Note: Descriptions are shown in the official language in which they were submitted.
CA 02718639 2010-09-15
WO 2009/117819 PCT/CA2009/000369
METHYLPHENIDATE EXTENDED RELEASE
THERAPEUTIC DRUG DELIVERY SYSTEM
FIELD OF THE INVENTION
The present invention relates to an extended release therapeutic drug
delivery system, a process for manufacturing same, as well as the composition
of the
dosage form. In particular, the present invention relates to an extended
release
therapeutic drug delivery system comprising methylphenidate as a
pharmaceutically acceptable active ingredient.
BACKGROUND OF THE INVENTION
Methylphenidate (CAS [113-45-11), a piperidine derivative, is chemically
designated as a-phenyl-2-piperidine-acetic acid methyl ester; methyl
phenidylacetate; methyl a-phenyl- a-(2-piperydl) acetate; methylphenidan, and
whereas methylphenidate hydrochloride (CAS [298-59-9]), a mild central nervous
system (CNS) stimulant, C14H19NO2 = HCI, is chemically designated as methyl a-
phenyl-2-piperidineacetate hydrochloride. Its structural formula is
o 0
H
N = HCI
Methylphenidate hydrochloride is known under various brand names, such
as Ciba 4311/B, Centedrin , Concerta , Equasym ; Metadate and Ritalin . This
compound is available in various forms of tablets, including 5, 10, and 20 mg
tablets
for oral administration, as well as sustained-release tablets of 20 mg for
oral
administration (for example Ritalin-SR).
Methylphenidate hydrochloride (HC1) is used in the treatment of Attention
Deficit Disorder ("ADD"), a commonly diagnosed nervous system illness in
children
that is characterized by both distractibility and impulsivity. Methylphenidate
HCl is
also used to treat a related disorder, Attention Deficit Hyperactivity
Disorder
CA 02718639 2010-09-15
WO 2009/117819 PCT/CA2009/000369
2
("ADHD"), in which symptoms of hyperactivity are present along with the
symptoms of ADD. The drug is additionally used in the symptomatic treatment of
narcolepsy, depression, the cognitive decline associated with Acquired
Immunodeficiency Syndrome ("AIDS") or AIDS-related conditions, as well as for
mood elevation, particularly in terminally ill patients with diseases such as
cancer.
The preparation of methylphenidate is described in L. Panizzon, Heiv. Chim.
Acta, 27, 1748 (1944), M. Hartmann, L. Panizzon and in U.S. Patent No.
2,507,631
(issued 1950 to Ciba Pharmaceutical Products Inc.).
Many formulations or dosage forms containing methylphenidate HCl have
been reported. For example, Concerta is currently marketed as a tablet
containing
three layers in which is found methylphenidate hydrochloride (it is a tri-
layer
capsule shaped tablet). The tablet contains three inner layers and a push
layer to
help release the drug from the system and a drug overcoat layer. The coating
layer
has holes which are made by laser, these holes form the controlled release
mechanism for the methylphenidate contained in this dosage form. This design
allows the controlled release of the drug in a unique and precise pattern.
Canadian Patent No. 2,264,852 (Gupta et al.) is directed to the use of a
composition comprising 100 ng to 500 mg methylphenidate or a pharmaceutically
acceptable salt thereof, together with a pharmaceutically acceptable carrier,
the
composition releasing methylphenidate, or a pharmaceutically acceptable salt,
thereof in a sustained-ascending dose over time, for regulation of tolerance
to
methylphenidate or a pharmaceutically acceptable salt thereof.
Canadian Patent Application No. 2,426,883 (Bettman et al.) (equivalent to U.S.
Patent No. 6,344,215) is directed to a pharmaceutical modified release (MR)
methylphenidate dosage form, such as a capsule of methylphenidate indicated
for
the treatment of children with ADHD, capable of delivering a portion of the
dose for
rapid onset of action and the remainder of the dose in a controlled manner for
about
12 hours. The dosage form is composed of a multitude of multicoated particles
CA 02718639 2010-09-15
WO 2009/117819 PCT/CA2009/000369
3
made of two populations of drug layered beads, one population for immediate
release and the other for extended release.
Canadian Patent Application No. 2,566,497 (Rubio Badia et al.) is directed to
a
multi-layered controlled release methylphenidate pellet, comprising an inert
core, a
first layer that contains methylphenidate and an acid buffering system, a
protective
layer, a layer of ethylcellulose (performs the function of controlling the
extended
release of most of the methylphenidate), and a second layer of
methylphenidate, that
is responsible for the immediate release of the aforesaid within one hour of
administration.
International Patent Application WO 99/03471 discloses a methylphenidate
preparation for extended release in which the innermost layer is coated in a
layer of
ammonium methacrylate polymer, and another layer that contains methylphenidate
for immediate release resting on the ammonium methacrylate polymer layer.
Methylphenidate HCl formulations of the prior art require complicated
manufacturing processes, which in turn consume significant amounts of time and
are cost intensive.
There is thus a need for an invention, as described hereafter, that overcomes
the problems of the prior art.
SUMMARY OF THE INVENTION
According to an aspect of the present invention, there is provided an
extended release therapeutic drug delivery system comprising a core matrix
composition. The core matrix composition comprises an active pharmaceutical
ingredient and a release controlling agent. The drug delivery system further
comprises a controlled release coating composition layer covering the core
matrix
composition.
Preferably, the active pharmaceutical ingredient is a central nervous system
stimulant. More preferably, the active pharmaceutical ingredient is
CA 02718639 2010-09-15
WO 2009/117819 PCT/CA2009/000369
4
methylphenidate or a pharmaceutically acceptable salt thereof. In a preferred
embodiment of the present invention, the active pharmaceutical ingredient is
methylphenidate HCI.
In further embodiments of the present invention, the extended release
therapeutic drug delivery system further comprises at least one
pharmaceutically
acceptable excipient, including binders, stabilizing agents, suspending
agents,
diluents, coating agents, lubricants, rate controlling polymers, emulsifying
agents,
solubilizing agents, glidants, absorbents, and disintegrants.
In a preferred embodiment of the present invention, the controlled release
coating composition layer comprises a controlled release polymer and at least
one
other pharmaceutically acceptable excipient. The controlled release polymer is
preferably an acrylic polymer such as Eudragit , and more preferably, the
Eudragit
is Eudragit RL 30D.
Preferably, the controlled release polymer accounts for between about 5 to
about 40 % w/w of the drug delivery system, and more preferably, the
controlled
release polymer accounts for between about 5 to about 25 % w/w of the drug
delivery system.
Preferably, the release controlling agent used in the core matrix composition
accounts for between about 5 to about 40% w/w of the drug delivery system.
More
preferably, the release controlling excipient used in the matrix accounts for
between
about 5 to about 25% w/w of the drug delivery system.
In a preferred embodiment, the release controlling agent present in the core
matrix composition is a hydrophilic polymer such as HPMC-K4M, HPMC-K 100M
CR and HPMC-K 15M CR.
In a preferred embodiment, the at least one other pharmaceutically acceptable
excipient present in the controlled release coating composition includes anti-
tacking
CA 02718639 2010-09-15
WO 2009/117819 PCT/CA2009/000369
agents, anti-caking, agents, glidants, diluents, lubricants, plasticizers,
additives, and
surface active agents.
In a further aspect of the present invention there is provided a solid oral
dosage form containing the extended release therapeutic drug delivery system
as
described herein. Preferably, the solid oral dosage form is in the form of a
capsule or
tablet. More preferably, the solid oral dosage form is in the form of a
tablet.
Preferably, the solid oral dosage form is for use in once daily administration
or twice
daily administration.
In another aspect of the present invention there is provided a process for
manufacturing the extended release therapeutic drug delivery system wherein
said
process comprises:
= a first step of combining an active pharmaceutical
ingredient and a release controlling agent to form
a mixture;
= a second step of blending the mixture;
= a third step of compressing the mixture from the
second step to form a controlled release core
matrix (the core matrix composition); and
= a fourth step of applying a controlled release
coating on the controlled release core.
Preferably, in the process according to the invention, the active
pharmaceutical ingredient is methylphenidate or a pharmaceutically acceptable
salt
thereof, the controlled release polymer is Eudragit RL 30D and the release
controlling agent used in the matrix is HPMC-K4M, HPMC-K 100M CR or HPMC-K
15M CR.
In a preferred embodiment, the amount of release controlling agent and
controlled release polymer used in the process, in steps 1 and 4,
respectively, results
in the release controlling agent present in the core matrix composition
accounting
for between about 5 to about 40% w/w of the drug delivery system and the
controlled release polymer accounts for between about 5 to about 40 % w/w of
the
CA 02718639 2010-09-15
WO 2009/117819 PCT/CA2009/000369
6
drug delivery system. More preferably, the amount of release controlling agent
and
controlled release polymer used is such that the release controlling agent
present in
the core matrix composition accounts for between about 5 to about 25% w/w of
the
drug delivery system and the controlled release polymer accounts for between
about
to 25 % w/ w of the drug delivery system.
Other embodiments and further scope of applicability of the present
invention will become apparent from the detailed description and examples
given
hereinafter. It should be understood, however, that this detailed description
and
examples, while indicating preferred embodiments of the invention, are given
by
way of illustration only, since various changes and modifications within the
spirit
and scope of the invention will become apparent to those skilled in the art.
An advantage associated with the present invention is an extended release
solid oral dosage form that allows for the manufacture of solid oral dosage
forms for
once daily or twice daily administration with a sustained effect, made by a
simplified production which is cost effective. An advantage associated with
the
present invention is that it gives the formulator the desired flexibility to
obtain
required in vitro dissolution characteristics. Another advantage of the
present
invention is that the composition can be formulated to obtain similar
dissolution
profiles regardless of the dosage strength of the active pharmaceutical
ingredient
("API"). In this connection, it is worth mentioning that conventionally made
controlled release matrix formulations cannot achieve this desired result, as
formulators using this conventional technology have to formulate particular
dosage
strengths to a desired dissolution profile. The formulation according to the
present
invention has surprisingly been found to overcome this drawback found in the
preparation of prior art formulations.
DETAILED DESCRIPTION OF THE INVENTION
Before the present formulations and methods of use are disclosed and
described, it is to be understood by a person skilled in the art that the
terminology
CA 02718639 2010-09-15
WO 2009/117819 PCT/CA2009/000369
7
used herein is for the purpose of describing particular embodiments only and
is not
intended to be limiting.
It must be noted that, as used in the disclosure and the claims, the singular
forms "a", "an" and "the" include plural referents unless the context clearly
dictates
otherwise. Thus, for example, reference to "an active agent" includes mixtures
of
active agents, reference to "a pharmaceutical carrier" includes combinations
of two
or more carriers, and the like.
"Optional" or "optionally" means that the subsequently described
circumstance may or may not occur, so that the description includes instances
where
the circumstance occurs and instances where it does not.
The terms or expressions "active agent", "drug", "pharmacologically active
agent", "pharmaceutically acceptable active agent", "pharmaceutically
acceptable
active substance" and "active pharmaceutical ingredient" are used
interchangeably
herein to refer to a chemical material or compound which, when administered to
an
organism (human or animal, generally human) induces a desired pharmacologic
effect. In the context of the present invention, the terms or expressions
refer to a
compound that is capable of being delivered orally.
The term "methylphenidate", as used herein, includes all optical isomers,
racemic mixtures and the like of the compound and all pharmaceutically
acceptable
salts, amides, prodrugs and analogs thereof. For example, the pharmaceutically
active substance can be for example, methylphenidate hydrochloride.
Similarly, a "pharmaceutically acceptable salt" or a "pharmaceutically
acceptable ester" of the compound as provided herein is a salt or ester which
is not
biologically or otherwise undesirable. A pharmaceutically acceptable salt of
methylphenidate is, for example, methylphenidate hydrochloride.
By the terms "effective amount" or "pharmaceutically effective amount" of an
agent as provided herein are meant a nontoxic but sufficient amount of the
agent to
CA 02718639 2010-09-15
WO 2009/117819 PCT/CA2009/000369
8
provide the desired therapeutic effect. The exact amount required will vary
from
subject to subject, depending on age, general condition of the subject, the
severity of
the condition being treated, and the particular active agent administered, and
the
like. Thus, it is not possible to specify an exact "effective amount".
However, an
appropriate "effective" amount in any individual case may be determined by
person
skilled in the art using routine experimentation.
The term "excipient" refers to a generally pharmaceutically inactive or inert
substance used as a diluent or vehicle for a drug. Different forms of drug
administration may require a different excipient and a "pharmaceutically
acceptable
excipient" includes a "pharmaceutically acceptable carrier". For example,
tablets,
troches, pills, capsules, and the like, may contain excipients including
binders, such
as gum tragacanth, acacia, corn starch or gelatin; a lubricant such as
magnesium
stearate; a sweetening agent such as sucrose, lactose or saccharin; and/or a
flavoring
agent such as peppermint, oil, wintergreen or cherry flavoring.
By "pharmaceutically acceptable carrier" is meant a carrier comprised of a
material that is not biologically or otherwise undesirable, i.e., the material
may be
administered to an individual along with the selected active agent without
causing
any undesirable biological effects or interacting in a deleterious manner with
any of
the other components of the pharmaceutical composition in which it is
contained.
The term "carrier" is used generically herein to refer to any components
present in
the pharmaceutical formulations other than the active agent or agents, and
thus
includes diluents, binders, lubricants, disintegrants, fillers, and coloring
agents.
As aforementioned, the present invention relates to an extended release
therapeutic drug delivery system comprising a core matrix composition and a
controlled release coating composition.
The Applicant has developed a novel controlled release composition (dosage
form) containing a combination of hydrophilic polymers, such as
hydroxypropylmethylcellulose (HPMC), as a release controlling agent (or
excipient)
CA 02718639 2010-09-15
WO 2009/117819 PCT/CA2009/000369
9
present in the core matrix composition, and a release controlling coating
(comprising
a controlled release polymer, such as Eudragit RL 30D) coated onto the HPMC
containing matrix core. As aforesaid, the present invention is directed to a
novel
controlled release dosage form for methylphenidate hydrochloride which may be
used in the treatment of certain ailments, such as ADD, and a process to
prepare
such dosage forms.
The core matrix composition of the present invention is made of several
components, including a pharmaceutically acceptable active substance (such as
a
CNS stimulant, in particular, methylphenidate or a pharmaceutically acceptable
salt
thereof) and a release controlling agent.
For example, the core matrix composition of the present invention can be
illustrated as follows:
# Description mg/tab % Function
1. Meth 1 henidate HCl 54.0 9.0 API
2. Lactose monohydrate 447.0 74.5 diluent/Binder
3. HPMC-K4M 90.0 15.0 release controlling
polymer
4. Stearic acid 3.0 0.5 tablet lubricant
5. Colloidal Silicon dioxide 6.0 1.0 glidant
Total 600 100 -
The controlled release coating composition of the present invention is made
of a plurality of components. In the preferred embodiment, the controlled
release
coating composition contains a rate controlling polymer (i.e. a controlled
release
polymer, such as Eudragit) and at least one other pharmaceutically acceptable
excipient. The one other pharmaceutically acceptable excipient includes anti-
tacking
agents, anti-caking agents, rate controlling polymers, glidants, diluents,
lubricants,
plasticizers, additives, and solvents.
The controlled release coating composition of the present invention can be
illustrated as follows:
CA 02718639 2010-09-15
WO 2009/117819 PCT/CA2009/000369
# Description mg/tab Function
1. Eudragit RL 30D 72.0 controlled release polymer
2. Talc 33.0 anti-tacking agent
3. Triethyl citrate 15.0 plasticizer
4. Purified water g.s. solvent
Total 120 -
Preferably, the polymer used in the core matrix composition should account
for between 5 and 25 % by weight of the dosage form. Also preferably, the
polymer
used in the controlled release coating composition of the tablet should
account for
between 5 and 25 % by weight of the dosage form.
In a preferred embodiment, the polymer used in the core matrix composition
is HPMC-K4M and the polymer used in the controlled release coating composition
of the tablet is Eudragit RL 30D.
Active pharmaceutical ingredient
The pharmaceutically acceptable active agents contemplated by the present
invention include CNS stimulants, including analeptic agents and
psychostimulants.
In particular, the preferred CNS stimulants include, but are not limited to,
the
following: amphetamine (racemic), d-amphetamine, amphetamine and d-
amphetamine phosphate, amphetamine and d-amphetamine sulfate, amphetamine
and d-amphetamine hydrochloride, amphetamine and d-amphetamine saccharate,
and amphetamine and d-amphetamine aspartate, amphetaminil, bemegride,
benzphetamine, benzphetamine hydrochloride, brucine, chlorphentermine,
clofenciclan, clortermine, deanol acetamidobenzoate, demanyl phosphate,
dexoxadrol, diethpropion, doxapram hydrochloride, N-ethylamphetamine,
ethamivan, etifelmin, etryptamine, fencamfamine, fenethylline, fenosolone,
fenfluramine, flurothyl, hexacyclonate sodium, homocamfin, mazindol,
megexamide, methamphetamine, methylphenidate, methylphenidate
hydrochloride, nicotinic agonists, nikethamide, pemoline, pentylenetetrazole,
phenidimetrazine, phendimetrazine tartrate, phenmetrazine, phenmetrazine
hydrochloride, phentermine, picrotoxin, pipradrol, pipradrol hydrochloride,
CA 02718639 2010-09-15
WO 2009/117819 PCT/CA2009/000369
11
prolintane, pyrovalerone, racephedrine, racephedrine hydrochloride, and
tetrahydrobenzothienopyridines. The preferred pharmaceutically acceptable
active
agent of the present invention is methylphenidate and pharmaceutically
acceptable
salts thereof.
The pharmaceutically acceptable active agent or substance of the present
invention could also be co-administered with another active agent or agents,
for
example, being co-administered with antidepressant agents, anti-anxiety
agents, or
other agents known to a person skilled in the art.
Each of the active agents in the individual tablets may be in the form of a
pharmaceutically acceptable salt, ester, amide, prodrug or other derivative or
analog, including active agents modified by appending one or more appropriate
functionalities to enhance selected biological properties. Such modifications
are
considered to be part of the common general knowledge of a person skilled in
the
art.
Salts of the active agents used in conjunction with the present dosage forms
may be obtained commercially or can be prepared using standard procedures
known to those skilled in the art of synthetic organic chemistry and
described, for
example, in J. March, Advanced Organic Chemistry: Reactions, Mechanisms and
Structure, 4th Ed. (New York: Wiley-Interscience, 1992). Suitable acids for
preparing
acid addition salts may be weak acids, medium acids, or strong acids, and
include
both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic
acid, oxalic
acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid,
aspartic acid,
saccharic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,
mandelic acid,
methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic
acid, and
the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic
acid,
sulfuric acid, nitric acid, phosphoric acid, and the like. Preparation of
basic salts of
acid moieties which may be present (e.g., carboxylic acid groups) are prepared
using
a pharmaceutically acceptable base such as sodium hydroxide, potassium
CA 02718639 2010-09-15
WO 2009/117819 PCT/CA2009/000369
12
hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide,
trimethylamine, or the like. Preparation of esters involves functionalization
of
hydroxyl and/or carboxyl groups which may be present. These esters are
typically
acyl-substituted derivatives of free alcohol groups, i.e., moieties which are
derived
from carboxylic acids of the formula RCOOH where R is alkyl, and preferably is
lower alkyl. Pharmaceutically acceptable esters may be prepared using methods
known to those skilled in the art and/or described in the pertinent
literature.
Amides, prodrugs, and other analogs and derivatives can be readily prepared as
well, using conventional means.
As aforesaid, the core matrix composition and controlled release coating
composition can contain, in addition to the pharmaceutically acceptable active
agents or substances active, several other components such as: diluents,
binders, rate
or release controlling polymers, lubricants, glidants, controlled release
polymers,
anti-tacking agents, plasticizers, solvents, and the like.
Diluents, also termed "fillers" are typically necessary to increase the bulk
of a
tablet so that a practical size is provided for compression. Suitable diluents
include,
for example, dicalcium phosphate dihydrate, dicalcium sulfate, calcium
sulfate,
sorbitol, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch,
hydrolyzed
starches, starch, pregelatinized starch, silicon dioxide, titanium oxide,
alumina, talc,
microcrystalline cellulose, and powdered sugar.
Binders are used to impart cohesive qualities to a tablet formulation, and
thus
ensure that a tablet remains intact after compression. Suitable binder
materials
include, but are not limited to, starch (including corn starch and
pregelatinized
starch), gelatin, sugars (including sucrose, glucose, dextrose, lactose and
sorbitol),
polyethylene glycol, waxes, natural and synthetic gums (e.g., acacia,
tragacanth,
sodium alginate), polyvinylpyrrolidone, celluloses, "Veegum" , synthetic
polymers
such as polymethacrylates and polyvinylpyrrolidone (povidone), ethylcellulose,
hydroxyethyl cellulose, HPMC, methylcellulose, polyethylene oxide, and the
like.
CA 02718639 2010-09-15
WO 2009/117819 PCT/CA2009/000369
13
Suitable rate or release controlling polymers include cellulosic polymers such
as HPMC, methacrylic acid copolymer, methacrylic acid copolymer dispersion,
ethylcellulose, xanthun gum, polyethylene oxide, methylcellulose, and the
like. Of
course, other hydrophilic polymers can be used, including hydrophilic
controlled
release polymers (see hereinbelow).
Lubricants are used to facilitate tablet manufacture. Suitable lubricants
include, for example, magnesium stearate, calcium stearate, stearic acid,
glyceryl
behenate, and polyethylene glycol, talc, stearic acid (chemically designated
as
octadecanoic acid, C18H3602), zinc stearate, sodium stearyl fumerate, calcium
stearate. The lubricants are preferably present at no more than approximately
2 %
by weight of the tablet.
Suitable glidants include colloidal silicon dioxide, silicon dioxide (Si02),
magnesium silicate, starch, talc, and magnesium trisilicate. Colloidal silicon
dioxides
are also known to function as an absorbent, anti-caking agent, emulsion
stabilizer,
glidant, suspending agent, tablet disintegrant, thermal stabilizer, and
viscosity-
increasing agent.
Controlled release polymers include HPMC K100M CR, HPMC K15M CR,
ethylcellulose, Eudragit RL 30D, Eudragit RS 30D and combinations of these
polymers. In this connection, Eudragit RL 30D (Rohm GmbH), Eudragit NE 30D
(Rohm GmbH), designated as poly(methyl acrylate, methyl methacrylate,
methacrylic acid) 7:3:1 and poly(ethyl acrylate, methyl methacrylate,
trimethylammonioethyl methacrylate chloride) 1:2:0.2, can function as a film-
former,
tablet binder or tablet diluent. Eudragit RL is used to form water-insoluble
film
coats for sustained release products. Eudragit RL films are more permeable
than
those of Eudragit RS, and films of varying permeability can be obtained by
mixing
the two types together.
Anti-tacking agents include talc, colloidal silicon dioxide, magnesium
stearate
and PlasacrylTM.
CA 02718639 2010-09-15
WO 2009/117819 PCT/CA2009/000369
14
Plasticizing agents include triethyl citrate and the related esters
acetyltriethyl
citrate, tributyl citrate, and acetyltributyl, which are known to be used to
plasticize
polymers in formulated pharmaceutical coatings. Triethyl citrate is also known
to
be used as a direct food additive for flavouring, for solvency and as a
surface active
agent.
Water or purified water, is used as a vehicle and/or solvent for the
manufacture of drug products and pharmaceutical preparations. However, organic
solvents may also be used for coating.
The novel drug dosage forms of the present invention are intended for oral
administration for use in a mammal. In accordance with the present invention,
administration of methylphenidate may be carried out in order to treat any
disorder,
condition or disease for which methylphenidate is generally indicated. Such
disorders, conditions and diseases include, for example, ADD, ADHD,
narcolepsy,
and acute depression. Methylphenidate may also be used in the treatment of
individuals suffering from cognitive decline associated with AIDS or AIDS-
related
conditions, and for mood elevation in terminally ill patients suffering from a
disease
such as cancer.
For administration of methylphenidate HC1, the typical daily dose is in the
range of approximately 5 mg to 100 mg, and preferably in the range of
approximately 5 mg to 60 mg. The exact dosage regimen will depend on a number
of factors, including age, the general condition of the patient, the
particular
condition or disorder being treated, the severity of the patient's condition
or
disorder, and the like.
It is to be understood that while the invention has been described in
conjunction with the preferred specific embodiments thereof, that the
description
above as well as the examples which follow are intended to illustrate and not
limit
the scope of the invention. Other aspects, advantages and modifications within
the
CA 02718639 2010-09-15
WO 2009/117819 PCT/CA2009/000369
scope of the invention will be apparent to persons skilled in the art to which
the
invention pertains.
EXAMPLES
The following examples are illustrative of the applicability of the present
invention and are not intended to limit its scope. Modifications and
variations can
be made therein without depending from the spirit and scope of the invention.
Although any method and material whether similar or equivalent to those
described
herein can be used in the practice for testing the present invention, the
preferred
methods and materials as described.
All of the percentages given hereinabove and below are percentages by
weight.
Example #1: Methylphenidate HCl Extended Release (XR) 54mg Tablets
According to the Present Invention
TABLE I - Core Matrix Co position
# Description m tab % Function
1. Meth 1 henidate HCl 54.0 9.0 API
2. Lactose monohydrate 447.0 74.5 diluent/binder
3. HPMC-K4M 90.0 15.0 release controlling
polymer
4. Stearic acid 3.0 0.5 tablet lubricant
5. Colloidal Silicon dioxide 6.0 1.0 glidant
Total 600 100 -
TABLE II - Controlled Release Coating Composition
# Description mg/tab Function
1. Eudragit RL 72.0 controlled release polymer
30D
2. Talc 33.0 anti-tacking agent
3. Triethyl citrate 15.0 plasticizer
4. Water q.s.* solvent
Total 120 -
*q.s. = quantity sufficient. Lost during the coating process.
CA 02718639 2010-09-15
WO 2009/117819 PCT/CA2009/000369
16
Manufacturing Process
In the first step (step #1), methylphenidate HCl (the API), lactose
monohydrate, HPMC-K4M (the release controlling excipient) are mixed together
in
a suitable blender. In the second step (step #2), stearic acid and colloidal
silicon
dioxide were dispersed together in a poly bag and then passed through 40 mesh
manual screen. After passing these products through the screen they were mixed
with the contents of step #1 in a suitable blender. Afterwards, in step #3,
the final
blend, containing the elements of steps #1 and #2, was compressed using a
rotary
press, so as to form tablets.
The tablets manufactured in step #3 can then be coated with, for example a
functional coat, containing the composition described in Table II. The coating
process can be performed with conventional coating equipment, for example
O'HARA Lab CoatTM equipped with a 15 inch pan.
In other words, the process for manufacturing a matrix controlled release
drug delivery system according to the present invention generally comprises:
- a first step of combining a pharmaceutically acceptable
active substance with at least one pharmaceutically
acceptable excipient and mixing in a suitable blender;
- a second step of adding additional excipients and
mixing in a suitable blender;
- a third step of compressing the blend formed from the
first two steps into tablets; and
- a fourth step of applying a controlled release coating
composition on to the compressed tablets as a coating.
CA 02718639 2010-09-15
WO 2009/117819 PCT/CA2009/000369
17
Example #2: Comparative Dissolution Between 18 and 54 mg
Dosages of Methylphenidate
TABLE III - Core Matrix Composition
Description 54mg Stren h 18mg Stren h
mg/tab %(w/w) mg/tab %(w/w)
Meth 1 henidate HCl 54.0 9.0 18.0 4.0
Lactose monohydrate 447.0 74.5 357.75 79.50
HPMC-K 4M 90.0 15 67.50 15.0
Stearic acid 3.0 0.5 2.25 0.5
Colloidal silicon dioxide 6.0 1.0 4.50 1.0
Total 600 100 450 100
TABLE IV - Controlled Release Coating Composition
Description 54mg strength 18 mg strength
mg/tab mg/tab
Eudragit RL 30D 72.0 54
Talc LM 33.0 24.75
Triethyl citrate 15.0 11.25
Purified water* g.s. g.s.
Total 120 90
*q.s. = quantity sufficient. Lost during the coating process.
Manufacturing Process
In a first step (i.e. step #1), methylphenidate HCl (the API), lactose
monohydrate, HPMC K4M (rate controlling polymer) are mixed together in a
suitable blender. In a second step (i.e. step #2), stearic acid and colloidal
silicon
dioxide were dispersed together in a poly bag and then passed through 40 mesh
manual screen. After passing these products through the screen they were mixed
with the contents of step #1 in a suitable blender. Afterwards, in step #3,
the final
blend, containing the elements of steps #1 and #2, was compressed using a
rotary
press, so as to form tablets.
The tablets manufactured in step #3 can then be coated with a functional coat,
such as the controlled release coating composition described in Table IV. The
coating process can be performed with conventional coating equipment, for
example
a lab coat equipped with a 15 inch pan.
CA 02718639 2010-09-15
WO 2009/117819 PCT/CA2009/000369
18
Direct compression of powder is a preferred manufacturing technique,
though other dosage forms can be envisaged. For the purposes of the present
invention, the tablet form is preferred.
TABLE V - Dissolution Data of testing in triplicate for both dosage forms
Time (hrs) 18mg strength 54mg Strength
Avg. % dissolution Avg. % dissolution
0.5 4 5
1 20 20
2 43 41
3.5 66 62
82 77
7 95 90
9 101 96
11 102 98
The dissolution parameters are listed as follows:
= USP Apparatus: II;
= paddle speed: 50rpm;
= media: 0.001N HCL; and
= media volume: 900ml.
As it is evident from the dissolution data disclosed above in Table V, both
the
strengths exhibit similar dissolution profiles (f2 value = 74). Example 2
illustrates one
of the advantages of the drug delivery system according to the present
invention in
achieving similar dissolution profiles for different strengths.
Example #3: Formulation Composition of Methylphenidate HCL XR 54mg Tablets
The tablets of this example were made in accordance with the manufacturing
process set out at in Example #1.
CA 02718639 2010-09-15
WO 2009/117819 PCT/CA2009/000369
19
Table VI - Core Matrix Composition
Description 54mg Stren h
mg/tab % w/w
Meth 1 henidate HC1 54.0 10.80
Lactose monohydrate 338.50 77.7
HPMC-K 100M CR 50.0 10
Stearic acid 2.50 0.5
Colloidal silicon dioxide 5.0 1.0
Total 500 100
Table VII - Controlled Release Coating Composition
Description m tab
Eudragit RL 30D 30.0
Talc LM 13.75
Triethyl citrate 6.25
Purified water* g.s.
Total 50.0
*q.s. = quantity sufficient. Lost during the coating process.
Example #4: Dissolution of the Formulation Composition of Methylphenidate
HC1 XR 54mg Tablets According to Example #3
The dissolution testing was done on the above mentioned formulation and
the results are set out below in Table VIII.
Table VIII - Dissolution Profile
Time (hrs) `Yo Dissolved
0.5 15
1 28
2 40
3 53
63
7 71
9 75
11 77
Dissolution Method:
= Apparatus I (USP Paddles) with sinkers;
= paddle speed: 50rpm;
= media: 0.5 and 1hr in 0.001N HCl and then change over to pH 6.8
phosphate buffer; and
CA 02718639 2010-09-15
WO 2009/117819 PCT/CA2009/000369
= media volume: 900m1.
Example #5: Formulation Composition of Methylphenidate HC1 XR 54mg Tablets
The tablets of this example were made in accordance with the manufacturing
process set out at in Example #1.
TABLE IX - Core Matrix Composition
Description 54mg Stren h
mg/tab % w/w
Meth 1 henidate HC1 54.0 10.80
Lactose monohydrate 338.50 77.7
HPMC-K 100M CR 50.0 10
Stearic acid 2.50 0.5
Colloidal silicon dioxide 5.0 1.0
Total 500 100
*q.s. = quantity sufficient. Lost during the coating process.
TABLE X - Controlled Release Coating Composition
Description m tab
Eudragit RL 30D 45.0
Talc LM 20.625
Triethylcitrate 9.375
Purified water* g.s.
Total 75.0
*q.s. = quantity sufficient. Lost during the coating process.
Example #6 - Dissolution of the Formulation Composition of Methylphenidate
HC1 XR 54mg Tablets According to Example #5
The dissolution testing was done on the above mentioned formulation and
the results are set out below in Table XI.
TABLE XI - Dissolution Profile
Time (hrs) % Dissolved
0.5 11
1 24
2 37
3 50
5 60
7 68
9 73
11 75
CA 02718639 2010-09-15
WO 2009/117819 PCT/CA2009/000369
21
Dissolution Method:
= Apparatus I (USP Paddles) with sinkers;
= paddle speed: 50rpm;
= media: 0.5 and 1hr in 0.001N HCl and then change over to pH 6.8
phosphate buffer; and
= media volume: 900ml.
Example #7: Formulation Composition of Methylphenidate HC1 XR 54mg Tablets
The tablets of this example were made in accordance with the manufacturing
process set out at in Example #1.
TABLE XII - Core Matrix Composition
Description 54mg Stren h
mg/tab % w/w
Meth 1 henidate HCl 54.0 10.80
Lactose monohydrate 338.50 77.7
HPMC-K 15M CR 50.0 10
Stearic acid 2.50 0.5
Colloidal silicon dioxide 5.0 1.0
Total 500 100
TABLE XIII - Controlled Release Coating Composition
Description mg/tab
Eudragit RL 30D 30.0
Talc LM 13.75
Triethylcitrate 6.25
Purified water* g.s.
Total 50.0
*q.s. = quantity sufficient. Lost during the coating process.
Example #8: Dissolution of the Formulation Composition of Methylphenidate
HC1 XR 54mg Tablets According to Example #7
The dissolution testing was done on the above mentioned development lot
and the results are set out below in Table XIV.
CA 02718639 2010-09-15
WO 2009/117819 PCT/CA2009/000369
22
TABLE XIV - Dissolution Profile
Time (hrs) % Dissolved
0.5 19
1 34
2 48
3 63
75
7 78
9 83
11 82
Dissolution Method:
= Apparatus I (USP Paddles) with sinkers;
= paddle speed: 50rpm;
= media: 0.5 and 1hr in 0.001N HC1 and then change over to pH 6.8
phosphate buffer; and
= media volume: 900m1.
