Drug – bio-affecting and body treating compositions – Lymphokine – Interferon
Reexamination Certificate
1999-07-21
2001-10-09
Stucker, Jeffrey (Department: 1648)
Drug, bio-affecting and body treating compositions
Lymphokine
Interferon
C424S085100, C424S085400, C435S069510
Reexamination Certificate
active
06299871
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to an orally-administrable therapeutic and/or prophylactic agent for HTLV-1 (Human T-cell Lymphotropic Virus Type 1) related diseases, and more particularly to an orally-administrable therapeutic and/or prophylactic agent for HTLV-1-related diseases, which comprises an interferon-&ggr; (abbreviated as IFN-&ggr; hereinafter) as an effective ingredient.
2. Description of the Prior Art
Adult T-cell leukemia (abbreviated as ATL hereinafter) is a T-cell leukemia with characteristic symptoms, found and reported by Cache TAKATSUKI in 1976. The disease is an intractable and district-specific disease, and in some cases it may cause a malignant lymphoma-like symptom; In Japan, there found many patients in the South and East Japan including Kyushu-, Okinawa- and Shikoku-Islands. In overseas, in the tropical regions such as the Caribbean Sea and the South India. Most of the leukemia cells induced by ATL have CD4-positive and CD8-negative helper T-cell surface antigens, and show a specific change in nuclear. It was revealed that ATL is induced by HTLV-1, a C-type retrovirus, as a causative virus thereof.
Epidemiological research revealed that HTLV-1-infected patients or HTLV-1 carriers may cause not only ATL but induce malignant tumors at a relatively-high efficiency, as well as neuropathies and immunopathies called HAM (HTLV-1-associated myelopathy). HTLV-1 is now being researched that, in addition to ATL, it correlates to another diseases. Furthermore, it is pointed out that HTLV-1 may relate to chronic rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus (SLE), uveitis, etc.
HTLV-1 infection can be easily diagnosed by detecting an HTLV-specific antibody in blood and by confirming the presence of an HTLV-1 proviral DNA. Symptoms and developments of HTLV-1-infected patients are varied, and the patients may become to show the symptoms at their age of 50th. Physiologically, there observed the downfall of myelin sheathes and the loss of axons from the upper part of cervicals through lumbars, the invasion of mononuclear cells such as lymphocytes and macrophages, the proliferation of astrogrias, and a slight level of the mononuclear cells' invasion in the part of brain stem and the substantia alba of cerebrum and cerebellum.
The percentage of the incidence of ATL induced by HTLV-1 is relatively low. However, once occurred, the symptom of the patients infected with the virus is rapidly worsened, and the treatment is quite difficult. Conventional therapies include the administration of a relatively-large amount of adrenal cortical hormone, and chemical- and radio-therapies in accordance with those for malignant tumors. They are, however, merely temporal symptomatic therapies which are far from intrinsic therapy. As another clinical-test-treatment for ATL as an HTLV-1-related disease, Kazuyuki ISHIHARA proposed in
Skin Cancer
, Vol. 12, No. 2, pp. 301-314 (1997) an intramuscular injection of IFN-&ggr;, where several millions units of IFN-&ggr; are injected to a patient daily for over eight weeks. In such a treatment, patients are forced to stay in hospitals or allowed to go to hospitals frequently, resulting in physical- and mental-pains and economical burdens. In the latter case, when patients unexpectedly could not go to hospitals on their prescribed administration dates, the medicinal administration control is not sufficiently conducted, and as a drawback, this hinders the expected therapeutic effect. Although IFN-&ggr; is per se a safer medicine which scarcely induces side effects even when administered to patients at a relatively-high dose, the above daily high-dose as much as several hundreds units of IFN-&ggr; may result in side effects such as serious depression of liver function, leukopenia, neutropenia, calcium lowering, and fervescence. In the most serious case, the administration must be ceased.
Under these backgrounds, greatly expected is the establishment of a relatively-safe medicine which can intrinsically and effectively treat and/or prevent HTLV-1-related diseases, and lower the patients' mental, physical, and economical burdens.
SUMMARY OF THE INVENTION
The present invention aims to provide a medicament with lesser side effects, which can intrinsically and effectively treat and/or prevent HTLV-1-related diseases.
The present inventors energetically researched on medicaments which can intrinsically and effectively treat and/or prevent HTLV-1-related diseases, and on the administration route. As a result, they solved the above object by establishing an orally-administrable therapeutic and/or prophylactic agent for HTLV-1-related diseases, which comprises an IFN-&ggr; as an effective ingredient. As a characteristic feature of the present invention, the oral administration of IFN-&ggr; as an effective ingredient more effectively treats and/or prevents HTLV-1-related diseases at an extremely-lower dose than another administrations.
DETAILED DESCRIPTION OF THE INVENTION
Explaining the preferred embodiments of the present invention, the IFN-&ggr;, which is incorporated as an effective ingredient into the present orally-administrable therapeutic and/or prophylactic agent for HTLV-1-related diseases, includes natural IFN-&ggr;s produced from IFN-&ggr;-producing human leukocytes and established cell lines, and recombinant IFN-&ggr;s obtained by introducing genes for encoding the above IFN-&ggr;s into animal cells or microorganisms such as the species
Escherichia coli
to transform them by the recombinant DNA technology. These IFN-&ggr;s arbitrarily used in the present invention include not only those in a highly-purified form having a specific activity of at least 1×10
7
units/mg protein but those in a crude form which contain merely pharmaceutically-acceptable impurities as long as they attain the present object. Because the present agent is orally administrable, it does not necessarily require the highest possible purity of IFN-&ggr; requisite for intramuscular- and intravenous-injections, and it can be arbitrarily prepared even with a relatively-low purity IFN-&ggr;. Using these IFN-&ggr;s, the present orally-administrable agent can be prepared at a relatively-low cost. In the present invention, two or more types of IFN-&ggr;s can be used as the IFN-&ggr;s. With a viewpoint of antigenicity, human IFN-&ggr;s, in particular, natural types of IFN-&ggr;s, can be more advantageously used.
Into the present orally-administrable agent can be arbitrarily incorporated one or more pharmaceutically-acceptable diluents, excipients, fillers, stabilizers, pH-controlling agents, biologically-active substances, etc., in addition to the IFN-&ggr; as an effective ingredient.
The stabilizers used in the present invention mean agents capable of stabilizing the IFN-&ggr;; saccharides and sugar alcohols such as glucose, galactose, xylose, fructose, sucrose, maltose, trehalose, neotrehalose, isotrehalose, sorbitol, mannitol, maltitol, lactitol, lactosucrose, maltooligo-saccharides, and polysaccharides; cyclodextrins, hydroxyethyl starches, dextrins, and dextrans; salts such as sodium glucronate, phosphates, and metal salts; and serum albumin, gelatin, amino acids, and non-ionic surfactants. Among these stabilizers, maltose and trehalose stably retain the present effective ingredient(s) for a relatively-long period of time.
Except for the non-ionic surfactants, the percentage of the above stabilizers which are incorporated into the present orally-administrable agent is not specifically restricted; Generally, it is in the range of about 0.01 to below 100 w/w %, preferably, about 0.1 to below 100 w/w %, and more preferably about 1 to below 100 w/w %, based on the weight of the present orally-administrable agent. The percentage of the non-ionic surfactants is from one microgram to one milligram, and preferably 10 micrograms to one milligram per gram of the present orally-administrable agent. Depending on the form of the present orally-administrable agent, the addition of the stabilizers in an a
Kurimoto Masashi
Ohashi Kunihiro
Browdy and Neimark
Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo
Stucker Jeffrey
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