WO1998031370A1

WO1998031370A1 - Ready-to-use solution drug product and closure system

Info

Publication number: WO1998031370A1
Application number: PCT/US1997/017115
Authority: WO
Inventors: Glenn F. Wickes, Jr.; Tak-Yee Lee
Original assignee: Meridian Medical Technologies Inc
Current assignee: Meridian Medical Technologies Inc
Priority date: 1997-01-22
Filing date: 1997-09-26
Publication date: 1998-07-23
Anticipated expiration: 1999-07-22
Also published as: AU4498497A

Abstract

A ready-to-use solution drug product and closure system comprises 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.

Description

READY-TO-USE SOLUTION DRUG PRODUCT AND CLOSURE SYSTEM

Field of the Invention

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.

Background of the Invention

A ready to use liquid injectable solution is preferred for its convenience over the lyophilized injectable that requires reconstitution with appropriate diluents before use.

However, issues with drug product stability and/or a suitable container closure system are usually the factors that prohibit the development of a ready to use liquid injectable solution.

Development of a ready-to-use liquid injectable solution for a drug requiring a high pH due to solubility is problematic because current glass containers delaminate when exposed to high pH . Consequently, this problem with glass containers prohibits the availability of ready to use solution injectables. Of particular interest and need is a non-glass container closure system, which is suitable for pharmaceutical use, and is stable against delamination and ensures the stability of a ready-to-use injectable drug product having a pH of 9 or greater. Typical plastics are problematic for use in a container in that they are subject to gas permeation to and from the container. In addition, typical rubber stoppers for containers are problematic in that they may become unstable and thereby contaminate solutions having a pH of 9 or greater.

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. However, 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. Any decrease in the 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. In order to prevent this physical instability, an alternative container closure system is required. With a non-glass container, such as conventional plastics, gas permeation, especially carbon dioxide as described above, will potentially affect the pH of the drug solution.

It is an object of the present invention to overcome the problems noted above. Accordingly, 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.

It is a further object of the present invention to provide a simple method of method of storing and administering liquid solution acyclovir, without the need for a user to first form a acyclovir liquid solution from its freeze dried form . 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.

Other objects, aspects as well as the several advantages of the invention, will be apparent upon studying the specification, drawings and the appended claims.

Detailed Description of the Preferred Embodiments

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.

Also, 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. Generally, 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 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.

4,915,243 and U.S. 5,288,560 which are incorporated herein by reference.

The body of the stopper can be made from synthetic or natural rubber such as butyl rubber, isoprene rubber, butadiene rubber, halόgenated 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. Particularly, the present invention relates to the problems associated with storing Acyclovir (I) in an injectable liquid solution form. Acyclovir (I) has the formula

Acyclovir (I)

In this invention, the plastic container and closure system described herein is compatible with a high pH solution from both physical and chemical stability aspects. In addition, the plastic container and closure minimizes the effects of the environment on the pH of the drug product. Furthermore, potential pharmaceutical buffer systems that can assist the drug product to maintain a stable pH can be used.

As noted above, 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. In the examples, the phosphate buffer solution used was prepared from tribasic sodium phosphate (Na₃ PO₄) 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. As demonstrated in the examples, a non-buffered acyclovir sodium solution is acceptable as a ready to use formulation having an acceptable storage shelf-life.

Description of the Drawings

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 .

Referring to Figure 1, there is shown at 10 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. In the preferred embodiment of the present invention, 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.

Referring now to Figure 2, 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 CO₂.

In one embodiment of Figure 2, it is preferred to inject an inert gas into the space between the interior of bag 29 and exterior of plastic bottle 10

Plastic bag 29 is provided with a label 30 on the exterior of the bag. Similarly, referring to Figure 1, 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.

The following examples are given in order to illustrate the present invention in detail without limiting the same.

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):

Table 1 : Experimental Design to Evaluate the Feasibility and Stability of a Ready to

Use Solution for Acyclovir Sodium in Water or Injection.

For each study, vials were placed at 40° and 55°C storage condition for up to three (3) month except the units stored under CO₂ environment which were only placed at 40°C. Samples were taken at 1, 2, and 3 month intervals and analyzed for acyclovir and its degradation products by high performance liquid chromatography (HPLC). The pH of the samples was also determined. The results are summarized in Table 2. Table 2: Summary of Three (3) Month Stability of 25 mg/mL Acyclovir Sodium in

Water for Injection

Based on the results obtained, the following is concluded:

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.

2. 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.

3. Degradation of acyclovir sodium was observed as a function of temperature and time. In conjunction with the loss of acyclovir, the pH of the solution decreased which may have caused the precipitation of acyclovir. Even though the three (3) month data on 40° and

55°C suggests that the pH decrease may not be an issue when the product is stored at 25°C; however, a buffer system that can inhibit the change of pH should benefit the shelf- life of acyclovir sodium solution.

4. No physical instability, including paniculate matter and precipitation, was observed for vials packaged in ambient or argon environment. It appears that use of the CZ resin vial has corrected the glass delamination due to high pH of the solution.

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

HPLC, and pH determination in addition to visual inspection. The results of these studies are summarized in Table 3.

Table 3: Stability of Acyclovir Sodium in Water for Injection, USP

Table 3: Stability of Acyclovir Sodium in Water for Injection, USP (Cont.)

Example 3: Acyclovir Sodium in 0.1 N Tribasic Sodium Phosphate (Na₃PO ) Solution

Since 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

0.5M of glycine buffer (see Figure 3) and tribasic sodium phosphate buffer (see Figure 4), both buffer should provide adequate buffer capacity for acyclovir sodium solution. As the titration curves indicated, tribasic sodium phosphate buffer system has a better buffering effect. A study similar to that described above in Example 1 was conducted using a 0.1 M tribasic sodium phosphate buffer. The formulation is listed below:

Ingredient Amount per mL

Acyclovir Sodium 25.0 mg Tribasic Sodium Phosphate, USP 38.0 mg Water for Injection, USP q.s. ad. 1.0 mL Sodium Hydroxide, NF pH Adjustment

The results of the three (3) month stability when stored at 40° and 55°C are summarized in Table 4.

Table 4: Summary of the Stability -of 25 mg/mL Acyclovir Sodium in 0.1N Tribasic Sodium Phosphate Solution

Based on these results, it is concluded:

1. 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.

3. The label used appears to inhibit the C0₂ permeation as indicated by the stress test involving C0₂ environment.

Example 4: Acyclovir Sodium (25 and 50 mg/mL) in Tribasic Phosphate Buffered Solution(0.05M, 0.1M, and 0.2M)

To further investigate the effect of any buffer effect on the stability of acyclovir sodium solution, the concentration of acyclovir sodium as well as tribasic sodium phosphate was varied. All these solutions were filtered and filled in CZ Resin vial and stoppered with 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 HPLC, and pH determination in addition to visual inspection. The results of these studies are summarized in Table 5.

Table 5: Stability of Acyclovir Sodium in Tribasic Sodium Phosphate Solution

Table 5 (continued)

Table 5 (continued)

It thus will be seen that the objects of this invention have been fully an defectively accomplished. It will be realized, however, that the foregoing preferred specific embodiments have been shown and described for the purpose of this application and is subject to change without departure from such principles. Therefore, this invention includes all modifications encompassed within the spirit and scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. 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; liquid solution acyclovir having a pH of at least 9 disposed within the plastic container; and a closure for closing said plastic container.

2. A ready-to-use solution drug product and closure system according to claim 1, wherein said closure comprises a rubber stopper constructed and arranged to be inserted in an open end of the plastic container, wherein at least a portion of said stopper which is to contact said liquid solution acyclovir is laminated with a non-reactive resin to reduce stopper-drug product interaction.

3. A ready-to-use solution drug product and closure system according to claim 2, wherein said polyolefin resin comprises CZ resin.

4. A ready-to-use solution drug product and closure system according to claim 3, wherein said non-reactive resin comprises a fluororesin.

5. A ready-to-use solution drug product and closure system according to claim 4, further comprising a flexible wrapping surrounding the plastic container to reduce or prevent permeation of CO and other environmental gases into a space between the wrapping and an exterior of the plastic container.

6. A ready-to-use solution drug product and closure system according to claim 5, further comprising a charge of inert gas filling the space between the wrapping and the exterior of the plastic container.

7. A ready-to-use solution drug product and closure system according to claim 5 wherein the wrapping is an aluminum foil bag.

8. A ready-to-use solution drug product and closure system according to claim 1 wherein the liquid solution acyclovir contained within the plastic container further comprises a buffer system to maintain a pH of at least 10 and to extend shelf-life.

9. A ready-to-use solution drug product and closure system according to claim 8 wherein the buffer system comprises a phosphate or glycine buffer.

10. A ready-to-use solution drug product and closure system according to claim 1 wherein the liquid solution acyclovir is a non-buffered acyclovir sodium solution.

11. A ready-to-use solution drug product and closure system according to claim 1 wherein the liquid solution acyclovir is a buffered acyclovir sodium solution.

12. A ready-to-use solution drug product and closure system according to claim 11 wherein the acyclovir sodium solution is buffered with a tribasic sodium phosphate or glycine buffer system.

13. A ready-to-use solution drug product and closure system according to claim 5 wherein the liquid solution acyclovir is a non-buffered acyclovir sodium solution and the flexible wrapping is aluminum foil.

14. A ready-to-use solution drug product and closure system according to claim 13 wherein the space between the aluminum foil and the exterior of the plastic container is filled with a charge of inert gas to minimize permeation of CO₂ and other environmental gases into said space.

15. A ready-to-use liquid drug product and closure system according to claim 1 wherein said liquid solution acyclovir is an aqueous solution of acyclovir sodium.

16. A ready-to-use liquid drug product and closure system according to claim 15 wherein the aqueous solution of acyclovir sodium contains a pH stabilizing amount of a buffer solution to maintain a pH of 10 to 12.

17. A ready-to-use liquid drug product and closure system according to claim 16 wherein the buffer solution is a glycine or tribasic sodium phosphate solution.

18. A ready-to-use liquid solution and closure system according to claim 1, wherein said resin material of said plastic container has phase transition that withstands 121°C.

19. A ready-to-use liquid solution and closure system according to claim 1, further comprising a label formed at least in part by aluminum foil adhered to said plastic container for inhibiting or preventing permeation of atmospheric gasses into said container.

20. A method of storing and administering liquid solution acyclovir comprising 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 said container through said needle; and injecting directly the withdrawn liquid solution acyclovir into a patient in its stored form without alteration thereto.

21. A method according to claim 20 further comprising: wrapping the plastic container with an amount of film sufficient to surround the plastic container to provide an enclosure that minimizes permeation of environmental gases into a space between the film and an exterior of the plastic container, and providing an inert gas into the space between the film and exterior of the plastic container to reduce or prevent permeation of CO , and other gases into said space.