Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1994-09-06
1996-10-08
Russel, Jeffrey E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 21, 514769, 514777, 514970, 530344, A61K 3829, A61K 4702, A61K 4726
Patent
active
055631223
DESCRIPTION:
BRIEF SUMMARY
FIELD OF INVENTION
The present invention relates to a method of stabilizing parathyroid hormone (hereinafter generally designated as PTH) and compositions containing parathyroid hormone as the active ingredient.
1. PRIOR ART
PTH is a hormone which has activity, similar to calcitonin and vitamin D, in controlling serum calcium levels, and which can be used as a diagnostic reagent for hypoparathyroidism. Generally a sugar such as mannitol or polymer substance such as gelatin is added to a lyophilized preparation of an injectable solution containing trace amount of PTH. (Japanese Patent applications No. 63-60940 and No. 2-111)
2. PROBLEMS TO BE SOLVED BY THE INVENTION
Mannitol is the conventional stabilizing agent used in lyophilized preparations of peptides or proteins for injectable solutions. However, when mannitol is used as a stabilizing agent for lyophilized preparations of PTH used for injectable solutions, its stabilizing effect is unsatisfactory. Polymer substances, such as gelatin, give high stabilizing effects, however its immunological safety is still uncertain.
3. MEANS FOR SOLVING PROBLEMS
During continuing studies to find a stable preparation of PTH, it was unexpectedly discovered that dramatically improved stability for lyophilized preparations of PTH can be obtained by combining a constant amount of sodium chloride with a sugar together before lyophilization, as compared with the use of a sugar alone.
As a result, excellent heat stable lyophilized preparations of PTH can be prepared using a combination of sugar and sodium chloride as stabilizing agents.
An object of the present invention is to provide a lyophilized preparation of PTH containing PTH as the active ingredient and effective amounts of a sugar and sodium chloride as the stabilizing agents.
Another object of the present invention is to provide a method of stabilizing a preparation of PTH comprising dissolving PTH, together with effective amounts of a sugar and sodium chloride in an aqueous medium, and lyophilizing the same.
As an active ingredient PTH is a peptide possessing the activity of increasing serum calcium. PTH has a molecular weight of approx. 4,000-10,000, and consists of an amino acid sequence of 34-84 amino acids for natural PTH or its analogues. Examples thereof are; human PTH(h-PTH)(1-84)[Biochemistry, 17, 5723 (1978)]; h-PTH(1-38) (Japanese Patent Unexamined Publication No. 57-81448); h-PTH(1-34)[Hoppe Seyler's Z. Physiol. Chem., 355, 415 (1974)]; h-PTH(1-34)NH.sub.2, (Japanese Patent Unexamined Publication No. 58-96052); [Nle.sup.8, .sup.18 ]h-PTH(1-34); [Nle.sup.8, .sup.18, Tyr.sup.34 ]h-PTH(1-34) (ibid., No.55-113753); [Nle.sup.8, .sup.18 ]h-PTH(1-34)NH.sub.2 (ibid., No.61-24598); [Nle.sup.8, .sup.18,Tyr.sup.34 ]h-PTH(1-34)NH.sub.2 (ibid., No.60-24996); rat-PTH(1-84) [J. Biol. Chem., 259(5), 3320 (1984) ]; rat-PTH(1-34) [Endocrinol., 117 (3) , 1230(1985)]; bovine-PTH(1-84)[Am. J. Med., 50, 639(1971)]; bovine -PTH(1-34); and, bovine-PTH(1-34)NH.sub.2 [Phytho biology Annual, 11, 53 (1981)].
A preferred example of PTH is h-PTH(1-34) having a molecular weight of approx. 4,400, with an amino acid sequence of 34 amino acids.
Examples of sugar in the present invention are, preferably a monosaccharide or disaccharide. Examples of monosaccharides are mannitol, glucose, sorbitol or inositol, and among these mannitol is the most preferred. Examples of disaccharides are sucrose, maltose, lactose and trehalose. These disaccharides can be used alone or in combination with other sugars. The most preferred examples of disaccharides are sucrose, maltose and lactose.
The amount of sugar to be added is preferably greater than one weight part of sugar per weight part of PTH. It is preferred to use from 50-1,000 weight parts of sugar per weight part of PTH.
The larger the amount of sodium chloride to be added to that of sugar, the more stable the PTH preparation will be. However, when the amount of sodium chloride exceeds 20% of the weight of sugar, a lyophilized cake of the preparation will suffer shrinkage and the stability tends
REFERENCES:
patent: 4806343 (1989-02-01), Carpenter et al.
patent: 5344644 (1994-09-01), Igari et al.
patent: 5496801 (1996-03-01), Holthuis et al.
Halsted, ed, "The Laboratory In Clinical Medicine", published 1976 by W. P. Saunders Co. (Phil.), pp. 792-796.
Archives of Pathology & Laboratory Medicine, vol. 110, issued Jul. 1986, Klee et al, "CAP Survey of Parathyroid Hormone Assays", pp. 588-591.
Endo Ken
Ohno Masaru
Sakakibara Hideo
Sato Shinji
Sugiyama Yoshinori
Asahi Kasei Kogyo Kabushiki Kaisha
Russel Jeffrey E.
LandOfFree
Stabilized parathyroid hormone composition does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Stabilized parathyroid hormone composition, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Stabilized parathyroid hormone composition will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-57068