Method for filling a container with a foamable composition

Abstract

The present invention relates to a process for preparation of a composition comprising gas microbubbles. More particularly the invention relates to a process for filling of such composition into a container. The composition prepared is preferably an ultrasound contrast media composition made available in a container wherein the headspace of the container comprises the same gas as the gas of the microbubbles.

Claims

1. A process for preparing a container filled with a liquid ultrasound contrast medium composition comprising gas microbubbles in a liquid carrier, the process comprising the sequential steps of (a) purging air from a container by filling the container with a halogenated headspace gas, wherein the halogenated headspace gas is added to the container at a rate of 200 to 800 cc/minute through a needle positioned proximate the bottom of the container at the start of the filling; and (b) filling the liquid composition into the container after step (a), wherein the filled container comprises a headspace and 40-100% of the headspace volume comprises the headspace gas.

2. The process of claim 1, wherein the headspace gas used in step a) is the same gas as the gas of the micro bubbles.

3. The process of claim 1, wherein the headspace gas is a biocompatible gas being heavier than air.

4. The process of claim 1, wherein the microbubbles comprise a polymeric stabilizing material.

5. The process of claim 4, wherein the polymeric stabilizing material of the micro bubbles is a protein-based material.

6. The process of claim 1, further comprising a step of closing the container.

7. The process of claim 1, wherein the filled container comprises a headspace and at least 60% of the headspace volume comprises the headspace gas.

8. The process of claim 1, wherein the purging continues while the needle is withdrawn from the container.

9. The process of claim 1, wherein the halogenated headspace gas is added to the container at a rate of 400 to 600 cc/minute.

10. The process of claim 1, wherein the halogenated headspace gas is added to the container at a rate of about 500 cc/minute.

11. The process of claim 1, wherein the halogenated headspace gas lays on top of the liquid composition after step (b).

12. The process of claim 11, wherein the container is closed within 5 seconds after purging air from the container.

13. The process of claim 1, wherein the container is closed within 10 seconds after purging air from the container.

14. The process of claim 1, wherein the container is closed within 5 seconds after purging air from the container.

15. The process of claim 1, wherein the halogenated headspace gas is added through a needle positioned proximate the bottom of the container at the start of the filling.

16. The process of claim 1, further comprising closing the container after step b) without a post-fill purge of halogenated headspace gas.

17. The process of claim 1, wherein the halogenated headspace gas is perflutren.

18. A process for preparing a container filled with a liquid ultrasound contrast medium composition comprising gas microbubbles in a liquid carrier, the process comprising the sequential steps of (a) purging air from a container by filling the container with a halogenated headspace gas; and (b) filling the liquid composition into the container after step (a), followed by closing the container without a post-fill purge of halogenated headspace gas; wherein the filled container comprises a headspace and 40-100% of the headspace volume comprises the headspace gas.

19. The process of claim 18, wherein the halogenated headspace gas is perflutren.

20. The process of claim 18, wherein the purging continues while the needle is withdrawn from the container.

Description

EXAMPLES

Example 1

(1) Comparison Example—Filling of Optison™ into Containers using Post-Purging of Air

(2) A Groninger Filling Machine was used to aseptically dispense, stopper, cap and crimp Optison™ filled vials.

(3) The Optison solution was pumped from a bulk container by means of a peristaltic pump and dispensed into 500 vials of 3 ml. The pump speed was set at 140 rpm and the pump acceleration at 100%. The vials were then purged of air by flowing perfluoropropane gas (OFP) into and under a tunnel at a flow rate of 300 cc/minute. The Groninger Filling Machine then inserted stoppers, caps and crimps on the caps.

(4) During testing of perfluoropropane headspace on a production lot, 90 samples were tested and of these 3 failed the headspace criteria of at least 60% headspace. The three failing samples were taken towards the end of the run. To verify the test results, repeats and additional laboratory testing was performed. These tests involved re-testing the 3 failing headspace samples and several passing samples. Based on the test results, both passing and failing samples were identical to the original test. Using this process the mean content of perfluoropropane headspace obtained was 65%.

(5) During the filling of the Optison composition into the vials large bubbles were observed in the vials. During a step of post purging, the gas inside the large bubble was not replaced with perfluoropropane. During storage the large bubbles popped and the gas of these mixed with the headspace gas. As the gas inside the large bubble is air, the total perfluoropropane gas content in the head space was reduced as a result. The vials including large bubbles were tested for perfluorpropane headspace content after the bubbles had popped. All of the vials which included large air bubbles failed the perfluoropropane headspace specification, and values were as low as 40% perfluoropropane in headspace.

Example 2

(6) Filling of Optison™ into Containers using the Claimed Process with Pre-Purging of Air

(7) A Groninger Filling Machine was used to aseptically dispense, stopper, cap and crimp Optison™ filled vials.

(8) Investigational studies, referred to in Example 1, indicated that the use of a post fill purge was not optimizing the perfluoropropane head space content. It was however determined that a pre-fill perfluoropropane purge of the empty vial, prior to filling, at a purge rate of 500 cc/minutes improved the perfluoropropane head space content considerable.

(9) 500 vials of 3 ml were purged of air by flowing perfluorpropane gas into and around the empty vials at a flow rate of 500 cc/minute. The Optison solution was then pumped from a bulk container by means of a peristaltic pump and dispensed into the vials. The pump speed was set at 100 rpm and the pump acceleration at 50%. The Groninger Filling Machine then inserted stoppers, caps and crimps on the caps.

(10) Of the 500 vials 90 vials were pulled out for headspace analysis during the process, and inspected for any big bubbles being generated.

(11) To provide for this pre fill purge process the product filling needle was moved down one position to where the post fill perfluoropropane purge needle had previously been located. The purging needle was lowered to the bottom of the vials during purging. This positioning of the pre-fill purge needle and the product fill needle further optimized the perfluoropropane head space.

(12) Using this pre-purge process the mean content of perfluoropropane headspace obtained was 75%. Hence this has been demonstrated to be improved from a mean of 65% to 75% by pre-purging the empty vial with 500 cc/minutes of perfluoropropane gas in lieu of post fill purging the dispensed vial at 300 cc/minutes. All vials fulfilled the headspace criteria of at least 60% headspace. Further, the Perfluoropropane headspace was found to have less variation and the standard deviation was reduced from 7.4 to 1.9.

(13) It was important that the purging needle was lowered to the bottom of the vials during purging to be able to flush out the air. If the needle was only lowered to the top of the neck of the vial the perfluoropropane would mix with the gas in the vial and not flush out the air. Using this process any large bubble generated during filling would contain perfluoropropane instead of air, and would not reduce the perfluoropropane headspace content.

(14) A process capability calculation was performed using 6 Sigma limits on the data from filled vials and it was concluded that the filling process was stable and no vials should fail using the recommended pre-purge parameters.