U.S. patent application number 16/200127 was filed with the patent office on 2019-03-28 for controlled release dosage form for once daily administration of dimethyl fumarate.
This patent application is currently assigned to Biogen MA Inc.. The applicant listed for this patent is Biogen MA Inc.. Invention is credited to Jinquan Dong, Shyam B. Karki, Michael Kaufman, Cheuk-Yui Leung, Ernest Quan, Kalyan Vasudevan, Peter Zawaneh.
Application Number | 20190091146 16/200127 |
Document ID | / |
Family ID | 52293226 |
Filed Date | 2019-03-28 |
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United States Patent
Application |
20190091146 |
Kind Code |
A1 |
Zawaneh; Peter ; et
al. |
March 28, 2019 |
Controlled Release Dosage Form for Once Daily Administration of
Dimethyl Fumarate
Abstract
A controlled release dosage form containing monomethyl fumarate,
a compound that can be metabolized into monomethyl fumarate in
vivo, or a pharmaceutically acceptable salt thereof or combinations
thereof wherein the monomethyl fumarate, a compound that can be
metabolized into monomethyl fumarate in vivo, or a pharmaceutically
acceptable salt thereof or combinations thereof is delivered to the
subject. Also provided is a method of treating a disease or
disorder (e.g., multiple sclerosis) by orally administering a
controlled release dosage form containing monomethyl fumarate, a
compound that can be metabolized into monomethyl fumarate in vivo,
or a pharmaceutically acceptable salt thereof or combinations
thereof, wherein the monomethyl fumarate, a compound that can be
metabolized into monomethyl fumarate in vivo, or a pharmaceutically
acceptable salt thereof or combinations thereof.
Inventors: |
Zawaneh; Peter; (Brookline,
MA) ; Karki; Shyam B.; (Hillsborough, NJ) ;
Kaufman; Michael; (Lexington, MA) ; Leung;
Cheuk-Yui; (Acton, MA) ; Dong; Jinquan;
(Stoneham, MA) ; Quan; Ernest; (East Lyme, CT)
; Vasudevan; Kalyan; (Cambridge, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Biogen MA Inc. |
Cambridge |
MA |
US |
|
|
Assignee: |
Biogen MA Inc.
Cambridge
MA
|
Family ID: |
52293226 |
Appl. No.: |
16/200127 |
Filed: |
November 26, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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15102306 |
Jun 7, 2016 |
10172794 |
|
|
PCT/US2014/070058 |
Dec 12, 2014 |
|
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16200127 |
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61916115 |
Dec 13, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/5042 20130101;
A61K 31/22 20130101; A61K 9/2031 20130101; A61K 9/2853 20130101;
A61K 9/5026 20130101; A61P 25/00 20180101; A61K 9/5047 20130101;
A61K 9/2086 20130101; A61K 9/2027 20130101; A61K 9/5031 20130101;
A61K 9/5073 20130101; A61K 9/2866 20130101; A61K 9/0065 20130101;
A61K 9/4808 20130101; A61K 9/14 20130101; A61K 9/2054 20130101;
A61K 9/0004 20130101; A61K 9/2846 20130101; A61K 9/2886
20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 9/20 20060101 A61K009/20; A61K 9/28 20060101
A61K009/28; A61K 9/50 20060101 A61K009/50; A61K 9/14 20060101
A61K009/14; A61K 9/48 20060101 A61K009/48; A61K 31/22 20060101
A61K031/22 |
Claims
1. A controlled release dosage form comprising an active agent
selected from the group consisting of monomethyl fumarate, a
compound that can be metabolized into monomethyl fumarate in vivo,
or a pharmaceutically acceptable salt thereof and combinations
thereof, wherein the active agent is retained in the stomach and/or
small intestine of a subject treated for at least 3 hours.
2. The controlled release dosage form of claim 1, wherein the
dosage form swells when exposed to gastric fluid, thereby retaining
the active agent in the stomach.
3. The controlled release dosage form of claim 1, wherein the
dosage form floats when exposed to gastric fluid, thereby retaining
the active agent in the stomach.
4. The controlled release dosage form of claim 1, wherein the
dosage form is a mucoadhesive dosage form, wherein the active agent
is retained in the small intestine.
5. The controlled release dosage form of claim 1, wherein the
active agent has a particle size of about 50 um to about 500 um,
wherein the active agent is retained in the small intestine.
6. The controlled release dosage form of claim 1, wherein the
dosage form is in the form of a matrix.
7. The controlled release dosage form of claim 1, wherein the
dosage form is an osmotic dosage form.
8. The controlled release dosage form of any one of claims 1-7,
wherein subjects administered the controlled release dosage exhibit
one or more of the pharmacokinetic parameters consisting of (a) a
mean plasma MMF AUC.sub.overall m ranging from about 4.81 hmg/L to
about 11.2 hmg/L; (b) a mean plasma MMF AUC.sub.0-12 ranging from
about 2.4 hmg/L to about 5.5 hmg/L; and (c) a mean
AUC.sub.0-infinity ranging from about 2.4 hmg/L to about 5.6
hmg/L.
9. A unit dosage form comprising (a) a first dosage component
comprising a first dose of monomethyl fumarate, a compound that can
be metabolized into monomethyl fumarate in vivo, or a
pharmaceutically acceptable salt thereof or combinations thereof;
and (b) a second dosage component comprising a second dose of
monomethyl fumarate, a compound that can be metabolized into
monomethyl fumarate in vivo, or a pharmaceutically acceptable salt
thereof or combinations thereof; wherein when the unit dosage form
is administered to a subject orally, the first and second doses of
monomethyl fumarate, a compound that can be metabolized into
monomethyl fumarate in vivo, or a pharmaceutically acceptable salt
thereof or combinations thereof are delivered in a sustained or
pulsatile manner, and wherein the second dose is retained in the
stomach and/or small intestine of a subject treated for at least 3
hours.
10. The unit dosage form of claim 9, wherein first and the second
doses are delivered in a pulsatile manner and the pulsatile manner
is characterized by a lag time of about 2 hours to about 14 hours
between delivery of the first and second doses of monomethyl
fumarate, a compound that can be metabolized into monomethyl
fumarate in vivo, or a pharmaceutically acceptable salt thereof or
combinations thereof.
11. The unit dosage form of claim 10, wherein the lag time is about
8 hours to about 12 hours.
12. The unit dosage form of any of claims 9-11, wherein the second
dosage component is a controlled release dosage form selected from
the group consisting of a swellable dosage form, a floating dosage
form, a mucoadhesive dosage form, a matrix, an osmotic dosage form,
and a combination thereof.
13. The unit dosage form of claim 12, wherein the controlled
release dosage form has a gastric residence time of about 4 hours
to about 18 hours.
14. The unit dosage form of claim 13, wherein the second dosage
component has a gastric residence time of about 8 hours to about 14
hours.
15. The unit dosage form of any of claims 9-14, wherein the first
dosage component is in a form of micro-pellets, micro-tablets,
capsules, granulates, or tablets.
16. The unit dosage form of claim 9 or 10, wherein the first dosage
component is an enterically coated immediate release dosage
form.
17. The unit dosage form of any of claims 9 or 10, wherein the
first dosage component is in the form of microtablets, wherein the
microtablets are enteric-coated.
18. The unit dosage form of any of claims 9 or 10, wherein the
first dosage component is in the form enteric-coated crystals or
particles.
19. The controlled release dosage form of any of claims 1-7,
wherein the controlled release dosage form contains about 80 mg to
about 1000 mg monomethyl fumarate, a compound that can be
metabolized into monomethyl fumarate in vivo, or a pharmaceutically
acceptable salt thereof or combinations thereof.
20. The unit dosage form of any of claims 9-18, wherein the first
dose of monomethyl fumarate, a compound that can be metabolized
into monomethyl fumarate in vivo, or a pharmaceutically acceptable
salt thereof or combinations thereof in the first dosage component
is about 80 mg to about 1000 mg monomethyl fumarate, a compound
that can be metabolized into monomethyl fumarate in vivo, or a
pharmaceutically acceptable salt thereof or combinations
thereof.
21. The unit dosage form of any of claims 9-18, wherein the second
dose of monomethyl fumarate, a compound that can be metabolized
into monomethyl fumarate in vivo, or a pharmaceutically acceptable
salt thereof or combinations thereof in the second dosage component
is about 80 mg to about 1000 mg monomethyl fumarate, a compound
that can be metabolized into monomethyl fumarate in vivo, or a
pharmaceutically acceptable salt thereof or combinations
thereof.
22. The unit dosage form of any one of claims 9-18, 20, and 21,
wherein subjects administered the unit dosage form exhibit one or
more of the pharmacokinetic parameters consisting of (a) a mean
plasma MMF AUC.sub.overall ranging from about 4.81 hmg/L to about
11.2 hmg/L; (b) a mean plasma MMF AUC.sub.0-12 ranging from about
2.4 hmg/L to about 5.5 hmg/L; and (c) a mean AUC.sub.0-infinity
ranging from about 2.4 hmg/L to about 5.6 hmg/L.
23. The unit dosage form of any of claims 9-18 and 20-22, wherein
the first dosage component consists essentially of a plurality of
enteric-coated monomethyl fumarate, a compound that can be
metabolized into monomethyl fumarate in vivo, or a pharmaceutically
acceptable salt thereof or combinations thereof microtablets or
micropellets.
24. The unit dosage form of claim 23, wherein the enteric-coated
monomethyl fumarate, a compound that can be metabolized into
monomethyl fumarate in vivo, or a pharmaceutically acceptable salt
thereof or combinations thereof microtablets or micropellets in the
first dosage component have a mean diameter of 5,000 microns or
less.
25. A method for the treatment or prophylactic treatment of a
disease or disorder in a subject in need thereof, the method
comprising administering to the subject a controlled release dosage
form or unit dosage form of any of claims 1-24 once per day,
wherein the disease or disorder is (1) an autoimmune disease
selected from the group consisting of polyarthritis, especially
rheumatoid arthritis, multiple sclerosis, graft-versus-host
reactions, juvenile-onset diabetes, Hashimoto's thyroiditis,
Grave's disease, systemic Lupus erythematodes (SLE), Sjogren's
syndrome, pernicious anaemia and chronic active (=lupoid)
hepatitis, psoriasis, psoriatic arthritis, neurodermatitis and
enteritis regionalis Crohn; (2) a mitochondrial disease selected
from the group consisting of Parkinson syndrome, Alzheimer's
disease, Chorea Huntington disease, retinopathia pigmentosa or
forms of mitochondrial encephalomyopathy; (3) a NF-kappaB mediated
diseases selected from the group consisting of progressive systemic
sclerodermia, osteochondritis syphilitica (Wegener's disease),
cutis marmorata (livedo reticularis), Behcet disease,
panarteriitis, colitis ulcerosa, vasculitis, osteoarthritis, gout,
artenosclerosis, Reiter's disease, pulmonary granulomatosis, types
of encephalitis, endotoxic shock (septic-toxic shock), sepsis,
pneumonia, encephalomyclitis, anorexia nervosa, hepatitis (acute
hepatitis, chronic hepatitis, toxic hepatitis, alcohol-induced
hepatitis, viral hepatitis, jaundice, liver insufficiency and
cytomegaloviral hepatitis), Rennert T-lymphomatosis, mesangial
nephritis, post-angioplastic restenosis, reperfusion syndrome,
cytomegaloviral retinopathy, adenoviral diseases such as adenoviral
colds, adenoviral pharyngoconjunctival fever and adenoviral
ophthalmia, AIDS, Guillain-Barre syndrome, post-herpetic or
post-zoster neuralgia, inflammatory demyelinising polyneuropathy,
mononcuropathia multiplex, mucoviscidosis, Bcchterew's disease,
Barett ocsophagus, EBV (Epstein-Barr virus) infection, cardiac
remodeling, interstitial cystitis, diabetes mellitus type II, human
tumour radiosensitisation, multi-resistance of malignant cells to
chemotherapeutic agents (multidrug resistance in chemotherapy),
granuloma annulare and cancers such as mamma carcinoma, colon
carcinoma, melanoma, primary liver cell carcinoma, adenocarcinoma,
kaposi's sarcoma, prostate carcinoma, leukaemia such as acute
myeloid leukaemia, multiple myeloma (plasmocytoma), Burkitt
lymphoma and Castleman tumour; (4) a cardiovascular disease
selected from the group consisting of cardiac insufficiency,
myocardial infarct, angina pectoris and combinations thereof; (5) a
respiratory disease selected from the group consisting of asthma,
chronic obstructive pulmonary diseases, PDGF induced thymidine
uptake of bronchial smooth muscle cells, bronchial smooth muscle
cell proliferation, and combinations thereof; (6) a
neurodegeneration or neuroinflammation selected from the group
consisting of Adrenal Leukodystrophy (ALD), Alcoholism, Alexander's
disease, Alper's disease, Alzheimer's disease, Amyotrophic lateral
sclerosis (Lou Gehrig's Disease), Ataxia telangiectasia, Batten
disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease),
Bovine spongiform encephalopathy (BSE), Canavan disease, Cerebral
palsy, Cockayne syndrome, Corticobasal degeneration,
Creutzfeldt-Jakob disease, Familial Fatal Insomnia, Frontotemporal
lobar degeneration, Huntington's disease, HIV-associated dementia,
Kennedy's disease, Krabbe's disease, Lewy body dementia,
Neuroborreliosis, Machado-Joseph disease (Spinocerebellar ataxia
type 3), Multiple System Atrophy, Multiple sclerosis, Narcolepsy,
Niemann Pick disease, Parkinson's disease, Pelizaeus-Merzbacher
Disease, Pick's disease, Primary lateral sclerosis, Prion diseases,
Progressive Supranuclear Palsy, Refsum's disease, Sandhoff disease,
Schilder's disease, Subacute combined degeneration of spinal cord
secondary to Pernicious Anaemia, Spielmeyer-Vogt-Sjogren-Batten
disease (also known as Batten disease), Spinocerebellar ataxia,
Spinal muscular atrophy, Steele-Richardson-Olszewski disease, Tabes
dorsalis, Toxic encephalopathy, LHON (Leber's Hereditary optic
neuropathy), MELAS (Mitochondrial Encephalomyopathy; Lactic
Acidosis; Stroke), MERRF (Myoclonic Epilepsy; Ragged Red Fibers),
PEO (Progressive External Opthalmoplegia), Leigh's Syndrome, MNGIE
(Myopathy and external ophthalmoplegia; Neuropathy;
Gastro-Intestinal; Encephalopathy), Kearns-Sayre Syndrome (KSS),
NARP, Hereditary Spastic Paraparesis, Mitochondrial myopathy, and
Friedreich Ataxia; or (7) a demyelinating neurological disorder
selected from the group consisting of optic neuritis, acute
inflammatory demyelinating polyneuropathy (AIDP), chronic
inflammatory demyelinating polyneuropathy (CIDP), acute transverse
myelitis, progressive multifocal leukoencephalopathy (PML), acute
disseminated encephalomyelitis (ADEM) or other hereditary disorders
(e.g., leukodystrophies, Leber's optic atrophy, and
Charcot-Marie-Tooth disease).
26. A method of treating multiple sclerosis in a subject in need
thereof, comprising administering to the subject a controlled
release dosage form or a unit dosage form of any of claims 1-24
once per day.
Description
FIELD OF INVENTION
[0001] The present invention generally relates to controlled
release dosage form for once daily administration of dimethyl
fumarate (DMF) and uses thereof.
BACKGROUND OF THE INVENTION
[0002] TECFIDERA.TM. has been approved by the U.S. Food and Drug
Administration for the treatment of patients with relapsing forms
of multiple sclerosis (MS). TECFIDERA.TM. contains dimethyl
fumarate (DMF), which has the following structure:
##STR00001##
[0003] The starting dose for TECFIDERA.TM. is 120 mg twice a day
orally. After 7 days, the dose is to be increased to the
maintenance dose of 240 mg twice a day orally. TECFIDERA.TM. can be
taken with or without food.
[0004] There is currently no FDA approved once a day dosing
regimen, i.e., QD dosing, for DMF. One objective of the present
invention is to develop a formulation (e.g., a unit dosage form)
that is suitable for once a day dosing.
BRIEF SUMMARY OF THE INVENTION
[0005] In various embodiments, the invention provides a controlled
release dosage form that releases MMF, a compound that can be
metabolized into MMF in vivo (e.g., DMF), or a pharmaceutically
acceptable salt thereof or combinations thereof (collectively
"API"), in the gastrointestinal ("GI") tract of a subject in a
sustained or pulsatile manner. In some embodiments, the API in the
controlled release dosage form is retained in the stomach and/or
small intestine of a subject treated for at least 3 hours (e.g.,
about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7
hours, about 8 hours, about 9 hours, about 10 hours, about 11
hours, about 12 hours, about 13 hours, about 14 hours, about 15
hours, about 16 hours, about 17 hours, or any ranges thereof). In
some embodiments, the controlled release dosage form is a matrix
dosage form, an osmotic dosage form, a gastric retention dosage
form, an intestinal retention dosage form, or a combination
thereof. In some embodiments, a daily amount of the API (e.g., 480
mg of DMF) is provided by one or more units of the controlled
release dosage system alone. In some embodiments, the daily amount
of the API is provided by one or more units of the controlled
release dosage form in combination with one or more units of an
enterically coated immediate release dosage form.
[0006] In some embodiments, the invention provides a matrix dosage
form for delivering an API to a subject treated. In some aspects,
the matrix dosage form releases the API in the GI tract of a
subject in a sustained period of time from about 2 to about 24
hours (e.g., about 2, about 4, about 6, about 8, about 10, about
12, about 14, about 16, about 18, about 20, about 22, or about 24
hours). In some aspects, the matrix dosage form exhibits zero-order
release of the API. In some embodiments, the matrix dosage form
comprises a bilayer or monolithic tablet. In some aspects, the
matrix dosage form comprises a plurality of microtablets. In some
aspects, the bilayer or monolithic tablet or the microtablets are
coated (e.g., enterically coated).
[0007] In some embodiments, the invention provides an osmotic
dosage form for delivering an API to a subject treated. In some
aspects, the osmotic dosage form releases the API in the GI tract
of a subject in a sustained period of time from about 2 to about 24
hours (e.g., about 2, about 4, about 6, about 8, about 10, about
12, about 14, about 16, about 18, about 20, about 22, or about 24
hours). In some aspects, the osmotic dosage form comprises an
osmotic monolithic tablet.
[0008] In some embodiments, the invention provides a gastric
retention dosage form for delivering an API to a subject treated.
In some aspects, the gastric retention dosage form releases the API
in the GI tract of a subject (e.g. in the stomach or the small
intestine) treated in a sustained period of time (e.g., about 2,
about 4, about 6, about 8, about 10, about 12, about 14, about 16,
about 20, or about 24 hours). In some aspects, the gastric
retention dosage form, by itself or in combination with a second
dosage form (enterically coated immediate release or delayed
release), releases the API in the GI tract of a subject in a
pulsatile manner with a lag time from about 2 hours to about 14
hours (e.g., about 2 hours, about 4 hours, about 6 hours, about 8
hours, about 10 hours, about 12 hours, about 14 hours, or any
ranges thereof).
[0009] In some aspects, the gastric retention dosage form is
retained in the stomach, for example, has a gastric retention time
of from about 0.2 hour to about 18 hours (e.g., about 0.2 hour,
about 0.5 hour, about 1 hour, about 2 hours, about 3 hours, about 4
hours, about 6 hours, about 8 hours, about 10 hours, about 12
hours, about 14 hours, about 16 hours, about 18 hours, or any
ranges thereof).
[0010] In some aspects, the gastric retention dosage form is a
floating dosage form. In some aspects, the floating dosage form is
a floating tablet (e.g., a bilayer or a trilayer tablet) or a
floating capsule. In some aspects, the floating dosage form is a
sustained release dosage form. In some aspects, the floating dosage
form is a delayed release dosage form, which when administered
together with a second dosage form (e.g., an enterically coated
immediate release dosage form, or a delayed release dosage form)
provides a pulsatile release of the API with a lag time from about
2 hours to about 14 hours (e.g., about 2 hours, about 4 hours,
about 6 hours, about 8 hours, about 10 hours, about 12 hours, about
14 hours, or any ranges thereof).
[0011] In some aspects, the gastric retention dosage form is a
swelling dosage form. In some aspects, the swelling dosage form is
a swelling tablet (e.g., a monolithic, bilayer, or trilayer tablet)
or a swelling sheet. In some aspects, the swelling dosage form is a
sustained release dosage form. In some aspects, the swelling dosage
form is a delayed release dosage form, which when administered
together with a second dosage form (e.g., an enterically coated
immediate release dosage form, or a delayed release dosage form)
provides a pulsatile release of the API with a lag time from about
2 hours to about 14 hours (e.g., about 2 hours, about 4 hours,
about 6 hours, about 8 hours, about 10 hours, about 12 hours, about
14 hours, or any ranges thereof).
[0012] In some embodiments, the invention provides an intestinal
retention dosage form for delivering an API to a subject treated.
In some aspects, the intestinal retention dosage form releases the
API in the GI tract of a subject in a sustained period of time
(e.g., about 2, about 4, about 6, about 8, about 10, about 12,
about 14, about 16, about 18, about 20, about 22, or about 24
hours). In some aspects, the intestinal retention dosage form
comprises a mucoadhesive dosage form, which is adhesive to mucosal
surface of the gastrointestinal tract (e.g., small intestine) of a
subject treated. In some aspects, the intestinal retention dosage
form comprises a dosage form comprising a plurality of particles
having a mean diameter of about 50 microns to about 1000 microns
(e.g., about 50, 100, 150, 200, 300, 400, 500, 750, 1,000 microns,
or any ranges thereof) that are retained in the GI tract (e.g.,
small intestine) for an extended period of time from about 2 hours
to about 12 hours (e.g., about 2, 3, 4, 5, 6, 7, 8, 10, 12, or any
ranges thereof). In some aspects, the particles have a mean
diameter of about 100 microns to about 500 microns.
[0013] In some embodiments, a daily amount of the API is provided
by one or more units (e.g., 1, 2, 3, 4, or 5) of the controlled
release dosage form described above (e.g., matrix dosage form,
osmotic dosage form, gastric retention dosage form, or intestinal
retention dosage form). In some embodiments, the daily amount of
the API is provided by a single unit of the controlled release
dosage form described above, i.e., one unit per day. In some
embodiments, the daily amount of the API is provided by one or more
units (e.g., 1, 2, 3, 4, or 5) of the controlled release dosage
form described above and one or more units (e.g., 1, 2, 3, 4, or 5)
of an enterically coated immediate release dosage form (e.g., as
described herein).
[0014] Certain embodiments of the invention are directed to
pulsatile delivery of an API to a subject treated. In some
embodiments, the invention provides a system that delivers to the
GI tract (e.g., upper GI tract or lower GI tract (e.g., the small
intestine)) of a subject treated, more than one dose of the API, in
a pulsatile manner.
[0015] Certain embodiments of the invention are directed to a
pharmaceutical formulation, wherein the pharmaceutical formulation
when orally dosed to a subject, delivers to the GI tract (e.g.,
upper GI tract or lower GI tract (e.g., the small intestine)) of
the subject treated more than one dose of an API, in a pulsatile
manner.
[0016] In some embodiments, the invention provides a unit dosage
form. In some aspects, the unit dosage form is a single unit of one
of the controlled release dosage forms described above (e.g., one
unit of matrix dosage form, osmotic dosage form, gastric retention
dosage form, or intestinal retention dosage form). In some aspects,
the unit dosage form, which when orally dosed to a subject,
delivers more than one dose of an API, wherein the unit dosage form
comprises:
[0017] (a) a first dosage component comprising a first dose of the
API; and
[0018] (b) a second dosage component comprising a second dose of
the API.
[0019] In some aspects, the second dosage component is one of the
controlled release dosage forms described above. In another
embodiment, the first dosage component is an enterically coated
immediate release dosage form.
[0020] In some aspects, the pulsatile manner is characterized by a
lag time of about 2 hours to about 14 hours (e.g., about 8 hours to
about 12 hours) between delivery of the first and second doses of
the API.
[0021] In some aspects, a subject orally administered a controlled
release dosage form or an unit dosage form described above (with or
without food) once daily exhibits one or more of the following
pharmacokinetic parameters: (a) a mean plasma MMF AUC.sub.overall
ranging from about 4.81 hmg/L to about 11.2 hmg/L; (b) a mean
plasma MMF AUC.sub.0-12 ranging from about 2.4 hmg/L to about 5.5
hmg/L; and (c) a mean AUC.sub.0-infinity ranging from about 2.4
hmg/L to about 5.6 hmg/L.
[0022] In some embodiments, the invention provides a method of
treating a disease or disorder (e.g., multiple sclerosis) in a
subject in need thereof, wherein the method comprises administering
to the subject a controlled release dosage form or a unit dosage
form described above once per day.
[0023] In some aspects, the controlled release dosage form
comprises 80 mg to 1000 mg of an API (e.g., 480 mg API).
[0024] In some aspects, the unit dosage form comprises
(a) a first dosage component comprising a first dose of about 80 mg
to about 1000 mg (e.g., about 120 mg or about 240 mg) of an API;
and (b) a second dosage component comprising a second dose of about
80 mg to about 1000 mg (e.g., about 120 mg or about 240 mg) of the
API;
[0025] In some embodiments, the first and second dosage components
are physically separated from each other (e.g., as two capsules,
two tablets, or one capsule and one tablet) and are provided in a
kit (e.g., a blister pack). In some embodiments, the first and
second dosage components are both part of one dosage form (e.g., a
pill, a tablet, or a capsule).
[0026] In some embodiments, the only active ingredient in the
controlled release dosage form or unit dosage form described above
is DMF.
BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES
[0027] FIGS. 1A and 1B show a design of a delayed release tablet
formulation. FIG. 1A shows a design of a coated delayed release
minitablet/microtablet which contains a core tablet matrix, a seal
coating layer, a semipermeable coating layer, and a pH7 release
coating layer. FIG. 1B shows a picture and a microscopic view of a
delayed release tablet prepared according to Example 1 with three
coating layers: an inner seal coating layer, a semipermeable
coating layer, and an outer pH 7 release coating layer.
[0028] FIG. 2A shows the in vitro dissolution profile of six
microtablets of one formulation tested according to United States
Pharmacopeia apparatus II (paddle), 100 rpm, 37.degree. C., 2 hours
in pH 0.1N HCl, followed by 10 hours in pH 7.4 phosphate buffer
(USP). FIG. 2B shows screen shots of delayed release tablets
prepared according to Example 1 before and after drug release.
[0029] FIG. 3 shows a design of a polymer matrix system which
contains a core containing DMF and a polymer, a seal coating
encapsulating the core, and an outer enteric coating. In this
design, DMF may be released through matrix erosion over a sustained
period of time (e.g., about 6 hours).
[0030] FIG. 4 shows in vitro dissolution profile of six different
matrix formulations. Formulations 090913A, 090913F, 101413F and
101413G each contains a plurality of microtablets. Formulations
101413FT and 101413GT have the same ingredients as 101413F and
101413G, respectively, but are made as monolithic tablets. The
dissolution tests were performed according to USP apparatus II
(paddle) at an agitation speed of 75 rpm.
[0031] FIG. 5 shows a design of an osmotic dosage form which
contains an osmotic core containing DMF and a semipermeable
membrane coating encapsulating the core. The semi-permeable
membrane allows water into the tablet which creates osmotic
pressure that forces the drug out of the coated tablet through a
laser drilled hole in the coating. In this design, DMF may be
released over a sustained period of time (e.g., about 6 hours).
[0032] FIG. 6A shows three different designs of a floating dosage
formulation: a bilayer, a trilayer, and a double tablet. Each
design has an active layer, which contains DMF, and a floating
layer. The bilayer design contains only one active layer and one
floating layer. The trilayer design contains two floating layers
and one active layer in between. The double tablet design has the
floating layer encapsulating the active layer. FIG. 6B shows a
picture of a trilayer floating tablet, which contains two
effervescent floating layer with one enterically coated active
layer containing DMF, floating in simulated gastric fluid.
[0033] FIG. 7A shows a design of swellable tablet formulation for
sustained release. The swellable tablet contains an API (e.g., DMF)
that is seal coated and enterically coated and one or more swelling
polymers. FIG. 7B shows that the swcllable tablet can expand
significantly which allows the swelled tablet to be retained in the
stomach of a subject treated. FIG. 7C shows a design of swellable
tablet formulation for delayed release. The swellable tablet
contains a core containing an API (e.g., DMF) that is seal coated
and enterically coated and one or more swelling polymers
encapsulating the core. FIG. 7D shows another design of swellable
tablet formulation for delayed release. The swellable tablet
contains two layers: an active layer containing an API (e.g., DMF)
that is seal coated and enterically coated and a swelling layer
containing one or more swelling polymers. The two layers are joined
together to form a bilayer tablet structure.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0034] As used herein, "a" or "an" means one or more unless
otherwise specified.
[0035] Unless specifically stated or obvious from context, as used
herein, the term "about" is understood as within a range of normal
tolerance in the art, for example, within 20% of the stated value.
As used herein, "about" a specific value also includes the specific
value, for example, about 10% includes 10%.
[0036] As used herein, the term "DMF," "BG-12," or "BG00012" refers
to the compound dimethyl fumarate. And the term "MMF" refers to the
compound, or an ionized form of monomethyl fumarate. A compound
that can be metabolized into MMF in vivo, as used herein, includes
DMF. A compound that can be metabolized into MMF in vivo, as used
herein also includes, for example, any compound described in U.S.
application Ser. No. 13/760,916, the content of which is
incorporated herein by reference in its entirety.
[0037] As used herein, the abbreviation API refers to MMF, a
compound that can be metabolized into MMF in vivo (e.g., DMF), or a
pharmaceutically acceptable salt thereof or combinations thereof.
In some embodiments, the API can include more than one compound,
for example, a combination of MMF and DMF. In some embodiments, the
API is a single compound, e.g., DMF.
[0038] Open terms such as "include," "including," "contain,"
"containing" and the like mean "comprising."
[0039] The term "treating" refers to administering a therapy in an
amount, manner, or mode effective to improve a condition, symptom,
or parameter associated with a disease or disorder.
[0040] The term "prophylaxis" or the term "prophylactic treatment"
refers to preventing a disorder or preventing progression of a
disorder, to either a statistically significant degree or to a
degree detectable to one skilled in the art.
[0041] As used herein, a controlled release dosage form may be any
dosage form that is capable of releasing a drug in a body over an
extended period of time. The controlled release dosage form herein
includes, without limiting to, sustained release dosage form,
delayed release dosage form, and pulsatile release dosage form. In
some embodiments, the controlled release dosage form herein is
gastric retentive, which is retained in the stomach for a period
(i.e., the gastric retention time) that is longer than the normal
emptying time from the stomach, e.g., longer than about 0.2 hours,
following an average meal. In any of the embodiments described
herein, the gastric retention time of a gastric retentive
controlled release dosage form may be about 0.2 hours to about 18
hours. In some embodiments, a gastric retentive controlled release
dosage form is retained in the stomach for about 0.2 hour, about
0.5 hour, about 1 hour, about 2 hours, about 3 hours, about 4
hours, about 6 hours, about 8 hours, about 10 hours, about 12
hours, about 14 hours, about 16 hours, about 18 hours, or any
ranges thereof.
[0042] The term "microtablet" means a compact in the form of a
small (micro) tablet having a mean diameter of less than 5,000
microns (e.g., about 1,000 microns to about 3,000 microns),
excluding any coating, that comprises the active ingredient(s) and
one or more excipients. The active ingredient(s) and excipients can
be homogeneously or heterogeneously mixed in the microtablet. In
any of the embodiments described herein, the microtablets may be
coated, for example, by a seal coating, an enteric coating, or a
combination thereof.
[0043] As used herein, when an object (e.g., a first or second
dosage component, drug product layer, etc.) is said to be "coated"
or have a "coating," it is to be understood that the object can be
fully or partially coated by one or more coatings. Similarly, when
an object (e.g., a first or second dosage component, drug product
layer, etc.) is said to be "encapsulated," it is to be understood
that the object can be fully or partially encapsulated.
[0044] Delivering a drug (e.g., DMF) in a pulsatile manner or in
pulses may be understood as involving rapid and transient release
of a dose of the drug (e.g., DMF) within a short time period
immediately after a lag time.
[0045] The term "lag time" as used herein refers to the time
between the time of the beginning of delivery of a drug (e.g., DMF)
from one component and the subsequent beginning of delivery of the
drug (e.g., DMF) from another component. For example, the lag time
may refer to the time between the beginning of delivery of the
first and second doses of an API upon administering a unit dosage
form (e.g., as described herein).
[0046] As used herein, a pre-determined lag time of a pulsatile
dosage form refers to the lag time that may be determined by in
vitro dissolution experiments. For example, for a pulse dosage form
containing only one dose of a drug (e.g., DMF), a pre-determined
lag time may refer to the time duration between the time when the
dosage form is in contact with a gastric liquid or simulations
thereof (i.e., the time around when an immediate release dosage
form would release the drug) and the time when substantially all of
the drug (e.g., DMF) is released from the gastro-retentive dosage
form. Alternatively, for dosage forms that contain more than one
dose of a drug (e.g., DMF), the pre-determined lag time may refer
to the time between releases of any two consecutive doses as
determined by in vitro dissolution experiments. The pre-determined
lag time herein may be from about 2 hours to about 14 hours. In
some embodiments, the pre-determined lag time is about 2 hours,
about 4 hours, about 6 hours, about 8 hours, about 10 hours, about
12 hours, about 14 hours, or any ranges thereof. In some
embodiments, the pre-determined lag time is about 8 hours to about
12 hours. A pre-determined lag time may be controlled via various
techniques. For example, by varying polymer components and/or
thickness of lag time control coatings or layers (e.g., pulsatile
coatings described herein) in the controlled release dosage forms,
different pre-determined lag times can be achieved.
[0047] The term "subject" as used herein generally refers to human,
including healthy human or a patient with certain diseases or
disorders.
Controlled Release Dosage Form
[0048] In various embodiments, the invention provides a controlled
release dosage form that release an API in the GI tract of a
subject in a sustained or pulsatile manner. In some embodiments,
the API in the controlled release dosage form is retained in the
stomach and/or small intestine of a subject treated for at least 3
hours (e.g., about 3 hours, about 4 hours, about 5 hours, about 6
hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours,
about 11 hours, about 12 hours, about 13 hours, about 14 hours,
about 15 hours, about 16 hours, about 17 hours, or any ranges
thereof). In some embodiments, the API in the controlled release
dosage form is retained in the stomach and/or small intestine for
about 3 hours to about 17 hours. In some embodiments, the API in
the controlled release dosage form is retained in the stomach
and/or small intestine of a subject treated for at least 4 hours,
at least 5 hours, at least 6 hours, at least 7 hours, or at least 8
hours. In some embodiments, the API in the controlled release
dosage form is retained in the stomach and/or small intestine of a
subject treated for at least 5 hours, at least 6 hours, or at least
7 hours.
[0049] The controlled release dosage form can be a matrix dosage
form, an osmotic dosage form, a gastric retention dosage form, an
intestinal retention dosage form, or a combination thereof.
[0050] In some embodiments, a subject administered one or more
units (e.g., 1, 2, 3, 4, 5, or 6) of the controlled release dosage
form (with or without food) once daily produces one or more of the
following pharmacokinetic parameters in the subject: (a) a mean
plasma MMF AUC.sub.overall ranging from about 4.81 hmg/L to about
11.2 hmg/L; (b) a mean plasma MMF AUC.sub.0-12 ranging from about
2.4 hmg/L to about 5.5 hmg/L; and (c) a mean AUC.sub.0-infinity
ranging from about 2.4 hmg/L to about 5.6 hmg/L. In some
embodiments, the subject treated exhibits a pharmacokinetic profile
characterized by both (a) and (b), both (a) and (c), or both (b)
and (c). In some embodiments, the subject treated exhibits a
pharmacokinetic profile characterized by (a), (b), and (c).
[0051] In some embodiments, a subject administered a single unit of
the controlled release dosage form (with or without food) or a unit
dosage form described herein once daily produces one or more of the
following pharmacokinetic parameters in the subject: (a) a mean
plasma MMF AUC.sub.overall ranging from about 4.81 hmg/L to about
11.2 hmg/L; (b) a mean plasma MMF AUC.sub.0-12 ranging from about
2.4 hmg/L to about 5.5 hmg/L; and (c) a mean AUC.sub.0-infinity
ranging from about 2.4 hmg/L to about 5.6 hmg/L. In some
embodiments, the subject treated exhibits a pharmacokinetic profile
characterized by both (a) and (b), both (a) and (c), or both (b)
and (c). In some embodiments, the subject treated exhibits a
pharmacokinetic profile characterized by (a), (b), and (c).
[0052] In some embodiments, a subject orally administered a single
unit of the controlled release dosage form or a unit dosage form
described herein (with or without food) once daily exhibits a mean
MMF plasma area under the curve 0-12 (AUC.sub.0-12) of about 2.36
hmg/L to about 5.50 hmg/L, from about 2.75 hmg/L to about 5.10
hmg/L, or from about 3.14 hmg/L to about 4.91 hmg/L. In one
embodiment, the subject exhibits a mean AUC.sub.0-12 of about 3.93
hmg/L.
[0053] In some embodiments, a subject orally administered a single
unit of the controlled release dosage form or a unit dosage form
described herein (with or without food) once daily exhibits a mean
MMF plasma overall area under the curve (AUC.sub.overall) of about
4.81 hmg/mL to about 11.2 hmg/mL, or from about 6.40 hmg/L to about
10.1 hmg/L. In one embodiment, the subject exhibits a mean
AUC.sub.overall of about 8.02 hmg/L.
[0054] In some embodiments, suitable amounts of API for the
controlled release dosage form include those that can provide, by
itself or in combination with one or more doses from, for example,
a second dosage form (e.g., a controlled release dosage form or an
enterically coated immediate release dosage form), a daily amount
of the respective compound (e.g., DMF) ranging from about 1 mg/kg
to about 50 mg/kg (e.g., from about 2.5 mg/kg to about 20 mg/kg or
from about 2.5 mg/kg to about 15 mg/kg).
[0055] The controlled release dosage form contains any
therapeutically effective dose of an API, e.g., an amount that is
effective in treating multiple sclerosis. For example, suitable
doses of DMF in the controlled release dosage form may be any dose
from about 20 mg to about 1 g of DMF. In some embodiments, the
suitable doses of DMF in the controlled release dosage form may be
any dose from about 80 mg to about 1000 mg of DMF. In some
embodiments, the suitable doses of DMF in the controlled release
dosage form may be any dose from about 100 mg to about 750 mg of
DMF. In some embodiments, the suitable doses of DMF in the
controlled release dosage form is about 200 to about 600 mg. In
some embodiments, the suitable doses of DMF in the controlled
release dosage form may be any dose from about 300 to about 600 mg.
In some embodiments, the suitable doses of DMF in the controlled
release dosage form is about 480 mg.
[0056] In some embodiments, the DMF in the controlled release
dosage form is about 60 mg, about 80 mg, about 100 mg, about 120
mg, about 160 mg, about 200 mg, about 240 mg, about 320 mg, about
360 mg, about 400 mg, about 480 mg, about 600 mg, about 720 mg,
about 800 mg, about 900 mg, about 1000 mg of DMF, or any ranges
thereof.
[0057] The controlled release dosage form can contain an amount of
a compound that that can metabolize into MMF that provides an
equivalent amount of MMF as the doses of DMF described above.
[0058] In some embodiments, the daily amount of the API is provided
by one or more units (e.g., 1, 2, 3, 4, or 5) of the controlled
release dosage form herein. In some embodiments, the daily amount
of the API is provided by a single unit of the controlled release
dosage form herein, i.e., one unit per day. In some embodiments,
one or more units (e.g., 1, 2, 3, 4, or 5) of the controlled
release dosage form herein is co-administered with one or more
units (e.g., 1, 2, 3, 4, or 5) of a second dosage form (e.g., as
described herein) to provide the daily amount of the API to a
subject. In some embodiments, the daily amount of the API is
provided by one or more units (e.g., 1, 2, 3, 4, or 5) of the
controlled release dosage form described herein and one or more
units (e.g., 1, 2, 3, 4, or 5) of an enterically coated immediate
release dosage form (e.g., as described herein). For example, in
some embodiments, two units of the controlled release dosage form
(e.g., two of the osmotic dosage form described herein) and one
enterically coated immediate release dosage form is combined, for
example, in a capsule, or a tablet, to provide the daily amount of
the API (e.g., DMF) to a subject.
[0059] In some embodiments, the controlled release dosage form
comprises an acid soluble outer coating. Suitable acid soluble
coatings for the first dosage component are known in the art and
include those coatings that dissolve at a pH less than 6.0.
Non-limiting examples of acid soluble coatings include gelatin,
Eudragit.RTM. E-100, polyvinyl acetyl diethylaminoacetate, and
chitosan coatings. The acid-soluble coating may be applied using
various techniques (e.g., spray techniques) known to one skilled in
the art.
[0060] In addition to the components listed below for each
controlled release dosage form, the controlled release dosage form
may also comprise one or more pharmaceutically acceptable
excipients in addition to those described above. Suitable
pharmaceutically acceptable excipients are those known in the art,
for example, binders, fillers, disintegrants, glidants, lubricants,
diluents, plasticizers, etc. as described in Remington's
Pharmaceutical Science, 18.sup.th Edition, 1990, Mack Publishing
Company, Easton, Pa. ("Remington's").
Matrix Dosage Form
[0061] In some embodiments, the invention provides a matrix dosage
form for delivering an API to a subject treated. The matrix dosage
form herein comprises a core comprising an API, one or more release
modifying polymers, and one or more pharmaceutically acceptable
excipients. Suitable release modifying polymers for a matrix dosage
form include cellulose and cellulose derivatives, such as
microcrystalline cellulose, hydroxypropyl methyl cellulose,
hydroxypropyl cellulose and methylcellulose, Eudragit polymers
(e.g., Eudragit RS, RL), povidone, polyvinyl acetate,
poly(ethyleneoxide) (PEO), polyethylene glycol (PEG), poly (vinyl
alcohol) (PVA), xanthan gum, carrageenan and other synthetic
materials. The amount of the release modifying polymers can be from
about 2% to about 50% by weight of the matrix dosage form. In some
embodiments, the amount of the release modifying polymers can be
about 2%, about 5%, about 10%, about 15%, about 20%, about 25%,
about 30%, about 35%, about 40%, about 45%, about 50%, or any
ranges thereof, by weight of the matrix dosage form. Various
techniques for preparing a matrix dosage form are known.
[0062] The matrix dosage form herein may also be coated. In some
embodiments, the matrix dosage form comprises a seal coating
encapsulating the core. In some embodiments, the matrix dosage form
comprises an outer enteric coating. In some embodiments, the outer
enteric coating encapsulates a seal coating. Various techniques for
coating are known.
[0063] In some embodiments, the matrix dosage form exhibits
zero-order release of the API. In some embodiments, the matrix
dosage form releases the API in the GI tract of a subject in a
sustained period of time from about 2 to about 24 hours (e.g.,
about 2, about 4, about 6, about 8, about 10, about 12, about 14,
about 16, about 18, about 20, about 22, about 24 hours, or any
ranges thereof). In some embodiments, the matrix dosage form
releases the API in the GI tract of a subject in about 2 to about
10 hours. In some embodiments, the matrix dosage form releases the
API in the GI tract of a subject in about 4 to about 6 hours. In
some embodiments, the API is released in the stomach. In some
embodiments, the API is released in the upper GI tract. In some
embodiments, the API is released in the lower GI tract. In some
embodiments, the API is released in the small intestine.
[0064] The rate of release can be modified by varying the amount,
type, and ratio of the one or more release modifying polymers.
[0065] The rate of release can also depend on the form (e.g.,
tablet or microtablets) of the matrix dosage form. In some
embodiments, the matrix dosage form comprising the API is a bilayer
or monolithic tablet. In some embodiments, the matrix dosage form
comprises a plurality of microtablets comprising the API. In some
embodiments, the bilayer or monolithic tablet, or the microtablets
are coated (e.g., enterically coated).
[0066] The release profile of the matrix dosage form herein can be
determined by an in vitro dissolution method. Standard test
protocols for in vitro dissolution are known. In some embodiments,
the release profile of the matrix dosage form is characterized in
that more than about 80% of the API is released in less than about
8 hours (e.g., about 6 hours, about 4 hours), when tested by United
State Pharmacopoeia (USP) Dissolution Apparatus 2 according to
standardized and specified in USP General Chapter <711>
Dissolution, at an agitation speed of 75 rpm. In some embodiments,
the release profile of the matrix dosage form is characterized in
that more than about 80% of the API is released in less than about
8 hours (e.g., about 6 hours, about 4 hours), when tested by United
State Pharmacopoeia (USP) Dissolution Apparatus 2 according to
standardized and specified in USP General Chapter <711>
Dissolution, at an agitation speed of 100 rpm.
Osmotic Dosage Form
[0067] In any of the embodiments described herein, the controlled
release dosage form is an osmotic dosage form. Various techniques
for preparing an osmotic dosage form that include, but are not
limited to monolithic tablets, bilayer tablets, and trilayer
tablets, are known.
[0068] An osmotic dosage form can be a tablet with a semi-permeable
membrane. The semi-permeable membrane allows water into the tablet
which dissolves an osmotic agent that creates osmotic pressure
and/or a hydrophilic polymer that suspends and carries the drug out
of the coated tablet through a laser drilled hole in the
coating.
[0069] The osmotic dosage form herein can include an osmotic core
comprising an API, one or more osmotic agents, one or more
pharmaceutically acceptable excipients, and optionally one or more
release modifying polymers. In some embodiments, the semi-permeable
membrane coated tablets could be encapsulated in a gelatin capsule.
Suitable material for the semi-permeable membrane coatings includes
those known in the art, for example, cellulose products such as
cellulose acetate, ethyl cellulose, hydroxyalkyl cellulose (e.g.,
hydroxypropyl cellulose, hydroxypropyl methyl cellulose,
hydroxyethyl cellulose). Suitable osmotic agents include those
known in the art, for example, a sugar such as sorbitol, mannitol,
xylitol, fructose or salts (e.g. sodium chloride). In some
embodiments, the osmotic agents can be in an amount of about 10%,
about 20%, about 30%, about 40%, about 50%, about 60%, or any
ranges thereof, by weight of total weight of the osmotic dosage
form. In some embodiments, the semi-permeable membrane coatings can
be in an amount of about 2% to about 20% (e.g., about 2%, about 5%,
about 10%, about 15%, about 20%, or any ranges thereof) by weight
of total weight of the osmotic dosage form.
[0070] Other suitable material for the osmotic dosage form include
those known in the art, for example, the osmotic dosage form may
comprise a water swellable polymer (e.g. polyethylene oxide), a
water soluble polymer, a water insoluble polymer (e.g. sodium
carboxyl methyl cellulose), a water insoluble and water swellable
polymer, a water insoluble and water permeable polymer, or
combinations thereof.
[0071] In some embodiments, the osmotic dosage form comprises a
polymer selected from the group consisting of homopolymer of
N-vinyl pyrrolidone, copolymer of N-vinyl pyrrolidone, copolymer of
N-vinyl pyrrolidone and vinyl acetate, copolymer of N-vinyl
pyrrolidone and vinyl propionate, methylcellulose, ethylcellulose,
hydroxyalkylcelluloses, hydroxypropylcellulose,
hydroxyalkylalkylcellulose, hydroxypropylmethylcellulose, cellulose
phthalate, cellulose succinate, cellulose acetate phthalate,
hydroxypropylmethylcellulose phthalate,
hydroxypropylmethylcellulose succinate,
hydroxypropylmethylcellulose acetate succinate, polyethylene oxide,
polypropylene oxide, copolymer of ethylene oxide and propylene
oxide, methacrylic acid/ethyl acrylate copolymer, methacrylic
acid/methyl methacrylate copolymer, butyl
methacrylate/2-dimethylaminoethyl methacrylate copolymer,
poly(hydroxyalkyl acrylate), poly(hydroxyalkyl methacrylate),
copolymer of vinyl acetate and crotonic acid, partially hydrolyzed
polyvinyl acetate, carrageenan, galactomannan or xanthan gum
polyethylene oxide, and hydroxypropyl methylcellulose.
[0072] In some embodiments, the osmotic dosage form comprises a
polymer selected from the group consisting of
hydroxypropylcellulose, cross-linked polyvinylpyrrolidone,
cross-linked carboxymethylcellulose, pregelatinized starch, sodium
starch glycolate, polyvinyl acetate, polyacrylic acid,
acrylate-co-polymer, carboxymethylcellulose calcium,
carboxymethylcellulose sodium, poly(hydroxyethyl-methacrylate),
poly(methacrylic acid), poly(acrylamide), sodium starch glycolate,
starch, poly(hydroxyalkyl methacrylate) with a molecular weight of
32,000 to 5,500,000, poly(electrolyte) complexes, poly(vinyl
alcohol), acrylate polymers with water absorbability of roughly 400
times its original weight, a mixture of poly(vinyl alcohol) and
poly(N-vinyl-2-pyrrolidone), poly(acrylic acid) with a molecular
weight of 80,000 to 200,000, polyoxy polyethylene oxide polymers
with a molecular weight of 100,000 to 5,000,000, polysaccharides,
agar, acacia, karaya, tragacanth and algins, pectin with a
molecular weight of 30,000 to 300,000, and
polyoxybutylenepolyethylene block polymer.
[0073] In some embodiments, the osmotic dosage form comprises a
polymer selected from the group consisting of cellulose acylate,
cellulose acetate, cellulose diacylate, cellulose diacetate,
cellulose triacylate, cellulose triacetate, mono-, di-, and
tri-cellulose alkanylate, mono-, di- and tri-alkenylates, mono-,
di- and tri-aroylates, cellulose trivalerate, cellulose trilaurate,
cellulose tripalmitate, cellulose trioctanoate, cellulose
tripropionate, cellulose diesters, cellulose disuccinate, cellulose
dipalmitate, cellulose dioctanoate, cellulose dicarpylate,
cellulose actate heptonate, cellulose valerate palmitate, cellulose
acetate octonoate, cellulose propionate succinate, cellulose
acetate valerate, cellulose acetaldehyde, dimethyl cellulose
acetate, cellulose acetate ethylcarbamate,
hydroxypropylmethylcellulose, semipermeable polyamylsulfanes,
semipermeable urethane, cellulose acetate methylcarbamate,
cellulose dimethylaminoacetate, semipermeable sulfonated
polystyrenes, semipermeable silicone rubbers, semipermeable
styrenes, sulfonated polystyrenes, polyurethanes,
polydiethylaminomethylstyrene, cellulose acetate methylcarbamate,
ethylcellulose, shellac, polymethylstyrene, polyvinylacetate,
scimpermeble (polysodium styrenesulfonate), and semipermeable
poly(vinylbenzymtrimethylammonium chloride.
[0074] In some embodiments, the osmotic dosage form comprises a
polyethylene oxide or hydroxypropyl methylcellulose. Various
commercially available polyethylene oxide (e.g., Polyox N-80, WSR
N-750 or WSR-205) and hydroxypropyl methylcellulose (e.g., Methocel
K 100 Premium LV or E50 Premium LV) are suitable for use in the
osmotic dosage form.
[0075] In some embodiments, the osmotic dosage form releases the
API and exhibits zero-order release of the API. In some
embodiments, the osmotic dosage form releases the API in the GI
tract of a subject in a sustained period of time from about 2 to
about 24 hours (e.g., about 2, about 4, about 6, about 8, about 10,
about 12, about 14, about 16, about 18, about 20, about 22, about
24 hours, or any ranges thereof). In some embodiments, the osmotic
dosage form releases the API in the GI tract of a subject in about
2 to about 10 hours. In some embodiments, the osmotic dosage form
releases the API in the GI tract of a subject in about 4 to about 6
hours. In some embodiments, the API is released in the stomach. In
some embodiments, the API is released in the upper GI tract. In
some embodiments, the API is released in the lower GI tract. In
some embodiments, the API is released in the small intestine.
[0076] The release profile of the osmotic dosage form herein can
also be determined by an in vitro dissolution method. Standard test
protocols for in vitro dissolution are known. In some embodiments,
the release profile of the osmotic dosage form is characterized in
that more than about 80% of the API is released in less than about
8 hours (e.g., about 6 hours, about 4 hours), when tested by USP
Dissolution Apparatus 2 according to standardized and specified in
USP General Chapter <711> Dissolution, at 75 rpm. In some
embodiments, the release profile of the matrix dosage form is
characterized in that more than about 80% of the API is released in
less than about 8 hours (e.g., about 6 hours, about 4 hours), when
tested by USP Dissolution Apparatus 2 according to standardized and
specified procedures in USP General Chapter <711>
Dissolution, at 100 rpm.
Gastric Retention Dosage Form
[0077] In some embodiments, the invention provides a gastric
retention dosage form for delivering an API to a subject treated.
In some embodiments, the gastric retention dosage form releases the
API in the GI tract of a subject in a sustained period of time
(e.g., about 2, about 4, about 6, about 8, about 10, about 12,
about 14, about 16, about 18, about 20, about 22, or about 24
hours). In some embodiments, the gastric retention dosage form
releases the API in the GI tract of a subject in a pulsatile manner
with a lag time from about 2 hours to about 14 hours (e.g., about 2
hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours,
about 12 hours, about 14 hours, or any ranges thereof).
[0078] In some embodiments, the gastric retention dosage form is
retained in the stomach of a subject treated, for example, has a
gastric retention time of from about 0.2 hour to about 18 hours
(e.g., about 0.2 hour, about 0.5 hour, about 1 hour, about 2 hours,
about 3 hours, about 4 hours, about 6 hours, about 8 hours, about
10 hours, about 12 hours, about 14 hours, about 16 hours, about 18
hours, or any ranges thereof). In some embodiments, the API in the
gastric retention dosage form is retained in the stomach of a
subject treated, for example, for about 0.2 hour to about 18 hours
(e.g., about 0.2 hour, about 0.5 hour, about 1 hour, about 2 hours,
about 3 hours, about 4 hours, about 6 hours, about 8 hours, about
10 hours, about 12 hours, about 14 hours, about 16 hours, about 18
hours, or any ranges thereof). In some embodiments, the API in the
gastric retention dosage form is retained in the stomach of a
subject treated for at least 3 hours (e.g., about 3 hours, about 4
hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours,
about 9 hours, about 10 hours, about 11 hours, about 12 hours,
about 13 hours, about 14 hours, about 15 hours, about 16 hours,
about 17 hours, or any ranges thereof). In some embodiments, the
API in the gastric retention dosage form is retained in the stomach
of a subject treated for about 3 hours to about 17 hours. In some
embodiments, the API in the gastric retention dosage form is
retained in the stomach of a subject treated for at least 4 hours,
at least 5 hours, at least 6 hours, at least 7 hours, or at least 8
hours. In some embodiments, the API in the gastric retention dosage
form is retained in the stomach of a subject treated for at least 5
hours, at least 6 hours, or at least 7 hours. Various means to
achieve gastric retention are known. For example, in some
embodiments, the gastric retention dosage form is a floating dosage
form or a swelling dosage form.
[0079] Floating Dosage Form
[0080] In some embodiments, the controlled release dosage form is a
floating dosage form that floats when exposed to gastric fluid and
thereby retaining the API in the stomach of a subject treated.
Various techniques for preparing a floating dosage form are known.
In some embodiments, the floating dosage form is a floating tablet
(e.g., a bilayer or a trilayer tablet) or a floating capsule.
[0081] The floating dosage form described herein can include an
active layer and a floating layer, wherein the active layer
comprises an API and one or more release modifying polymers. In
some embodiments, the gastric retention time of the floating dosage
form is from about 0.2 hour to about 18 hours (e.g., about 0.2
hour, about 0.5 hour, about 1 hour, about 2 hours, about 3 hours,
about 4 hours, about 6 hours, about 8 hours, about 10 hours, about
12 hours, about 14 hours, about 16 hours, about 18 hours, or any
ranges thereof). In some embodiments, the floating dosage form
floats in the stomach until the active layer releases all the API.
In some embodiments, the floating dosage form floats in the stomach
before the active layer releases all the API. The gastric retention
time of the floating dosage form can be controlled by adjusting the
floating layer, for example, by adjusting the amount of gas that
can be generated and the speed of gas generation. Other techniques
for adjusting the gastric retention time are known.
[0082] Materials suitable for the floating layer include
pharmaceutical excipients that can lower the density of the
pharmaceutical composition. In some embodiments, the floating layer
comprises one or more low density excipients selected from the
group consisting of hydroxypropyl methylcellulose, hydrogenated
castor oil, carboxymethylcellulose, ethylcellulose, cross-linked
povidone, chitosan and combinations thereof. In some embodiments,
the weight ratio for the one or more low density excipients are
adjusted such that the density of the floating dosage form is lower
than the density of the gastric fluid in a subject.
[0083] In some embodiments, the floating layer comprises a porous
mineral material, such as calcium silicate. In some embodiments,
the porous mineral material having air entrapped within are coated
with a polymer (e.g., hydroxypropylcellulose or ethylcellulose)
such that the air within the porous mineral material is retained.
In some embodiments, the floating layer comprises a porous mineral
material that further comprises one or more low density excipients
as described herein.
[0084] In some embodiments, the floating layer comprises hollow
microspheres or polycarbonate resin that floats in a gastric fluid
of a subject.
[0085] In some embodiments, the floating layer comprises a
gas-generating system. Suitable gas-generating systems are known in
the art. In some embodiments, the floating layer comprises at least
one gas-generating system (e.g., a carbon-dioxide generating
system, e.g., comprises an alkali or alkaline earth metal carbonate
or bicarbonate) and at least one hydrophilic polymer (e.g.,
polysaccharide substances, protein substances, poloxamers, high
molecular weight polyethylene glycols, polymers of methacrylic
acids, polymers of acrylic acids, derivatives of methacrylic acid,
or derivatives of acrylic acid), a cellulose polymer such as
hydroxyalkyl alkylcellulose (e.g., hydroxypropyl methylcellulose),
or a porous mineral compound (e.g., a silica or silica derivative).
In some embodiments, the floating layer comprises sodium carbonate
and Methocel K100M. In some embodiments, the weight ratio of sodium
carbonate to Methocel K100M is from about 1:50 to about 50:1 (e.g.,
about 1:1 to about 1:10, about 1:2 to about 1:5, or about 1:3). In
some embodiment, the floating layer comprises an effervescent
couple, wherein upon oral administration of the controlled release
dosage form to a subject, the effervescent couple in the floating
dosage form generates gas and causes the gastric retention dosage
form to float in the gastric liquid of the subject.
[0086] The floating dosage form described herein can take various
forms. For example, in some embodiments, the floating dosage form
is a bilayer or a trilayer tablet, wherein the floating layer and
the active layer are compressed or otherwise joined to form a
tablet structure. In some embodiments, the floating dosage form is
a double tablet structure, wherein the floating layer encapsulates
the active layer. In some embodiments, the floating dosage form is
a capsule (e.g., a soft gel or hard gel capsule) encapsulating the
floating layer and the active layer. In some embodiments, the
capsule is partially coated with acid insoluble polymer.
[0087] The floating dosage form described herein can be a sustained
release dosage form or a delayed release dosage form depending on
the configuration of the active layer.
[0088] In some embodiments, the floating dosage form can be a
sustained release dosage form. For example, in some embodiments,
the active layer is a matrix dosage form described herein or an
osmotic dosage form described herein.
[0089] The floating dosage form can also be a delayed release
dosage form. For example, in some embodiments, the active layer is
a delayed release dosage form, which, when administered together
with a second dosage form (e.g., an enterically coated immediate
release dosage form, or a delayed release dosage form), provides a
pulsatile release of the API with a lag time from about 2 hours to
about 14 hours (e.g., about 2 hours, about 4 hours, about 6 hours,
about 8 hours, about 10 hours, about 12 hours, about 14 hours, or
any ranges thereof). Suitable methods for preparing a delayed
release dosage form comprising an API (e.g., coated API) include
those known. In some embodiments, the delayed release dosage form
may contain an enterically coated active layer and/or an
enterically coated API. In some embodiments, the delayed release
dosage form comprises about 90% by weight of a coated API (e.g.,
coated DMF particles) and about 10% by weight of a cellulose
polymer (e.g., hydroxypropyl methylcellulose, Methocel E3 LV). In
some embodiments, the delayed release dosage form may contain a
core comprising an API, an inner seal coating, followed by a
semipermeable coating. In some embodiments, the delayed release
dosage form may further comprise an outer enteric coating. See
examples in Example 1.
[0090] More than one active layers and/or more than one floating
layers can also be included in the floating dosage form described
herein. In some embodiments, the floating dosage form comprises two
floating layers. In some embodiments, the active layer is placed
between the two floating layers. In any of the embodiments
described herein, wherein the floating dosage form comprises three
layers (e.g., two active layers one floating layer, or two floating
layers one active layer), the floating dosage form may be a
trilayer tablet or a capsule encompassing the three layers.
[0091] In some embodiments, the floating dosage form comprises a
second active layer. In some embodiments, the second active layer
is an enterically coated immediate release dosage component,
provided that the enterically coated immediate release dosage
component is not placed between the active layer and the floating
layer in a trilayer tablet structure. In some embodiments, the
floating dosage form comprises both a sustained release dosage
component and an enterically coated immediate release dosage
component. In some embodiments, the floating dosage form comprises
both a delayed release dosage component and an enterically coated
immediate release dosage component, wherein when administered, the
floating dosage form provides a pulsatile release of the API with a
lag time from about 2 hours to about 14 hours.
[0092] Swellable Dosage Form
[0093] In any of the embodiments described herein, the controlled
release dosage form is a dosage form that swells when exposed to
gastric fluid and thereby retaining the API in the stomach of a
subject treated. Various techniques for preparing a swellable
dosage form are known. For example, U.S. Pat. Nos. 5,972,389 and
6,723,340 B2, incorporated by reference herein, disclose a
swellable dosage form that can be utilized in the embodiments
disclosed herein.
[0094] The swelling dosage form described herein can include an API
and one or more swelling polymer. Suitable swelling polymers
include those known in the art, for example, polyethylene oxide
(e.g., Polyox 205-NF) and/or hydroxyalkyl alkylcellulose (e.g.,
hydroxypropyl methyl cellulose, e.g., Methocel K4M, K100M) may be
used. In some embodiments, the one or more swelling polymers are a
combination of poly(ethylene oxide) and hydroxypropyl
methylcellulose in various weight ratios (e.g., from about 10:1 to
about 1:10).
[0095] In some embodiments, the swelling dosage form is a swelling
tablet (e.g., a monolithic, bilayer, or trilayer tablet) or a
swelling sheet (e.g., an Accordion Pill.TM., in which an API,
optionally coated, is embedded in one section of the swellable
polymer sheets). In some embodiments, the swelling dosage form is a
monolithic tablet comprising an active layer comprising an API and
a swelling layer. In some embodiments, the swelling layer
encapsulates the active layer. In some embodiments, the swelling
dosage form is a bilayer tablet comprising an active layer
comprising an API and a swelling layer. In some embodiments, more
than one active layer are present in the swelling dosage form. In
some embodiments, more than one swelling layer are present in the
swelling dosage form.
[0096] The swellable dosage form herein may be a sustained release
or delayed release dosage form.
[0097] In some embodiments, the swelling dosage form is a sustained
release dosage form. In some embodiments, the API together with the
swelling polymer form a swellable matrix. In some embodiments, the
API is coated (e.g., seal coated, enterically coated, or a
combination thereof). In some embodiments, the API in the swellable
dosage form may be in an amount of about 20%, about 30%, about 40%,
about 50%, about 60%, about 70%, about 80%, or any ranges thereof,
by weight of total weight of the swellable dosage form. The one or
more swelling polymers in the swellable dosage form may be in an
amount of about 10%, about 15%, about 20%, about 25%, about 30%,
about 35%, about 40%, about 45%, about 50%, or any ranges thereof,
by weight of total weight of the swellable dosage form. The
swellable dosage form may also include pharmaceutical excipients in
an amount of about 0.1%, about 0.5%, about 1%, about 2%, about 5%,
about 10%, or any ranges thereof, by weight of total weight of the
swellable dosage form. For example, the swellable dosage form may
be composed of about 60% coated DMF; about 24% Polyox 205-NF (PEO);
about 15% Methocel K4M (HPMC); and about 1% magnesium stearate.
[0098] In some embodiments, the swellable matrix releases the API
in a sustained manner over a period of from about 2 to about 24
hours (e.g., about 2 hours, about 4 hours, about 6 hours, about 8
hours, about 10 hours, about 12 hours, about 14 hours, about 16
hours, about 18 hours, about 20 hours, about 22 hours, about 24
hours, or any ranges thereof). In some embodiments, the swellable
matrix exhibits zero-order release of the API.
[0099] In some embodiments, the swelling dosage form is a delayed
release dosage form, which, when administered together with a
second dosage form (e.g., an enterically coated immediate release
dosage form, or a delayed release dosage form), provides a
pulsatile release of the API with a lag time from about 2 hours to
about 14 hours (e.g., about 2 hours, about 4 hours, about 6 hours,
about 8 hours, about 10 hours, about 12 hours, about 14 hours, or
any ranges thereof). In some embodiments, the swellable pulsatile
release dosage form comprises one or more swelling polymers and an
API. In some embodiments, the API is coated (e.g., seal coated,
enterically coated, or a combination thereof). Suitable swellable
polymers are described above.
[0100] In some embodiments, the swelling dosage form comprises both
a delayed release dosage component and an enterically coated
immediate release dosage component, wherein when administered, the
swelling dosage form provides a pulsatile release of the API with a
lag time from about 2 hours to about 14 hours.
Intestinal Retention Dosage Form
[0101] In some embodiments, the invention provides an intestinal
retention dosage form for delivering an API to a subject treated.
In some embodiments, the intestinal retention dosage form releases
the API in the GI tract of a subject in a sustained period of time
between about 0.25 and about 24 hours (e.g., about 2, about 4,
about 6, about 8, about 10, about 12, about 14, about 16, about 18,
about 20, about 22, or about 24 hours). Various methods for
achieving intestinal retention are known, for example, via
mucoadhesion or mechanical retention.
[0102] Mucoadhesive Dosage Form
[0103] In some embodiments, the intestinal retention dosage form is
a mucoadhesive dosage form, which is adhesive to mucosal surface of
the gastrointestinal tract (e.g., small intestine) of a subject
treated. In some embodiments, the API in the mucoadhesive dosage
form is retained in the small intestine of a subject treated.
Various techniques for preparing a mucoadhesive dosage form are
known. For example, U.S. Pat. No. 6,022,562, incorporated by
reference herein, discloses microcapsules containing particles of
drug that are coated with a film-forming polymer derivative, a
hydrophobic plasticizer, a functional agent, and a
nitrogen-containing polymer. These microparticles remain in the
small intestine and release the drug over a period of time. Methods
for evaluating effectiveness of mucoadhesive dosage forms are also
known.
[0104] U.S. Publication No. 2004/0234601 A1, incorporated by
reference herein, also discloses a mucoadhesive dosage form.
[0105] Another example of a mucoadhesive dosage form is disclosed
in U.S. Pat. No. 8,298,574 B2, incorporated by reference
herein.
[0106] Mucoadhesive dosage forms herein can comprise an API and one
or more mucoadhesive polymers. In some embodiments, the API is seal
coated, enterically coated, or seal and enterically coated. In some
embodiments, the only active pharmaceutical ingredient in the
mucoadhesive dosage form is DMF. Suitable mucoadhesive polymers are
known and include any polymer that is or becomes adhesive to a
mucosal membrane (e.g., mucosal membrane of small intestine) upon
hydration. The mucoadhesive polymers can be cationic, anionic, or
neutral. The mucoadhesive polymers can be natural or synthetic. The
mucoadhesive polymer can be biocompatible. The mucoadhesive polymer
can be water soluble or water insoluble.
[0107] Non-limiting synthetic mucoadhesive polymers suitable for
the invention include, for example, poly(acrylic acid), polyvinyl
alcohol, polyamides, hydroxypropyl methylcellulose (HPMC),
poly(methylacrylate) derivatives, polycarbonates, polyalkylene
glycols, polyvinyl ethers/esters/halides, methylcellulose (MC),
sodium carboxymethylcellulose (CMC), polymethylmethacrylic acid,
and hydroxypropyl cellulose (HPC).
[0108] Non-limiting biocompatible mucoadhesive polymers suitable
for the invention also include, for example, cellulose based
polymers, ethylene glycol polymers and its copolymers, oxyethylene
polymers, polyvinyl alcohol, polyvinyl acetate, and esters of
hyaluronic acid.
[0109] Non-limiting synthetic mucoadhesive polymers suitable for
the invention also include, for example, cellulose derivatives
(e.g., CMC, sodium CMC, thiolated CMC, hydroxylethyl cellulose
(HEC), HPC, HPMC, methyl cellulose (MC),
methylhydroxyethylcellulose) and poly(acrylic acid)-based polymers
(e.g., polyacrylic acid (PAA), polyacrylates,
poly(methylvinylether-comethacrylic acid), poly(2-hydroxyethyl
methacrylate), poly(acrylic acid-co-ethylhcxylacrylate),
poly(methacrylate), poly(alkylcyanoacrylate),
poly(isohexylcyanoacrylate), poly(isobutylcyanoacrylate), or
copolymer of acrylic acid and PEG).
[0110] Non-limiting natural mucoadhesive polymers suitable for the
invention include, for example, agarose, chitosan, gelatin, pectin,
sodium alginate, and various gums (e.g., guar, xanthan, gellan,
carrageenan).
[0111] Non-limiting cationic mucoadhesive polymers suitable for the
invention include, for example, aminodextran, chitosan,
trimethylated chitosan, and dimethylaminoethyl dextran.
[0112] Non-limiting anionic mucoadhesive polymers suitable for the
invention include, for example, Chitosan-EDTA, Cellulose Propionate
(CP), CMC, pectin, PAA, polycarbonate (PC), sodium alginate, sodium
CMC, and xanthan gum.
[0113] Non-limiting neutral mucoadhesive polymers suitable for the
invention include, for example, hydroxyethyl starch, HPC,
poly(ethylene oxide), Poly(Vinyl Acetate) (PVA), poly(vinyl
pyrrolidonc) (PVP), and scleroglucan.
[0114] Non-limiting water soluble mucoadhcsive polymers suitable
for the invention include, for example, CP, hydroxylethylcellulose
(HEC), HPC, HPMC, PAA, sodium CMC, and sodium alginate.
[0115] Non-limiting water insoluble mucoadhesive polymers suitable
for the invention include, for example, chitosan, ethyl cellulose
(EC), and PC.
[0116] In some embodiments, the one or more mucoadhesive polymers
comprises chitosan, lectin, or a combination thereof. In some
embodiments, the one or more mucoadhesive polymer can be any
combination of the suitable mucoadhesive polymers described
above.
[0117] In any of the embodiments described herein, the mucoadhesive
dosage form may be in any suitable forms (e.g., microspheres,
microparticles, nanoparticles, films, or tablets). In some
embodiments, the mucoadhesive dosage form is in the form of
microspheres. In some embodiments, the mucoadhesive dosage form is
in the form of tablets.
[0118] In some embodiments, the mucoadhesive dosage form releases
the API (e.g., DMF) in the GI tract of a subject in a sustained
period of time (e.g., about 2, about 4, about 6, about 8, about 10,
about 12, about 14, about 16, about 18, about 20, about 22, or
about 24 hours).
[0119] Mechanical Retention
[0120] In some embodiments, the intestinal retention dosage form is
a dosage form comprising a plurality of API containing
microparticles having a mean diameter of about 50 microns to about
1000 microns (e.g., about 50, 100, 150, 200, 300, 400, 500, 750,
1,000 microns, or any ranges thereof) that are retained (e.g.,
mechanically retained) in the GI tract (e.g., small intestine) for
an extended period of time from about 2 hours to about 12 hours
(e.g., about 2, 3, 4, 5, 6, 7, 8, 10, 12, or any ranges thereof).
In some embodiments, the API in the intestinal retention dosage
form is retained in the small intestine of a subject treated. In
some embodiments, the microparticles have a mean diameter of about
100 microns to about 500 microns. In some embodiments, the
microparticles have a mean diameter of about 50 microns to about
500 microns. In some embodiments, the only active pharmaceutical
ingredient in the intestinal retention dosage form is DMF. Methods
for preparing a mechanically retained intestinal retention dosage
form are known, for example, via the Micropump.RTM. method.
Unit Dosage Forms
[0121] The controlled release dosage form described herein may be
provided as a unit dosage form or part of a unit dosage form or in
a kit.
[0122] In some embodiments, a kit (e.g., a blister pack) comprises
one or more pharmaceutical formulations, wherein the pharmaceutical
formulation when orally dosed to a subject delivers to the GI tract
(e.g., upper GI tract or lower GI tract) of the subject treated,
the total daily dose of API, in a sustained or pulsatile manner
(e.g., to the upper gastrointestinal tract or lower GI tract (e.g.,
small intestine) of a subject treated). In some embodiments, the
kit (e.g., a blister pack) comprises at least two physically
separated dosage forms (e.g., two capsules, two tablets, or one
capsule and one tablet), wherein at least one of the dosage forms
is a controlled release dosage form described herein. In some
embodiments, the only active ingredient in the pharmaceutical
formulation(s) of the kit (e.g., a blister pack) is DMF.
[0123] In some embodiments, the invention provides a unit dosage
form. In some embodiments, the unit dosage form is a single unit of
a controlled release dosage form described herein. In some
embodiments, the unit dosage form is a combination of one or more
units of a controlled release dosage form described herein and one
or more units of a second dosage form (e.g., a controlled release
dosage form described herein, an enterically coated immediate
release dosage form, a combination thereof). In some embodiments,
the controlled release dosage form is a sustained release dosage
form. In some embodiments, the second dosage form is a delayed
release dosage form.
[0124] In some embodiments, the unit dosage form, when orally dosed
to a subject, delivers to the GI tract (e.g., upper GI tract or
lower GI tract (e.g., small intestine)) of the subject treated,
more than one dose of the API, in a sustained or pulsatile manner,
wherein the unit dosage form comprises
(a) a first dosage component comprising a first dose of the API;
and (b) a second dosage component comprising a second dose of the
API.
[0125] In some embodiments, the second dose of the API in the unit
dosage form is retained in the stomach and/or small intestine of a
subject treated for at least 3 hours (e.g., about 3 hours, about 4
hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours,
about 9 hours, about 10 hours, about 11 hours, about 12 hours,
about 13 hours, about 14 hours, about 15 hours, about 16 hours,
about 17 hours, or any ranges thereof). In some embodiments, the
second dose of the API in the unit dosage form is retained in the
stomach and/or small intestine for about 3 hours to about 17 hours.
In some embodiments, the second dose of the API in the unit dosage
form is retained in the stomach and/or small intestine of a subject
treated for at least 4 hours, at least 5 hours, at least 6 hours,
at least 7 hours, or at least 8 hours. In some embodiments, the
second dose of the API in the unit dosage form is retained in the
stomach and/or small intestine of a subject treated for at least 5
hours, at least 6 hours, or at least 7 hours.
[0126] In some embodiments, the second dosage component of the unit
dosage form is a controlled release dosage form described
above.
[0127] In some embodiments, the first and second dosage components
may be in one dosage form (e.g., a tablet or a capsule). In some
embodiments, the only active ingredients in the unit dosage form is
DMF.
[0128] In some embodiments, the unit dosage form (e.g., as
described herein) releases MMF, or a compound that can be
metabolized into MMF in vivo, in a bimodal or multi-modal manner in
which a first dose of the API after an initial delay time to
provide a pulse of drug release and one or more additional doses of
the API are released each after a respective lag time to provide
additional pulses of drug release. In some embodiments, the pulses
of drug release are delivered to the upper gastrointestinal tract
of a subject treated. In some embodiments, the pulses of drug
release are delivered to the lower gastrointestinal tract of a
subject treated. In some embodiments, one pulse of drug release is
delivered to the upper gastrointestinal tract of a subject treated
and a second pulse of drug release is delivered to the lower
gastrointestinal tract of the subject treated.
[0129] It may be advantageous to deliver DMF in pulses to the upper
GI tract rather than to the lower GI tract for absorption. In some
embodiments, the pulses of DMF are delivered to the upper
gastrointestinal tract of a subject treated.
[0130] In some embodiments, the invention provides a unit dosage
form that delivers MMF, or a compound that can be metabolized into
MMF in vivo, in pulses to the upper GI tract upon oral
administration of the unit dosage form. In some embodiments, the
unit dosage form comprises
(a) a first dosage component comprising a first dose of API; and
(b) a second dosage component comprising a second dose of API;
wherein when the unit dosage form is administered to a subject
orally, the first and second doses of API, are delivered to the
upper GI tract of the subject in a pulsatile manner.
[0131] In some embodiments, the second dosage component of the unit
dosage form is a controlled release dosage form described
above.
[0132] In some embodiments, patients orally administered a unit
dosage form described herein (with or without food) once daily
exhibit one or more of the following pharmacokinetic parameters in
the subject: (a) a mean plasma MMF AUC.sub.overall ranging from
about 4.81 hmg/L to about 11.2 hmg/L; (b a mean plasma MMF
AUC.sub.0-12 ranging from about 2.4 hmg/L to about 5.5 hmg/L; and
(c) a mean AUC.sub.0-infinity ranging from about 2.4 hmg/L to about
5.6 hmg/L. In some embodiments, the subject treated exhibits a
pharmacokinetic profile characterized by both (a) and (b), both (a)
and (c), or both (b) and (c). In some embodiments, the subject
treated exhibits a pharmacokinetic profile characterized by (a),
(b), and (c).
[0133] In some embodiments, a subject orally administered a unit
dosage form described herein once daily exhibits a mean MMF plasma
area under the curve 0-12 (AUC.sub.0-12) of about 2.36 hmg/L to
about 5.50 hmg/L, from about 2.75 hmg/L to about 5.10 hmg/L, or
from about 3.14 hmg/L to about 4.91 hmg/L. In one embodiment, the
subject exhibits a mean AUC.sub.0-12 of about 3.93 hmg/L.
[0134] In some embodiments, a subject orally administered a unit
dosage form described herein (with or without food) once daily
exhibits a mean MMF plasma overall area under the curve
(AUC.sub.overall) of about 4.81 hmg/mL to about 11.2 hmg/mL, or
from about 6.40 hmg/L to about 10.1 hmg/L. In one embodiment, the
subject exhibits a mean AUC.sub.overall of about 8.02 hmg/L.
First Dosage Component
[0135] Upon oral administration of the unit dosage form to a
subject, the first dosage component comprising a first dose of API,
may provide the first dose, for example, as a first pulse of an
API, for absorption in the upper GI tract of the subject. In any of
the embodiments described herein, the first dosage component can be
an enterically coated immediate release or a delayed release dosage
form. In some embodiments, the only active ingredient in the first
dosage component is DMF.
[0136] In some embodiments, suitable amounts of API for the first
dosage component include those that can provide, by itself or in
combination with one or more doses from, for example, a second
dosage component, a daily amount of the respective compound ranging
from about 1 mg/kg to about 50 mg/kg (e.g., from about 2.5 mg/kg to
about 20 mg/kg or from about 2.5 mg/kg to about 15 mg/kg).
[0137] Suitable doses of DMF for the first dosage component may be
any therapeutically effective dose, e.g., an amount that is
effective in treating multiple sclerosis. For example, suitable
doses of DMF for the first dosage component may be any dose from 20
mg to 1 g of DMF. In some embodiments, the suitable doses of DMF in
the first dosage component may be any dose from about 80 mg to
about 1000 mg of DMF. In some embodiments, the suitable doses of
DMF in the first dosage component may be any dose from about 100 mg
to about 750 mg of DMF. In some embodiments, the suitable doses of
DMF in the first dosage component is about 200 to about 600 mg. In
some embodiments, the suitable doses of DMF in the first dosage
component may be any dose from about 300 to about 600 mg.
[0138] In some embodiments, the DMF in the first dosage component
is about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 160
mg, about 200 mg, about 240 mg, about 320 mg, about 360 mg, about
400 mg, about 480 mg, about 600 mg, about 720 mg, about 800 mg,
about 900 mg, about 1000 mg of DMF, or any ranges thereof.
[0139] The first dosage component can contain an amount of a
compound that that can metabolize into MMF that provides an
equivalent amount of MMF as the doses of DMF described above.
[0140] Suitable first dosage component may be in a form of a
micro-pellet, a micro-tablet, a capsule (such as a soft or hard
gelatine capsule), a granulate, or a tablet. In some embodiments,
the first dosage component is in the form of microtablets or
micropellets (e.g., enteric-coated microtablets or micropellets).
Suitable microtablets or micropellets are, without limitation,
those having a mean diameter of 5,000 microns or less (e.g., 4,000
microns or less, 3,000 microns or less, 2,000 microns or less,
1,000 microns or less, or 500 microns or less) exclusive of any
optional coating applied to the microtablets or micropellets.
Methods for preparing microtablets or micropellets (e.g.,
enteric-coated microtablets or micropellets) comprising DMF are
known in the art, for example, as described in U.S. Pat. No.
6,509,376 and incorporated by reference in its entirety herein.
[0141] In some embodiments, the first dosage component comprises an
acid soluble outer coating. For example, in some embodiments, the
first dosage component is in the form of enteric-coated
microtablets or micropellets, and the enteric-coated microtablets
or micropellets are encapsulated with an acid soluble coating,
e.g., in a soft-shell or hard-shell gelatin capsule.
[0142] Other suitable acid soluble coatings for the first dosage
component are known in the art and include those coatings that
dissolve at a pH less than 6.0. Non-limiting examples of acid
soluble coatings include gelatin, Eudragit.RTM. E-100, polyvinyl
acetyl diethylaminoacetate, and chitosan coatings. The acid-soluble
coating may be applied using various techniques (e.g., spray
techniques) known to one skilled in the art.
[0143] The first dosage component may also comprise one or more
pharmaceutically acceptable excipients in addition to those
described above. Suitable pharmaceutically acceptable excipients
are those known in the art, for example, binders, fillers,
disintegrants, glidants, lubricants, diluents, plasticizers, etc.
as described in Remington's Pharmaceutical Science, 18.sup.th
Edition, 1990, Mack Publishing Company, Easton, Pa.
("Remington's").
Second Dosage Component
[0144] The second dosage component is a controlled release dosage
form described above. In some embodiments, the only active
ingredient in the second dosage form is DMF.
[0145] In some embodiments, suitable amounts of API for the second
dosage component include those that can provide, by itself or in
combination with one or more doses from, for example, a first
dosage component, a daily amount of the respective compound (e.g.,
DMF) ranging from about 1 mg/kg to about 50 mg/kg (e.g., from about
2.5 mg/kg to about 20 mg/kg or from about 2.5 mg/kg to about 15
mg/kg).
[0146] Suitable doses of DMF for the second dosage component may be
any therapeutically effective dose, e.g., an amount that is
effective in treating multiple sclerosis. For example, suitable
doses of DMF for the second dosage component may be any dose from
20 mg to 1 g of DMF. In some embodiments, the suitable doses of DMF
in the second dosage component may be any dose from about 80 mg to
about 1000 mg of DMF. In some embodiments, the suitable doses of
DMF in the second dosage component may be any dose from about 100
mg to about 750 mg of DMF. In some embodiments, the suitable doses
of DMF in the second dosage component is about 200 to about 600 mg.
In some embodiments, the suitable doses of DMF in the second dosage
component may be any dose from about 300 to about 600 mg.
[0147] In some embodiments, the DMF in the second dosage component
is about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 160
mg, about 200 mg, about 240 mg, about 320 mg, about 360 mg, about
400 mg, about 480 mg, about 600 mg, about 720 mg, about 800 mg,
about 900 mg, about 1000 mg of DMF, or any ranges thereof.
[0148] The second dosage component can contain an amount of a
compound that that can metabolize into MMF that provides an
equivalent amount of MMF as the doses of DMF described above.
[0149] In some embodiments, the second dosage component comprises
an acid soluble outer coating as described for the first dosage
component.
Relationship of First and Second Dosage Components
[0150] In some embodiments, the first dosage component and the
second dosage component are both part of a capsule. In some
embodiments, the second dosage component is a floating capsule
comprising an acid soluble cap (e.g., gelatin cap), and the first
dosage component is placed between a pulsatile coating or layer of
the second dosage component and the acid soluble cap (e.g., gelatin
cap). Upon oral administration, the acid soluble cap (e.g., gelatin
cap) is dissolved in the gastric fluid and releases the first dose
of drug (e.g., DMF) from the first dosage component. At the same
time, the second dosage component floats in the gastric fluid and
is slowly eroded by the gastric fluid until a pulsatile coating or
layer is disintegrated and releases the second dose of drug (e.g.,
DMF).
[0151] In some embodiments, the first dosage component encapsulates
the second dosage component. In some embodiments, the first dosage
component is further encapsulated by an acid soluble coating. In
some embodiments, the second dosage component comprises an outer
acid resistant coating.
[0152] In some embodiments, the first dosage component and the
second dosage components are not physically attached to each other
(e.g., as two capsules, two tablets, or one capsule and one
tablet), which are provided (e.g., packaged) in a kit (e.g., a
blister pack). For example, in some embodiments, the first dosage
component is a non-gastro-retentive capsule (e.g., containing 120
mg or 240 mg DMF) and the second dosage component is a controlled
release dosage form (e.g., as described herein). Thus, oral
administration of the unit dosage form requires orally
administering a non-gastro-retentive capsule (e.g., containing 120
mg or 240 mg DMF) and one controlled release dosage form (e.g., as
described herein) at the same or substantially the same time as a
single dose.
Unit Dosage Form Comprising More than Two Dosage Components
[0153] In some embodiments, the unit dosage form is configured to
have more than two dosage components, e.g., to provide a sustained
release, or more than two pulses of releases of the API. In some
embodiments, the unit dosage form comprising the first and second
dosage components further comprises one or more dosage components
comprising one or more doses of the API, wherein upon oral
administration of the unit dosage form to a subject, the first,
second, and the one or more doses of the API, are delivered to GI
tract (e.g., upper GI tract or lower GI tract) of the subject in a
sustained or pulsatile manner. The time between two consecutive
pulses (e.g., between the first and second pulse, or the second and
third pulses, etc.) in a pulsatile delivery system may be the same
or different, each may be about 2 hours, about 4 hours, about 6
hours, about 8 hours, about 10 hours, about 12 hours, about 14
hours, or any ranges thereof.
Method of Treatment
[0154] DMF and its active metabolite MMF have been indicated as
useful for the treatment or prophylactic treatment of various
diseases or disorders. Thus, in some embodiments, the invention
also provides a method of treatment or prophylactic treatment of
diseases or disorders where administering DMF is helpful, the
method comprising orally administering to a subject in need thereof
a unit dosage form (e.g., as described herein) once per day (i.e.,
QD dosing). The treatment or prophylactic treatment may be acute or
chronic (e.g., more than 1, 2, 3, 4, 5, 8, 10, or 12 weeks)
treatments.
[0155] In some embodiments, the disease or disorder where
administering DMF is helpful is
(1) an autoimmune disease selected from the group consisting of
polyarthritis, rheumatoid arthritis, multiple sclerosis,
graft-versus-host reactions, juvenile-onset diabetes, Hashimoto's
thyroiditis, Grave's disease, systemic Lupus erythematodes (SLE),
Sjogren's syndrome, pernicious anaemia and chronic active (=lupoid)
hepatitis, psoriasis, psoriatic arthritis, neurodermatitis and
enteritis regionalis Crohn; (2) a mitochondrial disease selected
from the group consisting of Parkinson syndrome, Alzheimer's
disease, Chorea Huntington disease, retinopathia pigmentosa or
forms of mitochondrial encephalomyopathy; (3) a NF-kappaB mediated
diseases selected from the group consisting of progressive systemic
sclerodermia, osteochondritis syphilitica (Wegener's disease),
cutis marmorata (livedo reticularis), Behcet disease,
panarteriitis, colitis ulcerosa, vasculitis, osteoarthritis, gout,
artenosclerosis, Reiter's disease, pulmonary granulomatosis, types
of encephalitis, endotoxic shock (septic-toxic shock), sepsis,
pneumonia, encephalomyclitis, anorexia nervosa, hepatitis (acute
hepatitis, chronic hepatitis, toxic hepatitis, alcohol-induced
hepatitis, viral hepatitis, jaundice, liver insufficiency and
cytomegaloviral hepatitis), Rennert T-lymphomatosis, mesangial
nephritis, post-angioplastic restenosis, reperfusion syndrome,
cytomegaloviral retinopathy, adenoviral diseases such as adenoviral
colds, adenoviral pharyngoconjunctival fever and adenoviral
ophthalmia, AIDS, Guillain-Barre syndrome, post-herpctic or
post-zoster neuralgia, inflammatory demyclinising polyneuropathy,
mononeuropathia multiplex, mucoviscidosis, Bechterew's disease,
Barett oesophagus, EBV (Epstein-Barr virus) infection, cardiac
remodeling, interstitial cystitis, diabetes mellitus type II, human
tumour radiosensitisation, multi-resistance of malignant cells to
chemotherapeutic agents (multidrug resistance in chemotherapy),
granuloma annulare and cancers such as mamma carcinoma, colon
carcinoma, melanoma, primary liver cell carcinoma, adenocarcinoma,
kaposi's sarcoma, prostate carcinoma, lcukacmia such as acute
mycloid leukaemia, multiple myeloma (plasmocytoma), Burkitt
lymphoma and Castleman tumour; (4) a cardiovascular disease
selected from the group consisting of cardiac insufficiency,
myocardial infarct, angina pectoris and combinations thereof; (5) a
respiratory disease selected from the group consisting of asthma,
chronic obstructive pulmonary diseases, PDGF induced thymidine
uptake of bronchial smooth muscle cells, bronchial smooth muscle
cell proliferation, and combinations thereof; (6) a
neurodegeneration or neuroinflammation selected from the group
consisting of Adrenal Leukodystrophy (ALD), Alcoholism, Alexander's
disease, Alper's disease, Alzheimer's disease, Amyotrophic lateral
sclerosis (Lou Gehrig's Disease), Ataxia telangiectasia, Batten
disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease),
Bovine spongiform encephalopathy (BSE), Canavan disease, Cerebral
palsy, Cockayne syndrome, Corticobasal degeneration,
Creutzfeldt-Jakob disease, Familial Fatal Insomnia, Frontotemporal
lobar degeneration, Huntington's disease, HIV-associated dementia,
Kennedy's disease, Krabbe's disease, Lewy body dementia,
Neuroborreliosis, Machado-Joseph disease (Spinocerebellar ataxia
type 3), Multiple System Atrophy, Multiple sclerosis, Narcolepsy,
Niemann Pick disease, Parkinson's disease, Pelizaeus-Merzbacher
Disease, Pick's disease, Primary lateral sclerosis, Prion diseases,
Progressive Supranuclear Palsy, Refsum's disease, Sandhoff disease,
Schilder's disease, Subacute combined degeneration of spinal cord
secondary to Pernicious Anaemia, Spielmeyer-Vogt-Sjogren-Batten
disease (also known as Batten disease), Spinocerebellar ataxia,
Spinal muscular atrophy, Steele-Richardson-Olszewski disease, Tabes
dorsalis, Toxic encephalopathy, LHON (Leber's Hereditary optic
neuropathy), MELAS (Mitochondrial Encephalomyopathy; Lactic
Acidosis; Stroke), MERRF (Myoclonic Epilepsy; Ragged Red Fibers),
PEO (Progressive External Opthalmoplegia), Leigh's Syndrome, MNGIE
(Myopathy and external ophthalmoplegia; Neuropathy;
Gastro-Intestinal; Encephalopathy), Kearns-Sayre Syndrome (KSS),
NARP, Hereditary Spastic Paraparesis, Mitochondrial myopathy, and
Friedreich Ataxia; or (7) a demyelinating neurological disorder
selected from the group consisting of optic neuritis, acute
inflammatory demyelinating polyneuropathy (AIDP), chronic
inflammatory demyelinating polyneuropathy (CIDP), acute transverse
myelitis, progressive multifocal Icucoencephalopathy (PML), acute
disseminated encephalomyelitis (ADEM) or other hereditary disorders
(e.g., leukodystrophies, Leber's optic atrophy, and
Charcot-Marie-Tooth disease).
[0156] In some embodiments, the disease or disorder where
administering DMF is helpful is a neutrophil mediated disease or
disorder (e.g., an allergic disease or disorder, an inflammatory
disease or disorder, an autoimmune disease or disorder, or a
tumor).
[0157] Non-limiting examples of autoimmune diseases or disorders
include autoimmune Addison's disease, autoimmune hemolytic anemia,
autoimmune hepatitis, autoimmune inner ear disease, autoimmune
lymphoproliferative syndrome (ALPS), autoimmune thrombocytopenic
purpura (ATP), or autoimmune skin blistering diseases (AIBD).
[0158] Non-limiting examples of autoimmune skin blistering diseases
include epidermolysis bullosa acquistita (EBA), pemphigoid disease
(e.g., bullous pemphigoid, mucous membrane pemphigoid, or
pemphigoid gestationis), IgA-mediated bullous dermatoses (e.g.,
Dermatitis Herpetiformis or Linear IgA Bullous Dermatosis), and
pemphigus disease (e.g., IgA Pemphigus).
[0159] Non-limiting neutrophil mediated diseases or disorders also
include an inflammatory skin or subcuteneous disease selected from
the group consisting of Pyodcrma Gangrcnosum, Erosive Pustular
Dcrmatosis of the Scalp, Sweet's Syndrome, Bowel-associated
Dermatosis-arthritis Syndrome, Pustular Psoriasis, Acute
Generalized Exanthematous Pustulosis, Keratoderma Blenorrhagicum,
Sneddon-Wilkinson Disease, Amicrobial Pustulosis of the Folds,
Infantile Acropustulosis, Transient Neonatal Pustulosis,
Neutrophilic Eccrine Hidradenitis, Rheumatoid Neutrophilic
Dermatitis, Neutrophilic Urticaria, Still's Disease, Erythema
Marginatum, Unclassified Periodic Fever Syndromes/Autoinflammatory
Syndromes, Bullous Systemic Lupus Erythcmatosus, and Ncutrophilic
Dermatosis of the Dorsal Hands (Pustular Vasculitis);
[0160] Non-limiting neutrophil mediated diseases or disorders also
include: [0161] a) an allergic condition selected from the group
consisting of anaphylaxis, allergic rhinitis and allergic asthma;
[0162] b) neutrophil mediated respiratory disease selected from the
group consisting of lung cancer, severe asphyxic episodes of
asthma, acute lung injury, and Acute Respiratory Distress Syndrome;
[0163] c) an acute tissue injury selected from the group consisting
of acute kidney injury, ischemia reperfusion injury, sepsis, and
septicemia with multiorgan failure; [0164] d) an inflammatory bowel
disease selected from the group consisting of ulcerative colitis,
Crohn's disease, and inderteminate colitis; and [0165] e) sickle
cell crisis or acute chest syndrome.
[0166] In some embodiments, the disease or disorder where
administering DMF is helpful is a disease or disorder that is
associated with aberrant PI3K/AKT signaling including cancer,
chronic inflammation and allergy, neurodegerative disease,
cardiovascular disease and metabolic diseases. Non-limiting
examples of disease or disorders that are associated with aberrant
PI3K/AKT signaling include all forms of cancer, precancerous
lesions, cardiovascular disease, rheumatologic disease, pulmonary
disease, dermatologic disease, gynecological diseases, vascular
disease, neurologic disease, and infectious disease including
bacterial, viral, retroviral, and parasitic diseases. In some
embodiments, the disease or disorder to be treated is cancer.
Non-limiting examples of cancer include breast cancer, lung cancer,
ovarian cancer, uterine cancer, brain cancer, sarcoma, melanoma,
leukemia, lymphoma, colorectal cancer, prostate cancer, and liver
cancer. In some embodiments, the disease or disorder to be treated
is rheumatologic disease, e.g., rheumatoid arthritis or
osteoarthritis. In some embodiments, the disease or disorder to be
treated is pulmonary disease, e.g., allergic rhinitis, chronic
obstructive pulmonary disease (COPD).
[0167] In some embodiments, the disease or disorder where
administering DMF is helpful is a disease or disorder that is
associated with aberrant p38 MAPK signaling. Non-limiting examples
of such diseases include COPD (including chronic bronchitis and
emphysema), asthma, paediatric asthma, cystic fibrosis,
sarcoidosis, idiopathic pulmonary fibrosis, allergic rhinitis,
rhinitis, sinusitis, allergic conjunctivitis, conjunctivitis,
allergic dermatitis, contact dermatitis, psoriasis, ulcerative
colitis, inflamed joints secondary to rheumatoid arthritis or
osteoarthritis, rheumatoid arthritis, pancreatitis, cachexia,
inhibition of the growth and metastasis of tumours including
non-small cell lung carcinoma, breast carcinoma, gastric carcinoma,
colorectal carcinomas and malignant melanoma.
[0168] In some embodiments, the invention provides a method of
treating multiple sclerosis (e.g., relapsing-remitting MS,
secondary progressive MS, primary progressive MS, progressive
relapsing MS) in a subject in need thereof, wherein the method
comprises administering to the subject a controlled release dosage
form or an unit dosage form (e.g., as described herein) once per
day.
[0169] In some embodiments, the unit dosage form comprises
(a) a first dosage component comprising a first dose of about 80 mg
to about 360 mg (e.g., about 120 mg or about 240 mg) of an API; and
(b) a second dosage component comprising a second dose of about 80
mg to about 720 mg (e.g., about 120 mg or about 240 mg) of the API;
wherein when the unit dosage form is administered to a subject
orally, the first and second doses of the API are delivered to the
upper GI tract of the subject in a sustained or pulsatile
manner.
[0170] In any of the embodiments described herein, the controlled
release dosage form or unit dosage form may be administered to a
subject with or without food.
[0171] In some embodiments, the first and second dosage components
of the unit dosage form are physically separated from each other
(e.g., as two capsules, two tablets, or one capsule and one tablet)
and are provided in a kit (e.g., a blister pack). In some
embodiments, the first and second dosage components of the unit
dosage form are both part of one dosage form (e.g., a pill, a
tablet, or a capsule).
[0172] In some embodiments, the only active ingredient in the
controlled release dosage form or unit dosage form is DMF.
[0173] In some embodiments, the method comprises orally
administering to the subject the controlled release dosage form or
unit dosage form with or without food once per day, wherein the
subject exhibits one or more of the following pharmacokinetic
parameters: (a) a mean plasma MMF AUC.sub.overall ranging from
about 4.81 hmg/L to about 11.2 hmg/L; (b) a mean plasma MMF
AUC.sub.0-12 ranging from about 2.4 hmg/L to about 5.5 hmg/L; and
(c) a mean AUC.sub.0-infinity ranging from about 2.4 hmg/L to about
5.6 hmg/L. In some embodiments, the subject treated exhibits a
pharmacokinetic profile characterized by both (a) and (b), both (a)
and (c), or both (b) and (c). In some embodiments, the subject
treated exhibits a pharmacokinetic profile characterized by (a),
(b), and (c).
[0174] In some embodiments, the subject exhibits a mean MMF plasma
area under the curve 0-12 (AUC.sub.0-12) of about 2.36 hmg/L to
about 5.50 hmg/L, from about 2.75 hmg/L to about 5.10 hmg/L, or
from about 3.14 hmg/L to about 4.91 hmg/L. In some embodiments, the
subject exhibits a mean AUC.sub.0-12 of about 3.93 hmg/L.
[0175] In some embodiments, the subject exhibits a mean MMF plasma
overall area under the curve (AUC.sub.overallu) of about 4.81
hmg/mL to about 11.2 hmg/mL, or from about 6.40 hmg/L to about 10.1
hmg/L. In some embodiments, the subject exhibits a mean
AUC.sub.overall of about 8.02 hmg/L.
EXAMPLES
Example 1
Preparation of Coated Pulsatile Microtablets
[0176] Multiple coating layers were applied onto core microtablets
in order to provide a fast and complete release after a predefined
delay time anywhere from 4 to 12 hours. See FIG. 1A. The core
microtablets, .about.2 mm in diameter and .about.2 mm in thickness,
were coated with a seal coating layer from 2% to 20% weight gain
with respect to core microtablet weight. The seal coating (inner
coating), which is based on either an enteric polymer such as
Eudragit series polymers or a polyethylene glycol, was applied in
order to minimize potential loss of active through sublimation
during subsequent coatings. The seal coated microtablets were then
coated with a semipermeable, rupture-able membrane for pulsatile
release characteristics. The pulse release coating consisted of a
water-insoluble polymer, either ethylcellulose (EC) or cellulose
acetate (CA), and a water-soluble polymer, either hydroxypropyl
cellulose (HPC, Klucel JF) or polyethylene glycol (PEG). The weight
gain for pulsatile coating was around 5% to 20%. A third coating,
with a target weight gain of 5% to 20%, was applied onto the
pulsatile coated microtablets. The third coating, based on enteric
polymer such as Eudragit FS 30D from Evonik, was intended to have
pH 7.0 enteric release characteristics for colonic delivery.
[0177] Coating Solution/Suspension Preparations: [0178] a) Inner
coating solution--6.6% Eudragit L100/Triethyl citrate (w/w, 100/10)
in isopropyl alcohol. Add 210 g Eudragit L100 into 1494 g IPA, stir
until a clear or slightly hazy solution is formed; Add 46 g water,
and mix well; Add 21 g triethyl citrate, and mix well; Add 1729 g
IPA to the solution above, and stir to mix well. [0179] b)
Pulsatile coating solution--6% Ethylcellulose
(EC)/Hydroxypropylcellulose (HPC) (w/w, 60/30, 65/35, 70/30) in
isopropyl alcohol/water. Example given here is for EC/HPC of
65/35only. Dissolve 74 g hydroxypropylcellulose in 395 g water;
Dissolve 137 g ethylcellulose in 2895 g IPA; Mix both solutions for
the final coating solution. [0180] c) Enteric coating
suspension--20% Eudragit FS 30D in aqueous suspension. Homogenize
129 g talc and 13 g triethyl citrate in 998 g water for 20 minutes;
Add talc suspension slowly into 860 g Eudragit FS 30D dispersion
while stirring gently; Pass the suspension preparation through a
0.5 mm sieve for the final coating suspension.
[0181] Manufacturing Steps: [0182] a) Core microtablets. Core
microtablets were prepared by conventional tablet press equipped
with multi-tip microtablet toolings. Powder blends were prepared by
direct blends of API with excipients. [0183] b) Inner coating.
Inner coating of Eudragit L100/triethyl citrate was applied to the
core microtablets via a fluid bed coater with a Wurster column. A
non-perforated pan coater was also found suitable for the coating.
Microtablet weight gains were monitored throughout the coating
process. [0184] c) Pulsatile coating. Pulsatile coating of
Ethylcellulose/Hydroxypropylcellulose was applied to the core
microtablets via a fluid bed coater with a Wurster column. A
non-perforated pan coater was also found suitable for the coating.
Microtablet weight gains were monitored throughout the coating
process. [0185] d) Enteric coating. Enteric coating of Eudragit
FS30D was applied to the core microtablets via a fluid bed coater
with a Wurster column. A non-perforated pan coater was also found
suitable for the coating. Microtablet weight gains were monitored
throughout the coating process.
[0186] Test Protocol for In-Vitro Dissolution on Microtablets:
[0187] a) For group of microtablets. USP apparatus II (paddle), 100
rpm, 37.degree. C., 2 hours in pH 0. IN HCl, followed by 10 hours
in pH 7.4 phosphate buffer (USP) [0188] b) For single microtablet.
USP apparatus IV (flow through cell), 37.degree. C., 8 mL/min, pH
7.4 phosphate buffer (USP).
Results:
[0189] Coating was successfully applied on a fluid bed coater with
Wurster column insert and a non-perforated pan coater.
[0190] Microtablets coated with all three coating layers: inner
coating, pulsatile coating, and top enteric coating.
[0191] Core microtablets with different disintegrant levels, 5% and
7%, were coated in order to evaluate potential effects on lag time
prior to coating rupture as well as the speed of release after
coating rupture.
[0192] Inner coatings were varied from 2% to 15% weight gain with
Eudragit L100 with or without the presence of triethyl citrate
(TEC).
[0193] Pulsatile coatings were tested using mixed polymer of
ethylcellulose/hydroxypropyl cellulose with EC:HPC (w:w) polymer
ratios of 60:40, 65:35, and 70:30. Coating weight gains of 3% to
20% were studied.
[0194] Enteric coatings were performed using Eudragit FS 30D
enteric polymer dispersion. A weight gain of 5% to 20% was
studied.
[0195] Characterization on the coated microtablets was performed
using scanning electric microscope (SEM), disintegration and
various in-vitro dissolution techniques.
[0196] Pulsatile release was obtained with the 3-layer coating
system. Lag (delayed release) times of 0.5-6 hours were achieved
with the combination of pulsatile coating and inner coating alone.
Additional top coating with pH 7.0 enteric polymer resulted in
additional 4-6 hours delay time. As a result, the coating system
delivered 4 to 12 hours delayed release time.
[0197] FIG. 1B shows a picture and a microscopic view of a delayed
release tablet prepared according to this example with three
coating layers: an inner seal coating layer, a semipermeable
coating layer, and an outer pH 7 release coating layer.
[0198] FIG. 2A shows the in vitro dissolution profile of six
microtablets of one formulation.
[0199] FIG. 2B shows screen shots of a pulsatile formulation before
and after drug release.
Example 2
API Particle Coating
[0200] DMF particle coating can be either coated with enteric or
other release modifying coating. Coated DMF particles could be
filled into capsules directly for final dosage forms. Enteric
coated APIs could be formulated into tablets or capsules, and
therefore no additional enteric coating will be necessary for
enteric protection of the final dosage forms. These formulations
have fewer tendencies for any potential dose dumping. Fluid bed
coater with Wurster column insert and bottom spray or top spray can
be used for DMF particle coating.
[0201] Coating Solution:
TABLE-US-00001 Coating solution in IPA (L100/TEC 6.6% w/w)
Ingredients Batch quantity (g) Eudragit L100 210 IPA 1494 Water 46
Triethyl citrate 21 IPA 1729 TOTAL 3500
[0202] A coating solution containing Eudragit L100 and triethyl
citrate (TEC) in 6.6% w/w ratio was prepared by the following
process. First, 210 g Eudragit L100 was added into 1494 g IPA while
stirring. The resulted mixture is either a clear solution or
slightly hazy. This mixture was then mixed with 46 g of water and
21 g TEC consecutively. Finally, 1729 g IPA was added to the
solution and mixed to afford the coating solution.
[0203] Coating:
[0204] DMF particle coating was performed with a fluid bed coater
using bottom spray (Wurster). 658 g DMF particles (mesh cut #40/#60
with 0.25% SiO2 added) was coated with 1408 g of the coating
solution prepared above with the following process parameter.
Atomization pressure was set at 2 bar, inlet temperature as needed,
product temperature was set at about 33.degree. C., out let
temperature was set at about 30.degree. C., pump rate was set at
2.5 g/minute.
TABLE-US-00002 Fluid Bed Coating - Under Coat (Eudragit L100/TEC)
Batch number: 17252-131 Description: Coated Crystals (seal coating)
Coating substrate Substrate: Drug Substance Crystals (#40/#60 mesh
cut) Substrate batch #: lot I12JS4281) Substrate quantity: 658
grams PROCESS PARAMETERS Start SPRAYING Drying Time (HH:MM) 9:32
10:02 10:32 11:02 11:32 12:02 13:32 14:02 14:32 15:03 15:32 16:02
16:07 Time (min.) 0 30 60 90 120 150 240 270 300 330 360 390 5 Air
Flow Set 13 13 13 13 13 13 13 13 13 13 13 13 13 (m3/min) Inlet Air
45 45 45 45 45 45 45->40 40->38 38 38 38 38 38 temperature
Set (.degree. C.) Inlet Air 55 44 59 53 44 64 53 58 38 43 53 53 --
temperature (.degree. C.) Core Temperature 34 34 37 36 34 36 36 34
33 33 34 32 -- (.degree. C.) Outlet Air 29 29 30 30 30 31 32 30 30
30 30 30 -- Temperature (.degree. C.) Spray rate Set 4 4 4 5->6
6 6 6 6 6 6 6 -- -- Spray rate (ml/min) 0 1.9 1.9 2.7 5.4 3.4 3.4
4.8 3.4 3.4 3.6 -- -- Spay pressure (bar) 2 2 2 2 2 2 2 2 2 2 2 2
-- Amount solution -- 56.5 114.2 195.9 356.6 458 768 911.3 1014.1
1117.4 1225.7 1408 1408 consumed (g)
[0205] The coated DMF particles was dried for 5 minutes and samples
were taken for testing. Coated DMF samples were characterized by
both Scanning electron microscope (SEM) and in-vitro dissolution
techniques.
[0206] Results
[0207] The weight of the coated DMF particle was determined to be
42.53 mg. The amount of DMF in these coated particles were
calculated to be 35.09 mg. Thus, the coating weight gain here was
determined to be 21.2%.
[0208] In vitro dissolution of the coated API particles were
determined by USP paddle method in 0.1 N HCl solution at 100 rpm,
n=3. The table below shows the dissolution rate of the coated
API.
TABLE-US-00003 Vessel # 1 2 3 Label Time 17252-131 Point 17252-131
17252-131 17252-131 (14%)_AVE min (14%)_1 (14%)_2 (14%)_3 AVE 1, 2,
3 SD 1, 2, 3 0 0.00 0.00 0.00 0.0% 0.0% 10 0.06 0.08 0.12 8.4% 3.2%
120 0.20 0.22 0.31 24.2% 6.1% 135 0.22 0.24 0.33 26.3% 6.2%
infinite 250 rpm @ 2 hr 15 min AVE: Average; SD: Standard
Deviation.
[0209] Conclusion:
[0210] Coating DMF particles can be successful done on a fluid bed
coater. DMF particle sizes of .about.130 .mu.m to .about.350 .mu.m
were successfully coated with Eudragit L100/TEC using similar
methods as described above. The coating weight gains were from 9%
to 20%. DMF particle sizes of 130 m to .about.350 .mu.m were also
successfully coated with either Ethyl cellulose (EC)/Hydroxylpropyl
cellulose (HPC) or Cellulose acetate/Polyethylene glycol (PEG)
coatings. The coating weight gains were from 9% to 20%.
[0211] Addition of 0.25% (w/w) colloidal SiO.sub.2 to DMF particles
prior to fluid bed coating greatly improved the powder bed
flowability, and thus ensured a uniform coating of the
particles.
Example 3
Osmotic Dosage Form
[0212] An example of an osmotic dosage form composition is as below
that can be manufactured using dry blending, dry granulation, or
wet granulation process:
Monolithic tablet (weight 502.6 mg):
TABLE-US-00004 DMF Drug Substance 47.75% Sorbitol Osmotic Agent
40.00% HEC 250H or 250L Rate Controlling Polymer 8.00% HPC EF
Binder 3.00% Silicon Dioxide Glidant 0.125% SLS Wetting Aid 0.125%
Mg-Stearate Lubricant 1.00%
Coating Semi-permeable Membrane Weight Gain .about.10% of
tablet)
TABLE-US-00005 Cellulose Acetate 320 3.0% Hydroxypropyl Cellulose
EF 1.0% Acetone 86.4% Water 9.6%
Example 4
Capsule Containing One Immediate Release Tablet and Two Osmotic
Tablets
Immediate Release Tablet
TABLE-US-00006 [0213] TABLE 1 IR tablet WT (mg) 275 BATCH(g) 25.0
MATERIAL INTRA % PERCENT MG/TAB GRAMS DMF 99.00 87.270 240.0 21.8
COLLOIDAL 0.75 0.661 1.8 0.2 SILICON DIOXIDE SLS 0.25 0.220 0.6 0.1
PREBLEND 100.00 MCC AVICEL PH105 5.848 16.1 1.5 AC-DI-SOL 5.000
13.8 1.3 MAG-STEARATE 1.000 2.8 0.3 100.000 275.0 25.0 SEAL COATING
% SOLIDS 5 BATCH(g) 25.0 MEMBRANE MATERIAL % PERCENT -- GRAMS
EUDRAGIT L100 75.00 3.750 0.9 TEC 25.00 1.250 0.3 Solids 100.00 %
PERCENT -- GRAMS IPA 100.00 95.000 23.8 Water 0.00 0.000 -- 0.0
Solvent 100.00 100.000 25.0 ENTERIC COATING % SOLIDS 30 BATCH(g)
25.0 ENTERIC MATERIAL % PERCENT -- GRAMS EUDRAGIT FS 30D 96.77
29.031 7.3 PLASACRYL T20 3.23 0.969 0.2 Solids 100.00 % PERCENT --
GRAMS IPA 0.00 0.000 0.0 Water 100.00 70.000 -- 17.5 Solvent 100.00
100.000 25.0
Osmotic Tablet
TABLE-US-00007 [0214] TABLE 2 Osmotic Tablet WT (mg) 275 BATCH(g)
25.0 MATERIAL INTRA % PERCENT MG/TAB GRAMS DMF 99.00 43.640 120.0
10.9 COLLOIDAL 0.75 0.331 0.9 0.1 SILICON DIOXIDE SLS 0.25 0.110
0.3 0.0 PREBLEND 100.00 SORBITOL 43.919 120.8 11.0 HEC 250H OR 250
L 8.000 22.0 2.0 HPC EXF 3.000 8.3 0.8 MAG-STEARATE 1.000 2.8 0.3
100.000 275.0 25.0 MEMBRANE COATING % SOLIDS 5 BATCH(g) 25.0
MEMBRANE MATERIAL % PERCENT -- GRAMS CA-320 75.00 3.750 0.9 HPC EF
25.00 1.250 0.3 Solids 100.00 % PERCENT -- GRAMS Acetone 90.00
85.500 21.4 Water 10.00 9.500 -- 2.4 Solvent 100.00 100.000
25.0
Example 5
Matrix Microtablet Dosage Form
TABLE-US-00008 [0215] Formu- Formu- Formu- Formu- Formu- lation
lation lation lation lation Component 090913A 090913B 090913C
090913D 090913E DMF 59.4% 59.4% 59.4% 59.4% 59.4% Flowlac 100 29.7%
19.8% 19.8% 29.7% 19.8% HPMC 0.0% 19.8% 0.0% 0.0% 0.0% K 4M HPMC K
0.0% 0.0% 19.8% 0.0% 0.0% 100M Kollidon SR 0.0% 0.0% 0.0% 9.9%
19.8% Ethocel 10 9.9% 0.0% 0.0% 0.0% 0.5% Magnesium 0.5% 0.5% 0.5%
0.5% 0.5% Stearate Aerosil 0.5% 0.5% 0.5% 0.5% 0.5% Formulation
090913F: DMF, 46%; Lactos Fast Flo, 22%; HPMC K100LV, 30%; Aerosil
200, 0.5%; and Magnesium Stearate, 1%. Formulation 090913G: DMF,
46%; DCP anhydrous, 22.5%; HPMC K4M, 30%; Aerosil 200, 0.5%; and
Magnesium Stearate, 1%.
[0216] A brief procedure for preparing formulations 090913A-G is
below.
[0217] Pass the DMF through a Co-mil U5 using a round impeller and
a 7L039R conical plate. Run the mill at approximately 2400 rpm.
Return the milled material to the blender. Charge the pre-weighed
matrix filler and aerosil and blend the mixture for 15 min at 25
RPM minutes. Charge the blender with the pre-weighed magnesium
stearate and blend for 2 minutes. Tablet half the final blend on a
Picola press using 16 micro-tipped tools 8 mg weight. Adjust the
compression force to required compression force. Record IPC
measurements on run sheet. Tablet the second half into monolithic
tablets 550 mg tablet weight-9 mm.
Example 6
Matrix Microtablet or Tablet Formulation
[0218] Formulation 101413F Drug load (DL)=65%
TABLE-US-00009 Ingredient Amount (grams) DMF - 1300 Flowlac - 580
Kollidon SR - 100 Magnesium Stearate - 10 Acrosil - 10 Total -
2000.0
[0219] Formulation 101413G DL=50%
TABLE-US-00010 Ingredient Amount (grams) DMF - 1000 DCP anhydrous -
400 HPMC K4M - 580 Magnesium Stearate 10 Aerosil 10 Total
2000.0
[0220] Procedure: Pass the DMF through a Comil U5 using a round
impeller and a 7L039R conical plate. Run the mill at approximately
2400 rpm. (You can comil all the API and dispense the required
amount per each lot). Charge the DMF, pre-weighed matrix fillers
and acrosil and blend the mixture for 15 min at 25 RPM. Charge the
blender with the pre-weighed magnesium stearate and blend for 2
minutes. Tablet half the final blend on a Piccola press using 16
micro-tipped tools 8 mg weight. Adjust the compression force to
required compression force 5 kN@ 15 rpm. Record IPC measurements on
run sheet. Save the second half of the blend. For tableting on the
10 mm round flat faced tablets.
[0221] Manufactured the blend formulations above and compressed
them into microtablets and 10 mm round flat face tablets.
[0222] In vitro dissolution were performed according to USP
apparatus II (paddle) at an agitation speed of 75 rpm. The
parameters are shown below:
TABLE-US-00011 Dissolution Parameters Method No.: Apparatus: 2
Medium: Water Agitation (rpm): 75 Volume (mL): 500 Temp. (.degree.
C.): 37 Dilution Factor (mL) 40
[0223] FIG. 4 shows in vitro dissolution profile of six different
matrix formulations. Formulations 090913A, 090913F, 101413F and
101413G each contains a plurality of microtablets. Formulations
101413FT and 101413GT have the same ingredients as 101413F and
101413G, respectively, but are made as monolithic tablets.
Example 7
Bilayer Floating Tablet
[0224] Floating tablets for sustained release: 10 mm pellets with
50-200 mg of floating layer and 400 mg of active layer are made
using 10-mm punch and die and a manual pellet press. The force
applied is about 15001b and 20001b.
[0225] For example, the active layer and floating layer have the
following ingredients:
[0226] Active Layer:
60% coated DMF
24% Plyox 205-NF (PEO)
15% Methocel K4M (HPMC)
[0227] 1% magnesium stearate
[0228] Floating Layer:
25% sodium bicarbonate
75% Methocel K 100M (HPMC)
[0229] Floating tablets for pulsatile release: 10 mm pellets with
50-200 mg of floating layer and 200-300 mg of active layer are made
using 10-mm punch and die and a manual pellet press. The force
applied is about 15001b and 20001b.
[0230] For example, the active layer and floating layer can have
the following ingredients:
Active layer: 90% coated API of DMF [0231] 10% Methocel E3 LV
(HPMC) Floating layer: 25% Sodium Bicarbonate [0232] 75% Methocel
K100M (HPMC).
Example 8
Swellable Tablets
[0233] Swellable tablets for sustained release:
[0234] A mixture of 60% coated DMF, 24% Polyox 205-NF (PEO), 15%
Methocel K4M (HPMC), and 1% magnesium stearate will be prepared
according to the procedure below.
[0235] 10 mm pellets weighed about 400 mg (active+swelling layer)
are made using 10-mm punch and die and a manual pellet press. The
force applied is about 15001b and 2000 lb.
[0236] Swellable Tablets for Pulse Release Mechanism
[0237] The same procedure above is sued for preparing a swellable
tablets for pulse release mechanism except that the tablet includes
312 mg of the active layer and 200 mg of the swelling layer.
[0238] Active layer: 90% coated API of DMF; 10% Methocel E3 LV
(HPMC)
[0239] Swelling layer: 75% Polyox 205-NF (PEO) [0240] 24% Methocel
K4M (HPMC) [0241] 1% Magnesium Stearate.
* * * * *