Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/26—Glucagons
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/28—Insulins
• • 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
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• the present invention relates to the fields of biology, pharmacology, and medicine.
• the invention relates to compositions and methods of using compositions for the control of blood glucose levels.
• Insulin is produced by the beta cells and glucagon by the alpha cells of the Pancreatic Islets of Langerhans.
• One of insulin's major effects is to lower blood glucose by suppressing hepatic glucose output and stimulating peripheral glucose uptake. Endogenous insulin levels may be low or undetectable in some patients with diabetes mellitus. Exogenous insulin is usually administered to reduce hyperglycemia in situations where circulating insulin levels are either low or ineffective.
• Glucagon generally has effects opposite to those of insulin, including, primarily, increasing hepatic glucose output and thereby increasing blood glucose levels. Glucagon levels tend to increase when blood glucose levels fall to abnormally low levels, particularly in patients who utilize exogenous insulin.
• hypoglycemia characterized by low blood glucose levels, results in autonomic and adrenergic, as well as neuroglycopenic, symptoms; these symptoms typically are encountered as a result of inadvertent excessive insulin administration.
• hypoglycemia is defined as a blood glucose of ⁇ 70 mg/dl, e.g., greater than 50 or 60 mg/dl.
• Frequent recurrent bouts of hypoglycemia can be associated with hypoglycemic unawareness which can further contribute to development of hypoglycemia which is sometimes severe.
• efforts to achieve normal glucose levels with insulin can result in the development of hypoglycemia of varying frequency and severity in patients.
• hypoglycemia and the lack of awareness of its presence are serious complications of insulin therapy that occur with greater frequency and severity when impaired counter-regulatory (anti-insulin) responses are present in diabetic patients.
• One of the major counter-regulatory hormones that normally responds to hypoglycemia is glucagon. Not infrequently, the glucagon response to acute hypoglycemia is impaired or lost in patients with advanced Type 1 and Type 2 diabetes.
• compositions comprising both insulin and glucagon in amounts that can be administered to a diabetic patient not only to achieve therapeutically effective control of diabetes but also to prevent hypoglycemia.
• the formulations can include, for example, formulations suitable for injection, including by subcutaneous (s.c.) administration, formulations suitable for administration orally, formulations suitable for transdermal administration, formulations suitable for ocular administration, and formulations suitable for inhalation.
• the composition is configured for s.c. administration and comprises sufficient glucagon for the administration of 5 to about 20 ng/kg/min. (e.g., more than 5 to 20 ng of glucagon for each kg of a person for each minute of effectiveness) of glucagon.
• 5 to about 20 ng/kg/min. of glucagon is administered to 1-20 units of insulin.
• Administered ratios can be, for example, administered once an hour.
• the composition is suitable for administration of more 5 to about 20 ng/kg/min of glucagon for each 1-2 units of insulin administered.
• the glucagon and insulin can be kept in separate containers and are not administered at the same time, but the appropriate ratios between the two are maintained.
• the separate containers are contained in a single device suitable for administration of the glucagon and insulin, for example for administration subcutaneously; in another, two devices are used, one for each agent.
• compositions comprising insulin and glucagon are administered to a patient before the symptoms of mild, moderate or severe hypoglycemia are present.
• methods of the invention are practiced to prevent nocturnal hypoglycemia in a Type I diabetic patient being treated with insulin therapy, including intensive insulin therapy.
• the methods comprise co-administration of insulin and glucagon, wherein said insulin is administered in amounts therapeutically effective for the control of diabetes, and said glucagon is administered in amounts therapeutically effective for the prevention of hypoglycemia, and wherein both insulin and glucagon are preferably administered simultaneously with one another or contemporaneously with one another, i.e., within about four hours of each other (as when regular, LISPRO, and ASPART insulins are used) or within about six to twelve hours of each other (as when longer acting insulins are used), and in any event prior to the onset of clinically observable hypoglycemia.
• glucagon is administered before the insulin is administered.
• insulin is administered before glucagon is administered.
• the method involves maintaining the level of blood sugar above 70 mg/dL and below 180 mg/dL by the co-administration of insulin and glucagon to a diabetic patient.
• the method involves administering glucagon s.c. in an amount between about 6 and 18 ng/kg per minute of glucagon.
• 1-20 or 2-20 units of insulin are administered to a diabetic patient receiving glucagon in an amount between 6 and 18 ng/kg/min s.c.
• the method involves administering between about 8 and 12 ng/kg per minute of glucagon s.c.
• 0.1 to 2 or 2-20 units of insulin are administered to a diabetic patient receiving glucagon in an amount between 8 and 12 ng/kg/min. s.c.
• the glucagon is administered by a means other than intravenously or subcutaneously, and a dose equivalent to the s.c. dosing provided above is administered.
• methods to maintain blood glucose levels in a range that is neither hyperglycemic nor hypoglycemic comprise the co ⁇ administration of insulin and glucagon.
• glucagon formulations and modified glucagon suitable for co ⁇ administration with insulin in accordance with the present methods are provided.
• kits for preventing hypoglycemia.
• the kits preferably include insulin, glucagon, and instructions for simultaneously administering the appropriate combination thereof.
• kits include insulin, a long acting form of glucagon, and instructions for use.
• methods for restoring or preventing loss of hypoglycemic awareness or sensitivity comprise administering an amount of glucagon to a patient over a period of time that is sufficient to prevent or restore hypoglycemic awareness to the patient.
• the patient is administered insulin concurrently with the administration of glucagon.
• a pharmaceutical formulation that comprises insulin in an amount effective for the control of diabetes and glucagon in an amount effective for the prevention of hypoglycemia in a human or other mammal.
• the pharmaceutical formulation is configured to be administered subcutaneously and the ratio of insulin to glucagon is typically about 1 unit of insulin to between more than 40 milliunits to 200 milliunits of glucagon. In some embodiments, the amount of glucagon is between about 50 and 100 milliunits.
• the glucagon is a longer-acting form of glucagon. In some embodiments, the longer- acting form of glucagon contains iodine. In some embodiments, the longer-acting form of glucagon contains zinc.
• the longer-acting form of glucagon further comprises protamine.
• methods of treating diabetes in a human or other mammal without inducing hypoglycemia comprise administering insulin in an amount therapeutically effective for the control of diabetes.
• the insulin can be in an amount between 0.5 and 20 Units of insulin.
• the methods further comprise administering glucagon in a time and an amount therapeutically effective for the prevention of hypoglycemia.
• the glucagon can be administered subcutaneously and in an amount between more than 5 and less than or equal to 100 ng per kg of patient per minute of desired glucagon effectiveness.
• the amount of glucagon administered is between 6 and 18 ng per kg of patient per minute of desired glucagon effectiveness.
• the glucagon is a glucagon with a prolonged duration of action.
• the glucagon is contained in a liposomal formulation.
• the glucagon is contained in a microsphere.
• the insulin and glucagon are contained in a pump that controls administration of a drug to a patient.
• the glucagon is administered simultaneously with insulin.
• the ratio of glucagon to insulin is about more than 40 to 200 milliunits of glucagon to 1 unit of insulin. In some embodiments, 2 units of insulin are administered. In some embodiments, 10 units of insulin are administered and between 30 and 90 ng per kg per minute of glucagon are administered subcutaneously.
• kits for the administration of glucagon and insulin in amounts to prevent hypoglycemia comprise glucagon and insulin.
• the glucagon and insulin are in a ratio of 1-20 units of insulin to 32-480 milliunits of glucagon.
• the kits further comprise a means for administering glucagon subcutaneously and instructions for the administration of insulin and glucagon so that the glucagon prevents a hypoglycemic event.
• the concentration of glucagon when completely dissolved in a glycerine solution is more than 500 micrograms per milliliter but less than 2000 micrograms per milliliter.
• the glucagon and insulin are in a ratio of 1-3 units of insulin to 32-96 milliunits of glucagon.
• the means for administering the glucagon subcutaneously is a pump and said pump is configured to deliver between about 6 to 20 ng/kg/minute of glucagon.
• glucagon in another aspect, is used in an amount sufficient to prevent an onset of hypoglycemia, wherein a ratio of glucagon to insulin is between more than 40 micrograms and less than 500 micrograms of glucagon to 1-20 units of insulin. In some embodiments, the amount is sufficient to prevent an onset of hypoglycemia unawareness. In some embodiments, the amount of insulin is between 1 and 20 units and the amount of glucagon is between 41 and 200 milliunits.
• a ratio of insulin to glucagon is about between 1 and 3 units of insulin to between more than 40 and less than or equal to about 96 milliunits glucagon.
• the glucagon further comprises protamine.
• Figure 1 is a graph illustrating idealized pharmacokinetics for a mixture of regular and intermediate acting (Lente or NPH) insulin.
• Figure 2 is a graph illustrating the insulin profile of a hypothetical patient, as described in Example 1, Part A(i), showing a very simple, flat line graph (basal level set by the GLARGINE (LANTUS)) punctuated by peaks corresponding to prandial LISPRO (HUMALOG) insulin injections.
• GLARGINE LANTUS
• Figure 3 is a schematic of a drug delivery pump configured for practice of an embodiment described in Example 2.
• Figure 4 is a schematic of a drug delivery pump configured for practice of an embodiment described in Example 2.
• Figure 5 is a schematic of a drug delivery pump configured for practice of an embodiment described in Example 2.
• Figure 6 illustrates the effect of molecular weight and lipophilicity on the rate of transdermal transport in case of permeation (upper and lower gray curve for the more or less lipophilic substances, respectively) or of the TRANSFEROME® mediated penetration (black line and bullets). Dotted black bullets represent the commercial drugs in transdermal patches.
• Figure 7 is a graph illustrating the insulin and glucagon profiles of a hypothetical patient, as described in Example 3, showing for both drugs a very simple, flat line graph (basal insulin and glucagon infusions) punctuated by peaks (corresponding to prandial insulin and glucagon infusions) corresponding to when glucagon and insulin are administered in an admixed formulation.
• Figure 8 is a graph illustrating the effect of continuous glucagon infusion on mean glucagon levels, as described in Example 7.
• Figure 9 is a graph illustrating the effect of continuous glucagon infusion on mean glucose levels, as described in Example 7.
• Figure 10 is a graph comparing the effect of continuous glucagon infusion at 12 ng/kg/min. on mean glucose and glucagon levels, as described in Example 7.
• Figure 11 is a graph comparing the effect of continuous glucagon infusion at 16 ng/kg/min. on mean glucose and glucagon levels, as described in Example 7.
• Figure 12 is a graph comparing the effect of various doses of glucagon (0, 8, and 16 ng/kg/min. of glucagon) on increasing insulin levels (from about 1 to about 2.7 units). The graph demonstrates that low doses of glucagon are capable of preventing insulin induced hypoglycemia, as described in Example 8.
• Figure 13 is a graph displaying the effect of a low dose of glucagon on blood glucose levels and how it can prevent hypoglycemia, as described in Example 8.
• Methods and compositions are provided that can prevent, or significantly reduce the frequency and severity of, hypoglycemia in insulin-treated diabetic patients (both Type 1 and 2).
• the methods and compositions are employed to treat diabetes while regulating glucose levels above the levels of hypoglycemia.
• the methods and compositions can be used to replenish or restore the abnormally low glucagon responses often coincident with insulin administration, thereby preventing hypoglycemia.
• compositions and methods that can prevent or reverse the loss of hypoglycemic awareness are desirable.
• One method by which this can be achieved is to administer glucagon, or another agent that elevates levels of blood glucose as described herein, in a relatively low dose over the time period in which insulin is to act to prevent the onset of mild hypoglycemia. This can also be used to reverse or prevent a loss of hypoglycemic awareness.
• the invention provides pharmaceutical formulations of two hormones, insulin and glucagon, that are combined in molar ratios that optimize glycemic management and attenuate the incidence of or prevent hypoglycemia.
• methods and compositions for the simultaneous but separate administration of insulin and glucagon to achieve this benefit are provided. While the simultaneous administration of two hormones with activities viewed as counteracting would traditionally have appeared to have no beneficial effect, some of the present embodiments arise in part from the realization that such administration achieves the beneficial effect of preventing hypoglycemia by virtue of the buffering or blunting effects of glucagon without diminishing the beneficial effects of glucose regulation provided by insulin.
• a low amount of glucagon is continuously administered to a patient that is, has, or is going to receive insulin.
• a hyperglycemic agent such as glucagon
• a hyperglycemic agent is used to prevent the onset of iatrogenic hypoglycemia.
• some of the embodiments provide a method for controlling diabetes with a reduced risk of hypoglycemia by simultaneous administration of insulin and glucagon to a diabetic patient.
• a method of preventing hypoglycemia in a diabetic patient who is being treated with insulin and who is not suffering hypoglycemic symptoms comprising administering glucagon to the patient in an amount therapeutically effective for the prevention of hypoglycemia.
• the glucagon is administered simultaneously with the insulin.
• the glucagon is administered 10 minutes to hours before additional insulin is administered, and more preferably, 30 minutes to 60 minutes before additional insulin is administered.
• the glucagon is administered within about one minute to about four hours after said patient has last been administered insulin.
• the prevention of hypoglycemia comprises preventing the symptoms associated with hypoglycemia from becoming evident in a subject.
• the prevention of hypoglycemia is achieved through maintaining an average blood glucose level of a subject above about 70 mg/dL, or above about 50- 60 mg/dL.
• the blood glucose level of the subject is maintained under about 140-200 and at least under about 350 mg/dL.
• the subject's blood glucose level is maintained so that normoglycemia is maintained.
• any of the many different forms of insulin as well as any of the many different routes of administration of insulin, including those both approved by the FDA and in development, can be used in the presently disclosed methods and formulations.
• any of the currently available formulations of glucagon can similarly be used in the methods and formulations.
• the present disclosure provides new glucagon derivatives, new formulations of glucagon and glucagon derivatives, and methods of administering glucagon and glucagon derivatives that are particularly suited to achieve the benefits provided by some of the present embodiments, including delayed and/or extended action glucagon.
• the dosage for any patient can be determined, in light of the present disclosure, by one of skill in the art.
• the beneficial effects of some of the embodiments can generally be achieved by administering both insulin and glucagon in the ratio of about 1 unit of Insulin to about 0.02 - 40 milliunits of glucagon (0.02 to 40 micrograms), when the glucagon is administered LV.
• a unit of insulin is defined as the term is typically used for the treatment of diabetes, e.g., approximately 34.2 micrograms to approximately 40 micrograms. The amount of insulin can also be measured in international units (IU).
• a unit of glucagon corresponds to 1 milligram of glucagon. In one embodiment, the ratio is 1 unit of insulin to 0.2 to 4.0 milliunits of glucagon (0.2 to 4.0 micrograms), when the glucagon is administered LV. and the insulin is administered s.c.
• 1 unit of insulin can be administered in the amount of more than 40 to 200 milliunits of glucagon, e.g., 40 to 200 milliunits per hour to a 100 kg person for each unit of insulin administered.
• 48-150 mU, 50-120 mU, or 80-100 mU of glucagon is administered for each unit of insulin.
• the glucagon is administered subcutaneously and the ratio is about 1 unit of insulin to more than 5 to about 20 ng/kg glucagon, which amount of glucagon is administered each minute during the period of effectiveness of the insulin dose.
• 1 unit of insulin is administered, and the glucagon is administered at a rate of 8-12 ng/kg/min.
• a standard dose can be created, for example, for treating a 100 kg person for 1 hour in association with 1 unit of insulin. As will be appreciated by one of skill in the art, this dose can be for basal insulin rates. When postprandial levels of insulin are desired, the amount of glucagon in the dose will be increased accordingly.
• the glucagon is administered subcutaneously in an amount between more than 5 ng/kg/min. and less than about 20 ng/kg/min. More preferably, the amount is between about 8 and 16 ng of glucagon/kg/min for subcutaneous administration.
• the amount of glucagon administered, even through s.c. administration is less than the 5-20 ng/kg/min values described as effective in the prevention of insulin-induced hypoglycemia.
• the amount of glucagon can be increased several fold over what is disclosed herein for Type 1 diabetes.
• Type 2 diabetes can require 1.5 to 5 fold more glucagon, and preferably involves two to three fold more glucagon than Type 1 diabetes.
• any of the currently available forms of insulin including but not limited to recombinant human soluble (regular) insulin, human insulin analogs, animal insulins, derived, for example, from beef, pork and other species, as well as delayed release forms, including intermediate and long acting insulin may be used for the herein disclosed compositions and methods.
• any of the currently used routes of administration, as well as newer routes in development can be employed, including but not limited to subcutaneous, intramuscular, and intravenous injection, as well as oral, buccal, nasal, transdermal, sublingual, and pulmonary airway administration.
• Typical doses and dose ranges for the administration of insulin to control diabetes known in the art are suitable for use in the methods and compositions of some of the embodiments.
• prandial short-acting insulins such as regular insulin and the LISPRO, ASPART, and GLULISINE derivatives thereof, are well known in the art and commonly used to treat diabetes.
• Such insulins can be used to illustrate the embodiments in a manner applicable to other forms, including but not limited to NPH, LENTE, SEMI-LENTE, DETEMIR, ULTRA-LENTE, and GLARGINE (LANTUS), and pre-mixed formulations of regular and long- acting insulins.
• the molecular weights ascribed to all three of these prandial short- acting insulins are similar, with LISPRO at 5808, ASPART at 5825.8, GLULISINE at 5823 and regular insulin at 5807.
• the molecular weight ascribed to glucagon is 3483.
• the usual range of prandial insulin injections in Type 1 diabetes can be approximated as two standard deviations from the mean, resulting in an insulin dose range of 2 - 20 units. More than 95% of Type 1 diabetics will be administered a prandial insulin dose within this range.
• the three prandial insulins noted above all achieve peak serum concentrations within 1-2 hours after subcutaneous administration and have a duration of effectiveness of about 5 hours.
• hypoglycemia is treated by a single parenteral injection of glucagon in a dose of about 1 mg (1 unit); it has been determined that this dose is a gross excess of the dose actually required to control hypoglycemia.
• glucagon is given subcutaneously or intramuscularly, serum glucagon peaks within an hour, and its effects can persist for several hours.
• currently marketed forms of glucagon are not stable in liquid form, either isolated or in vivo, for prolonged periods of time, and in one embodiment, the present invention provides new pharmaceutical formulations of glucagon that are more stable, and new methods for using the stabler forms of glucagon that are currently available but not in widespread use.
• glucagon refers to a glucagon that has a half-life greater than that of standard glucagon, including both natural extract and rDNA produced synthetic glucagon.
• glucagon replacement dose a dose that approximates the basal replacement dose.
• the usual basal glucagon replacement dose by IV infusion is 0.5-0.75 ng/kg/min; one can assume that a wider range of glucagon infusions, from as low as 0.10 to 5.00 ng/kg/min (more often, 0.10 to 3.00 ng/kg/min) can be effective, depending on the patient, the insulin dose, the method of administration (e.g., LV. vs. s.c), and other factors. For example, in s.c.
• the present inventors have discovered that the amount of glucagon administered can be higher, as the bioavailability of glucagon administered by subcutaneous infusion can be as low as 10%, and as low as about 35% for bolus subcutaneous administration.
• the dose will be increased or decreased accordingly to obtain the equivalent therapeutic effect of administering glucagon at a rate of 5 to 20 ng/kg/min.
• these glucagon infusion rates would be continued for a period of time ranging from 150 minutes to 300 minutes. In some embodiments, the period of time of infusion can last longer than 6 hours, for example 6-7, 7-10, 10-15, 15-20, 20-24 hours, or longer.
• the insulin/glucagon ratios can be calculated as shown in Table 1 below (showing the ratios for s.c. administration). In one embodiment, the same calculations described above are used to determine the amount of delayed or extended release forms of glucagon to administer to a patient, taking into account that there will be a lower level of glucagon available initially and a higher amount of glucagon available later.
• glucagon While the amount of glucagon released at any point in time may not be precisely known, enough glucagon is released per unit of time from the administered formulation so that, on average, about 0.1 to 5.0 ng/kg/min. is released into the patient for embodiments in which the glucagon is administered through an LV. In one embodiment, 0.5, 2, 3, or 4 times as much glucagon may be released on any given unit of time, depending on the patient, the type of diabetes being treated, and the mode of administration.
• the glucagon is administered subcutaneously and is administered in an amount between about more than 5.0 to about 30 ng/kg/min, about 6 to 25 ng/kg/min, 6 to 20 ng/kg/min, or about 8.0 to about 12.0 ng/kg/min.
• Glue Means that a TOTAL of 2 Units of Insulin are administered over the given infusion period, and that Glucagon is administered over the period of infusion at a rate of 6 ng/kg/min.
• the glucagon is administered at, or is present in a composition at ⁇ 225% of the weight of insulin.
• the amount of glucagon administered can vary depending upon many factors. Thus, ranges of the percent of glucagon to insulin can vary between 5.6 to 675%, e.g., more than 188% to less than 675%.
• the amount of glucagon administered is expressed as a ratio to the amount of insulin administered; for example, the ratio of glucagon administered can be from 5.6 to 11.3 percent of the amount of insulin administered.
• the amount of glucagon administered is 112 to 225% of the amount of insulin administered. As shown in Example 7 below, these amounts of glucagon can induce elevated blood glucose levels that approach hyperglycemia, as such, it is likely that lower dose ranges can be sufficient to prevent hypoglycemia, without risking hyperglycemia. Lower ranges or doses can be from 0.09% to 188% of the weight of insulin, for example. As will be appreciated by one of skill in the art, the weight of the patient can vary, from infants, e.g., 2 kg to full adults, e.g., 150 kg to 200 kg, or more.
• the amount of glucagon administered can be described as an amount of glucagon by weight or activity independent of the amount of insulin administered; for example, in one embodiment, the amount of glucagon administered is 360-900 micrograms over a nine hour period. Ih one embodiment, the glucagon administered ranges from more than 5 ng/kg/min to about 30 ng/kg/min s.c. In one embodiment, the amount is about 8 to about 16 ng/kg/min, or about 12 ng/kg/min. s.c. In some embodiments, substantially lower values can be sufficient as well, depending upon the circumstances and mode of administration.
• hypoglycemia is a blood glucose level of less than about 50-60, and generally less than about 70 mg/dL
• hyperglycemia is a blood glucose level more than about 140 to 200 mg/dL
• excessive hyperglycemia is defined as a blood glucose level above 350 mg/dL.
• the ratio of glucagon to insulin and amounts of each is set, in accordance with the methods of the invention, to keep the blood sugar level effectively between the hypoglycemic level and the hyperglycemia level.
• the blood sugar level is maintained between the hypoglycemic level and the excessive hyperglycemia level.
• the blood sugar level is maintained between the hyperglycemia level and the excessive hyperglycemia level.
• the dose to be administered to a patient is therapeutically equivalent to a dose of 0.5 to 0.75 ng/kg/min of glucagon administered I.V. or is therapeutically equivalent to a dose of above 5 to about 20 ng/kg/min. s.c, i.e., 8-16 ng/kg/min of glucagon via s.c. administration.
• the same amount of glucagon or effective ratio of glucagon to insulin is used, even if an agent other than insulin is used to lower or control blood sugar levels.
• the method of the invention may be practiced with an agent other than insulin, as the co-administration of glucagon, in light of the present disclosure, with a hypoglycemic agent is contemplated.
• a hyperglycemic agent other than glucagon is used to prevent the onset of hypoglycemia in insulin treated diabetics.
• neither insulin nor glucagon is used, and a diabetic patient is simultaneously administered both a hyperglycemic agent (an agent that causes blood sugar levels to rise) and a hypoglycemic agent (an agent that causes blood sugar levels to decline).
• the amount of glucagon or insulin administered to a patient can' vary depending upon the mode of administration
• the amount of glucagon (or ratio of insulin to glucagon) to be added can be described in terms of the amount to be administered via an LV. (as in PCT Pub. No: WO 2004/060387, incorporated herein by reference).
• This amount can differ greatly depending upon how the glucagon is to be administered, e.g., subcutaneously or via inhalation.
• the amount of glucagon required to achieve an equivalent result can be described as a "dose equivalent.”
• a dose equivalent For example, a "10 ng/kg/min. s.c.
• dose equivalent is the amount required to achieve the same result as would be achieved by administering 10 ng/kg/min. to a patient subcutaneously.
• a "s.c. dose equivalent for I. V. administration” is the amount of glucagon administered intravenously that is required to obtain the same amount of glucose or glucagon in the blood achieved by subcutaneous administration of the amount of glucagon.
• the first method of administration describes what the dose administered is going to be an equivalent to using another mode of administration, and the second mode of administration recited is the mode of administration actually employed.
• An LV. dose equivalent of glucagon administered subcutaneously will typically be more than the amount recited for LV. administration, as can be seen by comparing the table above to Table 1 in PCT Pub.
• a unit to be delivered LV. is in some patients 0.1 ng/kg/min., while the amount for the same effect to be delivered subcutaneously can be 8 ng/kg/min. in those patients.
• the amounts of glucagon required to be administered to induce hyperglycemia in an insulin-treated diabetic were for some patients in the 8 - 16 ng/kg/min. range (although lower doses were seen to be effective as well), so the amounts of glucagon required merely to prevent hypoglycemia will be below that range in some patients. Given the present disclosure, one of skill in the art will be able to determine the appropriate amount in each circumstance.
• the "amount of glucagon administered" is not necessarily the amount of glucagon that actually enters the bloodstream of a patient. Rather, for example, administering 9 ng/kg/min. s.c. of glucagon to a patient means that an initial solution of an initial known amount was created, and based on that amount, 9 ng/kg/min. of glucagon is administered to a patient. If there is a loss or degradation of the glucagon prior to administration, then less glucagon enters the patient, and if there is a loss or degradation of glucagon as it progresses to the patient's bloodstream and tissues, the effective therapeutic dose is lower still. As will be appreciated by one of skill in the art, the actual amount of glucagon that is active and enters the patient's circulation will in such instances be less than, in this example, 9 ng/kg/min.
• glucagon administered through an LV. is 100% bioavailable
• certain glucagon formulations administered through a s.c. bolus can have about 35% bioavailability
• the same glucagon formulation administered by continuous subcutaneous infusion can have a bioavailability of 10%, as shown with patient data in the Examples below.
• differences between the method of administration of insulin and of glucagon can also be taken into account and determined through the methods and examples provided herein. One way this can be determined is through various assays of insulin, glucose and glucagon in a patient following various routes of administration of the glucagon, e.g., as illustrated in Example 7.
• compositions for use in many embodiments of the invention can comprise those compositions useful in conventional methods for the control of diabetes and treatment of hypoglycemia.
• conventional methods include those approved by the FDA, those in development, and those described in Diagnosis and Management of Type II Diabetes, by S. V. Edelman and R.R. Henry (5 th Ed. PCI Publishers), the entire text of which is incorporated herein by reference, and Chapters 7 and 8 of which are especially pertinent.
• a pharmaceutical formulation or pharmaceutical composition may contain a pharmaceutically acceptable excipient, diluent or carrier.
• phrases "pharmaceutically acceptable” means that the carrier, diluent or excipient is compatible with the other ingredients of the formulation and administration equiopment and not deleterious to the recipient thereof.
• Pharmaceutically acceptable excipients are well known in the art. See, e.g., Remington: TIie Science and Practice of Pharmacy (19th edition, 1995, Gennavo, ed.).
• the glucagon or similar substance is administered in a buffer.
• buffers are those that maintain the mixture at a pH range from about 6.0 to about 9.0, but which do not interfere with the function of glucagon.
• buffers include, but are not limited to, Goode's buffers, HEPES, Tris, ammonium acetate, sodium acetate, Bis-Tris, phosphate, citrate, arginine, histidine, and Tris acetate. The selection of one or more appropriate buffers is within the skill of one of ordinary skill in the art.
• the control of diabetes by insulin therapy, as well as the control of hypoglycemia by glucagon therapy, can involve parenteral administration of the insulin or glucagon.
• Parenteral administration may be performed by subcutaneous or intramuscular injection by means of a syringe, optionally a pen-like syringe.
• Some of the embodiments of the methods can be practiced using such methodology, although, as noted above, it may be preferable in some instances to provide glucagon in a manner that ensures that its duration of action more closely matches that of the insulin employed such that the glucagon is present when the risk of hypoglycemia is greatest - typically a relatively long time after eating but still within the period in which the insulin administered continues to exert its effect.
• glucagon where subcutaneous administration of insulin and glucagon are desired, a variety of methods may be employed to achieve the benefits of diabetes control and prevention of hypoglycemia.
• a glucagon with a shorter duration of action than the insulin is administered within about one to four hours after the insulin is administered.
• This method provides benefit in that most hypoglycemic episodes begin several hours after the patient has last eaten, and many patients administer insulin shortly before a meal.
• Certain embodiments provide methods for controlling diabetes with reduced risk of inducing hypoglycemia by administering insulin in continuation with a long acting glucagon and formulations thereof.
• compositions having a long acting form of glucagon are provided.
• long acting forms are also known as extended release, prolonged release or controlled release (or similar term) forms.
• delayed or slow acting glucagon is a particular form of an extended or long release form of glucagon. Delayed acting glucagon is within the general class of long acting glucagon, as delayed or slow acting glucagon will allow for glucagon activity to occur after a period of time following the administration of glucagon; however, delayed acting glucagon is effective in lower amounts at the initial administration and increases in effectiveness over time.
• the glucagon itself may be long acting in nature, or it may be combined with other components that allow its release over an extended amount of time.
• the insulin and glucagon can be administered simultaneously, with the insulin and optionally the glucagon delivered parenterally, typically by subcutaneous injection.
• a glucagon with a longer duration of action is preferably employed, or the glucagon is administered by a route that provides a longer duration of action, e.g., as by continuous infusion, as illustrated in the Examples below.
• Such glucagon includes, but is not limited to, the glucagon, glucagon formulations, and routes of administration described in U.S. patent application publication No. 2002114829 and U.S. Patent Nos. 6,197,333 and 6,348,214, which describe liposome formulations of glucagon that provide for reduced dosage effect and are long acting;
• PCT patent publication No. WO0243566 which describes the delivery of glucagon via trans-dermal patch;
• U.S. Patent No. 5,445,832 which describes a long-acting glucagon formulation in polymeric microspheres;
• PCT patent publication No. WO0222154 which describes a slow-release glucagon that can have a duration of action measured in weeks; and U.S.
• the glucagon is administered as a slow-release or depot formulation (e.g., comprising polyethylene glycol).
• an iodination method of increasing half life (as described in U.S. Patent No. 3,897,551; see form I3G) is employed.
• Iodinated glucagon has extended activity (measured in terms of elevated glucose levels) of between 1 and 3 hours, depending on the extent of iodination.
• LISPRO insulin and 13 Glucagon are admixed so that the modified glucagon is present at approximately 1.5% by weight of the insulin in the mixture (keeping the concentration of insulin per ml in the LISPRO formulation constant). Because of the longer lasting effect of the modified glucagon, a smaller proportion of glucagon to insulin by weight will be required to prevent hypoglycemia in some patients.
• Zinc protamine-glucagon formulations are known in the art (See, for example, Kaindl et al., Verh Dtsch Ges Inn Med. 1972;78:1099-101; Kaindl and Kuhn, Z Automate Inn Med. 1972 Dec 15 ;27(24): 1097-8; Christiansen and Tonnensen, Med Scand. 1974 Dec;196(6):495-6; Gamba et al., Minerva Med. 1977 Nov 3;68(53):3613-26; Kollee et al., Arch Dis Child.
• glucagon is combined with zinc without protamine, as described in Tarding et al., (European Journal of Pharmacology, 7:206-210 (1969), hereby incorporated in its entirety by reference). This also results in a long acting form of glucagon.
• the mixture involves a 1 to 2 ratio of zinc to glucagon.
• the zinc protamine glucagon is made in a manner similar to how zinc protamine insulin is made, apart from the replacement of insulin with glucagon.
• zinc glucagon and zinc protamine glucagon is made as described in Tarding et al. (European Journal of Pharmacology 7:206-210 (1969)).
• zinc glucagon can be made by suspending freeze-dried zinc glucagon crystals in a zinc acetate buffer, for a final concentration of 1 mg glucagon/ml, 0.05 mg zinc/ml.
• the zinc protamine glucagon can be prepared by suspending freeze-dried zinc glucagon crystals in a zinc acetate buffer containing protamine to a final concentration of 2 mg glucagon/ml, 0.15 mg zinc/ml, and 0.5 mg protamine/ml.
• Another example of an agent that can be included with glucagon in compositions useful in the present methods includes a protamine sulfate, as described in combination with GLP-I in U.S. Patent 6,703,365, (issued March 4, 2004, to Galloway et al.).
• the GLP-I combination therein disclosed displays an increased half-life and an increased shelf life as well. Any glucagon which displays an increased half-life can be useful in the present methods and compositions.
• the half-life of the protein may be extended is through the use of "serum binders", such as can be achieved through the conjugation of albumin to glucagon by a connector.
• the glucagon contains a moiety which allows it to attach itself to albumin in vivo.
• the glucagon may be modified such that it is able to connect to a connector, which will then allow the glucagon molecule to be associated with a protein such as albumin in vivo.
• the modified glucagon can be directly added to a patient, where it will subsequently bind to albumin in the host, which will in turn result in the extension of the useful life of glucagon in the system.
• glucagon in one embodiment, the binding between glucagon and albumin occurs with the aid of biotin and avidin or streptavidin.
• glucagon can be attached to other proteins through the use of maleimide groups and sulfur groups.
• the glucagon can be attached to any suitable protein, not only albumin.
• a prolonged release form of glucagon is a gel or fibril based form of glucagon. These may be prepared as described in Gratzer and Davies (European J. Biochem., 11 :37-42 (1969), hereby incorporated in its entirety by reference.) [0066] Other forms of prolonged release glucagon are also contemplated for use in the present methods. Long release preparations may be made using polymers to complex or absorb the glucagon. The controlled delivery may be exercised by selecting appropriate macromolecules and the concentration of macromolecules as well as the methods of incorporation to control release. For example, diffusion controlled systems may be used.
• Such materials include particles of a polymeric material such as polyesters, polyamino acids, polyvinylpyrrolidone, methylcellulose, carboxymethylcellulose, hydrogels, poly (lactic acid), or ethylene vinylacetate copolymers.
• a polymeric material such as polyesters, polyamino acids, polyvinylpyrrolidone, methylcellulose, carboxymethylcellulose, hydrogels, poly (lactic acid), or ethylene vinylacetate copolymers.
• colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano
• an osmotic pump system is used to provide a prolonged release of glucagon, allowing the rate of release of the drug to be controlled by the inflow of water across a semipermeable membrane into a reservoir that has an osmotic agent.
• ion exchange resins are used to control the release of glucagon.
• the extended release form of glucagon is a preproglucagon [Lund, et al., Proc. Natl. Acad. Sci. U.S.A. 79:345-349 (1982)].
• This polypeptide is subsequently processed to form proglucagon, which is subsequently cleaved into glucagon and a second polypeptide (Patzelt, C, et al., Nature, 282:260-266 (1979)).
• glucagon a preproglucagon
• glucagon is administered in a form that allows substantially no release of active glucagon initially, and then allows for a small amount of release of glucagon over time.
• a form of glucagon is useful when prolonged periods between drug intake will occur and the desired result is an effect towards the end of the prolonged period, for example, during nocturnal periods.
• the form may be inherent in the glucagon protein itself, i.e., a semi-synthetic glucagon variant, due to compositions associated with the protein, due to the formulations in which the glucagon is administered, due to the route and method by which the glucagon is administered, as well as other reasons as described herein.
• Glucagon with a low activity level is desirable in some circumstances. As the delivery of precise amounts of small volumes can be difficult, especially over prolonged periods of time, compositions of glucagon comprising components that lower the activity of glucagon may be desirable in some situations to allow the administration of larger volumes of sample. Alternatively, variants or mutants of glucagon with a lower activity level can be used to achieve this result.
• the term "glucagon” can encompass both wild-type glucagon and variants or derivatives of glucagon.
• a combination of an insulin component and a slow release form of a glucagon provided by the invention is employed in the methods of the invention.
• the combination may be achieved through a single or multiple formulations and single or multiple means of administering the insulin component or the glucagon component.
• parenteral administration is performed by means of an infusion pump.
• a variety of insulin pumps are available and in common use that are suitable for delivery of the insulin and glucagon compositions (as well as suitable for the delivery of insulin, with glucagon being delivered by another route, such as transdermal).
• Such pumps include, for example and without limitation, the pumps marketed by Medtronic (such as the MiniMed), Animas Corporation, Disetronic, and Dana.
• the glucagon can optionally be administered with the insulin, and a glucagon with a short duration of action can be employed, as the glucagon can be administered as necessary.
• the glucagon is administered subcutaneously and is administered in an amount between about more than 5 up to 30 ng/kg/min, about more than 5.0 up to 25 ng/kg/min, about 8.0 to 20 ng/kg/min, or about 8.0 to 12.0 ng/kg/min.
• Lower amounts of glucagon can be administered (0.1-5 or 2-5 ng/kg/min.) subcutaneously to prevent hypoglycemia in some patients.
• a dose will prevent hypoglycemia without causing excessive hyperglycemia.
• Hyperglycemia is a blood glucose above the normal range.
• Glucagon can elevate blood glucose above where it would be without the administration of exogenous glucagon, and in a preferred embodiment, the dose administered is one that is still protective against hypoglycemia but only minimally elevates blood glucose above the levels maintained in the patient when not suffering from hypoglycemia.
• the present invention provides a new drug delivery device, a pump suitable for the delivery of insulin for the control of diabetes, and for the delivery of glucagon for the control of hypoglycemia in a human, i.e., the pump contains both insulin and glucagon.
• the pump may include a reservoir containing both insulin and glucagon.
• the pump includes insulin and glucagon in two separately controlled reservoirs.
• a method of controlling diabetes in a human patient to reduce the risk of hypoglycemia is provided, said method comprising administering both insulin and glucagon to the diabetic patient using a pump of one of the embodiments described above.
• either the insulin or the glucagon or both is provided in a formulation that is a powder or a liquid suitable for administration as a nasal or pulmonary spray or for ocular administration.
• a formulation that is a powder or a liquid suitable for administration as a nasal or pulmonary spray or for ocular administration.
• a variety of such formulations are known for insulin and glucagon, and the present disclosure provides methods for using these known formulations for administering either one independently, as well as for administering the corresponding formulations of the embodiments that comprise both insulin and glucagon to control diabetes with a reduced risk of inducing hypoglycemia.
• Methods and formulations for nasal, pulmonary, or ocular administration include those in PCT patent publication Nos. WOO 182874 and WOO 182981, which describe aerosolized insulin and glucagon; European patent publication EP1224929 and U.S. Patent No. 6,004,574, which describe an inhaled glucagon with melezitose diluent; U.S. Patent No. 5,942,242, which describes formulations of insulin and formulations of glucagon suitable for nasal administration; U.S. Patent No. 5,661,130, which describes formulations suitable for ocular, nasal and nasolacrimal or inhalation routes of administration; U.S. Patent No.
• compositions and methods are provided for controlling diabetes with a reduced risk of inducing hypoglycemia by administering insulin and glucagon, in which one or both of the insulin and glucagon is administered transdermally, e.g. from a patch, optionally a iontophoretic patch, or transmucosally, e.g. bucally.
• transdermal delivery devices are well known in the art (see, e.g., US Pat. Nos. 4,943,435 and 4,839,174; and patent publication no. US 2001033858).
• the transdermal delivery of glucagon, and a patent publication describing transdermal formulations of glucagon has been cited above, and U.S. Patent No. 5,707,641 describes methods and formulations for the transdermal delivery of insulin.
• some embodiments of the methods can be practiced by oral administration of both insulin and/or glucagon in the therapeutically effective amounts and their dose equivalents described herein.
• Methods and formulations for the oral administration of insulin and of glucagon include those described in PCT patent publication No. WO9703688.
• the insulin and/or glucagon employed in the methods and formulations can be supplemented with or replaced by compounds and compositions that have similar activities or effects.
• glucagon may be replaced with glucagon mimetics or variants of glucagon.
• Insulin can be replaced or supplemented with hypoglycemic agents, including but not limited to Insulin Sensitizers, DPP IV inhibitors, and GLPl analogs, insulin secretagogues including, but not limited to, sulfonylureas such as Acetohexamide (DYMELOR), Chlorpropamide (DIABINESE), Tolazamide (TOLINASE), Tolbutamide (ORINASE), Glimepiride (AMARYL), Glipizide (GLUCOTROL), Glipizide Extended Release (GLUCOTROL XL), Glyburide (DIABETA, MICRONASE), Glyburide Micronized (GLYNASE, PRESTAB); Meglitinides such as Nateglinide (STARLIX) and Repaglinide (PRANDIN); Gastric Inhibitory Polypeptide (GIP); Glucagon-like peptide (GLP)-I; Morphilinoguanide BTS 67582; Phosphodiesterase inhibitors;
• variants of glucagon are contemplated. Such variants may comprise a single or many amino acid changes, for example, from one to all of the amino acids may be changed, relative to the native human glucagon sequence, so long as the resulting variant functions as required herein.
• the HELIX content is adjusted at the C-terminus, as well as partial agonists are combined to provide more of a "basal" input.
• transient PEG-modif ⁇ cations at the N-terminus, to control activation can be complemented with mutations introduced at the C-terminus, for controlling affinity. Examples of such variant glucagon molecules, and their resulting characteristics and activities, are available in the art.
• the variant glucagon has a Lys substitution at positions 17 and 18, and a GIu substitution at position 21, resulting in a variant with a 500 percent binding affinity and a 700 percent relative potency.
• the variant glucagon amide has only a Lys substitution at position 17, resulting in a variant with a 220 percent binding affinity and a 230 percent potency.
• the variant glucagon amide has a NIe substitution at position 17, a Lys substitution at position 18, and a GIu substitution at position 21, resulting in a variant with 150 percent binding affinity and a 300 percent potency.
• the variant glucagon molecules display low binding ability or low activity.
• a glucagon amide variant with a lysine at position 18 may be used, as it only has 36 percent of the normal binding affinity and only 12 percent of the normal potency.
• Another example would be a glucagon variant with a Phe at position 18, which has only 4.7 percent of the normal binding affinity and 0.9 percent of the relative potency.
• the only pharmaceutically active components of the formulation are insulin and glucagon.
• the pharmaceutical composition (e.g., containing both insulin and glucagon) is not formulated as an aerosol and/or does not contain troglitazone hydrochloride (and may not contain any thiazolidinedione).
• the formulation is not administered orally and/or is not administered nasally.
• the pharmaceutically active components of the formulation are administered transdermally, but not through a patch.
• the active components can be administered through the use of a cream.
• the combination of glucagon and insulin is administered to a patient to prevent the loss of hypoglycemic awareness by the subject.
• the glucagon and insulin are administered so as to ⁇ restore hypoglycemic awareness to the subject. This can be achieved by administering an amount of glucagon so that additional episodes of hypoglycemia are reduced or prevented.
• the amount can vary, e.g., 8-16 ng/kg/min. administered subcutaneously.
• these therapies and compositions can be useful not only for people with diabetes but with anyone taking insulin or other hypoglycemia inducing agent.
• hypoglycemia need not be prevented in every case and can be delayed in some embodiments. Any amount of delay can be useful, for example, a delay of 1-10, 10-30, 30-60, 60- 120, 120-300, 300-600 or more minutes.
• not all of a patient's sensitivity to hypoglycemia needs to be restored or preserved e.g., 1-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-99, 99-100% can be restored or prevented from loss.
• "Hypoglycemic sensitivity" or “hypoglycemia unawareness” can be based on the individual's ability to detect the occurrence of a hypoglycemic event.
• hypoglycemia unawareness can be an inability to detect 1-20, 20-40, 40-50, 50- 70, or more percent of the hypoglycemic events (e.g., glucose levels fall below 50 mg/dL in the blood).
• the inability to detect a particular symptom of hypoglycemia can also be used to determine hypoglycemia unawareness and how successfully it is being treated. Signs and symptoms include, for example, shakiness, dizziness, sweating, hunger, headache, irritability, pale skin color, sudden moodiness or behaviour changes, clumsy or jerky movements, difficulty paying attention, confusion, and a tingling sensation around the mouth.
• hypoglycemia A description of various possible categories of hypoglycemia can be found in "Defining and Reporting Hypoglycemia in Diabetes” Diabetes Care, 28:1245-1249 (2005), hereby incorporated by reference in its entirety/
• symptomatic, asymptomatic, and probably symptomatic hypoglycemia involve plasma glucose levels below or equal to 70 mg/dl.
• lower levels of blood glucose can also be used as a threshold. Kits
• the compositions described herein are provided in kit form.
• the kit comprises a vial of glucagon, a vial of insulin, a means for administration, such as a syringe or pump, and instructions for the administration of the glucagon and insulin.
• the glucagon and insulin are premixed in a single vial.
• the insulin and glucagon are premixed in a syringe.
• the particular instructions will vary depending upon the desired use of the kit, e.g., for nocturnal control of hypoglycemia or otherwise. The instructions can be determined by one of skill in the art, given the present disclosure and the particular use intended for the kit. In one embodiment, the instructions will describe the methods disclosed herein.
• kits contain glucagon and one or more of the following packaged together: (1) insulin; (2) a solution (e.g., excipient) for resuspending or diluting glucagon (3) a device for administering glucagon and/or insulin; and (4) instructions.
• the device (3) contains the glucagon and/or contains insulin.
• a kit may comprise glucagon in a powder form within a sterile vial with a standard septum seal.
• the vial contains a mixture of 1 mg of lyophilized glucagon, 49 mg lactose, and hydrochloric acid to adjust the pH (glucagon is soluble below pH 3 or above pH 9.5).
• the kit also has a pre-filled glycerine syringe, which contains 12 mg/ml of glycerine in a mixture of water, and hydrochloric acid.
• a second container holds a 1 mg/mL solution of insulin, which may be stored in liquid form in a syringe.
• the kit further has instructions, instructing the user to inject 1 mL of diluent from the pre-filled glycerine syringe into the vial.
• the instructions then direct the user to collect an amount of the glucagon/glycerine solution into the syringe containing the insulin. This amount will vary depending upon intended use and the particular user and may be determined by a physician. [0089] In one embodiment, the volume of glucagon collected in the syringe is between 0-5% of the volume of insulin to be injected.
• the kit may comprise tables and/or charts allowing for ease of use and customization to determine what amount or ratios should be used for each user and situation.
• the entire dose in the insulin syringe can then be injected (children are typically administered 50% of a standard dose, and the kit can be modified accordingly).
• the insulin syringe and the glycerine syringe are one and the same, in which case the starting amount of glucagon is lower to maintain the appropriate ratio of glucagon to insulin that is injected.
• the insulin, glucagon and glycerine are premixed in the kit. Instructions are adjusted accordingly for the particular embodiment used.
• the kit comprises a glucagon kit, an insulin kit, and instructions for how to combine the two kits.
• any of the above discussed compositions or methods may be included in the kit as components or instructions.
• various methods of administration, various compositions of insulin or glucagon, and various buffers or solvents may be used in the kits.
• a means of administering insulin rapidly is combined with a means of administering glucagon more slowly.
• the kit comprises only a form of glucagon with a set of instructions.
• the instructions can direct the user to administer more than 5 to 20, e.g., 6 to 16, ng/kg/min. of glucagon subcutaneously.
• the kit can include a device for subcutaneous administration.
• the units of glucagon are in a 36 microgram size dose for a 50 kg person, one dose to be taken each hour.
• the units of glucagon are in 36 to 96 microgram size doses, for a 100 kg person, one to be taken each hour.
• kits include instructions regarding doses for the age, weight, and sex of the individual.
• the instructions include information concerning doses to take in view of future activities, such as sleeping, eating (e.g., how much and what type of food), sitting, or exercising.
• an LV. or s.c. dose equivalent can also be used if glucagon is to be administered in another manner.
• kits contain unit doses of glucagon to be added with the insulin.
• a unit dose can be about 50 or 100 micrograms (or milliunits), which can be sufficient to protect a 100 kg subject for a one hour period from hypoglycemia.
• Unit doses can be prepared for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24 or more hours or days. Smaller doses for smaller people or fractional hours are also contemplated.
• Unit doses of Glucagon can be about 50 or 100 micrograms (or milliunits), which can be sufficient to protect a 100 kg subject for a one hour period from hypoglycemia.
• Unit doses can be prepared for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24 or more hours or days. Smaller doses for smaller people or fractional hours are also contemplated.
• Unit doses of Glucagon are also contemplated.
• unit doses of glucagon alone are provided so as to be readily administrable to a subject as required, to prevent insulin-induced hypoglycemia.
• the amount of glucagon in the unit dose can also be low.
• the actual amount of glucagon in each dose will depend upon the characteristics of the individual, possible activities that the individual is going to do or has done, how the dose is to be administered and the form of the glucagon.
• the doses described below are only representative of some of the possible doses. The dosage can be determined by the skilled practitioner in view of the present disclosure.
• a unit dosage form of glucagon contains a discrete quantity of glucagon for administration, and may be in the format of tablets, capsules, or powders in a container such as a vial or ampoule, cartridge, syringe, inhaler, transdermal patch, or other container or package.
• the amount of glucagon in a unit dose can be, for example, from 0.036 mg to 0.4 mg for a 100 kg person, which dose should be effective for at least 1 hour.
• the unit dose is between about 40 micrograms and 300 micrograms, and more preferably, between about 50 and 100 micrograms.
• these numbers can be adjusted based on the size of the average person to be treated and the duration of hypoglycemia prevention desired per unit dose. For example, with slow release formulations, it can be particularly advantageous to include sufficient glucagon for release over 2-3, 3-5, 5-8, or more hours. Thus, larger doses are possible, in certain circumstances. Lower amounts, even through s.c. administration, can also be used to ensure that hyperglycemia does not even transiently occur.
• a single unit dosage form contains sufficient glucagon for a single administration of glucagon as described herein.
• Unit dosages can be designed for particular events. For example, they can be designed for use before or after the administration of insulin. Alternatively, they can be designed for administration in view of activities such as eating or exercising or going to sleep. As the amount of glucagon to be administered will depend upon various factors of a patient, such as lifestyle and weight, the unit dose can be expressed in universal units for ease of adjusting the dose. Additionally, how the unit is to be administered can also alter the amount of glucagon one places in each unit dose. These universal unit dosages are actually unit doses that are divided into smaller individual parts.
• a 50 kg individual can take 5 parts of these universal unit doses, while a 100 kg individual might take 10 parts.
• This allows greater customization of the glucagon intake.
• lower amounts of glucagon e.g., similar to LV. administration, can also be used if lower levels of elevated blood sugar are satisfactory.
• a unit dose can be between 0.036 mg and 0.2 mg, for example.
• a pharmaceutical preparation of glucagon in daily unit dosage form contains sufficient glucagon for one day, including the case in which glucagon is administered multiple times during a single day as described herein.
• glucagon is administered multiple times during a single day as described herein.
• 960 to 4800 micrograms of glucagon can be provided for administration over a day.
• the glucagon is in a slow release form that is given all at once. In another embodiment it is in the form of, for example, 6 pills, one to be taken every four hours.
• a pharmaceutical preparation of glucagon in multiple dosage form is provided.
• a multiple dosage form of glucagon can contain a sufficient dose for administration for one, two, three, four, five, or six days, one week, or even more than one week.
• 0.02 to 0.036 mg to 1 mg of glucagon is provided in a container accompanied by instructions (e.g., a label) that the glucagon should be administered as separate doses over the course of a day or more than one day.
• a daily dose or multiple dose of glucagon is prepared by resuspending a powder in a liquid excipient, and a portion of the resulting solution can be administered at each administration during the day (or several days in the case of some multiple dose forms).
• the unit dosage form, daily dosage form or multiple dosage form can include other components, such as excipients, buffers, stabilizers, carriers and the like, as well as other pharmaceutically active agents.
• the unit dose includes insulin or an insulin secretagogue.
• glucagon e.g., multiple daily doses
• glucagon can be packaged together in a box, bubble-wrap, or in other well known formats.
• the dosage forms will be labeled or will be accompanied by instructions for proper dosing.
• the daily dosage form may be labeled to indicate the number and/or weight or volume of unit doses in the container.
• the dosage forms may also be labeled or otherwise indicate the age of the patient for whom the preparation is intended.
• the dosage form may be indicated as suitable for adults, children over 15 years of age, children over 10 years of age, children over 5 years of age, and the like.
• any of the above glucagon dosages may comprise a extended release glucagon.
• the dosage is appropriately adjusted, as disclosed herein, to maintain a blood glucose level within the desired ranges.
• Administration of low doses of glucagon can be inconvenient using formulations prepared according to conventional methods (e.g., resulting in an approximately 1 mg/ml solution). Accordingly, in some embodiments, a lower concentration glucagon solution is made and/or administered.
• Administration includes self-administration (whether by injection, by infusion using a pump, or other methods) and administration by another.
• glucagon is administered as a solution having a concentration of less than about 0.25 mg/ml, for example, less than about 0.2 mg/ml, less than about 0.1 mg/ml, less than about 0.05 mg/ml, less than about 0.01 mg/ml, or even less than about 0.005 mg/ml of glucagon.
• concentration of less than about 0.25 mg/ml for example, less than about 0.2 mg/ml, less than about 0.1 mg/ml, less than about 0.05 mg/ml, less than about 0.01 mg/ml, or even less than about 0.005 mg/ml of glucagon.
• Such amounts can be appropriate for LV. administration and dose equivalent amounts can be created for other methods of administration. For example, if the method of administration is s.c.
• the concentration of glucagon can be higher, at least about 0.01 mg/ml, or 0.05 mg/ml, or, 0.2 mg/ml, 0.5 mg/ml, or between about 0.5 mg/ml and 2 mg/ml of glucagon.
• these doses are combined with a device that can administer the doses in low amounts over a prolonged period of time, such as a pump.
• Glucagon can be resuspended in any pharmaceutically acceptable carrier, diluent or excipient.
• a pharmaceutically acceptable formulation of glucagon contains a concentration of less than about 0.25 mg/ml, less than about 0.2 mg/ml, less than about 0.1 mg/ml, less than about 0.05 mg/ml, less than about 0.01 mg/ml, or even less than about 0.005 mg/ml when it is to be administered I. V., or a dose equivalent amount for other methods of administration.
• a pharmaceutically acceptable formulation of glucagon contains between 0.5 and 2 mg/ml of glucagon.
• a method of preparing a glucagon formulation for therapeutic use involves adding an aqueous solution to a composition comprising glucagon (such as, but not limited to, a single unit dose, daily dose or multiple doses of glucagon as described above) in a quantity that results in a solution containing glucagon at a concentration of less than about 0.25 mg/ml, less than about 0.2 mg/ml, less than about 0.1 mg/ml, less than about 0.05 mg/ml, less than about 0.1 mg/ml, or even less than about 0.05 mg/ml for LV. administration. Concentrations 2 to 10 fold higher (or more) can be used for other methods of administration, such as subcutaneous administration.
• the solution can contain other agents, both pharmaceutically active and/or inactive.
• the glucagon solution is loaded into, or is contained in, a device for delivery to a patient.
• the device contains at least about 0.1 ml, at least about 0.2 ml, at least about 0.3 ml, at least about 0.4 ml, at least about 0.5 ml or more than 0.5 ml of a glucagon solution.
• the further step of administration or self-administration to a human subject with diabetes is provided.
• the subject does not exhibit symptoms of hypoglycemia.
• the human is an adult.
• the human is older than 10 years old, and optionally older than 15 years old or older.
• the subject is not suffering from a stomach ailment.
• any of the above glucagon solutions may comprise an extended release glucagon.
• the dosage is appropriately adjusted, as disclosed herein, to maintain a blood glucose level within the desired ranges described herein.
• the methods and compositions disclosed herein may be used to treat human patients as well as other mammals (e.g., rats, mice, pigs, non-human primates, and others).
• the human patient is a child or juvenile; in one embodiment the human patient is an adult.
• the patient is a Type I diabetic.
• the patient is a Type ⁇ diabetic.
• the patient is a brittle Type I or Type II diabetic.
• the non-human mammal is an animal model for the study of diabetes, e.g., Zucker diabetic-fatty (ZDF) rats, and db/db mice.
• ZDF Zucker diabetic-fatty
• subcutaneous doses described herein are generally greater than 5 and less than 20 ng/kg/min.
• other doses are also contemplated for the various embodiments described herein.
• doses from 0.1 to 5 ng/kg/min. for LV. or s.c. administration, especially in combination with long acting forms of glucagon (such as zinc protamine), various kits, and unit doses are contemplated along with the more than 5 to 20 or 30 ng/kg/min. doses.
• doses at 4 ng/kg/min., and lower, of s.c. glucagon can also be effective in preventing or delaying hypoglycemia.
• the dose administered subcutaneously to prevent or delay hypoglycemia is about 0.1-5, 1, 1-2, 2-3, 3-4, 4-5, more than 5, 5-6, 6-8, 8-12, 12-16, 16-20, or 20-30 ng/kg/min.
• Corresponding amounts for unit doses, other doses for administration, or kits are also contemplated. For example, a 1 hour unit doses of glucagon for a 100 kg person at 4 ng/kg/min.
• any of the disclosed doses can be turned into one hour unit doses or other aspects described herein given the present disclosure. This can depend upon dose amount (e.g., 0.1 to 30 ng/kg/min. or 6 to 16 ng/kg/min.), presence and amount of insulin (e.g., 0 or 2-20 Units), the size of the patient (e.g., 3-200 kg), and the number of hours of desired effectiveness (e.g., 0.5-24 or more).
• dose amount e.g., 0.1 to 30 ng/kg/min. or 6 to 16 ng/kg/min.
• presence and amount of insulin e.g., 0 or 2-20 Units
• the size of the patient e.g., 3-200 kg
• the number of hours of desired effectiveness e.g., 0.5-24 or more.
• the glucagon currently available in the North American market is human glucagon of rDNA origin produced either by Eli Lilly & Co or Bedford Labs (Novo).
• Four brand names are known: Glucagon Diagnostic Kit (Lilly); Glucagon Emergency Kit (Lilly); Glucagon Emergency Kit for Low Blood Sugar (Lilly); and GLUCAGEN (Bedford Labs).
• Novo produces glucagon under its own name outside of North America. Novo produces its glucagon in yeast, and Lilly produces its glucagon in E. coli.
• the following examples illustrate practice of some of the methods using such commercially available glucagons and insulins administered via a variety of routes.
• the Lilly glucagon is typically provided in kit form.
• the glucagon within the kit is in the form of a powder within a sterile vial with a standard rubber-sealed neck.
• the vial contains a mixture of 1 mg of lyophilized glucagon, 49 mg lactose, and hydrochloric acid to adjust the pH (glucagon is soluble below pH 3 or above pH 9.5).
• the patient injects 1 ml of diluent from a pre-filled syringe (which contains 12 mg/ml of glycerine in a mixture of water, and hydrochloric acid) into the vial.
• the vial is shaken until the solution is clear.
• the liquid is returned to the syringe, and the entire dose is injected (children are typically administered 50% of the standard dose).
• Glucagon is administered parenterally by subcutaneous, intramuscular, and intravenous routes, with the pharmacokinetic properties differing accordingly as understood by those of skill in the art.
• Maximum plasma concentration is achieved approximately 20 minutes after subcutaneous administration. The half life in vivo ranges from 8 to 18 minutes. Peak plasma concentration of approximately 8 ng/ml are achieved after approximately 20 minutes, and elevated glucose levels persist for approximately Wi hours after administration and begin rising almost immediately following administration. Patients with insulin-induced coma will typically recover consciousness within 15 minutes of glucagon administration.
• Parenteral glucagon when given to treat hypoglycemia, does so primarily by increasing serum glucose availability through increased output of glucose by the liver (the conversion of glycogen to glucose and formation of new glucose by gluconeogenesis).
• insulin dosage regimes There are a wide variety of insulin dosage regimes in use. The regime used depends on whether Type 1 or Type 2 diabetes is being treated and on a large number of factors specific to the individual being treated. It is normal medical practice to replace insulin using a combination of parenterally administered insulins (usually subcutaneously) of rapid onset/short acting duration (LISPRO (HUMALOG) or ASPART (NOVOLOG)), slower onset/short acting duration (regular human insulin), intermediate duration (NPH or LENTE), long acting duration (ULTRALENTE), BASULIN (Bristol Myers Squibb) and 24 hour peak-less duration (GLARGINE (LANTUS) and DETEMIR).
• parenterally administered insulins usually subcutaneously
• LISPRO HUMALOG
• ASPART NOVOLOG
• slower onset/short acting duration regular human insulin
• NPH or LENTE intermediate duration
• UTRALENTE long acting duration
• BASULIN Billristol Myers Squibb
• GLARGINE LANTUS
• the dosage regimes can be quite complex.
• a typical twice-daily regimen might involve administering short acting and intermediate duration insulin before breakfast and supper.
• the insulin profile thus obtained has a number of peaks, which roughly correspond to the anticipated post-prandial glucose output, as well as providing a basal insulin level throughout any 24 hour period. This is illustrated in Figure 1, which shows the idealized pharmacokinetics for a mixture of regular and intermediate acting insulin.
• the graph shows the effect of a twice-daily insulin regimen: Twice-daily administration of regular (solid lines) and intermediate-acting LENTE or NPH (dashed lines) insulins before breakfast and the evening meal provides peaks of insulin after the injections as well as a relatively constant baseline level of insulin throughout the day after injections of the intermediate-acting insulins.
• Insulin levels can vary significantly between individuals and even within the same individual, depending on factors such as site and depth of injection, local blood flow, total volume and type of insulin injection, and other factors appreciated by those of skill in the art. Thus, there can be significant inter and intra-patient variability in subcutaneous absorption of insulin, which increases the likelihood of variations in serum glucose, including the possibility of hypoglycemia.
• GLARGINE LANTUS
• DETEMIR is a long acting insulin in development
• ULTRALENTE is a long acting insulin but tends to have some peak effect in most patients
• the basic methodology is to replace basal insulin and prandial insulin through the combined use of insulin preparations having different rates of onset and durations of action. This may involve the use of separately administered insulins of differing onset, (e.g. GLARGINE and LISPRO) or the use of various pre-mixed formulations (e.g. 70/30 - 70% NPH and 30% regular combined), which are commercially available for this purpose.
• the point at which the glucagon is administered is before, during, or immediately prior to the period when insulin action is most unopposed, for example when significant insulin action persists in the absence of sufficient serum glucose availability.
• insulin-induced hypoglycemia may occur whenever there is a mismatch between circulating insulin and glucose levels (a relative excess of insulin effect to glucose availability).
• the patient (all patients referred to herein are fictitious, except for any reference to patients in the examples describing actual clinical testing; any resemblance to an actual person is coincidental) is an adult male, 50 years of age, weighing 75 kg, with 5 L of blood, suffering from type-2 diabetes and using insulin therapy (without concomitant oral combination therapy). He has been using insulin for over 10 years and his glucagon response to hypoglycemia is minimal.
• His insulin regimen involves basal insulin replacement using GLARGINE (LANTUS) subcutaneous injections at a dosage level of 20 units administered at bedtime in addition to prandial insulin injections of LISPRO (HUMALOG), ASPART (NOVOLOG), GLULISINE (APIDRA) of between 5 and 10 units (depending on the amount of carbohydrate consumed) administered at mealtimes.
• GLARGINE LANTUS
• His insulin profile is very simple, being a flat line (basal level set by the GLARGINE (LANTUS)) punctuated by peaks corresponding to the prandial LISPRO (HUMALOG), ASPART (NOVOLOG), GLULISINE (APIDRA) insulin injections. This insulin profile is shown in Figure 2.
• glucagon In this patient, the risk of hypoglycemia typically arises between 2 and 5 hours after the meal. It is during this period that administering glucagon is most efficacious and effective in preventing the possibility of a hypoglycemic episode.
• glucagon In non-diabetics, glucagon usually falls following a carbohydrate meal (in response to increased glucose levels) and then recovers subsequently as glucose levels return to normal.
• type-1 diabetics and type-2 diabetics of 5 years or more
• the glucagon response to low serum glucose is limited. Hence, if insulin causes the serum glucose level to drop well below the basal level, hypoglycemia will ensue.
• hypoglycemic symptoms are typically observed in diabetics at glucose levels less than 50 mg/dl, or sometimes less than 40 mg/dl.
• glucagon release would be augmented (by about 40 pg/ml or higher, e.g. augmented by about 60 pg/ml or higher) before glucose levels fell this low and would prevent the onset of hypoglycemic symptoms.
• glucagon production or regulation
• administering glucagon to achieve these levels during the period of susceptibility will prevent or attenuate the severity of hypoglycemic attack.
• the s.c. dose of glucagon required to provide prophylaxis is in some embodiments about 6-20 ng/kg/min. for basal insulin levels, and a proportionally higher amount for higher levels of insulin.
• this patient is administered 41 to 90 micrograms of glucagon subcutaneously after the meal.
• Two similar doses are administered hourly for an additional two hours. This makes three doses at hours 2, 3, and 4, providing protection from hypoglycemia for 3 hours beginning 2 hours after the meal.
• formulations comprising both insulin and glucagon, one can use a lower percentage of glucagon (5.6%), as the risk and degree of hypoglycemia is (in part) insulin-dose-dependent.
• the glucagon concentration from the dose administered 2 hours after the meal will have fallen back to approximately basal levels after an hour, the elevation of blood glucose due to this dose will persist for more than one hour, giving time for the second dose to take effect.
• the same pharmacokinetics applies to the third dose of glucagon.
• two doses or even one dose of glucagon can be administered.
• a typical diabetic patient is an adult male, 63 years of age, weighing 75 kg, suffering from Type 2 diabetes for 18 years and using combination insulin therapy (without concomitant oral anti-diabetic therapy).
• oral anti-diabetic medications including Glyburide and Glipizide, but these will have been stopped and insulin started when his serum glucose levels were consistently above 250 mg/dl.
• He will have been using insulin of one type or another for over 10 years and will have developed evidence of background retinopathy, mild renal impairment with a serum creatinine of 1.9 mg/dl and creatinine clearance of 60 ml/min, mild proteinuria, bilateral distal symmetrical neuropathy in both feet, and exertional angina.
• His insulin regimen would typically involve a split-mixed regimen of subcutaneous NPH insulin, 20 units before breakfast and 15 units before dinner, which is intended to provide day-long basal insulin coverage plus modest postprandial coverage for lunch and the evening meal (and bedtime snack).
• regular insulin of between 6 and 10 units (depending on the level of pre-meal serum glucose as well as the size and carbohydrate content of the meal) before these meals.
• His insulin profile is similar to that shown in Figure 1, with less rapid peaks and slower decays resulting from the prandial injections of regular insulin and slower onset and delayed decay effects from the twice daily intermediate acting NPH insulin.
• His fasting glucose levels are typically well controlled in the range of 90-130 mg/dl, but his 1-2 hour postprandial glucose levels are suboptimal and generally range from 180 to 240 mg/dl.
• Glycosylated hemoglobin is elevated at 7.9% (normal range 4-6%).
• Efforts to increase his breakfast or evening meal dose of prandial regular insulin to reduce postprandial glucose levels is usually accompanied by frequent intermittent hypoglycemia, of mild to moderate severity, often 1-2 hours before lunch or several hours after dinner.
• hypoglycemia can be quite severe and associated with symptoms of sweating, tremors, nausea, and headaches, particularly when he is late for meals. He has never had insulin-induced hypoglycemic coma but is reluctant to increase his insulin dosage in case this happens. He fears that he could lose his driver's license if this occurs or perhaps his job as a night watchman. Because of this patient's long history of diabetes and presence of significant complications, it is expected that he will exhibit impaired glucose counter-regulation to hypoglycemia, especially manifest as a blunted or absent glucagon response.
• hypoglycemia In this patient, the risk of hypoglycemia is usually greatest between 3 and 5 hours after a meal (late postprandial hypoglycemia), when circulating insulin levels are still increased above fasting level but glucose availability (from gastrointestinal absorption and liver production) is minimal. It is during this period, prior to the onset of hypoglycemia, that the administration of glucagon would be most efficacious and effective in preventing the possibility of hypoglycemic episodes by increasing circulating glucose availability. In non-diabetic individuals, both insulin and glucagon are tightly regulated following a meal to balance glucose production and utilization so as to maintain normoglycemia. Should insulin effects become pronounced, glucagon levels will rise to offset this hypoglycemic potential.
• this patient is administered 36-96 milliunits of glucagon, administered subcutaneously (optionally using Eli Lilly's Glucagon Emergency Kit, as described above) two to three hours after each meal.
• the glucagon is added when glucose measurements indicate glucose levels are approaching hypoglycemic levels. This administration provides the required protection between hours 3 and 5, as described above.
• glucagon injections are optimally timed and vary depending on the insulin regimen used but are designed to achieve sustained glucagon levels during the expected periods of relatively unopposed insulin action.
• this situation tends to occur at several times throughout the day. For example, hypoglycemia is prone to occur when the "tail" of injected regular insulin absorption combines with peaking insulin availability from the intermediate acting NPH. This situation occurs several hours after breakfast when serum glucose availability (primarily from gut absorption and liver production) is minimal or decreasing. Similar situations also often occur before dinner, at bedtime, and in the middle of the night. Thus, for all insulin dosage regimens, the timing of glucagon injection can vary depending upon the pharmacologic characteristics and timing of the insulin(s) used.
• Example l.A.i uses a pump to administer his insulin requirement. Instead of administering basal insulin by GLARGINE (LANTUS) once daily as in Example l.A.i, the patient's insulin pump is programmed to provide a continuous stream of rapid-onset insulin (e.g. LISPRO or ASPART). In this example, he administers ASPART in doses of between 5 and 10 units at mealtimes according to the pre-meal glucose level and the amount of carbohydrate and calories consumed. The patient will then, in accordance with this method, administer glucagon (using Bedford Lab's GLUCAGEN product, for example) two hours after the meal and repeat the dose hourly for another two hours.
• GLARGINE LANTUS
• ASPART rapid-onset insulin
• This amount can be about 36 to 96 micrograms of glucagon, delivered s.c.
• the glucagon is administered subcutaneously. This administration provides protection from hypoglycemia between hours 2 and 5, as described in Example LA.i.
• the glucagon can also be administered via a pump. In an alternative example, the amount of glucagon is scaled up per unit of insulin; thus, 36-96 micrograms are used per unit of insulin.
• the patient is a 62 year old, lean Type 2 diabetic of 6 years duration. He was initially treated with Glyburide 20 mg twice daily and subsequently with the addition of Metformin 1 gram twice daily, but fasting and postprandial blood glucoses were consistently in the range of 200-350 mg/dl. He is advised by his physician that insulin is required. The oral anti-diabetic medications are discontinued and GLARGINE (LANTUS) insulin 15 units is administered at bedtime to provide his day-long basal insulin replacement needs.
• GLARGINE LANTUS
• Postprandial insulin is administered by transdermal patch to provide 2-6 units of rapidly acting insulin (patches available in 2 unit increments; although this example refers to use of a patch, those of skill in the art will appreciate that substantially similar methodology can be employed to practice the embodiment with insulin or glucagon delivered transdermally by other means, such as creams or lotions).
• he is offered the 24-hour basal insulin replacement patch instead of once daily GLARGINE.
• the basal insulin replacement patch contains insulin in a unique formulation designed to provide steady continuous absorption and low constant serum insulin levels throughout the day. Because of persistent elevation of fasting plasma glucose, his physician progressively increases his dose of GLARGINE insulin over 6 months to 24 units and transdermal patches to 4-10 units. With this increase in GLARGME and transdermal insulin dosage, fasting glucose levels ranged from 70- 110 mg/dl and 1-2 hour postprandial glucose levels from 130-180 mg/dl within 3 months.
• the patient applies the rapidly-acting insulin patches 30-60 minutes prior to meals. This timing is chosen so that absorption of the meal coincides with insulin patch absorption kinetics and action.
• This patient has near normal glycemic control as indicated above but begins to suffer from early morning hypoglycemia, typically at 1 or 2 a.m. At these times, this hypothetical patient is frequently confused, irritable, and at times anxious.
• Several readings of finger-stick glucose taken during these events reveal blood glucose values of 35- ⁇ 0 mg/dl with prompt resolution of symptoms with ingestion of juice.
• his physician gradually decreases the evening dose of GLARGINE, but this is associated with deterioration in glycemic control and, primarily, elevation of pre-prandial glucose levels.
• the physician increases the GLARGINE insulin back to 24 units at bedtime and prescribes administration of subcutaneous glucagon at 18 ng/kg/min. of intended protection (using Bedford Labs Glucagon product) immediately following the injection of GLARGINE at ⁇ 23:00.
• the time of administration of glucagon depends primarily on the rate of absorption, which is rapid, reaching peak levels within 15-30 minutes, and a duration of action of approximately 2 - 3 hours.
• plasma glucagon approximating "high normal basal levels" is maintained during this period and prevents an unopposed action of insulin from GLARGINE insulin or a delayed action of the early evening (pre- dinner) patch.
• glucose levels of more than 120-160 mg/dl are contemplated.
• the low end of the normal glycemic levels are set as a goal for the blood glucose level. This therapy provides the required protection from hypoglycemia for approximately 3 hours after the GLARGINE injection, as described above. With the addition of bedtime glucagon to his diabetes regimen, the early morning hypoglycemic episodes should resolve and day-long near- normal glycemia be preserved.
• a s.c. or i.v. dose equivalent of glucagon can also be administered in the same manner as the insulin (e.g., transdermally via patch or cream).
• D. Insulin by Inhalation including Pulmonary. Buccal, Nasal and Sublingual]
• Example l.Ai This example is similar to Example l.Ai, except the patient administers insulin by inhalation rather than by subcutaneous injection. It will be understood by those skilled in the art that similar methods apply when insulin is administered buccaly, nasally, or sublingually in accordance with these methods, although a dose equivalent amount will be applied.
• the patient will either continue to administer his basal need via GLARGINE (LANTUS) or he will utilize an insulin inhaler to administer basal insulin needs.
• the patient will administer his prandial insulin need (equivalent to between 5 and 10 units administered by subcutaneous administration) using his insulin inhaler (either pulmonary, nasally, buccaly, or sublingually).
• the patient will then subcutaneously administer 45 micrograms of glucagon (optionally using Lilly's Glucagon kit) two hours after the meal and another two doses hourly thereafter. He will administer the glucagon subcutaneously. This will provide the required protection from hypoglycemia between hours 2 and 5, as described in Example l.A.i.
• the glucagon can also be administered via inhalation, in a dose equivalent amount. As will be appreciated by one of skill in the art, the precise amount of glucagon administered can vary and can be determined for various amounts of insulin, via the method shown in Example 8 below.
• insulin can be administered by pump.
• pumps There are a number of pumps commercially available (or soon to be available) in the US market and elsewhere that are suitable for use in the present methods. These include but are not limited to:
• a single device with a single pump and two reservoirs for dual reservoir pumps, see, for example, U.S. Patent No. 5,474,552) with each drug delivered through 2 separate lines that are merged prior to cannulization;
• implantable pumps may be used in almost exactly the same way as is achieved using external pumps.
• Embodiment (1) above minimizes trauma to the patient on cannulization, reduces cost, simplifies infusions, and minimizes complexity.
• the single pump can be programmed to deliver appropriate volumes from each reservoir, each containing different concentrations of one of the two hormones.
• An example of such a pump is provided herein.
• the internal pump mechanism usually comprises an electromagnetically driven pulsatile pump having a solenoid operated piston mounted for reciprocation within a cylinder to draw medication from an internal storage chamber (reservoir), and to deliver such medication through the delivery line and then via a cannula or micro-cannula to the patient.
• an electromagnetically driven pulsatile pump having a solenoid operated piston mounted for reciprocation within a cylinder to draw medication from an internal storage chamber (reservoir), and to deliver such medication through the delivery line and then via a cannula or micro-cannula to the patient.
• delivery lines used with pump insulin are typically one-half to one meter in length with lumen diameters of the order of 1/1 Oth of a millimeter (dead volume of the order of a 1/lOth of a milliliter or about 10 IU of Insulin), the time delay between a new drug reaching the body and the time at which the pump starts infusing it is likely to be substantial (about half a day).
• one embodiment provides pumps with lines of much shorter length and/or of very small internal lumen diameter that enable the lag time between a switch in drugs to be much shorter.
• the present embodiment also provides peristaltic type pumps acting on two delivery lines.
• One embodiment provides a system comprising a pump and a set of four valves, two immediately before and two immediately after the pump, which when operated in pairs, control which drug is pumped.
• the two lines are, in one embodiment, merged at the point of cannulization, thereby eliminating the lag or (dead volume) time.
• the extra space required for the electronically actuated micro-valves is minimal and adds little bulk or expense and can be assembled using commercially available devices. Additional possibilities involving the use of fewer than 4 valves are described below.
• an economical pump system suitable for use in some of the methods is a micro-pump known as MEMS (Micro-Electro-Mechanical System), being developed for diabetes by Debiotech under the brand name Chronojet.
• MEMS Micro-Electro-Mechanical System
• the use of two such micro-pumps in a unitary device adds little bulk and only minimal expense to existing designs.
• the two delivery lines can be merged (in the sense that the two drugs come into direct contact) at the point at which they connect to the cannula or similar micro-needle device used to puncture the skin and deliver the drug.
• a single split-lumen (dual lumen) line is used instead of two physically separate lines.
• This method has the advantage that the patient has only to route one flexible delivery line rather than two.
• two standard lines physically adhered along their lengths can be used in accordance with some embodiments of the methods to achieve the same advantage.
• the pump is a currently used insulin pump modified to have two drug reservoirs instead of one, each being independently administered by a single (or dual) pump and a single control system to manage the quantity and relative timing of administration of the two drugs.
• the device can in some embodiments comprise 1, 2 or 4 valves and appropriate connective tubing. Schematics of devices that can be used in accordance with some of the methods are shown in Figure 3, 4, and 5.
• the insulin reservoir (1) and the glucagon reservoir (2) have lines in fluid communication with pump (3) and then on to the cannula (5) via split lumen delivery line (4) by way of 4 valves (6) and (7). When valves (6) are open and valves (7) are closed, only insulin is pumped.
• valves (6) When valves (6) are closed and valves (7) are open, only glucagon is pumped. In this way, a single pump may be used to deliver insulin or glucagon to the patient, either simultaneously or separately, with minimal mixing of the two substances by virtue of delivery through a split lumen delivery line in which the liquids only mix at the cannula, i.e. the point of deliver.
• the insulin reservoir (1) and the glucagon reservoir (2) have lines in fluid communication with pump (3) and then on to the cannula (5) via split lumen delivery line (4) by way of 2 valves (6) and (7). These are 2-way valves that allow either the insulin path or the glucagon path to be open - but only one at a time.
• the glucagon delivery is automatically administered over the appropriate period (for example continuously between the 3rd and 5th hours following the manual instruction to deliver the prandial insulin).
• the control logic required to produce such a sequence of events can be programmed into the pump.
• FIG. 1 This example illustrates how some of the methods can be practiced using pump- based administration.
• a typical hypothetical patient is an adult male, 35 years of age, weighing 75 kg, having type-1 diabetes since the age of 15 and using insulin therapy from the time of diagnosis. He has been on a number of different insulin regimens previously with less than optimal glycemic control. In the last 5 years, he has begun to develop significant background retinopathy, mild renal insufficiency, and hypertension, and is concerned that these complications will continue to progress rapidly unless he is able to improve glycemic control from his current glycosylated hemoglobin level of 7.8%.
• ULTRALENTE 22 units, at bedtime and LISPRO insulin, 4-8 units, just prior to each meal and snack.
• the dose of ULTRALENTE has been adjusted to provide basal replacement of insulin, while the dose of prandial LISPRO varies depending upon the prevailing pre-injection serum glucose and total calories and carbohydrate content of each meal.
• the pump provides a continuous feed to simulate basal insulin over the long term.
• the patient uses ASPART (NOVOLOG) as his insulin of choice.
• the pump, reservoir, and control mechanism in this illustrative case, the MEDTRONIC MINIMED PARADIGM INSULIN PUMP
• the patient has programmed the device to deliver 1 IU of insulin every 50 minutes (20 units a day).
• the device programs the device to release an amount of insulin (between 3 and 8 units) appropriate to his meal situation (pre-meal glucose, total calories, and carbohydrate content). He does this by pushing the appropriate buttons on the device (or by use of a remote control device, if available) to select the size of the insulin bolus required.
• the patient is instructed to practice as follows. After taking a meal, the patient administers his prandial insulin (3-8 units) and at the same time programs his glucagon pump to administer about 162 ⁇ g of glucagon per hour subcutaneously over three hours and timed to begin 2-3 hours after administration of his prandial insulin.
• the above instructions are included in a kit with a composition for the control of hypoglycemia.
• the continuous release of glucagon produces a smoother profile with less of a peaked appearance and decay period than with a single subcutaneous injection of glucagon.
• glucagon The increased availability of glucagon during this patient's period of greatest susceptibility to hypoglycemia substantially decreases both the likelihood and severity of such events.
• the dosage of infused insulin can be increased to maintain euglycemia during the period of glucagon administration.
• the patient is provided with sufficient glucagon to serve as a cushion or buffer to the unopposed action of insulin so as to prevent the risk of a hypoglycemic episode.
• the administration of glucagon enables the patient to maintain good glycemic control without the excessive risk of frequent and severe hypoglycemia.
• glucagon can be administered by pump and insulin administered parenterally, including by pump or other subcutaneous administration.
• pumps suitable for insulin administration are also suitable for glucagon administration.
• Insulin can be administered parenterally as described in Example l.A.i. Instead of injecting glucagon as described in Example l.A.i, however, the pump is programmed (or actuated) to deliver glucagon continuously between hours 2 and 5 after the meal. The total dose of glucagon released is approximately 121-324 milliunits over those three hours, this being sufficient to provide protection from hypoglycemia.
• insulin can be administered transdermally.
• the patient administers his insulin needs by use of transdermal patch (or cream).
• the patient uses an insulin pump (containing not insulin but glucagon) to administer glucagon to prevent hypoglycemia in the early morning.
• the patient programs his pump to deliver 50-120 milliunits of glucagon to be administered subcutaneously between the hours of 01:00 and 02:00, the period during which he is most susceptible to hypoglycemia.
• the patient is able to maintain euglycemia using the methods of the present embodiment, without the risk of hypoglycemia occurring during his sleep.
• Example l.A.i the patient administers insulin by inhalation rather than by subcutaneous injection. It will be understood by those skilled in the art that similar methods can be employed when insulin is administered buccaly, nasally or sublingually. The patient will either continue to administer his basal need via GLARGINE (LANTUS), or he will utilize an insulin inhaler to administer basal insulin needs. The patient will administer his prandial insulin need (equivalent to between 5 and 10 units administered by subcutaneous administration) using his insulin inhaler (either pulmonary, nasally, buccaly or sublingually).
• GLARGINE LANTUS
• an insulin pump (containing glucagon rather than insulin) is programmed (or actuated) to subcutaneously deliver glucagon continuously between hours 2 and 5 after the meal.
• the total dose of glucagon released is approximately 121-500 milliunits over those three hours, this being sufficient to provide the patient with protection from hypoglycemia during his period of greatest susceptibility.
• Some embodiments of the methods of the invention can also be practiced using pump-based administration of an admixture of both insulin and glucagon.
• This method provides protection from hypoglycemia in direct proportion to the amount insulin used and with a built in delay. It also replaces basal levels of glucagon throughout the day and especially after meals, as it will also be administered with the basal insulin administered by the pump.
• This embodiment can be practiced using standard pumps currently available and described in Example 2.
• the insulin cartridges used will contain a mixture of insulin and glucagon (optionally modified release glucagon), with the glucagon component being between 41-96 mU to be administered each hour of desired protection (prevention of hypoglycemia).
• the amount of glucagon administered subcutaneously can be about 6 ng/kg/min. of desired protection to about 20 ng/kg/min. of desired protection and is in some embodiments 12 ng/kg/min.
• the insulin/glucagon mixture is then administered by pump (for both basal and prandial insulin).
• the resulting glucagon (modified glucagon) plasma concentrations will map onto the insulin profile but with the attenuating characteristics of the glucagon variant used. This is illustrated in Figure 7. This method will provide protection from hypoglycemia over the period of susceptibility as required.
• the pump is equipped with a glucose sensor (see U.S. Patent No. 5,474,552).
• CO-ADMINISTRATION OF GLUCAGON AND INSULIN, ORALLY, FOR THE CONTROL OF DIABETES AND PREVENTION OF HYPOGLYCEMIA [0166]
• the delivery of large molecules (e.g. proteins) orally is well known in the art. Typically this involves enteric administration (see U.S. Patent. No. 5,641,515).
• similar methods are used to deliver glucagon orally.
• the patient takes an enteric tablet containing insulin appropriate to his prandial up to an hour before eating.
• the insulin component is designed for rapid onset once it begins release.
• the glucagon component is designed to release later than the insulin component, in one embodiment by 2-3 hours.
• modified glucagon with a long half life can be used to ensure that glucagon levels are elevated over an extended period. Administered in this way, the glucagon will be correctly and appropriately timed to prevent hypoglycemia.
• the patient administers his insulin using any of the methods described herein and administers a glucagon pill as required, for example, with each of his meals, to prevent hypoglycemia.
• This Example demonstrates one composition of one embodiment of the invention that was found to be useful for the storage of a glucagon and a method of one embodiment of the invention for verifying that the composition for storing glucagon provides the desired degree of stability for the glucagon.
• GlucaGen ® was mixed in 5% mannitol in Water For Injection at 200 ⁇ g/mL and 500 ⁇ g/mL in infusion pump cartridges. This solution was kept at 3O 0 C for set durations of time. Following the set durations, the pH and remaining percent glucagon were tested. The percent of remaining glucagon was determined by HPLC analysis.
• Results are presented below in Table 2 for 200 ⁇ g/mL GlucaGen ® and Table 3 for 500 ⁇ g/mL GlucaGen ® . Results are from 3 sets of tests and the data is expressed as mean ⁇ s.e.m.
• This example demonstrates a composition and one method of one embodiment of the invention by which such a composition can be analyzed to determine the lifetime of a glucagon solution experiencing active, or "wear," use.
• Samples of Glucagon Infusate at 200 ⁇ g/mL and 500 ⁇ g/mL in 5% mannitol solution were prepared.
• An aliquot of approximately 3 mL of each Glucagon Infusate sample was added to an individual cartridge in triplicate.
• Cartridges were inverted 10 times and a 0.5-mL aliquot was removed from each as "Time Zero" for HPLC analysis.
• the filled cartridges were placed on a Platform Shaker set at 50 RPM and incubated at 3O 0 C for 24 hours. At 3, 6, 9, 12 and 24 hours the cartridges were removed from the oven, inverted 10 times and a 0.5-mL aliquot was dispensed from each for HPLC analysis. Appearance and pH were also recorded at each time-point.
• GlucaGen® in 5% mannitol at 200 ⁇ g/mL showed 25 % glucagon loss after being stored at 30 0 C for 12 hours, and about 50% glucagon loss after being stored at 30 0 C for 24 hour.
• GlucaGen® in 5% mannitol at 500 ⁇ g/mL exhibited 7% loss over 24 hours.
• concentrations of glucagon e.g. 200 ⁇ g/mL
• a substantial amount of glucagon remains in solution after extended periods of time.
• the greater concentration of glucagon results in a more stable formulation, even through active shaking of the formulation for 24 hours.
• the glucagon or variant thereof is stored at high concentrations.
• High concentrations may be, for example, greater than 100 micrograms/mL.
• high concentrations are more than 200, 200-300, 300-400, 400-500, 500, 500-600, 600-800, 800 or more ⁇ g/mL glucagon, up to the saturation (or super-saturation) limit,.
• less active forms of glucagon are stored at higher concentrations. This allows for greater stability of the glucagon solution and for one to administer a larger volume of glucagon solution to a recipient.
• This example demonstrates the effectiveness of applying a low dose of glucagon to a patient via a particular route of administration to elevate the blood glucose level of the patient.
• This example describes clinical testing in which the level of glucagon required to increase glucagon and glucose blood levels was examined. As explained in more detail below, the results show that the methods of some embodiments of the invention can be used to avert insulin induced hypoglycemia.
• glucagon was administered subcutaneously by continuous infusion pump. The specific doses administered were 8, 12 and 16 ng/kg/min; each dose level was infused for 3 hours. Patients were maintained on their standard basal levels of insulin by continuous subcutaneous pump administration prior to the administration of the glucagon.
• glucagon doses may be used to prevent hypoglycemia in other patients, but the doses of 8 ng/kg/min. and higher exemplified here are effective in preventing hypoglycemia.
• the actual minimal amount can vary between patients, and given the present disclosure, one of skill in the art can readily determine what the minimal amount can be for a particular patient.
• the levels achieved in the present example with VLD glucagon in amounts of 12 to 16 ng/kg/min are similar to the levels seen in non-diabetics in response to conditions of experimentally-induced hypoglycemia.
• This example demonstrates that insulin induced hypoglycemia (a blood glucose less than 50 mg/dl for this example) can be prevented with low doses of continuously administered glucagon.
• the study was arranged in three visits. The first visit involved increasing the amount of insulin administered to the subjects without supplying any glucagon; the subjects' blood glucose levels were monitored. This first study defined the insulin challenge needed to induce hypoglycemia in these patients.
• two different doses of glucagon were administered to the patients and the patients' blood glucose levels monitored to determine whether the glucagon prevented or delayed any hypoglycemia that would have otherwise been induced by the insulin challenge.
• the glucose levels measured in the first visit with those in the later two visits, one is able to determine whether the glucagon prevented hypoglycemia.
• each subject's basal insulin rate was titrated upward (in 50% increments every 90 minutes (for example, from a basal rate of 1.0 unit/hour, to 1.5 units per hour for 90 minutes, to 2.0 for 90 minutes, to 2.5)) to induce hypoglycemia (blood glucose less than 50 gm/dl).
• hypoglycemia blood glucose less than 50 gm/dl.
• the results for one patient are shown in Figure 12, with visit 1 represented by squares.
• the lower set of lines trace the increases or decrease of insulin administered to the subject.
• the insulin administered was returned to basal rate of infusion (and glucose administered) after 12:30; thus, the spike after 12:30 is to be expected.
• Blood sugar levels were allowed to vary between 50 mg/dL and 350 mg/dL. Glucose levels lower than 50 mg/dL were considered indicative of hypoglycemia.
• glucagon Two different doses of glucagon were examined, a dose at 8 ng/kg/min. (triangles) and a dose at 16 ng/kg/min. (circles). The results of these low doses of continuous glucagon on blood glucose levels are shown in Figure 12. As shown in Figure 12, the 8 ng/kg/min. dose of glucagon (triangles) maintained a higher level of blood glucose in the patient compared to the test in which no glucagon was administered. Again, the control line, (no glucagon, only increasing insulin, squares) effectively ended at 12:30; past this point on the graph, no insulin was administered, and thus the comparison should be made between 7:00 and 12:30. Hypoglycemia was delayed for approximately two hours.
• the 16 ng/kg/min. dose (circles) maintained blood glucose levels substantially above the control level and even above the 8 ng/kg/min. (triangles) glucagon dose for a substantial period of time. Additionally, while the 8 ng/kg/min. dose was able to prevent hypoglycemia and kept blood glucose levels above 50 mg/dL, the 16 ng/kg/min. dose maintained blood glucose levels closer to 100 mg/dL. This indicates the effectiveness of both of these ranges, as well as dose dependency.
• the lines in the lower section of the graph represent the steps in insulin infusion over the time of the test.
• the lower square marked line is indicative of insulin levels during visit 1
• the lower circle and triangle marked lines are indicative of insulin levels during visits 3 and 2 respectively.
• the above methodology can be used to determine the appropriate amount of glucagon to administer to a particular patient. For example, testing patients who take greater amounts of insulin, for example 2-10, 10-20, 20-30, or more units of insulin per hour in this fashion can be used to determine the appropriate dosing regimen for glucagon to prevent hypoglycemia. In the above example, insulin amounts were increased by 1.5 to about 2.5 fold. In one embodiment, one increases the amount of glucagon proportionally as one increases the amount of insulin and then determines (via the above methodology) if the new glucagon dose is correct to prevent hypoglycemia. In this fashion, one can determine the appropriate dosage of glucagon for a particular patient.
• glucagon is administered only 99-90, 90-80, 80-60, 60-40, 40-20, 20-10, 10-1 percent, or less of the time.
• variations in the method of administration can also be examined using this methodology.
• this methodology can be modified to determine the appropriate timing of the administration of glucagon to the patient.
• the glucagon can be administered 1 hour before the insulin level is adjusted, and can be increased to 90 minutes or more or decreased to 45 minutes or less, for example, to determine if better control of glucose blood levels is maintained.
• the time of administration and method of administration can influence the dose requirements. Additionally, the importance of various additives can also be examined through the above methodology.
• This example describes a clinical trial for demonstrating that glucagon administered in accordance with the present methods will function as desired in maintaining a desired blood glucose level.
• the method also provides means to determine the optimal ratio of insulin to glucagon for administration to a particular patient to prevent insulin-induced hypoglycemia.
• the plasma glucose is maintained between approximately 100 and 125 mg/dl through adjusting the basal insulin rate and, if necessary, with the use of IV 5% Dextrose (if the plasma glucose decreases below 90 mg/dl) and IV Insulin (if their plasma glucose increases above 160 mg/dl).
• Blood is also drawn to measure free fatty acids, ketone bodies, glucagon and insulin levels every 15-30 minutes from 0800 to 1200 hr.
• CSII continuous subcutaneous insulin infusion
• the plasma glucose levels of the study subjects does not decrease to hypoglycemic levels ( ⁇ 60 mg/dl), due to the simultaneous continuous subcutaneous infusion of glucagon, which counteracts the glucose lowering effects of the high basal dose of insulin.
• the dose of the continuous glucagon infusion is titrated upwards by 25% to counter the fall in plasma glucose.
• This example demonstrates one method for demonstrating that a composition, for example, of glucagon, glucagon variants, or formulations thereof, is effective in preventing blunt insulin induced nocturnal hypoglycemia in humans. Additionally, it provides a method for testing the effectiveness of a glucagon or variant or formulation of either for preventing nocturnal hypoglycemia.
• glucagon subcutaneously to the subject to prevent the blood glucose level from entering an undesirable, hypoglycemic level (e.g., less than 50 mg/dL).
• blood glucose levels can be measured throughout various time points in a test period to ensure that the subject's glucose level does not drop below a certain point (e.g., less than 50 mg/dL). Such testing can also be used to optimize the dose of glucagon administered to the patient.
• glucagon chronic, i.e., through the preventive administration of a low dose of glucagon, a patient will avoid hypoglycemia and so not develop hypoglycemic unawareness due to repeated hypoglycemic episodes through prolonged insulin use.
• a patient suffering from a loss of hypoglycemic awareness can be identified by screening to determine if the patient can identify when his or her blood glucose levels have dropped below 70 mg/dl of blood glucose. Once identified, one then administers an appropriate dose, in one embodiment that dose is 8-16 ng/kg/min., of glucagon subcutaneously to the subject to prevent the blood glucose level from declining to a level (e.g., less than 50 mg/dL).
• an appropriate dose in one embodiment that dose is 8-16 ng/kg/min., of glucagon subcutaneously to the subject to prevent the blood glucose level from declining to a level (e.g., less than 50 mg/dL).
• Blood glucose levels can be taken throughout various time points to determine that the subject's glucose level has not dropped to a hypoglycemic point. These measurements can also be used to optimize the amount of glucagon administered to the patient. Through the administration of glucagon, a patient will experience fewer hypoglycemic episodes, and his or her awareness of hypoglycemia will improve. The subject's awareness of hypoglycemia can be tested, as described above, by determining if the subject can identify when his or her blood glucose level is below a certain point (e.g., 70 mg/dl).
• a certain point e.g. 70 mg/dl
• transdermal patches for the delivery of therapeutic drugs is increasingly more common. Patches provide a non-invasive and easy method of delivering some drugs to the bloodstream. Nicotine and hormone replacement therapies are perhaps the best known uses of this technology.
• One of the characteristics of drug delivery by transdermal patch is that the rate of delivery is typically constant and persists for a long period of time (as long as the patch is worn). This characteristic has proven beneficial in the area of pain management (FENTANYL) and nicotine replacement therapy, in which long duration flat profiles are ideal. This characteristic makes the transdermal patch suitable for basal replacement of insulin or glucagon. See PCT patent publication No. WO0243566, incorporated herein by reference.
• a variety of possible patch structures and matrices can be employed, with the specific type selected according to the specific mode of use intended.
• Glucagon patches can be formulated to provide post-prandial glucagon for protection from hypoglycemia or basal glucagon replacement.
• the invention can be practiced using patch matrices comprising combinations of these basic types, either together in the same matrix or separately in sub-matrices.
• a matrix containing insulin and glucagon for basal replacement of both insulin and glucagon • matrices which are composed of 2 or more sub-matrices, each sub matrix being one of the matrices described above.
• Topical creams can be used as an alternative to a patch.
• prandial insulin matrices For prandial insulin matrices, short acting insulins such as LISPRO (HUMALOG), ASPART (NOVOLOG), or GLULISINE (APIDRA) can be used.
• the prandial insulin matrix is typically applied at or at some time before mealtimes, according to its rapidity of onset.
• a prandial insulin patch which minimizes the time to onset can be used so that the patch is applied near to mealtimes.
• the time to onset depends on the insulin concentration and the nature of the formulation. For example, a simple wet-matrix of insulin has slower onset than an insulin patch formulated according to U.S. Patent No. 5,707,641. Monomeric insulin will act faster and be more easily absorbed than larger clusters of insulin molecules, because molecular size impacts bioavailability from transdermal patches.
• a number of different methods of managing the delivery of prandial insulin can be utilized.
• patches of different concentrations can be used for fixed periods of time, and the concentration selected by the patient would depend on the amount of carbohydrate eaten.
• the duration for which the patch is worn could be fixed.
• the patch would not necessarily be exhausted on removal, i.e. it could deliver a fixed concentration throughout its use.
• single concentration prandial patches could be employed as follows. The time the patch is worn is varied according to the amount of carbohydrate eaten. The patch would not necessarily be exhausted on removal, i.e. it could deliver a fixed concentration throughout its use.
• prandial patches containing fixed doses of insulin could be used.
• the advantage of a self-exhausting patch is that failure to remove them does not of itself carry the risk of hypoglycemia. Such a patch would be substantially exhausted on removal and the rate of infusion would be front loaded.
• the prandial insulin patch used has a variable insulin concentration (appropriate to the amount of carbohydrate consumed), has a very rapid onset (preferably immediate but not more than one hour), is removed or deactivated after a fixed length of time (preferably from between 3 and 5 hours) and activated at (or no longer than one hour before) mealtimes.
• Prandial glucagon patches are applied at mealtimes or at some predetermined time after the meal according to the rapidity of onset associated with the patch.
• the rate of onset is determined both by the concentration of the glucagon used and the nature of the formulation used. For example, a simple wet-matrix of glucagon would be expected to have a slower onset than a glucagon patch formulated according to the techniques described in U.S. Patent No. 5,707,641.
• the glucagon patch is constructed so that peak output of glucagon is reached at some time between 2 and 5 hours after application. This patch is applied at mealtimes.
• the amount of glucagon in the patch will be an amount sufficient to deliver to the patient an amount equivalent to more than 5-30 ng/kg/min., and even more preferably, 8-16 ng/kg/min. of glucagon administered subcutaneously.
• a number of different patch constructions can be used. These include:
• prandial insulin and prandial glucagon are administered by transdermal patch.
• This can be achieved in a variety of ways, including: (i) use of a single matrix of glucagon and insulin admixed; (ii) use of a single compartment with two sub matrices, one containing insulin and the other containing glucagon; (iii) use of a single patch containing two compartments, one containing insulin and the other containing glucagon, both compartments being activated and deactivated simultaneously; and (iv) use of two separate patches (or two compartments in a unitary patch), one containing insulin and the other containing glucagon, each patch or compartment being independently activated and deactivated.
• Basal insulin is delivered parenterally as described in Example l.A.i by subcutaneous injection of a long-acting insulin such as GLARGINE or ULTRALENTE.
• a long-acting insulin such as GLARGINE or ULTRALENTE.
• method (i) is used. If different matrices are used to achieve the desired pharmacokinetics, then method (ii) or (iii) can be used. If the timing of insulin onset and glucagon onset is not matched, then method (iv) can be used.
• method (ii) above is used.
• the user activates the prandial patch at mealtimes (or preferably within one hour before mealtimes), thereby activating both sub-matrices at the same time.
• a fixed concentration patch is used, the user removes the patch after a period of time proportionate to the amount of carbohydrate ingested.
• a variable concentration patch is used, then the user removes the patch after a fixed period of time, typically between 1 and 3 hours after eating. In one embodiment, fixed concentrations are used. In such an embodiment, the amount of glucagon administered can be increased with the amount of insulin administered.
• both the insulin and glucagon are administered transdermally.
• Two different types of patch or independently actuated compartments can be employed.
• One patch (or compartment) contains a matrix designed to replace basal insulin over a 24 hour period.
• a single patch (or compartment) containing both the prandial insulin and glucagon in separate sub-matrices with onset times appropriate to applying the prandial patch (or activating the prandial compartment) at (or near) mealtimes can be used.
• a unitary device containing four independently actuable compartments is used, one containing basal insulin, which is activated on application and left active for 24 hours, and the other 3 compartments containing the prandial insulin and glucagon in separate sub-matrices within the same compartment, each compartment being separately activated at mealtimes and deactivated at some time after the meal, the time of activation being proportional to the amount of carbohydrate consumed.
• the patient activates one of these prandial compartments [e.g. by pulling away a hermetic plastic seal between the patch and the skin], a process which initiates the transdermal infusion of the insulin and glucagon.
• the prandial compartment is deactivated [e.g. by replacing the barrier used to activate the compartment or the total removal of that compartment from the end of the patch].
• the insulin formulation in the insulin sub-matrix is short acting insulin, and the patch is designed for rapid onset.
• the glucagon formulation in glucagon sub-matrix is designed to reach efficacious concentrations in the bloodstream between 1 and 3 hours after activation of the compartment, hence providing protection from hypoglycemia at the appropriate part of the cycle as described in Example 13.A.i.
• a unitary device which allows for more than 3 meals a day may easily be devised by allowing for more than 3 prandial compartments.
• the prandial drugs may be contained in totally separate (and independently actuated) prandial patches.
• the prandial patch may consist of separate insulin and glucagon compartments so that each may be independently activated and deactivated.
• a unitary device containing separate and independently controlled compartments for insulin and glucagon could have 7 separate compartments, one for basal insulin, 3 for prandial insulin, and 3 for prandial glucagon.
• the basal patch is designed to replace basal insulin (worn for 24 hours before being replaced).
• the insulin used may be any insulin suitable for transdermal delivery.
• the basal insulin compartment may also optionally contain an amount of glucagon (admixed or in a sub-matrix) sufficient to supply basal glucagon over each 24 hour period. This would have the beneficial effect of providing protection from hypoglycemia throughout the day and in particular during sleep.
• the amount of glucagon in the patch can be an amount sufficient to deliver to the patient an amount equivalent to more than 5-30 ng/kg/min. of subcutaneously administered glucagon, for example, more than 6-20 ng/kg/min., and for another example, 8-16 ng/kg/min. of glucagon. Greater amounts of glucagon can be present when more than 0-3 Units of insulin are to be administered. For example, a greater amount of glucagon can be present when 3-20 Units of insulin are to be applied in one hour. Alternatively, the same amount of glucagon is present regardless of the amount of insulin.
• insulin is delivered by inhalation, as described above.
• Inhalation can be the mode for delivery of only the prandial insulin delivery (basal being delivered parenterally), or all insulins used can be delivered by inhalation.
• the patient administers an amount of insulin appropriate to his or her meal by inhalation (in one or more actuations).
• the patient can optionally increase the insulin after a meal as appropriate.
• the glucagon is administered by patch as described in Example 13.A.i.
• the patch (or set of glucagon compartments in a unitary patch) is attached to the skin, and the patch or (sub compartment) is activated at mealtimes.
• the patch is designed to have slow onset, so that the glucagon is only present in the body in efficacious quantity after 2 hours.
• the patch is worn for 4 hours before being removed, the residual glucagon in the body being sufficient to provide protection from hypoglycemia over the required period of 2-5 hours.
• the glucagon in the patch is a long acting glucagon (e.g. iodinated glucagon).
• the patch may then, in some embodiments, be worn for a shorter time while still ensuring that the protection afforded by the modified glucagon is provided over a period of 2-5 hours.
• the user can apply the glucagon by means of a transdermal cream, which acts similarly to a transdermal patch (an amount equivalent to at least about 8-16 ng/kg/min. of glucagon administered subcutaneously can be administered through the cream).
• a transdermal cream which acts similarly to a transdermal patch (an amount equivalent to at least about 8-16 ng/kg/min. of glucagon administered subcutaneously can be administered through the cream).
• the formulation of such a cream can differ from the formulation used in a patch but perform essentially the same function.
• Example l.A.i the patient's insulin needs are met by parenteral administration.
• the glucagon is administered by patch as described in Example 13.A.i.
• the patch (or set of glucagon compartments in a unitary patch) is attached to the skin and the patch or (sub compartment) is activated at mealtimes.
• the patch is designed to have slow onset, so that the glucagon is only present in the body in efficacious quantity after 2 hours.
• the patch is worn for 4 hours before being removed, the residual glucagon in the body being sufficient to provide protection from hypoglycemia over the required period of 2-5 hours.
• the glucagon in the patch is a long acting glucagon (e.g. iodinated glucagon).
• the patch may then be worn for a shorter time while still ensuring that the protection afforded by the modified glucagon is provided over the required period of 2— 5 hours.
• the user may apply the glucagon by means of a transdermal cream, which acts similarly to a transdermal patch.
• the formulation of such a cream can differ from the formulation used in a patch but performs essentially the same function.
• glucagon When glucagon is administered in this way, it may be advantageous to encapsulate the glucagon in liposomes or TRANSFEROMEs® to prevent the glucagon from drying on the skin and reducing bioavailability.
• liposomes or TRANSFEROMEs® When glucagon is administered in this way, it may be advantageous to encapsulate the glucagon in liposomes or TRANSFEROMEs® to prevent the glucagon from drying on the skin and reducing bioavailability.
• the patient's insulin needs are administered by pump as described in Example 2.
• the glucagon is administered by patch as described in Example 13.A.i.
• the patch (or set of glucagon compartments in a unitary patch) is attached to the skin and the patch or (sub compartment) is activated at mealtimes.
• the patch is designed to have slow onset, so that the glucagon is only present in the body in efficacious quantity after 2 hours.
• the patch is worn for 4 hours before being removed, the residual glucagon in the body being sufficient to provide protection from hypoglycemia over the required period of 2-5 hours.
• the glucagon in the patch is a long acting glucagon (e.g. iodinated glucagon).
• the patch may then be worn for a shorter time while still ensuring that the protection afforded by the modified glucagon is provided over the required period of 2-5 hours.
• the user may apply the glucagon by means of a transdermal cream, which acts similarly to a transdermal patch.
• the formulation of such a cream may differ from the formulation used in a patch but performs essentially the same function.
• glucagon is administered in this way, it may be advantageous to encapsulate the glucagon in liposomes or TRANSFEROMEs® to prevent the glucagon from drying on the skin and reducing bioavailability.
• a number of dry powder inhalation technologies are currently in development, including: Aradigm's AERx®, Inhale Therapeutics' Exubera®, Alkermes' and EH Lilly's AIR, Insulin Technospheres (Mannkind/PDC), and Aerogen's and Disetronic's Aerodose.
• Methods and devices for delivering insulin to the pulmonary alveoli, where it may be absorbed into the blood stream are described in U.S. Patent Nos. 5,997,848; 6,131,567; 6,024,090; 5,970,973; 5,672,581; 5,660,166; 5,404,871; and 5,450,336.
• the main difficulties that had to be overcome to enable aerosol macromolecular delivery were: low system efficiency (bioavailability); low drug mass per inhalation (c.f. asthma); and poor dosing reproducibility.
• Bioavailability depends primarily on the aerosol particle size (most existing systems only deliver 10%-20% of the drug administered to the alveoli) rather than on the nature of the drug being administered. When the drug being delivered actually reaches the alveoli, its bioavailability is then very high almost regardless of the drug in question. Because the technical problems (and solutions) associated with delivering insulin are similar to those for delivering glucagon, the solutions enabling delivery of insulin are directly applicable to similarly sized macromolecules like glucagon.
• One embodiment provides dry powdered formulations prepared by admixing insulin and glucagon. The use of inhalers for delivering insulin is primarily aimed at supplying rapid insulins for prandial purposes. Long acting insulins can be delivered by inhalation if desired.
• Some embodiments can be practiced using inhalers in a number of ways, including with insulin and glucagon in separate inhalers; with insulin and glucagon admixed in a fixed ratio in an inhaler; with a dual chamber inhaler in which insulin and glucagon are administered separately; and with dual chamber inhalers in which insulin and glucagon are administered simultaneously.
• prandial inhalers typically contain rapid acting insulins, they are unsuitable (in the way that insulin pumps are) for the delivery of basal insulin.
• a separate pump or chamber can be provided if both prandial and basal insulins are to be delivered by inhalation.
• A. Insulin Administered by Inhalation [Including Pulmonary. Buccal. Nasal and Sublingual]
• the hypothetical patient administers basal insulin using ULTRALENTE by subcutaneous injections at a dosage level of 20 units administered at bedtime.
• he may choose to administer the same drug (in a dose that would provide a daily bioavailability of 20 units) by inhalation.
• It may also be beneficial or desirable for him to administer the basal dose by inhaler at a number of times during the day, for example, at mealtimes in addition to bedtime. Because there is a slight delay (approximately 20 minutes) before insulin attains significant serum concentration when compared to subcutaneous delivery, the user will administer his prandial insulin requirement approximately 20 minutes before eating. He does this by administering between 25 and 50 units (assuming a bioavailability of approximately 20%) of insulin by means of a metered dose inhaler.
• the inhaler may be dose alterable (see U.S. Patent Nos. 5,970,973; 5,672,581; 5,660,166; 5,404,871; and 5,450,336) or similar to currently used asthmatic devices, which deliver fixed and preset doses on each actuation. Whichever type is used, it may be desirable to administer the insulin in multiple actuations. By so doing, the patient can tailor his intake according to the amount of carbohydrate he actually consumes, rather than the amount he expects to eat, by "topping up" his dose at some time after beginning the meal. Furthermore, the more actuations used to administer the insulin, the better the corresponding dose reliability (reproducibility), because inhalation administration tends to vary from actuation to actuation, and multiple actuation delivery has an averaging or smoothing effect.
• a glucagon inhaler is used to administer a s.c. dose equivalent of more than 5 to 16 ng/kg/min. of glucagon administered through inhalation between hours 2 and 5 following the meal.
• different inhalers for each type of insulin and for glucagon are used.
• a unitary inhaler with at least 2 drug chambers (for prandial insulin, glucagon and/or optionally basal insulin) and capable of independent actuation is used.
• the patient administers his basal and prandial insulin parenterally. Because the risk of hypoglycemia associated with using LISPRO insulin typically occurs between 2 and 5 hours after eating, the glucagon inhaler is used to administer a s.c. dose equivalent of 6 to 16 ng/kg/min. (i.e., an amount through inhalation to get the same effect on blood glucose as though 6-16 ng/kg/min. of glucagon administered subcutaneously) between hours 2 and 5 following the meal.
• a modified glucagon of long-acting duration e.g. iodinated glucagon
• a modified glucagon of delayed onset is used in the glucagon inhaler and administered at mealtimes with the prandial insulin.
• basal and prandial insulin are delivered by pump.
• the risk of hypoglycemia arises after 2 to 3 hours, and so the patient administers glucagon by inhaler 2 hours after eating. He administers one puff from a metered dose inhaler at hours 2, 3 and 4, thus providing protection during the period of susceptibility.
• the dose per actuation corresponds to a s.c. dose equivalent amount of more than 5 to 16 ng/kg/min. of glucagon.
• a modified glucagon of long-acting duration e.g. iodinated glucagon
• iodinated glucagon e.g. iodinated glucagon
• Example 3.A.ii the patient administers his insulin (both basal and prandial) by transdermal patch or by topical cream.
• the risk of hypoglycemia arises after 2 to 3 hours, and so the patient administers glucagon by inhaler 2 hours after eating. He administers one puff from a metered dose inhaler at hours 2, 3, and 4, thus providing protection during the period of susceptibility.
• the dose per actuation corresponds to a s.c. dose equivalent amount of more than 5 to 16 ng/kg/min. glucagon.
• a modified glucagon of long-acting duration e.g. iodinated glucagon
• a modified glucagon of long-acting duration e.g. iodinated glucagon
• onset is used in the glucagon inhaler and administered at mealtimes with the prandial insulin.
• Example 1 the insulin and glucagon were administered parenterally and separately.
• the two drugs are administered simultaneously in admixed form.
• Insulin and glucagon may be admixed with little if any interaction or degradation of either product.
• glucagon output it is typically found that following the increased insulin output after a meal of carbohydrate there is an associated increase in glucagon output (actually a restoration of output following the initial depression of glucagon output due to the initial gut-induced rise in blood glucose after the ingestion of carbohydrate). This pattern of insulin production followed by glucagon production assumes a relatively fixed relationship.
• the glucagon provides protection over the period required, one can increase the amount of the glucagon component in the admixture so that it is present in the required concentrations when desired (to prevent hypoglycemia between 2 and 5 hours after the meal, in a s.c. dose equivalent of more than 5 to 30 ng/kg/min., and preferably 8-16 ng/kg/min., or one can use a glucagon formulation with delayed onset.
• the formulation of glucagon has both a delayed release and an extended release (e.g., delayed by 2 to 3 hours and releasing over approximately 3 hours).
• any of the formulations discussed herein may be used.
• an iodination method of increasing half life (as described in U.S. Patent No. 3,897,551; see form DG) is employed.
• the LISPRO insulin and DGlucagon are admixed so that the modified glucagon is present at approximately 1.5% by weight of the insulin in the mixture (keeping the concentration of insulin per ml in our LISPRO formulation constant). Because of the longer lasting effect of the modified glucagon, a smaller proportion of glucagon to insulin by weight will be required.
• the hypothetical patient then administers between 5 and 10 units (measured in terms of the insulin contained therein) of the insulin-glucagon formulation at mealtimes in the standard way. In so doing, he administers a s.c. dose equivalent of more than 5 to up to 16 ng/kg/min. of modified glucagon. Given the longer action of the modified glucagon, this provides (assuming the modified glucagon has, for example, twice the effect on glucose levels compared to standard glucagon) the same protection as described in Example 1.A. The glucagon so administered will be efficacious continuously between hours 2 and 5 as required.
• both the insulin and glucagon are administered by transdermal delivery.
• the prandial insulin and glucagon are admixed in the same matrix or cream.
• Two different types of patch can be employed.
• One patch (or compartment) will contain a matrix designed to replace basal insulin over a 24 hour period.
• This patch can contain an amount of glucagon so that a s.c. dose equivalent of more than 5 to up to 20 ng/kg/min. of glucagon is delivered to the patient.
• the other patch (or independently controlled compartment) provides prandial glucagon and insulin in a single matrix.
• the onset times of the glucagon and insulin are matched so that when the patch is actuated, insulin reaches efficacious plasma levels very quickly whereas the glucagon only reaches efficacious levels after 2-3 hours.
• the patch is applied at mealtimes and preferably no more than one hour before the meal.
• a unitary device containing four independently actuable compartments is used, one containing basal insulin, which is activated on application and left active for 24 hours, and the other 3 compartments containing the prandial insulin and glucagon in the same matrix, each compartment being separately activated at (or near) mealtimes and deactivated at some time after the meal, the time of activation being proportional to the amount of carbohydrate consumed.
• the patient activates one of these prandial compartments (e.g., by pulling away a hermetic plastic seal between the patch and the skin), a process which initiates the transdermal infusion of the admixed insulin and glucagon.
• the prandial compartment is deactivated (e.g. by replacing the barrier used to activate the compartment or the total removal of that compartment from the end of the patch).
• the combined insulin and glucagon formulation in the prandial compartment contains short acting insulin, and the patch is designed for rapid onset of the insulin.
• the glucagon component is designed to reach efficacious concentrations in the bloodstream between 1 and 3 hours after activation of the compartment, hence providing protection from hypoglycemia at the appropriate part of the cycle.
• a unitary device which allows for more than 3 meals a day can be used and contains more than 3 prandial compartments.
• the basal patch is designed to replace basal insulin (worn for 24 hours before being replaced).
• the insulin used may be any insulin suitable for transdermal delivery. It may be advantageous to use intermediate duration insulin in preference to short-acting insulin so that any variation in insulin absorption over the lifetime of the patch would be minimized by the relatively long lifetimes of the insulin involved.
• the basal insulin compartment may also optionally contain an amount of glucagon (admixed) sufficient to supply basal glucagon over each 24 hour period. This would have the beneficial effect of providing protection from hypoglycemia throughout the day and in particular during sleep.
• the present embodiment provides methods and pharmaceutical formulations for delivery of glucagon admixed with insulin by inhalation.
• a long acting glucagon such as, for example, iodinated glucagon as described in US Patent No. 3,897,551, e.g. I2G, or a zinc protamine glucagon
• LISPRO insulin is admixed with LISPRO insulin and delivered by a typical insulin inhaler (e.g. as disclosed in patent US Patent No. 5,970,973).
• Basal insulin may be delivered in the standard way by subcutaneous injection, as described in Example IA, or it may be delivered by inhaler.
• Glucagon may optionally be included in this formulation in an extended release formulation if desired to provide basal glucagon replacement.
• the insulin powder used is admixed with the modified glucagon so that the modified glucagon content is a s.c. dose equivalent of more than 5 to 20 ng/kg/min., and more preferably between 8 and 16 ng/kg/min. for 1-3 units of insulin used.
• Proportionally larger amounts of glucagon can be used when larger amounts of insulin are used (although the amount of glucagon can stay constant regardless of the amount of insulin used). The amount can be adjusted as need, in light of the results from the previous examples for this particular embodiment.
• the patient will administer the combined insulin and glucagon at mealtimes to provide systemic insulin equivalent to between 5 and 10 units.

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• 2005
  • 2005-06-27 CN CNA2005800270476A patent/CN101001638A/zh active Pending
  • 2005-06-27 WO PCT/US2005/022812 patent/WO2006004696A2/en active Application Filing
  • 2005-06-27 AU AU2005260025A patent/AU2005260025A1/en not_active Abandoned
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