Drug – bio-affecting and body treating compositions – Lymphokine – Interleukin
Reexamination Certificate
2000-02-25
2002-01-08
Riley, Jezia (Department: 1656)
Drug, bio-affecting and body treating compositions
Lymphokine
Interleukin
C424S085100, C530S351000
Reexamination Certificate
active
06337067
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a foam inhibitor which effectively inhibits foaming (bubbling) caused when dissolving a dry composition and to a water-soluble dry composition which comprises the foam inhibitor so that foaming (bubbling) is significantly inhibited.
BACKGROUND ART
In dry compositions containing pharmacologically active proteinaceous substances as active ingredients, various saccharides including sucrose have conventionally been used as stabilizer for the active ingredients (see Japanese Unexamined Patent Publications Nos. 92619/1983, 48933/1985 and 138222/1990).
The conventional dry compositions of pharmacologically active proteinaceous substances containing saccharides, however, tend to foam severely when dissolved at the time of utilization depending on the amount of saccharides contained therein. The foaming may cause problems such as erroneous assessment or identification of insoluble foreign matters, introduction of bubbles into a syringe together with solution in preparing an injection solution, a longer time required for the preparation of the solution, etc.
Further, in the case where solutions of medical compositions containing saccharides are freeze-dried, the freeze-dried cakes obtained are prone to shrinkage, resulting in deterioration of appearances of drugs. Moreover, if an excessive amount of saccharides is blended in a preparation, a relatively long time is unavoidably required for the freeze-drying.
DISCLOSURE OF INVENTION
An object of the present invention is to provide a foam inhibitor which effectively inhibits foaming caused when dissolving a conventional dry composition containing a saccharide. Another object of the present invention is to provide a dry composition wherein the foaming usually observed at the time of redissolving the dry compositions is effectively inhibited.
The inventors have conducted an extensive study to achieve the above objects. Consequently, the inventors have found that a group of amino acids have characteristics to effectively inhibit the foaming associated with the dissolving of the conventional dry compositions containing saccharides, especially, the dry compositions containing saccharides and pharmacologically active proteinaceous substances, and that a desired dry composition which is free of the above-mentioned problems can be prepared by utilizing the amino acids as foam inhibitor.
The present invention has been accomplished based on the above findings.
Specifically, the present invention provides a foam inhibitor containing hydrophobic amino acid as essential ingredient which is suitable for inhibiting foaming usually observed when dissolving a conventional dry composition containing a saccharide. The foam inhibitors of the invention include the following modes of embodiments.
1. A foam inhibitor comprising a hydrophobic amino acid having a hydropathy index of any one of the following values of not less than 2, not less than 2.8, not less than 3.8 or 3.8-4.5.
2. A foam inhibitor wherein the hydrophobic amino acid is at least one species selected from the group consisting of valine, leucine, isoleucine and phenylalanine.
3. A form inhibitor wherein the concentration of hydrophobic amino acid is in the range of 1-100 wt. % based on 100 wt. % of saccharide contained in the dry composition.
4. A foam inhibitor wherein the saccharide is at least one species selected from the group consisting of sucrose, maltose, lactose, trehalose, mannitol, xylitol, dextran and chondroitin sulfate.
5. A foam inhibitor whose object dry composition is a freeze-dried composition.
The present invention further provides a water-soluble dry composition containing a pharmacologically active proteinaceous substance, saccharide and hydrophobic amino acid having a hydropathy index of about not less than 2, wherein the concentration of the hydrophobic amino acid is from 0.05 wt. % to less than 40 wt. % based on the total amount of dry composition. The water-soluble dry compositions of the invention include the following modes of embodiments.
a. A water-soluble dry composition wherein a hydrophobic amino acid has a hydropathy index of any one of the values of not less than 2.8, not less than 3.8 or 3.8-4.5.
b. A water-soluble dry composition wherein the saccharide is at least one species selected from the group consisting of sucrose, maltose, lactose, trehalose, mannitol, xylitol, dextran and chondroitin sulfate.
c. A water-soluble dry composition which comprises at least one pharmacologically active substance selected from the group consisting of antiviral polypeptides, immunomodulator polypeptides and hematinic polypeptides.
d. A water-soluble dry composition wherein the pharmacologically active substance is at least one species selected from the group consisting of antiviral polypeptides, immunomodulator polypeptides and hematinic polypeptides, and the saccharide is at least one species selected from the group consisting of disaccharides, sugar alcohols and polysaccharides.
e. A water-soluble dry composition wherein the concentration of the hydrophobic amino acid is in the range of 1-10 wt. % based on 100 wt. % of the saccharide contained in the water-soluble dry composition.
f. A water-soluble dry composition wherein the concentration of hydrophobic amino acid is in the range of 0.1-30 wt. % based on the total amount of the dry composition.
g. A water-soluble dry composition wherein the concentration of the hydrophobic amino acid is in the range of 2-50 wt. % based on 100 wt. % of the saccharide.
h. A water-soluble dry composition wherein the concentration of the hydrophobic amino acid is in the range of 0.5-30 wt. % based on the total amount of the dry composition.
i. A water-soluble dry composition wherein the pharmacologically active substance is at least one species selected from the group consisting of antiviral polypeptides, immunomodulator polypeptides and hematinic polypeptides, and the saccharide is at least one species selected from the group consisting of disaccharides, sugar alcohols and polysaccharides.
j. A water-soluble dry composition wherein the pharmacologically active proteinaceous substance is interleukin and/or interferon, and the saccharide is disaccharide.
k. A water-soluble dry composition wherein the dry composition is a freeze-dried composition.
l. A water-soluble dry composition which is substantially free of human serum albumins, but contains polar amino acid having a hydropathy index of not more than 0 and surfactant.
According to the invention, it is possible to effectively inhibit foaming prone to occur when dissolving a dry composition containing saccharide and to prepare a solution excellent in clarity. Further, even in the case where lyophilization is employed as drying step, it is possible to effectively prevent shrinkage of the freeze-dried cakes, thereby obtaining dry products excellent in the appearance.
Moreover, in the dry compositions of the invention, especially in the freeze-dried products, the moisture content is satisfactorily reduced in a shorter drying time than that required for the conventional freeze-dried products which do not contain hydrophobic amino acid having a hydropathy index of not less than about 2. Thus, the present invention enables to reduce the drying time in the whole process of preparing a dry composition, which is advantageous in the industrial production.
The invention will hereinafter be described in more detail.
(1) Foam Inhibitor
The present invention provides a foam inhibitor which contains hydrophobic amino acid as essential ingredient. The foam inhibitor has the characteristics of effectively inhibiting foaming usually induced at the time of dissolving a dry composition, especially a dry composition containing saccharide.
The hydrophobic amino acids to be used in the invention are those having the hydropathy index of at least about 2 (see “A Simple Method for Displaying the Hydropathic Character of a Proteins”, Jack Kyte and Russel F. Doolittel, J. Mol. Biol., (1982)157, 105-132). Any amino acids having the above physical property may be used in t
Odomi Masaaki
Yamashita Chikamasa
Otsuka Pharmaceutical Co. Ltd.
Riley Jezia
Sughrue & Mion, PLLC
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