CA2233286A1 - Flexible container or bottle with barrier coating - Google Patents

Abstract

A flexible container (10) is provided which includes an elastomeric material permeable to a select drug formulation, formed into a shape having side walls (12) and hollow interior volume (16) for containing the drug formulation. A
layer (30) of parylene is provided on an inside surface (32) of the side walls (12) with a thickness effective in establishing a flexible barrier to the passage of the drug formulation into the elastomeric material and adsorption of BAK by the elastomeric material.

Description

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~

. . . , ~, ,, ~
., ~ ~ . . . . . .

--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~

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 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~

. . , ~,, 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~

W O 97/11988 PCT~US96/15104 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

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~

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.~

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 ~ , ~ , .

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~

W O 97/11988 PCT~US96/15104 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 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) WO 97/1l988 PCT~US96/15104 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) W O 97/11988 PCT~US96/1~104 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) 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) WO97/11988 PCT~S96/15104 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 WO 97/11988 PCT~US96/15104 the scope of the present invention as defined in the appended claims.

~ t3

Claims (8)

1. A flexible container system having a flexible container made of an elastomeric material formed into a shape having side walls and a hollow interior volume and a drug formulation containing benzalkonium chloride characterized in that a layer of parylene is coated on an inside surface of the side walls to prevent adsorption of benzalkonium chloride on the side walls in order to maintain benzalkonium chloride concentration in the drug formulation during storage, the parylene being selected from the group consisting of parylene C, parylene N, parylene D and mixtures thereof.

2. The flexible container according to claim 1 wherein the elastomeric material comprises a block copolymer rubber.

3. The flexible container according to claim 2 wherein the elastomeric material is selected from the group consisting of KRATONR, plasticized PVC, SILASTICR, C-Flex and LDPE.

4. The flexible container according to claim 2 wherein the side walls have a thickness of between about 0.25 mm and about 10 mm.

5. The flexible container according to claim 3 wherein the parylene layer has a thickness of between about 0.1 um and 5.0 um.

6. A pliable bottle dispensing system having a flexible container made of elastomeric material formed into a shape having side walls and a hollow interior volume and a drug formulation containing benzalkonium chloride and a tip, in fluid communication with the interior chamber, for dispensing the drug formulation upon squeezing of the side walls characterized in that the side walls of elastomeric material are permeable to the drug formulation, a layer, of sufficient thickness, of parylene is coated on an inside surface of the side walls to prevent adsorption of benzalkonium chloride on the side walls in order to maintain benzalkonium chloride concentration in the drug formulation during storage, and a layer, of sufficient thickness, of parylene coated on an outside surface of the side walls to provide a flexible barrier to passage of the drug formulation through the side walls, the parylene being selected from the group consisting of parylene C, parylene N, parylene D and mixtures thereof.

7. The flexible container according to claim 12 wherein the side walls have a thickness of between about 0.25 mm and about 10 mm.

8. The flexible container according to claim 13 wherein the parylene layers have a thickness of between about 0.1 um and about 5.0 um.