WO1997011988A1 - Flexible container or bottle with barrier coating - Google Patents
Flexible container or bottle with barrier coating Download PDFInfo
- Publication number
- WO1997011988A1 WO1997011988A1 PCT/US1996/015104 US9615104W WO9711988A1 WO 1997011988 A1 WO1997011988 A1 WO 1997011988A1 US 9615104 W US9615104 W US 9615104W WO 9711988 A1 WO9711988 A1 WO 9711988A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- parylene
- bak
- drug formulation
- flexible container
- side walls
- Prior art date
Links
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D23/00—Details of bottles or jars not otherwise provided for
- B65D23/02—Linings or internal coatings
Definitions
- 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.
- 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.
- container materials are particularly important for 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.
- polymers suit ⁇ able for the construction of flexible containers, such as polyethylene, KRATON, C-Flex, SARLINK, and the like are not suitable due to the absorption or permeation of drug formulations therethrough, such as, for example, but not limited to Liquifilm*, Prefrin*, Betagan ® or preservatives such as BAK.
- 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.
- a flexible container 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 containing 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 a drug 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 formulation 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 effective in preventing passage of the drug formulation therethrough.
- 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 0.00002 inch (0.5 ⁇ m) and about 0.0003 inch
- Figure 1 is a cross-sectional view of a pliable bottle dispensing system utilizing the present invention
- 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
- Figure 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 parylene-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
- Figure 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 for 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;
- Figure 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- coated pouches at 25°C
- Figure 17 shows pH values for the thick parylene- coated pouches at 25°C.
- FIG. 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 formulation.
- 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 will 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 pouch 12 through a poach neck 24 to a full liquid level 26 from a pouch end 28.
- a coating 30 on inside surface 32 of container 12 has a thickness effective in establishing a flexible barrier to the passage of the formulation into and through the elastomeric pouch 12.
- the pouch 12 may include a coating 34 disposed on an outside surface 36 of the pouch, as hereinafter discussed in greater detail.
- the elastomeric material which may be employed in accordance with the present invention includes those elastomers known in the art, such as block copolymer rubbers, which are suitable for forming flexible 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.
- /-'-blockers e.g., Levobunolol, ti olol, betaxolol
- ⁇ -agonists e.g., brimonidine
- prostaglandins e.g., Latanoprost
- ketorolac dipivalyl
- epinedphrine epinedphrine
- flurbiprofen 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 parylene coated on the inside surface 38 thereof.
- parylene N parylene N
- parylene C parylene D
- mixtures thereof 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 aromatic 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.
- 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 IO "5 torr or below.
- the parylenes are formed at about 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 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 of 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.
- the parylene layer prefer ⁇ ably should have a thickness between about 0.1 ⁇ m and
- Liquifilm* and Prefrin* were formulated with a BAK concentration of 100 ppm.
- Betagan ® was formulated without BAK.
- the formulations were filled by Pharmaceutical Sciences Operations into flexible pouches manufactured from various polymers including: ALCRYN, C-FLEX, plasticized PVC, SARLINK, KRATON, and KRATON-A
- 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.
- 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 formulations. PPVC and SARLINK appear to contain an extractable in their formulation that migrated into the products tested.
- KRATON-Thick pouches (having a thickness of about 0.5 to about 1.5 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 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 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 from 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.
- BAK benzalkonium chloride
- Weight loss at two months/40'C is 3% w/w in the
- 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) .
Landscapes
- Engineering & Computer Science (AREA)
- Mechanical Engineering (AREA)
- Medical Preparation Storing Or Oral Administration Devices (AREA)
- Laminated Bodies (AREA)
- Packages (AREA)
- Bag Frames (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP09513510A JP2000510419A (en) | 1995-09-29 | 1996-09-23 | Flexible container or bottle-type container with barrier coating |
AU70771/96A AU7077196A (en) | 1995-09-29 | 1996-09-23 | Flexible container or bottle with barrier coating |
EP96931658A EP0852597A1 (en) | 1995-09-29 | 1996-09-23 | Flexible container or bottle with barrier coating |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US53620295A | 1995-09-29 | 1995-09-29 | |
US08/536,202 | 1995-09-29 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1997011988A1 true WO1997011988A1 (en) | 1997-04-03 |
WO1997011988B1 WO1997011988B1 (en) | 2001-04-05 |
Family
ID=24137571
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1996/015104 WO1997011988A1 (en) | 1995-09-29 | 1996-09-23 | Flexible container or bottle with barrier coating |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0852597A1 (en) |
JP (1) | JP2000510419A (en) |
AU (1) | AU7077196A (en) |
CA (1) | CA2233286A1 (en) |
WO (1) | WO1997011988A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2340759A (en) * | 1998-08-26 | 2000-03-01 | Bespak Plc | Drug delivery device |
EP2561774A3 (en) * | 2011-05-02 | 2015-06-10 | Beiersdorf AG | Containers for cosmetic and dermatological products |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP4698020B2 (en) * | 2000-12-19 | 2011-06-08 | テルモ株式会社 | Drug storage container |
JP5226031B2 (en) * | 2010-04-13 | 2013-07-03 | テルモ株式会社 | Drug container |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1988008012A1 (en) * | 1987-04-13 | 1988-10-20 | Pharma-Gummi Wimmer West Gmbh | Elastomeric closure piece |
EP0302457A2 (en) * | 1987-08-03 | 1989-02-08 | SYREMONT S.p.A. | Containers having a low permeability to hydrocarbon vapours, and process for producing them |
US4882210A (en) * | 1988-09-26 | 1989-11-21 | The West Company | Glass container |
EP0368103A1 (en) * | 1988-11-07 | 1990-05-16 | Pharma-Gummi Wimmer West GmbH | Method of filling and closing of containers with pharmaceutically pure contents |
US5064083A (en) * | 1990-03-08 | 1991-11-12 | The West Company, Incorporated | Closure device |
US5067491A (en) * | 1989-12-08 | 1991-11-26 | Becton, Dickinson And Company | Barrier coating on blood contacting devices |
JPH06336531A (en) * | 1993-05-27 | 1994-12-06 | Nippon Pariren Kk | Formation of poly-p-xylylene film on ionomer resin |
-
1996
- 1996-09-23 JP JP09513510A patent/JP2000510419A/en active Pending
- 1996-09-23 EP EP96931658A patent/EP0852597A1/en not_active Withdrawn
- 1996-09-23 WO PCT/US1996/015104 patent/WO1997011988A1/en not_active Application Discontinuation
- 1996-09-23 CA CA 2233286 patent/CA2233286A1/en not_active Abandoned
- 1996-09-23 AU AU70771/96A patent/AU7077196A/en not_active Abandoned
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1988008012A1 (en) * | 1987-04-13 | 1988-10-20 | Pharma-Gummi Wimmer West Gmbh | Elastomeric closure piece |
EP0302457A2 (en) * | 1987-08-03 | 1989-02-08 | SYREMONT S.p.A. | Containers having a low permeability to hydrocarbon vapours, and process for producing them |
US4882210A (en) * | 1988-09-26 | 1989-11-21 | The West Company | Glass container |
EP0368103A1 (en) * | 1988-11-07 | 1990-05-16 | Pharma-Gummi Wimmer West GmbH | Method of filling and closing of containers with pharmaceutically pure contents |
US5067491A (en) * | 1989-12-08 | 1991-11-26 | Becton, Dickinson And Company | Barrier coating on blood contacting devices |
US5064083A (en) * | 1990-03-08 | 1991-11-12 | The West Company, Incorporated | Closure device |
JPH06336531A (en) * | 1993-05-27 | 1994-12-06 | Nippon Pariren Kk | Formation of poly-p-xylylene film on ionomer resin |
Non-Patent Citations (1)
Title |
---|
DATABASE WPI Section Ch Week 9508, Derwent World Patents Index; Class A26, AN 95-057370, XP002024610 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2340759A (en) * | 1998-08-26 | 2000-03-01 | Bespak Plc | Drug delivery device |
GB2340759B (en) * | 1998-08-26 | 2003-05-07 | Bespak Plc | Improvements in drug delivery devices |
EP2561774A3 (en) * | 2011-05-02 | 2015-06-10 | Beiersdorf AG | Containers for cosmetic and dermatological products |
Also Published As
Publication number | Publication date |
---|---|
AU7077196A (en) | 1997-04-17 |
WO1997011988B1 (en) | 2001-04-05 |
EP0852597A1 (en) | 1998-07-15 |
CA2233286A1 (en) | 1997-04-03 |
JP2000510419A (en) | 2000-08-15 |
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