Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1998-12-09
2001-09-04
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S450000
Reexamination Certificate
active
06284277
ABSTRACT:
This application is a 371 of PCT/FR 96/01706 filed Oct. 30, 1996.
The present invention relates to a pharmaceutical formulation provided in the form of a freeze-dried product and containing at least one active ingredient of nonprotein nature. More particularly, the invention relates to such a formulation, stable at temperatures which may be as high as 25° C. to 40° C., which may be either reconstituted in liquid form by addition of a solvent for its administration via the parenteral or oral route, or directly administered via the oral route, to man or to animals.
The active ingredient contained in the formulation according to the invention may be alone or else combined with another active ingredient of protein or nonprotein nature.
It is known that freeze-drying may have a considerable effect on the degradation of the pharmaceutical active ingredients in a formulation, as well as a strong impact on their stability in freeze-dried form. The various variables which affect these parameters are mainly the pH, the quantity of salts present, the type and quantity of excipients in the formulation, the type of cryoprotection chosen, as well as the temperatures, pressure and time chosen for the freezing, sublimation and drying operations. These different variables influence the physical state of the freeze-dried product obtained, namely: vitreous amorphous, soft amorphous, crystalline or a combination of these states.
For the preservation of the freeze-dried products, amino acids, preferably glycine, and polyols, preferably mannitol, are often used; but the literature, which is highly abundant on the subject, gives no information on the solution to the general problem of obtaining a stable pharmaceutical formulation which takes into account the different parameters involved in the operations for formulating and freeze-drying a nonprotein active ingredient in combination with an amino acid and a polyol.
More particularly, the literature teaches that the presence of an amino acid, of a polyol, for example mannitol, of a crystalline phase or of an amorphous phase may have, besides certain advantages, disadvantages which lead, in the case of freeze-dried products containing particularly sensitive active ingredients, to relatively short shelf lives and/or storage temperatures for these freeze-dried products which are less than 8° C. It would, however, be particularly advantageous, especially for an ambulatory treatment, to be able to obtain a formulation which is stable at room temperature until it is reconstituted and to thereby avoid its storage in a refrigerator before or during treatment.
The role of the polyol and of amino acid has been studied separately in the case of the human growth hormone (hGH), but their synergistic effect is still poorly elucidated (Pikal M. J., Dellermann K. M., Roy M. L., Riggin M. N., The effects of formulation variables on the stability of freeze-dried Human Growth Hormone, Pharm. research., 1991, 8, No. 4, 427-436).
The advantages and disadvantages linked to the presence of amino acids, of mannitol, of a crystalline phase or of an amorphous phase are listed below.
Advantages linked to the presence of amino acids.
It has been demonstrated that the presence of glycine in a freeze-dried product induced crystallization of the molecules present in solution during the freezing stage of the freeze-drying (Korey D. J., Schwartz J. B., Effects of excipients on the cristallization of pharmaceutical compounds during lyophylization, J. Parenteral Sci. Tech., 1989, 43, 2, 80-83). This crystallization of the active ingredient makes it possible to enhance its stability.
Alanine, in crystallized form, has the advantage of preventing the collapse of the freeze-dried product during sublimation and drying and or allowing the production of a freeze-dried product with a greater specific surface area and therefore allows a more rapid drying (Pikal M. J., Freeze-drying of proteins, Biopharm., 26-30 October 1990).
Disadvantages linked to the presence of amino acids.
The addition of an amino acid to a sugar or to a polyol in a solution to be freeze-dried generally has the effect of decreasing the glass transition temperature of the sugar (te Booy M. P. W. M., de Ruiter R. A., de Meere A. L. J., Evaluation of the physical stability of freeze-dried sucrose containing formulations by differential scanning calorimetry, Pharm. Research., 1992, 9, 109-114). Now, a decrease in the glass transition temperature is generally synonymous with a lower stability of a freeze-dried product (Franks F., Freeze-drying; from empiricism to predictability, Cryo-letters, 1990, 11, 93-110).
Advantages linked to the presence of mannitol.
The presence of mannitol in the composition of a freeze-dried product is generally justified as freeze-drying ballast, that is to say that it makes it possible both to maintain the solid and rigid structure of the volume of the freeze-dried product corresponding to the volume of solution to be freeze-dried, but its presence also makes it possible to adjust the isotonicity of the reconstituted solution to be injected. When mannitol is the predominant excipient in the composition of a freeze-dried product, it is most often in crystalline form (Lyophilized formulations recombinant tumor necrosis factor, Hora M. S., Rana R. K., Smith F. W., Pharm. Res., 1992, 9 (1), 33-36).
Disadvantages linked to the presence of mannitol.
It has been reported that the degree of hydrolysis of methylprednisolone sodium succinate, in freeze-dried form, was greater in the presence of mannitol than in the presence of lactose, and that this level increased with the quantity of mannitol present in the freeze-dried product. This has been explained by the fact that the crystallization of mannitol during freeze-drying changes the distribution of water in the matrix of the freeze-dried product. The increase in the quantity of water present in the microenvironment of the active ingredient resulting therefrom enhances the hydrolysis of the active ingredient and reduces its stability (The effect of bulking agent on the solid state stability of freeze dried methylprednisolone sodium succinate, Herman B. D., Sinclair B. D., Milton N., Nail S. L., Pharma. Res., 1994, 11 (10), 1467-1473).
Advantages linked to the presence of a crystalline phase.
The presence of a crystallized solute in a frozen solution is a means of stabilizing the proteins during drying (Carpenter J. F. & Crowe J. H., Modes of stabilization of a protein by organic solutes during dessiccation, Cryobiology, 1988, 25, 459-470). Furthermore, the crystallization, during freezing, of the predominant excipients present in a solution to be freeze-dried makes the secondary sublimation and drying operations more effective by increasing the specific surface area for exchange between the atmosphere in the freeze-drying vessel and the solid to be sublimed. This increase in the specific surface area of the crystalline forms compared with the amorphous forms facilitates heat exchanges during freeze-drying. The consequence of this increased efficiency in the freeze-drying is the production of freeze-dried forms whose residual water content is lower, which means an increased stability of the freeze-dried product at higher temperatures (Korey D. J., Schwartz. J. B., Effects of excipients on the cristallization of pharmaceutical compounds during lyophylization, J. Parenteral Sci. Tech., 1989, 43, 2, 80-83).
Disadvantages linked to the presence of a crystalline phase.
In general, the crystallized substances have less rapid dissolution rates than the amorphous substances. Indeed, more energy is required to detach a molecule from an organized lattice of a crystalline arrangement than to detach it from a disorganized assembly of an amorphous state. Sometimes, the dissolution rate becomes insufficient to allow a sufficiently rapid absorption of these substances, which may lead to a decrease in their activity, especially in the case of molecules which are not very stable in solution. Likewise, the perfect regularity of crystals being an ideal case, the heterogenei
Bouloumie Colette
Breul Thierry
Colliere Laurence
Faure Philippe
Alexander Michael D.
Dupont Paul E.
Joynes R.
Page Thurman K.
Sanofi-Synthelabo
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