Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-01-28
2001-05-29
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S514000
Reexamination Certificate
active
06239124
ABSTRACT:
This invention relates to certain novel pharmaceutical compositions comprising a rapamycin, e.g., 40-O-(2-hydroxyethyl)-rapamycin, and an IL-2 transcription inhibitor, in particular FK-506 or cyclosporin A, and to synergistic combinations of an IL-2 transcription inhibitor and 40-O-(2-hydroxyethyl)-rapamycin.
40-O-(2-hydroxyethyl)-rapamycin has the following structure:
This compound is further described in WO 94/09010, example 8. 40-O-(2-hydroxyethyl)-rapamycin is a semisynthetic derivative of rapamycin. The structure of rapamycin is given in Kesseler, H., et al.; 1993
; Helv. Chim. Acta
; 76: 117, and numerous immunosuppressive derivatives and analogues of rap amycin are known. Rapamycin is an immunosuppressant, but although it was first discovered over twenty years ago, it has yet to reach the market. Rapamycin is difficult to formulate, being poorly soluble and having poor oral bioavailability. The 40-O-(2-hydroxyethyl) derivative of rapamycin has improved formulation and pharmacokinetic properties. However, both rapamycin and 40-O-(2-hydroxyethyl)-rapamycin exhibit side effects on in vivo administration at higher dosages.
Cyclosporin A (also known as Ciclosporin or Cyclosporine) is an immunosuppressive, cyclic undecapeptide. Its structure is disclosed, e.g., in The Merck Index, 11th Edition; Merck & Co., Inc.; Rahway, N.J., USA (1989) under listing 2759. Formulations of cyclosporin A are available commercially under the trademark SANDIMMUN or SANDIMMUNE, and a microemulsion preconcentrate formulation of cyclosporin A is sold under the trademark NEORAL or OPTORAL. Cyclosporin A is widely used as an immunosuppressant, e.g., in the prevention and treatment of graft rejection following organ transplant and of graft versus host disease, e.g., following bone marrow transplant. At higher dosages, however, it may affect kidney and liver function. Moreover, cyclosporin A is difficult to formulate, as it is essentially insoluble in most pharmaceutically acceptable solvents, e.g. aqueous pharmaceutical systems, and its oral bioavailability in most formulations is variable. Finally, although cyclosporin A is highly effective in preventing and treating acute rejection episodes in transplant patients and hence contributes to long-term graft survival, chronic rejection, manifest as arteriostenosis due to vascular smooth muscle proliferation in the graft (graft-vessel disease), remains a serious problem for some patients after transplantation, for example heart transplant recipients. Cyclosporin A, which inhibits primarily T-cells, is also not particularly effective to prevent antibody-mediated rejection as is seen following xenotransplantation.
FK506 is a macrolide immunosuppressant produceable by
Streptomyces tsukubaensis
No 9993. The structure of FK506 is given in the appendix to the Merck Index, supra, as item A5. FK506 is also used as an immunosuppressant. Although it is structurally very different from cyclosporin A, it has a similar mechanism of action, i.e., inhibition of T-cells via cytokine suppression, in particular IL-2 suppression. It is somewhat more potent than cyclosporin A, but also more toxic, and is also difficult to formulate, having low solubility and variable bioavailability and metabolism.
Immunosuppressive compounds whose immunosuppressive activity derives principally or in significant part from their direct or indirect inhibition of IL-2 gene transcription (e.g., corticosteroids, ascomycins, and cyclosporins; in particular cyclosporin A, FK506, and their various immunosuppressive derivatives and analogues; especially compounds which are at at least as active as cyclosporin A in an IL-2 reporter gene assay) are hereinafter referred to as “IL-2 transcription inhibitors”.
It is now surprisingly discovered that IL-2 transcription inhibitors and 40-O-(2-hydroxyethyl)-rapamycin, in particular cyclosporin A and 40-O-(2-hydroxyethyl)-rapamycin, act synergistically, so that effective immunosuppression is seen upon co-administration at dosages which would be well below the effective dosages individually. Moreover, this synergistic combination is useful to treat, e.g. ameliorate, or prevent not only acute rejection, but also chronic rejection and xenograft rejection. Co-administration of the two compounds in synergistically effective amounts allows for significantly lower dosages of each compound in immunosuppression, thereby reducing the side effects, and by preventing chronic rejection and xenograft rejection, enhances the pharmaceutical utility of the treatment.
Synergy is calculated as described in Berenbaum, Clin. Exp. Immunol. (1977) 28:1, using an interaction term to correct for differences in mechanism between the two drugs, as described in Chou, et al. Transpl. Proc. (1994) 26: 3043. The index of synergy is calculated as
Dose
of
A
A
E
+
Dose
of
B
B
E
+
(
Dose
A
)
×
(
Dose
B
)
A
E
×
B
E
in which the doses of the compounds A and B represent those used in a particular combination, and A
E
and B
E
are the individual doses of A and B respectively giving the same effect. If the result is less than 1, there is synergy; if the result is 1, the effect is additive; if the result is greater than 1, A and B are antagonistic. As described below, cyclosporin A and 40-O-(2-hydroxyethyl)-rapamycin show an index of synergy of from about 0.3 to about 0.7 in vivo, and about 0.8 in vitro. By plotting an isobologram of dose of A/A
E
vs. dose of B/B
E
, the combination of maximum synergy can be determined. The synergistic ratio expressed in terms of the ratio by weight of the two compositions at synergistic amounts along this isobologram, especially at or near the point of maximum synergy, can then be used to determine formulations containing an optimally synergistic ratio of the two compounds.
Remarkably, IL-2 transcription inhibitors and 40-O-(2-hydroxethyl)-rapamycin exhibit synergy at two levels. At a mechanistic level e.g., as seen in in-vitro results, the intrinsic immunosuppressive activity of the two compounds is synergistically enhanced on co-administration. Moreover, at a pharmacokinetic level, the observed blood levels of both compounds on co-administration are significantly improved over blood levels achieved by administration of either compound individually and correspondingly, the observed in vivo synergy is greater even than would be predicted based on the in vitro results. The mechanistic synergy in combination with the pharmacokinetic interaction synergy is extremely surprising, and indeed, this combination of drugs is believed to be the first reported wherein significant synergy exists at both the mechanistic level and the pharmacokinetic level. The practical effect of this from the patient's perspective is that both drugs are more effective, at lower dosages, with fewer side effects, and improved bioavailability. Surprisingly, it is feasible that the drugs can be formulated into a fixed combination, which greatly enhances the convenience for the patient.
The indications for which this combination is of interest include in particular autoimmune and inflammatory conditions and conditions associated with or causal to transplant rejection, e.g., treatment (including amelioration, reduction, elimination or cure of etiology or symptoms) or prevention (including substantial or complete restriction, prophylaxis or avoidance) of the following:
a) Acute organ or tissue transplant rejection, e.g. treatment of recipients of e.g. heart, lung, combined heart-lung, liver, kidney, pancreatic, skin, bowel, or corneal transplants, especially prevention and/or treatment of T-cell mediated rejection, as well as graft-versus-host disease, such as following bone marrow transplantation.
b) Chronic rejection of a transplanted organ, in particular, prevention of graft vessel disease, e.g., characterized by stenosis of the arteries of the graft as a result of intima thickening due to smooth muscle cell proliferation and associated effects.
c) Xenograft rejection, includ
Haeberlin Barbara
Meinzer Armin
Schuurman Hendrik
Zenke Gerhard
Furman Diane E.
Lopez Gabriel
Novartis AG
Weddington Kevin E.
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