Surgery – Respiratory method or device – Means for mixing treating agent with respiratory gas
Reexamination Certificate
1999-03-11
2003-12-02
Lo, Weilun (Department: 3761)
Surgery
Respiratory method or device
Means for mixing treating agent with respiratory gas
C128S205240
Reexamination Certificate
active
06655379
ABSTRACT:
FIELD OF THE INVENTION
The present invention is related to the pulmonary delivery of an active agent formulation. More particularly, it is a method and device for pulmonary delivery of an active agent formulation for increased systemic bioavailability of the active agent via absorption in the deep lung. Average inspiratory flow rates of less than 17 liters per minute of active agent formulation must be maintained in order to achieve increased bioavailability.
BACKGROUND OF THE INVENTION
Effective delivery to a patient is a critical aspect of any successful drug therapy. Various routes of delivery exist, and each has its own advantages and disadvantages. Oral drug delivery of pills, capsules, elixirs, and the like is perhaps the most convenient method, but many drugs are degraded in the digestive tract before they can be absorbed. Subcutaneous injection is frequently an effective route for systemic drug delivery, including the delivery of proteins, but enjoys a low patient acceptance. Since injection of drugs, such as insulin, one or more times a day can frequently be a source of poor patient compliance, a variety of alternative routes of administration have also been developed, including transdermal, intranasal, intrarectal, intravaginal, and pulmonary delivery.
Insulin is a 50 amino acid polypeptide hormone having a molecular weight of about 6,000 daltons which is produced in the pancreatic &bgr;-cells of normal (non-diabetic) individuals. Insulin is necessary for regulating carbohydrate metabolism by reducing blood glucose levels. Where the body's ability to regulate blood glucose levels has been impaired, diabetes will result. There are two main types of diabetes. In Type I, the insulin-secreting cells of the pancreas are destroyed. Insulin production is therefore nearly completely halted. In Type II, either the body produces insulin but in quantities that are insufficient to regulate blood sugar levels to within a normal range or the insulin receptors are unable to adequately process the insulin in the blood. Survival of Type I diabetic patients depends on the frequent and long-term administration of insulin to maintain acceptable blood glucose levels. Type II diabetics may require insulin administration, but diet, exercise or oral medications are often used to avoid the necessity of daily injections of insulin.
Insulin is most commonly administered by subcutaneous injection, typically into the abdomen or upper thighs. In order to maintain acceptable blood glucose levels, it is often necessary to inject basal insulin at least once or twice per day, with supplemental injections of rapid-acting insulin being administered when necessary, usually prior to meals. Blood glucose levels should typically remain between 50 mg/dl and 300 mg/dl, preferably between about 80 mg/dl and 120 mg/dl with a target blood glucose level of 100 mg/dl. Aggressive treatment of diabetes can require even more frequent injections, in conjunction with the close monitoring of blood glucose levels by patients using home diagnostic kits.
The administration of insulin by injection is undesirable in a number of respects. First, many patients find it difficult and burdensome to inject themselves as frequently as necessary to maintain acceptable blood glucose levels. Such reluctance can lead to non-compliance with recommended therapeutic regimens, which in the most serious cases can be life-threatening. Moreover, systemic absorption of insulin from subcutaneous injection is relatively slow when compared to the normal release of insulin by the pancreas, frequently requiring from 45 to 90 minutes, even when fast-acting insulin formulations are employed. Thus, it has long been a goal to provide alternative insulin formulations and routes of administration which avoid the need for physically invasive injections and which can provide rapid systemic blood levels of the insulin as seen in normal subjects.
Elliot et al, Aust. Paediatr. J.(1987)23:293-297 described the nebulized delivery of semi-synthetic human insulin to the respiratory tracts of six diabetic children and determined that it was possible to control diabetes in these children, although the efficiency of absorption was low (20-25%) as compared to subcutaneous delivery. Laube et al., U.S. Pat. No. 5,320,094, noting Elliot and a number of other studies, stressed that although insulin had been delivered to the lung, none of the patients had responded to the pulmonary insulin therapy sufficient for lowering of blood glucose levels to within a normal range. Laube et al. hypothesized that this problem resulted from the loss of drug in the delivery system and/or in the oropharynx as a result of the method of delivery and that the maximization of deposition within the lungs should improve glucose control in the blood. In order to achieve maximum delivery, Laube et al controlled the inspiratory flow rate at the time of aerosol inhalation at flow rates of less than 30 liters/minute and, preferably about 17 liters/minute. The delivery system included a medication chamber for receiving the insulin, an outlet aperture through which the insulin was withdrawn, and a flow rate limiting aperture to control the inspiratory flow rate.
Rubsamen et al, U.S. Pat. Nos. 5,364,838 and 5,672,581 describe the delivery of a measured amount of aerosolized insulin. The insulin is automatically released into the inspiratory flow path in response to information obtained from determining the inspiratory flow rate and inspiratory volume of a patient. A monitoring device continually sends information to a microprocessor, and when the microprocessor determines that an optimal point in the respiratory cycle is reached, the microprocessor actuates the opening of a valve allowing release of insulin. The inspiratory flow rate is in the range of from about 0.1 to 2.0 liters/second and the volume is in the range of from about 0.1 to 0.8 liters.
Even with the amount of work that has been done to optimize delivery of inhaled insulin, there has not been a system and method of delivery that has provided sufficient delivery of insulin to the lung for maintaining target blood glucose levels in diabetic patients. Such a system and method for delivery would be useful for the delivery of many other active agents as well.
SUMMARY OF THE INVENTION
Accordingly, in one aspect, the present invention is directed to a method for delivering an active agent formulation to the lungs of a human patient, said method comprising providing the active agent formulation at an inspiratory flow rate of below 17 liters per minute. The active agent formulation may be provided in dry powder or nebulized form, or it may be in the form of aerosolized particles in admixture with a propellant.
In another aspect, the present invention is directed to a method for delivering insulin to the lungs of a human patient, said method comprising providing insulin at an inspiratory flow rate of below 17 liters per minute. The is preferably provided in dry powder form, but it may also be in nebulized form, or it may be in the form of aerosolized particles in admixture with a propellant.
In yet another aspect, the present invention is directed to a device for increasing the bioavailability of an aerosolized active agent, said device comprising a flow restricter for limiting the flow of the aerosolized active agent formulation to below 17 liters per minute. The flow restricter may be in the form of a simple orifice, a valve that provides for increasing resistance with increasing flow rate, a valve that provides for decreasing resistance with increasing flow rate, or a valve that provides for high resistance at all flow rates except the desired flow rate.
In a further aspect, the present invention is directed to a device for delivering an active agent to the lungs of a human patient wherein the device delivers an aerosolized active agent formulation at an inspiratory flow rate of less than 17 liters per minute.
The present invention is also directed to a device for delivering insulin to the lungs of a human patient wherein the device deli
Clark Andrew
Foulds George H.
Cagan Felissa H.
Lo Weilun
Nektar Therapeutics
Patel Mital
Tucker Guy V.
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