Surgery – Controlled release therapeutic device or system – Osmotic or diffusion pumped device or system
Reexamination Certificate
2000-08-15
2002-10-29
Tanner, Harry B. (Department: 3744)
Surgery
Controlled release therapeutic device or system
Osmotic or diffusion pumped device or system
C604S288010, C424S424000
Reexamination Certificate
active
06471689
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to the field of drug delivery systems and, more particularly, to a drug delivery device with a capillary interface that permits tissue ingrowth while facilitating rapid uptake of the drug into the circulation of a mammal.
BACKGROUND OF THE INVENTION
Intravenous (IV), intramuscular, subcutaneous, intraperitoneal and transdermal delivery are the major routes of parenteral drug administration in mammals. Drug absorption from the subcutaneous, transdermal, and intramuscular sites occurs by simple diffusion once a gradient exists from the tissue drug depot to the plasma. The rate of drug absorption is, however, limited by the area of the absorbing capillary membranes (i.e., the capillary density), the portion of open versus closed capillaries, molecular size versus capillary pore size, the skin (transdermal delivery), and the solubility of the substance in the interstitial fluid. While intravenous drug administration circumvents many of these drug absorption problems, it requires that a permanent IV catheter be maintained in a blood vessel. The implanting of IV catheters for an extended period of time typically leads to complications, such as infection and obstruction of the catheter. Also, the delivery of insulin into the peripheral circulation, as opposed to the portal vein, which is the physiologic location for insulin delivery, results in a much lower portal to peripheral insulin concentration ratio compared to normal physiology. (See, Home, PD, “Insulin Therapy”,
International Textbook of Diabetes Mellitus,
p. 899-928, 1997).
Another drawback to current methods of parenteral drug administration is that they pose an obstacle to achieving physiologic control and proper management in several debilitating diseases, such as diabetes. For example, the treatment of type I diabetes by subcutaneous insulin administration is unphysiological as absorption and elimination are not rapid enough to effectively maintain normoglycemia. (See, for example, Tarnborlane V W, Sherwin R S, Genel M, and Felig P, “Reduction to Normal of Plasma Glucose in Juvenile Diabetes by Subcutaneous Administration of Insulin with a Portable Infusion Pump”, N. Engl. J. Med., 300 (11):574-580, 1979; Hepp K D, “Implantable Insulin Pumps and Metabolic Control”, Diabetologia, 37 [Suppl 2]:S 108-S 111, 1994; Hanssen K F, Bangstad H J, Brinchmann-Hansen D, and Dah Jorgensen K, “Blood Glucose Control and Diabetic Microvascular Complications: Long-term Effects of Near-normoglycemia”, Diabetic Med., 9:697-705, 1992; “The Diabetes Control and Complications Trial (DCC)”, N. Engl. J. Med., 329: 683-689, 1993).
Optimal physiologic insulin therapy requires: 1) delivery of basal levels of insulin between meals and sleep; 2) a prompt increase in insulin levels following meals to prevent hyperglycemia; and 3) a rapid decline toward basal levels after meals to prevent postprandial hypoglycemia. (See, Santiago J V, White N H, and Skor D A, “Mechanical Devices for Insulin Delivery”, Recent Advances in Diabetes, Nattrass M, Santiago JV, eds., Edinburgh: Churchill Livingstone. 145-63, 1984; White NH and Santiago J V: “What Can Be Achieved with and What Are the Complications of the Insulin Pump?”, Diabetes Mellitus
Achievements and Skepticism,
L'Etang HJC ed . . . Royal Society of Medicine, London, 111-25, 1984).
There are many factors that have been identified as having an influence on subcutaneous drug absorption, such as subcutaneous blood flow, injection location, skinfold thickness, injection depth, orthostatic changes, exercise, ambient temperature, smoking, ketosis, and hypoglycemia. Subcutaneous drug delivery, with either a needle or catheter, can have many diverse complications, such as pain, infection, sore skin, lipodystrophy, subcutaneous abscess formation, redness, eczema, and catheter occlusion. Also, there is a high replacement cost associated with infusion sets.
Currently, approximately 10% of insulin dependent diabetics use Continuous Subcutaneous Insulin Infusion (CSII). The 1992 Diabetes Control and Complications Trial (DCCT) findings in Type I diabetics showed that three or more daily insulin injections, or treatment with an insulin pump, delays the onset or slows the progression of diabetic retinopathy, nephropathy, and neuropathy. CSII is an alternative to multiple dose injections while providing improved blood glucose control and greatest degree of lifestyle flexibility. The pump contains a reservoir of insulin which connects to a catheter inserted by the patient into subcutaneous tissues, usually the abdomen. The pump is programmed to deliver a continuous infusion to provide the patient with an adjustable basal rate for night time and morning. Although CSII has several advantages, there are several problems unique to insulin pump therapy which can lead to deterioration of diabetic control in a matter of hours. Common problems identified in failure to deliver insulin are catheter blockage at the tip due to acute fibrous tissue encapsulation, insulin precipitation, needle misplacement, loss of battery charge and an empty insulin reservoir. As a result, CSII patients experience hyperglycemia and ketoacidosis, especially with the short acting insulin (smaller subcutaneous depot) before the external pump registers an alarm condition of failure to deliver.
There is also a physiologic limitation of subcutaneously infused insulin. The slow absorption prevents a more rapid systemic uptake, even when a needle is left in situ due to slow diffusion from the depot to the surrounding capillaries, dissociation of the hexamer form of insulin to monomer form, and absorption into the pores of the capillary. There is a day to day coefficient of variation of about 30%.
In recent years, implantable catheters have been developed for use as access ports for chemotherapy, nutrition, peritoneal dialysis, and, in some cases, insulin therapy. Examples of such catheters are disclosed in Tenckoff, U.S. Pat. No. 3,685,680 and Hickman, U.S. Pat. No. 4,405,313. These cavity catheters provide intravenous or peritoneal drug delivery but do not provide a tissue interface with neovascularization at the interface. The Tenckoff catheter was developed for use in peritoneal dialysis patients to permit the patients to administer dialysate at home. The Hickman catheter was designed to provide central access to the circulation system within the patient for drug delivery, but has limited long-term effectiveness as an intravascular device. One major drawback to the Hickman catheter is the high incidence of infection and obstruction associated with its use.
To date the only implantable insulin delivery methods have been the implantation of intravenous and peritoneal catheters. It has been reported that 56% of the problems associated with implantable pump use were catheter related. Nonfunctional intravenous catheters all showed an organized blood clot on the tip of the catheter. Angiographic exploration of those catheters, before removal, showed tissue formation dividing the vessel lumen and encapsulating the catheter. Nonfunctional intraperitoneal catheters were examined under laparoscopy and showed intraluminal fibrinous and cellular deposition; dense fibrous deposition around the tip of the catheter; and full or partial encapsulation by omentum. The repair of intraperitoneal catheters by laparoscopic access has yielded a relapse failure rate of 50%.
Another device known as the infusaport is a totally implanted drug delivery catheter system. While this type of device has a lower incidence of infection, it has a high incidence of obstruction and clogging of the catheter after a few months, limiting its long-term use. A variety of companies make infusaports, such as Baxter Healthcare.
With regard to insulin therapy it is currently thought that catheters are the weakest link in the chain of the components of a closed loop system. (See, Selam J L: “Development of Implantable Insulin Pumps: Long is the Road”, Diabetic
Med.,
5 (8):724-733, 1988). The International Study Gro
Joseph Jeffery I
Torjman Marc C.
Drinker Biddle & Reath LLP
Tanner Harry B.
Thomas Jefferson University
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