Insoluble compositions for controlling blood glucose

Abstract

The present invention relates to insoluble compositions comprising a protein selected from the group consisting of insulin, insulin analogs, and proinsulins; a derivatized protein selected from the group consisting of derivatized insulin, derivatized insulin analog, and derivatized proinsulin; a complexing compound; a hexamer-stabilizing compound; and a divalent metal cation. Formulations of the insoluble composition are suitable for both parenteral and non-parenteral delivery for treating hyperglycemia and diabetes. Microcrystal forms of the insoluble precipitate are pharmaceutically analogous to the neutral protamine Hagedorn (NPH) insulin crystal form. Surprisingly, it has been discovered that suspension formulations of such insoluble compositions possess unique and controllable dissolution properties that provide therapeutically advantageous glucodynamics compared with insulin NPH formulations.

Description

[0001] 1. Field of the Invention[0002] This invention is in the field of human medicine. More particularly, this invention is in the field of pharmaceutical treatment of the diseases of diabetes and hyperglycemia.[0003] 2. Description of Related Art[0004] It has long been a goal of insulin therapy to mimic the pattern of endogenous insulin secretion in normal individuals. The daily physiological demand for insulin fluctuates and can be separated into two phases: (a) the absorptive phase requiring a pulse of insulin to dispose of the meal-related blood glucose surge, and (b) the post-absorptive phase requiring a sustained delivery of insulin to regulate hepatic glucose output for maintaining optimal fasting blood glucose.[0005] Accordingly, effective therapy for people with diabetes generally involves the combined use of two types of exogenous insulin formulations: a rapid acting meal time insulin provided by bolus injections and a long-acting, so-called, basal insulin, administered ...

AI Technical Summary

Benefits of technology

[0096] A major advantage of the present invention is that it is a controlled release system where the pharmacokinetics of insulin release can be more conveniently controlled than other proposed controlled release technologies. That is, an insoluble composition comprised of a protein insulin with a derivatized protein provides a convenient means to adjust the dissolution rate and hence make controlled-release possible. While not intended to be limiting, it is believed that the pharmacological efficacy of the insoluble compositions of the present invention is based on the slow release of a consistent proportion of protein and derivatized protein from the composition. It is further believed, without limiting the invention, that a significant underlying feature of this invention is the complete or nearly complete homogeneity of the insoluble composition. For microcrystals, it is believed that every individual microcrystal in the suspension is comprised of very nearly the same ratio of protein and derivatized protein. This ratio closely reflects the ratio of protein to derivatized protein combined in solution prior to crystallization. It is also believed that, as the microcrystals dissolve, a consistent and predetermined proportion of protein and derivatized protein is released throughout the entire duration of dissolution. The significance of this behavior is considerable because it results in a constant, but reduced rate of release of the two active molecules from the site of injection to the bloodstream. In order to achieve this object, particular attention must be given to the process for preparing the compositions.

Problems solved by technology

Therapy using currently-available NPH insulin preparations fails to provide the ideal "flat" pharmacokinetics necessary to maintain optimal fasting blood glucose for an extended period of time between meals.

Consequently, treatment with NPH insulin can result in undesirably high levels of insulin in the blood, which may cause life-threatening hypoglycemia.

In addition to failing to provide an ideal flat pharmacokinetic profile, the duration of action of NPH insulin also is not ideal.

In particular, a major problem with NPH therapy is the "dawn phenomenon" which is hyperglycemia that results from the loss of effective glucose control overnight while the patient is sleeping.

These deficiencies in glycemic control contribute to serious long-term medical complications of diabetes and impose considerable inconvenience and quality-of-life disadvantages to the patient.

PZI, however, is not an ideal basal insulin pharmaceutical because it is not mixable with a soluble meal-time insulin, and the high zinc and protamine can cause irritation or reaction at the site of administration.

Human ultralente preparations provide moderate time action that is not suitably flat, and they do not form stable mixtures with insulin.

Furthermore, they are difficult to resuspend.

However, the time action of these preparations may not be sufficiently long enough, or flat enough, to provide ideal basal control, and they are less potent than insulin, thereby requiring administration of greater amounts of the drug agent [Radziuk, J., et al., Diabetologia 41:116-120, 489-490 (1998)].

Whittingham, et al. do not disclose any pharmaceutical or pharmacological properties of the crystal that was formed, nor do they suggest that such a crystal would have any advantageous properties for treating diabetes or hyperglycemia.

It is not possible to predict from Whittingham, et al. whether protamine-containing crystals of the NPH type could be formed with derivatized insulins and insulin analogs, or what the pharmacokinetics or pharmacodynamic response of such crystals would be.

There was great variability within and between preparations.

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