Claims:1. A drug delivery system comprising a cartridge comprising a liquid pharmaceutical composition comprising an insulin, insulin analogue or derivative or combination thereof, wherein the cartridge is configured to contain and deliver more than 3ml of the liquid composition.

2. A drug delivery system comprises a pen shaped syringe with a cartridge, wherein the cartridge comprises a pharmaceutical composition comprising 40IU to 1000IU per ml of insulin, insulin analogue or derivative or combination thereof optionally along with one or more pharmaceutically active agent, wherein the cartridge delivers more than 3.5ml of the said pharmaceutical composition per pen.

3. The drug delivery system of claim 1 wherein the cartridge (2a) in the pen type injector is of 6 ml comprising insulin, insulin analogue or derivative or combination thereof optionally along with one or more pharmaceutically active agent.

4. A drug delivery system comprising a cartridge and a liquid pharmaceutical composition comprising insulin, insulin analogue, insulin derivative or combination thereof, wherein the insulin, insulin analogue or derivative is present in the concentration range of 40IU to 1000IU per ml and the cartridge is configured to hold and delivery more than 3ml of the liquid composition.

5. A cartridge adapted to deliver a liquid pharmaceutical composition comprising a therapeutically effective amount of an insulin, insulin analogue, derivative or combination thereof optionally along with one or more pharmaceutically active agent, wherein the cartridge is configured to contain more than 3ml of the liquid composition.

6. A method for delivering a pharmaceutical composition comprising a therapeutic effective amount of an insulin, insulin analogue, derivative or combination thereof for a period of more than 30 days, wherein the method comprises using a drug delivery system comprising a pen shaped syringe with a cartridge, wherein the cartridge is configured to hold and deliver more than 3ml of the said pharmaceutical composition.

7. The drug delivery system of claim 1, wherein the insulin, insulin analogue or derivative is present in the concentration range of 40IU to 1000IU per ml.

8. The drug delivery system of claim 6, wherein the insulin, insulin analogue or derivative is present in the concentration range of 105IU to 1000IU per ml.

9. The drug delivery system of claim 1, wherein the cartridge contains 3.5 to 10ml of the liquid composition.

10. The drug delivery system of claim 1, wherein the insulin, insulin analogue or derivative is selected from the group consisting of Insulin, Insulin lispro, Insulin Aspart, Insulin Glulisine, Insulin lispro protamine, Insulin protamine, Insulin aspart protamine, Insulin glargine, Insulin detemir, Insulin degludec, premixed insulin and combination of the foregoings.

11. The drug delivery system of claim 1, wherein the drug delivery system delivers the pharmaceutical composition to a patient in need thereof for a period of more than one month.

12. A method of treating diabetes, wherein the method comprise administering a liquid pharmaceutical composition comprising an insulin, insulin analogue or derivative or combination thereof through drug delivery system claimed in claim 1.
, Description:FIELD OF INVENTION

The invention is related to the development of an economical and safe drug delivery system for the delivery of insulin, insulin analogues, derivatives or combination thereof wherein a cartridge is configured to deliver more than 3 ml of the pharmaceutical composition of insulin, insulin analogues, derivatives or combination thereof from a pen type injector containing a cartridge of greater than 3 ml. Use of higher size of cartridge than the conventional 3 ml cartridge may ensure delivery of more number of doses of the insulin(s) and also may result in extending the use of same device for more number of days.

BACKGROUND OF INVENTION

Diabetes is categorized as a metabolic disorder which is characterized by abnormally high blood glucose levels and inadequate levels of insulin. Diabetes can be referred as the disorder in which the person suffering from it has excessive urine excretion. Many long term complications can be related from long-standing diabetes as blindness, kidney failure, and limb amputations. Insulin-dependent diabetes mellitus (IDDM) accounts for 10 to 15% of all cases of diabetes mellitus.

Insulin is a polypeptide of 51 amino acids, which are divided into 2 amino acid chains: the A chain having 21 amino acids and the B chain having 30 amino acids. The chains are connected to one another by means of two disulfide bridges. Insulin delivery injection has been a prescribed treatment for diabetes for many years.

Insulin dosage exogenously is ideally administered at times and dosage such that it mimics patient’s plasma profile endogenously in a normal individual. Naturally occurring insulin in the market varies in a number of factors like origin of insulin (e.g. bovine, porcine, human insulin, mammalian, animal insulin) and composition, whereby the profile of action (onset of action and duration of action) can be influenced.

A number of insulin, insulin analogs and derivatives are available in the market that may be categorized as:

Rapid-acting Insulin analogs (Bolus): For example insulin aspart (Novolog®); Insulin lispro (Humalog®), Insulin Glulisine (Aprida®), Rapid acting human insulin (Viaject®). These analogs begin to work within 5 to 15 minutes of administration and are active for 3 to 4 hours.

Short-acting insulin (Bolus): For example Regular insulin (Humulin® or Novolin®). Regular insulin starts working within 30 minutes after administration and duration of action lasts from about 5 to 8 hours.

Intermediate-acting insulin: For example as Isophane insulin, Aspart protamine, Lispro protamine. It starts working in 1 to 3 hours after administration. Its duration of action varies between 16 to 24 hours.

Long-acting Insulin (Basal): For example Insulin glargine and Insulin detemir. Both these analogs starts working within 1 to 2 hours and their duration of action vary from about 12 to about 24 hours.

Mixed Insulin’s: For example mixture of NPH and regular insulin. There are several variations with different proportions of the mixed insulin’s. The onset of action of these mixed preparations is about 30 minutes. The mixed insulin’s comprise same type of insulin. Two different types of insulin’s cannot be mixed i.e. insulin lispro cannot be mixed with insulin detemir, insulin aspart or insulin glargine. The mixed formulation of insulin Lispro can only comprise insulin lispro regular and insulin lispro protamine – two forms of insulin lispro.

The amount of insulin dosage required varies from patient to patient which depends on various factors like type of insulin required (slow, medium, fast acting, or specific combinations of these), patients medical condition, patient lifestyle, circumstances, etc. Hence, self-administration of insulin is normally preferred for a diabetic patient so that it can be taken at an appropriate time, dosage and can be taken at places with non-availability of health centres, such as their homes, offices, restaurants etc. Thus a delivery device for use in such circumstances must be easy, convenient, as well as non-embarrassing to use, and carry around in public.

A number of methods are available for injecting insulin in the body as:

1. Syringe: Most common form of delivery system utilizing needle and syringe. The capacity of syringe, needle gauge and needle length can be accommodated according to the dosage requirement and comfort.

2. Insulin pens: A convenient and discrete way of insulin uptake in which dosage that has to be administered can be adjusted by a built-in dial. Depending upon the prefitted or replaceable insulin cartridge, they can be categorized as disposable or durable pens respectively.

3. Insulin jet injectors: Insulin is injected in the form of fine spray into the skin by utilizing a pressurized jet of air instead of a needle.

4. Insulin pumps: They are a small device of pager size that can be utilized for slow and continuous insulin delivery throughout the day or large quantities release after the meal. Insulin is delivered utilizing a catheter that is attached to a reservoir.

5. Insulin patches: Active delivery system that utilize external force like ultrasound or electrical current to disrupt the skin barrier and deliver insulin to the body.

6. Insulin inhalers: Like asthma inhalers they are a method of oral drug delivery in which drug is delivered in the form of dry powder.

The diabetic patients require insulin to keep their blood glucose level to normal. It is essential for people with diabetes to manage their blood glucose level to within a normal range. Complications from diabetes can include heart disease (cardiovascular disease), blindness (retinopathy), nerve damage (neuropathy), and kidney damage (nephropathy). Conventional insulin therapies typically involve administration of one or two injections a day. The low number of injections has the disadvantage of allowing larger variations in a person's insulin levels. Some people with diabetes manage their blood glucose level with multiple daily injections (MDI). Multiple daily injections may involve more than three injections a day and four or more blood glucose tests a day. So that it is important for a diabetic patient to be treated with the proper amount of insulin.

Among the different drug delivery devices, insulin pens have emerged as a major drug delivery system among diabetic patients with daily requirement of insulin injection. Its popularity is largely governed by a number a advantages associated with it like user friendliness, ease of cartridge replacement, insulin-dose setting dial use leading to high dosage accuracy, availability of pens with variable insulin formulations, memory functions to recall previous dosing, less amount of training required for its utilization, colour code to assist patients in visual distinction between different insulin formulations, to reduce patient pen-selection errors.

Insulin pens are mainly comprised of housing and a cartridge. Cartridge is referred as a cylindrical ampoule containing the medicament. It consists of puncturable membrane on one side and movable plug on other side to close the cartridge. Due to non-standardization of content and dimensions of cartridges, conventional medicament delivery pens can only accept a single cartridge size. Manufacturing a pen that can accommodate different cartridge sizes is inculcated with a problem that the ratio between the number of units of medication delivered and the linear displacement of the piston in the cartridge is different for each size cartridge. Cartridges are utilized widely for various medicament delivery systems, especially insulin. Cartridges for delivery of Insulins are usually supplied pre-filled with either 1.5 ml or 3.0 ml of insulin with 1.5 ml cartridge contain 150 IU and a 3.0 ml cartridge containing 300 IU of insulin or their analogues.

Several literature, articles and patents disclose the use of cartridge in the delivery of insulin. Disetronic Medical system formulated an Accu-Chek Sprit IP Cartridge with a volume of 3.15 ml for insulin Accu-Chek Insulin pump system. PCT Patent Publication No WO 2013170052; WO 2011014704; US Patent No. 8197454 are some of the patents which elaborate such therapies.

The available insulin pen devices in the market such as Novo Nordisk’s Flexpen®, Eli Lilly’s HumaPen MEMOIR®, HumaPen Luxura®, and KwikPen®, Sanofi Aventis’s Opticlick® Pen, Aprida SoloSTAR®, Lantus SoloSTAR® and other pen devices from Owen Mumford has cartridge which contains 1.5 and 3.0ml of the different insulin compositions.

The amount of insulin dosage required varies from one patient to another with some patients requiring as much as 300IU per day, in which case the recommended volume of cartridge is 3.0 ml. The cartridge is loaded by the patient in the device and insulin is injected or infused in the body as per the prescribed dosage. The cartridge needs to be disposed of and replaced by new ones after its complete utilization. The most common volumes of cartridge available in the market are 1.5 and 3.0 ml which limits the number of times by which it can be utilized which reduces the cost efficiency of the device.

US patent publication US 20130041241 claims a prefilled medical syringe or cartridge comprising a capped pre-assembly comprising: insulin aprida or glargine or other type of insulin. The specification discloses a 5 ml cartridge.

US patent publication US 20120123345 claims a package containing a pharmaceutical composition, the package comprising: a container comprising a protein or peptide wherein at least a portion of the wall of the container defining the lumen is made of cyclic olefin polymer. The specification discloses the container can be a cartridge for use in auto injector whose volumes can be 5 ml to 10 ml.

Therefore, there is need for development of newer, economical delivery system which can deliver the insulin for a longer period of time.

SUMMARY OF THE INVENTION

The inventors while working on the development of an economical and safe drug delivery system for the delivery of insulin, insulin analogues, derivatives or combination thereof, have surprisingly found that if a cartridge is configured to deliver more than 3ml of the pharmaceutical composition of insulin, insulin analogues, derivatives or combination thereof, the same pen type of injector containing higher size cartridge than the conventional 3 ml cartridge may be able to deliver more number of doses of the insulin(s), which may result in extending the use of same device for more number of days. There are significant secondary benefits in the use of cartridges of larger than 3 ml in a pen type of injectors in terms of reducing the number of injectors when the injector is a disposable one. This leads to a significant reduction in the cost of the pen type of injector to the patient. Further the use of cartridge having a volume larger than conventional 3 ml cartridges in a reusable pen device reduces the frequency of changing the cartridges.

The secondary benefit of carrying out the present invention is illustrated as follows. For example a typical conventional disposable pen type injector contains 100 IU insulin in a 3 mL cartridge. Hence 600 IU insulin can be delivered by two disposable pen type injectors. Alternatively if 200 IU insulin is loaded in a 3 mL conventional cartridge, the dose setting mechanism of the pen type injector has to be fine tuned and a new design pen type injector is required which would be prohibitively costly to deliver same 600 IU. However if the pen type injector may be modified to incorporate a larger cartridge of size of more than 3.5 mL i.e. say 6 mL comprising 100 IU insulin then a single conventional disposable pen type injector without any modification can deliver 600 IU insulin. Hence by increasing the size of the cartridge from 3 mL to 6 mL, a single disposable pen type injector can be used with the secondary benefits of more number of user days and the reduced frequency of changing the pen type injectors.

The secondary benefits of using a larger size cartridge in reusable pen type injector would be more pronounced in reduced cost as only cartridges will have to be changed.

In one of the embodiments the drug delivery system of the invention comprises a cartridge comprising liquid pharmaceutical composition comprising an insulin, insulin analogue or derivative or combination thereof, wherein the cartridge is configured to contain and deliver more than 3 ml of the liquid composition.

In another embodiment of the invention the drug delivery system comprises a pen shaped injector with a cartridge wherein the cartridge comprises a liquid pharmaceutical composition comprising insulin, insulin analogue or derivative or combination thereof in the concentration range of 40 IU to 1000 IU per ml of insulin, insulin analogue or derivative or combination thereof optionally along with one or more pharmaceutically active agent, wherein the cartridge is configured to hold and deliver more than 3.5 ml of the said pharmaceutical composition per pen.

In another embodiment of the invention the cartridge in the pen type injector is of 6 ml wherein the cartridge comprises insulin, insulin analogue or derivative or combination thereof optionally along with one or more pharmaceutically active agent.

In another embodiment of the invention the drug delivery system comprises a cartridge and a liquid pharmaceutical composition comprising insulin, insulin analogue or derivative or combination thereof wherein the insulin, insulin analogue or derivative is present in the concentration range of 40IU to 1000IU per ml and the cartridge is configured to hold and deliver more than 3 ml of the liquid composition.

In another embodiment of the invention the drug delivery system comprises a cartridge adapted to deliver a liquid pharmaceutical composition comprising a therapeutically effective amount of an insulin, insulin analogue, derivative or combination thereof optionally along with one or more pharmaceutically active agent, wherein the cartridge is configured to contain more than 3ml of the liquid composition.

In another embodiment of the drug delivery system of the invention is a method for delivering a pharmaceutical composition comprising a therapeutic effective amount of an insulin, insulin analogue, derivative or combination thereof for a period of more than 30 days, wherein the method comprises using a drug delivery system comprising a pen shaped syringe with a cartridge, wherein the cartridge is configured to hold and deliver more than 3 ml of the said pharmaceutical composition.

In another embodiment of th invention the cartridge contains 3.5 mL to 10 mL of liquid composition.

In another embodiment the drug delivery system wherein the insulin, insulin analogue or derivative is present in the concentration range of 40 IU to 1000 per ml.

In another embodiment the drug delivery system wherein the insulin, insulin analogue or derivative is present in the concentration range of 105IU to 1000IU per ml.

In another embodiment of the drug delivery system wherein the cartridge contains 3.5 to 10 ml of the liquid composition.

The drug delivery system of the invention comprises the insulin, insulin analogue or derivative is selected from the group consisting of Insulin, Insulin lispro, Insulin Aspart, Insulin Glulisine, Insulin lispro protamine, Insulin protamine, Insulin aspart protamine, Insulin glargine, Insulin detemir, Insulin degludec, premixed insulin and combination thereof.

In another embodiment of the drug delivery system wherein the drug delivery system delivers the pharmaceutical composition to a patient in need thereof for a period of more than one month.

In another embodiment drug delivery system claimed in claim 1 is a method of treating diabetes, wherein the method comprise administering a liquid pharmaceutical composition comprising an insulin, insulin analogue or derivative or combination thereof.

DETAILED DESCRIPTION

While working on the development of an economical and safe drug delivery system for the delivery of insulin, insulin analogues, derivatives or combination thereof, applicants have surprisingly found that if a cartridge is configured to deliver more than 3ml of the pharmaceutical composition of insulin, insulin analogues, derivatives or combination thereof, the same pen type of injector containing the said cartridge may be able to deliver more number of doses of the insulin(s), which may result in extending the use of same device for more number of days. The drug delivery device of the present invention may be cost effective for the patients, which may require frequent administration of the Insulin(s) or administration of higher strength of Insulin(s). Further the increase in the capacity of cartridge for holding more volume of insulin may not not lead to significant increase in the size of the pen. The drug delivery system of the present invention are easy to carry and easy to use.

A typical pen type injector in its fully assembled and capped form is as shown in Fig. 1 and referenced in as published Indian patent application 1008/MUM/2014. This Figure exemplifies that embodiment of the present invention, wherein the delivery device has the overall shape and appearance of a pen. Thus, FIG. 1 exemplifies the pen cap insert (PC3), the pen cap clip (PC2), dose dial window (OB6), dose dial grip (DDT2), dose index (DDT6) and dose dial knob (DDT3).

With reference to the embodiments shown in Fig. 2, the fluid delivery pen can be described as comprising two regions. The distal half of the pen comprises the cartridge cover (1) for holding the fluid (6) containing cartridge (2). On the distal end of the cartridge cover (1) may be mounted the needle hub (3), that carries the needle (4). The portion of the needle (4) that projects out of the cartridge cover (1) may, in turn, is enclosed by a protective needle cover (5). The proximal end of the needle may communicate with the fluid (6) of the cartridge. The cartridge (2), comprising the fluid (6), may be loaded inside the cartridge cover (1) such that the head (7) and neck (8) of the cartridge may be snugly fixed into the neck region (9) of the cartridge cover (1). The distal end of the cartridge may be sealed, but the proximal portion of the needle may traverse through it in order to communicate with cartridge fluid (6). The proximal end of the cartridge may be enclosed by an airtight, but movable, plunger (10, 10d) (10d) being the plunger after all the available medication has been completely ejected). The outer surface of the cartridge cover (1), on its proximal end, may have helical threads (11).

The cartridge (2) as shown in Fig 2 is a conventional 3 mL cartridge. The cartridge (2a) of the present invention is of a larger size i.e. greater than 3.5 mL preferably of 6 mL; the larger size cartridge i.e. 6 mL may be filled with 100 IU insulin or insulin analogue and may be fitted on to the pen type Injector shown in Fig 3. The plunger 10(d) of the cartridge (2a) is as shown in Fig 3. This may allow the use of the same dose setting mechanism and dose delivery mechanism of the pen type injector to deliver the insulin dosage regimen for a longer period of time without any change in value of dosage by the patient.