isotropic, k.sub.LL and k.sub.RL are in the range of about 0.25 to
4 (this includes, but is not limited to a range of 0.5 to 2).
[0221] More models for estimating the dosage form's expansion rate
that are obvious to a person of ordinary skill in the art are all
within the spirit and scope of this disclosure.
(e) Drug Release by the Dosage Forms
[0222] Because the drug in the non-limiting examples herein is
sparingly soluble (e.g., the mass of drug in the expanded fiber per
unit volume of the expanded fiber initially is greater than the
drug solubility in the expanded fiber), as water diffuses into the
fiber, the drug molecules in the fiber may precipitate as
particles. The fiber may then be a "uniform" semi-solid or viscous
mass of water, drug molecules, and drug particles. From this
semi-solid or viscous fiber mass, drug molecules may diffuse out
into the fluid-filled void or free space of the dosage form, and
subsequently be transported into the dissolution fluid. Moreover,
as the drug molecules diffuse out of the fibers, the drug particles
in the fibers may dissolve back until they may be depleted.
[0223] Three cases may be differentiated, FIG. 9. If the volume
fraction of fibers in the dosage form is very small, as in FIG. 9a,
the rate-determining diffusion length may be the radius of the
thin, single fiber, and the drug release rate may be fast. If the
fiber volume fraction is very large, however, as in FIG. 9c, the
rate-determining diffusion length may be the half-thickness of the
corresponding thick, monolithic slab, and the drug release rate may
be very slow. If the fiber volume fraction is intermediate, as in
FIG. 9b, the drug release rate may be between these two extremes.
The two extreme cases are modeled below.
(e1) Case 1: Drug Release Limited by Diffusion Through the Fiber
(2R/.lamda..about.0)
[0224] In the first case, the fibers are very far apart and the
fluid velocity around the fibers is so large that the drug release
rate by the fibrous dosage form is limited by the rate of diffusion
within the fibers. In the fibers, two regions may be
differentiated, as shown in the non-limiting FIG. 10: a drug
particle-dispersed region and a drug particle-depleted region
containing only dissolved drug molecules. The two regions may be
delineated by a thin, inward-moving boundary with thickness of the
order of the inter-particle distance.
[0225] In the particle-dispersed region, the total drug mass (drug
particles plus drug molecules) per unit volume may be the initial
value, and far greater than the drug solubility, FIG. 7b. In the
particle-free region, the drug concentration may be governed by the
diffusion equation:
.differential. c d .differential. t = 1 r .times. .differential.
.differential. r ( r .times. D d .times. .differential. c d
.differential. r ) .times. R * ( t ) .ltoreq. r .ltoreq. R ( 9
.times. a ) ##EQU00007##
subject to the initial, interfacial, and boundary conditions
c.sub.d=c.sub.d,0 t=0, r.ltoreq.R (9b)
c.sub.d=c.sub.s t>0, r=R*(t) (9c)
c.sub.d=0 r.gtoreq.R (9d)
where D.sub.d is the diffusivity of drug molecules, c.sub.d,0 is
the "initial" drug mass (drug particles plus drug molecules) in the
expanded fiber per unit volume of the expanded fiber, c.sub.s the
drug solubility in the expanded fiber, R*(t) the radius of the
particle-dispersed region, and R the radius of the expanded
fiber.
[0226] Condition (9c) may stipulate that the mass of drug particles
depleted from the moving boundary can be equal to the mass of drug
that diffuses out as molecules. Thus, by mass conservation in a
differential volume at the interface the following condition may be
written:
(c.sub.d,0-c.sub.s).DELTA.R*=D.sub.d(dc.sub.d/dr).DELTA.t r=R*(t)
(9e)
where .DELTA.R* is the change in the radius of the interface in the
time interval .DELTA.t. Rearranging and rewriting in differential
form
d .times. R * d .times. t = D d c d , 0 - c s .times. dc d dr
.times. r = R * ( t ) ( 9 .times. f ) ##EQU00008##
[0227] An analytical solution to Eq. (9a) subject to the conditions
(9b) to (9f) may not be available at present. However, if
c.sub.d,0>>c.sub.s, as in the present, non-limiting case, the
concentration profile in the particle-depleted region may be
assumed quasi-steady (for further details related to the
quasi-steady state, see, e.g., J. Crank, "The Mathematics of
Diffusion", second edition, Oxford University Press, 1975). That
is, the drug concentration in the particle-free region may be
expressed as:
c d = c s .times. ln .function. ( r / R ) ln .function. ( R * ( t )
/ R ) .times. R * ( r ) .ltoreq. r .ltoreq. R ( 10 )
##EQU00009##
Differentiating, the concentration gradient at the interface way be
written as:
d .times. c d dr = c s r .times. ln .function. ( R * ( t ) / R )
.times. r = R * ( t ) ( 11 ) ##EQU00010##
Combining Eq. (9f) and Eq. (11) can give the velocity of the
interface as:
d .times. R * d .times. t = D d c d , 0 - c s .times. c s R * ( t )
.times. ln .function. ( R * ( t ) / R ) ( 12 ) ##EQU00011##
Rearranging and rewriting in integral form
.intg. R R * ( t ) R * ( t ) .times. ln .function. ( R * ( t ) R )
.times. dR * = .intg. 0 t D d .times. c s c d , 0 - c s .times. dt
( 13 ) ##EQU00012##
Integrating,
[0228] 1 4 .times. R * ( t ) 2 .times. ( 2 .times. ln .function. (
R * ( t ) R ) - 1 ) + 1 4 .times. R 2 = D d .times. c s c d , 0 - c
s .times. t ( 14 ) ##EQU00013##
Rewriting,
[0229] ( R * ( t ) R ) 2 .times. ( 1 - 2 .times. ln .function. ( R
* ( t ) R ) ) = 1 - 4 .times. c s c d , 0 - c s .times. D d .times.
t R 2 ( 15 ) ##EQU00014##
[0230] From geometry the fraction of drug released by the fiber in
time t may be written as:
m d M 0 = 1 - ( R * ( t ) R ) 2 ( 16 ) ##EQU00015##
[0231] Combining Eqs. (15) and (16) gives an implicit equation for
the fraction of drug released based on the relevant geometric and
physico-chemical parameters:
( 1 - m d M 0 ) .times. ( 1 - ln .function. ( 1 - m d M 0 ) ) = 1 -
4 .times. c s c d , 0 - c s .times. D d .times. t R 2 ( 17 )
##EQU00016##
For small times, Eq. (17) can be simplified by expanding
m.sub.d/M.sub.0 as a power series (e.g., substituting
ln(1-m.sub.d/M.sub.0)=-m.sub.d/M.sub.0) as:
m d M 0 = 2 .times. ( c s c d , 0 - c s ) 1 / 2 .times. ( D d
.times. t R 2 ) 1 / 2 ( 18 ) ##EQU00017##
[0232] Moreover, substituting m.sub.d/M.sub.0=0.8 in Eq. (18) and
rearranging, the time to release 80 percent of the drug content may
be estimated by:
t 0.8 = 0 . 1 .times. 2 .times. ( c d , 0 - c s ) .times. R 2 c s
.times. D d ( 19 ) ##EQU00018##
[0233] Thus, by Eq. (19) the drug release time may increase if the
concentration of drug in the fiber divided by the solubility and
the fiber radius are increased, and the diffusivity of drug through
the fiber is decreased.
[0234] For further information related to the diffusion of drug out
of fibers or other geometries, see, e.g., J. Crank, "The
Mathematics of Diffusion", second edition, Oxford University Press,
1975. More models for estimating the drug release rate and time by
single fibers in a reasonably-well stirred dissolution fluid
obvious to a person of ordinary skill in the art are all within the
spirit and scope of this disclosure.
(e2) Case 2: Drug Release Limited by Diffusion Through the
Monolithic Semi-Solid Dosage Form (2R/.lamda..about.1)
[0235] In the second case, the fibers are so tightly packed that
the expanded semi-solid or viscous dosage form is essentially a
monolithic slab, as illustrated in the non-limiting FIG. 10. If the
dissolution fluid is stirred and the dosage form several
millimeters thick, drug release is limited by diffusion through the
slab. In analogy to the single-fiber diffusion, the
particle-dispersed and particle-depleted regions are delineated by
an inward-moving interface, FIG. 11. At the moving interface the
mass of depleted drug particles may be the same as the mass of drug
that diffuses out. Thus
(c.sub.d,0-c.sub.s).DELTA.X=D.sub.d(dc.sub.d/dx).DELTA.t x=H-X(t)
(20)
where c.sub.d,0 is the initial drug mass per unit volume of the
slab, H the half-thickness of the slab, X(t) the advancement of the
interfacial position at time t, and .DELTA.X the incremental
advancement of the interfacial position in the time interval
.DELTA.t. Rearranging and rewriting in differential form
d .times. X d .times. t = D d c d , 0 - c s .times. .differential.
c d .differential. x .times. x = H - X .function. ( t ) ( 21 )
##EQU00019##
[0236] According to the quasi-steady state assumption, now the
concentration profile may be linear, FIG. 10b. Thus the velocity of
the interface toward the origin, dX/dt, may be expressed as:
d .times. X d .times. t .apprxeq. c s c d , 0 .times. D d X ( 22 )
##EQU00020##
Rearranging and integrating,
X = ( 2 .times. c s .times. D d .times. t c d , 0 ) 1 / 2 ( 23 )
##EQU00021##
[0237] The fraction of drug released, m.sub.d/M.sub.0, may be about
equal to X/H, where H is the half-thickness of the semi-solid or
viscous dosage form mass. Thus the fraction of drug released may be
approximated by
m d M 0 .apprxeq. ( 2 .times. c s .times. D d .times. t c d , 0
.times. H 2 ) 1 / 2 ( 24 ) ##EQU00022##
and the time to release eighty percent of the drug content,
t 0.8 = 0.32 ( c d , 0 - c s ) .times. H 2 c s .times. D d ( 25 )
##EQU00023##
From Eq. (25), t.sub.0.8 may be proportional to H.sup.2.
[0238] More models for estimating the drug release rate and time by
a monolithic slab would be obvious to a person of ordinary skill in
the art. All are within the spirit and scope of this
disclosure.
(f) Disintegration of the Dosage Form
[0239] The rate of disintegration of the semi-solid or viscous
dosage form generally depends greatly on the forces it is exposed
to. Because a preferred application of the dosage form herein is
prolonged drug release into the stomach, herein a highly
approximate model for estimating the disintegration time of the
dosage form in the stomach is developed.
[0240] In the stomach, the dosage form generally is exposed to
cyclic compressive forces by the stomach walls. A non-limiting
force field acting on the expanded semi-solid or viscous dosage
form comprises diametrically opposed cyclic loads per unit length,
P, with maximum load per unit length, P.sub.max, as shown
schematically in FIG. 12. The corresponding maximum cyclic stress
(tension) along the axis of symmetry may be approximated as (for
further details, see, e.g., A. H. Blaesi and N. Saka, Int. J.
Pharm. 509 (2016) 444-453):
.sigma. max = P max .pi. .times. R d .times. f ( 26 )
##EQU00024##
where .sigma..sub.max is the maximum cyclic tensile stress along
the axis of symmetry of dosage form, P.sub.max the maximum load
intensity (load per unit length) applied by the stomach walls, and
R.sub.df the radius of the expanded dosage form.
[0241] To avoid immediate fracture of the dosage form, the tensile
strength of the expanded, semi-solid or viscous dosage form should
be greater than .sigma..sub.max. If the tensile strength of the
expanded, semi-solid or viscous dosage form is greater than
.sigma..sub.max, the dosage form may exhibit fatigue fracture after
a number of compression pulses, N.sub.f.
[0242] Assuming that P.sub.max, .sigma..sub.max, and the stiffness,
strength, geometry, etc. of the dosage form are time-invariant, in
analogy with Basquin's equation, a power function for the fatigue
life, or number of compression pulses to failure, N.sub.f, of the
dosage form may be proposed as:
.sigma..sub.max=.sigma..sub.f,dfN.sub.f.sup.b (27)
where .sigma..sub.f,df is the tensile strength of the dosage form,
and b is a constant, typically of the order -0.12.
[0243] Generally, the tensile strength of the expanded, semi-solid
or viscous dosage form may predominantly be determined by the
characteristics of the strength-enhancing excipient network. Under
the highly approximate assumption that the strength-enhancing
excipient network in or around the fibers or elements may be
considered a cellular material, the tensile strength of the dosage
form may be expressed as (for further details, see, e.g., M. F.
Ashby, Metall. Trans. A 14A (1983) 1755-1769):
.sigma..sub.f,df=.sigma..sub.f,seC.sub.8.phi..sub.se.sup.3/2
(28)
where .sigma..sub.f,se is the fracture strength of the acidic
water-soaked strength-enhancing excipient, .phi..sub.se its volume
fraction in the dosage form, and C.sub.8 a constant, typically
about equal to 0.65.
[0244] Substituting Eq. (28) in Eq. (27) and rearranging gives:
N f = ( .sigma. max .sigma. f , se .times. C 8 .times. .phi. se 3 /
2 ) 1 / b ( 29 ) ##EQU00025##
[0245] The gastric residence time,
t.sub.r.about.N.sub.f.times.t.sub.pulse, where t.sub.pulse is the
period of a compression cycle by the stomach walls Substituting
this term in Eq. (29) and rearranging gives:
t r .about. t pulse ( .sigma. max .sigma. f , se .times. C 8
.times. .phi. se 3 / 2 ) 1 / b ( 30 ) ##EQU00026##
where t.sub.pulse is the period of a compression cycle by the
stomach walls.
[0246] Combining Eq. (30) with Eq. (26) gives:
t r .about. t pulse ( P max .pi. .times. R df .times. .sigma. f ,
se .times. C 8 .times. .phi. se 3 / 2 ) 1 / b ( 31 )
##EQU00027##
[0247] By Eq. (31), the parameters that may be changed to alter the
gastric residence time are the radius of the dosage form, R.sub.df,
the fracture strength of the acidic water-soaked excipient in
monotonic loading, .sigma..sub.f,se, and the volume fraction of the
strength-enhancing excipient in the dosage form, .sigma..sub.se.
The radius of the dosage form, however, cannot be changed over a
large range. Similarly, for the given formulation, .sigma..sub.f,se
is generally given. Thus the primary variable that may be adjusted
to control the gastric residence time is .sigma..sub.se. From the
non-limiting experimental results shown later, for
.sigma..sub.se.about.0.2-0.5 the gastric residence time of the
fibrous dosage form may be prolonged to greater than about a day.
Such gastric residence time is sufficient to prolong the delivery
of drug into the upper gastrointestinal tract, and improve the
efficacy, safety, and convenience of a myriad of drug
therapies.
Embodiments of the Dosage Form
[0248] In view of the theoretical models and non-limiting examples
above, which are suggestive and approximate rather than exact, and
other considerations, the dosage forms disclosed herein may further
comprise the following embodiments.
a) Outer Geometry of Drug-Containing Solid and Three Dimensional
Structural Framework of Elements
[0249] In some embodiments, the average length, and/or the average
width, and/or average thickness of the drug-containing solid (e.g.,
the three dimensional structural framework of one or more elements)
is/are greater than 1 mm. This includes, but is not limited to an
average length, and/or average width, and/or average thickness of
the drug-containing solid greater than 1.5 mm, or greater than 2
mm, or greater than 3 mm, or in the ranges 1 mm-30 mm, 1.5 mm-30
mm, 2 mm-30 mm, 5 mm-20 mm, 5 mm-18 mm, 6 mm-20 mm, 7 mm-20 mm, 7
mm-19 mm, 7 mm-18 mm, 7 mm-17 mm, 7 mm-16 mm, 8 mm-20 mm, 8 mm-18
mm, 8 mm-16 mm, 8 mm-15 mm, 8 mm-14 mm, 8 mm-13 mm, 8 mm-12 mm. In
the invention herein, the length is usually referred to a measure
of distance in direction of the longest distance, the thickness is
usually referred to a measure of distance in direction of the
shortest distance, and the width is smaller than the length but
greater than the thickness. Moreover, in some embodiments the
direction of the "width" may be perpendicular to the direction of
the length and/or to the direction of the thickness.
[0250] In some embodiments, moreover, a width perpendicular to the
direction of the longest dimension of the dosage form or
drug-containing solid herein is greater than 6 mm. This includes,
but is not limited to a width perpendicular to the direction of the
longest dimension of the dosage form or drug-containing solid
greater than 7 mm, or greater than 8 mm, or greater than 9 mm, or
in the ranges 6 mm-18 mm, 6 mm-16 mm, 6 mm-15 mm, 7 mm-18 mm, 7
mm-16 mm, 7 mm-15 mm, or 8 mm-18 mm, 8 mm-16 mm, or 8 mm-15 mm.
[0251] The dosage forms or drug-containing solids or three
dimensional structural frameworks herein can have any common or
uncommon outer shape of a drug-containing solid. For non-limiting
examples of common tablet shapes, see, e.g., K. Alexander, Dosage
forms and their routes of Administration, in M. Hacker, W. Messer,
and K. Bachmann, Pharmacology: Principles and Practice, Academic
Press, 2009. Any other geometries, outer shapes, or dimensions of
dosage forms, drug-containing solids, or three dimensional
structural frameworks of elements obvious to a person of ordinary
skill in the art are all within the spirit and scope of this
invention.
b) Surface Composition of Elements and Segments
[0252] In some embodiments, for enabling rapid percolation of
dissolution fluid into the interior of the dosage form structure
(e.g., into interconnected free space of the drug-containing
solid), the surface composition of at least one element is
hydrophilic. Such embodiments include, but are not limited to
embodiments where the surface composition of one or more structural
elements and/or the surface composition of one or more segments
and/or the surface composition of the three dimensional structural
framework of elements is hydrophilic. In this disclosure, a surface
or surface composition is hydrophilic, also referred to as
"wettable by a physiological fluid", if the contact angle of a
droplet of physiological fluid on said surface in air is no more
than 90 degrees. This includes, but is not limited to a contact
angle of a droplet of said fluid on said solid surface in air no
more than 80 degrees, or no more than 70 degrees, or no more than
60 degrees, or no more than 50 degrees, or no more than 40 degrees,
or no more than 30 degrees. It may be noted that in some
embodiments the contact angle may not be stationary. In this case,
a solid surface may be understood "hydrophilic" if the contact
angle of a droplet of physiological fluid on said solid surface in
air is no more than 90 degrees (including but not limiting to no
more than 80 degrees, or no more than 70 degrees, or no more than
60 degrees, or no more than 50 degrees, or no more than 40 degrees)
at least 20-360 seconds after the droplet has been deposited on
said surface. A non-limiting schematic of a droplet on a surface is
presented in U.S. application Ser. No. 15/482,776 titled "Fibrous
dosage form".
[0253] Generally, the percolation rate of physiological fluid into
interconnected free space is increased if the contact angle between
said fluid and the surface of the three dimensional structural
framework of one or more elements is decreased. Thus, in some
embodiments, at least one element, or at least one segment of an
element, or the three dimensional structural framework of elements
comprises a hydrophilic or highly hydrophilic coating for enhancing
the rate of fluid percolation into the dosage form structure. In
the context herein, a solid surface (e.g., a solid material or a
solid compound or a surface or a coating) is understood "highly
hydrophilic" if the contact angle of a droplet of physiological
fluid on the surface of said solid in air is no more is no more
than 45 degrees. This includes, but is not limited to a contact
angle of a droplet of said fluid on said solid surface in air no
more than 35 degrees, or no more than 30 degrees, or no more than
25 degrees, or no more than 20 degrees, or no more than 15
degrees.
[0254] Non-limiting examples of hydrophilic (or highly hydrophilic)
compounds that may serve as coating of elements (or segments of
elements, or the three dimensional structural framework of
elements) include polyethylene glycol, polyvinyl alcohol, polyvinyl
alcohol-polyethylene glycol copolymer, polyvinyl pyrrolidone,
silicon dioxide, sugars or polyols (e.g., mannitol, maltitol,
xylitol, maltitol, isomalt, lactitol, sucrose, glucose, fructose,
galactose, erythritol, maltodextrin, etc.), and so on.
[0255] In preferred embodiments, the coating of one or more
elements comprises at least a polyol. In other preferred
embodiments, the coating of one or more elements comprises at least
a sugar, such as sucrose, fructose, glucose, or galactose. In other
preferred embodiments, the coating of one or more elements
comprises at least silicon dioxide.
[0256] Any other compositions or coatings of the surface of one or
more elements or the three dimensional structural framework that
would be obvious to a person of ordinary skill in the art are all
included in this invention.
c) Microstructure of Drug-Containing Solid and Three Dimensional
Structural Framework
[0257] In some embodiments, dissolution fluid may percolate into
the interior of the structure (e.g., into at least one free space
or into the free spaces) if the drug-containing solid comprises at
least a continuous channel or free space having at least two
openings in contact with said fluid. The more such channels exist
with at least two ends in contact with a dissolution fluid the more
uniformly may the structure be percolated. Also, the greater the
space over which a continuous channel having at least two ends in
contact with a dissolution fluid extends, the more uniformly may
the structure be percolated. Uniform percolation is desirable in
the invention herein.
[0258] Thus, in the invention herein a plurality of adjacent free
spaces may combine to define one or more interconnected free spaces
(e.g., free spaces that are "contiguous" or "in direct contact" or
"merged" or "without any wall in between") forming an open pore
network that extends over a length at least half the thickness of
the drug-containing solid, or over a length greater than at least
twice the thickness of one or more elements. This includes, but is
not limited to a plurality of adjacent free spaces combining to
define one or more interconnected free spaces forming an open pore
network that extends over a length at least two thirds the
thickness of the drug-containing solid, or over a length at least
equal to the thickness of the drug-containing solid, or over a
length at least equal to the side length of the drug-containing
solid, or over a length and width at least equal to half the
thickness of the drug-containing solid, or over a length and width
at least equal to the thickness of the drug-containing solid, or
over a length, width, and thickness at least equal to half the
thickness of the drug-containing solid, or over a length, width,
and thickness at least equal to two thirds the thickness of the
drug-containing solid, or over a length, width, and thickness at
least equal to the thickness of the drug-containing solid, or over
the entire length, width, and thickness of the drug-containing
solid.
[0259] Also, in some embodiments an open pore network comprises or
occupies at least 30 percent (e.g., at least 40 percent, or at
least 50 percent, or at least 60 percent, or at least 70 percent,
or at least 80 percent, or 100 percent) of the free space of the
drug-containing solid (e.g., at least 30 percent, or at least 40
percent, or at least 50 percent, or at least 60 percent, or at
least 70 percent, or at least 80 percent, or at least 85 percent,
or at least 90 percent, or at least 95 percent, or at least 98
percent, or 100 percent of the free space of the drug-containing
solid are part of the same open pore network).
[0260] In preferred embodiments, all free spaces are interconnected
forming a continuous, single open pore network. In the invention
herein, if all free spaces of a drug-containing solid are
interconnected the free space of said drug-containing solid is also
referred to as "contiguous". The elements or three dimensional
structural framework may essentially form a three dimensional
lattice structure surrounded by contiguous or interconnected free
space. In preferred embodiments, moreover, one or more
interconnected free spaces terminate at the outer surface of the
drug-containing solid.
[0261] In drug-containing solids with contiguous free space that
terminates at the outer surface of the drug-containing solid, no
walls (e.g., walls comprising the three dimensional structural
framework of elements) must be ruptured to obtain an interconnected
cluster of free space (e.g., an open channel of free space) from
the outer surface of the drug-containing solid (or from any point
within the free space) to a point (or to any point) in the free
space within the internal structure. The entire free space or
essentially all free spaces is/are connected and accessible from
(e.g., connected to) the outer surface of the drug-containing
solid.
[0262] FIG. 13 schematically illustrates a pharmaceutical dosage
form 1300 comprising a drug-containing solid 1301 having an outer
surface 1302 and an internal three dimensional structural framework
1304 comprising a plurality of criss-crossed stacked layers of one
or more fibrous elements 1310. Said framework 1304 is contiguous
with and terminates at said outer surface 1102. The fibrous
elements 1310 further have segments spaced apart from like segments
of adjoining elements, thereby defining free spaces 1320. A
plurality of adjacent free spaces 1325 combine to define one or
more interconnected free spaces forming an open pore network
1330.
[0263] As shown in the non-limiting schematic of section A-A, free
space 1320 is interconnected through the drug-containing solid
1301, and said open pore network 1330 extends over the entire
length and thickness of the drug-containing solid 1301 or the
dosage form 1300. In other words, the length, L.sub.pore, over
which the open pore network 1330 extends is the same as the length
or diameter, D, of the dosage form 1300 or drug-containing solid
1301; the thickness, H.sub.pore, over which the open pore network
1330 extends is the same as the thickness, H, of the dosage form
1300 or drug-containing solid 1301. It may be noted that the term
"section" is understood herein as "plane" or "surface". Thus a
"section" is not a "projection" or "projected view".
[0264] Moreover, in the non-limiting example of FIG. 13 the
microstructure is rotationally symmetric. If the plane or section
A-A is rotated by 90 degrees about the central axis the
microstructure (e.g., the microstructural details) is/are the same.
Thus, the open pore network 1330 also extends over the entire width
of the drug-containing solid 1301 or the dosage form 1300. In other
words, the width over which the open pore network 1330 extends is
the same as the width or diameter, D, of the dosage form 1100 or
drug-containing solid 1101.
[0265] Furthermore, in the non-limiting microstructure of FIG. 13,
as shown in section A-A the open pore network 1330 or free space
1320 or free spaces 1325 is/are contiguous, and free space 1320
terminates at the outer surface 1302 of the drug-containing solid
1301. No walls (e.g., walls comprising the three dimensional
structural framework 1304 of elements) must be ruptured to obtain
an interconnected cluster of free spaces (e.g., an open channel of
free space) from the outer surface 1302 of the drug-containing
solid 1301 to a point (or to any point or position) in the free
space 1320, 1325, 1330. The entire free space 1320, 1325, 1330 is
accessible from the outer surface 1302 of the drug-containing solid
1301. Also, no walls (e.g., walls comprising the three dimensional
structural framework 1304 of elements) must be ruptured to obtain
an interconnected cluster of free space (e.g., an open channel of
free space) from any point or position within the free space 1320,
1325, 1330 to any other point or position in the free space 1320,
1325, 1330. The entire free space 1320, 1325, 1330 is accessible
from any point, location, or position within the free space 1320,
1325, 1330.
[0266] Additionally, the structure shown in FIG. 13 comprises
fibers (or fiber segments) in a layer that are aligned
unidirectionally (e.g., parallel). The fibers (or fiber segments)
in the layers above and below said layer are aligned
unidirectionally, too, and are aligned orthogonally to the fibers
in said layer (e.g., the fibers in the the layers above and below
said layer are aligned orthogonally to the fibers in said layer,
and vice versa). The fibers in the layers above and below said
layer further touch or "merge with" fibers in said layer at
inter-fiber point contacts. Thus the structural framework, network,
or 3D-lattice structure may be considered a network comprising
nodes or vertices at the inter-fiber point contacts and edges
defined by the fiber segments between adjacent nodes or vertices.
In the specific example of FIG. 13 the distance, .lamda., of fiber
segments between adjacent point contacts is uniform or constant
across the network.
[0267] Therefore, in some embodiments, the three dimensional
structural framework herein comprises a fibrous network having
inter-fiber point contacts and fiber segments between adjacent
contacts, and wherein the length of fiber segments between adjacent
point contacts is uniform across the fibrous network. It may be
noted that in some embodiments of the invention herein, a variable
(e.g., a length, distance, width, angle, concentration, etc.) is
uniform across the structural framework (e.g., across the fibrous
network) if the standard deviation of multiple (e.g., multiple,
randomly selected, e.g., at least three or at least 4 or at least 5
or at least 6 or at least 10 or at least 20 randomly selected)
counts of said variable across the structural framework is less
than the average value. This includes, but is not limited to a
standard deviation of multiple (e.g., multiple, randomly selected,
e.g., at least three or at least 4 or at least 5 or at least 6 or
at least 10 or at least 20 randomly selected) counts of said
variable across the structural framework less than half the average
value, or less than one third of the average value, or less than a
quarter of the average value, or less than one fifth of the average
value, or less than one sixth of the average value, or less than
one eight of the average value, or less than one tenth of the
average value, or less than one fifteenth of the average value. The
term "uniform" is also referred to herein as "constant" or "almost
constant" or "about constant".
[0268] The graph of FIG. 14 is a histogram of the length, .lamda.,
of fiber segments between adjacent point contacts. The .lamda.
values in this non-limiting example are distributed in a very
narrow window or zone around the average, .lamda..sub.avg. Thus the
standard deviation of the .lamda. values is very small; .lamda. is
precisely controlled; the structure is regular, deterministic, and
ordered.
[0269] In some embodiments, therefore, the three dimensional
structural network herein comprises a fibrous network having
inter-fiber point contacts 1475 and fiber segments 1410, 1411
between adjacent contacts, and wherein the length of fiber segments
between adjacent point contacts is precisely controlled. It may be
noted that the dosage form properties (e.g., the uniformity of
fluid percolation into the drug-containing solid, the expansion
rate, the drug release rate, etc.) can be optimized if the
microstructural parameters are precisely controlled. In the
invention herein, the term "precisely controlled" is also referred
to as "ordered" or "orderly arranged". A variable or a parameter
(e.g., the spacing of fiber segments between point contacts, the
contact width, the fiber thickness, the spacing between fibers,
etc.) is precisely controlled if it is deterministic and not
stochastic (or random). A variable or parameter may be
deterministic if, upon multiple repetitions of a step that includes
said variable (e.g., if multiple dosage forms are produced under
identical or almost identical conditions), the standard deviation
of the values of said variable is smaller than the average value.
This includes, but is not limited to a standard deviation of the
values of said variable smaller than half the average value, or
smaller than one third of the average value, or smaller than a
quarter of the average value, or smaller than one fifth or the
average value, or smaller than one sixth, or smaller than one
seventh, or smaller than one eight, or smaller than one ninth, or
smaller than one tenth, or smaller than 1/12, or smaller than 1/15,
or smaller than 1/20, or smaller than 1/25 of the average value of
said variable, or smaller than 1/30 of the average value of said
variable.
[0270] Moreover, in some embodiments, the three dimensional
structural network or framework herein comprises a fibrous network
having inter-fiber point contacts and fiber segments between
adjacent contacts, and wherein the average length of fiber segments
between adjacent point contacts is between 1 and 15 times the
average thickness of the one or more fibers. This includes, but is
not limited to fibrous networks having inter-fiber point contacts
and fiber segments between adjacent contacts, and wherein the
average length of fiber segments between adjacent point contacts is
between 1 and 12 times, or between 1 and 10 times, or between 1 and
9 times, or between 1 and 8 times, or between 1 and 7 times, or
between 1 and 6 times, or between 1 and 5 times, or between 1 and
4.5 times, or between 1 and 4 times the average thickness of the
one or more fibers.
[0271] More generally, in some embodiments, the volume fraction of
elements (e.g., fibers) in the drug-containing solid (e.g., the
element (e.g., fiber) volume divided by the volume of the
drug-containing solid) is in the range of 0.1 to 0.95. This
includes, but is not limited to a volume fraction of elements in
the drug-containing solid in the ranges 0.15-0.95, 0.15-0.9,
0.15-0.85, 0.2-0.95, 0.2-0.9, 0.2-0.85, 0.25-0.95, 0.25-0.9, or
0.25-0.85.
[0272] As shown in the structure of FIG. 15, moreover, at the
inter-fiber point contacts 1575 the two tangents of two contacting
fibers or fiber segments 1580, may form an angle, .alpha.. If the
distance, .lamda., of fiber segments between point contacts is
uniform or constant across the network, the angle, .alpha., formed
by two tangents of contacting fiber segments (e.g., the angle of
intersection) at the contact is about 90.degree.. It may be noted,
however, that the angle formed by two tangents of contacting fiber
segments (e.g., the angle of intersection) can also assume other
values, including without limitation an average value greater than
0 degrees. This includes, but is not limited to an angle formed by
two tangents of contacting fiber segments (e.g., the angle of
intersection) in the ranges between 20 and 90 degrees, or 30-90, or
40-90, or 50-90, or 60-90, or 70-90 degrees. Furthermore, also the
angle formed by two tangents of contacting fiber segments (e.g.,
the angle of intersection) can be precisely controlled. Thus, in
some embodiments herein, the three-dimensional structural network
of fibers comprises a fibrous network having inter-fiber point
contacts defined by intersecting fibers or fiber segments, and
wherein the angle of intersection at said point contacts is
precisely controlled across said fibrous network.
[0273] More examples of fibrous structures according to the
invention herein would be obvious to a person of ordinary skill in
the art. All of them are within the scope of this disclosure.
[0274] It may further be noted, however, that in some embodiments
the three dimensional structural framework comprises stacked layers
(or plies) of particles, fibers, or sheets, or any combinations
thereof. In some embodiments, moreover, one or more layers or plies
are bonded to the layers above or below said one or more
layers.
[0275] Furthermore, many of the above features and characteristics
may also apply to (e.g., the features or characteristics may be
similar to the features or characteristics of) three-dimensional
structural frameworks of stacked layers of sheets, or beads (e.g.,
particles) shown, for example, in the co-pending International
Application No. PCT/US2019/052030 filed on Sep. 19, 2019, and
titled "Dosage form comprising structured solid-solution framework
of sparingly-soluble drug and method for manufacture thereof". Such
features or characteristics are obvious to a person of ordinary
skill in the art who is given all information disclosed in this
specification. Application of such features or characteristics to
three-dimensional structural frameworks of stacked layers of beads
(e.g., particles) or even sheets (e.g., two-dimensional elements),
or any combinations of fibers, beads, and/or sheets, is included in
the invention herein.
[0276] Further non-limiting embodiments of the dosage form
structure are presented in U.S. application Ser. No. 15/482,776
titled "Fibrous dosage form", U.S. application Ser. No. 15/964,058
titled "Method and apparatus for the manufacture of fibrous dosage
forms", the U.S. application Ser. No. 15/964,063 and titled "Dosage
form comprising two-dimensional structural elements", and the
International Application No. PCT/US19/19004 titled "Expanding
structured dosage form". More examples of how the elements may be
structured or arranged in the three dimensional structural
framework of one or more solid elements would be obvious to a
person of ordinary skill in the art. All of them are within the
spirit and scope of this invention.
(g) Inter-Element or Inter-Fiber Contact and Bonding
[0277] Because the individual elements (e.g., fibers, beads,
sheets, etc.) are generally thin and slender they may bend or
deform due to the application of mechanical load. Thus, in some
embodiments, to provide mechanical support to the structure the
three dimensional structural framework of elements may comprise
contacts between elements or segments. Such inter-element contacts
include, but are not limited to point contacts or line
contacts.
[0278] In the invention herein, a point contact is referred to as
having a contact area or contact zone (e.g., the common surface of
the two elements or segments in contact) that extends over a length
and width no greater than 2.5 mm. This includes, but is not limited
to a contact width between two elements (or two segments) no
greater than 2 mm, or no greater than 1.75 mm, or no greater than
1.5 mm. In other examples without limitation, a contact width, 2a,
between two elements (or two segments) at a point contact may be no
greater than 1.1 times the thickness of the contacting elements (or
segments) at the position of the contact. This includes, but is not
limited to a contact width, 2a, between two elements (or two
segments) no greater than 1 time, or no greater 0.8 times, or no
greater than 0.6 times the thickness of the contacting fibers (or
segments) at the position of the contact. A line contact is
referred to as having a contact area or contact zone that extends
over a contact length far greater than the contact width. The
contact width is typically no greater than 2.5 mm. Moreover, at the
contact (e.g., at the contact zone of a point contact or at the
contact zone of a line contact), elements or segments may be
deformed. The geometry of said elements or segments at or near the
contact (e.g., at or near a point contact or at or near a line
contact) then is different form the geometry elsewhere. In some
embodiments, at the contact an element is "flat" or
"flattened".
[0279] FIG. 16 is a non-limiting example of a point contact 1680
between two orthogonally aligned fiber segments 1610. FIG. 16a is
the front view and FIG. 16b the top view of the two segments. The
contact area is circular. The diameter of the circle or "contact
width", 2a, is designated in the Figure. FIG. 17 is a non-limiting
example of a line contact 1780 between two unidirectionally aligned
fiber segments 1710. FIG. 17a is the front view and FIG. 17b the
top view. As shown in the Figure the contact width, 2a, is much
smaller than the contact length, .lamda.. Generally, because point
contacts can enable better connectivity of free space, they may be
preferred in some embodiments herein. For further information
related to point contacts and line contacts, see, e.g., K. L.
Johnson, "Contact mechanics", Cambridge University Press, 1985.
[0280] In some embodiments, the number of point contacts in the
three dimensional structural network is at least 10. This includes,
but is not limited to a number of point contacts in the three
dimensional structural network at least 20, or at least 50, or at
least 75, or at least 100, or at least 125, or at least 150, or at
least 175, or at least 200, or at least 250, or at least 300. In
some embodiments, moreover, the number of point contacts in the
three dimensional structural network is precisely controlled. In
some embodiments, moreover, the number of line contacts in the
three dimensional structural network is at least 10. In some
embodiments, however, the number of line contacts in the three
dimensional structural network is no greater than 10. In some
embodiments, moreover, the number of line contacts in the three
dimensional structural network is precisely controlled.
[0281] At the contact zone (e.g., at one or more point contacts or
at one or more line contacts, etc.) two elements or segments may be
bonded, which is understood herein as "fixed", "joined",
"attached", "welded" (e.g., by interdiffusion of molecules at the
contact, such as interdiffusion of absorptive excipient from one
element or segment to another contacting element or segment or
interdiffusion of strength-enhancing excipient from one element or
segment to another contacting element or segment, etc.), etc.
Generally, the bond strength is a fraction of the bulk strength of
the contacting elements or segments. Said fraction is typically no
greater than 1. This includes, but is not limited to a bond
strength no greater than 0.8, or no greater than 0.6, or no greater
than 0.4 times the strength of the bulk of elements or segments.
For providing mechanical support to the dosage form structure,
however, the bond strength should generally be greater than 0.01,
or greater than 0.02, or greater than 0.05, or greater than 0.1, or
greater than 0.2, or greater than 0.3, or greater than 0.4, or
greater than 0.5 times the bulk strength of elements or segments.
In some embodiments, moreover, the bond strength is in the ranges
0.001-1, 0.01-1, 0.02-1, 0.05-1, 0.1-1, 0.2-1, 0.3-1, 0.4-1, 0.5-1,
0.001-0.95, 0.001-0.9, 0.005-1, 0.005-0.95, or 0.01-0.9 times the
strength of the bulk of elements or segments. For further
information about determining and measuring strength of solid
materials, see, e.g., J. M Gere, S. Timoshenko, "Mechanics of
materials", fourth edition, PWS Publishing Company, 1997; M. F.
Ashby, "Materials selection in mechanical design", fourth edition,
Butterworth-Heinemann, 2011; K. L. Johnson, "Contact mechanics",
Cambridge University Press, 1985.
[0282] Thus, in some embodiments, the three dimensional structural
framework is a solid forming a continuous structure wherein at
least one element (e.g., at least one fiber, etc.) or at least one
segment of an element is bonded to another element or another
segment. This includes, but is not limited to a three dimensional
structural framework of elements forming a continuous solid
structure wherein at least two elements or at least two segments,
or at least three elements or at least three segments, or at least
four elements or at least four segments, or at least five elements
or at least five segments, are bonded to another element or another
segment of an element.
[0283] Furthermore, the inter-element contacts may provide adequate
or improved mechanical support to the three dimensional structural
framework of elements, or to a semi-solid or viscous mass formed
after immersion of said framework in a dissolution fluid, if the
contact width between elements or segments is large enough. In some
embodiments, therefore a contact width, 2a, between two elements
(or two segments) is greater than 1 .mu.m. This includes, but is
not limited to a contact width between two elements or two segments
greater than 2 .mu.m, or greater than 5 .mu.m, or greater than 10
.mu.m. Moreover, in some embodiments, the average contact width
between elements or segments across the three dimensional
structural framework of elements is greater than 0.02 times the
average thickness of said elements. This includes, but is not
limited to average contact width between elements or segments
across the three dimensional structural framework of elements
greater than 0.05, or greater than 0.1, or greater than 0.2, or
greater than 0.3, or greater than 0.4, or greater than 0.5 times
the average thickness of elements or segments across the three
dimensional structural framework. Moreover, in some embodiments
average contact width between elements (or segments) across the
three dimensional structural framework is in the ranges 1 .mu.m-1
mm, 1 .mu.m-2 mm, 2 .mu.m-2 mm, 2 .mu.m-1 mm, 5 .mu.m-1.5 mm, 5
.mu.m-1 mm, 10 .mu.m-1.5 mm, 10 .mu.m-1 mm, 15 .mu.m-1 mm, 20
.mu.m-1 mm, or 25 .mu.m-1 mm.
[0284] It may be noted, moreover, that in some embodiments, the
contact width of contacts between elements or segments in a dosage
form or drug-containing solid or three dimensional structural
framework of elements is precisely controlled. In some embodiments,
furthermore, the number of contacts between elements (e.g., fibers,
fiber segments, beads, sheets, etc.) or segments in a dosage form
or drug-containing solid or three dimensional structural network is
precisely controlled.
[0285] Any other features or characteristics of inter-element
contacts or bonds obvious to a person of ordinary skill in the art
are all included in this invention.
d) Free Spacing Between Fibers or Elements
[0286] Typically, moreover, for dissolution fluid to percolate into
the interior of the structure the channel size or diameter (e.g.,
channel width, or pore size, or free spacing, or effective free
spacing) must be on the micro- or macro-scale. Thus, in some
embodiments, the effective free spacing, .lamda..sub.f,e, (or
average effective free spacing) between elements or segments across
one or more free spaces (e.g., interconnected free spaces through
the drug-containing solid, or the pore size or pore diameter) is
greater than 1 .mu.m. This includes, but is not limited to
.lamda..sub.f,e (or average effective free spacing) greater than
1.25 .mu.m, or greater than 1.5 .mu.m, or greater than 1.75 .mu.m,
or greater than 2 .mu.m, or greater than 5 .mu.m, or greater than 7
.mu.m, or greater than 10 .mu.m, or greater than 15 .mu.m, or
greater than 20 .mu.m, or greater than 25 .mu.m, or greater than 30
.mu.m, or greater than 40 .mu.m, or greater than 50 .mu.m.
[0287] Because the dosage form volume is generally limited,
however, the drug and excipient masses that can be loaded in the
dosage form may be too small if the effective free spacing is too
large. Moreover, the free spacing between elements (and the volume
fraction of elements) should not be too small to assure that the
strength or viscosity of the semi-solid or viscous mass formed
after immersion in a physiological fluid is sufficiently large. For
these and/or other reasons, in some embodiments, the effective free
spacing (or average effective free spacing) across an free space
(e.g., an interconnected free space through the drug-containing
solid or an open pore network) may be in the ranges 1 .mu.m-5 mm, 1
.mu.m-3 mm, 1 .mu.m-2 mm, 1 .mu.m-1.5 mm, 2 .mu.m-4 mm, 2 .mu.m-3
mm, 2 .mu.m-2 mm, 5 .mu.m-2.5 mm, 5 .mu.m-2 mm, 5 .mu.m-1.5 mm, 10
.mu.m-2 mm, 10 .mu.m-1.5 mm, 10 .mu.m-3 mm, 15 .mu.m-3 mm, 15
.mu.m-1.5 mm, 20 .mu.m-3 mm, 30 .mu.m-3 mm, 40 .mu.m-3 mm, or 40
.mu.m-2 mm.
[0288] In some embodiments, moreover, the average effective free
spacing between segments or elements across the one or more free
spaces (e.g., across all free spaces of the dosage form) is in the
range 1 .mu.m-3 mm. This includes, but is not limited to an average
effective free spacing between segments or elements across the one
or more free spaces in the ranges 1 .mu.m-2.5 mm, or 1 .mu.m-2 mm,
or 2 .mu.m-3 mm, or 2 .mu.m-2.5 mm, or 5 .mu.m-3 mm, or 5 .mu.m-2.5
mm, or 10 .mu.m-3 mm, or 10 .mu.m-2.5 mm, or 15 .mu.m-3 mm, or 15
.mu.m-2.5 mm, or 20 .mu.m-3 mm, or 20 .mu.m-2.5 mm. The effective
free spacing may be determined experimentally from microstructural
images (e.g., scanning electron micrographs, micro computed
tomography scans, and so on) of the drug-containing solid.
Non-limiting examples describing and illustrating how an effective
free spacing may be determined from microstructural images are
described and illustrated in the U.S. application Ser. No.
15/482,776 titled "Fibrous dosage form".
[0289] It may be noted, moreover, that in some embodiments herein
the free spacing or effective free spacing between elements or
segments across the drug-containing solid, or across one or more
interconnected free spaces, or across one or more open pore
networks is precisely controlled.
[0290] Furthermore, the free spacing between elements and the
surface composition of elements are generally designed to enable
percolation of physiological, body, or dissolution fluid into the
dosage form structure upon immersion of the dosage form in said
fluid. Thus, in some embodiments the free spacing between segments
and the composition of the surface of the one or more elements are
so that the percolation time of physiological/body fluid into one
or more free spaces (e.g., one or more interconnected free spaces)
of the drug-containing solid is no greater than 30 minutes under
physiological conditions.
[0291] In addition, in some embodiments, upon immersion of the
drug-containing solid in a physiological fluid, said fluid
percolates more than 20 or 40 percent of the free spaces of said
drug-containing solid in no more than 600 seconds of immersion.
[0292] It should be obvious to a person of ordinary skill in the
art that the free spaces, free spacings, or effective free spacings
herein may comprise many more dimensions, characteristics, and
features. All of them are included in this disclosure and
invention.
(e) Composition of Free Space
[0293] Generally, one or more free spaces (e.g., one or more
interconnected free spaces) are filled with a matter that is
removable by a physiological fluid under physiological conditions.
Such matter that is removable by a physiological fluid under
physiological conditions can, for example, be a gas which escapes
the free space upon percolation by said physiological fluid. Such
matter that is removable by a physiological fluid under
physiological conditions can, however, also be a solid that is
highly soluble in said physiological fluid, and thus dissolves
rapidly upon contact with or immersion in said physiological
fluid.
[0294] Non-limiting examples of biocompatible gases that may fill
free space include air, nitrogen, CO.sub.2, argon, oxygen, and
nitric oxide, among others.
[0295] Non-limiting examples of solids that are removed or
dissolved after contact with physiological/body fluid include
sugars or polyols, such as Sucrose, Fructose, Galactose, Lactose,
Maltose, Glucose, Maltodextrin, Mannitol, Maltitol, Isomalt,
Lactitol, Xylitol, Sorbitol, among others. Other examples of solids
include polymers, such as polyethylene glycol, polyvinyl
pyrrolidone, polyvinyl alcohol, among others. Typically, a solid
material should have a solubility in physiological/body fluid
(e.g., an aqueous physiological or body fluid) under physiological
conditions greater than 50 g/l to be removed or dissolved rapidly
after contact with dissolution medium. This includes, but is not
limited to a solubility greater than 75 g/l, or greater than 100
g/l, or greater than 150 g/l, or greater than 200 g/l. The
diffusivity of the solid material (as dissolved molecule in
physiological/body fluid under physiological conditions) should
typically be greater than 4.times.10.sup.-12 m.sup.2/s if the solid
material must be dissolved rapidly after contact with dissolution
medium. This includes, but is not limited to a diffusivity in
physiological fluid under physiological conditions greater than
6.times.10.sup.-12 m.sup.2/S or greater than 8.times.10.sup.-12
m.sup.2/s, or greater than 1.times.10.sup.-11 m.sup.2/s, or greater
than 2.times.10.sup.-11 m.sup.2/s, or greater than
5.times.10.sup.-11 m.sup.2/s.
[0296] In some embodiments, moreover, a solid that may fill free
space has a molecular weight (e.g., average molecular weight, such
as number average molecular weight or weight average molecular
weight) no greater than 80 kg/mol. This includes, but is not
limited to a molecular weight (e.g., average molecular weight, such
as number average molecular weight or weight average molecular
weight) no greater than 70 kg/mol, or no greater than 60 kg/mol, or
no greater than 50 kg/mol, or no greater than 45 kg/mol, or no
greater than 40 kg/mol, or no greater than 35 kg/mol, or no greater
than 30 kg/mol.
[0297] Further compositions of free space obvious to a person of
ordinary skill in the art who is given all information of this
specification are all included in this invention.
(f) Element or Fiber Geometry
[0298] After percolation of free space or one or more
interconnected free spaces, dissolution fluid or physiological
fluid may surround one or more elements or segments (e.g., fibers,
fiber segments, etc.). For achieving a large specific surface area
(i.e., a large surface area-to-volume ratio) of solid in contact
with dissolution fluid, in some embodiments the one or more
elements (e.g., fibers, etc.) have an average thickness, h.sub.0,
no greater than 2.5 mm. This includes, but is not limited to
h.sub.0 no greater than 2 mm, or no greater than 1.75 mm, or no
greater than 1.5 mm, or no greater than 1.25 mm, or no greater than
1 mm, or no greater than 750 .mu.m, or no greater than 700 .mu.m,
or no greater than 650 .mu.m, or no greater than 600 .mu.m, or no
greater than 550 .mu.m, or no greater than 500 .mu.m, or no greater
than 450 .mu.m.
[0299] It may be noted, however, that if the elements are very thin
and tightly packed, the spacing and free spacing between the
elements can be so small that the rate at which dissolution fluid
percolates or flows into the free space is limited. Furthermore,
dosage forms with very thin elements may be difficult to
manufacture by, for example, 3D-micro-patterning or 3D-printing.
Thus, in some embodiments the one or more elements have an average
thickness, h.sub.0, greater than 1 .mu.m, or greater than 2 .mu.m,
or greater than 5 .mu.m, or greater than 10 .mu.m, or greater than
20 .mu.m, or in the ranges of 5 .mu.m-2 mm, 5 .mu.m-1.5 mm, 5
.mu.m-1.25 mm, 5 .mu.m-1 mm, 5 .mu.m-750 m, 5 .mu.m-500 .mu.m, 10
.mu.m-2 mm, 10 .mu.m-1.5 mm, 10 .mu.m-1.25 mm, 10 .mu.m-1 mm, 15
.mu.m-1 mm, 20 .mu.m-1 mm, 25 .mu.m-1 mm, 30 .mu.m-1 mm, 20
.mu.m-1.5 mm, 25 .mu.m-1.5 mm, 25 .mu.m-1.25 mm, 25 .mu.m-1 mm, 30
.mu.m-1.5 mm, 30 .mu.m-1.25 mm, 30 .mu.m-1 .mu.m, 40 .mu.m-1.5 mm,
or 40 .mu.m-1 mm.
[0300] In some embodiments, moreover, the average thickness of the
one or more elements (e.g., fibers, etc.) comprising (e.g.,
producing, making up, etc.) the three dimensional structural
network (e.g., the average thickness of the elements (e.g., fibers,
etc.) in the three dimensional structural network) is precisely
controlled. Moreover, for ensuring constraint-free expansion, in
some embodiments the thickness of one or more elements (e.g.,
wetted or wettable elements, fibers, wetted or wettable fibers,
etc.) is uniform across said one or more elements. This includes,
but is not limited to the thickness of elements uniform across the
three dimensional structural framework of elements or the thickness
of elements uniform across the drug-containing solid.
[0301] The element thickness, h, may be considered the smallest
dimension of an element (i.e., h.ltoreq.w and h.ltoreq.l, where h,
w and l are the thickness, width and length of the element,
respectively). The average element thickness, h.sub.0, is the
average of the element thickness along the length and/or width of
the one or more elements. A non-limiting example illustrating how
the average element thickness may be derived is presented in U.S.
application Ser. No. 15/482,776 titled "Fibrous dosage form".
[0302] Generally, moreover, one or more elements (e.g., fibers,
etc.) or segments (e.g., fiber segments, etc.) may comprise a
continuous (e.g., a single, or internally connected) solid matrix
through their thickness. In other words, the elements may comprise
an outer element surface and an internal, continuous solid matrix
that is contiguous with, terminating at, and/or defining said outer
element surface.
[0303] In some embodiments, furthermore, at least one outer surface
of an element (e.g., the outer surface or one or more fibers or the
outer surface of a fiber segment) comprises a coating. Said coating
may cover part of or the entire outer surface of one or more
elements or segments. Said coating may further have a composition
that is different or distinct from the composition of one or more
elements or a segment. The coating may be a solid, and may or may
not comprise or contain a drug.
(f) Micro- and Nano-Structure and Composition of Drug-Containing
Elements or Fibers
[0304] In the invention herein, the at least two excipients may
have complementary functions or functionalities that may be
required or necessary for producing an expandable, gastroretentive
dosage form as disclosed herein. The micro- or nanostructure of the
elements greatly affects their properties.
[0305] FIG. 18a presents a non-limiting example of an element 1810
(e.g., a fiber) comprising a solid solution 1812 of drug 1815, one
or more physiological fluid-absorptive excipients 1816, and one or
more strength-enhancing excipients 1818. The solid solution 1812 is
a phase comprising strength-enhancing excipient 1818; it 1812 is
connected along the length, L.sub.0, of the element 1810. Thus, a
phase 1812 comprising strength enhancing excipient 1818 is
connected along the length of the element 1810.
[0306] Upon exposure to physiological fluid 1890, such as saliva,
gastric fluid, a fluid that resembles a physiological fluid, and so
on, the one or more strength-enhancing excipients 1818 form a
fluid-permeable, semi-solid network 1819 to mechanically support
the element 1811, FIG. 18b. Also, the one or more fluid-absorptive
excipients 1816 transition to a viscous mass, or a viscous solution
1817, expanding said element 1810, 1811 along at least one
dimension (or in all dimensions) with absorption of said
physiological fluid 1890.
[0307] Because, a phase 1812 comprising strength enhancing
excipient 1818 is connected along the length of the element 1810
prior to exposure to said physiological fluid 1890, a semi-solid
network 1819 of strength-enhancing excipient 1818 is connected
along the length, L, of the expanded element 1811. The connected,
semi-solid network 1819 of strength-enhancing excipient 1818
mechanically supports or enforces the expanded element 1811.
[0308] FIG. 18c presents a non-limiting example of an element 1820
(e.g., a fiber) comprising a core 1823 of drug 1825 and absorptive
excipient 1826 (without any dissolved molecules of
strength-enhancing excipient), said core 1823 is surrounded by a
layer or shell 1824 of strength-enhancing excipient 1828. The layer
or shell 1824 of strength-enhancing excipient 1828 is connected
along the length, L.sub.0, of the element 1820. Thus, a phase 1824
comprising strength enhancing excipient 1828 is connected along the
length of the element 1820.
[0309] Upon exposure to physiological fluid 1892, such as saliva,
gastric fluid, a fluid that resembles a physiological fluid, and so
on, the one or more strength-enhancing excipients 1828 form a
fluid-permeable, semi-solid network 1829 to mechanically support
the element 1821, FIG. 18d. Also, the one or more fluid-absorptive
excipients 1826 transition to a viscous mass, or a viscous solution
1827, expanding said element 1820, 1821 along at least one
dimension (or in all dimensions) with absorption of said
physiological fluid 1892.
[0310] Because, a phase 1824 comprising strength enhancing
excipient 1828 is connected along the length of the element 1820
prior to exposure to said physiological fluid 1892, a semi-solid
network 1829 of strength-enhancing excipient 1828 is connected
along the length, L, of the expanded element 1821. The connected,
semi-solid network 1829 of strength-enhancing excipient 1828
mechanically supports or enforces the expanded element 1821.
[0311] FIG. 18e presents a non-limiting example of an element 1830
(e.g., a fiber) comprising dispersed particles 1833 of drug 1835
and absorptive excipient 1836 (without any dissolved molecules of
strength-enhancing excipient) in a matrix 1834 of
strength-enhancing excipient 1838. The matrix 1834 of
strength-enhancing excipient 1838 is connected along the length of
the element 1830. Thus, a phase 1834 comprising strength enhancing
excipient 1838 is connected along the length of the element
1830.
[0312] Upon exposure to physiological fluid 1894, such as saliva,
gastric fluid, a fluid that resembles a physiological fluid, and so
on, the one or more strength-enhancing excipients 1838 form a
fluid-permeable, semi-solid network 1839 to mechanically support
the element 1831, FIG. 18f. Also, the one or more fluid-absorptive
excipients 1836 transition to a viscous mass, or a viscous solution
1837, expanding said element 1830, 1831 along at least one
dimension (or in all dimensions) with absorption of said
physiological fluid 1894.
[0313] Because, a phase 1834 comprising strength enhancing
excipient 1838 is connected along the length of the element 1830
prior to exposure to said physiological fluid 1894, a semi-solid
network 1839 of strength-enhancing excipient 1838 is connected
along the length, L, of the expanded element 1831. The connected,
semi-solid network 1839 of strength-enhancing excipient 1838
mechanically supports or enforces the expanded element 1831.
[0314] FIG. 18g presents a non-limiting example of an element 1840
(e.g., a fiber) comprising a matrix 1843 of drug 1845 and
absorptive excipient 1846 (without any dissolved molecules of
strength-enhancing excipient), and dispersed particles 1844 of
strength-enhancing excipient 1848. The dispersed particles 1844 of
strength-enhancing excipient 1848 are not connected along the
length, L.sub.0, of the element 1840. Thus, the element or fiber
1840 does not include a phase comprising strength enhancing
excipient 1848 that is connected along the length of the element
1840.
[0315] Upon exposure to physiological fluid 1896, such as saliva,
gastric fluid, a fluid that resembles a physiological fluid, and so
on, the one or more fluid-absorptive excipients 1846 transition to
a viscous mass, or a viscous solution 1847, expanding said element
1840, 1841 along at least one dimension (or in all dimensions) with
absorption of said physiological fluid 1896, FIG. 18h.
[0316] Because, a phase 1844 comprising strength enhancing
excipient 1848 is not connected along the length of the element
1840 prior to exposure to said physiological fluid 1896, however, a
semi-solid network of strength-enhancing excipient 1848 may not
form along the length, L, of the expanded element 1841. (The
strength-enhancing excipient 1848 may comprise dispersed particles
1849 in the expanded element 1841.) A semi-solid network of
strength-enhancing excipient 1848 may not mechanically support or
enforce the expanded element 1841 substantially. Such embodiments
are generally not preferred in the invention herein. In some
embodiments, therefore, one or more phases comprising
strength-enhancing excipient form a connected or continuous or
contiguous (or substantially connected or substantially continuous
or substantially contiguous) network or structure or matrix within
one or more elements or within the three dimensional structural
framework of elements. In some embodiments, moreover, one or more
phases comprising strength-enhancing excipient are substantially
connected or substantially contiguous along the lengths of one or
more structural elements or through the three dimensional
structural framework.
[0317] It may be noted that generally, a phase or one or more
phases comprising strength enhancing excipient is/are substantially
connected along the length of one or ore elements or through a
structural framework if the mechanical strength or stiffness (e.g.,
the elastic modulus) of said elements or framework after exposure
to a physiological fluid is substantially greater than the
mechanical strength or stiffness of an element or framework
comprising fluid-absorptive excipient alone (e.g., no
strength-enhancing excipient) after exposure to said physiological
fluid. By way of example but not by way of limitation, one or more
phases comprising strength enhancing excipient are connected along
the length of an element if the tensile strength or the elastic
modulus of said element after exposure to a physiological fluid is
at least two times greater than that of a corresponding element
comprising fluid-absorptive excipient alone (e.g., no
strength-enhancing excipient) after exposure to said physiological
fluid. This includes, but is not limited to the tensile strength or
the elastic modulus of an element after exposure to a physiological
fluid at least three times greater, or at least four times greater,
or at least five times greater, or at least six times greater, or
at least seven times greater than that of a corresponding element
comprising fluid-absorptive excipient alone (e.g., no
strength-enhancing excipient) after exposure to said physiological
fluid.
[0318] In some embodiments, moreover, one or more phases comprising
strength-enhancing excipient form a single continuous (e.g., a
connected) structure or a single continuous (e.g., a connected)
network structure along or through the elements of the three
dimensional structural framework.
[0319] In some embodiments, moreover, the concentration of at least
a strength-enhancing excipient is substantially uniform within or
through or across one or more elements or the three dimensional
structural framework of elements.
[0320] In some embodiments, the concentration of at least an
absorptive excipient is substantially uniform within or through or
across one or more elements or the three dimensional structural
framework of elements.
[0321] In some embodiments, moreover, one or more elements comprise
a plurality of (e.g., two or more) segments having substantially
the same weight fraction of physiological fluid-absorptive
excipient distributed within the segments (e.g., the standard
deviation of the weight fraction of absorptive excipient within the
elements or segments is no greater than the average value).
[0322] In some embodiments, moreover, one or more elements comprise
a plurality of (e.g., two or more) segments having substantially
the same weight fraction of strength-enhancing excipient
distributed within the segments (e.g., the standard deviation of
the weight fraction of strength-enhancing excipient within the
elements or segments is no greater than the average value).
[0323] In some embodiments, moreover, the at least two excipients
(e.g., at least an absorptive excipient and at least a
strength-enhancing excipient) form a solid solution.
[0324] The properties of the combined at least two excipients
together may further depend on the weight fractions of the
individual constituents. More specifically, by altering the weight
fractions of absorptive and strength-enhancing excipient in the
three dimensional structural framework, relevant properties, such
as expansion rate, extent of expansion, disintegration rate of the
three dimensional structural framework, dissolution rate of the
drug, etc. may be altered, adjusted, or controlled.
[0325] In some embodiments the weight fraction of absorptive
polymeric excipient in at least one element with respect to the
total weight of said element is greater than 0.1. This includes,
but is not limited to a weight fraction of absorptive polymeric
excipient in an element with respect to the total weight of said
element greater than 0.15, or greater than 0.2, or greater than
0.25, or greater than 0.3, or greater than 0.35, or greater than
0.4.
[0326] Similarly, in some embodiments the weight fraction of
absorptive polymeric excipient in the three dimensional structural
framework of one or more elements with respect to the total weight
of said framework is greater than 0.1. This includes, but is not
limited to a weight fraction of absorptive, polymeric excipient in
the structural framework with respect to the total weight of said
framework greater than 0.15, or greater than 0.2, or greater than
0.25, or greater than 0.3, or greater than 0.35, or greater than
0.4.
[0327] In some embodiments, moreover, the weight fraction of
absorptive polymeric excipient in at least one element with respect
to the total weight of absorptive excipient and strength-enhancing
excipient in said element is greater than 0.3. This includes, but
is not limited to a weight fraction of absorptive polymeric
excipient in an element with respect to the total weight of
absorptive excipient and viscosity-enhancing excipient in said
element greater than 0.4, or greater than 0.5, or greater than 0.6,
or greater than 0.65, or greater than 0.7.
[0328] Similarly, in some embodiments the weight fraction of
absorptive polymeric excipient in the three dimensional structural
framework of one or more elements with respect to the total weight
of absorptive excipient and strength-enhancing excipient in said
framework is greater than 0.1. This includes, but is not limited to
a weight fraction of absorptive, polymeric excipient in the
structural framework with respect to the total weight of absorptive
excipient and strength-enhancing excipient in said framework
greater than 0.2, or greater than 0.3, or greater than 0.4, or
greater than 0.5, or greater than 0.55.
[0329] In some embodiments, the weight fraction of
strength-enhancing excipient with respect to the total weight of
functional excipient (e.g., strength-enhancing excipient and
absorptive excipient) is no greater than 0.9. This includes, but is
not limited to a weight fraction of strength-enhancing excipient
with respect to the total weight of functional excipient no greater
than 0.85, or no greater than 0.8, or no greater than 0.75, or no
greater than 0.7, or in the ranges 0.1-0.9, 0.1-0.85, 0.15-0.85,
0.15-0.9, 0.2-0.85, 0.2-0.9, 0.25-0.9, 0.25-0.85, 0.3-0.9,
0.3-0.85, 0.15-0.8, or 0.15-0.7.
[0330] In some embodiments, the volume of strength-enhancing
excipient per unit volume of the dosage form or of a
drug-containing solid (e.g., the volume fraction of
strength-enhancing excipient in the dosage form or in a
drug-containing solid with respect to the volume of said dosage
form or of said drug-containing solid) is greater than 0.05. This
includes, but is not limited to a volume of strength-enhancing
excipient per unit volume of the dosage form or of a
drug-containing solid (e.g., the volume fraction of
strength-enhancing excipient in the dosage form or in a
drug-containing solid with respect to the volume of said dosage
form or of said drug-containing solid) greater than 0.1, or greater
than 0.15, or greater than 0.2, or greater than 0.25.
[0331] In some embodiments, the weight of strength-enhancing
excipient per unit volume of the dosage form or of a
drug-containing solid (e.g., the density of strength-enhancing
excipient in the dosage form or in a drug-containing solid with
respect to the volume of said dosage form or of said
drug-containing solid) is greater than 50 kg/m.sup.3. This
includes, but is not limited to a weight of strength-enhancing
excipient per unit volume of the dosage form or of a
drug-containing solid (e.g., the density of strength-enhancing
excipient in the dosage form or in a drug-containing solid with
respect to the volume of said dosage form or of said
drug-containing solid) greater than 100 kg/m.sup.3, or greater than
150 kg/m.sup.3, or greater than 200 kg/m3.
[0332] Any further microstructures of elements would be obvious to
a person of ordinary skill in the art. All of them are within the
spirit and scope of this invention.
(f) Properties and Composition of Absorptive Excipient
[0333] The drug-containing elements herein comprise at least one
ore more physiological fluid-absorptive excipients. In some
specific embodiments embodiments, an absorptive excipient may be
mutually soluble with a relevant physiological fluid under
physiological conditions, and thus "absorb" or "mix with" said
physiological fluid until its concentration is uniform across said
fluid. Accordingly, absorptive excipient may promote expansion and
dissolution and/or disintegration of a drug-containing solid or a
semi-solid or viscous mass.
[0334] In some embodiments, moreover the effective diffusivity of
physiological/body fluid in an absorptive excipient (and/or an
element or a segment) is greater than 0.05.times.10.sup.-11
m.sup.2/s under physiological conditions. This includes, but is not
limited to an effective diffusivity of physiological/body fluid in
an absorptive excipient (and/or an element or a segment) greater
than 0.1.times.10.sup.-11 m.sup.2/s or greater than
0.2.times.10.sup.-11 m.sup.2/s, or greater than
0.5.times.10.sup.-11 m.sup.2/s or greater than
0.75.times.10.sup.-11 m.sup.2/s or greater than 1.times.10.sup.-11
m.sup.2/s, or greater than 2.times.10.sup.-11 m.sup.2/s or greater
than 3.times.10.sup.-11 m.sup.2/s or greater than
4.times.10.sup.-11 m.sup.2/s under physiological conditions.
[0335] Alternatively, for absorptive excipients where diffusion of
physiological/body fluid to the interior may or may not be Fickian,
a rate of penetration may be specified. In some embodiments, the
rate of penetration of a physiological/body fluid into a solid,
absorptive excipient (and/or an element or a segment) is greater
than an average thickness of the one or more drug-containing
elements divided by 3600 seconds (i.e., h.sub.0/3600 .mu.m/s). In
other examples without limitation, rate of penetration may be
greater than h.sub.0/1800 .mu.m/s, greater than h.sub.0/1200
.mu.m/s, greater than h.sub.0/800 .mu.m/s, greater than h.sub.0/600
.mu.m/s, or greater than h.sub.0/500 .mu.m/s, or greater than
h.sub.0/400 .mu.m/s, or greater than h.sub.0/300 .mu.m/s.
[0336] For determining the effective diffusivity (and/or the rate
of penetration) of dissolution medium in a solid, absorptive
excipient (and/or an element or a segment) the following procedure
may be applied. An element (e.g an element or segment of the dosage
form structure, or preferably an element or segment that just
consists of the absorptive excipient) may be placed in a still
dissolution medium at 37.degree. C. The time t.sub.1 for the
element to break apart or deform substantially may be recorded. (By
way of example but not by way of limitation, a deformation of an
element may generally be considered substantial if either the
length, width, or thickness of the element differs by at least 20
to 80 percent (e.g., at least 20 percent, or at least 30 percent,
or at least 40 percent, or at least 50 percent, or at least 60
percent, or at least 70 percent, or at least 80 percent, etc.) from
its initial value.) The effective diffusivity, D.sub.eff, may then
be determined according to D.sub.eff=h.sub.init.sup.2/4t.sub.1
where h.sub.init is the initial element or segment thickness (e.g.,
the thickness of the dry element or segment). Similarly, the rate
of penetration of a physiological/body fluid into the element or
segment may be equal to h.sub.init/2t.sub.1. Further non-limiting
examples for deriving the effective diffusivity or rate of
penetration are presented in U.S. application Ser. No. 15/482,776
titled "Fibrous dosage form".
[0337] To ensure that the drug-containing solid expands
substantially, and that the integrity of the expanded semi-solid
mass is preserved for prolonged time within a physiological fluid
under physiological conditions, the molecular weight of the one or
more physiological fluid-absorptive excipients should be quite
large. In some embodiments, therefore, the molecular weight of at
least one absorptive polymeric excipient is greater than 30 kg/mol.
This includes, but is not limited to a molecular weight of an
absorptive polymeric excipient greater than 40 kg/mol, or greater
than 50 kg/mol, or greater than 60 kg/mol, or greater than 70
kg/mol, or greater than 80 kg/mol.
[0338] To ensure that the dosage form can be processed by
patterning a viscous drug-excipient paste, and for other reasons,
the molecular weight of at least one absorptive excipient (or the
absorptive polymeric excipient in its totality) may be limited.
[0339] By way of example but not by way of limitation, the
molecular weight of at least one absorptive excipient (or the
average molecular weight of the absorptive excipient in its
totality) may be in the ranges 30 kg/mol-10,000,000 kg/mol, 50
kg/mol-10,000,000 kg/mol, 70 kg/mol-10,000,000 kg/mol, 80
kg/mol-10,000,000 kg/mol, 70 kg/mol-5,000,000 kg/mol, 70
kg/mol-2,000,000 kg/mol. Preferably, a physiological
fluid-absorptive excipient comprises hydroxypropyl methylcellulose
with a molecular weight in the range between about 50 kg/mol and
500 kg/mol (e.g., 70 kg/mol-300,000 kg/mol).
[0340] Thus, in some embodiments, at least one absorptive excipient
(or the absorptive excipient in its totality) may comprise a
plurality of individual chains or molecules that dissolve or
disentangle upon immersion in a physiological fluid.
[0341] In some embodiments, moreover, at least one absorptive
excipient has a solubility greater than 20 g/l in a relevant
physiological/body fluid under physiological conditions. This
includes, but is not limited to at least one absorptive excipient
(or the absorptive excipient in its totality) having a solubility
in a relevant physiological/body fluid under physiological
conditions greater than 50 g/l, or greater than 75 g/l, or greater
than 100 g/l, or greater than 150 g/l, or greater than 175 g/l, or
greater than 200 g/l, or greater than 250 g/l, or greater than 300
g/l, or greater than 350 g/l. In the extreme case, absorptive
excipient (e.g., at least one absorptive excipient or the
absorptive excipient in its totality) is mutually soluble with a
relevant physiological fluid under physiological conditions. The
solubility of a material is referred to herein as the maximum
amount or mass of said material that can be dissolved at
equilibrium in a given volume of physiological fluid under
physiological conditions divided by the volume of said fluid or of
the solution formed. By way of example but not by way of
limitation, the solubility of a solute in a solvent may be
determined by optical methods.
[0342] Preferably, moreover, at least one absorptive polymeric
excipient (or the absorptive polymeric excipient in its totality)
comprises an amorphous molecular structure (e.g., an amorphous
arrangement of molecules, or an arrangement of molecules without
long-range order) in the solid state. A non-limiting method for
determining the molecular structure of a solid (e.g.,
distinguishing amorphous molecular structure from crystalline
molecular structure, etc.) is Differential scanning
calorimetry.
[0343] Non-limiting examples of excipients that satisfy some or all
the requirements of an absorptive polymeric excipient include but
are not limited to hydroxypropyl methylcellulose, hydroxyethyl
cellulose, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl
methylcellulose acetate succinate, sodium alginate, hydroxypropyl
cellulose, hydroxyethyl cellulose, methyl cellulose, hydroxypropyl
methyl ether cellulose, starch, chitosan, pectin, polymethacrylates
(e.g., poly(methacrylic acid, ethyl acrylate) 1:1, or
butylmethacrylat-(2-dimethylaminoethyl)methacrylat-methylmathacrylat-copo-
lymer), vinylpyrrolidone-vinyl acetate copolymer, among others.
(f) Properties and Composition of Strength-Enhancing Excipient
[0344] The drug-containing elements herein further comprise at
least one ore more strength-enhancing excipients. Generally, at
least one strength-enhancing excipient (or the strength-enhancing
excipient in its totality), too, may be somewhat permeable to a
relevant physiological fluid under physiological conditions to
promote rapid expansion of the dosage form or drug-containing solid
or framework upon immersion. In some embodiments, therefore, the
diffusivity of a relevant physiological fluid under physiological
conditions in at least one strength-enhancing excipient (or in the
strength-enhancing excipient in its totality) is greater than
1.times.10.sup.-13 m.sup.2/s. This includes, but is not limited to
a diffusivity of a relevant physiological fluid under physiological
conditions in at least one strength-enhancing excipient (or in the
strength-enhancing excipient in its totality) greater than
2.times.10.sup.-13 m.sup.2/s, or greater than 5.times.10.sup.-13
m.sup.2/s, or greater than 7.times.10.sup.-13 m.sup.2/s, or greater
than 1.times.10.sup.-12 m.sup.2/s, or greater than
2.times.10.sup.-12 m.sup.2/s, or greater than 3.times.10.sup.-12
m.sup.2/s, or greater than 4.times.10.sup.-12 m.sup.2/s, or greater
than 5.times.10.sup.-12 m.sup.2/s, or greater than
6.times.10.sup.-12 m.sup.2/s.
[0345] In some embodiments, moreover, upon immersion of an element,
the three dimensional structural framework, or the dosage form in a
relevant physiological fluid under physiological conditions,
strength-enhancing excipient reduces or decreases or slows down the
rate at which physiological fluid-absorptive excipient is removed,
eroded, or dissolved from said element, or said three dimensional
structural framework, or said the dosage form or semi-solid mass.
By way of example but not by way of limitation, in some
embodiments, upon immersion of an element (e.g., a fiber, etc.) in
a relevant physiological fluid under physiological conditions, due
to the presence of strength-enhancing excipient at a relevant
quantity in said element, the rate at which physiological
fluid-absorptive excipient is removed, eroded, or dissolved from
said element can be substantially limited by the rate of diffusion
of said absorptive excipient through said element.
[0346] In some embodiments, accordingly, upon immersion of an
element in a relevant physiological fluid under physiological
conditions, the diffusivity of at least one physiological
fluid-absorptive excipient in or through said element is no greater
than 5.times.10.sup.-12 m.sup.2/s. This includes, but is not
limited to a diffusivity of at least one physiological
fluid-absorptive excipient in or through an element no greater than
2.times.10.sup.-12 m.sup.2/s, or no greater than 1.times.10.sup.-12
m.sup.2/s, or no greater than 5.times.10.sup.-13 m.sup.2/s, or no
greater than 2.times.10.sup.-13 m.sup.2/s, or no greater than
1.times.10.sup.-13 m.sup.2/s, or no greater than 5.times.10.sup.-14
m.sup.2/s, or no greater than 2.times.10.sup.-14 m.sup.2/s.
[0347] In some embodiments, furthermore, upon immersion of an
element in a relevant physiological fluid under physiological
conditions, the diffusivity of at least one physiological
fluid-absorptive excipient through an element (e.g., through a
semi-solid element, or through a physiological fluid-penetrated
element) is no greater than 0.3 times the self-diffusivity of said
at least one absorptive excipient in a relevant physiological fluid
under physiological conditions. This includes, but is not limited
to the diffusivity of at least one absorptive excipient through an
element (e.g., through a viscous element, or through a
water-penetrated element) no greater than 0.2 times, or no greater
than 0.1 times, or no greater than 0.05 times, or no greater than
0.02 times, or no greater than 0.01 times, or no greater than 0.005
times, or no greater than 0.002 times, or no greater than 0.001
times the self-diffusivity of said at least one absorptive
excipient in a relevant physiological fluid under physiological
conditions.
[0348] Generally, to assure that a strength-enhancing excipient
remains a semi-solid or viscoelastic material and stabilizes, or
mechanically supports or enforces one or more elements after
exposure to a physiological fluid (e.g., gastric fluid, etc.), the
solubility of said physiological fluid in said strength-enhancing
excipient may be limited. In some embodiments, therefore, at least
one strength-enhancing excipient has a solubility no greater than 1
g/l in a relevant physiological/body fluid under physiological
conditions. This includes, but is not limited to at least one
strength-enhancing excipient (or one or more strength-enhancing
excipients, or the strength-enhancing excipient in its totality)
having a solubility in a relevant physiological/body fluid under
physiological conditions no greater than 1 g/l, or no greater than
0.5 g/l, or no greater than 0.2 g/l, or no greater than 0.1 g/l, or
no greater than 0.05 g/l, or no greater than 0.02 g/l, or no
greater than 0.01 g/l, or no greater than 0.005 g/l, or no greater
than 0.002 g/l, or no greater than 0.001 g/l. In the extreme case,
strength-enhancing excipient (e.g., at least one strength-enhancing
excipient or the strength-enhancing excipient in its totality) may
be insoluble or at least practically insoluble in a relevant
physiological fluid under physiological conditions.
[0349] It may be noted that even if the solubility of a relevant
physiological fluid is low in a strength-enhancing excipient, said
strength-enhancing excipient may soften or plasticize somewhat upon
contact with or immersion in said physiological fluid under
physiological conditions. As a result, at least a
strength-enhancing excipient can be a solid in the dry state, but
upon immersion in or exposure to a relevant physiological fluid
(e.g., gastric fluid, etc.) under physiological conditions, it may
transition to a semi-solid or viscoelastic material.
[0350] Generally, the mechanical properties (such as stiffness,
yield strength, tensile strength, etc.) of physiological
fluid-soaked strength-enhancing excipient should be large enough to
stabilize or mechanically support the dosage form or
drug-containing solid or framework. However, the stiffness, yield
strength, tensile strength, etc. of physiological fluid-soaked
strength-enhancing excipient should not be too large, so that the
expansion of the dosage form or drug-containing solid or framework
after exposure to said physiological fluid is not excessively
impaired or constrained. Thus, strength-enhancing excipients that
comprise or form a semi-solid material upon exposure to a relevant
physiological fluid are typically preferred herein.
[0351] In some embodiments, physiological fluid-soaked
strength-enhancing excipient (e.g., a film that is immersed in a
relevant physiological fluid (e.g., acidic water) for so long that
the water concentration in the film is roughly at equilibrium)
comprises an elastic modulus, or an elastic-plastic modulus, or a
plastic modulus greater than 0.02 MPa. This includes, but is not
limited to physiological fluid-soaked strength-enhancing excipient
(e.g., a film that was immersed in a relevant physiological fluid
(e.g., acidic water) for so long that the water concentration in
the film is roughly at equilibrium) comprising an elastic modulus,
or an elastic-plastic modulus, or a plastic modulus greater than
0.05 MPa, or greater than 0.1 MPa, or greater than 0.2 MPa, or
greater than 0.3 MPa, or greater than 0.4 MPa, or greater than 0.5
MPa, or greater than 0.6 MPa, or greater than 0.7 MPa, or greater
than 0.8 MPa, or greater than 0.9 MPa, or greater than 1 MPa. In
some embodiments, moreover, physiological fluid-soaked
strength-enhancing excipient (e.g., a film that was immersed in a
relevant physiological fluid (e.g., acidic water) for so long that
the water concentration in the film is roughly at equilibrium)
comprises an elastic modulus, or an elastic-plastic modulus, or a
plastic modulus no greater than about 1000 MPa (e.g., no greater
than 500 MPa, or no greater than 200 MPa, or no greater than 100
MPa, or no greater than 50 MPa, or no greater than 20 MPa, or no
greater than 10 MPa). Preferably, an elastic modulus of a
physiological fluid-soaked strength-enhancing excipient should be
greater than about 0.1 MPa and no greater than about 500 MPa.
[0352] In some embodiments, moreover, physiological fluid-soaked
(e.g., acidic water-soaked) strength-enhancing excipient (e.g., a
film that was immersed in a relevant physiological fluid (e.g.,
acidic water) for so long that the water concentration in the film
is roughly at equilibrium) comprises a yield strength greater than
0.005 MPa. This includes, but is not limited to physiological
fluid-soaked strength-enhancing excipient (e.g., a film that was
immersed in a relevant physiological fluid (e.g., acidic water) for
so long that the water concentration in the film is roughly at
equilibrium) comprising a yield strength greater than 0.0075 MPa,
or greater than 0.01 MPa, or greater than 0.02 MPa, or greater than
0.05 MPa, or greater than 0.1 MPa, or greater than 0.2 MPa. In some
embodiments, moreover, physiological fluid-soaked
strength-enhancing excipient (e.g., a film that was immersed in a
physiological fluid (e.g., acidic water) for so long that the water
concentration in the film is roughly at equilibrium) comprises a
yield strength no greater than 500 MPa (e.g., no greater than 200
MPa, or no greater than 100 MPa, or no greater than 75 MPa, or no
greater than 50 MPa, or no greater than 20 MPa, or no greater than
10 MPa, or no greater than 5 MPa).
[0353] In some embodiments, moreover, physiological fluid-soaked
strength-enhancing excipient (e.g., a film that was immersed in a
relevant physiological fluid (e.g., acidic water) for so long that
the water concentration in the film is roughly at equilibrium)
comprises a tensile strength greater than 0.02 MPa. This includes,
but is not limited to physiological fluid-soaked strength-enhancing
excipient (e.g., a film that was immersed in a relevant
physiological fluid (e.g., acidic water) for so long that the water
concentration in the film is roughly at equilibrium) comprising a
tensile strength greater than 0.05 MPa, or greater than 0.08 MPa,
or greater than 0.1 MPa, or greater than 0.2 MPa, or greater than
0.3 MPa, or greater than 0.4 MPa, or greater than 0.5 MPa, or
greater than 0.6 MPa. In some embodiments, moreover, physiological
fluid-soaked strength-enhancing excipient (e.g., a film that was
immersed in a relevant physiological fluid (e.g., acidic water) for
so long that the water concentration in the film is roughly at
equilibrium) comprises a tensile strength no greater than 500 MPa
(e.g., no greater than 200 MPa, or no greater than 100 MPa, or no
greater than 75 MPa, or no greater than 50 MPa, or no greater than
20 MPa, or no greater than 10 MPa).
[0354] In some embodiments, moreover, physiological fluid-soaked
strength-enhancing excipient (e.g., a film that was immersed in a
relevant physiological fluid (e.g., acidic water) for so long that
the water concentration in the film is roughly at equilibrium)
comprises a strain at fracture greater than 0.2. This includes, but
is not limited to physiological fluid-soaked strength-enhancing
excipient (e.g., a film that was immersed in a relevant
physiological fluid (e.g., acidic water) for so long that the water
concentration in the film was roughly at equilibrium) comprising a
strain at fracture greater than 0.5, or greater than 0.75, or
greater than 1, or greater than 1.25, or greater than 1.5, or
greater than 1.75, or greater than 2, or greater than 2.25, or
greater than 2.5. Preferably, the strain at fracture of a
physiological fluid-soaked strength-enhancing excipient should be
greater than about 1.
[0355] Furthermore, in some embodiments, the solubility of at least
one strength-enhancing excipient (or the solubility of the
strength-enhancing excipient in its totality) can differ in
different physiological fluids under physiological conditions. By
way of example but not by way of limitation, in some embodiments
the solubility of at least one strength-enhancing excipient in
aqueous physiological fluid may depend on the pH value of said
physiological fluid. More specifically, in some embodiments at
least one strength-enhancing excipient can be sparingly-soluble or
insoluble or practically insoluble in an aqueous physiological
fluid that is acidic (e.g., in gastric fluid, or in fluid with a pH
value smaller than about 4, or in fluid with a pH value smaller
than about 5, etc.), but it can be soluble in an aqueous
physiological fluid having a greater pH value (e.g., in a fluid
with a pH value greater than about 6, or greater than about 6.5, or
greater than about 7, or greater than about 7.5, etc.), such as
intestinal fluid. A strength-enhancing excipient comprising a
solubility that is smaller in acidic solutions than in basic
solutions is also referred to herein as "enteric excipient".
[0356] In some embodiments, therefore, at least one
strength-enhancing excipient comprises a solubility in aqueous
fluid with a pH value no greater than 4 at least 10 (e.g., at least
20, or at least 50, or at least 100, or at least 200, or at least
500) times smaller than the solubility of said strength-enhancing
excipient in an aqueous fluid with pH value greater than 7.
[0357] A non-limiting example of such a strength-enhancing
excipient that is sparingly-soluble in gastric or acidic fluid, but
dissolves in intestinal fluid (e.g., aqueous fluid with a pH value
greater than about 5.5), is methacrylic acid-ethyl acrylate
copolymer.
[0358] Other non-limiting examples of strength-enhancing excipients
herein may include hydroxypropyl methyl cellulose acetate
succinate, methacrylic acid-ethyl acrylate copolymer,
methacrylate-copolymers (e.g., poly(ethyl acrylate-co-methyl
methacrylate-co-trimethylammonioethyl methacrylate chloride)
1:2:0.2, poly(ethyl acrylate-co-methyl
methacrylate-co-trimethylammonioethyl methacrylate chloride)
1:2:0.1, Poly(ethyl acrylate-co-methyl methacrylate) 2:1, etc.),
and so on.
(h) Expansion of Drug-Containing Solid and Formation of a
Semi-Solid Mass
[0359] FIG. 19 presents a non-limiting example of a pharmaceutical
dosage form 1900 comprising a drug-containing solid 1901 having an
outer surface 1902 and an internal three dimensional structural
framework 1904 of one or more substantially orderly arranged thin
structural elements 1910. The framework 1904 is contiguous with and
terminates at said outer surface 1902. The structural elements
comprise a hydrophilic surface composition. The structural elements
1910 further comprise segments spaced apart from adjoining segments
1910, thereby defining free spaces 1915. A plurality of adjacent
free spaces 1915 may combine to define one or more interconnected,
free spaces 1915 forming an open pore network that extends over a
length at least half the thickness of the drug-containing solid
1901 (e.g., over the entire length, width, and thickness of the
drug-containing solid and terminating at its outer surface 1902) or
over a length at least twice the thickness of one or more elements
1910. The structural elements 1910 further comprise at least one
active ingredient (e.g., at least one drug) dissolved as drug
molecules 1920 or dispersed as particles in an excipient matrix
1930, 1950. Thus the drug forms a solid solution or a solid
dispersion with said excipient matrix 1930, 1950. The excipient
matrix 1930, 1950 comprises at least an absorptive polymeric
excipient 1930 and at least a strength-enhancing polymeric
excipient.
[0360] Upon immersion in a relevant physiological fluid, said fluid
percolates interconnected free space and diffuses into one or more
said elements, so that the framework expands in all dimensions.
Because dosage forms (or drug-containing solids) herein may
comprise a structural framework of thin elements with hydrophilic
surface composition surrounded by interconnected free space that
may terminate at the outer surface of the drug-containing solid,
the rates of fluid percolation and diffusion, and consequently also
the rate of expansion of the drug-containing solid or three
dimensional structural framework of elements can be
substantial.
[0361] In some embodiments of the invention herein, accordingly, at
least one dimension (e.g., a side length or the thickness) of the
drug-containing solid expands to at least 1.3 times the initial
value (e.g., the initial length prior to exposure to said
physiological fluid) as it transitions to a fluidic or viscous
medium within no more than 300 minutes of immersion in a
physiological or body fluid under physiological conditions. This
includes, but is not limited to at least one dimension of the
drug-containing solid reaching a length at least 1.3 times the
initial length within no more than 250 minutes, or within no more
than 200 minutes, or within no more than 150 minutes, or within no
more than 100 minutes, or within no more than 50 minutes, or within
no more than 40 minutes, or within no more than 30 minutes, or
within no more than 20 minutes of immersion in said physiological
or body fluid under physiological conditions. This may also
include, but is not limited to at least one dimension of the
drug-containing solid or framework expanding to a length at least
1.35 times the initial length, or at least 1.4 times the initial
length, or at least 1.45 times the initial length, or at least 1.5
times the initial length, or at least 1.55 times the initial
length, or at least 1.6 times the initial length, or at least 1.65
times the initial length within no more than 300 minutes of
immersing in or exposing to a physiological or body fluid under
physiological conditions.
[0362] Furthermore, in some embodiments the drug-containing solid
expands to at least 2 times its initial volume within no more than
about 300 minutes of immersing in a physiological or body fluid
under physiological conditions. This includes, but is not limited
to a drug-containing solid that expands to at least 3 times, or at
least 4 times, or at least 4.5 times, or at least 5 times, or at
least 5.5 times, or at least 6 times, or at least 6.5 times its
initial volume within no more than about 300 minutes of immersing
in a physiological or body fluid under physiological
conditions.
[0363] In some embodiments, the drug-containing solid (or the three
dimensional structural framework) expands isotropically (e.g.,
uniformly in all directions) while transitioning to a semi-solid
mass. In the invention herein, a solid mass is generally understood
to expand isotropically if the normalized expansion (e.g., the
ratio of a length difference and the initial length, such as
(L(t)-L.sub.0)/L.sub.0, (H(t)-H.sub.0)/H.sub.0, etc.) deviates by
less than about 50-75 percent of its maximum value by changing
direction or orientation. Thus, in an isotropically expanding
solid, semi-solid mass, or framework, the normalized expansion is
roughly the same in all directions. FIG. 19 shows a non-limiting
schematic illustration of a drug-containing solid that expands
isotropically. For further information related to isotropic
expansion of a drug-containing solid, see, e.g., the International
Application No. PCT/US19/19004 filed on Feb. 21, 2019 and titled
"Expanding structured dosage form".
[0364] In some embodiments, upon prolonged exposure to a
physiological fluid (e.g., longer than 2, 4, 6, 8, or 10 hours in a
lightly stirred dissolution fluid such as acidic water), said
expanded framework or semi-solid mass maintains its length between
1.3 and 4 times the initial length for prolonged time.
[0365] In some embodiments, the semi-solid mass comprises a
substantially continuous or connected network of one or more
strength-enhancing excipients.
[0366] In some embodiments, the semi-solid mass comprises a
substantially continuous or connected network of strength-enhancing
excipient that extends over the length, width, and thickness of
said semi-solid mass.
j) Mechanical Properties of Expanded Semi-Solid Mass
[0367] In some embodiments, moreover a semi-solid mass (e.g., an
expanded drug-containing solid or dosage form) formed after
immersion of a drug-containing solid in a physiological fluid under
physiological conditions comprises an elastic modulus greater than
0.005 MPa. This includes, but is not limited to a viscous or
semi-solid mass (e.g., an expanded drug-containing solid or dosage
form) formed after immersion of a drug-containing solid in a
dissolution fluid comprising an elastic modulus greater than 0.007
MPa, or greater than 0.01 MPa, or greater than 0.015 MPa, or
greater than 0.02 MPa, or greater than 0.025 MPa, or greater than
0.03 MPa, or greater than 0.035 MPa, or greater than 0.04 MPa, or
greater than 0.045 MPa, or greater than 0.05 MPa, or greater than
0.055 MPa, or greater than 0.06 MPa, or greater than 0.065 MPa, or
greater than 0.07 MPa, or greater than 0.075 MPa. In some
embodiments, therefore, a viscous or semi-solid mass (e.g., an
expanded drug-containing solid or dosage form) formed after
immersion of a drug-containing solid in a dissolution fluid is a
highly elastic mass or semi-solid or structure that may not break
or permanently deform for prolonged time in a stomach (e.g., under
the compressive forces of stomach walls, etc.).
[0368] In some embodiments, moreover a viscous or semi-solid mass
(e.g., an expanded drug-containing solid or dosage form) formed
after immersion of a drug-containing solid in a dissolution fluid
comprises an elastic modulus no greater than 50 MPa (e.g., no
greater than 40 MPa, or no greater than 30 MPa, or no greater than
20 MPa, or no greater than 10 MPa, or no greater than 5 MPa).
[0369] In some embodiments, moreover a semi-solid mass formed after
immersion of a drug-containing solid in a dissolution fluid
comprises a yield strength or a fracture strength greater than
0.002 MPa. This includes, but is not limited to a viscous or
semi-solid mass formed after immersion of a drug-containing solid
in a dissolution fluid comprising a yield strength or a fracture
strength greater than 0.005 MPa, or greater than 0.007 MPa, or
greater than 0.01 MPa, or greater than 0.02 MPa, or greater than
0.025 MPa, or greater than 0.03 MPa, or greater than 0.035 MPa, or
greater than 0.04 MPa, or greater than 0.045 MPa, or greater than
0.05 MPa, or greater than 0.055 MPa, or greater than 0.06 MPa, or
greater than 0.065 MPa, or greater than 0.07 MPa, or greater than
0.075 MPa, or greater than 0.8 MPa.
[0370] In some embodiments, moreover a semi-solid mass (e.g., an
expanded drug-containing solid or dosage form) formed after
immersion of a drug-containing solid in a dissolution fluid
comprises a yield strength or a fracture strength no greater than
50 MPa (e.g., no greater than 20 MPa, or no greater than 10 MPa, or
no greater than 5 MPa, or no greater than 2 MPa, or no greater than
1 MPa).
[0371] In some embodiments, therefore, upon ingestion the dosage
form is retained in the stomach for a prolonged time to deliver
drug into the blood stream over a prolonged time (e.g., 80 percent
of the drug is released in 30 mins-200 hours, 1 hour to 200 hours;
1 hour-150 hours; 3 hours-200 hours; 5 hours-200 hours; 3 hours-60
hours; 5 hours-60 hours; 2 hours-30 hours; 5 hours-24 hours; 30
mins-96 hours, 30 mins-72 hours, 30 mins-48 hours, 30 mins-36
hours, 30 mins-24 hours, 1-10 hours, 45 min-10 hours, 30 min-10
hours, 45 min-8 hours, 45 min-6 hours, 30 min-8 hours, 30 min-6
hours, 30 min-5 hours, 30 min-4 hours, etc.) and at a precisely
controlled rate. This enables improved control of drug
concentration in the blood stream, and improved efficacy or reduced
side effects of numerous drug therapies.
j) Drug Release Properties of Drug-Containing Solid, Dosage Form,
and Viscous Mass
[0372] In some embodiments, moreover, eighty percent of the drug
content in the drug-containing solid is released in more than 30
minutes after immersion in a physiological or body fluid under
physiological conditions. This includes, but is not limited to a
drug-containing solid that releases eighty percent of the drug
content in more than than 40 minutes, or in more than 50 minutes,
or in more than 60 minutes, or in more than 100 minutes, or in 30
minutes-150 hours, 30 minutes-48 hours, 30 minutes-36 hours, or 45
minutes-24 hours after immersion in a physiological fluid under
physiological conditions.
k) Mechanical Properties of Drug-Containing Solid and Solid Dosage
Form
[0373] In some embodiments the tensile strength of a
drug-containing solid or a three dimensional structural framework
of one or more elements is between 0.01 MPa and 100 MPa (this
includes, but is not limited to tensile strength of at least one
element is greater than 0.02 MPa, or greater than 0.05 MPa, or
greater than 0.1 MPa, or greater than 0.2 MPa, or greater than 0.5
MPa, or greater than 1 MPa, or greater than 1.5 MPa, or greater
than 2 MPa, or greater than 3 MPa, or greater than 5 MPa).
[0374] Finally, in some embodiments the tensile strength of a
drug-containing solid or a three dimensional structural framework
of one or more elements is between 0.01 MPa and 100 MPa (this
includes, but is not limited to tensile strength of at least one
element is greater than 0.02 MPa, or greater than 0.05 MPa, or
greater than 0.1 MPa, or greater than 0.2 MPa, or greater than 0.5
MPa, or greater than 1 MPa, or greater than 1.5 MPa, or greater
than 2 MPa, or greater than 3 MPa, or greater than 5 MPa).
EXPERIMENTAL EXAMPLES
Part 1
[0375] The following examples present ways by which the fibrous
dosage forms may be prepared and analyzed, and will enable one of
skill in the art to more readily understand the principle thereof.
The examples are presented by way of illustration and are not meant
to be limiting in any way.
Example 1.1: Preparation of Fibrous Dosage Forms
[0376] The non-limiting experimental examples 1-7 refer to single
fibers and fibrous dosage forms consisting of 20 wt % ibuprofen
drug, 60 wt % hydroxypropyl methyl cellulose (HPMC) with a
molecular weight of 120 kg/mol (an absorptive excipient), and 20 wt
% methacrylic acid-ethyl acrylate copolymer (1:1) with a molecular
weight of about 250 kg/mol (a strength-enhancing and enteric
excipient, also referred to herein as "Eudragit L100-55").
[0377] To prepare the dosage forms, ibuprofen drug particles were
first dissolved in dimethyl sulfoxide (DMSO) solvent to form a
uniform solution with a drug concentration of 60 mg/ml DMSO. Then
the ibuprofen-DMSO solution was mixed with the excipients (75 wt %
hydroxypropyl methylcellulose (HPMC) with a molecular weight of 120
kg/mol and 25 wt % Eudragit L100-55) at the ratio 240 mg
excipient/ml DMSO.
[0378] The mixture was extruded through a laboratory extruder to
form a uniform viscous paste. The viscous paste was then put in a
syringe equipped with a hypodermic needle of inner radius,
R.sub.n=76 .mu.m. The paste was extruded through the needle to form
a wet fiber that was either deposited as a single fiber or as a
fibrous dosage form with cross-ply structure as in previous
disclosures (for further details, see, e.g., the U.S. application
Ser. No. 15/482,776 filed on Apr. 9, 2017 and titled "Fibrous
dosage form", the U.S. application Ser. No. 15/964,058 filed on
Apr. 26, 2018 and titled "Method and apparatus for the manufacture
of fibrous dosage forms", or the International Application No.
PCT/US19/52030 filed on Sep. 19, 2019 and titled "Dosage form
comprising structured solid-solution framework of sparingly-soluble
drug and method for manufacture thereof").
[0379] As mentioned above and listed in Table 1, single fibers with
nominal fiber radius, R.sub.n=76 .mu.m, were deposited. Also, three
dosage forms with the same R.sub.n and the nominal inter-fiber
spacing,.lamda..sub.n=1250 .mu.m (dosage form A), 500 .mu.m (dosage
form B), and 350 .mu.m (dosage form C) were prepared.
[0380] After depositing or patterning, to solidify the fibers and
the dosage forms, the solvent was evaporated by blowing warm air at
about 40-60.degree. C. and 1 m/s over them for a day. Post
evaporation, the solvent concentration in the solid fibers and
dosage forms was below the limit specified by the regulatory
authorities, 0.5 wt %.
[0381] Finally, the solid dosage forms were trimmed with a
microtome blade to square disks of nominal dimensions about 7.5
mm.times.7.5 mm.times.2 mm.
Example 1.2: Estimation of Microstructural Parameters
[0382] A non-limiting example to estimate some microstructural
parameters of the dosage forms is as follows. Under the rough
assumption that the fibers and dosage forms contract isotropically
during solvent evaporation, the radius, R.sub.0, and length or
inter-fiber spacing, .lamda..sub.0, of the solid fibers and the
solid dosage forms may be derived as:
R 0 R n = .lamda. 0 .lamda. n = ( 1 - c solv .rho. solv ) 1 / 3 (
32 ) ##EQU00028##
where R.sub.n is the nominal fiber radius, .lamda..sub.n the
nominal inter-fiber spacing, c.sub.solv the concentration of
solvent in the wet fiber (e.g., in the viscous paste during
depositing or micro-patterning the fibers), and .rho..sub.solv is
the density of the solvent (e.g., DMSO).
[0383] The volume fraction of fibers in the solid cross-ply
structure of the dosage forms may be expressed as (for further
details, see, e.g., A. H. Blaesi, N. Saka, Mater. Sci. Eng. C
(2021) 110211, and references therein):
.phi. = .xi. .times. .pi. .times. R 0 2 .times. .lamda. 0 ( 33
.times. a ) ##EQU00029##
where .xi. is the ratio of the "nominal" thickness of the dosage
form (point contacts between fibers) and the "real" thickness of
the dosage form (flattened fiber-to-fiber contacts):
.xi. = 2 .times. R 0 .times. n l 2 .times. H 0 = R 0 .times. n l H
0 ( 33 .times. b ) ##EQU00030##
Here n.sub.l is the number of stacked layers, and H.sub.0 the
half-thickness of the solid dosage form with flattened
contacts.
[0384] Table 1 below lists the nominal and estimated
microstructural parameters of the various dosage forms prepared as
described in the non-limiting experimental example 1.1.
TABLE-US-00001 TABLE 1 Microstructural parameters of single fibers
and fibrous dosage forms. R.sub.n .lamda..sub.n R.sub.0
.lamda..sub.0 (.mu.m) (.mu.m) 2R.sub.n/.lamda..sub.n (.mu.m)
(.mu.m) .phi. Single fibers 76 -- -- 46 -- -- Fibrous dosage forms
A 76 1250 0.12 46 763 0.16 B 76 500 0.30 46 305 0.39 C 76 350 0.43
46 214 0.56 R.sub.n: nominal fiber radius; .lamda..sub.n: nominal
inter-fiber distance; R.sub.0: solid fiber radius; .lamda..sub.0:
inter-fiber distance in solid dosage form; .phi.: fiber volume
fraction in solid dosage form. R.sub.0 and .lamda..sub.0 were
calculated by Eq. (32) using c.sub.solv = 850 mg/ml and p.sub.solv
= 1100 mg/ml. .phi. was calculated by Eq. (33) using .xi. =
R.sub.0n.sub.layers/H.sub.0 .apprxeq. 1.65, where R.sub.0 = 46
.mu.m, n.sub.1 = 36, and H.sub.0 .apprxeq. 1 mm.
Example 1.3: Measurement of Microstructural Parameters
[0385] A fiber and a dosage form were imaged by a Zeiss Merlin High
Resolution SEM with a GEMINI column. Images were taken without any
preparation of the sample. Imaging was done with an in-lens
secondary electron detector. An accelerating voltage of 5 kV and a
probe current of 95 pA were applied to operate the microscope.
[0386] FIG. 20a is a scanning electron micrograph of the single
fiber. The average fiber radius was about 49.5 .mu.m. FIG. 20b
presents a top view of the microstructure of a fibrous dosage form
B. The fiber radius, R.sub.0=45.2.+-.6 .mu.m and the inter-fiber
distance, .lamda..sub.0=390.3.+-.18 .mu.m. Both values are in rough
agreement with the estimated values presented in Table 1.
[0387] It may be noted, furthermore, that cross-sectional images of
the fibers or dosage forms may be taken to further characterize the
microstructures. (For non-limiting examples of cross sectional
images of fibrous cross-ply structures, see, e.g., the U.S.
application Ser. No. 15/482,776 filed on Apr. 9, 2017 and titled
"Fibrous dosage form", the U.S. application Ser. No. 15/964,058
filed on Apr. 26, 2018 and titled "Method and apparatus for the
manufacture of fibrous dosage forms", or the International
Application No. PCT/US19/52030 filed on Sep. 19, 2019 and titled
"Dosage form comprising structured solid-solution framework of
sparingly-soluble drug and method for manufacture thereof").
Example 1.4: Expansion of Single Fibers
[0388] To determine the expansion rate of a single fiber, the fiber
was immersed in a beaker filled with 400 ml dissolution fluid (0.1
M hydrogen chloride (HCl) in deionized water at a temperature of
37.degree. C.). The fluid was stirred with a paddle rotating at 50
rpm. The immersed sample was continuously imaged by a Nikon DX
camera.
[0389] Images of the single fiber at various times after immersion
in the dissolution fluid are shown in FIG. 21. The fiber
transitioned from solid to semi-solid or viscous and expanded in
both radial and axial directions. The integrity of the expanded
fiber was preserved for more than an hour.
[0390] FIGS. 22a and 22b present plots of the normalized radial and
axial expansions, .DELTA.R/R.sub.0 and .DELTA.L/L.sub.0, of the
single fiber versus time. Both .DELTA.R/R.sub.0 and
.DELTA.L/L.sub.0 steadily increased with time, but at a decreasing
rate. The radial expansion was slightly greater than the axial
expansion. Eight minutes after immersion, .DELTA.R/R.sub.0 was 0.8
and .DELTA.L/L.sub.0 was about 0.63.
[0391] FIGS. 22c and 22d are plots of the normalized radial and
axial expansions of the single fiber versus t.sup.1/2/R.sub.0. In
agreement with the model Eq. (7), for short times (e.g., t.ltoreq.5
min):
.DELTA. .times. R R 0 = k R ( t R 0 2 ) 1 / 2 .times. and ( 34
.times. a ) ##EQU00031## .DELTA. .times. L L 0 = k L ( t L 0 2 ) 1
/ 2 ( 34 .times. b ) ##EQU00031.2##
where k.sub.R and k.sub.L, respectively, are radial and
longitudinal expansion rate constants.
[0392] From Eqs. (34) and (7) the diffusivity of dissolution fluid
in the fiber may be estimated as:
D w = 9 .times. .pi. 1 .times. 6 .times. ( .rho. w c b ) 2 .times.
k R 2 .times. and ( 35 .times. a ) ##EQU00032## D w = 9 .times.
.pi. 1 .times. 6 .times. ( .rho. w c b ) 2 .times. k L 2 ( 35
.times. b ) ##EQU00032.2##
[0393] Using .rho..sub.w/c.sub.b.about.1 and the k.sub.R and
k.sub.L values from FIG. 22, by Eq. (35a)
D.sub.w.about.1.76.times.10.sup.-11 m.sup.2/s, and by Eq. (35b)
D.sub.w.about.1.05.times.10.sup.-11 m.sup.2/s.
Example 1.5: Expansion of Fibrous Dosage Forms
[0394] To determine the expansion rate of fibrous dosage forms, the
dosage form was immersed in a beaker filled with 400 ml dissolution
fluid (0.1 M HCl in deionized water at 37.degree. C.). The fluid
was stirred with a paddle rotating at 50 rpm. The immersed sample
was continuously imaged by a Nikon DX camera.
[0395] For all dosage forms A, B, and C, upon immersion of the
dosage form in the dissolution fluid, the fluid percolated the
inter-fiber void space rapidly. The solid dosage form then expanded
isotropically and transformed into a highly viscous or semi-solid
mass, FIG. 23. The geometry of the expanded viscous or semi-solid
masses (or the expanded viscous or semi-solid dosage forms) A, B,
and C was stabilized by the enteric excipient and preserved or
maintained for more than 2, 10, and 50 hours, respectively.
[0396] FIG. 24a is a plot of the normalized longitudinal expansion,
.DELTA.L/L.sub.0, versus time. The ratio .DELTA.L/L.sub.0 increased
with time at decreasing rate. The ratio of the dosage form length
after 15 minutes and the initial length, L.sub.15/L.sub.0, was
about two, Table 2. After about 20 minutes, the dosage form did not
expand any further.
[0397] FIG. 24b is a plot of .DELTA.L/L.sub.0 versus
t.sup.1/2/R.sub.0. In agreement with Eqs. (7) and (8),
.DELTA.L/L.sub.0 was proportional to t.sup.1/2/R.sub.0 initially.
Thus
.DELTA. .times. L L 0 .apprxeq. k e .times. x ( t R 0 2 ) 1 / 2 (
36 ) ##EQU00033##
where k.sub.ex is an expansion rate constant.
[0398] From FIGS. 23 and 24, k.sub.ex was about the same as k.sub.L
and k.sub.R of the single fiber. The constants,
k.sub.LL=k.sub.ex/k.sub.L.about.1.2, and
k.sub.RL=k.sub.ex/k.sub.R.about.0.92.
[0399] Thus, the normalized longitudinal expansion rate of the
dosage forms was about the same as the normalized axial and radial
expansion rates of the single fibers.
Example 1.6: Drug Release by Single Fibers
[0400] Drug release by single fibers was monitored using the same
setup and under the same conditions as in Example 1.4. In addition,
at regular time intervals an aliquot of the dissolution fluid was
sampled, and its UV absorbance spectrum was measured using a Perkin
Elmer Lambda 950 UV/Vis Spectrophotometer. The fraction of drug
released was determined by subtracting the UV absorbance at a
wavelength of 235 nm from that at 230 nm, and dividing the
resulting value with the value obtained at "infinite" time (i.e.,
when all drug was dissolved).
[0401] The fraction of drug released by single fibers,
m.sub.d/M.sub.0, is plotted versus time, t, in FIG. 25a. The time
to release 80 percent of the initial amount of drug, t.sub.0.8, was
42 minutes. Moreover, as predicted in the modeling section, the
fraction of drug released obeyed an equation of the form (FIG.
25b):
m d M 0 = k d ( t R 2 ) 1 / 2 ( 37 ) ##EQU00034##
where k.sub.d is a drug release rate constant.
[0402] From Eqs. (24) and (37) the diffusivity of drug through the
expanded fiber may be written as:
D d = ( c d , 0 - c s ) .times. k d 2 4 .times. c s ( 38 )
##EQU00035##
[0403] For the non-limiting parameters c.sub.d,0.about.37.9 mg/ml,
c.sub.s.about.0.05 mg/ml, and k.sub.d.about.1.27.times.10.sup.-6
m/s.sup.1/2 (FIG. 25), the diffusivity,
D.sub.d.about.3.times.10.sup.-10 m.sup.2/s. This is about half of
that of the drug molecules in water. Thus, neither the absorptive
excipient nor the strength-enhancing excipient appeared to
substantially block drug diffusion out.
TABLE-US-00002 TABLE 2 Microstructural parameters and expansion and
drug release properties of single fibers and fibrous dosage forms.
R.sub.0 .lamda..sub.0 t.sub.0.8 (.mu.m) (.mu.m)
2R.sub.0/.lamda..sub.0 .phi. L.sub.15/L.sub.0 (min) Single fibers
46 -- -- -- -- 42 Fibrous dosage forms A 46 763 0.12 0.16 2.2 120 B
46 305 0.3 0.39 1.95 620 C 46 214 0.43 0.56 2.0 2280 R.sub.0: solid
fiber radius; .lamda..sub.0: inter-fiber distance in solid dosage
form; .phi.: fiber volume fraction in solid dosage form;
L.sub.15/L.sub.0: ratio of the side length at 15 minutes and the
initial length; t.sub.0.8: time to release 80% of the drug content.
R.sub.0, .lamda..sub.0, and .phi. are as derived in Table 1.
L.sub.15/L.sub.0 is the average of two samples obtained from the
results shown in FIG. 24a. The values of the individual samples
were 2.216 and 2.113 (A), 2 and 1.903 (B), and 2.011 and 1.933 (C).
t.sub.0.8 is the average of two samples obtained from the results
shown in FIG. 26a. The values of the individual samples were 42 and
43 min (single fiber), 112 and 120 min (A), 600 and 640 min (B),
and 37 and 38 h (C).
Example 1.7: Drug Release by Fibrous Dosage Forms
[0404] Drug release by fibrous dosage forms was monitored using the
same setup and under the same conditions as in Example 1.5. In
addition, at regular time intervals an aliquot of the dissolution
fluid was sampled, and its UV absorbance spectrum was measured
using a Perkin Elmer Lambda 950 UV/Vis Spectrophotometer. The
fraction of drug released was determined by subtracting the UV
absorbance at a wavelength of 235 nm from that at 230 nm, and
dividing the resulting value with the value obtained at "infinite"
time (i.e., when all drug was dissolved).
[0405] FIG. 26a is a plot of the fraction of drug released by the
dosage forms versus time. The t.sub.0.8 times of the dosage forms
with fiber volume fractions, .phi.=0.16, 0.39, and 0.56 were 2, 10,
and 38 hours, respectively, Table 2. Thus, t.sub.0.8 increased
greatly with .phi..
[0406] The derivation of analytical equations for calculating the
fraction of drug released and the t.sub.0.8 time of fibrous dosage
forms is beyond the scope of this disclosure. However,
semi-analytical equations may be obtained as shown below.
[0407] From the drug release models shown in the section "Models of
expansion, drug release, and disintegration of the dosage form", if
the initial drug concentration in the expanded fibers,
c.sub.d,0>>c.sub.s, the solubility, the fraction of drug
released by the single fiber (.phi.=0) may be written as:
m d ( .phi. = 0 ) M 0 = 2 .times. ( c s .times. D d .times. t c d ,
0 .times. R 2 ) 1 / 2 ( 39 .times. a ) ##EQU00036##
and that by the monolithic dosage form (.phi.=1) may be expressed
as:
m d ( .phi. = 1 ) M 0 = 2 .times. ( c s .times. D d .times. t c d ,
0 .times. H 2 ) 1 / 2 ( 39 .times. b ) ##EQU00037##
Both Eqs. (39a) and (39b) are of the same form. Thus, the fraction
of drug released by the fibrous dosage form may follow the
equation:
m d ( .phi. ) M 0 = .kappa. .function. ( .phi. ) .times. ( c s
.times. D d .times. t c d , 0 .times. .zeta. .function. ( .phi. ) 2
) 1 / 2 ( 40 ) ##EQU00038##
where .kappa.(.phi.) is a dimensionless constant and .zeta.(.phi.)
a diffusion length.
[0408] The constant .kappa.(.phi.) may be assumed to follow the
weighted geometric mean of the constant of the single fiber
(.kappa.=2) and that of the monolithic slab (.kappa.= 2):
.kappa.(.phi.)=2.sup.1-.phi. {square root over (2)}.sup..phi.
(41a)
Similarly, .zeta.(.phi.) may be assumed to be the weighted
geometric mean of the fiber radius, R, and the half-thickness of
the monolithic dosage form, H:
.zeta.(.phi.)=R.sup.1-.phi.H.sup..phi. (41b)
Substituting Eqs. (41a) and (41b) in Eq. (40) gives:
m d ( .phi. ) M 0 = ( 2 2 .phi. ) .times. ( c s c d , 0 ) 1 / 2
.times. D d 1 / 2 .times. t 1 / 2 R 1 - .phi. .times. H .phi. ( 42
) ##EQU00039##
FIG. 26b plots the calculated curves of m.sub.d/M.sub.0 versus
t.sup.1/2 for the non-limiting experimental parameters
(c.sub.s=0.05 mg/ml, c.sub.d,0=37.9 mg/ml,
D.sub.d=3.24.times.10.sup.-10 m.sup.2/s, R=83 .mu.m, H=2 mm), and
compares them with the experimental data points. Indeed, for all
dosage forms, the calculated and measured values agree. Thus, the
model may be valid.
[0409] The time to release eighty percent of the drug content may
be obtained by substituting m.sub.d/M.sub.0=0.8 in Eq. (42) and
rearranging as:
t 0.8 ( .phi. ) = 0.16 .times. 2 .phi. .times. ( c d , 0 c s )
.times. ( R 1 - .phi. .times. H .phi. D d 1 / 2 ) 2 ( 43 )
##EQU00040##
Thus, t.sub.0.8 may scale with the square of the weighted diffusion
length, R.sup.1-.phi.H.sup..phi..
[0410] By simplifying Eq. (16), the t.sub.0.8 time may be written
as an exponential function of .phi. as:
t 0.8 ( .phi. ) = 0 .16 ( c d , 0 c s ) .times. ( R 2 D d ) .times.
( 2 .times. H R ) 2 .times. .phi. ( 44 ) ##EQU00041##
Taking the logarithm on both sides of Eq. (44) and rearranging,
ln .function. ( t 0.8 ( .phi. ) ) = ln .function. ( 0 .16 ( c d , 0
c s ) .times. ( R 2 D d ) ) + .phi.ln .function. ( 2 .times. H 2 R
2 ) ( 45 ) ##EQU00042##
Exponentiating and rearranging again, Eq. (45) may be rewritten
as:
t 0 . 8 ( .phi. ) = .alpha. .times. exp .function. ( .beta. .times.
.phi. ) .times. where ( 46 .times. a ) ##EQU00043## .alpha. = 0. 1
.times. 6 .times. ( c d , 0 c s ) .times. ( R 2 D d ) ( 46 .times.
b ) ##EQU00043.2## .beta. = ln .function. ( 2 .times. H 2 R 2 ) (
46 .times. c ) ##EQU00043.3##
FIG. 27 plots the calculated values of log(t.sub.0.8) versus .phi.
for the relevant experimental parameters (c.sub.d,0=37.9 mg/ml,
c.sub.s=0.05 mg/ml, R=83 .mu.m, D.sub.d=3.24.times.10.sup.-10
m.sup.2/s H=2 mm), and compares them with the experimental data
points. The calculated and measured values roughly agree.
[0411] Thus, by varying .phi. the t.sub.0.8 time of the
non-limiting experimental fibrous dosage forms increased
exponentially from that of the thin, single fibers to that of the
thick, monolithic dosage form.
Example 1.8: Diffusivity of Absorptive Excipient (e.g., HPMC 120 k)
Through the Disintegrating Single Fiber
[0412] A single fiber of radius .about.80 .mu.m was immersed in a
dissolution fluid (deionized water with 0.1 M HCl at 37 degree
Celsius) that was stirred with a paddle rotating at 50 rpm. The
fiber was removed from the dissolution bath at specific time
points, and the weight of the disintegrating fiber was determined
by a Mettler Toledo analytical balance.
[0413] In the experiments, the time to remove 63 percent of the
initial weight of HPMC excipient in the fiber was greater than 8
hours.
[0414] For an approximate, order-of-magnitude analysis of the
diffusivity of absorptive excipient through the expanded fiber, the
diffusivity of absorptive excipient molecules, D.sub.ae, through
the fiber is assumed constant. The absorptive excipient
concentration in the expanded fiber, c.sub.ae(t), may then be
governed by:
.differential. c a .times. e .differential. t = D a .times. e
.times. .differential. 2 c a .times. e .differential. r 2 .times. r
.ltoreq. R f ( 47 .times. a ) ##EQU00044##
subject to the initial and boundary conditions:
c.sub.ae=c.sub.0 r.ltoreq.R.sub.f t=0 (47b)
c.sub.ae=0 r=R.sub.f (47c)
where r is the radial coordinate, t is time, R.sub.f the radius of
the expanded fiber, and c.sub.0 is the initial concentration of
absorptive excipient in the expanded fiber.
[0415] According to Crank, an analytical solution of Eq. (47) may
be written as:
c 0 - c a .times. e c 0 = 1 - 2 .times. i = 1 .infin. J 0 ( r
.times. .beta. i / R f ) .beta. i .times. J 1 ( .beta. i ) .times.
exp .function. ( - .beta. i 2 .times. D a .times. e .times. t / R f
2 ) ( 48 ) ##EQU00045##
where the .beta..sub.i's are the roots of
J.sub.0(.beta..sub.i)=0 (49)
Here J.sub.0 is the Bessel function of the first kind of order
zero.
[0416] The ratio of the mass of absorptive excipient in the fiber
at time t, M(t), to the mass at t=0, M.sub.0, may then be
approximated by an adapted form of the equation presented by
Crank:
M .function. ( t ) M 0 = i = 1 .infin. 4 .beta. i 2 .times. exp
.function. ( - .beta. i 2 .times. D ae .times. t / R f 2 ) ( 50
.times. a ) ##EQU00046##
Substituting only the first root, .beta..sub.1=2.4, gives:
M .function. ( t ) M 0 .apprxeq. exp .function. ( - 5.76 .times. D
a .times. e .times. t / R f 2 ) ( 50 .times. b ) ##EQU00047##
[0417] From Eq. (50b), a rough estimate of the time constant for
removing the absorptive excipient from the expanded fiber may be
written as:
.tau. f .apprxeq. R f 2 5.76 D a .times. e ( 51 ) ##EQU00048##
[0418] In the non-limiting experiment, the time constant,
.tau..sub.f.about.R.sub.f.sup.2/5.76D.sub.HPMC, was greater than
about 8 hours. Thus, using R.sub.f.about.80 .mu.m, the diffusivity,
D.sub.ae.about.R.sub.f.sup.2/5.76.tau..sub.f, was smaller than
about 4.times.10.sup.-14 m.sup.2/s.
[0419] By contrast, the self-diffusivity of an absorptive
excipient, D.sub.self, in water or a physiological fluid may be
estimated by an adapted form of the Stokes-Einstein equation:
D self = k b .times. T 6 .times. .pi. .times. r e .times. .mu. ( 52
) ##EQU00049##
where k.sub.b is Boltzmann's constant, T the temperature of the
fluid, r.sub.e is the radius of the excipient molecule, and .mu.
the viscosity of water or the physiological fluid. The radius of an
excipient molecule may be approximated as:
r e .apprxeq. ( 3 .times. M w , e 4 .times. .pi. .times. N A
.times. .rho. e ) 1 / 3 ( 53 ) ##EQU00050##
where M.sub.w,e is the molecular weight of the excipient, N.sub.A
is Avogadro's number, and .rho..sub.e the density of the excipient.
For the non-limiting parameters of HPMC 120 k in water,
M.sub.w,e=120 kg/mol, .rho..sub.e=1300 kg/m.sup.3, T=310 K, and
.mu.=0.001 Pas, k.sub.b=1.38.times.10.sup.-23 m.sup.2kg/s.sup.2K,
N.sub.A=6.022.times.10.sup.23/mol, the self-diffusivity,
D.sub.self.apprxeq.6.7.times.10.sup.-11 m.sup.2/s.
[0420] The results and calculations above suggests that the
diffusivity of HPMC 120 k through the fiber was at least about 3
orders of magnitude smaller than the self-diffusivity of HPMC 120 k
in water at 37 degree Celsius.
EXPERIMENTAL EXAMPLES
Part 2
[0421] The following examples present additional ways by which the
disclosed dosage forms may be prepared and analyzed, and will
enable one of skill in the art to more readily understand the
principle of the invention herein. The examples are presented by
way of illustration and are not meant to be limiting in any
way.
Example 2.1: Preparation of Fibrous Dosage Forms
[0422] First, particles of ibuprofen (a non-limiting model drug),
Eudragit L100-55 (a strength-enhancing, enteric excipient), and
barium sulfate (a gastrointestinal contrast agent) were mixed with
liquid dimethylsolfoxide (DMSO) solvent to form a uniform
suspension. Then the hydroxypropyl methylcellulose with a molecular
weight of 120 kg/mol (HPMC 120 k) was mixed with the suspension.
The masses of ibuprofen, Eudragit L100-55, barium sulfate, and HPMC
120 k per ml of DMSO in the formulation were 64, 64, 137, and 192
mg.
[0423] The mixture was extruded through a laboratory extruder to
form a uniform viscous paste. The viscous paste was then put in a
syringe equipped with a hypodermic needle of inner radius,
R.sub.n=84 .mu.m. The paste was extruded through the needle to form
a wet fiber that was patterned layer-by-layer as a fibrous dosage
form with cross-ply structure. The nominal fiber radius in the
dosage forms, R.sub.n, was 84 .mu.m, and the nominal inter-fiber
spacing, .lamda..sub.n, in a layer was 450 .mu.m.
[0424] After patterning, the solvent was evaporated to solidify the
dosage forms. The dosage forms were first put in a vacuum chamber
maintained at a pressure of 100 Pa and a temperature of 20.degree.
C. for a day. Then they were exposed to an airstream of 60.degree.
C. and velocity 1 m/s for 60 min at ambient pressure.
[0425] After solvent evaporation, the solid dosage forms consisted
of 42% HPMC 120 k, 30% barium sulfate, 14% ibuprofen, and 14%
Eudragit L100-55 by weight. They were trimmed to 5 mm thick
circular disks with nominal diameter 13-14 mm.
[0426] Two types of dosage form were produced. The first dosage
form was coated with a hydrophilic sugar coating. The coating
solution consisted of ethanol saturated with sucrose; it was held
at -20.degree. C. The dosage form was dipped into the coating
solution and exposed to a pressure of 200 Pa right after for about
an hour to evaporate the ethanol. The dipping-evaporation process
was repeated three times. Because the hydrophilic sugar coating
dissolves rapidly upon contact with water, this dosage form is
referred to in the non-limiting experimental examples herein as
"uncoated".
[0427] The second dosage form was coated with an enteric coating.
Two coating solutions were used: (I) 1.33 mg Eudragit L100-55 in 40
ml acetone, and (II) 2 ml Kollicoat SR in 20 ml deionized water.
Both coating solutions were held at room temperature. The dosage
form was dipped into the coating solution and exposed to a pressure
of 200 Pa right after for about an hour to evaporate the solvent.
The dipping-evaporation process was repeated 6 times for solution
I, and 3 times for solution II. Because the enteric coating does
not dissolve in acidic water, this dosage form is referred to in
the non-limiting experimental examples herein as "coated".
Example 2.2 Scanning Electron Micrographs
[0428] The microstructures of the fibrous dosage forms dip-coated
with enteric excipient were imaged by a Zeiss Merlin High
Resolution SEM with a GEMINI column. The top surfaces were imaged
after coating the sample with a 10-nm thick layer of gold. The
cross-sections were imaged after the sample was cut with a thin
blade (MX35 Ultra, Thermo Scientific, Waltham, Mass.) and coated
with gold as above. The specimens were imaged with either an
in-lens secondary electron or a backscattered electron detector, at
an accelerating voltage of 5 kV, and a probe current of 95 pA.The
microstructures of the dosage forms dip-coated with enteric
excipient are shown in FIGS. 28a-28c. FIG. 28a illustrates the top
view of the dosage form. The top layer was mostly covered by the
coating, but voids of about 100-300 .mu.m in diameter were also
present.
[0429] FIGS. 28b and 28c show the cross-sectional images. The
fibers in the interior were coated; the coating bridged the
neighboring fibers vertically, but not horizontally. Thus, the
microstructure of the enteric-excipient-coated dosage forms
comprised vertical walls of thickness, 2R.sub.0, and vertical
square channels of width, .lamda..sub.0-2R.sub.0. From FIGS. 28b
and 28c, the fiber radius, R.sub.0, was about 55 .mu.m, and the
inter-fiber spacing, .lamda..sub.0, was 294 .mu.m, Table 3.
TABLE-US-00003 TABLE 3 Microstructural parameters of the fibrous
dosage forms. R.sub.0 (.mu.m) .lamda..sub.0 (.mu.m) .phi..sub.s
.phi..sub.f .phi..sub.ec Enteric coated 55 294 0.61 0.40 0.21
R.sub.0: fiber radius; .lamda..sub.0: inter-fiber distance;
.phi..sub.s: volume fraction of solid; .phi..sub.f: volume fraction
of fibers; .phi..sub.ec: volume fraction of enteric coating.
R.sub.0 and .lamda..sub.0 were obtained from FIG. 28. The volume
fractions were obtained from Eqs. (54)-(58). The nominal process
parameters were: R.sub.n = 84 .mu.m, .lamda..sub.n = 450 .mu.m.
Moreover, the half-thickness of the dosage form, H.sub.0 = 2.5 mm,
and the number of patterned layers, n.sub.l = 60.
[0430] Several microstructural parameters can be derived for this
microstructure. The volume fraction of voids may be expressed
as:
.phi. v = ( .lamda. 0 - 2 .times. R 0 ) 2 .lamda. 0 2 ( 54 )
##EQU00051##
[0431] The volume fraction of the solid walls (fiber and coating)
may be written as:
.phi. s = 1 - .phi. v = 1 - ( .lamda. 0 - 2 .times. R 0 ) 2 .lamda.
0 2 = 4 .times. R 0 .lamda. 0 - 4 .times. R 0 2 .lamda. 0 2 ( 55 )
##EQU00052##
[0432] The volume fraction of fibers (without the coating) may be
expressed as:
.phi. f = .xi. .times. .pi. .times. R 0 2 .times. .lamda. 0 ( 56 )
##EQU00053##
where .xi. is the ratio of the "nominal" thickness of the dosage
form (point contacts between fibers) and the "real" thickness of
the dosage form (flattened fiber-to-fiber contacts):
.xi. = 2 .times. R 0 .times. n l 2 .times. H 0 = R 0 .times. n l H
0 ( 57 ) ##EQU00054##
Here n.sub.l is the number of stacked layers and H.sub.0 the
half-thickness of the solid dosage form.
[0433] The volume fraction of the enteric coating may be written
as:
.phi. e .times. c = .phi. s - .phi. f = 4 .times. R 0 .lamda. 0 - 4
.times. R 0 2 .lamda. 0 2 - .xi. .times. .pi. .times. R 0 2 .times.
.lamda. 0 ( 58 ) ##EQU00055##
As listed in Table 3, for the relevant parameters of the dosage
forms with enteric-excipient-coated fibers, .phi..sub.s=0.61,
.phi..sub.f=0.4, and .phi..sub.ec=0.21.
[0434] The microstructures of the dosage forms dip-coated with
sugar were similar to those with enteric-excipient coating. Because
the sugar coating only serves the purpose to minimize the
percolation time into the dosage form, and dissolves upon contact
with water or gastric fluid, its volume fraction is not further
characterized.
Example 2.3 Expansion of the Dosage Forms Due to Water
Diffusion
[0435] The dosage forms were immersed in a beaker filled with 800
ml of the dissolution fluid (0.1 M hydrochloric acid (HCl) in
deionized (DI) water at 37.degree. C.). The fluid was stirred with
a paddle rotating at 50 rpm. The samples were imaged at different
times by a Nikon DX camera. Expansion was monitored by imaging the
samples at regular time intervals with a Nikon DX digital
camera.
[0436] Images of the dosage forms at various times after immersion
in the dissolution fluid are shown in FIG. 29. The normalized
radial expansion of the dosage form, .DELTA.R.sub.df/R.sub.df,0, is
plotted versus time in FIG. 30.
[0437] The uncoated dosage form rapidly expanded and transformed
into a semi-solid or highly viscous mass, FIG. 29a. The normalized
expansion was 0.56 by 5 min and 0.76 by 20 min. The semi-solid or
viscous mass was stabilized for over 10 hours, albeit the
normalized expansion slightly decreased, from 0.77 at 200 minutes
to 0.6 at 800 minutes, FIGS. 29a and 30.
[0438] The enteric coated dosage form expanded slower;
.DELTA.R.sub.df/R.sub.df,0 was about 0.08 at 50 minutes, and then
it increased gradually to 0.53 by 200 minutes, and plateaued to 0.7
by 500 min, FIGS. 29b and 30. The dimensions of the expanded dosage
form then were essentially unchanged for more than a day.
Example 2.4 Diametral Compression Tests
[0439] To determine the mechanical properties of the expanded,
semi-solid masses (or dosage forms), the dosage forms were first
soaked in a dissolution fluid (0.1 M HCl in deionized water at
37.degree. C.) until they did not expand any further. The uncoated
dosage forms were soaked for 30 mins, and the
enteric-excipient-coated forms for 6 hours.
[0440] Diametral compression tests were then conducted using a
Zwick Roell mechanical testing machine equipped with a 10 kN load
cell and compression platens. The relative velocity of the platens
was 2 mm/s. The test was stopped as soon as the specimen fractured
visibly.
[0441] FIG. 31 presents images of diametral compression of the
expanded semi-solid masses or dosage forms. The expanded, uncoated
dosage form barely supported its own weight, FIG. 31a. Upon
compression the dosage form deformed further and fractured. As the
load was released, the dosage form did not regain its original
shape.
[0442] The expanded, coated dosage form, by contrast, was much
stiffer, FIG. 31b. Upon compression, the dosage form deformed, and
as the load was released it sprang back and regained a shape and
size similar to that of the original form. Nonetheless, the dosage
form exhibited a crack along the axis of symmetry after
compression, as shown in FIG. 32.
[0443] FIG. 33a presents the results of the load per unit length,
P, versus displacement, .delta., during diametral compression of
the two types of dosage form. The slopes, dP/d.delta., are plotted
in FIG. 33b. For all dosage forms, up to a displacement of about
10-13 mm the load and its slope increased with displacement. But
after that the P-.delta. curve exhibited an inflection point and
the slope decreased. At a given displacement, both P and
dP/d.delta. of the dosage forms with enteric-excipient-coated
fibers were about 20-30 times those of the dosage forms with
sugar-coated fibers.
[0444] For data analysis, the expanded dosage form is considered a
linear elastic cylinder of radius, R.sub.df, subjected to diametral
compression by two hard, flat platens as shown in the inset of FIG.
33a. From the equations of elasticity, for small displacements the
relative displacement of the platens may be approximated by (for
further details, see, e.g., A. H. Blaesi, N. Saka, Int. J. Pharm.
509 (2016) 444-453; or K. L. Johnson, "Contact Mechanics",
Cambridge University Press, Cambridge, UK, 1985):
.delta. = 2 .times. P .times. 1 - v 2 .pi. .times. E df .times. ( 2
.times. ln .times. 4 .times. .pi. .times. R df .times. E df P - 1 )
( 59 ) ##EQU00056##
where P is the force per unit length along the cylinder surface
(e.g., the load per unit length along the thickness of the expanded
dosage form), v the Poisson's ratio, and E.sub.df the elastic
modulus of the expanded dosage form.
[0445] By inserting the experimental P and .delta. values from FIG.
33a in Eq. (59), and using v.apprxeq.0.5, the elastic modulus of
the dosage form can be estimated. For the expanded, uncoated dosage
form, E.sub.df=0.0075 MPa (7.5 kPa or .about.10.sup.-5 GPa), Table
4. This elastic modulus is of the order of that of gelatin (e.g.,
as in Jello); it is so low that the dosage form may also be
considered a viscous gel or a viscous mass rather than an elastic
solid or semi-solid (for further details related to materials
classification, see, e.g., M. F. Ashby, Materials selection in
mechanical design, Third ed., Butterworth-Heinemann, Oxford, UK,
2005). For the expanded, coated dosage form, E.sub.df=0.098 MPa
(.about.10.sup.-4 GPa). This value is comparable to the modulus of
low-stiffness, highly flexible polymer foams, such as foams of
natural rubber or silicone (for further details related to
materials classification, see, e.g., M. F. Ashby, Materials
selection in mechanical design, Third ed., Butterworth-Heinemann,
Oxford, UK, 2005).
[0446] Excessive plastic deformation, or fracture, of the dosage
form may be observed if Eq. (59) is severely violated, i.e., if
dP/d.delta. is at a maximum or P is at an inflection point. From
FIG. 33 the inflection points, or loads at fracture,
P.sub.f,df=0.18 N/mm for the uncoated dosage form, and
P.sub.f,df=4.66 N/mm for the coated dosage forms, Table 4.
[0447] From the load at fracture the tensile strength of the dosage
form may be estimated:
.sigma. f , df .apprxeq. P f , df .pi. .times. R df ( 60 )
##EQU00057##
As listed in Table 4, for the expanded, uncoated dosage form,
.sigma..sub.f,df.apprxeq.0.005 MPa, and for the coated,
.sigma..sub.f,df.apprxeq.0.135 MPa. Again, the tensile or fracture
strength of the expanded uncoated dosage form was so low that the
dosage form may also be considered a viscous gel rather than an
elastic solid. The tensile or fracture strength of the expanded
coated form was more than an order of magnitude greater than that
of the uncoated, and comparable to that of low-stiffness, highly
flexible polymer foams (for further details related to materials
classification, see, e.g., M. F. Ashby, Materials selection in
mechanical design, Third ed., Butterworth-Heinemann, Oxford, UK,
2005, and references therein).
[0448] Thus, the stiffness and strength of the expanded dosage
forms was substantially increased by the enteric coating (e.g., by
coating the fibers with strength-enhancing excipient). In other
words, the stiffness and strength of the expanded dosage forms
increase greatly by increasing the weight fraction of
strength-enhancing excipient in the dosage form, or by increasing
the density of strength-enhancing excipient in the dosage form
(e.g., by increasing the mass of strength-enhancing excipient in
the dosage form per unit volume of the dosage form).
[0449] Moreover, it should be noted that both the expanded uncoated
and the expanded coated dosage forms were soft materials that are
unlikely to injure the gastrointestinal mucosa.
TABLE-US-00004 TABLE 4 Mechanical properties of expanded fibrous
dosage forms. E.sub.df (MPa) P.sub.f,df (N/mm) .sigma..sub.f,df
(MPa) Uncoated dosage form Sample 1 0.0075 0.18 0.005 Coated dosage
forms Sample 1 0.076 3.31 0.096 Sample 2 0.117 5.61 0.162 Sample 3
0.102 5.05 0.146 Average 0.098 4.66 0.135 Std 0.017 0.98 0.028
E.sub.df: elastic modulus of expanded dosage form; P.sub.f,df: load
per unit length at fracture; .sigma..sub.f,df: stress at fracture
The properties were obtained from the diametral compression tests
reported in FIG. 33, and Eqs. (59) and (60). The properties of the
acidic water-soaked enteric coating, E = 5.7 MPa and .sigma..sub.f
= 1.8 MPa (Table 6).
Example 2.5 Gastric Residence Time of the Dosage Forms in Dogs
[0450] Two healthy beagle dogs (13-15 kg; three-year old; female;
not castrated) were assigned five experiments comprising either
coated and uncoated dosage forms. The dogs fasted for 18 hours
prior to the experiment.
[0451] All dosage forms were administered to an awake dog, together
with 30 ml water. The position of the dosage form was monitored by
fluoroscopic imaging at the time points shown in FIGS. 34-36 (using
a Philips Allura Clarity biplanar fluoroscopy system). Between
imaging the dogs were allowed to roam about freely.
[0452] At 4-6 hours and at 30 hours after ingestion, 180 grams of
basic dry food (Sensinesse 25/13, Petzeba AG, Alberswil,
Switzerland) was given. No sedatives, anesthesia, or other
supplements were administered before, during, or after the
experiment.
[0453] The study was designed aiming to Replace animal experiments
with non-sentient alternatives, Reduce animal experiments to
minimize the number of animals used, and Refine animal experiments
so that they cause minimum pain and distress. All procedures were
conducted in compliance with the Swiss animal welfare act, and were
approved by governmental authorities.
[0454] FIGS. 34 and 35 present fluoroscopic images of the dosage
forms at various times after administration to a dog.
[0455] As shown in FIG. 34, the uncoated dosage form passed from
the mouth into the stomach in less than a minute. In the stomach it
expanded to a normalized radial expansion,
.DELTA.R.sub.df/R.sub.fd,0=0.63 by 100 minutes, and then plateaued
to .DELTA.R.sub.df/R.sub.df,0=0.67, FIG. 36a and Table 5. Thus the
in vivo expansion rate was about a tenth of that measured in vitro,
FIG. 36b. After about 300 minutes, as food was given to the dog,
the dosage form showed visible cracks. The cracks grew rapidly and
resulted in fracture at about 350 minutes. The fragments then
passed into the intestines where they dissolved. By about 380
minutes (6.3 hours) the entire dosage form was essentially
dissolved.
[0456] As shown in FIG. 35, the coated dosage form, too, passed
from the mouth into the stomach in less than a minute. Similar to
the in vitro results, it then expanded at a moderate rate to a
normalized radial expansion, .DELTA.R.sub.df/R.sub.df,0=0.5 by 200
minutes, and 0.6 by 500 minutes (FIG. 36b and Table 5). The
integrity of the dosage form was mostly preserved until 2200-2700
minutes (37-45 hours) after ingestion. At 2700 minutes, fragments
were seen in the intestine. The fragments dissolved rapidly; by
2900 minutes (48 hours), they were essentially invisible.
TABLE-US-00005 TABLE 5 Properties of fibrous dosage forms in vivo.
t.sub.exp (min) .DELTA.R.sub.df/R.sub.df,0 .delta..sub.max (mm)
t.sub.res (h) Uncoated Sample 1 100 0.67 10 6.3 Sample 2 50 0.11 10
5.5 Sample 3 100 0.68 11 2.5 Average 83 0.71 10.3 4.8 Coated Sample
1 200 0.60 6.5 41 Sample 2 200 0.58 6.5 20 Average 200 0.59 6.5
30.5 t.sub.exp: time to expand dosage form to greater than 90% of
the terminal value; .DELTA.R.sub.df/R.sub.df,0: terminal nominal
expansion; .delta..sub.max: maximum deformation due to contracting
stomach walls; t.sub.res: gastric residence time The data were
derived from FIGS. 34-37.
[0457] Thus, unlike in vitro, in vivo the dosage forms fragmented
and dissolved eventually. Fragmentation was due to contraction
pulses by the stomach walls that occurred about every 10-30
seconds.
[0458] FIG. 37a shows a fluoroscopic image sequence of an uncoated
dosage form during a contraction pulse by the stomach walls at
about 2 hours after ingestion. The (expanded) dosage form was
circular and of diameter 23 mm initially. At 2.6 s, the dosage form
was squeezed by about 11 mm to a width of roughly 12 mm. At 5 s the
dosage form regained a round shape of roughly the initial diameter.
Soon after the images were taken, however, the dosage form
fractured.
[0459] FIG. 37b shows a fluoroscopic image sequence of a coated
dosage form during a contraction pulse at about 7 hours after
ingestion. Initially, the (expanded) dosage form was circular and
of diameter 23 mm. At 1 s, the dosage form was diametrically
pinched, and at 2.3 s it was diametrically compressed by about 6.5
mm to a width of about 16.5 mm. The dosage form regained its
original shape after about 5 s. The compression-spring back cycles
were repeated for several more hours as the coated dosage form was
retained in the stomach.
[0460] For an analysis of the forces applied on the dosage form and
the gastric residence, we may consider the non-limiting force field
shown in FIG. 12 comprising diametrically opposed cyclic loads per
unit length, P, with maximum load per unit length, P.sub.max,
acting on the expanded semi-solid or viscous dosage form. From the
results, the maximum compression, .delta..sub.max, was about 6.5 mm
in vivo, FIG. 37b and Table 5. In the in vitro experiments, at
.delta.=6.5 mm P was about 1 N/mm, FIG. 33a. Thus, in the in vivo
experiments the maximum cyclic load intensity imposed by the
stomach walls, P.sub.max.about.1 N/mm.
[0461] The corresponding cyclic stress (tension) along the axis of
symmetry may be approximated as:
.sigma. max = P max .pi. .times. R df ( 61 ) ##EQU00058##
where R.sub.df is the radius of the expanded dosage form. For
P.sub.max=1 N/mm and R.sub.df=11.5 mm, by Eq. (61)
.sigma..sub.max=0.028 MPa. This is one-fifth of the fracture
strength, .sigma..sub.f,df=0.135 MPa, obtained from the monotonic,
in vitro diametral compression test, Table 4. Thus, in vivo the
dosage form may have exhibited fatigue fracture.
[0462] By Eq. (31), if the dosage form disintegrates due to fatigue
fracture, the gastric residence time may be estimated as:
t r .about. t pulse ( P max .pi. .times. R df .times. .sigma. f ,
se .times. C 8 .times. .phi. se 3 / 2 ) 1 / b ( 62 )
##EQU00059##
where .sigma..sub.f,se is the fracture strength of the
strength-enhancing excipient, .sigma..sub.se the volume fraction of
the strength-enhancing excipient in the dosage form (e.g., the
volume fraction of the enteric coating), and C.sub.8 a constant,
typically about 0.65.
[0463] Thus, for t.sub.pulse=20 s, P.sub.max=1 N/mm, R.sub.df=11.5
mm, .sigma..sub.f,se=1.8 N/mm.sup.2, C.sub.8=0.65, and
.phi..sub.se.apprxeq..phi..sub.c=0.21, by Eq. (62) the gastric
residence time, t.sub.r.about.31 hours if the constant,
b.about.-0.162.
Example 2.6 Solubility and Sorption of Deionized Water with 0.1 M
HCl in Strength-Enhancing Excipient
[0464] Strength-enhancing excipient (Methacrylic acid-ethyl
acrylate copolymer (1:1), with a molecular weight of about 250
kg/mol, also referred to herein as "Eudragit L100-55") was received
from Evonik, Essen, Germany.
[0465] Solid films of the strength-enhancing excipient were
prepared by dissolution of Eudragit L100-55 in DMSO to form a
viscous solution, pouring the solution in a metal dish to form a
film, and evaporating DMSO in a vacuum chamber at a pressure of
about 1 mbar and a temperature of about 50.degree. C. for about a
day. The thickness of the solid, frozen films, h.sub.0, was about
250 .mu.m.
[0466] For determining the properties of the solid films, the solid
films were first immersed in a relevant dissolution fluid (water
with 0.1 M HCl at 37.degree. C.). The weight of the film was then
measured at specific time points with a Mettler Toledo analytical
balance. The weight fraction of water (or dissolution fluid) in the
film, w.sub.w, was determined by:
w w = m .function. ( t ) - m 0 m .function. ( t ) ( 63 )
##EQU00060##
where m(t) is the mass of the water-soaked film at time t after
immersion in the dissolution fluid, and m.sub.0 is the mass of the
solid film initially.
[0467] FIG. 38a is a plot of the weight fraction of water (or
dissolution fluid) in the films versus time after immersion. The
weight fraction of water increased with time at a degressive rate,
and plateaued out at about 2000 seconds to a value of about 0.39.
Thus, the "solubility" of the dissolution fluid in the
strength-enhancing Eudragit L100-55 excipient film was about 39
weight percent, or roughly 390 mg/ml.
[0468] FIG. 38b is a plot of the mass of dissolution fluid absorbed
by the film at time t, m.sub.w(t)=m(t)-m.sub.0, divided by the mass
absorbed at "infinite" time (e.g., at 2000 seconds),
m.sub.w,.infin.=m(t=2000 s)-m.sub.0, versus t.sup.1/2/h.sub.0. For
small times, the fit of the data was linear; thus, initially the
data followed a curve of the form
m w ( t ) m w , .infin. = k s ( t h 0 2 ) 1 / 2 ( 64 )
##EQU00061##
where k.sub.s is a sorption constant. From FIG. 38b, the sorption
constant, k.sub.s=10.2.times.10.sup.-6 m/s.sup.1/2.
[0469] According to Crank, in Fickian diffusion, for small times
the mass of water sorbed at time t, m.sub.w(t) divided by the mass
of water (or physiological fluid) sorbed at "infinite" time,
m.sub.w,.infin., by a plane film may be approximated by:
m w ( t ) m w , .infin. .apprxeq. 4 .pi. .times. ( D w .times. t h
0 2 ) 1 / 2 ( 65 ) ##EQU00062##
where D.sub.w is the diffusivity of water (or physiological fluid)
in the film.
[0470] Thus, D.sub.w, may be estimated from the data plotted in
FIG. 38b as:
D w .apprxeq. .pi. .times. k s 2 1 .times. 6 ( 66 )
##EQU00063##
For k.sub.s.about.10.2.times.10.sup.-6 m/s.sup.1/2,
D.sub.w.about.2.04.times.10.sup.-11 m.sup.2/s.
Example 2.7 Mechanical Properties of Acidic Water-Penetrated
Eudragit L100-55 Films
[0471] Solid films of Eudragit L100-55 were prepared by dissolving
3 g Eudragit powder in 40 ml Acetone, pouring the solution in a
polyethylene box with dimensions about 100 mm.times.60 mm to form a
film, and drying at room temperature for about a day. The solid,
frozen films were then punched into tensile specimen according to
DIN 53504, type S 3A. The specimen thickness was 150-250 .mu.m.
[0472] The tensile specimens were soaked in a dissolution fluid
(water with 0.1 M HCl at 37.degree. C.) for about an hour.
Subsequently, the water-soaked specimen were loaded in a Zwick
Roell Mechanical Testing machine equipped with a 20-N load cell.
The initial distance between grips was 28 mm. During tensile
testing the grips receded at a relative velocity of 2 mm/s, and the
force and distance between grips were recorded. The test was
stopped when the sample ruptured, and the load decreased to less
than 80% of the maximum load.
[0473] From the recordings of force and distance and the geometry
of the tensile specimen, the nominal stress, .sigma., and strain,
.epsilon., in the specimen can be derived as:
.sigma. = F W .times. h ( 67 ) ##EQU00064## .epsilon. = .DELTA.
.times. L L 0 ( 68 ) ##EQU00064.2##
where F is the tensile force applied on the film, W the width of
the narrow section of the water-soaked tensile specimen, h its
thickness, .DELTA.L the distance travelled by the grips, and
L.sub.0 the initial distance.
[0474] FIG. 39 plots the nominal stress, .sigma., versus
engineering strain, .epsilon., of the acidic water-soaked tensile
specimen films comprising strength-enhancing Eudragit L100-55
excipient. Initially, the stress increased steeply and roughly
linearly with strain. At a strain of about 0.06-0.12, the slope
decreased substantially. The stress then increased with strain at a
non-linear, progressive rate. Eventually, when the sample ruptured,
the stress dropped abruptly.
[0475] From the stress-strain curves several properties of the
acidic water-soaked films can be derived. The elastic modulus,
E = .DELTA. .times. .sigma. .DELTA. .times. .epsilon. .sigma. <
.sigma. y ( 69 ) ##EQU00065##
where the yield strength, .sigma..sub.y, is defined here as the
first stress on the curve at which an increase in strain occurs
without an increase in stress. The fracture strength,
.sigma..sub.f, (also referred to herein as "tensile strength") is
the maximum stress on the curve.
[0476] As listed in Table 6, the average values of the measured
properties, E=5.7 MPa (5.times.10.sup.-3 GPa), .sigma..sub.y=0.26
MPa, and .sigma..sub.f=1.8 MPa. These values are comparable to the
properties of typical low-strength elastomers or rubbers (for
further details related to materials classification, see, e.g., M.
F. Ashby, Materials selection in mechanical design, Third ed.,
Butterworth-Heinemann, Oxford, UK, 2005).
TABLE-US-00006 TABLE 6 Properties of acidic water-soaked Eudragit
L100-55 films derived from tension tests. E (MPa) .sigma..sub.y
(MPa) .epsilon..sub.y .sigma..sub.f (MPa) .epsilon..sub.f Sample 1
3.6 0.19 0.10 1.48 3.43 Sample 2 4.9 0.26 0.12 1.52 3.21 Sample 3
5.7 0.21 0.06 1.70 3.76 Sample 4 7.3 0.34 0.08 2.14 3.47 Sample 5
6.9 0.30 0.09 2.18 3.64 Average 5.7 0.26 0.09 1.80 3.50 Std 1.35
0.06 0.02 0.3 0.19 E: elastic modulus; .sigma..sub.y: yield
strength; .epsilon..sub.y: strain at yield; .sigma..sub.f: of
stress at fracture; .epsilon..sub.f: strain at fracture. The
properties were obtained from tensile tests reported in FIG. 39.
The elastic modulus, E, was derived from Eq. (69). .sigma..sub.y
was defined as the first stress at which an increase in strain
occured without an increase in stress. .sigma..sub.f the maximum
stress.
APPLICATION EXAMPLES
[0477] In some embodiments, the amount of active ingredient
contained in a dosage form disclosed in this invention is
appropriate for administration in a therapeutic regimen that shows
a statistically significant probability of achieving a
predetermined therapeutic effect when administered to a relevant
population. By way of example but not by way of limitation, active
ingredients may be selected from the group consisting of
acetaminophen, aspirin, caffeine, ibuprofen, an analgesic, an
anti-inflammatory agent, an anthelmintic, anti-arrhythmic,
antibiotic, anticoagulant, antidepressant, antidiabetic,
antiepileptic, antihistamine, antihypertensive, antimuscarinic,
antimycobacterial, antineoplastic, immunosuppressant, antihyroid,
antiviral, anxiolytic and sedatives, beta-adrenoceptor blocking
agents, cardiac inotropic agent, corticosteroid, cough suppressant,
diuretic, dopaminergic, immunological agent, lipid regulating
agent, muscle relaxant, parasympathomimetic, parathyroid,
calcitonin and biphosphonates, prostaglandin, radiopharmaceutical,
anti-allergic agent, sympathomimetic, thyroid agent, PDE IV
inhibitor, CSBP/RK/p38 inhibitor, or a vasodilator.
[0478] Moreover, while useful for improving almost any drug
therapy, the disclosed dosage forms can be particularly beneficial
for therapies that require tight control of the concentration in
blood of drugs that are soluble or fairly soluble in acidic but
sparingly soluble or practically insoluble in basic solution.
[0479] More specifically, as shown schematically in the
non-limiting FIG. 40a, upon ingestion of a traditional, granular
dosage form comprising drug that is soluble in acidic but insoluble
in basic solution, the dosage form may fragment into its
constituent particulates in the stomach, and release drug as
particles and molecules. As the drug molecules may pass into the
upper, acidic part of the intestines, they may enter the blood
stream, and the drug concentration in blood may increase steeply,
as shown in the non-limiting FIG. 40b. As the drug molecules may
enter the lower, basic part, however, they may precipitate back as
particles, which may not (or only very slowly) be absorbed, and the
drug concentration in blood may decrease with time, FIG. 40b.
Moreover, because drug may be excreted the bioavailability,
understood herein as the mass of drug absorbed by the blood after
ingestion of a dosage form divided by the mass of drug in the
dosage form initially, may be low. The bioavailability may further
be variable, because the transit times through and physico-chemical
environment in the stomach and upper intestines can be variable.
Consequently, the drug concentration in blood may fluctuate beyond
the optimal range, and the efficacy and safety of the drug therapy
may be compromised, FIG. 40b.
[0480] The disclosed dosage forms, by contrast, enable retention of
the dosage form in the stomach and slower drug delivery rate over a
prolonged time. For example, the disclosed dosage forms may be
smaller than the diameter of the oesophagus (.about.15-20 mm) to
facilitate ingestion, as shown in the non-limiting FIG. 40c. But in
the stomach they may expand rapidly to a size greater than the
diameter of the pylorus (.about.13-20 mm). Moreover, as the dosage
forms expand they may transition from solid to semi-solid or highly
viscous, and remain in a semi-solid or highly viscous state for
prolonged time, thus precluding their immediate passage into the
small intestine and eliminating any risk of mechanically injuring
the gastric mucosa. Drug molecules may be released into the stomach
slowly and over prolonged time, and be predominantly absorbed in
the upper part of the gastrointestinal tract after their release.
As a result, the drug absorption rate may be fairly steady over
prolonged time, the bioavailability may be high, and the
variability of the bioavailability may be low. Consequently, the
drug concentration in blood may be well controlled within the
optimal range, as shown in the non-limiting FIG. 40d; the efficacy
of the drug therapy may be increased, and/or side effects of the
therapy may be decreased.
[0481] In some embodiments, therefore, the dosage forms herein
comprise one or more active ingredients or drugs that are more
soluble in acidic solutions (e.g., in the stomach or duodenum) than
in basic solutions (e.g., in the bowel or large intestine). Thus,
in some embodiments, the dosage form comprises at least one active
pharmaceutical ingredient having a pH-dependent solubility in a
physiological or body fluid.
[0482] Furthermore, in some embodiments, the dosage form herein
comprises at least one active pharmaceutical ingredient having a
solubility that is at least five times greater in acidic solution
than in basic solution. This includes, but is not limited to at
least one active ingredient having a solubility that is at least 10
times, or at least 15 times, or at least 20 times, or at least 30
times, or at least 50 times greater in acidic solution than in
basic solution. In the invention herein, a solution is understood
"acidic" if the pH value of said solution is no greater than about
5.5. A solution is understood "basic" if the pH value of said
solution is greater than about 5.5.
[0483] Moreover, in some embodiments, the dosage form herein
comprises at least one active pharmaceutical ingredient that is a
basic compound. In the invention herein, a compound is understood
"basic" if the acid dissociation constant (e.g., the pKa value) of
said compound is greater than about 5.5.
[0484] More generally, furthermore, the disclosed dosage forms can
be beneficial for therapies that require tight or fairly tight
control of the concentration in blood of drugs that are
sparingly-soluble (e.g., poorly soluble) in an aqueous
physiological fluid or gastro-intestinal fluid.
[0485] Thus, in some embodiments, the dosage form herein comprises
at least one active pharmaceutical ingredient having a solubility
no greater than 5 g/l in an aqueous physiological/body fluid under
physiological conditions. This includes, but is not limited to at
least one active ingredient having a solubility no greater than 2
g/l, or no greater than 1 g/l, or no greater than 0.5 g/l, or no
greater than 0.2 g/l, or no greater than 0.1 g/l in an aqueous
physiological or body fluid under physiological conditions.
[0486] It may be noted, moreover, that due to the greater
bioavailability, with the disclosed dosage form the mass of drug a
patient is recommended to or supposed to ingest to achieve a
therapeutic effect may be lower than with the traditional dosage
form.
[0487] Additionally, due to the capability of releasing drug into
the upper gastrointestinal tract over prolonged time, the disclosed
dosage form may enable to reduce the dosing frequency for treatment
of a specific disease or medical condition. The "dosing frequency"
is understood herein as the number of times a patient may ingest,
or is recommended to ingest (e.g., by medical personnel such as a
doctor, pharmacist, etc.), a drug dose in a given time. In other
words, the "dosing frequency" may be understood as the reciprocal
of the recommended time interval between two drug doses to be
ingested by or administered to a patient. A "drug dose" may be
understood as a specific drug mass to be ingested by or
administered to a patient at a specific time. The specific drug
mass may be included in one or more dosage forms.
[0488] The disclosed dosage form, therefore, can be beneficial for
therapies comprising a drug with short half-life in blood or a
human or animal body. The "half-life" is understood herein as the
period of time required for a "maximum" concentration or "maximum"
amount of drug in blood or in the body to be reduced by one-half,
under the condition that no drug is delivered into the blood or
body during said time period. The concentration of drug in blood
may generally be estimated from measurements of the concentration
of drug in blood plasma.
[0489] In some embodiments, accordingly, the dosage form herein
comprises at least one active pharmaceutical ingredient having a
half-life in a human or animal body (e.g., a physiological system)
no greater than one day or 24 hours. This includes, but is not
limited to a half-life in a human or animal body no greater than 22
hours, or no greater than 20 hours, or no greater than 18 hours, or
no greater than 16 hours, or no greater than 14 hours, or no
greater than 12 hours, or no greater than 10 hours, or no greater
than 8 hours, or no greater than 6 hours, or no greater than 4
hours, or in the ranges 0.5-24 hours, 0.5-20 hours, 0.5-16 hours,
0.5-12 hours, 0.5-10 hours, 0.5-8 hours, or 0.5-6 hours.
[0490] Finally, the disclosed dosage forms can be manufactured by
an economical process enabling more personalized medicine.
* * * * *