Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-03-30
2003-05-06
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S004300, C514S866000, C530S303000, C530S399000, C435S808000
Reexamination Certificate
active
06559122
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to formulations containing mixtures of oppositely-charged polypeptides such as insulin-like growth factor (IGF-I) and insulin. In particular, this invention entails a formulation containing selected excipients that enable the mixing of oppositely-charged proteins in the same formulation, the excipients preventing the interaction of the proteins that normally would make them precipitate from the solution.
2. Description of Related Art
Human IGF-I is a 7649-dalton polypeptide (Rinderknecht and Humbel,
Proc. Natl. Acad. Sci. USA
, 73: 2365 (1976); Rinderknecht and Humbel,
J. Biol. Chem
., 253: 2769 (1978)) belonging to a family of somatomedins with insulin-like and mitogenic biological activities that modulate the action of growth hormone (GH). Van Wyk et al.,
Recent Prog. Horm. Res
., 30: 259 (1974); Binoux,
Ann. Endocrinol
., 41: 157 (1980); Clemmons and Van Wyk,
Handbook Exp. Pharmacol
., 57: 161 (1981); Baxter,
Adv. Clin. Chem
., 25: 49 (1986); U.S. Pat. No. 4,988,675; WO 91/03253; and WO 93/23071. IGF-I contains three disulfide bonds, and has a pI of 8.65 and molar absorptivity of 0.645 at 276 nm. IGF-I naturally occurs in human body fluids, for example, blood and human cerebral spinal fluid. Most tissues and especially the liver produce IGF-I together with specific IGF-binding proteins. Like GH, IGF-I is a potent anabolic protein. See Tanner et al.,
Acta Endocrinol
., 84: 681-696 (1977); Uthne et al.,
J. Clin. Endocrinol. Metab
., 39: 548-554 (1974). See also Ross et al.,
Intensive Care Med
., 19 Suppl. 2: S54-57 (1993), which is a review of the role of insulin, growth hormone, and IGF-I as anabolic agents in the critically ill.
IGF-I may be purified from natural sources, e.g., human serum (Rinderknecht and Humbel,
J. Biol. Chem
., supra), or made recombinantly (e.g., EP 123,228 and 128,733). Various methods for formulating IGF-I have been described. These include, for example, EP 440,989, which discloses a method for preparing a dried composition of IGF-I, which comprises drying a solution containing IGF-I together with a strong acid, WO 91/18621 on formulating IGF-I in a citrate buffer at pH 6, U.S. Pat. No. 5,374,620 on formulating IGF-I and GH in a growth-promoting composition, U.S. Pat. No. 5,681,814 on formulating IGF-I in an acetate buffer, WO 94/15584 on a stable solution containing IGF-I in a phosphate buffer in an amount of 50 mmol or less, giving a pH of 5.5 to 6.5, which is isotonic and suitable for injection, and WO 95/34318 on a solution comprising IGF-I in an aqueous solution with a reduced concentration of oxygen.
IGF-I has hypoglycemic effects in humans similar to insulin when administered by intravenous bolus injection, but also promotes positive nitrogen balance. Underwood et al.,
Hormone Research
, 24: 166 (1986). IGF-I is known to exert glucose-lowering effects in both normal (Guler et al.,
N. Engl. J. Med
., 317: 137-140 (1987)) and diabetic individuals (Schoenle et al.,
Diabetologia
, 34: 675-679 (1991); Zenobi et al.,
J. Clin. Invest
., 90: 2234-2241 (1992)) (see also Sherwin et al.,
Hormone Research
, 41 (Suppl. 2): 97-101 (1994); Takano et al.,
Endocrinol. Japan
, 37: 309-317 (1990); Guler et al.,
Acta Paediatr. Scand
. (
Suppl
.), 367: 52-54 (1990)), with a time course described as resembling Regular insulin. See also Kerr et al., “Effect of Insulin-like Growth Factor 1 on the responses to and recognition of hypoglycemia,” American Diabetes Association (ADA), 52nd Annual Meeting, San Antonio, Tex., Jun. 20-23, 1992, which reported an increased hypoglycemia awareness following rhIGF-I administration. In addition, single administration of rhIGF-I reduces overnight GH levels and insulin requirements in adolescents with IDDM. Cheetham et al.,
Clin. Endocrinol
., 40: 515-522 (1994); Cheetham et al.,
Diabetologia
, 36: 678-681 (1993).
Recombinant human IGF-I administered to Type II diabetics as reported by Schalch et al.,
J. Clin. Endocrinol. Metab
., 77: 1563-1568 (1993) demonstrated a fall in both serum insulin as well as a paralleled decrease in C peptide levels which indicated a reduction in pancreatic insulin secretion after five days of IGF-I treatment. This effect has been independently confirmed by Froesch et al.,
Horm. Res
., 42: 66-71 (1994). In vivo studies in normal rats also illustrate that IGF-I infusion inhibits pancreatic insulin release. Furnsinn et al.,
Endocrinology
, 135: 2144-2149 (1994). In addition, in pancreas perfusion preparations IGF-I also suppresses insulin secretion. Leahy et al.,
Endocrinology
, 126: 1593-1598 (1990). Despite these clear in vivo inhibitory effects of IGF-I on insulin secretion in humans and animals, in vitro studies have not yielded such uniform results.
In vitro studies using multiple concentrations of both IGF-I and glucose have shown various degrees of inhibition of insulin secretion, e.g., from no effect (Sieradzki et al.,
J. Endocrinol
., 117: 59-62 (1988)) to a 30% decrease in insulin release utilizing physiological levels of IGF-I. Van Schravendijk et al.,
Diabetologia
, 33: 649-653 (1990). In a recent study using human pancreatic islets, Eizirik et al.,
Eur. J. Endocr
., 133: 248-250 (1995) found no effect of IGF-I on medium insulin accumulation or on glucose-stimulated insulin release. The investigators speculate that the effect of IGF-I seen in vivo on insulin secretion may be secondary to the extra-pancreatic effects of IGF-I rather than its direct effects on the pancreas. Therefore, the mode and site of action of IGF-I on insulin secretion are not fully understood.
A number of biochemical changes induced by short-term rhIGF-I administration are described in the literature. Prominent among these is a phosphate- and potassium-lowering effect of recombinant human IGF-I (rhIGF-I) reported in healthy subjects during euglycemic clamp. Boulware et al., “Phosphate and potassium lowering effects of insulin-like growth factor I in humans: comparison with insulin” The Endocrine Society, 74th Annual Meeting, San Antonio, Tex., 1992June 24-27 See also Guler et al.,
Acta Paediatr. Scand
. (
suppl
.), 367, supra.
Recombinant human IGF-I (rhIGF-I) has the ability to improve insulin sensitivity. For example, rhIGF-I (70 &mgr;g/kg bid) improved insulin sensitivity in non-diabetic, insulin-resistant patients with myotonic dystrophy. Vlachopapadopoulou et al.,
J. Clin. Endo. Metab
., 80: 3715-3723 (1995). Saad et al.,
Diabetologia
, 37. Abstract 40 (1994) reported dose-dependent improvements in insulin sensitivity in adults with obesity and impaired glucose tolerance following 15 days of rhIGF-I treatment (25 &mgr;g and 100 &mgr;g/kg bid). RhIGF-I also improved insulin sensitivity and glycemic control in some patients with severe type A insulin resistance (Schoenle et al.,
Diabetologia
, 34: 675-679 (1991); Morrow et al.,
Diabetes
, 42 (Suppl.): 269 (1993) (abstract); Kuzuya et al.,
Diabetes
, 42: 696-705 (1993)) or others with non-insulin dependent diabetes mellitus. Schalch et al., “Short-term metabolic effects of recombinant human insulin-like growth factor I (rhIGF-I) in type II diabetes mellitus”, in: Spencer EM, ed.,
Modern Concepts of Insulin
-
like Growth Factors
(New York: Elsevier: 1991) pp. 705-713; Zenobi et al.,
J. Clin. Invest
., 90: 2234-2241 (1992).
Though insulin resistance has not been considered a prominent feature of type I diabetes, it is clearly present in some individuals and may be most clinically important during adolescence. As GH has well-known anti-insulin effects, the elevated GH levels during adolescence may mediate much of this insulin resistance. Press et al., supra; Defeo et al., supra; Campbell et al.,
N. Eng. J. Med
., supra, Campbell et al.,
Metabolism
, supra; Arias et al., supra; Davidson et al., supra.
A general scheme for the etiology of some clinical phenotypes that give rise to insulin resistance and the possible effects of administration of IGF-I on selected representative subjects are given in several references. See, e.g., Elahi et al., “Hemodynamic and met
Oeswein James Q.
Smikahl John R.
Wang Sharon X.
Yeung Douglas A.
Genentech Inc.
Hasak Janet E.
Low Christopher S. F.
Mohamed Abdel A.
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