U.S. patent application number 17/275790 was filed with the patent office on 2022-02-17 for formulations of cycloserine compounds and applications thereof.
This patent application is currently assigned to SyneuRx International (Taiwan) Corp.. The applicant listed for this patent is SyneuRx International (Taiwan) Corp.. Invention is credited to Guochuan Emil Tsai, Hsuan-Ang Tsai, Chih-Chien Wang, Hsin-Hsin Yang.
Application Number | 20220047560 17/275790 |
Document ID | / |
Family ID | 1000005940945 |
Filed Date | 2022-02-17 |
United States Patent
Application |
20220047560 |
Kind Code |
A1 |
Tsai; Guochuan Emil ; et
al. |
February 17, 2022 |
FORMULATIONS OF CYCLOSERINE COMPOUNDS AND APPLICATIONS THEREOF
Abstract
A solid dosage form comprises an inner core containing a
cycloserine compound and an outer layer attached to the inner core.
The dosage form can be enteric tablet or transdermal patch,
suitable for treating a neuropsychiatric disorder or
tuberculosis.
Inventors: |
Tsai; Guochuan Emil;
(Pasadena, CA) ; Wang; Chih-Chien; (New Taipei,
TW) ; Yang; Hsin-Hsin; (New Taipei City, TW) ;
Tsai; Hsuan-Ang; (New Taipei City, TW) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SyneuRx International (Taiwan) Corp. |
New Taipei City |
|
TW |
|
|
Assignee: |
SyneuRx International (Taiwan)
Corp.
New Taipei City
TW
|
Family ID: |
1000005940945 |
Appl. No.: |
17/275790 |
Filed: |
September 12, 2019 |
PCT Filed: |
September 12, 2019 |
PCT NO: |
PCT/CN2019/105635 |
371 Date: |
March 12, 2021 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
16130747 |
Sep 13, 2018 |
|
|
|
17275790 |
|
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/2018 20130101;
A61P 31/06 20180101; A61K 9/2009 20130101; A61K 9/2063 20130101;
A61K 9/2086 20130101; A61K 9/4858 20130101; A23L 33/10 20160801;
A61K 9/4866 20130101; A61P 25/18 20180101; A61P 25/24 20180101;
A61K 9/2054 20130101; A61K 9/2886 20130101; A23V 2200/322 20130101;
A61K 9/2846 20130101; A61K 9/485 20130101; A23V 2002/00 20130101;
A61K 9/282 20130101; A61P 25/28 20180101; A61K 9/4891 20130101;
A61K 31/42 20130101; A61P 25/22 20180101; A61K 9/2866 20130101;
A61K 9/2059 20130101; A61P 25/16 20180101 |
International
Class: |
A61K 31/42 20060101
A61K031/42; A61K 9/48 20060101 A61K009/48; A61K 9/20 20060101
A61K009/20; A61K 9/28 20060101 A61K009/28; A23L 33/10 20060101
A23L033/10; A61P 25/28 20060101 A61P025/28; A61P 25/24 20060101
A61P025/24; A61P 25/22 20060101 A61P025/22; A61P 25/18 20060101
A61P025/18; A61P 25/16 20060101 A61P025/16; A61P 31/06 20060101
A61P031/06 |
Claims
1. A solid dosage form, comprising: (i) an inner core, which
comprises a cycloserine compound and a pharmaceutically acceptable
excipient, wherein the pharmaceutically acceptable excipient
comprises a filler, a binder, a disintegrating agent, a lubricant,
a carrier, a pH adjuster, a dispersion reagent, an
anti-sedimentation reagent, an enhancer, a sustained release
reagent, or a mixture thereof; and (ii) an outer layer attached to
the inner core; wherein the solid dosage form contains about 10 mg
to about 1500 mg of the cycloserine compound.
2. The solid dosage form of claim 1, wherein the outer layer is an
enteric layer, which comprises polymethacrylate, phthalate,
cellulose ester, shellac, alginate, or a mixture thereof.
3. The solid dosage form of claim 2, further comprising (iii) an
isolation layer between the inner core and the enteric layer,
wherein the isolation layer comprises a cellulose polymer.
4. The solid dosage form of claim 2, wherein in the inner core: (a)
the filler is selected from the group consisting of starch,
lactose, sucrose, glucose, mannitol, calcium phosphate,
microcrystalline cellulose, and a mixture thereof; (b) the binder
is selected from the group consisting of carboxymethylcellulose,
microcrystalline cellulose (MCC), hydroxypropyl cellulose,
alginates, gelatin, polyvinylpyrrolidinone, acacia, and a mixture
thereof; (c) the disintegrating agent is selected from the group
consisting of agar, calcium carbonate, potato or tapioca starch,
alginic acid, certain silicates, sodium starch glycolate (SSG),
croscarmellose, crospovidone, sodium carbonate, and a mixture
thereof; and/or (d) the lubricant is selected from the group
consisting of magnesium stearate, colloidal silicon dioxide, talc,
calcium stearate, solid polyethylene glycol, sodium lauryl sulfate,
and a mixture thereof.
5. The solid dosage form of claim 2, wherein the pharmaceutically
acceptable excipient in the inner core comprises about 50-500 mg of
the filler, about 10-100 mg of the binder, about 10-200 mg of the
disintegrating agent, and about 5-100 mg of the lubricant.
6. The solid dosage form of claim 2, wherein the filler comprises
microcrystalline cellulose (MCC) pH 102, the binder comprises
hydroxylpropyl cellulose (HPC), the disintegrating agent comprises
croscarmellose, and the lubricant comprises magnesium stearate.
7. The solid dosage form of claim 2, wherein the enteric layer
comprises: (a) polymethacrylate, which is selected from the group
consisting of poly(methacrylic acid-co-ethyl acrylate) in a molar
ratio of 1:1, poly(methacylic acid-co-methyl methacrylate) in a
molar ratio of 1:1, poly(methacylic acid-co-methyl methacrylate) in
a molar ratio of 1:2, and poly(methyl acrylate-co-methyl
methacrylate-co-methacrylic acid) in a molar ratio of 7:3:1; (b)
phthalate, which is selected from the group consisting of polyvinyl
acetate phthalate, hydroxypropyl methylcellulose phthalate, diethyl
phthalate, and cellulose acetate phthalate; and/or (c) cellulose
ester, which is selected from the group consisting of cellulose
acetate trimellitate, cellulose acetate succinate, and
hydroxypropyl methylcellulose acetate succinate.
8. The solid dosage form of claim 2, wherein the enteric layer
comprises 90.5%-98.49% of poly(methacrylic acid-co-ethyl acrylate)
in a ratio of 1:1 by weight, 0.5%-2% of sodium lauryl sulfate by
weight, 0.01%-2.5% of triethyl citrate by weight, 0.5%-2.5% of
colloidal silicon dioxide by weight, and 0.5%-2.5% of talc by
weight.
9. The solid dosage form of claim 2, wherein the cellulose polymer
is hydroxypropyl methylcellulose (HPMC).
10. The solid dosage form of claim 9, wherein the HPMC has an
average molecular weight of 50,000 to 125,000 Dalton.
11. The solid dosage form of claim 3, wherein the isolation layer
comprises 95.5%-99.49% of hydroxypropyl methylcellulose by weight,
0.5%-2.5% of talc by weight, and 0.01%-2% of triacetin by
weight.
12. The solid dosage form of claim 3, which comprises about 10 mg
to about 300 mg of the enteric layer and/or about 10 mg to about
100 mg of the isolation layer.
13. The solid dosage form of claim 3, wherein the pharmaceutically
acceptable excipient comprises MCC pH 102, croscarmellose,
hydroxypropyl cellulose (HPC), and magnesium stearate; wherein the
enteric layer comprises polymethacrylate; and wherein the isolation
layer comprises HPMC having a molecular weight of 50,000 to 125,000
Dalton.
14. The solid dosage form of claim 1, wherein the solid dosage form
is a transdermal patch and wherein the outer layer is a backing
layer of the transdermal patch.
15. The solid dosage form of claim 14, wherein the backing layer
comprises a polymer of polyethylene, polyurethane, ethylene vinyl
acetate, polyvinyl chloride, polyethylene, terephthalate, or a
mixture therefore.
16. The solid dosage form of claim 14, wherein the inner core
comprises a carrier, a dispersion reagent, an anti-sedimentation
reagent, an enhancer, a sustained release reagent, a pH adjuster,
or a mixture thereof.
17. The solid dosage form of claim 16, wherein the carrier is
selected from the group consisting of propylene glycerol,
dipropylene glycol, hexylene glycerol, tetrathyleneglycol
monomethylether, copolymers of acrylic and methacrylic acids or
esters, hydroxypropyl methylcellulose, ethyl cellulose, polyvinyl
alcohol, polyvinylpyrrolidone, cellulose acetate phthalate,
cellulose acetate, polymerized rosin, crosslinked polyacrylic acid
polymers, acrylate copolymer, polyisobutylene, xanthan gum, and
silicon gum, or combination thereof.
18. The solid dosage form of claim 16, wherein the dispersion
reagent is selected from the group consisting of sodium lauroyl
sarcosinate, polyethylene glycol, sodium dodecyl sulfate, and
cetyltrimethylammonium bromide, or combination thereof.
19. The solid dosage form of claim 16, wherein the
anti-sedimentation reagent is selected from the group consisting of
corn oil, eucalyptus oil, peppermint oil, benzyl benzoate, and
sesame oil, or combination thereof.
20. The solid dosage form of claim 16, wherein the enhancer is
selected from the group consisting of terpene, fatty acid, ester,
essential oil, pyrrolidone, mannitol, 2-pyrrolidone,
1-methyl-2-pyrrolidone, and vitamin E, or combination thereof.
21. The solid dosage form of claim 16, wherein the sustained
released reagent is polyvinylpyrrolidone (PVP), ethyl cellulose
(EC), HPMC, polyacrylate, or a combination thereof.
22. The solid dosage form of any one of claims 16-21, wherein the
pH adjuster comprises a pharmaceutically acceptable base.
23. The solid dosage form of claim 22, wherein the pH adjuster is
sodium hydroxide, sodium acetate, or sodium bicarbonate.
24. The solid dosage form of claim 1, wherein the cycloserine
compound is in nanocrystalline form.
25. The solid dosage form of claim 1, wherein the cycloserine
compound is in particle form having a D.sub.90 value ranging from
about 0.05 .mu.m to about 500 .mu.m.
26. The solid dosage form of claim 1, wherein the cycloserine
compound is D-cycloserine or L-cycloserine, or a pharmaceutically
acceptable salt thereof.
27. The solid dosage form of claim 1, which is a pharmaceutical
composition, a nutraceutical composition, a health food, or a
medical food.
28. A method for alleviating a symptom associated with a
neuropsychiatric disease or tuberculosis, the method comprising
administering to a subject in need thereof an effective amount of
the solid dosage form of claim 1.
29. The method of claim 28, wherein the neuropsychiatric disorder
is selected from the group consisting of schizophrenia, psychotic
disorders, Alzheimer's disease, frontotemporal dementia, vascular
dementia, dementia with Lewy bodies, senile dementia, mild
cognitive impairment, benign forgetfulness, ataxia symptoms,
spinocerebellar, degeneration, closed head injury, autistic
spectrum disorder, Asperger's disorder, pervasive developmental
disorder--not otherwise specified (PDD-NOS), fragile X syndrome,
attention deficit hyperactivity disorders, attention deficit
disorder, obsessive compulsive disorder, tic disorders, childhood
learning disorders, premenstrual syndrome, depression, major
depressive disorder, anhedonia, suicidal ideation and/or behaviors,
bipolar disorder, anxiety disorders, panic disorder, anorexia,
nervosa, phobia, agoraphobia, claustrophobia, post-traumatic stress
disorder, chronic mild and unpredictable stress, eating disorders,
addiction disorders, personality disorders, Parkinson's disorder,
Huntington's disorder, multiple sclerosis, amyotrophic lateral
sclerosis, Tourette's syndrome, nocturnal enuresis, non-epileptic
seizures, blepharospasm, Duchenne muscular dystrophy, stroke,
chronic pain, neuropathic pain including hyperalgesia and
allodynia, diabetic polyneuropathy, and chronic pain syndromes.
30. The method of claim 28, wherein the solid dosage form is
administered to the subject three times a day to one time every
three months.
31. The method of claim 28, wherein the subject is on an additional
treatment for the neuropsychiatric disorder or wherein the subject
is on an additional treatment of tuberculosis.
32. The method of claim 28, further comprising administering to the
subject an additional therapeutic agent for treating the
neuropsychiatric disorder or tuberculosis.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. patent
application Ser. No. 16/130,747, entitled "Formulations of
Cycloserine Compounds and Applications Thereof," filed Sep. 13,
2018, the contents of which are incorporated by reference herein in
its entirety.
BACKGROUND OF THE INVENTION
[0002] D-Cycloserine (i.e., 4-amino-3-isoxazolidinone), is a
natural product of Streptomyces orchidaceus and Streptomyces
garyphalus, which acts as a competitive antagonist of D-alanine,
one component of bacterial cell walls. D-cycloserine inhibits
alanine racemase and alanine synthetase, resulting in bacterial
cell walls damaging due to deficiency of D-alanine. D-cycloserine
has been known as an antibiotic drug since the late 1950s and
marketed in the gelatin capsule form under a brand name
Seromycin.RTM.. It was classified on the World Health
Organization's List of Essential Medicines as a second-line drug
for the treatment of multidrug-resistant tuberculosis (MDR-TB).
However, D-cycloserine is found to be unstable under acidic and/or
aqueous conditions and the gelatin capsule form is unable to
improve such instability, resulting in less favorable absorption in
the gastrointestinal tract.
[0003] In addition to be an antibiotic, D-cycloserine is found to
be a partial agonist/antagonist of the glycine/D-serine coagonist
site of N-methyl-D-aspartate (NMDA) receptors and is readily
available for the central nervous system (CNS) after administration
peripherally. As a selective partial NMDA-agonist, it was later
proven that D-cycloserine improves long-term potentiation (LTP), a
neuronal mechanism thought to be relevant for learning processes.
D-cycloserine plays dual function in regulating NMDA receptors--it
acts as a positive modulator at low doses but as a negative
modulator at high doses. Overdosing with D-cycloserine may result
in paresis, seizures, and coma. Other side effects associated with
improper dosing of D-cycloserine include headaches, drowsiness,
depression, dizziness, vertigo, confusion, paresthesias,
dysarthria, hyperirritability, psychosis, convulsions, and shaking
(tremors).
SUMMARY OF THE INVENTION
[0004] The present disclosure is based, at least in part, on the
development of solid dosage forms (e.g., enteric formulations and
transdermal patches) comprising cycloserine compounds, which
exhibited superior, unexpected features, for example, stable under
moisture and/or acidic environments (e.g., gastrointestinal tract),
superior dissolution efficiency at a neutral pH condition (e.g., pH
6.8), capable of penetrating hydrophobic membrane (which mimics the
human skin condition), and/or enhanced bioavailability.
[0005] Accordingly, one aspect of the present disclosure provides a
solid dosage form, comprising: (i) an inner core, which comprises a
cycloserine compound and a pharmaceutically acceptable excipient,
(ii) an outer layer attached to (e.g., directly or indirectly) the
inner core; and optionally (iii) an isolation layer between the
inner core and the outer layer. The pharmaceutically acceptable
excipient may comprise a filler, a binder, a disintegrating agent,
a lubricant, a carrier, a pH adjuster, a dispersion reagent, an
anti-sedimentation reagent, an enhancer, a sustained release
reagent or a mixture thereof.
[0006] In at least some embodiments, the outer layer is an enteric
layer. In some examples, the enteric layer may comprise
polymethacrylate, phthalate, cellulose ester, shellac, alginate, or
a mixture thereof. Alternatively or in addition, The isolation
layer comprises a cellulose polymer, for example, hydroxypropyl
methylcellulose (HPMC). In some embodiments, the solid dosage form
contains about 10 mg to about 1500 mg of the cycloserine compound.
In some embodiments, the cycloserine compound (e.g., D-cycloserine,
L-cycloserine, or a pharmaceutically salt thereof) can be in
particle form having a D90 value ranging from about 0.05 .mu.m to
about 500 .mu.m.
[0007] In some embodiments, the solid dosage form is a transdermal
patch and the outer layer can be a backing layer of the transdermal
patch. In some examples, the backing layer comprises the polymer of
polyethylene, polyurethane, ethylene vinyl acetate, polyvinyl
chloride, polyethylene, terephthalate or the mixture therefore.
[0008] In some embodiments, the pharmaceutical excipients in the
inner core of any of the solid dosage forms disclosed herein may
comprise one or more fillers, one or more binders, one or more
disintegrating agents, one or more lubricants, one or more
carriers, one or more pH adjusters, one or more dispersion
reagents, one or more anti-sedimentation reagents, one or more
enhancers, one or more sustained release reagents and/or a mixture
thereof.
[0009] Examples of fillers include starch, lactose, sucrose,
glucose, mannitol, calcium phosphate, microcrystalline cellulose,
or a mixture thereof. Examples of binders include
carboxymethylcellulose, microcrystalline cellulose (MCC) (e.g., MCC
pH 102 or MCC pH 112), hydroxypropyl cellulose, alginates, gelatin,
polyvinylpyrrolidinone, acacia, or a mixture thereof.
[0010] Exemplary disintegrating agents include agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates, sodium starch glycolate (SSG), croscarmellose,
crospovidone, sodium carbonate, or a mixture thereof.
[0011] Exemplary lubricants include magnesium stearate, colloidal
silicon dioxide, talc, calcium stearate, solid polyethylene glycol,
sodium lauryl sulfate, or a mixture thereof.
[0012] Exemplary carriers include propylene glycerol, dipropylene
glycol, hexylene glycerol, tetrathyleneglycol monomethylether,
copolymers of acrylic and methacrylic acids or esters thereof (e.g.
Eudragit series, and Kollicoat MAE 30DP), hydroxypropyl
methylcellulose, ethyl cellulose, polyvinyl alcohol,
polyvinylpyrrolidone (e.g. PVP K30), cellulose acetate phthalate,
cellulose acetate, polymerized rosin, crosslinked polyacrylic acid
polymers (e.g. Carbopol 934 NF, Carbopol 940 NF), acrylate
copolymer, polyisobutylene, xanthan gum, silicon gum or combination
thereof.
[0013] Exemplary pH adjusters include sodium hydroxide, sodium
acetate, sodium bicarbonate or other pharmaceutically acceptable
base.
[0014] Exemplary dispersion reagents include sodium lauroyl
sarcosinate, polyethylene glycol (PEG) 400, PEG 1000, PEG 4000,
sodium dodecyl sulfate, cetyltrimethylammonium bromide, or
combination thereof.
[0015] Exemplary anti-sedimentation reagents include corn oil,
eucalyptus oil, peppermint oil, benzyl benzoate, sesame oil, or
combination thereof. Exemplary enhancers include terpenes, fatty
acids, esters, pyrrolidones, essential oils, mannitol,
2-pyrrolidone, 1-methyl-2-pyrrolidone, vitamin E, or combination
thereof. Exemplary sustained release reagents include PVP, EC,
HPMC, polyacrylate, or a combination thereof. Optionally the PVP is
povidone K12.
[0016] In some examples, the pharmaceutically acceptable excipient
in the inner core may comprise about 50-500 mg of the filler, about
10-100 mg of the binder, about 10-200 mg of the disintegrating
agent, and about 5-100 mg of the lubricant. In some examples, the
solid dosage described herein may comprise a filler, which
comprises MCC pH 102, a binder, which comprises hydroxylpropyl
cellulose (HPC), a disintegrating agent, which comprises
croscarmellose, and a lubricant, which comprises magnesium
stearate.
[0017] In some embodiments, the enteric layer of the solid dosage
form may comprise: (a) polymethacrylate, which can be
poly(methacrylic acid-co-ethyl acrylate) in a molar ratio of 1:1,
poly(methacylic acid-co-methyl methacrylate) in a molar ratio of
1:1, poly(methacylic acid-co-methyl methacrylate) in a molar ratio
of 1:2, or poly(methyl acrylate-co-methyl
methacrylate-co-methacrylic acid) in a molar ratio of 7:3:1; (b)
phthalate, which can be polyvinyl acetate phthalate, hydroxypropyl
methylcellulose phthalate, diethyl phthalate, or cellulose acetate
phthalate; and/or (c) cellulose ester, which can be cellulose
acetate trimellitate, cellulose acetate succinate, or hydroxypropyl
methylcellulose acetate succinate. In some examples, the enteric
layer may comprise 90.5%-98.49% of poly(methacrylic acid-co-ethyl
acrylate) in a ratio of 1:1 by weight, 0.5%-2% of sodium lauryl
sulfate by weight, 0.01%-2.5% of triethyl citrate by weight,
0.5%-2.5% of colloidal silicon dioxide by weight, and 0.5%-2.5% of
talc by weight.
[0018] In some embodiments, the isolation layer may comprise
hydroxypropyl methylcellulose (HPMC), which may have an average
molecular weight of 50,000 to 125,000 Dalton. In some examples, the
isolation layer comprises 95.5%-99.49% of hydroxypropyl
methylcellulose by weight, 0.5%-2.5% of talc by weight, and
0.01%-2% of triacetin by weight.
[0019] In some embodiments, the solid dosage form of claim 2, which
comprises about 10 mg to about 300 mg of the enteric layer and/or
about 10 mg to about 100 mg of the isolation layer.
[0020] In one example, the solid dosage form described herein
comprises (a) an inner core that comprises a cycloserine compound
(e.g., D-cycloserine, L-cycloserine, or a pharmaceutically
acceptable salt thereof) and a pharmaceutically acceptable
excipient, which comprises MCC pH 102, croscarmellose, HPC, and
magnesium stearate; (b) an enteric layer, which comprises
polymethacrylate; and (c) an isolation layer, which comprises HPMC
having a molecular weight of 50,000 to 125,000 Dalton. The
isolation layer is located between the inner core and the enteric
layer.
[0021] In one example, the solid dosage form comprises (a) an inner
core that comprises cycloserine compound (e.g., D-cycloserine,
L-cycloserine, or a pharmaceutically acceptable salt thereof) and a
pharmaceutically acceptable excipient, which comprises a carrier, a
pH adjuster, a dispersion reagent, an anti-sedimentation reagent,
an enhancer, and a sustained release reagent; and (b) a backing
layer.
[0022] Any of the solid dosage forms described herein may be a
pharmaceutical composition, a nutraceutical composition, a health
food, or a medical food.
[0023] In another aspect, the present disclosure provides a method
for alleviating a symptom associated with a neuropsychiatric
disease or tuberculosis, the method comprising administering to a
subject in need thereof (e.g., a human patient) an effective amount
of any of the solid dosage forms described herein. Exemplary
neuropsychiatric disorders include schizophrenia, psychotic
disorders, Alzheimer's disease, frontotemporal dementia, vascular
dementia, dementia with Lewy bodies, senile dementia, mild
cognitive impairment, benign forgetfulness, ataxia symptoms,
spinocerebellar degeneration, closed head injury, autistic spectrum
disorder, autism, Asperger's disorder, pervasive developmental
disorder--not otherwise specified (PDD-NOS), fragile X syndrome,
attention deficit hyperactivity disorders, attention deficit
disorder, obsessive compulsive disorder, tic disorders, childhood
learning disorders, premenstrual syndrome, depression, major
depressive disorder, anhedonia, suicidal ideation and/or behaviors,
bipolar disorder, anxiety disorders, panic disorder, anorexia
nervosa, phobia, agoraphobia, claustrophobia, post-traumatic stress
disorder, chronic mild and unpredictable stress, eating disorders,
addiction disorders, personality disorders, Parkinson's disorder,
Huntington's disorder, multiple sclerosis, amyotrophic lateral
sclerosis, Tourette's syndrome, nocturnal enuresis, non-epileptic
seizures, blepharospasm, Duchenne muscular dystrophy, stroke,
chronic pain, neuropathic pain including hyperalgesia and
allodynia, diabetic polyneuropathy, and chronic pain syndromes.
[0024] In some embodiments, the solid dosage form is administered
to the subject three times a day to one time every three months. In
some embodiments, the subject is on an additional treatment for the
neuropsychiatric disorder or on an additional treatment of
tuberculosis. In some embodiments, the method may further comprise
administering to the subject an additional therapeutic agent for
treating the neuropsychiatric disorder or tuberculosis.
[0025] Also within the scope of the present disclosure are any of
the solid dosage forms described herein for use in treating a
neuropsychiatric disease as described herein or tuberculosis; or
for manufacturing a medicament for use in treating the target
disorder.
[0026] The details of one or more embodiments of the disclosure are
set forth herein. Other features, objects, and advantages of the
disclosure will be apparent from the Detailed Description, the
Examples, and the Claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] FIG. 1 is a photo showing enteric coated capsules containing
D-cycloserine (Formulations 19, 20, and 22) and only excipient
(Formulation 21) after exposure to 0.1N HCl for 2 hours.
[0028] FIG. 2 is a diagram showing the releasing curve and release
kinetics for patch formulations C-G, according to an exemplary
embodiment of the present disclosure.
DETAILED DESCRIPTION
[0029] The present disclosure is based, at least in part, on the
development of solid cycloserine compound formulations (e.g., in
tablet, capsule, or transdermal patch format), which exhibit
superior features such as stability under acidic environment,
efficient dissolution at neutral pH, capability of penetrating
hydrophobic membranes, and/or high bioavailability. As such, the
solid formulations described herein would significantly enhance
treatment efficacy of cycloserine compounds for neuropsychiatric
disorders and bacterial infections such as tuberculosis.
[0030] Accordingly, provided herein are solid dosage forms of
cycloserine compounds and uses thereof in treating the target
diseases as described herein or alleviating one or more symptoms
thereof.
Formulations of Cycloserine Compounds
[0031] The formulation (e.g., solid formulation) of cycloserine
compounds as disclosed herein may comprise an inner core that
contains a cycloserine compound (an active ingredient) and an outer
layer, which may be attached to the inner core directly or
indirectly. In some instances, the formulation may further comprise
an isolation layer, which may be located between the inner core and
the outer layer.
[0032] The inner core may comprise a cycloserine compound and a
pharmaceutically acceptable carrier or excipient. The term
"cycloserine compound" refers to cycloserine (in D- or L form or a
racemic mixture of the DL-form pharmaceutically acceptable salts or
esters thereof, or functional derivatives thereof. In some
embodiments, a cycloserine compound can be nano-crystalline
D-cycloserine. In some embodiments, a cycloserine compound can be
nano-crystalline L-cycloserine. In other embodiments, a cycloserine
compound can be a racemic mixture of DL-cycloserine in
nano-crystalline form. The chemical structure of cycloserine is
provided below:
##STR00001##
A functional derivative of cycloserine can be a compound having the
same core structure of cycloserine with one or more substituents,
for example, alkyl, alkenyl, alkynyl, and/or a halogen.
[0033] In some instances, a cycloserine compound is a
pharmaceutically acceptable salt of cycloserine. The
pharmaceutically acceptable salt can be either an inorganic salt or
an organic salt. The term "salt" refers to ionic compounds that
result from the neutralization reaction of an acid and a base. A
salt is composed of one or more "cations" (positively charged ions)
and one or more "anions" (negatively charged ions) so that the salt
is electrically neutral (without a net charge). Salts described
herein may include those derived from suitable organic acids as
disclosed herein, for example, dicarboxylic acids. Examples of
organic and inorganic acids include but not limited to acetic acid,
ascorbic acid, aspartic acid, benzoic acid, formic acid, fumaric
acid, galic acid, gluconic acid, lactic acid, lauric acid,
methansulfonic acid, niconitic acid, oxalic acid, oxalic acid,
maleic acid, malonic acid, L-tartaric acid, D-tartaric acid,
meso-tartaric acid, malic acid, citric acid, succinic acid, stearic
acid, pentetic acid, propinoic acid, p-toluenesulfonic acid,
undecanoic acid, valeric acid, ethylenediaminetetraacetic acid,
boric acid, hydrochloric acid, hydrobromic acid, chromic acid,
nitric acid, phosphoric acid, phosphorous acid, hypophosphorus
acid, sulfuric acid, and sulfonic acid.
[0034] In some examples, a salt of the cycloserine compound has the
formula [A][B], in which [A] is a cation form of a cycloserine
compound and [B] is an anion form of a compound of formula (I):
##STR00002##
In formula (I):
[0035] X is --NH.sub.2 or --OH;
[0036] each of L.sub.1 and L.sub.2, independently, is C.sub.1-6
alkylene, C.sub.2-6 alkenylene, or C.sub.2-6 alkynylene, or one of
L.sub.1 and L.sub.2 is N, O, or S, and the other one is C.sub.1-6
alkylene, C.sub.2-6 alkenylene, or C.sub.2-6 alkynylene, as valency
permits;
[0037] is either a single or double bond; and
[0038] the ratio of [A] and [B] in the salt ranges from 10:1 to
1:10.
[0039] In some embodiments, X is --NH.sub.2. In some embodiments, X
is --OH.
[0040] In some embodiments, each of L.sub.1 and L.sub.2,
independently, is C.sub.1-6 alkylene, C.sub.2-6 alkenylene, or
C.sub.2-6 alkynylene, or one of L.sub.1 and L.sub.2 is N, O, or S,
and the other one is C.sub.1-6 alkylene, C.sub.2-6 alkenylene, or
C.sub.2-6 alkynylene, as valency permits. In some embodiments, each
of L.sub.1 and L.sub.2, independently, is C.sub.1-6 alkylene,
C.sub.2-6 alkenylene, or C.sub.2-6 alkynylene, wherein each of
C.sub.1-6 alkylene, C.sub.2-6 alkenylene, or C.sub.2-6 alkynylene.
In some embodiments, each of L.sub.1 and L.sub.2, independently, is
C.sub.1-6 alkylene, C.sub.2-6 alkenylene, or C.sub.2-6 alkynylene.
In some embodiments, one of L.sub.1 and L.sub.2 is N, O, or S, and
the other one is C.sub.1-6 alkylene, C.sub.2-6 alkenylene, or
C.sub.2-6 alkynylene, as valency permits. In some embodiments, at
least one of L.sub.1 and L.sub.2 is C.sub.1-6 alkylene, C.sub.2-6
alkenylene, or C.sub.2-6 alkynylene. As disclosed herein, C.sub.1-6
alkylene, C.sub.2-6 alkenylene, or C.sub.2-6 alkynylene can be
either unsubstituted or optionally substituted with halogen, --CN,
--NO.sub.2, --OH, --O(C.sub.1-6 alkyl), --NH.sub.2, or
--N.sub.3.
[0041] In some embodiments, at least one of L.sub.1 and L.sub.2 is
C.sub.1-6 alkylene, which may be substituted or unsubstituted
C.sub.1-6 alkylene. In some embodiments, at least one of L.sub.1
and L.sub.2 is methylene, which may be substituted or unsubstituted
methylene. In some embodiments, at least one of L.sub.1 and L.sub.2
is methylene. As used herein, methylene can be either unsubstituted
or optionally substituted with halogen, --CN, --NO.sub.2, --OH,
--O(C.sub.1-6 alkyl), or --NH.sub.2. In some embodiments, at least
one of L.sub.1 and L.sub.2 is methylene. In some embodiments, each
of L.sub.1 and L.sub.2 is methylene substituted with halogen, --CN,
--NO.sub.2, --OH, --O(C.sub.1-6 alkyl), or --NH.sub.2. In some
embodiments, each of L.sub.1 and L.sub.2 is methylene substituted
with --OH. In some embodiments, at least one of L.sub.1 and L.sub.2
is unsubstituted methylene. In some embodiments, both L.sub.1 and
L.sub.2 are methylene, which both may be substituted methylene or
both may be unsubstituted methylene. In some embodiments, at least
one of L.sub.1 and L.sub.2 is C.sub.2-6 alkenylene, which may be
substituted or unsubstituted C.sub.2-6 alkenylene. In some
embodiments, at least one of L.sub.1 and L.sub.2 is C.sub.2-6
alkynylene, which may be substituted or unsubstituted C.sub.2-6
alkynylene.
[0042] In some embodiments, X is --OH; and is a single bond. In
some embodiments, X is --OH; is a single bond; and each of L.sub.1
and L.sub.2 is methylene substituted with --OH. In some
embodiments, X is --OH; is a double bond; and each of L.sub.1 and
L.sub.2 is optionally substituted methylene.
[0043] In some embodiments, at least one of L.sub.1 and L.sub.2 is
N, O, or S, and the other one is C.sub.1-6 alkylene, C.sub.2-6
alkenylene, or C.sub.2-6 alkynylene, as valency permits. In some
embodiments, at least one of L.sub.1 and L.sub.2 is N and the other
one is C.sub.1-6 alkylene, C.sub.2-6 alkenylene, or C.sub.2-6
alkynylene, as valency permits. In some embodiments, at least one
of L.sub.1 and L.sub.2 is substituted N and the other one is
C.sub.1-6 alkylene, C.sub.2-6 alkenylene, or C.sub.2-6 alkynylene,
as valency permits. In some embodiments, at least one of L.sub.1
and L.sub.2 is O and the other one is C.sub.1-6 alkylene, C.sub.2-6
alkenylene, or C.sub.2-6 alkynylene, as valency permits. In some
embodiments, at least one of L.sub.1 and L.sub.2 is S and the other
one is C.sub.1-6 alkylene, C.sub.2-6 alkenylene, or C.sub.2-6
alkynylene, as valency permits.
[0044] In some embodiments, is a single bond. In some embodiments,
is a double bond.
[0045] In some embodiments, the ratio of [A] and [B] in the salt
ranges from 10:1 to 1:10, 9:1 to 1:9, 8:1 to 1:8, 7:1 to 1:7, 6:1
to 1:6, 5:1 to 1:5, 4:1 to 1:4, 3:1 to 1:3, 2:1 to 1:2, or 2:1 to
1:1, wherein [A] is a cation form of a cycloserine compound and [B]
is an anion form of a compound of formula (I):
##STR00003##
In some embodiments, the ratio of [A] and [B] in the salt ranges
from 10:1 to 1:10. In some embodiments, the ratio of [A] and [B] in
the salt ranges from 9:1 to 1:9. In some embodiments, the ratio of
[A] and [B] in the salt ranges from 8:1 to 1:8. In some
embodiments, the ratio of [A] and [B] in the salt ranges from 7:1
to 1:7. In some embodiments, the ratio of [A] and [B] in the salt
ranges from 6:1 to 1:6. In some embodiments, the ratio of [A] and
[B] in the salt ranges from 5:1 to 1:5. In some embodiments, the
ratio of [A] and [B] in the salt ranges from 4:1 to 1:4. In some
embodiments, the ratio of [A] and [B] in the salt ranges from 3:1
to 1:3. In some embodiments, the ratio of [A] and [B] in the salt
ranges from 2:1 to 1:2. In some embodiments, the ratio of [A] and
[B] in the salt ranges from 2:1 to 1:1. In some embodiments, the
ratio of [A] and [B] in the salt is 7:1, 6:1, 5:1, 4:1, 3:1, 2:1,
or 1:1.
[0046] In some embodiments, the cycloserine compound is of
formula:
##STR00004##
In some embodiments, the cycloserine compound is:
##STR00005##
In some embodiments, the cycloserine compound is:
##STR00006##
In some embodiments, the compound of formula (I) is of formula:
##STR00007##
wherein each of A and B, independently, is --NH.sub.2, --OH, or H;
and C.sub.1C.sub.2 is C.sub.1-C.sub.2 or C.sub.2.dbd.C.sub.1.
[0047] In some embodiments, at least one of A and B is --NH.sub.2.
In some embodiments, at least one of A and B is --OH. In some
embodiments, A and B are both --OH. In some embodiments, the
compound of formula (I) is succinic acid, D-tartaric acid,
L-tartaric acid, meso-tartaric acid, fumaric acid, maleic acid, or
malic acid.
[0048] In some embodiments, the compound of formula (Ia) is of
formula:
##STR00008##
wherein each of A and B, independently, is --OH or --H. In some
embodiments, at least one of A and B is --OH. In some embodiments,
A and B are both --OH.
[0049] In some embodiments, the compound of formula (Ib) is:
##STR00009##
[0050] In some embodiments, the compound of formula (Ib) is
selected from the group consisting of: succinic acid, D-tartaric
acid, and L-tartaric acid. In some embodiments, the compound of
formula (Ib) is selected from the group consisting of: succinic
acid, D-tartaric acid, L-tartaric acid, and meso-tartaric acid, and
the ratio between [A] and [B] ranges from 5:1 to 1:1. In some
embodiments, the compound of formula (Ib) is
##STR00010##
and the ratio between [A] and [B] is 4:1. In some embodiments, the
compound of formula (Ib) is
##STR00011##
and the ratio between [A] and [B] is 2:1. In some embodiments, the
compound of formula (Ib) is
##STR00012##
and the ratio between [A] and [B] is 1:1.
[0051] In some embodiments, the compound of formula (Ia) is a
compound of formula (Ic):
##STR00013##
wherein each of A and B, independently, is --OH or --H. In some
embodiments, at least one of A and B is --OH. In some embodiments,
A and B are both --OH.
[0052] In some embodiments, the compound of formula (Ic) is
selected from
##STR00014##
j or
##STR00015##
In some embodiments, the compound of formula (Ic) is fumaric acid.
In some embodiments, the compound of form (Ic) is maleic acid. In
some embodiments, the compound of formula (Ic) is
##STR00016##
and the ratio between [A] and [B] described herein is 1:1.
[0053] Definitions of specific functional groups and chemical terms
are described in more detail below. The chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 75.sup.th Ed.,
inside cover, and specific functional groups are generally defined
as described therein. Additionally, general principles of organic
chemistry, as well as specific functional moieties and reactivity,
are described in Thomas Sorrell, Organic Chemistry, University
Science Books, Sausalito, 1999; Smith and March, March's Advanced
Organic Chemistry, 5.sup.th Edition, John Wiley & Sons, Inc.,
New York, 2001; Larock, Comprehensive Organic Transformations, VCH
Publishers, Inc., New York, 1989; and Carruthers, Some Modern
Methods of Organic Synthesis, 3.sup.rd Edition, Cambridge
University Press, Cambridge, 1987. The disclosure is not intended
to be limited in any manner by the exemplary listing of
substituents described herein.
[0054] Compounds described herein can comprise one or more
asymmetric centers, and thus can exist in various isomeric forms,
e.g., enantiomers and/or diastereomers. For example, the compounds
described herein can be in the form of an individual enantiomer,
diastereomer or geometric isomer, or can be in the form of a
mixture of stereoisomers, including racemic mixtures and mixtures
enriched in one or more stereoisomer. Isomers can be isolated from
mixtures by methods known to those skilled in the art, including
chiral high pressure liquid chromatography (HPLC) and the formation
and crystallization of chiral salts; or preferred isomers can be
prepared by asymmetric syntheses. See, for example, Jacques et al.,
Enantiomers, Racemates and Resolutions (Wiley Interscience, New
York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel,
Stereochemistry of Carbon Compounds (McGraw-Hill, N Y, 1962); and
Wilen, Tables of Resolving Agents and Optical Resolutions p. 268
(E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind.
1972). The disclosure additionally encompasses compounds described
herein as individual isomers substantially free of other isomers,
and alternatively, as mixtures of various isomers.
[0055] When a range of values is listed, it is intended to
encompass each value and sub-range within the range. For example,
"C.sub.1-6" is intended to encompass, C.sub.1, C.sub.2, C.sub.3,
C.sub.4, C.sub.5, C.sub.6, C.sub.1-6, C.sub.1-5, C.sub.1-4,
C.sub.1-3, C.sub.1-2, C.sub.2-6, C.sub.2-5, C.sub.2-4, C.sub.2-3,
C.sub.3-6, C.sub.3-5, C.sub.3-4, C.sub.4-6, C.sub.4-5, and
C.sub.5-6.
[0056] The term "alkyl" refers to a radical of a straight-chain or
branched saturated hydrocarbon group having from 1 to 10 carbon
atoms ("C.sub.1-10 alkyl"). In some embodiments, an alkyl group has
1 to 9 carbon atoms ("C.sub.1-9 alkyl"). In some embodiments, an
alkyl group has 1 to 8 carbon atoms ("C.sub.1-8 alkyl"). In some
embodiments, an alkyl group has 1 to 7 carbon atoms ("C.sub.1-7
alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon
atoms ("C.sub.1-6alkyl"). In some embodiments, an alkyl group has 1
to 5 carbon atoms ("C.sub.1-5 alkyl"). In some embodiments, an
alkyl group has 1 to 4 carbon atoms ("C.sub.1-4 alkyl"). In some
embodiments, an alkyl group has 1 to 3 carbon atoms ("C.sub.1-3
alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon
atoms ("C.sub.1-2 alkyl"). In some embodiments, an alkyl group has
1 carbon atom ("C.sub.1 alkyl"). In some embodiments, an alkyl
group has 2 to 6 carbon atoms ("C.sub.2-6 alkyl"). Examples of
C.sub.1-6 alkyl groups include methyl (C.sub.1), ethyl (C.sub.2),
propyl (C.sub.3) (e.g., n-propyl, isopropyl), butyl (C.sub.4)
(e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C.sub.5)
(e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl,
tertiary amyl), and hexyl (C.sub.6) (e.g., n-hexyl). Additional
examples of alkyl groups include n-heptyl (C.sub.7), n-octyl
(C.sub.8), and the like. Unless otherwise specified, each instance
of an alkyl group is independently unsubstituted (an "unsubstituted
alkyl") or substituted (a "substituted alkyl") with one or more
substituents (e.g., halogen, such as F). In certain embodiments,
the alkyl group is an unsubstituted C.sub.1-10 alkyl (such as
unsubstituted C.sub.1-6 alkyl, e.g., --CH.sub.3). In certain
embodiments, the alkyl group is a substituted C.sub.1-10 alkyl
(such as substituted C.sub.1-6 alkyl, e.g., --CF.sub.3).
[0057] "Alkenyl" refers to a radical of a straight-chain or
branched hydrocarbon group having from 2 to 20 carbon atoms, one or
more carbon-carbon double bonds, and no triple bonds ("C.sub.2-20
alkenyl"). In some embodiments, an alkenyl group has 2 to 10 carbon
atoms ("C.sub.2-10 alkenyl"). In some embodiments, an alkenyl group
has 2 to 9 carbon atoms ("C.sub.2-9 alkenyl"). In some embodiments,
an alkenyl group has 2 to 8 carbon atoms ("C.sub.2-8 alkenyl"). In
some embodiments, an alkenyl group has 2 to 7 carbon atoms
("C.sub.2-7 alkenyl"). In some embodiments, an alkenyl group has 2
to 6 carbon atoms ("C.sub.2-6 alkenyl"). In some embodiments, an
alkenyl group has 2 to 5 carbon atoms ("C.sub.2-5 alkenyl"). In
some embodiments, an alkenyl group has 2 to 4 carbon atoms
("C.sub.2-6 alkenyl"). In some embodiments, an alkenyl group has 2
to 3 carbon atoms ("C.sub.2-3 alkenyl"). In some embodiments, an
alkenyl group has 2 carbon atoms ("C.sub.2 alkenyl"). The one or
more carbon-carbon double bonds can be internal (such as in
2-butenyl) or terminal (such as in 1-butenyl). Examples of
C.sub.2-6 alkenyl groups include ethenyl (C.sub.2), 1-propenyl
(C.sub.3), 2-propenyl (C.sub.3), 1-butenyl (C.sub.4), 2-butenyl
(C.sub.4), butadienyl (C.sub.4), and the like. Examples of
C.sub.2-6 alkenyl groups include the aforementioned C.sub.2-4
alkenyl groups as well as pentenyl (C.sub.5), pentadienyl
(C.sub.5), hexenyl (C.sub.6), and the like. Additional examples of
alkenyl include heptenyl (C.sub.7), octenyl (C.sub.8), octatrienyl
(C.sub.8), and the like. Unless otherwise specified, each instance
of an alkenyl group is independently optionally substituted, i.e.,
unsubstituted (an "unsubstituted alkenyl") or substituted (a
"substituted alkenyl") with one or more substituents. In certain
embodiments, the alkenyl group is unsubstituted C.sub.2-10 alkenyl.
In certain embodiments, the alkenyl group is substituted C.sub.2-10
alkenyl. In an alkenyl group, a C.dbd.C double bond for which the
stereochemistry is not specified (e.g., --CH.dbd.CHCH.sub.3 or
##STR00017##
may be an (E)- or (Z)-double bond.
[0058] "Alkynyl" refers to a radical of a straight-chain or
branched hydrocarbon group having from 2 to 20 carbon atoms, one or
more carbon-carbon triple bonds, and optionally one or more double
bonds ("C.sub.2-20 alkynyl"). In some embodiments, an alkynyl group
has 2 to 10 carbon atoms ("C.sub.2-10 alkynyl"). In some
embodiments, an alkynyl group has 2 to 9 carbon atoms ("C.sub.2-9
alkynyl"). In some embodiments, an alkynyl group has 2 to 8 carbon
atoms ("C.sub.2-8 alkynyl"). In some embodiments, an alkynyl group
has 2 to 7 carbon atoms ("C.sub.2-7 alkynyl"). In some embodiments,
an alkynyl group has 2 to 6 carbon atoms ("C.sub.2-6 alkynyl"). In
some embodiments, an alkynyl group has 2 to 5 carbon atoms
("C.sub.2-5 alkynyl"). In some embodiments, an alkynyl group has 2
to 4 carbon atoms ("C.sub.2-6 alkynyl"). In some embodiments, an
alkynyl group has 2 to 3 carbon atoms ("C.sub.2-3 alkynyl"). In
some embodiments, an alkynyl group has 2 carbon atoms ("C.sub.2
alkynyl"). The one or more carbon-carbon triple bonds can be
internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
Examples of C.sub.2-6 alkynyl groups include, without limitation,
ethynyl (C.sub.2), 1-propynyl (C.sub.3), 2-propynyl (C.sub.3),
1-butynyl (C.sub.4), 2-butynyl (C.sub.4), and the like. Examples of
C.sub.2-6 alkenyl groups include the aforementioned C.sub.2-6
alkynyl groups as well as pentynyl (C.sub.5), hexynyl (C.sub.6),
and the like. Additional examples of alkynyl include heptynyl
(C.sub.7), octynyl (C.sub.8), and the like. Unless otherwise
specified, each instance of an alkynyl group is independently
optionally substituted, i.e., unsubstituted (an "unsubstituted
alkynyl") or substituted (a "substituted alkynyl") with one or more
substituents. In certain embodiments, the alkynyl group is
unsubstituted C.sub.2-10 alkynyl. In certain embodiments, the
alkynyl group is substituted C.sub.2-10 alkynyl.
[0059] Alkyl, alkenyl, and alkynyl groups, which are divalent
bridging groups, are further referred to using the suffix -ene,
e.g., alkylene, alkenylene, and alkynylene.
[0060] The term "substituted" is contemplated to include
substitution with all permissible substituents of organic
compounds, any of the substituents described herein that results in
the formation of a stable compound. The present disclosure
contemplates any and all such combinations in order to arrive at a
stable compound. For purposes of this disclosure, heteroatoms such
as nitrogen may have hydrogen substituents and/or any suitable
substituent as described herein which satisfy the valencies of the
heteroatoms and results in the formation of a stable moiety. In
certain embodiments, the substituent is a carbon atom substituent.
In certain embodiments, the substituent is a nitrogen atom
substituent. In certain embodiments, the substituent is an oxygen
atom substituent. In certain embodiments, the substituent is a
sulfur atom substituent.
[0061] The cycloserine compound in the solid formulation disclosed
herein may be in particle form, for example, having a D.sub.90
value ranging from about 0.05-500 .mu.m (e.g., about 0.05-300
.mu.m, about 0.05 to 200 .mu.m, about 0.05-100 .mu.m, about 0.05 to
50 .mu.m, about 0.05-20 .mu.m, about 0.05-10 .mu.m, about 0.05-5
.mu.m, about 0.05-2 .mu.m, about 0.05-1 .mu.m, about 5-200 .mu.m,
about 100-300 .mu.m, or about 100-250 .mu.m). D-values (D.sub.10,
D.sub.50 or D.sub.90) are commonly used to reflect particle size
(diameter) distribution in a population. The D.sub.90 value refers
to .gtoreq.90% of the particles in the population having a diameter
falling in the ranges noted above.
[0062] The pharmaceutically acceptable carrier or excipient in the
inner core of the solid formulation disclosed herein may comprise a
filler, a binder, a disintegrating agent, a lubricant, or a
combination thereof. Exemplary fillers include, but are not limited
to, lactose, microcrystalline cellulose, calcium hydrogen
phosphate, or a mixture thereof. Microcrystalline cellulose can be
used as a stabilizing and anti-moisture agent, which can be
replaced with cellulose's derivatives, starch, calcium phosphate
dibasic anhydrous and mixtures thereof.
[0063] Exemplary binders include, but are not limited to,
pregelatinised maize starch, polyvinylpyrrolidone, hydroxypropyl
methylcellulose, carboxymethylcellulose, microcrystalline cellulose
(MCC), hydroxypropyl cellulose, alginates, gelatin, acacia, or a
mixture thereof.
[0064] Exemplary lubricants include, but are not limited to,
magnesium stearate, talc, silica, colloidal silicon dioxide,
calcium stearate, solid polyethylene glycol, sodium lauryl sulfate,
or a mixture thereof. Exemplary disintegrating agents
(disintegrants) include, but are not limited to, agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates, sodium starch glycolate (SSG), croscarmellose,
crospovidone, sodium carbonate, or a mixture thereof.
[0065] In some instances, the pharmaceutically acceptable excipient
or carrier may also comprise one or more of the followings: wetting
agents (e.g., sodium lauryl sulphate, cetyl alcohol, and glycerol
monostearate); solution retarding agents (e.g., paraffin);
absorption accelerators (e.g., quaternary ammonium compound); and
absorbents (e.g., kaolin and bentonite clay). Alternatively or in
addition, the solid formulation may also contain sodium citrate
and/or dicalcium phosphate. In some instances, the solid
formulation may comprise inert diluents, dispersing and/or
granulating agents, surface active agents and/or emulsifiers,
preservatives, buffering agents and/or pH adjusters, sustained
release reagents, anti-sedimentation agents, oils, or mixtures
thereof. Excipients such as cocoa butter and suppository waxes,
coloring agents, coating agents, sweetening, flavoring, and
perfuming agents may also be present in the composition.
[0066] In some embodiments, the solid dosage form of cycloserine
described herein may be a solid enteric formulation (e.g., in
tablet or capsule format) comprising an enteric layer (as the outer
layer disclosed herein), which may be composed of one or more
enteric materials. In some instances, the solid dosage form may
contain about 10 to 500 mg (e.g., about 30-400 mg, about 30-300 mg,
about 30-200 mg, about 30-150 mg, about 50-150 mg, about 50 mg-125
mg, or about 75-100 mg) of the enteric materials. Enteric layer or
enteric coating typically refers to a polymer-based barrier coated
on oral medication that prevents dissolution or disintegration of
the medication in the gastric environment.
[0067] Exemplary enteric materials for use in making the solid
dosage form described herein include polymethacrylate-based coating
material, phthalate-based coating material, cellulose ester-based
coating material, shellac, sodium alginate, or a mixture
thereof.
[0068] In some embodiments, the polymethacrylate-based coating
material can be poly(methacrylic acid-co-ethyl acrylate) in a molar
ratio of 1:1 (i.e. Eudragit L 100-55, Eudragit L 30 D-55, Eastacryl
30 D series, Kollicoat MAE 30 DP, Kollicoat MAE 100 P, Acryl-EZE 93
series and Acryl-EZE MP series), poly(methacylic acid-co-methyl
methacrylate) in a molar ratio of 1:1 (i.e. Eudragit L 100,
Eudragit L 12.5, Eudragit L 12.5 P, and Opadry 94 series),
poly(methacylic acid-co-methyl methacrylate) in a molar ratio of
1:2 (i.e. Eudragit S 100, Eudragit S 12.5, Eudragit S 12.5 P, and
Opadry 95 series), and poly(methyl acrylate-co-methyl
methacrylate-co-methacrylic acid in a molar ratio of 7:3:1 (i.e.,
Eudragit FS 30 D).
[0069] In some embodiments, the phthalate-based coating material
can be polyvinyl acetate phthalate (i.e. Opadry 91 series, and
Sureteric series), hydroxypropyl methylcellulose phthalate (i.e.
HPmcp-HP Grades series), diethyl phthalate, and cellulose acetate
phthalate (i.e., Eastman.TM. C-A-P).
[0070] In some embodiments, the cellulose ester-based coating
material can be cellulose acetate trimellitate, cellulose acetate
succinate, and hydroxypropyl methylcellulose acetate succinate
(i.e. AQOAT AS series, and ENTERACT.TM. HPMCAS).
[0071] In some examples, the enteric materials in the solid dosage
form may comprise (by weight) 90.5%-98.49% of poly(methacrylic
acid-co-ethyl acrylate) in a molar ratio of 1:1, 0.5%-2% of sodium
lauryl sulfate, 0.01%-2.5% of triethyl citrate, 0.5%-2.5% of
colloidal silicon dioxide, and 0.5%-2.5% of talc. In some
embodiments, the amount of poly(methacrylic acid-co-ethyl acrylate)
in a molar ratio of 1:1 in enteric layer can be (by weight)
91%-98%, 92%-97.5%, 93%-97%, 94%-96.5%, 95%-96%, or 95%-95.5%.
[0072] In some embodiments, the solid dosage form described herein
may further comprise an isolation layer, which may be located
between the inner core and the outer layer or enteric layer. The
isolation layer may comprise materials such as hydroxypropyl
methylcellulose-based coating materials. In some examples, the
average molecular weight of the hydroxypropyl methylcellulose can
be about 50,000 dalton to 125,000 dalton. Other commercially
available isolation layer materials can also be used in the solid
dosage form described herein. In one example, a solid dosage form
may contain about 10-100 mg of the isolation layer, for example,
about 15-95 mg, about 15-80 mg, about 20-60 mg, about 20-50 mg,
about 25-40 mg or about 25-30 mg. In one example, the isolation
layer may comprise (by weight) 95.5%-99.49% of hydroxypropyl
methylcellulose, 0.5%-2.5% of talc, and 0.01%-2% of triacetin. In
some embodiments, the amount of hydroxypropyl methylcellulose
comprised in the isolation layer can be (by weight) 96%-99%, or
97%-98%.
[0073] In certain embodiments, the solid dosage form described
herein may contain about 10 to 1500 mg, about 50 to 1000 mg, about
100 to 800 mg, 250 to 600 mg, 300 to 550 mg, 350 to 500 mg, or 400
to 450 mg of a cycloserine compound (e.g., D-cycloserine or an
acceptable salt thereof as described herein). The cycloserine
compound may be mixed with pharmaceutically acceptable excipients
containing about 50-500 mg of a filler (e.g., MCC pH 102), about
10-100 mg of a binder (e.g., HPC), about 10-200 mg of a
disintegrating agent (e.g., croscarmellose), and about 5-100 mg of
a lubricant (e.g., magnesium stearate).
[0074] The solid dosage form described herein may further contain
one or more enteric materials as those described herein in an
amount of about 50 to 150 mg, about 50 to 100 mg, about 55 to 95
mg, about 60 to 90 mg, about 65 to 85 mg, about 70 to 80 mg, or
about 70 to 75 mg. The enteric materials may comprise (by weight)
90.5%-98.49% of poly(methacrylic acid-co-ethyl acrylate) in a molar
ratio of 1:1, 0.5%-2% of sodium lauryl sulfate, 0.01%-2.5% of
triethyl citrate, 0.5%-2.5% of colloidal silicon dioxide, and
0.5%-2.5% of talc.
[0075] Optionally, the solid dosage form may further comprise an
isolation layer of about 10-50 mg of the isolation layer, for
example, about 15-45 mg, about 20-35 mg, about 25-30 mg, or about
35-40 mg. The isolation layer may comprise (by weight) 95.5%-99.49%
of hydroxypropyl methylcellulose, 0.5%-2.5% of talc, and 0.01%-2%
of triacetin.
[0076] In some embodiments, the solid formulation disclosed herein
is in a dosage form (also known as a unit dose), which refers to
compositions ready for delivering to subjects in need of the
treatment via a suitable route. A dosage form typically contains a
mixture of active ingredients and inactive components (excipients)
in a particular configuration (e.g., tablet, capsule, transdermal
pad, granule, powder, sachet, etc.) and apportioned into a
particular dose. A "unit dose" is a discrete amount of the
pharmaceutical composition comprising a predetermined amount of the
active ingredient. The amount of the active ingredient is generally
equal to the dosage of the active ingredient, which would be
administered to a subject and/or a convenient fraction of such a
dosage, such as one-half or one-third of such a dosage.
[0077] The solid dosage forms described herein may be for oral
administration and may be in form of a capsule or a tablet. All
commercially available capsules can be used here for making the
solid dosage form, including hard and soft gelatin capsules, HPMC
capsules, and the like. Exemplary materials, including commercially
available ones, for making the capsule include, but are not limited
to, hydroxypropyl methylcellulose (HPMC), gelatin, methyl paraben
(i.e., methyl-4-hydroxybenzoate), propyl paraben (i.e.,
propyl-4-hydroxybenzoate), sodium lauryl sulphate, Brilliant Blue
FCF, new coccin, titanium dioxide, Sunset Yellow FCF, tartrazine,
water, or combination thereof.
[0078] In some embodiments, the solid dosage form disclosed herein
is in the form of enteric tablets. Such an enteric tablet may
comprise cycloserine (e.g., D-cycloserine), MCC pH102,
croscarmellose sodium, and magnesium stearate. Optionally, the
enteric tablets may further comprise HPC. In some examples, the
enteric tablets disclosed herein may be substantially free of
mannitol. In some embodiments, the enteric tablets have an
isolation layer coating weight from about 2.0% to about 6.0%, or
from about 2.5% to about 5.0%, or from about 3.0% to about 5.0% or
from about 3.5% to about 5.0% by weight of the total weight of the
inner core of the enteric tablet. In some embodiments, the enteric
tablets have an enteric layer coating weight in the range of from
about 10% to about 15%, or from about 10% to about 14%, or from
about 12% to about 15%, by weight of the total weight of the inner
core of the enteric tablet.
[0079] In some embodiments, the solid dosage form disclosed herein
is in the form of capsules, which may be enteric coated. For
example, the capsule solid form disclosed herein may comprise an
inner core comprising cycloserine and a mixture of specific
excipients (e.g., those disclosed herein), and an outer enteric
layer. In some embodiments, the mixture of excipients comprises
lactose. In some embodiments, the enteric coated capsules and/or
the inner core of the enteric coated capsules may be substantially
free of mannitol. In some embodiments, the inner core of the
enteric coated capsule includes a filler comprising lactose and/or
includes a filler substantially free of mannitol. In some
embodiments, the enteric coated capsules comprise lactose in an
amount from about 20% to about 40%, or from about 25% to about 35%,
or from about 27% to about 33% by weight of the total weight of the
enteric coated capsule.
[0080] The capsule formulations disclosed herein may comprise an
enteric coating on the surface of the capsule. All commercially
available enteric coatings can be applied on the surface of the
capsule for the capsule formulation described herein. In some
examples, the enteric coating can be composed of copolymers of
methacrylic acid and ethyl acrylate, e.g., Kollicoat.RTM. MAE 30 DP
(BASF). In some instances, the molar ratio of methacrylic acid and
ethyl acrylate in the copolymer is 1:1 and the solid content is 30%
(by weight). In some examples, the enteric coating may comprise the
same enteric materials disclosed herein. For the coating purpose,
the material of the enteric coating can be resolved in an organic
solvent, for example, propylene glycol.
[0081] In some examples, the cycloserine compound used in the
capsule formulation disclosed herein may be in nanocrystalline
form. Such nanocrystalline form of cycloserine may have a D.sub.90
value ranging from about 0.05 .mu.m to about 500 .mu.m.
[0082] In some embodiments, the solid dosage forms described herein
may be in a format suitable for topical administration, for
example, formulated as a transdermal patch. Transdermal delivery of
D-cycloserine, a hydrophilic drug, is difficult due the hydrophobic
nature and compact structure of the skin. Surprisingly, the
transdermal delivery system disclosed herein have been shown to be
effective in transdermal delivery of D-cycloserine. In particular,
as demonstrated in Example 7 below, the transdermal patch
formulations disclosed herein, comprising nano-crystalline
D-cycloserine, exhibits superior skin penetration and
pharmacokinetic properties.
[0083] In the transdermal formulations disclosed herein, the inner
core comprising the cycloserine compound as disclosed herein may be
spread on an outer layer as disclosed herein, which can be an
impermeable support, to obtain a patch. In instances in which the
solid dosage form is a transdermal patch, the outer layer of the
solid dosage form is a backing layer of the transdermal patch. The
backing layer may be attached to the inner core, for example, the
inner core can be spread on the backing layer. In at least some
instances, the backing layer may comprise a polymer of
polyethylene, polyurethane, ethylene vinyl acetate, polyvinyl
chloride, polyethylene, terephthalate, or a mixture therefore.
[0084] In some examples, the impermeable support used in the
transdermal patch is a support for a matrix system (e.g.,
matrix-dispersion system and drug in-adhesive), a reservoir patch
system or a microreservoir system. In such examples, the
impermeable support may comprise an inner core in a drug reservoir
with a backing layer coating the inner core. In some embodiments,
the inner core is a liquid or a gel. In some embodiments, the
transdermal patch may further comprises a protective peel strip
and/or a control membrane.
[0085] The cycloserine-containing inner core of a transdermal patch
may include a carrier, a dispersion reagent, an anti-sedimentation
reagent, an enhancer, a sustained release reagent, a pH adjuster,
or a mixture thereof.
[0086] The carrier used in the transdermal patch as disclosed
herein may contribute to product attributes such as stability,
biopharmaceutical profile, appearance and patient acceptability and
to the ease with which the product can be manufactured. Examples
include, but are not limited to, propylene glycerol, dipropylene
glycol, hexylene glycerol, tetrathyleneglycol monomethylether,
copolymers of acrylic and methacrylic acids or esters,
hydroxypropyl methylcellulose, ethyl cellulose, polyvinyl alcohol,
polyvinylpyrrolidone, cellulose acetate phthalate, cellulose
acetate, polymerized rosin, crosslinked polyacrylic acid polymers,
acrylate copolymer, polyisobutylene, xanthan gum, and silicon gum,
and any combination thereof. In some instances, the transdermal
formulation may contain from about 0.1-1 g of the carrier, e.g.,
about 0.1-0.8 g, about 0.2-0.6 g, or about 0.2-0.5 g.
[0087] Exemplary dispersion reagents include, but are not limited
to, sodium lauroyl sarcosinate, polyethylene glycol, sodium dodecyl
sulfate, and cetyltrimethylammonium bromide, and any combination
thereof. In some instances, the transdermal formulation may contain
from about 0.1-2 g of the dispersion reagent, e.g., about 0.3-1.5
g, about 0.5-1.0 g, or about 0.4-0.8 g.
[0088] Exemplary anti-sedimentation reagents include, but are not
limited to, corn oil, eucalyptus oil, peppermint oil, benzyl
benzoate, and sesame oil, and any combination thereof. In some
instances, the transdermal formulation may contain from about 0.1-1
g of the anti-sedimentation reagent, e.g., about 0.1-0.8 g, about
0.1-0.5 g, or about 0.2-0.6 g.
[0089] The enhancer used herein can be a component that promotes
bioavailability of the active substance(s) (e.g., cycloserine) in
the transdermal patch, for example, capable of modifying the
penetration of the active substances through the skin and therefore
could influence significantly the in-vivo performance of the
transdermal formulation. In certain examples, the enhancer used
herein can contribute a constant and persistent release of the
active substances over several hours, or even days, is necessary
for therapeutic efficacy. Exemplary enhancers include, but are not
limited to, terpene, fatty acid, ester, essential oil, pyrrolidone,
mannitol, 2-pyrrolidone, 1-methyl-2-pyrrolidone, and vitamin E, and
any combination thereof. In some embodiments, the transdermal
formulation may comprise from about 0.1-1000 mg, about 0.1-1 mg,
about 1-10 mg, about 10-100 mg, or about 100-1000 mg enhancer.
[0090] The sustained released reagent may be PVP, EC, HPMC,
polyacrylate, and any combination thereof. In some embodiments, the
transdermal formulation may comprise from about 1-100 mg, about
5-50 mg, about 5-20 mg, or about 5-10 mg of the sustained release
reagents.
[0091] The pH adjuster used herein may be a pharmaceutically
acceptable base. Examples include sodium hydroxide, sodium acetate,
or sodium bicarbonate. In some embodiments, the transdermal
formulation may comprise from about 0.01-10 mL, about 0.01-0.1 mL,
about 0.1-0.3 mL, about 0.3-1 mL, about 1-3 mL, or about 3-10 mL of
the pH adjuster. In some instances, the concentration of the pH
adjuster may be from about 0.1-10N, about 0.1-0.3N, about 0.3-1N,
about 1-3N, or about 3-10N.
[0092] The cycloserine compound used in the transdermal patch may
be in nanocrystalline form. In some instances, the cycloserine
compound used in the transdermal patch may be in particle form
having a D.sub.90 value ranging from about 0.05 .mu.m to about 500
.mu.m.
[0093] In specific examples, the inner core of any of the
transdermal formulations (e.g., patches) disclosed herein (e.g., in
a unit dosage form) may comprise cycloserine (e.g., D-cycloserine,
which may be in nanocrystalline form) in an amount of about 15-30
mg, di-propylene glycol (DPG) as a carrier in an amount of about
0.2-0.6 g, a pH adjuster (e.g., 1-5-2.0 N NaOH), PEG as a
dispersion reagent in an amount of about 0.5-1.0 g, corn oil as a
anti-sedimentation reagent in an amount of about 0.15-0.45 g, and
povidone as a sustained release reagent in an amount of about 10
mg. Optionally, the inner core of the transdermal formulation may
further comprise mannitol as an enhancer in an amount of about 5
mg.
[0094] In any of the solid dosage forms disclosed herein, relative
amounts of the cycloserine compound, the pharmaceutically
acceptable excipient, the isolation layer and enteric layer
materials, and/or any additional ingredients in the compositions
described herein may vary, depending upon the identity, size,
and/or condition of the subject treated and further depending upon
the route by which the composition is to be administered. The
composition may comprise between 0.1% and 99.5% (w/w) active
ingredient.
[0095] Compositions comprising cycloserine compounds such as any of
the solid forms disclosed herein may be a pharmaceutical
composition, a nutraceutical composition, a health food or health
food product, or a medical food.
[0096] In certain embodiments, the compositions described herein
can be a health food or a health food product. The terms "health
food" or "health food product" refers to any kind of liquid and
solid/semi-solid materials that are used for nourishing humans and
animals, for improving basic behavioral functioning, hyperactivity,
anxiety, depression, suicidal ideation and/or behavior sensorimotor
gating, pain threshold, memory and/or cognitive functioning, body
weight, or for facilitating treatment of any of the target diseases
noted herein. The term "nutraceutical composition" refers to
compositions containing components from food sources and conferring
extra health benefits in addition to the basic nutritional value
found in foods.
[0097] The healthy food or healthy food product can be any kinds of
liquid and solid/semi-solid materials that are used for nourishing
humans and animals, for improving basic behavioral functioning,
hyperactivity, anxiety, depression, suicidal ideation and/or
behavior, sensorimotor gating, pain threshold, memory and/or
cognitive functioning, or for facilitating treatment of any of the
target diseases noted herein (e.g., a neuropsychiatric disorder,
including those described herein). The health food product may be a
food product (e.g., tea-based beverages, juice, soft drinks,
coffee, milk, jelly, cookies, cereals, chocolates, snack bars,
herbal extracts, dairy products (e.g., ice cream, and yogurt)), a
food/dietary supplement, or a nutraceutical formulation. Such
liquid form healthy food product may be prepared by dissolving any
of the solid dosage formulations disclosed herein in a suitable
solution.
[0098] The health food product described herein, may comprise one
or more edible carriers in addition to the active ingredient. The
edible carriers may confer one or more of the benefits to the
product as described herein. Examples of edible carriers include
starch, cyclodextrin, maltodextrin, methylcellulose, carbon methoxy
cellulose, xanthan gum, and aqueous solutions thereof. Other
examples include solvents, dispersion media, coatings, surfactants,
antioxidants, preservatives (e.g., antibacterial agents, antifungal
agents), isotonic agents, absorption delaying agents, stabilizers,
gels, binders, excipients, disintegration agents, lubricants,
sweetening agents, flavoring agents, dyes, such like materials and
combinations thereof, as would be known to one of ordinary skill in
the art. In some examples, the health food products described
herein may further include neuroprotective foods, such as fish oil,
flax seed oil, and/or benzoate.
[0099] In some examples, the health food product is a nutraceutical
composition, which refers to compositions containing components
from food sources and conferring extra health benefits in addition
to the basic nutritional value found in foods. A nutraceutical
composition as described herein may comprises the cycloserine
compound as an active ingredient and other components described
herein, e.g., pharmaceutically acceptable carrier or excipient,
enteric layer, and/or isolation layer, which would promote good
health and/or enhance stability and bioactivity of the cycloserine
compound.
[0100] The nutraceutical compositions may be contained in an edible
material, for example, as a dietary supplement or a pharmaceutical
formulation. As a dietary supplement, additional nutrients, such as
vitamins, minerals or amino acids may be included. The composition
can also be a drink or a food product, e.g., tea, soft drink,
juice, milk, coffee, cookie, cereal, chocolate, and snack bar. If
desired, the composition can be sweetened by adding a sweetener
such as sorbitol, maltitol, hydrogenated glucose syrup and
hydrogenated starch hydrolyzate, high fructose corn syrup, cane
sugar, beet sugar, pectin, or sucralose.
[0101] The nutraceutical composition can also be in the form of
powder, paste, jelly, capsule, or tablet. Lactose and corn starch
are commonly used as diluents for capsules and as carriers for
tablets. Lubricating agents, such as magnesium stearate, are
typically added to form tablets.
[0102] The health food products may be formulated for a suitable
administration route, for example, oral administration.
[0103] In certain embodiments, the composition (e.g., the solid
formulation described herein) is a medical food. A medical food
product is a food product formulated to be consumed or administered
enterally. Such a food product is usually used under the
supervision of a physician for the specific dietary management of a
target disease, such as those described herein. In some instances,
such a medical food composition is specially formulated and
processed (as opposed to a naturally occurring foodstuff used in a
natural state) for a patient in need of the treatment (e.g., human
patients who suffer from illness or who requires use of the product
as a major active agent for alleviating a disease or condition via
specific dietary management). In some examples, a medical food
composition described herein is not one of those that would be
simply recommended by a physician as part of an overall diet to
manage the symptoms or reduce the risk of a disease or
condition.
[0104] In some embodiments, the medical food composition described
herein may comprise at least one component, which can be either
naturally-occurring or synthetic (non-naturally occurring), would
confer one or more benefits to the cycloserine compound in the
composition, for example, stability, bioavailability, and/or
bioactivity. Any of the carriers, enteric materials, and/or
isolation layer described herein may be used for making the medical
food composition. In some embodiments, the medical food composition
may further comprise one or more additional ingredients selected
from the group including, but not limited to natural flavors,
artificial flavors, major trace and ultra-trace minerals, minerals,
vitamins, oats, nuts, spices, milk, egg, salt, flour, lecithin,
xanthan gum and/or sweetening agents. The medical food composition
may be placed in a suitable container, which may further comprise
at least an additional therapeutic agent such as those described
herein.
[0105] Any of the compositions such as solid form formulations
described herein may contain an effective amount of a cycloserine
compound. An "effective amount" of the cycloserine compound
described herein refers to an amount sufficient to elicit the
desired biological response, i.e., treating the condition. As will
be appreciated by those of ordinary skill in this art, the
effective amount of the cycloserine described herein may vary
depending on such factors as the desired biological endpoint, the
pharmacokinetics of the cycloserine compound, the condition being
treated, the mode of administration, and the age and health of the
subject. In certain embodiments, an effective amount is a
therapeutically effective amount. In certain embodiments, an
effective amount is a prophylactic effective amount.
[0106] The compositions such as solid dosage forms may be suitable
for human use. Such compositions may also be suitable for use in
animals. Modification of pharmaceutical compositions suitable for
administration to humans in order to render the compositions
suitable for administration to various animals is well understood,
and the ordinarily skilled veterinary pharmacologist can design
and/or perform such modification with ordinary experimentation.
[0107] Pharmaceutical compositions described herein can be prepared
by any method known in the art of pharmacology. In general, such
preparatory methods include bringing a cycloserine compound such as
D-cycloserine or an acceptable salt thereof described herein (i.e.,
the "active ingredient") into association with one or more carriers
or excipients (e.g. isolation layer and/or enteric layer
materials), and/or one or more other accessory ingredients, and
then, if necessary and/or desirable, shaping, and/or packaging the
product into a desired single- or multi-dose unit.
[0108] The compositions described herein can be formulated in
dosage unit form for ease of administration and uniformity of
dosage. It will be understood, however, that the total daily usage
of the compositions described herein will be decided by a physician
within the scope of sound medical judgment. The specific
therapeutically effective dose level for any particular subject or
organism will depend upon a variety of factors including the
disease being treated and the severity of the disorder; the
activity of the specific active ingredient employed; the specific
composition employed; the age, body weight, general health, sex,
and diet of the subject; the time of administration, route of
administration, and rate of excretion of the specific active
ingredient employed; the duration of the treatment; drugs used in
combination or coincidental with the specific active ingredient
employed; and like factors well known in the medical arts.
[0109] In the case of capsules, the active ingredient can be
encapsulated into capsule shells. In some instances, the active
ingredient as disclosed herein is not mixed with any excipient or
carrier. In other instances, the active ingredient is mixed with
suitable excipients or carriers as disclosed herein. Any of the
outer layers such as enteric layers disclosed herein may be coated
on the surface of the capsule shell.
[0110] Solid compositions of a similar type (e.g., the inner core
as disclosed herein) can be employed as fillers in soft and
hard-filled gelatin capsules using such excipients as lactose or
milk sugar as well as high molecular weight polyethylene glycols
and the like. The solid dosage forms of tablets, dragees, capsules,
pills, and granules can be prepared with coatings and shells such
as isolation layer coating, enteric coatings, release controlling
coatings, and other coatings well known in the art of pharmacology.
They may optionally comprise opacifying agents and can be of a
composition that they release the active ingredient(s) only, or
preferentially, in a certain part of the digestive tract,
optionally, in a delayed manner. Examples of encapsulating
compositions which can be used include polymeric substances and
waxes. Solid compositions of a similar type can be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like.
[0111] In some embodiments, the solid dosage form described herein
can be a transdermal drug delivery system. In some embodiments, the
transdermal drug delivery system is a patch. In some embodiments,
the transdermal drug delivery system comprises an inner core in a
drug reservoir and a backing layer. In some embodiments, the
transdermal drug delivery system further comprises a protective
peel strip and/or a control membrane. In some embodiments, the
inner core is a liquid or a gel.
[0112] The active ingredient can be in a micro-encapsulated form
with one or more excipients as noted above. In such solid dosage
forms the active ingredient can be admixed with at least one inert
diluent such as sucrose, lactose, or starch. Such dosage forms may
comprise, as is normal practice, additional substances other than
inert diluents, e.g., tableting lubricants and other tableting aids
such a magnesium stearate and microcrystalline cellulose. In the
case of capsules, tablets and pills, the dosage forms may comprise
buffering agents. They may optionally comprise opacifying agents
and can be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain part of the
digestive tract, optionally, in a delayed manner. Examples of
encapsulating agents which can be used include, but not limited to,
polymeric substances and waxes.
Kits
[0113] Also encompassed by the disclosure are kits (e.g.,
pharmaceutical packs), which may comprise a pharmaceutical
composition such as a solid dosage form described herein and a
container (e.g., a vial, ampule, bottle, syringe, and/or dispenser
package, or other suitable container) for placing the composition.
Such kits may be useful in treating and/or reducing the risk for a
neuropsychiatric disorder or tuberculosis in a subject in need
thereof.
[0114] In certain embodiments, a kit described herein may further
include instructions for using the composition described herein
included in the kit. A kit described herein may also include
information as required by a regulatory agency such as the U.S.
Food and Drug Administration (FDA). In certain embodiments, the
information included in the kits is prescription information. In
certain embodiments, the kits and instructions provide for treating
and/or reducing the risk for a neuropsychiatric disorder or
tuberculosis.
[0115] A kit described herein may include one or more additional
pharmaceutical agents described herein as a separate
composition.
Method of Treatment
[0116] Any of the compositions (e.g., solid dosage forms)
comprising a cycloserine compound may help achieve short-term or
long-term health objectives in patients having improve basic
behavioral functioning, hyperactivity, anxiety, depression,
suicidal ideation and/or behavior, sensorimotor gating, pain
threshold, memory and/or cognitive functioning in, e.g., human
subjects who have or are at risk for a neuropsychiatric
disorder.
[0117] Accordingly, also provided herein are methods for treating a
neuropsychiatric disorder (e.g., a central nervous system disorder)
or a bacterial infectious disease (e.g., tuberculosis) in a subject
in need of the treatment, by administering to the subject an
effective amount of the composition (e.g., solid dosage form)
described herein. An effective amount of the composition may be a
therapeutically effective amount or a prophylactically effective
amount.
[0118] A "therapeutically effective amount" of the composition
described herein is an amount sufficient to provide a therapeutic
benefit in the treatment of a condition or to delay or minimize one
or more symptoms associated with the condition. A therapeutically
effective amount of the composition described herein means an
amount of therapeutic agent, alone or in combination with other
therapies, which provides a therapeutic benefit in the treatment of
the condition. The term "therapeutically effective amount" can
encompass an amount that improves overall therapy, reduces or
avoids symptoms, signs, or causes of the condition, and/or enhances
the therapeutic efficacy of another therapeutic agent. In some
instances, the amount of the cycloserine compound in the
composition is effective in modulating N-methyl-D-aspartate
receptor a in a subject with neuropsychiatric disorder.
[0119] A "prophylactically effective amount" of the composition
described herein is an amount sufficient to prevent a condition, or
one or more symptoms associated with the condition or prevent its
recurrence. A prophylactically effective amount of the composition
described herein means an amount of a therapeutic agent, alone or
in combination with other agents, which provides a prophylactic
benefit in the prevention of the condition. The term
"prophylactically effective amount" can encompass an amount that
improves overall prophylaxis or enhances the prophylactic efficacy
of another prophylactic agent.
[0120] The term "neuropsychiatric disorder," including either
neurological diseases or psychiatric disorders or CNS disorders, or
refers to a disorder that involves either psychiatric symptoms or
syndromes caused by organic brain disorders. The main
characteristics of neuropsychiatric symptoms include occurrence of
the various psychiatric symptoms, cognitive impairment,
neurological symptoms or the possibility of early cerebral
development symptoms.
[0121] In some embodiments, the neuropsychiatric disorder can be
schizophrenia, psychotic disorders, Alzheimer's disease,
frontotemporal dementia, vascular dementia, dementia with Lewy
bodies, senile dementia, mild cognitive impairment, benign
forgetfulness, ataxia symptoms, spinocerebellar degeneration,
closed head injury, autistic spectrum disorder, autism, Asperger's
disorder, pervasive developmental disorder--not otherwise specified
(PDD-NOS), fragile X syndrome, attention deficit hyperactivity
disorders, attention deficit disorder, obsessive compulsive
disorder, tic disorders, childhood learning disorders, premenstrual
syndrome, depression, major depressive disorder, anhedonia,
suicidal ideation and/or behaviors, bipolar disorder, anxiety
disorders, panic disorder, anorexia nervosa, phobia, agoraphobia,
claustrophobia, post-traumatic stress disorder, chronic mild and
unpredictable stress, eating disorders, addiction disorders,
personality disorders, Parkinson's disorder, Huntington's disorder,
multiple sclerosis, amyotrophic lateral sclerosis, Tourette's
syndrome, nocturnal enuresis, non-epileptic seizures,
blepharospasm, Duchenne muscular dystrophy, stroke, chronic pain,
neuropathic pain including hyperalgesia and allodynia, diabetic
polyneuropathy, or chronic pain syndromes.
[0122] The compositions described herein are useful in treating
and/or preventing a neuropsychiatric disorder or bacterial
infection such as tuberculosis. To perform the methods described
herein, an effective amount of the solid dosage form may be
administered to a subject in need of the treatment via a suitable
route (e.g., oral administration or topical administration). The
exact amount of the cycloserine compound such as D-cycloserine or
an acceptable salt thereof described herein required to achieve an
intended effect may vary from subject to subject, depending, for
example, on species, age, and general condition of a subject,
severity of the side effects or disorder, identity of cycloserine
compound described herein, mode of administration, and the
like.
[0123] An effective amount of the cycloserine compound may be
included in a single dose (e.g., single oral dose) or in multiple
doses (e.g., multiple oral doses). In certain embodiments, when
multiple doses are administered to a subject, any two doses of the
multiple doses may include different or substantially the same
amounts of the cycloserine compound described herein. The
composition comprising a cycloserine compound may be given to the
subject at a frequency of three times a day to one time every three
months. In certain embodiments, the composition comprising a
cycloserine compound may be given to the subject at a frequency of
two times a day to one time every month. In certain embodiments,
the composition comprising a cycloserine compound may be given to
the subject at a frequency of one time a day to one time every
week.
[0124] In certain embodiments, when multiple doses are administered
to a subject, the frequency of administering the multiple doses to
the subject can be three doses a day, two doses a day, one dose a
day, one dose every other day, one dose every third day, one dose
every week, one dose every other week, one dose monthly one dose
every other month, or one dose every three months. In certain
embodiments, the frequency of administering the multiple doses to
the subject or applying the multiple doses to the tissue or cell is
one dose per day. In certain embodiments, the frequency of
administering the multiple doses to the subject can be two doses
per day.
[0125] In certain embodiments, the solid dosage form is a
transdermal drug delivery system. In certain embodiments, the
transdermal drug delivery system is a sustained-release drug
delivery system. In certain embodiments, the sustained-release drug
delivery system is placed and left on skin for 4-12 hours, 12-24
hours, 1-3 days, 3-5 days or 5-7 days.
[0126] When multiple doses are administered to a subject, the
duration between the first dose and last dose of the multiple doses
can be 4 hours, 8 hours, 12 hours, 24 hours, one day, two days,
four days, one week, two weeks, three weeks, one month, two months,
three months, four months or six months.
[0127] In certain embodiments, a single dose of the cycloserine
compound such as D-cycloserine or a pharmaceutically acceptable
salt thereof may be between 1 mg and 3 mg, between 3 mg and 10 mg,
between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg
and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g,
inclusive. In certain embodiments, a dose of the cycloserine
compound may be between 100 mg and 1500 mg, inclusive, or between
300 mg and 1000 mg, inclusive.
[0128] Dose ranges as described herein may be for use in adult
human patients. The amount to be administered to, for example, a
child or an adolescent can be determined by a medical practitioner
or person skilled in the art and can be lower or the same as that
administered to an adult.
[0129] The composition described herein can be administered in
combination with one or more additional pharmaceutical agents
(e.g., therapeutically and/or prophylactically active agents)
useful in treating and/or reducing the risk for a neuropsychiatric
disorder or bacterial infection such as tuberculosis. The
composition can be administered in combination with one or more
additional pharmaceutical agents that improve the activity (e.g.,
activity (e.g., potency and/or efficacy) in treating and/or
reducing the risk for a neuropsychiatric disorder or tuberculosis
in a subject in need thereof, improve bioavailability, improve
safety, reduce drug resistance, reduce and/or modify metabolism,
inhibit excretion, and/or modify distribution in a subject,
biological sample, tissue, or cell. It will also be appreciated
that the therapy employed may achieve a desired effect for the same
disorder, and/or it may achieve different effects.
[0130] The compositions (e.g., the solid dosage forms) described
herein can be administered concurrently with, prior to, or
subsequent to the one or more additional pharmaceutical agents for
treating the target disease.
[0131] The additional pharmaceutical agents, which include
prophylactically active agents, may be of any type, for example,
small organic molecules, peptides, proteins (e.g., antibodies,
nucleoproteins, lipoproteins, mucoproteins, glycoproteins),
carbohydrates (e.g., monosaccharides, oligosaccharides, or
polysaccharides)lipoproteins, small molecule-conjugated proteins
such as antibody-drug conjugates (ADCs), steroids, nucleic acids
(e.g., DNAs, RNAs, nucleotides, nucleosides, oligonucleotides such
as antisense oligonucleotides), lipids, hormones, vitamins, and
cells.
[0132] Each additional pharmaceutical agent may be administered at
a dose and/or on a time schedule determined for that pharmaceutical
agent. The additional pharmaceutical agents may also be
administered together with each other and/or with the composition
described herein in a single dose or administered separately in
different doses. The particular combination to employ in a regimen
will take into account compatibility of the composition described
herein with the additional pharmaceutical agent(s) and/or the
desired therapeutic and/or prophylactic effect to be achieved. In
general, it is expected that the additional pharmaceutical agent(s)
in combination be utilized at levels that do not exceed the levels
at which they are utilized individually. In some embodiments, the
levels utilized in combination will be lower than those utilized
individually.
[0133] In certain embodiments, the additional pharmaceutical agent
described herein can be an antipsychotic, an antidepressant, a
psychostimulant, a mood stabilizer, an anxiolytic, an agent for
treating attention deficit hyperactivity disorder (ADHD) or an
agent for treating Alzheimer's disease (AD) or dementia.
[0134] Examples of antipsychotic drugs include, but not limited to,
butyrophenone, haloperidol, phenothiazine, fluphenazine,
perphenazine, prochlorperazine, thioridazine, trifluoperazine,
mesoridazine, promazine, triflupromazine, levomepromazine,
promethazine, thioxanthene, chlorprothixene, flupentixol,
thiothixene, zuclopenthixol, clozapine, norclozapine, olanzapine,
risperidone, quetiapine, ziprasidone, amisulpride, asenapine,
paliperidone, aripiprazole, lamotrigine, cannabidiol, LY2140023,
droperidol, pimozide, butaperazine, carphenazine, remoxipride,
piperacetazine, sulpiride, acamprosate, and tetrabenazine.
[0135] The antidepressants can be monoamine oxidase inhibitors
(MAOIs), tricyclic antidepressants (TCAs), tetracyclic
antidepressants (TeCAs), selective serotonin reuptake inhibitors
(SSRIs), noradrenergic and specific serotonergic antidepressants
(NASSAs), norepinephrine (noradrenaline) reuptake inhibitors,
norepinephrine-dopamine reuptake inhibitors,
serotonin-norepinephrine reuptake inhibitors (SNRIs), or
serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRIs).
Examples of the antidepressants include, but not limited to,
fluoxetine, paroxetine, escitalopram, citalopram, sertraline,
fluvoxamine, venlafaxine, milnacipran, duloxetine, mirtazapine,
mianserin, reboxetine, bupropion, amitriptyline, nortriptyline,
protriptyline, desipramine, trimipramine, amoxapine, bupropion,
clomipramine, desipramine, doxepin, isocarboxazid, tranylcypromine,
trazodone, nefazodone, phenelzine, lamatrogine, lithium,
topiramate, gabapentin, carbamazepine, oxcarbazepine, valproate,
maprotiline, brofaromine, gepirone, moclobemide, isoniazid, and
iproniazid.
[0136] In certain embodiments, the additional pharmaceutical agent
is an agent for treating and/or reducing the risk for bacterial
infection such as tuberculosis. Examples include, but are not
limited to, isoniazid, rifampin, ethambutol, pyrazinamide,
rifabutin, rifapentine, capreomycin, kanamycin, amikacin,
streptomycin, fluoroquinolone antibiotics (e.g. ciprofloxacin,
levofloxacin, moxifloxacin, ofloxzcin, gatifloxacin),
prothionamide, para-aminosalicylic acid, ethionamide, terizadone,
clofazimine, clarithromycin, linezolid, amoxicillin-clavulanate,
thiacetazone, bedaquiline, delamanid, carbapenmem antibiotics (e.g.
imipenem, meropenem and doripenem). capreomycin, viomycin,
enviomycin, rifabutin, macrolides, thioridazine, arginine, vitamin
D, and bedaquiline.
[0137] In certain embodiments, the additional pharmaceutical agent
is selected from the group consisting of 5-hydroxytryptophan
(5-HTP), idebenone, amantadine, physostigmine, L-carnitine or
derivatives, trimethoprim/sulfamethoxazole, vigabatrin,
phosphatidylcholine, acetazolamide, 4-aminopyridine, buspirone,
Q10, vitamin E and N-Acetyl-Leucine.
[0138] Without further elaboration, it is believed that one skilled
in the art can, based on the above description, utilize the present
invention to its fullest extent. The following specific embodiments
are, therefore, to be construed as merely illustrative, and not
limitative of the remainder of the disclosure in any way
whatsoever. All publications cited herein are incorporated by
reference for the purposes or subject matter referenced herein.
EXAMPLES
Example 1: Stability Tests of Commercially Available
D-cycloserine
[0139] 1. Stress Testing of D-Cycloserine
[0140] Stability test was held with 500 mg of commercially
available D-cycloserine from Macleods Pharma, opened and stored
under high humidity (>90% RH or 75% RH) at room temperature, a
high temperature (40.degree. C. or 60.degree. C.) or a light
condition for 10 days. The results indicate that the D-cycloserine
is sensitive to high humidity, relatively sensitive to light, and
relatively stable at 40.degree. C. and 60.degree. C., as shown in
Table 1. In the following experiments, the total impurity was set
up to confirm the stability of D-cycloserine.
TABLE-US-00001 TABLE 1 Stability tests of D-cycloserine
D-cycloserine (Macleods Pharma) Moisture-absorption Total Condition
Appearance Weight Gain (%) Impurity (%) 0 day White Powder N/A 0.59
60.degree. C., 10 days White Powder N/A 0.66 40.degree. C., 10 days
White Powder N/A 0.70 25.degree. C., >90% RH, White Powder,
21.11 86.64 10 days Caking 25.degree. C., 75% RH, White Powder,
0.25 1.71 10 days Caking Light, 10 days White Powder N/A 0.96
[0141] 2. Stability of Compositions Comprising D-Cycloserine, and
Various Excipients
[0142] Since humidity is a major fact affecting the stability of
D-cycloserine, several excipients were chosen to test their
influences on the stability under a stress condition (75% RH and
40.degree. C.). The results are shown in Table 2. Comparing with
lactose and microcrystalline cellulose pH-102 (MCC pH-102, also
named as Avicel pH-102, a microcrystalline cellulose having a
moisture content of 3-5%) (sample 1) or mannitol and
microcrystalline cellulose pH-102 (sample 2), microcrystalline
cellulose pH-102 alone (sample 3) has a better effect in
stabilizing D-cycloserine in the composition. The findings reveal
the samples 2 and 3 perform better in the stability tests.
TABLE-US-00002 TABLE 2 Stability tests of D-cycloserine mixed with
different excipients Sample 1 2 3 D-cycloserine (mg) 250 250 250
Lactose (mg) 80 -- -- Mannitol (mg) -- 80 -- MCC pH 102 (mg) 160
160 374 Sodium Croscarmellose (mg) 15.23 15.23 19.5 Magnesium
stearate (mg) 5.77 5.77 6.5 TOTAL (mg) 511 511 650 Total impurity
in 30 days (%) 2.76 1.40 0.89
Example 2: Preparation of Enteric Coated Tablets Comprising
D-Cycloserine
[0143] There are three steps of preparing enteric coated tablets.
The first step is preparing the core tablets compressed by S250
.mu.mart tablet press machine. The second step is preparing core
tablets coated with an isolation layer material by P MINI LAB
coating machine. The final step is preparing isolation layer
tablets coated with an enteric layer material by P MINI LAB coating
machine.
1. Compression
[0144] The active ingredients (e.g. any of the D-cycloserine
compounds) were sieved by a 60-mesh screen, and the excipients were
sieved by a 30-mesh screen separately. The sieved powders were
mixed in a blending machine for 5 minutes to form a mixture 1. The
mixture 1 was then blended with magnesium stearate as a lubricant
for approximately 5 minutes, and the blend was compressed by S250
.mu.mart tablet press machine into tablets. The obtained tablets
which called core tablets were weighed, and their hardness,
friability, and disintegration time were tested. The dissolution
release time would be tested after the enteric coating process.
2. Isolation Layer Coating
2.1. Preparing the Isolation Layer Coating Material Solution.
[0145] 7493.2 g of purified water and 9894.8 g of 95% ethanol were
weighed and put in a container to get a 52.47% ethanol solution.
Then the isolation layer coating material (Opadry.RTM. 295K680002,
purchased from Shanghai Colorcon Coating Technology Ltd.) was
slowly added into the 52.47% ethanol solution and stirred for 45
minutes at room temperature to get an isolation coating solution
having 8% solids content. The isolation coating solution had to be
continuously stirred during the coating process.
2.2 Isolation Layer Coating
[0146] P MINI LAB coating machine was preheated by setting the
inlet air temperature to 40.degree. C.-60.degree. C. and the pan
speed to 2 rpm. Then the core tablets were put into the coating
machine until the exhaust temperature reached about 42.degree. C.,
and then the isolation coating solution was sprayed onto the core
tablets under the parameters shown in Table 3. When the coating
weight gain reached the target range of 3.0.+-.0.5%, the spraying
and heating processes were stopped.
2.3 Cooling
[0147] After spraying and heating processes were stopped, the
coating pan speed was adjusted to 5 rpm, and the inlet air flow was
adjusted to 200-500 m.sup.3/h, to cool down for 5 minutes and then
the tablets coated with the isolation layer were discharged.
3. Enteric Layer Coating
3.1 Preparing the Enteric Layer Coating Material Solution.
[0148] An enteric coating material (Acryl-EZE.RTM. 930640017,
purchased from Shanghai Colorcon Coating Technology Ltd.) was
dissolved in purified water and stirred continuously for at least
45 minutes at room temperature to obtain an enteric coating
solution. Final concentration of the enteric coating solution is
20% by weight. The enteric coating solution had to be continuously
stirred during the coating process with a digital overhead
stirrer.
3.2 Enteric Layer Coating
[0149] P MINI LAB coating machine was preheated by setting the
inlet air temperature to 40.degree. C.-60.degree. C. and the pan
speed to 2 rpm. Then put the tablets coated with the isolation
layer into the coating machine until the exhaust temperature
reached about 35.degree. C., and then the enteric coating solution
was further sprayed onto the tablets coated with the isolation
layer under the parameters shown in Table 3. The coating process
should be closely monitored to ensure the pan temperature and the
quality of the spray were satisfactory and no sticking tablets were
observed. When the coating weight gain reached the target range of
12.36 f 0.5%, the spraying and heating processes were stopped.
3.3 Cooling
[0150] After the spraying and heating processes were stopped, the
coating pan speed was adjusted to 5 rpm, and the inlet air flow was
adjusted to 200-500 m.sup.3/h, to cool down for 5 minutes and then
the enteric coated tablets were discharged.
TABLE-US-00003 TABLE 3 Parameters for spraying isolation layer
coating and enteric layer coating Isolation layer Enteric layer
Parameters coating coating Inlet Air Temperature (.degree. C.)
30-70 30-60 Exhaust Temperature (.degree. C.) 42 35 Pan Speed (rpm)
6-10 6-10 Inlet Air Flow Rate (m.sup.3/h) 400-600 300-600 Pump flow
rate (mL/min) 40-100 40-100 Atomization Pressure (bar) 0.8-1.0
0.6-1.0 Atomization Angle Pressure 0.5-1.0 0.5-1.0 (bar)
4. Hardness Test
[0151] The obtained tablets were subjected to a hardness test, and
the power (N) needed for breaking the tested tablet was recorded.
The harness of tablets was controlled between 120 to 160 N.
5. Friability Test
[0152] Ten tablets were put in a tablet friability apparatus and
rotated at 25.+-.1 rpm for 100 circles. The test was determined as
failed if any of the tested tablets were broken. When the tablets
were not broken, they would be weighted to calculate their weight
loss (%). The weight loss (%) should be lower than 1%.
6. Disintegration Test
[0153] Six tablets were put into water at 37.+-.2.degree. C. The
test was determined as failed if these tablets were not
disintegrated within 30 minutes. The disintegration time (minutes)
of these tablets was recorded.
7. Dissolution Test
[0154] The dissolution test was performed based on the USP method
for dissolution of delayed-release dosage forms, including acid
stage and buffer stage. In acid stage, six tablets were added into
the first dissolution medium (0.1 N hydrochloric acid, pH 2.0) in a
vessel and subjected to the dissolution test. The volume of the
dissolution medium was 900 mL and the rotation speed was 100 rpm.
Since the enteric coating would resist the acidic environment in
stomach, the test was determined as failed if these tablets were
dissolved within 120 minutes. The dissolution time (minutes) of
these tablets in acid stage was recorded.
[0155] After 2 hours of operation in 0.1 N hydrochloric acid, the
fluid in the vessel was withdrawn, replaced with the second
dissolution medium (phosphate buffer, pH 6.8) and proceed
immediately as directed under buffer stage. In buffer stage, the
volume of the second dissolution medium was 900 mL and the rotation
speed was of 100 rpm. The test was determined as failed if these
tablets were dissolved in the 0.1N HCl acid and/or not dissolved no
more than 80% of the label content (i.e. D-cycloserine) at 45
minutes. The dissolution time (minutes) of these tablets in buffer
stage was recorded.
Example 3: Preparation of Core Tablets Comprising D-cycloserine
[0156] Several formulations were used to prepare core tablets, as
shown in Table 4. Microcrystalline cellulose pH-102 (MCC pH-102),
microcrystalline cellulose pH-112 (MCC pH-112, also named as Avicel
pH-112, a microcrystalline cellulose having a moisture content of
less than 1.5%), Starch 1500 and pregelatinized starch were used as
diluents in the formulations. The formulation 2 comprising MCC
pH-112 and Starch 1500 and the formulation 3 comprising MCC pH-112
and pregelatinized starch showed a lower hardness and a larger
friability than the formulation 1.
TABLE-US-00004 TABLE 4 Formulations for core tablets and their
hardness and friability results Formulation 1 2 3 D-cycloserine
(mg) 525 525 525 MCC pH-102 (mg) 339 -- 249 MCC pH-112 (mg) --
227.5 -- Pregelatinized starch (mg) -- -- 90 Starch 1500 (mg) --
227.5 -- Croscarmellose sodium (mg) 27 10 27 Magnesium stearate
(mg) 9 10 9 Total core tablets (mg) 900 1000 900 Hardness (N) 110
48.3 40 Friability (%) 0.32% >1% >1%
[0157] In addition, other formulations for core tablets were also
prepared, as shown in Table 5. These core tablets were also
subjected to the second part of the dissolution test (buffer stage)
to determine if they could be disintegrated properly, wherein the
core tablets were directly added into the second dissolution medium
(phosphate buffer, pH 6.8) for the dissolution test.
[0158] Hydroxypropyl cellulose (HPC) and Povidone K30 are binder
agents which can improve the defect of a lower hardness and a
larger friability. In formulations 4-6, HPC showed a better ability
of increasing the hardness, and HPC was chosen to increase
hardness. In formulations 7-10, the formulations 7 and 10 showed a
shorter and satisfactory dissolution time, but the core tablet
formulations 8-9 containing a high amount of HPC showed a much
longer dissolution time. Therefore, the core tablet formulations
8-9 were determined as failed in the dissolution test.
TABLE-US-00005 TABLE 5 Formulations for core tablets and results of
hardness, friability and dissolution test Formulation 4 5 6 7 8 9
10 D-cycloserine (mg) 525 525 525 525 525 525 498 MCC pH-102 (mg)
-- -- -- 219 405 375 246 MCC pH-112 (mg) 227.5 227.5 227.5 -- -- --
-- Starch 1500 (mg) 227.5 227.5 227.5 -- -- -- -- Povidone K30 (mg)
-- 30 -- -- -- -- -- HPC (mg) -- -- 30 24 50 80 24 Croscarmellose
10 10 10 24 10 10 24 sodium (mg) Magnesium stearate (mg) 10 10 10 8
10 10 8 Total core tablets (mg) 1000 1030 1030 800 1000 1000 800
Hardness (N) 48.3 27.2 50.35 120 177 165 155 Friability (%) >1
>1 >1 0.3 0.28 0.27 0.26 Dissolution test (buffer stage only)
NLT 80% in buffer N/A N/A N/A 95 <80 <80 92 stage (%)
Example 4: Preparation of Enteric Tablet Formulations Comprising
D-Cycloserine
[0159] The enteric tablets were prepared in accordance with Example
2. The isolation layer and enteric layer protected the active
pharmaceutical ingredients from the acidic environment of the
stomach. Therefore, the amounts of isolation layer material and
enteric layer material were investigated, as shown in Table 6.
[0160] Formulations 11-13 showed no acid resistance even when their
enteric layer coating amount was increased. The core tablet may
also play a role in acid resistance. For the content of isolation
layer, isolation layer coating weight in range of 2.5-5.0% in
Formulation 14-17 was suggested. For the content of enteric layer,
the range of 10-14% was sufficient for the enteric tablets to
resist the acidic environment of the stomach, as shown in
Formulation 14, 15 and 17. The enteric tablets of formulation 16
absorbed little water and the shape of the tablets changed (i.e.
puffed), which might be caused by its less enteric layer coating
weight By contrast, formulations 14, 15, 17 and 18 showed better
results including superior acid resistance as well as superior
dissolution efficiency at pH 6.8. In summary, both isolation layer,
enteric layer, and their combination are important for the
successful acid-resistant formulation.
TABLE-US-00006 TABLE 6 Formulations of enteric tablets and results
of dissolution test Formulation 11 12 13 14 15 16 17 18
D-cycloserine (mg) 250 250 250 250 250 250 250 498 MCC pH 102 (mg)
157 157 157 374 374 374 374 246 Mannitol (mg) 157 157 157 -- -- --
-- -- HPC (mg) -- -- -- -- -- -- -- 24 Croscarmellose 30 30 30 19.5
19.5 19.5 19.5 24 sodium (mg) Magnesium stearate 6 6 6 6.5 6.5 6.5
6.5 8 (mg) Total core tablets 600 600 600 650 650 650 650 800 (mg)
Isolation layer (mg) 18 18 18 32.5 32.5 16.25 16.25 24 coating
weight (%) 3 3 3 5 5 2.5 2.5 3 Enteric layer (mg) 49.4 61.8 74.2
68.2 95.5 53.5 66.6 96 coating weight (%) 8 10 12 10 14 8 10 12
Dissolution test NMT 10% at 120 4 0 1 0 0 0 0 0 min in acid stage
(%) NLT 80% at 45 35 80 79 95 95 79 96 95 min in buffer stage
(%)
Example 5: Pharmaceutical Kinetic (PK) Studies of Enteric Capsules
Comprising Nano-Crystalline D-Cycloserine and Commercial
D-Cycloserine in an Animal Model
1. Preparation of the Nano-Crystalline D-Cycloserine
[0161] Process A:
[0162] 100 mg of crude D-cycloserine powder (purchased from Stride
Shasun) were dissolved in 1 mL deionized water to prepare a
saturated D-cycloserine aqueous solution. 10 mL of the saturated
D-cycloserine solution were slowly added into 20 mL of tert-butanol
or 70% methyl ethyl ketone (MEK) in ethanol or 90% MEK in ethanol
and milled by sonication at 40 Hz for 1 minute simultaneously. The
solution was filtered by suction filtration using a 0.2 .mu.m
filter membrane. The filtered solution was centrifuged by 10,000
rpm for 10 minutes. The collection was vacuum-dried to obtain the
nano-crystalline D-cycloserine (average yield: 40.9%). The
nano-crystalline D-cycloserine prepared by Process A was used for
the following experiments and tests.
[0163] Process B:
[0164] The saturated aqueous solution of D-cycloserine was dried by
a spray dryer and the spray dried D-cycloserine powder was ground
by a planetary ball mill. The diameter of ground D-cycloserine
powder was less than 0.2 .mu.m.
[0165] Process C:
[0166] The saturated aqueous solution of D-cycloserine was dried by
spray dryer, and the spray dried D-cycloserine powder was prepared
to a second saturated aqueous solution of D-cycloserine by the same
step as shown in Process A. 10 mL of the second saturated aqueous
solution of D-cycloserine was slowly added into 50 mL of 70% methyl
ethyl ketone in ethanol and stirred at 150 rpm by a propeller
stirrer for 10 minutes, and the D-cycloserine precipitated. The
precipitated D-cycloserine was collected by vacuum filtration, and
dried by vacuum dry oven at 70.degree. C. overnight. The obtained
D-cycloserine was ground by a planetary ball mill. The diameter of
the ground D-cycloserine powder was less than 0.2 .mu.m.
2. Preparation of Capsule Formulations of the Nano-Crystalline
D-Cycloserine and Commercial D-Cycloserine
Preparation of Capsule Formulations:
[0167] (1) Formulation A: the nano-crystalline D-cycloserine in
size 9 in-house enteric capsule. 5.66 g Kollicoat.RTM. enteric
coating material was brushed evenly on the surface of the opened
size 9 Empty Porcine Hard Gelatin Capsules (Torpac), and then
air-dried until the coated capsules became hard and dry. After
repeating the coating and drying steps for 5 times, the opened
capsules could be closed intact were ready for use. Approximately
10 mg of the nano-crystalline D-cycloserine was filled in each
capsule. [0168] (2) Formulation B: the commercial D-cycloserine
(diameter of 73 .mu.m) in size 9 in-house enteric capsule.
Formulation B was prepared by the method for preparing Formulation
A except the nano-crystalline D-cycloserine was substituted with
the commercial D-cycloserine (purchased from Strides Shasun).
[0169] (3) PK Studies in a Rat Model:
[0170] Sprague-Dawley rats at age 8 weeks old were divided into
different groups with 3 rats in each group. All rats were fasted
overnight with free access to water before test article
administration. These rats were given with single dose of the
Formulations A to B by oral administration, respectively. Blood
samples were collected at different time points after the oral
administration in each experiment. The volume of blood collected
from each animal was greater than 300 .mu.L and these blood samples
were processed to obtain plasma (greater than 150 .mu.L) for
subsequent analysis. Plasma samples were analyzed by LC-MS/MS
method to determine the amount of D-cycloserine. After obtaining
blood sample, brains were collected and immediately frozen and
stored at -70.degree. C. until use.
[0171] (4) LC-MS/MS Analysis:
[0172] 2 .mu.L of each plasma sample was transferred into a well of
a 96-well plate. 100 .mu.L of 0.1 ng/.mu.L of IS (Piracetam) in
acetonitrile was added into each well to precipitate proteins. The
96-well plate was vortexed for 1 min and then centrifuged at 3000
rpm for 5 mins. The supernatant is analyzed by LC-MS/MS.
[0173] The D-cycloserine analysis for plasma samples was developed
by LC-MS/MS. Chromatographic column used was Atlantis HIPIC Silica
100 A 3.0.times.50 mm, 3 um. The mobile phase was consisted of (A)
acetonitrile/Formic acid (100/0.5 (v/v)) and (B) DI water/Formic
acid (100/0.5 (v/v)) with a gradient condition as shown in Table 7.
The flow rate was 0.6 mL/min. The auto sampler temperature was
maintained at 25.degree. C. and the injection volume was kept at 3
.mu.L. The total LC run time was 5.5 mins. The ionization and
detection of the analyte were performed on a triple quadrupole mass
spectrometer, in the positive ion mode. Quantitation was done using
the MRM mode to monitor the protonated precursor.fwdarw.product ion
transition of m/z 103.1.fwdarw.75.0 for the nano-crystalline
D-cycloserine and to monitor the protonated
precursor.fwdarw.product ion transition of nm/z 143.2.fwdarw.97.8
for piracetam as an internal standard. The PK results were shown in
Table 8.
TABLE-US-00007 TABLE 7 Mobile phase of LC-MS/MS for plasma samples
Flow Rate Time (mins) (.mu.L/min) A (%) B (%) 0.00 600 95.0 5.0
0.50 600 95.0 5.0 1.00 600 50.0 50.0 2.50 600 50.0 50.0 2.60 600
95.0 5.0 5.50 600 95.0 5.0
TABLE-US-00008 TABLE 8 PK Parameters of Enteric Capsules Containing
nano-crystalline D- cycloserine and commercial D-cycloserine in
Rats through Oral Administration Tmax Cmax AUC last AUC Inf
Formulation (hr) (ng/mL) (h*ng/mL) (h*ng/mL) A 0.833# 94068#
141669# 141752# B 1.167# 74132# 129027# 129121# #mean value (n =
3)
[0174] When the nano-crystalline D-cycloserine was loaded in the
enteric capsules, the major differences of the PK parameters were
the C.sub.max and AUC as shown in Table 8. The C.sub.max and AUC of
enteric capsules comprising the nano-crystalline D-cycloserine are
26% and 10% higher respectively as compared to the corresponding
values of enteric capsules comprising the commercial D-cycloserine.
These data indicate that nano-crystalline D-cycloserine has a
better adsorption rate in pharmaceutical kinetics; for example, a
greater surface area as compared to the commercial
D-cycloserine.
Example 6: Preparation of Enteric Coated Capsules Comprising
D-Cycloserine
[0175] Enteric-coated kangke 0.sup.# HPMC capsules were obtained
from the Shaoxing Comco capsule Co. Ltd. First, the API
(cycloserine) and all other excipients were passed through a 40
mesh sieve. Second, the API, microcrystalline cellulose, mannitol
or lactose, and sodium croscarmellose were weighed, respectively,
into a plastic bag and manually mixed for 3 minutes to obtain
mixture 1. Third, magnesium stearate was weighed and combined with
mixture 1 and manually mixed for 1 min to obtain mixture 2.
Finally, mixture 2 was direct filled into the enteric-coated
capsules and an acid resistance dissolution test was conducted.
[0176] Four formulations were prepared. As shown in Table 9,
Formulations 19 and 20 comprised D-cycloserine and the indicated
excipients, while Formulation 21 comprised the same excipients as
those used in Formulation 19 but did not comprise D-cycloserine.
After being incubated in an acidic solution for 2 hours (In 0.1N
HCl, 2 hr, simulated gastric fluid), the capsules of Formulations
19 and 20 were broken and the components inside the capsules were
wet while Formulation 21 remained intact with dry components inside
the capsule as shown in FIG. 1. Similar results were observed using
capsules obtained from Jiangsu lifan capsule Co., Ltd. and Dah Feng
capsule industry Co., Ltd. This example demonstrates the difficulty
in making a D-cycloserine enteric-coated capsule due to the
hygroscopicity of D-cycloserine. Finally, it was discovered that
Formulation 22 was stable in an acidic solution.
TABLE-US-00009 TABLE 9 Formulations for enteric-coated capsules and
their acid resistance results Formulation 19 20 21 22 D-cycloserine
(mg) 250 250 -- 250 MCC pH-102 (mg) 80 -- 80 80 Mannitol (mg) 160
-- 160 Lactose, FLOWLAC 160 100 (mg) Croscarmellose 15.23 -- 15.23
15.23 sodium (mg) Magnesium stearate 2.54 -- 2.54 2.54 (mg) Total
weight (mg) 507.77 250 257.77 507.77 Enteric Coated KANGKE 0.sup.#
HPMC Capsule In 0.1N HCl, 2 hr Capsules Capsules Capsules Capsules
(Acid stage) are are are not are not broken broken broken
broken
Example 7: Preparation of Patch Formulations and In-Vitro
Transdermal Delivery of Nano-Crystalline D-Cycloserine
[0177] 1. Preparation of the patch Formulations
[0178] (1) Patch Formulation C: First, 10 mg of povidone was added
in a 0.05 mL of NaOH solution. The povidone solution was then added
with 0.5 mL of di-propylene glycol, 0.6 mL of PEG400, and 0.2 mL of
corn oil to form an emulsion solution by vortex and sonication. 15
mg of the nano-crystalline D-cycloserine was added to the 1.35 mL
of the emulsion solution with a stirred condition. When the
nano-crystalline D-cycloserine was well suspended in the emulsion
solution, the final formulation was obtained and then added to the
donor compartment of the Franz diffusion cell system for the
transdermal delivery test. The formulation and the test results are
shown in Table 11.
[0179] (2) Patch Formulation D: First, 5 mg of mannitol and 10 mg
of povidone were added in a 0.05 mL of NaOH solution. This
mannitol/povidone solution was then added with 0.2 mL of
di-propylene glycol, 0.8 mL of PEG400, and 0.3 mL of corn oil to
form an emulsion solution by vortex and sonication. 30 mg of the
nano-crystalline D-cycloserine was added to the 1.35 mL of the
emulsion solution with a stirred condition. When the D-cycloserine
nano-crystal was well suspended in the emulsion solution, the final
formulation was obtained and then added to the donor compartment of
the Franz diffusion cell system for the transdermal delivery test.
The formulation and the test results are shown in Table 11.
[0180] (3) Patch Formulation E: First, 5 mg of mannitol and 10 mg
of povidone were added in a 0.05 mL of NaOH solution. This
mannitol/povidone solution was then added with 0.2 mL of
di-propylene glycol, 0.8 mL of PEG400, and 0.3 mL of corn oil to
form an emulsion solution by vortex and sonication. 30 mg of the
nano-crystalline D-cycloserine was added to the 1.35 mL of the
emulsion solution with a stirred condition. When the D-cycloserine
nano-crystal was well suspended in the emulsion solution, the final
formulation was obtained and then added to the donor compartment of
the Franz diffusion cell system for the transdermal delivery test.
The formulation and the test results are shown in Table 11.
[0181] (4) Patch Formulation F: First, 5 mg of mannitol and 10 mg
of povidone were added in a 0.05 mL of NaOH solution. This
mannitol/povidone solution was then added with 0.2 mL of
di-propylene glycol, 0.8 mL of PEG400, and 0.3 mL of corn oil to
form an emulsion solution by vortex and sonication. 30 mg of a
D-cycloserine commercial product (purchased from Stride Shasun) was
added to the 1.35 mL emulsion solution with a stirred condition.
When the D-cycloserine commercial product was well suspended in the
emulsion solution, the final formulation was obtained and then
added to the donor compartment of the Franz diffusion cell system.
The formulation and the test results are shown in Table 11.
[0182] (5) Patch Formulation G: First, 10 mg of povidone was added
in a 0.05 mL of NaOH solution. The povidone solution was then added
with 0.5 mL of di-propylene glycol, 0.6 mL of PEG400, and 0.2 mL of
corn oil to form an emulsion solution by vortex and sonication. 15
mg of a D-cycloserine commercial product (purchased from Stride
Shasun) was added to the 1.35 mL of the emulsion solution with a
stirred condition. When the D-cycloserine commercial product was
well suspended in the emulsion solution, the final formulation was
obtained and then added to the donor compartment of the Franz
diffusion cell system. The formulation and the test results are
shown in Table 11.
2. In-Vitro Transdermal Delivery Experiment
[0183] A START-M.RTM. membrane which has a pore size of 450 nm
(purchased from Merck) was mounted on a Franz diffusion cell
(purchased from PermeGear, Riegelsville, Pa., USA). The receptor
compartment contained 8 mL of DI water. 1-1.35 mL of the
above-mentioned formulations, were respectively applied to the
membrane over an area of 1 cm.sup.2 area across the donor
compartment. The donor compartment was exposed to ambient
temperature and covered with parafilm to prevent evaporation, and
then the formulation applied on the membrane would diffuse into the
DI water of the receptor compartment. The solution in the receptor
compartment (i.e. release medium) was stirred continuously with a
Teflon-coated magnetic bar at 32.degree. C. Samples (0.2 mL) were
withdrawn from the release medium of Formulations C to G after 6,
24, 48, 72, 96, 120, and 144 hr and replaced with an equal volume
of DI water to maintain their sink conditions. Another set of
samples (0.2 mL) was withdrawn and diluted with methanol and then
analyzed by LC-MS/MS.
3. LC-MS/MS Analysis
[0184] The analysis for D-cycloserine is developed by LC-MS/MS
method. The chromatographic column used for the LC-MS/MS analysis
was a C18 column from Thermo Fisher Scientific. The mobile phase
was consisted of (A) 0.1% tri-fluroacetic acid in acetonitrile and
(B) 0.1% tri-fluroacetic acid in DI water with a gradient condition
as shown in Table 10. The flow rate was 0.5 mL/min. The auto
sampler temperature was maintained at 4.degree. C. and the
injection volume was kept at 5 .mu.L. The total LC run time was 20
minutes. Ionization and detection of the analyte was performed on a
triple quadrupole mass spectrometer, API-2000, in the positive ion
mode. Quantitation was done using the MRM mode to monitor the
transition from protonated precursor to product ion (m/z 103.1 to
75.0).
TABLE-US-00010 TABLE 10 Mobile phase of LC-MS/MS for samples
withdrawn from the release Medium Time (mins) A (%) B (%) 0 80 20
10 50 50 11 80 20 20 80 20
4. In-Vitro Long Term Transdermal Release Kinetic Calculation
[0185] Long term transdermal release kinetics of each formulation
was simulated and then calculated by non-linear equation. The ideal
maximum release amount and T.sub.1/2 (time at half-maximum
D-cycloserine released to the receptor compartment) for each
formulation are shown in Table 11, and the release kinetics of each
formulation are shown in FIG. 2.
TABLE-US-00011 TABLE 11 Composition of all the formulations and the
releasing results in in-vitro transdermal study Formulations C (n =
2) D (n = 3) E (n = 2) F (n = 3) G (n = 3) Carrier (mL) DPG 0.5 DPG
0.2 DPG 0.5 DPG 0.2 DPG 0.5 mL mL mL mL mL (0.51 g) (0.2 g) (0.51
g) (0.2 g) (0.51 g) pH adjuster 1.5N 2N 2N 2N 1.5N (mL/conc.) NaOH
NaOH NaOH NaOH NaOH 0.05 mL 0.05 mL 0.05 mL 0.05 mL 0.05 mL (0.003
g) (0.004 g) (0.004 g) (0.004 g) (0.003 g) Dispersion PEG 400 PEG
400 PEG 1000 PEG 400 PEG 400 reagent 0.6 mL 0.8 mL 0.5 mL 0.8 mL
0.6 mL (mL or g) (0.68 g) (0.90 g) (0.55 g) (0.90 g) (0.68 g) Anti-
Corn oil Corn oil Corn oil Corn oil Corn oil sedimentation 0.2 mL
0.3 mL 0.45 mL 0.3 mL 0.2 mL reagent (mL) (0.18 g) (0.27 g) (0.41
g) (0.27 g) (0.18 g) Enhancer (mg) -- Mannitol Mannitol Mannitol --
5 mg 5 mg 5 mg Sustained Povidone Povidone Povidone Povidone
Povidone release 10 mg 10 mg 10 mg 10 mg 10 mg reagent (mg)
D-cycloserine 15 mg*/ 30 mg*/ 30 mg*/ 30 mg.sup.#/ 15 mg.sup.#/
(mg/final 1.35 mL 1.35 mL 1.0 mL 1.35 mL 1.35 mL conc.) Releasing
Rate 7.23 mg 10.62 mg 10.46 mg 0.46 mg 0.18 mg of ideal Max.
D-cycloserine (mg/hr) T.sub.1/2(hr) 41 43 34 48 40 *is the
nano-crytalline D-cycloserine .sup.#is the commercial
D-cycloserine
DPG: Di-Propylene Glycol
[0186] As shown in Table 11 and FIG. 2, the nano-crystalline
D-cycloserine patch formulations disclosed in this Example
demonstrate greater penetration ability in the in-vitro transdermal
delivery system as compared to formulations that include commercial
D-cycloserine (purchased from Stride Shasun). When commercial
D-cycloserine was applied in the formulation for in-vitro
transdermal delivery experiment, it was found that an obvious cake
was obtained on the START-M.RTM. membrane after the 6-day
experiment. However, the same phenomenon was not observed in the
formulation containing nano-crystalline D-cycloserine. Therefore,
the nano-crystalline D-cycloserine patch formulations disclosed
herein demonstrate greater penetration through human skin.
[0187] In addition, the skin is the largest organ of the human body
and it constitutes a great protective barrier against entry of
harmful microbial species and foreign materials into the body. The
barrier function is a result of the highly hydrophobic nature and
compact structure of the outermost skin layer, which makes the
transdermal delivery of hydrophilic drugs difficult, for example,
D-cycloserine (log p=-1.72). The results disclosed herein showed
that the nano-crystalline D-cycloserine patch Formulations C-E can
penetrate through the START-M.RTM. membrane, which was very
hydrophobic. These results suggest that the nano-crystalline
D-cycloserine patch formulations disclosed herein can penetrate
hydrophobic membranes, thereby reducing the hydrophobic boundary of
human skin.
[0188] In sum, this example demonstrates that the patch
formulations disclosed herein are suitable for use in a reservoir
patch system or other transdermal delivery system for D-cycloserine
transdermal delivery.
EQUIVALENTS AND SCOPE
[0189] In the claims, articles such as "a," "an," and "the" may
mean one or more than one unless indicated to the contrary or
otherwise evident from the context Claims or descriptions that
include "or" between one or more members of a group are considered
satisfied if one, more than one, or all of the group members are
present in, employed in, or otherwise relevant to a given product
or process unless indicated to the contrary or otherwise evident
from the context. The invention includes embodiments in which
exactly one member of the group is present in, employed in, or
otherwise relevant to a given product or process. The invention
includes embodiments in which more than one, or all of the group
members are present in, employed in, or otherwise relevant to a
given product or process.
[0190] Furthermore, the invention encompasses all variations,
combinations, and permutations in which one or more limitations,
elements, clauses, and descriptive terms from one or more of the
listed claims is introduced into another claim. For example, any
claim that is dependent on another claim can be modified to include
one or more limitations found in any other claim that is dependent
on the same base claim. Where elements are presented as lists,
e.g., in Markush group format, each subgroup of the elements is
also disclosed, and any element(s) can be removed from the group.
It should be understood that, in general, where the invention, or
aspects of the invention, is/are referred to as comprising
particular elements and/or features, certain embodiments of the
invention or aspects of the invention consist, or consist
essentially of, such elements and/or features. For purposes of
simplicity, those embodiments have not been specifically set forth
in haec verba herein. It is also noted that the terms "comprising"
and "containing" are intended to be open and permits the inclusion
of additional elements or steps. Where ranges are given, endpoints
are included. Furthermore, unless otherwise indicated or otherwise
evident from the context and understanding of one of ordinary skill
in the art, values that are expressed as ranges can assume any
specific value or sub-range within the stated ranges in different
embodiments of the invention, to the tenth of the unit of the lower
limit of the range, unless the context clearly dictates
otherwise.
[0191] This application refers to various issued patents, published
patent applications, journal articles, and other publications, all
of which are incorporated herein by reference. If there is a
conflict between any of the incorporated references and the instant
specification, the specification shall control. In addition, any
particular embodiment of the present invention that falls within
the prior art may be explicitly excluded from any one or more of
the claims. Because such embodiments are deemed to be known to one
of ordinary skill in the art, they may be excluded even if the
exclusion is not set forth explicitly herein. Any particular
embodiment of the invention can be excluded from any claim, for any
reason, whether or not related to the existence of prior art.
[0192] Those skilled in the art will recognize or be able to
ascertain using no more than routine experimentation many
equivalents to the specific embodiments described herein. The scope
of the present embodiments described herein is not intended to be
limited to the above Description, but rather is as set forth in the
appended claims. Those of ordinary skill in the art will appreciate
that various changes and modifications to this description may be
made without departing from the spirit or scope of the present
invention, as defined in the following claims.
[0193] The term "about" or "approximately" as used herein means
within an acceptable error range for the particular value as
determined by one of ordinary skill in the art, which will depend
in part on how the value is measured or determined, i.e., the
limitations of the measurement system. For example, "about" can
mean within an acceptable standard deviation, per the practice in
the art. Alternatively, "about" can mean a range of up to f 20%,
preferably up to f 10%, more preferably up to f 5%, and more
preferably still up to f 1% of a given value. Alternatively,
particularly with respect to biological systems or processes, the
term can mean within an order of magnitude, preferably within
2-fold, of a value. Where particular values are described in the
application and claims, unless otherwise stated, the term "about"
is implicit and in this context means within an acceptable error
range for the particular value.
[0194] The phrase "and/or," as used herein in the specification and
in the claims, should be understood to mean "either or both" of the
elements so conjoined, i.e., elements that are conjunctively
present in some cases and disjunctively present in other cases.
Multiple elements listed with "and/or" should be construed in the
same fashion, i.e., "one or more" of the elements so conjoined.
Other elements may optionally be present other than the elements
specifically identified by the "and/or" clause, whether related or
unrelated to those elements specifically identified. Thus, as a
non-limiting example, a reference to "A and/or B", when used in
conjunction with open-ended language such as "comprising" can
refer, in one embodiment, to A only (optionally including elements
other than B); in another embodiment, to B only (optionally
including elements other than A); in yet another embodiment, to
both A and B (optionally including other elements); etc.
[0195] As used herein in the specification and in the claims, "or"
should be understood to have the same meaning as "and/or" as
defined above. For example, when separating items in a list, "or"
or "and/or" shall be interpreted as being inclusive, i.e., the
inclusion of at least one, but also including more than one, of a
number or list of elements, and, optionally, additional unlisted
items. Only terms clearly indicated to the contrary, such as "only
one of" or "exactly one of," or, when used in the claims,
"consisting of," will refer to the inclusion of exactly one element
of a number or list of elements. In general, the term "or" as used
herein shall only be interpreted as indicating exclusive
alternatives (i.e. "one or the other but not both") when preceded
by terms of exclusivity, such as "either," "one of," "only one of,"
or "exactly one of." "Consisting essentially of," when used in the
claims, shall have its ordinary meaning as used in the field of
patent law.
[0196] As used herein in the specification and in the claims, the
phrase "at least one," in reference to a list of one or more
elements, should be understood to mean at least one element
selected from any one or more of the elements in the list of
elements, but not necessarily including at least one of each and
every element specifically listed within the list of elements and
not excluding any combinations of elements in the list of elements.
This definition also allows that elements may optionally be present
other than the elements specifically identified within the list of
elements to which the phrase "at least one" refers, whether related
or unrelated to those elements specifically identified. Thus, as a
non-limiting example, "at least one of A and B" (or, equivalently,
"at least one of A or B," or, equivalently "at least one of A
and/or B") can refer, in one embodiment, to at least one,
optionally including more than one, A, with no B present (and
optionally including elements other than B); in another embodiment,
to at least one, optionally including more than one, B, with no A
present (and optionally including elements other than A); in yet
another embodiment, to at least one, optionally including more than
one, A, and at least one, optionally including more than one, B
(and optionally including other elements); etc.
* * * * *