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WO1998031370A1 - Produit pharmaceutique en solution pret a l'emploi et systeme de fermeture - Google Patents

Produit pharmaceutique en solution pret a l'emploi et systeme de fermeture Download PDF

Info

Publication number
WO1998031370A1
WO1998031370A1 PCT/US1997/017115 US9717115W WO9831370A1 WO 1998031370 A1 WO1998031370 A1 WO 1998031370A1 US 9717115 W US9717115 W US 9717115W WO 9831370 A1 WO9831370 A1 WO 9831370A1
Authority
WO
WIPO (PCT)
Prior art keywords
solution
acyclovir
ready
plastic container
drug product
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1997/017115
Other languages
English (en)
Inventor
Glenn F. Wickes, Jr.
Tak-Yee Lee
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Meridian Medical Technologies Inc
Original Assignee
Meridian Medical Technologies Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Meridian Medical Technologies Inc filed Critical Meridian Medical Technologies Inc
Priority to AU44984/97A priority Critical patent/AU4498497A/en
Publication of WO1998031370A1 publication Critical patent/WO1998031370A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • B65D23/08—Coverings or external coatings
    • 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
    • B65D51/00—Closures not otherwise provided for
    • B65D51/002—Closures to be pierced by an extracting-device for the contents and fixed on the container by separate retaining means
    • 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
    • B65D51/00—Closures not otherwise provided for
    • B65D51/005—Closures provided with linings or internal coatings so as to avoid contact of the closure with the contents

Definitions

  • This invention is in the field of parenteral drug delivery systems and specifically relates to container closure systems which contain ready-to-use solutions of high pH for medical use.
  • a ready to use liquid injectable solution is preferred for its convenience over the lyophilized injectable that requires reconstitution with appropriate diluents before use.
  • the present invention particularly relates to the problems associated with maintaining Acyclovir (I) stable in a closure system.
  • Acyclovir (I) is an antiviral compound used to treat viral infections, particularly Herpes.
  • Acyclovir is available as oral dosage form as well as injectable dosage form.
  • the currently marketed injectable dosage form is only available as a freeze-dried sterile powder in a glass vial and must be made into solution form prior to administration.
  • injectable acyclovir has heretofore not been available as a ready to use injectable solution in a container primarily because of two challenges. The first challenge is that acyclovir liquid solution must maintain a high pH to provide adequate solubility for clinical use.
  • a decrease in pH of the solution results in the undesirable precipitation of acyclovir free acid.
  • a decrease in pH may be caused by, but not limited to, potential gas permeation to or from the solution container, such as permeation of carbon dioxide from the environment into a plastic container, and leachables from the container or closure, such as acidic leachables from an elastomer closure.
  • the second challenge is that a high pH solution in a glass vial is physically unstable due to potential glass delamination.
  • an alternative container closure system is required.
  • gas permeation especially carbon dioxide as described above, will potentially affect the pH of the drug solution.
  • the present invention provides a ready-to-use solution drug product and closure system comprising a plastic container formed from an amorphous, colorless, and substantially transparent polyolefin resin having no polar functional groups in its molecular structure, a liquid solution acyclovir having a pH of at least 9 disposed within the plastic container, and a closure for closing the plastic container.
  • This method comprises filling a plastic container formed from an amorphous, colorless and substantially transparent thermoplastic polyolefin resin having no polar functional groups in its molecular structure with liquid solution acyclovir having a pH of at least about 9; sealing the plastic container with an elastic member so as to sealingly store the liquid solution acyclovir within the plastic container; piercing the elastic member with a needle and withdrawing an amount of said liquid solution acyclovir from the container through the needle; and injecting directly the withdrawn liquid solution acyclovir into a patient in its stored form without alteration thereto.
  • the container of the invention is made from a thermoplastic high molecular weight polyolefin resin containing only carbon and hydrogen and having no polar functional groups.
  • the polymer is amorphous, colorless and transparent, exhibits high heat resistance and excellent low temperature properties and is compatible with drugs or other materials having pH values of 9-12.
  • the resin advantageously has a phase transition that withstands 121 °C, which is an industry standard as being the minimum temperature for sterilization.
  • the plastic container of the invention is environmentally friendly and readily disposable by incineration with virtually no residual ash remaining.
  • the containers are preferably made from CZ resin, available from Daikyo Seiko Ltd.
  • the plastic containers made from the polyolefin resin can be any desired or required shape for solution drug products and can be formed by blow molding or other known molding techniques.
  • the container generally is a vial or bottle having an open end and a closed end.
  • the closure or stopper for inserting into the open end of the vial or bottle comprises an elastic, preferably rubber composition coated in the drug contact area with a suitable non-reactive resin which significantly reduces stopper-drug interaction and maintains effective sealability.
  • suitable resins that can be used include the fluoro-resins, polytetrafluoroethylene (teflon), and continuous poly (p-xylylene) which is also known as polyparaxylylene.
  • the laminated rubber closure or stopper comprises a head portion and a leg portion which is to be inserted in the open end of the container wherein at least a leg portion is laminated with a non-reactive resin such as a fluoro-resin.
  • a non-reactive resin such as a fluoro-resin.
  • a suitable fluoro-resin laminate that can be used is Fluorotec from Daikyo Seiko Ltd. Methods and materials of forming a resin-laminated rubber closure for a medical vial are disclosed in U.S.
  • the body of the stopper can be made from synthetic or natural rubber such as butyl rubber, isoprene rubber, butadiene rubber, hal ⁇ genated butyl rubber, silicone rubber and the like.
  • the stopper is constructed and arranged to be pierced by a hypodermic needle, for example on a syringe, to enable an amount of stored liquid drug product within the container to be withdrawn and administered to a patient.
  • the invention is directed to a container and closure system for liquid drug products having a pH of at least 9, generally 10-12.
  • the present invention relates to the problems associated with storing Acyclovir (I) in an injectable liquid solution form.
  • Acyclovir (I) has the formula
  • the plastic container and closure system described herein is compatible with a high pH solution from both physical and chemical stability aspects.
  • the plastic container and closure minimizes the effects of the environment on the pH of the drug product.
  • potential pharmaceutical buffer systems that can assist the drug product to maintain a stable pH can be used.
  • the preferred plastic container and closure of the invention consists of a clear plastic vial made of CZ resin and a fluoro-resin laminated rubber closure.
  • the laminated rubber closure minimizes the potential leachables from the rubber that can affect the pH of the drug solution.
  • the plastic container can be wrapped with an aluminum foil backed plastic label, for example, MYLAR, or other suitable gas impermeable barrier, to prevent potential carbon dioxide ingress through the plastic container wall which adversely affects the pH of acyclovir sodium solution within the vial and consequently causes precipitation of the drug.
  • the injectable acyclovir liquid solution of the present invention has a pH of at least 9 and can be non-buffered or buffered with any suitable buffer that maintains the required pH of the drug product during storage and transport.
  • suitable buffer systems that can be used include phosphate and glycine buffer solutions.
  • the phosphate buffer solution used was prepared from tribasic sodium phosphate (Na 3 PO 4 ) at concentrations ranging from 0.05 to 0.2 M and the glycine buffer was made from glycine and sodium hydroxide with varying glycine concentrations.
  • a non-buffered acyclovir sodium solution is acceptable as a ready to use formulation having an acceptable storage shelf-life.
  • Figure 1 is a schematic partially cutaway view of a polyolefin resin, plastic container and laminated rubber closure containing a high pH liquid drug product.
  • Figure 2 is a schematic view of a plastic container filled with a liquid drug product and sealed within a flexible wrapping to protect the drug product from environmental gases.
  • Figure 3 is a graph illustrating an acid-base titration curves of both 0.3 M and 0.5M of glycine buffer.
  • Figure 4 is a graph illustrating an acid-base titration curve of tribasic sodium phosphate buffer .
  • a plastic container or vial filled with a liquid drug product 11 The plastic container is an elongate bottle having an enclosed end 12 ( Figure 2) and an open end 13. A laminated rubber closure or stopper 14 is positioned in sealing engagement in the open end 13 of the plastic container 10.
  • the wall 15 of plastic container 10 is comprised of a high molecular weight polyolefin thermoplastic resin containing only carbon and hydrogen and having no polar functional groups and a phase transition temperature of at least about 121°C.
  • the plastic has high heat resistance and excellent low temperature properties and is compatible with liquid drug products having pH values of 9-12.
  • the plastic material of the container 10 is CZ resin.
  • Top portion 16 at the open end 13 of plastic container 10 includes annular shoulders or lips 17 and 18 protruding and extending outwardly for engagement with an annular metal ring 19 which holds laminated rubber stopper 14 in sealing engagement with open end 13.
  • Laminated stopper 14 comprises a head portion 21 and a leg portion 22.
  • the body of the stopper comprising the head portion and leg portion can be made of any conventional rubber material.
  • the rubber material can contain suitable additives to maintain and improve the physical properties and heat resistance of the rubber material.
  • the stopper 14 comprises a rubber composition covered in the drug contact area with a thin coating layer 23 of suitable non-reactive resin which reduces stopper-drug interaction.
  • Layer 23 comprises any suitable resin that is non-reactive with high pH liquid products contained within plastic bottle 10.
  • the non-reactive resin coating can be applied to the leg portion 22 of stopper 14 in any suitable manner such as by applying a liquid coating solution of the resin or by applying a film of the resin to leg portion 22 of the stopper 14.
  • the thickness of layer 23 can range from 0.002 to 0.5 mm.
  • Presently preferred resins that are non- reactive with high pH liquid drug products include fluoro-resins being the most preferred.
  • Use of polytetrafluoroethylene (Teflon) and polyparaxylylene as a laminate are also contemplated by the present invention.
  • Plastic bottle 10 is closed at its open end 13 with laminated rubber stopper 14 which is fastened and held in place in sealing engagement by annular metal ring 19 that surrounds protruding shoulders or lips 17 and 18.
  • the lower end 24 of metal ring 19 is inclined inwardly beneath shoulder 18 so that stopper 14 is held securely within the open end 13 of plastic bottle 10.
  • Metal ring 19 can be made of any lightweight metal but aluminum is presently preferred.
  • Metal ring 19 in a plan view is donut-shaped having an axial circular opening on the top above stopper 14 to provide access to the liquid drug product within the plastic bottle by piercing the rubber stopper 14 with a needle, e.g., on a syringe.
  • the circumference or outer edge of the circular opening in member 19 is provided with breakaway tabs 25 extending upwardly from the top of member 19 and integral therewith and terminating with a collar 26 of the same metal surrounding a flange 27 extending downwardly and outwardly from the underside of a flip-off plastic cap 28.
  • the flip-off plastic cap 28 can be readily removed from the assembled plastic container by lifting upwardly to break tabs 25 and then discarded. The removal of plastic cap 28 uncovers the top metal ring 19 which provides access through a circular opening to the interior of the plastic container 10 by inserting a needle (not shown) through the exposed portion of the top of rubber stopper 14.
  • plastic bottle 10 which is sealed and filled with liquid drug product is stored within a flexible pouch or bag 29.
  • the bag is sealed after plastic container 10 and contents are placed in the bag.
  • the bag can be a thin gage plastic film or aluminum foil. It is preferred to use a flexible bag that is substantially impermeable to atmospheric gases, particularly CO 2 .
  • Plastic bag 29 is provided with a label 30 on the exterior of the bag.
  • the exterior of plastic container 10 is wrapped with an aluminum foil backed Mylar label 31.
  • Label 31 is secured to the exterior of bottle 10 by bonding with a suitable adhesive 32.
  • Example 1 Acyclovir Sodium in Water for Injection, 25 mg/mL
  • Acyclovir sodium was dissolved in Water for Injection, USP, at a concentration of 25 mg/mL. The solution was filled into a CZ resin vial and stoppered with a fluoro-resin laminated elastomer closure. These vials were packaged in the following setups (Table 1):
  • the CZ resin is subject to gas permeation.
  • the carbon dioxide appeared to permeate through the vial to the solution which caused the decrease of pH values as observed in conjunction with the precipitation of acyclovir. Protection of vials against carbon dioxide permeation is required.
  • the ambient environment produced similar stability as the argon environment which indicates that the permeation of carbon dioxide through the CZ resin vial at ambient condition is not as severe as the one observed when under the pure carbon dioxide environment.
  • Example 2 Acyclovir Sodium (25, 50, and 100 mg/mL) in Water for Injection, USP The feasibility and stability of acyclovir sodium in water for injection at different concentration was evaluated. Solutions of each concentration were filtered and filled in a CZ resin vial and stoppered with the Fluorotec stopper as described in Example 1. These samples were labeled with aluminum foil backed Mylar label and placed at 25°, 40°, 50°, and 55°C incubator for a three month period. At each month time interval, the sample was retrieved and analyzed for acyclovir content by HPLC, degradation product analysis by
  • acyclovir degrades to an acidic species that can decrease the pH of the solution and consequently may force the precipitation of acyclovir it may be advantageous to use a buffered system that can minimize this phenomenon.
  • Various pharmaceutical acceptable buffer systems that are suitable for a pH between 10.5-12.5 were evaluated, specifically, the glycine and phosphate buffer systems. Based on the acid-base titration of both 0.3M and
  • the Buffered solution improved the pH of the acyclovir solution when compared with a non- buffered solution as described in Example 1. 2.
  • the buffered solution exhibits a satisfactory stability, bom physical and chemical, for acyclovir sodium ready to use solution.
  • Example 4 Acyclovir Sodium (25 and 50 mg/mL) in Tribasic Phosphate Buffered Solution(0.05M, 0.1M, and 0.2M)

Landscapes

  • Health & Medical Sciences (AREA)
  • Mechanical Engineering (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)

Abstract

L'invention a trait à un produit pharmaceutique en solution prêt à l'emploi ainsi qu'à son système de fermeture. Il s'agit d'un récipient en plastique fabriqué à partir d'une résine de polyoléfine, amorphe, incolore et sensiblement transparente. La structure moléculaire de cette résine est dépourvue de groupes polaires fonctionnels. La solution liquide d'acyclovir, possédant un pH d'au moins 9, est, quant à elle, contenue dans le récipient en plastique, lequel récipient possède un système de fermeture.
PCT/US1997/017115 1997-01-22 1997-09-26 Produit pharmaceutique en solution pret a l'emploi et systeme de fermeture Ceased WO1998031370A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU44984/97A AU4498497A (en) 1997-01-22 1997-09-26 Ready-to-use solution drug product and closure system

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US78739297A 1997-01-22 1997-01-22
US08/787,392 1997-01-22

Publications (1)

Publication Number Publication Date
WO1998031370A1 true WO1998031370A1 (fr) 1998-07-23

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/017115 Ceased WO1998031370A1 (fr) 1997-01-22 1997-09-26 Produit pharmaceutique en solution pret a l'emploi et systeme de fermeture

Country Status (2)

Country Link
AU (1) AU4498497A (fr)
WO (1) WO1998031370A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1380511A1 (fr) * 2002-07-08 2004-01-14 Gianfilippo Pagliacci Bouteille en plastique stérilisable à chaud
EP4458723A4 (fr) * 2021-12-28 2025-11-05 Dainippon Printing Co Ltd Récipient contenant un liquide, récipient combiné contenant un liquide, récipient, bouchon et procédé de fabrication de récipient contenant un liquide

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5288560A (en) * 1991-01-30 1994-02-22 Daikyo Gomu Seiko, Ltd. Laminated sanitary rubber article
US5344036A (en) * 1992-06-04 1994-09-06 Akzo N.V. Container system
JPH07157610A (ja) * 1993-12-09 1995-06-20 Daikyo Seiko:Kk ポリスルホン系樹脂組成物及びそれよりなる医療用，医薬品用器具

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5288560A (en) * 1991-01-30 1994-02-22 Daikyo Gomu Seiko, Ltd. Laminated sanitary rubber article
US5344036A (en) * 1992-06-04 1994-09-06 Akzo N.V. Container system
JPH07157610A (ja) * 1993-12-09 1995-06-20 Daikyo Seiko:Kk ポリスルホン系樹脂組成物及びそれよりなる医療用，医薬品用器具

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
NATURE, 13 April 1978, Volume 272, SCHAEFFER et al., "9-(2-Hydroxyethoxymethyl)Guanine Activity Against Viruses of the Herpes Group", pages 583-85. *
WINDHOLTZ et al., Merck Index, RAHWAY, NJ: MERCK SHARP & DOHM., 1984, Abstract 140. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1380511A1 (fr) * 2002-07-08 2004-01-14 Gianfilippo Pagliacci Bouteille en plastique stérilisable à chaud
WO2004005144A1 (fr) * 2002-07-08 2004-01-15 Iniziative Generali '96 S.P.A. Bouteille de plastique thermosterilisable
EP4458723A4 (fr) * 2021-12-28 2025-11-05 Dainippon Printing Co Ltd Récipient contenant un liquide, récipient combiné contenant un liquide, récipient, bouchon et procédé de fabrication de récipient contenant un liquide

Also Published As

Publication number Publication date
AU4498497A (en) 1998-08-07

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