Drug – bio-affecting and body treating compositions – Lymphokine – Interferon
Reexamination Certificate
1997-05-09
2002-03-26
Eyler, Yvonne (Department: 1646)
Drug, bio-affecting and body treating compositions
Lymphokine
Interferon
C424S085100, C424S085500, C424S085600, C424S085700, C514S002600
Reexamination Certificate
active
06361769
ABSTRACT:
This invention relates to methods of stimulation of host defense mechanisms against pathological conditions in a host mammal by administration of interferon via the oromucosa. In particular, the invention is applicable to methods of treatment of autoimmune, mycobacterial, neurodegenerative, parasitic, and viral diseases.
BACKGROUND OF THE INVENTION
Interferon-&agr; (IFN-&agr;) is used widely for the treatment of a variety of disorders including leukemia, lymphoma, AIDS-related Kaposi's sarcoma, and hepatitis. (Gutterman, J. U.,
Proc. Natl. Acad Sci. USA
, 1994 91: 1198-1205). Interferon-&bgr; (IFN-&bgr;) is licensed for clinical use in treatment of relapsing-remitting multiple sclerosis and of chronic infection with Hepatitis B virus. Interferon-&agr; and Interferon-&bgr; are both type I interferons. Although a number of routes of administration, including intravenous, subcutaneous, intramuscular, topical, and intralesional injection, are commonly employed for the administration of type I interferons, the oral route has not been generally used, because interferons are proteins which are considered to be inactivated by proteolytic enzymes and which are not absorbed appreciably in their native form in the gastrointestinal tract. Indeed a number of studies have failed to detect interferons in the blood following oral administration (Cantell and Pyhäla,
J Gen. Virol
., 1973 20: 97-104; Wills et al,
J IFN Res
., 1984 4: 399-409; Gilson et al,
J IFN Res
., 1985 5: 403-408).
It has been shown that inducers of interferon are able to protect mice against experimental infection with
Plasmodium berghei
malaria, and that this protection is much more effective against sporozoite-induced infection than against infection induced by blood forms of the parasite (Jahiel et al,
Science
, 1986 16: 1802
; Nature
, 1968 220: 710; Amer.
J. Trop. Med Hyg
., 1969 18: 823). Mice injected intraperitoneally or intravenously with interferon in pooled serum of Newcastle disease virus-infected mice were protected against sporozoite-induced
Plasmodium berghei
malaria. However, interferon from rabbit serum was ineffective. Protection was obtained when the interferon was injected during the pre-erythrocytic phase of parasite development (i.e. three hours before or up to about 40 hours after sporozoite inoculation [Jahiel et al,
Nature
1970 227: 1350-1351]).
There have been a number of anecdotal reports of efficacy of low doses of interferon administered as a nasal spray or as an oral liquid formulation in the treatment of a variety of viral conditions, particularly influenza. However, in most of these reports the interferon preparations used were relatively crude. Placebo-controlled trials of high dose intranasal interferon for treatment of rhinovirus infection showed that the treatment was effective, but that there was a significant incidence of side-effects (Hayden et al,
J Infect. Dis
., 1983 148: 914-921; Douglas et al,
New Engl. J. Med
., 1986 314: 65-80; Hayden et al;
New Engl. J. Med
., 1986 314: 71-75).
More recently a series of patent specifications has described the use of low doses of orally administered interferon of heterologous species origin for the treatment of infectious rhinotracheitis (“shipping fever”) in cattle, and of feline leukemia, and also treatment of other conditions, for enhancement of efficiency of vaccines; for improving the efficiency of food utilization; and for prevention of bovine theileriosis. See U.S. Pat. No. 4,462,985, Australian Patent No. 608519, Australian Patent No. 583332 and U.S. Pat. No. 5,215,741 respectively. In these specifications, the interferon used was human interferon &agr; prepared by the method of Cantell, administered in phosphate buffered saline, at a dose of 0.01 to 5 IU per pound body weight. While these specifications suggest that such low doses of interferon administered to the oropharyngeal mucosa, preferably in a form adapted for prolonged contact with the oral mucosa, may be efficacious for treatment of a wide variety of conditions, the experimental evidence for conditions other than shipping fever, feline leukemia, canine parvovirus and theileriosis is largely anecdotal.
More recent studies on the effects of very low doses of interferon administered by the oral or oropharyngeal mucosa have been reviewed (Bocci,
Clin. Pharmacokinet
., 1991 21: 411-417
; Critic. Rev. Therap. Drug Carrier Systems
, 1992 9: 91-133; Cummins and Georgiades,
Archivum Immun. Therap. Exp
., 1993 41: 169-172). It has been proposed that this type of treatment is particularly useful for treatment of HIV infection, and can at least improve quality of life in AIDS patients (Kaiser et al,
AIDS
, 1992 6: 563-569; Koech et al,
Mol. Biol. Ther
., 1990 2: 91-95). However, other reports indicate that such treatments provide no clinical benefit. A Phase I study of use of oral lozenges containing low doses of interferon for treatment of hepatitis B has also been reported (Zielinska et al,
Archiv. Immunol Therap. Exp
., 1993 41: 241-252).
SUMMARY OF THE INVENTION
This invention provides a method for stimulating host defense mechanisms in a mammal via the oromucosal administration of an interferon. In one aspect, the invention may be considered as a method of stimulating the immune response in a mammal by administering to the mammal an immunostimulating amount of an interferon via oromucosal contact.
This invention provides a method for treating autoimmune, mycobacterial, neurodegenerative, parasitic, and viral diseases in a mammal via administering to the mammal a therapeutically effective amount of an interferon via oromucosal contact. The amount of interferon administered is less than an amount which induces a pathological response when administered parenterally. This invention provides a method for treating autoimmune diseases such as arthritis, diabetes, lupus, and multiple sclerosis, mycobacterial diseases such as leprosy and tuberculosis, neurodegenerative disorders such as encephalitis and Creutzfeldt-Jakob syndrome, parasitic diseases such as malaria, and viral diseases such as cervical cancer, genital herpes, hepatitis B and C, HIV, HPV, and HSV-1 and 2.
The oromucosal administration may involve administering an effective dose of interferon in a single dose or the effective dose may be administered in a plurality of smaller doses over a period of time sufficient to elicit host defense stimulation equivalent to that of a single dose. Likewise, the effective dose of interferon may be administered continuously over a period of time sufficient to elicit host defense stimulation equivalent to that of a single dose.
The method may be practiced by administering from about 1500 IU, preferably from about 5000 IU, to about 20×10
6
IU of interferon per day, more preferably from about 1×10
4
IU to about 20×10
6
IU of interferon per day, most preferably from about 1×10
4
to about 1×10
6
IU of interferon per day, provided that the chosen dose does not induce a pathological response when administered parenterally, or is less than a dose which would induce a pathological response when administered parenterally. These dose ranges generally refer to homologous interferon a in man. A physician treating a patient with a particular interferon will be able to readily identify the suitable therapeutic dose range according to the invention.
In another embodiment, the invention provides a pharmaceutical composition for oromucosal administration comprising a therapeutically effective amount of at least one interferon. The composition may be provided as a solution, tablet, lozenge, gel, syrup, paste, or controlled release oromucosal delivery system. Optionally, the composition may contain buffers, stabilizers, thickening agents, absorption, and viscosity enhancers, and the like.
In one embodiment, the pharmaceutical composition is provided in unit dosage form having from about 1500 IU, preferably from about 5000 IU, to about 20×10
6
IU of interferon, more preferably from about 1×10
4
IU to about 20×10
6
IU of in
Andres J. L.
Browdy and Neimark PLLC
Eyler Yvonne
Pharma Pacific Pty Ltd
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