U.S. patent application number 12/590195 was filed with the patent office on 2010-10-14 for oral pharmaceutical dosage forms.
Invention is credited to Michael H. Arenberg, Jan J. Scicinski, Jaymin Shah, Huey-Ching Su, William W. van Osdol.
Application Number | 20100260844 12/590195 |
Document ID | / |
Family ID | 42934577 |
Filed Date | 2010-10-14 |
United States Patent
Application |
20100260844 |
Kind Code |
A1 |
Scicinski; Jan J. ; et
al. |
October 14, 2010 |
Oral pharmaceutical dosage forms
Abstract
Controlled release oral dosage forms suitable for administration
of methylphenidate are provided. Abuse-resistant controlled release
oral dosage forms suitable for administration of methylphenidate
are also provided. Methods of treating ADD and ADHD using the oral
dosage forms are also provided.
Inventors: |
Scicinski; Jan J.;
(Sunnyvale, CA) ; van Osdol; William W.; (Mountain
View, CA) ; Su; Huey-Ching; (San Jose, CA) ;
Arenberg; Michael H.; (Campbell, CA) ; Shah;
Jaymin; (Sunnyvale, CA) |
Correspondence
Address: |
DURECT CORPORATION;THOMAS P. MCCRACKEN
2 RESULTS WAY
CUPERTINO
CA
95014
US
|
Family ID: |
42934577 |
Appl. No.: |
12/590195 |
Filed: |
November 3, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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61198244 |
Nov 3, 2008 |
|
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61201015 |
Dec 5, 2008 |
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Current U.S.
Class: |
424/484 ;
514/317 |
Current CPC
Class: |
A61K 9/1617 20130101;
A61K 9/5084 20130101; A61K 31/4458 20130101; A61K 9/1623 20130101;
A61K 9/4858 20130101; A61P 25/00 20180101; A61K 9/0053 20130101;
A61K 9/4808 20130101 |
Class at
Publication: |
424/484 ;
514/317 |
International
Class: |
A61K 31/445 20060101
A61K031/445; A61K 9/00 20060101 A61K009/00; A61P 25/00 20060101
A61P025/00 |
Claims
1. An oral controlled release dosage form comprising
methylphenidate and a controlled release carrier system, wherein
said dosage form is characterized by providing: (i) an initial
increasing in vivo rate of release of methylphenidate from the
controlled release system suitable to provide an initial
increasing-rate phase of less than or equal to about 2 hours, and
sufficient to provide a therapeutically effective amount of
methylphenidate for a rapid onset of action; (ii) a second,
non-ascending in vivo rate of release of methylphenidate from the
controlled release system that provides a subsequent non-ascending
phase sufficient to provide a therapeutically effective amount of
methylphenidate through at least about 11 to 12 hours post
administration; and (iii) a single T.sub.max of about 5.5 to 7.5
hours post administration.
2. The controlled release oral dosage form of claim 1, wherein the
initial increasing-rate phase is sufficient to provide an onset of
action within about 1 to 1.5 hours post administration.
3. The controlled release oral dosage form of claim 1, wherein the
single T.sub.max occurs at about 6 to 7 hours post
administration.
4. The controlled release oral dosage form of claim 1, wherein the
subsequent non-ascending phase is sufficient to provide a
therapeutically effective amount of methylphenidate through at
least about 12 to 14 hours post administration
5. The controlled release oral dosage form of claim 1, wherein the
dosage form is further characterized by having a food effect.
6. The controlled release oral dosage form of claim 5, wherein the
oral bioavailability of the methylphenidate from the dosage form is
increased upon co-administration with food.
7. The controlled release oral dosage form of claim 6, wherein the
rate of absorption of methylphenidate is decreased and the extent
of absorption of methylphenidate is increased upon
co-administration with food.
8. The controlled release oral dosage form of claim 1, wherein the
controlled release (CR) carrier system is selected from an Osmotic
CR carrier system, a Liquid CR carrier system, a Particulate CR
carrier system, a CR Matrix carrier system, or a CR Melt-Extrusion
Matrix carrier system.
9. The controlled release oral dosage form of claim 1, wherein the
dosage form is abuse-resistant.
10. The abuse-resistant controlled release oral dosage form of
claim 9, wherein the controlled release carrier system provides a
decreased risk of misuse or abuse.
11. The abuse-resistant controlled release oral dosage form of
claim 10, wherein said decreased risk of misuse or abuse is
characterized by a low in vitro solvent extractability value of the
methylphenidate from the dosage form.
12. The abuse-resistant controlled release oral dosage form of
claim 10, wherein said decreased risk of misuse or abuse is
characterized by the absence of any significant effect on
absorption of the methylphenidate from the dosage form upon
co-ingestion of the dosage form and alcohol by a subject.
13. The abuse-resistant controlled release oral dosage form of
claim 10, wherein said decreased risk of misuse or abuse is
characterized by a low injectability potential.
14. The abuse-resistant controlled release oral dosage form of
claim 9, wherein said dosage form is not susceptible to common
forms of abuse comprising injection, inhalation (crushing and
sniffing) and volatilization (smoking).
15. The abuse-resistant controlled release oral dosage form of
claim 9, wherein the controlled release carrier system comprises a
high viscosity liquid carrier material (HVLCM).
16. The controlled release oral dosage form of claim 1, wherein the
initial increasing-rate phase and subsequent non-ascending phase
are sufficient to provide the methylphenidate in vivo PK profile
depicted in FIG. 7 when the dosage form is administered to a
subject.
17. A method of treating Attention Deficit Disorder (ADD) or
Attention Deficit Hyperactivity Disorder (ADHD) in a subject, said
method comprising administering the controlled release oral dosage
form of claim 1 to the subject on a once-day (QD) basis.
18. An abuse-resistant oral controlled release dosage form
comprising methylphenidate and a controlled release carrier system,
wherein said dosage form is characterized by providing: (i) an
initial increasing in vivo rate of release of methylphenidate from
the controlled release system suitable to provide an initial
increasing-rate phase of less than or equal to about 2 hours, and
sufficient to provide a therapeutically effective amount of
methylphenidate for a rapid onset of action; (ii) a second,
non-ascending in vivo rate of release of methylphenidate from the
controlled release system that provides a subsequent non-ascending
phase sufficient to provide a therapeutically effective amount of
methylphenidate through at least about 11 to 12 hours post
administration; and (iii) a single T.sub.max of about 5.5 to 7.5
hours post administration, and further wherein said controlled
release carrier system comprises an HVLCM, a network former, and at
least one viscosity enhancing agent.
19. The abuse-resistant controlled release oral dosage form of
claim 18, wherein the initial increasing-rate phase is sufficient
to provide an onset of action within about 1 to 1.5 hours post
administration.
20. The abuse-resistant controlled release oral dosage form of
claim 18, wherein the single T.sub.max occurs at about 6 to 7 hours
post administration.
21. The abuse-resistant controlled release oral dosage form of
claim 18, wherein the subsequent non-ascending phase is sufficient
to provide a therapeutically effective amount of methylphenidate
through at least about 12 to 14 hours post administration
22. The abuse-resistant controlled release oral dosage form of
claim 18, wherein the dosage form is further characterized by
having a food effect.
23. The abuse-resistant controlled release oral dosage form of
claim 22, wherein the oral bioavailability of the methylphenidate
from the dosage form is increased upon co-administration with
food.
24. The abuse-resistant controlled release oral dosage form of
claim 22, wherein the rate of absorption of methylphenidate is
decreased and the extent of absorption of methylphenidate is
increased upon co-administration with food.
25. The abuse-resistant controlled release oral dosage form of
claim 18, wherein the viscosity enhancing agent is a synthetic
polymer.
26. The abuse-resistant controlled release oral dosage form of
claim 25, wherein the synthetic polymer is a cellulose
derivative.
27. The abuse-resistant controlled release oral dosage form of
claim 18, wherein the controlled release carrier system further
comprises a surfactant.
28. The abuse-resistant controlled release oral dosage form of
claim 18, wherein the controlled release carrier system further
comprises a plurality of hydrophilic excipients.
29. The abuse-resistant controlled release oral dosage form of
claim 18, wherein the controlled release carrier system further
comprises a second viscosity enhancing agent.
30. The abuse-resistant controlled release oral dosage form of
claim 29, wherein the second viscosity enhancing agent comprises a
stiffening agent.
31. The abuse-resistant controlled release oral dosage form of
claim 30, wherein the second viscosity enhancing agent comprises a
SiO.sub.2.
32. The abuse-resistant controlled release oral dosage form of
claim 18, wherein the controlled release carrier system further
comprises a plurality of solvents.
33. The abuse-resistant controlled release dosage form of claim 32,
wherein the solvents comprise a hydrophobic solvent and a
hydrophilic solvent.
34. The abuse-resistant controlled release oral dosage form of
claim 18, wherein the controlled release carrier system provides a
decreased risk of misuse or abuse.
35. The abuse-resistant controlled release oral dosage form of
claim 34, wherein said decreased risk of misuse or abuse is
characterized by a low in vitro solvent extractability value of the
methylphenidate from the dosage form.
36. The abuse-resistant controlled release oral dosage form of
claim 34, wherein said decreased risk of misuse or abuse is
characterized by the absence of any significant effect on
absorption of the methylphenidate from the dosage form upon
co-ingestion of the dosage form and alcohol by a subject.
37. The abuse-resistant controlled release oral dosage form of
claim 34, wherein said decreased risk of misuse or abuse is
characterized by a low injectability potential.
38. The abuse-resistant controlled release oral dosage form of
claim 34, wherein said dosage form is not susceptible to common
forms of abuse comprising injection, inhalation (crushing and
sniffing) and volatilization (smoking).
39. The abuse-resistant controlled release oral dosage form of
claim 18, wherein the initial increasing-rate phase and subsequent
non-ascending phase are sufficient to provide the methylphenidate
in vivo PK profile depicted in FIG. 7 when the dosage form is
administered to a subject.
40. A method of treating Attention Deficit Disorder (ADD) or
Attention Deficit Hyperactivity Disorder (ADHD) in a subject, said
method comprising administering the abuse-resistant controlled
release oral dosage form of claim 18 to the subject on a once-day
(QD) basis.
41. An abuse-resistant oral controlled release dosage form
comprising methylphenidate and a controlled release carrier system,
wherein said dosage form is characterized by providing: (i) an
initial increasing in vivo rate of release of methylphenidate from
the controlled release system suitable to provide an initial
increasing-rate phase of less than or equal to about 2 hours, and
sufficient to provide a therapeutically effective amount of
methylphenidate for a rapid onset of action; (ii) a second,
non-ascending in vivo rate of release of methylphenidate from the
controlled release system that provides a subsequent non-ascending
phase sufficient to provide a therapeutically effective amount of
methylphenidate through at least about 11 to 12 hours post
administration; and (iii) a single T.sub.max of about 5.5 to 7.5
hours post administration, and further wherein said controlled
release carrier system comprises an HVLCM, a network former, a
rheology modifier and a hydrophilic agent.
42. The abuse-resistant oral controlled release dosage form of
claim 41, wherein the controlled release carrier system further
comprises a viscosity enhancing agent.
43. The abuse-resistant oral controlled release dosage form of
claim 42, wherein the hydrophilic agent also serves as a second
viscosity enhancing agent.
44. The abuse-resistant oral controlled release dosage form of
claim 41, wherein the hydrophilic agent is hydroxyethyl cellulose
(HEC).
45. The abuse-resistant oral controlled release dosage form of
claim 41, wherein the HVLCM is sucrose acetate isobutyrate
(SAIB).
46. The abuse-resistant oral controlled release dosage form of
claim 41 further comprising a solvent.
47. The abuse-resistant oral controlled release dosage form of
claim 46, wherein the solvent is triacetin.
48. The abuse-resistant oral controlled release dosage form of
claim 42, wherein the viscosity enhancing agent is a silicon
dioxide.
49. The abuse-resistant oral controlled release dosage form of
claim 41, wherein the network former is cellulose acetate butyrate
(CAB).
50. The abuse-resistant oral controlled release dosage form of
claim 41, wherein the rheology modifier is isopropyl myristate
(IPM).
51. The abuse-resistant controlled release oral dosage form of
claim 41, wherein the controlled release carrier system provides a
decreased risk of misuse or abuse.
52. The abuse-resistant controlled release oral dosage form of
claim 51, wherein said decreased risk of misuse or abuse is
characterized by a low in vitro solvent extractability value of the
methylphenidate from the dosage form.
53. The abuse-resistant controlled release oral dosage form of
claim 51, wherein said decreased risk of misuse or abuse is
characterized by the absence of any significant effect on
absorption of the methylphenidate from the dosage form upon
co-ingestion of the dosage form and alcohol by a subject.
54. The abuse-resistant controlled release oral dosage form of
claim 51, wherein said decreased risk of misuse or abuse is
characterized by a low injectability potential.
55. The abuse-resistant controlled release oral dosage form of
claim 51, wherein said dosage form is not susceptible to common
forms of abuse comprising injection, inhalation (crushing and
sniffing) and volatilization (smoking).
56. The abuse-resistant controlled release oral dosage form of
claim 41, wherein the initial increasing-rate phase and subsequent
non-ascending phase are sufficient to provide the methylphenidate
in vivo PK profile depicted in FIG. 7 when the dosage form is
administered to a subject.
57. A method of treating Attention Deficit Disorder (ADD) or
Attention Deficit Hyperactivity Disorder (ADHD) in a subject, said
method comprising administering the abuse-resistant controlled
release oral dosage form of claim 41 to the subject on a once-day
(QD) basis.
Description
CROSS REFERENCE TO RELEVANT APPLICATIONS
[0001] This application claims the priority entitlement and full
benefit of U.S. Provisional Application Nos. 61/198,244, filed 3
Nov. 2008, and 61/201,015, filed 5 Dec. 2008, pursuant to 35 U.S.C.
.sctn.119(e).
FIELD OF THE INVENTION
[0002] The invention relates to oral pharmaceutical dosage forms
and the use thereof. More specifically, this invention relates to
controlled release oral pharmaceutical dosage forms and their use
to deliver methylphenidate.
BACKGROUND
[0003] Formulation of drugs for delivery, particularly oral
delivery, poses certain challenges. One challenge is to produce an
oral controlled-release dosage form that provides for a relatively
steady dose of drug over the approximately eight hours during which
the dosage form passes through the gastrointestinal tract.
Sustained release is often achieved by providing the tablet with a
coating that delays release, or by formulating the tablet in such a
way that it disintegrates relatively slowly, releasing drug as it
does so. A tablet, however, once ingested, is subject to
considerable mechanical and chemical stresses as it passes through
the esophagus, stomach, duodenum, jejunum, ileum, large intestine
and colon, thus providing a significant challenge in maintaining
controlled release of the drug formulation. Acids, enzymes and
peristalsis can cause the tablet to break apart, resulting in
exposure of the inside of the tablet and an increase in surface
area of the tablet material. This will tend to increase the
delivery rate of the drug or otherwise adversely affect the
controlled release properties of the dosage form.
[0004] Another challenge is to produce a dosage form, including an
oral dosage form, that reduces the potential for drug abuse. In
particular, opioids, CNS-depressants, and stimulants are commonly
abused. According to a 1999 study by the National Institute on Drug
Abuse (NIDA), an estimated 4 million people, about 2 percent of the
population age 12 and older, were (at the time of the study) using
prescription drugs "non-medically."
[0005] While many prescription drugs can be abused, the most common
classes of abused drugs are: (1) Opioids--often prescribed to treat
pain, (2) CNS Depressants--used to treat anxiety and sleep
disorders, and (3) Stimulants--prescribed to treat narcolepsy and
attention deficit/hyperactivity disorder.
[0006] Stimulants are a class of drugs that enhance brain
activity--they cause an increase in alertness, attention, and
energy that is accompanied by increases in blood pressure, heart
rate, and respiration. Stimulants are frequently prescribed for
treating narcolepsy, attention-deficit hyperactivity disorder
(ADHD), and depression. Stimulants may also be used for short-term
treatment of obesity, and for patients with asthma. Stimulants such
as dextroamphetamine (Dexedrine.TM.) and methylphenidate
(Ritalin.TM.) have chemical structures that are similar to key
brain neurotransmitters called monoamines, which include
norepinephrine and dopamine. Stimulants increase the levels of
these chemicals in the brain and body. This, in turn, increases
blood pressure and heart rate, constricts blood vessels, increases
blood glucose, and opens up the pathways of the respiratory
system.
[0007] The abuse of stimulants has been a growing problem. Over 1.4
million Americans over 12 years old reported abusing stimulants.
2004 National Survey on Drug Use & Health, SAMHSA, U.S.
Department of HHS. Twenty-nine percent (29%) of all prescribed
stimulants are diverted to someone other than the patient.
Stimulants are typically abused in two distinct ways. In one way,
prescribed drugs are sold or diverted to individuals who ingest the
oral formulations at or around a typical daily dose to promote
wakefulness or to increase performance and concentration at a
specific time, such as when studying for or taking exams.
Stimulants also give rise to euphoria and liking when rapidly
absorbed. Abusers in search of this effect are likely to take a
much large than normal oral dose, or to extract the active agent
(stimulant drug) from the formulation and, after grinding, inhale
the resulting powder. A further mechanism of abuse is the
extraction of the stimulant drug from the rest of the formulation,
dissolution and then injection. 80% of substance abusers use short
acting (i.e., immediate release) formulations for ease of
availability and in extraction of the stimulant drug. While oral
administration of stimulants is the preferred route for abuse,
forty percent (40%) of abusers have taken stimulant drugs by
grinding and then inhaling. Only a small number of abusers inject
stimulant drugs.
[0008] A common and particularly dangerous cocktail of drugs is
produced when stimulants are mixed with antidepressants or
over-the-counter cold medicines containing decongestants.
Anti-depressants may enhance the effects of a stimulant, and
stimulants in combination with decongestants may cause blood
pressure to become dangerously high or lead to irregular heart
rhythms, which in extreme cases may be fatal.
[0009] Solid dosage forms are particularly susceptible to abuse.
For example, tablets for oral drug delivery can be ground down into
a powder. Drug addicts and abusers grind down the tablet in order
to nasally inhale the drug. Addicts also grind the tablet to
extract the drug into alcohol or water to make a concentrated
injectable drug solution. Administration of various abused drugs in
this way produces a sudden high dose of drug into the blood stream
making the user euphoric. These well-known techniques for drug
abuse have been used for many years with all manner of drugs.
[0010] Attention Deficit Disorders are the most common psychiatric
disorders in children with reported rates ranging from 4% to 9%.
Attention Deficit Disorder (ADD) is characterized by inattention
and impulsivity and may be present with hyperactivity (ADHD). Other
characteristics may include aggressiveness, stealing, lying,
truancy, setting fires, running away, explosiveness, cognitive and
learning problems as well as poor social skills. It is four to five
times more frequent in boys than girls.
[0011] Stimulant medication, such as amphetamines, have been shown
to be the most effective agents in the treatment of children with
disorders of activity modulation and attention regulation and
result in significant improvement in 70 to 80 percent of affected
children. Positive effects of stimulants have been documented in a
variety of areas including behavioral, social, perceptual
performance, motor activity, impulse control, attention regulation
and cognitive performance.
[0012] Methylphenidate
{dl-threo-methyl-2-phenyl-2-(2-piperidyl)acetate} is the
psychostimulant used most frequently in the treatment of
hyperactivity and attention deficit disorder. It appears to have a
higher incidence of positive effects and a lower incidence of
adverse effects than other psychostimulants. The efficacy of
methylphenidate ("MPH") in improving attention and behavioral
symptoms has been supported by many studies.
SUMMARY OF THE INVENTION
[0013] Controlled release oral pharmaceutical dosage forms that
include methylphenidate and a controlled release carrier system are
provided. It is thus a primary object of the present invention to
provide a controlled release oral dosage form that includes
methylphenidate and a controlled release carrier system. The dosage
form is characterized by providing:
[0014] (i) an initial increasing in vivo rate of release of
methylphenidate from the controlled release system suitable to
provide an initial increasing-rate phase of less than or equal to
about 2 hours, and sufficient to provide a therapeutically
effective amount of methylphenidate for a rapid onset of
action;
[0015] (ii) a second, non-ascending in vivo rate of release of
methylphenidate from the controlled release system that provides a
subsequent non-ascending phase sufficient to provide a
therapeutically effective amount of methylphenidate through at
least about 11 to 12 hours post administration; and
[0016] (iii) a single T.sub.max of about 5.5 to 7.5 hours post
administration. In related objects of the invention, the
above-described controlled release oral dosage forms are further
characterized as follows: (a) where the initial increasing-rate
phase is sufficient to provide an onset of action within about 1 to
1.5 hours post administration; (b) where the single T.sub.max
occurs at about 6 to 7 hours post administration; and (c) where the
subsequent non-ascending phase is sufficient to provide a
therapeutically effective amount of methylphenidate through at
least about 12 to 14 hours post administration. In further related
objects of the invention, the above-described controlled release
oral dosage forms are further characterized by having a food
effect, such as wherein oral bioavailability of the methylphenidate
form the dosage form is increased upon co-administration with food
and/or wherein the rate of absorption of methylphenidate is
decreased and the extent of absorption of methylphenidate is
increased upon co-administration with food. In the practice of the
invention, the controlled release (CR) carrier system can be
selected from an Osmotic CR carrier system, a Liquid CR carrier
system, a Particulate CR carrier system, a CR Matrix carrier
system, or a CR Melt-Extrusion Matrix carrier system. In addition,
in certain preferred embodiments, the controlled release oral
dosage form is abuse-resistant. In such cases, the abuse-resistant
controlled release oral dosage forms of the invention can be
characterized as follows: (a) the controlled release carrier system
provides a decreased risk of misuse or abuse; (b) the
abuse-resistant controlled release oral dosage provides a decreased
risk of misuse or abuse characterized by a low in vitro solvent
extractability value of the methylphenidate from the dosage form;
(c) the abuse-resistant controlled release oral dosage provides a
decreased risk of misuse or abuse characterized by the absence of
any significant effect on absorption of the active agent from the
dosage form upon co-ingestion of the dosage form and alcohol by a
subject; (d) the abuse-resistant controlled release oral dosage
provides a decreased risk of misuse or abuse characterized by a low
injectability potential; and/or (e) the abuse-resistant controlled
release oral dosage provides a decreased risk of misuse or abuse
characterized by the dosage form is not susceptible to common forms
of abuse comprising injection, inhalation (crushing and sniffing)
and volatilization (smoking). Any of the above-described
abuse-resistant controlled release oral dosage forms can be further
characterized wherein the controlled release carrier system
includes a high viscosity liquid carrier material (HVLCM). The
controlled release oral dosage forms (whether or not
abuse-resistant) provide unique in vivo release kinetics such that
the initial increasing-rate phase and subsequent non-ascending
phase are sufficient to provide the methylphenidate in vivo PK
profile depicted in FIG. 7 when the dosage form is administered to
a subject. It is a further related object of the invention to
provide a method of treating Attention Deficit Disorder (ADD) or
Attention Deficit Hyperactivity Disorder (ADHD) in a subject, where
the method comprises administering the controlled release oral
dosage form of the invention to the subject on a once-day (QD)
basis.
[0017] It is also a primary object of the present invention to
provide an abuse-resistant controlled release oral dosage form that
includes methylphenidate and a controlled release carrier system.
The abuse-resistant dosage form is characterized by providing:
[0018] (i) an initial increasing in vivo rate of release of
methylphenidate from the controlled release system suitable to
provide an initial increasing-rate phase of less than or equal to
about 2 hours, and sufficient to provide a therapeutically
effective amount of methylphenidate for a rapid onset of action;
100191 (ii) a second, non-ascending in vivo rate of release of
methylphenidate from the controlled release system that provides a
subsequent non-ascending phase sufficient to provide a
therapeutically effective amount of methylphenidate through at
least about 11 to 12 hours post administration; and
[0019] (iii) a single T.sub.max of about 5.5 to 7.5 hours post
administration, wherein the controlled release carrier system
includes an HVLCM, a network former and at least one viscosity
enhancing agent. In related objects of the invention, the
above-described abuse-resistant controlled release oral dosage
forms are further characterized as follows: (a) where the initial
increasing-rate phase is sufficient to provide an onset of action
within about 1 to 1.5 hours post administration; (b) where the
single T.sub.max occurs at about 6 to 7 hours post administration;
and (c) where the subsequent non-ascending phase is sufficient to
provide a therapeutically effective amount of methylphenidate
through at least about 12 to 14 hours post administration. It
further related objects of the invention, the above-described
abuse-resistant controlled release oral dosage forms are further
characterized by having a food effect, such as wherein oral
bioavailability of the methylphenidate form the dosage form is
increased upon co-administration with food and/or wherein the rate
of absorption of methylphenidate is decreased and the extent of
absorption of methylphenidate is increased upon co-administration
with food. The abuse-resistant controlled release oral dosage forms
of the invention can be further characterized as follows: (a) the
controlled release carrier system provides a decreased risk of
misuse or abuse; (b) the abuse-resistant controlled release oral
dosage provides a decreased risk of misuse or abuse characterized
by a low in vitro solvent extractability value of the
methylphenidate from the dosage form; (c) the abuse-resistant
controlled release oral dosage provides a decreased risk of misuse
or abuse characterized by the absence of any significant effect on
absorption of the active agent from the dosage form upon
co-ingestion of the dosage form and alcohol by a subject; (d) the
abuse-resistant controlled release oral dosage provides a decreased
risk of misuse or abuse characterized by a low injectability
potential; and/or (e) the abuse-resistant controlled release oral
dosage provides a decreased risk of misuse or abuse characterized
by the dosage form is not susceptible to common forms of abuse
comprising injection, inhalation (crushing and sniffing) and
volatilization (smoking). In each of the above-described related
objects of the invention, the controlled release carrier system can
be further characterized by a unique set of pharmaceutical
excipients including solvents, carrier materials, network formers
and viscosity enhancing agents. The abuse-resistant controlled
release oral dosage forms provide unique in vivo release kinetics
such that the initial increasing-rate phase and subsequent
non-ascending phase are sufficient to provide the methylphenidate
in vivo PK profile depicted in FIG. 7 when the dosage form is
administered to a subject. It is a further related object of the
invention to provide a method of treating Attention Deficit
Disorder (ADD) or Attention Deficit Hyperactivity Disorder (ADHD)
in a subject, where the method comprises administering the
abuse-resistant controlled release oral dosage form of the
invention to the subject on a once-day (QD) basis.
[0020] It is a still further primary object of the present
invention to provide an abuse-resistant controlled release oral
dosage form that includes methylphenidate and a controlled release
carrier system. The abuse-resistant dosage form is characterized by
providing:
[0021] (i) an initial increasing in vivo rate of release of
methylphenidate from the controlled release system suitable to
provide an initial increasing-rate phase of less than or equal to
about 2 hours, and sufficient to provide a therapeutically
effective amount of methylphenidate for a rapid onset of
action;
[0022] (ii) a second, non-ascending in vivo rate of release of
methylphenidate from the controlled release system that provides a
subsequent non-ascending phase sufficient to provide a
therapeutically effective amount of methylphenidate through at
least about 11 to 12 hours post administration; and
[0023] (iii) a single T.sub.max of about 5.5 to 7.5 hours post
administration, wherein the controlled release carrier system
includes an HVLCM, a network former, a rheology modifier and a
hydrophilic agent. In related objects of the invention, the
above-described abuse-resistant controlled release oral dosage
forms are further characterized as follows: (a) where the initial
increasing-rate phase is sufficient to provide an onset of action
within about 1 to 1.5 hours post administration; (b) where the
single T.sub.max occurs at about 6 to 7 hours post administration;
and (c) where the subsequent non-ascending phase is sufficient to
provide a therapeutically effective amount of methylphenidate
through at least about 12 to 14 hours post administration. It other
related objects of the invention, the above-described
abuse-resistant controlled release oral dosage forms are further
characterized by having a food effect, such as wherein oral
bioavailability of the methylphenidate form the dosage form is
increased upon co-administration with food and/or wherein the rate
of absorption of methylphenidate is decreased and the extent of
absorption of methylphenidate is increased upon co-administration
with food. The abuse-resistant controlled release oral dosage forms
of the invention can be further characterized as follows: (a) the
controlled release carrier system provides a decreased risk of
misuse or abuse; (b) the abuse-resistant controlled release oral
dosage provides a decreased risk of misuse or abuse characterized
by a low in vitro solvent extractability value of the
methylphenidate from the dosage form; (c) the abuse-resistant
controlled release oral dosage provides a decreased risk of misuse
or abuse characterized by the absence of any significant effect on
absorption of the active agent from the dosage form upon
co-ingestion of the dosage form and alcohol by a subject; (d) the
abuse-resistant controlled release oral dosage provides a decreased
risk of misuse or abuse characterized by a low injectability
potential; and/or (e) the abuse-resistant controlled release oral
dosage provides a decreased risk of misuse or abuse characterized
by the dosage form is not susceptible to common forms of abuse
comprising injection, inhalation (crushing and sniffing) and
volatilization (smoking). In each of the above-described related
objects of the invention, the controlled release carrier system can
be further characterized by a unique set of pharmaceutical
excipients including solvents, carrier materials, network formers
and viscosity enhancing agents. The abuse-resistant controlled
release oral dosage forms provide unique in vivo release kinetics
such that the initial increasing-rate phase and subsequent
non-ascending phase are sufficient to provide the methylphenidate
in vivo PK profile depicted in FIG. 7 when the dosage form is
administered to a subject. It is a further related object of the
invention to provide a method of treating Attention Deficit
Disorder (ADD) or Attention Deficit Hyperactivity Disorder (ADHD)
in a subject, where the method comprises administering the
abuse-resistant controlled release oral dosage form of the
invention to the subject on a once-day (QD) basis.
[0024] It is an advantage of the present invention that the
controlled release oral dosage forms provide enhanced delivery
kinetics of methylphenidate. It is also an advantage of the present
invention that the abuse-resistant controlled release oral dosage
forms are able to provide enhanced safety features and/or
abuse-resistance properties in addition to enhanced in vivo
pharmacological performance as compared with prior dosage forms. It
is a further advantage of the invention that the inventive dosage
forms can be readily constructed and used to provide a wide range
of safer and more efficacious pharmacological solutions to the
medical field. These and other objects, aspects and advantages of
the present invention will readily occur to the skilled person upon
reading the instant disclosure and specification.
BRIEF DESCRIPTION OF THE FIGURES
[0025] FIG. 1 depicts the chemical structure of the d- and l-threo
isomers of methylphenidate.
[0026] FIG. 2 depicts a comparison of mean pharmacokinetic profiles
of immediate release ("IR") methylphenidate Ritalin SR and a
generic sustained release methylphenidate.
[0027] FIG. 3 depicts a comparison of plasma concentrations
achieved with the Ritalin LA, Metadate CD, Concerta and Ritalin SR
products.
[0028] FIG. 4 show the PK profiles from a 3-way crossover study of
IR methylphenidate TID and Concerta without food (fasted) and after
high-fat breakfast (taken from Swanson et al. (2003) Arch Gen
Psychiatry 60:46-63) and mean plasma methylphenidate concentrations
compared to TID methylphenidate (taken from Concerta label).
[0029] FIG. 5 shows a direct comparison of pharmacokinetics of
methylphenidate released from Concerta (tablet formulation) and
Metadate CD (capsule formulation), and Ritalin LA
[0030] FIG. 6 depicts the PK profile of Focalin XR compared to two
IR doses of Focalin IR.
[0031] FIG. 7 depicts the methylphenidate PK profile provided by
the oral controlled release dosage forms of the present
invention.
[0032] FIG. 8 depicts a comparison of the methylphenidate PK
profile provided by the oral controlled release dosage forms of the
present invention with the PK profiles from Metadate CD and
Concerta products.
[0033] FIG. 9 depicts the dose-normalized results of a
deconvolution analysis of Metadate CD and Concerta used to define a
target input rate for a controlled release oral dosage form
produced in accordance with the present invention.
[0034] FIGS. 10A and 10B depict the results obtained in Example 2b,
where FIG. 10A depicts the cumulative release profiles obtained in
the study and compares them with cumulative release data presented
in the U.S. Pat. No. 6,919,373; and FIG. 10B depicts the cumulative
release in vitro results obtained in the study plotted against
input in vivo obtained via deconvolution (open symbols) for both
Metadate CD and Concerta.
[0035] FIG. 11 depicts how the Weibull model for Metadate CD can be
applied to calculate target cumulative release in vitro from the
target cumulative input in vivo in the practice of the
invention.
[0036] FIG. 12 depicts the target in vitro cumulative release
profile of a controlled release oral dosage form produced in
accordance with the present invention compared against the release
profiles obtained from Metadate CD and Concerta.
[0037] FIG. 13 depicts the chemical structure of sucrose acetate
isobutyrate (SAIB).
[0038] FIG. 14 depicts a flow chart for a GMP manufacturing process
described in Example 1.
[0039] FIG. 15 is a pictorial representation of the modified
dissolution vessel and paddle described in Example 2.
[0040] FIGS. 16A and 16B show the mean dissolution data results
from the in vitro dissolution study of MPH1-MPH3 and MPH11-MPH13
Test Capsules as described in Example 2a.
[0041] FIGS. 17A, 17B and 17C depict the results of Example 2b,
where the in vitro dissolution cumulative release of
methylphenidate from a number of candidate abuse-resistant
methylphenidate oral dosage forms produced according to the
invention are compared to a target in vitro methylphenidate release
profile developed in accordance with the invention.
[0042] FIG. 18 depicts results from Example 3d, where the in vitro
dissolution cumulative release of methylphenidate from a number of
candidate abuse-resistant methylphenidate oral dosage forms
produced according to the invention are compared to a target in
vitro methylphenidate release profile developed in accordance with
the invention.
DETAILED DESCRIPTION
[0043] Before describing the present invention in detail, it is to
be understood that this invention is not limited to particularly
exemplified carrier materials or process parameters as such may, of
course, vary. It is also to be understood that the terminology used
herein is for the purpose of describing particular embodiments of
the invention only, and is not intended to be limiting.
[0044] All publications, patents and patent applications cited
herein, whether supra or infra, are hereby expressly incorporated
by reference in their entirety.
[0045] It must be noted that, as used in this specification and the
appended claims, the singular forms "a," "an" and "the" include
plural referents unless the content clearly dictates otherwise.
Thus, for example, reference to "a non-polymeric carrier material"
includes a mixture of two or more such carrier materials, reference
to "a solvent" includes a mixture of two or more such solvents,
reference to "an excipient" includes mixtures of two or more such
materials, and the like.
[0046] The mechanism of action of methylphenidate in ADD/ADHD is
not fully understood, however the primary effects appear to be
mediated through the blockage of the presynaptic dopamine
transporter. Methylphenidate also exerts a relatively minor effect
on norepinephrine reuptake that also contributes to activity.
Volkow, et al. (1998) Am J Psychiatry 155:1325-1331; Volkow et al.
(1999) Life Sci 65:PL7-12; and Volkow et al. (2002) Synapse
43:181-187. Unlike amphetamine, methylphenidate blockade of the
dopamine receptor is not thought to induce transporter conformation
change resulting in the release of dopamine into the synaptic cleft
as the receptor returns to its former conformation. Markowitz, et
al. (2003) Pharmacotherapy 23:1281-1299. With the exception of
Focalin, of the four possible methylphenidate isomers, a mixture of
the d,l-threo enantiomers is used in all current immediate and
controlled release formulations; the erythro-isomer pair being much
less active. Srinivas et al. (1992) Clin Pharmacol Ther 52:561-568.
The d-threo isomer is the most active of the two threo isomers (a
2:1 potency compared to the d,l-threo-mixture) and is the sole
active constituent in the Focalin brand methylphenidate product.
The chemical structure of the d- and l-threo isomers of
methylphenidate is shown in FIG. 1.
[0047] Oral absorption of methylphenidate is essentially complete
and rapid, wherein the T.sub.max following oral administration of
immediate release methylphenidate has been found to be between 1
and 3 hour (mean 1.5 h). The drug crosses the blood-brain barrier
readily and the systemic half-life of methylphenidate is
approximately 3 hours. Bioavailability is limited and is widely
variable between patients due to extensive first-pass metabolism.
CPS Compendium of Pharmaceuticals and Specialties, 34th ed.;
Gillis, M., Ed. Canadian Pharmacists Association: Ottawa, 1999; pp
1573-4. About 70% of the dose is deesterified to the inactive major
metabolite, ritalinic acid, which is excreted in the urine.
Metabolism of the active d-threo isomer is slower than that of the
inactive l-threo isomer resulting in approximately a 10:1 d-threo
to l-threo plasma concentration ratio. Food may increase absorption
rate but does not affect the extent of absorption. These
pharmacokinetic parameters do not differ greatly between adults and
children. Markowitz et al. (2003) Pharmacotherapy 23:1281-1299.
[0048] Immediate release methylphenidate preparations, because of
their short half-life, require frequent administration at short
intervals to ensure adequate treatment throughout a child's school
day. The rapid onset and offset of immediate release
methylphenidate preparations means that a medicated child with
attention deficit disorder will be maximally affected only for
relatively brief periods during the day. Due to its short
half-life, immediate release MPH is usually given twice per day,
usually once after breakfast and once during the school day, an
event that some children and some school personnel apparently
avoid, resulting in poor compliance with prescribed regimens.
Compliance is a major problem for children who require a midday or
mid-afternoon dose as many schools prohibit children from taking
medications during the school day and others often insist that all
medications be given by a nurse. Poor compliance in taking
medication may explain, in part, the variable and conflicting
results reported in many studies of the effect of medication on
improving the behavior of hyperactive children.
[0049] The rapid clearance of methylphenidate has led to the
development of a number of controlled formulations to overcome the
so-called treatment "bounce" that resulted from large changes in
plasma methylphenidate levels over the course of a day, to increase
patient compliance and reduce the stigma associated with having to
take medication at school. The first extended release formulations
of methylphenidate, Ritalin SR brand and, subsequently, the
Metadate ER and Methylin ER brands, used wax-based release systems
and were not considered to be useful improvements over immediate
release methylphenidate. The poor efficacy of these drugs has been,
in part, attributed to a relatively long onset period of 2-3 hours
(Greydanus, D. E. (2008) Psychopharmacology for ADHD in
Adolescents: Quo Vadis?
http://www.psychiatrictimes.com/p030544.html) that does not allow
for behavioral management in the early morning and insufficient
duration of action (4-6 hours), failing to eliminate the need for
an afternoon dose and, consequently, these products have not been
generally recognized as a true QD dose. A comparison of mean
pharmacokinetic profiles of immediate release ("IR")
methylphenidate, Ritalin SR and a generic sustained release
methylphenidate is depicted in FIG. 2. As can be seen, based on PK
parameters, the Ritalin SR product has a slower onset and shorter
duration than two IR methylphenidate doses. Erratic
pharmacokinetics arising from the wax-based release technology and
limited available dosage strengths (Ritalin SR provided as only 20
mg strength; Metadate ER and Methylin ER: provided only as 10 and
20 mg strengths) seem to have further limited the attractiveness of
the first generation extended release products.
[0050] In addition to these factors, a study suggested that a
flattened plasma concentration curve after establishment of peak
concentration, such as that which could be achieved using the
Ritalin-SR product, was not as efficacious as a rising plasma
concentration profile. Swanson et al. (1999) Clin Pharmacol Ther
66:295-305. The concept of "acute tolerance" was proposed to
rationalize the superior efficacy of the rising plasma
concentration. This concept is discussed in more detail below.
[0051] New, second generation, extended release methylphenidate
formulations have been developed to overcome the above-described
limitations of the first generation products (e.g., Ritalin-SR). In
particular, Concerta (ALZA, US launch 2000), Ritalin LA (Novartis,
US launch 2002) and Metadate CD (UCB, US launch 2001) all have an
earlier onset and longer duration of action than Ritalin-SR. A
comparison of plasma concentrations achieved with the Ritalin LA,
Metadate CD, Concerta and Ritalin SR products (taken from Patrick
et al. (2005) Expert Opin Drug Deliv 2:121-143) is provided in FIG.
3. The Concerta product is based upon an osmotic capsule ("OROS")
controlled release technology and was designed to mimic a TID
dosing regimen with two different release formulations within the
capsule and a drug "overcoat" to provide an immediate release
portion of the total methylphenidate dose. FIG. 4 presents the PK
profiles from a 3-way crossover study of IR methylphenidate TID and
Concerta without food (fasted) and after high-fat breakfast (taken
from Swanson et al. (2003) Arch Gen Psychiatry 60:46-63) and mean
plasma methylphenidate concentrations compared to TID
methylphenidate (taken from Concerta label). As a result, the
initial rate of rise for the Concerta product's plasma profile is
very similar to that seen with an immediate release dose.
Comparison of the pharmacokinetics of Concerta with a TID dose of
immediate release methylphenidate is shown in FIG. 4.
[0052] Both of the Ritalin LA and Metadate CD second-generation
methylphenidate products use microbead technology to deliver an
immediate release dose of methylphenidate followed by a second
delayed dose, mimicking a BID delivery schedule. Ritalin LA uses a
technology ("SODAS") to deliver half the dose immediately followed
by the remainder after an interval of 4 hours. Metadate CD uses a
different technology ("Diffucaps") to deliver thirty percent (30%)
of the methylphenidate dose by immediate release and the remaining
seventy percent (70%) after an interval of 3-4 hours. For Metadate
CD, this dose schedule was determined in a clinical study to give
more consistent results than ratios of, e.g., 20:80 or 40:60, and
to approximate to a biphasic plasma concentration versus time
profile similar to Ritalin BID in healthy adult subjects and in
children with ADHD. Wigal et al. (2003) Journal of Applied Research
3:46-63.
[0053] A methylphenidate delivery rate that results in a
substantially ascending plasma concentration profile has been
proposed as a requirement for superior efficacy against ADHD. This
hypothesis arose from a dose-sipping study carried out to determine
the optimal pharmacokinetic profile for a new methylphenidate
formulation. Swanson et al. (1999) Clin Pharmacol Ther 66:295-305.
The study was carried out by dosing identical capsules containing
different quantities of drug at 30 min intervals. The dosing
schedules were designed to mimic BID, flat and ascending profiles.
For example, a flat profile was achieved by dosing an initial large
drug bolus followed by small doses during the day to maintain a
steady profile. Surprisingly, a dose schedule mimicking an
ascending profile was found to have superior efficacy compared to
the flat profile. These studies showed that an ascending
methylphenidate dosing regimen became as efficacious as the
standard BID dosing regimen by the afternoon, suggesting that a
large morning bolus is not required for significant improvement in
ADHD symptoms. It was speculated that this large morning bolus dose
could potentially give rise to acute tolerance, thereby requiring a
larger dose to maintain efficacy later in the day. Swanson et al.
(1999) Clin Pharmacol Ther 66:295-305. However, a major limitation
of this study was that dosing schedules derived from calculated
plasma concentrations were modeled from published immediate release
methylphenidate data and no pharmacokinetic measurements or actual
comparisons with Ritalin SR were undertaken. Nevertheless, the
results of these studies led to the development of the Concerta
controlled release methylphenidate product (Pelham et al. (2001)
Pediatrics 107:E105; Wolraich et al. (2001) Pediatrics
108:883-892), which since its launch in 2000 has been the most
successful methylphenidate formulation for the treatment of ADHD,
dominating the market.
[0054] The concept of "acute tolerance" was proposed to rationalize
the findings described above. Swanson et al. (1999) Clin Pharmacol
Ther 66:295-305. This hypothesis was supported by previous studies
on the PK and effects of intravenously delivered methylphenidate on
the brain. Volkow et al. (1999) Life Sci 65:PL7-12; Volkow et al.
(1996) Psychopharmacology (Berl) 123:26-33; Volkow et al. (1996)
Proc Natl Acad Sci USA 93:10388-92. In these PET studies, it was
found that uptake of .sup.11C-labeled methylphenidate into the
brain after an IV dose was very fast (T.sub.max<10 min) and was
followed by relatively slow clearance (half life=90 min). The rapid
onset of methylphenidate into the brain resulted in feelings of
euphoria, however these faded rapidly while there were still
appreciable methylphenidate brain levels and receptor occupancy. In
contrast, when methylphenidate was dosed orally, the brain
T.sub.max was similar to that measured in plasma and euphoria was
not observed, even though the same receptor occupancy levels were
reached for the same dose. Volkow, et al. (1998) Am J Psychiatry
155:1325-1331; Swanson et al. (2002) Behav Brain Res 130:73-78. The
differences in brain effects between oral and IV methylphenidate
were attributed to acute tolerance at the dopamine transporter. The
authors suggested that after IV dosing, the initial rise in
dopamine levels was unchecked by acute tolerance thus leading to
euphoria, whereas after oral dosing, the comparatively slower
increase in brain dopamine levels resulted in acute tolerance which
prevented the reinforcing effects seen with IV dosing. This
hypothesis was extrapolated to account for the perceived
differences in efficacy over time at lower, pharmacological oral
doses of methylphenidate.
[0055] However, there were no data presented to support this
hypothesis of acute tolerance, and moreover alternative hypotheses
suggest that the selective euphoric effect of an intravenous dose
was due to its effects in a brain region, e.g., mesolimbic vs
mesostriatal (Wightman et al. (2002) J Neurochem 82:721-735), that
is not affected by oral doses of methylphenidate and that has been
implicated in the reinforcing effects of abused drugs. Swanson et
al. (2003) Neurosci Biobehav Rev 27:615-621. The clinical relevance
of acute tolerance and the importance of a rising plasma profile
therefore remain to be fully substantiated.
[0056] The pharmacokinetics of Concerta have been compared directly
with Metadate CD (Gonzalez et al. (2002) Int J Clin Pharmacol Ther
40:175-184), a formulation mimicking BID dosing of methylphenidate
and Ritalin LA (Markowitz et al. (2003) Clin Pharmacokinet
42:393-401), a bimodal BID-like formulation. FIG. 5 shows a direct
comparison of pharmacokinetics of methylphenidate released from
Concerta (tablet formulation) and Metadate CD (capsule
formulation), and Ritalin LA. From the PK profiles, it appears that
Concerta has significantly lower plasma concentration between 1 and
about 6 hours after dosing (compared to Metadate CD) and between 1
and about 8 hours (for Ritalin LA). After about 8 hours post dose,
the plasma concentration of Concerta is higher than that of the
other two competitor formulations.
[0057] The efficacy and duration of action of Concerta has also
been compared directly with Metadate CD and Ritalin LA in two
separate studies. Both studies were carried out in children using a
laboratory school setting that controls for the structure of the
day and enables monitoring of efficacy at different timepoints
during the day. Swanson et al. (1998) Psychopharmacol Bull
34:55-60. Similar established and validated measures of attention
and deportment ("SKAMP") as well as structured math tests were used
to assess the patients. In both trials, all the evaluated drugs
were found to be effective, however the different release profiles
of each formulation resulted in distinct differences between the
effects on measures of attention and deportment.
[0058] In the first study, Concerta was found to be longer acting
than Metadate CD, and Concerta was found to be superior in the
period 8 to 12 hours post dose. However, Concerta was found to be
less efficacious than the comparator drug in the period up to about
6-8 hours post dose. Swanson et al. (2004) Pediatrics 113:e206-216.
In this comparative study with Metadate CD no significant
differences between the pharmacodynamic trends were seen for
measures of SKAMP deportment and PERMP (math test-based
measurements) for the different dose levels. However, the effect of
dose on SKAMP attention was significant. A high correlation of the
initial bolus dose released from the two formulations with Effect
Size (a parameter derived from the difference of the active mean
and the placebo) for the morning time points was observed. The
authors investigated this observation further by normalizing the
Effect Size by dose, and hence anticipated plasma concentration, to
probe whether the correlation seen was dose-related or whether
there was an additional effect, such as acute tolerance, in play.
Once this adjustment had been made, the difference in response was
found to be insignificant. Based on this observation, the authors
proposed that the low dose group may have benefited from a higher
dose in the early morning.
[0059] In the second study comparing Ritalin LA against Concerta
(Lopez et al. (2003) Paediatr Drugs 5:545-555), patients were
assessed at time increments up to 8 hours rather than the 12 hour
duration described in the first study. In the time period between
dose and 8 hours, Ritalin LA was found to be more effective than
Concerta. At the 8 hour time point, the two drugs were
indistinguishable. Interestingly, in the interval between 2 and 4
hours post dose, Ritalin LA was found to be more efficacious than
Concerta. This period corresponds to a rapid decrease of
methylphenidate plasma concentration resulting from the Ritalin LA
formulation. If a smoothly ascending profile were key to activity,
it would be expected that Concerta would have superior activity at
these time points even if the plasma concentration was lower.
[0060] By considering the long-acting methylphenidate formulations
as equivalent to BID or TID immediate release dosing, it has been
suggested that if acute tolerance were to occur, then the optimum
serum concentration at the peak of the equivalents of 2.sup.nd or
3.sup.rd immediate release dose in the PK profile of the
formulation would need to be higher than the optimal serum
concentration at the equivalent peak for the first immediate
release dose to ensure adequate efficacy and to override the acute
tolerance effect. Swanson et al. (2002) Behav Brain Res 130:73-78.
Although Concerta does have a PK profile in which the points in the
plasma profile that correspond to the 2.sup.nd and 3.sup.rd TID
equivalent doses are higher than the first peak, data from the
comparative trials suggests that, in contradiction to the acute
tolerance hypothesis, a higher earlier plasma concentration may be
preferred for better efficacy during the morning hours. Of the
other long acting formulations of methylphenidate, Ritalin LA and
Metadate CD both have bimodal kinetics and have a higher second
plasma peak and Focalin XR, a bimodal formulation of the pure
d-threo isomer has equal plasma peaks and has been reported to
effective for 8-12 hours. See, e.g., FIG. 6 which depicts the PK
profile of Focalin XR compared to two IR doses of Focalin IR (taken
from the Focalin XR label).
[0061] It is therefore a primary object of the present invention to
provide for improved oral controlled release dosage forms for the
delivery of methylphenidate for use in the treatment of ADD and
ADHD. As used herein, "methylphenidate" includes all forms of the
active pharmaceutical ingredient, including dexmethylphenidate,
d-threo methylphenidate, and dl-threo-methylphenidate. Contrary to
the theories commonly held by key opinion leaders in the ADHD field
that dictate the design of current "state-of-the-art" controlled
release methylphenidate dosage forms, the inventors believe that
the clinical significance of acute tolerance remains theoretical
and thus the need for ramping plasma concentrations (ascending
release profiles) is not necessary for achieving optimal plasma
concentrations in individual patients. The improved oral controlled
release dosage forms of the present invention are designed to
provide a longer duration of action than that provided by existing
CR methylphenidate dosage forms, as well as a rapid onset of
action. The controlled release dosage forms are thus characterized
by: (i) a first, increasing in vivo rate of release of
methylphenidate from the controlled release system that provides an
initial increasing-rate phase of less than or equal to about 2
hours, and is sufficient to provide a therapeutically effective
amount of methylphenidate for a rapid onset of action; (ii) a
second, zero-order or decreasing (i.e., non-ascending) in vivo rate
of release of methylphenidate from the controlled release system
that provides a subsequent zero order- or decreasing-rate phase
sufficient to provide a therapeutically effective amount of
methylphenidate through at least about 11 to 12 hours post
administration; and (iii) a single T.sub.max of about 5.5 to 7.5
hours post administration. The novel and unique in vivo
methylphenidate release kinetics provided by the oral controlled
release dosage forms of the present invention are sufficient to
provide the methylphenidate in vivo PK profile depicted in FIG. 7.
A comparison of the methylphenidate in vivo PK profile provided by
the present oral dosage forms with the PK profiles from Metadate CD
and Concerta products is provided in FIG. 8.
[0062] It is generally recognized that the mere presence of an
active substance in the gastrointestinal fluids does not, by
itself, ensure bioavailability and/or PK performance.
Bioavailability is the degree or amount to which a drug substance
is absorbed into the systemic circulation in order to be
therapeutically available. In order to be absorbed, an active drug
substance must be in a solution. The time required for a given
proportion of an active drug substance contained in a controlled
release dosage form to enter into solution in appropriate
physiological fluids is known as the dissolution time. The
dissolution time for an active substance from a dosage form is
determined as the proportion of the amount of active drug substance
released from the dosage unit over a specified time by a test
method conducted under standardized conditions. Thus, for oral
dosage forms such as the controlled release oral dosage forms of
the present invention, physiological fluids mimicking the
gastrointestinal tract are used as the media for determining
dissolution time. The present state-of-the-art test procedures for
establishing dissolution time for controlled release pharmaceutical
compositions are well known by the skilled person and described in
official compendia world wide.
[0063] Although there are many diverse factors that may influence
the dissolution of a drug substance from a controlled release
system, the dissolution time determined for a pharmacologically
active substance from a specific composition is relatively constant
and reproducible. Among the different factors affecting the
dissolution time are the surface area of the drug substance
presented to the dissolution solvent medium, the pH of the
solution, the solubility of the substance in the specific solvent
medium, and the driving forces of the saturation concentration of
dissolved materials in the solvent medium. Thus, the dissolution
concentration of an active drug substance is dynamically modified
in this steady state as components are removed from the dissolution
medium. Under physiological conditions, the saturation level of the
dissolved materials is replenished from the controlled release
dosage form reserve to maintain a relatively uniform and constant
dissolution concentration in the solvent medium, providing for a
steady-state absorption.
[0064] The transport across a tissue absorption site in the
gastrointestinal tract is influenced by the Donnan osmotic
equilibrium forces on both sides of the membrane, since the
direction of the driving force is the difference between the
concentrations of active substance on either side of the membrane,
i.e. the amount dissolved in the gastrointestinal fluids and the
amount present in the blood. Since the blood levels are constantly
being modified by dilution, circulatory changes, tissue storage,
metabolic conversion and systemic excretion, the flow of active
materials is directed from the gastrointestinal tract into the
blood stream.
[0065] Notwithstanding the diverse factors influencing both
dissolution and absorption of a drug substance, in many cases an
important correlation can be established between the in vitro
dissolution release performance determined for an oral controlled
release dosage form and the in vivo bioavailability/PK performance
for that product. This correlation is so firmly established in the
art that dissolution time has become generally descriptive of
bioavailability potential for many classes of active components
contained in a particular dosage form. In view of this
relationship, the in vitro dissolution release performance
determined for an oral controlled release dosage form is one of the
important fundamental characteristics for consideration when
evaluating whether a controlled release formulation should be
tested in vivo.
[0066] The concept of in vitro/in vivo correlation (IVIVC)
determination for oral controlled release dosage forms is thus a
well-known tool used by pharmaceutical scientists, allowing for the
prediction of expected bioavailability and other pharmacological
performance characteristics from in vitro dissolution profile
characteristics. Information and guidance regarding IVIVC
determination can be found on the US FDA website and in other
pharmacological reference sites.
[0067] Keeping the above general considerations in mind, optimal in
vitro release profiles for an oral controlled release dosage form
produced in accordance with the present invention can be defined as
follows. The methylphenidate plasma profile of FIG. 7 can be
defined in relation to plasma profiles reported in the patent
literature for Metadate CD and Concerta controlled release
methylphenidate products (40 and 36 mg strengths, respectively).
This relationship is depicted in FIG. 8. According to the linear
theory of pharmacokinetics (PK), the plasma profile of a compound
can be written as the convolution of the rate of input into the
systemic circulation, I(t), and the unit impulse response, UIR,
derived from the plasma profile measured following intravenous (IV)
bolus injection. Thus, a target input rate can be defined from the
target plasma profile and UIR for methylphenidate by the process of
deconvolution.
[0068] The next step is to link the input rate in vivo to release
rates in vitro. If no human plasma profiles for a candidate
methylphenidate formulation are available, this can only be done
approximately as follows. Using the human data available for
Metadate CD and Concerta, the input rates via deconvolution can be
calculated for the two products. In addition, the in vitro
methylphenidate release rates can be determined using standard in
vitro dissolution testing methods as described herein above, and in
the working examples below. This allows one to establish the
functional relationships (IVIVC) between the cumulative
methylphenidate input rates in vivo and cumulative release in vitro
for the Metadate CD and Concerta products as defined by the
following:
C.sub.p(t)=.intg..sub.0I(.tau.)UIR(t-.tau.)d.tau.
[0069] wherein the units of the input rate (I(.tau.)) are mg/hour;
and the unit impulse response (UIR) is in units of ng/mL/mg dose;
and the human plasma profile (C.sub.p(t)) is in units of ng/mL. The
integral involves the variable (.tau.) which denotes time. Time is
fixed during any given evaluation of the integral.
[0070] Using the IVIVC relationship for Metadate CD, one may then
calculate an in vitro release profile from the target in vivo input
rate. This profile of cumulative methylphenidate release in vitro
provides a target that candidate formulations can match, with a
reasonable confidence that such formulations would achieve the
target human plasma profile.
[0071] Next, definition of an approximate impulse response from PK
parameters found in Table A-II-1 of The Pharmacological Basis of
Therapeutics (11th edition, Eds: Brunton et al., McGraw Hill, New
York, 2006) can be carried out. Specifically, values of the
clearance (CL) and volume of distribution (V.sub.d) for the (+) and
(-) dextro forms of MPH are averaged and weighted according to
their respective bioavailabilities (BA). For plasma data in units
of ng/mL, the unit impulse response can be defined as
UIR=10.sup.6exp(-k.sub.elt)/V.sub.d ng/mL/mg; wherein (k.sub.el) is
the terminal elimination rate of methylphenidate from the body,
which can be evaluated inter alfa, from a non-compartmental
analysis of intervenous bolus data. It is defined in terms of two
other pharmacokinetic parameters, the whole body clearance (CL)
i.e., the volume of blood cleared of a compound in unit time;
(V.sub.d) which is a measure of the extent to which a compound
distributes initially from the systemic circulation to other
tissues such that: k.sub.el=CL/V.sub.d Deconvolution of Metadate
CD, Concerta and the target plasma profiles can then be done in
WinNonLin (version 5.2, Pharsight Corp., Mountain View, Calif.).
The dose-normalized results of such a deconvolution analysis are
depicted in FIG. 9.
[0072] As described in Example 2b, below, the in vitro release for
Metadate CD (40 mg) and for various doses of Concerta (18, 27 and
36 mg) were measured. The results of this initial analysis are
depicted in FIGS. 10A and 10B. In FIG. 10A, the cumulative release
profiles obtained in the measurements are compared with cumulative
release data presented in the U.S. Pat. No. 6,919,373 for the
Concerta product. In FIG. 10B, the measured cumulative release in
vitro is plotted against input in vivo obtained via deconvolution
(open symbols) for both Metadate CD and Concerta. The results
presented in these figures are described well by Weibull
functions:
y=(100-.alpha.)[1-e.sup.-(x/.chi.).beta.]+.alpha.
[0073] where .alpha., .beta. and .chi. are constants; particularly,
where .alpha. is the percent of dose that is released from the
dosage form immediately; .chi. is a scale factor (the extent of
input in vivo at which 62.5% of the remaining dose is release in
vitro); and .beta. alters the shape of the fitting curve. In the
case at hand, by a least squares fit of the in vitro and in vivo
data, .alpha.=29.7% (27, 32.5); .chi.=6.60 (6.24, 6.95); and
.beta.=1.94 (1.65, 2.23), where the parenthetical values define the
95% confidence intervals. The fit for Metadate CD is shown by the
dotted line in the graph of FIG. 10B (r.sup.2.sub.adj=99.6%). An
advantage of the Weibull representation is that it can be inverted
analytically. This advantage is useful in order to predict
cumulative input in vivo and human plasma profiles from in vitro
release profiles of selected candidate oral controlled release
formulations in the practice of the invention.
[0074] Accordingly the Weibull model for Metadate CD can now be
applied to calculate target cumulative release in vitro from the
target cumulative input in vivo. The results of such a calculation
are presented in FIG. 11, where confidence intervals for the in
vitro release profile are defined by the 95% confidence intervals
for the parameters of the Weibull model. In addition, the target in
vitro release profile thus obtained can be compared to the
methylphenidate in vitro dissolution profiles for candidate
formulations as described in Example 2b below.
[0075] It is accordingly also an object of the present invention to
provide a controlled release oral dosage form containing
methylphenidate, wherein the dosage form is characterized by
providing the target in vitro cumulative release profile as
depicted in FIG. 12.
[0076] In one aspect of the invention, a controlled release oral
pharmaceutical dosage form is provided that comprises
methylphenidate in a controlled release carrier system. The subject
dosage form is characterized by: (i) a first, increasing in vivo
rate of release of methylphenidate from the controlled release
system that provides an initial increasing-rate phase of less than
or equal to about 2 hours, and is sufficient to provide a
therapeutically effective amount of methylphenidate for a rapid
onset of action; (ii) a second, zero-order or decreasing (i.e.,
non-ascending) in vivo rate of release of methylphenidate from the
controlled release system that provides a subsequent zero order- or
decreasing-rate phase sufficient to provide a therapeutically
effective amount of methylphenidate through at least about 11 to 12
hours post administration; (iii) a single T.sub.max of about 5.5 to
7.5 hours post administration; and (iv) the controlled release
carrier system provides enhanced in vivo pharmacokinetic
performance. The novel and unique in vivo methylphenidate release
kinetics provided by the oral controlled release dosage forms of
the present invention are sufficient to provide the methylphenidate
in vivo PK profile depicted in FIG. 7. In certain aspects, the in
vivo release of methylphenidate from the carrier system is
substantially free from food effect. In other aspects, the carrier
system has a food effect such that the in vivo absorption of
methylphenidate from the carrier system is actually enhanced when
administered in the presence of food.
[0077] In this regard, the physiological behavior of the stomach is
usually determined by whether it contains food (fed state) or is
empty (fasted state). In the fed state, food is mixed and partially
digested in the distal stomach as the stomach undergoes
contractions, helping to move materials into the main part of the
stomach for further digestion. At the end of a digestive period,
the stomach enters the fasting stage and begins a cycle called the
interdigestive myoelectric motor cycle. These changes in
physiological behavior, as well as certain concomitant chemical
changes (e.g., pH) as the stomach switches between fed and fasted
states may give rise to variability in the rate and/or amount of
delivery of methylphenidate from an oral dosage form. More
particularly, a variety of formulation-dependent food-induced
absorption changes (hereinafter "food effect") can occur with
controlled release compositions. These changes can include
decreases in the rate and/or extent, increases in the rate and/or
extent when taken in fed or fasted states, and erratic or variable
absorption of methylphenidate from a controlled release composition
such as differences in absorption when the composition is taken
with low-fat or high-fat meals. In extreme cases, a controlled
release composition can have a significant food effect such that
when the composition is taken with food, or with different kinds of
food (high fat versus low fat meals), there can be a significant
increase in absorption (dose dumping) that can cause such a dosage
form to be unsafe. In these cases, that is, where a formulation
exhibits a pronounced food effect, the dosing relative to meal
intake may be made part of the product labeling to assure
consistent and safe absorption. If the difference in both the rate
and extent of absorption of an active agent from an oral dosage
form varies significantly when it is administered in a fed versus a
fasted state, the dosage form is characterized as having a food
effect. In some cases, a dosage form can have a food effect wherein
administration of the dosage form with food will enhance the
bioavailability of the methylphenidate active agent. On the other
hand, if there is not a significant difference in both the rate and
extent of absorption of an active agent from an oral dosage form as
between fed and fasted states, the dosage form is characterized as
being substantially free from a food effect (e.g.,
co-administration with food may still have an effect on the maximal
plasma concentration of the methylphenidate active agent).
[0078] The controlled release carrier systems used to produce the
oral dosage forms of the present invention can characterized as:
(i) having a food effect (administration of the dosage form with
food will have a significant effect on both the rate and extent of
absorption of methylphenidate from the dosage form, i.e., the rate
of absorption is decreased and the extent of absorption is
increased); (ii) having a consistent food effect (administration of
the dosage form with food will effect both the rate and extent of
absorption of methylphenidate from the dosage form; however, there
is not a significant difference or variability in this food effect
as between different types of meals or diets); or (iii)
substantially free from a food effect (administration of the dosage
form with or without food does not significantly effect both the
rate to maximal plasma concentration, or T.sub.max and the extent
of absorption of the methylphenidate active agent, or AUC, although
co-administration with food may still have an effect on the maximal
plasma concentration, or C.sub.max, of the methylphenidate active
agent).
[0079] Accordingly, as used herein, "absence from food effect"
means that the ratio of mean AUC fed/fasted is within the accepted
80% to 125% bioequivalence limits for pharmaceutical dosage forms,
and the ratio of mean T.sub.max fed/fasted is likewise within the
accepted 80% to 125% bioequivalence limits. In addition, as used
herein, "enhanced in vivo absorption" means that the ratio of mean
AUC fed/fasted is at least greater than the 125% upper
bioequivalence limit and the ratio of mean T.sub.max fed/fasted is
greater than the 125% upper bioequivalence limit. As used herein, a
"consistent food effect" means that there is enhanced in vivo
absorption and the ratio of mean AUC fed high-fat/fed low-fat is
within the accepted 80% to 125% bioequivalence limits for
pharmaceutical dosage forms, and the ratio of mean T.sub.max
fed/fasted is likewise within the accepted 80% to 125%
bioequivalence limits. By "C" is meant the concentration of
methylphenidate in the blood plasma of a subject, generally
expressed as mass per unit volume, typically nanograms per
milliliter. By "C.sub.max" is meant the maximum concentration of
methylphenidate in the blood plasma of a subject, generally
expressed as mass per unit volume, typically nanograms per
milliliter, within a specified time interval "T" after
administration of the methylphenidate to a subject, or "T.sub.max".
As used herein, "fasted" means that, under a clinical trial
setting, a dosage form is administered to a subject that has fasted
overnight for at least 10 hours, fasted for an additional 4 hours
after dosage administration, and then received a standardized
high-fat (breakfast) meal. As used herein, "fed" means that, under
a clinical trial setting, a dosage form is administered to a
subject immediately after having ingested a high-fat or low-fat
standardized meal. A "high-fat" standardized meal consists of 2
slices of toasted white bread spread with butter, two eggs fried in
butter, two slices of bacon, 2 oz hash-browned potatoes, and 8 oz
whole milk (approximately 33 g protein, 58 to 75 g fat, 58 g
carbohydrate, 870 to 1020 calories). A "low-fat" standardized meal
consists of one slice of toasted white bread spread with butter or
jelly, 1 oz dry cereal (corn flakes), 8 oz skim milk, 6 oz orange
juice, and one banana (approximately 17 g protein, 8 g fat, 103 g
carbohydrate, 583 calories). All of the above-described
pharmacokinetic values can be readily determined by the skilled
person using established in vivo clinical trail procedures such as
those described below in Example 5, below. Reference may also be
made to "Guidance for Industry", Food-Effect Bioavailability and
Fed Bioequivalence Studies, US Dept Health and Human Services, FDA,
Center for Drug Evaluation and Research (CDER), December 2002.
[0080] The methylphenidate can be present in the formulations used
to make the dosage forms of the present invention in a neutral
form, as a free base form, or in the form of a pharmaceutically
acceptable salt. The term "pharmaceutically acceptable salt," as
used herein, intends those salts that retain the biological
effectiveness and properties of neutral active agents and are not
otherwise unacceptable for pharmaceutical use. Pharmaceutically
acceptable salts include salts of acidic or basic groups.
Pharmaceutically acceptable acid addition salts suitable for use
herein are those that form non-toxic acid addition salts, i.e.,
salts comprising pharmacologically acceptable anions, such as the
hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate,
bisulfate, phosphate, acid phosphate, isonicotinate, acetate,
lactate, salicylate, citrate, tartrate, pantothenate, bitartrate,
ascorbate, succinate, maleate, gentisinate, fumarate, gluconate,
glucaronate, saccharate, formate, benzoate, glutamate,
methanesulfonate, ethanesulfonate, benzenesulfonate,
p-toluenesulfonate and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Suitable base
salts can be formed from bases which form non-toxic salts, for
example, aluminium, calcium, lithium, magnesium, potassium, sodium,
zinc and diethanolamine salts. See, e.g., Berge et al. (1977) J.
Pharm. Sci. 66:1-19.
[0081] In the controlled release oral dosage forms of the present
invention, the methylphenidate will be dissolved (fully or
partially) or dispersed within the controlled release carrier
system. The phrase "dissolved or dispersed" is intended to
encompass all means of establishing a presence of the
methylphenidate active agent in the subject controlled release
carrier system and includes dissolution, dispersion, partial
dissolution and dispersion, and/or suspension and the like. In
addition, in certain embodiments of the invention wherein the
methylphenidate is in a solid particulate form suspended within the
controlled release carrier system, the methylphenidate particulate
may be pre-treated with a micronization process to provide a
particle population having a substantially homogeneous particle
size the bulk of which fall within the micron (.mu.m) range.
[0082] The methylphenidate will be present in the formulation used
to make the present dosage forms in an amount of from about 95 to
about 0.1 percent by weight relative to the total weight of the
formulation (wt %), in an amount of from about 40 to 1 wt %, in an
amount of from about 35 to 1.3 wt %, or in an amount of about 30 to
5 wt %, depending upon the he desired dose required for the dosage
form, and the intended use thereof. In certain preferred
embodiments, the methylphenidate is present in the formulation in
an amount of about 1 to about 10 wt %, and can thus be loaded into
a suitable dosage form to provide single dosages ranging from about
0.01 mg to 1000 mg, or from about 0.1 mg to 500 mg, or from about 2
mg to 250 mg, or from about 2 mg to 250 mg, or from about 2 mg to
150 mg, or from about 5 mg to 100 mg, or from about 5 mg to 80 mg.
10, 12, 15, 20, 24, 25, 30, 35, 36, 40, 45, 48 and 60 mg single
doses are preferred. The precise amount of methylphenidate desired
can be determined by routine methods well known to pharmacological
arts.
[0083] In addition, the controlled release oral dosage forms of the
present invention may be formulated to provide multi-phase (e.g.,
bimodal) delivery kinetics, for example by the provision of two
different components in a single dosage form, one providing an
early drug delivery phase and the second, an extended drug delivery
phase. This can be achieved in liquid CR carrier systems using, for
example, two different formulations in a single dosage form (such
as a liquid or solid core formulation placed within a second liquid
formulation in a gel cap, or as a capsule containing a liquid or
solid formulation placed with a second capsule containing a second
formulation, or as a dual compartment dosage form). For particulate
CR Carrier systems, this can be achieved using, for example, a
capsule containing two different populations of particles, one in
immediate release form the other in a delayed release form (see,
e.g, U.S. Pat. No. 6,344,215 to Bettman et al.), or as two
different populations of particle sizes of the same
formulation.
[0084] The controlled release oral dosage forms of the present
invention may be produced using any suitable oral controlled
release system known in the art. Accordingly, in certain
embodiments, the dosage forms of the present invention are
formulated into dosage forms administrable to patients in need
thereof. Specific controlled release dosage forms and methods of
using the same will now be described. It will be appreciated that
the specific controlled release dosage forms described below are
merely exemplary.
[0085] Osmotic CR Carrier Systems
[0086] In an embodiment, osmotic CR carrier systems can be used to
practice the present invention (to provide osmotic dosage forms).
Osmotic dosage forms in general utilize osmotic pressure to
generate a driving force for imbibing fluid into a compartment
formed, at least in part, by a semipermeable membrane that permits
free diffusion of fluid but not drug or osmotic agent(s), if
present. A significant advantage to osmotic systems is that
operation is pH-independent and thus continues at the osmotically
determined rate throughout an extended time period even as the
dosage form transits the gastrointestinal tract and encounters
differing microenvironments having significantly different pH
values. A review of such dosage forms can be found in: Santus et al
(1995) Journal of Controlled Release 35:1-21. In addition, U.S.
Pat. Nos. 3,845,770; 3,916,899; 3,995,631; 4,008,719; 4,111,202;
4,160,020; 4,327,725; 4,578,075; 4,681,583; 5,019,397 and 5,156,850
each disclose osmotic devices for the continuous dispensing of
active agent. Osmotic dosage forms in which a drug composition is
delivered as a slurry, suspension or solution from a small exit
orifice by the action of an expandable layer are disclosed in U.S.
Pat. Nos. 5,633,011; 5,190,765; 5,252,338; 5,620,705; 4,931,285;
5,006,346; 5,024,842; and 5,160,743. Typical devices suitable for
use in the practice of the invention include an expandable push
layer and a drug layer surrounded by a semipermeable membrane. An
example of an osmotic methylphenidate dosage form exhibiting a
substantially ascending release rate profile is Concerta which is
designed to deliver the active agent at a substantially ascending
rate of release for up to about 8 hours.
[0087] One preferred embodiment of controlled release dosage form
for use herein comprises an osmotic controlled release dosage form,
which is disclosed for instance in published US Patent Publication
No. 2005/0208132. A first drug layer comprises osmotically active
components, and a lower amount of active agent than in second drug
layer. The osmotically active component(s) in the first component
drug layer comprises an osmagent such as salt and one or more
osmopolymer(s) having relatively small molecular weights which
exhibit swelling as fluid is imbibed such that release of these
osmopolymers through an exit occurs. Additional excipients such as
binders, lubricants, antioxidants and colorants may also be
included in the first drug layer.
[0088] The second drug layer comprises active agent in an admixture
with selected excipients adapted to provide an osmotic activity
gradient for driving fluid from an external environment through the
membrane and for forming a deliverable drug formulation upon
imbibition of fluid. The excipients may include a suitable
suspending agent, but no osmotically active agent "osmagent" such
as salt, sodium chloride. It has been discovered that the omission
of salt from this second drug layer, which contains a higher
proportion of the overall drug in the dosage form, in combination
with the salt in the first drug layer, provides an ascending rate
of release creating a longer duration of ascending rate.
[0089] The drug layers used in such dosage forms further comprise a
hydrophilic polymer carrier. The hydrophilic polymer provides a
particle in the drug composition that contributes to the controlled
delivery of the active drug. Representative examples of these
polymers are poly(alkylene oxide) of 100,000 to 750,000
number-average molecular weight, including poly(ethylene oxide),
poly(methylene oxide), poly(butylene oxide) and poly(hexylene
oxide); and a poly(carboxymethylcellulose) of 40,000 to 400,000
number-average molecular weight, represented by poly(alkali
carboxymethylcellulose), poly(sodium carboxymethylcellulose),
poly(potassium carboxymethylcellulose) and poly(lithium
carboxymethylcellulose). The drug layers may be formed from
particles by comminution that produces the size of the drug and the
size of the accompanying polymer used in the fabrication of the
drug layer, typically as a core containing the compound.
[0090] The ratio of drug concentration between the first drug layer
and the second drug layer alters the release rate profile. Release
rate profile is calculated as the difference between the maximum
release rate and the release rate achieved at the first time point
after start-up (for example, at 6 hours), divided by the average
release rate between the two data points.
[0091] The membrane is formed to be permeable to the passage of an
external fluid, such as water and biological fluids, and is
substantially impermeable to the passage of osmagent, osmopolymer
and the like. As such, it is semipermeable. The selectively
semipermeable compositions used for forming the membrane are
essentially nonerodible and substantially insoluble in biological
fluids during the life of the dosage form. The cellulosic polymers
typically have a degree of substitution, "D.S.", on their
anhydroglucose unit from greater than 0 up to 3 inclusive. The
semipermeable compositions typically include a member selected from
the group consisting of cellulose acylate, cellulose diacylate,
cellulose triacylate, cellulose triacetate, cellulose acetate,
cellulose diacetate, cellulose triacetate, mono-, di- and
tri-cellulose alkanylates, mono-, di-, and tri-alkenylates, mono-,
di-, and tri-aroylates, and the like.
[0092] The push layer comprises an expandable layer in contacting
layered arrangement with the second drug layer. The push layer
comprises a polymer that imbibes an aqueous or biological fluid and
swells to push the drug composition through the exit of the device.
An immediate release drug coating may be provided on the surface of
the dosage form in circumstances where quick drug release is
desired.
[0093] Pan coating may be conveniently used to provide such dosage
forms, except for the exit orifice. In the pan coating system, the
wall-forming composition for the inner wall or the outer wall, as
the case may be, is deposited by successive spraying of the
appropriate wall composition onto the compressed trilayered or
multilayered core comprising the drug layers, optional barrier
layer and push layer, accompanied by tumbling in a rotating pan.
One or more exit orifices are drilled in the drug layer end of the
dosage form, and optional water soluble overcoats, which may be
colored (e.g., Opadry colored coatings) or clear (e.g., Opadry
Clear), may be coated on the dosage form to provide the finished
dosage form. Drilling, including mechanical and laser drilling,
through the semipermeable wall can be used to form the exit
orifice. Such exits and equipment for forming such exits are
disclosed in U.S. Pat. Nos. 3,916,899 and 4,088,864.
[0094] Liquid CR Carrier Systems
[0095] An alternative controlled release carrier system suitable
for use herein is a liquid controlled release dosage form as
described in U.S. Pat. No. 4,961,932. While this patent discloses
multiple embodiments useful in the practice of the present
invention, a preferred embodiment is as follows. The preferred
embodiment comprises a plurality of tiny pills that release a drug
by osmotic principles. The tiny pills comprise a wall that releases
a beneficial agent, such as a drug, by the process of osmotic
bursting over time. The drug is present in the form of an osmotic
solute, such as a therapeutically acceptable salt, that exhibits an
osmotic pressure gradient across the wall against distilled water,
or the drug can be mixed with an osmotically effective solute that
exhibits an osmotic pressure gradient across the wall against
distilled water. The tiny pills are placed in a fluidic means that
comprises a concentration substantially equal to or larger than the
concentration of the drug in the tiny pills thereby providing an
initial concentration gradient substantially equal to zero. The
wall forming composition used to manufacture the wall comprises
those materials permeable to the passage of an external fluid
present in an environment of use and substantially impermeable to
the passage of drug and osmotic solute. Typical materials include a
member selected from the group consisting of cellulose acylate,
cellulose diacylate, cellulose triacylate, cellulose acetate,
cellulose diacetate, cellulose triacetate, cellulose acetate having
a degree of substitution "D.S." of up to 1 and an acetyl content of
21%; cellulose diacetate having a D.S. of 1 to 2 and an acetyl
content of 21% to 35%; cellulose triacetate having a D.S. of 2 to 3
and an acetyl content of 35% to 44.8%, cellulose acetate
propionate, cellulose acetate butyrate, ethyl cellulose
semipermeable polyurethane, and the like. The osmotic wall can be
coated around the drug in varying thicknesses by pan coating,
spray-coating, Wurster.TM. fluid air-suspension coating,
coacervation techniques, and the like. The wall is applied using
organic solvents such as methylene chloride-methanol, methylene
chloride-acetone, methanol-acetone, ethylene dichloride-acetone,
and the like. Osmotic wall forming materials, and procedures for
forming the wall, and osmotic bursting procedures are disclosed in
U.S. Pat. Nos. 2,799,241; 3,952,741; 4,014,334; and 4,016,880. The
drug, neat, or a combination of the drug and an osmotically
effective solute in the tiny pills typically has a particle size of
0.1 to 1000 micron, and a presently preferred particle size of
about 0.5 to 300 microns, average.
[0096] Particulate CR Carrier Systems
[0097] In certain other alternative embodiments, the
methylphenidate is provided in a particulate controlled release
carrier system, wherein it is incorporated into or onto a substrate
and a controlled release coating is applied thereto. For example,
the methylphenidate may be contained within or on a substrate as
follows: (i) incorporated into matrix spheroids (e.g., together
with a pharmaceutically acceptable spheronizing agent such as
microcrystalline cellulose), (ii) coated onto inert
pharmaceutically acceptable beads (e.g., nonpareil beads); (iii)
incorporated into a normal release tablet core; or (iv)
incorporated into a tablet core which comprises a matrix including
a controlled release carrier material. Thereafter, a controlled
release coating is applied onto substrates such as those mentioned
in (i)-(iv) above. The dosage forms of the present invention may
optionally be coated with one or more materials suitable for the
regulation of release or for the protection of the formulation. In
one embodiment, coatings are provided to permit either pH-dependent
or pH-independent release, e.g., when exposed to gastrointestinal
fluid. A pH-dependent coating serves to release the drug in desired
areas of the gastro-intestinal (GI) tract, e.g., the stomach or
small intestine. When a pH-independent coating is desired, the
coating is designed to achieve optimal release regardless of
pH-changes in the environmental fluid, e.g., the GI tract. It is
also possible to formulate compositions that release a portion of
the methylphenidate dose in one desired area of the GI tract, e.g.,
the stomach, and release the remainder of the dose in another area
of the GI tract, e.g., the small intestine.
[0098] Formulations according to the invention that utilize
pH-dependent coatings may also impart a repeat-action effect
whereby unprotected methylphenidate is coated over the enteric coat
and is released in the stomach, while the remainder, being
protected by the enteric coating, is released further down the
gastrointestinal tract. Coatings which are pH-dependent may be used
in accordance with the present invention include shellac, cellulose
acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP),
hydroxypropytmethylcellulose phthalate, and methacrylic acid ester
copolymers, zein, and the like.
[0099] In certain preferred embodiments, the substrate (e.g.,
tablet core bead, matrix particle) comprising the methylphenidate
is coated with a hydrophobic material selected from (i) an
alkylcellulose; (ii) an acrylic polymer; or (iii) mixtures thereof.
The coating may be applied in the form of an organic or aqueous
solution or dispersion. The coating may be applied to obtain a
weight gain from about 2 to about 25% of the substrate in order to
obtain a targeted controlled release profile as described herein.
Such formulations are described, e.g., in detail in U.S. Pat. Nos.
5,273,760 and 5,286,493. The particles are preferably film-coated
with a material that permits release of the methylphenidate so as
to achieve, in combination with the other stated properties the
desired in vitro release rate and in vivo plasma levels as
determined using the teaching of the present invention. The
controlled release coating formulations of the present invention
should be capable of producing a strong, continuous film that is
smooth and elegant, capable of supporting pigments and other
coating additives, non-toxic, inert, and tack-free.
[0100] Other examples of controlled release formulations and
coatings that may be used in accordance with the present invention
include those described in U.S. Pat. Nos. 5,324,351; 5,356,467, and
5,472,712.
[0101] Cellulosic materials and polymers, including
alkylcelluloses, provide hydrophobic materials well suited for
coating the beads according to the invention. Simply by way of
example, one preferred alkylcellulosic polymer is ethylcellulose,
although the artisan will appreciate that other cellulose and/or
alkylcellulose polymers may be readily employed, singly or in any
combination, as all or part of a hydrophobic coating according to
the invention.
[0102] One commercially available aqueous dispersion of
ethylcellulose is the Aquacoat brand (FMC Corp., Philadelphia, Pa.,
U.S.A.). Aquacoat is prepared by dissolving the ethylcellulose in a
water-immiscible organic solvent and then emulsifying the same in
water in the presence of a surfactant and a stabilizer. After
homogenization to generate submicron droplets, the organic solvent
is evaporated under vacuum to form a pseudolatex. The plasticizer
is not incorporated in the pseudolatex during the manufacturing
phase. Thus, prior to using the same as a coating, it is necessary
to intimately mix the Aquacoat with a suitable plasticizer prior to
use.
[0103] Another aqueous dispersion of ethylcellulose is commercially
available as Surelease brand (Colorcon, Inc., West Point, Pa.,
U.S.A.). This product is prepared by incorporating plasticizer into
the dispersion during the manufacturing process. A hot melt of a
polymer, plasticizer (dibutyl sebacate), and stabilizer (oleic
acid) is prepared as a homogeneous mixture, which is then diluted
with an alkaline solution to obtain an aqueous dispersion which can
be applied directly onto substrates.
[0104] The hydrophobic material comprising the controlled release
coating may comprise a pharmaceutically acceptable acrylic polymer,
including but not limited to acrylic acid and methacrylic acid
copolymers, methyl methacrylate copolymers, ethoxyethyl
methacrylates, cyanoethyl methacrylate, poly(acrylic acid),
poly(methacrylic acid), methacrylic acid alkylamide copolymer,
poly(methyl methacrylate), polymethacrylate, poly(methyl
methacrylate)copolymer, polyacrylamide, aminoalkyl methacrylate
copolymer, poly(methacrylic acid anhydride), and glycidyl
methacrylate copolymers.
[0105] In certain preferred embodiments, the acrylic polymer is
comprised of one or more ammonio methacrylate copolymers. Ammonio
methacrylate copolymers are well known in the art, and are
described as fully polymerized copolymers of acrylic and
methacrylic acid esters with a low content of quaternary ammonium
groups.
[0106] In order to obtain a desirable in vitro or in vivo
dissolution profile in the practice of the invention, it may be
necessary to incorporate two or more ammonio methacrylate
copolymers having differing physical properties, such as different
molar ratios of the quaternary ammonium groups to the neutral
(meth)acrylic esters.
[0107] Certain methacrylic acid ester-type polymers are useful for
preparing pH-dependent coatings that may be used in accordance with
the present invention. For example, there are a family of
copolymers synthesized from diethylaminoethyl methacrylate and
other neutral methacrylic esters, also known as methacrylic acid
copolymer or polymeric methacrylates, commercially available as
Eudragit brand (Rohm Tech, Inc.). There are several different types
of Eudragit polymers. For example, Eudragit "E" is an example of a
methacrylic acid copolymer which swells and dissolves in acidic
media. Eudragit "L" is a methacrylic acid copolymer which does not
swell at about pH<5.7 and is soluble at about pH>6. Eudragit
"S" does not swell at about pH<6.5 and is soluble at about
pH>7. Eudragit "RL" and Eudragit "RS" are water swellable, and
the amount of water absorbed by these polymers is pH-dependent,
however, dosage forms coated with Eudragit "RL" and "RS" are
pH-independent.
[0108] In certain preferred embodiments, the acrylic coating
comprises a mixture of two acrylic resin lacquers commercially
available from Rohm Pharma under the Tradenames Eudragit "RL30D"
and Eudragit "RS30D", respectively. Eudragit "RL30D" and "RS30D"
are copolymers of acrylic and methacrylic esters with a low content
of quaternary ammonium groups, the molar ratio of ammonium groups
to the remaining neutral (meth)acrylic esters being 1:20 in
Eudragit "RL30D" and 1:40 in Eudragit "RS30D". The mean molecular
weight is about 150,000. The code designations RL (high
permeability) and RS (low permeability) refer to the permeability
properties of these agents. Eudragit RL/RS mixtures are insoluble
in water and in digestive fluids. However, coatings formed from the
same are swellable and permeable in aqueous solutions and digestive
fluids.
[0109] Eudragit RL/RS dispersions used in the practice of the
present invention may be mixed together in any desired ratio in
order to ultimately obtain a controlled release formulation having
a desirable dissolution profile. Desirable controlled release
formulations may be obtained, for instance, from a retardant
coating derived from 100% Eudragit RL, 50% Eudragit RL and 50%
Eudragit RS, and 10% Eudragit RL: 90% Eudragit RS. Of course, one
skilled in the art will recognize that other acrylic polymers may
also be used, such as, for example, Eudragit L.
[0110] In embodiments of the present invention where the coating
comprises an aqueous dispersion of a hydrophobic material such as
an alkylcellulose or an acrylic polymer, the inclusion of an
effective amount of a plasticizer in the aqueous dispersion of
hydrophobic material will further improve the physical properties
of the controlled release coating. For example, because
ethylcellulose has a relatively high glass transition temperature
and does not form flexible films under normal coating conditions,
it is preferable to incorporate a plasticizer into an
ethylcellulose coating containing controlled release coating before
using the same as a coating material. Generally, the amount of
plasticizer included in a coating solution is based on the
concentration of the film-former, e.g., most often from about 1 to
about 50 percent by weight of the film-former. Concentration of the
plasticizer, however, can only be properly determined after careful
experimentation with the particular coating solution and method of
application.
[0111] Examples of suitable plasticizers for ethylcellulose include
water insoluble plasticizers such as dibutyl sebacate, diethyl
phthalate, triethyl citrate, tributyl citrate, and triacetin,
although it is possible that other water-insoluble plasticizers
(such as acetylated monoglycerides, phthalate esters, castor oil,
etc.) may be used. Triethyl citrate is an especially preferred
plasticizer for aqueous dispersions of ethyl cellulose.
[0112] Examples of suitable plasticizers for the acrylic polymers
used in the present invention include, but are not limited to
citric acid esters such as triethyl citrate NF XVI, tributyl
citrate, dibutyl phthalate, and possibly 1,2-propylene glycol.
Other plasticizers which have proved to be suitable for enhancing
the elasticity of the films formed from acrylic films such as
Eudragit RL/RS lacquer solutions include polyethylene glycols,
propylene glycol, diethyl phthalate, castor oil, and triacetin.
Triethyl citrate is an especially preferred plasticizer for aqueous
dispersions of ethyl cellulose.
[0113] It has further been found that the addition of a small
amount of talc reduces the tendency of the aqueous dispersion to
stick during processing, and acts as a polishing agent.
[0114] When the aqueous dispersion of hydrophobic material is used
to coat a substrate including the methylphenidate, for example,
inert pharmaceutical beads such as nonpariel 18/20 beads, a
plurality of the resultant stabilized solid controlled release
beads may thereafter be placed in a gelatin capsule in an amount
sufficient to provide an effective controlled release oral dosage
form when ingested and contacted by an environmental fluid, e.g.,
gastric fluid or dissolution media. Alternatively, the substrate
may be a tablet core coated with the controlled release coating,
and optionally a further film-forming agent or colorant, such as
Opadry brand (Colorcon, Inc).
[0115] In formulations where an aqueous dispersion of an
hydrophobic polymer such as an alkylcellulose is applied to the
substrate, it is preferred that the coated substrate is cured at a
temperature above the glass transition temperature of the
plasticized polymer and at a relative humidity above ambient
conditions, until an endpoint is reached at which the coated
formulation attains a dissolution profile which is substantially
unaffected by exposure to storage conditions, e.g., of elevated
temperature and/or humidity. Generally, in such formulations the
curing time is about 24 hours or more, and the curing conditions
may be, for example, about 60.degree. C. and 85% relative humidity.
Detailed information concerning the stabilization of such
formulations is set forth in U.S. Pat. Nos. 5,273,760; 5,681,585;
and 5,472,712.
[0116] In formulations where an aqueous dispersion of an acrylic
polymer is applied to the substrate, it is preferred that the
coated substrate is cured at a temperature above the glass
transition temperature of the plasticized polymer until an endpoint
is reached at which the coated formulation attains a dissolution
profile which is substantially unaffected by exposure to storage
conditions, e.g., of elevated temperature and/or humidity.
Generally, the curing time is about 24 hours or more, and the
curing temperature may be, for example, about 45.degree. C.
Detailed information concerning the stabilization of such
formulations is set forth in U.S. Pat. Nos. 5,286,493; 5,580,578;
and 5,639,476.
[0117] The controlled release profile of the coated formulations of
the invention can be altered, for example, by varying the amount of
overcoating with the aqueous dispersion of hydrophobic material,
altering the manner in which the plasticizer is added to the
aqueous dispersion of hydrophobic material, by varying the amount
of plasticizer relative to hydrophobic material, by the inclusion
of additional ingredients or excipients, by altering the method of
manufacture, etc. The dissolution profile of the ultimate product
may also be modified, for example, by increasing or decreasing the
thickness of the retardant coating.
[0118] Spheroids or beads coated with methylphenidate are prepared,
e.g., by dissolving the methylphenidate in water and then spraying
the solution onto a substrate, for example, nonpariel 18/20 beads,
using a Wuster insert. Optionally, additional ingredients are also
added prior to coating the beads in order to assist the binding of
the methylphenidate to the beads, and/or to color the solution,
etc. For example, a product which includes
hydroxypropylmethylcellulose, etc., with or without colorant e.g.,
Opadry, may be added to the solution and the solution mixed (e.g.,
for about 1 hour) prior to application of the same onto the beads.
The resultant coated substrate, in this example beads, may then be
optionally overcoated with a barrier agent, to separate the
methylphenidate from the hydrophobic controlled release coating. An
example of a suitable barrier agent is one which comprises
hydroxypropylmethylcellulose. However, any film-former known in the
art may be used. It is preferred that the barrier agent does not
affect the dissolution rate of the final product.
[0119] The beads may then be overcoated with an aqueous dispersion
of the hydrophobic material. The aqueous dispersion of hydrophobic
material preferably further includes an effective amount of
plasticizer, e.g. triethyl citrate. Pre-formulated aqueous
dispersions of ethyl-cellulose, such as Aquacoat or Surelease
brands, may be used. If Surelease is used, it is not necessary to
separately add a plasticizer. Alternatively, pre-formulated aqueous
dispersions of acrylic polymers such as Eudragit can be used.
[0120] The coating solutions preferably contain, in addition to the
film-former, plasticizer, and solvent system (i.e., water), a
colorant to provide elegance and product distinction. Color may be
added to the solution of the methylphenidate instead, or in
addition to the aqueous dispersion of hydrophobic material. For
example, color can be added to Aquacoat via the use of alcohol or
propylene glycol based color dispersions, milled aluminum flakes
and opacifiers such as titanium dioxide by adding color with shear
to water soluble polymer solution and then using low shear to the
plasticized Aquacoat. Alternatively, any suitable method of
providing color to the formulations of the present invention may be
used. Suitable ingredients for providing color to the formulation
when an aqueous dispersion of an acrylic polymer is used include
titanium dioxide and color pigments, such as iron oxide pigments.
The incorporation of pigments, may, however, increase the retarding
effect of the coating.
[0121] The plasticized aqueous dispersion of hydrophobic material
may be applied onto the substrate comprising the methylphenidate by
spraying using any suitable spray equipment known in the art. In a
preferred method, a Wurster fluidized-bed system is used in which
an air jet, injected from underneath, fluidizes the core material
and effects drying while the acrylic polymer coating is sprayed on.
A sufficient amount of the aqueous dispersion of hydrophobic
material to obtain a predetermined sustained release of the
methylphenidate when the coated substrate is exposed to aqueous
solutions, e.g. gastric fluid, is preferably applied, taking into
account the physical characteristics of the methylphenidate active
agent, the manner of incorporation of the plasticizer, etc. After
coating with the hydrophobic material, a further overcoat of a
film-former, such as Opadry, is optionally applied to the beads.
This overcoat is provided, if at all, in order to substantially
reduce agglomeration of the beads.
[0122] The release of methylphenidate from the sustained release
formulation of the present invention can be further influenced,
i.e., adjusted to a desired rate, by the addition of one or more
release-modifying agents, or by providing one or more passageways
through the coating. The ratio of hydrophobic material to
water-soluble material is determined by, among other factors, the
release rate required and the solubility characteristics of the
materials selected.
[0123] The release-modifying agents that function as pore-formers
may be organic or inorganic, and include materials that can be
dissolved, extracted or leached from the coating in the environment
of use. The pore-formers may comprise one or more hydrophilic
materials such as hydroxypropylmethylcellulose.
[0124] The controlled release coatings of the present invention can
also include erosion-promoting agents such as starch and gums.
[0125] The controlled release coatings of the present invention can
also include materials useful for making microporous lamina in the
environment of use, such as polycarbonates comprised of linear
polyesters of carbonic acid in which carbonate groups reoccur in
the polymer chain.
[0126] The release-modifying agent may also comprise a
semi-permeable polymer.
[0127] In certain preferred embodiments, the release-modifying
agent is selected from hydroxypropylmethylcellulose, lactose, metal
stearates, and mixtures of any of the foregoing.
[0128] The controlled release coatings of the present invention may
also include an exit means comprising at least one passageway,
orifice, or the like. The passageway may be formed by such methods
as those disclosed in U.S. Pat. Nos. 3,845,770; 3,916,889;
4,063,064; and 4,088,864. The passageway can have any shape such as
round, triangular, square, elliptical, irregular, etc.
[0129] The substrate used in the practice of the present invention
may be prepared by a spheronizing agent together with the
methylphenidate that can be spheronized to form spheroids.
Microcrystalline cellulose is preferred. A suitable
microcrystalline cellulose is, for example, the material sold as
Avicel PH 101 (FMC Corporation). In such embodiments, in addition
to the methylphenidate and spheronizing agent, the spheroids may
also contain a binder. Suitable binders, such as low-viscosity,
water-soluble polymers, will be well known to those skilled in the
pharmaceutical art. However, water-soluble hydroxy lower alkyl
cellulose, such as hydroxypropylcellulose, are preferred.
Additionally (or alternatively) the spheroids may contain a water
insoluble polymer, especially an acrylic polymer, an acrylic
copolymer, such as a methacrylic acid-ethyl acrylate copolymer or
ethyl cellulose. In such embodiments, the controlled release
coating will generally include a water insoluble material such as
(a) a wax, either alone or in admixture with a fatty alcohol; or
(b) shellac or zein.
[0130] In one embodiment of the invention, the controlled release
methylphenidate formulation is prepared as a multilayered release
(MLR) formulation comprising coated inert beads. A summary of one
method of manufacturing such a formulation is outlined as follows.
First, immediate release (IR) methylphenidate beads are prepared by
spraying a solution of methylphenidate in water over sugar beads in
a fluid bed dryer with a drug load of about 8%. The spray process
is carried out in a fluid bed dryer, equipped with a Wurster
column. A clear overcoat of HPMC is applied using an Opadry
material (e.g., Opadry Clear (Formula No: YS-1-7006)), to a weight
gain of about 1%. Next, a controlled release coating is applied to
the IR beads, which converts the same into controlled release (CR)
beads. This is accomplished by spraying a solution of Eudragit RS
30 D, triethyl citrate (plasticizer) and talc (glidant), onto the
IR beads. Next, the coated beads are cured in order to obtain a
stabilized release rate of the methylphenidate. In preferred
embodiments of the present invention where the CR coating utilizes
an acrylic resin to control the release of the methylphenidate, the
CR beads at this stage are subjected to oven curing at a
temperature above the Tg of the plasticized acrylic polymer of the
required time period, the optimum values of the temperature and
time for the particular formulation being determined
experimentally. In certain embodiments of the present invention,
the stabilized product is obtained via oven curing conducted at a
temperature of about 40-50.degree. C. for a time period of about 12
to about 24 hours or longer. An enteric coating is then applied
onto the CR beads to convert the same into enteric coated CR (ECCR)
beads. This is accomplished by spraying a solution of Eudragit L 30
D-55 dispersion, triethyl citrate (plasticizer) and talc (glidant)
onto the CR beads. Finally, an immediate release coating is applied
onto the ECCR beads (referred to as, e.g., an IR Topcoat). This is
accomplished by spraying a solution of methylphenidate in water
over EC CR beads.
[0131] Matrix CR Carrier Systems
[0132] In certain preferred embodiments of the present invention,
the controlled release oral dosage form is produced using a
formulation that comprises a matrix controlled release carrier
system including the methylphenidate and a controlled release
carrier material (which may comprise one or more hydrophobic
materials, such as an alkylcellulose and/or an acrylic polymer as
previously defined herein). The materials suitable for inclusion in
a controlled release matrix will depend on the method used to form
the matrix.
[0133] Suitable materials for inclusion in the controlled release
matrices of the invention, in addition to methylphenidate,
include:
[0134] (A) hydrophilic and/or hydrophobic materials, such as gums;
alkylcelluloses; cellulose ethers, including hydroxyalkylcelluloses
and carboxyalkylcelluloses; acrylic resins, including all of the
acrylic polymers and copolymers discussed above, and
protein-derived materials. This list is not meant to be exclusive,
and any pharmaceutically acceptable hydrophobic material or
hydrophilic material that is capable of imparting the desired
controlled release profile of methylphenidate is meant to be
included herein. The dosage form may comprise, e.g., from about 1%
to about 80% by weight of such material.
[0135] In certain embodiments of the present invention, the
hydrophobic material is a pharmaceutically acceptable acrylic
polymer, including but not limited to acrylic acid and methacrylic
acid copolymers, methyl methacrylate, methyl methacrylate
copolymers, ethoxy-ethyl methacrylates, cyanoethyl methacrylate,
aminoalkyl methacrylate copolymer, poly(acrylic acid),
poly(methacrylic acid), methacrylic acid alkylamine copolymer,
poly(methyl methacrylate), poly(methacrylic acid)(anhydride),
polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride),
and glycidyl methacrylate copolymers. In other embodiments, the
hydrophobic material is selected from materials such as
hydroxyalkylcelluloses such as hydroxypropylmethylcellulose and
mixtures of the foregoing. In yet other embodiments, the
hydrophobic material is an alkylcellulose.
[0136] (B) digestible, long chain (C.sub.8-C.sub.50, especially
C.sub.12-C.sub.40), substituted or unsubstituted hydrocarbons, such
as fatty acids, fatty alcohols, glyceryl esters of fatty acids,
mineral and vegetable oils and natural or synthetic waxes,
polyhydric alcohols, including polyalkylene glycols. The oral
dosage form may contain up to 60% (by weight) of such material. In
certain embodiments, a combination of two or more hydrocarbon
materials are included in the matrix formulations. If an additional
hydrocarbon material is included, it is preferably selected from
natural and synthetic waxes, fatty acids, fatty alcohols, and
mixtures of the same.
[0137] Preferred hydrocarbons are water-insoluble with more or less
pronounced hydrophilic and/or hydrophobic trends, and have a
melting point from about 30.degree. C. to about 200.degree. C.,
preferably from about 45.degree. C. to about 90.degree. C.
[0138] For purposes of the present invention, a wax-like substance
is defined as any material that is normally solid at room
temperature and has a melting point of from about 30.degree. C. to
about 100.degree. C. Suitable waxes include, for example, beeswax,
glycowax, castor wax and carnauba wax.
[0139] Aliphatic alcohols used in the above compositions may be,
for example, lauryl alcohol, myristyl alcohol or stearyl, cetyl
and/or cetostearyl alcohol. The amount of aliphatic alcohol, if
included in the present controlled oral dosage forms, will be
determined, as above, by the precise rate of methylphenidate
release required. In certain embodiments, the oral dosage form
contains between 20% and 50% (by wt) aliphatic alcohol. When at
least one polyalkylene glycol is present in the oral dosage form,
then the combined weight of the at least one aliphatic alcohol and
the at least one polyalkylene glycol preferably constitutes between
20% and 50% (by wt) of the total dosage.
[0140] In one embodiment, the ratio of, e.g., the at least one
hydroxyalkyl cellulose or acrylic resin to the at least one
aliphatic alcohol/polyalkylene glycol used in the controlled
release formulation determines, to a considerable extent, the
release rate of the methylphenidate from the dosage form.
[0141] Suitable polyalkylene glycols include, for example,
polypropylene glycol or polyethylene glycol. The number average
molecular weight of the at least one polyalkylene glycol is
preferred between 1,000 and 15,000 especially between 1,500 and
12,000.
[0142] In addition to the above ingredients, a controlled release
matrix may also contain suitable quantities of other materials,
e.g. diluents, lubricants, binders, granulating aids, colorants,
flavorants and glidants that are conventional in the pharmaceutical
art.
[0143] In order to facilitate the preparation of a solid controlled
release oral dosage form according to this invention, any method of
preparing a matrix formulation known to those skilled in the art
may be used. For example incorporation in the matrix may be
effected, for example, by (a) forming granules comprising at least
one water-soluble hydroxyalkyl cellulose and methylphenidate; (b)
mixing the hydroxyalkyl cellulose containing granules with at least
one C.sub.2-C.sub.36 aliphatic alcohol; and (c) optionally,
compressing and shaping the granules. Preferably, the granules are
formed by wet granulating the hydroxyalkyl
cellulose/methylphenidate with water. In a particularly preferred
embodiment of this process, the amount of water added during the
wet granulation step is preferably between 1.5 and 5 times,
especially between 1.75 and 3.5 times, the dry weight of the
methylphenidate.
[0144] In yet other alternative embodiments, a spheronizing agent,
together with the methylphenidate can be spheronized to form
spheroids. Microcrystalline cellulose is preferred. A suitable
microcrystalline cellulose is, for example, the material sold as
Avicel PH 101 (FMC Corporation). In such embodiments, in addition
to the methylphenidate and spheronizing agent, the spheroids may
also contain a binder. Suitable binders, such as low viscosity,
water-soluble polymers, will be well known to those skilled in the
pharmaceutical art. However, water-soluble hydroxy lower alkyl
celluloses, such as hydroxypropylcellulose, are preferred.
Additionally (or alternatively) the spheroids may contain a
water-insoluble polymer, especially an acrylic polymer, an acrylic
copolymer, such as a methacrylic acid-ethyl acrylate co-polymer, or
ethyl cellulose. In such embodiments, the controlled release
coating will generally include a hydrophobic material such as a
wax, either alone or in admixture with a fatty alcohol; or shellac
or zein.
[0145] Melt-Extrusion Matrix CR Carrier Systems
[0146] In certain other embodiments of the present invention, the
controlled release matrices used in the dosage form may be prepared
via melt-granulation or melt-extrusion techniques. Such
formulations are described in U.S. Pat. Nos. 5,965,161 and
5,958,452. Generally, melt-granulation techniques involve melting a
normally solid hydrophobic material, e.g. a wax, and incorporating
a powdered drug therein. To obtain a controlled release dosage
form, it may be necessary to incorporate an additional hydrophobic
substance, e.g. ethylcellulose or a water-insoluble acrylic
polymer, into the molten wax hydrophobic material. Examples of
controlled release formulations prepared via melt-granulation
techniques are found in U.S. Pat. No. 4,861,598.
[0147] The additional hydrophobic material may comprise one or more
water-insoluble wax-like thermoplastic substances possibly mixed
with one or more wax-like thermoplastic substances being less
hydrophobic than said one or more water-insoluble, wax-like
substances. In order to achieve constant release, the individual
wax-like substances in the formulation should be substantially
non-degradable and insoluble in gastrointestinal fluids during the
initial release phases. Useful water-insoluble, wax-like substances
may be those with a water-solubility that is lower than about
1:5,000 (w/w).
[0148] In addition to the above ingredients, a controlled release
matrix may also contain suitable quantities of other materials,
e.g., diluents, lubricants, binders, granulating aids, colorants,
flavorants and glidants that are conventional in the pharmaceutical
art. The quantities of these additional materials will be
sufficient to provide the desired effect to the desired
formulation. In addition to the above ingredients, a controlled
release matrix incorporating melt-extruded multiparticulates may
also contain suitable quantities of other materials, e.g. diluents,
lubricants, binders, granulating aids, colorants, flavorants and
glidants that are conventional in the pharmaceutical art in amounts
up to about 50% by weight of the particulate if desired.
[0149] Specific examples of pharmaceutically acceptable carriers
and excipients that may be used to formulate oral dosage forms are
described in the Handbook of Pharmaceutical Excipients, American
Pharmaceutical Association (1986).
[0150] The preparation of a suitable melt-extruded controlled
release matrix according to the present invention may, for example,
include the steps of blending the methylphenidate together with at
least one hydrophobic material and preferably the additional
hydrophobic material to obtain a homogeneous mixture. The
homogeneous mixture is then heated to a temperature sufficient to
at least soften the mixture sufficiently to extrude the same. The
resulting homogeneous mixture is then extruded to form strands. The
extrudate is preferably cooled and cut into multiparticulates by
any means known in the art. The strands are cooled and cut into
multiparticulates. The multiparticulates are then divided into unit
doses. The extrudate preferably has a diameter of from about 0.1 to
about 5 mm and provides controlled release of the therapeutically
active agent for up to about 24 hours. The multiparticulates may be
divided into unit doses via placement into a gelatin capsule, or
may be compressed into a suitable tablet form.
[0151] An optional process for preparing the melt extrusions
includes directly metering into an extruder a hydrophobic material,
the methylphenidate, and an optional binder; heating the homogenous
mixture; extruding the homogenous mixture to thereby form strands;
cooling the strands containing the homogeneous mixture; cutting the
strands into particles having a size from about 0.1 mm to about 12
mm; and dividing said particles into unit doses.
[0152] The diameter of the extruder aperture or exit port can also
be adjusted to vary the thickness of the extruded strands.
Furthermore, the exit part of the extruder need not be round; it
can be oblong, rectangular, etc. The exiting strands can be reduced
to particles using a hot wire cutter, guillotine, etc.
[0153] Melt extruded multiparticulate systems can be provided in
the form of granules, spheroids or pellets depending upon the
extruder exit orifice. For purposes of the present invention, the
terms "melt-extruded multiparticulate(s)" and "melt-extruded
multiparticulate system(s)" and "melt-extruded particles" shall
refer to a plurality of units, preferably within a range of similar
size and/or shape and containing methylphenidate and one or more
excipients, preferably including a hydrophobic material as
described above. In this regard, the melt-extruded
multiparticulates will be of a range of from about 0.1 to about 12
mm in length and have a diameter of from about 0.1 to about 5 mm.
In addition, it is to be understood that the melt-extruded
multiparticulates can be any geometrical shape within this size
range. Alternatively, the extrudate may simply be cut into desired
lengths and divided into unit doses of the therapeutically active
agent without the need of a spheronization step.
[0154] In one particular embodiment, controlled release oral dosage
forms are prepared to include an effective amount of melt-extruded
multiparticulates within a capsule. For example, a plurality of the
melt-extruded multiparticulates may be placed in a gelatin capsule
in an amount sufficient to provide an effective controlled release
dose when ingested and contacted by gastric fluid.
[0155] In another embodiment, a suitable amount of the
multiparticulate extrudate is compressed into an oral tablet using
conventional tableting equipment using standard techniques.
Techniques and compositions for making tablets (compressed and
molded), capsules (hard and soft gelatin) and pills are also
described in Remington's Pharmaceutical Sciences, (Arthur Osol,
editor), 1553-1593 (1980).
[0156] In yet another embodiment, the extrudate can be shaped into
tablets as set forth in U.S. Pat. No. 4,957,681.
[0157] Optionally, the controlled release melt-extruded
multiparticulate systems or tablets can be coated, or the gelatin
capsule can be further coated, with a controlled release coating
such as the controlled release coatings described above. Such
coatings preferably include a sufficient amount of hydrophobic
material to obtain a weight gain level from about 2 to about 30
percent, although the overcoat may be greater.
[0158] The melt-extruded unit dosage forms of the present invention
may further include combinations of melt-extruded multiparticulates
containing methylphenidate before being encapsulated. Furthermore,
the unit dosage forms can also include an amount of an immediate
release methylphenidate for prompt therapeutic effect. The
immediate release methylphenidate may be incorporated, e.g., as
separate pellets within a gelatin capsule, or may be coated on the
surface of the multiparticulates after preparation of the dosage
forms (e.g., controlled release coating or matrix-based). The unit
dosage forms of the present invention may also contain a
combination of controlled release beads and matrix
multiparticulates to achieve a desired effect.
[0159] In other embodiments, the melt-extruded material is prepared
without the inclusion of the methylphenidate, which is added
thereafter to the extrudate. Such formulations typically will have
the methylphenidate blended together with the extruded matrix
material, and then the mixture would be tableted in order to
provide a slow release formulation.
[0160] The substrates of the present invention may be also be
prepared via a melt pelletization technique. In such circumstances,
the methylphenidate in finely divided form is combined with a
binder (also in particulate form and other optional inert
ingredients, and thereafter the mixture is pelletized, e.g., by
mechanically working the mixture in a high shear mixer to form the
pellets (granules, spheres). Thereafter, the pellets (granules,
spheres) may be sieved in order to obtain pellets of the requisite
size. The binder material is preferably in particulate form and has
a melting point above about 40.degree. C. Suitable binder
substances include, for example, hydrogenated castor oil,
hydrogenated vegetable oil, other hydrogenated fats, fatty acid
esters, fatty acid glycerides, and the like.
[0161] In accordance with the present invention, all of the
above-described controlled release oral methylphenidate dosage
forms (formed using Osmotic Controlled Release (CR) carrier
systems, Liquid CR carrier systems, Particulate CR carrier systems,
CR Matrix carrier systems and CR Melt-Extrusion Matrix carrier
systems) may be formulated so as to produce targeted plasma levels
of methylphenidate over a particular period. This is obviously of
great importance in maintaining a methylphenidate plasma level
within an appropriate therapeutic range to provide: (i) an initial
increasing in vivo rate of release of methylphenidate from the
controlled release system suitable to provide an initial
increasing-rate phase of less than or equal to about 2 hours, and
sufficient to provide a therapeutically effective amount of
methylphenidate for a rapid onset of action; (ii) a second,
zero-order or decreasing (i.e., non-ascending) in vivo rate of
release of methylphenidate from the controlled release system that
provides a subsequent zero order- or decreasing-rate phase
sufficient to provide a therapeutically effective amount of
methylphenidate through at least about 11 to 12 hours post
administration; and (iii) a single T.sub.max of about 5.5 to 7.5
hours post administration. The exact time to maximum plasma
concentration may be adjusted by adjusting various components of
the controlled release carrier system as taught herein. The novel
and unique in vivo methylphenidate release kinetics provided by the
oral controlled release dosage forms of the present invention are
sufficient to provide the methylphenidate in vivo PK profile
depicted in FIG. 7.
[0162] Once per day (QD) is typically used to maintain a sufficient
clinical effect, e.g., to treat ADD or ADHD. Other dosage regimens
may be determined by a physician in accordance with standard
practices.
[0163] Abuse-Resistant Controlled Release Systems
[0164] In U.S. Patent Publication No. US 2004/0161382, hereinafter
referred to as the "382 Publication", certain pharmaceutical dosage
forms and drug-delivery devices suitable for oral delivery of
pharmacologically active agents are described. These novel dosage
forms and devices feature a unique combination of pharmaceutical
excipients including an HVLCM, a network former, and an optional
rheology modifier and/or a solvent that together provide a
controlled release carrier system. The controlled release carrier
system is loaded with an active agent of interest, and will release
the same over a period of time when in an aqueous environment, and
in particular, an environment similar to that of the GI tract of a
mammal. The controlled release carrier system can further provide
the added benefit of enhanced abuse-resistance, wherein the carrier
system resists various physical disruption and other in vitro
extraction techniques (e.g., extraction into ethanol, water or
other common solvents) that could be employed by someone wishing to
disable the controlled release function of the system to access
substantially all or most of the sequestered active agent in an
immediate release form that can be ingested, inhaled or injected to
provide a euphoric effect. The 382 Publication therefore describes
a number of controlled release carrier systems that can be used to
produce oral dosage forms or delivery devices that provide
desirable controlled release kinetics and/or abuse-resistance
characteristics.
[0165] It is a primary object of the present invention to provide
for improved methylphenidate controlled release oral dosage forms,
where such improved dosage forms are based upon the controlled
release carrier systems described in the 382 Publication. In this
regard, there has remained a need in the art to provide a
controlled release carrier system that provides all of the benefits
of those described in the 382 Publication as well as providing
enhanced safety features and/or abuse-resistance properties in
addition to enhanced in vivo pharmacological performance. One of
the key hindrances facing the skilled person desiring to provide
such a controlled release carrier system resides in the very nature
of the carrier system itself. More particularly, the unique
controlled release carrier system is responsible for in vivo
pharmacological performance, where the active agent must be
delivered from the system by diffusion from the system as it
transits the GI tract. This same controlled release carrier system
is also responsible for the in vitro abuse-resistance and in vivo
safety performance, that is, the carrier system must prevent active
agent from leaving the system when contacted with very efficient
aqueous solvents and/or prolonged exposure to aqueous environments
having a low or high pH.
[0166] Thus, manipulations that can be made to the controlled
release system in order to, for example, increase overall delivery
efficiency (AUC) or to provide for extended release rates
(manipulations designed to increase release of the active agent
from the controlled release carrier system) typically will
frustrate the in vitro abuse-resistance and in vivo safety
performance of that same system. This is because, generally,
formulation manipulations that increase C.sub.max or decrease
T.sub.max can frustrate abuse-resistance by allowing more/faster
extractability (e.g., changes designed to increase rate/extent of
in vivo drug release also increase rate/extent of in vitro drug
release when attempts are made to defeat the controlled release
mechanism of a dosage form).
[0167] The term "AUC" means the area under the curve obtained from
an in vivo assay in a subject by plotting blood plasma
concentration of the active agent in the subject against time, as
measured from the time of administration, to a time "T" after
administration. The time T will correspond to the delivery period
of the active agent to a subject. In like manner, manipulations
that can be made to the controlled release system in order to
enhance in vitro abuse-resistance and in vivo safety performance
(manipulations designed to decrease release of active agent from
the controlled release carrier system) typically will frustrate the
in vivo pharmacological performance of that same system. As used
throughout this specification and the attached claims, the terms
"abuse-resistance" and abuse-resistant" are completely
interchangeable with the related terms "abuse-deterrence" and
"abuse-deterrent", as well as "tamper-resistance" and
"tamper-resistant", and thus mean exactly the same thing.
[0168] Accordingly, it is a primary object of the invention to
provide a controlled release oral pharmaceutical dosage form that
comprises methylphenidate in a controlled release carrier system.
The subject dosage form is characterized by: (i) a first,
increasing in vivo rate of release of methylphenidate from the
controlled release system that provides an initial increasing-rate
phase of less than or equal to about 2 hours, and is sufficient to
provide a therapeutically effective amount of methylphenidate for a
rapid onset of action; (ii) a second, zero-order or decreasing
(i.e., non-ascending) in vivo rate of release of methylphenidate
from the controlled release system that provides a subsequent zero
order- or decreasing-rate phase sufficient to provide a
therapeutically effective amount of methylphenidate through at
least about 11 to 12 hours post administration; (iii) a single
T.sub.max of about 5.5 to 7.5 hours post administration; and (iv)
the dosage form is abuse-resistant. The novel and unique in vivo
methylphenidate release kinetics provided by the abuse-resistant
oral dosage forms of the present invention are sufficient to
provide the methylphenidate in vivo PK profile depicted in FIG. 7.
By "abuse-resistant", herein, it is meant that the dosage form is
resistant to extraction in ethanol (80 proof) such that: less than
about 50%, preferably less than about 45% and more preferably less
than about 25 to 40% of the active agent is extracted after 60
minutes of extraction in ethanol at ambient temperature (RT); and
less than about 30%, more preferably less than about 28% and more
preferably less than about 25 to 27% of the active agent is
extracted after 60 minutes of extraction in ethanol at 60.degree.
C. By the term "ambient temperature", used interchangeably herein
with "room temperature" and/or "RT", is meant the normal
temperature of a working area or laboratory and ranges from about
18 to 25.degree. C., and is more particularly used herein to denote
a normal temperature of 25.degree. C. Suitable in vitro test
methodology, techniques, apparatus and equipment to determine if a
dosage form is properly resistant to extraction in ethanol are
described below in Example 3. In certain preferred embodiments, the
"abuse-resistant" dosage form is also resistant to extraction in a
panel of common household solvents, that is, the dosage form is
further resistant to extraction in one or more of the following
solvents: hot and cold water; hot tea; cola soft drinks; saturated
baking soda solution; vinegar; strong acid (e.g., HCl); and aqueous
buffers ranging from pH1 to pH12.
[0169] In certain other preferred embodiments of the invention, the
abuse-resistant oral pharmaceutical dosage forms comprise a
controlled release carrier system that can provide a decreased risk
of misuse or abuse. An important advantage of the dosage forms
disclosed herein is that they have abuse-resistant characteristics
and/or reduced risk of diversion. In this regard, the formulation
contained within the dosage form (the controlled release carrier
system and the methylphenidate) is neither susceptible to common
crushing, pulverization or attrition techniques, nor susceptible to
extraction using common household solvents such as ethanol. In
addition, the formulation contained within the dosage form (the
controlled release carrier system and the methylphenidate) is also
not susceptible to common heat extraction techniques (e.g.,
microwaving), vaporization techniques (e.g., volatilization or
smoking), nor injection techniques due to very poor syringeability
and/or injectability properties of the formulation.
[0170] Specifically, since the abuse-resistant dosage forms of the
present invention are provided as a highly viscous liquid, the
formulations avoid the possibility of crushing for the purpose of
inhalation. However, in a particular aspect of the invention,
enhanced safety features can further be provided by the controlled
release carrier system. In this regard, the subject dosage forms
are characterized as having either one or both of the following
enhanced safety features: the controlled release carrier system is
characterized by a low in vitro solvent extractability value of the
methylphenidate from the dosage form; and/or the carrier system is
characterized by the absence of any significant effect on
absorption of the methylphenidate from the dosage form upon
co-ingestion of the dosage form with ethanol by a subject, or upon
chewing (masticating) or holding the tablet within the mouth
(buccal cavity) instead of swallowing the dosage form whole as
intended. This second feature, so-called "dose-dumping" is of
critical concern to regulatory agencies concerned with the safety
of potent pharmaceutical agents. This is because, unlike the
standard concerns about intentional abuse, a patient may
inadvertently take a controlled release dosage form containing a
high potency or dangerous active agent with a glass of wine, or a
cocktail, or a child may find a dropped capsule and chew the same.
If this activity is enough to defeat the controlled release system,
the dosage form could be considered unsafe for this important
safety reason.
[0171] Accordingly, in certain particularly preferred embodiments
of the invention, an abuse-resistant oral methylphenidate dosage
form is provided that is characterized by: (i) a first, increasing
in vivo rate of release of methylphenidate from the controlled
release system that provides an initial increasing-rate phase of
less than or equal to about 2 hours, and is sufficient to provide a
therapeutically effective amount of methylphenidate for a rapid
onset of action; (ii) a second, zero-order or decreasing (i.e.,
non-ascending) in vivo rate of release of methylphenidate from the
controlled release system that provides a subsequent zero order- or
decreasing-rate phase sufficient to provide a therapeutically
effective amount of methylphenidate through at least about 11 to 12
hours post administration; (iii) a single T.sub.max of about 5.5 to
7.5 hours post administration; and (iv) the controlled release
carrier system provides a decreased risk of misuse or abuse,
characterized by the absence of any significant effect on
absorption of the methylphenidate from the dosage form upon
co-ingestion of the dosage form with ethanol by a subject. The
novel and unique in vivo methylphenidate release kinetics provided
by the abuse-resistant oral dosage forms of the present invention
are sufficient to provide the methylphenidate in vivo PK profile
depicted in FIG. 7. The ability of an abuse-resistant oral dosage
form to avoid this dose-dumping effect can be assessed using
carefully controlled in vivo human clinical trial methods such as
those described below in Example 5. By "no significant effect", it
is meant that both the C.sub.max ratio and the AUC ratio of
absorption of the methylphenidate from the dosage form when taken
with water, or with 4%, 20% or 40% ethanol is within a range of
about 0.8 to 1.2.
[0172] In another particularly preferred embodiment of the
invention, an abuse-resistant oral methylphenidate dosage form is
provided that is characterized by: (i) a first, increasing in vivo
rate of release of methylphenidate from the controlled release
system that provides an initial increasing-rate phase of less than
or equal to about 2 hours, and is sufficient to provide a
therapeutically effective amount of methylphenidate for a rapid
onset of action; (ii) a second, zero-order or decreasing (i.e.,
non-ascending) in vivo rate of release of methylphenidate from the
controlled release system that provides a subsequent zero order- or
decreasing-rate phase sufficient to provide a therapeutically
effective amount of methylphenidate through at least about 11 to 12
hours post administration; (iii) a single T.sub.max of about 5.5 to
7.5 hours post administration; and (iv) a controlled release
carrier system that provides for a decreased risk of misuse or
abuse, characterized by a low in vitro solvent extractability value
of the methylphenidate from the dosage form. The novel and unique
in vivo methylphenidate release kinetics provided by the
abuse-resistant oral dosage forms of the present invention are
sufficient to provide the methylphenidate in vivo PK profile
depicted in FIG. 7. Suitable in vitro test methodology, techniques
and apparatus to determine if a dosage form is properly
characterized as having "a low in vitro solvent extractability
value" are described below in Example 3. In summary, a test dosage
form can be placed within a suitable amount of a liquid that my be
readily obtained, for example water, alcohol (ethanol), soft
drinks, vinegar, baking soda solutions, and the like. After a
suitable time (and, for example, with suitable agitation or
application of heat), the liquid "extraction solvent" can be tested
for the presence of extracted methylphenidate. Any number of such
liquids can be assembled into a "panel" of extraction solvents for
the purposes of such testing. Accordingly, in these preferred
embodiments, the abuse-resistant dosage form is resistant to
extraction across a panel of common household solvents.
[0173] The controlled release carrier systems that are employed in
the abuse-resistant oral pharmaceutical dosage forms disclosed and
claimed herein are formed by the combination of a High Viscosity
Liquid Carrier Material ("HVLCM"), a network former, and a rheology
modifier. An HVLCM is a non-polymeric, non-water soluble liquid
material having a viscosity of at least 5,000 cP at 37.degree. C.
that will not crystallize neat under ambient or physiological
conditions. The term "non-water soluble" refers to a material that
is soluble in water to a degree of less than one percent by weight
under ambient conditions. The term "non-polymeric" refers to esters
or mixed esters having essentially no repeating units in the acid
moiety of the ester, as well as esters or mixed esters having acid
moieties wherein functional units in the acid moiety are repeated a
small number of times (i.e., oligomers). Generally, materials
having more than five identical and adjacent repeating units or
mers in the acid moiety of the ester are excluded by the term
"non-polymeric" as used herein, but materials containing dimers,
trimers, tetramers, or pentamers are included within the scope of
this term. When the ester is formed from hydroxy-containing
carboxylic acid moieties that can further esterify, such as lactic
acid or glycolic acid, the number of repeat units is calculated
based upon the number of lactide or glycolide moieties, rather than
upon the number of lactic acid or glycolic acid moieties, where a
lactide repeat unit contains two lactic acid moieties esterified by
their respective hydroxy and carboxy moieties, and where a
glycolide repeat unit contains two glycolic acid moieties
esterified by their respective hydroxy and carboxy moieties. Esters
having 1 to about 20 etherified polyols in the alcohol moiety
thereof, or 1 to about 10 glycerol moieties in the alcohol moiety
thereof, are considered non-polymeric as that term is used herein.
HVLCMs may be carbohydrate-based, and may include one or more
cyclic carbohydrates chemically combined with one or more
carboxylic acids. HVLCMs also include non-polymeric esters or mixed
esters of one or more carboxylic acids, having a viscosity of at
least 5,000 cP at 37.degree. C., that do not crystallize neat under
ambient or physiological conditions, wherein when the ester
contains an alcohol moiety (e.g., glycerol). The ester may, for
example comprise from about 2 to about 20 hydroxy acid moieties.
Various HVLCMs used with the present controlled release carrier
systems are described in U.S. Pat. Nos. 5,747,058; 5,968,542; and
6,413,536. The present invention may employ any HVLCM described in
these patents but is not limited to any specifically described
materials. The HVLCM is typically present in a dosage form
according to the invention in an amount of from 30 to 60%, for
example from 35 to 45%, by weight.
[0174] In certain preferred embodiments of the invention, the
controlled release carrier system comprises Sucrose Acetate
Isobutyrate ("SAIB") as the HVLCM. SAIB is a non-polymeric highly
viscous liquid at temperatures ranging from -80.degree. C. to over
100.degree. C., it is a fully esterified sucrose derivative. The
chemical structure of SAIB is depicted herein as FIG. 13. The SAIB
material is available from a variety of commercial sources
including Eastman Chemical Company, where it is available as a
mixed ester that does not crystallize but exists as a very highly
viscous liquid. It is a hydrophobic, non-crystalline, low molecular
weight molecule that is water insoluble and has a viscosity that
varies with temperature. For example, pure SAIB exhibits a
viscosity of approximately 2,000,000 centipoise (cP) at ambient
temperature (RT) and approximately 600 cP at 80.degree. C. The SAIB
material has unique solution-viscosity relationship in that a SAIB
solution established in a number of organic solvents has a
significantly lower viscosity value than the pure SAIB material,
and therefore the SAIB-organic solvent solutions render themselves
capable of processing using conventional equipment such as mixers,
liquid pumps and capsule production machines. SAIB also has
applications in drug formulation and delivery, for example as
described in U.S. Pat. Nos. 5,747,058; 5,968,542; 6,413,536; and
6,498,153. In the present invention, SAIB may be used as the HVLCM
and may be present in quantities that vary significantly. For
example, quantities of at least about 30, 35, 40, 50, 60, or from
61 to 99.9 percent by weight of the HVLCM, which can include one or
more suitable HVLCM, relative to the total weight of the
formulation (wt %) used to make the dosage form can be used.
Typically, SAIB is present in a dosage form according to the
invention in an amount of from 30 to 60% by weight, for example
from 35 to 45% by weight.
[0175] In certain circumstances, it may be beneficial to provide a
SAIB carrier material having a lower peroxide level to avoid
peroxide-based degradation of various components of the controlled
release carrier system and/or active agent. See, e.g., U.S. Patent
Publication Number US 2007/0027105, "Peroxide Removal From Drug
Delivery Vehicle". Various specific pharmaceutical formulations
containing SAIB at about 40 wt % that are used to produce suitable
dosage forms are discussed in the examples.
[0176] A "rheology modifier", as used herein, refers to a substance
that possesses both a hydrophobic and a hydrophilic moiety.
Rheology modifiers used in the practice of the invention generally
have a logarithm of octanol-water partition coefficient ("LogP") of
between about -7 and +15, preferably between -5 and +10, more
preferable between -1 and +7. In addition, the rheology modifier
will typically have a molecular weight of around 1,000 daltons or
less. Rheology refers to the property of deformation and/or flow of
a liquid material, and rheology modifiers are used to modify
(lower) viscosity and (increase) flowability of the HVLCM and other
constituents used in the controlled release carrier system, that
is, to plasticize the HVLCM and other constituents. The rheology
modifier may thus be a plasticizer, typically a plasticizer for the
HVLCM. Rheology modifiers that are useful herein include, for
example, caprylic/capric triglyceride (Migliol 810), isopropyl
myristate ("IPM"), ethyl oleate, triethyl citrate, dimethyl
phthalate, labrafil, labrasol, Gelucires, and benzyl benzoate. In
certain preferred embodiments of the invention, the rheology
modifier is IPM. The IPM material is a pharmaceutically acceptable
hydrophobic solvent. The rheology modifier, which can include one
or more suitable rheology modifier material, can be present in the
formulations at from about 0.1 to about 20 percent by weight
relative to the total weight of the formulation (wt %) used to
produce the dosage forms of the present invention, preferably at
from about 1 to about 18 wt %, and more preferably at from about 2
to about 15 wt %.
[0177] A "network former" refers to a material or compound that
forms a network structure when introduced into a liquid medium
(such as a HVLCM or a controlled release carrier system comprising
an HVLCM). Network formers may be added to the liquid formulation
such that, upon exposure to an aqueous environment, they form a
three dimensional network within the formulation. While not wishing
to be bound by any particular theory, it is believed that the
network former allows the formation of a micro-network within the
formulation upon exposure to an aqueous environment. This
micro-network formation appears to be due, at least in part, to a
phase inversion (e.g., a change in glass transition temperature,
T.sub.g) of the network former. The result is believed to be a skin
or surface layer of precipitated network former at the interface
between the dosage form and the aqueous environment of the GI
tract, as well as the formation of a three-dimensional
micro-network of precipitated network former within the dosage
form. The network forwer is selected so as to have good solubility
in the selected solvent used in the formulations, for example a
solubility of between about 0.1 and 20 wt %. Additionally, good
network formers will typically have a LogP between about -1 to 7.
Suitable network formers include, for example, cellulose acetate
butyrate ("CAB"), carbohydrate polymers, organic acids of
carbohydrate polymers and other polymers, hydrogels, cellulose
acetate phthalate, ethyl cellulose, Pluronic, Eudragit, Carbomer,
hydroxyl propyl methyl cellulose, other cellulose acetates such as
cellulose triacetate, PMMA, as well as any other material capable
of associating, aligning or congealing to form three-dimensional
networks in an aqueous environment. A particularly preferred
network former for use in the practice of the invention is
cellulose acetate butyrate grade 381-20 BP ("CAB 381-20" available
from Eastman Chemicals). CAB 381-20 is a non-biodegradible polymer
material that has the following chemical and physical
characteristics: butyryl content of 36%, acetyl content of 15.5%,
hydroxy content of 0.8%, a melting point of 185-196.degree. C.,
glass transition temperature of 128.degree. C., and a molecular
weight number average of 66,000 to 83,000. Preferably, if a CAB
material is used in the present formulations, it should be
subjected to an ethanol washing step (and subsequent drying step)
prior to addition to the formulation in order to remove potential
contaminants therefrom. The network former, which can include one
or more suitable network former materials, can be present in the
formulations at from about 0.1 to about 20 percent by weight
relative to the total weight of the formulation (wt %), preferably
at from about 1 to about 18 wt %, more preferably at from about 2
to about 10 wt %, and even more preferably at from about 4 to about
6 wt %.
[0178] In addition to the combination of the HVLCM, network former
and rheology modifier materials discussed above, the controlled
release carrier systems that are employed in the abuse-resistant
oral methylphenidate dosage forms disclosed and claimed herein can
further include a number additional excipient materials including
solvents, viscosity enhancing agents, hydrophilic agents,
surfactants, and stabilizing agents.
[0179] The term "solvent", as used herein, refers to any substance
that dissolves another substance (solute). Solvents may be used in
the controlled release carrier systems of the present invention to
dissolve one or more of the following constituents: HVCLMs; active
agents; network formers; rheology modifiers; viscosity enhancing
agents; hydrophilic agents; surfactants; and stabilizing agents.
Preferably, the solvent can dissolve both the HVLCM and the network
former. In addition, materials that can serve as rheology modifiers
in certain controlled release carrier systems can also serve the
function as a solvent to one or more constituent (e.g., the HVLCM,
or the methylphenidate), or serve solely as a solvent in other
carrier systems. One example of such a solvent is IPM, which is a
hydrophobic solvent. In one embodiment of the invention, therefore,
a dosage form may comprise both a hydrophilic solvent and a
hydrophobic solvent. Organic solvents suitable for use with the
present invention include, but are not limited to: substituted
heterocyclic compounds such as N-methyl-2-pyrrolidone (NMP) and
2-pyrrolidone (2-pyrol); triacetin; esters of carbonic acid and
alkyl alcohols such as propylene carbonate, ethylene carbonate and
dimethyl carbonate; fatty acids such as acetic acid, lactic acid
and heptanoic acid; alkyl esters of mono-, di-, and tricarboxylic
acids such as 2-ethyoxyethyl acetate, ethyl acetate, methyl
acetate, ethyl lactate, ethyl butyrate, diethyl malonate, diethyl
glutonate, tributyl citrate, diethyl succinate, tributyrin,
isopropyl myristate (IPM), dimethyl adipate, dimethyl succinate,
dimethyl oxalate, dimethyl citrate, triethyl citrate, acetyl
tributyl citrate, glyceryl triacetate; alkyl ketones such as
acetone and methyl ethyl ketone; ether alcohols such as
2-ethoxyethanol, ethylene glycol dimethyl ether, glycofurol and
glycerol formal; alcohols such as benzyl alcohol, ethanol and
propanol; polyhydroxy alcohols such as propylene glycol,
polyethylene glycol (PEG), glycerin (glycerol), 1,3-butyleneglycol,
and isopropylidene glycol (2,2-dimethyl-1,3-dioxolone-4-methanol);
Solketal; dialkylamides such as dimethylformamide,
dimethylacetamide; dimethylsulfoxide (DMSO) and dimethylsulfone;
tetrahydrofuran; lactones such as E-caprolactone and butyrolactone;
cyclic alkyl amides such as caprolactam; aromatic amides such as
N,N-dimethyl-m-toluamide, and 1-dodecylazacycloheptan-2-one; and
the like; and mixtures and combinations thereof Preferred solvents
include triacetin, N-methyl-2-pyrrolidone, 2-pyrrolidone,
dimethylsulfoxide, ethyl lactate, propylene carbonate, and
glycofurol. In one particular preferred embodiment, the solvent is
triacetin which is a hydrophilic solvent. The hydrophilic triacetin
solvent can preferably be combined with the IPM rheology modifier
which is a hydrophobic solvent to provide a solvent
hydrophobic/hydrophilic solvent system within the controlled
release carrier system. The solvent, which can include one or more
suitable solvent materials, can be present in the formulations at
from about 0.1 to about 40 percent by weight relative to the total
weight of the formulation (wt %), preferably at from about 1 to
about 35 wt %, more preferably at from about 10 to about 30 wt %,
and even more preferably at from about 15 to about 28 wt %.
[0180] A "viscosity enhancing agent" or "second viscosity enhancing
agent" is a material that can be added to the controlled release
carrier system in order to increase the viscosity of the resulting
carrier system. Viscosity enhancing agents can be selected to have
good hydrogen bonding capability, such as a bonding capability
greater than or equal to one per molecule. In certain cases, the
viscosity enhancing agent has very low to no significant solubility
in the formulation. If the agent is soluble, then preferably the
solubility is less than 50 wt %. For inorganic or mineral viscosity
enhancing agents, it is preferable if the material has a specific
surface area greater than or equal to about 100 m2/g. For those
skilled in the use of pharmaceutical systems using an HVLCM,
particularly SAIB, it is generally known that as the viscosity of
the controlled release system increases, e.g., as a solvent for the
HVLCM leaves the system or by addition of a polymer material,
release of the active agent from that carrier system will typically
slow down since the HVLCM carrier matrix material has become more
resistant to diffusion of the agent from the matrix material.
Accordingly, it may be counter-intuitive for the skilled person to
purposefully enhance (increase) the overall viscosity of the
present controlled release carrier systems when it is desired to
enhance the in vivo pharmacological performance of such systems to,
for example, extend and/or increase the release performance to
increase bioavailability of an active agent. However, it has been
found that in certain dosage forms of the present invention, the
addition of a viscosity enhancing agent can be used to provide
dosage forms having enhanced in vivo pharmacological performance as
well as enhanced safety features and/or abuse-resistance properties
as required herein. Suitable viscosity enhancing agents include
biodegradable and non-biodegradable polymer materials. Non-limiting
examples of suitable biodegradable polymers and oligomers include:
poly(lactide), poly(lactide-co-glycolide), poly(glycolide),
poly(caprolactone), polyamides, polyanhydrides, polyamino acids,
polyorthoesters, polycyanoacrylates, poly(phosphazines),
poly(phosphoesters), polyesteramides, polydioxanones, polyacetals,
polyketals, polycarbonates, polyorthocarbonates, degradable
polyurethanes, polyhydroxybutyrates, polyhydroxyvalerates,
polyalkylene oxalates, polyalkylene succinates, poly(malic acid),
chitin, chitosan, and copolymers, terpolymers, oxidized cellulose,
hydroxyethyl cellulose, or combinations or mixtures of the above
materials. Suitable non-biodegradable polymers include:
polyacrylates, ethylene-vinyl acetate polymers, cellulose and
cellulose derivatives, acyl substituted cellulose acetates and
derivatives thereof including cellulose acetate butyrate (CAB),
which is also used herein as a network former, non-erodible
polyurethanes, polystyrenes, polyvinyl chloride, polyvinyl
fluoride, polyvinyl (imidazole), chlorosulphonated polyolefins,
polyethylene oxide, and polyethylene. Other suitable viscosity
enhancing materials include stiffening agents such as clay
compounds, including, talc, bentonite and kaolin, and metal oxides
including silicon dioxide, zinc oxide, magnesium oxide, titanium
oxide, and calcium oxide. In one preferred embodiment of the
invention, a colloidal silicon dioxide (Cab-O-Sil) is used as a
viscosity enhancing agent in a controlled release carrier system
that further contains CAB as a network former. The colloidal
silicon dioxide may further be characterized as a thixtropic agent
since it is thought to enhance viscosity at resting conditions,
which may be useful for product stability purposes, while also
serving as viscosity thinning agent under conditions of mechanical
stress which may be useful for controlled release performance. The
viscosity enhancing agent, which can include one or more suitable
viscosity enhancing material, can be present in the formulations at
from about 0.01 to about 10 percent by weight relative to the total
weight of the formulation (wt %) used to produce the dosage forms
of the present invention, preferably at from about 0.1 to about 6
wt %, and more preferably at from about 1 to about 2 wt %.
[0181] Materials that can be used as "hydrophilic agents" in the
practice of the invention include those that have natural affinity
for aqueous systems. A material may be regarded as a hydrophilic
agent for the purposes of this invention if the material displays a
water sorption between about 10 to 100% (w/w). Hydrophilic agents
will have a low LogP value. As discussed herein above, there are a
number of constituents used to produce the controlled release
carrier systems of the present invention that can be classed as a
hydrophilic material (e.g., a hydrophilic solvent), or at least a
material having a hydrophilic portion (e.g., a rheology modifier).
Since the HVLCM material used in the present carrier systems is
hydrophobic, it may be useful to include other materials in the
carrier system that are hydrophilic in order to provide a carrier
system that is balanced to have both hydrophobic and hydrophilic
characteristics. For example, it is believed that the inclusion of
one or more hydrophilic agent in the controlled release carrier
systems of the present invention may participate in the control of
methylphenidate diffusion from the carrier system. Accordingly,
suitable hydrophilic agents include, but are not limited to, sugars
such as sorbitol, lactose, mannitol, fructose, sucrose and
dextrose, salts such as sodium chloride and sodium carbonate,
starches, hyaluronic acid, glycine, fibrin, collagen, polymers such
as hydroxylpropylcellulose ("HPC"), carboxymethylcellulose,
hydroxyethyl cellulose ("HEC"); polyethylene glycol and
polyvinylpyrrolidone, and the like. In a particularly preferred
embodiment, a controlled release carrier system is provided that
includes HEC as a hydrophilic agent. The hydrophilic agent, which
can include one or more suitable hydrophilic agent material, can be
present in the formulations at from about 0.1 to about 10 percent
by weight relative to the total weight of the formulation (wt %)
used to produce the dosage forms of the present invention,
preferably at from about 1 to about 8 wt %, and more preferably at
from about 3 to about 6 wt %. The hydrophilic agent may
alternatively constitute the "first viscosity enhancing agent" of
an embodiment of the invention.
[0182] Materials that can be used as "surfactants" in the practice
of the invention include neutral and/or anionic/cationic
excipients. Accordingly, suitable charged lipids include, without
limitation, phosphatidylcholines (lecithin), and the like.
Detergents will typically be a nonionic, anionic, cationic or
amphoteric surfactant. Examples of suitable surfactants include,
for example, Tergitol.RTM. and Triton.RTM. surfactants (Union
Carbide Chemicals and Plastics); polyoxyethylenesorbitans, e.g.,
TWEEN.RTM. surfactants (Atlas Chemical Industries); polysorbates;
polyoxyethylene ethers, e.g. Brij; pharmaceutically acceptable
fatty acid esters, e.g., lauryl sulfate and salts thereof;
ampiphilic surfactants (glycerides, etc.); Gelucires (saturated
polyglycolized glyceride (e.g., Gattefosse brand); and like
materials. Surfactants, which can include one or more suitable
surfactant material, can be present in the formulations at from
about 0.01 to about 5 percent by weight relative to the total
weight of the formulation (wt %) used to produce the dosage forms
of the present invention, preferably at from about 0.1 to about 5
wt %, and more preferably at from about 0.1 to about 3 wt %.
[0183] Materials that can be used as stabilizing agents in the
practice of the invention include any material or substance that
can inhibit or reduce degradation (e.g., by chemical reactions) of
other substances or substances in the controlled release carrier
system with which the stabilizer is mixed. Exemplary stabilizers
typically are antioxidants that prevent oxidative damage and
degradation, e.g., sodium citrate, ascorbyl plamitate, vitamin A,
and propyl gallate and/or reducing agents. Other examples include
ascorbic acid, vitamin E, sodium bisulfite, butylhydroxyl toluene
("BHT"), BHA, acetylcysteine, monothioglycerol,
phenyl-alpha-nathylamine, lecithin, and EDTA. These stabilizing
materials, which can include one or more suitable such materials,
can be present in the formulations at from about 0.001 to about 2
percent by weight relative to the total weight of the formulation
(wt %) used to produce the dosage forms of the present invention,
preferably at from about 0.01 to about 0.1 wt %, and more
preferably at from about 0.01 to about 0.02 wt %.
[0184] An oral abuse-resistant methylphenidate dosage form
comprising a controlled release carrier system which comprises a
HVLCM, a network former, a rheology modifier, a hydrophilic agent
and a solvent can thus contain: (a) from 1.3 to 35 wt % such as 5
to 10 wt % of the methylphenidate; (b) from 2 to 10 wt % such as 4
to 6 wt % of the network former; (c) from 0.1 to 20 wt % for
example 2 to 15 wt % of the rheology modifier; (d) from 1 to 8 wt %
for example 3 to 6 wt % of the hydrophilic agent; (e) from 10 to 40
wt % for example from 10 to 30 wt % of the solvent; and (f) from 30
to 60 wt % such as 35 to 45 wt % of the HVLCM. Typically, the HVLCM
is sucrose acetate isobutyrate (SAIB); the network former is
selected from cellulose acetate butyrate (CAB), cellulose acetate
phthalate, ethyl cellulose, hydroxypropylmethyl cellulose and
cellulose triacetate; the rheology modifier is selected from
isopropyl myristate (IPM), caprylic/capric triglyceride, ethyl
oleate, triethyl citrate, dimethyl phthalate and benzyl benzoate;
the hydrophilic agent is selected from hydroxyethylcellulose (HEC),
hydroxypropylcellulose, caboxymethylcellulose, polyethylene glycol
and polyvinylpyrrolidone; and the solvent is selected from
triacetin, N-methyl-2-pyrrolidone, 2-pyrrolidone,
dimethylsulfoxide, ethyl lactate, propylene carbonate and
glycofurol. Preferably, the HVLCM is SAIB, the network former is
CAB, the rheology modifier is IPM, the hydrophilic agent is HEC,
and the solvent is triacetin.
[0185] The controlled release carrier system can further comprise a
viscosity enhancing agent such as silicon dioxide. The viscosity
enhancing agent is typically present in an amount from 0.1 to 6 wt
% such as 1 to 2 wt %.
[0186] In an alternative embodiment, an oral abuse-resistant
methylphenidate dosage form comprising a controlled release carrier
system which comprises a HVLCM, a network former, a first viscosity
enhancing agent, a hydrophilic solvent and a hydrophobic solvent,
can contain: (a) from 1.3 to 35 wt % such as 5 to 10 wt % of the
methylphenidate; (b) from 2 to 10 wt % such as 4 to 6 wt % of the
network former; (c) from 1 to 8 wt % for example 3 to 6 wt % of the
first viscosity enhancing agent; (d) from 10 to 40 wt % for example
10 to 30 wt % of the hydrophilic solvent; (e) from 0.1 to 20 wt %
for example from 2 to 15 wt % of the hydrophobic solvent; and (f)
from 30 to 60 wt % such as 35 to 45 wt % of the HVLCM. Typically in
this embodiment the HVLCM is SAIB; the network former is selected
from CAB, cellulose acetate phthalate, ethyl cellulose,
hydroxypropylmethyl cellulose and cellulose triacetate; the first
viscosity enhancing agent is HEC, hydroxypropylcellulose,
carboxymethylcellulose, polyethylene glycol and
polyvinylpyrrolidone; the hydrophilic solvent is selected from
triacetin, N-methyl-2-pyrrolidone, 2-pyrrolidone,
dimethylsulfoxide, ethyl lactate, propylene carbonate and
glycofurol; and the hydrophobic solvent is IPM. Preferably, the
HVLCM is SAIB, the network former is CAB, the first viscosity
enhancing agent is HEC, the hydrophilic solvent is triacetin, and
the hydrophobic solvent is IPM.
[0187] The controlled release system can further comprise a second
viscosity enhancing agent such as silicone dioxide. The second
viscosity enhancing agent is typically present in an amount from
0.1 to 6 wt % such as 1 to 2 wt %.
[0188] Once all of the constituents have been selected to produce a
controlled release carrier system in accordance with the present
invention, a liquid pharmaceutical formulation can be prepared by
simply mixing, for example a HVLCM, a rheology modifier, a network
former, the methylphenidate, a solvent and any additional
additives. The formulations of the present invention are produced
as liquid mixtures, and have a number of excipient ingredients that
are in solution, suspension, or in partial solution within the
final formulation. Suitable methods for compounding or
manufacturing the formulations make use of typical
pharmaceutical/chemical mixing and handling apparatus and
techniques. Since the liquid formulations of the invention are
formed from a mixture number of highly viscous liquids and solids,
they will tend to have exceptionaly high final viscosities.
Accordingly, the specific equipment and techniques employed in the
manufacture of such formulations are preferably selected so as to
accommodate such material demands. In particular, various
excipients, such as network formers, are typically added to the
formulation mixture in the solid or semi-solid state, and as such
they may be screened or otherwise size-reduced prior to addition to
a formulation mixing apparatus. Other solid excipients may require
melting prior to addition to the liquid mixture. The HVLCM
materials are very high viscosity liquid materials, however they
tend to exhibit a dramatic reduction in viscosity with increases in
heat, and as such the mixing apparatus may be heated to accommodate
the addition of the HVLCM material or other similar materials.
However, the mixing and processing conditions must take into
account the final integrity of the formulation, and as such the
mixing conditions are preferably selected so as to have a low-sheer
effect on the formulation, and to avoid any extended or pronounced
excursions into high or low heat conditions. Once the formulation
has been properly combined, an appropriate amount of the resulting
liquid mixture can be placed into a suitable capsule, such as a
gelatin capsule or the like to provide an oral methylphenidate
dosage form. Alternative liquid formulations may include
emulsifying the mixture in water, and introducing this emulsion
into a capsule.
[0189] With regard to a formulation that is formed from the mixture
of methylphenidate, a HVLCM, a network former, a rheology modifier,
a hydrophilic agent and a solvent, one suitable manufacturing or
compounding process would include the steps of: preheating the
HVLCM; mixing the solvent with the preheated HVLCM to form a
uniform solution of the HVLCM in the solvent; adding and mixing the
rheology modifier; optionally, adding and mixing a viscosity
enhancing agent; homogenizing the formulation, adding and mixing
the methylphenidate; and then adding and mixing the hydrophilic
agent. Furthermore, the process can include the step of filling
capsules with the formulation obtained in the process and,
optionally, packaging the filled capsules into unit dose blisters
or multidose plastic bottles.
[0190] With regard to a formulation that is formed from the mixture
of methylphenidate, a HVLCM, a network former, a first viscosity
enhancing agent, a hydrophilic solvent and a hydrophobic solvent, a
suitable manufacturing or compounding process may include the steps
of: preheating the HVLCM; mixing the hydrophilic solvent with the
preheated HVLCM to form a uniform solution of the HVLCM in the
solvent; adding the hydrophobic solvent; optionally, adding and
mixing a viscosity enhancing agent; homogenizing the formulation,
adding and mixing the methylphenidate; and then optionally adding
and mixing a hydrophilic agent. Furthermore, the process can
include the step of filling capsules with the formulation obtained
in the process and, optionally, packaging the filled capsules into
unit dose blisters or multidose plastic bottles.
[0191] A suitable GMP manufacturing method for producing the
abuse-resistant dosage forms and formulations of the present
invention is described in Example 1 below.
[0192] In certain preferred embodiments, the oral dosage form is
composed of a liquid formulation containing the methylphenidate and
the controlled release carrier system encapsulated within an
enclosure or capsule, preferably biodegradable, such as a capsule
or a gelatin capsule ("gelcap"), wherein the capsule is made of a
substance that degrades or otherwise dissociates when exposed to
conditions present in the gastro-intestinal tract of a mammal.
Capsules and gelcaps are well known in drug delivery technology and
one of ordinary skill could select such a capsule as appropriate
for delivery of a particular active agent. Once the capsule has
dissolved or dissociated from the formulation, the formulation of
the invention generally remains intact, especially for hydrophobic
formulations, and passes through the GI tract without
emulsification or fragmentation.
[0193] In certain more specific embodiments the invention
encompasses an oral dosage form comprising a liquid formulation
contained within a biodegradable capsule, wherein the formulation
comprises methylphenidate and a HVLCM, and wherein the capsule is
made of a substance that degrades when exposed to conditions
present in the gastro-intestinal tract of a mammal. In certain
embodiments the capsule comprises gelatin or synthetic polymers
such as hydroxyl ethyl cellulose and hydroxyl propylmethyl
cellulose. Gelcaps can be of the hard or soft variety, including,
for example, polysaccharide or hypromellose acetate succinate based
caps (e.g., Vegicaps brand, available from Catalent). The capsule
can also be coated with an enteric coating material such as AQIAT
(Shin-Etsu) to delay release. Gelatin capsules are well suited for
delivering liquid formulations such as vitamin E and cod-liver oil.
Gelatin capsules are stable in storage, but once in the acid
environment of the stomach (low pH less than about pH 4-5), the
gelcap dissolves over a 1-15 minute period.
[0194] In accordance with the present invention, the
abuse-resistant oral methylphenidate dosage forms may be formulated
so as to produce targeted plasma levels of methylphenidate over a
particular period. This is obviously of great importance in
maintaining a methylphenidate plasma level within an appropriate
therapeutic range to provide: (i) an initial increasing in vivo
rate of release of methylphenidate from the controlled release
system suitable to provide an initial increasing-rate phase of less
than or equal to about 2 hours, and sufficient to provide a
therapeutically effective amount of methylphenidate for a rapid
onset of action; (ii) a second, zero-order or decreasing (i.e.,
non-ascending) in vivo rate of release of methylphenidate from the
controlled release system that provides a subsequent zero order- or
decreasing-rate phase sufficient to provide a therapeutically
effective amount of methylphenidate through at least about 11 to 12
hours post administration; and (iii) a single T.sub.max of about
5.5 to 7.5 hours post administration. The novel and unique in vivo
methylphenidate release kinetics provided by the abuse-resistant
oral dosage forms of the present invention are sufficient to
provide the methylphenidate in vivo PK profile depicted in FIG. 7.
The exact time to maximum plasma concentration may be adjusted by
adjusting various components of the controlled release carrier
system as taught herein.
[0195] Once per day (QD) is typically used to maintain a sufficient
clinical effect, e.g., to treat ADD or ADHD. Other dosage regimens
may be determined by a physician in accordance with standard
practices.
Examples
[0196] Please note that the examples described herein are
illustrative only and in no way limit the scope of the
invention.
Example 1
Preparation of Formulations
[0197] (GMP Manufacturing Process)
[0198] A GMP manufacturing process for the dosage forms of the
present invention was developed and carried out as follows. The
following raw materials were used to create the formulations:
methylphenidate ("MPH"); Isopropyl Myristate, NF ("IPM"); Colloidal
silicon dioxide (Cabosil.RTM., Cabot Corp) ("SiO.sub.2"); Butylated
hydroxyl toluene, NF ("BHT"); Hydroxyethyl cellulose, NF ("HEC");
Sucrose Acetate Isobutyrate (Eastman Chemicals), ("SAIB");
Triacetin USP ("TA"); Cellulose Acetate Butyrate, grade 381-20 BP,
ethanol washed (Eastman Chemicals) ("CAB"); Gelucire 50/13
(Gattefosse) ("GEL"); and Miglyol 812 ("MIG"). The formulations
were filled into size #3 gelatin capsule shells. The specific
details for the three different formulations produced using the GMP
manufacturing processes of this Example 1 are disclosed below in
Tables 1 and 2. The batch sizes were up to 500 g.
TABLE-US-00001 TABLE 1 Formulation by Weight Percent (wt %) MPH1
MPH2 MPH3 MPH11 MPH12 MPH13 Component 40 mg 48 mg 48 mg 48 mg 48 mg
48 mg MPH 20.00 20.00 20.00 20.00 20.00 20.00 SAIB 33.35 34.31
34.55 34.31 29.25 34.55 TA 22.23 22.87 23.03 22.87 20.89 23.03 CAB
4.80 5.20 6.40 5.21 5.58 6.42 IPM 13.60 12.80 12.80 12.80 -- 12.80
MIG -- -- -- -- 16.0 -- HEC 0.00 2.40 0.00 2.40 4.80 -- SiO.sub.2
2.00 1.60 1.60 1.60 1.60 1.60 BHT 0.02 0.02 0.02 0.02 0.02 0.02 GEL
4.00 0.80 1.60 0.80 1.84 1.60
TABLE-US-00002 TABLE 2 Formulation by Mass (mg) MPH1 MPH2 MPH3
MPH11 MPH12 MPH13 Component 40 mg 48 mg 48 mg 48 mg 48 mg 48 mg MPH
40.00 48.00 48.00 48.00 48.00 48.00 SAIB 66.70 82.34 82.92 82.30
70.20 82.90 TA 44.46 54.89 55.27 54.90 50.10 55.30 CAB 9.60 12.48
15.36 12.50 13.40 15.40 IPM 27.20 30.72 30.72 30.70 -- 30.70 MIG --
-- -- -- 38.40 -- HEC 0.00 5.76 0.00 5.80 11.50 -- SiO.sub.2 4.00
3.84 3.84 3.80 3.80 3.80 BHT 0.04 0.05 0.05 0.05 0.05 0.05 GEL 8.00
1.92 3.84 1.90 4.40 3.80 Total 200.00 240.00 240.00 240.00 240.00
240.00
[0199] The primary mixing apparatus used in the GMP manufacturing
process was a Ross Model No. HSM 100 LCI, equipped with propeller
type impeller (4 blade) with a diameter of 2.25 inches. The mixing
container that was used was a 2 liter Glass Jar with an internal
Diameter (mixing area) of 4.181 inches. Temperature control was
carried out using a VWR immersion circulator and a VWR gravity
convection oven model 1320. A micro mixer homogenizing assembly for
the Ross mixer was used for the final homogenization step. After
the final mixing step, bulk formulations were allowed to cool to
room temperature for a minimum of 16 hours (overnight) prior to
filling into capsules. The flow chart for the instant GMP
manufacturing process is depicted in FIG. 14.
Example 2
Analysis of Formulations
[0200] (In Vitro Dissolution Testing Procedures)
[0201] Two in vitro dissolution test methods were developed in
order to assess the controlled release performance of
abuse-resistant dosage forms produced according to the present
invention such as the methylphenidate dosage forms recited herein.
The first dissolution method (Method 1) was based upon USP
<711> Method A for delayed-release dosage forms and uses an
USP dissolution apparatus Type 2 (without basket) with a two-stage
media (an initial volume of 750 mL of 0.1N HCl acid as the
dissolution medium, followed by adjustment to pH 6.8 by addition of
250 mL of sodium phosphate buffer after 2 hours). The two-stage
media was selected to simulate the pH range over which a dosage
form will release active agent during transit through the GI tract.
Stainless steel coiled wire type 316 is used as a sinker to ensure
that the dosage forms remain at the bottom of the dissolution
vessel during release rate testing.
[0202] The second dissolution method (Method 2) was optimized to
assess the controlled release performance of the abuse-resistant
dosage forms having 5, 10, 20, 30 and 40 mg of the active agent. In
this regard, the unique controlled release characteristics of the
abuse-resistant dosage forms used in the practice of the invention
are such that standard dissolution methodology and apparatus may
not bear a close relationship to the rate or extent of active agent
release as observed in in vivo pharmacokinetic studies. This is due
in large part to the use of very hydrophobic excipients in the
inventive dosage forms (e.g., SAIB and IPM), resulting in
compositions that result in a controlled release mass with low
water permeability. Accordingly, this second method represents an
enhancement of the earlier method (Method 1) to provide a better
reflection of in vivo release. The new method uses the paddle
configuration of an USP dissolution apparatus Type 2 with a
stainless steel stationary basket assembly (type 316, 20-mesh
basket with 20-mesh screen ceiling modification) attached to a
modified conical low-loss evaporation cover on the dissolution
vessel. These changes to the traditional apparatus were carried out
in order to place the dosage form in the high shear flow zone of
the USP dissolution apparatus, with an increased paddle speed to
increase medium flow within the dissolution vessel. This new, fixed
high-flow zone is located just above the rotating paddle. During
testing, the dissolution media perfuses the stationary basket,
facilitating release of the active agent from the full surface area
of the dosage form and thus overcoming any surface boundary layer
limitations that could result from placement of the dosage form at
the bottom of the dissolution vessel. A pictorial representation of
the modified dissolution vessel and paddle, with the stationary
basket assembly is provided as FIG. 15. In addition to the
stationary basket assembly, a screen ceiling inside the mesh basket
was developed to prevent the dosage forms from floating within the
basket.
[0203] Suitable stationary basket assemblies are commercially
available and can be purchased from Varian as a kit. The kit
contains a mesh basket (10, 20 or 40 mesh), which attaches to a
basket shaft. A hole in the evaporation cover of the dissolution
vessel allows the basket shaft to be secured to it. However, the
evaporation covers provided with the kit are not ideal for use in
an extended controlled release test. This is because the covers are
flat and also contain a large cut out which allows them to be
easily removed from the dissolution apparatus. Over the course of a
24-hour dissolution test, use of the covers provided with the kit
would cause significant media loss due to evaporation. Evaporative
media loss would ultimately lead to higher than expected release
rate profiles. Previous dissolution studies with the dosage forms
of the present invention have in fact given controlled release rate
profiles well in excess of 100% release. An alternative to the kit
evaporation cover was therefore developed.
[0204] The dissolution profiles using 20-Mesh Basket/20-Mesh
Screen
[0205] Ceiling and 40-Mesh Basket/without ceiling were determined
to be the same. The 20-Mesh Baskets were chosen in order to
maximize the hydrodynamic flow of dissolution media through the
basket while minimizing leakage of the dosage form from the basket.
The screen ceiling is used to confine the dosage form within the
basket and improve assay variability.
[0206] In addition, Method 2 uses a single-phase dissolution medium
(0.1N HCl with 0.5% (w/v) sodium dodecyl sulfate (SDS). The
addition of the surfactant (SDS) to the dissolution medium improves
the ability of the medium to wet the hydrophobic controlled release
mass during testing.
[0207] Finally, a reverse phase HPLC method is used for determining
the active agent concentration of the dosage form samples obtained
from the dissolution testing methods of this Example 2. The mobile
phase for the first dissolution method (Method 1) is prepared in
two steps while the mobile phase for the second dissolution method
(Method 2) is prepared in one step. A summary of the method
parameters for Methods 1 and 2 is provided below as Table 3.
TABLE-US-00003 TABLE 3 Test Method Method 1 Method 2 Media 750 mL
0.1N HCl (2 hours) 0.1N HCl/0.5% SDS 250 mL 0.2N Na Phosphate (1000
mL) Paddle Speed 50 RPM 100 RPM Bath 37.degree. C. 37.degree. C.
Temperature Sample Coiled Sinker Stationary Basket Assembly
Containment (Type 316 stainless steel) (20 Mesh with Ceiling)
Sample 0.25, 0.5, 1, 2, 3, 6, 10, 12, 0.25, 0.5, 1, 2, 3, 6, 10,
12, Timepoints 18 and 24 hours 18 and 24 hours Mobile Phase 65% SDS
Buffer/35% CAN 0.35% SDS/0.7% Acetic SDS Buffer (0.5% SDS/1%
Acid/44% ACN/56% Water Acetic Acid/20% CAN) HPLC Column Waters
XTerra C18, 5 .mu.m, Waters XTerra C18, 5 .mu.m, 4.6 .times. 150 mm
4.6 .times. 150 mm Flow Rate 1.0 mL/min 1.0 mL/min Run Time 8 min 8
min UV Detection 240 nm 240 nm Injection 20 .mu.L 20 .mu.L Volume
Column 40.degree. C. 40.degree. C. Temperature
Example 2a
[0208] The following in vitro dissolution test was carried out to
characterize the in vitro release of abuse-resistant
methylphenidate oral dosage forms across several different
formulations.
[0209] The abuse-resistant methylphenidate oral dosage forms used
in this Example 2a were prepared using the following raw materials:
methylphenidate ("MPH"); Isopropyl Myristate, NF ("IPM"); Colloidal
silicon dioxide (Cabosil.RTM., Cabot Corp) ("SiO.sub.2"); Butylated
hydroxyl toluene, NF ("BHT"); Hydroxyethyl cellulose, NF ("HEC");
Sucrose Acetate Isobutyrate (Eastman Chemicals), ("SAIB");
Triacetin USP ("TA"); Cellulose Acetate Butyrate, grade 381-20 BP,
ethanol washed (Eastman Chemicals) ("CAB"); Gelucire 50/13
(Gattefosse) ("GEL"); and Miglyol 812 ("MIG"). The formulations
were produced using the manufacturing process as described in
Example 1 above, and then filled into size #3 gelatin capsule
shells to produce the dosage forms that were used as Test Capsules.
The details of the formulations and the dosage forms containing the
formulations of this Example 2a are disclosed below in Tables 4 and
5.
TABLE-US-00004 TABLE 4 Formulation by Weight Percent (wt %) MPH1
MPH2 MPH3 MPH11 MPH12 MPH13 Component 40 mg 48 mg 48 mg 48 mg 48 mg
48 mg MPH 20.00 20.00 20.00 20.00 20.00 20.00 SAIB 33.35 34.31
34.55 34.31 29.25 34.55 TA 22.23 22.87 23.03 22.87 20.89 23.03 CAB
4.80 5.20 6.40 5.21 5.58 6.42 IPM 13.60 12.80 12.80 12.80 -- 12.80
MIG -- -- -- -- 16.0 -- HEC 0.00 2.40 0.00 2.40 4.80 -- SiO.sub.2
2.00 1.60 1.60 1.60 1.60 1.60 BHT 0.02 0.02 0.02 0.02 0.02 0.02 GEL
4.00 0.80 1.60 0.80 1.84 1.60
TABLE-US-00005 TABLE 5 Formulation by Mass (mg) MPH1 MPH2 MPH3
MPH11 MPH12 MPH13 Component 40 mg 48 mg 48 mg 48 mg 48 mg 48 mg MPH
40.00 48.00 48.00 48.00 48.00 48.00 SAIB 66.70 82.34 82.92 82.30
70.20 82.90 TA 44.46 54.89 55.27 54.90 50.10 55.30 CAB 9.60 12.48
15.36 12.50 13.40 15.40 IPM 27.20 30.72 30.72 30.70 -- 30.70 MIG --
-- -- -- 38.40 -- HEC 0.00 5.76 0.00 5.80 11.50 -- SiO.sub.2 4.00
3.84 3.84 3.80 3.80 3.80 BHT 0.04 0.05 0.05 0.05 0.05 0.05 GEL 8.00
1.92 3.84 1.90 4.40 3.80 Total 200.00 240.00 240.00 240.00 240.00
240.00
[0210] The dissolution study was carried out using the apparatus,
reagents and methods of the Method 1 dissolution test described
above, with the following exceptions: sample timepoints were at 0.5
hour, 1, 1.5, 2, 3, 6, 9, 12 and 24 hour. Dissolution results were
obtained on the following Test Capsules: four (n=4) each of
formulations MPH1 and MPH11-MPH12, and eight (n=8) each of
formulations MPH2 and MPH3. The mean dissolution data from the six
sets of Test Capsules are summarized below in Table 6, and depicted
in FIGS. 16A and 16B.
TABLE-US-00006 TABLE 6 Mean Cumulative Drug Released 0.5 hr 1 hr
1.5 hr 2 hr 3 hr 6 hr 9 hr 12 hr 24 hr Formulation # MPH1 15.2%
26.4% 35.1% 42.5% 53.0% 77.6% 90.6% 96.3% 98.9% Mean 0.8 0.8 0.9
1.1 1.3 1.7 1.2 0.8 1.0 SD Formulation # MPH2 11.1% 19.27% 26.4%
32.5% 42.0% 62.1% 74.5% 83.1% 94.5% Mean 1.3 2.0 2.8 3.5 4.8 6.2
5.9 5.7 7.0 SD Formulation # MPH3 7.9% 12.0% 15.1% 17.6% 21.6%
31.3% 39.1% 45.7% 64.7% Mean 1.3 2.0 2.5 3.0 3.6 5.2 6.5 7.9 11.4
SD Formulation # MPH11 15.3% 27.5% 34.8% 42.3% 54.0% 78.0% 92.5%
99.5% 104.3% Mean 1.7 3.1 2.2 1.9 2.2 1.4 1.9 1.3 1.3 SD
Formulation # MPH12 15.8% 28.0% 36.9% 44.3% 55.8% 79.3% 93.2%
100.7% 104.4% Mean 1.0 1.3 1.3 1.2 1.2 1.4 1.8 2.3 2.8 SD
Formulation # MPH13 14.9% 27.6% 37.5% 45.7% 58.5% 84.9% 97.6%
101.7% 104.3% Mean 1.0 1.4 1.9 2.3 3.2 4.0 2.0 1.0 0.4 SD
Example 2b
[0211] The following in vitro dissolution tests were carried out in
order to compare a target in vitro release profile of a
methylphenidate oral dosage form produced according to the
invention against several candidate abuse-resistant methylphenidate
formulations produced according to the present invention.
[0212] The abuse-resistant methylphenidate oral dosage forms used
in this Example 2b were prepared using the following raw materials:
methylphenidate ("MPH"); Isopropyl Myristate, NF ("IPM"); Colloidal
silicon dioxide (Cabosil.RTM., Cabot Corp) ("SiO.sub.2"); Butylated
hydroxyl toluene, NF ("BHT"); Hydroxyethyl cellulose, NF ("HEC");
Sucrose Acetate Isobutyrate (Eastman Chemicals), ("SAIB");
Triacetin USP ("TA"); Cellulose Acetate Butyrate, grade 381-20 BP,
ethanol washed (Eastman Chemicals) ("CAB"); Miglyol 812 ("MIG");
and Gelucire 50/13 (Gattefosse) ("GEL"). The formulations were
produced using the manufacturing process as described in Example 1
above, and then filled into size #3 gelatin capsule shells to
produce the dosage forms that were used as Test Capsules. The
details of the formulations and the dosage forms containing the
formulations of this Example 2b are disclosed below in Tables 7a
and 7b.
TABLE-US-00007 TABLE 7a Formulation by Weight Percent (wt %) MPH1
MPH4 MPH5 MPH6 MPH7 MPH8 MPH9 MPH10 MPH11 MPH12 MPH13 40 mg 36 mg
40 mg 48 mg 48 mg 48 mg 29 mg 40 mg 48 mg 48 mg 48 mg MPH 20.00
13.04 20.00 20.00 15.00 15.00 10.25 20.00 20.00 20.00 20.00 SAIB
33.35 38.36 34.55 35.48 37.74 37.74 25.59 33.83 34.29 29.25 34.55
TA 22.23 25.57 23.03 23.66 25.16 25.16 46.43 22.55 22.87 20.89
23.03 IPM 13.60 13.92 12.80 12.54 13.33 13.35 9.68 12.80 12.80
12.80 CAB 4.80 5.66 6.40 5.10 5.43 5.32 3.93 5.21 5.21 5.58 6.42
SiO2 2.00 1.74 1.60 1.60 1.67 1.63 1.21 1.60 1.60 1.60 1.60 GEL
4.00 1.74 1.60 1.60 1.67 1.63 3.03 4.00 0.80 1.84 1.60 MIG 16.0 HEC
2.42 4.80 BHT 0.02 0.02 0.02 0.02 0.02 0.02 0.01 0.02 0.02 0.02
0.02 Total 100.00 100.04 100.00 100.00 100.01 99.85 100.13 100.00
100.01 99.98 100.02
TABLE-US-00008 TABLE 7b Formulation by Weight Mass (mg) MPH1 MPH4
MPH5 MPH6 MPH7 MPH8 MPH9 MPH10 MPH11 MPH12 MPH13 40 mg 36 mg 40 mg
48 mg 48 mg 48 mg 29 mg 40 mg 48 mg 48 mg 48 mg MPH 40.00 35.86
40.00 48.00 48.00 48.00 28.70 40.00 48.00 48.00 48.00 SAIB 66.70
105.49 69.10 85.15 120.77 120.77 71.65 67.66 82.30 70.20 82.90 TA
44.46 70.32 46.06 56.79 80.51 80.51 130.00 45.10 54.90 50.10 55.30
IPM 27.20 38.28 25.60 30.11 42.65 42.70 27.10 25.60 30.70 30.70 CAB
9.60 15.55 12.80 12.23 17.38 17.03 11.00 10.40 12.50 13.40 15.40
SiO2 4.00 4.79 3.20 3.84 5.33 5.22 3.39 3.20 3.80 3.80 3.80 GEL
8.00 4.79 3.20 3.84 5.33 5.22 8.48 8.00 1.90 4.40 3.80 MIG 38.40
HEC 5.80 11.50 BHT 0.03 0.05 0.03 0.04 0.05 0.05 0.03 0.03 0.05
0.05 0.05 Total 200.00 275.11 200.00 240.00 320.03 319.52 280.36
200.00 239.95 239.85 239.95
[0213] Initially, the dissolution testing methods and apparatus
described above in Example 2a were used to determine in vitro
dissolution release performance for comparator tablets (Concerta
and Metadate CD). The cumulative release results thus obtained were
compared against the cumulative release data presented in the U.S.
Pat. No. 6,919,373 (the Concerta patent), and then plotted against
input in vivo obtained via deconvolution (open symbols) for both
Metadate CD and Concerta. FIGS. 10A and 10B depict the results of
this initial study, where FIG. 10A depicts the cumulative release
profiles of the Concerta and Metadate CD comparators and compares
them with cumulative release data presented in the U.S. Pat. No.
6,919,373; and FIG. 10B depicts the cumulative release in vitro
results plotted against input in vivo obtained via deconvolution
(open symbols) for both Metadate CD and Concerta.
[0214] Next, cumulative release data for 11 Test Capsules (MPH1 and
MPH4-MPH13) were obtained. These results are reported below in
Table 8.
TABLE-US-00009 TABLE 8 Mean Cumulative Drug Released 0.5 hr 1 hr
1.5 hr 2 hr 3 hr 6 hr 9 hr 12 hr 24 hr Formulation # MPH4 15.4 29.0
39.6 48.3 61.0 85.8 95.7 98.8 99.5 Mean 2.3 3.5 4.1 4.3 4.5 2.5 0.8
2.3 3.4 Std Dev Formulation # MPH9 21.2 26.7 31.0 34.8 41.3 58.8
70.5 77.8 85.8 Mean 1.6 1.8 2.1 2.4 2.7 3.0 2.8 2.5 1.9 Std Dev
Formulation # MPH10 18.2 29.1 36.8 43.0 50.8 68.9 79.3 85.9 95.2
Mean 1.8 2.1 2.5 2.5 3.2 2.9 2.8 2.0 0.9 Std Dev Formulation # MPH1
15.2 26.4 35.1 42.5 53.0 77.6 90.6 96.3 99.0 Mean 0.8 0.8 0.9 1.1
1.3 1.7 1.2 0.8 1.0 Std Dev Formulation # MPH5 14.6 26.4 35.7 43.3
58.9 82.2 95.2 100.4 99.5 Mean 0.8 1.6 1.9 1.9 1.5 0.7 1.4 2.0 2.8
Std Dev Formulation # MPH6 19.0 32.3 41.7 49.1 58.0 76.9 87.5 91.4
90.9 Mean 1.9 2.4 2.9 3.1 3.2 3.0 2.2 1.2 0.3 Std Dev Formulation #
MPH7 14.8 27.7 37.3 45.0 55.3 76.7 87.8 92.3 92.7 Mean 0.9 2.0 2.8
3.2 3.9 4.1 3.4 3.3 3.9 Std Dev Formulation # MPH8 18.8 31.8 41.2
48.7 58.8 79.9 89.3 91.4 89.0 Mean 1.4 1.3 1.4 1.4 1.5 2.0 2.2 2.4
2.4 Std Dev Formulation MPH11 15.3 27.5 34.8 42.3 54.0 78.0 92.5
99.5 104.3 Mean 1.7 3.1 2.2 1.9 2.2 1.4 1.9 1.3 1.3 Std Dev
Formulation MPH12 15.8 28.0 36.9 44.3 55.8 79.3 93.2 100.7 104.4
Mean 1.0 1.3 1.3 1.2 1.2 1.4 1.8 2.3 2.8 Std Dev Formulation MPH13
14.9 27.6 37.5 45.7 58.5 84.9 97.6 101.7 104.3 Mean 1.0 1.4 1.9 2.3
3.2 4.0 2.0 1.0 0.4 Std Dev
[0215] Finally, the cumulative release results were compared
against the target in vitro release profile. FIGS. 17A, 17B and 17C
depict the results of this comparison, where the in vitro
dissolution cumulative release profiles of methylphenidate from the
Test Capsules are compared to a target in vitro methylphenidate
release profile developed in accordance with the invention. As can
be seen, the MPH 1 and MPH11-MPH13 release profiles best match the
target profile, except at short times.
Example 3
Analysis of Formulations
[0216] (In Vitro Extraction and Volatilization Testing
Procedures)
[0217] In order to assess the abuse-resistance performance of the
abuse-resistant dosage forms prepared according to the present
invention, the following in vitro extraction tests were developed.
In particular, intentional abuse of controlled release
pharmaceutical dosage forms will often times be carried out by
simple extraction techniques that can separate most or all of the
active agent from commercially available controlled release carrier
systems using common household solvents. Accordingly, a panel of in
vitro extraction tests was developed in order to assess the
abuse-resistant performance of the dosage forms produced according
to the instant invention.
Example 3a
Extraction in a Panel of Household Liquids
[0218] In order to assess the abuse-resistance performance of
abuse-resistant dosage forms produced according to the present
invention, a panel of tests to evaluate extraction of active agent
from a dosage form into the following commonly available household
solvents was developed as follows: vinegar (acetic acid), pH 2.5;
cola soft drink, pH 2.5; baking soda solution (sodium bicarbonate),
pH 8.2; 80 proof ethanol (40% v/v); and vegetable oil. The dosage
forms of the present invention can be tested against this panel of
common household solvents at both ambient or "room" temperature
(25.degree. C.) and with preheated extraction solvents (heated to
60.degree. C.). In addition, exceptional stressing, such as the use
of microwave and freeze-and-crush pretreatment of the dosage forms
prior to extraction in the above-noted solvents can also be carried
out.
[0219] The materials and apparatus used in the solvent extraction
panel study of this Example 3a are as follows. Standard laboratory
equipment includes a shaker (Jeio Tech Shaking Incubator, Model
SI-600), hot water bath, hot plate, centrifuge, microwave oven,
glass mortar and pestle, a 250 mL glass bottle with cap, and a
filtering unit (0.2 .mu.m nylon membrane). The solvent reagents
used in the extraction panel study are prepared as follows:
distilled water; 200 proof ethanol (Spectrum) mixed in distilled
water to provide 80 proof ethanol solvent; distilled white vinegar
5% acidity (Heinz); cola soft drink (Coke Cola Classic); vegetable
oil (Canola); baking soda (Arm & Hammer), saturated solution
prepared by adding 527 g of baking soda to 2 L distilled water,
mixed vigorously for approximately 1 hour, allowed to settle and
then filtered the supernatant using the 0.2 .mu.m nylon membrane.
The pH of the Vinegar, cola soft drink and saturated baking soda
solution are determined using a pH meter and recorded prior to
extraction studies.
[0220] The test procedures used for all of the solvents except the
vegetable oil solvent are as follows. 240 mL of each extraction
solvent is placed into separate extraction bottles. A dosage form
is then added (if the dosage form is a solid tablet, the form is
crushed and then dropped into the solvent, if the dosage form is a
liquid capsule, the capsule is cut to open the shell, and the
liquid contents are squeezed from the capsule into the solvent, and
then the empty shell is dropped into the solvent). Extraction is
initiated on the shaker using a constant speed of 150 rpm. Samples
(1 mL) are withdrawn at 5, 20 and 60 minute time points. The
samples are centrifuged at 10,000 rpm for 10 minutes, and about 0.5
mL of the supernatant is transferred into HPLC vials for analysis
(HP Model 1200 or similar model). This extraction panel is then
repeated wherein the extraction solutions are pre-warmed in a
60.degree. C. water bath. The actual initial and final temperatures
of the solvent solution are then taken.
[0221] Extraction in Oil
[0222] The test procedures used for the vegetable oil solvent are
as follows. 2 tablespoons of the oil is placed into an extraction
bottle. A dosage form is then added (if the dosage form is a solid
tablet, the form is crushed and then dropped into the solvent, if
the dosage form is a liquid capsule, the capsule is cut to open the
shell, and the liquid contents are squeezed from the capsule into
the solvent, and then the empty shell is dropped into the solvent).
Extraction is initiated on the shaker using a constant speed of 150
rpm. Samples (1 mL) are withdrawn at 5, 15, 30 and 60 minute time
points. The samples are centrifuged at 10,000 rpm for 10 minutes,
and about 0.5 mL of the supernatant is transferred into HPLC vials
for analysis (HP Model 1200 or similar model).
[0223] For the exceptional stressing test (microwave, and
freeze-and-crush pretreatment of the dosage forms prior to
extraction in the above-noted solvents), the test procedures are as
follows.
[0224] Extraction After Microwaving
[0225] For the microwave stress analysis, dosage forms are added to
empty extraction bottles (if the dosage form is a solid tablet, it
is crushed and then dropped into the bottle, if the dosage form is
a liquid capsule, the capsule is cut to open the shell, and the
liquid contents are squeezed from the capsule into the bottle). The
extraction bottles (4 at a time) are then microwaved for 2 min with
power level set at "High" (power=90). Upon removal from the
microwave, the appearance of the dosage form is recorded. Next,
either 240 mL of distilled water or 240 mL of ethanol solvent is
added to the extraction bottle (to assess extraction into water or
ethanol). Extraction is initiated on the shaker using a constant
speed of 150 rpm. Samples (1 mL) are withdrawn at 5-, 20- and
60-minute time points. The samples are centrifuged at 10,000 rpm
for 10 minutes, and about 0.5 mL of the supernatant is transferred
into HPLC vials for analysis (HP Model 1200 or similar model). This
extraction procedure is then repeated on untested dosage forms
after they have been allowed to equilibrate to room temperature
(.about.1.5 hr) after microwave treatment.
[0226] Extraction After Physical and Mechanical Stress
[0227] For the freeze-and-crush (physical and mechanical stress)
analysis, dosage forms are stored intact in a -80.degree. C.
freezer overnight (18 hrs). The test samples are then removed from
the freezer and kept on dry ice until they are ready to be ground
up. The frozen dosage forms are then placed into a freezer bag
(about 9.times.12 cm) and crushed by pressing immediately in a
glass mortar and pestle. Any excess (non-formulation containing)
portion of the freezer bag is then removed to provide about a
9.times.9 cm test article that is quantitatively transferred (with
the remaining freezer bag) into an extraction bottle. Next, either
240 mL of distilled water or 240 mL of the 100-proof ethanol
solvent is added to the extraction bottle (to assess extraction
into water or ethanol). Extraction is initiated on the shaker using
a constant speed of 150 rpm. Samples (1 mL) are withdrawn at 5-,
20- and 60-minute time points. The samples are centrifuged at
10,000 rpm for 10 minutes, and about 0.5 mL of the supernatant is
transferred into HPLC vials for analysis (HP Model 1200 or similar
model).
[0228] Volatilization Test
[0229] In order to further assess the abuse-resistance performance
of abuse-resistant dosage forms produced according to the present
invention, the following in vitro volatilization test was
developed. In particular, intentional abuse of controlled release
pharmaceutical dosage forms may alternatively be carried out by
volatilization (smoking, or free-basing) techniques that can
liberate active agent (in immediately active form) from
commercially available controlled release carrier systems.
Accordingly, a preliminary in vitro volatilization test was
developed in order to assess: (1) whether a free base form of an
active agent (in this case, oxycodone) was more volatile than the
salt (HCl) form; and (2) whether abuse-resistant dosage forms
produced according to the instant invention can prevent inhalation
abuse through volatilization.
[0230] For the study, 40 mg of neat active agent (oxycodone in free
base form, oxycodone in HCl salt form), 40 mg Test Capsules were
weighed into individual petri dishes. Each petri dish was fitted
with a watch glass as a cover, and the covered test dishes were
placed on a hot plate (setting 10). After 30 seconds each watch
glass was replaced with a fresh watch glass, and this step was
repeated three times (to obtain 4 time points). Any residue
deposited on the bottom side of the test watch glasses was
carefully transferred with an Alpha Swab (TX 761) into 40/60
ethanol/0.005M HCl solution, and the concentration of oxycodone
solution was determined by HPLC. The observations taken during the
test were as follows. The neat base form active agent (oxycodone
free base form) vaporizes/sublimes upon heating, whereas there was
extensive degradation and charring of the salt form active agent
(oxycodone HCl). It was noted that vaporized drug (and solvents
where present) escaped during each change of the watch glass, which
may be at least partially responsible for the low recovery noted in
the HPLC results below. In addition, the presence of solvents and
other excipients in the Test Capsules made it difficult to
volatilize the active agent, and there was a particularly noxious
smell noted when the Test Capsules were volatilized.
[0231] Extraction in Aqueous Buffers Over a Range of pH 1-pH 12
[0232] In order to further assess the abuse-resistance performance
of abuse-resistant dosage forms produced according to the present
invention, an additional solvent extraction test was developed as
follows. The extraction properties of six aqueous buffers over a
range of pH 1-pH 12 was assessed. Specific buffer strengths were pH
1, pH 4, pH 6, pH 8, pH 10 and pH 12. The pH 1 buffer consisted of
0.1N HCl, the pH 4 buffer consisted of 5 mM acetate, and buffers of
Ph 6, 10 and 12 consisted of 5 mM phosphate. Test Capsules were cut
open and squeezed to exude the liquid contents and assure intimate
contact of test solvents with the controlled release matrix. The
Test Capsules were placed into test jars containing 240 mL of each
buffer. The closed jars were vigorously shaken at 100 rpm for 60
minutes, with shaking interrupted to withdraw samples at 5, 20 and
60 minutes. The solvent samples taken at each testing interval were
centrifuged and assayed for extracted active agent content by
HPLC.
[0233] In Vitro Injection Abuse Resistance Evaluation
[0234] In order to further assess the abuse-resistance performance
of abuse-resistant dosage forms produced according to the present
invention, an in vitro Injection Abuse Resistance Evaluation was
carried out to characterize the ability of abuse-resistant
formulations such as those prepared according to the present
invention to resist injection-based forms of abuse. In this regard,
the characteristics of an injectable suspension are defined as
syringeability and injectability. Syringeability pertains to the
ability of a suspension to be drawn into an empty syringe through a
hypodermic needle, while injectability address the ability of a
suspension to be pushed from a pre-filled syringe through a
hypodermic needle. Both characteristics depend upon the viscosity
and physical characteristics of a test formulation.
[0235] For the test, placebo (no active agent) formulations were
evaluated for syringeability and injectability to assess resistance
to abuse by injection. The placebo formulations used in this study
were prepared using the following raw materials: Isopropyl
Myristate, NF ("IPM"); Colloidal silicon dioxide (Cabosil.RTM.,
Cabot Corp) ("SiO.sub.2"); Butylated hydroxyl toluene, NF ("BHT");
Hydroxyethyl cellulose, NF ("HEC"); Sucrose Acetate Isobutyrate
(Eastman Chemicals), ("SAIB"); Triacetin USP ("TA"); and Cellulose
Acetate Butyrate, grade 381-20 BP, ethanol washed (Eastman
Chemicals) ("CAB"). The details of the placebo formulation used in
this study are disclosed below in Table 9.
TABLE-US-00010 TABLE 9 SAIB TA CAB IPM HEC SiO.sub.2 BHT (total)
43.19 28.80 5.0 15.0 6.0 2.0 0.02 (wt %) 319.6 213.1 37.0 111.0
44.4 14.8 0.16 740.0 (mg)
[0236] The test equipment and apparatus used in this study included
syringe barrel (Becton Dickinson (B-D) 3 mL Disposable Syringe with
Leur-Lok Tip; hypodermic needles (B-D (305136) PrecisionGlide
Needle 27G1.25; B-D (305125) PrecisionGlide Needle 25G1; B-D
(305190) PrecisionGlide Needle IV 1.5, 21G; B-D (305185)
PrecisionGlide Needle Fill 1.5, 18G); and an Instron 5542 Load
Frame, controlled by BLUEHILL software.
[0237] Initially, syringeability was assessed in two ways: first by
attempting to draw the placebo formulation from a Test Capsule by
piercing the capsule shell with the hypodermic needle and
attempting to draw the formulation into the syringe; and second, by
attempting to squeeze the formulation from a cut capsule into the
posterior end of a syringe barrel (i.e., with the plunger removed).
The syringeability analysis was conducted using placebo
formulations equilibrated at room temperature (25.degree. C.). Both
of these techniques represent practices that may be employed by a
drug abuser. Any placebo formulation mass successfully drawn or
filled into the syringe was quantified and recorded.
[0238] Injectability was evaluated using the Instron Load Frame
instrument to push the plunger of a pre-loaded syringe in an
attempt to deliver the placebo formulation. The force required for
successful injection of the placebo formulation or the force at
which failure occurred was recorded by the instrument. The
single-use syringe barrels were filled with approximately 1 g of
the placebo formulation (range 0.64 to 1.14 g). Entrapped air was
removed by application of vacuum while depressing the plunger to
minimize variability in the injectability analysis. Testing was
performed on two sets of placebo formulations that were
equilibrated to either 25.degree. C. or 37.degree. C. Needles with
gauge sizes of 18, 21, 25 and 27 were joined by a Luer-Lok fitting
to the pre-loaded syringe barrel. Three different crosshead speeds
(i.e., plunger depression rates) were evaluated for each needle
gauge. Crosshead speeds of 150 mm/min, 550 mm/min, and 950 mm/min
were selected based upon documented typical injection rates for
parenteral administration. Three samples were tested at each set of
conditions.
[0239] The results of this abuse-resistance test were as
follows.
[0240] Syringeability: it was not possible to draw the placebo
formulation into the syringe using the largest bore needle (18
gauge) due to the high viscosity and thixotropy of the formulation.
As a result, evaluation using smaller bore needles (21, 25 and 27
gauge) were not performed. Placebo formulation at room temperature
was squeezed from an opened capsule into the posterior end of a
tared syringe barrel. The weights successfully transferred into
each of five syringes was recorded. A mean weight of 0.42 g (range
0.22-0.50 g, mean of 54%, range 28-64%) was transferred from the
Test Capsules. Accordingly, syringeability was not achieved for any
gauge needle in the study. In this regard, the high viscosity and
sticky character of the placebo formulation prevented quantitative
transfer of capsule contents into the syringe barrel.
[0241] Injectability of the placebo formulations at room
temperature was only achieved using an 18 gauge needle at the
slowest crosshead speed of 150 mm/min. At 37.degree. C., the
formulation is less viscous and injectability was achieved with all
three samples using the 18 gauge needle at a speed of 150 mm/min,
and with two of the three samples using an 18 gauge needle at a
speed of 550 mm/min. Either load failures of mechanical failures
occurred at both test temperatures, and at all three crosshead
speeds with the 21, 25 and 27 gauge needles.
[0242] The following information was considered in interpreting the
outcome of each test. Single use disposable syringes are rated to
withstand an internal barrel pressure of 45 lb.sub.f/in.sup.2 for
30 seconds (corresponding to a pressure exerted on the plunger rod
of 18.2 N). For 3 mL (ID=0.34 in.) disposable syringe barrels, 1
lb.sub.f applied to the plunger rod generates 11.0
lb.sub.f/in.sup.2 within the syringe barrel. The mean pinch force
(Palmer Pinch) exerted by healthy males is 23 to 23.4 lb.sub.f.
[0243] The following failure modes were used to assess
injectability in this study. Overall failure of the test was
concluded upon failure of at least one sample with a triplicate
test set. A Plunger Barrel failure occurs when excessive internal
pressure causes the syringe barrel to flex, resulting in fluid
bypassing the plunger stopper. This event is determined by
observing the sample, or is evidenced by a declining load force
profile in the Instron tracing. A Leur-Lok Coupling Failure occurs
when excessive internal pressure causes the needle to separate from
the syringe barrel. This failure event is determined by observing
incomplete sample delivery from the syringe, or is evidenced by a
precipitous drop in the load force profile in the Instron tracing.
An Excessive Force failure occurs when the force required to
successfully deliver fluid from the syringe exceeds 23.4 lb.sub.f
(104 N), the average (Palmer) pinch force of a healthy male. This
event is evident from the Instron tracing.
[0244] Successful injection of placebo formulation required
comparable performance of all three test samples. The criterion for
success was at least 80% delivery of the initial pre-filled mass.
In addition, the Instron tracing should display a consistent
profile of force applied during plunger travel. Even in cases where
the force profile remained consistent during the test and resulted
in delivery of placebo mass from the syringe, a force greater than
62 N was required to achieve delivery. This magnitude of force
generates a barrel pressure of 153 lb.sub.f/in.sup.2, which is 340%
of the pressure rated by the manufacturer.
[0245] These results of both the syringeability and injectability
evaluations demonstrate the improbability of delivering an
abuse-resistant controlled release formulation prepared according
to the invention using common hypodermic needles such as those
available to drug abusers. This is thought to be due to a
combination of limitations of suitable syringe pressures,
limitations of human strength and the highly viscous nature of the
instant formulations.
Example 3b
[0246] The following in vitro Abuse Resistance Evaluation was
carried out to characterize the in vitro abuse resistance
performance of abuse resistant methylphenidate oral dosage forms
prepared according to the present invention. More particularly,
abuse-resistant methylphenidate oral dosage forms across a range of
formulations were assessed for resistance to extraction in an
ethanol solution. The abuse-resistant methylphenidate oral dosage
forms used in this Example 3b were prepared using the following raw
materials: methylphenidate ("MPH"); Isopropyl Myristate, NF
("IPM"); Colloidal silicon dioxide (Cabosil.RTM., Cabot Corp)
("SiO.sub.2"); Butylated hydroxyl toluene, NF ("BHT"); Hydroxyethyl
cellulose, NF ("HEC"); Sucrose Acetate Isobutyrate (Eastman
Chemicals), ("SAIB"); Triacetin USP ("TA"); Cellulose Acetate
Butyrate, grade 381-20 BP, ethanol washed (Eastman Chemicals)
("CAB"); Gelucire 50/13 (Gattefosse) ("GEL"); and Miglyol 812
("MIG"). The formulations were produced using the manufacturing
process described in Example 1 above, and then filled into size #3
gelatin capsule shells to produce the dosage forms that were used
as Test Capsules. The details of the formulations and the dosage
forms containing the formulations of this Example 3b are disclosed
below in Tables 10 and 11.
TABLE-US-00011 TABLE 10 Formulation by Weight Percent (wt %) MPH1
MPH2 MPH3 MPH11 MPH12 MPH13 Component 40 mg 48 mg 48 mg 48 mg 48 mg
48 mg MPH 20.00 20.00 20.00 20.00 20.00 20.00 SAIB 33.35 34.31
34.55 34.31 29.25 34.55 TA 22.23 22.87 23.03 22.87 20.89 23.03 CAB
4.80 5.20 6.40 5.21 5.58 6.42 IPM 13.60 12.80 12.80 12.80 -- 12.80
MIG -- -- -- -- 16.0 -- HEC 0.00 2.40 0.00 2.40 4.80 -- SiO.sub.2
2.00 1.60 1.60 1.60 1.60 1.60 BHT 0.02 0.02 0.02 0.02 0.02 0.02 GEL
4.00 0.80 1.60 0.80 1.84 1.60
TABLE-US-00012 TABLE 11 Formulation by Mass (mg) MPH1 MPH2 MPH3
MPH11 MPH12 MPH13 Component 40 mg 48 mg 48 mg 48 mg 48 mg 48 mg MPH
40.00 48.00 48.00 48.00 48.00 48.00 SAIB 66.70 82.34 82.92 82.30
70.20 82.90 TA 44.46 54.89 55.27 54.90 50.10 55.30 CAB 9.60 12.48
15.36 12.50 13.40 15.40 IPM 27.20 30.72 30.72 30.70 -- 30.70 MIG --
-- -- -- 38.40 -- HEC 0.00 5.76 0.00 5.80 11.50 -- SiO.sub.2 4.00
3.84 3.84 3.80 3.80 3.80 BHT 0.04 0.05 0.05 0.05 0.05 0.05 GEL 8.00
1.92 3.84 1.90 4.40 3.80 Total 200.00 240.00 240.00 240.00 240.00
240.00
[0247] The in vitro Abuse Resistance Evaluation used the following
Test Capsules: three (n=3) each of formulations MPH1-MPH3 and
MPH11-MPH13.
[0248] The ethanol solution extraction study was carried out
substantially as described herein above, using the same apparatus,
reagents and methods described above, with the following
exceptions: the extraction solution was 60 mL of 80 proof ethanol
(40%); and sampling was conducted at time=0.5 hr and 3 hours. The
results of the extraction study are provided below in Table 12.
TABLE-US-00013 TABLE 12 Amount of Methylphenidate Extracted in 80
Proof Ethanol (% of dose) Time (hr.) 0.5 3 MPH1 Mean 18.4 63.0 Std
Dev. 0.9 0.9 MPH2 Mean 7.2 25.7 Std Dev. 0.5 1.7 MPH3 Mean 6.1 22.9
Std Dev. 0.6 1.3 MPH11 Mean 10 32 Std Dev. 1 3 MPH12 Mean 10 40 Std
Dev. 1 2 MPH13 Mean 11 43 Std Dev. 2 4
Example 3c
[0249] The following in vitro Abuse Resistance Evaluation was
carried out to compare the in vitro abuse resistance performance of
abuse resistant methylphenidate oral dosage forms prepared
according to the present invention over a greater number of
sampling points. More particularly, abuse-resistant methylphenidate
oral dosage forms across a range of formulations were assessed for
resistance to extraction in an ethanol solution. The
abuse-resistant methylphenidate oral dosage forms used in this
Example 3c were prepared using the following raw materials:
methylphenidate ("MPH"); Isopropyl Myristate, NF ("IPM"); Colloidal
silicon dioxide (Cabosil.RTM., Cabot Corp) ("SiO.sub.2"); Butylated
hydroxyl toluene, NF ("BHT"); Hydroxyethyl cellulose, NF ("HEC");
Sucrose Acetate Isobutyrate (Eastman Chemicals), ("SAIB");
Triacetin USP ("TA"); Cellulose Acetate Butyrate, grade 381-20 BP,
ethanol washed (Eastman Chemicals) ("CAB"); Gelucire 50/13
(Gattefosse) ("GEL"); and Miglyol 812 ("MIG"). The formulations
were produced using the manufacturing process described in Example
1 above, and then filled into size #3 gelatin capsule shells to
produce the dosage forms that were used as Test Capsules. The
details of the formulations used in this Example 3c are disclosed
below in Table 13.
TABLE-US-00014 TABLE 13 Formulation by Weight Percent (wt %) MPH1
MPH5 MPH6 MPH7 MPH10 MPH11 MPH12 MPH14 MPH15 40 mg 40 mg 48 mg 48
mg 40 mg 48 mg 48 mg 40 mg 36 mg MPH 20.00 20.00 20.00 15.00 20.00
20.00 20.00 13.09 20.00 SAIB 33.35 34.55 35.48 37.74 33.83 34.29
29.25 38.32 35.99 TA 22.23 23.03 23.66 25.16 22.55 22.87 20.89
25.54 23.99 IPM 13.60 12.80 12.54 13.33 12.80 12.80 -- 13.91 12.80
CAB 4.80 6.40 5.10 5.43 5.21 5.21 5.58 5.65 4.00 SiO.sub.2 2.00
1.60 1.60 1.67 1.60 1.60 1.60 1.74 1.60 GEL 4.00 1.60 1.60 1.67
4.00 0.80 1.84 1.74 1.60 MIG -- -- -- -- -- -- 16.0 -- -- HEC -- --
-- -- -- 2.42 4.80 -- -- BHT 0.02 0.02 0.02 0.02 0.02 0.02 0.02
0.02 0.02 Total 100.00 100.00 100.00 100.01 100.00 100.01 99.98
100.01 100.00
[0250] The in vitro Abuse Resistance Evaluation used the following
Test Capsules: three (n=3) each of formulations MPH1, MPH5-MPH7,
MPH10-MPH12, MPH14 and MPH15.
[0251] The ethanol solution extraction study was carried out
substantially as described herein above, using the same apparatus,
reagents and methods described above, with the following
exceptions: the extraction solution was 60 mL of 80 proof ethanol
(40%); and sampling was conducted at time=20 minutes, 45 minutes, 1
hour and then at 3 hours. The results of the extraction study are
provided below in Table 14.
TABLE-US-00015 TABLE 14 Amount of Methylphenidate Extracted in 80
Proof Ethanol (% of dose) Time 20 min 45 min 1 hr 3 hrs MPH1 Mean
15 29 35 63 Std Dev. 3 2 2 4 MPH5 Mean 5 10 13 27 Std Dev. 1 2 1 2
MPH6 Mean 4 7 9 19 Std Dev. 0 2 2 2 MPH7 Mean 3 6 8 18 Std Dev. 1 1
2 2 MPH10 Mean 12 24 30 57 Std Dev. 1 1 0 2 MPH11 Mean 4 8 10 22
Std Dev. 0 1 0 1 MPH12 Mean 9 18 22 43 Std Dev. 0 1 1 3 MPH14 Mean
9 23 29 55 Std Dev. 1 2 2 2 MPH15 Mean 20 35 43 72 Std Dev. 2 2 0
2
Example 3d
[0252] The following in vitro dissolution tests and Abuse
Resistance
[0253] Evaluations were carried out to compare both the in vitro
controlled release and abuse resistance performance of
methylphenidate oral dosage forms prepared in two different
manners. More particularly, abuse-resistant methylphenidate oral
dosage forms were prepared using two distinct manufacturing
processes. The sample dosage forms were then tested for cumulative
release performance and also for resistance to extraction in an
ethanol solution. Finally, the cumulative release results for one
of the sample dosage forms were compared against the target in vito
release profile developed in Example 2b above. The abuse-resistant
methylphenidate oral dosage forms used in this Example 3d were
prepared using the following raw materials: methylphenidate
("MPH"); Isopropyl Myristate, NF ("IPM"); Colloidal silicon dioxide
(Cabosil.RTM., Cabot Corp) ("SiO.sub.2"); Butylated hydroxyl
toluene, NF ("BHT"); Hydroxyethyl cellulose, NF ("HEC"); Sucrose
Acetate Isobutyrate (Eastman Chemicals), ("SAIB"); Triacetin USP
("TA"); Cellulose Acetate Butyrate, grade 381-20 BP, ethanol washed
(Eastman Chemicals) ("CAB"); Triethyl Citrate ("TEC"); Precirol
ATO5 ("PREC"); Ethyl Cellulose ("EC"); Miglyol 812 ("MIG"); Tween
80 ("TW80"); Gelucire 50/13 (Gattefosse) ("GEL"); and Poloxamer 124
("PLX").
[0254] Five different formulations were produced using the
manufacturing process described in Example 1 above, and then filled
into size #3 gelatin capsule shells to produce dosage forms that
were used as the first series of Test Capsules. Details of the
formulations produced using the first manufacturing process are
disclosed below in Table 15.
TABLE-US-00016 TABLE 15 Formulation by Weight Percent (wt %) MPH16
MPH17 MPH18 MPH19 MPH20 48 mg 48 mg 48 mg 36 mg 48 mg MPH 20.00
20.00 20.00 20.00 20.00 SAIB 30.00 31.42 33.16 33.16 32.46
SiO.sub.2 -- 1.60 1.60 1.60 1.60 PREC 15.00 11.20 11.20 11.20 --
TEC 35.00 24.17 -- -- -- MIG -- 9.60 25.51 25.51 11.20 TW80 -- --
6.52 -- -- PLX -- -- -- 6.52 -- EC -- 2.00 2.00 2.00 -- CAB -- --
-- -- 6.40 TA -- -- -- -- 24.97 GEL -- -- -- -- 0.96 HEC -- -- --
-- 2.40 BHT 0.02 0.02 0.02 0.02 0.02 Total 100.02 100.01 100.01
100.01 100.01
[0255] Next, five different formulations were produced using a
three-stage manufacturing processes to provide an initial (early)
increasing release component, a second (non-ascending) controlled
release component, and a barrier layer that were then combined into
single size #3 gelatin capsule shells to produce dosage forms that
were used as the second series of Test Capsules.
[0256] The initial increasing release components were prepared
using the following raw materials: methylphenidate HCl ("MPH");
Colloidal silicon dioxide (Cabosil.RTM., Cabot Corp) ("SiO.sub.2");
Butylated hydroxyl toluene, NF ("BHT"); Sucrose Acetate Isobutyrate
(Eastman Chemicals), ("SAIB"); Triacetin USP ("TA"); Cellulose
Acetate Butyrate, grade 381-20 BP, ethanol washed (Eastman
Chemicals) ("CAB"); Miglyol 812 ("MIG"); Tween 80 ("TW80");
Gelucire 50/13 (Gattefosse) ("GEL"); Precirol ATOS ("PREC"); and
Ac-Di-Sol (Croscarmellose Sodium), ("ADS"). Details of each of the
initial increasing release components of the formulations produced
using the three stage manufacturing process are disclosed below in
Table 16.
TABLE-US-00017 TABLE 16 Formulation of Increasing Release
Components by Weight Percent (wt %) MPH21 MPH22 MPH23 MPH24 MPH25 8
mg 8 mg 8 mg 8 mg 8 mg MPH 20.00 6.67 6.67 20.00 20.00 SAIB 37.00
43.0 33.00 35.99 35.99 SiO.sub.2 1.00 1.00 1.00 1.60 1.60 ADS --
4.00 -- 4.00 4.00 MIG 43.0 44.00 35.99 35.99 CAB 1.00 -- -- -- --
TA 37.00 -- -- -- -- GEL 4.00 2.00 2.40 2.40 PREC -- 7.5 -- -- TW80
-- 7.5 -- -- BHT -- -- -- 0.02 0.02 Total 100.00 99.67 101.00
100.00 100.00
[0257] The second (non-ascending) controlled release components
were prepared using the following raw materials: methylphenidate
HCl ("MPH"); Colloidal silicon dioxide (Cabosil.RTM., Cabot Corp)
("SiO.sub.2"); Butylated hydroxyl toluene, NF ("BHT"); Sucrose
Acetate Isobutyrate (Eastman Chemicals), ("SAIB"); Triacetin USP
("TA"); Cellulose Acetate Butyrate, grade 381-20 BP, ethanol washed
(Eastman Chemicals) ("CAB"); Miglyol 812 ("MIG"); Tween 80
("TW80"); Gelucire 50/13 (Gattefosse) ("GEL"); Precirol ATOS
("PREC"); Ethyl Cellulose ("EC"); and Hydroxyethyl cellulose, NF
("HEC"). Details of each of the second (non-ascending) controlled
release components of the formulations produced using the three
stage manufacturing process are disclosed below in Table 17.
TABLE-US-00018 TABLE 17 Formulation of Second (Non-Ascending) CR
Components by Weight Percent (wt %) MPH21 MPH22 MPH23 MPH24 MPH25
40 mg 40 mg 40 mg 40 mg 40 mg MPH 20.00 33.33 33.33 20.00 20.00
SAIB 33.00 30.67 30.67 33.16 33.16 SiO.sub.2 1.00 1.00 1.00 1.60
1.60 PREC -- -- -- 11.20 11.20 MIG 11.00 25.00 25.00 25.51 25.51
CAB 6.00 -- -- -- -- TA 26.00 -- -- -- -- GEL 1.00 10.00 10.00 --
-- HEC 2.00 -- -- -- -- TW80 -- -- -- 6.52 6.52 EC -- 1.00 1.00
2.00 2.00 BHT -- -- -- 0.02 0.02 Total 100.00 101.00 101.00 100.01
100.01
[0258] The barrier layer was made from the combination of Paraffin
140/145 (25 wt %) and Mineral Oil, White, Light (75 wt %).
[0259] The initial increasing release component for the MPH23
formula was compounded as follows. The SAIB was pre-heated to
65.degree. C..+-.5.degree. C. over night. The compound mixture was
then maintained at 60.degree. C..+-.5.degree. C. for the remainder
of the compounding process. Next, the MIG was added to the SAIB and
mixed at 600 rpm for 15 minutes, after which the GEL was added to
the mixture and mixed at 600 rpm for 15 minutes. A pre-made MIG/BHT
solution was added to the compounding mixture and mixed at 600 rpm
for 15 minutes, after which the SiO.sub.2 was added and then mixed
at 1,000 rpm for 20 minutes followed by a homogenization step at
9,600 rpm for 10 minutes. Next, the ADS was added to the
compounding mixture and mixed at 1,500 rpm for 20 minutes, followed
by addition of the MPH with mixing at 1,500 rpm for 30 minutes, and
finished with a homogenization step at 9,600 rpm for 10 minutes to
provide the initial increasing release component.
[0260] The second (non-ascending) controlled release component for
the MPH23 formulation was compounded as follows. The SAIB was
pre-heated to 65.degree. C..+-.5.degree. C. over night. The
compound mixture was then maintained at 60.degree. C..+-.5.degree.
C. for the remainder of the compounding process. Next, the MIG was
added to the SAIB and mixed at 600 rpm for 15 minutes, after which
the TW80 was added to the mixture and mixed at 600 rpm for 20
minutes. A pre-made MIG/BHT solution was added to the compounding
mixture and mixed at 600 rpm for 15 minutes, after which the PREC
was added to the compounding mixture and mixed at 800 rpm for 20
minutes. Next, the SiO.sub.2 was added and then mixed at 1,000 rpm
for 20 minutes followed by a homogenization step at 9,600 rpm for
10 minutes. The EC was then added to the compounding mixture and
mixed at 1,500 rpm for 20 minutes, followed by addition of the MPH
with mixing at 1,500 rpm for 30 minutes, and finished with a
homogenization step at 9,600 rpm for 10 minutes to provide the
second (non-ascending) controlled release component.
[0261] The barrier layer was compounded at 65.degree.
C..+-.5.degree. C. by mixing the mineral oil at 600 rpm for 15
minutes, adding the paraffin and then mixing at 600 rpm for 30
minutes.
[0262] The three components for the other formulations were made in
substantially the same manner as the MPH23 components.
[0263] The capsules were filled into size #3 gelatin capsule shells
to produce dosage forms that were used as the first series of Test
Capsules as follows: the second (non-ascending) controlled release
component was filled into the bottom of the bottom of the capsule
and allowed to cool; next the barrier layer was filled over the
cooled layer, followed by filling of the initial increasing release
component; and then the capsule cap was placed over the top. The
Test Capsules were then ready for dissolution testing and the Abuse
Resistance Evaluation.
[0264] The dissolution study was carried out using the apparatus,
reagents and methods of the Method 1 dissolution test described
above, with the following exceptions: sample timepoints were either
at 0.25 hour, 0.5 hour, 1, 1.5, 2, 3, 6, 12 and 24 hour; or at 0.25
hour, 1, 3, 12 and 24 hour. Dissolution results were obtained on
the following Test Capsules: four (n=4) each of formulations
MPH16-MPH25. The mean dissolution data from the Test Capsules are
summarized below in Table 18.
TABLE-US-00019 TABLE 18 Mean Cumulative Drug Released 0.25 hr 0.5
hr 1 hr 1.5 hr 2 hr 3 hr 6 hr 12 hr 24 hr Formulation # MPH16 6%
12% 20% 26% 32% 40% 61% 82% 96% Mean 0 0 1 1 1 2 3 5 6 SD
Formulation # MPH17 4% 8% 13% 17% 20% 26% 41% 61% 86% Mean 1 1 1 1
2 3 4 5 4 SD Formulation # MPH18 8% 17% 30% 40% 47% 59% 80% 95% 96%
Mean 1 1 1 1 1 1 1 2 2 SD Formulation # MPH19 5% 10% 17% 24% 29%
37% 55% 76% 95% Mean 0 1 1 1 1 1 2 2 SD Formulation # MPH20 7% 29%
60% 103% 104% Mean SD Formulation # MPH21 12% 20% 34% 44% 51% 64%
86% 100% 103% Mean SD Formulation # MPH22 13% 22% 36% 45% 53% 65%
84% 92% 94% Mean SD Formulation # MPH23 11% 19% 31% 40% 46% 58% 80%
94% 97% Mean SD Formulation # MPH24 23% 29% 36% 42% 48% 55% 73% 93%
100% Mean 2 1 2 2 2 2 2 2 2 SD Formulation # MPH25 23% 31% 40% 47%
53% 64% 87% 100% 101% Mean 1 2 33 3 4 5 5 2 1 SD
[0265] The in vitro Abuse Resistance Evaluation used the following
Test Capsules: three (n=3) each of formulations MPH16-MPH20, MPH22
and MPH23.
[0266] The ethanol solution extraction study was carried out
substantially as described herein above, using the same apparatus,
reagents and methods described above, with the following
exceptions: the extraction solution was 60mL of 80 proof ethanol
(40%); and sampling was conducted either: (i) at time=30 minutes
and then at 3 hours; or (ii) at time=20 minutes, 45 minutes, 1 hour
and then at 3 hours. The results of the extraction study are
provided below in Table 19.
TABLE-US-00020 TABLE 19 Amount of Methylphenidate Extracted in 80
Proof Ethanol (% of dose) Time 20 min 30 min 45 min 1 hr 3 hrs
MPH16 Mean 5 -- 12 16 37 Std Dev. 1 -- 2 1 3 MPH17 Mean 9 -- 15 18
33 Std Dev. 1 -- 0 1 2 MPH18 Mean 10 -- 17 20 32 Std Dev. 0 -- 2 1
2 MPH19 Mean 5 -- 9 11 18 Std Dev. 1 -- 2 2 3 MPH20 Mean -- 8 -- --
43 Std Dev. -- -- -- MPH22 Mean -- 28 -- -- 53 Std Dev. -- -- --
MPH23 Mean -- 14 -- -- 49 Std Dev. -- -- --
[0267] Finally, the cumulative release results from the MPH24 and
MPH25 Test Capsules were compared against the target in vitro
release profile developed in Example 2b above. FIG. 18 depicts the
results of this comparison, where the in vitro dissolution
cumulative release profiles of methylphenidate from the Test
Capsules are compared to a target in vitro methylphenidate release
profile developed in accordance with the invention. As can be seen,
the MPH24 and MPH25 release profiles match the target profile.
Example 4
Analysis of Formulations
[0268] (Formulation Viscosity Testing Procedures)
[0269] In order to assess the viscosity of abuse resistant oral
dosage forms produced according to the present invention, the
following viscosity tests were developed. Both standard and dynamic
viscosity measurements may be obtained using these tests. The
viscosity testing apparatus used in the methods described in this
Example 4 are Brookfield Digital Rheometers. The two specific
models used are the following: JPII, Model HBDV-III+CP with a
programmable/digital Controller Model 9112; and JPI, Model
LVDV-III+CP, with an Immersion Circulator Model 1122S. For both
rheometer models the CPE Spindle 52 was used. For Dynamic Rheology,
the dynamic rheology of the formulations can be measured using an
Anton Paar Physica MCR301 rheometer (Anton Paar USA, Ashland, Va.)
that is equipped with temperature and oscillatory strain control
modules.
[0270] Sample formulations can be presented in two different
formats for the viscosity testing methods, either as bulk
formulation or as single dosage forms (e.g., gelatin capsules). For
bulk formulation testing, 0.5 mL of the formulation is injected
directly into the rheometer cup. When testing dosage forms, two
gelatin capsules are needed for each measurement. The gelatin
capsules are opened using a razor blade and a clean cutting
surface. The contents are then squeezed out and placed in the
rheometer cup.
[0271] Typical temperature conditions for the viscosity testing
methods are 37.degree. C. for most single point measurements, and
30.degree. C., 40.degree. C., 50.degree. C., and 60.degree. C. for
temperature profiles. For each sample two different shear rates
measured: 1.sup.st--low shear, an rpm setting is selected to
provide a torque value between 10-15%; and 2.sup.rd--high shear, an
rpm setting is selected to give a torque value between 20-90%
[0272] Data collection of the viscosity measurements is carried out
using standard techniques. For example, the Brookfield Digital
Rheometer data report screen automatically displays the rotational
speed, spindle number, torque value (%), and the viscosity for
manual recording.
[0273] Finally, complex viscosity of formulation samples can be
measured using varying oscillatory strain in the linear
viscoelastic regime. Here, the intrinsic complex viscosity of a
sample formulation at rest can be obtained based on a mathematical
curve fit of empirical data points. The advantage of the dynamic
oscillatory experiment is that it probes the sample formulation
material without destroying the material's microstructure.
Example 5
In Vivo Analysis of Formulations
[0274] (Human Clinical Trials, Pharmacokinetic Studies)
[0275] In order to assess the in vivo abuse resistance performance
of abuse-resistant methylphenidate oral dosage forms prepared in
accordance with the present invention, the following human clinical
trails are carried out.
Example 5a
[0276] The following in vivo Abuse Resistance Evaluation study is
designed as a single-center, four-way crossover PK study to assess
the effect of physical disruption of the controlled release carrier
system on the release of the methylphenidate active agent from
abuse-resistant oral dosage forms produced according to the present
invention. The study dosage forms (capsules containing
methylphenidate) are administered either intact or crushed with
alcohol. For comparison, methylpheniate controlled release tablets
such as Concerta or Metadate CD of equal dosage strength are
administered intact or crushed with alcohol, as well as an equal
dose of an oral solution of methylphenidate as a comparator of an
immediate release in order to represent a "worst-case
scenario".
[0277] All administrations are in the fasted state unless a Test
Capsule or comparison tablet is subject to a food effect, in which
case administrations are in the fed state (30 minutes after a
standardized breakfast).
[0278] During each study period, 3 mL blood samples are obtained
prior to each dosing and following each dose at selected times
through 96 hours post-dose. Blood samples are collected in
vacutainer tubes containing EDTA as a preservative.
[0279] Plasma samples are analyzed for methylphenidate and its
major metabolites using a validated LC-MS-MS procedure.
Concentration-time data are transferred into WinNonlin, and
analyzed using noncompartmental methods. These PK analyses are
suitable to determine pharmacokinetic parameters such as mean
C.sub.max, T.sub.max, AUC, etc. Effects of crushing Test Capsules
are then assessed for evidence of dose dumping, and compared to PK
performance of intact Test Capsules, intact and crushed controlled
release control tablets, and the IR control.
Example 5b
[0280] The following in vivo Abuse Resistance Evaluation study is
designed as a single-center, three-way crossover PK study to
determine the release rate of methylphenidate after dissolving the
study abuse-resistant oral dosage forms in the buccal cavity of
healthy volunteers. The study dosage forms (Test Capsules) are
administered and allowed to dissolve in the buccal cavity for 10
minutes to compare with same strength study dosage forms
administered intact and swallowed immediately as intended, and an
oral solution of immediate release (IR) methylphenidate in order to
represent a "worst-case scenario".
[0281] All administrations are in the fasted state unless a Test
Capsule or IR comparator is subject to a food effect, in which case
administrations are in the fed state (30 minutes after a
standardized breakfast).
[0282] During each study period, 3 mL blood samples are obtained
prior to each dosing and following each dose at selected times
through 96 hours post-dose. Blood samples are collected in
vacutainer tubes containing EDTA as a preservative.
[0283] Plasma samples are analyzed for methylphenidate and its
major metabolites using a validated LC-MS-MS procedure.
Concentration-time data are transferred into WinNonlin, and
analyzed using noncompartmental methods. These PK analyses are
suitable to determine pharmacokinetic parameters such as mean
C.sub.max, T.sub.max, AUC, etc. Effects of holding Test Capsules in
the buccal cavity are then assessed for evidence of dose dumping,
and compared to PK performance of intact Test Capsules and the IR
control.
Example 5c
[0284] The following in vivo Abuse Resistance Evaluation study is
designed as a single-center, randomized crossover study to assess
the effect of rigorous mastication on the rate and extent of
absorption of methylphenidate in abuse-resistant oral dosage forms
in comparison with the same dosage forms swallowed whole (both
under fed conditions) and methylphenidate IR solution. The study
dosage forms (Test Capsules) are administered and chewed vigorously
before swallowing to compare with same strength study dosage forms
administered intact and swallowed immediately as intended, and an
oral solution of immediate release (IR) methylphenidate in order to
represent a "worst-case scenario".
[0285] All administrations are in the fasted state unless a Test
Capsule or IR comparison tablet is subject to a food effect, in
which case administrations are in the fed state (30 minutes after a
standardized breakfast).
[0286] During each study period, 3 mL blood samples are obtained
prior to each dosing and following each dose at selected times
through 96 hours post-dose. Blood samples are collected in
vacutainer tubes containing EDTA as a preservative.
[0287] Plasma samples are analyzed for methylphenidate and its
major metabolites using a validated LC-MS-MS procedure.
Concentration-time data are transferred into WinNonlin, and
analyzed using noncompartmental methods. These PK analyses are
suitable to determine pharmacokinetic parameters such as mean
C.sub.max, T.sub.max, AUC, etc. Effects of chewing the Test
Capsules prior to swallowing are then assessed for evidence of dose
dumping, and compared to PK performance of intact Test Capsules and
the IR control.
Example 5d
[0288] The following In Vivo Abuse Resistance Evaluation study is
designed as a single-center, four-way crossover PK study to
determine the rate and extent of absorption of methylphenidate in
abuse-resistant oral dosage forms (Test Capsules) when
co-administered with 240 mL of 4% ethanol, 20% ethanol and 40%
ethanol in comparison to 240 mL of water.
[0289] All administrations are in the fasted state unless the Test
Capsule is subject to a food effect, in which case administrations
are in the fed state (30 minutes after a standardized
breakfast).
[0290] During each study period, 3 mL blood samples are obtained
prior to each dosing and following each dose at selected times
through 96 hours post-dose. Blood samples are collected in
vacutainer tubes containing EDTA as a preservative.
[0291] Plasma samples are analyzed for methylphenidate and its
major metabolites using a validated LC-MS-MS procedure.
Concentration-time data are transferred into WinNonlin, and
analyzed using noncompartmental methods. These PK analyses are
suitable to determine pharmacokinetic parameters such as mean
C.sub.max, T.sub.max, AUC, etc. Effects of co-administration of the
Test Capsules with alcohol are compared to PK performance of
co-administration with water, and assessed for evidence of dose
dumping.
Example 5e
[0292] In order to assess the in vivo controlled release
performance of abuse-resistant methylphenidate oral dosage forms
prepared in accordance with the present invention, the following
human clinical trail is carried out. The study is designed as a
single-center, three-way crossover, food effect, PK study to
determine the rate and extent of absorption of methylphenidate in
abuse-resistant oral dosage forms (Test Capsules) when administered
in a fasted state, after consumption of a low fat meal, and after
consumption of a high fat meal.
[0293] All study groups fast overnight for at least 10 hours. Study
groups receiving the "high-fat" standardized meal are provided 2
slices of toasted white bread spread with butter, two eggs fried in
butter, two slices of bacon, 2 oz hash-browned potatoes, and 8 oz
whole milk (approximately 33 g protein, 58 to 75 g fat, 58 g
carbohydrate, 870 to 1020 calories) at least 30 minutes prior to
dosing. Study groups receiving the "low-fat" standardized meal are
provided one slice of toasted white bread spread with butter or
jelly, 1 oz dry cereal (corn flakes), 8 oz skim milk, 6 oz orange
juice, and one banana (approximately 17 g protein, 8 g fat, 103 g
carbohydrate, 583 calories) at least 30 minutes prior to
dosing.
[0294] During each study period, 3 mL blood samples are obtained
prior to each dosing and following each dose at selected times
through 96 hours post-dose. Blood samples are collected in
vacutainer tubes containing EDTA as a preservative.
[0295] Plasma samples are analyzed for methylphenidate and its
major metabolites using a validated LC-MS-MS procedure.
Concentration-time data are transferred into WinNonlin, and
analyzed using noncompartmental methods. These PK analyses are
suitable to determine pharmacokinetic parameters such as mean
C.sub.max, T.sub.max, AUC, etc. Effects of co-administration of the
Test Capsules with high-fat or low-fat meals are compared against
study groups administered Test Capsules in the fasted state.
Example 5f
[0296] In order to assess the in vivo controlled release
performance of abuse-resistant methylphenidate oral dosage forms
prepared in accordance with the present invention, the following
human clinical trail is carried out. The study is designed as a
single-center, randomized, open-label, Phase 1 study to assess the
safety and pharmacokinetics of three prototype Test Capsules
(methylphenidate formulations, 48 mg) relative to Metadate CD.RTM.
(40 mg) and Concerta.RTM. (36 mg) formulations in healthy male and
female volunteers under fed condition. The prototype formulation
evaluation is carried out in a five-way open-label, crossover study
in 20 healthy subjects. A standard 5.times.5 Latin square design is
used to assign subjects to treatments. In each sequence, subjects
are given a single dose of Test Capsules (MPH1, MPH2 or MPH3) or
Metadate CD.RTM. (40 mg) and Concerta.RTM. (36 mg) as reference
drugs. Subjects receive the other dosing treatments in subsequent
study periods according to the randomization scheme. A minimum
7-Day washout period separates each study treatment. A 48 mg dose
is selected to match the C.sub.max of the reference products and to
allow quantification of blood levels of Methylphenidate over a
48-hour time interval.
[0297] Subjects are admitted to the clinic in the evening,
approximately 13 hours before each scheduled dose. At each
treatment period check-in, site staff reconfirm that subjects meet
inclusion and exclusion criteria and restrictions have not been
violated since screening or previous confinement period. In
addition, a urine sample is collected for urinalysis and to test
for and drugs of abuse and pregnancy for women, a physical
examination is performed and a blood sample is collected for
haematology/biochemistry. A test for alcohol is also performed
using a breath test. Subjects remain at the clinic until completion
of the 36-hour post dose blood collection and are instructed to
return to the clinic for the 48-hour post dose blood samples. After
check-in, each subject receives dinner. On the next day, following
an overnight fast in the morning of Study Day 1 of each treatment
period, subjects are provided with a standardized high fat
breakfast approximately 20 minutes prior to dosing and after the
pre-dose (0-hour) blood sample is drawn. The breakfast consists of
one English muffin with butter, one fried egg, one slice of cheese,
one slice of bacon, one 2-oz serving of hash brown potatoes, and 8
fluid oz (230 mL) whole milk. The breakfast contains an estimated
Carbohydrates 41.8 g, estimated Protein 25.7 g, and estimated Fat
31.0 g.
[0298] Within 5 minutes of completion of the breakfast, each
subject receives a single oral dose of the assigned study treatment
to be administered with 240 mL of room temperature, non-carbonated
drinking water. A mouth check will be performed after dosing to
ensure that the study medication was swallowed.
[0299] A standard meal schedule with lunch, dinner and an evening
snack will begin on Day 1 of each study treatment. Meals are served
5 minutes after the pre-treatment blood collection. The same menu
and meal schedule is administered uniformly for all subjects and
for all treatment periods. Subjects are restricted from food or
beverages containing alcohol, caffeine, any xanthine-containing
products, and fruit juices (including grapefruit juice) containing
ascorbic acid for 48 hours before and during each treatment period
of confinement. Additionally, subjects are restricted from
strenuous exercise during confinement and may not lie down for the
first two hours after drug administration to ensure proper stomach
emptying, subjects are allowed to sit or stand during this
time.
[0300] Plasma Sample Collection:
[0301] Plasma samples are collected in a 5 mL Li+heparin vacutainer
tube at prescribed time points during each study periods. The
samples are processed and frozen and retained at the site until
they are forwarded to a laboratory for testing.
[0302] Beginning on dosing day, 17 blood samples (5 mL/sample) are
collected through the 48-hour post dose interval during each study
period to determine the plasma concentration of methylphenidate.
Blood samples are collected at 30 minutes before dose (pre-dose)
and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 36 and 48
hours after administration of the study treatment.
[0303] In addition, blood is collected for screening clinical
laboratory evaluation and for women subjects, blood is collected
for serum pregnancy test. For women, urine pregnancy testing is
conducted on the evening prior to treatment. Clinical laboratory
measures (biochemistry and haematology) are performed at screening,
on the evening prior to each treatment and 24 hours post-treatment
(non-fasted).
[0304] Plasma samples are analyzed for methylphenidate and its
major metabolites using a validated LC-MS-MS procedure.
Concentration-time data are transferred into WinNonlin, and
analyzed using noncompartmental methods. These PK analyses are
suitable to determine pharmacokinetic parameters such as mean
C.sub.max, T.sub.max, AUC, etc.
Example 5g
[0305] In order to compare a target pharmacokinetic profile
(developed in accordance with the present invention) with a QD
comparator and placebo, the following human clinical trail is
carried out. The methods of the study are based on a report by
Swanson et al. (2002) J Am Acad Child Adolesc Psychiatry
41:1306-1314. The study is carried out in a Laboratory School
setting.
[0306] Patient Selection:
[0307] Children aged 7-12 years, meeting the DSM-IV criteria for a
diagnosis of ADHD and taking 5 to 15 mg of methylphenidate BID or
TID, or taking an equivalent dose of a long acting methylphenidate
formulation selected from Concerta, Metadate CD, Focalin XR are
selected for the study. Children are excluded from the study if
they have abnormal blood pressure, are physically ill or if they
have a primary diagnosis of defiant disorder or conduct disorder or
if their diagnosis includes comorbid mood or anxiety disorder, as
defined by DSM-IV criteria. Children are also excluded if they are
unable to understand that they may withdraw from the study at any
time.
[0308] Dosing:
[0309] The trial is designed to compare the target pharmacokinetic
profile of the present invention against placebo and a QD
comparator. The study is carried out using the "dose-sipping"
methodology described by Swanson et al. (Swanson et al. (2002) J Am
Acad Child Adolesc Psychiatry 41:1306-1314; Swanson et al. (2003)
Arch Gen Psychiatry 60:204-211). For each arm of the three-arm
study, capsules are given every 30 minutes over a 12-hour time
period as shown in Table 13 below. In the experimental
pharmacokinetic profile group, the capsules contain differing
quantities of methylphenidate designed to result in the
pharmacokinetic profile being investigated as determined by
simulation that is based on published methylphenidate properties.
Swanson et al. (1999) Clin Pharmacol Ther 66:295-305. In the
placebo group, the capsules do not contain methylphenidate. In the
comparator group, the first capsule incorporates the comparator
formulation in an over-encapsulated form. Subsequent capsules are
identical to placebo. The study uses a crossover design so that
each subject is scheduled to experience one study day on the
experimental medication, one on the comparator and one on
placebo.
[0310] Study Protocol:
[0311] The study follows the laboratory school protocol that has
been established at the University of California, Irvine Child
Development Center and is carried out after an initial practice day
to acquaint the children with the protocol, the laboratory school
and the Center staff. The subjects, divided into two cohorts of 16
subjects, are further subdivided by age into two classes of eight
that are evaluated over 3 consecutive days in the laboratory
school.
[0312] The laboratory school schedule includes Seatwork sessions,
five classroom observations during Groupwork sessions, and five
playground observations during Recess sessions as outlined in Table
20. The laboratory school activity schedule is standardized to
maintain comparability over multiple repetitions across the day
(Swanson et al. (1999) Ritalin, 2.sup.nd ed.; Greenhill et al. Eds,
Mary Ann Liebert, Larchmont, N.Y.; pp405-430) establishing a 1.5
hour cycle of activities with 20 minute period activities buffered
by 5 minute transition time intervals at the beginning and end.
[0313] Seatwork sessions are standardized by requiring the students
to remain seated and quiet while performing written schoolwork.
Groupwork sessions are standardized by choosing activities
characteristic of schoolwork (i.e., participation in a class
presentation and discussion) that require cooperation but do not
require students to remain seated or silent. The Recess sessions
are standardized by having playground counselors lead group games.
Simple rules that define appropriate and inappropriate behavior are
clearly communicated to the students by teachers (in the classroom
settings) and by counselors (during recess). Formal behavior
modification procedures are not used.
[0314] Measures and Assessments:
[0315] Measures of behavior defined as Attention and Deportment are
obtained from the Swanson, Kotkin, Agler, M-Flynn, and Pelham
(SKAMP) rating scale. SKAMP scores are assigned by teachers for the
classroom situations and by counselors for the Recess sessions.
Using the standard classroom version of this scale (Wigal et al.
(1998) Psychopharmacol Bull 34:47-53) 10 items (Table 21, below)
are rated on a 7-point impairment scale (none, slight, mild,
moderate, severe, very severe, or maximal). Averages are calculated
to reflect rating-per-item for subsets of items in two subscales: a
five-item "nonschoolwork" Attention Index (without ratings of
written work) (items 1 to 5) and a five-item Deportment Index
(items 6 to 10). A 10-item recess version of the SKAMP rating scale
adapted from Swanson et al. is also used in this study, with five
parallel items for Attention (items 1, 2, 3, 4, and 9) and five
parallel items for Deportment (items 5, 6, 7, 8, and 10) to measure
the playground behavior of children in the Recess setting.
[0316] The subjective measures of behavior (ratings of Attention
and
[0317] Deportment) are analyzed with mixed-effects analysis of
variance (ANOVA) models. These ANOVA models include the fixed
effects of treatment arms (experimental profile, placebo and
comparator), situation (Seatwork, Groupwork, and Recess), session
(at 2-hour intervals across the day), sequence (the six orders of
treatments used), and day (test days 1, 2, and 3). Pairwise
comparisons are made with the least significant difference (LSD)
method.
TABLE-US-00021 TABLE 20 Dosing and Activity Schedule. (S =
seatwork, G = groupwork, R = recess) lab school Class 1 Class 2
activities 7:00 7:30 First dose 7:30 8:00 S1 8:00 8:30 G1 8:30 9:00
S1 9:00 9:30 R1 9:30 10:00 S2 10:00 10:30 G2 10:30 11:00 S2 11:00
11:30 R2 11:30 12:00 S3 12:00 12:30 G3 12:30 13:00 S3 13:00 13:30
R3 13:30 14:00 S4 14:00 14:30 G4 14:30 15:00 S4 15:00 15:30 R4
15:30 16:00 S5 16:00 16:30 G5 16:30 17:00 S5 17:00 17:30 R5 17:30
18:00 S6 18:00 18:30 G6 18:30 19:00 S6 19:00 19:30 R6 19:30 20:00
Finish
TABLE-US-00022 TABLE 21 The SKAMP Rating Scales The 10 SKAMP Items
The Recess SKAMP Scale 1. Getting started (on assignments) 1.
Getting started (on play activities) 2. Sticking with task (for
entire period) 2. Staying on task (over entire recess) 3.
Completing assigned work 9. Completing games 4. Performing work
accurately 4. Interacting with peers (at recess) 5. Being careful
and neat when writing 7. Interacting with playground staff 6. a.
Interacting with other students 5. Verbal interactions b.
Interacting with the teacher 7. Remaining quiet 6. Staying in
assigned area 8. Remaining seated 3. Carelessness or recklessness
9. Complying with teacher's requests 8. Participation in group
activities 10. Following school rules 10. Stopping and making
transitions
* * * * *
References