U.S. patent application number 16/960866 was filed with the patent office on 2021-03-18 for dosage forms with desired release profiles and methods of designing and making thereof.
The applicant listed for this patent is Triastek Inc.. Invention is credited to Senping CHENG, Feihuang DENG, Xiaoling LI.
Application Number | 20210078244 16/960866 |
Document ID | / |
Family ID | 1000005237055 |
Filed Date | 2021-03-18 |
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United States Patent
Application |
20210078244 |
Kind Code |
A1 |
DENG; Feihuang ; et
al. |
March 18, 2021 |
DOSAGE FORMS WITH DESIRED RELEASE PROFILES AND METHODS OF DESIGNING
AND MAKING THEREOF
Abstract
In some aspects, the present disclosure provides dosage forms,
such as oral drug dosage forms, configured to provide a desired
release profile, the dosage forms comprising a multi-layered
structure comprising a plurality of layers of a first erodible
material admixed with a compound (e. g., a drug) or a reagent,
wherein the first erodible material is embedded in a second
material not admixed with the compound (e. g., the drug) or the
reagent. In other aspects, the present disclosure provides methods
of designing, such as obtaining a thickness and/or surface area of
a layer comprising an erodible material admixed with a compound (e.
g., a drug) or areagent, and/or amount of the compound (e. g., the
drug) or the reagent admixed in the erodible material, and methods
of making, such as three-dimensional printing, dosage forms
configured to provide desired release profiles.
Inventors: |
DENG; Feihuang; (Nanjing,
CN) ; LI; Xiaoling; (Dublin, CA) ; CHENG;
Senping; (Nanjing, CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Triastek Inc. |
Nanjing |
|
CN |
|
|
Family ID: |
1000005237055 |
Appl. No.: |
16/960866 |
Filed: |
December 25, 2018 |
PCT Filed: |
December 25, 2018 |
PCT NO: |
PCT/CN2018/123399 |
371 Date: |
July 8, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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16049713 |
Jul 30, 2018 |
10350822 |
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16960866 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61J 3/07 20130101; A61K
31/4458 20130101; B29C 64/393 20170801; B33Y 70/00 20141201; A61K
9/4808 20130101; A61K 9/2027 20130101; A61K 9/2086 20130101; A61J
3/00 20130101; B33Y 50/02 20141201; B33Y 80/00 20141201; A61K
31/415 20130101; A61K 9/2054 20130101; A61K 9/2095 20130101; B29C
64/118 20170801; B33Y 10/00 20141201; A61K 9/0053 20130101; B29K
2105/0035 20130101 |
International
Class: |
B29C 64/118 20060101
B29C064/118; A61K 9/00 20060101 A61K009/00; B33Y 10/00 20060101
B33Y010/00; B33Y 50/02 20060101 B33Y050/02; B29C 64/393 20060101
B29C064/393; A61K 9/20 20060101 A61K009/20; A61K 9/48 20060101
A61K009/48; A61J 3/00 20060101 A61J003/00; A61J 3/07 20060101
A61J003/07 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 9, 2018 |
CN |
PCT/CN2018/071967 |
Claims
1-30. (canceled)
31: A drug dosage form comprising a multi-layered structure
comprising a plurality of layers of a first erodible material
admixed with a drug, wherein the multi-layered structure is
embedded in a second material not admixed with the drug, wherein
each layer of the plurality of layers of the multi-layered
structure has a top surface having a surface area, wherein the
surface area of the top surface of each layer of the multi-layered
structure decreases sequentially based on the order, from top to
bottom, in which each layer will be exposed to a bodily fluid,
wherein each layer of the plurality of layers of the multi-layered
structure has a thickness and drug mass fraction (mF).
32: The drug dosage form of claim 31, further comprising a top
layer comprising an erodible material not admixed with the drug,
wherein the top layer is positioned on top of a topmost layer of
the multi-layered structure, and wherein a bottom surface of the
top layer has a surface area that is the same or larger than the
surface area of the top surface of the topmost layer of the
multi-layered structure.
33: The drug dosage form of claim 32, wherein the top layer has a
thickness configured to delay the release of the drug from the drug
dosage form for a desired amount of time.
34: The drug dosage form of claim 32, wherein the erodible material
of the top layer comprises the same material as the first erodible
material.
35: The drug dosage form of claim 32, wherein the erodible material
of the top layer is different than the first erodible material.
36: The drug dosage form of claim 32, wherein the top layer
comprises another drug.
37: The drug dosage form of claim 31, wherein two or more layers of
the plurality of layers of the multi-layered structure have the
same thickness.
38: The drug dosage form of claim 37, wherein two or more layers of
the plurality of layers of the multi-layered structure have a
different drug mF.
39: The drug dosage form of claim 31, wherein the second material
is erodible.
40: The drug dosage form of claim 31, wherein the second material
is an insulating material that is impermeable to the bodily fluid,
wherein the insulating material forms a barrier between the bodily
fluid and at least a portion of the multi-layered structure.
41: The drug dosage form of claim 31, wherein the multi-layered
structure further comprises an intermediate layer comprising an
erodible material not admixed with the drug, and wherein the
intermediate layer is positioned between two layers of the
plurality of layers of the multi-layered structure.
42: The drug dosage form of claim 41, wherein the intermediate
layer comprises the same material as the first erodible
material.
43: The drug dosage form of claim 31, further comprising one or
more additional multi-layered structures.
44: A drug dosage form comprising a multi-layered structure
comprising a plurality of layers of a first erodible material
admixed with a drug, wherein the multi-layered structure is
embedded in a second material not admixed with the drug, wherein
each layer of the plurality of layers of the multi-layered
structure has a top surface having a surface area, wherein the
surface area of the top surface of each layer of the multi-layered
structure increases sequentially based on the order, from top to
bottom, in which each layer will be exposed to a bodily fluid,
wherein each layer of the plurality of layers of the multi-layered
structure has a thickness and drug mass fraction (mF).
45: The drug dosage form of claim 44, further comprising a top
layer comprising an erodible material not admixed with the drug,
wherein the top layer is positioned on top of a topmost layer of
the multi-layered structure, and wherein a bottom surface of the
top layer has a surface area that is the same or larger than the
surface area of the top surface of the topmost layer of the
multi-layered structure.
46: The drug dosage form of claim 44, wherein the second material
is an insulating material that is impermeable to the bodily fluid,
wherein the insulating material forms a barrier between the bodily
fluid and at least a portion of the multi-layered structure.
47: A drug dosage form comprising a multi-layered structure
comprising a plurality of layers of a first erodible material
admixed with a drug, wherein the multi-layered structure is
embedded in a second material not admixed with the drug, wherein
each layer of the plurality of layers of the multi-layered
structure has a top surface having a surface area, wherein the
plurality of layers of the multi-layered structure comprises, in
sequential order, a first layer, a second layer, and a third layer,
wherein the first layer, the second layer, and the third layer are
configured such that when the dosage form is exposed to a bodily
fluid the top surface of the first layer will be exposed to the
bodily fluid prior the top surface of the second layer, and the top
surface of the second layer will be exposed to the bodily fluid
prior to a top surface of the third layer, wherein: (i) the top
surface of the first layer and the top surface of the third layer
have a larger surface area than the top surface of the second
layer; or (ii) the top surface of the first layer and the top
surface of the third layer have a smaller surface area than the top
surface of the second layer, and wherein each layer of the
plurality of layers of the multi-layered structure has a thickness
and drug mass fraction (mF).
48: The drug dosage form of claim 47, further comprising a top
layer comprising an erodible material not admixed with the drug,
wherein the top layer is positioned on top of a topmost layer of
the multi-layered structure, and wherein a bottom surface of the
top layer has a surface area that is the same or larger than the
surface area of the top surface of the topmost layer of the
multi-layered structure.
49: The drug dosage form of claim 48, wherein the topmost layer of
the multi-layered structure is the first layer.
50: The drug dosage form of claim 47, wherein the second material
is an insulating material that is impermeable to the bodily fluid,
wherein the insulating material forms a barrier between the bodily
fluid and at least a portion of the multi-layered structure.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority benefit under 35 U.S.C.
.sctn. 365(a) of International PCT Application No.
PCT/CN2018/071967, filed on Jan. 9, 2018, entitled "DOSAGE FORMS
WITH DESIRED RELEASE PROFILES AND MEHTODS OF DESIGNING AND MAKING
THEREOF," the entire contents of which are incorporated herein by
reference for all purposes.
TECHNICAL FIELD
[0002] In some aspects, the present disclosure provides dosage
forms, such as drug dosage forms, configured to provide a desired
release profile, the dosage forms comprising a multi-layered
structure comprising a plurality of layers of a first erodible
material admixed with a drug or a reagent, wherein the first
erodible material is embedded in a second material not admixed with
the compound (e.g., the drug) or the reagent. In other aspects, the
present disclosure provides methods of designing and methods of
making, such as three-dimensional printing, dosage forms configured
to provide desired release profiles.
BACKGROUND
[0003] The growing understanding of the mechanisms of drugs and
reagents involved with use, efficacy, and toxicity illustrates the
importance of precision delivery both in location and timing. To
achieve improved use, efficacy, and safety, certain drugs and
reagents, such as drug combinations, may require complex
administration schemes or release profiles to control release of
one or more drug or reagent components to achieve a desired
absorption, distribution, metabolism, and elimination profile.
However, the demands required to achieve consistent precision
delivery often run counter to ensuring proper use and patient
compliance via simplicity of administration, e.g., a once-daily
pill.
[0004] Three-dimensional (3D) printing enables precise placement of
materials on a substrate to form three-dimensional structures from
computer-generated designs. For example, in an application of 3D
printing for producing drug dosage forms, a negative mold was 3D
printed and subsequently used to form a shape of an erodible
material admixed with a drug by pouring the erodible material
admixed with the drug into the negative mold (WO2017010938). The
molded erodible material admixed with a drug was then manually
assembled into the final drug dosage form. However, such techniques
are limited, e.g., limited throughput, need for extra manufacturing
steps required when using a mold process, and limited drug dosage
form design capability/flexibility due to the molding process.
[0005] All references cited herein, including patent applications
and publications, are incorporated by reference in their
entirety.
BRIEF SUMMARY
[0006] The present disclosure provides, e.g., dosage forms
configured and formulated to provide a desired release profile, and
methods of designing and methods of making thereof. Although much
of the application discusses drug dosage forms, such as oral drug
dosage forms, one of ordinary skill in the art will readily
understand that this disclosure also pertains to and teaches other
dosage forms configured and formulated to provide a desired release
profile of, e.g., a compound, such an implant drug dosage form or a
dosage form comprising a reagent (reagent dosage form) configured
and formulated to provide a desired reagent release profile.
[0007] In one aspect, the present disclosure provides methods for
three-dimensional printing of a dosage form, such as a drug dosage
form (for example oral drug dosage form), formulated and configured
to provide a desired release profile, such as a desired drug
release profile, comprising: dispensing a first erodible material
admixed with a compound (e.g., a drug) and a second material not
admixed with the compound (e.g., the drug) to produce a
multi-layered structure comprising a plurality of layers of the
first erodible material, wherein the first erodible material is
embedded in the second material, wherein each layer of the first
erodible material has a pre-determined surface area, thickness, and
mass fraction, such as a drug mass fraction, wherein the
pre-determined surface area, thickness, and/or drug mass fraction
correlate with the desired release profile, and wherein upon
exposure to a bodily fluid, such as a gastrointestinal fluid, the
compound (e.g., drug) is released in accordance with the desired
release profile.
[0008] In some embodiments, the methods further comprise providing
the desired release profile, such as the desired rug release
profile, prior to the dispensing step.
[0009] In some embodiments, the methods further comprise creating a
virtual image of the dosage form prior to the dispensing step.
[0010] In some embodiments, the methods further comprise creating a
computer model that contains the pre-determined parameters prior to
the dispensing step.
[0011] In some embodiments, the methods further comprise feeding
the pre-determined parameters to the three-dimensional printer
prior to the dispensing step.
[0012] In some embodiments, the first erodible material admixed
with the compound (e.g., the drug) and the second material not
admixed with the compound (e.g., the drug) are dispensed
separately.
[0013] In some embodiments, the first erodible material admixed
with the compound (e.g., the drug) and the second material not
admixed with the compound (e.g., the drug) are dispensed
sequentially.
[0014] In some embodiments, the surface areas of the first erodible
material in at least two of the layers are different from each
other.
[0015] In some embodiments, the thicknesses of each of the
plurality of layers of the first erodible material are the
same.
[0016] In some embodiments, the thickness of at least two of the
layers of the first erodible materials are different from each
other.
[0017] In some embodiments, the mass fraction, such as the drug
mass fraction, in each of the plurality of layers of the first
erodible material are the same.
[0018] In some embodiments, the mass fractions, such as drug mass
fractions, in at least two of the layers of the first erodible
materials are different from each other.
[0019] In some embodiments, the second material is a second
erodible material.
[0020] In some embodiments, the first erodible material and the
second erodible material are different from each other. In some
embodiments, the first erodible material and the second erodible
material are the same.
[0021] In some embodiments, the second material is an insulating
material that is impermeable to the bodily fluid, such as
gastrointestinal fluid, wherein the insulating material forms a
barrier between the bodily fluid and at least a portion of the
multi-layered structure. In some embodiments, the methods further
comprise dispensing an insulating material that is impermeable to
the bodily fluid, such as gastrointestinal fluid, wherein the
insulating material forms a barrier between the bodily fluid and at
least a portion of the multi-layered structure.
[0022] In some embodiments, the first erodible material and the
second material are dispensed by different printing heads. In some
embodiments, the first erodible material, the second material, and
the insulating material are dispensed by different printing
heads.
[0023] In some embodiments, the three-dimensional printing is
carried out by fused deposition modeling (FDM). In some
embodiments, the FDM is a non-filament FDM. In some embodiments,
the FDM is a filament FDM. In some embodiments, the
three-dimensional printing is carried out by hot melt extrusion
coupled with a three-dimensional printing technique, such as
FDM.
[0024] In some embodiments, the first erodible material and the
second material have the same erosion rate.
[0025] In some embodiments, the thickness of each layer is no more
than about 0.2 mm.
[0026] In some embodiments, the methods further comprise dispensing
an intermediate material not admixed with the drug, wherein the
intermediate material forms an intermediate layer between two or
more layers of the first erodible material. In some embodiments,
the intermediate material is the same as the first erodible
material or the second material.
[0027] In some embodiments, the methods further comprise dispensing
an intermediate material not admixed with the drug, wherein the
intermediate material forms an intermediate layer between two or
more layers of the first erodible material. In some embodiments,
the intermediate material is the same as the first erodible
material.
[0028] In some embodiments, the compound (e.g., drug) is to be
released at an increasing rate. In some embodiments, the compound
(e.g., drug) is to be released at a decreasing rate. In some
embodiments, the compound (e.g., drug) is to be released at an
increasing rate followed by a decreasing rate, or vice versa. In
some embodiments, the compound (e.g., drug) is to be released in an
oscillating pattern, such as an alternating pattern.
[0029] In some embodiments, the dosage form, such as a drug dosage
form, further comprises a, e.g., second drug. In some embodiments,
e.g., the second drug is admixed with the first erodible
material.
[0030] In some embodiments, the methods further comprise dispensing
a third erodible material admixed with a, e.g., second drug,
wherein the multi-layered structure further comprises a plurality
of layers of the third erodible material, wherein the third
material is embedded in the second material. In some embodiments,
each layer of the third erodible material has a pre-determined
surface area, thickness, and mass fraction, such as drug mass
fraction, wherein the pre-determined surface area, thickness,
and/or mass fraction correlate with a second desired release
profile, and wherein upon exposure to the bodily fluid, such as
gastrointestinal fluid, the, e.g., second drug is released in
accordance with the second desired release profile. In some
embodiments, the third erodible material is the same as the first
erodible material.
[0031] In some embodiments, the erosion of the first erodible
material is pH dependent. In some embodiments, the erosion of the
third erodible material is pH dependent.
[0032] In some embodiments, the drug dosage form is an oral drug
dosage form. In some embodiments, the bodily fluid is
gastrointestinal fluid.
[0033] In another aspect, the present disclosure provides methods
of designing a dosage form, such as a drug dosage form, to provide
a desired release profile, such as a desired drug release profile,
wherein the dosage form comprises a multi-layered structure
comprising a plurality of layers of a first erodible material
admixed with a compound (e.g., a drug), wherein the first erodible
material is embedded in a second material not admixed with the
compound (e.g., the drug), the methods comprising: (a) selecting
the first erodible material and the second material for forming the
multi-layered structure; (b) obtaining an erosion rate of first
erodible material; and (c) determining the thickness, surface area,
and/or mass fraction, such as drug mass fraction, in each layer
based on the release rate of the compound (e.g., the drug) and the
desired release profile.
[0034] In some embodiments, the methods further comprise obtaining
the desired release profile, such as the desired drug release
profile.
[0035] In some embodiments, the methods further comprise dispensing
the first erodible material admixed with the compound (e.g., the
drug) and the second material not admixed with the compound (e.g.,
the drug) based on the determined thickness, surface area, and/or
mass fraction, such as drug mass fraction.
[0036] In some embodiments, the methods further comprise obtaining
a desired release profile, such as a desire drug release
profile.
[0037] In some embodiments, the multi-layered structure further
comprises a plurality of second layers of a third erodible material
admixed with a, e.g., second drug, and wherein the method further
comprises: determining the release rate of the, e.g., second drug
from the third erodible material; and determining the thickness,
surface area, and/or mass fraction, such as drug mass fraction, in
each second layer based on the release rate of the, e.g., second
drug and the desired release profile.
[0038] In some embodiments, the methods further comprise dispensing
the third erodible material admixed with the, e.g., second drug
based on the determined thickness, surface area, and/or mass
fraction, such as drug mass fraction.
[0039] In one aspect, the present disclosure provides methods for
three-dimensional ("3D) printing of a dosage form, such as a drug
dosage form, formulated and configured to provide a desired release
profile, such as a desired drug release profile, wherein the dosage
form comprises a multi-layered structure comprising a plurality of
layers of a first erodible material admixed with a compound (e.g.,
a drug), wherein the first erodible material is embedded in a
second material not admixed with the compound (e.g., the drug), the
method comprising: (a) determining the thickness, surface area,
and/or mass fraction, such as drug mass fraction, in each layer
based on the release rate of the compound (e.g., the drug) and the
desired release profile; and (b) dispensing the first erodible
material admixed with the compound (e.g., the drug) and the second
material not admixed with the compound (e.g., the drug) based on
the determined thickness, surface area, and/or mass fraction, such
as drug mass fraction.
[0040] In some embodiments, the thickness (H) of the layer of the
first erodible material is determined based on the erosion rate of
the first erodible material admixed with the drug (v.sub.E) and the
time interval between two different datapoints on the drug release
profile (t.sub.E), wherein
H=t.sub.E*v.sub.E.
[0041] In some embodiments, the mass fraction (m.sub.F), such as
drug mass fraction, in the first erodible material is determined
based on the percentage, in decimal form, of the total compound
(e.g., drug) in the dosage form that is in the layer of the
erodible material admixed with the compound (e.g., drug) (% L), the
total mass of the compound (e.g., the drug) in the drug dosage form
(m.sub.DTot), the density of the erodible material admixed with the
compound (e.g., the drug) (.rho.), and the volume (V.sub.vol) of
the layer of the erodible material, wherein
m F = % L * m DT ot .rho. * V vol . ##EQU00001##
[0042] In some embodiments, the total surface area (S.sub.t) of the
layers of the first erodible material that are exposed to the
bodily fluid, such as gastrointestinal fluid, at the same time is
determined by the mass fraction (m.sub.F), such as drug mass
fraction, and the thickness of the layers of first erodible
material, wherein
S t = % L * m DT ot .rho. * H * m F . ##EQU00002##
[0043] In some embodiments, the methods further comprise: (i)
determining the release profile, such as the drug release profile,
of the produced dosage form; (ii) comparing the release profile of
the dosage form with the desired release profile; and (iii)
adjusting the design of the dosage form by altering one or more of:
the first erodible material, the second material, the surface area
of the one or more of the layers of the first erodible material,
the thickness of one or more layers of the first erodible material,
and the mass fraction of the compound (e.g., the drug) in one or
more layers of the first erodible material.
[0044] In some embodiments, there is provided a method for
three-dimensional ("3D") printing of an oral drug dosage form
formulated and configured to provide a desired drug release
profile, wherein the drug dosage form comprises a multi-layered
structure comprising a plurality of layers of a first erodible
material admixed with a drug having a pre-determined drug mass
faction (m.sub.F), wherein the first erodible material is embedded
in a second material not admixed with the drug, the method
comprising: (a) dividing the desired drug release profile into a
plurality of time intervals (t.sub.n), each time interval
corresponding to a layer in the multi-layered structure; (b)
calculating the percentage of drugs to be released during each time
interval (%.sub.L); (c) calculating the thickness of each layer
(H.sub.n) of the multi-layered structure based on the erosion rate
of the first erodible material(V), wherein H.sub.n=t.sub.n*V; (d)
calculating the surface area of each layer based on %.sub.L,
H.sub.n, m.sub.F, total amount of drug in the oral drug dosage form
(m.sub.DTot), and the density of the first erodible material
(.rho.), wherein:
S n = % L * m DT ot .rho. * Hn * m F ##EQU00003##
(e) dispensing the first erodible material admixed with the drug
based on the determined H.sub.n and S.sub.n for each layer, thereby
printing the multi-layered structure; and (f) before, after, or
during step (e), dispensing the second material not admixed with
the drug.
[0045] In some embodiments, the 3D printing method further
comprises dispensing a top erodible material not admixed with the
drug on top of the multi-layered structure to form a top layer,
wherein the surface area of the top layer is the same or larger
than the first layer of the multi-layered structure immediately
underneath the top layer. In some embodiments, the thickness of the
top layer is determined based on the delay time needed for the drug
release from the multi-layered structure. In some embodiments, the
top erodible material is the same as the first erodible material.
In some embodiments, the top erodible material is different from
the first erodible material.
[0046] In some embodiments according any one of the 3D printing
methods described above, the second material is erodible, and can
have the same or a different erosion rate as that of the first
erodible material. In other embodiments, the second material is an
insulating material that is impermeable to bodily fluid, wherein
the insulating material forms a barrier between the bodily fluid
and at least a portion of the multi-layered structure.
[0047] In some embodiments according to any one of the 3D printing
methods described above, further comprising dispensing an
insulating material that is impermeable to bodily fluid, wherein
the insulating material forms a barrier between the bodily fluid
and at least a portion of the multi-layered structure.
[0048] In some embodiments according to any one of the 3D printing
methods described above, further comprising dispensing an
intermediate material not admixed with the drug, wherein the
intermediate material forms one or more intermediate layers between
two or more layers of the first erodible material. In some
embodiments, the intermediate material is the same as the first
erodible material. In some embodiments, the intermediate layer is
different from the first erodible material.
[0049] In some embodiments according to any of the 3D printing
methods described above, wherein the three-dimensional printing is
carried out by fused deposition modeling (FDM), such as
non-filament FDM. In some embodiments, the first erodible material
and the second material are printed by different printing heads. In
some embodiments, the first erodible material and the top erodible
material are printed by different printing heads. In some
embodiments, the first erodible material, the second erodible
material (if any), and the insulating material are printed by a
different printing heads.
[0050] The method of any one of the 3D printing methods described
above, further comprising: i) determining the drug release profile
of the oral drug dosage form produced by the method of any one of
the 3D printing methods described above; ii) comparing the drug
release profile of the oral drug dosage form with the desired drug
release profile; iii) adjusting one or more parameters selected
from: the first erodible material, the second material, the surface
area of the one or more of the layers of the first erodible
material, the thickness of one or more layers of the first erodible
material, and the mass fraction of the drug in one or more layers
of the first erodible material; and iv) three-dimensional printing
of a second oral drug dosage form based on the adjusted
parameters.
[0051] In some embodiments according any one of the 3D printing
method described above, wherein the release profile of the oral
drug dosage form or second drug oral dosage form is equivalent to
the desired release profile based on Chow's method or similarity
factor calculation method.
[0052] In some embodiments according to any one of the 3D printing
method described above, the method further comprises creating a
virtual image of the drug dosage form prior to the dispending
steps, creating a computer model that contains the pre-determined
parameters prior to the dispensing step, and/or feeding the
pre-determined parameters to the three-dimensional printer prior to
the dispensing step.
[0053] In some embodiments according to any one of the 3D printing
method described above, the surface area of each of the plurality
of the layers of the first erodible material in the multi-layered
structure decreases sequentially from the surface to the interior
of the oral dosage form, wherein when the oral dosage form is
exposed to a bodily fluid the plurality of layers are exposed to
the bodily fluid in a sequential pattern, with the layer with the
largest surface area exposed to the bodily fluid first.
[0054] In some embodiments according to any one of the 3D printing
method described above, the oral drug dosage form comprises two or
more multi-layered structures.
[0055] In some embodiments, there is provided a method for
three-dimensional ("3D") printing of an oral drug dosage form
formulated and configured to provide a first desired drug release
profile and a second desired drug release profile, wherein the drug
dosage form comprises a first multi-layered structure comprising a
plurality of layers of a first erodible material admixed with a
drug having a pre-determined drug mass faction (m.sub.F), wherein
the first erodible material is embedded in a second material not
admixed with a first drug, and a second multi-layered structure
comprising a plurality of layers of a third erodible material
admixed with a second drug having a pre-determined drug mass
faction, wherein the third erodible material is embedded in a
fourth material not admixed with the drug, the method comprising:
(a) dividing each of the desired drug release profile into a
plurality of time intervals (t.sub.n), each time interval
corresponding to a layer in a corresponding multi-layered
structure; (b) calculating the percentage of drugs to be released
during each time interval (%.sub.L); (c) calculating the thickness
of each layer (H.sub.n) of the multi-layered structures based on
the erosion rate of the first erodible material or third erodible
material (V), wherein H.sub.n=t.sub.n*V; (d) calculating the
surface area of each layer based on % L, H.sub.n, m.sub.F, total
amount of drug in the oral drug dosage form (m.sub.DTot), and the
density of the first or first erodible material (.rho.),
wherein:
S n = % L * m DT ot .rho. * Hn * m F ##EQU00004##
(e) dispensing the first erodible material admixed with the first
drug and third erodible material admixed with the second drug based
on the determined H.sub.n and S.sub.n for each layer, thereby
printing the two multi-layered structures; and (f) before, after,
or during step (e), dispensing the second material and fourth
material not admixed with the drug. In some embodiments, the first
erodible material and the third erodible material are the same. In
some embodiments, the second and fourth materials are the same. In
some embodiments, the first drug and the second drug are the same.
In some embodiments, the first drug and the second drug are
different.
[0056] In another aspect, the present disclosure provides dosage
forms, such as oral dosage forms, produced according to any one of
the methods described herein. In some embodiments, the dosage form,
such as drug dosage form, further comprises an enteric coating.
[0057] These and other aspects and advantages of the present
disclosure will become apparent from the subsequent detailed
description and the appended claims. It is to be understood that
one, some, or all of the properties of the various embodiments
described herein may be combined to form other embodiments of the
present disclosure.
BRIEF DESCRIPTION OF THE DRAWINGS
[0058] FIG. 1 shows an exemplary schematic 100 for designing a drug
dosage form 160 formulated and configured to provide a desired drug
release profile 105.
[0059] FIGS. 2A-2C show exemplary drug dosage forms 200, 240, 265
formulated and configured to provide a desired drug release
profile. FIG. 2A shows a cross-sectional view of the exemplary
dosage form 200. FIG. 2B and FIG. 2C show external views of
exemplary drug dosage forms 240, 265 having the cross-section
illustrated in FIG. 2A.
[0060] FIGS. 3A-3B show an exemplary drug dosage form 300. FIG. 3A
shows an external view of the exemplary drug dosage form 300 with
translucently illustrated components to illustrate internal
features of the drug dosage form. FIG. 3B shows a cross-sectional
view of the exemplary drug dosage form 300.
[0061] FIGS. 4A-4C show exemplary drug dosage forms 400, 425
formulated and configured to provide a desired drug release
profile. FIG. 4A shows a cross-sectional view of the exemplary
dosage form 400. FIG. 4B shows a cross-sectional view of the
exemplary dosage form 425. FIG. 4C shows an external view of the
exemplary drug dosage form 425 having the cross-section illustrated
in FIG. 4B.
[0062] FIG. 5 shows a cross-sectional view of an exemplary drug
dosage form 500 formulated and configured to provide a desired drug
release profile.
[0063] FIG. 6 shows a cross-sectional view of an exemplary drug
dosage form 600 formulated and configured to provide a desired drug
release profile.
[0064] FIG. 7 shows a schematic of techniques for modulating a
layer of an erodible material admixed with a drug.
[0065] FIGS. 8A-8B show an exemplary drug dosage form 800. FIG. 8A
shows an external view of the exemplary drug dosage form 800 with
translucently illustrated components to illustrate internal
features of the drug dosage form. FIG. 8B shows a cross-sectional
view of the exemplary dosage form 800.
[0066] FIGS. 9A-9B show an exemplary drug dosage form 900. FIG. 9A
shows an external view of the exemplary drug dosage form 900 with
translucently illustrated components to illustrate internal
features of the drug dosage form. FIG. 9B shows a cross-sectional
view of the exemplary dosage form 900.
[0067] FIG. 10 shows a graph of a desired drug release profile
(drug release (%) versus time (hour)).
DETAILED DESCRIPTION
[0068] The present application provides methods of making, e.g.,
three-dimensional printing of drug dosage forms comprising a
multi-layered structure comprising a plurality of layers of a first
erodible material admixed with a drug, wherein the erosion of the
first erodible material admixed with the drug correlates with
release rate of the drug from the drug dosage form. Using the
methods disclosed herein, drug dosage forms, such as oral drug
dosage forms or implant drug dosage forms, may provide any desired
drug release profile based on controlling various parameters, e.g.,
thickness of a layer of a first erodible material admixed with a
drug, surface area of the layer of the first erodible material, and
drug mass fraction of the layer of the first erodible material.
Drug dosage forms with a desired drug release profile of a drug, or
multiple drugs, may be readily designed and printed using
three-dimensional printing techniques. Such drug dosage forms may
be designed to, e.g., improve treatment efficacy, reduce toxicity,
and increase patient compliance.
[0069] Methods of calibrating, such as adjusting, the dosage forms
based on a dissolution profile, such as an in vitro dissolution
profile, to improve similarity of an experimentally determined
release profile with a desired release profile are also provided
herein.
[0070] Although much of the application discusses drug dosage
forms, such as oral drug dosage forms or implant drug dosage forms,
one of ordinary skill in the art will readily understand that this
disclosure also applies and pertains to other dosage forms
configured and formulated to provide a desired release profile of
any compound, such as a dosage form comprising a reagent (i.e.,
reagent dosage form) configured and formulated to provide a desired
reagent release profile. Thus, the present disclosure provides, in
some aspects, dosage forms, such as drug dosage forms or reagent
dosage forms, configured to provide a desired release profile of a
compound (e.g., a drug) or reagent, as well as methods of designing
and methods of 3D printing thereof, wherein the dosage forms
comprise a multi-layered structure comprising a plurality of layers
of a first erodible material admixed with the compound (e.g., the
drug) or reagent, wherein the first erodible material is embedded
in a second material not admixed with the compound (e.g., the drug)
or reagent.
Definitions
[0071] The term "comprises" and grammatical equivalents thereof are
used herein to mean that other components, ingredients, steps, etc.
are optionally present. For example, an article "comprising"
components A, B, and C can consist of (i.e., contain only)
components A, B, and C, or can contain not only components A, B,
and C but also one or more other components. It is understood that
"comprises" and grammatical equivalents thereof include "consisting
of" or "consisting essentially of."
[0072] Where a range of value is provided, it is understood that
each intervening value, to the tenth of the unit of the lower limit
unless the context clearly dictate otherwise, between the upper and
lower limit of that range and any other stated or intervening value
in that stated range, is encompassed within the disclosure, subject
to any specifically excluded limit in the stated range. Where the
stated range includes one or both of the limits, ranges excluding
either or both of those included limits are also included in the
disclosure.
[0073] Reference to "about" a value or parameter herein includes
(and describes) variations that are directed to that value or
parameter per se. For example, description referring to "about X"
includes description of "X."
[0074] As used herein and in the appended claims, the singular
forms "a," "or," and "the" include plural referents unless the
context clearly dictates otherwise.
[0075] As used herein, the term "individual" refers to a mammal and
includes, but is not limited to, human, bovine, horse, feline,
canine, rodent, or primate. In some embodiments, the individual is
human.
[0076] The term "layer" described herein in the context of a
multi-layered structure refers to one of the plurality of layers in
the multi-layer structure, the thickness of which is determined or
pre-determined during the design of the dosage forms. The thickness
of a layer in a multi-layered structure may or may not have the
same thickness as that of the unit deposition layer during a
layer-by-layer 3D printing process.
[0077] In the embodiments herein, use of a specific mathematical
equation is not intended to limit the determination of a
characteristic of the drug dosage form, or materials thereof, and
it is recognized that there are other means, e.g., mathematical
equations, or variables for obtaining characteristics of drug
dosage forms, or materials thereof, useful for designing a drug
dosage form with a desired release profile.
Methods of Designing a Dosage Form
[0078] The present disclosure provides methods of designing a
dosage form, such as an oral drug dosage form, an implant dosage
form, or a reagent dosage form, to provide a desired release
profile of a compound (e.g., a drug), wherein the dosage form
comprises a multi-layered structure comprising a plurality of
layers of a first erodible material admixed with the compound
(e.g., the drug), wherein the first erodible material is embedded
in a second material not admixed with the compound (e.g., the
drug).
[0079] As illustrated in the schematic 100 of FIG. 1, there are
multiple steps and routes for designing a dosage form, such as an
oral drug dosage form, to provide a desired release profile. The
methods disclosed herein may be guided by possible design
restrictions, e.g., pre-selection of a material such as a first
erodible material admixed with a drug 130 or pre-selection of
thickness of a layer of a first erodible material admixed with a
drug 125 (FIG. 1). In view of the disclosure herein, one of
ordinary skill in the art will understand the relationships between
the steps and, under a set of circumstances, a method or methods of
designing a drug dosage form to provide a desired drug release
profile of a drug.
[0080] In some embodiments, the method of designing a dosage form,
such as an oral drug dosage form, to provide a desired release
profile, wherein the dosage form comprises a multi-layered
structure comprising a plurality of layers of a first erodible
material admixed with a compound (e.g., a drug), and wherein the
first erodible material is embedded in a second material not
admixed with the drug, comprises: (a) selecting the first erodible
material and the second material for forming the multi-layered
structure; (b) obtaining an erosion rate of first erodible
material; and (c) determining the thickness, surface area, and/or
mass fraction, such as drug mass fraction, in each layer based on
the release rate of the compound (e.g., the drug) and the desired
release profile. In some embodiments, the multi-layered structure
further comprises a plurality of second layers of a third erodible
material admixed with a, e.g., second drug, wherein the method
further comprises: determining the drug release rate of the second
drug from the third erodible material; and determining the
thickness, surface area, and/or drug mass fraction in each second
layer based on the release rate of the second drug and the desired
drug release profile.
[0081] As shown in FIG. 1, in some embodiments, the method of
designing a drug dosage form to provide a desired drug release
profile of a drug comprises obtaining, e.g., selecting, a desired
drug release profile of the drug 105. In some embodiments, the
method comprises dividing the desired drug release profile into
time intervals 110 (e.g., based on the number of layers of a first
erodible material admixed with the drug intended for the drug
dosage form) and then determining the fraction of total drug
released 115 during said time interval. In some embodiments, the
method comprises determining an erosion rate of the first erodible
material admixed with the drug 120 and the thickness of the layer
of the first erodible admixed with the drug 125 using said time
interval and the selected material for the first erodible material
admixed with the drug 130. In some embodiments, the method
comprises determining a surface area of the layer of first erodible
material admixed with the drug 140 and the drug mass fraction of
the layer of the first erodible material admixed with the drug 135
using the fraction of total drug released during said time interval
and the thickness of the layer of the first erodible material
admixed with the drug. In some embodiments, the method further
comprises determining the thickness and surface area of an
intermediate layer 145. In some embodiments, the method further
comprises selecting an insulating material 150.
[0082] In some embodiments, the methods described herein may be
useful for designing a drug dosage form comprising a multi-layered
structure comprising a plurality of layers of a first erodible
material admixed with a drug, wherein the first erodible material
is embedded in a second material, wherein the plurality of layers
comprises a first layer and a second layer, wherein the first layer
will be exposed to a bodily fluid prior to the second layer, and
wherein the surface area of the first layer is larger than the
second layer (e.g., FIG. 2A). In some embodiments, the second layer
is positioned so that once the first layer has eroded, the complete
surface area of the second layer will be exposed to the bodily
fluid (e.g., FIG. 2A, 220). In some embodiments, the drug dosage
form may comprise two or more plurality of layers of a first
erodible material admixed with a drug, wherein each of the
plurality of layers comprises a first layer and a second layer,
wherein the first layer will be exposed to a bodily fluid prior to
the second layer, and wherein the surface area of the first layer
is larger than the second layer (e.g., FIG. 4A).
[0083] In some embodiments, the methods of designing a drug dosage
form described herein may be performed, in whole or in part, on a
computer system. In some embodiments, the computer system comprises
a user interface. In some embodiments, the method comprises
inputting one or more parameters of the drug dosage form into the
computer system. In some embodiments, the computer system is used
to calculate the parameters of the drug dosage form to provide a
desired drug release profile. In some embodiments, the computer
system comprises three-dimensional drawing software. In some
embodiments, the computer system is used to create a
three-dimensional drawing of a drug dosage form based on the
pre-determined parameters of the drug dosage form. In some
embodiments, the computer system comprises slicing software. In
some embodiments, the computer system is used to convert a
three-dimensional drawing of a drug dosage form into
three-dimensional printing code, e.g., G code. In some embodiments,
the computer system executes the three-dimensional printing code,
thereby printing a drug dosage form.
A. Desired Release Profile
[0084] The methods disclosed herein of designing a dosage form,
such as an oral drug dosage form, to provide a desired release
profile of a compound (e.g., a drug) may be used to design the
dosage form with any desired release profile. In some embodiments,
the desired drug release profile comprises the fraction or
percentage of total (i.e., cumulative) drug to be released from the
drug dosage form by time points following administration or
subsequent commencement of drug release from the drug dosage form
(e.g., for enteric-coated oral drug dosage forms). In some
embodiments, the desired drug release profile comprises the actual
amount or concentration of a drug to be released from a release
medium.
[0085] In some embodiments, the method of designing a drug dosage
form to provide a desired drug release profile, wherein the drug
dosage form comprises a multi-layered structure comprising a
plurality of layers of a first erodible material admixed with a
drug, wherein the first erodible material is embedded in a second
material not admixed with the drug, comprises obtaining or
selecting the desired drug release profile of the drug dosage form.
In some embodiments, the desired drug release profile is
pre-determined.
[0086] In some embodiments, the drug dosage form comprises two or
more drugs, such as about any of 5 or more, 10 or more, 20 or more,
30 or more, or 50 or more, wherein each drug has a desired drug
release profile. In some embodiments, the drug dosage form
comprises two or more drugs, wherein at least two drugs have a
different desired drug release profile.
[0087] In some embodiments, the drug will start to be released from
a drug dosage form once a layer of a first erodible material
comprising the drug is exposed to a solution, such as bodily fluid,
e.g., gastrointestinal (GI) fluid. In some embodiments, the desired
drug release profile of a drug dosage form is for the period of
time from oral administration to complete release of a drug
contained in the drug dosage form. In some embodiments, the desired
drug release profile comprises an initial delay period prior to a
desired drug release period, wherein the initial delay period is a
patient-specific period of time or an estimated period of time,
e.g., due to use of an enteric-coated oral dosage form.
[0088] In some embodiments, the desired drug release profile of a
drug dosage form comprises a zero-order release profile, a
first-order release profile, a delayed release profile, a pulsed
release profile, an iterative pulsed release profile, an immediate
release profile, a sustained release profile, or a combination
thereof.
[0089] In some embodiments, the total time of a desired release
profile of a dosage form is about 1 hour to about 12 months. In
some embodiments, the total time of a desired release profile of a
dosage form is greater than about any of 1 hour, 6 hours, 12 hours,
24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9
days, 10 days, 11 days, 12 days, 20 days, 1 month, 2 months, 3
months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months,
10 months, 11 months, or 12 months. In some embodiments, the total
time of a desired release profile of a dosage form is about any of
1 hour, 6 hours, 12 hours, 24 hours, 2 days, 3 days, 4 days, 5
days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 20
days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7
months, 8 months, 9 months, 10 months, 11 months, or 12 months.
[0090] In some embodiments, the total time of a desired drug
release profile of a drug dosage form is about 1 hour to about 72
hours, such as any of about 1 hour to about 6 hours, about 1 hour
to about 12 hours, about 1 hour to about 18 hours, about 1 hour to
about 24 hours, about 1 hour to about 30 hours, about 1 hour to
about 36 hours, about 1 hour to about 42 hours, about 1 hour to
about 48 hours, about 1 hour to about 54 hours, about 1 hour to
about 60 hours, or about 1 hour to about 66 hours. In some
embodiments, the total time of a desired drug release profile of a
drug dosage form is about any of 1 hour, 2 hours, 3 hours, 6 hours,
8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20
hours, 22 hours, 24 hours, 26 hours, 28 hours, 30 hours, 32 hours,
34 hours, 36 hours, 40 hours, 42 hours, 44 hours, 46 hours, 48
hours, 50 hours, 52 hours, 54 hours, 56 hours, 58 hours, 60 hours,
62 hours, 64 hours, 66 hours, 68 hours, 70 hours, or 72 hours. In
some embodiments, the total time of a desired drug release profile
of a drug dosage form is greater than or about 6 hours, greater
than or about 12 hours, greater than or about 18 hours, greater
than or about 24 hours, greater than or about 30 hours, greater
than or about 36 hours, greater than or about 42 hours, greater
than or about 48 hours, greater than or about 54 hours, greater
than or about 60 hours, greater than or about 66 hours, or greater
than or about 72 hours. In some embodiments, the total time of a
desired drug release profile of a drug dosage form is less than or
about 6 hours, less than or about 12 hours, less than or about 18
hours, less than or about 24 hours, less than or about 30 hours,
less than or about 36 hours, less than or about 42 hours, less than
or about 48 hours, less than or about 54 hours, less than or about
60 hours, less than or about 66 hours, or less than or about 72
hours.
[0091] As shown in the schematic 100 of FIG. 1, a desired drug
release profile 105 may provide information regarding one or more
time intervals (t.sub.E) of the desired drug release profile 110
and a fraction or percentage of total drug released over each time
interval 115.
[0092] In some embodiments, the method of designing a drug dosage
form to provide a desired drug release profile of a drug comprises:
obtaining or selecting one or more time points forming one or more
time intervals over at least a portion of time of the desired drug
release profile; and subsequently obtaining the corresponding
fraction of the total drug released from the drug dosage form
during each time interval.
[0093] The time points used in the methods disclosed herein may be
of any suitable size, e.g., seconds, minutes, and/or hours. In some
embodiments, the one or more time points over the time of the
desired drug release profile are based on a uniform time intervals
(e.g., at 1, 2, and 3 hours post-administration or commencement of
drug release), a non-uniform time interval (e.g., at 1, 2, 4, and 8
hours post-administration or commencement of drug release), or a
combination thereof. In some embodiments, the time points over the
time of the desired drug release profile are at about any of 5
minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45
minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes, 240
minutes, 300 minutes, or 360 minutes. In some embodiments, the time
points over the time of the desired drug release profile are at
about any of 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90
minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10
hours, 12 hours, or 24 hours.
[0094] In some embodiments, the number of time points, and thus
time intervals, is based on the number of layers of a first
erodible material admixed with a drug in a drug dosage form. In
some embodiments, the number of time points or time intervals is
between about 1 to about 100, such as between any of about 1 to
about 5, about 5 to about 10, about 10 to about 15, about 5 to
about 20, about 10 to about 20, about 15 to about 20, about 5 to
about 50, or about 10 to about 100. In some embodiments, the number
of time points or time intervals is about any of 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35,
40, 45, 50, 75, or 100.
[0095] In some embodiments, the method of designing a drug dosage
form to provide a desired drug release profile of a drug comprises:
obtaining or selecting one or more fractions of the total drug
released from the drug dosage form during the desired drug release
profile; and subsequently obtaining the corresponding time points
and/or time intervals of the desired drug release profile for each
fraction of the total drug released.
[0096] The fractions or percentages of the one or more fractions or
percentages of the total drug released used in the methods
disclosed herein may be of any suitable size, e.g., tenth or
integer values. In some embodiments, the fractions or percentages
of the total drug released are based on a uniform fraction or
percentage (e.g., all percentages being a single value),
non-uniform fractions or percentages (e.g., including increasing
percentage values), or a combination thereof.
[0097] In some embodiments, the number of the one or more fractions
or percentages is based on the number of layers of a first erodible
material admixed with a drug in a drug dosage form. In some
embodiments, the number of fractions or percentages of the one or
more fractions or percentages is between about 1 to about 100, such
as between any of about 1 to about 5, about 5 to about 10, about 10
to about 15, about 5 to about 20, about 10 to about 20, about 15 to
about 20, about 5 to about 500, or about 10 to about 100. In some
embodiments, the number of fractions or percentages of the one or
more fractions or percentages is about any of 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40,
45, 50, 75, or 100.
[0098] In some embodiments, the method of designing a drug dosage
form to provide a desired drug release profile comprises evaluating
an in vitro dissolution rate of the drug dosage form. In some
embodiments, the desired drug release profile of a drug dosage form
is similar, e.g., equivalent or bioequivalent, to the in vitro
dissolution rate of the drug dosage form. In some embodiments, the
desired drug release profile of a drug dosage form is similar,
e.g., equivalent or bioequivalent, to the in vivo drug release
profile of the drug dosage form. In some embodiments, the in vivo
drug release profile of the drug dosage form is based on evaluation
of the in vitro dissolution rate of the drug dosage form. In some
embodiments, the desired drug release profile of a drug dosage form
is similar, e.g., equivalent or bioequivalent, to a reference drug
release profile. Methods for in vitro dissolution testing and
determining dissolution similarity are known in the art and the
U.S. Food and Drug Administration has provided industry guidance on
such methods (see Guidance for Industry; Dissolution Testing of
Immediate Release Solid Oral Dosage Forms; CDER; August 1997).
[0099] Methods for in vitro dissolution testing include a
logarithmic curve method, probability unit method, exponential
model method, Weibull method, and Gompertz method. Statistical
analysis methods for determining dissolution similarity of two
dissolution profiles, e.g., an experimentally determined
dissolution profile and a desired drug release profile, comprise
regression analysis, ANOVA, similarity factor method, varying
factor method, Splitpolt method, and Chow's method. In some
embodiments, the dissolution similarity is evaluated using the
similarity factor. In some embodiments, the dissolution similarity
is evaluated using Chow's method.
B. First Erodible Material Admixed with a Compound
[0100] The disclosure provides methods of designing a dosage form,
such as an oral drug dosage form, comprising a multi-layered
structure comprising a plurality of layers of a first erodible
material admixed with a compound, such as a drug or a reagent,
wherein the dosage form provides a desired release profile of the
compound, such as a drug or a reagent. In some embodiments, the
erosion of a layer of a first erodible material admixed with a drug
correlates with the release rate of the drug from a drug dosage
form. In some embodiments, designing a drug dosage form formulated
and configured to provide a desired drug release profile comprises
controlling various parameters of a layer of a first erodible
material admixed with a drug, e.g., the first erodible material
(which has characteristics, such as an erosion rate), thickness of
the layer of the first erodible material admixed with the drug, the
surface area of the layer of the first erodible material admixed
with the drug, and drug mass fraction of the layer of the first
erodible material admixed with the drug.
[0101] As shown in the schematic 100 of FIG. 1, a relationship
exists between the time interval (t.sub.E) established for the
erosion of a layer of a first erodible material admixed with a drug
110, the erosion rate of the layer of the erodible material admixed
with the drug 120, and thickness of the layer of the erodible
material admixed with the drug 125. In some embodiments, the
relationship may be expressed using Formula I:
V E = H t E , Formula I , ##EQU00005##
[0102] wherein v.sub.E is the erosion rate of a layer of an
erodible material, such as a layer of a first erodible material
admixed with a drug, H is the thickness of the layer of the
erodible material, as measured substantially in line with the
direction of erosion from a surface that will first be exposed to a
dissolution medium, and t.sub.E is the time interval for erosion of
the layer of the erodible material. As illustrated in the schematic
100 of FIG. 1, designing a drug dosage form to provide a desired
drug release profile of a drug may comprise different routes for
establishing a first erodible material admixed with a drug (which
has an erosion rate) 120, 130 and thickness of the layer of the
first erodible material admixed with the drug 125.
[0103] In some embodiments, the method of designing a drug dosage
form to provide a desired drug release profile comprises selecting
a first erodible material admixed with a drug based on a
hypothetical erosion rate, or range of suitable hypothetical
erosion rates (such as determined based on characteristics of the
size of the drug dosage form), of a layer of the first erodible
material admixed with the drug. In some embodiments, the thickness
of an erodible material admixed with a drug is based on the erosion
rate of the selected first erodible material admixed with the
drug.
[0104] In some embodiments, the method of designing a drug dosage
form to provide a desired drug release profile comprises selecting
a first erodible material admixed with a drug based on a
hypothetical thickness, or range of suitable hypothetical
thicknesses (such as a pre-determined thickness or range of
thicknesses), of a layer of the first erodible material admixed
with the drug. In some embodiments, the thickness of an erodible
material admixed with a drug is based on the erosion rate of the
selected first erodible material admixed with the drug.
[0105] In some embodiments, the method of designing a drug dosage
form to provide a desired drug release profile comprises
determining a thickness of a layer of a first material admixed with
a drug based on pre-determination of the first material admixed
with the drug, wherein the first material admixed with the drug has
an erosion rate.
[0106] In some embodiments, the method of designing a drug dosage
form to provide a desired drug release profile comprises adjusting
the time interval for erosion of a layer of a first erodible
material admixed with a drug based on the erosion rate of the first
erodible material admixed with the drug and/or thickness of the
layer of the first erodible material admixed with the drug.
i. First Erodible Material
[0107] The disclosure provides methods of designing a dosage form,
such as an oral drug dosage form, comprising a multi-layered
structure comprising a plurality of layers of a first erodible
material admixed with a compound (e.g., a drug). In some
embodiments, the method of designing a drug dosage form to provide
a desired drug release profile comprises selecting a first erodible
material admixed with a drug. In some embodiments, the first
erodible material admixed with a drug is pre-determined.
[0108] In some embodiments, the erodible material comprises a
thermoplastic material. In some embodiments, the erodible material
is a thermoplastic material. In some embodiments, the erodible
material is edible (i.e., suitable for consumption by an
individual). In some embodiments, the erodible material is
biocompatible (e.g., suitable for use in an implant). In some
embodiments, the thermoplastic material is selected from the group
consisting of a hydrophilic polymer, a hydrophobic polymer, a
swellable polymer, a non-swellable polymer, a porous polymer, a
non-porous polymer, an erodible polymer (such as a dissolvable
polymer), a pH sensitive polymer, a natural polymer (such as
shellac), a wax-like material, and a combination thereof. In some
embodiments, the thermoplastic material is selected from the group
consisting of polyvinyl caprolactam-polyvinyl acetate-polyethylene
glycol graft copolymer 57/30/13,
polyvinylpyrrolidone-co-vinyl-acetate (PVP-VA),
polyvinylpyrrolidone-polyvinyl acetate copolymer (PVP-VA) 60/40,
polyvinylpyrrolidone (PVP), polyvinyl acetate (PVAc) and
polyvinylpyrrolidone (PVP) 80/20, vinylpyrrolidone-vinyl acetate
copolymer (VA64), polyethylene glycol-polyvinyl alcohol graft
copolymer 25/75, kollicoat IR-polyvinyl alcohol 60/40, polyvinyl
alcohol (PVA or PV-OH), poly(vinyl acetate) (PVAc), an (optionally
alkyl-, methyl-, or ethyl-) acrylate, a methacrylate copolymer, an
ethacrylate copolymer, poly(butyl
methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl
methacrylate) 1:2:1,
poly(dimethylaminoethylmethacrylate-co-methacrylic esters),
poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl
methacrylate chloride), poly(methyl acrylate-co-methyl
methacrylate-co-methacrylic acid) 7:3:1, poly(methacrylic
acid-co-methylmethacrylate) 1:2, poly(methacylic acid-co-ethyl
acrylate) 1:1, poly(methacylic acid-co-methyl methacrylate) 1:1,
poly(ethylene oxide) (PEO), poly(ethylene glycol) (PEG),
hyperbranched polyesteramide, hydroxypropyl methylcellulose
phthalate, hypromellose phthalate, hydroxypropyl methylcellulose or
hypromellose (HMPC), hydroxypropyl methylcellulose acetate
succinate or hypromellose acetate succinate (HPMCAS),
poly(lactide-co-glycolide) (PLGA), carbomer, poly(ethylene-co-vinyl
acetate), ethylene-vinyl acetate copolymer, polyethylene (PE), and
polycaprolactone (PCL), a cellulose or cellulose derivative,
hydroxyl propyl cellulose (HPC), polyoxyl 40 hydrogenerated castor
oil, methyl cellulose (MC), ethyl cellulose (EC), poloxamer,
hydroxypropyl methylcellulose phthalate (HPMCP), poloxamer,
hydrogenated castor and soybean oil, glyceryl palmitostearate,
carnauba wax, polylactic acid (PLA), polyglycolic acid (PGA),
cellulose acetate butyrate (CAB), colloidal silicon dioxide, a
saccharide, glucose, polyvinyl acetate phthalate (PVAP), a wax,
beeswax, hydrogel, gelatin, hydrogenated vegetable oil, polyvinyl
acetal diethyl aminolactate (AEA), paraffin, shellac, sodium
alginate, cellulose acetate phthalate (CAP), fatty oil, arabic gum,
xanthan gum, glyceryl monostearate, octadecanoic acid, and a
combination thereof.
[0109] In some embodiments, the erodible material comprises a
non-thermoplastic material. In some embodiments, the erodible
material is a non-thermoplastic material. In some embodiments, the
non-thermoplastic material is selected from the group consisting of
starch, pregelatinized starch, sodium starch glycolate (CMS-Na),
sucrose, dextrin, lactose, microcrystalline cellulose (MCC),
mannitol, magnesium stearate (MS), powdered silica gel, sodium
alginate, titanium dioxide, glycerin, syrup, lecithin, soybean oil,
tea oil, ethanol, propylene glycol, glycerol, Tween, animal fats,
silicone oils, cacao butter, fatty acid glycerides, vaseline,
chitosan, cetyl alcohol, stearyl alcohol, and a combination
thereof.
[0110] In some embodiments, the erodible material comprises a
plasticizer. In some embodiments, the plasticizer comprises a block
copolymer of polyoxyethylene-polyoxypropylene, vitamin e
polyethylene glycol succinate, hydroxystearate, polyethylene glycol
(such as PEG400), macrogol cetostearyl ether 12, polyoxyl 20
cetostearyl ether, polysorbate 20, polysorbate 60, polysorbate 80,
acetin, acetylated triethyl citrate, tributyl citrate, tributyl
o-acetylcitrate, triethyl citrate, polyoxyl 15 hydroxystearate,
peg-40 hydrogenated castor oil, polyoxyl 35 castor oil, dibutyl
sebacate, diethylphthalate, glycerine, methyl 4-hydroxybenzoate,
glycerol, castor oil, oleic acid, tryacetin, or polyalkylene
glycol.
[0111] In some embodiments, the first erodible material admixed
with a drug is a material that substantially erodes (e.g.,
substantially complete erosion or substantially complete
dissolution) during the time a drug dosage form is in an
individual. In some embodiments, substantially all of a first
erodible material admixed with a drug in a drug dosage form erodes
during the time the drug dosage form is in an individual. In some
embodiments, substantially all of a first erodible material admixed
with a drug in a drug dosage form erodes during a desired time
frame that the drug dosage form is in an individual. In some
embodiments, substantially all of a first erodible material admixed
with a drug in a drug dosage form erodes in less than about 72
hours, such as less than about any of 66 hours, 60 hours, 54 hours,
48 hours, 42 hours, 36 hours, 30 hours, 24 hours, 18 hours, 12
hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4
hours, 3 hours, 2 hours, 1 hour, or 30 minutes. In some
embodiments, substantially all of a first erodible material admixed
with a drug in a drug dosage form erodes in about 72 hours, such
about any of 66 hours, 60 hours, 54 hours, 48 hours, 42 hours, 36
hours, 30 hours, 24 hours, 18 hours, 12 hours, 10 hours, 9 hours, 8
hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1
hour, or 30 minutes.
[0112] In some embodiments, the erosion rate of a first erodible
material admixed a drug is between about 0.1 mm/hour to about 4
mm/hour. In some embodiments, the erosion rate of a first erodible
material admixed with a drug is greater than about 0.1 mm/hour,
such as greater than about any of 0.2 mm/hour, 0.3 mm/hour, 0.4
mm/hour, 0.5 mm/hour, 0.6 mm/hour, 0.7 mm/hour, 0.8 mm/hour, 0.9
mm/hour, 1.0 mm/hour, 1.1 mm/hour, 1.2 mm/hour, 1.3 mm/hour, 1.4
mm/hour, 1.5 mm/hour, 1.6 mm/hour, 1.7 mm/hour, 1.8 mm/hour, 1.9
mm/hour, 2.0 mm/hour, 2.1 mm/hour, 2.2 mm/hour, 2.3 mm/hour, 2.4
mm/hour, 2.5 mm/hour, 2.6 mm/hour, 2.7 mm/hour, 2.8 mm/hour, 2.9
mm/hour, 3.0 mm/hour, 3.1 mm/hour, 3.2 mm/hour, 3.3 mm/hour, 3.4
mm/hour, 3.5 mm/hour, 3.7 mm/hour, 3.8 mm/hour, 3.9 mm/hour, or 4.0
mm/hour. In some embodiments, the erosion rate of a first erodible
material admixed with a drug is less than about 0.1 mm/hour, such
as less than about any of 0.2 mm/hour, 0.3 mm/hour, 0.4 mm/hour,
0.5 mm/hour, 0.6 mm/hour, 0.7 mm/hour, 0.8 mm/hour, 0.9 mm/hour,
1.0 mm/hour, 1.1 mm/hour, 1.2 mm/hour, 1.3 mm/hour, 1.4 mm/hour,
1.5 mm/hour, 1.6 mm/hour, 1.7 mm/hour, 1.8 mm/hour, 1.9 mm/hour,
2.0 mm/hour, 2.1 mm/hour, 2.2 mm/hour, 2.3 mm/hour, 2.4 mm/hour,
2.5 mm/hour, 2.6 mm/hour, 2.7 mm/hour, 2.8 mm/hour, 2.9 mm/hour,
3.0 mm/hour, 3.1 mm/hour, 3.2 mm/hour, 3.3 mm/hour, 3.4 mm/hour,
3.5 mm/hour, 3.7 mm/hour, 3.8 mm/hour, 3.9 mm/hour, or 4.0 mm/hour.
In some embodiments, the erosion rate of a first erodible material
admixed with a drug is about any of 0.1 mm/hour, 0.2 mm/hour, 0.3
mm/hour, 0.4 mm/hour, 0.5 mm/hour, 0.6 mm/hour, 0.7 mm/hour, 0.8
mm/hour, 0.9 mm/hour, 1.0 mm/hour, 1.1 mm/hour, 1.2 mm/hour, 1.3
mm/hour, 1.4 mm/hour, 1.5 mm/hour, 1.6 mm/hour, 1.7 mm/hour, 1.8
mm/hour, 1.9 mm/hour, 2.0 mm/hour, 2.1 mm/hour, 2.2 mm/hour, 2.3
mm/hour, 2.4 mm/hour, 2.5 mm/hour, 2.6 mm/hour, 2.7 mm/hour, 2.8
mm/hour, 2.9 mm/hour, 3.0 mm/hour, 3.1 mm/hour, 3.2 mm/hour, 3.3
mm/hour, 3.4 mm/hour, 3.5 mm/hour, 3.7 mm/hour, 3.8 mm/hour, 3.9
mm/hour, or 4.0 mm/hour.
[0113] In some embodiments, the first erodible material is suitable
for admixture with a drug. In some embodiments, the first erodible
material is chemically unreactive with a drug. In some embodiments,
the erodible material is selected based on suitability for
admixture with a drug. In some embodiments, the first erodible
material is selected based on being chemically unreactive with a
drug.
ii. Erosion Rate
[0114] In some embodiments, the method of designing a dosage form,
such as an oral drug dosage form, to provide a desired release
profile, such as a desired drug release profile, comprises
obtaining, such as determining, the erosion rate (v.sub.E) of an
erodible material, such as a first erodible material admixed with a
drug.
[0115] The erosion rate of an erodible material can be obtained,
such as determined or measured, by methods known in the art or, for
example, the methods disclosed herein. In some embodiments, the
erosion rate (v.sub.E) of an erodible material, such as a layer of
a first erodible material admixed with a drug, may be obtained
using Formula I.
[0116] In some embodiments, obtaining the erosion rate (v.sub.E) of
a first erodible material admixed with a drug comprises using a dye
form, such as methylene blue powder, to indicate when a certain
thickness of the first erodible material has eroded to release the
dye form into solution, such as a dissolution medium. In some
embodiments, the dissolution medium replicates in vivo conditions.
In some embodiments, the dissolution medium is selected from the
group consisting of hydrochloric acid buffer, acid phthalate
buffer, neutralized phthalate buffer, phosphate buffer, alkaline
borate buffer, acetate buffer, simulated intestinal fluid,
simulated gastric fluid, and a combination thereof. In some
embodiments, the dissolution medium is stirred or agitated. In some
embodiments, the dissolution medium is maintained at a temperature
of about 37.degree. C. For example, if a layer of a first erodible
material admixed with a drug having a thickness of 1 mm (as
measured substantially in line with the direction of erosion from a
top surface of the erodible material exposed to a dissolution
medium to a groove containing the dye form) erodes and releases the
dye form into the dissolution medium in 2 hours, then the erosion
rate (v.sub.E) of the first erodible material admixed with a drug
is 0.5 mm/hour.
[0117] In some embodiments, obtaining the erosion rate of a first
erodible material admixed with a drug comprises obtaining the
erosion rate of the first material admixed with a substitute drug.
In some embodiments, the substitute drug and the drug have one or
more similar chemical properties, e.g., molecular weight,
hydrophilicity, hydrophobicity, functional groups, and/or core
structure.
[0118] In some embodiments, Formula I may be used to obtain the
erosion rate (v.sub.E) of a first erodible material admixed with a
drug, wherein the drug is homogenously admixed with the erodible
material. In some embodiments, Formula I may be used to obtain the
erosion rate (v.sub.E) of a first erodible material admixed with a
drug, wherein for a thickness of the erodible material the drug
forms a gradient substantially in line with the thickness of the
erodible material.
[0119] In some embodiments, the erosion rate (v.sub.E) of a first
erodible material admixed with a drug may be obtained with data
from a first time point (t.sub.1) and a subsequent second time
point (t.sub.2) using Formula II
V E = ( % t 2 * H ) - ( % t 1 * H ) t 2 - t 1 , Formula II ,
##EQU00006##
wherein H is the thickness of the erodible material prior to
erosion, %.sub.t1 is the percentage, in decimal form, of the drug
in solution at t.sub.1, and wherein %.sub.t2 is the percentage, in
decimal form, of the drug in solution at t.sub.2. In some
embodiments, the volume of a dissolution medium comprising a drug
removed at a time point, for purposes of measuring the amount of
the drug in solution, is replaced with dissolution medium following
removal.
[0120] In some embodiments, Formula II may be used to obtain the
erosion rate (v.sub.E) of a first erodible material admixed with a
drug, wherein the drug is homogenously admixed with the first
erodible material.
[0121] In some embodiments, the drug and/or another non-drug agent
admixed with a first erodible material alters the erosion rate of
the first erodible material not admixed with the drug. For example,
properties of a drug and/or amount of the drug, such as high drug
mass fractions, admixed in a first erodible material may alter the
erosion rate of the first erodible material admixed with the drug
as compared to the first erodible material not admixed with the
drug. In some embodiments, the methods of designing a drug dosage
form to provide a desired drug release profile comprise obtaining,
such as determining or measuring, erosion rates of a first material
admixed with a plurality of amounts of a drug. In some embodiments,
the erosion rate of a first erodible material admixed with a drug
is the same as the first erodible material not admixed with the
drug. In some embodiments, the erosion rate of a first erodible
material admixed with a drug is different than the first erodible
material not admixed with the drug.
[0122] In some embodiments, obtaining the erosion rate of an
erodible material, such as a first erodible material admixed with a
drug, comprises performing multiple assessments of the erodible
material, e.g., with varying thicknesses, replicates, and different
dissolution media.
[0123] In some embodiments, the method of designing a drug dosage
form to provide a desired drug release profile of a drug comprises
creating a database comprising at least one property of a first
erodible material admixed with a drug, e.g., erosion rate. In some
embodiments, the at least one property comprises the erosion rate
of a first erodible material admixed with a drug.
[0124] In some embodiments, erosion rates of a first erodible
material admixed with a drug may be obtained from the art or a
database. In some embodiments, the method of designing a drug
dosage form to provide a desired drug release profile comprises
obtaining the erosion rate (v.sub.E) of a first erodible material
admixed with a drug from a database. In some embodiments, the
method of designing a drug dosage form to provide a desired drug
release profile comprises selecting a first erodible material
admixed with a drug from a database.
[0125] In some embodiments, the method of designing a drug dosage
form to provide a desired drug release profile comprises selecting
a first erodible material admixed with a drug, wherein the first
erodible material is selected based on a property of the first
erodible material or the first erodible material admixed with the
drug. In some embodiments, selecting a first erodible material
admixed with a drug is based on the erosion rate of the first
erodible material admixed with the drug.
[0126] In some embodiments, the method of designing a drug dosage
form to provide a desired drug release profile comprises selecting
a first erodible material admixed with a drug based on a
hypothetical erosion rate, or range of hypothetical erosion rates,
of a layer of the first erodible material admixed with the drug. In
some embodiments, the hypothetical erosion rate, or range of
hypothetical erosion rates, of a first erodible material admixed
with a drug is based on suitable erosion rates that will provide a
desired rug release profile. In some embodiments, the hypothetical
erosion rate, or range of hypothetical erosion rates, of a first
erodible material admixed with a drug is based on correlating
erosion rates with the size of a drug dosage form. In some
embodiments, the hypothetical erosion rate, or range of
hypothetical erosion rates, of a first erodible material admixed
with a drug is based on erosion rates that satisfy Formula I based
on the size of a drug dosage form, such as the maximum size of the
drug dosage form.
[0127] In some embodiments, the method of designing a drug dosage
form to provide a desired drug release profile comprises selecting
a first erodible material admixed with a drug from a plurality of
erodible materials admixed with the drug having a property that
satisfies a hypothetical desired property.
[0128] In some embodiments, the method of designing a drug dosage
form to provide a desired drug release profile comprises using a
first erodible material admixed with a drug that is
pre-determined.
iii. Thickness
[0129] In some embodiments, the method of designing a dosage form,
such as a drug dosage form, to provide a desired release profile,
such as a desired drug release profile, comprises obtaining, such
as determining, thickness of an erodible material, such as a first
erodible material admixed with a drug.
[0130] In some embodiments, based on Formula I, the thickness (H)
of a layer of an erodible material, such as a first erodible
material admixed with a drug, is obtained using Formula III:
H=t.sub.E.times.v.sub.E, Formula III,
wherein t.sub.E is the total time of erosion of the layer of the
erodible material and v.sub.E is the erosion rate of the erodible
material.
[0131] In some embodiments, the method of designing a drug dosage
form to provide a desired drug release profile comprises
determining a thickness of a layer of a first material admixed with
a drug based on the first material admixed with the drug, wherein
the first material admixed with the drug has an erosion rate. In
some embodiments, the method of designing a drug dosage form to
provide a desired drug release profile comprises determining a
thickness of a layer of a first material admixed with a drug based
on pre-determination of the first material admixed with the drug,
wherein the first material admixed with the drug has an erosion
rate.
[0132] In some embodiments, the method of designing a drug dosage
form to provide a desired drug release profile comprises selecting
a first erodible material admixed with a drug based on a
hypothetical thickness, or range of suitable hypothetical
thicknesses (such as a pre-determined thickness or range of
thicknesses), of a layer of the first erodible material admixed
with the drug. In some embodiments, the hypothetical thickness of a
layer of a first erodible material admixed with a drug is used to
obtain a hypothetical erosion rate of the first erodible material
admixed with the drug. In some embodiments, the hypothetical
erosion rate is then used to select a first erodible material
admixed with a drug, wherein the first erodible material admixed
with the drug has an erosion rate. In some embodiments, the
hypothetical erosion rate and the erosion rate of a first erodible
material admixed with a drug are the same. In some embodiments, the
hypothetical erosion rate and the erosion rate of a first erodible
material admixed with a drug are different. In some embodiments,
the erosion rate of a first erodible material admixed with a drug
is then used to obtain a thickness of the first erodible material
admixed with the drug. In some embodiments, the hypothetical
thickness and thickness of a first erodible material admixed with a
drug are the same. In some embodiments, the hypothetical thickness
and thickness of a first erodible material admixed with a drug are
different.
[0133] In some embodiments, the hypothetical thickness, or range of
hypothetical thicknesses, of a layer of a first erodible material
admixed with a drug is based on the size of a drug dosage form,
number of layers in the drug dosage form, the printable resolution
of a layer in the drug dosage form (e.g., the minimum printable
thickens), a desired drug release profile of the drug dosage form,
or a combination thereof. In some embodiments, the hypothetical
thickness, or range of hypothetical thicknesses, of a layer of a
first erodible material admixed with a drug is based on thicknesses
that satisfy Formula I.
[0134] FIG. 2A shows a drug dosage form 200 having three layers of
a first erodible material admixed with a drug 215, 220, 225,
wherein the thickness of a layer 220, as measured substantially in
line with the direction of erosion 230, is indicated 235. In some
embodiments, when a first erodible material admixed with a drug
having a known erosion rate is selected, e.g., pre-selected, the
thickness 235 of a layer of the erodible material admixed with the
drug 220 may be calculated according to Formula III (FIG. 2A). In
some embodiments, a hypothetical thickness, or range of
hypothetical thickness, based on a first model of a drug dosage
form 200 may be used to select a first erodible material admixed
with a drug having an erosion rate, wherein the erosion rate of the
first erodible material admixed with a drug is used to calculate
the thickness 235 of a layer of the erodible material admixed with
the drug 220 according to Formula III (FIG. 2A).
iv. Mass Fraction and Surface Area of a Layer of a First Erodible
Material Admixed with a Compound
[0135] As shown in the schematic 100 of FIG. 1, a relationship
exists between the mass fraction, such as drug mass fraction, of a
layer of a first erodible material admixed with a compound a
compound (e.g., a drug) or reagent, 135 of a dosage form, such as a
drug dosage form, and the surface area of the layer of the first
erodible material admixed with the compound (e.g., the drug) or
reagent 140.
[0136] In some embodiments, the drug mass fraction (m.sub.F) of a
drug in a layer of an erodible material admixed with the drug is
obtained using Formula IV:
m F = m D m Tot , Formula IV , ##EQU00007##
wherein m.sub.D is the mass of the drug in the layer of the
erodible material admixed with the drug, and wherein m.sub.Tot is
the total mass of the layer of the erodible material admixed with
the drug.
[0137] In some embodiments, based on, e.g., Formula IV, the
relationship between the drug mass fraction of a layer of a first
erodible material admixed with a drug and the volume of the layer
(V.sub.vol) of the first erodible material admixed with the drug is
based on Formula V:
m F = % L * m D T o t .rho. * V vol , Formula V , ##EQU00008##
wherein m.sub.F is the drug mass fraction of the drug in the layer
of the first erodible material admixed with the drug, % L is the
percentage, in decimal form, of the total drug in the drug dosage
form that is in the layer of the erodible material admixed with the
drug, m.sub.DTot is the total mass of the drug in the drug dosage
form, and p is the density of the layer of the erodible material
admixed with the drug. In some embodiments, mathematically
equivalent terms may be substituted for terms recited in Formula V.
For example, in some embodiments, when the shape of a layer of a
first erodible material admixed with a drug allows, such as for a
cylinder, V.sub.vol can be substituted with thickness (H) of the
layer of the first erodible material admixed with the drug
multiplied by the surface area (S) of the layer of the first
erodible material admixed with the drug.
[0138] In some embodiments, when the total mass of a drug in a drug
dosage form, the percentage of the total drug in a layer of an
erodible material admixed with the drug, and thickness of the layer
of the erodible material admixed with the drug are held constant
for a first layer and a second layer, the first layer, which has a
higher drug m.sub.F in the layer as compared to the second layer,
may have the same desired drug release profile as the second layer
if the first layer has a smaller surface area as compared to the
second layer.
[0139] As illustrated in the schematic 100 of FIG. 1, designing a
drug dosage form to provide a desired drug release profile of a
drug may comprise different routes for establishing the drug mass
fraction of a layer of a first erodible material admixed with a
drug 135 and the surface area of the layer of the first erodible
material admixed with the drug 140.
[0140] In some embodiments, the method of designing a drug dosage
form with a desired drug release profile comprises obtaining, such
as determining or selecting, a hypothetical surface area, or range
of hypothetical surface areas, of a layer of a first erodible
material admixed with a drug. In some embodiments, the hypothetical
surface area, or range of hypothetical surface areas, of a layer of
a first erodible material admixed with a drug is based on the size
of a drug dosage form, e.g., the maximum and minimum size of a drug
dosage form. In some embodiments, the method of designing a drug
dosage form with a desired drug release profile comprises obtaining
a hypothetical drug mass fraction, or range of hypothetical drug
mass fractions, of a layer of a first erodible material admixed
with a drug based on a hypothetical surface area, or range of
hypothetical surface areas, of the layer of the first erodible
material admixed with the drug. In some embodiments, the method of
designing a drug dosage form with a desired drug release profile
comprises obtaining, such as selecting, a drug mass fraction of a
layer of a first erodible material admixed with a drug based on a
hypothetical drug mass fraction, or range of hypothetical drug mass
fractions, of the layer of the first erodible material admixed with
the drug. In some embodiments, the drug mass fraction of a layer of
a first erodible material admixed with a drug is selected based on
a property of the first erodible material admixed with the drug,
e.g., erosion rate. In some embodiments, the erosion rate of a
first erodible material is the same as the erosion rate of the
first material admixed with a drug, wherein the drug is present in
the first erodible material admixed with the drug at the selected
drug mass fraction. In some embodiments, method of designing a drug
dosage form with a desired drug release profile comprises obtaining
the surface area of a layer of a first erodible material admixed
with a drug based on the selected drug mass fraction of the first
erodible material admixed with the drug.
[0141] In some embodiments, the method of designing a drug dosage
form with a desired drug release profile comprises obtaining, such
as determining or selecting, a hypothetical drug mass fraction
area, or range of hypothetical drug mass fractions, of a layer of a
first erodible material admixed with a drug. In some embodiments,
the hypothetical drug mass fraction, or range of hypothetical drug
mass fraction, of a layer of a first erodible material admixed with
a drug is based on a property of the first erodible material
admixed with the drug, e.g., erosion rate. In some embodiments, the
erosion rate of a first erodible material is the same as the
erosion rate of the first material admixed with a drug, wherein the
drug is present in the first erodible material admixed with the
drug at the hypothetical drug mass fraction, or range of
hypothetical drug mass fractions. In some embodiments, the method
of designing a drug dosage form with a desired drug release profile
comprises obtaining a hypothetical surface area, or range of
hypothetical surface areas, of a layer of a first erodible material
admixed with a drug based on a hypothetical drug mass fraction, or
range of hypothetical drug mass fraction, of the layer of the first
erodible material admixed with the drug. In some embodiments, the
method of designing a drug dosage form with a desired drug release
profile comprises obtaining, such as selecting, a surface area of a
layer of a first erodible material admixed with a drug based on a
surface area, or range of hypothetical surface areas, of the layer
of the first erodible material admixed with the drug. In some
embodiments, the surface of a layer of a first erodible material
admixed with a drug is selected based on a property of a drug
dosage form, e.g., size. In some embodiments, method of designing a
drug dosage form with a desired drug release profile comprises
obtaining the drug mass fraction of a layer of a first erodible
material admixed with a drug based on the selected surface area of
the first erodible material admixed with the drug.
[0142] As disclosed herein, the methods of designing a dosage form,
such as a drug dosage form, with a desired release profile, such as
a desired drug release profile, may have a surface area of a layer
of a first erodible material admixed with a compound (e.g., a drug)
of any shape suitable for 3D printing of a dosage form. For
example, the drug dosage form 240 illustrated in FIG. 2B may have
the same desired drug release profile of the drug dosage form 265
illustrated in FIG. 2C, where the surface area of a layer of a
first erodible material 255 in the drug dosage form 240 of FIG. 2B
is a circle and the surface area of a layer of a first erodible
material 280 in the drug dosage form 265 of FIG. 2C is a
square.
[0143] As illustrated in FIG. 3A and FIG. 3B, a drug dosage form
300 with a desired drug release profile comprising a multi-layered
structure comprising a plurality of layers of a first erodible
material admixed with the drug 315, wherein the first erodible
material embedded in a second material not admixed with the drug
310 may comprise the plurality of layers of similar surface area
shapes and/or tapers.
[0144] In some embodiments, the method of designing a drug dosage
form with a desired drug release profile comprises separating,
e.g., partitioning, an obtained surface area of a layer of a first
erodible material admixed with a drug. In some embodiments, the
surface area of a layer of a first erodible material admixed with a
drug is continuous. In some embodiments, the surface area of a
layer of a first erodible material admixed with a drug is
discontinuous. For example, as illustrated in the exemplary oral
dosage forms of FIGS. 4A-4C, a multi-layered structure comprising a
plurality of layers of a first erodible material admixed with a
drug, wherein the first erodible material embedded in a second
material may have more than one layer of the first erodible
material admixed with a drug simultaneously exposed to a solution,
such as bodily fluid, e.g., gastrointestinal (GI) fluid. As
illustrated in FIG. 4A, the drug dosage form 400 comprising a
multi-layered structure comprising a plurality of layers of a first
erodible material admixed with a drug embedded in a second material
not admixed with the drug 420 comprise six layers 402, 404, 406,
412, 414, 416 of the first erodible material admixed with the drug,
wherein at least a first layer 406 and a second layer 416 are
simultaneously exposed to a solution following administration. As
illustrated in FIGS. 4B-4C, the drug dosage form 425 comprising a
multi-layered structure comprising a plurality of layers of a first
erodible material admixed with a drug embedded in a second material
not admixed with the drug 429 comprises 18 layers of the first
erodible material admixed with the drug (12 layers are shown in
FIG. 4B: 426-428, 431-439), wherein, as labeled in FIG. 4C, six
layers, including a first layer 428, a second layer 433, and a
third layer 441, are simultaneously exposed to a solution following
administration.
[0145] In some embodiments, the surface of a layer of a first
erodible material admixed with a drug is designed to control the
surface area exposed to a solution, such as bodily fluid, e.g.,
gastrointestinal (GI) fluid. In some embodiments, the surface of a
layer of a first erodible material admixed with a drug is designed
to increase the surface area exposed to a solution, as compared to
a planar surface of the same dimensions. In some embodiments, the
surface of a layer of a first erodible material admixed with a drug
is planar (e.g., FIG. 2A-4C). In some embodiments, the surface of a
layer of a first erodible material admixed with a drug is curved
(e.g., FIG. 5 and FIG. 6). In some embodiments, the surface of a
layer of a first erodible material admixed with a drug comprises at
least one projection, such as villi.
[0146] For use in Formula V, in some embodiments, density (p) of a
layer of an erodible material, whether or not admixed with a drug,
is obtained using Formula VI:
.rho. = m V v o l , Formula VI , ##EQU00009##
wherein, when the erodible material is not admixed with the drug, m
is the total mass of the layer of the erodible material not admixed
with the drug, wherein, when the erodible material is admixed with
the drug, m is the total mass of the layer of the erodible material
admixed with the drug (including the mass of the drug), and wherein
V.sub.vol is the volume of the layer.
[0147] In some embodiments, the method of designing a drug dosage
form to provide a desired drug release profile comprises adjusting
the pre-determine parameters of a layer comprising a first erodible
material admixed with a drug, e.g., surface area, thickness, drug
mass fraction, to create new parameters for the layer, wherein an
equal amount of the drug is released from the prior layer
parameters and the adjusted layer parameters over the erosion time
of the layers. In some embodiments, the layer is a layer of a
multi-layered structure of a drug dosage form. In some embodiments,
the layer is the top layer of a multi-layered structure of a drug
dosage form.
[0148] In some embodiments, the volume of the layer is adjusted. In
some embodiments, the volume of the layer is increased. In some
embodiments, the top layer of the multi-layered structure is
increased in volume. In some embodiments, the relative amount of a
drug per amount of material in the adjusted layer is less than in
the layer prior to adjustment. For example, as shown in FIG. 7, the
original layer parameters provide a layer comprising a first
erodible material admixed with a drug embedded in a second erodible
material not admixed with the drug. In some embodiments, the
original layer parameters are adjusted to increase the thickness of
the original layer, wherein the relative amount of the drug in the
layer (layer includes the first erodible material and second
erodible material) after adjustment is decreased as compared to the
layer prior to adjustment. In some embodiments, the original layer
parameters are adjusted to increase the volume of the second
erodible material not admixed with the drug.
[0149] In some embodiments, the layer comprising a first erodible
material admixed with a drug is adjusted by adding one or more
additional layers of a second erodible material not admixed with
the drug. For example, as shown in FIG. 7, an additional layer of a
second erodible material not admixed with the drug may be added on
top of or below the layer comprising a first erodible material
admixed with the drug. In some embodiments, a layer of a second
erodible material not admixed with a drug is added above the top
layer comprising a first erodible material admixed with the drug of
a multi-layered structure. In some embodiments, a layer of a second
erodible material not admixed with a drug is added directly below
the top layer comprising a first erodible material admixed with the
drug of a multi-layered structure.
[0150] In some embodiments, the layer comprising a first erodible
material admixed with a drug is adjusted by selecting a substitute
erodible material, wherein the parameters of the layer are adjusted
according to the erosion rate of the substitute erodible material.
In some embodiments, the substitute erodible material has a slower
erosion rate than the first erodible material. In some embodiments,
the substitute erodible material has a faster erosion rate than the
first erodible material. In some embodiments, the top layer
comprising a first erodible material admixed with a drug of a
multi-layered structure is adjusted by selecting a substitute
erodible material to admixed with the drug. In some embodiments,
the top layer comprising a first erodible material admixed with a
drug of a multi-layered structure is adjusted by selecting a
substitute erodible material to admixed with the drug, wherein the
substitute erodible material has a slower erosion rate than the
first erodible material. In some embodiments, the top layer
comprising a first erodible material admixed with a drug of a
multi-layered structure is adjusted by selecting a substitute
erodible material to admixed with the drug, wherein the substitute
erodible material has a faster erosion rate than the first erodible
material.
[0151] In some embodiments, the top n number of layers of a
multi-layered structure are adjusted by merging the top n number of
layers into a single layer with parameters that will meet the
desired drug release profile of the top n number of layers.
[0152] It will be understood by those skilled in the art that the
methods provided herein also encompass methods of printing and
designing based on one or more of the adjusted parameters discussed
herein.
C. Second Erodible Material not Admixed with a Compound
[0153] The present disclosure provides methods of designing a
dosage form, such as an oral drug dosage form, to provide a desired
release profile, such as a desired drug release profile, wherein
the dosage form comprises a multi-layered structure comprising a
plurality of layers of a first erodible material admixed with a
compound a compound (e.g., a drug) or reagent, wherein the first
erodible material is embedded in a second material not admixed with
the compound (e.g., the drug) or reagent. In some embodiments, the
method of designing a drug dosage form to provide a desired drug
release profile comprises selecting a second material not admixed
with a drug. In some embodiments, the second material not admixed
with a drug is pre-determined.
[0154] In some embodiments, the second material comprises a
thermoplastic material. In some embodiments, the second material is
a thermoplastic material. In some embodiments, the second material
is edible (i.e., suitable for consumption by an individual). In
some embodiments, the second material is biocompatible (e.g.,
suitable for use in an implant). In some embodiments, the
thermoplastic material is selected from the group consisting of a
hydrophilic polymer, a hydrophobic polymer, a swellable polymer, a
non-swellable polymer, a porous polymer, a non-porous polymer, an
erodible polymer (such as a dissolvable polymer), a non-erodible
polymer, a pH sensitive polymer, a natural polymer (such as
shellac), a wax-like material, and a combination thereof.
[0155] In some embodiments, the thermoplastic material is selected
from the group consisting of a hydrophilic polymer, a hydrophobic
polymer, a swellable polymer, a non-swellable polymer, a porous
polymer, a non-porous polymer, an erodible polymer (such as a
dissolvable polymer), a pH sensitive polymer, a natural polymer
(such as shellac), a wax-like material, and a combination thereof.
In some embodiments, the thermoplastic material is selected from
the group consisting of polyvinyl caprolactam-polyvinyl
acetate-polyethylene glycol graft copolymer 57/30/13,
polyvinylpyrrolidone-co-vinyl-acetate (PVP-VA),
polyvinylpyrrolidone-polyvinyl acetate copolymer (PVP-VA) 60/40,
polyvinylpyrrolidone (PVP), polyvinyl acetate (PVAc) and
polyvinylpyrrolidone (PVP) 80/20, polyethylene glycol-polyvinyl
alcohol graft copolymer 25/75, kollicoat IR-polyvinyl alcohol
60/40, polyvinyl alcohol (PVA or PV-OH), poly(vinyl acetate)
(PVAc), an (optionally alkyl-, methyl-, or ethyl-) acrylate, a
methacrylate copolymer, an ethacrylate copolymer, poly(butyl
methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl
methacrylate) 1:2:1,
poly(dimethylaminoethylmethacrylate-co-methacrylic esters),
poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl
methacrylate chloride), poly(methyl acrylate-co-methyl
methacrylate-co-methacrylic acid) 7:3:1, poly(methacrylic
acid-co-methylmethacrylate) 1:2, poly(methacylic acid-co-ethyl
acrylate) 1:1, poly(methacylic acid-co-methyl methacrylate) 1:1,
poly(ethylene oxide) (PEO), poly(ethylene glycol) (PEG),
hyperbranched polyesteramide, hydroxypropyl methylcellulose
phthalate, hypromellose phthalate, hydroxypropyl methylcellulose or
hypromellose (HMPC), hydroxypropyl methylcellulose acetate
succinate or hypromellose acetate succinate (HPMCAS),
poly(lactide-co-glycolide) (PLGA), carbomer, poly(ethylene-co-vinyl
acetate), ethylene-vinyl acetate copolymer, polyethylene (PE), and
polycaprolactone (PCL), hydroxyl propyl cellulose (HPC), polyoxyl
40 hydrogenerated castor oil, methyl cellulose (MC), ethyl
cellulose (EC), poloxamer, hydroxypropyl methylcellulose phthalate
(HPMCP), poloxamer, hydrogenated castor and soybean oil, glyceryl
palmitostearate, carnauba wax, polylactic acid (PLA), polyglycolic
acid (PGA), a cellulose or cellulose derivative, cellulose acetate
butyrate (CAB), colloidal silicon dioxide, a saccharide, glucose,
polyvinyl acetate phthalate (PVAP), a wax, beeswax, hydrogel,
gelatin, hydrogenated vegetable oil, polyvinyl acetal diethyl
aminolactate (AEA), paraffin, shellac, sodium alginate, cellulose
acetate phthalate (CAP), fatty oil, arabic gum, xanthan gum,
glyceryl monostearate, octadecanoic acid, and a combination
thereof.
[0156] In some embodiments, the second material comprises a
non-thermoplastic material. In some embodiments, the second
material is a non-thermoplastic material. In some embodiments, the
non-thermoplastic material is selected from the group consisting of
starch, pregelatinized starch, sodium starch glycolate (CMS-Na),
sucrose, dextrin, lactose, microcrystalline cellulose (MCC),
mannitol, magnesium stearate (MS), powdered silica gel, sodium
alginate, titanium dioxide, glycerin, syrup, lecithin, soybean oil,
tea oil, ethanol, propylene glycol, glycerol, Tween, animal fats,
silicone oils, cacao butter, fatty acid glycerides, vaseline,
chitosan, cetyl alcohol, stearyl alcohol, and a combination
thereof.
[0157] In some embodiments, the second material comprises a
plasticizer. In some embodiments, the plasticizer comprises a block
copolymer of polyoxyethylene-polyoxypropylene, vitamin e
polyethylene glycol succinate, hydroxystearate, polyethylene glycol
(such as PEG400), macrogol cetostearyl ether 12, polyoxyl 20
cetostearyl ether, polysorbate 20, polysorbate 60, polysorbate 80,
acetin, acetylated triethyl citrate, tributyl citrate, tributyl
o-acetylcitrate, triethyl citrate, polyoxyl 15 hydroxystearate,
peg-40 hydrogenated castor oil, polyoxyl 35 castor oil, dibutyl
sebacate, diethylphthalate, glycerine, methyl 4-hydroxybenzoate,
glycerol, castor oil, oleic acid, tryacetin, or polyalkylene
glycol.
[0158] In some embodiments, the method of designing a drug dosage
form to provide a desired drug release profile comprises selecting
a second material not admixed with a drug. In some embodiments, the
method of designing a drug dosage form to provide a desired drug
release profile comprises selecting: (a) a first erodible material
admixed with a drug; and (b) a second material not admixed with a
drug. In some embodiments, the first erodible material admixed with
a drug and a second material not admixed with the drug are the
same. In some embodiments, the second material not admixed with a
drug is an erodible material, such as a second erodible material.
In some embodiments, the first erodible material admixed with a
drug and the second material not admixed with the drug are the
same, wherein the second material is a second erodible material. In
some embodiments, the first erodible material admixed with a drug
and the second material not admixed with the drug are different,
wherein the second material is a second erodible material.
[0159] In some embodiments, the second material not admixed with a
drug, wherein the second material is a second erodible material, is
a material that erodes (e.g., completely erodes or undergoes
complete dissolution) during the time a drug dosage form is in an
individual. In some embodiments, the second material not admixed
with a drug, wherein the second material is a second erodible
material, is a material that does not completely erode during the
time a drug dosage form is in an individual.
[0160] In some embodiments, the method of designing a drug dosage
form to provide a desired drug release profile comprises selecting
a second material not admixed with a drug, wherein the second
material is a second erodible material, and wherein the second
erodible material is selected based on a property of the second
erodible material. In some embodiments, selecting a second material
not admixed with a drug, wherein the second material is a second
erodible material, is based on the erosion rate of the second
erodible material.
[0161] In some embodiments, the method of designing a drug dosage
form to provide a desired drug release profile comprises selecting:
(a) a first erodible material admixed with a drug; and (b) a second
material not admixed with a drug, wherein the second material is a
second erodible material, and wherein selection of the second
material is based on the erosion rate of the first erodible
material. In some embodiments, the method of designing a drug
dosage form to provide a desired drug release profile comprises
selecting: (a) a first erodible material admixed with a drug; and
(b) a second material not admixed with a drug, wherein the second
material is a second erodible material, and wherein selection of
the first erodible material is based on the erosion rate of the
second erodible material. In some embodiments, the erosion rate of
a second material not admixed with a drug, wherein the second
material is a second erodible material, is selected to control the
exposure of a layer of a first erodible material admixed with the
drug to a dissolution medium. In some embodiments, the erosion rate
of a first erodible material admixed with a drug and a second
material not admixed with a drug, wherein the second material is a
second erodible material, is the same. In some embodiments, the
erosion rate of a first erodible material admixed with a drug and a
second material not admixed with a drug, wherein the second
material is a second erodible material, is different. In some
embodiments, the erosion rate of a first erodible material admixed
with a drug is faster than a second material not admixed with a
drug, wherein the second material is a second erodible material. In
some embodiments, the erosion rate of a first erodible material
admixed with a drug is slower than a second material not admixed
with a drug, wherein the second material is a second erodible
material.
[0162] For example, in the drug dosage form 200 illustrated in FIG.
2A, a second material not admixed with a drug 210 may be selected
based on the erosion rate of the second material, wherein each
layer of a first erodible material admixed with the drug 215, 220,
225 is exposed to solution with the desired surface area to provide
the desired drug release profile, e.g., for the second layer of the
first erodible material admixed with the drug 220, only the top
surface area (i.e., not the sides where, e.g., thickness is
indicated 235) is exposed to solution after the first layer of the
first erodible material admixed with the drug 215 dissolves.
[0163] In some embodiments, the second material is an enteric
material. In some embodiments, the first erodible material is
embedded in the second material, wherein the second material is an
enteric material, and wherein the second material encapsulates the
first material. The term "encapsulates," as used herein,
encompasses embodiments wherein the second material fully
encapsulates (e.g., encloses) the first material and embodiments
wherein the second material partially encapsulates the first
material (e.g., via a plug comprising the second material). In some
embodiments, the first erodible material is embedded in the second
material, wherein the second material is an enteric material, and
wherein the second material fully encapsulates the first material.
In some embodiments, the first erodible material is embedded in the
second material, wherein the second material is an enteric
material, and wherein the second material partially encapsulates
the first material. In some embodiments, the first erodible
material is embedded in the second material, wherein the second
material is an enteric material, and wherein the second material
forms a plug.
[0164] In some embodiments, the method of designing a drug dosage
form to provide a desired drug release profile comprises designing
a layer of a second material not admixed with the drug that forms a
rim, wherein the rim forms a space, and wherein the space is on top
of a multi-layered structure comprising a plurality of layers of a
first erodible material admixed with a drug. The top of the
multi-layered structure refers to the layer of the first erodible
material admixed with a drug of the multi-layered structure that is
first contacted with bodily fluid, such as gastrointestinal fluid,
upon oral administration. For example, as shown in FIG. 8A, the
exemplary drug dosage form 800 comprises a second material that
forms a rim 805 above the top of the multi-layered structure
comprising a plurality of layers of the first erodible material
admixed with the drug 810. The rim form the space 815 shown in FIG.
8A. In some embodiments, the space is not filled with a material.
In some embodiments, the space is filled with another erodible
material, e.g., another erodible material admixed with a different
drug.
[0165] In some embodiments, the method of designing a drug dosage
form to provide a desired drug release profile comprises obtaining,
such as selecting, a thickness (as measured substantially in line
with the direction of erosion from the top of the multi-layered
structure to the most exterior surface of the rim) of a rim formed
by a second material not admixed with the drug. In some
embodiments, the thickness of the rim is at least about 0.01 mm,
such as at least about any of 0.05 mm, 0.1 mm, 0.15 mm, 0.2 mm,
0.25 mm, 0.3 mm, 0.35 mm, 0.4 mm, 0.45, 0.5 mm, 0.55 mm, 0.6 mm,
0.65 mm, 0.7 mm, 0.75 mm, 0.8 mm, 0.85 mm, 0.9 mm 0.95 mm, or 1 mm.
In some embodiments, the thickness of the rim is about any of 0.01
mm, 0.05 mm, 0.1 mm, 0.15 mm, 0.2 mm, 0.25 mm, 0.3 mm, 0.35 mm, 0.4
mm, 0.45, 0.5 mm, 0.55 mm, 0.6 mm, 0.65 mm, 0.7 mm, 0.75 mm, 0.8
mm, 0.85 mm, 0.9 mm 0.95 mm, or 1 mm. In some embodiments, the
thickness of the rim is about 0.52 mm.
D. Intermediate Material not Admixed with a Compound
[0166] The present disclosure provides methods of designing a
dosage form, such as an oral drug dosage form, to provide a desired
release profile, such as a desired drug release profile, wherein
the dosage form comprises a multi-layered structure comprising a
plurality of layers of a first erodible material admixed with a
compound a compound (e.g., a drug) or reagent, wherein the first
erodible material is embedded in a second material not admixed with
the compound (e.g., the drug) or reagent, and wherein an
intermediate material not admixed with the compound (e.g., the
drug) or reagent forms an intermediate layer between two or more
layers of the first erodible material. In some embodiments, the
intermediate material is an erodible material. In some embodiments,
the intermediate material is an erodible material, wherein the
intermediate material forms a plug. In some embodiments, the method
of designing a drug dosage form to provide a desired drug release
profile comprises selecting an intermediate material not admixed
with a drug, wherein the intermediate material is an erodible
material. In some embodiments, the intermediate material not
admixed with a drug is pre-determined, wherein the intermediate
material is an erodible material.
[0167] In some embodiments, the intermediate material comprises a
thermoplastic material. In some embodiments, the intermediate
material is a thermoplastic material. In some embodiments, the
intermediate material is edible (i.e., suitable for consumption by
an individual). In some embodiments, the intermediate material is
biocompatible (e.g., suitable for use in an implant). In some
embodiments, the thermoplastic material is selected from the group
consisting of a hydrophilic polymer, a hydrophobic polymer, a
swellable polymer, a non-swellable polymer, a porous polymer, a
non-porous polymer, an erodible polymer (such as a dissolvable
polymer), a non-erodible polymer, a pH sensitive polymer, a natural
polymer (such as shellac), a wax-like material, and a combination
thereof.
[0168] In some embodiments, the thermoplastic material is selected
from the group consisting of a hydrophilic polymer, a hydrophobic
polymer, a swellable polymer, a non-swellable polymer, a porous
polymer, a non-porous polymer, an erodible polymer (such as a
dissolvable polymer), a pH sensitive polymer, a natural polymer
(such as shellac), a wax-like material, and a combination thereof.
In some embodiments, the thermoplastic material is selected from
the group consisting of polyvinyl caprolactam-polyvinyl
acetate-polyethylene glycol graft copolymer 57/30/13,
polyvinylpyrrolidone-co-vinyl-acetate (PVP-VA),
polyvinylpyrrolidone-polyvinyl acetate copolymer (PVP-VA) 60/40,
polyvinylpyrrolidone (PVP), polyvinyl acetate (PVAc) and
polyvinylpyrrolidone (PVP) 80/20, polyethylene glycol-polyvinyl
alcohol graft copolymer 25/75, kollicoat IR-polyvinyl alcohol
60/40, polyvinyl alcohol (PVA or PV-OH), poly(vinyl acetate)
(PVAc), an (optionally alkyl-, methyl-, or ethyl-) acrylate, a
methacrylate copolymer, an ethacrylate copolymer, poly(butyl
methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl
methacrylate) 1:2:1,
poly(dimethylaminoethylmethacrylate-co-methacrylic esters),
poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl
methacrylate chloride), poly(methyl acrylate-co-methyl
methacrylate-co-methacrylic acid) 7:3:1, poly(methacrylic
acid-co-methylmethacrylate) 1:2, poly(methacylic acid-co-ethyl
acrylate) 1:1, poly(methacylic acid-co-methyl methacrylate) 1:1,
poly(ethylene oxide) (PEO), poly(ethylene glycol) (PEG),
hyperbranched polyesteramide, hydroxypropyl methylcellulose
phthalate, hypromellose phthalate, hydroxypropyl methylcellulose or
hypromellose (HMPC), hydroxypropyl methylcellulose acetate
succinate or hypromellose acetate succinate (HPMCAS),
poly(lactide-co-glycolide) (PLGA), carbomer, poly(ethylene-co-vinyl
acetate), ethylene-vinyl acetate copolymer, polyethylene (PE), and
polycaprolactone (PCL), hydroxyl propyl cellulose (HPC), polyoxyl
40 hydrogenerated castor oil, methyl cellulose (MC), ethyl
cellulose (EC), poloxamer, hydroxypropyl methylcellulose phthalate
(HPMCP), poloxamer, hydrogenated castor and soybean oil, glyceryl
palmitostearate, carnauba wax, polylactic acid (PLA), polyglycolic
acid (PGA), a cellulose or cellulose derivative, cellulose acetate
butyrate (CAB), colloidal silicon dioxide, a saccharide, glucose,
polyvinyl acetate phthalate (PVAP), a wax, beeswax, hydrogel,
gelatin, hydrogenated vegetable oil, polyvinyl acetal diethyl
aminolactate (AEA), paraffin, shellac, sodium alginate, cellulose
acetate phthalate (CAP), fatty oil, arabic gum, xanthan gum,
glyceryl monostearate, octadecanoic acid, and a combination
thereof.
[0169] In some embodiments, the intermediate material comprises a
non-thermoplastic material. In some embodiments, the intermediate
material is a non-thermoplastic material. In some embodiments, the
non-thermoplastic material is selected from the group consisting of
starch, pregelatinized starch, sodium starch glycolate (CMS-Na),
sucrose, dextrin, lactose, microcrystalline cellulose (MCC),
mannitol, magnesium stearate (MS), powdered silica gel, sodium
alginate, titanium dioxide, glycerin, syrup, lecithin, soybean oil,
tea oil, ethanol, propylene glycol, glycerol, Tween, animal fats,
silicone oils, cacao butter, fatty acid glycerides, vaseline,
chitosan, cetyl alcohol, stearyl alcohol, and a combination
thereof.
[0170] In some embodiments, the intermediate material comprises a
plasticizer. In some embodiments, the plasticizer comprises a block
copolymer of polyoxyethylene-polyoxypropylene, vitamin e
polyethylene glycol succinate, hydroxystearate, polyethylene glycol
(such as PEG400), macrogol cetostearyl ether 12, polyoxyl 20
cetostearyl ether, polysorbate 20, polysorbate 60, polysorbate 80,
acetin, acetylated triethyl citrate, tributyl citrate, tributyl
o-acetylcitrate, triethyl citrate, polyoxyl 15 hydroxystearate,
peg-40 hydrogenated castor oil, polyoxyl 35 castor oil, dibutyl
sebacate, diethylphthalate, glycerine, methyl 4-hydroxybenzoate,
glycerol, castor oil, oleic acid, tryacetin, or polyalkylene
glycol.
[0171] In some embodiments, the method of designing a drug dosage
form to provide a desired drug release profile comprises selecting
an intermediate material not admixed with a drug. In some
embodiments, the method of designing a drug dosage form to provide
a desired drug release profile comprises selecting: (a) a first
erodible material admixed with a drug; (b) a second material not
admixed with a drug; and (c) an intermediate material not admixed
with the drug. In some embodiments, the intermediate material not
admixed with a drug is the same as a first erodible material
admixed with the drug and/or a second material not admixed with the
drug. In some embodiments, the intermediate material not admixed
with a drug is different than a first erodible material admixed
with the drug and/or a second material not admixed with the
drug
[0172] In some embodiments, the intermediate material not admixed
with a drug is an erodible material. In some embodiments, the
intermediate material not admixed with a drug is a material that
erodes (e.g., completely erodes or undergoes complete dissolution)
during the time a drug dosage form is in an individual.
[0173] In some embodiments, the method of designing a drug dosage
form to provide a desired drug release profile comprises selecting
an intermediate material not admixed with a drug, wherein the
intermediate erodible material is selected based on a property of
the intermediate erodible material. In some embodiments, selecting
an intermediate material not admixed with a drug is based on the
erosion rate of the intermediate erodible material. In some
embodiments, selecting an intermediate material not admixed with a
drug is based on a desired drug release profile of an oral dosage
form. In some embodiments, selecting an intermediate material not
admixed with a drug is based on a desired drug release profile of a
drug dosage form, wherein thickness of the intermediate material
may allow for control of the release rate of the drug from the drug
dosage form, e.g., a pause or reduction in release of the drug from
the drug dosage form. In some embodiments, thickness of a layer of
an intermediate material is obtained based on Formula III.
E. Insulating Material
[0174] The present disclosure provides methods for designing a
dosage form, such as an oral drug dosage form, to provide a desired
release profile, such as a desired drug release profile, wherein
the dosage form comprises a multi-layered structure comprising a
plurality of layers of a first erodible material admixed with a
compound (e.g., a drug), wherein the first erodible material is
embedded in a second material not admixed with the compound (e.g.,
the drug), wherein the dosage form comprises an insulating material
that is impermeable to bodily fluid, such as gastrointestinal
fluid, and wherein the insulating material forms a barrier between
the bodily fluid and a portion of the multilayer structure. In some
embodiments, the second material is an insulating material. In some
embodiments, the second material is not an insulating material. In
some embodiments, the methods further comprise designing a drug
dosage form with an intermediate material not admixed with a drug
forms an intermediate layer between two or more layers of a first
erodible material admixed with the drug.
[0175] In some embodiments, the insulating material forms a barrier
between the bodily fluid, such as gastrointestinal fluid, and a
portion of a layer of a first erodible material admixed with a
drug. In some embodiments, the insulating material forms a barrier
between the bodily fluid, such as gastrointestinal fluid, and a
portion of a second material not admixed with a drug, wherein the
second material is a second erodible material. In some embodiments,
the insulating material forms a barrier between the bodily fluid,
such as gastrointestinal fluid, and a portion of a multi-layered
structure comprising a plurality of layers of a first erodible
material admixed with a drug, wherein the first erodible material
is embedded in a second material not admixed with the drug, wherein
the second material is a second erodible material. In some
embodiments, the insulating material forms a barrier between the
bodily fluid, such as gastrointestinal fluid, and a portion of a
multi-layered structure comprising a plurality of layers of a first
erodible material admixed with a drug and an intermediate erodible
material not admixed with the drug, wherein the first erodible
material is embedded in a second material not admixed with the
drug, and wherein the second material is a second erodible
material.
[0176] In some embodiments, the insulating material comprises a
thermoplastic material. In some embodiments, the insulating
material is a thermoplastic material. In some embodiments, the
insulating material is edible (i.e., suitable for consumption by an
individual). In some embodiments, the insulating material is
biocompatible (e.g., suitable for implantation). In some
embodiments, the insulating material is selected from the group
consisting of cellulose ethers, cellulose esters and acrylic
resins. In some embodiments, the insulating material is selected
from the group consisting of ethylcellulose,
hydroxypropylmethylcellulose, hydroxypropyl cellulose,
hydroxymethylcellulose, poly(meth)acrylic acid and derivatives
thereof, such as the salts, amides or esters thereof are suitable
for use as thermoplastic materials. In some embodiments, the
insulating material is selected from the group consisting of mono-
or diglycerides of C12-C30 fatty acids, C12-C30 fatty alcohols,
waxes, and a combination thereof.
[0177] In some embodiments, the insulating material comprises a
non-thermoplastic material. In some embodiments, the insulating
material is a non-thermoplastic material. In some embodiments, the
non-thermoplastic material is selected from the group consisting of
ethyl cellulose (EC), polymethacrylate, non-toxic polyvinyl
chloride, polyethylene, ethylene-vinyl acetate copolymer, silicone
rubber, and a combination thereof.
[0178] In some embodiments, the insulating material is a
non-erodible material. In some embodiments, the insulating material
will not substantially erode for a period of at least about 36
hours after administration, such as at least about any of 42 hours,
48 hours, 54 hours, 60 hours, 66 hours, or 72 hours. In some
embodiments, the insulating material is selected based on an
erosion property of the insulating material, e.g., erosion at a
specific pH.
Methods for Three-Dimensional Printing a Dosage Form
[0179] The present disclosure provides methods of printing a dosage
form, such as a drug dosage form, formulated and configured to
provide a desired release profile, such as a desired drug release
profile, the methods comprising: dispensing a first erodible
material admixed with a compound (e.g., a drug) and a second
material not admixed with the compound (e.g., the drug) to produce
a multi-layered structure comprising a plurality of layers of the
first erodible material embedded in the second material, wherein
each layer of the first erodible material has a pre-determined
surface area, thickness, and mass fraction, such as drug mass
fraction, wherein the pre-determined surface area, thickness,
and/or mass fraction correlate with the desired release profile,
and wherein upon exposure to the bodily fluid the drug is released
in accordance with the desired drug release profile.
[0180] As used herein, "printing," "three-dimensional printing,"
"3D printing," "additive manufacturing," or equivalents thereof,
refers to a process that produces three-dimensional objects, such
as drug dosage forms, layer-by-layer using digital designs. The
basic process of three-dimensional printing has been described in
U.S. Pat. Nos. 5,204,055; 5,260,009; 5,340,656; 5,387,380;
5,503,785; and 5,633,021. Additional U.S. patents and patent
applications that related to three-dimensional printing include:
U.S. Pat. Nos. 5,490,962; 5,518,690; 5,869,170; 6,530,958;
6,280,771; 6,514,518; 6,471,992; 8,828,411; U.S. Publication Nos.
2002/0015728; 2002/0106412; 2003/0143268; 2003/0198677;
2004/0005360. The content of the above U.S. patents and patent
applications is hereby incorporated by reference in their
entirety.
[0181] In some embodiments, an additive manufacturing technique is
used to produce the drug dosage forms described herein. In some
embodiments, a layer-by-layer technique is used to produce the drug
dosage forms described herein.
[0182] Different 3D printing methods have been developed for drug
dosage form manufacturing in terms of raw materials, equipment, and
solidification. These 3D printing methods include binder deposition
(see Gibson et al., Additive Manufacturing Technologies: 3D
Printing, Rapid Prototyping, and Direct Digital Manufacturing., 2
ed. Springer, New York, 2015; Katstra et al., Oral dosage forms
fabricated by three dimensional printing, J Control Release, 66,
2000; Katstra et al., Fabrication of complex oral delivery forms by
three dimensional printing, Dissertation in Materials Science and
Engineering, Massachusetts Institute of Technology, 2001; Lipson et
al., Fabricated: The New World of 3D printing, John Wiley &
Sons, Inc., 2013; Jonathan, Karim 3D printing in pharmaceutics: a
new tool for designing customized drug delivery systems, Int J
Pharm, 499, 2016), material jetting (see Jonathan, Karim, 3D
printing in pharmaceutics: a new tool for designing customized drug
delivery systems, Int J Pharm, 499, 2016), extrusion (see Gibson et
al., Additive Manufacturing Technologies: 3D Printing, Rapid
Prototyping, and Direct Digital Manufacturing. 2 ed. Springer, New
York, 2015), and photopolymerization (see Melchels et al., A review
on stereolithography and its application in biomedical engineering.
Biomaterials, 31, 2010).
[0183] In some embodiments, the drug dosage forms disclosed herein
are 3D printed using an extrusion method. In some embodiments, the
method of 3D printing comprises using a double screw extrusion
method. In an extrusion process, material is extruded from
robotically-actuated printing heads through printing nozzles.
Unlike binder deposition, which requires a powder bed, extrusion
methods can print on any substrate. A variety of materials can be
extruded for three-dimensional printing, including thermoplastic
materials disclosed herein, pastes and colloidal suspensions,
silicones, and other semisolids. One common type of extrusion
printing is fused deposition modeling, which uses solid polymeric
filaments for printing. In fused deposition modeling, a gear system
drives the filament into a heated nozzle assembly for extrusion
(see Gibson et al., Additive Manufacturing Technologies: 3D
Printing, Rapid Prototyping, and Direct Digital Manufacturing, 2
ed. Springer, New York, 2015).
[0184] In some embodiments, the 3D printing methods disclosed
herein comprise a continuous feed method.
[0185] In some embodiments, the 3D printing methods disclosed
herein comprise a batch feed method.
[0186] The method instructions for 3D printing a drug dosage form
disclosed herein may be generated a variety of ways, including
direct coding, derivation from a solid CAD model, or other means
specific to the 3D printing machine's computer interface and
application software. These instructions may include information on
the number and spatial placement of droplets, and on general 3D
print parameters such as the drop spacing in each linear dimension
(X, Y, Z), and volume or mass of fluid per droplet. For a given set
of materials, these parameters may be adjusted in order to refine
the quality of structure created. The overall resolution of the
structure created is a function of the powder particle size, the
fluid droplet size, the print parameters, and the material
properties.
[0187] Because 3D printing may handle a range of pharmaceutical
materials and control both composition and architecture locally, 3D
printing is well suited to the fabrication of drug dosage forms
with complex geometry and composition in accordance with the
present invention.
[0188] Manufacturing the drug dosage forms using 3D printing
methods also facilitates personalized medicine. Personalized
medicine refers to stratification of patient populations based on
biomarkers to aid therapeutic decisions and personalized dosage
form design. Modifying digital designs is easier than modifying
physical equipment. Also, automated, small-scale three-dimensional
printing may have negligible operating cost. Hence, 3D printing can
make multiple small, individualized batches economically feasible
and enable personalized dosage forms designed to improve
adherence.
[0189] Personalized drug dosage forms allow for tailoring the
amount of drug delivered based on a patient's mass and metabolism.
3D printed dosage forms could ensure accurate dosing in growing
children and permit personalized dosing of highly potent drugs.
Personalized dosage forms can also combine all of patients'
medications into a single daily dose, thus improve patients'
adherence to medication and treatment compliance.
[0190] The drug dosage forms disclosed in the present application
can be printed on a commercial scale. For example, in some
embodiments, the methods disclosed herein may be used to 3D print
10,000 to 100,000 tablets of a drug dosage form per hour. In some
embodiments, the methods disclosed herein may be used to 3D print
10,000 to 100,000 drug dosage forms per hour.
[0191] In some embodiments, the method for 3D printing of a drug
dosage form formulated to provide a desired drug release profile
comprises dispensing a first erodible material admixed with a drug
and a second material not admixed with the drug to produce a
multi-layered structure comprising a plurality of layers of the
first erodible material embedded in the second material. In some
embodiments, each printed layer of a first erodible material
admixed with a drug has a pre-determined surface area, thickness,
and drug mass fraction, wherein the pre-determined surface area,
thickness, and/or drug mass fraction correlate with a desired drug
release profile, and wherein upon exposure to the bodily fluid,
such as gastrointestinal fluid, the drug is released in accordance
with the desired drug release profile.
[0192] In some embodiments, the surface areas of a first erodible
material in at least two of the layers are different from each
other. In some embodiments, the surface areas of a first erodible
material in at least two of the layers are the same as each
other.
[0193] In some embodiments, the thicknesses of each of a plurality
of layers of a first erodible material are the same. In some
embodiments, the thickness of at least two layers of a first
erodible material are different from each other.
[0194] In some embodiments, the drug mass fraction in each of a
plurality of layers of a first erodible material are the same. In
some embodiments, the drug mass fractions in at least two layers of
a first erodible materials are different from each other.
[0195] In some embodiments, the second material is a second
erodible material. In some embodiments, the first erodible material
and a second erodible material are different from each other. In
some embodiments, the first erodible material and a second erodible
material are the same.
[0196] In some embodiments, the second material is an insulating
material that is impermeable to bodily fluid, such as
gastrointestinal fluid, wherein the insulating material forms a
barrier between the bodily fluid and a portion of the multi-layered
structure. In some embodiments, the insulating material is
non-erodible.
[0197] In some embodiments, the methods for 3D printing of a drug
dosage form formulated and configured to provide a desired drug
release profile further comprise dispensing an insulating material
that is impermeable to bodily fluid, such as gastrointestinal
fluid, wherein the insulating material forms a barrier between the
bodily fluid and a portion of the multi-layered structure.
[0198] In some embodiments, the first erodible material and a
second material are dispensed by different printing heads.
[0199] In some embodiments, the first erodible material, a second
material, and an insulating material are dispensed by different
printing heads.
[0200] In some embodiments, the 3D printing is carried out by fused
deposition modeling (FDM). In some embodiments, the 3D printing is
carried out by non-filament FDM. In some embodiments, the 3D
printing is carried out by inkjet printing. In some embodiments,
the 3D printing is carried out by selective laser sintering (SLS).
In some embodiments, the 3D printing is carried out by
stereolithography (SLA or SL). In some embodiments, the 3D printing
is carried out by PolyJet, Multi-Jet Printing System (MJP),
Perfactory, Solid Object Ultraviolet-Laser Printer, Bioplotter, 3D
Bioprinting, Rapid Freeze Prototyping, Fused Deposition Modelling
(FDM), Benchtop System, Selective Deposition Lamination (SDL),
Laminated Objet Manufacutring (LOM), Ultrasonic Consolidation,
ColorJet Printing (CJP), EOSINT Systems, Laser Engineered Net
Shaping (LENS) and Aerosol Jet System, Electron Beam Melting (EBM),
Laser CUSING@, Selective Laser Melting (SLM), Phenix PXTM Series,
Microsintering, Digital Part Materialization (DPM), or VX
System.
[0201] In some embodiments, the three-dimensional printing is
carried out by hot melt extrusion coupled with a three-dimensional
printing technique, such as FDM.
[0202] In some embodiments, the first erodible material and a
second material, wherein the second material is a second erodible
material, have the same erosion rate.
[0203] In some embodiments, the thickness of each layer is no more
than about 22 mm, such as no more than about any of 21 mm, 20 mm,
19 mm, 18 mm, 17 mm, 16 mm, 15 mm, 14 mm, 13 mm, 12 mm, 11 mm, 10
mm, 9 mm, 8 mm, 7 mm, 6 mm, 5 mm, 4 mm, 3 mm, 2 mm, 1 mm, 0.9 mm,
0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm, 0.2 mm, 0.1 mm,
0.09 mm, 0.08 mm, 0.07 mm, 0.06 mm, 0.05 mm, 0.04 mm, 0.03 mm, 0.02
mm, or 0.01 mm. In some embodiments, the thickness of a layer is no
more than about 22 mm, such as no more than about any of 21 mm, 20
mm, 19 mm, 18 mm, 17 mm, 16 mm, 15 mm, 14 mm, 13 mm, 12 mm, 11 mm,
10 mm, 9 mm, 8 mm, 7 mm, 6 mm, 5 mm, 4 mm, 3 mm, 2 mm, 1 mm, 0.9
mm, 0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm, 0.2 mm, 0.1 mm,
0.09 mm, 0.08 mm, 0.07 mm, 0.06 mm, 0.05 mm, 0.04 mm, 0.03 mm, 0.02
mm, or 0.01 mm. In some embodiments, the thickness of a layer is
about any of 22 mm, 21 mm, 20 mm, 19 mm, 18 mm, 17 mm, 16 mm, 15
mm, 14 mm, 13 mm, 12 mm, 11 mm, 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, 5
mm, 4 mm, 3 mm, 2 mm, 1 mm, 0.9 mm, 0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm,
0.4 mm, 0.3 mm, 0.2 mm, 0.1 mm, 0.09 mm, 0.08 mm, 0.07 mm, 0.06 mm,
0.05 mm, 0.04 mm, 0.03 mm, 0.02 mm, or 0.01 mm.
[0204] In some embodiments, the methods for 3D printing of a drug
dosage form formulated and configured to provide a desired drug
release profile further comprise dispensing an intermediate
material not admixed with the drug, wherein the intermediate
material forms an intermediate layer between two or more layers of
the first erodible material. In some embodiments, the intermediate
material is the same as a first erodible material and/or a second
material. In some embodiments, the intermediate material is
different than a first erodible material and/or a second
material.
[0205] In some embodiments, the methods for 3D printing of a drug
dosage form formulated and configured to provide a desired drug
release profile further comprise dispensing an intermediate
material not admixed with the drug, wherein the intermediate
material forms an intermediate layer between two or more layers of
the first erodible material. In some embodiments, the intermediate
material is the same as a first erodible material and/or a second
material.
[0206] In some embodiments, the drug dosage forms 3D printed by the
methods disclosed herein further comprises a second drug. In some
embodiments, the second drug is admixed with a first erodible
material. In some embodiments, the second drug is admixed with an
insulating material, wherein the second drug is released from the
insulating material.
[0207] In some embodiments, the methods for 3D printing of a drug
dosage form formulated and configured to provide a desired drug
release profile further comprise dispensing a third erodible
material admixed with a second drug, wherein a multi-layered
structure further comprises a plurality of layers of the third
erodible material embedded in a second material. In some
embodiments, each layer of a third erodible material has a
pre-determined surface area, thickness, and drug mass fraction,
wherein the pre-determined surface area, thickness, and/or drug
mass fraction correlate with a second desired drug release profile,
and wherein upon exposure to bodily fluid, such as gastrointestinal
fluid, the second drug is released in accordance with the second
desired drug release profile. In some embodiments, the third
erodible material is the same as a first erodible material and/or
second material.
[0208] In some embodiments, the erosion of a first erodible
material is pH dependent.
[0209] In some embodiments, the erosion of a third erodible
material is pH dependent.
[0210] The 3D printing methods of the present disclosure encompass
printing the materials in any order that will allow for production
of a drug dosage form disclosed herein. In some embodiments, the
method for three-dimensional printing of a drug dosage form
comprises dispensing an insulating material to form a structure of
a specific thickness, wherein the multi-layered structure is
dispensed into the structure of the insulating material. In some
embodiments, the method for three-dimensional printing of a drug
dosage form further comprises dispensing an insulating material to
form a structure of a specific thickness on top of a previously
dispensed structure of the insulating material. In some
embodiments, the method for three-dimensional printing of a drug
dosage form comprises dispensing an insulating material after
dispensing of a first erodible material and/or a second
material.
[0211] In some embodiments, the method for three-dimensional
printing of a drug dosage form comprises dispensing a first
erodible material and dispensing a second material, wherein the
first erodible material and the second material are dispensed by
different printing heads. In some embodiments, the method for
three-dimensional printing of a drug dosage form comprises
dispensing a first erodible material, dispensing a second material,
and dispensing an insulating material, wherein the first erodible
material, the second material, and the insulating material are
dispensed by different printing heads.
[0212] In some embodiments, the method for three-dimensional
printing of a drug dosage form comprises designing the drug dosage
form, in whole or in part, on a computer system. In some
embodiments, the method comprises inputting parameters of the
desired drug release profile and/or a drug dosage form into the
computer system. In some embodiments, the method comprises
providing one or more parameters of the drug dosage form, e.g.,
layer surface area, thickness, drug mass fraction; erosion rate. In
some embodiments, the method comprises providing the desired drug
release profile. In some embodiments, the methods comprise creating
a virtual image of a drug dosage form. In some embodiments, the
method comprises creating a computer model that contains the
pre-determined parameters. In some embodiments, the method
comprises feeding the pre-determined parameters to a
three-dimensional printer and printing a drug dosage form according
to such pre-determined parameters. In some embodiments, the method
comprises creating a three-dimensional drawing of a drug dosage
form based on the pre-determined parameters of the drug dosage
form, wherein the three-dimensional drawing is created on a
computer system. In some embodiments, the method comprises
converting, such as slicing, a three-dimensional drawing of a drug
dosage form into three-dimensional printing code, e.g., G code. In
some embodiments, the method comprises using the computer system to
execute three-dimensional printing code, thereby printing a drug
dosage form described herein.
[0213] In some embodiments, there is provided a method for
three-dimensional printing (e.g., 3D printing by FDM, for example
non-filament FDM) of an oral drug dosage form formulated and
configured to provide a desired drug release profile, wherein the
drug dosage form comprises a multi-layered structure comprising a
plurality of layers of a first erodible material admixed with a
drug having a pre-determined drug mass faction (m.sub.F), wherein
the first erodible material is embedded in a second material not
admixed with the drug, the method comprising: (a) dividing the
desired drug release profile into a plurality of time intervals
(t), each time interval corresponding to a layer in the
multi-layered structure; (b) determining (or calculating) the
percentage of drugs to be released during each time interval
(%.sub.L); (c) determining (or calculating) the thickness of each
layer (H.sub.n) of the multi-layered structure based on the erosion
rate of the first erodible material(V), wherein H.sub.n=t.sub.n*V;
(d) determining (or calculating) the surface area of each layer
based on %.sub.L, H.sub.n, m.sub.F, total amount of drug in the
oral drug dosage form (m.sub.DTot), and the density of the first
erodible material (.rho.), wherein:
S n = % L * m D T o t .rho. * Hn * m F ##EQU00010##
(e) dispensing (or depositing) the first erodible material admixed
with the drug based on the determined H.sub.n and S.sub.n for each
layer, thereby printing the multi-layered structure; and (f)
before, after, or during step (e), dispensing the second material
not admixed with the drug. In some embodiments, the release profile
of the oral drug dosage form is equivalent to the desired release
profile based on Chow's method or similarity factor calculation
method. In some embodiments, the method further comprises creating
a virtual image of the drug dosage form prior to the dispending
steps. In some embodiments, the method further comprises creating a
computer model that contains the pre-determined parameters prior to
the dispensing step. In some embodiments, the method further
comprises feeding the pre-determined parameters to the
three-dimensional printer prior to the dispensing step.
[0214] In some embodiments, a top layer is printed at the top of
the multi-layered structure. The top layer can be printed before or
after the multi-layered structure. For example, in some
embodiments, there is provided a method for three-dimensional
printing (e.g., 3D printing by FDM, for example non-filament FDM)
of an oral drug dosage form formulated and configured to provide a
desired drug release profile, wherein the drug dosage form
comprises a multi-layered structure comprising a plurality of
layers of a first erodible material admixed with a drug having a
pre-determined drug mass faction (m.sub.F), wherein the first
erodible material is embedded in a second material not admixed with
the drug, the method comprising: (a) dividing the desired drug
release profile into a plurality of time intervals (t.sub.n), each
time interval corresponding to a layer in the multi-layered
structure; (b) determining (or calculating) the percentage of drugs
to be released during each time interval (%.sub.L); (c) determining
(or calculating) the thickness of each layer (H.sub.n) of the
multi-layered structure based on the erosion rate of the first
erodible material(V), wherein H.sub.n=t.sub.n*V; (d) determining
(or calculating) the surface area of each layer based on % L,
H.sub.n, m.sub.F, total amount of drug in the oral drug dosage form
(m.sub.DTot), and the density of the first erodible material
(.rho.), wherein:
S n = % L * m D T o t .rho. * Hn * m F ##EQU00011##
(e) dispensing (or disposing) the first erodible material admixed
with the drug based on the determined H.sub.n and S.sub.n for each
layer, thereby printing the multi-layered structure; (f) dispensing
(or depositing) a top erodible material not admixed with the drug
on top of the multi-layered structure to form a top layer, wherein
the surface area of the top layer is the same or larger than the
first layer of the multi-layered structure immediately underneath
the top layer; and (g) before, after, or during step (e),
dispensing the second material not admixed with the drug. In some
embodiments, the thickness of the top layer is determined based on
the delay time needed for the drug release from the multi-layered
structure. In some embodiments, the top erodible material is the
same as the first erodible material. In some embodiments, the top
erodible material is different from the first erodible material. In
some embodiments, the release profile of the oral drug dosage form
is equivalent to the desired release profile based on Chow's method
or similarity factor calculation method. In some embodiments, the
method further comprises creating a virtual image of the drug
dosage form prior to the dispending steps. In some embodiments, the
method further comprises creating a computer model that contains
the pre-determined parameters prior to the dispensing step. In some
embodiments, the method further comprises feeding the
pre-determined parameters to the three-dimensional printer prior to
the dispensing step.
[0215] In some embodiments, the method further comprises dispending
dispensing an insulating material that is impermeable to bodily
fluid, wherein the insulating material forms a barrier between the
bodily fluid and at least a portion of the multi-layered structure.
In some embodiments, the method further comprises dispensing an
intermediate material not admixed with the drug, wherein the
intermediate material forms one or more intermediate layers between
two or more layers of the first erodible material.
[0216] In some embodiments, there is provided a method for
three-dimensional printing (e.g., 3D printing by FDM, for example
non-filament FDM) of an oral drug dosage form formulated and
configured to provide a desired drug release profile, wherein the
drug dosage form comprises a multi-layered structure comprising a
plurality of layers of a first erodible material admixed with a
drug having a pre-determined drug mass faction (mF), wherein the
first erodible material is embedded in a second material not
admixed with the drug, the method comprising: (a) dividing the
desired drug release profile into a plurality of time intervals
(tn), each time interval corresponding to a layer in the
multi-layered structure; (b) determining (or calculating) the
percentage of drugs to be released during each time interval (% L);
(c) determining (or calculating) the thickness of each layer (Hn)
of the multi-layered structure based on the erosion rate of the
first erodible material(V), wherein Hn=tn*V; (d) determining (or
calculating) the surface area of each layer based on % L, Hn, mF,
total amount of drug in the oral drug dosage form (mDTot), and the
density of the first erodible material (.rho.), wherein:
S n = % L * m D T o t .rho. * Hn * m F ##EQU00012##
(e) dispensing (or disposing) the first erodible material admixed
with the drug based on the determined H.sub.n and S.sub.n for each
layer, thereby printing the multi-layered structure; (f) dispensing
(or depositing) a top erodible material not admixed with the drug
on top of the multi-layered structure to form a top layer, wherein
the surface area of the top layer is the same or larger than the
first layer of the multi-layered structure immediately underneath
the top layer; (g) before, after, or during step (e), dispensing
the second material not admixed with the drug; (h) determining the
drug release profile of the oral drug dosage form produced by steps
(a)-(g); (i) comparing the drug release profile of the oral drug
dosage form with the desired drug release profile; (j) adjusting
one or more parameters selected from: the first erodible material,
the second material, the surface area of the one or more of the
layers of the first erodible material, the thickness of one or more
layers of the first erodible material, and the mass fraction of the
drug in one or more layers of the first erodible material; and (k)
three-dimensional printing a second oral drug dosage form based on
the adjusted parameters. In some embodiments, the release profile
of the oral drug dosage form is equivalent to the desired release
profile based on Chow's method or similarity factor calculation
method. In some embodiments, the method further comprises creating
a virtual image of the drug dosage form prior to the dispending
steps. In some embodiments, the method further comprises creating a
computer model that contains the pre-determined parameters prior to
the dispensing step. In some embodiments, the method further
comprises feeding the pre-determined parameters to the
three-dimensional printer prior to the dispensing step.
[0217] In some embodiments, there is provided a method for
three-dimensional printing (e.g., 3D printing by FDM, for example
non-filament FDM) of an oral drug dosage form formulated and
configured to provide a desired drug release profile, wherein the
drug dosage form comprises a multi-layered structure comprising a
plurality of layers of a first erodible material admixed with a
drug having a pre-determined drug mass faction (mF), wherein the
first erodible material is embedded in a second material not
admixed with the drug, the method comprising: (a) determining the
drug release profile of an original oral drug dosage form; (b)
comparing the drug release profile of the oral drug dosage form
with the desired drug release profile; (c) adjusting one or more
parameters selected from: the first erodible material, the second
material, the surface area of the one or more of the layers of the
first erodible material, the thickness of one or more layers of the
first erodible material, and the mass fraction of the drug in one
or more layers of the first erodible material; and (d)
three-dimensional printing of the oral drug dosage form based on
the adjusted parameters. In some embodiments, the release profile
of the oral drug dosage form is equivalent to the desired release
profile based on Chow's method or similarity factor calculation
method. In some embodiments, the method further comprises creating
a virtual image of the drug dosage form prior to the dispending
steps. In some embodiments, the method further comprises creating a
computer model that contains the pre-determined parameters prior to
the dispensing step. In some embodiments, the method further
comprises feeding the pre-determined parameters to the
three-dimensional printer prior to the dispensing step.
[0218] In some embodiments, there is provided a method for
three-dimensional printing (e.g., 3D printing by FDM, for example
non-filament FDM) of an oral drug dosage form formulated and
configured to provide a desired drug release profile, wherein the
drug dosage form comprises a multi-layered structure comprising a
plurality of layers of a first erodible material admixed with a
drug having a pre-determined thickness and a predetermined surface
area, wherein the first erodible material is embedded in a second
material not admixed with the drug, wherein the surface area of
each of the plurality of the layers of the first erodible material
in the multi-layered structure decreases sequentially from the
surface to the interior of the oral dosage form, wherein when the
oral dosage form is exposed to a bodily fluid the plurality of
layers are exposed to the bodily fluid in a sequential pattern,
with the layer with the largest surface area exposed to the bodily
fluid first, the method comprising: (a) dispensing (or depositing)
the first erodible material admixed with the drug based on the
determined H.sub.n and S.sub.n for each layer, thereby printing the
multi-layered structure; and (b) before, after, or during step (a),
dispensing the second material not admixed with the drug. In some
embodiments, the method further comprises dispensing a top erodible
material not admixed with the drug on top of the multi-layered
structure to form a top layer, wherein the surface area of the top
layer is the same or larger than the first layer of the
multi-layered structure immediately underneath the top layer. In
some embodiments, the thickness of the top layer is determined
based on the delay time needed for the drug release from the
multi-layered structure. In some embodiments, the method further
comprises creating a computer model that contains the
pre-determined parameters prior to the dispensing step. In some
embodiments, the method further comprises feeding the
pre-determined parameters to the three-dimensional printer prior to
the dispensing step.
[0219] In some embodiments, the oral drug dosage form comprises two
or more multi-layered structures, and optionally each of the
multi-layered structure is produced sequentially or simultaneously
by any of the methods described herein. Thus, for example, in some
embodiments, there is provided a method for three-dimensional
printing of an oral drug dosage form formulated and configured to
provide a first desired drug release profile and a second desired
drug release profile, wherein the drug dosage form comprises a
first multi-layered structure comprising a plurality of layers of a
first erodible material admixed with a drug having a pre-determined
drug mass faction (m.sub.F), wherein the first erodible material is
embedded in a second material not admixed with a first drug, and a
second multi-layered structure comprising a plurality of layers of
a third erodible material admixed with a fourth drug having a
pre-determined drug mass faction, wherein the third erodible
material is embedded in a fourth material not admixed with the
drug, the method comprising: (a) dividing each of the desired drug
release profile into a plurality of time intervals (t.sub.n), each
time interval corresponding to a layer in a corresponding
multi-layered structure; (b) calculating the percentage of drugs to
be released during each time interval (%.sub.L); (c) calculating
the thickness of each layer (H.sub.n) of the multi-layered
structures based on the erosion rate of the first erodible material
or third erodible material (V), wherein H.sub.n=t.sub.n*V; (d)
calculating the surface area of each layer based on %.sub.L,
H.sub.n, m.sub.F, total amount of drug in the oral drug dosage form
(m.sub.DTot), and the density of the first or first erodible
material (.rho.), wherein:
S n = % L * m D T o t .rho. * Hn * m F ##EQU00013##
[0220] (e) dispensing the first erodible material admixed with the
first drug and third erodible material admixed with the second drug
based on the determined H.sub.n and S.sub.n for each layer, thereby
printing the two multi-layered structures; (f) before, after, or
during step (e), dispensing the second material and fourth material
not admixed with the drug. In some embodiments, the first erodible
material and the third erodible material are the same. In some
embodiments, the second and fourth materials are the same. In some
embodiments, the first drug and the second drug are the same. In
some embodiments, the first drug and the second drug are
different.
Dosage Forms
[0221] The present application also provides any of the dosage
claim produced by the 3D printing methods described herein. The
present disclosure provides, using any of the methods for designing
or methods of 3D printing disclosed herein, a dosage form, such as
a drug dosage form or a reagent dosage form, to provide a desired
release profile, such as a desired drug release profile, wherein
the dosage form comprises a multi-layered structure comprising a
plurality of layers of a first erodible material admixed with the
compound (e.g., the drug), wherein the first erodible material is
embedded in a second material not admixed with the compound (e.g.,
the drug). In some embodiments, the materials of a drug dosage
form, e.g., a first erodible material admixed with a drug, a second
material not admixed with the drug, an intermediate material, an
insulating material, are integrated (e.g., do not form components
that may be readily separated).
[0222] In some embodiments, the plurality of layers of a first
erodible material is between about 5 layers to about 2500 layers,
such as between any of about 10 layers to about 2500 layers, about
25 layers to about 100 layers, about 50 layers to about 200 layers,
about 100 layers to about 200 layers, about 150 layers to about 250
layers, about 200 layers to about 250 layers, about 500 layers to
about 1000 layers, or about 2000 layers to about 2400 layers.
[0223] In some embodiments, the surface areas of a first erodible
material in at least two of the layers are different from each
other. In some embodiments, the surface areas of a first erodible
material in at least two of the layers are the same as each
other.
[0224] In some embodiments, the thicknesses of each of a plurality
of layers of a first erodible material are the same. In some
embodiments, the thickness of at least two layers of a first
erodible material are different from each other.
[0225] In some embodiments, the drug mass fraction in each of a
plurality of layers of a first erodible material are the same. In
some embodiments, the drug mass fractions in at least two layers of
a first erodible materials are different from each other.
[0226] In some embodiments, the second material is a second
erodible material. In some embodiments, the first erodible material
and a second erodible material are different from each other. In
some embodiments, the first erodible material and a second erodible
material are the same.
[0227] In some embodiments, the second material is an insulating
material that is impermeable to bodily fluid, such as
gastrointestinal fluid, wherein the insulating material forms a
barrier between the bodily fluid and a portion of the multi-layered
structure. In some embodiments, the insulating material is
non-erodible.
[0228] In some embodiments, the drug dosage form further comprises
an insulating material that is impermeable to bodily fluid, such as
gastrointestinal fluid, wherein the insulating material forms a
barrier between the bodily fluid and a portion of the multi-layered
structure.
[0229] In some embodiments, the first erodible material and a
second material, wherein the second material is a second erodible
material, have the same erosion rate.
[0230] In some embodiments, the thickness of each layer is no more
than about 22 mm, such as no more than about any of 21 mm, 20 mm,
19 mm, 18 mm, 17 mm, 16 mm, 15 mm, 14 mm, 13 mm, 12 mm, 11 mm, 10
mm, 9 mm, 8 mm, 7 mm, 6 mm, 5 mm, 4 mm, 3 mm, 2 mm, 1 mm, 0.9 mm,
0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm, 0.2 mm, 0.1 mm,
0.09 mm, 0.08 mm, 0.07 mm, 0.06 mm, 0.05 mm, 0.04 mm, 0.03 mm, 0.02
mm, or 0.01 mm. In some embodiments, the thickness of a layer is no
more than about 22 mm, such as no more than about any of 21 mm, 20
mm, 19 mm, 18 mm, 17 mm, 16 mm, 15 mm, 14 mm, 13 mm, 12 mm, 11 mm,
10 mm, 9 mm, 8 mm, 7 mm, 6 mm, 5 mm, 4 mm, 3 mm, 2 mm, 1 mm, 0.9
mm, 0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm, 0.2 mm, 0.1 mm,
0.09 mm, 0.08 mm, 0.07 mm, 0.06 mm, 0.05 mm, 0.04 mm, 0.03 mm, 0.02
mm, or 0.01 mm. In some embodiments, the thickness of a layer is
about any of 22 mm, 21 mm, 20 mm, 19 mm, 18 mm, 17 mm, 16 mm, 15
mm, 14 mm, 13 mm, 12 mm, 11 mm, 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, 5
mm, 4 mm, 3 mm, 2 mm, 1 mm, 0.9 mm, 0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm,
0.4 mm, 0.3 mm, 0.2 mm, 0.1 mm, 0.09 mm, 0.08 mm, 0.07 mm, 0.06 mm,
0.05 mm, 0.04 mm, 0.03 mm, 0.02 mm, or 0.01 mm.
[0231] In some embodiments, the drug dosage form further comprises
an intermediate material not admixed with the drug, wherein the
intermediate material forms an intermediate layer between two or
more layers of the first erodible material. In some embodiments,
the intermediate material is the same as a first erodible material
and/or a second material. In some embodiments, the intermediate
material is different than a first erodible material and/or a
second material.
[0232] The drug dosage forms described herein may comprise any
number of drugs. In some embodiments, the drug dosage forms
comprise two or more drugs, such as any of 3, 4, 5, 6, 7, 8, 9 or
10 drugs. In some embodiments, the drug dosage forms further
comprise a second drug. In some embodiments, the second drug is
admixed with a first erodible material. In some embodiments, the
second drug is admixed with an insulating material, wherein the
second drug is released from the insulating material.
[0233] In some embodiments, the drug dosage form further comprises
a third erodible material admixed with a second drug, wherein a
multi-layered structure further comprises a plurality of layers of
the third erodible material embedded in a second material. In some
embodiments, each layer of a third erodible material has a
pre-determined surface area, thickness, and drug mass fraction,
wherein the pre-determined surface area, thickness, and/or drug
mass fraction correlate with a second desired drug release profile,
and wherein upon exposure to bodily fluid, such as gastrointestinal
fluid, the second drug is released in accordance with the second
desired drug release profile. In some embodiments, the third
erodible material is the same as a first erodible material and/or
second material.
[0234] In some embodiments, the erosion of an erodible material is
pH dependent. In some embodiments, the erosion of a first erodible
material is pH dependent. In some embodiments, the erosion of a
second erodible material is pH dependent. In some embodiments, the
erosion of a third erodible material is pH dependent. In some
embodiments, the erosion of an intermediate material is pH
dependent. In some embodiments, the erosion of an erodible material
occurs above a pH of about 5.5 to about 7. In some embodiments, the
erosion of an erodible material occurs above a pH of about 5.5,
about 6, about 6.5, or about 7. In some embodiments, the erodible
material is an enteric coating.
[0235] In some embodiments, the dosage form, such as an oral drug
dosage form, is coated, such as embedded, encased, or attached
thereto, with a film or a coating, e.g., sugar coating or gelatin
layer.
[0236] In some embodiments, the total mass of drugs in a drug
dosage form is between about 1500 mg to about 0.01 mg. In some
embodiments, the total mass of drugs in a drug dosage form is less
than about 1500 mg, such as less than about any of 1400 mg, 1300
mg, 1200 mg, 1100 mg, 1000 mg, 900 mg, 800 mg, 700 mg, 600 mg, 500
mg, 450 mg, 400 mg, 350 mg, 300 mg, 250 mg, 200 mg, 150 mg, 100 mg,
75 mg, 50 mg, 45 mg, 40 mg, 35 mg, 30 mg, 25 mg, 20 mg, 15 mg, 10
mg, 5 mg, 4 mg, 3 mg, 2 mg, 1 mg, 0.75 mg, 0.5 mg, 0.25 mg, or 0.1
mg. In some embodiments, the total mass of drugs in a drug dosage
form is about 1500 mg, such as about any of 1400 mg, 1300 mg, 1200
mg, 1100 mg, 1000 mg, 900 mg, 800 mg, 700 mg, 600 mg, 500 mg, 450
mg, 400 mg, 350 mg, 300 mg, 250 mg, 200 mg, 150 mg, 100 mg, 75 mg,
50 mg, 45 mg, 40 mg, 35 mg, 30 mg, 25 mg, 20 mg, 15 mg, 10 mg, 5
mg, 4 mg, 3 mg, 2 mg, 1 mg, 0.75 mg, 0.5 mg, 0.25 mg, or 0.1
mg.
[0237] In some embodiments, the mass of a drug in a drug dosage
form is between about 1500 mg to about 0.01 mg. In some
embodiments, the mass of a drug in a drug dosage form is less than
about 1500 mg, such as less than about any of 1400 mg, 1300 mg,
1200 mg, 1100 mg, 1000 mg, 900 mg, 800 mg, 700 mg, 600 mg, 500 mg,
450 mg, 400 mg, 350 mg, 300 mg, 250 mg, 200 mg, 150 mg, 100 mg, 75
mg, 50 mg, 45 mg, 40 mg, 35 mg, 30 mg, 25 mg, 20 mg, 15 mg, 10 mg,
5 mg, 4 mg, 3 mg, 2 mg, 1 mg, 0.75 mg, 0.5 mg, 0.25 mg, or 0.1 mg.
In some embodiments, the mass of a drug in a drug dosage form is
about 1500 mg, such as about any of 1400 mg, 1300 mg, 1200 mg, 1100
mg, 1000 mg, 900 mg, 800 mg, 700 mg, 600 mg, 500 mg, 450 mg, 400
mg, 350 mg, 300 mg, 250 mg, 200 mg, 150 mg, 100 mg, 75 mg, 50 mg,
45 mg, 40 mg, 35 mg, 30 mg, 25 mg, 20 mg, 15 mg, 10 mg, 5 mg, 4 mg,
3 mg, 2 mg, 1 mg, 0.75 mg, 0.5 mg, 0.25 mg, or 0.1 mg.
[0238] In some embodiments, the materials of the drug dosage forms
described herein, including a first erodible material, a second
material, a second erodible material, an intermediate material, an
intermediate erodible material, and an insulating material, further
comprise another agent. In some embodiments, the other agent is an
excipient. In some embodiments, the other agent is a bulking agent.
In some embodiments, the other agent is a light shielding agent,
such as an opacifier.
[0239] In some embodiments, the drug dosage form is suitable for
oral administration. The drug dosage forms of the present invention
can be, for example, any size, shape, or weight that is suitable
for oral administration to specific patients, such as children and
adults. In some embodiments, the drug dosage form is suitable for
oral administration to an individual, wherein selection of size,
shape, or weight of the drug dosage form is based on an attribute
of the individual. In some embodiments, the attribute of the
individual is one or more of height, weight, or age.
[0240] In some embodiments, the drug dosage form has a dimension
that is less than about 22 mm, such as less than about 21 mm, less
than about 20 mm, less than about 19 mm, less than about 18 mm,
less than about 17 mm, less than about 16 mm, less than about 15
mm, less than about 14 mm, less than about 13 mm, less than about
12 mm, less than about 11 mm, less than about 10 mm, less than
about 9 mm, less than about 8 mm, less than about 7 mm, less than
about 6 mm, less than about 5 mm, less than about 4 mm, less than
about 3 mm, less than about 2 mm, or less than about 1 mm. In some
embodiments, the drug dosage form has a dimension that is about 1
mm to about 22 mm, such as about 21 mm, about 20 mm, about 19 mm,
about 18 mm, about 17 mm, about 16 mm, about 15 mm, about 14 mm,
about 13 mm, about 12 mm, about 11 mm, about 10 mm, about 9 mm,
about 8 mm, about 7 mm, about 6 mm, about 5 mm, about 4 mm, about 3
mm, or about 2 mm.
[0241] In some embodiments, the drug dosage form is of a suitable
size and shape for its intended use, e.g., implantation.
[0242] In some embodiments, the drug dosage form has a total weight
of about 50-600 mg, such as about any of 50-100, 100-150, 150-200,
200-250, 250-300, 300-350, 350-400, 400-450, 450-500, 500-550, or
550-600 mg. In some embodiments, the drug dosage form has a total
weight of about 50-400 mg. In some embodiments, the drug dosage
form has a total weight of about 75-300 mg. In some embodiments,
the drug dosage form has a total weight of about 100-200 mg. In
some embodiments, the drug dosage form has a total weight of less
than about 600 mg, 550 mg, 500 mg, 450 mg, 400 mg, 350 mg, 300 mg,
250 mg, 200 mg, 150 mg, 100 mg, 75 mg, or 50 mg.
[0243] FIG. 2B shows an exemplary drug dosage form 240 formulated
and configured to provide a desired drug release profile comprising
a multi-layered structure comprising a plurality of layers of a
first erodible material admixed with a drug 255, wherein the first
erodible material is embedded in a second material not admixed with
the drug 250. The exemplary drug dosage form 240 further comprises
an insulating material 245 around all surfaces except the top
surface. The direction of erosion of the first erodible material
admixed with a drug is indicated by an arrow 260. Optionally, the
second material not admixed with the drug 250 is a second erodible
material.
[0244] FIG. 2C shows an exemplary drug dosage form 265 formulated
and configured to provide a desired drug release profile comprising
a multi-layered structure comprising a plurality of layers of a
first erodible material admixed with a drug 280, wherein the first
erodible material is embedded in a second material not admixed with
the drug 275. The exemplary drug dosage form 265 further comprises
an insulating material 270 around all surfaces except the top
surface. The direction of erosion of the first erodible material
admixed with a drug is indicated by an arrow 285. Optionally, the
second material not admixed with the drug 275 is a second erodible
material.
[0245] FIG. 3A shows an exemplary drug dosage form 300 formulated
and configured to provide a desired drug release profile comprising
a multi-layered structure comprising a plurality of layers of a
first erodible material admixed with a drug 315, wherein the first
erodible material is embedded in a second material not admixed with
the drug 305 (pictured as a translucent material to allow for
visualization of other components). The exemplary drug dosage form
300 further comprises an insulating material 305 around all
surfaces except the top surface. The direction of erosion of the
first erodible material admixed with a drug is indicated by an
arrow 320. Optionally, the second material not admixed with the
drug 305 is a second erodible material.
[0246] FIG. 4C shows an exemplary drug dosage form 425 formulated
and configured to provide a desired drug release profile comprising
a plurality of multi-layered structures comprising a plurality of
layers of a first erodible material admixed with a drug 428, 433,
441 wherein the first erodible material is embedded in a second
material not admixed with the drug 429. The exemplary drug dosage
form 430 further comprises an insulating material 430 that serves
to control the exposure of each multi-layered structure comprising
a plurality of layers of the first erodible material admixed with
the drug to bodily fluid, such as gastrointestinal fluid (see also
FIG. 4B). Optionally, the second material not admixed with the drug
429 is a second erodible material.
[0247] FIG. 5 shows a cross-sectional view of an exemplary drug
dosage form 500 formulated and configured to provide a desired drug
release profile comprising a multi-layered structure comprising a
plurality of layers of a first erodible material admixed with a
drug 505, 510, 515, wherein the first erodible material is embedded
in a second material not admixed with the drug 520. Optionally, the
second material not admixed with the drug 520 is a second erodible
material.
[0248] FIG. 6 shows a cross-sectional view of an exemplary drug
dosage form 600 formulated and configured to provide a desired drug
release profile comprising a multi-layered structure comprising a
plurality of layers of a first erodible material admixed with a
drug 612-618, 622-628, 632-638, 642-648, wherein the first erodible
material is embedded in a second material not admixed with the drug
610, 620, 630, 640. Optionally, one or more of the second material
not admixed with the drug 610, 620, 630, 640 is a second erodible
material.
[0249] FIG. 8A shows an exemplary drug dosage form 800 formulated
and configured to provide a desired drug release profile comprising
a multi-layered structure comprising a plurality of layers of a
first erodible material admixed with a drug 810, wherein the first
erodible material is embedded in a second material not admixed with
the drug 820 (pictured as a translucent material to allow for
visualization of other components). The drug dosage form 800
comprises a rim formed from the second material not admixed with
the drug 805, wherein the rim forms a space 815 on top of the
multi-layered structure (FIG. 8A). A cross-sectional view of the
drug dosage form 800 is illustrated in FIG. 8B. The direction of
erosion of the first erodible material admixed with the drug 810 is
indicated by an arrow 830 (FIG. 8B).
[0250] FIG. 9A shows an exemplary drug dosage form 900 formulated
and configured to provide a desired drug release profile comprising
a multi-layered structure comprising a plurality of layers of a
first erodible material admixed with a drug 910, wherein the first
erodible material is embedded in a second material not admixed with
the drug 920 (pictured as a translucent material to allow for
visualization of other components). The drug dosage form further
comprises a layer of a third erodible material admixed with another
drug 925, wherein the layer of the third erodible material admixed
with the other drug is embedded in the second material not admixed
with the drug (FIG. 9A). The drug dosage form 900 comprises a rim
formed from the second material not admixed with the drug 905,
wherein the rim forms a space 915 on top of the multi-layered
structure (FIG. 9A). A cross-sectional view of the drug dosage form
900 is illustrated in FIG. 9B. The direction of erosion of the
first erodible material admixed with the drug 910 is indicated by
an arrow 930, and the direction of erosion of the third erodible
material admixed with another drug 925 is indicated by an arrow 935
(FIG. 9B).
ADDITIONAL EXEMPLARY EMBODIMENTS
[0251] Embodiment 1. A method for three-dimensional printing of a
drug dosage form formulated and configured to provide a desired
drug release profile, comprising: dispensing a first erodible
material admixed with a drug and a second material not admixed with
the drug to produce a multi-layered structure comprising a
plurality of layers of the first erodible material, wherein the
first erodible material is embedded in the second material, wherein
each layer of the first erodible material has a pre-determined
surface area, thickness, and drug mass fraction, wherein the
pre-determined surface area, thickness, and/or drug mass fraction
correlate with the desired drug release profile, and wherein upon
exposure to a bodily fluid the drug is released in accordance with
the desired drug release profile.
[0252] Embodiment 2. The method of embodiment 1, further comprising
providing the desired drug release profile prior to the dispensing
step.
[0253] Embodiment 3. The method of embodiments 1 or 2, further
comprising creating a virtual image of the drug dosage form prior
to the dispensing step.
[0254] Embodiment 4. The method of any one of embodiments 1-3,
further comprising creating a computer model that contains the
pre-determined parameters prior to the dispensing step.
[0255] Embodiment 5. The method of any one of embodiments 1-4,
further comprising feeding the pre-determined parameters to the
three-dimensional printer prior to the dispensing step.
[0256] Embodiment 6. The method of any one of embodiments 1-5,
wherein the first erodible material admixed with the drug and the
second material not admixed with the drug are dispensed
separately.
[0257] Embodiment 7. The method of any one of embodiments 1-6,
wherein the first erodible material admixed with the drug and the
second material not admixed with the drug are dispensed
sequentially.
[0258] Embodiment 8. The method of any one of embodiments 1-7,
wherein the surface areas of the first erodible material in at
least two of the layers are different from each other.
[0259] Embodiment 9. The method of any one of embodiments 1-8,
wherein the thicknesses of each of the plurality of layers of the
first erodible material are the same.
[0260] Embodiment 10. The method of anyone of embodiments 1-8,
wherein the thickness of at least two of the layers of the first
erodible materials are different from each other.
[0261] Embodiment 11. The method of anyone of embodiments 1-10,
wherein the drug mass fraction in each of the plurality of layers
of the first erodible material are the same.
[0262] Embodiment 12. The method of anyone of embodiments 1-10,
wherein the drug mass fractions in at least two of the layers of
the first erodible materials are different from each other.
[0263] Embodiment 13. The method of anyone of embodiments 1-12,
wherein the second material is a second erodible material.
[0264] Embodiment 14. The method of embodiment 13, wherein the
first erodible material and the second erodible material are
different from each other.
[0265] Embodiment 15. The method of embodiment 13, wherein the
first erodible material and the second erodible material are the
same.
[0266] Embodiment 16. The method of any one of embodiments 1-12,
the second material is an insulating material that is impermeable
to bodily fluid, wherein the insulating material forms a barrier
between the bodily fluid and at least a portion of the
multi-layered structure.
[0267] Embodiment 17. The method of any one of embodiments 13-15,
further comprising dispensing an insulating material that is
impermeable to bodily fluid, wherein the insulating material forms
a barrier between the bodily fluid and at least a portion of the
multi-layered structure.
[0268] Embodiment 18. The method of anyone of embodiments 1-17,
wherein the first erodible material and the second material are
dispensed by different printing heads.
[0269] Embodiment 19. The method of embodiment 17, wherein the
first erodible material, the second material, and the insulating
material are dispensed by different printing heads.
[0270] Embodiment 20. The method of anyone of embodiments 1-19,
wherein the three-dimensional printing is carried out by fused
deposition modeling (FDM).
[0271] Embodiment 21. The method of embodiment 20, wherein the FDM
is non-filament FDM.
[0272] Embodiment 22. The method of anyone of embodiments 1-15,
wherein the first erodible material and the second material have
the same erosion rate.
[0273] Embodiment 23. The method of any one of embodiments 1-22,
wherein the thickness of each layer is no more than about 0.2
mm.
[0274] Embodiment 24. The method of anyone of embodiments 1-15 and
17-23, further comprising dispensing an intermediate material not
admixed with the drug, wherein the intermediate material forms an
intermediate layer between two or more layers of the first erodible
material.
[0275] Embodiment 25. The method of embodiment 24, wherein the
intermediate material is the same as the first erodible material or
the second material.
[0276] Embodiment 26. The method of embodiment 16, further
comprising dispensing an intermediate material not admixed with the
drug, wherein the intermediate material forms an intermediate layer
between two or more layers of the first erodible material.
[0277] Embodiment 27. The method of embodiment 26, wherein the
intermediate material is the same as the first erodible
material.
[0278] Embodiment 28. The method of any one of embodiments 1-27,
wherein the drug is to be released at an increasing rate.
[0279] Embodiment 29. The method of any one of embodiments 1-27,
wherein the drug is to be released at a decreasing rate.
[0280] Embodiment 30. The method of any one of embodiments 1-27,
wherein the drug is to be released at an increasing rate followed
by a decreasing rate, or vice versa.
[0281] Embodiment 31. The method of any one of embodiments 1-27,
wherein the drug is to be released in an oscillating pattern.
[0282] Embodiment 32. The method of anyone of embodiments 1-31,
wherein the drug dosage form further comprises a second drug.
[0283] Embodiment 33. The method of embodiment 32, wherein the
second drug is admixed with the first erodible material.
[0284] Embodiment 34. The method of any one of embodiments 1-33,
further comprising dispensing a third erodible material admixed
with a second drug, wherein the multi-layered structure further
comprises a plurality of layers of the third erodible material,
wherein the third material is embedded in the second material.
[0285] Embodiment 35. The method of embodiment 34, wherein each
layer of the third erodible material has a pre-determined surface
area, thickness, and drug mass fraction, wherein the pre-determined
surface area, thickness, and/or drug mass fraction correlate with a
second desired drug release profile, and wherein upon exposure to
the bodily fluid the second drug is released in accordance with the
second desired drug release profile.
[0286] Embodiment 36. The method of embodiment 34 or 35, wherein
the third erodible material is the same as the first erodible
material.
[0287] Embodiment 37. The method of any one of embodiments 1-36,
wherein the erosion of the first erodible material is pH
dependent.
[0288] Embodiment 38. The method of any one of embodiments 34-37,
wherein the erosion of the third erodible material is pH
dependent.
[0289] Embodiment 39. The method of anyone of embodiments 1-38,
wherein the drug dosage form is an oral drug dosage form.
[0290] Embodiment 40. The method of any one of embodiments 1-39,
wherein the bodily fluid is gastrointestinal fluid.
[0291] Embodiment 41. A method of designing a drug dosage form to
provide a desired drug release profile, wherein the drug dosage
form comprises a multi-layered structure comprising a plurality of
layers of a first erodible material admixed with a drug, wherein
the first erodible material is embedded in a second material not
admixed with the drug, the method comprising: (a) selecting the
first erodible material and the second material for forming the
multi-layered structure; (b) obtaining an erosion rate of first
erodible material; and (c) determining the thickness, surface area,
and/or drug mass fraction in each layer based on the release rate
of the drug and the desired drug release profile.
[0292] Embodiment 42. The method of embodiment 41, further
comprising obtaining the desired drug release profile.
[0293] Embodiment 43. The method of embodiment 41 or 42, further
comprising dispensing the first erodible material admixed with the
drug and the second material not admixed with the drug based on the
determined thickness, surface area, and/or drug mass fraction.
[0294] Embodiment 44. The method of any one of embodiments 41-43,
wherein the multi-layered structure further comprises a plurality
of second layers of a third erodible material admixed with a second
drug, and wherein the method further comprises: determining the
drug release rate of the second drug from the third erodible
material; and determining the thickness, surface area, and/or drug
mass fraction in each second layer based on the release rate of the
second drug and the desired drug release profile.
[0295] Embodiment 45. The method of embodiment 44, further
comprising dispensing the third erodible material admixed with the
second drug based on the determined thickness, surface area, and/or
drug mass fraction.
[0296] Embodiment 46. A method for three-dimensional printing of a
drug dosage form formulated and configured to provide a desired
drug release profile, wherein the drug dosage form comprises a
multi-layered structure comprising a plurality of layers of a first
erodible material admixed with a drug, wherein the first erodible
material is embedded in a second material not admixed with the
drug, the method comprising: (a) determining the thickness, surface
area, and/or drug mass fraction in each layer based on the release
rate of the drug and the desired drug release profile; and (b)
dispensing the first erodible material admixed with the drug and
the second material not admixed with the drug based on the
determined thickness, surface area, and/or drug mass fraction.
[0297] Embodiment 47. The method of any one of embodiments 41-46,
wherein thickness (H) of the layer of the first erodible material
is determined based on the erosion rate of the first erodible
material admixed with the drug (v.sub.E) and the time interval
between two different datapoints on the drug release profile
(t.sub.E), wherein H=t.sub.E*v.sub.E.
[0298] Embodiment 48. The method of embodiment 47, wherein the drug
mass fraction (m.sub.F) in the first erodible material is
determined based on the percentage, in decimal form, of the total
drug in the drug dosage form that is in the layer of the erodible
material admixed with the drug (% L), the total mass of the drug in
the drug dosage form (m.sub.DTot), the density of the erodible
material admixed with the drug (.rho.), and the volume (V.sub.vol)
of the layer of the erodible material, wherein
m F = % L * m DTot .rho. * V vol ##EQU00014##
[0299] Embodiment 49. The method of embodiment 48, wherein the
total surface area (S.sub.t) of the layers of the first erodible
material that are exposed to the bodily fluid at the same time is
determined by the drug mass fraction (m.sub.F) and the thickness of
the layers of first erodible material, wherein
S t = % L * m DTot .rho. * H * m F ##EQU00015##
[0300] Embodiment 50. The method of any one of embodiments 1-40 and
46-49, wherein the method further comprises: i) determining the
drug release profile of the produced drug dosage form; ii)
comparing the drug release profile of the drug dosage form with the
desired drug release profile; and iii) adjusting the design of the
drug dosage form by altering one or more of: the first erodible
material, the second material, the surface area of the one or more
of the layers of the first erodible material, the thickness of one
or more layers of the first erodible material, and the mass
fraction of the drug in one or more layers of the first erodible
material.
[0301] Embodiment 51. A drug dosage form produced according to
anyone of the methods of embodiments 1-50.
[0302] Embodiment 52. The drug dosage form of claim 51, wherein the
drug dosage form further comprises an enteric coating.
[0303] Embodiment 1'. A method for three-dimensional printing of an
oral drug dosage form formulated and configured to provide a
desired drug release profile, wherein the drug dosage form
comprises a multi-layered structure comprising a plurality of
layers of a first erodible material admixed with a drug, wherein
the first erodible material is embedded in a second material not
admixed with the drug, and wherein the second material is an
insulating material that is impermeable to bodily fluid, and
wherein the insulating material forms a barrier between the bodily
fluid and at least a portion of the multi-layered structure, the
method comprising: (a) providing a thickness and drug mass fraction
in each layer; (b) determining the surface area of each layer based
on the release rate of the drug and the desired drug release
profile; and (b) dispensing the first erodible material admixed
with the drug based on the provided thickness and drug mass faction
and determined thickness; and (c) before, after, or during step
(b), dispensing the second material not admixed with the drug.
[0304] Embodiment 2'. The method of embodiment 1', wherein the
surface area on each layer of the first erodible material in the
multi-layered structure is continuous.
[0305] Embodiment 3'. The method of embodiment 1', wherein the
surface area on each layer of the first erodible material in the
multi-layered structure is discontinuous.
[0306] Embodiment 4'. The method of embodiment 1', wherein the
method further comprises dividing the desired drug release profile
into time intervals (t.sub.E) between two different data points on
the drug release profile based on the number of layers of the first
erodible material in the dosage form.
[0307] Embodiment 5'. The method of embodiment 4', wherein the
thickness (H) of the layer of the first erodible material is based
on the erosion rate of the first erodible material admixed with the
drug (v.sub.E) and the time interval (t.sub.E) based on:
H=t.sub.E*v.sub.E
[0308] Embodiment 6'. The method of embodiment 5', wherein the drug
mass fraction (m.sub.F) in the first erodible material is
determined based on the percentage of a total drug in the drug
dosage form that is in the layer of the erodible material admixed
with the drug (% L), a total mass of the drug in the drug dosage
form (m.sub.DTot), a density of the erodible material admixed with
the drug (.rho.), and a volume (V.sub.vol) of the layer of the
erodible material, wherein
m F = % L * m DTot .rho. * V vol ##EQU00016##
[0309] Embodiment 7'. The method of embodiment 6', wherein the
total surface area (S) of the layers of the first erodible material
that are exposed to the bodily fluid at the same time is determined
by a drug mass fraction (m.sub.F) and the thickness of the layers
of first erodible material, wherein
S t = % L * m DTot .rho. * H * m F ##EQU00017##
[0310] Embodiment 8'. The method of any one of embodiments 1'-7',
further comprising: i) determining the drug release profile of the
produced drug dosage form; ii) comparing the drug release profile
of the drug dosage form with the desired drug release profile; and
iii) adjusting the design of the drug dosage form by altering one
or more of: the first erodible material, the second material, the
surface area of the one or more of the layers of the first erodible
material, the thickness of one or more layers of the first erodible
material, and the mass fraction of the drug in one or more layers
of the first erodible material.
[0311] Embodiment 9'. The method of any one of embodiments 1'-8',
further comprising: dispensing a third erodible material admixed
with a second drug and the second material not admixed with the
second drug to produce a structure of the third erodible material,
wherein the third erodible material is embedded in the second
material, and wherein upon exposure to a bodily fluid the second
drug is released in accordance with a second desired drug release
profile.
[0312] Embodiment 10'. The method of any one of embodiments 1'-9',
further comprising: selecting the first erodible material and the
second material for forming the multi-layered structure and
obtaining an erosion rate of the first erodible material prior to
determining the thickness, surface area, and drug mass fraction in
each layer.
[0313] Embodiment 11'. The method of any one of embodiments 1'-10',
further comprising providing the desired drug release profile prior
to the determining step.
[0314] Embodiment 12'. The method of any one of embodiments 1'-11',
further comprising creating a virtual image of the drug dosage form
based on the determined parameters prior to the dispending
step.
[0315] Embodiment 13'. The method of any one of embodiments 1'-12',
wherein the first erodible material admixed with the drug and the
second material not admixed with the drug are dispensed
separately.
[0316] Embodiment 14'. The method of any one of embodiments 1'-13',
wherein the thickness of each layer is no more than about 0.2
mm.
[0317] Embodiment 15'. The method of any one of embodiments 1'-14',
wherein the surface area of each of the plurality of the layers of
the first erodible material in the multi-layered structure
decreases sequentially from the surface to the interior of the oral
dosage form, wherein when the oral dosage form is exposed to a
bodily fluid the plurality of layers are exposed to the bodily
fluid in a sequential pattern, with the layer with the largest
surface area exposed to the bodily fluid first.
[0318] Embodiment 16'. The method of any one of embodiments 1'-15',
wherein the three-dimensional printing is carried out by fused
deposition modeling (FDM).
[0319] Embodiment 17'. The method of embodiment 16', wherein the
FDM is non-filament FDM.
[0320] Embodiment 18'. The method of any one of embodiments 1'-17',
wherein the desired release profile is a pulsed release
profile.
[0321] Embodiment 19'. The method of any one of embodiments 1'-17',
wherein the drug is to be released in a first order release
profile.
[0322] Embodiment 20'. An oral dosage form produced by the method
of any one of embodiments 1'-19'.
[0323] Embodiment 21'. A method or designing an oral drug dosage
form to provide a desired drug release profile, wherein the drug
dosage form comprises a multi-layered structure comprising a
plurality of layers of a first erodible material admixed with a
drug, wherein the first erodible material is embedded in a second
material not admixed with the drug, the method comprising: (a)
selecting the first erodible material and the second material for
forming the oral dosage form comprising the multi-layered
structure; (b) obtaining an erosion rate of first erodible
material; and (c) determining the thickness, surface area, and drug
mass fraction in each layer based on the release rate of the drug
and the desired drug release profile.
[0324] Embodiment 22'. The method of embodiment 24, further
comprising dispensing the first erodible material admixed with the
drug and the second material not admixed with the drug based on the
determined thickness, surface area, and drug mass fraction.
[0325] Embodiment 1''. A method for three-dimensional printing of
an oral drug dosage form formulated and configured to provide a
desired drug release profile, wherein the drug dosage form
comprises a multi-layered structure comprising a plurality of
layers of a first erodible material admixed with a drug, wherein
the first erodible material is embedded in a second material not
admixed with the drug, the method comprising: (a) determining the
thickness, surface area, and drug mass fraction in each layer based
on the release rate of the drug and the desired drug release
profile; and (b) dispensing the first erodible material admixed
with the drug based on the determined thickness, surface area, and
drug mass fraction; and (c) before, after, or during step (b),
dispensing the second material not admixed with the drug.
[0326] Embodiment 2''. The method of embodiment 1, wherein the
second material is a second erodible material.
[0327] Embodiment 3''. The method of embodiment 1, wherein the
second material is an insulating material that is impermeable to
bodily fluid, and wherein the insulating material forms a barrier
between the bodily fluid and at least a portion of the
multi-layered structure.
[0328] Embodiment 4''. The method of anyone of embodiments 1''-3'',
wherein the thickness and drug fraction of each layer of the first
erodible material in the multi-layered structure are constant and
the surface area of in each layer correlates with the desired drug
release profile.
[0329] Embodiment 5''. The method of embodiment 4'', wherein the
surface areas of the first erodible material in at least two of the
layers are different from each other.
[0330] Embodiment 6''. The method of anyone of the embodiments
1''-5'', wherein the surface area of each layer of the first
erodible material in the multi-layered structure is continuous.
[0331] Embodiment 6''. The method of anyone of embodiments 1''-5'',
wherein the surface area of each layer of the first erodible
material in the multi-layered structure is discontinuous.
[0332] Embodiment 7''. The method of any one of embodiments 1-6,
wherein the method further comprises dividing the desired drug
release profile into time intervals (t.sub.E) between two different
data points on the drug release profile based on the number of
layers of the first erodible material in the dosage form.
[0333] Embodiment 8''. The method of embodiment 7'', wherein the
thickness (H) of the layer of the first erodible material is based
on the erosion rate of the first erodible material admixed with the
drug (v.sub.E) and the time interval (t.sub.E) based on:
H=t.sub.E*v.sub.E
[0334] Embodiment 9''. The method of embodiment 8, wherein the drug
mass fraction (m.sub.F) in the first erodible material is
determined based on the percentage, in decimal form, of a total
drug in the drug dosage form that is in the layer of the erodible
material admixed with the drug (% L), a total mass of the drug in
the drug dosage form (m.sub.DTot), a density of the erodible
material admixed with the drug (.rho.), and a volume (V.sub.vol) of
the layer of the erodible material, wherein
m F = % L * m DTot .rho. * V vol ##EQU00018##
[0335] Embodiment 10''. The method of embodiment 9'', wherein the
total surface area (S) of the layers of the first erodible material
that are exposed to the bodily fluid at the same time is determined
by a drug mass fraction (m.sub.F) and the thickness of the layers
of first erodible material, wherein
S t = % L * m DTot .rho. * H * m F ##EQU00019##
[0336] Embodiment 11''. The method of anyone of embodiments
1''-10'', further comprising: i) determining the drug release
profile of the produced drug dosage form; ii) comparing the drug
release profile of the drug dosage form with the desired drug
release profile; and iii) adjusting the design of the drug dosage
form by altering one or more of: the first erodible material, the
second material, the surface area of the one or more of the layers
of the first erodible material, the thickness of one or more layers
of the first erodible material, and the mass fraction of the drug
in one or more layers of the first erodible material.
[0337] Embodiment 12''. The method of any one of embodiments
1''-11'', further comprising: dispensing a third erodible material
admixed with a second drug and the second material not admixed with
the second drug to produce a structure of the third erodible
material, wherein the third erodible material is embedded in the
second material, wherein upon exposure to a bodily fluid the second
drug is released in accordance with a second desired drug release
profile.
[0338] Embodiment 13''. The method of any one of embodiments
1''-12'', further comprising: selecting the first erodible material
and the second material for forming the multi-layered structure and
obtaining an erosion rate of the first erodible material prior to
determining the thickness, surface area, and drug mass fraction in
each layer.
[0339] Embodiment 14''. The method of any one of embodiments
1''-13'', further comprising providing the desired drug release
profile prior to the determining step.
[0340] Embodiment 15''. The method of any one of embodiments
1''-14'', further comprising creating a virtual image of the drug
dosage form based on the determined parameters prior to the
dispending step.
[0341] Embodiment 16''. The method of any one of embodiments
1''-15'', wherein the first erodible material admixed with the drug
and the second material not admixed with the drug are dispensed
separately.
[0342] Embodiment 17''. The method of any one of embodiments
1''-16'', wherein the thickness of each layer is no more than about
0.2 mm.
[0343] Embodiment 18''. The method of any one of embodiments
1''-17'', wherein the surface area of each of the plurality of the
layers of the first erodible material in the multi-layered
structure decreases sequentially from the surface to the interior
of the oral dosage form, wherein when the oral dosage form is
exposed to a bodily fluid the plurality of layers are exposed to
the bodily fluid in a sequential pattern, with the layer with the
largest surface area exposed to the bodily fluid first.
[0344] Embodiment 19''. The method of any one of embodiments
1''-18'', wherein the three-dimensional printing is carried out by
fused deposition modeling (FDM).
[0345] Embodiment 20''. The method of embodiment 19'', wherein the
FDM is non-filament FDM.
[0346] Embodiment 21''. The method of any one of embodiments
1''-20'', wherein the desired release profile is a pulsed release
profile.
[0347] Embodiment 22''. The method of any one of embodiments
1''-20'', wherein the drug is to be released in a first order
release profile.
[0348] Embodiment 23''. An oral dosage form produced by the method
of any one of embodiments 1''-23''.
[0349] Embodiment 24''. A method or designing an oral drug dosage
form to provide a desired drug release profile, wherein the drug
dosage form comprises a multi-layered structure comprising a
plurality of layers of a first erodible material admixed with a
drug, wherein the first erodible material is embedded in a second
material not admixed with the drug, the method comprising: (a)
selecting the first erodible material and the second material for
forming the oral dosage form comprising the multi-layered
structure; (b) obtaining an erosion rate of first erodible
material; and (c) determining the thickness, surface area, and drug
mass fraction in each layer based on the release rate of the drug
and the desired drug release profile.
[0350] Embodiment 25''. The method of embodiment 24'', further
comprising dispensing the first erodible material admixed with the
drug and the second material not admixed with the drug based on the
determined thickness, surface area, and drug mass fraction.
[0351] Embodiment 1'''. A method for three-dimensional printing of
an oral drug dosage form formulated and configured to provide a
desired drug release profile, wherein the drug dosage form
comprises a multi-layered structure comprising a plurality of
layers of a first erodible material admixed with a drug having a
pre-determined drug mass faction (m.sub.F), wherein the first
erodible material is embedded in a second material not admixed with
the drug, the method comprising: (a) dividing the desired drug
release profile into a plurality of time intervals (t.sub.n), each
time interval corresponding to a layer in the multi-layered
structure; (b) calculating the percentage of drugs to be released
during each time interval (%.sub.L); (c) calculating the thickness
of each layer (H.sub.n) of the multi-layered structure based on the
erosion rate of the first erodible material(V), wherein
H.sub.n=t.sub.n*V; (d) calculating the surface area of each layer
based on %.sub.L, H.sub.n, m.sub.F, total amount of drug in the
oral drug dosage form (m.sub.DTot), and the density of the first
erodible material (.rho.), wherein:
S n = % L * m DTot .rho. * Hn * m F ##EQU00020##
[0352] (e) dispensing the first erodible material admixed with the
drug based on the determined H.sub.n and S.sub.n for each layer,
thereby printing the multi-layered structure; (f) before, after, or
during step (e), dispensing the second material not admixed with
the drug.
[0353] Embodiments 2'''. The method of embodiment 1''', further
comprising dispensing a top erodible material not admixed with the
drug on top of the multi-layered structure to form a top layer,
wherein the surface area of the top layer is the same or larger
than the first layer of the multi-layered structure immediately
underneath the top layer.
[0354] Embodiment 3'''. The method of embodiment 2''', wherein the
thickness of the top layer is determined based on the delay time
needed for the drug release from the multi-layered structure.
[0355] Embodiment 4'''. The method of embodiment 2''' or 3''',
wherein the top erodible material is the same as the first erodible
material.
[0356] Embodiment 5'''. The method of embodiment 2''' or 3''',
wherein the top erodible material is different from the first
erodible material.
[0357] Embodiment 6'''. The method of any one of embodiments
1'''-5''', wherein the second material is erodible.
[0358] Embodiment 7'''. The method of embodiment 6''', wherein the
first erodible material and the second material have the same
erosion rate.
[0359] Embodiment 8'''. The method of any one of embodiments
1'''-5''', wherein the second material is an insulating material
that is impermeable to bodily fluid, wherein the insulating
material forms a barrier between the bodily fluid and at least a
portion of the multi-layered structure.
[0360] Embodiment 9'''. The method of any one of embodiments
1'''-8''', further comprising dispensing an insulating material
that is impermeable to bodily fluid, wherein the insulating
material forms a barrier between the bodily fluid and at least a
portion of the multi-layered structure.
[0361] Embodiment 10'''. The method of any embodiments 1'''-9''',
further comprising dispensing an intermediate material not admixed
with the drug, wherein the intermediate material forms one or more
intermediate layers between two or more layers of the first
erodible material.
[0362] Embodiment 11'''. The method of embodiment 10''', wherein
the intermediate material is the same as the first erodible
material.
[0363] Embodiment 12'''. The method of embodiment 10''', wherein
the intermediate layer is different from the first erodible
material.
[0364] Embodiment 13'''. The method of anyone of embodiments
1'''-12''', wherein the three-dimensional printing is carried out
by fused deposition modeling (FDM).
[0365] Embodiment 14'''. The method of embodiment 14''', wherein
the FDM is non-filament FDM.
[0366] Embodiment 15'''. The method of anyone of embodiments
1'''-14'', wherein the first erodible material and the second
material are printed by different printing heads.
[0367] Embodiment 16'''. The method of anyone of embodiments
2'''-15''', wherein the first erodible material and the top
erodible material are printed by different printing heads.
[0368] Embodiment 17'''. The method of anyone of embodiments
9'''-16''', wherein the first erodible material, the second
erodible material, and the insulating material are printed by a
different printing heads.
[0369] Embodiment 18'''. The method of anyone of embodiments
1'''-17''', further comprising: i) determining the drug release
profile of the oral drug dosage form produced by the method of any
one of embodiments 1-17; ii) comparing the drug release profile of
the oral drug dosage form with the desired drug release profile;
iii) adjusting one or more parameters selected from: the first
erodible material, the second material, the surface area of the one
or more of the layers of the first erodible material, the thickness
of one or more layers of the first erodible material, and the mass
fraction of the drug in one or more layers of the first erodible
material; and iv) three-dimensional printing of a second oral drug
dosage form based on the adjusted parameters.
[0370] Embodiment 19'''. The method of anyone of embodiments
1'''-18''', wherein the release profile of the oral drug dosage
form or second drug oral dosage form is equivalent to the desired
release profile based on Chow's method or similarity factor
calculation method.
[0371] Embodiment 20'''. The method of anyone of embodiments
1'''-19''', further comprising creating a virtual image of the drug
dosage form prior to the dispending steps.
[0372] Embodiment 21'''. The method of anyone of embodiments
1'''-20''', further comprising creating a computer model that
contains the pre-determined parameters prior to the dispensing
step.
[0373] Embodiment 22'''. The method of any one of embodiments
1'''-21''', further comprising feeding the pre-determined
parameters to the three-dimensional printer prior to the dispensing
step.
[0374] Embodiment 23'''. The method of anyone of embodiments
1'''-22''', wherein the surface area of each of the plurality of
the layers of the first erodible material in the multi-layered
structure decreases sequentially from the surface to the interior
of the oral dosage form, wherein when the oral dosage form is
exposed to a bodily fluid the plurality of layers are exposed to
the bodily fluid in a sequential pattern, with the layer with the
largest surface area exposed to the bodily fluid first.
[0375] Embodiment 24'''. The method of anyone of embodiments
1'''-23''', wherein the oral drug dosage form comprises two or more
multi-layered structures.
[0376] Embodiment 25'''. A method for three-dimensional printing of
an oral drug dosage form formulated and configured to provide a
first desired drug release profile and a second desired drug
release profile, wherein the drug dosage form comprises a first
multi-layered structure comprising a plurality of layers of a first
erodible material admixed with a drug having a pre-determined drug
mass faction (m.sub.F), wherein the first erodible material is
embedded in a second material not admixed with a first drug, and a
second multi-layered structure comprising a plurality of layers of
a third erodible material admixed with a fourth drug having a
pre-determined drug mass faction, wherein the third erodible
material is embedded in a fourth material not admixed with the
drug, the method comprising: (a) dividing each of the desired drug
release profile into a plurality of time intervals (ta), each time
interval corresponding to a layer in a corresponding multi-layered
structure; (b) calculating the percentage of drugs to be released
during each time interval (%.sub.L); (c) calculating the thickness
of each layer (H.sub.n) of the multi-layered structures based on
the erosion rate of the first erodible material or third erodible
material (V), wherein H.sub.n=t.sub.n*V; (d) calculating the
surface area of each layer based on %.sub.L, H.sub.n, m.sub.F,
total amount of drug in the oral drug dosage form (m.sub.DTot), and
the density of the first or first erodible material (.rho.),
wherein:
S n = % L * m DTot .rho. * Hn * m F ##EQU00021##
(e) dispensing the first erodible material admixed with the first
drug and third erodible material admixed with the second drug based
on the determined H.sub.n and S.sub.n for each layer, thereby
printing the two multi-layered structures; and (f) before, after,
or during step (e), dispensing the second material and fourth
material not admixed with the drug.
[0377] Embodiment 26'''. The method of embodiment 25''', wherein
the first erodible material and the third erodible material are the
same.
[0378] Embodiment 27'''. The method of embodiment 25''' or 26''',
wherein the second and fourth materials are the same.
[0379] Embodiment 28'''. The method of anyone of embodiments
25'''-27''', wherein the first drug and the second drug are the
same.
[0380] Embodiment 29'''. The method of any one of embodiments
25-28, wherein the first drug and the second drug are
different.
[0381] Embodiment 30'''. An oral dosage form produced by the method
of any one of embodiments 1'''-29'''.
[0382] It will also be understood by those skilled in the art that
changes in the form and details of the implementations described
herein may be made without departing from the scope of this
disclosure. In addition, although various advantages, aspects, and
objects have been described with reference to various
implementations, the scope of this disclosure should not be limited
by reference to such advantages, aspects, and objects. Rather, the
scope of this disclosure should be determined with reference to the
appended claims.
[0383] The disclosure is illustrated further by the following
examples, which are not to be construed as limiting the disclosure
in scope or spirit to the specific procedures described in
them.
EXAMPLES
Example 1
Designing an Oral Drug Dosage Form to Provide Desired Drug Release
Profiles
[0384] This example demonstrates designing an oral drug dosage form
comprising an ADHD non-stimulant (clonidine, 0.1 mg) and an ADHD
stimulant (dextromethylphenidate, 2.5 mg), wherein the ADHD
non-stimulant has a sustained release profile and the ADHD
stimulant has a fast release profile.
[0385] The desired drug release profile was selected for the
sustained release profile of clonidine (see FIG. 10). The desired
drug release profile of the ADHD non-stimulant was segmented into
six time sections. The time after administration (hours) was then
tabulated with the cumulative percentage of clonidine released from
the drug dosage form after administration (Table 1).
TABLE-US-00001 TABLE 1 Cumulative percentage of clonidine release
after administration. Time after Cumulative percentage
administration of clonidine released (hours) (%) 1 25 2 40 4 65 6
80 10 95 12 100
[0386] Using this information, the percentage of total clonidine
released form the drug dosage form was tabulated per time section
(Table 2). As shown in Table 2, each time section corresponds to a
layer of the multi-layered structure of the drug dosage form.
TABLE-US-00002 TABLE 2 Percentage of total clonidine released per
layer. Percentage of total Erosion time clonidine released Layer
No. (hour) (%) 1 1 25 2 1 15 3 2 25 4 2 15 5 4 15 6 2 5
[0387] Using the information from Table 2, a hypothetical erosion
rate of the erodible material for the layers of the multi-layered
structure was calculated using hypothetical ranges of layer
thicknesses that were appropriate for a 3D printed oral drug dosage
form (e.g., an oral dosage form that may be printed, e.g., minimum
overall dimensions greater than 2 mm, but was not too large for
oral administration, e.g., less than 25 mm).
[0388] From a database of possible erodible materials that would
provide the desired erosion rate, hydroxyl propyl cellulose (HPC)
admixed with triethyl citrate (TEC) (weight ratio of HPC: TEC of
79.68:19.92) was selected as the erodible material for the
multi-layered structure (erosion rate of 0.13 mm/hour). The erosion
rate of HPC admixed with TEC was confirmed not to change when the
material was admixed with an appropriate range of amounts of
clonidine. Using the erosion rate of HPC admixed with TEC and the
information in Table 2, the thickness of each of the six layers of
the multi-layered structure was calculated using Formula III. The
thickness of each of the six layers is listed in Table 3.
TABLE-US-00003 TABLE 3 Thickness of each layer. Erosion time Layer
thickness Layer No. (hour) (mm) 1 1 0.13 2 1 0.13 3 2 0.26 4 2 0.26
5 4 0.52 6 2 0.26
[0389] Next, the surface area and amount of drug compound (e.g.,
drug) mass fraction, of each layer of the multi-layered structure
were calculated using Formula V. A single drug mass fraction of the
HPC:TEC admixed with clonidine was selected to allow for use of one
printer head containing the erodible material comprising clonidine
for production of the oral drug dosage form. Using this
information, the layers of the multi-layered structure were
selected to be cylindrical in shape and the multi-layered structure
was drawn for 3D printing conforming to the surface area and
thickness calculated for each layer.
[0390] The fast release profile, e.g., instant or immediate
release, of the ADHD stimulant dextromethylphenidate was selected
to provide release at least 80% of the total dextromethylphenidate
within 15 minutes of oral administration. Vinylpyrrolidone-vinyl
acetate copolymer (VA64) admixed with TEC (weight ratio of VA64:
TEC of 79.2:8.10) was selected as the erodible material for
admixture with dextromethylphenidate (2.5 mg). The total weight of
the VA64:TEC:dextromethylphenidate material was measured as 25 mg.
Then the density and volume of the VA64:TEC:dextromethylphenidate
material were determined. Using this information, the
VA64:TEC:dextromethylphenidate material structure was drawn for 3D
printing (cylindrical structure with a 0.52 mm thickness and a
diameter of 6.8 mm).
[0391] Using the parameters of the multi-layered structure
comprising clonidine and the single-layered disc comprising
dextromethylphenidate, an oral drug dosage form was compiled by
embedding the structures in an insulating material, namely,
EUDRAGIT.RTM. RSPO (RSPO), wherein the multi-layered structure and
the single-layered disc were separated with insulating material
(such as shown in FIG. 9B). The oral drug dosage form was printed
using non-filament FDM (for initial printing and testing
dextromethylphenidate was substituted with propranolol HCl).
[0392] The oral drug dosage form was tested using in vitro
dissolution testing (similarity factor (f2) testing was used for
statistical analysis). It was determined that the top layer (layer
no. 1) of the multi-layered structure eroded at a faster rate than
expected. In order to improve the clonidine release profile of the
oral drug dosage form, the top three layers (layer nos. 1-3; Table
2) were merged into a single layer with parameters that would meet
the desired drug release profile. Furthermore, the surface area of
the original top layer was adjusted to reduce the surface area as
compared to the original layer. The adjusted oral drug dosage form
was printed using non-filament FDM (for initial printing and
testing dextromethylphenidate was substituted with propranolol HCl)
and in vitro dissolution testing was performed to demonstrate
compliance with the desired drug release profiles. The in vitro
dissolution release profile of the adjusted printed oral drug
dosage form demonstrated statistical similarity using similarity
factor (f2) statistical analysis.
* * * * *