WO2007075839A2

WO2007075839A2 - Glucagon injector for emergency treatment of hypoglycemia

Info

Publication number: WO2007075839A2
Application number: PCT/US2006/048691
Authority: WO
Inventors: Richard Rylander; Daniel T. Green
Original assignee: Diobex, Inc.
Priority date: 2005-12-19
Filing date: 2006-12-19
Publication date: 2007-07-05
Also published as: WO2007075839A3

Abstract

The invention relates to a method of treating a hypoglycemic patient by administering emergency glucagon to the patient using a pen injector device containing (i) glucagon mixed with an excipient and (ii) a sterile diluent. In a related aspect the invention provides a single-use pen injector device for injecting a therapeutic solution containing glucagon. The device may include a housing, a first chamber, containing glucagon in powdered form, a second chamber, containing a diluent, a hypodermic needle, and actuation system(s) for mixing the glucagons and diluent to form a glucagons solution and expel the solution through the needle.

Description

Patent Application

Glucagon Injector for Emergency Treatment of Hypoglycemia

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of U.S. provisional patent application No. 60/597,756 (filed December 19, 2005) and No. 60/797,629 (filed May 3, 2006), the entire disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The invention relates to emergency treatment of hypoglycemia and has application in the field of medicine.

BACKGROUND

[0003] Hypoglycemia, a potentially a life-threatening condition for diabetic patients, is treated by raising the patient's blood glucose levels. Mild hypoglycemia can be treated by oral administration of some form of glucose. However, in the case of severe hypoglycemia the patient loses consciousness (and may slip into a coma if not treated). When the patient is unconscious the only method of increasing blood glucose levels is intravenous glucose infusion or glucagon injection.

[0004] Diabetic patients are counseled to keep an emergency glucagon kit on hand for such emergencies. Currently marketed emergency kits include a syringe pre- filled with a diluent and a vial of powdered glucagon. The patient has to rely on a third party to find the kit, remove the plastic cover seal from the vial, then remove the protective cap from the syringe, insert the needle of the syringe into the vial through the rubber stopper, mix the diluent with the glucagon, withdraw the solution into the syringe without picking up too much air, and administer the injection. The multiple steps required to prepare the injection include the potential for errors that could render the preparation useless. There are therefore real risks that a number of possible mistakes could lead to failure of administration in a situation where time is critical, and where backup supplies are not available. Fear, complexity of administration and stress are key issues when the lay person needs to administer emergency glucagon.

[0005] Many diabetic patients keep the emergency kit on hand but may never use it. Emergency glucagon is a form of insurance against a need. When it is needed it has to be so simple to administer that even a child could do it. It also has to be readily available for use.

BRIEF SUMMARY

[0006] In one aspect the invention provides a method of treating a hypoglycemic patient by administering emergency glucagon to the patient using a pen injector device containing (i) glucagon mixed with an excipient and (ii) a sterile diluent. The excipient may be, for example, lactose, mannitol, sorbitol, methyl alpha-D- mannopyranoside, trehalose, and cellobiose. In a particular embodiment the excipient is mannitol. In one embodiment the patient is unconscious at the time of glucagon administration.

[0007] In a related aspect the invention provides a method of treating a hypoglycemic patient by administering emergency glucagon to the patient using a pen injector device containing glucagon where the device has an indicator from which a user can determine whether the glucagon has expired or is otherwise no longer suitable for administration.

[0008] In one aspect the invention provides a single-use pen injector device for injecting a therapeutic solution containing glucagon, where the device has (i) a housing; (ii) a first chamber containing glucagon in powdered form (iii) a second chamber containing a diluent; (iv) a hypodermic needle; and, (v) actuation system(s) for mixing the glucagon and diluent to form a glucagon solution and to expel the solution though the needle. The first and second chambers may be together in a cartridge. [0009] In one embodiment the first chamber contains the glucagon and an excipient, such as mannitol. In one embodiment the excipient does not include lactose. In one embodiment the diluent is water for injection. In one embodiment the device includes an indicator from which a user can determine whether the glucagon has expired or is otherwise no longer suitable for administration. In one embodiment a telephone number is printed on the device.

[0010] In certain embodiments the device delivers a fixed dose of glucagon, such as about 1 mg or about 0.5 mg of glucagon. In one embodiment the device or housing is color coded to indicate the dose.

[0011] In one aspect the invention provides a kit for emergency treatment of hypoglycemia, where the kit includes a glucagon injector and instructions for use.

In some embodiments the kit also includes a sticker or magnet on which the purchase or expiration date of the glucagon injector is, or can be, written or printed.

BRIEF DESCRIPTION OF THE FIGURE

[0012] Figure 1 A shows an exemplary glucagon injector device, for illustration and not limitation. Cassette 1 contains two chambers. During manufacture of the device first chamber 2 is filled with a glucagon solution which is then lyophilized. Second chamber 3 is filled with a sterile solution after the lyophilization step. Cassette 1 is inserted into pen device housing 4. For use, cap 5 is removed exposing needle 6 which is held against the skin as the injection occurs. Liquid crystal label 7 undergoes a color change as the age and temperature exposure limits of the product are reached. Figures 1B-D show the process by which the illustrative device is activated, mixing the solution with the lyophilized powder and thus injected.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions [0013] As used herein, a "patient" is a person to whom glucagon is administered. [0014] As used herein, a "user" is a person who administers glucagon to the patient.

[0015] As used herein, an "actuation system" is a mechanical, electromechanical, pneumatic or other system that translates a user signal (the actuation trigger) into a desired result. Examples of actuation triggers include depressing a plunger, twisting a knob, and the like. Examples of desired results include translocation of a chamber, piercing a barrier, extending a needle, and the like.

II. Overview

[0016] The invention relates to method of administering emergency glucagon to a patient using a pen-type injector device to inject a therapeutically effective dose of a glucagon solution intradermal^ or subcutaneously. In some embodiments the patient is unconscious. In other embodiments the patient is conscious but disoriented or in a state where they are unable to help himself.

[0017] The invention also relates to a pen-type injector device for administering emergency glucagon to a patient. The pen-type injector is sometimes referred to herein as a Glucagon Injector. In one contemplated commercial embodiment, the device is known as the "GlucaJet™ pen injector." The invention also relates to methods for manufacturing a Glucagon Injector. The invention also provides cartridges having at least two different chambers and containing glucagon and a diluent in separate chambers.

[0018] The invention also relates to methods of doing business in which Glucagon Injectors are manufactured and sold.

[0019] The present invention has a number of advantages over currently available emergency glucagon systems. Using the Glucagon injector, it is easier and faster to prepare and administer glucagon in an emergency context. The Glucagon injector is safer than current methods because, for example, it allows accurate dosing for different patient populations (e.g. pediatric vs. aduit patients), is designed to make contamination of the glucagon solution less likely than in syringe and vial systems, and has reduced needle stick potential. In addition, administration of glucagon using the Glucagon injector avoids loss of glucagon solution due to syringe error (e.g. spills), avoids errors made in combining or mixing or delivering (due to, e.g., reduction of number of steps required to administer), and does not require refrigeration. The present invention provides many other benefits, as will be apparent upon review of this disclosure.

111. The Glucagon Injector

[0020] The Glucagon Injector is a disposable, single use, fuily assembled device that contains a therapeutically effective amount of glucagon, in powder form, and a pharmaceutically acceptable diluent sufficient to reconstitute the powder into a solution suitable for injection in emergency situations.

[0021] In a particular embodiment, the Glucagon Injector comprises a lyophilized powder containing glucagon and mannitol.

[0022] Because the device is fully assembled, minimal manipulation is required by the user prior to use. For example, it is not necessary for the user to insert or replace a glucagon or diluent-containing vial or cartridge, or otherwise introduce glucagon or recipient into the device. Similarly, the device includes all components for injection and the user is not required to, for example, attach a needle prior to use. In some embodiments, the user will remove a protective covering, packaging, cap or the like from the device immediately before use.

[0023] In one embodiment, the Glucagon Injector comprises (1) a housing, often in the shape of an elongated cylinder, having a proximal end and a distal end (the "needle end" or "leading end"); (2) a first chamber (the "glucagon chamber") containing glucagon in the form of a lyophilized powder or other dry form; (3) a second chamber (the "diluent chamber") containing a diluent such as water, both chambers being enclosed in the housing; (5) a hypodermic needle positioned near the distal end of the housing; and (6) actuation system(s) for (a) mixing glucagon and diluent, and (b) expelling the glucagon solution through the needle into the patient's tissue. When the housing is in the shape of an elongated cylinder, having a proximal end and a distal end the Glucagon Injector device can be referred to as a "pen device." [0024] The chambers are fluidically isolated from each other until the Glucagon Injector is used. When it is necessary to use the device, the chambers are fluidically coupled, such that the diluent and glucagon are combined to produce a glucagon solution. For illustration and not limitation, the chambers can be fluidically coupled by piercing a septum between them, by connecting the chambers with a cannula, by using a plunger to apply pressure to the diluent liquid (which then displaces an intervening septum into the glucagon chamber and allows the diluent to enter the chamber) or other means. When a septum is used to fluidically isolate two chambers it may be made from rubber, plastic, polymer, or any of numerous other art-known materials. The glucagon solution is expelled through the needle, which is fluidically coupled to the chamber in which the glucagon was reconstituted. Alternatively, the glucagon solution is transported to a reservoir from which it is expelled through the needle.

[0025] Thus, when glucagon administration is necessary, the user: (i) positions the device so that the needle penetrates or is positioned to penetrate the patient's skin for intradermal or subcutaneous injection; (ii) initiates the process of mixing of the glucagon and diluent to produce a glucagon solution; and (iii) initiates the process of expelling the glucagon solution through the needle into the patient tissue. It will be appreciated that the designations (i) (ii) and (iii) do not specify a particular sequence. For example they can be accomplished in a single action, (ii) can precede (i), etc.

[0026] Steps (i), (ii) and (iii) can be accomplished in any of several ways, which will vary with the specific design of the device. The following two examples are for illustration and not limitation:

[0027] In the first example, all three steps (i) - (iii) are initiated by a single action by the user. For example, the user can push the distal (needle) end of the device against surface of the patient's skin, and the force or pressure of the contact can trigger actuation systems that combine the diluent with the glucagon powder, usually by displacing the diluent into the glucagon chamber, and fluidically connects the hypodermic needle with the chamber containing the resulting glucagon solution. The trigger in this case is analogous to that used in the EpiPen^® epinephrine auto-injector (U.S. Pat. No. 4,031 ,893). The EpiPen^® user grasps an outer cylindrical sleeve of the injector and delivers the leading end of the device to the injection site with a force sufficient to cause release of a spring-loaded needle. More specifically, when the device is ready to be used, the outer cylindrical sleeve trails an inner cylinder from which the needle extends so that when the leading end of the outer cylindrical sleeve hits \he user's skin, the movement of the trailing end of the outer cylindrical sleeve releases a spring and the spring drives a piston that pushes liquid medicament out of a cartridge and into the user's tissue through the cannula. In a related embodiment of the present invention, a protrusion (button) at the distal (leading) end of the device is depressed and activates the actuation system(s). In one embodiment the needle is recessed and the actuation system causes the needle to protrude from the device for injection.

[0028] In the second example, the three steps (i) - (iii) are initiated by two or three different actions by the user. For example, the user may activate a first actuation system to combine the glucagon and diluent. User actions that trigger actuation systems can include depressing a button on the proximal end of the device to release a drive spring, depressing a plunger, twisting a knob, sliding a switch, removing a covering or cap, twisting a housing cover (e.g., rotation of an outer barrel), and the like. In one embodiment the needle is protected by a removable cover and removal of the cover activates the actuation system for mixing. In a second step the user may place the needle-end of the device at the injection site, and in a third step activate a second actuation system to expel the glucagon solution through the needle into tissue, for example, by pushing a button at the proximal end. Alternatively, a second actuation system may be activated concurrently with the action of positioning the device (for example, the force or pressure of the leading end of the device against the skin can activate the step of expelling the solution). In another example, a protrusion (button) at the distal (leading) end of the device is depressed and activates the actuation system(s).

[0029] The particular mechanism selected for the injector is not critical to this aspect of the invention. For example, injector mechanisms such as those described in U.S. Pat. No. 6,280,421 to Kirchhofer, or U.S. Pat. No. 5,281 ,198 to Haber may be used (with appropriate modification). Similarly, pen-type injectors designed for delivering a liquid formulation can be modified to deliver a glucagon solution according to the invention by, for example, replacing a single-chamber cartridge or ampoule with a multi-chamber cartridge or ampoule, and similar modifications. A variety of pen-type injectors are known (see, e.g., US 2005/0222539; and US Pat. Nos. 6,767,336; 4,983,164; 5,728,074 and 4,529,403). A variety of pen-type injectors and cartridges are available from suppliers such as Ypsomed (Ypsomed AG, Brunnmattstrasse 6, Postfach, 3401 Burgdorf, Switzerland; see worldwideweb ypsomed.com/en/) and Vetter Pharma-Fertigung GmbH & Co. KG (Schuetzenstraβe 87, 88212 Ravensburg, Germany; see worldwideweb vetter-pharma.com) and may be modified for use in the present invention. For illustration, one useful device is shown in Figure 1. In Figure 1 , cartridge 1 is based on a device by Vetter Pharma- Fertigung. Pen 4 and steps 1 B-D are based on a device by Ypsomed

[0030] It is expected also that new cartridges, chambers, and actuation systems may be designed in the future, which are particularly suited to use according to the present invention and/or have new and useful features or new combinations of features.

IV. Glucagon & Diluent Diluent

[0031] Any pharmaceutically acceptable diluent can be used in conjunction with the present invention. In one embodiment the diluent is water. In another embodiment, the diluent contains glycerin (e.g., 12 mg/mL) and a pH lowering agent (e.g., hydrochloric acid). The volume of diluent is usually in the range of 0.25 ml to 2.5 ml, such as in the range of 0.5 ml to 1.5 ml. In the preferred embodiment, the volume of diluent is 1 ml .

Glucagon Powder & Excipients

[0032] Glucagon is a 29-amino acid single-chain polypeptide which is relatively insoluble in water but is soluble at a pH of less than 3 or more than 9.5. Recombinants expressed glucagon is commercially available form a number of sources (e.g., Novo Nordisk PJS). Alternatively a glucagon analog can be used. [0033] For use in the present invention, glucagon is provided as a lyophilized powder combined with one or more carriers, stabilizers, or bulking agents. Exemplary excipients include, but are not limited to, lactose, mannitol, sorbitol, methyl alpha-D-mannopyranoside, trehalose, and cellobiose. In a particular embodiment, the glucagon powder of the invention comprises glucagon and mannitol. In selecting an excipient it is preferred that the glucagon/excipient mixture go into solution rapidly. In one embodiment, the amount of glucagon is 0.25 to 2 mgs and the amount of mannitol present is from 10 to 100 mgs. Most often the amount of glucagon is about 0.5 mg or about 1 mg (see discussion of "doses" below) and the amount of mannitol is from 25 to 75 mgs, most usually about 50 mgs, and often 50 mgs. In a related embodiment the glucagon powder is substantially free of lactose. In this context, "about" means +/- 25% and more preferably +/- 5%.

V. Fixed and Adjustable Doses

[0034] The standard dose of glucagon for treatment of hypoglycemia is 0.5 to 1 U (0.5 to 1 mg) in adults, with 1 mg being the usual dose. The standard dose of glucagon for treatment of hypoglycemia in children weighing less than 45 pounds is 0.5 mg.

[0035] Glucagon Injectors of the invention may deliver a fixed or variable (adjustable) glucagon dose. Fixed dose versions can contain, for example, about 1 mg glucagon (adult dose) or about 0.5 mg (pediatric dose) or other doses suitable for administration to children and adults. A variable dose device can be set to deliver an adult dose, a pediatric dose, or other doses as selected by the user. Other doses, but are not limited to, "minidoses" such as 20 micrograms (children 2 or under), 10 micrograms g per year of age for children from 2 to 14 years, and 150 μg children 15 years or older. See, e.g., Haymond and Schreiner, 2001, Diabetes Care. 24:643-5; Hartley et al., 2006, J Paediatr Child Health 42:108-11; and worldwideweb at childrenwithdiabetes.com/d_0j_20w.htm. In one embodiment the variable dose device can be set to deliver more than two different doses. In one embodiment, the dose can be adjusted in 10 microgram increments. [0036] The user can select the dose setting using a dial, switch, or other-type selector on the body of the device, without the use of tools. In one embodiment, the dose is selected by moving an outer portion of the housing (e.g., an outer cylinder) or other geometric form relative to an inner portion of the device housing. In one embodiment, the dose is set at the pharmacy or by a pharmacist.

[0037] The fixed dose versions of the device generally deliver all, or essentially all, of the reconstituted glucagon solution to the patient. The adjustable dose version can be set to deliver only a portion of the solution when lower doses are selected. Alternatively, all of the reconstituted glucagon solution can be delivered but the volume of diluent adjusted so that the glucagon concentration varies.

Vl. Chambers & Cartridges

[0038] The Glucagon injector can comprise two or more chambers. Generally the injector includes at least a first (i.e., "glucagon") chamber and a second (i.e., "diluent") chamber, but may include other chambers as well. For example, in one embodiment the glucagon and diluent are each displaced into a third ("mixing") chamber. Many other two-chamber and multiple-chamber configurations will be apparent to persons of ordinary skill in the art.

[0039] One or more of the chambers may be integral to the device, i.e., formed from the housing material. Alternatively, the chambers may be assembled in the housing during manufacture of the device. In a preferred embodiment, the chambers are fabricated together as a single unit, i.e., a cartridge comprising both the glucagon and diluent chambers, which facilitates filling and sterilization. The cartridge or chambers, along with the actuation systems, needle and housing, are assembled together in the manufacture of the Glucagon Injector device. A variety of dual- chamber cartridges are known which are suitable for injectors of various designs (see, e.g., US Pat. No. 5,817,055 to Ljungquist) and other cartridges useful in the present invention may be developed in the future. Similarly, methods for filing cartridges and lyophilizing their contents under sterile conditions are known (see, e.g., Vetter, Delivering Complex Injectables OnDrugDelivery Issue 2, worldwideweb at ondrugdelivery. com). The cartridge may be made from a variety of materials, including glass, plastics, other polymers and the like. In one embodiment all or a portion of the cartridge is transparent, to allow viewing of the glucagon solution (as discussed below).

VII. Device Housing & Status Indicators

[0040] The housing component of the Glucagon Injector, forming the "body" of the device, may be constructed of a variety of materials, including, but not limited to, plastic, glass, and metal. The shape of the housing (and device) can vary. As noted above, the device often has the shape of an elongated cylinder (i.e., "pen-shaped") but any shape that allows the device to be held in the hand against the injection site may be used. Generally, the housing is comprised of more than one piece, which are fitted together during fabrication of the device. For example, the housing may comprise an inner position and a movable outer portion (e.g., an inner cylinder and a rotatable outer cylinder) where movement of one position relative to the other is used as an actuating mechanism, unlocking mechanism and the like.

[0041] The housing, or body, may be partially or completely colored so that the device is easily recognizable by users and medical personal. In addition, the device may be color coded to identify the dose contained in the device (e.g., to distinguish devices containing adult, pediatric or variable doses).

[0042] In one embodiment at least a portion of the housing is transparent. Specifically, the portion overlying or surrounding the diluent chamber and glucagon chamber may be transparent to allow the user to (1 ) confirm the integrity of the contents of each chamber periodically during the storage (non-use) period; (2) confirm at the time of use that the lyophilized material (e.g., glucagon and mannitol) are completely in solution and (3) confirm that the appropriate dose of glucagon (e.g. the full contents of the chamber) have been dispensed. In another embodiment, the housing includes a cut-out (i.e., window) through which chambers) may be viewed as described above.

[0043] In one embodiment the housing includes a status indicator to signal to the patient, user or other person when the device should be replaced, e.g., based on the age of the device and exposure to heat. The indicator changes state (e.g., changes color) in a way detectable to the user. In one embodiment the indicator is an adhered sticker (for example a liquid crystal sticker) that changes color depending on time and temperature. The inclusion of a readily detectable indicator of expiration date ensures the potency and effectiveness of the treatment and allows the device to be stored in many more locations than syringe-type systems.

[0044] The housing can also include printed instructions for use and/or disposal, as well as a bar code identifier. In one embodiment a telephone number (e.g., a toll- free telephone number) is printed on the housing material. By calling the number the user can reach a person who can answer questions or provide assistance. In another embodiment the phone number is printed on a sticker adhered to the device.

VIII. Needle

[0045] In preferred embodiments the device includes a needle (i.e., a needle is not inserted by the user at the time of use).

[0046] In one embodiment the needle is situated within the body of the housing and protrudes outside the body of the device during use. The needle may be translocated so that is protrudes or, alternatively, the distal portion of the body may retract, exposing the needle.

[0047] In one embodiment the needle protrudes from the body of the device and is protected by a removable cover, which is replaced following use.

[0048] Preferably the device includes a component that prevents secondary needle stick once the device is used. For example, in one embodiment, the needle protrudes from the device housing and is protected by a rigid sheath that surrounds the needle. When forced against the patient's skin for injection, the sheath retracts into the body of the device. When the needle is withdrawn following injection the sheath returns to the extended (needle-covering) position and is locked in place. The sheath then protects against a second injection or accidental needle stick. In another embodiment, the needle is contained within a protective housing or shield) during device storage, is extended out of the housing by the user (e.g., by pressing a button or triggering a plunger), and retracts after injection back into the housing or shield.

IX. Methods of Administration

[0049] In one aspect, the invention provides a method of treating a patient by (1) determining that the patient is in need of treatment for hypoglycemia and (2) administering a therapeutically effective dose of glucagon using a Glucagon Injector of the invention. In one embodiment, the glucagon is administered as a solution containing mannitol. In an embodiment, the solution is substantially free of lactose. In some embodiments the patient is unconscious.

[0050] In one aspect, the invention provides a method of preventing coma or death in a diabetic individual, by providing the individual with a Glucagon Injector as described herein.

[0051] As noted above, use of a Glucagon injector of the invention is much easier and requires fewer steps than currently available methods. For example current methods require about 15 steps to administer glucagon (e.g., 1) Remove from refrigerator; 2) Open plastic case; 3) Remove syringe; 4) Remove vial; 5) Remove needle cover from syringe; 6) Insert needle into the vial; 7) Inject diluents from syringe into vial; 8) Swirl the vial (with the syringe still inside) to mix the powder into solution; 9) Invert the vial/syringe moving the needle to the end of the vial without removing it; 10) Draw solution back into syringe; 11 ) Withdraw syringe from vial; 12) Discard vial; 13) Inject the solution into the patient; 14) Re-cover the needle to prevent secondary stick; 15) Dispose of vial and syringe) ) while administration using the Glucagon injector requires, in one embodiment, only 5 steps (e.g., 1) Find the Glucagon Injector; 2) Activate (e.g., by twisting the barrel); 3) Dial the pediatric or adult dose; 4) Remove the needle cover; 5) Place against the skin and press the plunger; 6) Dispose of the unit). In other embodiments even fewer steps may be required.

[0052] As will be apparent from the foregoing, in certain common embodiments of the invention administration occurs outside a hospital setting. The size, portability and safety features of the Glucagon injector allow it to be placed and used at many locations. For illustration, devices owned by patients may be kept at home, work, car, purse, with sporting equipment, and carried by the patient. Moreover, the ease of use and safety features of the device, such as the expiration indicator, encourage keeping Glucagon injectors available in public places and businesses at which need may arise. For example, devices may be kept in airplanes, trains, buses, schools, theaters, sports stadiums, museums, places of business and the like. They may be included in commercial first aid kits, especially those intended for disaster preparedness. Because of convenience they will be useful for physicians (e.g., for glucagon administration at a physician's office, clinic or hospital, and can be carried by emergency response (e.g., ambulance) technicians. In some embodiments administration occurs at the patient's home, school, or place of work. In other embodiments, administration occurs at a different location. In some embodiments the device is owned by the patient or his guardian. In other embodiments the device is owned by another person (including corporate persons), such as a person other than a physician or hospital or other person in the medical profession.

X. Kits and Packaging

[0053] In one aspect the invention provides a kit for emergency treatment of hypoglycemia comprising a Glucagon Injector packaged with instructions for use. In one embodiment, the kit includes the Glucagon Injector device and one or more of the following, packaged together in a container or other package:

1) instructions for use (printed and/or video);

2) a sticker on which the date of receipt of the device and/or expiration or replacement date of the device is, or can be, written or printed, to serve as a second reminder to the patient or user. The sticker can be adhered to a refrigerator, bulletin board, etc.;

3) a magnet on which the date of receipt of the device and/or expiration or replacement date is, or can be, written or printed, to serve as a second reminder to the patient or user. The sticker can be adhered to a refrigerator, bulletin board, etc.; 4) a sticker or magnet on which is printed a telephone number (e.g., a toll- free telephone number). By calling the number the user can reach a person who can answer questions or provide assistance.

Xl. Business Methods

[0054] One aspect of the invention relates to the commercial and other uses of the device, cartridge or method of the present invention. For example, the invention provides methods of conducting a hormone therapy business by (a) manufacturing a Glucagon Injector device, or having the device manufactured by a third party anywhere in the world; and (b) providing the Glucagon Injector to a patient, physician or medical services provider. In one embodiment, the device is manufactured in the United States. In a particular embodiment the device contains a powder comprising lyophilized glucagon and mannitol. In one embodiment a kit including the Glucagon Injector is provided to the patient, physician or medical services provider. Medical services providers include physicians, nurses (e.g. Diabetes Nurse Educators), school nurses, emergency medical technicians, pharmacies, and spouses, close friends and relatives of a diabetes patient susceptible to hypoglycemia.

[0055] In one aspect the invention provides a method of doing business involving advertising the use of a glucagon injector to diabetic patients and/or persons and institutions responsible or potentially responsible for care of diabetic patients, and selling glucagon injectors for use by such persons or institutions. In one aspect, the method results in acquisition, for the device, of an at least 5% share of the market for glucagon emergency treatment products.

[0056] In one aspect the invention provides a method of doing business involving marketing a product for emergency glucagon administration, wherein using said product to administer glucagon to a patient requires fewer steps to administer the product to a patient in need of treatment than conventional methods in which a syringe prefilled with diluent and separate glucagon-containing vial are used. In one aspect, the method results in acquisition, for the device, of an at least 5% share of the market for glucagon emergency treatment products. [0057] In one aspect the invention provides a method of doing business involving marketing a product for emergency glucagon administration, wherein said product includes an indicator that alerts a purchaser when said product has expired or is otherwise no longer suitable for administration. In one aspect, the method results in acquisition, for the device, of an at least 5% share of the market for glucagon.

[0058] In one embodiment, the Glucagon Injector device is configured as shown in the figure. The user dials the selected dose of the substance and then depresses the activator at the top of the pen. The resulting pressure forces the diluent solution into the chamber with the glucagon and excipient where it mixes with the diluent. After mixing, the user removes the protective cover from the injecting mechanism, places the needle against or close to the skin and then depresses the activator (at the top of the pen) a second time to inject the substance. The components work together by providing a protective environment for the substance and needle or injecting mechanism. They maintain the integrity and sterility of the medication until it is needed and mixed.

[0059] All publications and patent documents (patents, published patent applications, and unpublished patent applications) cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any such document is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description and example, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples are for purposes of illustration and not limitation of the following claims.

Claims

1. A method of treating a hypoglycemic patient comprising administering emergency glucagon to the patient using a pen injector device comprising (i) glucagon mixed with an excipient and (H) a sterile diluent.

2. The method of claim 1 wherein the excipient is selected from the group consisting of lactose, mannitol, sorbitol, methyl alpha-D-mannopyranoside, trehalose, and cellobiose.

3. The method of claim 1 wherein the excipient is mannitol.

4. A method of treating a hypoglycemic patient comprising administering emergency glucagon to the patient using a pen injector device comprising glucagon wherein said device comprises an indicator from which a user can determine whether the glucagon has expired or is otherwise no longer suitable for administration.

5. The method of any of claims 1 - 4 wherein the patient is unconscious at the time of glucagon administration.

6. A single-use pen injector device for injecting a therapeutic solution containing glucagon, said device comprising: i) a housing; ii) a first chamber, comprising glucagon in powdered form, iii) a second chamber, comprising a diluent; iv) a hypodermic needle; and, v) actuation system(s) for mixing the glucagon and diluent to form a glucagon solution and expel the solution though the needle, wherein the first chamber comprises the glucagon and an excipient and/or the device comprises an indicator from which a user can determine whether the glucagon has expired or is otherwise no longer suitable for administration and/or a telephone number is printed on the device.

7. The device of claim 6 wherein the first chamber comprises a glucagon formulation containing mannitoi.

8. The device of claim 7 wherein the formulation is substantially free of lactose.

9. The device of any of claims 6-8 wherein the diluent is water for injection.

10. The device of any of claims 6-9 that delivers a fixed dose of glucagon.

11. The device claim 10 wherein the fixed dose is about 1 mg or about 0.5 mg of glucagon.

12. The device of claim 10 wherein the housing is color coded to indicate the dose.

13. The device of claim 6 wherein the first and second chambers are fabricated together in a cartridge.

14. A kit for emergency treatment of hypoglycemia comprising a glucagon injector and instructions for use.

15. The kit of claim 14 that contains a sticker or magnet on which the purchase or expiration date of the glucagon injector is, or can be, written or printed.