Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-03-10
2002-01-01
Davenport, Avis M. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C530S300000, C530S324000
Reexamination Certificate
active
06335316
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention is in the field of human medicine. More particularly, the invention is in the field of the treatment of diabetes and hyperglycemia.
2. Description of Related Art
Diabetes mellitus is a serious and chronic disorder that affects 6% of the world's population and all ethnic groups. In the United States, approximately 5% of the population has diabetes. Symptoms of diabetes include hyperglycemia and reduced production or release of insulin. Diabetes mellitus is classified into two types, type I diabetes or insulin-dependent diabetes mellitus (IDDM) and type II diabetes or non-insulin-dependent diabetes mellitus (NIDDM). Type I diabetes, in which the pancreas has stopped producing insulin, affects 10% of all diabetics, often begins in childhood and is known as juvenile onset diabetes. In the more prevalent type II diabetes, affecting 90% of all diabetics, the pancreas can produce insulin, but insulin secretion in response to meals is diminished, and the diabetic's tissues, are not as responsive to insulin as tissues from a non-diabetic. Type II diabetes is also known as adult onset diabetes.
Diminished response to or low levels of insulin result in chronic high levels of blood glucose, which gradually alters normal body chemistry and leads to failure of the microvascular system in many organs. This leads to dire consequences. For example, in the United States, diabetes is the largest cause of blindness, is involved in about 70%. of amputations, and is the cause of kidney failure in 33% of patients requiring dialysis. Medical treatment of side effects of diabetes and lost productivity due to inadequate treatment of diabetes are estimated to have an annual cost of about $40 billion in the United States alone.
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. Accordingly, effective therapy for people with diabetes generally involves the combined use of two types of exogenous insulin formulations: a fast-acting meal time insulin provided by bolus injections and a long-acting, so-called, basal insulin, administered by injection once or twice daily to control blood glucose levels between meals.
The 9-year Diabetes Control and Complications Trial (DCCT), which involved 1441 type I diabetic patients, demonstrated that maintaining blood glucose levels within close tolerances reduces the frequency and severity of diabetes complications. Conventional insulin therapy involves only two injections per day. ThLe intensive insulin therapy in the DCCT study involved three or more injections of insulin each day. In this study the incidence of diabetes-side effects was dramatically reduced. For example, retinopathy was reduced by 50-76%, nephropathy by 35-56%, and neuropathy by 60% in patients employing intensive therapy.
Unfortunately, many diabetics are unwilling to undertake intensive therapy due to the discomfort associated with the many injections required to maintain close control of glucose levels. A non-injectable form of insulin is desirable for increasing patient compliance with intensive insulin therapy and lowering their risk of complications. Many investigators have studied alternate routes for administering insulin, such as oral, rectal, transdermal, and nasal routes. So far, these types of administration have not been effective due to poor insulin absorption, low serum insulin concentration, irritation at the site of delivery, or lack of significant decrease in serum glucose levels.
Due to its small relatively small molecular weight (5,800 daltons) insulin seems to be an ideal candidate for administration through inhalation into the lungs. In fact, administration of insulin as an inhalation aerosol to the lung was first reported in 1925. In the past 70 years, numerous human and animal studies have shown that some insulin formulations are well absorbed by the lungs. After administration by inhalation, small-sized proteins are absorbed and reach maximum plasma concentrations more quickly than larger proteins. As expected for a small protein, the previously-studied insulin formulations typically exhibit a rapid rise followed by a rapid fall in plasma insulin levels.
The intense effort devoted to developing an inhaled insulin formulation has failed to achieve a system for slower uptake and longer duration of action of insulin is needed to control blood glucose between meals, and overnight. Therefore, there remains a need for an effective system for administration of a long-acting insulin by inhalation.
SUMMARY OF THE INVENTION
The present invention is a method for administering long-acting, soluble insulin by inhalation. The invention also encompasses the use of a fatty acid-acylated human insulin or a fatty acid-acylated insulin analog in the manufacture of a medicament for the treatment of diabetes or hyperglycemia by inhalation, which treatment comprises administering to a patient in need thereof an effective amount of the medicament using an inhalation device, such that the medicament is deposited in the lungs of the patient. The present invention solves two problems currently not addressed by the art. First, previous pulmonary methods for delivering insulin do not provide adequate time action to control blood glucose between meals and overnight. Second, presently known soluble, long-acting insulins and insulin derivatives are delivered by subcutaneous injection, which involves the inconvenience of preparing a sample for injection, and the pain of a needle-stick. According to the present invention, a patient in need of insulin to control blood glucose levels will achieve advantageous slow uptake and prolonged persistence in the blood of-acylated insulin compared to inhalation of non-acylated insulin, and reduced inconvenience and pain compared with subcutaneous delivery. Preferably, the acylated insulin is delivered to the lower airway of the patient. The acylated insulin can be delivered in a carrier, as a solution or suspension, or as a dry powder, using any of a variety of devices suitable for administration by inhalation. The acylated insulin can be administered using an inhalation device such as a nebulizer, a metered-dose inhaler, a dry powder inhaler, a sprayer, and the like. Preferably, the acylated insulin is delivered-in a particle size effective for reaching the lower airways of the lung, preferably less than about 10 microns mass median aerodynamic diameter (MMAD), preferably about 1 to about 5 microns MMAD, and more preferably about 1 to about 3 microns MMAD or from about 1 to about 2 microns MMAD, and most preferably from about 2 to about 3 microns MMAD. Preferred acylated insulins include a fatty acid-acylated insulin and a fatty acid-acylated insulin analog. The invention also provides a method for administering acylated insulin or acylated insulin analog together with insulin or insulin analog to a patient in need thereof by inhalation. Administering such combinations of acylated and un-acylated insulins provides both post-prandial and basal control of blood glucose levels. Because the method avoids injections, patient comfort is improved, and patient compliance increased compared with conventional insulin delivery methods.
DETAILED DESCRIPTION OF THE INVENTION
The term “fatty acid-acylated insulin protein” refers to a protein, selected from the group consisting of mammalian insulin and mammalian insulin analogs, that is acylated with a fatty acid that is bonded through an amide bond formed between the acid group of the fatty acid and an amino group of the protein, and pharmaceutically acceptable salts and complexes thereof. The amino group may be the &agr;-amino group of an N
Hughes Benjamin Lee
Wolff Ronald Keith
Apelgren Lynn D.
Davenport Avis M.
Eli Lilly and Company
Kelley James J.
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