EP1620145A2 - Methode permettant de modifier la pharmacocinetique de l'insuline - Google Patents

Methode permettant de modifier la pharmacocinetique de l'insuline

Info

Publication number
EP1620145A2
EP1620145A2 EP04751427A EP04751427A EP1620145A2 EP 1620145 A2 EP1620145 A2 EP 1620145A2 EP 04751427 A EP04751427 A EP 04751427A EP 04751427 A EP04751427 A EP 04751427A EP 1620145 A2 EP1620145 A2 EP 1620145A2
Authority
EP
European Patent Office
Prior art keywords
insulin
insulin formulation
human subject
administration
skin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04751427A
Other languages
German (de)
English (en)
Other versions
EP1620145A4 (fr
Inventor
Ronald J. Pettis
Noel Harvey
Barry Ginsberg
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Becton Dickinson and Co
Original Assignee
Becton Dickinson and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US10/429,973 external-priority patent/US7722595B2/en
Priority claimed from US10/704,035 external-priority patent/US20050010193A1/en
Application filed by Becton Dickinson and Co filed Critical Becton Dickinson and Co
Publication of EP1620145A2 publication Critical patent/EP1620145A2/fr
Publication of EP1620145A4 publication Critical patent/EP1620145A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/46—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests having means for controlling depth of insertion
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/31—Details
    • A61M5/32—Needles; Details of needles pertaining to their connection with syringe or hub; Accessories for bringing the needle into, or holding the needle on, the body; Devices for protection of needles
    • A61M5/3286—Needle tip design, e.g. for improved penetration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to methods for administration of insulin into the intradermal compartment of subject's skin, preferably to the dermal vasculature of the intradermal compartment.
  • the methods of the present invention enhance the pharmacokinetic and pharmacodynamic parameters of insulin delivery and effectively result in a superior clinical efficacy in the treatment and/or prevention of diabetes mellitus.
  • the methods of the instant invention provide an improved glycemic control of both non-fasting (i.e., post-prandial) and fasting blood glucose levels and thus have an enhanced therapeutic efficacy in treatment, prevention and/or management of diabetes relative to traditional methods of insulin delivery, including subcutaneous insulin delivery.
  • certain delivery systems eliminate needles entirely, and rely upon chemical mediators or external driving forces such as iontophoretic currents or electroporation or thermal poration or sonophoresis to breach the stratum corneum, the outermost layer of the skin, and deliver substances through the surface of the skin.
  • chemical mediators or external driving forces such as iontophoretic currents or electroporation or thermal poration or sonophoresis to breach the stratum corneum, the outermost layer of the skin, and deliver substances through the surface of the skin.
  • such delivery systems do not reproducibly breach the skin barriers or deliver the pharmaceutical substance to a given depth below the surface of the skin and consequently, clinical results can be variable.
  • mechanical breach of the stratum corneum such as with needles, is believed to provide the most reproducible method of administration of substances through the surface of the skin, and to provide control and reliability in placement of administered substances.
  • Transdermal delivery includes subcutaneous, intramuscular or intravenous routes of administration of which, intramuscular (IM) and subcutaneous (SC) injections have been the most commonly used.
  • IM intramuscular
  • SC subcutaneous
  • the outer surface of the body is made up of two major tissue layers, an outer epidermis and an underlying dermis, which together constitute the skin (for review, see Physiology, Biochemistry, and Molecular Biology of the Skin, Second Edition, L.A. Goldsmith, Ed., Oxford University Press, New York, 1991).
  • the epidermis is subdivided into five layers or strata of a total thickness of between 75 and 150 ⁇ m. Beneath the epidermis lies the dermis, which contains two layers, an outermost portion referred to as the papillary dermis and a deeper layer referred to as the reticular dermis.
  • the papillary dermis contains vast microcirculatory blood and lymphatic plexuses, h contrast, the reticular dermis is relatively acellular and avascular and made up of dense collagenous and elastic connective tissue.
  • Beneath the epidermis and dermis is the subcutaneous tissue, also referred to as the hypodermis, which is composed of connective tissue and fatty tissue. Muscle tissue lies beneath the subcutaneous tissue.
  • both the subcutaneous tissue and muscle tissue have been commonly used as sites for administration of pharmaceutical substances.
  • the dermis has rarely been targeted as a site for administration of substances, and this may be due, at least in part, to the difficulty of precise needle placement into the intradermal space.
  • the dermis, in particular, the papillary dermis has been known to have a high degree of vascularity, prior to the instant invention it was not appreciated that one could take advantage of this high degree of vascularity to obtain an improved absorption profile for administered substances compared to subcutaneous administration.
  • Small drug molecules have been traditionally administered subcutaneously because they are rapidly absorbed after administration into the subcutaneous tissue and subcutaneous administration provides an easy and predictable route of delivery.
  • the need for improving the pharmacokinetics of administration of small molecules has not been appreciated.
  • Large molecules such as proteins are typically not well absorbed through the capillary epithelium regardless of the degree of vascularity of the targeted tissue. Effective subcutaneous administration for these substances has thus been limited.
  • this group injected into the lower portion of the reticular dermis rather than into the subcutaneous tissue, it would be expected that the substance would either be slowly absorbed in the relatively less vascular reticular dermis or diffuse into the subcutaneous region to result in what would be functionally the same as subcutaneous administration and abso ⁇ tion.
  • Such actual or functional subcutaneous administration would explain the reported lack of difference between subcutaneous and what was characterized as intradermal administration, in the times at which maximum plasma concentration was reached, the concentrations at each assay time and the areas under the curves.
  • Diabetes mellitus is characterized by a broad array of physiologic and anatomic abnormalities, for example, abnormal insulin secretion, altered glucose disposition, altered metabolism of lipid, carbohydrates, and proteins, hypertension, neuropathy, retinopathy, abnormal platelet activity, and an increased risk of complications from vascular disease.
  • Diabetics are generally divided into two categories. Patients who depend on insulin for the prevention of ketoacidosis have insulin-dependent diabetes mellitus (IDDM) or type 1 diabetes. Diabetics who do not depend on insulin to avoid ketoacidosis have non-insulin- dependent diabetes mellitus (NIDDM) or type 2 diabetes.
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM non-insulin- dependent diabetes mellitus
  • Type 2 diabetes type 2 diabetes.
  • Primary diabetes includes Insulin-dependent diabetes mellitus (IDDM Type 1), Non-insulin- dependent diabetes mellitus (NIDDM Type 2) which further includes Nonobese NIDDM, Obese NIDDM and Maturity-onset diabetes of the young.
  • IDDM Type 1 Insulin-dependent diabetes mellitus
  • NIDDM Type 2 Non-insulin- dependent diabetes mellitus
  • NIDDM Type 2 Non-insulin- dependent diabetes mellitus
  • Maturity-onset diabetes of the young Primary diabetes implies that no associated disease is present, while in secondary diabetes some other identifiable condition causes or allows a diabetic syndrome to develop. Examples of diabetic syndromes that may contribute to the development of secondary diabetes include pancreatic disease, hormonal abnormalities, drug or chemical induced conditions, and genetic syndromes.
  • Insulin dependence in this classification is not equivalent to insulin therapy, but means that the patient is at risk for ketoacidosis in the absence of insulin. It has been suggested that the terms insulin-dependent and non-insulin-dependent describe physiologic states (ketoacidosis-prone and ketoacidosis-resistant, respectively), while the terms Type 1 and Type 2 refer to pathogenetic mechanisms (immune-mediated and non-immune-mediated, respectively).
  • Type 1 diabetes insulin-dependent diabetes
  • Type 2 non-insulin-dependent diabetes type 2 non-insulin-dependent diabetes [NIDDM]
  • gestational diabetes Secondary forms of diabetes encompass a host of conditions such as pancreatic disease, hormonal abnormalities, genetic syndromes, and others.
  • IDDM Insulin-dependent diabetes mellitus often develops in childhood or adolescence while the onset of NIDDM generally occurs in middle or late life. Patients with NIDDM are usually overweight and constitute 90 to 95 percent of all diabetics. IDDM results from the destruction of beta cells by an autoimmune process that may be precipitated by a viral infection. NIDDM is characterized by a gradual decline in beta cell function and varying degrees of peripheral resistance to insulin. The annual incidence of IDDM ranges from 10 cases per 100,000 persons for nonwhite males to 16 cases per 100,000 persons for white males (LaPorte et al, 1981, Diabetes 30: 279).
  • IDDM insulin therapy
  • NIDDM will include dietary modification in a patient who is overweight and hypoglycemic agents, e.g., glipizide, glyburide and gliperimide, all of which act by stimulating the release of insulin from the beta cells and metformin, and thiazolidinediones which reduce insulin resistance.
  • hypoglycemic agents e.g., glipizide, glyburide and gliperimide, all of which act by stimulating the release of insulin from the beta cells and metformin, and thiazolidinediones which reduce insulin resistance.
  • the present invention relates to an improved parenteral administration method for delivering insulin to a subject, preferably humans, by directly targeting the dermal space whereby such method dramatically alters the pharmacokinetics (PK) and pharmacodynamics (PD) parameters of the administered insulin.
  • PK pharmacokinetics
  • PD pharmacodynamics
  • the altered PK and PD parameters enhance the therapeutic efficacy of the administered insulin.
  • the methods of the invention are particularly useful for the treatment, prevention and/or management of diabetes mellitus such as insulin-dependent diabetes mellitus and/or non-insulin dependent diabetes mellitus.
  • the methods of the invention ameliorate one or more symptoms associated with diabetes mellitus.
  • Intradermal delivery of insulin in accordance with the methods of the invention provides an improved glycemic control and thus has an enhanced therapeutic efficacy in treatment, prevention and/or management of diabetes relative to traditional methods of insulin delivery, including subcutaneous insulin delivery.
  • the methods of the invention provide an improved glycemic control without an increase in hypoglycemic events.
  • the improved glycemic control achieved using the intradermal delivery methods of the invention is due, in part, to the control of both non- fasting (i.e., post prandial) and fasting glucose levels.
  • the intradermal delivery methods of the invention lower fasting and/or post-prandial hyperglycemia more effectively than traditional methods of insulin delivery.
  • Intradermal delivery of insulin in accordance with the methods of the invention is particularly useful in controlling post-prandial hyperglycemia.
  • postprandial carries its ordinary meaning in the art and refers to plasma glucose concentrations after eating a meal (e.g., a non-fasted state), and is often measured 2 hours after the meal (i.e., 2 hour post-prandial glucose).
  • the intradermal delivery methods of the invention effectively control post-prandial glucose levels within the first two hours, preferably within the first hour after insulin delivery.
  • intradermal insulin delivery in accordance with the methods of the invention results in effective systemic absorption of insulin within the first hour which results in reduction of post-prandial glucose (PPG) levels.
  • PPG post-prandial glucose
  • insulin delivery results in reduction of PPG levels by at least 20 mg/dL, at least 30 mg/dL, at least 40 mg/dL or at least 50 mg/dL.
  • intradermal insulin delivery in accordance with the methods of the invention results in a reduction of PPG levels by 45 mg/dL.
  • Biopotency in general refers to the strength of a chemical substance on the body, and how well or how far it can act on a biological system.
  • Biopotency as used herein refers to how well or how far insulin can act on a biological system and includes its ability to affect glycemic control, including fasting blood glucose levels and post-prandial glucose levels.
  • the increased biopotency of insulin delivered in accordance with the methods of the invention is due, in part, to being systemically absorbed rapidly within the first hour of delivery.
  • the invention encompasses methods of administering solution forms of insulin (e.g., Humalog®), particulate forms of insulin, and mixtures thereof (e.g., Humalog® Mix 50/50TM).
  • the insulin formulations may be in different physical association states, including but not limited to monomeric, dimeric and hexameric states.
  • the chemical state of insulin may be modified by standard recombinant DNA technology to produce insulin of different chemical formulas in different association states.
  • solution parameters such as pH and Zn content, may be altered to result in formulations of insulin in different association states.
  • Other chemical modifications of insulin or addition of additives or excipients to alter absorption of insulin are also encompassed by the instant invention.
  • intradermal administration is intended to encompass administration of insulin into the dermis in such a manner that the substance readily reaches the dermal vasculature, including both the circulatory and lymphatic vasculature, and is rapidly absorbed into the blood capillaries and/or lymphatic vessels to become systemically bioavailable. It is believed that deposition of a substance predominately at a depth of at least about 0.3 mm, more preferably, at least about 0.4 mm and most preferably at least about 0.5 mm up to a depth of no more than about 2.5 mm, more preferably, no more than about 2.0 mm and most preferably no more than about 1.7 mm will result in rapid absorption-of insulin.
  • insulin is delivered in accordance with the present invention at a depth of 1.75 mm, 1.5 mm or 1.25 mm.
  • Directly targeting the dermal space, preferably the dermal vasculature, as taught by the invention provides more rapid onset of effects of insulin.
  • the inventors have found that insulin can be rapidly absorbed and systemically distributed via controlled ID administration that selectively accesses the circulatory and lymphatic microcapillaries, thus insulin may exert their beneficial effects more rapidly than SC administration.
  • the methods of the invention better facilitate some current therapies such as blood glucose control via insulin delivery.
  • improved pharmacokinetics means increased bioavailability, decreased lag time (T] ag ), decreased T ma , more rapid absorption rates, more rapid onset and/or increased C max for a given amount of compound administered, compared to conventional insulin delivery.
  • bioavailability is meant the total amount of a given dosage of the delivered substance that reaches the blood compartment. This is generally measured as the area under the curve in a plot of concentration vs. time.
  • lag time is meant the delay between the administration of the delivered substance and time to measurable or detectable blood or plasma levels.
  • T max is a value representing the time to achieve maximal blood concentration of the compound, and C max s the maximum blood concentration reached with a given dose and administration method.
  • the time for onset is a function of T] ag , T max and C max , as all of these parameters influence the time necessary to achieve a blood (or target tissue) concentration necessary to realize a biological effect.
  • T max and C max can be determined by visual inspection of graphical results and can often provide sufficient information to compare two methods of administration of a compound. However, numerical values can be determined more precisely by kinetic analysis using mathematical models and/or other means known to those of skill in the art.
  • delivery of insulin is done in a controlled manner, e.g., by controlling the volume of delivery to achieve a monophasic pharmacokinetic profile, e.g., a kinetic profile wherein the drug concentration vs. time profile can be mathematically fit using only one mode or route of absorption and distribution, preferably intradermal.
  • a monophasic pharmacokinetic profile e.g., a kinetic profile wherein the drug concentration vs. time profile can be mathematically fit using only one mode or route of absorption and distribution, preferably intradermal.
  • a particular advantage of the methods of the invention is an improved pharmacokinetic profile of insulin, wherein the pharmacokinetic profile resembles that of a biphasic (or multiphasic) mode of delivery, (i. e. , the PK profile can be mathematically fit using two or more modes or routes of absorption and distribution), and will exhibit both an initial or early phase characterized by rapid and high peak onset of insulin levels, followed by a later phase characterized by lower prolonged circulating levels of insulin over a more extended duration.
  • direct intradermal (ID) administration can be achieved using, for example, microneedle-based injection and infusion systems or any other means known to one skilled in the art to accurately target the intradermal space.
  • Particular devices include those disclosed in WO 01/02178, published January 10, 2002; and WO 02/02179, published January 10, 2002, U.S. Patent No. 6,494,865, issued December 17, 2002 and U.S. Patent No. 6,569,143 issued May 27, 2003 all of which are incorporated herein by reference in their entirety, as well as those exemplified in FIGs. 8-10.
  • the pharmacokinetics of insulin can be altered when compared to traditional methods of insulin delivery.
  • Improved pharmacokinetic parameters using methods of the invention can be achieved using not only microdevice-based injection systems, but other delivery systems such as needle-less or needle-free ballistic injection of fluids or powders into the ID space, Mantoux-type ID injection, enhanced ionotophoresis through microdevices, and direct deposition of fluid, solids, or other dosing forms into the skin.
  • Another benefit of the invention is to achieve more rapid systemic distribution and offset of insulin.
  • the methods of the invention also help achieve higher bio availabilities of insulin.
  • the direct benefit is that ID administration with enhanced bioavailability allows equivalent biological effects while using less active agent. This results in direct economic benefit to the drug manufacturer and perhaps consumer.
  • higher bioavailability may allow reduced overall dosing and decrease the patient's side effects associated with higher dosing.
  • the more rapid offset of insulin may produce a decreased rate of hypoglycemia.
  • Yet another benefit of the invention is the attainment of higher maximum concentrations of insulin in the plasma. The inventors have found that insulin administered in accordance with the methods of the invention is absorbed more rapidly, resulting in higher initial concentrations in the plasma. The more rapid onset allows higher C Max values to be reached with lesser amounts of insulin.
  • Another benefit of the invention is removal of the physical or kinetic barriers invoked when insulin passes through and becomes trapped in cutaneous tissue compartments prior to systemic absorption.
  • Direct ID administration by mechanical means in contrast to transdermal delivery methods overcomes the kinetic barrier properties of skin, and is not limited by the pharmaceutical or physicochemical properties of insulin or its formulation excipients.
  • insulin may be administered as a bolus, or by infusion.
  • bolus is intended to mean an amount that is delivered within a time period of less than ten (10) minutes.
  • Infusion is intended to mean the delivery of a substance over a time period greater than ten (10) minutes. It is understood that bolus administration or delivery can be carried out with rate controlling means, for example a pump, or have no specific rate controlling means, for example user self-injection.
  • the insulin formulations of the invention may be in any form suitable for intradermal delivery.
  • the intradermal insulin formulation of the invention is in the form of a flowable, injectible medium, i.e., a low viscosity formulation that may be injected in a syringe.
  • the flowable injectible medium may be a liquid.
  • the flowable injectible medium is a liquid in which particulate material is suspended, such that the medium retains its fluidity to be injectible and syringable, e.g., can be administered in a syringe.
  • the invention encompasses formulations in which insulin is in a particulate form, i.e., is not fully dissolved in solution.
  • At least 30%, at least 50%, at least 75% of the insulin is in particulate form.
  • formulations of the invention in which insulin is in particulate form have at least one agent which facilitates the precipitation of insulin.
  • Precipitating agents that may be employed in the formulations of the invention maybe proteinacious, e.g., protamine, a cationic polymer, or non-proteinacious, e.g., zinc or other metals or polymers.
  • the insulin formulation administered in accordance with the methods of the invention is Insulin Lispro (Eli Lilly & Company) at 100 U/mL. Preferably 1 to 50 U, most preferably 10 U, of Insulin Lispro are used in the methods of the invention. In another specific embodiment, the insulin formulation administered in accordance with the methods of the invention is 20 U 50% pre-mixed insulin Lispro (Humalog Mix 50/50TM, containing 50% insulin Lispro and 50% insulin Lispro protamine suspension).
  • Insulin can be formulated at any solution concentration ranging from 10 International Units/mL, up to, and including, 500 International Units/mL.
  • the invention preferably encompasses administering 1 to 50U of insulin formulations as disclosed herein. Using the methods of the invention lower doses of insulin are required to achieve a similar therapeutic efficacy as conventional methods of insulin therapy.
  • the insulin formulations delivered in accordance with the methods of the invention are particularly effective in decreasing serum glucose levels and have improved therapeutic efficacy compared to the conventional methods for treating and/or preventing diabetes mellitus.
  • the intradermal insulin formulations of the present invention can be prepared as unit dosage forms.
  • a unit dosage per vial may contain 0.1 to 0.5 mL of the formulation.
  • a unit dosage form of the intradermal formulations of the invention may contain 50 ⁇ L to 100 ⁇ L, 50 ⁇ L to 200 ⁇ L, or 50 ⁇ L to 500 ⁇ L of the formulation. If necessary, these preparations can be adjusted to a desired concentration by adding a sterile diluent to each vial.
  • the present invention improves the clinical utility of ID delivery of insulin to humans or animals.
  • the clinical utility of ID delivery is improved by delivering to the intradermal compartment, preferably the dermal vasculature.
  • Disclosed is a method to increase the rate of uptake for insulin without necessitating SC access. This effect provides a shorter T m x .
  • Potential corollary benefits include higher maximum concentrations for a given unit dose (C max ), higher bioavailability, more rapid onset of pharmacodynamics or biological effects, and reduced depot effects.
  • FIG. 1 PHARMACOKINETIC PROFILE OF INSULIN LISPRO DELIVERED ID
  • VS. SC Insulin Lispro levels over time after delivery of insulin into skin at three different ID depths are shown and compared to the profile obtained with SC delivery.
  • SC injection a 30 Ga, 8 mm standard insulin syringe and needle were used with a pinch up technique.
  • FIG. 2 BIOAVAILABILITY OF INSULIN LISPRO. This bar graph shows bioavailability upon ID administration of insulin to either 1.25 mm, 1.5 mm (result in duplicate), 1.75 mm depth, or SC administration of insulin. The absolute AUC is shown in light grey; and the %AUC is shown in dark grey.
  • FIGs. 3 A nd B PHARMACODYNAMIC PROFILE OF HUMALOG The glucose infusion rate needed in a euglycemic glucose clamp in the average of 10 subjects is shown. Panel A is the raw data and Panel B the filled curve. Done
  • FIG. 4 PROFILES OF INSULIN HUMALOG® 50/50 MIX. Plasma insulin levels of Humalog Mix 50/50TM containing 50% insulin Lispro and 50% insulin Lispro protamine suspension delivered ID at a depth of 1.5 mm were compared to insulin delivered SC.
  • FIG. 5 PHARMACODYNAMIC PROFILE OF INTRADEMAL HUMALOG® 50/50 MIX. Blood glucose needed in a glucose clamp in response to levels of Humalog ®Mix 50/50TM containing 50% insulin Lispro and 50% insulin Lispro protamine suspension delivered ID at a depth of 1.5 mm were compared to insulin delivered SC.
  • FIG. 6 EFFECT OF ID DELIVERY OF INSULIN ON POSTPRANDIAL BLOOD GLUCOSE. Post-prandial glucose levels were calculated based upon data from the pharmacokinetics and pharmacodynamics after intradermal delivery of insulin Lispro with a 1.5 mm needle.
  • FIG. 7 ANALYSIS OF THE INCREASE IN EARLY INSULIN LEVELS: COMPARISON OF ID AND SC DELIVERY. Insulin Lispro levels over time were calculated for ID and SC delivery. Data from insulin Lispro that was delivered into skin at an ID depth of 1.5 mm are presented. For SC injection, a 30 G, 8 mm standard insulin syringe and needle were used with a pinch up technique.
  • FIG. 8 NEEDLE DEVICE. An exploded, perspective illustration of a needle assembly designed according to this invention.
  • FIG. 9 NEEDLE DEVICE. A partial cross-sectional illustration of the embodiment in FIG. 8.
  • FIG. 10 NEEDLE DEVICE. Embodiment of FIG. 9 attached to a syringe body to form an injection device.
  • the present invention provides a method for treatment and/or prevention of diabetes mellitus such as insulin-dependent diabetes mellitus and /or non-insulin dependent diabetes mellitus by delivery of insulin to a mammal, preferably a human by directly targeting the intradermal space, where insulin is administered to the intradermal space.
  • insulin is deposited to the upper region of the dermis (i.e., the dermal vasculature).
  • the dermal vasculature Once insulin is infused according to the methods of the invention to the dermal vasculature it exhibits pharmacokinetics superior to, and more clinically desirable than that observed for insulin administered by conventional methods of insulin delivery, e.g., SC injection.
  • Intradermal delivery of insulin in accordance with the methods of the invention provides an improved glycemic control and thus has an enhanced therapeutic efficacy in treatment, prevention and/or management of diabetes relative to traditional methods of insulin delivery, including subcutaneous insulin delivery.
  • the methods of the invention provide an improved glycemic control without an increase in hypoglycemic events.
  • the improved glycemic control achieved using the intradermal delivery methods of the invention is due, in part, to control of both non-fasting (i.e., post-prandial) and fasting glucose levels.
  • the intradermal delivery methods of the invention lower fasting and/or post-prandial hyperglycemia more effectively than traditional methods of insulin delivery.
  • Intradermal delivery of insulin in accordance with the methods of the invention is particularly useful in controlling post-prandial hyperglycemia.
  • postprandial carries its ordinary meaning in the art and refers to plasma glucose concentrations after eating a meal (e.g., a non- fasting state).
  • fasting plasma glucose concentrations e.g., following an overnight 8 to 10 hour fast, generally ranges from 70 to 110 mg/dL.
  • Glucose concentrations begin to rise about 10 min after a meal as a result of absorption of dietary carbohydrates.
  • the post-prandial glucose (PPG) profile is thus determined by carbohydrate absorption, insulin and glucagon secretion, and their coordinated effects on glucose metabolism in the liver and peripheral tissues.
  • the magnitude and time of the peak of plasma glucose concentration depends on various factors including, but not limited to, timing, quantity and composition of the meal. In non-diabetic individuals, plasma glucose concentrations peak about 60 min after start of a meal and rarely exceed 140 mg/dL, and return to pre-prandial levels within 2-3 hours.
  • diabetic individuals e.g., patients with type 1 diabetes, who have no endogenous insulin secretion
  • the time and height of peak insulin concentration and resultant glucose levels are dependent on the amount, type, and route of insulin administration hi type 2 diabetes peak insulin levels are delayed and are insufficient to control PPG levels.
  • additional complications such as abnormalities in insulin and glucagon secretion, hepatic glucose uptake, suppression of hepatic glucose production, and peripheral glucose uptake contribute to higher and more prolonged PPG excursions, i.e., change in glucose concentration from before to after a meal, than in non-diabetic individuals. Therefore, elevated PPG concentrations contribute to suboptimal glucose control.
  • Insulin delivered in accordance with the methods of the invention results in a higher biopotency relative to traditional methods of insulin delivery, including subcutaneous insulin delivery.
  • Insulin delivery in accordance with the methods of the invention results in at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% higher biopotency relative to traditional methods of insulin delivery.
  • Biopotency as used herein refers to how well or how far insulin can act on a biological system and includes its ability to affect glycemic control, including fasting blood glucose levels, post-prandial glucose levels and the rate of utilization of glucose by the body.
  • the increased biopotency of insulin delivered in accordance with the methods of the invention is due in part to being absorbed rapidly within the first hour.
  • the methods of the invention control post-prandial glucose level and thus prevent or delay the onset of microvascular or macro vascular complications caused by diabetes, including but not limited to coronary heart disease, myocardial infarcation, stroke, retinopathy, neuropathy and renal failure.
  • diabetes including but not limited to coronary heart disease, myocardial infarcation, stroke, retinopathy, neuropathy and renal failure.
  • post prandial hyperglycemia is associated with endothelial dysfunction and one of the first steps in atherogenesis.
  • this invention encompasses methods of eliciting a prolonged circulation of insulin, while eliciting a more rapid onset of systemic availability of insulin than subcutaneous delivery, in a human subject, comprising delivering into an intradermal compartment of the human subject's skin an insulin formulation which comprises both particulate and solubilized forms of insulin.
  • the rate of release of insulin can be controlled by varying the ratio between the particulate and solution forms of insulin contained in the formulation to be administered using methods of the invention. Therefore, this invention also encompasses methods of modulating circulation half life of insulin in a human subject, comprising administering into an intradermal compartment of the human subject's skin a composition comprising both particulate and solution forms of insulin, wherein the ratio between the particulate and solution forms of insulin is varied. Methods of the invention thus provide a controlled means of modulating circulation half life of insulin, while achieving a rapid onset of systemic availability at the same time.
  • this invention encompasses methods of modulating circulation half life of a therapeutic agent in a human subject, comprising administering into an intradermal compartment of the human subject's skin a composition comprising both particulate and solution forms of the therapeutic agent, wherein the ratio between the particulate and solution forms of the therapeutic agent is varied.
  • the therapeutic agent is a protein.
  • Methods of the invention are particularly preferred for pain medications, oncological agents such as interferons, growth hormones, protein receptors, therapeutic antibodies, cell growth, or stimulatory factors such as GCSF (Neupogen), epogen.
  • agents that benefit from the methods of the invention are PEGylated forms or depot forms.
  • the present invention provides methods for administering antineoplastic agents.
  • antineoplastic agents include a variety of agents including cytokines, angiogenesis inhibitors, classic anticancer agents and therapeutic antibodies.
  • Cytokines immunomodulating agents and hormones that may be used in accordance with the invention include, but are not limited to interferons, interleukins (IL-1, -2, -4, -6, -8, -12) and cellular growth factors.
  • Angiogenesis inhibitors that can be used in the methods and compositions of the invention include but are not limited to: Angiostatin (plasminogen fragment); antiangiogenic antithrombin III; Angiozyme; ABT-627; Bay 12-9566; Benefin; Bevacizumab; BMS-275291; cartilage-derived inhibitor (CDI); CAI; CD59 complement fragment; CEP-7055; Col 3; Combretastatin A-4; Endostatin (collagen XNIII fragment); Fibronectin fragment; Gro-beta; Halofuginone; Heparinases; Heparin hexasaccharide fragment; HMN833; Human chorionic gonadotropin (hCG); EVI-862; hiterferon alpha/beta/gamma; terferon inducible protein (IP- 10); Interleukin-12; Kringle 5 (plasminogen fragment); Marimastat; Metalloproteinase inhibitors (TIMPs);
  • anti-cancer agents include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; car
  • anti-cancer drugs include, but are not limited to: 20-epi-l,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PT
  • CDP870 is a humanized anti-T ⁇ F- ⁇ Fab fragment (Celltech); IDEC- 151 is a primatized anti-CD4 IgGl antibody (IDEC Pharm/SmithKline Beecham); MDX- CD4 is a human anti-CD4 IgG antibody (Medarex/Eisai/Genmab); CDP571 is a humanized anti-T ⁇ F-c.
  • IgG4 antibody (Celltech); LDP-02 is a humanized anti-c.437 antibody (LeukoSite/Genentech); OrthoClone OKT4A is a humanized anti-CD4 IgG antibody (Ortho Biotech); A ⁇ TONATM is a humanized anti-CD40L IgG antibody (Biogen); A ⁇ TEGRE ⁇ TM is a humanized anti-NLA-4 IgG antibody (Elan); and CAT- 152 is a human anti-TGF-f ⁇ antibody (Cambridge Ab Tech).
  • the term "modulating circulation half life” means that increasing or decreasing the circulation half life of a therapeutic agent, which results in longer or shorter period duration of activity of that therapeutic agent, respectively.
  • circulation half life of a therapeutic agent can be modulated by varying the ratio between particulate and solution forms of the therapeutic agent to be delivered using methods of the invention in the mixture containing both forms, i principle, the higher the ratio between particulate and solution forms, the longer the circulation half life becomes.
  • the desired circulation half life of a particular agent can be readily achieved by those of ordinary skill in the art using methods of the invention, as well as those well-known in the art.
  • the circulation half life of a therapeutic agent can be determined using any methods known in the art, as well as those described herein.
  • the invention encompasses methods of administering solution forms of insulin, particulate forms of insulin and mixture thereof, including fast-acting, intermediate-acting, and long-acting insulin formulations that may be obtained from any species or generated by any recombinant DNA technology known to one skilled in the art or any other method of creating new insulin analogs.
  • Table 1 provides a non-limiting example of insulin formulations available and their mode of action, all of which are encompassed within the instant invention.
  • the insulin formulations used in the methods and formulations of the invention may be a mixture of one or more insulin formulations.
  • the invention encompasses methods of administering solution forms of insulin (e.g., Humalog®) particulate forms of insulin (e.g., Humalog® Mix 50/50TM), and mixtures thereof.
  • the insulin formulations may be in different physical association states, including but not limited to monomeric, dimeric and hexameric states.
  • the chemical state of insulin may be modified by standard recombinant DNA technology to produce insulin of different chemical formulas in different association states.
  • solution parameters such as pH and Zn content, may be altered to result in formulations of insulin in different association states.
  • Other chemical, biochemical or genetic modifications of insulin are also encompassed by the instant invention.
  • the methods of the invention lower doses of insulin are required to achieve a similar therapeutic efficacy as conventional methods of insulin therapy.
  • the insulin formulations delivered in accordance with the methods of the invention are particularly effective in decreasing serum glucose levels and have improved therapeutic efficacy compared to the conventional methods for treating and/or preventing diabetes mellitus.
  • Formulations of insulin may be from different animal species including, limited but not to, swine, bovine, ovine, equine, etc.
  • the chemical state of insulin may be modified by standard recombinant DNA technology to produce insulin of different chemical formulas in different association states.
  • solution parameters such as pH and Zn content, may be altered to result in formulations of insulin in different association states.
  • Formulations of insulins as commercially available are typically solutions of regular crystalline zinc insulin dissolved in a buffer at neutral pH. These preparations have rapid onset, e.g., 0.3-0.7 hours but a short duration of action, e.g., 5-8 hours.
  • a non-limiting example of insulin formulations are Humulin R® (Lilly & Company) Novolin R®, Actrapid, Nelosulin, Semilente.
  • the kinetics of abso ⁇ tion of Semilente and regular insulin are similar, however Semilente has a longer duration of action, i.e., 12-16 hours.
  • Lispro Lispro (Humalog®) and Aspart ( ⁇ ovoRapid®)
  • Other preparations that are most frequently used are neutral protamine Hagedorn ( ⁇ PH) insulin (isophane insulin suspension) and lente insulin (insulin zinc suspension).
  • ⁇ PH insulin is a suspension of insulin in a complex with zinc and protamine in a phosphate buffer.
  • Lente insulin is a mixture of crystallized and amo ⁇ hous insulin in acetate buffer, which reduces the solubility of insulin.
  • a non-limiting example of particulate or suspension insulin for formulations for use in the methods of the invention include ⁇ PH Iletin II, Lente Iletin II, Protaphane ⁇ PH, Lentard, Monotard, Mixtard, Humulin ⁇ , ⁇ ovolin ⁇ , ⁇ ovolin L, Humulin L, Humalog® Mix 50/50TM, Humalog® ⁇ PL)
  • ultralente insulin extended insulin zinc suspension
  • protamine zinc insulin suspension and Glargine are also encompassed by the invention. They have a very slow onset and a prolonged relatively "flat" peak of action. These insulins provide a low basal concentration of insulin through out the day.
  • these formulations include ultralente Iletin I, PZI Iletin II.
  • the invention encompasses formulations in which insulin is in a particulate form, i.e., is not fully dissolved in solution. In some embodiments, at least 30%, at least 50%, at least 75% of the insulin is in particulate form.
  • formulations of the invention in which insulin is in particulate form have at least one agent which facilitates the precipitation of insulin.
  • Precipitating agents that may be employed in the formulations of the invention may be proteinacious, e.g., protamine, a cationic polymer, or non-proteinacious, e.g., zinc or other metals or polymers.
  • the form of insulin to be delivered or administered include solutions thereof in pharmaceutically acceptable diluents or solvents, emulsions, suspensions, gels, particulates such as micro- and nanoparticles either suspended or dispersed, as well as in-situ forming vehicles of the same.
  • the insulin formulations of the invention may be in any form suitable for intradermal delivery.
  • the intradermal insulin formulation of the invention is in the form of a flowable, injectible medium, i.e., a low viscosity formulation that may be injected in a syringe or insulin pen.
  • the flowable injectible medium may be a liquid.
  • the flowable injectible medium is a liquid in which particulate material is suspended, such that the medium retains its fluidity to be injectible and syringable, e.g., can be administered in a syringe.
  • the insulin formulation administered in accordance with the methods of the invention is Insulin Lispro (Eli Lilly & Company) at 100 U/mL. Preferably 1-50 U, most preferably 10 U, of Insulin Lispro are used in the methods of the invention. In another specific embodiment, the insulin formulation administered in accordance with the methods of the invention is 20 U 50% pre-mixed insulin Lispro (Humalog Mix 50/50TM, containing 50% insulin lispro and 50% insulin lispro protamine suspension).
  • the intradermal insulin formulations of the present invention can be prepared as unit dosage forms.
  • a unit dosage per vial may contain 0.1 to 0.5 mL of the formulation, ha some embodiments, a unit dosage form of the intradermal formulations of the invention may contain 50 ⁇ L to 100 ⁇ L, 50 ⁇ L to 200 ⁇ L, or 50 ⁇ L to 500 ⁇ L of the formulation. If necessary, these preparations can be adjusted to a desired concentration by adding a sterile diluent to each vial.
  • Insulin formulations administered in accordance with the methods of the invention are not administered in volumes whereby the intradermal space might become overloaded leading to partitioning to one or more other compartments, such as the SC compartment.
  • the present invention encompasses methods for intradermal delivery of insulin formulations described and exemplified herein to the intradermal compartment of a subject's skin, preferably by directly and selectively targeting the intradermal space, particularly the dermal vasculature, without entirely passing through it.
  • the formulation is typically transferred to an injection device for intradermal delivery, e.g., a syringe or insulin pen.
  • the insulin may be in a commercial preparation, such as a vial or cartridge, specifically designed for intradermal injection.
  • the insulin formulations of the invention are administered using any of the intradermal devices and methods known in the art or disclosed in WO 01/02178, published January 10, 2002; and WO 02/02179, published January 10, 2002.
  • the actual method by which the intradermal administration of the insulin formulation is targeted to the intradermal space is not critical as long as it penetrates the skin of a subject to the desired targeted depth within the intradermal space without passing through it. In most cases, the device will penetrate the skin to a depth of about 0.5-2 mm.
  • the invention encompasses conventional injection needles, catheters or microneedles of all known types, employed singularly or in multiple needle arrays.
  • the dermal access means may comprise needle-less devices including ballistic injection devices.
  • needle and “needles” as used herein are intended to encompass all such needle-like structures with any bevel or even without a point.
  • microneedles as used herein are intended to encompass structure 30 gauge and smaller, typically about 31-50 gauge when such structures are cylindrical in nature.
  • Non-cylindrical structures encompass by the term microneedles would therefore be of comparable diameter and include pyramidal, rectangular, octagonal, wedged, and other geometrical shapes. They too may have any bevel, combination of bevels or may lack a point.
  • the methods of the invention also include ballistic fluid injection devices, powder-jet delivery devices, piezoelectric, electromotive, electromagnetic assisted delivery devices, gas- assisted delivery devices, of which directly penetrate the skin to provide access for delivery or directly deliver substances to the targeted location within the dermal space.
  • the device has structural means for controlling skin penetration to the desired depth within the intradermal space. This is most typically accomplished by means of a widened area or hub associated with the shaft of the dermal- access means that may take the form of a backing structure or platform to which the needles are attached.
  • the length of microneedles as dermal-access means are easily varied during the fabrication process and are routinely produced in less than 2 mm length. Microneedles are also a very sha ⁇ and of a very small gauge, to further reduce pain and other sensation during the injection or infusion.
  • microneedles may be used in the invention as individual single-lumen microneedles or multiple microneedles may be assembled or fabricated in linear arrays or two-dimensional arrays as to increase the rate of delivery or the amount of substance delivered in a given period of time.
  • the needle may eject its substance from the end, the side or both.
  • Microneedles may be inco ⁇ orated into a variety of devices such as holders and housings that may also serve to limit the depth of penetration.
  • the dermal-access means of the invention may also inco ⁇ orate reservoirs to contain the substance prior to delivery or pumps or other means for delivering the drug or other substance under pressure.
  • the device housing the dermal-access means may be linked externally to such additional components.
  • the intradermal methods of administration comprise microneedle-based injection and infusion systems or any other means to accurately target the intradermal space.
  • the intradermal methods of administration encompass not only microdevice-based injection means, but other delivery methods such as needle-less or needle-free ballistic injection of fluids or powders into the intradermal space, Mantoux-type intradermal injection, enhanced ionotophoresis through microdevices, and direct deposition of fluid, solids, or other dosing forms into the skin.
  • the formulations of the invention are administered using devices such as those exemplified in FIGs. 8-10, including a needle cannula having a forward needle tip and the needle cannula being in fluid communication with a substance contained in the drug delivery device and including a limiter portion surrounding the needle cannula and the limiter portion including a skin engaging surface, with the needle tip of the needle cannula extending from the limiter portion beyond the skin engaging surface a distance equal to approximately 0.5 mm to approximately 3.0 mm and the needle cannula having a fixed angle of orientation relative to a plane of the skin engaging surface of the limiter portion, inserting the needle tip into the skin of an animal and engaging the surface of the skin with the skin engaging surface of the limiter portion, such that the skin engaging surface of the limiter portion limits penetration of the needle cannula tip into the dermis layer of the skin of the animal, and expelling the substance from the drug delivery device through the needle cannula tip into the skin of the animal.
  • devices such as those exempl
  • the insulin formulations of the invention are administered to an intradermal compartment of a subject's skin, preferably the dermal vasculature using an intradermal Mantoux type injection, see, e.g., Flynn et al, 1994, Chest 106: 1463-5, which is inco ⁇ orated herein by reference in its entirety.
  • the insulin formulation of the invention is delivered to the intradermal compartment of a subject's skin using the following exemplary method.
  • the insulin formulation as prepared in accordance to methods disclosed in Section 5.1 is drawn up into a syringe, e.g., a 1 mL latex free syringe with a 20 gauge needle; after the syringe is loaded it is replaced with a 30 gauge needle for intradermal administration.
  • the skin of the subject e.g., mouse
  • the injection volume is then pushed in slowly over 0.1- 10 seconds forming the typical "bleb" and the needle is subsequently slowly removed.
  • the insulin is stored in a cartridge and placed into a specific insulin pen.
  • a micro-penneedle of 30-34 gauge is then placed into the septum of the cartridge and used in a method identical to the previous embodiment
  • improved pharmacokinetics it is meant that an enhancement of pharmacokinetic profile is achieved as measured, for example, by standard pharmacokinetic parameters such as time to maximal plasma concentration (T max ), the magnitude of maximal plasma concentration (C max ) or the time to elicit a minimally detectable blood or plasma concentration (Tj ag ).
  • T max time to maximal plasma concentration
  • C max magnitude of maximal plasma concentration
  • Tj ag time to elicit a minimally detectable blood or plasma concentration
  • abso ⁇ tion profile it is meant that abso ⁇ tion is improved or greater as measured by such pharmacokinetic parameters.
  • the measurement of pharmacokinetic parameters and determination of minimally effective concentrations are routinely performed in the art. Values obtained are deemed to be enhanced by comparison with a standard route of administration such as, for example, subcutaneous administration or intramuscular administration.
  • administration into the intradermal layer and administration into the reference site such as subcutaneous administration involve the same dose levels, i.e., the same amount and concentration of drug as well as the same carrier vehicle and the same rate of administration in terms of amount and volume per unit time.
  • administration of a given pharmaceutical substance into the dermis at a concentration such as 100 ⁇ g/ml and rate of 100 ⁇ L per minute over a period of 5 minutes would, preferably, be compared to administration of the same pharmaceutical substance into the subcutaneous space at the same concentration of 100 ⁇ g/ml and rate of 100 ⁇ L per minute over a period of 5 minutes.
  • PK and PD benefits are best realized by accurate direct targeting of the dermal capillary beds. This is accomplished, for example, by using microneedle systems of less than about 250 micron outer diameter, and less than 2mm exposed length. Such systems can be constructed using known methods of various materials including steel, silicon, ceramic, and other metals, plastic, polymers, sugars, biological and or biodegradable materials, and/or combinations thereof.
  • PK PD intradermal administration methods
  • placement of the needle outlet within the skin significantly affects PK/PD parameters.
  • the outlet of a conventional or standard gauge needle with a bevel has a relatively large exposed height (the vertical rise of the outlet).
  • the needle tip may be placed at the desired depth within the intradermal space, the large exposed height of the needle outlet causes the delivered substance to be deposited at a much shallower depth nearer to the skin surface.
  • the administration methods useful for carrying out the invention include both bolus and infusion delivery of insulin to humans or animals subjects.
  • a bolus dose is a single dose delivered in a single volume unit over a relatively brief period of time, typically less than about 10 minutes.
  • Infusion administration comprises administering a fluid at a selected rate that may be constant or variable, over a relatively more extended time period, typically greater than about 10 minutes.
  • the dermal-access means is placed adjacent to the skin of a subject providing directly targeted access within the intradermal space and the substance or substances are delivered or administered into the intradermal space where they can act locally or be absorbed by the bloodstream and be distributed systematically.
  • the dermal-access means may be connected to a reservoir containing the substance or substances to be delivered.
  • Delivery from the reservoir into the intradermal space may occur either passively, without application of the external pressure or other driving means to the substance or substances to be delivered, and/or actively, with the application of pressure or other driving means.
  • preferred pressure generating means include pumps, syringes, insulin pens, elastomer membranes, gas pressure, piezoelectric, electromotive, electromagnetic or osmotic pumping, or Belleville springs or washers or combinations thereof.
  • the rate of delivery of the substance may be variably controlled by the pressure-generating means. As a result, the substance enters the intradermal space and is absorbed in an amount and at a rate sufficient to produce a clinically efficacious result.
  • clinically efficacious result is meant a clinically useful biological response including both diagnostically and therapeutically useful responses, resulting from administration of a insulin.
  • diagnostic testing or prevention or treatment of a disease or condition is a clinically efficacious result.
  • clinically efficacious results include diagnostic results such as the measurement of glomerular filtration pressure following injection of insulin,
  • the therapeutic efficacy of insulin formulations of the invention may be determined using any standard method known to one skilled in the art or described herein.
  • the assay for determining the therapeutic efficacy of the insulin formulations of the invention may be in vivo or in vitro based assays, including animal based assays.
  • the therapeutic efficacy of the formulations of the invention is done in a clinical setting.
  • the pharmacokinetics and pharmacodynamic parameters of insulin delivery is determined, preferably quantitatively using standard methods known to one skilled in the art.
  • the pharmacodynamic and pharmacokinetic properties of insulin delivery using the methods of the invention are compared to other conventional modes of insulin delivery, e.g., SC delivery, to establish the therapeutic efficacy of insulin administered in accordance with the methods of the invention.
  • Pharmacokinetic parameters that may be measured in accordance with the methods of the invention include but are not limited to T max , C max , T] ag , AUC, etc.
  • the pharmacokinetic parameters determined are maximal serum insulin Lispro concentrations (INSmax), time to INSmax (TFNSmax), Area under the glucose infusion rates in defined time-intervals (e.g., AUChis 0-0.5h , AUCIns 0-lh, AUCIns 0-2h, AUCfris 0-4h, AUCIns 0-6h), and C-peptide concentrations.
  • Other pharmacokinetic parameters that may be measured in the methods of the invention include for example, half-life (t] /2 ), elimination rate constant and partial AUC values.
  • Standard statistical tests which are known to one skilled in the art may be used for the statistical analysis of the pharmacokinetic and pharmacodynamic parameters obtained.
  • the variables to be analyzed include for example pharmacodynamic measurements (based on the glucose infusion rates obtained), and serum C-peptide concentrations and pharmacokinetic measurements (based on the serum insulin Lispro concentrations).
  • the primary pharmacodynamic endpoint that may be measured under glucose clamp conditions is the area under the glucose infusion rates curve (AUC GIR ) in the two hours after insulin administration (AUC GIR 0-2h).
  • Another pharmacodynamic endpoint that may be measured is the overall decrease in blood glucose over time may also be measured.
  • GIR max Maximal glucose infusion rate
  • TGIR max time to G-R max
  • AUC G I R 0-lh Area under the glucose infusion rates in defined time-intervals
  • AUC G I R 0-lh Area under the glucose infusion rates in defined time-intervals
  • AUC G I R 0-lh Area under the glucose infusion rates in defined time-intervals
  • AUC G I R 0-lh Area under the glucose infusion rates in defined time-intervals
  • AUC GIR 0-2h AUC GIR 0-4h
  • AUCGIR 0-6h Area under the glucose infusion rates in defined time-intervals
  • time to early and late half-maximal glucose infusion rate early and late half-maximal glucose infusion rate
  • Glucose infusion rates registered after administration by two different routes, e.g., TD and SC, may be used to evaluate pharmacodynamic parameters. From these measurements, the area under the glucose infusion rate versus time curve from 0-6 hours (and other time intervals), the maximal glucose infusion rate, and time to the maximal glucose infusion rate may be determined. For the estimation of the pharmacodynamic summary measures fitting of a polynomial function to the GIR profile might be used. Other parameters, such as cumulative glucose infused over given intervals, may be determined.
  • An exemplary method for determining the pharmacokinetics and pharmacodynamic parameters of insulin delivery in accordance with the methods of the invention is the glucose clamp technique, see, e.g., DeFronzo et al, 1979, Am. J. Physiol. 237: 214-223; which is inco ⁇ orated herein by reference in its entirety.
  • the glucose clamp technique uses negative feedback from frequent blood glucose sample values to adjust a glucose infusion to maintain euglycemia. The glucose infusion rate therefore becomes a measure of the pharmacodynamic effect of any administered insulin.
  • the invention encompasses determining the therapeutic efficacy of insulin Lispro administered in accordance with the methods of the invention by comparing the pharmacokinetic profile to that of SC delivery.
  • An exemplary assay for determining the therapeutic efficacy of insulin Lispro may comprise the following: administering insulin Lispro (e.g., 10 U of 100 U/mL) with a 3 IG, 1.25 mm needle; or a 31G, 1.5 mm needle, with a 31G, 1.75 mm needle, or SC to humans.
  • insulin Lispro e.g., 10 U of 100 U/mL
  • a 3 IG, 1.25 mm needle or a 31G, 1.5 mm needle, with a 31G, 1.75 mm needle, or SC to humans.
  • an 8 hour glucose clamp technique is used to maintain the euglycemic condition, wherein the wash out period between the clamps may be 3-20 days.
  • Samples may be collected for determination of serum insulin Lispro concentrations and C-peptide levels and concentrations. Preferably sampling will occur from two hours before dosing and will continue for six hours after the dose is administered. Serum concentration of insulin Lispro and C-peptide maybe determined using any method known to one skilled in the art, such as a radioimmunoassay.
  • the blood samples are preferably centrifuged at 3000 ⁇ m for a period of at least fifteen minutes at a temperature between 2 to 8 °C, within one hour of sample collection.
  • the serum from the collection tube is transferred for analysis of serum levels.
  • Glucose infusion rates from the glucose clamp procedure may be monitored.
  • the euglycemic clamp procedure should preferably last 6 hours for stabilization of blood glucose concentrations at the desired clamp level (e.g., at least 12 hours for testing long acting insulin).
  • the invention encompasses any method known in the art for measuring fasting plasma glucose levels (FPGs) and non-fasting FPGs.
  • FPG s are typically maintained within target levels as specified by guidelines provided by the American Diabetes Association (ADA) and the World Health Organization (WHO) (See, e.g., DCCT Res. Group, New England J. Med, 1993, 329: 977-86; and Kannel et al, 1979, Circulation, 59: 8-13 which are inco ⁇ orated herein by reference in their entireties).
  • HbA lc Hemoglobin A lc levels
  • HbA lc levels reflect the exposure of erythrocytes to glucose in an irreversible and time and concentration dependent manner and provide an indication of the average blood glucose, concentration during the preceding 2-3 months, inco ⁇ orating both pre and post prandial glycemia.
  • PPG levels are determined within 1 hour after a meal, more preferably within 90 minutes, and most preferably within 2 hours.
  • the guidelines for target FPGs and PPGs are provided by ADA and WHO, and thus one skilled in the art practicing the methods of the invention would be able to determine the target desired levels in accordance with the methods of the invention. See, e.g., DCCT Res. Group, New England! Med, 1993, 329: 977-86; and Kannel et al, 1979 Circulation, 59: 8-13.
  • the ADA guidelines for example require the target FPG measurements to be ⁇ 120 mg/dL (6.7 mmol/L) and HbA lc levels ⁇ 7%; 2 hr PPG levels ⁇ 180 mg/dL ( ⁇ 10 mmol/L).
  • Other guidelines from the EASD and AACE require the 2 hr PPG to be ⁇ 140 mg/dL and the HbA lc levels to be ⁇ 6.5%.
  • the invention provides methods of treatment and/or prevention which involve administering an insulin formulation to a subject, preferably a mammal, and most preferably a human for treating, managing or ameliorating symptoms associated with diabetes mellitus.
  • the methods of the invention are useful for the treatment and/or prevention of diabetes or any related condition.
  • the subject is preferably a mammal such as a non-primate, e.g., cow, pig, horse, cat, dog, rat, and a primate, e.g., a monkey such as a Cynomolgous monkey and a human.
  • the subject is a human.
  • the diabetes and diabetes-related conditions which may be treated by the methods and formulations of the invention include, but are not limited to, diabetes characterized by the presence of elevated blood glucose levels, for example, hyperglycemic disorders such as diabetes mellitus, including both type 1, type 2 and gestational diabetes as well as other hyperglycemic related disorders such as obesity, increased cholesterol, kidney related disorders, cardiovascular disorders and the like.
  • hyperglycemic disorders such as diabetes mellitus, including both type 1, type 2 and gestational diabetes as well as other hyperglycemic related disorders such as obesity, increased cholesterol, kidney related disorders, cardiovascular disorders and the like.
  • diabetes mellitus that may be treated and/or prevented using the methods and formulations of the invention include for example, maturity onset diabetes of youth, insulinopathies, diabetes associated with other endocrine diseases (such as Cushing's syndrome, acromegaly, glucagonoma, primary aldosteronesim, insulin-resistant diabetes associated with acanthosis nigicans, lipoatrophic diabetes, diabetes induced by ⁇ -cell toxins, tropical diabetes, e.g., chronic pancreatitis associated with nutritional or toxic factors, diabetes secondary to pancreatic disease or surgery, diabetes associated with genetic syndrome, e.g., Prader-Willi Syndrome, diabetes secondary to endocrinopathies.
  • Other diabetes —like conditions that may be treated using the methods of the invention include states of insulin resistance, with or without elevations in blood glucose, such as the metabolic syndrome that is associated with hypertension, lipid abnormalities and cardiovascular disease or polycystic ovarian syndrome.
  • the methods of the invention may be employed to, for example, lower glucose levels, improve glucose tolerance, increase hepatic glucose utilization, normalize blood glucose levels, stimulate hepatic fatty acid oxidation, reduce hepatic triglyceride accumulation, normalize glucose tolerance, treat or prevent insulin resistance.
  • "normalize” means to reduce the blood glucose level to an acceptable or average range for a healthy individual, which means within 10%, preferably 8%, more preferably 5% of the normal average blood glucose level for the subject.
  • the methods of the invention have an enhanced therapeutic efficacy in the treatment and management of one or more pathophysiological states associated with diabetes and related conditions.
  • Pathophysiological conditions that may be improved using the methods and formulations of the invention include but are not limited to hyperglycemia, large vessel disease, microvascular disease, neuropathy, and ketoacidosis.
  • Hyperglycemia as used herein carries its ordinary and customary meaning in the art and refers to abnormally high blood glucose levels usually associated with diabetes. Hyperglycemia can result from a reduction in the level of insulin secretion and/or the inability of insulin to convert glucose into energy with the resultant associated alterations in lipid metabolism.
  • Large vessel disease as used herein carries its ordinary and customary meaning in the art and refers to an increased incidence, earlier onset and increased severity of atherosclerosis in the intima and calcification in the media of the arterial wall.
  • Microvascular disease as used herein refers to an abnormality of the basement membrane of the capillaries characterized by added layers and consequent increased thickness of the lamina.
  • Neuropathy as used herein refers to segmental injury to the nerves, associated with demyelination and Schwann cell degeneration which involves the sensory and motor neurons, nerve roots, the spinal cord, and the autonomous nervous system.
  • Ketoacidosis as used herein refers to accumulation of ketones due to depressed levels of insulin.
  • the methods and formulations of the invention are therapeutically effective in reducing or eliminating one or more symptoms associated with diabetes mellitus or related condition.
  • Symptoms that may be reduced or eliminated in accordance with the methods of the invention include but are not limited to symptomatic hyperglycemia, which may cause, blurred vision, fatigue, nausea, bacterial and fungal infections; nephropathy; sensory polyneuropathy, which causes sensory deficits, numbness, tingling, paresthesias in the extremities, etc.; foot ulcers and joint problems.
  • the invention encompasses intradermal delivery of formulations described herein in combination with one or more other therapies known in the art for the treatment and/or prevention of diabetes or a related disorder including but not limited to current and experimental therapies known to one skilled in the art.
  • the formulations of the invention may be administered in combination with a therapeutically or prophylactically effective amount of one or more other therapeutic agents for the treatment or prevention of diabetes or a related disorder.
  • therapeutic agents for treatment or prevention of diabetes or a related disorder include but are not limited to, agents that decrease FPG levels and agents that decrease PPG levels.
  • agents that decrease FPG levels include but are not limited to sulfonylureas (e.g., Glipizide), metformin, alpha- glucosidase inhibitors (e.g., Acarbose, Miglitol), Thiasohdinediones.
  • agents that decrease PPG levels include but are not limited to Repaglinide, Netiglinidem, Pioglitazone, and Rosiglitazone.
  • a formulation of the invention is administered to a mammal, preferably a human, concurrently with one or more other therapeutic agents useful for the treatment of diabetes.
  • the term "concurrently” is not limited to the administration of prophylactic or therapeutic agents at exactly the same time, but rather it is meant that a formulation of the invention and the other agent are administered to a mammal in a sequence and within a time interval such that the formulation of the invention can act together with the other agent to provide an increased benefit than if they were administered otherwise.
  • each prophylactic or therapeutic agent may be administered at the same time or sequentially in any order at different points in time; however, if not administered at the same time, they should be administered sufficiently close in time so as to provide the desired therapeutic or prophylactic effect.
  • Each therapeutic agent can be administered separately, in any appropriate form and by any suitable route.
  • the prophylactic or therapeutic agents are administered less than 1 hour apart, at about 1 hour apart, at about 1 hour to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, no more than 24 hours apart or no more than 48 hours apart, hi preferred embodiments, two or more components are administered within the same time period.
  • the prophylactic or therapeutic formulations are administered at about 2 to 4 days apart, at about 4 to 6 days apart, at about 1 week part, at about 1 to 2 weeks apart, or more than 2 weeks apart.
  • the prophylactic or therapeutic agents are administered in a time frame where both agents are still active.
  • One skilled in the art would be able to determine such a time frame by determining the half life of the administered agents.
  • the prophylactic or therapeutic formulations of the invention are cyclically administered to a subject. Cycling therapy involves the administration of a first agent for a period of time, followed by the administration of a second agent and/or third agent for a period of time and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improves the efficacy of the treatment.
  • prophylactic or therapeutic formulations are administered in a cycle of less than about 3 weeks, about once every two weeks, about once every 10 days or about once every week.
  • One cycle can comprise the administration of a therapeutic or prophylactic agent by infusion over about 90 minutes every cycle, about 1 hour every cycle, about 45 minutes every cycle.
  • Each cycle can comprise at least 1 week of rest, at least 2 weeks of rest, at least 3 weeks of rest.
  • the number of cycles administered is from about 1 to about 12 cycles, more typically from about 2 to about 10 cycles, and more typically from about 2 to about 8 cycles.
  • the primary objective of this study was to compare the pharmacokinetic and pharmacodynamic effects of 10 U insulin Lispro (100 U/mL from Eli Lilly and Company) delivered using BD microneedle injection system to that delivered subcutaneously. Secondary objectives of the study were to assess the optimal needle length for intradermal delivery of insulin Lispro reflected by the relative bioavailability following microneedle injection as compared to subcutaneous delivery. Furthermore, the study was designed to determine the intra-subject reproducibility of the delivery systems.
  • Study Design Ten healthy male volunteers were used in a randomized study. Each subject (age between 18 and 45 years, BMI ⁇ 27 kg/m 2 ) was randomized to a treatment sequence consisting of five different treatments: (a) 10 Units of insulin Lispro (100 U/mL from Eli Lilly and Company) with the 31 Ga, 1.25 mm needle; (b) 10 Units of insulin Lispro (100 U/mL from Eli Lilly and Company) with the 31 Ga, 1.5 mm needle ; (c) 10 Units of insulin Lispro (100 U/mL from Eli Lilly and Company) with the 31 Ga, 1.75 mm needle; (d) 10 Units of insulin Lispro (100 U/mL from Eli Lilly and Company) with the 31 Ga, 1.5 mm needle; (e); 10 Units of insulin Lispro (100 U/mL from Eli Lilly and Company) injected subcutaneously.
  • BD microneedle systems were manufactured under GMP compliance.
  • the insulin used was available commercially as Insulin Lispro (100 U/mL from Eli Lilly and Company) in 3.0 ml cartridge and was purchased from a local pharmacy.
  • Glucose Clamp Procedure Subjects fasted (except for water) for approximately 12 hours prior to each treatment and until completion of the treatment period. Strenuous physical activity, smoking, and alcohol intake were not permitted for the 24 hours prior to each admission to the clinical research unit. On the morning of the treatment, subjects were not allowed to drink coffee, tea, or caffeine-containing beverages. The study started in the morning. A 17-gauge PTFE catheter was inserted into an antecubital vein for blood sampling for measurement of blood glucose, C-peptide and serum insulin lispro concentrations. The line was kept patent with 0.15-mmol/L (0.9%) sterile saline.
  • a dorsal hand or a wrist vein of the same arm was cannulated in retrograde fashion for insertion of an 18-gauge PTFE double-lumen catheter, which was connected to the glucose sensor of a Biostator.
  • the catheterized hand was warmed to an air temperature of approximately 55°C.
  • a third vein was cannulated with an 18-gauge PTFE catheter to infuse glucose (20% in water).
  • insulin Huminsulin Normal (Regular Human Insulin), 100 U/mL from Eli Lilly and Company) was infused intravenously throughout the study with an infusion rate of 0.15 mU/kg/min to eliminate endogenous insulin secretion. This insulin does not interfere in the specific Lispro insulin assay.
  • the target level for both glucose clamp experiments were 5 mmol/L.
  • the clamp level was kept constant by a variable-rate intravenous infusion of 20% glucose. After insertion of the necessary venous lines the clamp level was kept constant automatically by the Biostator at the target value by varying the infusion rate of an intravenous glucose infusion.
  • insulin Lispro was administered by the BD Microneedle-System or by subcutaneous injection. The pharmacodynamic response elicited by the study medication was studied (and documented) for another 6 hours. No food intake was allowed during this period but water could be consumed as desired.
  • Pharmacokinetic Analyses For pharmacokinetic assessment the following parameters were calculated: Maximal serum insulin lispro concentrations (INS max ), time to INS ma ⁇ (TINS), area under the insulin concentration versus time curve in defined time-intervals (AUC Ins 0-lh , AUC ⁇ ns 0-2 h, AUC ⁇ ns o-4h, AUC ⁇ ns o-6h), and C-peptide concentrations. Parameters determined included also other pharmacokinetic parameters, such as half-life (tl/2), elimination rate constant ( ⁇ z) and other partial AUC values, may be calculated if considered appropriate. Parameters were calculated for each individual subject enrolled within the study. The primary analysis of this endpoint was to compare the intra subject variation of the two microneedle treatments. Comparison of the inter subject variation were a secondary analysis.
  • the primary pharmacodynamic endpoint was the area under the glucose infusion rates curve (AUC GIR ) in the two hours after drug administration (AUC GIR 0-2 h).
  • AUC GIR area under the glucose infusion rates curve
  • GIR max Maximal glucose infusion rate
  • TG_R. max time to G__ . max
  • AUCGIR o-i time to G__ . max
  • AUCGIR 0 -6h area under the glucose infusion rates in defined time-intervals
  • time to early and late half-maximal glucose infusion rate (early and late TGIR50%).
  • Glucose infusion rates registered after application by the two different routes were used to evaluate pharmacodynamic parameters. From these measurements, the area under the glucose infusion rate versus time curve from 0-6 hours (and other time intervals), the maximal glucose infusion rate, and time to the maximal glucose infusion rate were used. For the estimation of the pharmacodynamic summary measures fitting of a polynomial function to the GIR profile could be used. Standard statistical tests were used for the statistical analysis of the pharmacokinetic parameters obtained. If appropriate, a natural logarithmic transformation of the data was performed to ensure that the data are approximately normally distributed. Additional glucose measurements were analyzed as deemed appropriate, such as partial AUC values.
  • Insulin Lispro was injected intradermally with the BD Microneedle-System at varying depths, specifically at depth of 1.25 mm, 1.5 mm, and 1.75 mm.
  • the pharmacokinetic and pharmacodynamic parameters of the insulin delivered ID were compared to delivery of insulin subcutaneously.
  • the onset of systemically available insulin delivered ID is more rapid at all tliree depths as compared to SC (FIG. 1).
  • the time to reach maximum concentration is shorter (T max ) and the maximum concentration obtained is higher for ID vs. SC.
  • T max time to reach maximum concentration
  • the maximum concentration obtained is higher for ID vs. SC.
  • the depth of injection is 1.75 mm or 1.5 mm, the highest C max is obtained.
  • FIGs. 3A and B show the pharmacodynamic biological response to the administered insulin as measured by an increase in glucose infusion rate to compensate for the decrease in blood glucose due to the presence of insulin.
  • ID delivery at all depths shows a faster and greater change in the blood glucose levels as measured by glucose infusion rate.
  • the maximum glucose response levels, measured as the glucose infusion rate were similar between ID and SC delivery.
  • the primary objective of this study was to compare the pharmacokinetic and pharmacodynamic effect of 20 U 50% pre-mixed insulin lispro (Humalog® Mix 50/50TM, containing 50% insulin lispro and 50% insulin lispro protamine suspension in 100 U/mL (from Eli Lilly and Company) applied with a 1.5 mm BD Microneedle-Systems with that of 20 U 50% pre-mixed insulin Lispro applied subcutaneously.
  • Study Design 10 healthy, male subjects were used in a randomized study. Each subject was randomized to a treatment sequence consisting of three different treatments: (a) 20 Units of 50% pre-mixed insulin lispro (Humalog® Mix 50/50TM, containing 50% insulin lispro and 50% insulin lispro protamine suspension in 100 U/mL from Eli Lilly and Company) with the 31 Ga, 1.5 mm needle; (b) 20 Units of 50% pre-mixed insulin Lispro (Humalog® Mix50TM, containing 50% insulin lispro and 50% insulin lispro protamine suspension in 100 U/mL from Eli Lilly and Company) injected subcutaneously; (c) 20 Units of 50% pre-mixed insulin lispro (Humalog® Mix 50/50TM, containing 50% insulin lispro and 50% insulin lispro protamine suspension in 100 U/mL from Eli Lilly and Company) with the 31 Ga, 1.5 mm needle
  • Graphs of mean plasma insulin levels and median GIR rates are shown in FIGs. 4 and 5.
  • This study represents the pharmacokinetic (PK) and/or pharmacodynamic (PD) of particulates administered via ID administration.
  • ID administration of Lispro mix exhibits similar effects to Lispro solution (as shown in Example 6.1), i.e., faster onset (shorter T max ), higher AUC (bioavailability), higher C max .
  • ID delivery does show a reduced PD effect at later time points (>8h) indicating a reduction in late phase insulin activity vs SC delivery. This may have potential benefit for therapy by reducing the incidence of early morning hypoglycemia often encountered in diabetics on split mix therapy.
  • the primary objective of this analysis was to evaluate the effect of intradermal insulin delivery on post-prandial glucose levels.
  • the analysis focused on the effect of intradermal delivery of 10 U insulin Lispro (100 U/mL from Eli Lilly and Company) delivered using BD microneedle injection system (at a depth of 1.5 mm) and compared to Insulin Lispro delivered subcutaneously.
  • the data from Example 6.1 above was used to determine delta insulin which is the difference in the AUC of the insulin levels of the subjects who received Insulin via ID delivery with 1.5 mm microneedle and subcutaneous injection for the period indicated (e.g., 0-10 min "10", 11-20 min "20”, etc.).
  • ISF or insulin sensitivity factor was determined. ISF was determined in insulin units (not AUC) and for Insulin Lispro, this is typically determined by the "rule of 1500", i.e., dividing 1500 by the total daily insulin. For a typical patient with type 1 diabetes, the total daily insulin is about 60 U, so the ISF is 25 mg/dL/Unit insulin. From the data from Example 6.1, 10 Units of insulin produced an AUC of 780, i.e., 78 AUC units are equivalent to 1 insulin Unit. Thus, the ISF determined in AUC units was 0.33 mg/dL/ AUC unit (see, the last column of Table 2). The ISF values were used to determine the amount of extra glucose lowering expected from the extra insulin. A 25 minute delay in action of insulin was utilized. FIG. 6 shows the insulin levels for the subcutaneous injection, the intradermal injection and the difference between the 2 modes of delivery.
  • Table 3 shows the effect of the additional insulin on the expected insulin levels in a patient with type 1 diabetes.
  • the subcutaneous insulin column is the data that is often seen in patients with diabetes. After eating, glucose rises rapidly, peaks at 60-90 minutes, then as insulin acts, falls over the next few hours.
  • the column labeled TD insulin takes account of the additional and earlier insulin action (last column of table 2) to predict the glucose lowering effect of the additional insulin.
  • the effect on a glucose value measured at 2 hours would be about 60 mg/dL. The effect is plotted in FIG. 7.
  • intradermal insulin delivery results in a 60% higher biopotency relative to subcutaneous insulin delivery within the first hour of delivery. Within the first hour, insulin is absorbed rapidly and constitutes 25% of the total insulin. Intradermal insulin delivery is thus effective in controlling PPG levels.

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Abstract

La présente invention concerne des méthodes d'administration d'insuline dans le compartiment intradermique de la peau d'un patient, de préférence dans le système vasculaire dermique du compartiment intradermique. Les méthodes de la présente invention améliorent les paramètres pharmacocinétiques et pharmacodynamiques de l'injection d'insuline et aboutissent effectivement à une efficacité clinique supérieure dans le traitement et/ou la prévention du diabète sucré. Lesdites méthodes permettent une régulation glycémique améliorée de glycémies à jeun et non à jeun (c.-à-d. post-prandiale) et possèdent ainsi une efficacité thérapeutique améliorée dans le traitement, la prévention et/ou la gestion du diabète par rapport à des méthodes d'injection d'insuline classiques, y compris l'injection sous-cutanée d'insuline.
EP04751427A 2003-05-06 2004-05-06 Methode permettant de modifier la pharmacocinetique de l'insuline Withdrawn EP1620145A4 (fr)

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US10/429,973 US7722595B2 (en) 2002-05-06 2003-05-06 Method and device for controlling drug pharmacokinetics
US50095603P 2003-09-05 2003-09-05
US10/704,035 US20050010193A1 (en) 2002-05-06 2003-11-06 Novel methods for administration of drugs and devices useful thereof
US52383103P 2003-11-19 2003-11-19
PCT/US2004/014033 WO2004101023A2 (fr) 2003-05-06 2004-05-06 Methode permettant de modifier la pharmacocinetique de l'insuline

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US8465468B1 (en) 2000-06-29 2013-06-18 Becton, Dickinson And Company Intradermal delivery of substances
US10105317B2 (en) * 2009-07-07 2018-10-23 Anpac Bio-Medical Science Co., Ltd. Method of drug delivery
JP2017514810A (ja) * 2014-04-25 2017-06-08 サノフイ インスリン、インスリン類似体またはインスリンの誘導体の新規な投与経路

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WO2002083216A1 (fr) * 2001-04-13 2002-10-24 Becton Dickinson And Company Procede d'injection intradermique de substances
US20020156453A1 (en) * 1999-10-14 2002-10-24 Pettis Ronald J. Method and device for reducing therapeutic dosage
US20030050602A1 (en) * 2001-09-12 2003-03-13 Pettis Ronald J. Microneedle-based pen device for drug delivery and method for using same

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US6623457B1 (en) * 1999-09-22 2003-09-23 Becton, Dickinson And Company Method and apparatus for the transdermal administration of a substance
US20020198509A1 (en) * 1999-10-14 2002-12-26 Mikszta John A. Intradermal delivery of vaccines and gene therapeutic agents via microcannula
US6565532B1 (en) * 2000-07-12 2003-05-20 The Procter & Gamble Company Microneedle apparatus used for marking skin and for dispensing semi-permanent subcutaneous makeup
US6607513B1 (en) * 2000-06-08 2003-08-19 Becton, Dickinson And Company Device for withdrawing or administering a substance and method of manufacturing a device

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US20020156453A1 (en) * 1999-10-14 2002-10-24 Pettis Ronald J. Method and device for reducing therapeutic dosage
WO2002083216A1 (fr) * 2001-04-13 2002-10-24 Becton Dickinson And Company Procede d'injection intradermique de substances
US20030050602A1 (en) * 2001-09-12 2003-03-13 Pettis Ronald J. Microneedle-based pen device for drug delivery and method for using same

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BRPI0409984A (pt) 2006-05-09
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