U.S. patent application number 13/618276 was filed with the patent office on 2013-01-17 for pharmaceutical formulation containing phenytoin sodium and magnesium stearate.
This patent application is currently assigned to Taro Pharmaceuticals North America, Inc.. The applicant listed for this patent is Tamar Blumberg, Orit Brodzsky, Avraham Yacobi, Nataly Zissman. Invention is credited to Tamar Blumberg, Orit Brodzsky, Avraham Yacobi, Nataly Zissman.
Application Number | 20130017254 13/618276 |
Document ID | / |
Family ID | 38123411 |
Filed Date | 2013-01-17 |
United States Patent
Application |
20130017254 |
Kind Code |
A1 |
Blumberg; Tamar ; et
al. |
January 17, 2013 |
PHARMACEUTICAL FORMULATION CONTAINING PHENYTOIN SODIUM AND
MAGNESIUM STEARATE
Abstract
The present invention relates to a novel pharmaceutical
formulation comprising phenytoin sodium, a high amount of magnesium
stearate, and a low level of a hydrophilic polymer such as a
methocel, and a method of preparing the same by blending.
Inventors: |
Blumberg; Tamar; (Kfar Sava,
IL) ; Brodzsky; Orit; (Kiryat Haim, IL) ;
Zissman; Nataly; (Nesher, IL) ; Yacobi; Avraham;
(Englewood, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Blumberg; Tamar
Brodzsky; Orit
Zissman; Nataly
Yacobi; Avraham |
Kfar Sava
Kiryat Haim
Nesher
Englewood |
NJ |
IL
IL
IL
US |
|
|
Assignee: |
Taro Pharmaceuticals North America,
Inc.
Grand Cayman
KY
|
Family ID: |
38123411 |
Appl. No.: |
13/618276 |
Filed: |
September 14, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11633507 |
Dec 5, 2006 |
|
|
|
13618276 |
|
|
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|
60742319 |
Dec 5, 2005 |
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Current U.S.
Class: |
424/451 ;
514/392 |
Current CPC
Class: |
A61P 25/08 20180101;
A61K 31/4166 20130101; A61K 9/4858 20130101; A61K 9/4866 20130101;
A61K 9/146 20130101; A61K 31/415 20130101; A61K 9/143 20130101;
A61K 9/145 20130101 |
Class at
Publication: |
424/451 ;
514/392 |
International
Class: |
A61K 31/4166 20060101
A61K031/4166; A61P 25/08 20060101 A61P025/08; A61K 9/48 20060101
A61K009/48 |
Claims
1-20. (canceled)
21. A pharmaceutical formulation comprising a dry blended powder in
a capsule, the formulation comprising phenytoin sodium, magnesium
stearate and a hydrophilic polymer, and wherein the in vitro
dissolution profile for phenytoin sodium when tested using USP
apparatus I in water at 75 rpm is: (i) from about 20% (w/w) to
about 40% (w/w) released in 30 minutes; (ii) from about 40% (w/w)
to about 85% (w/w) released in 60 minutes; and (iii) not less than
70 percent (w/w) released in 120 minutes.
22. The pharmaceutical formulation of claim 21, comprising from
about 10% (w/w) to about 90% (w/w) phenytoin sodium.
23. The pharmaceutical formulation of claim 21, comprising from
about 6% (w/w) to about 20% (w/w) magnesium stearate.
24. The pharmaceutical formulation of claim 21, comprising from
about 1% (w/w) to about 7% (w/w) of a hydrophilic polymer.
25. The pharmaceutical formulation of claim 21, wherein the
hydrophilic polymer is selected from the group consisting of
hydroxypropylmethyl cellulose, hydroxypropyl starch, hydroxypropyl
cellulose, hydroxyethyl cellulose, carboxymethyl cellulose,
polyethylene oxide, acacia, guar gum, tragacanth gum, xanthan and
mixtures thereof
26. The pharmaceutical formulation of claim 21, wherein the
hydrophilic polymer is hydroxypropylmethyl cellulose.
27. The pharmaceutical formulation of claim 21, wherein the
hydrophilic polymer is hydroxypropyl cellulose.
28. The pharmaceutical formulation of claim 21, comprising from
about 40% (w/w) to about 45% (w/w) phenytoin sodium, from 6% (w/w)
to 10% (w/w) magnesium stearate, and from about 1% (w/w) to about
5% (w/w) hydroxypropylmethyl cellulose.
29. The pharmaceutical formulation of claim 21, comprising about
43% phenytoin sodium, about 9% (w/w) magnesium stearate and about
4% hydroxypropylmethyl cellulose.
30. The pharmaceutical formulation of claim 21, further comprising
from about 5% (w/w) to about 15% (w/w) talc.
31. The pharmaceutical formulation of claim 21, further comprising
from about 15% (w/w) to about 25% (w/w) lactose monohydrate.
32. The pharmaceutical formulation of claim 21, wherein the
pharmaceutical formulation provides a peak plasma level of
phenytoin from 4.5 hours to 11 hours after oral administration in a
human.
33. The pharmaceutical formulation of claim 21, further comprising
binders, glidants, lubricants, diluents, disintegrants and mixtures
thereof.
34. A pharmaceutical formulation comprising phenytoin sodium,
magnesium stearate and a hydrophilic polymer, wherein the
formulation is produced by a dry-mix process and wherein the in
vitro dissolution profile for phenytoin sodium when testing using
USP apparatus I in water at 75 rpm is: (i) from about 20% (w/w) to
about 40% (w/w) released in 30 minutes; (ii) from about 40% (w/w)
to about 85% (w/w) released in 60 minutes; and (iii) not less than
70 percent (w/w) released in 120 minutes.
35. The formulation of claim 34, wherein the dry-mix process
comprises the steps of: (a) screening a mixture of phenytoin sodium
and a hydrophilic polymer through a 30 mesh sieve; (b) screening
magnesium stearate through a 60 mesh screen; (c) mixing the
phenytoin sodium and hydrophilic polymer from step (a) and
magnesium stearate from step (b) together to form a dry blended
powder comprising magnesium stearate.
36. The pharmaceutical formulation of claim 35, wherein the process
comprises filling a capsule with the dry blended powder of step
(c).
37. The pharmaceutical formulation of claim 34, comprising from
about 10% (w/w) to about 90% (w/w) phenytoin sodium.
38. The pharmaceutical formulation of claim 34, comprising from
about 6% (w/w) to about 20% (w/w) magnesium stearate.
39. The pharmaceutical formulation of claim 34, comprising from
about 1% (w/w) to about 7% (w/w) of a hydrophilic polymer.
40. The pharmaceutical formulation of claim 34, wherein the
hydrophilic polymer is selected from the group consisting of
hydroxypropylmethyl cellulose, hydroxypropyl starch, hydroxypropyl
cellulose, hydroxyethyl cellulose, carboxymethyl cellulose,
polyethylene oxide, acacia, guar gum, tragacanth gum, xanthan and
mixtures thereof.
Description
FIELD OF THE INVENTION
[0001] The present invention pertains to a formulation containing
phenytoin sodium which exhibits an extended release profile. In
particular, the present invention concerns a pharmaceutical
composition comprising phenytoin sodium and magnesium stearate.
BACKGROUND
[0002] Epilepsy is a central nervous system disorder characterized
by the repeated occurrence of sudden and transitory episodes of
abnormal phenomena of motor, convulsion, sensory, autonomic, or
psychic origin. The disorder afflicts millions of people worldwide,
and occurs more commonly in children than in adults.
[0003] Phenytoin (5,5-diphenyl-2,4-imidazolidinedione) and its
alkali metal salts (e.g., sodium, lithium and potassium) represent
antiepileptic drugs. The indication for phentyoin includes control
of generalized tonic-clonic (grand mal) seizures and complex
partial seizures (temporal lobe psychomotor). See, Pharmaceutical
Sciences, Remington, 18th Ed., Mack Publishing Co. 1990, pp. 1078.
The primary site of action for phenytoin appears to be the cerebral
motor cortex where spread of seizure activity is inhibited.
[0004] Upon ingestion and exposure in the gastrointestinal pH range
of 1 to 8, phenytoin sodium is converted to phenytoin which is
practically insoluble because it is a relatively weak acid
(pKa=8.3). Phenytoin's insolubility makes it difficult to deliver a
dosage form of phenytoin which has a consistent dissolution profile
over an extended period of time. The plasma half-life in man after
oral administration of phenytoin averages 22 hours, with a range of
7 to 42 hours. Steady-state therapeutic levels are achieved at
least 7 to 10 days (5-7 half-lives) after initiation of therapy
with recommended doses of 300 mg/day. Because clinically
significant toxicity can be encountered after administration of
phenytoin, proper dosing is essential. Goodman & Gilman's, The
Pharmacological Basis of Therapeutics, J. Harman et al. eds., pg.
468-469, 9.sup.th Edition, McGraw-Hill, New York, 1996. In order to
control seizures while avoiding the side effects of the medication,
phenytoin dosing requires optimization. Serum level determination
is necessary for optimal dosage adjustments to maintain
concentrations of phenytoin in the therapeutic range of 10 and 20
.mu.g/mL. In general, the initial adult dosage of phenytoin is 100
mg three times daily. For most adults, a satisfactory maintenance
dose will be 300 mg or 400 mg a day. Peak levels indicate an
individual's threshold for dose-related side effects and are
obtained at the time of expected peak concentration. Conventional
dosage forms and their mode of operation, including dose peaks and
valleys, are discussed in details in Pharmaceutical Sciences,
Remington, 18th Ed., 1990, Mack Publishing Co. pp. 1676-1686; The
Pharmaceutical and Clinical Pharmacokinetics, 3rd Ed., 1984, Lea
and Febiger, Philadelphia, pp. 1-28; and in U.S. Pat. Nos.
3,598,122 and 3,598,123.
[0005] Phenytoin sodium is currently available in the U.S. in a
number of different dosage forms. For example, dosage forms include
an immediate release or "prompt" capsule, an extended release
capsule, a chewable tablet, an oral suspension, and a parenteral
solution. The "prompt" phenytoin sodium capsules exhibit a rapid
rate of absorption with peak blood concentration in 1.5 to 3 hours.
Because rapid release can lead to the development of undesirable
toxic effects, the use of "prompt" phenytoin sodium is not
recommended.
[0006] Several dosage systems have since been developed and
marketed to provide an extended release dosage form and for
reducing the number of daily administrations. For example, extended
release formulations containing 30 and 100 mg phenytoin sodium are
marketed by Warner-Lambert/Parke-Davis under the brand name
Dilantin.RTM.. Dilantin.RTM. capsules contain 30 or 100 mg
phenytoin sodium, lactose, confectioner's sugar, talc, and
magnesium stearate as a loose powder and band sealed. In contrast
to the "prompt" form of phenytoin sodium, the Dilantin.RTM.
formulation exhibits a slower dissolution with prolonged absorption
of the drug substance.
[0007] Other extended release formulations containing 200 and 300
mg phenytoin sodium are commercially available under the brand name
Phenytek.RTM.. These extended release capsules contain 200 or 300
mg phenytoin sodium in an erodible matrix that includes povidone,
hydroxyethyl cellulose, microcrystalline cellulose, magnesium
oxide, colloidal silicon dioxide and magnesium stearate as
disclosed in U.S. Pat. Nos. 6,274,168 and 6,620,432. The extended
release capsules provide a peak serum level at 4 to 12 hours after
administration.
[0008] Additional dosage forms exist and they involve enteric
coating modifications in order to control the drug release. For
example, U.S. Pat. No. 5,968,554 discloses a sustained release
formulation containing phenytoin, a first enteric coating over the
core, a second coating of the active ingredient, and a third
coating that is soluble in gastric juices. U.S. Pat. No. 5,863,558
discloses a sustained release formulation containing a nonionic
polymer that prevents the contact of phenytoin sodium with the
gastrointestinal environment. This dosage form includes at least
one exit in the inert wall surrounding the internal compartment and
the wall maintains its integrity during the drug release.
[0009] U.S. patent application Ser. No. 11/199,169 discloses an
extended release formulation containing phenytoin sodium and
hydroxypropyl methyl cellulose; however, the manufacturing process
in the application involves the use of methylene chloride and
isopropyl alcohol. Methylene chloride is considered a Class 2
solvent by the United States Food and Drug Administration and its
presence in any pharmaceutical product is strictly limited
(www.fda.gov, Guidance for Industry, Q3C--Tables and List).
[0010] Other modes of antiepileptic drug administration include a
nonrate-controlling, dose-dumping capsule, or a
nonrate-controlling, dose-dumping tablet, and usually at multiple,
repetitive dosing intervals. This prior-art mode of therapy leads
to an initial high dose of drug in the blood, followed by a
decreased dose of drug in the blood.
[0011] There is a continuing need for the development of
pharmaceutical formulations of phenytoin sodium that provide for a
controlled rate of release over an extended period of time.
SUMMARY OF THE INVENTION
[0012] The present invention provides for a pharmaceutical
formulation of phenytoin sodium comprising, from about 10% (w/w) to
about 90% (w/w) phenytoin sodium, from about 6% (w/w) to about 20%
(w/w) magnesium stearate and from about 1% (w/w) to about 7% (w/w)
of a hydrophilic polymer. The hydrophilic polymer may be
hydroxypropylmethyl cellulose, hydroxypropyl starch, hydroxypropyl
cellulose, hydroxyethyl cellulose, carboxymethyl cellulose,
polyethylene oxide, acacia, guar gum, tragacanth gum, xanthan and
mixtures thereof. In a preferred embodiment, the hydrophilic
polymer is hydroxypropylmethyl cellulose.
[0013] In one embodiment, the pharmaceutical formulation comprises
from about 40% (w/w) to about 45% (w/w) phenytoin sodium, from
about 6% (w/w) to about 10% (w/w) magnesium stearate, and from
about 1% (w/w) to about 5% (w/w) hydroxypropylmethyl cellulose; in
a preferred embodiment, the pharmaceutical formulations has about
40% phenytoin sodium, about 9% (w/w) magnesium stearate and about
4% hydroxypropylmethyl cellulose.
[0014] Additionally, the pharmaceutical formulation may have about
5% (w/w) to about 15% (w/w) talc and about 15% (w/w) to about 25%
(w/w/) lactose monohydrate.
[0015] The in vitro dissolution profile for phenytoin sodium when
testing using USP apparatus I in water at 75 rpm may be: (i) from
about 20% (w/w) to about 40% (w/w) released in 30 minutes; (ii)
from about 40% (w/w) to about 85% (w/w) released in 60 minutes;
and, (iii) not less than 70 percent (w/w) released in 120 minutes.
A peak plasma level of phenytoin may be obtained from about 4.5
hours to about 11 hours after oral administration.
[0016] Additionally, the pharmaceutical formulation may comprise
binders, glidants, lubricants, diluents, disintegrants and mixtures
thereof
[0017] The invention also describes a process for preparing a
pharmaceutical phenytoin sodium formulation comprising, the steps
of: (a) screening a mixture of phenytoin sodium and a hydrophilic
polymer through a 30 mesh sieve; (b) screening magnesium stearate
through a 60 mesh; and, (c) blending the phenytoin sodium,
hydrophilic polymer from step (a) and magneisum stearate from step
(b) together. The blend may be a dry blended powder. The
pharmaceutical formulation prepared by such process may comprise,
from about 10% (w/w) to about 90% (w/w) phenytoin sodium, from
about 6% (w/w) to about 20% (w/w) magnesium stearate and from about
1% (w/w) to about 7% (w/w) of a hydrophilic polymer, where the
hydrophilic polymer is selected from the group consisting of
hydroxypropylmethyl cellulose, hydroxypropyl starch, hydroxypropyl
cellulose, hydroxyethyl cellulose, carboxymethyl cellulose,
polyethylene oxide, acacia, guar gum, tragacanth gum, xanthan and
mixtures thereof In a preferred embodiment, the pharmaceutical
formulation comprises, from about 40% (w/w) to about 45% (w/w)
phenytoin sodium, from about 6% (w/w) to about 10% (w/w) magnesium
stearate, and from about 1% (w/w) to about 5% (w/w)
hydroxypropylmethyl cellulose. The pharmaceutical formulation
prepared by the process of the invention may comprise from about 5%
(w/w) to about 15% (w/w) talc and from about 15% (w/w) to about 25%
(w/w/) lactose monohydrate.
BRIEF DESCRIPTION OF THE DRAWING
[0018] FIG. 1 shows the mean plasma concentration over time of the
pharmaceutical formulation of the present invention as compared
with the reference standard product.
DETAILED DESCRIPTION
Definitions:
[0019] Unless defined otherwise, all technical and scientific terms
used herein have the meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. In the
specification, the following terms are defined: "PK" refers to an
abbreviation of pharmacokinetic; "Ln" refers to natural log; "AUC"
refers to the mean area under the plasma concentration-time curve;
"AUC.sub.0-t" refers to area under the concentration-time curve
from time zero to the time of the last sample collection;
"AUC.sub.0-.infin." refers to area under the concentration-time
curve from time zero to infinite hours; "C.sub.max" refers to
maximum observed plasma concentration; "T.sub.max" (or "t.sub.max")
refers to the time to achieve the C.sub.max; and, "t.sub.1/2"
refers to the apparent half-life and is calculated as (ln
2/K.sub.e), where K.sub.e refers to the elimination rate
constant.
[0020] In accordance with the present invention, pharmacokinetic
parameters were calculated using standard non-compartmental
methods, as implemented in WinNonlin.TM. 4.0.1. The mean, standard
deviation (SD) and percent coefficient of variations (CV (%)) were
calculated for plasma concentrations of phenytoin for each sampling
time and for each treatment.
[0021] Areas under the concentration-time curves (AUC) were
determined with respect for each human subject that received oral
administration of an extended-release formulation of phenytoin
salt. AUC.sub.0-t was calculated using the linear trapezoidal rule,
which employs an approximate integration formula. The area of each
trapezoid was calculated, and the sum of all the areas of all the
trapezoids yielded an estimate of the true area under the curve.
(See, Gibaldi et al. Pharmacokinetics. 2.sup.nd Ed. Marcel Dekker,
Inc., 1982; Yeh et al., A comparison of numerical integrating
algorithms by trapezoidal, lagrange, and spline approximations. J.
Pharmacokinet Biopharm. 6:79 (1978). C.sub.max and T.sub.max were
then determined for each concentration vs. time profile.
Elimination rate constant (K.sub.e) was calculated using regression
analyses on the natural log (ln) of plasma concentration values (y)
versus time (x).
[0022] The composition of the present invention comprises phenytoin
sodium and magnesium stearate in an amount sufficiently high enough
to control the release of phenytoin sodium over an extended period
of time, i.e., provide for a controlled or extended-release
formulation.
[0023] Magnesium stearate is hydrophobic. When incorporated into a
formulation containing an active pharmaceutical ingredient ("API"),
magnesium stearate may retard the dissolution of an API from a
solid dosage form; however, the rate of dissolution appears to be
very sensitive to the amount of magnesium stearate incorporated
into the formulation. Handbook of Pharmaceutical Excipients,
5.sup.th Edition, Rowe et al. eds., pp. 430-433, Pharmaceutical
Press, 2006. In addition, the rate of dissolution appears to depend
on the presence of other ingredients in the pharmaceutical
formulation. Because phenytoin can exhibit numerous side effects if
the plasma blood levels are too high, it is critical to develop a
formulation that will provide for proper dosing of the drug over an
extended period of time, for example for 96 hours, and will
overcome the problem of a comparatively high variability in the
dissolution rate of the phenytoin.
[0024] The inventors of the present invention have surprisingly
discovered that a comparatively high level of magnesium stearate,
when mixed with phenytoin sodium, will retard the release of
phenytoin sodium from the formulation to the same extent as the
brand product, Dilantin.RTM.. Magnesium stearate may be mixed with
phenytoin sodium in amounts ranging from about 6% (w/w) to about
20% (w/w). In a preferred embodiment, the amount of magnesium
stearate incorporated into the formulation is from about 6% (w/w)
to about 10% (w/w), more preferably about 9% (w/w). The
formulations of the present invention comprise a homogeneous
mixture of phenytoin salt and magnesium stearate. Using the
formulations of the present invention, the blood levels of
phenytoin sodium achieved after administration of these
formulations match that obtained with Dilantin.RTM. over an
extended period of time (0-96 hours).
[0025] The phenytoin used in the formulation of the present
invention is preferably sodium; however, other phenytoin salts are
encompassed by the invention, including, sodium, lithium,
potassium, calcium and the like. Procedures for the manufacture of
phenytoin sodium are well known (See, e.g., U.S. Pat. Nos.
4,696,814, 4,642,316, and 2,409,754). Additionally, any polymorphic
form of phenytoin sodium may be used. In a preferred embodiment,
the phenytoin sodium used in the pharmaceutical formulation of the
present invention is a white powder with 95% of the particles
having a particle size of less than 180 .mu.m. In another
embodiment, the phenytoin sodium is in the form of a bead, granule
or pellet.
[0026] Phenytoin sodium may constitute up to about 90% of the
dosage form. Preferably, the dosage form contains between about 25%
to about 90% phenytoin sodium. More preferably, the dosage form
contains between about 40% to about 60%. More preferably, the
dosage form contains about 50%.
[0027] The dosage form may be a tablet, capsule or a powder for
suspension. Preferably, the dosage form is formulated as a capsule.
The preferred range of phenytoin salt in a capsule ranges from
about 30 to 300 mg; more preferably, the phenytoin salt in a
capsule is present in the amount of about 90 mg to 230 mg; still
more preferably, the phenytoin salt is present in the amount of
about 100 mg.
[0028] The pharmaceutical formulation may also incorporate at least
one hydrophilic polymer. Examples of hydrophilic polymers, include,
but are not limited to, methylcelulose, hydroxypropylmethyl
cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, ethyl
cellulose, hydroxyethyl cellulose, polyethylene oxide, and the
like. Preferably, the polymer is hydroxypropylmethyl cellulose.
Preferably, the hydrophilic polymer is present in the amount from
about 1% (w/w) to about 7% (w/w); more preferably, the hydrophilic
polymer is present in the amount of about 4% (w/w). Various grades
of hydroxypropylmethyl cellulose may be used, including, Methocel
E15LV and Methocel K4M (Colorcon Inc, West Point, Pa., 19486).
[0029] Glidants or lubricants such as talc may be incorporated into
the pharmaceutical formulation of the invention. Preferably, talc
is present in the amount of about 5% (w/w) to about 15% (w/w). More
preferably, talc is present in the amount of about 10% (w/w).
[0030] In addition to magnesium stearate and a hydrophilic polymer
such as hydroxypropylmethyl cellulose, the pharmaceutical
formulation of the present invention may contain a variety of
additives or excipients. Examples of classes of additives include
fillers, glidants, surface active agents, lubricants, buffering
agents, disintegrating agents, stabilizers, water absorbing agents,
pigments, flavoring agent, sweeteners, adjuvants and the like. The
following represents a non-limiting list of these additives:
[0031] (i) fillers may include different grades of sugar,
microcrystalline cellulose, polyalcohols, calcium hydrogen
phosphate, calcium sulphate, pregelatinized starch;
[0032] (ii) glidants may include colloidal silicon oxide;
[0033] (iii) surface active agents may include sodium lauryl
sulphate;
[0034] (iv) lubricants may include magnesium stearate, stearic
acid, sodium stearyl fumarate;
[0035] (v) buffering agents may include sodium hydrogen phosphate
sodium acetate;
[0036] (vi) disintegrating agents may include sodium starch
glycolate, sodium stearyl fumarate, crospovidone;
[0037] (vii) water absorbing agents may include hydrophilic
polymers as hydroxypropylmethyl cellulose, carbomer, sodium
alginate;
[0038] (viii) pigments may include organic or inorganic pigments
such as oxides of iron or titanium;
[0039] (ix) flavorants may include both natural and artificial
flavors such as menthol, cinnamon; and,
[0040] (x) sweeteners may include sucralose, saccharin sodium and
confectioner's sugar.
[0041] These additives are to be used in amounts sufficient to
achieve their intended purpose. Generally, the combination of these
additives is used in amounts that do not modify the dissolution of
the pharmaceutical formulation of the present invention.
[0042] Other additives that may be used, include excipients such as
lactose monohydrate.
[0043] The pharmaceutical formulation of the present invention may
be prepared by dry blending or dry mix technology, which consists
of a thorough mixing of all ingredients to form a homogeneous
mixture. Remington, The Science and Practice of Pharmacy, Gennaro
A. ed., p. 681-699, 20.sup.th Edition, Lippincott, 2000. Dry mixing
is feasible and may advantageously be used due to the components of
the inventive formulations.
[0044] In one embodiment, lactose monohydrate, phenytoin sodium,
talc, sugar and hydroxypropylmethyl cellulose are sieved through a
30 mesh screen. Magnesium stearate is sieved through a 60 mesh
screen. The sieved materials are transferred to a V-blender and
mixed. Mixing may require from about 10 minutes to about 60
minutes. In a preferred embodiment, mixing requires about 20
minutes. The blend is then filled into a gelatin capsule.
[0045] The pharmaceutical formulation of the present invention may
include any solid dosage form suitable for oral administration. A
dosage unit of the present formulation may consist of, for example,
capsules, tablets, pills, pellets and the like. It is to be
understood that the present invention is not to be construed as
being limited to a particular dosage form. A preferred dosage form
is a capsule.
[0046] Numerous references, including patents and various
publications, are cited and discussed in the description of this
invention. The citation and discussion of such references is
provided merely to clarify the description of the present invention
and is not an admission that any reference is prior art to the
invention described herein. All references cited and discussed in
this specification are incorporated herein by reference in their
entirety.
[0047] The embodiments illustrated and discussed in this
specification are intended only to teach those skilled in the art
the best way known to the inventors to make and use the invention.
Nothing in this specification should be considered as limiting the
scope of the present invention. Modifications and variation of the
above-described embodiments of the invention are possible without
departing from the invention, as appreciated by those skilled in
the art in light of the above teachings. It is therefore understood
that, within the scope of the claims and their equivalents, the
invention may be practiced otherwise than as specifically
described.
[0048] The following examples illustrate various aspects of the
present invention. They are not to be construed to limit the claims
in any manner.
EXAMPLES
Example 1
Commercial Phenytoin Sodium Extended-Release Capsules: Comparative
Studies
[0049] Specific ingredients present in both Parke-Davis' and
Mylan's extended-release phenytoin sodium caspules (i.e.,
Dilantin.RTM. and Mylan) were determined through reverse
engineering. Table 1 summarizes some respective ingredients in the
two commercial phenytoin sodium capsules.
TABLE-US-00001 TABLE 1 Parke-Davis' Mylan's Extended Release
Ingredients Dilantin .RTM. 100 mg Phenytoin 100 mg Lactose.sup.(1)
20.7% Not tested Magnesium Stearate.sup.(2) 4.5% 1.15% Talc.sup.(3)
2.3% Not tested .sup.(1)Determined by HPLC .sup.(2)Determined by
both HPLC (stearic acid), and atomic absorption of magnesium.
.sup.(3)Determined by atomic absorption of Al, Mg and Si.
[0050] It is noteworthy that the level of magnesium stearate in the
two commercial extended-release phenytoin sodium capsules does not
exceed above 5%.
Example 2
Effect of Magnesium Stearate Level on Dissolution Rate
[0051] Magnesium stearate was blended with phenytoin sodium in a
sequential mixing sequence as follows: (i) 3 hours mixing of
phenytoin sodium and magnesium stearate; (ii) 30 minutes mixing
with talc; and, (iii) 20 minutes mixing with lactose and
compressible sugar. Capsules containing phenytoin sodium
(formulation #1) were prepared having the following
ingredients:
TABLE-US-00002 Formulation #1 Ingredients mg per capsule (% w/w)
Phenytoin Sodium 100.0 mg (42.6%) Lactose monohydrate 57.00 mg
(24.2%) Talc 11.75 mg (5%) Confectioner's Sugar 33.35 mg (14.9%)
Magnesium Stearate 32.90 mg .sup. (14%) Total weight 235 mg
(100%)
[0052] Dissolution Results:
TABLE-US-00003 TABLE 2 Method: 900 mL purified water USP, USP
apparatus 1, 50 rpm Formulation # 1 Dilantin .RTM. Time (%
dissolved) (% dissolved) 15 min 15 (10-20) 13 (9-19) 30 min 34
(30-41) 31 (24-37) 60 min 57 (52-61) 58 (51-66) 90 min 72 (68-81)
72 (67-81) 120 min 78 (76-80) 83 (76-88)
[0053] The dissolution results indicate in vitro equivalence of the
extended-release formulation #1 to that of the brand product (i.e.,
Dilantin.RTM.).
Example 3
Effect of Mixing Time
[0054] Phenytoin sodium was mixed with lactose, talc and
compressible sugar for 25 minutes. A high level of magnesium
stearate was added and the powders were mixed further for 180
minutes. Samples were pulled out at 30, 60, 120 and 180 minutes and
filled into capsules. The capsules dissolution results are
presented in table 3 below:
TABLE-US-00004 TABLE 3 Dissolution Results Method: 900 mL purified
water USP, USP apparatus 1, 50 rpm Mixing time with magnesium
stearate 30 min. 60 min. 120 min. 180 min. % % % % % % % % Time
(min) diss. RSD* diss. RSD diss. RSD diss. RSD 15 10 113.8 7 47.4
10 22.8 8 11.4 30 60 43.5 20 19.0 27 56.6 32 23.5 60 73 22.7 53
19.2 57 24.3 64 7.7 90 82 12.6 73 8.7 77 13.8 79 5.5 120 86 8 80
5.4 85 9.2 85 4.5 *RSD--relative standard deviation
[0055] Accordingly, these data indicate that the time of mixing is
critical in affecting in vitro dissolution rate when phenytoin
sodium capsules contain a high level of magnesium stearate. More
than 30 minutes mixing of phenytoin and magnesium stearate is
required.
Example 4
The Effect of Varying Magnesium Stearate Levels on Dissolution
[0056] Capsules containing phenytoin sodium were prepared according
to the following:
[0057] Formulations # 2, # 3, # 4 and #5 with different magnesium
stearate levels (i.e., 4.5, 7, 13 and 17% wt respectively), keeping
lactose / confectionery sugar constant and applying the same
multiple stages mixing sequences as in example 2.:3 hours mixing of
phenytoin sodium and magnesium stearate, 30 minutes mixing with
talc and 20 minutes mixing with lactose and compressible sugar.
TABLE-US-00005 TABLE 4 Dissolution Results Method: 900 mL purified
water USP, USP apparatus 1, 50 rpm Formu- Formu- Formu- Formu-
lation # 2 lation # 3 lation # 4 lation # 5 Ingredients Mg/cap
Mg/cap Mg/cap Mg/cap Phenytoin 100 100 100 100 Sodium Talc 12 12 12
12 Lactose DC-21 71 67.5 58.5 52.5 Confectionery 41.4 39 34 30.5
sugar Magnesium 10.6 (4.5%) 16.5 (7%) 30.5 (13%) 40.0 (17% wt)
Stearate Total weight 235 mg 235 mg 235 mg 235 mg
[0058] The following table 5 summarizes the effects of magnesium
stearate levels on dissolution rate.
TABLE-US-00006 TABLE 5 Method: 900 mL purified water USP, USP
apparatus 1, 50 rpm Formu- Formu- Formu- Formu- Time lation # 2
lation # 3 lation # 4 lation # 5 (min) (% diss) (% diss) (% diss)
(% diss) 15 -- 89 17 13 30 93 89 35 27 60 95 96 55 49 90 -- 95 68
63 120 96 95 76 71
[0059] Accordingly, the present data indicate that there is a
correlation between the level of magnesium stearate and the
dissolution rate. While 4.5% wt and 7% wt magnesium stearate
exhibited a dissolution rate similar to that of prompt formulation
of phenytoin sodium, when the levels of magnesium stearate were
increased to 13% wt and 17% wt, the dissolution rates for phenytoin
sodium capsule were reduced. The dissolution rates were similar to
that of Dilantin.RTM..
Example 5
The Effect of Blender Types
[0060] Capsules containing phenytoin sodium were prepared according
to the following: Formulation # 6 was prepared with magnesium
stearate (14% wt) and blended using different blender types.
V-blender and Key high shear mixer were used. All excipients,
except for magnesium stearate, were mixed for 25 minutes. The
optimal mixing time with magnesium stearate in each experiment was
determined by testing the dissolution rate at different blending
time points. A comparison between the optimal results for the two
blender types: V-blender--180 minutes mixing with magnesium
stearate, Key high shear mixer--10 minutes mixing with magnesium
stearate), indicated the preference of the V-blender based on the
variability in dissolution results. (see tables 6 and 7).
TABLE-US-00007 TABLE 6 Formulation # 6 Ingredients mg/cap Phenytoin
Sodium 100 Talc 11.75 Lactose DC-21 57 Compressible sugar 33.35
Magnesium Stearate 32.9 Total weight 235 mg
[0061] The following Table 7 summarizes the effect of different
blender types on dissolution rate.
TABLE-US-00008 TABLE 7 Method: 900 mL purified water USP, USP
apparatus 1, 50 rpm V-Blender Key Blender Time (180 min) (10 min)
Dilantin .RTM. (min) % diss. % RSD % diss. % RSD % diss. % RSD 15 8
11.4 5 65.4 11 17.3 30 32 23.5 31 66.5 30 11.8 60 64 7.7 58 24.4 60
4.5 90 79 5.5 73 11.4 75 2.7 120 85 4.5 80 7.6 82 1.7
[0062] These data indicate that when a comparatively high
percentage of magnesium stearate was used, the dissolution rate for
phenytoin sodium capsule matched that of the brand product,
Dilantin, irrespective of the blender type used.
Example 5
[0063] A) Effect of Storage Under Accelerated Conditions on
Dissolution Rate.
[0064] As further controls, an additional capsule formulation
containing phenytoin sodium and magnesium stearate was prepared
(formulation # 7). The ingredients are listed in Table 8.
Accelerated conditions represent storage at 40.degree. C. at 75%
relative humidity for 3 months.
TABLE-US-00009 TABLE 8 Formulation # 7 Ingredients mg/cap Phenytoin
Sodium 100 Talc 12 Pharmatose DCL-15 (Lactose) 58.5 Confectionary
Sugar 34 Magnesium Stearate 30.5 (13% wt) Total weight 235 mg
[0065] The following Table 9 summarizes the effect of storage of
phenytoin sodium (formulation #7) under accelerated conditions on
dissolution rate.
TABLE-US-00010 TABLE 9 Method: 900 mL purified water USP, USP
apparatus 1, 50 rpm Time % diss. % diss. % diss. (min) (T.sub.0) (1
month) (2 month) 15 17 9 8 30 35 26 22 60 55 47 43 90 68 57 56 120
76 64 65 T.sub.0: in vitro release was measured right after the
capsules were prepared 1 month: in vitro release was measured after
1 month storage (40.degree. C., 75% RH) 2 month: in vitro release
was measured after 2 month storage time (40.degree. C., 75% RH)
[0066] The present data confirm that reduction in dissolution rate
is achievable with high levels of magnesium stearate.
Example 6
Effect of Addition of Hydroxypropylmethyl Cellulose (HPMC,
Hypromellose)
[0067] A) Effects of Varying Concentrations and Different Types of
HPMC (Methocels) on Dissolution Rate
[0068] It was found that addition of HPMC to the pharmaceutical
formulation of the present invention keeps the dissolution rate
within the range of specifications throughout the product's shelf
life.
[0069] The following studies relate to capsule formulations
including phenytoin sodium, magnesium stearate and HPMC. Varying
concentrations of HPMC as well as different grades of HPMC were
used. The procedure of preparing these capsule formulations was the
same; namely, all the excipients except magnesium stearate were
mixed for 25 min, then magnesium stearate was added and the final
blend was mixed for 5 more minutes.
[0070] The ingredients of such phenytoin sodium formulation having
a high level of magnesium stearate and a low level of methocel are
listed in Table 12.
TABLE-US-00011 TABLE 12 Phenytoin Sodium 100 mg Capsules Formu-
Formu- Formu- Formu- lation # 9 lation # 10 lation # 11 lation # 12
Ingredients mg/cap mg/cap mg/cap mg/cap Phenytoin Sodium 100 100
100 100 Talc 12.0 23.75 23.75 23.75 Pharmatose DCL-15 63.2 46.75
46.75 46.75 Nu-Tab 29.3 29.25 29.25 29.25 HPMC (Methocel 7.0 11.75
7.05 9.4 K4M) HPMC (Methocel -- -- 4.7 -- K100LV) Magnesium
Stearate 23.5 23.5 23.5 23.5 Total weight 235 mg 235 mg 235 mg 235
mg
[0071] The following Table 13 summarizes the effect of the
phenytoin sodium formulation containing magnesium stearate and HPMC
on the dissolution rate.
TABLE-US-00012 TABLE 13 Method: 900 mL purified water USP, USP
apparatus 1, 50 rpm Formu- Formu- Formu- lation lation lation
Formulation # 10 # 11 # 12 Dilantin .RTM. Time # 9 % % % % % % %
(min.) % diss % RSD % diss RSD diss RSD diss RSD diss RSD 15 29
37.1 9 55.3 20 30.2 13 62.6 13 41.7 30 57 12.9 32 31.8 38 21.8 32
32.6 31 12.4 60 81 7.5 62 23.2 65 25.6 62 19.7 60 6.6 90 89 4.0 78
14.8 77 18.0 75 18.5 74 5.0 120 92 2.3 85 8.4 87 12.9 83 16.0 81
3.3
Example 7
Effect of Magnesium Stearate and/or HPMC (Methocel) Concentrations
on Dissolution Rate
[0072] We prepared additional capsule formulations containing
phenytoin sodium, high levels of magnesium stearate and varying
amounts of HPMC (methocel). The procedure in preparing these
capsule formulations was the same; namely, all the excipients
including magnesium stearate were mixed for 30 min. The specific
ingredients of such phenytoin sodium formulations are listed in
Table 14.
TABLE-US-00013 TABLE 14 Formu- Formu- Formu- Formu- lation # 13
lation # 14 lation # 15 lation # 16 Ingredients mg/cap mg/cap
mg/cap Mg/cap Phenytoin Sodium 100 100 100 100 Pharmatose DCL-15 47
52 52 49 Talc 24 24 24 24 Confectionery sugar 29 29 29 29 HPMC
(Methocel 9.5 (4%) 9.5 (4%) 12 (5%) 12 (5%) K4M) Magnesium Stearate
23.5 (10%) 18.5 (8%) 16 (7%) 19 (8%) Total weight 233 mg 233 mg 233
mg 233 mg
[0073] The following Table 15 summarizes the effect of the
phenytoin sodium formulations containing high levels of magnesium
stearate and varying amounts of HPMC (methocel) on dissolution
rate
TABLE-US-00014 TABLE 15 USP Method: 900 mL purified water USP, USP
apparatus 1, 75 rpm Formu- Formu- Formu- Formu- lation lation
lation lation # 13 # 14 # 15 # 16 Dilantin .RTM. Dilantin .RTM.
Time % % % % % % % % % % % % (min.) diss RSD diss RSD diss RSD diss
RSD diss RSD diss RSD 15 10 7.5 15 16.3 15 13.3 9 8.4 -- -- -- --
30 25 6.6 34 13.1 32 8.3 26 7.1 31 5.7 34 4.1 60 51 5.4 67 12.1 66
10.4 54 4.3 53 3.5 60 5.6 90 67 6.0 84 5 89 3.1 75 6.0 65 2.9 75
5.9 120 78 6.7 91 2.7 92 2.1 86 4.9 73 3.2 82 2.9
Example 8
Effect of Varying Concentrations of Talc on Dissolution Rate
[0074] We prepared two capsule formulations containing phenytoin
sodium, magnesium stearate and a varying amount of talc. The
formulations also contained a low level of HPMC (methocel). The
specific ingredients of such phenytoin sodium formulations are
listed in Table 16.
TABLE-US-00015 TABLE 16 Formulation # 17 Formulation # 18
Ingredients mg/cap mg/cap Phenytoin Sodium 100 100 Talc 23.75 (10%)
12 (5%) Lactose DC-21 46.75 58.5 Compressible Sugar 29.25 29.25
HPMC (Methocel 11.75 11.75 K4M) Magnesium Stearate 23.5 23.5 Total
weight 235 mg 235 mg
[0075] The following Table 17 summarizes the effects of the
phenytoin sodium formulation containing a high level of magnesium
stearate, a small amount of HPMC (methocel) and varying amount of
Talc on dissolution rate.
TABLE-US-00016 TABLE 17 USP dissolution method: 900 ml purified
water, USP apparatus 1, 50 rpm. Time Formulation # 17 Formulation #
18 Dilantin .RTM. (min.) % diss % RSD % diss % RSD % diss % RSD 15
6 28.6 7 31 11 22.0 30 19 18.4 20 22.4 30 12.0 60 51 19.7 53 9.5 54
7.0 90 71 17.1 84 3.6 68 5.0 120 80 13.5 92 3.6 76 3.0
[0076] Accordingly, the present data indicate that the amount of
Talc may affect dissolution rate when phenytoin sodium capsules
contain a comparatively high percentage of magnesium stearate as
well as a comparatively small amount of HPMC (methocel).
Example 9
Pharmacokinetic Profile
[0077] Bioavailability Study Under Fasting and Non-Fasting
Conditions
[0078] The present study was conducted to compare the relative
bioavailability (rate and extent of absorption) of pharmaceutical
formulation of the present invention with that of Dilantin.RTM.
Kapseals.RTM. by Parke-Davis following a single oral dosage
(1.times.100 mg) in healthy adult volunteers administered under
fasting and non-fasting conditions. Table 18 provides the
formulation used for the study.
TABLE-US-00017 TABLE 18 Formula for Phenytoin Sodium Capsules
Ingredient Mg/Capsule Phenytoin Sodium 100.0 Lactose Monohydrate
47.0 Talc 24.0 Confectioner's Sugar 31.5 Hypromellose (Methocel
K4M) 9.5 Magnesium Stearate 21.0 Total 233.0
Bioavailability Study Under Fasting and Non-Fasting Conditions
[0079] The present study was conducted to compare the relative
bioavailability (rate and extent of absorption) of present
extended-release formulation of phenytoin sodium (containing a high
level of magnesium stearate and a low level of hydroxoylmethyl
cellulose) with that of Dilantin.RTM. Kapseals.RTM. by Parke-Davis
following a single oral dosage (1.times.100 mg) in healthy adult
volunteers administered under fasting and non-fasting
conditions.
[0080] Evaluation of Study Participants: Subjects were selected
from non-institutionalized volunteers consisting of university
students and members of the community at large. All volunteers
selected for this study were healthy men 18 years of age or older
at the time of dosing. The weight range did not exceed .+-.20% for
height and body frame as per desirable weights for adults--1983
Metropolitan Height and Weight Table. Each volunteer completed the
screening process within 28 days prior to period I dosing. The
screening clinical laboratory procedures included: general
observation, physical examination, demographics, medical and
medication history, an electrocardiogram, sitting blood pressure
and heart rate, respiratory rate and temperature. Blood was
withdrawn to evaluate hematology, clinical chemistry, HIV antibody,
hepatitis B surface antigen, hepatitis C antibody. Urine was
collected to evaluate urinalysis and urine drug screen.
[0081] Study Design:
[0082] Fasting Study: A single-dose, two-way crossover, fasting
study was conducted. Two study periods were used. Approximately 10
hours prior to and until at least 24 hours after dosing each
period. Forty-four (44) healthy adult male volunteers and no
alternates were initiated for the study. At least 14 days were
allowed to permit washout between doses. After dosing, subjects
remained in an upright position for four hours. A sitting blood
pressure and radial heart rate were measured prior to dosing and at
12 and 24 hours after each dose.
[0083] One capsule of the present extended-release formulation (100
mg) was randomly given to subjects with 240 mL of room temperature
water after an overnight fast. One capsule of US reference product
(i.e., 100 mg Dilantin.RTM. Kapseals.RTM. by Parke-Davis was also
randomly provided to subjects with 24 mL of room temperature water
after an overnight fast. No fluid, except that given with drug
administration, was allowed from 1 hour prior to dose
administration until 2 hour after dosing. At 2 hours post-dose,
subjects were allowed to consume 240 mL of water. Clear fluids,
such as water, wereallowed during fasting. A light snack wasserved
approximately 10 hours prior to dose administration after which a
fast (except water) would be maintained until at least 4 hours
after dosing. Subjects were randomized prior to given a capsule of
either tested product or reference product.
[0084] Non-Fasting Study: A single-dose, two-wary crossover,
non-fasting study was conducted. Two study periods were used.
Approximately 10 hours prior to and until at least 24 hours after
dosing each period. Thirty-six (36) healthy adult male volunteers
and no alternates were initiated for the study. At least 14 days
were allowed to permit washout between doses. After dosing,
subjects remained in an upright position for four hours. A sitting
blood pressure and radial heart rate were measured prior to dosing
and at 12 and 24 hours after each dose.
[0085] One capsule of the present extended-release formulation (100
mg) was randomly given to subjects with 240 mL of room temperature
water 30 minutes after initiation of a standardized, high fat
breakfast preceded by an overnight fast. The standardized, high fat
breakfast consisting of the following: (i) two eggs fried in
butter; (ii) two strips of bacon; (iii) two slices of toast with
butter; (iv) four ounces of hash brown; (v) eight fluid ounces
(240mL of whole milk); and, (vi) potatoes.
[0086] One capsule of US reference product (i.e., 100 mg
Dilantin.RTM. Kapseals.RTM. by Parke-Davis was also randomly
provided to subjects with 24 mL of room temperature water 30
minutes after initiation of a standardized, high fat breakfast
preceded by an overnight fast. No fluid, except that given with
drug administration, was allowed from 1 hour prior to dose
administration until 2 hour after dosing. At 2 hours post-dose,
subjects were allowed to consume 240 mL of water. A light snack
wasserved approximately 10 hours prior to dose administration.
Following consumption of the standardized breakfast, a fast (except
water) would be maintained until at least 4 hours after dosing.
Clear fluids, such as water, wereallowed during fasting. Subjects
were randomized prior to being given a capsule of either tested
product or reference product.
[0087] Sampling Details: Blood sample (1.times.7 mL) was collected
EDTA vacutainers. Blood samples within one hour prior to dosing (0
hour) and after dosing administration at 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 16, 24, 48, 72 and 96 hours). 18 blood samples per
period.times.2 study periods (i.e., total of 36 samples, 252 mL
total volume) were collected. Blood samples were collected by
direct venipuncture, centrifuged at approximately 2,400 rpm and
4.degree. C. for 15 minutes, the plasma was pipetted into amber
polypropylene tubes, frozen, and stored at approximately
-20.degree. C. or colder until analysis.
[0088] Bioanalytical Analysis, and Statistical Analysis: Plasma
concentrations of phenytoin was measured using a validated
bioanalytical method. The statistical analysis was conducted using
appropriate pharmacokinetic parameters and statistical analysis of
the data.
[0089] Pharmacokinetics & Statistical Analysis:
[0090] Plasma phenytoin concentrations were determined and the
pharmacokinetic parameters were calculated using WinNonlin.TM.,
Version 4.1, software designed specifically for analyzing
pharmacokinetic data. WinNonlinTM Model 200 for extravascular input
was utilized. All other computations were completed using SAS.RTM.,
Version 8.2 for Windows. Microsoft.RTM. Excel.RTM. 97 and SAS.RTM.,
Version 8.2 for Windows, were used to produce the tables and
graphs.
[0091] The following pharmacokinetic parameters were computed from
the plasma concentration data using the actual sample collection
times:
[0092] AUC.sub.o-t Area under the plasma concentration-time curve
(ng.about.hr/mL) from time zero to the time of the last
quantifiable concentration (t), calculated using the linear
trapezoidal rule: .SIGMA.i(t.sub.i-t.sub.i.1)(C.sub.i+C.sub.i.1)/2,
i=1 to t, where C.sub.i is the plasma concentration at time
t.sub.i.
[0093] AUC.sub.0-.infin.--Area under the plasma concentration curve
from time zero extrapolated to infinity (ng-hr/mL), calculated by
AUC0-t+(C.sub.last/ke), where C.sub.last is the last quantifiable
concentration and ke is the terminal elimination rate constant.
[0094] C.sub.max--Maximum or peak concentration, obtained by
inspection (ng/mL).
[0095] T.sub.max--Time of maximum or peak concentration, obtained
by inspection (hr).
[0096] Ke--Terminal elimination rate constant (1/hr). This value
was estimated by linear regression on the terminal phase of the
semi-logarithmic concentration versus time curve.
[0097] T.sub.1/2--Half life of the product (hr), calculated by
ln(2)/ke (Natural logarithmic (In) transformations were computed
for AUC.sub.0-t, AUC.sub.0-.infin. and C.sub.max)
[0098] Statistical Analysis
[0099] An analysis of variance (ANOVA) was performed on each of the
pharmacokinetic parameters using SAS.RTM. software. The ANOVA model
containing factors for sequence of products, subjects within
sequence, periods and products was utilized in comparing the
effects between the test and reference products. Differences were
declared statistically significant at the 5% level.
[0100] Since the subjects were dosed in two groups, an analysis of
variance (ANOVA) was used to detect the presence of a
group-by-product interaction. The ANOVA model containing factors
for group, sequence, group-by-sequence, subject within
group-by-sequence, period within group, product, and
group-by-product was utilized to detect the presence of a
group-by-product interaction. If the group-by-product term was not
significant (p-value>0.1), the term was removed from the model.
This reduced model was then used to compare the effects between the
test and reference products. Differences were declared
statistically significant at the 5% level.
[0101] A 90% confidence interval about the ratio of the mean test
value to mean reference value was calculated for all of the
pharmacokinetic parameters. The power of the ANOVA to detect a
difference equal to 20% of the reference mean was also calculated
with the SAS.RTM. software. The calculations for the power and
confidence interval used the least squares means (LSMEANS) and the
standard error of the estimate, both generated by the SAS.RTM.
software. The ratio of the geometric means for the In-transformed
data and the corresponding 90% confidence intervals were calculated
for AUC.sub.0-t, AUC.sub.0-.alpha., and C.sub.max, as well.
[0102] The lower limit of quantitation for phenytoin was 50 ng/mL.
For statistical analysis, subject sample values below the lower
limit of quantitation (BLQ) were reported as zero.
[0103] The statistical analysis was done using SAS.RTM., Version
8.2 for Windows.
[0104] To establish bioequivalence under fasting conditions, the
90% confidence interval for the ratio of the geometric means
between the product were to fall within the interval 80-125% for
log-transformed AUC.sub.0-t, AUC.sub.0-.alpha., and C.sub.max.
[0105] Table 19 summarizes the results of the analyses performed on
the pharmacokinetic parameters.
TABLE-US-00018 TABLE 19(a) Summary of Ln Transformed
Pharmacokinetic Parameters Ln- Ln- Ln- Transformed Transformed
Transformed Phenytoin C.sub.max . . . AUC.sub.0-t
AUC.sub.0-.alpha., Test Product of 1160.31 29961.63 3692.43 the
present invention Geometric Mean Reference 1225.07 32505.03
35310.18 Product Geometric Mean % Ratio 94.71 92.18 95.42 90%
(89.14, 100.64) (87.45, 97.15) (92.16, 98.79) Confidence
Interval
TABLE-US-00019 TABLE 19(b) Phenytoin C.sub.max . . . AUC.sub.0-t
AUC.sub.0-.alpha., Test Product of 1190.16 32158.32 36110.54 the
present invention Least Squares Mean Reference Least 1266.49
35124.24 37998.76 Squares Mean % Ratio 93.97 91.56 95.03 90%
(88.28, 99.66) (86.97, 96.14) (92.18, 97.88) Confidence
Interval
TABLE-US-00020 TABLE 19 (c) Phenytoin T.sub.max . . . K.sub.e
t.sub.1/2 Test Product of 4.16 0.0444 17.11 the present invention
Least Squares Mean Reference Least 4.88 0.0450 16.70 Squares Mean %
Ratio 85.33 98.71 102.50 90% (63.16, 107.49) (94.08, 103.33)
(96.79, 108.22) Confidence Interval
[0106] FIG. 1 shows the mean plasma concentration over time of the
pharmaceutical formulation of the present invention as compared
with the reference standard product.
* * * * *