QD Diffucaps® Drug Delivery Systems for Weakly Basic

QD Diffucaps® Drug Delivery Systems for
Weakly Basic Pharmaceutical Actives
G. Venkatesh1, J. Lai1, N.H. Vyas1, P.J. Stevens1, M. Gosselin1, J. Clevenger1, P. Percel1, P. Gatti2, C. Strollberg2, F. Fabiani2,
L. Boltri2, L. Mapelli2, and I. Colombo2
1. Eurand Inc., Vandalia, OH 45377 (USA); 2. Eurand S.p.A., Pessano con Bornago, Milan (Italy)
Aptalis Pharmaceutical Technologies, formerly Eurand Pharmaceutical Technologies
For more information about our portfolio of proprietary pharmaceutical technologies,
please visit www.AptalisPharmaceuticalTechnologies.com.
Abstract
stomach: pH 1.2–3.5, duodenum: pH 4.6–6.0, small intestine:
pH 4.7–6.5, large intestine: pH 7.5–8.0); varying fluid volumes
(for example, 45 mL vs. 686 mL in the stomach, 105 mL vs.
54 mL in the small intestine, and 13 mL vs. 11 mL in the large
intestine in the fasted vs. fed states); surface area (stomach:
0.1–0.2 square meter (sq-m), small intestine: 4,500 sq-m, large
intestine: 0.5–1 sq-m); and transit times (stomach: 0.25–3 hrs,
duodenum: 1–2 hrs, small intestine: 1–10 hrs, large intestine:
4–20 hrs) that depend on factors such as dosage form and
fasted/fed conditions1–4. The drug must be released from
the dosage form in solution form; otherwise, it is generally
not absorbed. Consequently, the ability to apply enhanced
absorption systems to develop controlled-release (CR)
products has been limited.
Lack of compliance to dosing regimens is widespread largely due
to complicated regimens (e.g., too many medications, too frequent
dosing) and swallowing difficulties. Eurand’s Diffucaps® technology
enables the development of once-daily controlled-release (CR)
capsules or patient-compliant orally disintegrating tablet formulations
(ODT – CR) comprising immediate-release (IR), sustained-release
(SR), timed pulsatile-release (TPR) or timed sustained-release (TSR)
bead populations multicoated with a weakly basic drug, an organic
acid or an alkaline buffer, and a solid-solution and then further
coated with one or more functional polymers.
Introduction
• Complicated regimens (too many medications, too frequent
dosing) and physical difficulties in complying (e.g., handling
small tablets, swallowing difficulties, timely accessibility to
drinks) are often cited as factors responsible for non-compliance
or lack of adherence to dosing regimens, which has become a
major medical problem in America costing billions of dollars.
• Eurand’s Diffucaps® technology allows development and
commercialization of weakly basic drugs with varying pHdependent solubility profiles (e.g., ondansetron, carvedilol,
EUR-1057, nifedipine) based on lag-time coating and (1) use
of solubility-enhancing organic acids, (2) solubility-retarding
alkaline buffers, and/or (3) use of crystallization-inhibiting
polymers (solid-solution approach).
• Drug delivery systems such as sustained-release (SR) multiparticulate capsule or matrix tablet formulations, amorphous/
nanocrystalline or solid solution formulations, and organic
acid- or effervescent-containing formulations have been
developed to enhance absorption of the drug throughout
the human digestive tract to reduce the frequency of dosing.
• Eurand’s Diffucaps® technology allows development and
commercialization of drug delivery systems of weakly basic
drugs with varying but pH-independent solubility profiles (e.g.,
methylphenidate, propranolol, cyclobenzaprine) for customized
delivery as needed, i.e., to deliver drugs in quantities when
needed to mimic circadian rhythm variations of disease states.
• Many pharmaceutical actives are weakly basic and exhibit
pH-dependent solubility profiles. Further, in the human
digestive track, a drug will experience varying pHs (for example,
1
Fig. 1: Diffucaps® CR beads in capsules or in ODT - CR
Drug + Binder
Inert Core
Functional
Polymer Coating
Seal Coat
CR Capsules
ODT - CR
Diffucaps®
Experimental Methods
• Eurand’s Diffucaps® technology involves (1) the preparation of drug-containing cores such as immediate-release (IR) beads, pellets or
microtablets (e.g., typically 2 mm or less in diameter) obtained by (1) layering drug on inert cores, extrusion-spheronization, controlled
spheronization, or granulation-compression, (2) applying one or more coatings with proprietary functional polymers, and (3) combining
one or more coated, spherical, multi-layered bead populations (Fig. 1) into hard gelatin or hydroxypropyl methylcellulose (HPMC)
capsules2 or blending with rapidly dispersing granules and compressing into orally disintegrating tablets (ODTs)5 (Fig. 1).
• In case of weakly basic drugs requiring an organic acid to solubilize the drug prior to its release into the intestine, a drug-containing
core (e.g., an acid crystal or an inert core layered with the acid) is coated with a water-insoluble polymer to sustain the acid release
and to prevent the acid from coming into contact with the weakly basic drug. The SR acid-cores are coated with the drug as well as
one or more polymer membranes to produce CR capsules containing IR and/or timed pulsatile-release (TPR) bead populations6.
• A weakly basic drug and a crystallization-inhibiting/solubility-enhancing polymer are dissolved in a solvent mixture and coated onto
inert cores. The polymer inhibits the drug from returning to crystalline form while maintaining it in the thermodynamically activated
(i.e., amorphous) state7.
• IR beads containing extremely soluble drugs, such as EUR-1057, are coated with an alkaline buffer prior to coating with functional
polymers to create an alkaline pH microenvironment that retards drug release. The polymer-coated beads are further coated with a
compressible coating to eliminate/minimize membrane fracture during compression8.
Results and Discussion
• Cyclobenzaprine, freely water-soluble, is a novel centrally acting drug administered to relieve skeletal muscle spasm of local origin.
Cyclobenzaprine is well absorbed after oral administration with a relatively long half-life, but with a suspected short pharmacological
activity. Amrix® is the first and only FDA-approved, once-daily skeletal muscle relaxant (Fig. 2) providing significant reduction in
patient-rated daytime drowsiness9–11.
2
Plasma concentration (ng/mL)
20
15
Fig. 2: Plasma Profiles of cyclobenzaprine from Flexeril® (10 mg IR)
dosed 3 times daily vs. Amrix® (ER capsule) dosed once daily
10
20
Plasma concentration (ng/mL)
5 15
0
= Amrix® 30 mg
= Cyclobenzaprine 10 mg TID
= Therapeutic cyclobenzaprine level
10
0
8
16
5
0
24
Time (hours)
32
= Amrix® 30 mg
= Cyclobenzaprine 10 mg TID
= Therapeutic cyclobenzaprine level
0
8
16
24
Time (hours)
32
• Stimulant therapy of school-going– children
with
attention-deficit/hyperactivity
disorder to
(ADHD)
Amrix® with
reduced
sedation is better tolerated compared
Flexeril® with a scheduled drug such as
methylphenidate requires the development of a modified-release dosage form to avoid dispensing the drug during the school
Metadate CD®, a capsule formulation containing 30% of the dose as IR for rapid onset of action upon dosing at breakfast and
• Stimulant
of school-going
children
with attention-deficit/hyperactivity
disorder
(ADHD)
with ®a, scheduled
drug such
as
remaining
70% of therapy
the dose
for continued
action
until bedtime, is compared
with
Concerta
an expensive
osmotic
device that
methylphenidate
requires
the
development
of
a
modified-release
dosage
form
to
avoid
dispensing
the
drug
during
the
school
hours.
®
12,13
the OROS technology,
in Fig. 3 .
®
Metadate CD , a capsule formulation containing 30% of the dose as IR for rapid onset of action upon dosing at breakfast and the
remaining 70% of the dose for continued action until bedtime, is compared with Concerta®, an expensive osmotic device that uses
the OROS® technology, in Fig. 312,13.
Fig. 3: Plasma Profiles of Metadate CD® compared to expensive Concerta®
4.0
3.0
Concentration (ng/mL)
Concentration (ng/mL)
4.0
3.0
18 mg Concerta®
2.0
2.0
1.0
1.0
0.0
0.0
18 mg Concerta®
25 mg Metadate
25 mg Metadate
0
0
4
4
8
12
8
Time (hours)12
16
20
16
24
20
24
Time (hours)
– Metadate CD® containing a scheduled CNS stimulant was initially developed to avoid
medication of children with ADHD during school hours as it allows medicating just
once daily at breakfast
– The extended-release capsules comprise 30% of the dose as immediate-release (IR) beads
for rapid onset of action and 70% of the dose as extended-release (ER) beads for extended
effect during the day until bedtime
• InnoPran XL®, a chronotherapeutic dosage form designed to be dosed at bedtime, provides therapeutically effective concentrations in
the morning hours to prevent or minimize target organ damage from morning cardiovascular events (Fig. 4)14,15.
• InnoPran XL®, a chronotherapeutic dosage form designed to be dosed at bedtime, provides therapeutically effective concentra
3
the morning hours to prevent or minimize target organ damage from morning cardiovascular events (Fig. 4)14,15.
Concentration (ng/mL)
200
Fig. 4: Plasma Profiles of InnoPran XL vs. Inderal LA
150
Fig. 4: Plasma Profiles of InnoPran XL vs. Inderal LA
100
Fig. 4:200Plasma Profiles of InnoPran XL vs. Inderal LA
0
150
10:00 12:00
PM 100AM
250
200
200
Concentration (ng/mL)
Concentration
Concentration
(ng/mL)
(ng/mL)
50
Concentration (ng/mL)
250
250
Fig. 4:
Plasma Profiles of InnoPran XL vs. Inderal
LA
250
InnoPran XL®
200
150
150
150
100
100
100
2:00
AM
4:00
AM
6:00
AM
8:00
AM
10:00
AM
12:00
PM
2:00
PM
4:00
PM
6:00
PM
0
PM
12:00
AM
2:00
AM
® 10:00 12:00 2:00
4:00 6:00 8:00
®
InnoPran
XL
®
InnoPran
XL4:00
AM
6:00
PM
AM
PM
PMXLPM
InnoPran
AM
AM
me catecholamine levels
Clock Time (hr)
50
50
0
10:00
PM
XL®
Clock TimeInnoPran
(hr)
50
• Chronot
10:00
50
8:00
PM
cifically
designed to coincide with
8:00 10:00
PM
PM
• Ad
4:00 6:00 8:00 10:00 12:00 2:00 4:00
6:00 8:00 10:00
AM
AM
AM
AM
PM
PM
PM
PM
PM
PM
4
hour
delayed
release
to
achieve
C 6:00
incifically
the
early
morning
hours with
•
10:00
12:00
2:00
4:00
6:00
8:00
10:00
12:00
2:00 4:00
8:00
•
designed
to coincide
10:00 12:00 Chronot
2:00
4:00 Clock6:00
4:00max 6:00
8:00 10:00
10:00
Time (hr)8:00 10:00 12:00 2:00
PM
AM
AM
AM
AM
AM
AM
PM
PM
PM
PM
PM
PM
PM
AM
AM catecholamine
AM
AM
AM levels
PM
PM
PM thePMnight
PM when
PM less is needed
during
• AM me
®.
Clock
Time
(hr)
• Ad bioavailability
• Chronot • Superior
to
Inderal
LA
cifically
designed
to
coincide
with
Clock Time (hr)
10:00
00PM
12:00
AM
2:00
AM
delayed release to achieve Cmax in the early morning hours
• 4 hourlevels
me catecholamine
– Chronotherapeutic
release formulation specifically
coincide
• Ad
duringdesigned
the nightto
when
less is needed
•
•
Chronot
cifically
with
daytime
catecholamine
levels
• Chronot
release to bioavailability
achieve Cmax in the
early morning
• 4 hour delayed
cifically designed
designed to
to coincide
coincide with
with
• Superior
to Inderal
LA®. hours
• –Administration
at
bedtime
during
the night when less is needed
me
catecholamine
levels
me bioavailability
catecholamine
levels
• –4
hour
delayed release
to achieve
Superior
to Inderal
LA®. Cmax in the early morning hours
Ad
•
• Ad plasma concentration during the night when less is needed
–Lower
serotoninreceptor
antagonist,
is to
freely
soluble
<C pHin3.0
and is morning
practically insoluble > pH 6.0,
delayed
to
•
–Superior
Inderal
LA®
4 hour
hourbioavailability
delayed release
release
to achieve
achieve
Cmax in the
the early
early morning hours
hours
•4
• Ondansetron, a
max
to develop once-daily (q.d.) •
formulations. By creating an acidic
pH
microenvironment
within the polymer-coa
during
the
night
less
needed
during
the3.0
night
when
less is
isinsoluble
needed
•
• Ondansetron, a serotonin receptor antagonist, is freely soluble < pH
and when
is practically
> pH 6.0, thereby m
®
®..
drug
prior to
todevelop
its
release
into •
the
hostile
pH soluble
environment,
the
formulation
has> demonstrated
its suitability
for a
Superior
bioavailability
LA
• Ondansetron,
a serotonin
receptor
antagonist,
is freely
< pHto
3.0Inderal
and
is practically
insoluble
pH 6.0,within
thereby
making
it difficult bead
•
Superior
bioavailability
to
Inderal
LA
once-daily
(q.d.)
formulations.
By creating
an
acidic
pH
microenvironment
the
polymer-coated
8,16,17
to develop
(q.d.)
pH microenvironment
within has
the polymer-coated
to solubilize
.once-daily
(Fig.
5) drug
pHacidic
environment,
the formulation
demonstrated bead
its suitability
for the
a q.d. dosin
prior to
its formulations.
release into By
thecreating
hostile an
drug prior(Fig.
to its 5)
release
8,16,17. into the hostile pH environment, the formulation has demonstrated its suitability for a q.d. dosing regimen
(Fig. 5)8,16,17.
20
Concentration (ng/mL)
30
25
40
40
35
Concentration (ng/mL)
Concentration (ng/mL)
•
Ondansetron, aa serotonin
receptor
antagonist,
is
soluble
<
3.0
and
practically
insoluble
> pH
6.0,
ther
• Ondansetron,
serotonin
receptor
antagonist,
isoffreely
freely
soluble QD
< pH
pH
3.0
andvs.is
isvs.
practically
6.0, BID
ther
Fig.
5: Plasma
Profiles
Ondansetron
(EUR-1025)
Reference
(Zofran®
Dosed
®(Zofran®
Fig.
5:
Profiles
of
Ondansetron
(EUR-1025)
Reference
IR) Dosed
BID
Fig.
5: Plasma
Profiles
ofPlasma
Ondansetron
QD
(EUR-1025)
vs.
Reference
(Zofran
IR) insoluble
Dosed
BID>IR)pH
Fig. 5: Plasma
Profiles
of Ondansetron
QD
(EUR-1025)
vs. QD
Reference
(Zofran®
IR)
Dosed BID
to
to develop
develop once-daily
once-daily (q.d.)
(q.d.) formulations.
formulations. By
By creating
creating an
an acidic
acidic pH
pH microenvironment
microenvironment within
within the
the polymer-coated
polymer-coated
drug
drug prior
prior to
to its
its release
release into
into the
the hostile
hostile pH
pH environment,
environment, the
the formulation
formulation has
has demonstrated
demonstrated its
its suitability
suitability for
for aa q.d
q.d
45
8,16,17
45
8,16,17
.
(Fig.
5)
(Fig. 5)
.
45
40
TEST 1
35
30
Ondansetron TEST
QD 1
Ondansetron QD
TEST
Test Formulations
TEST 21
Ondansetron
QD
Test
Formulations
EUR-1025 provides
Ratios)
TEST
TEST 32
REFERENCE
Zofran® IR, BID
consistent therapy
Test
Formulations
Ratios)
REFERENCE
Zofran
TEST
3® IR, BID by eli
Ratios)
REFERENCE
Zofran® IR, BIDtrough in PK curve
(hours ~5–10)
of
bbetween dosesthe
IR Zofran
t
TEST 2
35
TEST 3
30
25
20Profiles of Ondansetron QD (EUR-1025) vs. Reference
Fig.
25
Fig.155:
5: Plasma
Plasma
Profiles of Ondansetron QD (EUR-1025) vs. Reference
10
5
0
0
45
450
Concentration
Concentration(ng/mL)
(ng/mL)
40
40
35
35
20
15
5
10
15
10
5
10
15
20
Time (hours)
0
0
5
0
5
25
10
15
0
0
5
10
he
30
15
35
20
Time (hours)
of
bbetween dosesthe
IR Zofran
t
40
25
30
35
40
TEST
TEST 1
1 Ondansetron QD
TEST 2
2 Ondansetron QD
TEST
Formulations
20
25 Test
35
Test 30
Formulations
TEST
TEST 3
3
Time (hours)
Ratios)
® Ratios)
REFERENCE
Zofran
REFERENCE
Zofran® IR,
IR, BID
BID
EUR-1025 provides
consistent
therapy provides
EUR-1025
by eli
consistent
therapy
(Zofran®
IR)
Dosed
BID
trough in PK
curve
(Zofran®
IR)
Dosed
BID
by
eli
(hours ~5–10)
dosesthe
ofin PK curve
bbetweentrough
IR Zofran
t
(hours ~5–10)
40
EUR-1025
EUR-1025 provides
provides
consistent
therapy
consistent
therapy
0
25
he
25
by
eli
– EUR-1025 achieved similar plasma concentration at 24 hours post dosing
by eli
20
trough
20
v. BID dosing of IR product • N = 12 healthy subjects
trough in
in PK
PK curve
curve
(hours
15
(hours ~5–10)
~5–10)
15
doses
of
b
he
• Maximizing the surface area
and optimizing the drug load and polymer-coating
composition while maintaining the drug
in the amorphous
between
dosesthe
of
bbetween
the
10
10
IR
Zofran
t
IR Zofran
state dramatically shifts the poorly soluble drug’s solubility/absorption kinetics, enabling the development of q.d. dosage
of poorly
t forms
30
30
5
5
soluble drugs (e.g., nifedipine)7.
• Maximizing the
surface area and optimizing the drug load and polymer-coating composition while maintaining the drug in
0
0
0
10
15
20
25
30
35
40
state dramatically
kinetics,
enabling
the development of q.d. dosage fo
0 shifts 5
5the poorly
10 soluble
15 drug’s
20 solubility/absorption
25
30
35
40
Time
(hours)
Time (hours)
soluble drugs (e.g., nifedipine)7.
0
0
4
• Maximizing the surface area and optimizing the drug load and polymer-coating composition while maintaining t
• EUR-1057, an atypical antipsychotic agent, is extremely soluble in the physiological pH range (e.g., > 700 mg/mL), thereby insufficiently
extending drug release/absorption from coated beads under 500 µm to provide patient-compliant, once-daily, orally disintegrating tablet
formulations. By creating an alkaline pH microenvironment at the drug-alkaline buffer interface within the polymer-coated bead, thereby
retarding drug’s solubility/release, Eurand could develop alternate bioequivalent dosage forms – CR capsules and ODT CR (Fig. 6 &
7)8,18.
Fig. 6: Release Profiles for EUR-1057 Once-daily ODT-CR and CR Capsules
% Drug Released
100
80
60
40
ODT - CR1 (Test 1)
ODT - CR2 (Test 2)
20
CR Capsules
0
0
4
8
12
16
20
24
Time (Hrs)
– Patient-friendly once-daily ODT CR also developed to improve patient compliance
– EUR-1057 CR beads are provided with a compressible coating to minimize membrane
fracture during tableting
5
Fig.
Profiles
forfor
EUR-1057
QD,
5050
mg
vs.
25
mg
Syrup
Fig.
7:Plasma
Plasma
Profiles
EUR-1057
QD,
50
mg
vs.
25
mg
Syrup
Fig.
7:7:Plasma
Profiles
EUR-1057
QD,
mg
vs.
25
mg
Syrup
Plasma
Concentration(ng/mL)
(ng/mL)
Plasma
Concentration
20
20
Ref.: Ref.:
Syrup,
25 mg25 mg
Syrup,
Test 1:
ODT
CR1 - CR1
Test
1: -ODT
Test 2: ODT - CR2
Test 2: ODT - CR2
Test 3: CR Capsules
16
16
Test 3: CR Capsules
12
12
8
8
4
4
0
00
0
•
4
8
4
12
8 Time (hour)12
16
20
16
24
20
24
Time (hour)
ndly once-daily ODT-CR1 and CR capsules are bioequivalent
••Patient-friendly
Cmax of 50 mgndly
ODT-CR1
and CRODT-CR1
capsules
comparable
thatare
of 25
mg
once-daily
andand
CR capsules
bioequivalent
–
once-daily
ODT-CR1
CRtocapsules
areSyrup
bioequivalent
•
C
of
50
mg
ODT-CR1
and
CR
capsules
comparable
to
that
of
25
–Cmaxmaxof 50 mg ODT-CR1 and CR capsules comparable to thatmg
ofSyrup
25 mg Syrup
• For a CR ODT, the most critical parameter is being able to develop a product with reproducible dissolution profiles. Coated beads are
typically rigid and encounter breakage issues upon compression into ODTs. The Diffucaps® beads are coated with a compressible
• For
a CR to
ODT,
the most critical
parameter
is being
abletabletting
to develop
product with reproducible dissolution profiles. Coated beads are
coating
eliminate/minimize
membrane
fracture
during
(Fig.a7).
typically rigid and encounter breakage issues upon compression into ODTs. The Diffucaps® beads are coated with a compressible
coating to eliminate/minimize membrane fracture during tabletting (Fig. 7).
Conclusion
• Combining one or more Diffucaps® bead populations into CR dosage forms provides therapeutically effective plasma concentration
Conclusion
profiles suitable for q.d. dosing regimens.
• Combining one or more Diffucaps® bead populations into CR dosage forms provides therapeutically effective plasma concentration
profiles suitable for q.d. dosing regimens.
RE FE RE N CE S:
1. Davis SS, Hardy JG, Fara JW. Transit of pharmaceutical dosage forms through the small intestine. Gut. 1986 Aug; 27(8): 886–92.
2. FE
Chawla
et al.S:Gastroretention: A means to address regional variability in intestinal drug absorption. Pharm Technol. 2003; July: 50–68.
RE
RE G,
N CE
Schiller
et al. JG,
Intestinal
fluidTransit
volumes
transit of dosage
as assessed
by magnetic
resonance
imaging.
Pharmacol
1.3.Davis
SS,C,Hardy
Fara JW.
of and
pharmaceutical
dosage
forms through
the small
intestine.
Gut.Aliment
1986 Aug;
27(8): Ther.
886–92.
2005; 22: 971–979.
2. Chawla G, et al. Gastroretention: A means to address regional variability in intestinal drug absorption. Pharm Technol. 2003; July: 50–68.
4. Gupta PK, Robinson JR. Oral controlled release delivery, In: Kydonieus A (ed). Treatise on controlled drug delivery. Marcel Dekker, Inc.
3. Schiller
C, et1992;
al. Intestinal
New York;
255–313. fluid volumes and transit of dosage as assessed by magnetic resonance imaging. Aliment Pharmacol Ther.
2005; 22: 971–979.
5. Venkatesh G. Diffucaps technology for controlled release drug delivery. In: Youan BC (ed). Chronotherapeutics: Science and Technology
4. Gupta
PK, Robinson
Oral Therapy
controlled
delivery,
In: Kydonieus
(ed).Wiley
Treatise
on controlled
drug delivery. Marcel Dekker, Inc.
for Biological
RhythmJR.
Guided
andrelease
Prevention
of Diseases.
New York:AJohn
& Sons;
2009: 122–142.
New
York;
1992;
255–313.
6. Ventakesh GM. Drug delivery systems comprising weakly basic drugs and organic acids. United States Patent 20070190145, August 23,
2007.
5. Venkatesh
G. Diffucaps technology for controlled release drug delivery. In: Youan BC (ed). Chronotherapeutics: Science and Technology
Biological
Therapy
of Diseases.
Newsolid
York:solutions
John Wiley
& Sons;
2009:
122–142.
7.for
Ventakesh
G,Rhythm
Boltri L, Guided
Colombo
I, et al. and
DrugPrevention
delivery systems
comprising
of weakly
basic
drugs.
United States Patent
20080069878.
2008. systems comprising weakly basic drugs and organic acids. United States Patent 20070190145, August 23,
6. Ventakesh
GM.March
Drug 20,
delivery
8.2007.
Ventakesh GM, Stevens PJ, Lai JW. Compositions comprising melperone. United States Patent 20100151021. June 17, 2010.
VentakeshG,
G, Boltri
Clevenger
JM. Modified
forms
of skeletal
muscle relaxants.
Unitedof
States
Patent
7, 387,793,
US 7,544,372,
7.9.Ventakesh
L, Colombo
I, et release
al. Drugdosage
delivery
systems
comprising
solid solutions
weakly
basic
drugs. United
States Patent
US
7,790,199.
20080069878. March 20, 2008.
8. Ventakesh GM, Stevens PJ, Lai JW. Compositions comprising melperone. United States Patent 20100151021. June 17, 2010.
9. Ventakesh G, Clevenger JM. Modified release dosage forms of skeletal
muscle relaxants. United States Patent 7, 387,793, US 7,544,372,
6
US 7,790,199.
10. Darwish M, Chang S, Hellriegel ET. A pharmacokinetic comparison of single doses of once-daily cyclobenzaprine extended-release 15
mg and 30 mg: a randomized, double-blind, two-period crossover study in healthy volunteers. Clin Ther. 2009; 31(1): 108–14.
11. Malanga GA, et al. Cyclobenzaprine ER for muscle spasm associated with low back and neck pain: two randomized, double-blind,
placebo-controlled studies of identical design. Curr Med Res Opin. 2009; 28: 1179–1196.
12. Battman MJ, Percel PJ, Hensley DL, Vishnupad KS, Ventakesh GM. Methylphenidate modified release formulations. US 6,344,215.
13. Swanson JM. A comparison of once-daily extended-release methylphenidate formulations in children with attention-deficit/hyperactivity
disorder in the laboratory school (the Comacs Study). 2004; 113 (3part 1): e206–216.
14. Percel PJ, Vishnupad KS, Ventakesh GM. Timed sustained release systems for propranolol. US 6,500,454.
15. Sica D, Frishman WH, Manowitz N. Pharmacokinetics of propranolol after single and multiple dosing with sustained release propranolol
or propranolol CR (innopran XL), a new chronotherapeutic formulation. Heart Dis. 2003 May–Jun; 5(3): 176–81.
16. Ventakesh G, Lai J, Vyas NH, Purohit V. Drug delivery systems comprising weakly basic drugs and organic acids. United States patent
20090232885. September 17, 2009.
17. Ventakesh G, Perrett S, Thieroff-Eherdt R. Methods of treating PDNV and PONV with extended release ondansetron compositions.
United States Patent Application Ser. No. 12/688,493 filed on July 6, 2010.
18. Ventakesh GM, Stevens PJ, Lai JW. Compositions comprising melperone. United States Patent 20100151021. June 17, 2010.
7