Note: Descriptions are shown in the official language in which they were submitted.
CA 02233286 1998-03-27
2111 FLEXIBLE CONTAINER OR BOTTLE WITH BARRIER COATING
The present invention is generally directed to a
flexible container or bottle and is more particularly
directed to a container or bottle having a multilayer
barrier structure or coating to prevent the adsorp-
tion, permeation, or passage of fluids therethrough.
It is well known that containers must be formed
from materials having little or no interaction with
the intended contents of the container or bottle both
in order to prevent contamination of the contained
fluid and the leakage of fluids through the bottle.
This selection of container materials is particularly
important ~or drug/pharmaceutical products since
changes in a particular drug formulation due to
impurities introduced by or through the container
wall, and changes in the drug formulation over time
due to migration of various components through the
container walls can have a profound effect on the
product's performance in both physical and chemical
terms. A barrier may be formed with parylene on a
bottle or plug, see Japanese patent application
publication JP, A, 93 146 730 in order to prevent
migration of a drug therethrough.
These effects are commonly observed with flexible
containers such as I/V infusion bags and multidose
nonpreserved and preserved drug delivery systems. An
improper selection of container materials can result
in water/weight loss, gas permeability, drug instabil-
ity and drug absorption and adsorption. The problem
of course is more acute for flexible or pliable con-
tainers designed for squeezing for the dispensing of
formulations contained therein. Most polymers suit-
able for the construction of flexible containers, such
p,~tE~o~~ S~
CA 02233286 1998-03-27
. . . , ~, ,, ~
., ~ ~ . . . . . .
--1~--
as polyethylene, KRATON~, C-Flex~, SARLINK~, are not
- suitable due to the absorption or permeation of drug
formulations therethrough, such as, for
AMEND~D S~
CA 02233286 1998-03-27
W O 97/11988 PCT~US96/15104
example, but not limited to Liquifilm~, Prefrin~,
Betagan~ or preservatives such as BAK.
In an effort to overcome these problems,
laminated systems have been developed to provide a
container with sufficient flexibility yet provide a
barrier to the migration of formulations, or
components thereof. Unfortunately, such systems are
expensive and are prone to lamination problems which
may severely restrict the use thereof.
The present invention overcomes the problems
identified in the prior art through the use of
commonly available and inexpensive elastomers in
combination with an interior coating to provide a
barrier without degradation of the flexible, or
pliable, nature of the elastomer material.
g~MNARY OF T~B lN V ~.. ~ lON
A flexible cont~;n~ is provided especially
suitable for drug formulations in which the flexible
container consists of elastomer permeable by the drug
formulation and formed into a shape having side walls
and a hollow interior volume for cont~;ning the drug
formulation.
A layer of parylene coated on an inside surface
side wall is effective in establishing a flexible
barrier to passage of the drug formulation into the
elastomer material. The parylene utilized is selected
from the group consisting of parylene C, parylene N,
parylene D and mixtures thereof.
The present invention further encompasses a
pliable bottle dispensing system which includes aidrug
CA 02233286 1998-03-27
-3-
formulation in combination with an elastic material
permeable to the drug formulation and formed into a
shape having an interior chamber for containing the
drug formulation. The interior chamber is bounded by
squeezable side walls and a tip, in fluid communica-
tion with the interior chamber, provides a means for
dispensing the drug ~ormulation upon squeezing of the
side walls.
A layer of parylene is disposed on an inside
surface of the interior chamber with the parylene
being selected from the group consisting of parylene
C, parylene N, parylene D, and mixtures thereof. The
layer of parylene has a thickness ef~ective in
preventing passage of the drug formulation
therethrough.
More particularly, the elastomeric material may
be selected from the group consisting of pure polymer
of modified block copolymer rubbers, e.g. KRATON, or
other medically suitable polymers, e.g. polyvinyl
chloride, SILASTIC~, C-FLEX~, and the side walls have
a thickness between about 0.01 inch and about 0.4
inch, while the parylene layer has a thickness of
between about 0.5 ~m (0.00002 inch) and about 4.62~um
(0.0003 inch).
BRIEF DESCRIPTION OF THE DRAWINGS
The advantages and features of the present
invention will be better understood by the following
description when considered in conjunction with the
accompanying drawings in which:
Figure 1 is a cross-sectional view of a pliable
bottle dispensing system utilizing the present
invention;
Al llEN~D S~
CA 02233286 1998-03-27
. . , ~,,
4 '~' ~ '- ~-
Figure 2 shows weight loss for the thin parylene-
coated pouches at 40~C;
Figure 3 shows weight loss for the thick
parylene-coated pouches at 40~C;
5Figure 4 shows weight loss for the thin parylene-
coated pouches at 25~C;
Figure 5 shows weight loss for the thick
parylene-coated pouches at 25~C;
Figure 6 shows BAK concentrations for the thin
10parylene-coated pouches at 40~C;
Figure 7 shows BAK concentrations for the thick
parylene-coated pouches at 40~C;
Figure 8 shows BAK concentrations for the thin
parylene-coated pouches at 25~C; ~
15Figure 9 shows BAK concentrations for the thick
parylene-coated pouches at 25~C;
Figure 10 shows Levobunolol~ HCl concentrations
for the thin parylene-coated pouches at 40~C;
Figure 11 shows Levobunolol~ HCl concentrations
20for the thick parylene-coated pouches at 40~C;
Figure 12 shows LeVobunolol~ HCl concentrations
for the thin parylene-coated pouches at 25~C;
Figure 13 shows Levobunolol~ HCl concentrations
for the thick parylene-coated pouches at 25~C;
25Figure 14 shows pH values for the thin parylene-
coated pouches at 40~C;
Figure 15 shows pH values for the thick parylene-
coated pouches at 40~C;
Figure 16 shows pH values for the thin parylene-
30coated pouches at 25~C;
Figure 17 shows pH values for the thick parylene-
coated pouches at 25~C.
~JI~Nl~D ~EE~
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W O 97/11988 PCT~US96/15104
--5--
DETAILED DB8cRIpTIoN
-
Turning now to Figure 1, there is generally shown
a flexible container, or pliable bottle dispensing
system, 10 in accordance with the present invention
generally showing an elastomer material formed into a
pouch 12 having interior volume, or chamber, 16 for
containing a drug formul~ation.
The container shape 12 is sized and shaped for
facilitating easy handling and the container wall 12
is formed with a thickness suitable for use with the
present invention, as wi~ be hereinafter discussed in
greater detail.
A pump system 18, not part of the present
invention, enables the dispensing, in a dropwise
fashion, of a liquid formulation from a nozzle 20.
The container may include a pouch funnel 22
suitable for filling the po~ch 12 through a poach neck
24 to a full liquid level 2~ from a pouch end 28. As
hereinafter discussed in greater detail, a coating 30
on inside surface 32 of container 12 has a thickness
effective in establishing a flexible barrier to the
passage of the formulati~n into and through the
elastomeric pouch 12.
In addition, the po~ch 12 may include a coating
34 disposed on an outside surface 36 of the pouch, as
hereinafter discussed in~reater detail.
The elastomeric materizl which may be employed in
accordance with the pres~t invention includes those
elastomers known in the art, such as block copolymer
rubbers, which are suitable for forming flexible
~ CA 02233286 1998-03-27
7 ~ ~ 7 ~ ~ , ,
containers such as I/V infusion bags and a multidose
dispensing system 10, shown in Figures 1, such as, for
example, PVC, C-FLEX~, SARLINK~, LDPE, KRATON~,
SILASTIC~
These materials are known to be permeable to drug
formulations such as ~-blockers (e.g., Levobunolol,
timolol, betaxolol), ~-agonists (e.g., brimonidine),
prostaglandins (e.g., Latanoprost), ketorolac,
dipivalyl, epinedphrine, flurbiprofen, preservatives,
e.g., benzalkonium chloride, chlorobutanol.
The pliable bottle dispensing system and flexible
container 10, in accordance with the present inven-
tion, has a layer comprising of at least one parylenecoated on the inside surface 38 thereof.
Specific examples of the parylene which can be
employed in the present invention include parylene N,
parylene C, parylene D, and mixtures thereof.
Parylene is the generic name for members of a
polymer series in which the basic member of the
series, called parylene N, is poly-para-xylylene.
Parylene C, the second commercially available member
of this series, is produced from the same monomer
modified only by the substitution of a chlorine atom
for one of the aromitic hydrogens.
Parylene D, the third member of the series, is
produced from the same monomer, modified by the sub-
stitution of a chlorine atom for two of the aromatic
hydrogens. These parylenes are available from
chemical suppliers of di-para-xylylene, poly-para-
xylylene, e.g., Specialty Coating Systems.
AME~CEDSYEET
CA 02233286 1998-03-27
7-
The parylene polymers are deposited on the inside
surface 38 of the container 12 from a vapor phase and
deposition is conducted at pressures of about 1.32x10
ATM (10 5) torr or below. The parylenes are formed
at about 0.13x10-3 ATM (0.1 torr) and under these
conditions, the mean free path of the gas molecules in
the deposition chambers is in the order of 0.1 cm.
This is important because the resulting deposition is
not dependent upon the line of sites and accordingly,
all of the inside surfaces 38 may be coated uniformly
with the container 12, disposed in the vacuum chamber
(not shown).
Conventional coating chambers (not shown) may be
utilized for depositing parylene which can be
deposited at about 0.2 ~m per minute.
The parylene deposition process includes three
steps in which the first is vaporization o~ the solid
di-para-xylylene at approximately 150~C, and the
second step is the cleavage or pyrolysis of the dimer
at the two methylene-methylene bonds at about 680~C to
yield the stable monomeric diradical para-xylylene.
Thereafter, the monomer enters a room temperature
deposition chamber where it simultaneously adsorbs and
polymerizes on the surface of the container. Only the
interior surface 38 may be exposed to the monomer,
thereby effecting a coating on the interior surface 38
only.
It has been found that the parylene layer prefer-
ably should have a thickness between about 0.1 ~m and
5.0 ~m.
~ SffE~
CA 02233286 1998-03-27
WO97/11988 PCT~S96/15104
Effectiveness of the parylene coating as a func-
tion of container 12, parylene thickness, and drug
formulation are shown in the following studies.
Exam~le I
METHODS
Lot Descriptions/Stability Discussion
LiquifilmG and Prefrin~ were formulated with a
BAK concentration of lOO ppm. Betagan~ was formulated
without BAK.
The formulations were filled by Pharmaceutical
Sciences Operations into flexible pouches manufactured
from various polymers including: AT~YN, C-FLEX,
plasticized PVC, SARLINK, KRATON, and KRATON-A
-
Prior to filling, all pouches were sub~ected to
gamma irradiation. KRATON-A was further autoclaved
after irradiation. The KRATON and KRATON-A pouches
were filled with pumps installed while all other
pouches were without pumps. Pouches filled with
Liquifilm~ or Betagan~ were stored at 40'C/75~
relative humidity and tested at l week and 2 weeks for
BAK, weight loss and levobunolol where applicable.
Prefrin~-filled units were stored at 40~C and tested
at l week, 2 weeks, and 3 months for BAK, weight loss,
pH and phenylephrine. A portion of the Prefrin~ were
stored at 25 C/60% relative humidity and tested at 3
months for weight loss and pH.
Standard analytical methods were used to assay
phenylephrine, BAK and levobunolol, respectively.
Weight loss was determined from the initial tare
weights of the pouches prior to filling. Product
weight at the appropriate time points and initial
product fill weight yielded the percent water loss for
~ '$.~ 3-~t.~
CA 02233286 1998-03-27
W 0 97/11988 PCTrUS96/15104
a particular unit. Analysis of the bulk formulation
- was used for the zero time point data of pH and BAK.
. Product SPecifications
The product specifications for Liquifilm~(7527X),
Prefrin~(7533X) and Betagan~ (7667X) in regards to
BAK, phenylephrine, levobunolol and pH are listed in
the following table:
Formulation Parameter Product Specification
Liquifilm~ BAK 0.004% - O.006% w/v
BAK 0.004% - O.006% w/v
Prefrin~ Phenylephrine 0.108% - 0.132~ w/v
pH 6.3 - 7.1
Betagan~ Levobunolol 0.47% - 0.54~ w/v
RESULTS AND DISCUSSION
The adsorption of the preservative, BAK, to the
flexible pouch was not resoled through the use of any
of the polymers. Results of the stability data for
BAK at 40~C are summarized in Tables 1 and 2. At 1
week, the BAK concentrations in the formulations fell
below the lower specification limit based on percent
loss for all polymers studied. The only exception was
the Liquifilm~ formulation in the KRATON pouch which
fell to the lower specification of 80% by 1 week. The
Alcryn and PPVC pouches performed exceptionally poorly
having completely adsorbed the BAK from all
formulations within 1 week. the SARLINK and KRATON
polymers performed equivalently with respect to BAK
adsorption from the formulations at 2 weeks.
Approximately 50% of the BAK remained in the
formulations filled into the SARLINK and KRATON
pouches. The C-FLEX pouch adsorbed approximately 53%
and 37% of the BAK from the Liquifilm~ and Prefrin8
' CA 02233286 1998-03-27
~ , ~ , .
--1 0--
formulations, respectively. A more significant
difference in the performance of C-FLEX~, SARLINK~ and
KRATON~ was detected at 3 months. C-FLEX~ and KRATON~
continued to adsorb BAK from the product for 90 days.
The Sarlink~ pouch, however, appeared to saturate with
BAK after 2 weeks, with a maximum of 50% of the BAK
being lost from the product. This indicates that
C-FLEX~ and KRATON~ possess a higher binding capacity
for BAK than SARLINK~. Although saturation of the
Sarlink0 with BAK appears to have occurred, it would
be necessary to use a 100% overage to keep the
Liquifilm~ and Prefrin~ within specification for 3
months at 40~C.
Significant water loss was observed from all
polymeric pouches. The stability data on the weight
loss is summarized in Tables III and IV. The weight
loss was most dramatic for the Alcryn pouches where an
18% and 16% w/w loss was noted at 40~C from the
Liquifilm~ and Prefrin~ formulations, respectively.
The PPVC pouches also lost a significant amount of
water from the Liquifilm~-filled, 7% w/w, and
Prefrin~-filled, 6.3%, pouches. The C-FLEX~ and
KRATON~ pouches lost approximately 1% w/w by 2 weeks,
increasing to -6.4% and 5.4% respectively at 3 months.
The SARLINK pouches performed the best in regard to
water loss, -3.6% at 3 months. In all pouches filled
with the Betagan~ formulation, weight loss was
marginally improved. (See Table 5) This most likely
resulted from less efficient wetting of the polymer
surface in the absence of BAK.
At 3 months, the phenylephrine concentration
increased above the upper specification limit for
Prefrin~ in all polymeric pouches examined. Based on
the water loss data, this increase in phenylephrine
AMEN~E~ SH~E~
CA 02233286 1998-03-27
W O 97/11988 PCT~US96/15104
--11--
was to be expected. The levobunolol remained within
- specifications for Betagan~, 0.5% for 2 weeks at 40~C.
All data for pH were within specification throughout
the study. At 40~C, the pH drifted in the Prefrin~
formulations to 6.4. However, there was no difference
in pH between the polymeric pouches and the glass
controls. (See table 6)
The W/Vis scans of the formulations in the Self-
Instill pouches revealed nothing suspect. However, anextraneous peak in the BAK assay was noted from the
SARLINK and PPVC pouches at 1 and 2 weeks. These
extraneous peaks indicate a possible W -absorbing
extractable migrating from the polymers into the
formulation.
Five polymeric pouches, including Alcryn, C-Flex,
PPVC, SARLINK and KRATON, were studied under acceler-
ated stability conditions at 40~C for formulation/
polymer compatibility. Water and BAK loss from the
formulations filled into the pouches was significant.
Alcryn and PPVC performed the worst of all polymers
studied. Water loss ranged from -18% w/w at 2 weeks
for ALCRYN to ~6.4%, 5.4% and 3.6% w/w for C-FLEX,
KRATON and SARLINK, respectively. A dramatic
preservative loss from all formulations in the
polymeric pouches was detected. The rank order for
the polymer adsorption of BAK was determined to be
ALCRYN>PPVC>C-FLEX>KRATON > SARLINK. Adsorption of
the preservative from the formulations onto the
SARLINK pouch was shown to saturate at an initial BAK
concentration of 100 ppm. However a 100% overage of
BAK would be necessary to keep the formulations within
specification for 3 months at 40'C. the BAK
adsorption to the polymeric pouches appears to be the
limiting issue in the compatibility of the
CA 02233286 1998-03-27
Wo97/11988 PCT~S96/15104
formulations. PPVC and SA~LINK appear to contain an
extractable in their formulation that migrated into
the products tested.
Table l.
BAK Stability ~esults at 40'C for Li~uifilm~
Filled into the Self-Instill Pouches
AGELiqui-ilm~
(Days) Glass ALCRYN C-FLEX pPVC SARLINK KRATON
0 0.103 0.103 0.103 0.103 0.103 0.103
7 0.104 0.002 0.058 0.001 0.054 0.084
0.100 0.002 0.058 0.001 0.056 0.084
0.002 0.058 0.001 0.056 0.084
Mean 0.102 0.002 0.058 0.001 0.055 0.084
S.D. 0.003 0.000 0.000 0.000 0.001 0.000
14 0.094 0.002 0.048 0.000 0.050 0.058
~ 0.094 0.000 0.050 0.000 0.054 0.058
0.002 0.050 0.000 0.052 0.060
Mean 0.094 0.001 0.049 0.000 0.052 0.059
S.D 0 001 0.001 0.000 0.002 0.001
SUBSTITUTE SHEET (RULE 26)
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WO 97/1l988 PCT~US96/15104
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Table 2.
BAK Stability Results at 40'C for Prefrin~
Filled into the Sel~-Instill Pouches
AGE Pref-in~
5(Days) Glass ALCRYN C-FLEX PPVC SARLINK XRATON
0 0.099 0.099 0.0990.099 0.099 0.099
7 0.090 0.000 0.0360.000 0.048 0.048
0.092 0.000 0.0380.002 0.050 0.052
0.002 0.0420.002 0.050 0.054
Mean 0.091 0.001 0.0390.001 0.049 0.051
S.D. 0.001 0.001 0.0030.001 0.001 0.003
14 0.084 0.002 0.0360.000 0.052 0.0S4
0.094 0.002 0.0360.000 0.054 0.054
0.002 0.0260.000 0.054 0.054
Mean 0.089 0.002 0.0330.000 0.053 0.054
S.D. 0.007 0.000 0.0060,000 0.001 0.00C
0.100 0.011 0.052 0.025
- 0.010 0.043 0.026
Mean 0.100 0.011 0.048 0.026
Table 3.
Weight Loss Results at 40-C for Liquifilm~
Filled into the Self-Instill Pouches
AGE Liquifilm~
(Days)ALCRYN C-F1LEXPPVC SARLINXXRATON
7.44 0.582.88 0.33 0.45
7.21 0.553.15 0.33 0.44
7.30 0.562.81 0.33 0.44
Mean 7.32 0.562.95 0.33 0.44
S.D. 0.12 0.020.18 0.00 0.01
14 17.76 1.307.06 0.76 1.13
17.68 1.337.38 0.80 1.14
18.06 1.327.02 0.78 1.15
Mean 17.83 1.327.15 0.78 1.14
S.D. 00.20 0.020.20 0.02 0.01
_
SUBSTITUTE SHEET (RULE 26)
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W O 97/11988 PCT~US96/1~104
-14-
Table 4.
Weight Loss Results at 40~C for Prefrin~
Filled into the Self-Instill Pouches
AGE Prefrin0
5(Day5)
40~CALCRYN C-FLEX PPVC .~RT.TN~KRATON
7 9.66 0.73 4.06 0.024
10.18 0.72 3.g7 0.026
9.69 0.75 4.07 0.44 0.027
10Mean 9.84 0.73 4.03 0.030
S.D. 0.29 0.02 0.06 0.000
14 16.01 1.23 6.48 0.67 1.010
16.08 1.23 6.26 0.68 1.050
15.29 1.24 6.01 0.69 1.050
15Mean15.79 1.23 6.25 0.68 1.040
S.D. 0.44 0.01 0.24 0.01 0.020
6.27 3.67 5.29~
6.54 3.55 5.490
Mean 6.41 3.61 5.39
20S.D. 0.19 0.08 0.14
AGE Prefrins
(Day~)
25~CAlcryn C-Flex PPVC Sarlink~raton
2~90 3.76 2.68 1.63
3.04 2 71 1.70
Table 5.
Stability Results for Weight Loss for Betagan~, O. 5%
Filled into the Self-Instill Pouches
AGE Betag n0
(Days)ALCRYN C-FLEX PPVC SARLINK KRATON KRATON-A
7 8.95 0.59 3.36 0.35 0.51 0.49
8.60 0.59 3.31 0.34 0.54 0.46
8.59 0.61 3.17 0.34 0.53 0.47
Mean 8.71 0.60 3.28 0.34 0.53 0.47
S.D. 0.21 0.01 0.10 0.01 0.02 0.02
14 13.70 0.94 5.11 0.55 0.84 0.74
13.52 0.93 5.17 0.55 0.84 0.76
14.06 0.93 5.23 0.55 0.83 0.72
Mean 13.76 0.93 5.17 0.55 0.84 0.74
S.D. 0.270 0.01 0.06 0.00 0.01 0.02
SU3STITUTE SHEET (RULE 25)
CA 02233286 1998-03-27
WO97/11988 PCT~S96/15104
Ta~le 6.
Phenylephrine, Levobunolol, and
pH Stability ~esults ~or
Formulations Filled into the Self-Instill Pouches
AGE "refrin~ Phenyleplrine (mg/ml)
(Days) Glaq~ ALCRYN C-FLEX PPVC ~T.TNR RRATON
14 1.30 1.45 1.25 1.28 1 21 1.20
2.05 1.48 1.25 1.28 1.18 1.09
1.49 1 29 1.29 1.21 1.20
1 20 1.35 1.40 1.38
1.31 1.38 1.32
Temp Pref-in~ pH at 90 Dayq
~C Glass ALCRYN C-FLEX PPVC .~RT.TN~ ~RATON
25~C 7.00 6.98 6.98 6.98
40~C 6.39 6.39 6.39 6.38
AGE Betagan~ Levo~unolol (mg/nl)
(Dayq) Glass ALCRYN C-FLEX PPVC ~T.T~ KRATON RRATON-A
14 5 20 3.24 5.02 4.64 5 51 5.11 4.93
' 4.75 5.39 4.61 5.93 4.84 4.91
5.33 5.01 5.17 4 65 5.48 5.08 4.8
Example II
MATERIALS AND MET~ODS
Three materials of the pouches were studied
coated at two different parylene-C thicknesses.
KRATON-Thick pouches (having a thickness of about O. 5
to about l. 5 mm) were coated with parylene at about
3.8 ~m and about 7.6 ~m on both inside and outside
surfaces. C-Flex pouches wee coated with parylene at
about 3.8 ~m and a~out 7.6 ~m. SARLINK pouches coated
with parylene at about 3.8 ~m and about 7.6 ~m.
Pouches were also sterilized by gamma irradiation at
-2 5 mrads before the coating process. Controls were
stored in amber glass ampules. The pouches and con-
trols were filled with Betagan~ (average fill volume
SUBSTITUTE SHEET (RULE 26)
CA 02233286 1998-03-27
WO97/11988 PCT~S96/15104
-16-
5.0-5.5 ml). During stability the samples were stored
at 40~C/75% RH and 25~C/60% RH. All samples were
stored without labels and in boxes for protection from
light. Assays occurred at 2 days, 4 weeks and 8
weeks. Samples were tested for the concentrations of
benzalkonium chloride (BAK) and levobunolol HCl.
Weight loss was calculated ~rom the filled weight at
testing and the initial average fill weight (deter-
mined by averaging weights of all units per lot).
Tare weights of the individual pouches were measured
after emptying, washing and drying. pH was measured
using a suitable pH meter and electrode at room
temperature after calibration.
RESULTS/DISCUSSION
Weight loss at two months/40-C is 3% w/w in the
Kraton with 7.6 ~m coating and Sarlink with 3.8 ~m
coating. Weight loss at two months/40-C is 3% w/w in
Sarlink with 7.6 ~m coating.
The data shows a loss in BAK of 15% w/v in the
KRATON-Thick pouches (both 3.8 ~m and 7.6 ~m
coatings). The BAK losses in KRATON-Thick are
significantly lower than those of 75-100% w/v seen in
pouches without the parylene coating (Example I).
Although there has been hereinabove described a
container in accordance with the present invention,
for the purpose of illustrating the manner in which
the invention may be used to advantage, it should be
appreciated that the invention is not limited thereto.
Accordingly, any and all modifications, variations, or
equivalent arrangements which may occur to those
skilled in the art, should be considered to be within
CA 02233286 1998-03-27
WO 97/11988 PCT~US96/15104
- 17 -
the scope of the present invention as defined in the
appended claims.
~ t3
