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Method of reducing serum proinsulin levels in type 2 diabetics

A technology for type 2 diabetes and serum insulin, applied in metabolic diseases, pharmaceutical formulations, cardiovascular system diseases, etc.

Inactive Publication Date: 2007-08-29
MANNKIND CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, a diagnosis of diabetes is associated with a 2 to 4 times greater risk of stroke and heart attack in affected individuals

Method used

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  • Method of reducing serum proinsulin levels in type 2 diabetics

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Example 1. Pulmonary Delivery of Technosphere to Rats  / Insulin produces rapid absorption

[0023] Pulmonary Technosphere administered as a dry powder aerosol in rats  / The pharmacokinetic (PK) profile of insulin particles compared to the PK profile of human insulin delivered by subcutaneous (s.c.) injection. The aerosol was administered using a flow-past, nose-only inhalation contact system. In the first experiment, all animals received the same formulation (9.1% insulin) but the duration of dosing was adjusted so that doses of approximately 1 IU and 3 IU were delivered per rat (200 g body weight). A linear dose-dependent response was observed: maximum serum insulin concentration (C MAX ) for a dose of 0.9IU of Technosphere  76±12 μIU / ml after insulin and 240±49 μIU / ml after the 2.7 IU dose. Maximum serum insulin levels were obtained in samples taken immediately after dosing was complete, shows Technosphere  / Insulin is rapidly absorbed into the systemic cir...

Embodiment 2

[0026] Example 2. In the primary cell culture model of alveolar epithelium, Technosphere  Fumaryl diketopiperazine particles enhance insulin absorption without signs of cytotoxicity

[0027] To study the Technosphere  / Mechanisms of insulin production through the epithelial barrier deep in the lung, experiments were performed using primary cultured monolayers of rat alveolar epithelial cells. Alveolar type II cells were isolated and cultured on semipermeable polycarbonate membranes until forming a compact monolayer with high transepithelial electrical resistance (TEER). Then use Technosphere at 37°C  Insulin transport experiments across these cell monolayers were performed in an apical-to-basal orientation for insulin product and unformulated insulin controls. Insulin exhibited 1.90 ± 0.34 × 10 -8 Apparent permeability in cm / s (P app ), while Technosphere  / insulin product exhibited 2.08±0.82×10 -7 Ten times higher P of cm / s app . There was no measurable change in...

Embodiment 3

[0028] Example 3. Treatment of Humans with Transpulmonary Insulin to Reduce Serum Proinsulin Levels Technosphere  Inhalation of insulin / insulin (TI) provided a rise in serum insulin comparable to the first phase response. This study investigated the pharmacodynamics of TI and its effect on natural proinsulin release (iPi release). Twenty-four patients with type 2 diabetes received Technosphere with 4 different loadings of insulin (i.e., 0, 12 IU, 24 IU, or 48 IU of recombinant regular human insulin) five minutes after the start of a standardized meal on alternate study days.  Dosage of substrate. Blood glucose (BG), serum insulin and serum iPi were measured before (0 min), 60 and 120 min after the start of each meal.

[0029] TI reduces dietary BG levels in a dose-dependent manner. BG (mg / dl) (±SD) sixty minutes after lunch was: placebo, 183.2 (±44.4); 12IU, 170.8 (±30.5) (p=0.266); 24IU, 156.3 (±31.9) (p= 0.020); and 48 IU, 132.6 (29.1) (p<0.001). All doses caused an i...

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Abstract

Methods are provided for reducing serum proinsulin levels, lessening post-prandial pancreatic stress, and reducing risk factors for atherosclerosis in subjects with diabetes mellitus, type 2. The method includes administration of insulin in a manner that mimics the meal-related first phase insulin response, using a dose sufficient to reduce serum levels of proinsulin. In some embodiments of the method insulin administration is commenced early in the course of the disease. Mimicking first phase kinetics, peak serum insulin levels can be reached within about 18 minutes of administration. In increasingly preferred embodiments peak serum insulin levels can be reached within about 15, 12, or 10 minutes of administration. Serum insulin levels return to baseline within about two hours of administration.

Description

[0001] This application claims priority to US Patent Application 60 / 535,945, filed January 12, 2004 in the U.S. Patent and Trademark Office. technical field [0002] The present invention relates generally to the field of treatment of type 2 diabetes and related sequelae using prandial insulin replacement therapy that mimics the first phase insulin response associated with feeding. In particular, the invention relates to reducing serum proinsulin levels, attenuating pancreatic stress, and reducing atherogenic factors in type 2 diabetic patients. Background technique [0003] Diabetes exists in 17 million Americans. Its incidence is increasing at a rate of 4.5% per year, especially type 2 diabetes, which is also known as maturity onset diabetes and non-insulin dependent diabetes. A typical defect of diabetes is the dysregulation of serum glucose levels. In addition to the deleterious effects of hyperglycemia, the inability to respond appropriately to high serum glucose leve...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/28
CPCA61K38/28A61P43/00A61P9/10A61P3/10
Inventor 韦曼·温德尔·奇塔姆安德烈亚斯·普菲茨纳安德斯·哈萨格尔·博斯
Owner MANNKIND CORP
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