Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-11-06
2004-07-27
Wax, Robert A. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S634000, C530S300000, C530S324000, C530S303000, C530S399000
Reexamination Certificate
active
06767892
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to pharmaceutical compositions. More particularly, the invention relates to IGF-I compositions that provide high concentrations of soluble IGF-I at desirable pHs.
BACKGROUND OF THE INVENTION
Insulin-like growth factor-I (IGF-I) belongs to a family of polypeptides known as somatomedins. IGF-I is structurally and functionally similar to, but antigenically distinct from, insulin. In this regard, IGF-I is a single-chain polypeptide with three intrachain disulfide bridges and four domains known as the A, B, C, and D domains, respectively. The A and B domains are connected by the C domain and are homologous to the corresponding domains of proinsulin. The D domain, a carboxy terminal extension, is present in IGF-I but is absent from proinsulin. IGF-I has 70 amino acid residues and a molecular mass of approximately 7.5 kDa (see Rinderknecht,
J. Biol. Chem.
(1978) 253:2769; and Rinderknecht,
FEBS Lett.
(1978) 89:293). For a review of IGF, see Humbel,
Eur. J. Biochem.
(1990) 190:445-462.
IGF-I stimulates growth and division of a variety of cell types, particularly during development. See, e.g., EP 560,723 A and 436,469 B. Thus, processes such as skeletal growth and cell replication are affected by IGF-I levels.
Due to the widely varied clinical applications for IGF-I, compositions with desirable characteristics are in great demand and several IGF-I formulations have been made. See, e.g., U.S. Pat. No. 5,126,324. In particular, compositions with high concentrations of IGF-I are preferable for certain indications. Additionally, it is preferable to administer IGF-I compositions at physiological pHs. It is also preferable that the IGF-I in such compositions remain soluble and that the compositions are capable of storage for extended periods of time at refrigerated temperatures.
Physical parameters such as temperature and pH affect the solubility of IGF-I. For example, below about pH 5.0, IGF-I is soluble at concentrations of about 80-100 mg/ml while above pH 5.5, the solubility drops about ten-fold. Additionally, IGF-I is less soluble at lower temperatures. Thus, in order to provide IGF-I compositions capable of refrigerated storage, e.g., to retain stability, while still maintaining acceptable IGF-I solubility levels, compositions are now generally kept at a pH less than 5.0. Unfortunately, administration of IGF-I compositions at such nonphysiological pHs causes pain and irritation at the site of injection.
In order to overcome this problem, experimenters have attempted to formulate IGF-I in various buffers. For example, Fransson and Espander-Jansson,
J. Pharm. Pharmacol.
(1996) 48:1012-1015, describe IGF-I compositions including 5 mg/ml IGF-I in isotonic saline, with phosphate buffer concentrations ranging from 5 to 50 mM, at pH 6.0-7.0. The authors found that pH 7.0 IGF-I preparations caused less pain than pH 6.0 preparations and that lower buffer strengths reduced pain at nonphysiological pHs. However, the authors concluded that IGF-I pH 7.0 preparations were not feasible due to the instability of IGF-I at this pH. International Publication No. WO 94/15584 describes isotonic IGF-I solutions at pH 5.5 to 6.5 with phosphate buffer present in an amount less than 50 mmol/L, which are reported to result in reduced pain upon injection.
Additionally, in order to avoid stability problems and prolong shelf life, protein formulations such as those including IGF-I are often provided in a freeze-dried form. See, e.g., U.S. Pat. No. 5,210,074, which describes dried IGF-I compositions that include a strong acid, such as hydrochloric acid, to increase the shelf life of the formulation. However, freeze-dried formulations require reconstitution prior to injection, which is inconvenient and can lead to dilution errors. Additionally, freeze drying is costly and time consuming. Thus, it would be advantageous to prepare IGF-I compositions with increased IGF-I solubility at pHs greater than pH 5.0 and at refrigerated temperatures.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides for IGF-I compositions in which IGF-I is highly soluble at pHs of about 5.5 or greater and at refrigerated temperatures. In the inventive compositions described herein, IGF-I is present at higher concentrations at higher pHs than previously possible. Therefore, smaller volumes of IGF-I at pHs above 5.5 may be delivered to a subject with reduced pain.
Accordingly, in one embodiment, the invention relates to a composition comprising:
(a) an IGF-I or an IGF-I analogue, wherein the IGF-I or IGF-I analogue is soluble in said composition at a concentration of at least about 12 mg/ml when said composition is at a temperature of about 4° C.; and
(b) a solubilizing compound comprising a guanidinium group, wherein the composition has a pH of at least about pH 5.5.
In another embodiment, the subject invention is directed to a composition comprising:
(a) an IGF-I or an IGF-I analogue, wherein the IGF-I or IGF-I analogue is soluble in said composition at a concentration of at least about 12 mg/ml when the composition is at a temperature of about 4° C.;
(b) a solubilizing compound selected from the group consisting of arginine, an arginine analogue, and guanidine hydrochloride; and
(c) a buffer such that the composition has a pH of about pH 5.5 to about pH 9.0.
In another embodiment, the subject invention is directed to a method of making an IGF-I composition comprising:
(a) providing an amount of an IGF-I or an IGF-I analogue such that the IGF-I or IGF-I analogue is soluble in said composition at a concentration of at least about 12 mg/ml when the composition is at a temperature of about 4° C.; and
(b) combining the IGF-I or IGF-I analogue with a solubilizing compound comprising a guanidinium group, wherein the pH of the composition is about pH 5.5 to about pH 9.0.
In yet a further embodiment, the invention is directed to a method of delivering an IGF-I composition to a vertebrate subject comprising:
(a) providing a composition as described above; and
(b) administering the IGF-I composition to the vertebrate subject.
In another embodiment, the invention is directed to a method of enhancing the solubility of IGF-I or an IGF-I analogue in a composition having a pH of from about pH 5.5 to about 9.0 The method comprises combining IGF-I or an IGF-I analogue with an amount of a solubilizing compound that comprises a guanidinium group sufficient to increase the solubility of IGF-I or the IGF-I analogue relative to the solubility of IGF-I or the IGF-I analogue in the absence of the solubilizing compound.
REFERENCES:
patent: 4769361 (1988-09-01), Burleigh et al.
patent: 5126324 (1992-06-01), Clark et al.
patent: 5231178 (1993-07-01), Holtz et al.
patent: 5352452 (1994-10-01), Kohnert et al.
patent: 5410026 (1995-04-01), Chang et al.
patent: 5597897 (1997-01-01), Ron et al.
patent: 5681814 (1997-10-01), Clark et al.
patent: 0 217 379 (1987-04-01), None
patent: WO 92/04363 (1992-03-01), None
patent: WO 94/15584 (1994-07-01), None
The Merck Index, 12th ed. Merck & Co. Inc., Whitehouse Station, N.J. p. 7724, 1996.*
Fransson, et al., “Local Tolerance of Subcutaneous Injections”Journal of Pharm. Pharmacol.(1996) pp. 1012-1015, vol. 48.
Bajwa Kamaljit
Shirley Bret A.
Chrion Corporation
Kam Chih-Min
Wax Robert A.
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