Drug – bio-affecting and body treating compositions – Designated organic nonactive ingredient containing other... – Solid synthetic organic polymer
Reexamination Certificate
1999-07-20
2001-07-17
Krass, Frederick (Department: 1646)
Drug, bio-affecting and body treating compositions
Designated organic nonactive ingredient containing other...
Solid synthetic organic polymer
C424S422000, C424S423000, C424S426000, C424S486000, C424S499000, C424S501000, C514S002600, C514S008100, C514S012200, C514S772100, C514S825000, C514S885000, C514S903000, C514S953000, C514S964000, C528S370000, C528S371000, C528S393000, C528S405000
Reexamination Certificate
active
06262127
ABSTRACT:
This invention relates to pharmaceutical compositions comprising polymeric matrices, especially those containing IL-6 for use in treating diseases mediated by IL-1 and/or TNF&agr;, e.g., chronic inflammatory conditions. The specific polymers of the invention, especially the poly(ethylene carbonate) polymers described herein, however, are shown to be more generally useful as matrix materials in sustained release compositions containing pharmacologically active compounds, and in particular to have the novel, unexpected, and highly desirable property of undergoing nonhydrolytic surface erosion in vivo. Therefore, matrices comprising other drugs are also exemplified and provided, together with processes for preparing the polymers and to pharmaceutical compositions containing them. Moreover, the use of IL-6 to treat conditions mediated by IL-1 and/or TNF&agr; is novel and unexpected (many such conditions were previously believed to be exacerbated by IL-6), thus the invention further provides a new use for IL-6 in the treatment of, e.g, chronic pathogen-induced inflammatory conditions, demyelinating diseases, and acute and hyperacute inflammatory conditions such as septic shock.
I. Treatment of Diseases Mediated by IL-1 and/or TNF&agr;
Many spontaneously occurring, chronic inflammatory conditions have an unknown, (possibly autoimmune) etiology and are believed to be mediated by IL-1 and/or TNF&agr;. For example, multiple sclerosis (MS), a crippling nerve disorder characterized by disseminated patches of demyelination in the brain and spinal cord, has occupied the attention of research organizations for many years. Although the precise etiology of multiple sclerosis is not fully understood, it is believed to have a strong autoimmune component, as indicated, e.g., by the increased incidence of certain HLA antigens in patients having the disease. Currently available anti-inflammatory drugs such as ACTH (adrenocorticotropic hormone) or corticosteroids, e.g., prednisone, appear to hasten recovery in acute attacks, especially when administered early in the episode, but do not affect the underlying etiology of the disease. Long term administration of corticosteroids or immunosuppressants carries risks of serious side effects. A recombinant form of IFN-&bgr;
I
was recently shown to reduce short term plaque formation, but has not been shown to affect the long term progression of the disease. Evaluation of treatment efficacy is complicated by the fact that the natural progression of the disease is one of spontaneous remission and chronic relapse. In short, despite many years of intensive research, there is so far no generally accepted specific therapy for this very serious disease.
Other chronic inflammatory conditions are believed to be induced by external agents, e.g., pathogens. For example, Lyme disease is a serious chronic condition initiated by infection with the tick-born spirochete
Borrelia burgdorferi
. Following an initial acute phase characterized by skin lesions and flu-like symptoms, the disease progresses to a chronic phase which may be characterized by arthritis and chronic neurologic abnormalities. The disease is usually treated with antibiotics and nonsteroidal anti-inflammatory agents, but an optimal therapy, particularly for the established disease, is not yet established.
Acute or hyperacute, uncontrolled inflammatory conditions may also be caused by external agents, e.g., severe burns or severe infections. For example, septic shock, and in particular adult respiratory distress syndrome (ARDS), is a life threatening condition for which no effective treatment exists at present. Onset is rapid, and mortality generally exceeds 50%. Septic shock usually results from severe bacterial infection and is typically characterized by fever often followed by hypothermia in the later stages, fluctuating blood pressure (hyperdynamic syndrome) followed by hypotension in the later stages, metabolic acidosis, impaired mental functioning, and widespread organ dysfunction, ultimately, in many cases, ending in death. Most commonly, septic shock results from gram-negative bacterial infection (endotoxic shock), but it may also result from gram-positive bacterial infections or other infections. The term “septic shock” as used herein is thus to be interpreted broadly to mean a shock state, including ARDS, resulting from a microbial infection, especially a bacterial infection, most especially a gram-negative bacterial infection.
IL-6 is a known cytokine. It is known to be useful in the treatment of various conditions, e.g., thrombocytopenia and certain cancers. It is produced by the body usually in response to bacterial infections and has been implicated in the mediation of inflammation, fever, and septic shock. It is a potent immunostimulant and indeed some literature suggests that IL-6 driven mechanisms cause certain autoimmune or inflammatory diseases, including systemic lupus erythematosis, multiple sclerosis, and rheumatoid arthritis, as well as septic shock.
It is thus very surprising to discover that IL-6 is useful in the treatment of chronic inflammatory diseases (other than glomerulonephritis), e.g., multiple sclerosis, and in the treatment of acute and hyperacute inflammatory conditions, e.g., septic shock. The mechanism of this action is unclear, but without intending to be bound by any particular theory, we believe that, through a feedback mechanism, IL-6 can suppress or inhibit the expression, release or function of other cytokines, particularly TNF&agr; and/or IL-I, possibly by upregulating the release of soluble TNF&agr; receptor and/or IL-I receptor antagonist, thereby suppressing the activity and resulting autoimmune, inflammatory, or shock conditions that are principally mediated by these cytokines. In the case of conditions characterized by IL-6 mediated complement-activating antigen-antibody (IgG) complexes, particularly glomerulonephritis (which is usually caused by aggregation of such complexes in the kidney), however, IL-6 is shown to exacerbate the condition. Thus, we have shown that IL-6 is curative in animal models for MS and Lyme arthritis, for example, which are believed to be driven primarily by IL-I and/or TNF&agr;, but exacerbates the glomerulonephritis in lupus mice, which is believed to be directly driven by IL-6. We have also shown that IL-6 is curative by itself in mouse models of endotoxic shock, which is likewise hypothesized to be driven principally by IL-I and/or TNF&agr;.
IL-6 is therefore considered to be useful as an agent for suppressing or inhibiting the expression, release or function of TNF&agr; and/or IL-I, and especially in the treatment of inflammatory conditions other than glomerulonephritis, and in the treatment of septic shock. Inflammatory conditions which may be treated using IL-6 include, for example, arthritic conditions, particularly pathogen-induced arthritic conditions, for example, Lyme disease arthritis, bacterially induced arthritis, and polioarthritis; multiple sclerosis and other demyelinating diseases (i.e., diseases characterized by demyelination in the nerves, brain, and/or spinal cord, including, e.g., multiple sclerosis, acute disseminated encephalomyelitis or postinfectuous encephalitis, optic neuromyelitis, tinnitus, diffuse cerebral sclerosis, Schilder's disease, adrenoleukodystrophy, tertiary Lyme disease, tropical spastic parapoesis, and other diseases wherein demyelination, especially autoimmune-mediated demyelination, is a major symptom); acute severe inflammatory conditions such as burns, septic shock, meningitis, and pneumonia; and autoimmune diseases including polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, psoriatic arthritis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (including e.g. ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves disease, sarcoidosis, primary billiary cirrhosis, juvenile diabetes (diabetes mellitus type I), uveitis (anterior and posterior), keratocon
Acemoglu Murat
Bantle Siegfried
Bodmer David
Cammisuli Salvatore
Hiestand Peter
Krass Frederick
Lopez Gabriel
Novartis AG
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