Note: Descriptions are shown in the official language in which they were submitted.
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Soluble Drug Extended Release System
CROSS-REFERENCE TO RELATED APPLICATIONS
[Ol] This application claims priority to U.S. Patent Application No.
10/007,877, filed
November 13, 2001, converted to U.S. Provisional Application No. -,
incorporated herein
by reference in its entirety for all proposes.
FIELD OF THE INVENTION
(02] This invention relates to novel oral sustained release formulations for
delivery of an
active agent (e.g., a drug), especially a highly water-soluble drug. More
particularly, this
invention relates to novel formulations comprising a micelle-forming drug
having a charge
and at least one polymer having an opposite charge.
BACKGROUND OF THE INVENTION
[03] Administration of drugs via conventional oral and intravenous methods
severely
limits the effectiveness of most drugs. Jnstead of maintaining drug levels
within therapeutic
windows, these methods cause an initial, rapid rise in plasma concentration
levels followed
by a rapid decline below therapeutic levels as the drugs are metabolized by
the body.
Therefore, repeated doses are necessary to maintain drugs at therapeutic
levels for a sufficient
period of time to achieve a therapeutic effect. To address this problem,
numerous sustained
release preparations have been developed to eliminate the initial burst effect
and allow drug
release at constant levels.
[04] Polymeric formulations are typically used to achieve extended drug
release (see,
Langer et al. Nature 392:6679 supp. (1998)). Various successful polymeric
sustained release
preparations have been developed for release of drugs with different physical
properties.
Such preparations have been extremely effective for increasing release times
for relatively
hydrophobic and water-insoluble drugs.
[05] However, due to rapid drug diffusion through polymer matrices, it has
been difficult
to achieve extended release for highly soluble drugs using current sustained
release
technologies. Thus, there is a need for new formulations and processes which
are capable of
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reducing drug diffusion and eliminating a burst effect of highly water-soluble
drugs. The
present invention fulfills these and other needs.
BRIEF SUMMARY OF THE INVENTION
[06] The present invention provides inter alia, an oral sustained release
preparation
comprising a micelle-forming drug and an oppositely charged polymer. Although
a concept
of a micelle is well known for the field of the surfactant or drug carrier,
application of a
micelle-forming drug to the sustained release formulation is not known at all.
Furthermore it
is really surprising that this formulation is excellent effective on the
extended release of
active agents, especially water-soluble drugs. A further advantage lies in the
ability of the
formulation to provide slow release even when the formulation contains large
drug loads.
[07] As such, the present invention provides an oral sustained release
pharmaceutical
formulation, comprising: a micelle forming drug having a charge; and at least
one polymer
having an opposite charge, further if necessary hydrogel-forming polymer
substance and
hydrophilic base. The micelle forming drug may have a positive charge or a
negative charge
at physiological pH.
[08] In another embodiment, the present invention provides a method for
modulating a
micelle forming drug release profile, comprising varying the molar ratio of
micelle forming
drug having a charge with at least one polymer having an opposite charge,
varying the
additional amount of polymer having an opposite charge, thereby modulating the
micelle
forming drug release profile. Suitable micelle forming drugs include, for
example,
antidepressants, (3-adrenoceptor blocking agents, anesthetics, antihistamines
and the like.
Preferably, the micelle forming drug is a water-soluble drug.
[09] In another embodiment, the present invention provides a method for
extending release
of a micelle forming drug, comprising: orally administering a pharmaceutical
formulation
comprising a micelle forming drug having a charge; and at Least one polymer
having an
opposite charge, thereby extending release of the micelle forming drug.
[10] In another embodiment, the present invention provides a method for
extending release
of a micelle forming drug, comprising: orally administering a pharmaceutical
formulation
comprising a micelle forming drug having a charge; and at least one polymer
having an
opposite charge, further if necessary hydrogel-forming polymer substance and
hydrophilic
base, thereby extending release of the micelle forming drug.
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[11] Further objects and advantages will become more apparent when read with
the
drawings and detailed description, which follow.
DEFINITIONS
[12] The term "active agent" means any drug that can be carried in a
physiologically
acceptable tablet fox oral administration. Preferred active agents include,
micelle forming
active agents capable of forming electrically charged colloidal particles.
[13] The term "cps" or "centipoise" is a unit of viscosity = m Pascal second.
The viscosity
is measured by Broolfield or other viscometers. See, e.g., Wang et al. Clih.
Hemorheol.
Microcirc. 19:25-31 (1998); Wang et al. J. Biochem. Biophys. Methods 28:251-6I
(1994);
Cooke et al. J. Clih. Pathol. 41:1213-1216 (1998).
[14] The term "carrageenan" as herein refers to all forms of a water-soluble
extract from
carrageenan, Irish moss, seaweed from the Atlantic coasts of Europe and North
America.
Sources include, e.g" Viscarin~ 109 and Gelcarin~, such as GP-911, GP-812, GP-
379, GP-
109, GP-209 commercially available from FMC. Carageenans are high molecular
weight,
highly sulfated, linear molecules with a galactose backbone. They are made up
of sulfated
and nonsulfated repeating units of galactose and 3,6 anhydrogalactose, which
are joined by
alternating cx (1-3) and ~3-(1-4) glycosidic linkages. Another commercial
source of
carageenans is Sigma and Hercules Inc.
[15] The term "polyacrylic acid" or "PAA" as used herein includes all forms
and MWs of
PAA polymers. Sources include, for example, Carbopol 971 from B.F. Goodrich.
[I6] The term "polyethylene oxide polymer" or "PEO" as used herein includes
all forms
and MWs of PEO polymers. Sources of PEO polymers include, e.g., Polyox WSR-
303T""
(average MW: 7 x I06; viscosity 7500-10000 cps, 1% in H2O, 2S°C);
Polyox WSR
CoagulantT"" (average MW S x 106; viscosity SS00-7500 cps, under the same
conditions as
above); Polyox WSR-301T"' (average MW 4 x I06; viscosity 1650-SS00 cps, under
the same
conditions as above); Polyox WSR-N-64KT"' (average MW 2 x 106; viscosity: 2000-
4000
cps, 2% in H20, 25°C); all of which are trade names of Union Carbide
Co. See also WO
94106414, which is incorporated herein by reference.
[17] The term "polyethylene glycol" or "PEG" as used herein includes all forms
and MWs
of PEG polymers. Sources of PEG polymers include Macrogol 400, Macrogol 1500,
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Macrogol 4000, Macrogol 6000, Macrogol 20000; all of which are trade names of
Nippon Oil
and Fats Co.
[18] The terms "hydroxypropylinethylcellulose," "sodium
carboxymethylcellulose,"
"hydroxyethylcellulose," and "carboxyvinyl polymer" incorporate their common
usages.
Sources include: for hydroxypropylmethylcellulose (HPMC), e.g., Metolose
90SH100000T""
(viscosity: 2900-3900 cps, under the same conditions as above); Metolose
90SH30000T""
(viscosity: 25000-35000 cps, 2% in H2O, 20°C); all of which are trade
names of Shin-Etsu
Chemicals Co. For sodium carboxymethyl-cellulose (CMC-Na), e.g., Sanlose F-
150MCT""
(average MW 2 x 105; viscosity 1200-1800 cps, 1% in H20, 25°C), Sanlose
F-1000MCT""
(average MW 4.2 x 104; viscosity 8000-12000 cps, under the same conditions as
above);
Sanlose F-300MCT"~ (average MW 3 x 105; viscosity 2500-3000 cps, under the
same
conditions as above), all of which are trade names of Nippon Seishi Co., Ltd.
For
hydroxyethylcellulose (HEC) (e.g., HEC Daicel SE850T""), average MW 1.48 x
106; viscosity:
2400-3000 cps, 1% in H20, 25°C; HEC Daicel SE900T"", average MW 1.56 x
106; viscosity
4000-5000 cps, under the same conditions as above; all of which are trade
names of Daicel
Chemical Industries. For carboxyvinyl polymers, e.g., Carbopol 940T"", average
MW ca. 25 x
105; B.F. Goodrich Chemical Co.
[19] The term "therapeutic drug" as used herein means any drug that can be
delivered in an
orally delivered physiologically acceptable tablet.
[20] The term "micelle forming" refers to any compound that is capable of
forming
electrically charged colloidal particles, ions consisting of oriented
molecules, or aggregates
of a number of compounds/molecules held loosely together by secondary bonds.
BRIEF DESCRIPTION OF THE DRAWINGS
[21] Figure 1 illustrates soluble drug (10 wt.%) release from a 400 mg PAA/PEO
matrix in
Simulated Intestinal Fluid (SIF).
[22] Figure 2 illustrates the correlation between Tso and log P for basic
highly soluble
drugs released from a 400 mg PAA/PEO (1:1.5) tablet.
[23] Figure 3 illustrates the correlation between critical micelle
concentration (CMC) and
log P.
[24] Figure 4 illustrates examples of charged drugs (either positive or
negative) suitable for
use in the release experiments.
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[25] Figure S illustrates the release of negatively charged drugs from a
PAA/PEO matrix.
[26] Figure 6 illustrates Diltiazem HCl release from PAA/polysaccharide matrix
tablets
(400 mg) in SGF (Fig. 6a) and SIF (Fig. 6b).
[27] Figure 7 illustrates Diltiazem HCl release from PAA/sulfated polymer
matrix tablets
5 (400 mg) in SGF (Fig. 7a) and SIF (Fig. 7b).
[28] Figure 8 illustrates Diltiazem HCl release from different matrix tablets
in SGF (Fig.
8a) and SIF (Fig. 8b).
[29] Figure 9 illustrates Diltiazem HCl (25 wt.%) release from PAA/carrageenan
(l:l)
matrix in SGF and SIF.
[30] Figure 10 illustrates PAAlcarrageenan ratio optimization for a
formulation with 25 wt
Diltiazem HCI.
[31] Figure 11 illustrates release rates of Diltiazem HCl (60 wt.%) from
matrix tablets with
different PAA/carrageenan ratios in SGF (Fig. l la) and SIF (Fig. l lb).
[32] Figure 12 illustrates Diltiazem HCl release from PAA/Viscarin 109 matrix
at different
drug loads in SGF (Fig. 12a) and SIF (Fig. 12b).
(33] Figure 13 illustrates Diltiazem HCl (25 wt. %) release from competitive
systems
based on carrageenan in SGF (Fig. 13a) and SIF (Fig. 13b).
(34] Figure 14 illustrates Diltiazem HCl (25 wt. %) release from competitive
systems
based on PAA in SGF .
[35] Figure 15 illustrates Diltiazem HCl (60 wt. %) release from competitive
systems in
SGF (Fig. 15a) and SIF (Fig. 15b).
[36] Figure 16 illustrates the effect of additional amount of PAA on Diltiazem
HCl (50 wt.
%) release in JP 2nd fluid.
[37] Figure 17 illustrates the effect of additional amount of PAA/carrageenan
on Diltiazem
HCl (50 wt. %) release in JP 2nd fluid.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS.
[38] This present invention provides, inter alia, an oral sustained release
preparation
comprising a micelle-forming active agent (i.e., drug) and an oppositely
charged polymer
forming a hydrogel matrix. The formulation is typically manufactured by direct
compression
of the drug and the polymeric excipient.
[39] Advantageously, this formulation provides an extremely low release rate
of active
agent. In a preferred aspect, hydrogen-bonded complexes between the oppositely
charged
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polymers and drug micelles prevent rapid diffusion of the drug. Without being
bound by any
particular theory, it is believed that drug release occurs when the charge of
the polymer is
neutralized by OH ions at the matrixldissolution border and these bonds are
disrupted.
[40] In one embodiment, the number of administrations of the formulation can
be reduced,
S thereby increasing patient compliance. Further, side effects of the drug can
be reduced by
suppressing rapid increases in blood concentration of the drug (seen in
standard
formulations). A further advantage of this formulation is that the release
rates of the
formulations are not significantly affected by loading with high amounts of
drug.
[41] Factors and events which form a theoretical basis for the embodiments of
the
invention are discussed herein. However, this discussion is not in any way to
be considered
as binding or limiting on the present invention. Those of skill in the art
will understand that
the various embodiments of the invention may be practiced regardless of the
model used to
describe the theoretical underpinnings of the invention.
I. Active Agents of the Invention
[42] Active agents of this invention can be any drugs which form micelles.
Micelle
formation has been observed for antidepressants,~3-adrenoceptor blocking
agents, anesthetics,
antihistamines, phenothiazines, antiacetylcholines, tranquilizers,
antibacterials, and
antibiotics (see, Attwood et al., J. PhaYm. Pharrnac., 30, 176-180 (1978);
Attwood et al., J.
Pharm. Pharmac., 31, 392-395 (1979); Attwood et al., J. Pharm. Pharmac., 38,
494-498
(1986); Attwood J. Pharm. Pharmac., 24, 751-752 (1972); Attwood et al. J.
Pharm. Scz.v.63,
no. 6, 988993 (1974); Attwood, .T. Phar. Pharmacol., 28, 407-409 (1976)).
Representative
micelle-forming antidepressant drugs include imipramine HCI, omipramol HCI,
and
amitriptuline HCI. Representative micelle-forming ~3-adrenoceptor blocking
agents include
oxprenolol HCl, acebutolol HCl and solatol HCI. Representative micelle-forming
anesthetics
include procaine HCI, lidocaine HCI, and amethocaine HCI. Representative
micelle-forming
antihistamines include diphenhydramine HCI, chlorcyclizine HCI,
diphenylpyraline HCI,
promethazine HCI, bromodiphenhydramine HCl, tripelennamine HCI, and mepyramine
maleate. Representative micelle-forming phenothiazines include chlorpromazine
HCI, and
promethazine HCI. Other micelle-forming drugs include tranquilizers,
antibacterials and
antibiotics.
[43] In certain aspects, the active agents include, but are not limited to,
betacaine
hemisulphate, cinchocaine hydrochloride BP and lignocaine hydrochloride
(Sigma);
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prilocaine hydrochloride BP bupivacaine hydrochloride (Astra Pharmaceuticals)
mepivacaine
hydrochloride (Leo) proparacaine hydrochloride (Squibb) and amethocaine
hydrochloride BP
(Smith and Nephew Pharmaceuticals). In certain other aspects, the following
active
ingredients are useful in the present invention. These include, but are not
limited to, (4'-(1-
hydroxy-2-Isopropyl-aminoethyl)methanesulphonanilfide) (Duncan, Flockhart);
labetolol [5-
(1-hydroxy-2-(1-methyl-3-phenyl-propylamino)ethyl) salicylamide] (Allen and
Hanburys);
aceburtolol ((~)-3'-acetyl-4'-(2-hydroxy-3-Isopropylaminopropoxy)-butyranilde)
(May and
Baker); propranolol f (~)-1-Isopropylamino-3-naphth-1'-yloxypropan-2-ol) (ICI)
and
oxprenolol {(~)-1-(o-allyloxyphenoxy)-3-Isopropylaminopropan-2-ol)) (Ciba);
timolol
maleate f (-)-1-butylamino-3(4-morpholino-1,2,5-thiediazol-3-yl-oxy)propan-2-
of maleate)
(Merck, Sharp and Dohme); metroprolol lartrale ((~)-1-Isopropylamino 3-p-(2-
methoxyethyl)
phenoxypropan-2-o 1 tartrate} (Geigy Pharmaceuticals). In another embodiment,
the active
ingredients include, but are not limited to, adiphenine hydrochloride (Ciba);
poldine
methylsulphate B.P. (Beecham Research); lachesino chloride B.P.C. (Vestric);
chlorphenoxamine hydrochloride (Evans Medical); piperiodolate hydrochloride
and
pipenzolate bromide (M.C.P. Pharmaceuticals); orphenadrine hydrochloride B.P.
(Brocades,
Gt Britain); benztropine mesylate B.P. (Merck Sharp and Dohme); clidinium
bromide
(Roche); ambutonium bromide (Wyeth) and benzilonitum bromide (Parke-Davis).
Diphenhydramine hydrochloride B.P. (2-diphenylmothoxy-NN-dimethylethylamine
hydrochloride) and chlorcyclizine hydrochloride B.P. [1-(p-
chlorodiphenylmethyl)-4-methyl
piperazine hydrochloride] obtained from Parke-Davis and Company and Burroughs
Wellcome and Company respectively. Bromodiphenhydramine hydrochloride [2-(a p-
bromophenyl-a phenylmethoxy)-NN-dimethylethylamine hydrochloride] and
dipenylpyraline
hydrochloride (4-diphenyl-methoxy-1-methylpiperidine hydrochloride)
respectively. Those
of skill in the art will know of other active ingredients suitable for use in
the present
invention.
[44] In preferred embodiments, active agents of this invention are highly
water soluble
drugs. And further preferred embodiments, active agents of this invention are
basic drugs.
This invention is particularly useful for such drugs, which exhibit a strong
burst effect due to
rapid diffusion through polymeric matrices. Highly water soluble drugs include
salts formed
with inorganic and organic acids (positively charged due to non-covalently
attached protons),
permanently positively (or negatively) charged molecules, and negatively
charged molecules
(salts of weak and strong acids). For example, highly water soluble drug means
that its
solubility is over 10 mglmL, more preferably over 100 mglmL.
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[45] Specific active agents suitable for use in formulations of this
invention, micelle
forming drug having a charge, can be selected based on critical micelle
concentration (CMC)
andlor log P, which are closely related (see, Example 3). Log P, the drug
distribution
coefficient between octanol and water, reflects the hydrophobic properties of
the uncharged
drug form. CMC, a measure of the concentration at which a particular compound
will form a
micelle, is a function of hydrophobicity, as well as molecular
stereochemistry, group rotation
ability, and counter ions. The presence of micelle-like charged drug
aggregates within a
hydrogel matrix containing oppositely charged polymers leads to cooperative
interaction. It
is this cooperative interaction that governs the release rate of drug from the
polymeric matrix.
Therefore, CMC and log P can be used to predict drug release rate and thus
identify those
drugs which will have extended release in formulations of this invention.
Drugs with a low
CMC andlor high log P would be released slowly in formulations of this
invention, while
those less likely to form micelles would be released with profiles similar to
those for standard
oral formulations.
[46] Accordingly, the release profile of a drug can be modulated using any
standard
methods known to those of skill in the art to modulate the critical micelle
concentration
andlor the degree of cooperative interaction between a micelle-forming drug
and the
oppositely charged polymers. Methods of modulating CMC andlor the degree of
cooperative
interaction would include altering the hydrophobicity of the drug by addition
of functional
groups and any other techniques to alter electrostatic interaction between the
drug and the
polymeric excipient. In certain aspects, the present invention provides a
method for
extending the release profile of a micelle forming drug, comprising:
decreasing the critical
micelle concentration of the micelle forming drug, thereby extending the
release profile of the
micelle forming drug.
[47] In certain other aspects, the present invention provides further methods
of extending
the release profile of a micelle forming drug. These include for example,
varying the
polymer compositions, changing the polymer-drug ratio, varying the additional
amount of
polymer having opposite charge as well as varying the tablet size and shape.
(48] One method to determine whether micelles exist, is to measure the
variation of light
scattering at an angle of 90° i.e., 590, as a function of concentration
in an appropriate
solution. Thereafter, scattering graphs can be analyzed. If scattering is
increasing
continuously with increasing the concentration, no micelle formation is
occurnng. If graphs
indicate clearly defined inflection in the S90 vs. concentration plots, it is
attributed to the
micelle formation. Critical micelle concentration is determined from the
inflection point of
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graphs of the scattering at an angle of 90° to the incident beam, 590,
as a function of the
molar concentration. Those of skill in the art will know of other methods to
determine
micelle formation.
[49) Advantageously, drug loads for formulations of this invention can be
extremely high.
Moreover, the release rate does not increase significantly with increase of
drug content (e.g.,
up to 60 wt. %) in SGF and actually decreases with increase of drug content in
SIF (see,
Example ~).
[50] In certain preferred aspects, the micelle forming drug has a positive
charge or a
negative charge at physiological pH. As used herein, physiological pH is about
0.5 to about
~, more preferably, about 0.5 to about 5.5. The positive charge or negative
charge at
physiological pH refers to the overall charge on the molecule. That is, it is
possible to have
more than one functional group contributing to the charge, as long as the
overall charge is
positive or negative.
[51] One assay method to determine whether the micelle forming drug or polymer
has a
positive charge or a negative charge at physiological pH is to empirically
determine the
charge on the molecule. For example, a suitable buffer solution or gel is made
having a
certain pH. A cathode and an anode are placed in the buffered solution or,
alternatively, a gel
electrophoresis is used. The micelle forming drug if positively charged
migrates to the
cathode. If the micelle forming drug is negatively charged, the drug migrates
to the anode.
The polymer having an opposite charge in the pharmaceutical formulation will
migrate to the
opposite electrode. For example, if the micelle forming drug is positively
charged, it will
migrate to the cathode. The polymer having an opposite charge will migrate to
the anode.
[S2] In another assay method, the charge on the micelle forming drug and/or
polymer is
assessed using the Henderson-Hasselbach equation. The Henderson-Hasselbach
equation is a
mathematical statement which defines the pH of a solution of a conjugate acid-
base pair in
terms of the dissociation constant of the weak acid and the equilibrium
concentrations of the
acid and its conjugate base. When pK = pH, then, [Ha] is equal to [A]. Values
of pK yield
quantitative information concerning acid strength, very strong acids being
characterized by
undefined pK values (pK = -log 0, example HCl); semi-strong acids being
characterized by
small pK values; and weak acids being characterized with large pK values.
Using the
Henderson-Hasselbach equation, the charge on the micelle forming drug and/or
polymer is
assessed to determine the charge thereon.
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II. Charged Polymeric Excipients of the Invention
[53] The formulation of this invention also comprises at least one polymeric
excipient or
polymer with a charge opposite that of the micelle-forming drug of the
invention. In a
preferred aspect, the cooperative interaction of the charged excipient with
the micelle-
s forming drug is the basis for the extended release properties of this
invention.
[54] The formulation can comprise negatively charged polymers, such as ones
with a
carboxylic group or a sulfate group. These include, but are not limited to,
sulfated polymers,
polyacrylic acid, polymethacrylic acid, methylmethacrylic-methacrylic acid
copolymer,
alginates, xanthan gum, gellan gum, guar gum, carboxymethylcellulose, locust
bean gum, and
10 hyaluronic acid.
[55] Especially preferred polymers with a negative charge include polyacrylic
acid and
sulfated polymers. Sulfated polymers include carrageenan (e.g., Viscariri
and/or Gelcarin~),
and dextran sulfate. Preferably, when polyacrylic acid is selected as one
polymer, sulfated
polymers can be selected as other polymers.
[56] Preferably, the formulation can also comprise a hydrogel-forming polymer
with
physical characteristics, such as high viscosity upon gelation, which permit
the preparation of
the present invention to withstand the contractile forces of the digestive
tract associated with
the digestion of food and more or less retain its shape during its travel down
to the lower
digestive tract, namely the colon. For example, a polymer showing a viscosity
of not less
than 1000 cps in 1% aqueous solution (at 25°C) is particularly
preferred.
[57] The properties of the polymer depend on its molecular weight. The
hydrogel-forming
polymer which can be used in the present invention is preferably a substance
of
comparatively high molecular weight, viz. a polymer having an average
molecular weight of
not less than 2 x 106 and more preferably not less than 4 x 106. Further, the
polymers can be
branched chain, straight chain, crossed linked or any combination thereof.
[58] Examples of said polymer substance are polyethylene oxide, such as
POLYOX~ WSR
303 (viscosity-average molecular weight: 7,000,000, viscosity: 7,500 to 10,000
cps (aqueous
1% solution at 25°C)), POLYOX~ WSR Coagulant (viscosity-average
molecular weight:
5,000,000, viscosity: 5,500 to 7,500 cps (aqueous 1% solution at
25°C)), POLYOX~ WSR-
301 (viscosity-average molecular weight of 4,000,000, viscosity: 1650-5500 cps
(aqueous 1%
solution at 25°C)), POLYOX~ WSR N-60K (viscosity-average molecular
weight: 2,000,000,
viscosity: 2,000 to 4,000 cps (2% aqueous solution at 25°C) (all made
by Union Carbide),
ALKOX~ E-75 (viscosity-average molecular weight: 2,000,000 to 2,500,000,
viscosity: 40 to
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70 cps (aqueous 0.5% solution at 25°C)), ALKOX~ E-100 (viscosity-
average molecular
weight of 2,500,000 to 3,000,000, viscosity: 90 to 110 cps (aqueous 0.5%
solution at 25°C)),
ALKOX~ E-130 (viscosity-average molecular weight: 3,000,000 to 3,500,000,
viscosity: 130
to 140 cps (aqueous 0.5% solution at 25°C)), ALKOX~ E-160 (viscosity-
average molecular
S weight: 3,600,000 to 4,000,000, viscosity: 150 to 160 cps (aqueous 0.5%
solution at 25°C)),
ALKOX~ E-240 (viscosity-average molecular weight: 4,000,000 to 5,000,000,
viscosity: 200
to 240 cps (aqueous 0.5% solution at 25°C)) (all made by Meisei Kagaku
Co., Ltd.), PEO-8
(viscosity-average molecular weight:1,700,000 to 2,200,000, viscosity: 20 to
70 cps (aqueous
0.5% solution at 25°C)), PEO-15 (viscosity-average molecular weight:
,3,300,000 to
3,800,000, viscosity: 130 to 250 cps (aqueous 0.5% solution at 25°C)),
PEO-18 (viscosity-
average molecular weight: 4,300,000 to 4,800,000, viscosity: 250 to 480 cps
(aqueous 0.5%
solution at 25°C)) (all made by Seitetsu Kagaku Kogyo Co., Ltd.), etc.
[59] In order to provide a hydrogel-type preparation suitable for sustained
release, it is
generally preferable that the preparation contains about 10 to about 95 weight
%, more
preferably, about 15 to about 90 weight % of a hydrogel-forming polymer of a
preparation
weighing less than 600 mg. Preferably, the preparation contains not less than
70 mg per
preparation and preferably not less than 100 mg per preparation of the
hydrogel-forming
polymer. The above-mentioned levels will insure that the formulation will
tolerate erosion in
the digestive tract for a sufficiently long time in order to achieve
sufficient sustained release.
[60] The above hydrogel-forming polymer may be used singly, or two or more
kinds) of
the above hydrogel-forming polymers in mixture may be used.
[61] Preferably, the particular combination and ratio of polymeric excipients
is that which
allows the slowest rate of release under both gastric and intestinal
conditions, pH
independently. The optimal combination and ratio can vary depending on the
particular active
agent and percent loading of active agent.
[62] Preferred combinations of excipients includePAA/PEO, PAA/carrageenan, and
PAAldextran sulfate. Preferably, the polymers are in a 1:0.5 ratio, 1:1 ratio,
or a 1:5 ratio;
most preferably, the polymers are in a 1: 1.5 ratio.
[63] Preferred combinations of excipients also include PAA/carrageenan/PEO.
Preferably,
PAA and carrageenan are in a 1:0.5 ratio, 1:1 ratio, or a 1:5 ratio; most
preferably, the
polymers are in a 1: 1.5 ratio. Preferably, PAA plus carrageenan, and PEO are
in a 1:0.5 ratio,
1:1 ratio, or a 1:2 ratio; most preferably, the polymers are in a 1: 1.5
ratio.
[64] In order for accomplishment of sustained drug release in the lower
digestive tract as
well as in upper digestive tract of humans, the preparation should be a gelled
at least 2 hours
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after administration and the tablet should be further eroded through moving
the lower
digestive tract so that the tablet is released.
(65] The term "percentage gelation of the formulation" used in the present
invention
means the ratio of the tablet that has been gelled once the compressed tablet
has been
moistened for a specific amount of time and is determined by the method of
determination of
the percentage gelation described below (see, Test Method 2). Because the
preparation
absorbs water when retained in the upper digestive tract and thereby almost
completely gels
(that is, percentage gelation is not less than 70%, preferably not less than
75%, more
preferably not less than 80%) and move to the lower digestive tract as the
surface of the
preparation is being eroded with drug being released by further erosion, the
drug is
continually and thoroughly released and absorbed. As a result, sustained
release performance
is realized, even in the lower digestive tract where there is little water.
Specifically, if the
percentage gelation is less than approximately 70%, sufficient release of the
drug will not be
obtained and there is a chance of a reduction in bioavailability of the drug
(EP No.
1,205,190A1).
[66] The term "upper digestive tract" in the present invention means the part
from the
stomach to the duodenum and jejunum "lower digestive tract" means the part
from the ileum
to the colon.
[67] The formulation can also comprise hydrophilic base to achieve the higher
percent
gelation. There are no particular restrictions to the hydrophilic base as long
as it can be
dissolved before above-mentioned hydrogel-forming polymer substance gels. For
example,
the amount of water needed to dissolve lg of this hydrophilic base is
preferably SmL or less
(at 20 ~ 5°C), more preferably 4mL of less (at same temperature).
[68] Examples of said hydrophilic base include water-soluble polymers such as
polyethylene glycol (for instance, Macrogol 4000, Macrogol 6000 and Macrogol
20000, all
of which are trade names of Nippon Oil and Fats Co.), polyvinyl pyrrolidone
(for instance,
PVP~ I~30, of which is trade name of BASF), sugar alcohols, such as D-
sorbitol, xylitol,
etc., saccharides, such as sucrose, maltose, lactulose, D-fructose, dextran
(for instance,
Dextran 40), glucose, etc., surfactants, such as polyoxyethylene hydrogenated
castor oil (for
instance, Cremophor~ RH40 (made by BASF), HCO-40, HCO-60 (made by Nikko
Chemicals), polyoxyethylene polyoxypropylene glycol (for instance, Pluronic~
F68 of which
is trade name of Asahi Denka), etc. Polyethylene glycol, sucrose, and
lactulose are preferred
and polyethylene glycol (particularly Macrogol 6000) is further preferred. The
above
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hydrophilic base can be used singly, or two or more kinds) of the above
hydrophilic base in
mixture can be used.
[69] When the hydrophilic base is added in the present invention, the ratio
used is
preferably approximately 5 to approximately 80 wt% per total preparation, more
preferably 5
to 60 wt% based on the total preparation.
[70] Preferred combinations of excipients include PAA/PEOlPEG. Preferably, PAA
and
PEO are in a 1:0.5 ratio, 1:1 ratio, or a 1:5 ratio. More preferably, the
amount of PEG is 5
wt.% to 60 wt.% based on the total preparation
[71] Preferred combinations of excipients also include
PAA/carrageenan/PEO/PEG.
Preferably, PAA and carrageenan are in a 1:0.5 ratio, 1:1 ratio, or a 1:5
ratio. Preferably,
PAA plus carrageenan, and PEO are in a 1:0.5 ratio, 1:1 ratio, or a 1:2 ratio.
More preferably,
the amount of PEG is 5 wt.% to 60 wt.% based on the total preparation.
[72] The formulation can also comprise a single positively charged polymer or
combinations of such polymers, including, but not limited to, polyethylene
imine, chitosan,
polyvinylpirridinium bromide, and polydimethylaminoethylmethacrylate.
[73] Depending on the polymers) viscosity, the polymer material can form a
matrix
comprising the active ingredient. For example, a polymer showing a viscosity
of not less than
1000 cps in 1 % aqueous solution is particularly preferred due to its matrix
forming ability.
[74] Extending release of a micelle forming drug can be achieved by a method
of oral
administrating formulation of this invention.
III. Other Tablet Modifications .
[75] Modification of drug release through the tablet matrix of the present
invention can
also be achieved by any known technique, such as, e.g., application of various
coatings, e.g.,
ion exchange complexes with, e.g., Amberlite IRP-69. The tablets of the
invention can also
include or be co-administered with GI motility-reducing drugs. The active
agent can also be
modified to generate a prodrug by chemical modification of a biologically
active compound
which will liberate the active compound in vivo by enzymatic or hydrolytic
cleavage, etc.
Additional layers or coating can act as diffusional barriers to provide
additional means to
control rate and timing of drug release.
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IV. Formulation Additives
[76] If desired, the preparation of the present invention may include
appropriate amounts
of other pharmaceutically acceptable additives such as vehicles (e.g.,
lactose, mannitol,
potato starch, wheat starch, rice starch, corn starch, and crystalline
cellulose), binders (e.g.,
hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, and gum
arabic),
swelling agents (e.g., carboxymethylcellulose and carboxy-methylcellulose
calcium),
lubricants (e.g., stearic acid, calcium stearate, magnesium stearate, talc,
magnesium meta-
silicate aluminate, calcium hydrogen phosphate, and anhydrous calcium hydrogen
phosphate), fluidizers (e.g., hydrous silica, light anhydrous silicic acid,
and dried aluminum
hydroxide gel), colorants (e.g., yellow iron sesquioxide and iron
sesquioxide), surfactants
(e.g., sodium lauryl sulfate, sucrose fatty acid ester), coating agents (e.g.,
zero,
hydroxypropylmethyl-cellulose, and hydroxypropylcellulose), buffering agents
(e.g., sodium
chloride, magnesium chloride, citric acid, tartaric acid, bibasic sodium
phosphate, monobasic
sodium phosphate, calcium hydrogen phosphate, ascorbic acid, ), aromas (e.g.,
.~-menthol,
peppermint oil, and fennel oil), preservatives (e.g., sodium sorbate,
potassium sorbate, methyl
p-benzoate, and ethyl-benzoate).
V. Manufacturing
[77] The preparation of the present invention is a solid preparation having a
certain shape,
and can be manufactured by any conventional processes. Typical processes
include, e.g.,
compression tableting manufacturing processes. These processes comprise
blending and if
necessary granulating the active agent, the charged polymers, and if desired,
additional
additives, and compression-molding the resulting composition/formulation.
Alternative
processes include, e.g., a capsule compression filling process, an extrusion
molding process
comprising fusing a mixture and setting the fused mixture, an injection
molding process, and
the like. Any coating treatments, such as, e.g., sugar coating, may also be
carried out.
[78] The following examples are intended to illustrate, but not to limit, the
present
invention.
EXAMPLES
Test Method 1
This Test Method illustrates the basic procedure for manufacturing
formulations of this invention, as well as measuring drug release.
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Several different formulations with different drugs were manufactured. Drugs
were manually mixed with the excipients in a mortar and compressed into 400 mg
tablets
using Carver press or Oil press with 1000 lb applied force. Flat face 11 mm
round tooling
was used.
5 Materials
Carbopol 971 (BF Goodrich); Polyox 303 (Union Carbide); two types of
carrageenan, Viscarin~ 109 and Gelcarin (FMC); XanturalTM 1~0 (Monsanto
Pharmaceutical
Ingredients), a xanthan gum Keltone LVCR (Monsanto Pharmaceutical
Ingredients); a
sodium alginate Chitosan (M. W. International , Inc.); Macrogol 6000 (Nippon
Oil and Fats
10 Co.); Methocel K100M (The Dow Chemical Company); a
hydroxypropylmethylcellulose
(HPMC); Cellulose Gum 12M31P TP (Hercules); a sodium carboxymethylcellulose
(CMC);
and Dextran Sulfate (Sigma).
Methods
Ira vitro drug release was measured by in vitro dissolution experiments. These
15 studies were carried out using USP apparatus II at a paddle speed of 100
rpm in 1000 ml
dissolution medium from Examples 1 to 10. Drug release was evaluated with
either
Simulated Gastric Fluid (SGF), pH=1.2 or Simulated Intestinal Fluid (SIF),
pH=7.5, both
prepared according to USP without enzyme added. Tablet sinkers were applied in
all
experiments. At predetermined time intervals, a sample was withdrawn from the
vessel and
assayed using a UV VIS spectrophotometer at a wavelength of 240 nm.
Example 1
This example illustrates that drug release rate does not correlate with drug
solubility, indicating that a specific interaction is influencing its release
rate.
The release behavior of a large group of basic highly soluble drugs (10 wt.
of drug ) from a directly compressed matrix tablet using 1:1.5 polyacrylic
acid/polyethylene
oxide (PAA/PEO) mix as excipient was studied under modified Simulated
Intestinal Fluid
(SIF) conditions. Release rate was characterized by TSO (time during which 50%
of drug has
been released from matrix to the solution) (Figure 1). Results of the study
are presented in
Table 1, where drug properties and release rate are summarized.
Identically charged drugs have significantly different release profiles in
modified SIF which do not correlate with drug solubility (Figure l, Tablel).
Therefore, it can
be concluded that a single electrostatic interaction does not by itself result
in extended release
of soluble drugs.
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Example 2
This example illustrates that the log P of a drug can be used to predict
whether
extended release will be achieved using the formulation of this invention. An
ability to
predict drug release behavior based on the log P characteristic is one of the
key advantages of
this invention.
The ability of a drug to bind to a particular polyelectrolyte is dependent on
its
critical micelle concentration (CMC). However, since the CMC value is rarely
available for
drugs, an attempt was made to relate the release rate to drug properties which
are commonly
used for drug characterization. For drags which were used in the above-
described release
experiments (Table 1), a variety of parameters such as molecular weight,
solubility, pKa, log
P, log D, and surface tension were analyzed in terms of their correlation with
the release time.
It appeared that log P (distribution coefficient of uncharged drug form
between octanol and
water) demonstrates a close to linear relationship with T5o (Figure 2). Log P
is closely related
to CMC. In fact, a practically linear relationship has been established
between log P and
CMC (Figure 3). Log P and CMC values for different drugs were extracted from
the
Attwood publications.
Example 3
This example illustrates that extended release can be achieved for permanently
positively charged molecules using a 1:1.5 PAA/PEQ excipient mixture.
The following positively charged molecules were tested: benzethonium
chloride and bethanechol chloride, which have one positive charge; thiamine
mononitrate and
thiamine hydrochloride, which have two positive charges; and betaine, which is
a dipole
(Figure 4). Although thiamine HCl showed slightly fast release, all the drugs
demonstrated
extended release with different rates (Table 2).
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Table 1. Model drug characteristics
Name MW Solubility,Tso Log P
m lml
Pyridoxine HC1 205.64 222 4 -1.9
Pseudoephedrine 201.73 250 4 1.0
HCl
Cevimeline HCl 244.79 766 4.5 1.1
Ranitidine HCl 350.91 200 11 1.3
Diphenhydramine 291.9 1000 15 3.4
HCl
Diltiazem HCl 450.98 800 18 3.6
Doxylamine Succinate388.8 1000 23 2.5
Tramadol HCl 299.8 > 1000 31 2.5
Amitriptuline 313.9 500 57 4.8
HCl
Chlorpromazine 354.4 400 56 5.4
HCl
Imipramine HCl 332.9 500 58 4.5
Benoxinate HCl 344.9 1000 22 4.0
These results demonstrate that even if a drug does not have strong
hydrophobic groups, specific interaction with charged polymeric excipients is
still possible
(see, for example bethanechol chloride), as long as the drug carries a
permanent positive
charge. On the other hand, drug structure and charge location can play an
important role in
the ability to interact with polymeric excipients (see, thiamine HCl).
Thiamine's location of
charges at the center of the molecule (Figure 4) may effect micelle formation.
Example 4
This example illustrates that oppositely charged drugs and polymeric
excipients are critical for extending drug release. As Figure 5 shows, the
highly soluble
negatively charged drugs, sodium cefazoline and sodium cefinatazole, diffuse
out the
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negatively charged PAA/PEO matrix with a TSO of about 5 hours without
achieving extended
release.
Example 5
This example demonstrates the effect of fluid environment on drug release
profiles for 1:1.5 PAA/PEO mixtures.
The initial experiments described in Examples 1- 4 were conducted under
Simulated Intestinal Fluid (SIF) conditions, where PAA is ionized. To evaluate
the release
kinetics under gastric conditions, dissolution of different types of soluble
drugs was
IO performed in modified Simulated Gastric Fluid (SGF). Table 3 compares T5o
values in SGF
and SIF for different drugs.
Table 2. Positively charged drug characteristics and Tso.
Name SolubilityT50,T10, Comments
h
,mg/ml h
Thiamine Mononitrate300 14 1 Two positive charges
Thiamine HCI 1000 7.5 1 Two positive charges
Betaine 650 22 6 Dipole
Bethanechol Chloride1700 55 10 Forms insoluble complex with
PAA
Benzethonium Chloride1000 25 Forms insoluble complex with
PAA
Table 3. T5o values in SGF and SIF.
Drug name T50 in SGF, T50 in SIF,
hours hours
Diltiazem HCl 8 18
Tramadol HCl 8 31
Diphenhydramine Citrate12 25
Bethanechol Chloride24 55
Betaine Hydrochloride4 22
Thiamine Mononitrate3 14
As Table 3 shows, release time in SIF is significantly longer that in SGF.
Obviously, in low pH media ionization of PAA is suppressed to a great extent.
This may
prevent formation of cooperative bonds between PAA/PEO and the drug. Another
possible
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reason for the short release times in SGF is that formation of a hydrogen-
bonded polymer
complex between the electronegative oxygen atom of PEO and the carboxylic
group of PA.A
at low pH conditions blocks the carboxylic groups from interaction with drug.
Example 6
This example illustrates polymeric excipient combinations which provide
sustained release under both SGF and SIF conditions.
Evaluation o~multiple polysacclaarides
Drug release rates were tested for seven different polysaccharides
(carrageenan, xanthan gum, sodium alginate, chitosan, HPMC, CMC-Na) combined
with
PAA, containing 25 wt. % Diltiazem HCl (DI) (Figure 6). The results
demonstrate that a
combination of PAA with carrageenan can provide the slowest release of drug in
SGF. This
effect is probably due to the strong acidic nature of carrageenan functional
groups (-S04 )
which stay negatively charged even at low pH conditions and enable interaction
between the
carrageenan and a drug.
Evaluation o~other~ sul ated pol fy ners
Different types of carrageenan, as well as dextran sulfate, were used in
combination with PAA or PEO at a 1:1 ratio and Diltiazem HCl (25 wt.%) and
release rate
was measured in SGF and SIF. Extended release was observed for all
combinations
containing sulfated polymers (Figure 7).
Further analysis o effect o~substitution ofP~ forPEO
When PAA in PAAICarrageenan (1:1) formulation is substituted by high MW
PEO, release profiles for PAA/Carrageenan (l:l) and PEO/Carrageenan (l:l)
formulations in
SGF overlap for about 6 hours (Figure 8, a). After this time, fast matrix
erosion causes faster
drug release from PEO/Carrageenan. matrix. In contrast, in SIF,
PAA/Carrageenan
formulation demonstrates slower drug release than PEO/Carrageenan formulation
over the
entire period of time (Figure 8, b). Therefore, combination of PAA and
Carrageenan can
provide the best in vitro drug release characteristics in both SGF and in SIF.
CompaYison of PAAICarra~eenaya release rates in SIF and SGF
Figure 9 demonstrates that DI (25 wt.%) release from the PA.A/Carrageenan
(l:l) matrix is linear in both SGF and SIF and that release rates in the two
media are
identical. A dissolution test for samples where the media was switched after 2
hours resulted
in a linear release profile very close to the profiles in Figure 9.
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Example 7
This example illustrates that the optimal polymer excipient composition is
media dependent (Figure 10).
For the formulation containing 25 wt.% DI, the lowest release rate in SGF was
5 achieved with 1:1 PAA/Carrageenan composition. In SIF, release rate
decreased with
increasing amounts of PAA in the formulation.
Interestingly, different optimal compositions were observed for a formulation
with high DI content (60 wt.%). In SGF, the drug release rate decreased with
an increase in
carrageenan content and in SIF, the release rate was practically independent
from excipient
10 ratio (Figure 11).
Based on these observations, we believe that the release behavior is most
likely governed by drug/excipient complex stoichiometry in different media.
Example 8
15 This example illustrates that an increase in drug loading has an
insignificant
effect on the release rate in SIF for drug loading up to 60 wt %. In SGF, the
increase in
release rate is relatively small for drug loads up to 50 wt.% (Figure 12).
Example 9
20 This example illustrates the superior ability of the formulations of this
invention to extend drug release.
DI (25%) release from PAA/Carrageenan (1:1) matrix was compared with
previously described formulations containing PAA and Carrageenan (Bonferoni et
al., RAPS
Pharm. Sci. Tech, 1 (2) article 15 (2000); Bubnis et al., Proceed. Int'l.
Symp. COrZtYOI. Rel.
Bioact. Mater., 25, p. 820 (1998); Devi et al., Pharm. Res., v.6, No 4, 313-
317 (1989); Randa
Rao et al., J. Contr. Rel., 12, 133-141 (1990); Baveja et al., Int. J. Pharm.,
39, 39-45 (1987);
Stockwel et al., J. Corztr. Rel. 3, 167-175 (1986); Perez-Marcos et al., J.
Phanm. Sei., v.85,
No. 3 (1996); Perez-Marcos et al., Int. J. PlZarm. 111, 251-259 (1994);
Dabbagh et al.,
Pharm. Dev. Tech., 4(3), 313-324 (1999); Bonferoni et al., J. Contr. Rel. 25,
119-127 (1993);
Bonferoni et al., J. Contr. Rel. 30, 175-182 (1994); Bonferoni et al., J.
Contr. Rel. S 1, 231-
239 (1998); US Patent 4,777,033; EU Patent 0 205 336 B1).
Carrageenan-containing systems described in the literature include
carrageenan/HPMC and carrageenan/CMC. All matrices were prepared in the same
way as
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the Viscarin 109lsecond polymer (l:l) mix. Formulations with the
PAA/carrageenan (1:1)
matrix demonstrated significantly slower DI release both in SGF and in SIF
(Figure 13).
An extended release system with PAA/HPMC (LTS Patent 4,777,033; EU
Patent 0 205 336 B1) has been described.
Formulations with the PAA/carrageenan (l:l and 3:2) matrix demonstrated
significantly slower DI release than that with PAA/HPMC (1:1) as a control in
SGF (Figure
14), although all preparations indicated an extended drug release in SIG with
a Tso of mo re
than 20 h.
When the amount of drug in the system is increased to 60 wt.%, the release
rate from PA.A/Carrageenan system remains the slowest compared to all other
competitive
systems (Figure 15).
Example 10
This example compares release rates of various drugs for the original
formulation (PAA/PEO) and the new PAA/carrageenan formulations.
Release rates of different drugs which previously demonstrated interaction
with PAA/PEO matrix were compared to the release rates from the
PAA/carrageenan (1:1)
matrix. It appeared that most of the drugs show extended close to zero-order
release from the
PAA/carrageenan matrix. Typically, release of the drugs from PAA/carrageenan
matrix was
slower both in SGF and in S1F compare to the release from PAA/PEO matrix,
although it was
not the case for all the drugs.
To illustrate, the following Table 4 sets forth TSO values (release times) in
SIF.
In this study, the PA.A/PEO (1:1.5) formulation contained 10% of active and
PAA/Carrageenan (1:1) formulation contained 25% of active.
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Table 4. T50 values in SIF.
Dru PAA/PEO PAAJCar Lo
P
Thiamin HCl 7.5 7.5
Ranitidine 11 15 1.3
HCl
Diphenhydramine15 8 3.4
HCl
Diltiazem HCl 18 21 3.6
Benoxinate 22 23 5.2
HCl
Naratriptan 22 25 1.8
HCl
Doxylamine 23 22 2.5
Succinate
Tamsulosin 26 25 2.24
HCl
.. I _.I
Test Method 2
Dissolution test
In vitro drug release was measured by in vitro dissolution experiments. These
studies were carned out using The Pharmacopeia of Japan XIV(referred to "JP"
hereinafter)
Dissolution Test Method 2 (paddle method) at a paddle speed of 200 rpm in 900
ml
dissolution medium. Drug release was evaluated with either JP Disintegration
Test Fluid 1
(referred to "JP 1 st fluid" hereinafter), pH=1.2 or JP Disintegration Test
Fluid 2 (referred to
"JP 2nd fluid" hereinafter), pH=6.8. Tablet sinkers were not applied in the
experiments. At
predetermined time intervals, a sample was withdrawn from the vessel and
assayed using a
UV-VIS spectrophotometer at a wavelength of 250 nm.
Gelation test
Using JP 1 st fluid and JP 2nd fluid, a gelation test was carned out as
follows.
The test tablet was moistened for 2 hours in test medium at 37°C, gel
layer was removed and
the core portion not forming a gel was taken out, followed by drying at
40°C for 5 days in a
dryer and dried core was weighted (W°bs). The percent gelation of the
formulations is
calculated by means of Equation 1. The value obtained by subtracting core
weight from
initial tablet weight (W;n~tial) ~d dividing this by initial tablet weight is
multiplied by 100 to
calculate the percent gelation (G).
The "percent gelation" as used herein represents the percentage of the portion
of the tablet which has undergone gelation. The method of calculating the
percent gelation is
not particularly limited but the following method may be mentioned as an
example.
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Thus, the test tablet is moistened for a predetermined time, the volume(or
weight)of the portion not forming a gel is then measured and the result is
subtracted from the
volume(or weight)of the tablet before the beginning of the test.
Percent gelation (G, %) _ (1- (W°bs Winitial)) x 100 (Equation 1)
W°bs: The weight of the portion not gelled after initiation of the
test
Winitial~ The weight of the preparation before initiation of the test
Example 11
This example illustrates the effect of additional amount of polymers having a
charge opposite that of the micelle-forming drug on drug release profiles.
Different amount of PAA was used in combination with the mixture of
PEO/PEG (1:1) at a 1:0 ratio (PA.A wt.% to the total amount is 50), 1:1 ratio
(PAA wt.% to
the total amount is 25), 3:1 ratio (PAA wt.% to the total amount is 37.5), 1:3
ratio (PAA wt.%
to the total amount is 12.5), or 1:9 ratio (PAA wt.% to the total amount is
5), containing 50
wt.% Diltiazem HCI. The Formulation comprising PEO/PEG at a 1:1 ratio without
PAA,
containing 50 wt.% Diltiazem HCl was prepared as a control. Drug release rate
was evaluated
in JP 2nd fluid according to the method as described in Test Method 2
(Figurel6). Extended
drug release was achieved for all preparations containing PAA, even in case of
containing a
small amount of PAA such as 5 wt.% of total preparation. The results also
demonstrated the
drug release rate decreased with increasing the amount of PA.A instead of
mixture of
PEO/PEG (1:1).
The effect of additional amount of PAA and carrageenan mixture on drug
release profiles was also investigated. The ratio of PAA and carrageenan, and
the ratio of
PEO/PEG was fixed l:l, respectively. Different amount of PAA/carrageenan (1:1)
was used
in combination with the mixture of PEO/PEG (l:l) at a 1:0 ratio(both PAA and
carrageenan
wt.% to the total amount is 25 and 25, respectively), 3:1 ratio (both PAA and
carrageenan
wt.% to the total amount is 18.75 and 18.75, respectively), l:l(both PAA and
carrageenan
wt.% to the total amount is 12.5 and 12.5, respectively) ratio to 1:3
ratio(both PAA and
carrageenan wt.% to the total amount is 6.25and 6.25, respectively),
containing 50 wt.%
Diltiazem HCl. (Figurel7). The Formulation comprising PEO/PEG at a 1:1 ratio
without
PAAlcarrageenan, containing 50 wt.% Diltiazem HCl was prepared as a control.
The results
also demonstrated the drug release rate decreased with increasing the amount
of mixture of
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PAA/carrageenan. Therefore, drug release rate can be controlled by varying the
additional
amount of polymers) having a charge opposite that of the micelle-forming drug.
Example 12
This example illustrates the superior ability of the formulations of this
invention to be gelled.
When the gelation test of the preparations comprising PAAlcarrageenan/ -
PEO/PEG at a 1:1:0:0, 1:1:1:1 or a 1:1:3:3 ratio, containing SO wt.% Diltiazem
HCI. was
performed according to the method described in Test Method 2. The percent
gelation of these
formulations demonstrated 75.0 %, 80.8 % and 80.7% in JP 1st fluid,
respectively.
In case of the preparation comprising PAAlPEO/PEG in a 1:9:9, the percent
gelation demonstrated 78.0 % and 76.9 % in JP 1 st fluid and JP 2nd fluid,
respectively.
Test Method 3
Pharnaacokinetic study in beagle do,~s,
Nine male beagle dogs weighing 9.3 to 13.4 kg were fasted for 18h before
administration. After oral administration of the test tablet containing 200mg
of Diltiazem
HCl with 30 mL water, they were allowed free access to water, but food was
withheld until
the last blood sample had been taken. Blood samples were collected at 0.5, 1,
2, 3, 4, 6, 8, 10,
12, and 24 h. after administration. Subsequently, plasma was separated by
centrifugation to
be applied to the quantitative analysis by HPLC system with UV detection.
Example 13
This example illustrates the influence of percent gelation of preparations on
in
vivo sustained drug release.
Two preparations (Preparation A; 63.4 % and Preparation B; 77.6 % of
percent gelation in JP 1st fluid) comprising different amount of PAA/PEO/PEG,
both
containing 200mg of Diltiazem HCl were used for pharmacokinetic study in
beagle dogs. The
results demonstrated that the Preparation B showed a sustained drug release in
the lower
digestive tract as well as in upper digestive tract, although Preparation A
released little drug
in the lower digestive tract.
To compare ira vivo drug release between two preparations in detail, the area
under the drug concentration in plasma curve (AUC) from 0 to 24 hr was
calculated as a
function of ifz vivo absorbed drug amount. The results demonstrated that the
AUC of
CA 02466657 2004-05-11
WO 03/041656 PCT/US02/36681
Preparation B (7541.2 ~ 2153.7 ng h/mL) was significantly higher than that of
Preparation A
(4346.1 ~ 1811.6 ng hlmL), which confirmed in vivo insufficient drug release
for the
preparation with lower percent gelation.
5 All publications, patents and patent applications mentioned in this
specification are herein incorporated by reference into the specification in
their entirety for all
purposes. Although the invention has been described with reference to
preferred
embodiments and examples thereof, the scope of the present invention is not
limited only to
those described embodiments. As will be apparent to persons skilled in the
art, modifications
10 and adaptations to the above-described invention can be made without
departing from the
spirit and scope of the invention, which is defined and circumscribed by the
appended claims.
