Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector
Reexamination Certificate
2001-02-28
2003-07-15
Park, Hankyel T. (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
C424S236100, C424S204100, C424S464000, C435S005000
Reexamination Certificate
active
06592869
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a stable compacted, compressed or tableted vaccine composition having a dense solid form, comprising one or more freeze dried (lyophilized) antigenic components and a dissolution aid. This stable dense vaccine composition retains all of the advantageous properties of the lyophilized components thereof, including titer stability and solubility while further providing complete and rapid dissolution in a diluent. Moreover, the vaccine composition of the present invention avoids the disadvantages of prior known lyophilized preparations. A method for immunizing a subject using the stable vaccine composition to form a vaccine solution is also provided.
BACKGROUND OF THE INVENTION
It is well-known, that biological materials in solutions such as vaccines are susceptible to varying influences including heat, oxidizing reagents, salts, pH, light, and proteolitic enzymes.
Several methods are known for reducing these detrimental effects in general and more specifically to improve the stability of a vaccine especially during storage. For example, storage below 0° C., and as low as −70° C., in a freezer is a well-known method. At even lower temperatures, e.g. in liquid nitrogen, many biological materials including living cells can successfully be stored for many years. However, such methods are not always convenient in those situations, for example, that involve the innoculation of free-ranging livestock.
Lyophilizing or freeze drying is another known way of conserving live cells and viruses for use as vaccines. During freeze drying, the solution containing the biological material is first frozen and the water is then evaporated by sublimation, usually under high vacuum and sub-zero temperatures. Previous approaches have used freeze drying or other techniques to formulate viral vaccines but still pose other difficulties with respect to preparation and administration of a stable final dosage form.
For example, U.S. Pat. No. 4,251,509 (Hanson and Abegunde) discloses a stable particulate viral vaccine intended to be orally administered to free ranging livestock in a dry state. However, the disclosed dosage form is not freeze dried but prepared by concentrating and extruding a paste dried to form pellets.
Antioxidants, the selection of which will depend on the particular virus, are required to promote thermostability. Such a formulation may be more complicated to prepare and is not particularly well-suited for those instances when it is desired to dissolve the vaccine before immunization.
U.S. Pat. Nos. 3,458,621 and 3,608,030 (Tint) disclose the use of freeze dried virus preparations to prepare a tablet for oral administration for the immunization of the intestinal tract. However, the tablets prepared are for oral administration and are provided with an enteric coating to delay disintegration. During in-vitro testing they did not rapidly disintegrate and were found to disintegrate only “within 25 minutes” with simulated intestinal fluid. Moreover, the time to disintegrate was measured in simulated intestinal fluid thereby discounting effects of the enteric coating. In addition, Tint further emphasizes that unless the tablets are “press coated” they will lose their titer as shown by a comparison between press coated and non-press coated tablets. Tint notes that the non-press coated tablets “not only failed to elicit an antibody response in all the antibody-negative individuals, but, in addition, the magnitude of the titer rise was significantly smaller.” (See column 4, line 40).
PCT Publication No. WO 99/21579 (Seager, et al.) assigned to the R. P. Scherer Corp. discloses a “fast” dispersing composition for a veterinary vaccine such as against New Castle disease that is freeze dried and “loosely compacted.” The dosage form is disclosed as an “open matrix network”, such as a “solid foam” referenced from U.S. Pat. No. 4,371,516 (counterpart to UK Patent No. 1,548,022), as opposed to a compressed form or hard tableting. Moreover, the vaccines are directed to oral administration and targeted towards retention at mucosal tissue. Adjuvants serve to provide sufficient residence time for absorption thereon. The disclosed vaccine formulation does not provide for preparation of a liquid dosage for later immunizing, nor a means to readily form a stable, measured vaccine solution for administration as a liquid dose, nor for providing a stable compressed or hard tableted lyophilisate to facilitate later administration thereof.
U.S. Pat. No. 5,587,180 (Allen, Jr. et al) describes a process for making a particulate support matrix for a rapidly dissolving tablet. The process teaches away from freeze drying and uses standard spray-drying techniques. The particulate support matrix is suitable for dosage administration when placed into the oral cavity. Moreover, no stable vaccine formulation is provided as a vaccine solution in a liquid dosage form.
U.S. Pat. No. 5,336,666 (Neway et al.) discloses a freeze dried liquid vaccine that may form a tablet to be reconstituted in liquid form. However, the vaccine is limited to a polar glycopeptide of a particular bacterium and does not provide for complete or rapid dissolution.
Although freeze drying of biological material can be performed according to lyophilizing procedures well known to one skilled in the art to provide a stable vaccine preparation, the titer of a live virus at the end of lyophilization is typically not the same as it was for the solution before the lyophilization process. In general it is not possible to conduct titration before lyophilization as the solution is not stable until it is freeze dried. In addition, the titer will change unpredictably during lyophilization. Consequently, an estimate for the initial titer based on experience is only validated by titration after freeze drying. As a result of all of the above, it is almost impossible to achieve a defined accurate target titer.
If lyophilization has been carried out with the lyophilisate already contained in vials, reworking of the batch is typically not possible, and in some cases a whole batch must be discarded if it is not up to specification.
U.S. Pat. No. 5,897,852 (Wilderbeek, et al.) attempts to solve such a problem using different “freeze dried bodies” with “lyospheres” to make up for shortfalls in the titer of a lyophilized cake. However, each lyosphere has its own titer thereby necessitating the titration of multiple bodies to arrive at a desired titer. Even in the best case, this method does not achieve the exact required titer as it is only an approximation due to the use of combined bodies to achieve the target titer. Furthermore, the production of lyospheres is relatively difficult compared with the more straightforward freeze drying of solutions to produce a cake or powder. Additionally, a special matrix is often required to prevent the lyosphere material from being pulverized after drying. In general, the method requires the preparation of separate solutions each having a different titer, additives and adjuvants. The method does not solve the problem that the titer for a batch of live virus is rarely homogenous, and varies from one vial to the next, particularly over the areas of the cold plates in the lyophiliser. Therefore, determination of the number of lyospheres needed per vial is always an approximation.
Freeze drying may also be useful for vaccines comprising more than one immunogenic component. For example, EP 290197A discloses a freeze dried tetravalent vaccine. The procedure discloses the mixing and subsequent freeze drying of four live virus vaccine components.
A disadvantage to current freeze drying techniques for vaccine preparation is that the process is very complex, having many variables, rendering it notoriously difficult to perform in a reproducible manner to achieve acceptable product and dosage uniformity. This is especially problematic for veterinary vaccines where a large number of doses are freeze dried in one vial. The problem is less common for human vaccine preparation, although equally ap
Frydman Norbert
Gallili Gilad
Brown Stacy S.
Cooper & Dunham LLP
Park Hankyel T.
Teva Pharmaceutical Industries Ltd.
White John P.
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