Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2002-09-16
2004-03-02
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S426000, C424S438000, C514S012200, C514S021800, C530S399000
Reexamination Certificate
active
06699490
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to novel compositions useful for the sustained-release of bioactive proteins. More particularly, the present invention provides a superior aqueous sustained release injectable formulation of bovine somatotropin. Also provided are methods of using these novel compositions for the sustained or prolonged release of bovine somatotropin.
With the advent of genetic engineering, the large-scale availability of many bioactive peptides and proteins has been achieved. However, the administration of these recombinantly produced peptides and proteins presents a unique set of problems. In many cases the maintenance of the biological effect of these proteins requires long-term administration. Since daily administration of these agents is inconvenient, sustained or prolonged release is preferred.
For numerous reasons, the art has long focused on the use of biocompatible oils as vehicles to achieve the sustained release of many drugs, including proteins and specifically somatotropins. Among the patents directed to this technology are U.S. Pat. No. 5,013,713 to Mitchell and U.S. Pat. No. 4,977,140 to Ferguson et al. Mitchell reports that prolonged parenteral release of bovine somatotropin (bSt;BGH) at desirably effective levels can be achieved using substantially non-aqueous compositions comprising at least about 10% by weight of a biologically active somatotropin and, as a continuous phase of the composition, a biocompatible oil such as corn oil. Ferguson et al. report that the injection of a sustained release formulation comprising bSt, wax and an oil increases daily milk production in a cow for an extended period of time.
The above patents illustrate the art's emphasis on the use of non-aqueous delivery systems for the prolonged release of somatotropins. Noticeably absent from the art is the use of an aqueous formulation to achieve the prolonged release of bSt. Among the reasons the art has avoided using aqueous systems for the sustained delivery of proteins, especially somatotropins, is the general view that proteins are highly unstable when exposed to aqueous environments for long periods of time. (Pitt,
Int. J. Pharmaceutics
59:173-196 (1990)). It is also generally thought that one could not obtain prolonged release of proteins or peptides using an aqueous formulation without making some effort to alter the solubility of the molecule or alter absorption of the molecule by, for example, absorption modifiers and viscosity inducing agents. Even when oils are used, Mitchell reports that antihydration agents are often added to a delivery system for bioactive proteins, or the protein is complexed with metals or metal compounds, to modify the release of the protein into an animal's bloodstream. Use of these absorption modifying agents, however, alter protein solubility or induce viscosity and can diminish convenient injectability of a composition and/or lead to significant tissue irritation at the injection site.
While it is difficult to determine the origin of the art's bias against the use of aqueous formulations to achieve the prolonged release of proteins such as bSt, it may be based upon research performed by J. B. Hutton (
J. Endocrin
. (1957) 16, 115-125). In his research, Hutton studied the effect of subcutaneous injections of graded doses (6.25, 12.5, 25.0, 50.0, 100.0 and 200.0 mg) of bovine growth hormone (bSt) dissolved in 5 ml saline (concentrations of 1.25, 2.5, 5, 10, 20 and 40 mg/ml, respectively) on the yield and composition of cow's milk. The primary parameter studied by Hutton was an increase in milk yield. Hutton reported that mean milk yield over a four day period was influenced by the dose of bSt administered. Hutton did not present any data, however, that the higher milk yield was sustained over the entire four day period. Hutton asserted that a single 50 mg (10 mg/ml) bSt injection would provide enhanced milk yield for four days. Hutton acknowledged, however, that this assertion was based upon calculations requiring certain assumptions. The nature of these assumptions was not disclosed nor was any supporting data provided regarding his assertions. Hutton also did not present any data regarding the impact of the graded bSt doses on bSt serum levels or to indicate that higher doses of bSt administered in higher concentrations can effect the sustained release of bSt into the circulatory system of a cow.
An opportunity for the art to overcome its bias against the use of aqueous formulations to achieve the prolonged release of bSt occurred when L. J. Machlin, building upon the work of Hutton and others, investigated the effects of high potency bSt preparations relatively free of thyrotrophin (TSH) and prolactin contamination on milk production in cows (
J. Dairy Sci
. (1972) Vol. 56, No. 5, 575-580). Machlin found that injection of bSt every third day (60 mg dose, unknown concentration, three injections total) improved milk production as much as the same total dose given daily (20 mg dose, unknown concentration, nine daily injections). Machlin did not consider, however, whether use of aqueous high potency bSt preparations would result in the sustained release of the growth hormone into the circulatory system of a cow. In fact, Machlin states that “[t]he half-life of BGH is 19-20 minutes in Holstein cows. Therefore, even with some delay in absorption from the subcutaneous site of injection, an increase in plasma BGH over endogenous levels could not be expected more than 12 hours past injection. Thus a prolonged increase in circulating BGH probably does not account for the effect.” Machlin also did not recognize the interrelationship between the dose and concentration of bSt in effecting sustained release of bSt from an aqueous formulation.
In order to better understand Machlin's observations, Bourne et al.,
J. Dairy Sci
., Vol. 60:1629-1635 (1977), undertook measurement of serum bSt levels following subcutaneous injection of similar doses. Bourne et al. observed that average serum bSt concentrations reached a maximum one to three hours after injection and returned to pre-injection concentrations within twenty-four hours. This data by Bourne et al. argues against the sustained release of BGH into the bovine circulatory system beyond 24 hours and is consistent with the suggestion by Machlin that an increase in plasma BGH over endogenous levels could not be expected more than 12 hours past injection.
Subsequent to the studies of Hutton, Machlin and Bourne et al., the art focused away from their work. Numerous investigators used aqueous solutions for daily regimens with bSt concentrations generally ranging from the 1-10 mg/ml and a dose of 5-45 mg. However, none of the cases reported any significant bSt serum levels exceeding 48-60 hours. Therefore, the art continued to assume that aqueous formulations were inappropriate vehicles for achieving the prolonged release of bSt into the circulatory system of a cow.
The present invention overcomes this misconception by the art and provides a sustained release aqueous injectable formulation of bSt and methods of using this formulation to achieve the sustained or prolonged release of bSt into the circulatory system of an animal.
INFORMATION DISCLOSURE
Machlin, L. J. (
J. Dairy Sci
. (1972) Vol. 56, No. 5, 575-580). Machlin reports that, over a nine day period, injection of bovine growth hormone every third day (60 mg dose, 180 mg total) improves milk production as much as the same total dose given daily (20 mg dose, 180 mg total). Machlin reports, however, that “[t]he half-life of BGH is 19-20 minutes in Holstein cows. Therefore, even with some delay in absorption from the subcutaneous site of injection, an increase in plasma BGH over endogenous levels could not be expected more than 12 hours past injection.” Further, Machlin does not consider the question of whether aqueous formulations can be used as vehicles for achieving the prolonged release of proteins into the circulatory system of an animal.
Hutton, J. B. (
J. Endocrin
. (1957) 16, 1
Hageman Michael John
Possert Margaret Luise
Kishore Gollamudi S.
Pharmacia & Upjohn Company
The Upjohn Co.
Wootton Thomas A.
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