FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
As amended by the Patents (Amendment) Act, 2005
& 5
THE PATENTS RULES, 2003
As amended by the Patents (Amendment) Rules, 2005
COMPLETE SPECIFICATION
(Section 10 and rule 13)
10
TITLE OF THE INVENTION
MEDICAL INFUSION PUMP SYSTEM FOR THE DELIVERY OF AN INSULIN COMPOUND 15
APPLICANTS 20
Arecor Limited, a Great Britain company, having its address at Chesterford Research Park, Little Chesterford, Saffron Walden CB10 1XL, Great Britain
25
30
35
40
PREAMBLE TO THE DESCRIPTION
The following specification particularly describes this invention and the manner in which it is to be performed:
2
FIELD OF THE INVENTION
This invention relates inter alia to a medical infusion pump system for the delivery of an insulin compound, particularly rapid acting aqueous liquid pharmaceutical compositions of insulin and insulin analogues. Such a system is suitable for the treatment of subjects suffering from diabetes mellitus, especially 5 Type 1 diabetes mellitus.
BACKGROUND OF THE INVENTION
Diabetes mellitus (“diabetes”) is a metabolic disorder associated with poor control of blood sugar levels leading to hypo or hyperglycaemia. Untreated 10 diabetes can lead to serious microvascular and macrovascular complications including coronary artery disease, peripheral artery disease, stroke, diabetic nephropathy, neuropathy and retinopathy. The two main types of diabetes are (i) Type 1 diabetes resulting from the pancreas not producing insulin for which the usual treatment is insulin replacement therapy and (ii) Type 2 diabetes where 15 patients either produce insufficient insulin or have insulin resistance and for which treatments include insulin sensitising agents (such as metformin or pioglitazone), traditional insulin secretagogues (such as sulfonylureas), SGLT2 inhibitors (such as dapagliflozin, canagliflozin and empagliflozin) which reduce glucose absorption in the kidneys and so promote glucose excretion, GLP-1 agonists 20 (such as exenatide and dulaglutide) which stimulate insulin release from pancreatic beta cells and DPPIV inhibitors (such as sitagliptin or vildagliptin) which inhibit breakdown of GLP-1 leading to increased insulin secretion. Patients with Type 2 diabetes may eventually require insulin replacement therapy.
25
For patients requiring insulin replacement therapy, a range of therapeutic options are possible. The use of recombinant human insulin has in recent times been overtaken by use of insulin analogues which have modified properties, for example, are longer acting or faster acting than normal insulin. Thus, a common regimen for a patient involves receiving a long acting basal insulin supplemented 30 by a rapid acting insulin around mealtimes.
Insulin is a peptide hormone formed of two chains (A chain and B chain, respectively 21 and 30 amino acids in length) linked via disulfide bridges. Insulin normally exists at neutral pH in the form of a hexamer, each hexamer comprising 35 three dimers bound together by zinc ions. Histidine residues on the insulin are known to be involved in the interaction with the zinc ions. Insulin is stored in the body in the hexameric form but the monomer form is the active form. Traditionally, therapeutic compositions of insulin have also been formulated in hexameric form in the presence of zinc ions. Typically, there are approximately 40 three zinc cations per one insulin hexamer. It has been appreciated that the hexameric form is absorbed from the injection site considerably more slowly than the monomeric and dimeric forms. Therefore, a faster onset of insulin action can be achieved if the hexameric form is destabilised allowing a more rapid
3
dissociation of the zinc-bound hexamer into dimers and monomers in the subcutaneous space following injection. Three insulin analogues have been genetically engineered with this principle in mind. A first is insulin lispro (HUMALOG®) in which residues 28 and 29 of the B chain (Pro and Lys respectively) are reversed, a second is insulin aspart (NOVORAPID®) in which 5 residue 28 of the B chain, normally Pro, is replaced by Asp, and a third is insulin glulisine (APIDRA®) in which residue 3 of the B chain, normally Asn is replaced by Lys and residue 29 of the B chain, normally Lys, is replaced by Glu.
Whilst the existing rapid acting insulin analogues can achieve a more 10 rapid onset of action, it has been appreciated that even more rapid acting (“ultra rapid acting”) insulins can be achieved by removing the zinc cations from insulin altogether. Unfortunately, the consequence of the hexamer dissociation is typically a considerable impairment in insulin stability both with respect to physical stability (e.g. stability to aggregation) and chemical stability (e.g. stability 15 to deamidation). For example, monomeric insulin or insulin analogues having a rapid onset of action are known to aggregate and become physically unstable very rapidly because the formation of insoluble aggregates proceeds via monomers of insulin. Various approaches to addressing this problem have been described in the art: 20
US5,866,538 (Norup) describes insulin preparations of superior chemical stability comprising human insulin or an analogue or derivative thereof, glycerol and/or mannitol and 5 mM to 100 mM of a halogenide (e.g. NaCl).
25
US7,205,276 (Boderke) addresses the stability problems associated with preparing zinc-free formulations of insulin and insulin derivatives and analogues and describes an aqueous liquid formulation comprising at least one insulin derivative, at least one surfactant, optionally at least one preservative and optionally at least one of an isotonicizing agent, a buffer and an excipient, 30 wherein the formulation is stable and free from or contains less than 0.4% (e.g. less than 0.2%) by weight of zinc based on the insulin content of the formulation. The preferred surfactant appears to be polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate).
35
US2008/0194461 (Maggio) describes formulations of peptides and polypeptides including insulin which contain an alkyl glycoside, which component is said to reduce aggregation and immunogenicity.
WO2012/006283 (Pohl) describes formulations containing insulin together 40 with a zinc chelator such as ethylenediaminetetraacetate (EDTA). Modulating the type and quantity of EDTA is said to change the insulin absorption profile. Calcium EDTA is the preferred form of EDTA since it is said to be associated with reduced pain at the injection site and is less likely to remove calcium from the
4
body. Preferred formulations also contain citrate which is said to further enhance absorption and to improve the chemical stability of the formulation.
US2010/0227795 (Steiner) describes a composition comprising insulin, a dissociating agent such as citric acid or sodium citrate, and a zinc chelator such 5 as EDTA wherein the formulation has a physiological pH and is a clear aqueous solution. The formulations are said to have improved stability and rapid onset of action.
WO2015/120457 (Wilson) describes stabilized ultra-rapid acting insulin 10 formulations comprising insulin in combination with a zinc chelator such as EDTA, a dissolution/stabilization agent such as citric acid, a magnesium salt, a zinc compound and optionally additional excipients.
Further approaches to accelerating the absorption and effect of insulin 15 through the use of specific accelerating additives have been described:
WO91/09617 (Jørgensen) reports that nicotinamide or nicotinic acid or a salt thereof increases the speed of absorption of insulin from aqueous preparations administered parenterally. 20
WO2010/149772 (Olsen) describes a formulation comprising insulin, a nicotinic compound and arginine. The presence of arginine is said to improve the chemical stability of the formulation.
25
WO2015/171484 (Christe) describes rapid-acting formulations of insulin wherein onset of action and/or absorption of insulin is faster due to the presence of treprostinil.
US2013/0231281 (Soula) describes an aqueous solution composition 30 comprising insulin or an insulin analogue and at least one oligosaccharide whose average degree of polymerisation is between 3 and 13 and whose polydispersity index is above 1.0, said oligosaccharide having partially substituted carboxyl functional groups, the unsubstituted carboxyl functional groups being salifiable. Such a formulation is said to be rapid acting. 35
WO2017/191464 (Arecor Limited) describes an aqueous liquid pharmaceutical formulation comprising insulin or an insulin analogue, ionic zinc, a chelating agent and polysorbate 80.
40
WO2016/100042 (Eli Lilly and Company) describes a composition of human insulin or insulin analogue that includes specific concentrations of citrate, chloride, in some cases including the addition of sodium chloride, zinc and, optionally magnesium chloride and/or surfactant, said to have faster
5
pharmacokinetic and/or pharmacodynamic action than commercial formulations of existing insulin analogue products. There are a number of devices that can be used to deliver insulin, including syringes, insulin pens and insulin pumps. 5 Syringes can typically be used to deliver basal (long-acting) insulins, typically as one injection per day. Whilst syringes are still used, they are gradually being replaced by more convenient insulin pens. 10 Insulin pens are a very convenient way of delivering both basal and prandial insulin. Insulin pens contain a cartridge that is filled with insulin and an apparatus for dispensing a required amount of insulin, as needed by the user. The required amount is first selected (this often referred to as being “dialed”) using a specifically designed mechanism and then dispensed via a very small 15 retractable needle whilst holding the pen against the body (typically the abdomen).
Insulin pumps represent the most advanced delivery system for insulin and are becoming increasingly popular. Insulin pumps have traditionally been 20 used primarily by people with Type 1 diabetes, but they are also slowly becoming a treatment of choice for Type 2 diabetes. All insulin pumps comprise a reservoir in which an aqueous insulin composition is held and a pumping mechanism that dispenses the insulin composition subcutaneously into the body via a fine cannula, either as a bolus dose or as a continuous infusion. 25
Currently, there are three main categories of insulin pumps, traditional “tethered pumps”, “patch pumps” and “implantable pumps”.
A traditional tethered pump is worn in a pocket or clipped to a belt and 30 uses a fine tubing to connect the pump to the cannula. The pump body contains buttons that allow programming the insulin delivery at a slow, continuous (basal) rate as well as in supplemental (bolus) doses before meals or suspending the insulin infusion, if necessary. Examples of traditional tethered pumps include MINIMED® 530G, MINIMED® 630G, MINIMED® 670G (Medtronic Diabetes). 35 A patch pump is worn directly on the body (typically the abdomen), attached via an adhesive layer. Patch pumps are controlled wirelessly by a separate device that allows programming the insulin delivery at a slow, continuous (basal) rate as well as in supplemental (bolus) doses before meals or 40 suspending the insulin infusion, if necessary. The cannula is an inherent part of the patch pump, so no additional tubing is necessary. The cannula is inserted automatically after attaching the patch on the skin by programming the activation of the patch from a remote device. Examples of insulin patch pumps include
6
OMNIPOD® (Insulet Corporation), T-SLIM® X2 (Tandem Diabetes Care), T-FLEX® (Tandem Diabetes Care), CELLNOVO® (Cellnovo). Implantable insulin pumps are extremely rare, with <500 users world-wide. The pump is surgically implanted under the skin and a catheter from the 5 pump extends into the peritoneal cavity. Delivery into the peritoneal cavity ensures a rapid delivery of insulin to the liver which is the normal target for insulin. The pump contains a reservoir in which the insulin composition is held and a mechanism for dispensing the composition at a required rate. The reservoir is re-fillable using a syringe via a specifically designed port. An example of an 10 implantable insulin pump is the MINIMED® Implantable Pump (MIP) model 2000 (Medtronic Diabetes).
Many pumps are now available that work in conjunction with continuous glucose monitors that can alert the user to high or low blood glucose levels. 15
Commercially available rapid-acting insulin formulations are available as 100 U/ml formulations (HUMALOG® (insulin lispro), NOVORAPID® (also known as NOVOLOG®, insulin aspart) and APIDRA® (insulin glulisine)) and 200 U/ml formulations (HUMALOG®). Regular human insulin products are available as 100 20 U/ml formulations (e.g.HUMULIN® R) and a 500 U/ml formulation HUMULIN® R U-500). However, a considerable disadvantage of the regular human insulin is a slow onset of action compared with the rapid acting analogues. The speed of onset of action is further reduced at the higher concentration, making such concentrated insulin unsuitable for prandial use. 25
Compositions having a higher concentration of insulin compound are desirable e.g. for patients that require higher insulin doses, such as obese patients or patients who have developed insulin resistance. Compositions having a higher concentration of insulin are thus desirable for these categories of 30 patients as the required high dose can be delivered in a smaller volume. Whilst the development of the 200 U/ml HUMALOG® formulation was an important step toward patient convenience in the situations described above, there remains a strong need to develop formulations of rapid-acting insulins at considerably higher concentrations, such as 400 U/ml or more or 500 U/ml or more or 1000 35 U/ml or more. It would also be advantageous to maintain the rapid onset of action of insulin in such high strength compositions.
Compositions having a higher concentration of insulin compound are also highly desirable for miniaturization of delivery devices, particularly of insulin patch 40 pumps. The ability to keep a given dose in a small volume means that the patch pump can be smaller and thus more convenient for the user. In addition, concentrated insulin compositions may allow longer use of the reservoir in the pump due to higher number of insulin units being held in a given volume.
7
A known problem associated with the use of formulations containing higher concentrations of insulin compound, in particular rapid-acting insulin compounds, is that the rapid-acting effects observed at low concentration (or low strength) formulations e.g. 100 U/ml of insulin compound, are reduced. Thus, increasing the concentration of insulin compound has been observed to lead to a 5 slower onset of action even if the same dose is delivered, see for example de la Peña et al. Pharmacokinetics and Pharmacodynamics of High-Dose Human Regular U-500 Insulin Versus Human Regular U-100 Insulin in Healthy Obese Subjects, Diabetes Care, 34, pp 2496-2501, 2011.
10
A known problem associated with the use of insulin pumps is an occlusion, i.e. a blockage (e.g. of the cannula, the tubing or any other part of the microfluidic system that delivers insulin from the reservoir to the injection site). The occlusion may be caused by a number of factors, but is most commonly associated with insulin aggregation and consequent formation of insoluble 15 particles. Avoidance of the risk of an occlusion leading to failure of a pump is a prerequisite for successful development of an autonomous insulin pump system, especially one which is to be implanted.
It would be desirable if a medical infusion pump system were available 20 which can deliver compositions of insulin or insulin analogues from a reservoir, which are rapid or ultra-rapid acting, and which remain stable upon storage and in-use at temperatures both inside and outside the body. In addition, in order to improve the convenience of use of such medical infusion pump systems it would be desirable to reduce the size of the system which would require reduction of 25 size of the reservoir and consequent increase in the concentration of insulin so that the total amount of insulin in the reservoir remains the same.
SUMMARY OF THE INVENTION
According to the invention there is provided a medical infusion pump 30 system comprising a pump and a reservoir comprising an aqueous liquid pharmaceutical composition for delivery by means of said pump to a mammal wherein the composition comprises (i) an insulin compound, (ii) ionic zinc and (iii) an alkyl glycoside as a non-ionic surfactant.
35
The compositions of the system of the invention provide insulin in a form with good physical and chemical stability, preferably in a form which is rapid or ultra-rapid acting. The present inventors have importantly identified that use of an alkyl glycoside as a non-ionic surfactant increases the storage stability of insulin compositions, which is expected to permit the use of a pump based 40 system to deliver aqueous liquid pharmaceutical compositions of insulin to the body of a mammal from one or more reservoirs with good in-use stability.
8
As noted in the background discussion above, use of EDTA to chelate zinc ions in hexameric insulin does increase the rapidity of action but at the cost of greatly reduced stability. Without being limited by theory, the present inventors have also appreciated that the use in certain embodiments of the invention of zinc together with species which bind zinc less strongly can achieve similar 5 effects in terms of speed of action and their moderately destabilising effects can be reduced or eliminated by using a non-ionic surfactant. The present inventors have further appreciated that the presence of such a zinc binding species accelerates the onset of action of a high concentration (high strength) insulin compound composition thereby mitigating the delaying effect on insulin onset of 10 action which has been observed when the concentration of insulin compound in a composition is increased.
Compositions of the system of the invention may be used in the treatment of subjects suffering from diabetes mellitus, particularly Type 1 diabetes mellitus. 15
As can be seen from the accompanying examples, example compositions of the system of the invention are significantly more stable than compositions without an alkyl glycoside as non-ionic surfactant including under stress conditions that model those of an infusion pump system. The example 20 compositions achieve a rapid speed of action of insulin and are more stable than prior art rapid acting insulin formulations containing EDTA. Furthermore, example compositions of the system of the invention contain high concentrations of insulin compound while maintaining good stability and a rapid onset of action.
25
DESCRIPTION OF THE SEQUENCE LISTING
SEQ ID NO: 1: A chain of human insulin
SEQ ID NO: 2: B chain of human insulin
SEQ ID NO: 3: B chain of insulin lispro
SEQ ID NO: 4: B chain of insulin aspart 30
SEQ ID NO: 5: B chain of insulin glulisine
FIGURES
Fig. 1. Pharmacodynamic profiles of Formulations 4A-4C of Example 4 in a validated diabetic Yucatan miniature pig model. 35
Fig. 2. Pharmacodynamic profile of Formulations 13A and 13B of Example 13 in a validated diabetic Yucatan miniature pig model.
Fig. 3. Pharmacodynamic profiles of formulations 14A-14D of Example 14 in a 40 validated diabetic Yucatan miniature pig model.
Fig. 4. Pharmacokinetic profiles of formulations 14A-14C of Example 14 in a validated diabetic Yucatan miniature pig model.
9
Fig. 5. Pharmacodynamic profiles of formulations 15A-15D of Example 15 in a validated diabetic Yucatan miniature pig model.
Fig. 6. Pharmacokinetic profiles of formulations 15A, 15B and 15D of Example 15 5 in a validated diabetic Yucatan miniature pig model.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, “insulin compound” refers to insulin and insulin analogues. 10
As used herein, “insulin” refers to native human insulin having an A chain and a B chain as set out in SEQ ID NOS: 1 and 2 and containing and connected by disulfide bridges as in the native molecule (Cys A6-Cys A11, Cys B7 to Cys A7 and Cys-B19-Cys A20). Insulin is suitably recombinant insulin. 15
“Insulin analogue” refers to an analogue of insulin which is an insulin receptor agonist and has a modified amino acid sequence, such as containing 1 or 2 amino acid changes in the sequence of the A or B chain (especially the B chain). Desirably such amino acid modifications are intended to reduce affinity of 20 the molecule for zinc and thus increase speed of action. Thus, desirably an insulin analogue has a speed of action which is the same as or preferably greater than that of insulin. The speed of action of insulin or an insulin analogue may be determined in the Diabetic Pig Pharmacokinetic/Pharmacodynamic Model (see Examples, General Methods (c)). Exemplary insulin analogues include faster 25 acting analogues such as insulin lispro, insulin aspart and insulin glulisine. These forms of insulin have the human insulin A chain but variant B chains – see SEQ ID NOS: 3-5. Further faster acting analogues are described in EP0214826, EP0375437 and EP0678522 the contents of which are herein incorporated by reference in their entirety. Suitably, the insulin compound is not insulin glargine. 30 Suitably, the insulin compound is not insulin degludec. Suitably, the insulin compound is a rapid-acting insulin compound, wherein “rapid-acting” is defined as an insulin compound which has a speed of action which is greater than that of native human insulin, e.g. as measured using the Diabetic Pig Pharmacokinetic/Pharmacodynamic Model (see Examples, General Methods 35 (c)).
In one embodiment, the insulin compound is recombinant human insulin. In another embodiment, it is insulin lispro. In another embodiment, it is insulin aspart. In another embodiment, it is insulin glulisine. In another embodiment, the 40 insulin compound is not recombinant human insulin.
The term “aqueous liquid pharmaceutical composition”, as used herein, refers to a composition suitable for therapeutic use in which the aqueous
10
component is or comprises water, preferably distilled water, deionized water, water for injection, sterile water for injection or bacteriostatic water for injection. The aqueous liquid pharmaceutical compositions of the system of the invention are solution compositions in which all components are dissolved in water.
5
The concentration of insulin compound in the composition is suitably in the range 10-1000 U/ml, e.g. 50-1000 U/ml, e.g. 400-1000 U/ml, e.g. 500-1000 U/ml, e.g. 600-1000 U/ml, e.g. 700-1000 U/ml, e.g. 800-1000 U/ml, e.g. 900-1000 U/ml, e.g. 1000 U/ml. In one embodiment, the concentration of insulin compound in the composition is 10-250 U/ml. 10
“U/ml” as used herein describes the concentration of insulin compound in terms of a unit per volume, wherein “U” is the international unit of insulin activity (see e.g. European Pharmacopoeia 5.0, Human Insulin, pp 1800-1802).
15
The compositions of the system of the invention contain ionic zinc i.e. Zn2+ ions. The source of the ionic zinc will typically be a water-soluble zinc salt such as ZnCl2, ZnO, ZnSO4, Zn(NO3)2 or Zn(acetate)2 and most suitably ZnCl2 or ZnO.
The ionic zinc in the composition is typically present at a concentration of 20 more than 0.05% e.g. more than 0.1% e.g. more than 0.2%, more than 0.3% or more than 0.4% by weight of zinc based on the weight of insulin compound in the composition. Thus, the concentration of the ionic zinc in the composition may be more than 0.5% by weight of zinc based on the weight of insulin compound in the composition, for example 0.5-1%, e.g. 0.5-0.75%, e.g. 0.5-0.6% by weight of zinc 25 based on the weight of insulin compound in the composition. For the purpose of the calculation the weight of the counter ion to zinc is excluded.
In a composition e.g. containing 1000 U/ml of insulin compound the concentration of the ionic zinc will typically be more than 0.15 mM e.g. more than 30 0.3 mM, e.g. more than 0.6 mM, more than 0.9 mM or more than 1.2 mM. Thus, the concentration of the ionic zinc in the composition may be more than 1.5 mM, for example 1.5-6.0 mM, e.g. 2.0-4.5 mM, e.g. 2.5-3.5 mM.
The compositions of the system of the invention may optionally comprise 35 a zinc binding species e.g. at a concentration of 1 mM or more and, for example, selected from species having a logK with respect to zinc ion binding in the range 4.5-12.3 at 25 °C. Suitably, the zinc binding species is selected from species having a logK with respect to zinc ion binding in the range 4.5-10 at 25 °C. Metal binding stability constants listed in the National Institute of Standards and 40 Technology reference database 46 (Critically Selected Stability Constants of Metal Complexes) can be used. The database typically lists logK constants determined at 25 °C. Therefore, the suitability of a zinc binding species for the present invention can be determined based on its logK metal binding stability
11
constant with respect to zinc binding, as measured at 25 °C and as quoted by the database. The zinc binding species may also be described as an “accelerator” in the compositions according to the invention. Exemplary zinc binding species include polydendate organic anions. Thus, in a preferred embodiment, the zinc binding species is citrate (logK = 4.93) which can, for example, be employed as 5 trisodium citrate or citric acid. Further examples include pyrophosphate (logK = 8.71), aspartate (logK = 5.87), glutamate (logK = 4.62), cysteine (logK = 9.11), cystine (logK = 6.67) and glutathione (logK = 7.98). Other possible zinc binding species include substances that can contribute a lone pair of electrons or electron density for interaction with ionic zinc such as polydendate amines including 10 ethylenediamine (logK = 5.69), diethylenetriamine (DETA, logK = 8.88) and triethylenetetramine (TETA, logK = 11.95); and aromatic or heteroaromatic substances that can contribute a lone pair of electrons especially those comprising an imidazole moiety such as histidine (logK = 6.51). Thus, in one embodiment, the zinc binding species having a logK with respect to zinc ion 15 binding in the range 4.5-12.3 is selected from citrate, pyrophosphate, aspartate, glutamate, cysteine, cystine, glutathione, ethylenediamine, histidine, DETA and TETA.
The most suitable concentration of the zinc binding species will depend 20 on the agent and its logK value and will typically be in the range 1-100 mM. The concentration of zinc binding species can be adjusted according to the particular concentration of insulin compound present in the composition, in order to provide the desired accelerating effect.
25
For example, the zinc binding species having a logK with respect to zinc ion binding in the range 4.5-12.3 may be present at a concentration of 1-60 mM. Suitably the concentration of the zinc binding species in the composition is 5-60 mM e.g. 5-60 mM, e.g. 10-60 mM, e.g. 20-60 mM, e.g. 30-60 mM, e.g. 40-60 mM, e.g. 40-50 mM, more preferably around 44 mM when the zinc binding 30 species is citrate or histidine for insulin compound 1000 U/ml compositions. In one embodiment, the zinc binding species having a logK with respect to zinc ion binding in the range 4.5-12.3 is present at a concentration of 1-50 mM.
Anionic zinc binding species may be employed as the free acid or a salt 35 form, such as a salt form with sodium or calcium ions, especially sodium ions.
A mixture of zinc binding species may be employed, although a single zinc binding species is preferred.
40
Suitably the molar ratio of ionic zinc to zinc binding species in the composition is 1:3 to 1:175.
12
The following ranges are particularly of interest especially for citrate or histidine as zinc binding species: e.g. 1:10-1:175 e.g. 1:10 to 1:100, e.g. 1:10-1:50, e.g. 1:10 to 1:30, e.g. 1:10 to 1:20 (especially for insulin compound 1000 U/ml composition).
5
For example, a composition containing 1000 U/ml of insulin compound may contain around 3 mM of ionic zinc (i.e. around 197 μg/ml of ionic zinc, i.e. around 0.54% by weight of zinc based on the weight of insulin compound in the composition) and around 30-60 mM e.g. 40-60 mM e.g. 40-50 mM zinc binding species (especially citrate). 10
In one embodiment, the ratio of insulin compound concentration (U/ml) to zinc binding species (mM) in the composition is in the range 100:1 to 2:1 e.g. 50:1 to 2:1, e.g. 40:1 to 2:1.
15
In one embodiment, the composition is substantially free of EDTA and any other zinc binding species having a logK with respect to zinc binding of more than 12.3 as determined at 25 °C. In an embodiment, the formulations of the invention are substantially free of EDTA (logK = 14.5). Further examples of zinc binding species which have a logK metal binding stability constant with respect to zinc 20 binding of more than 12.3 to be avoided include EGTA (logK = 12.6). In general, the composition of the system of the invention will be substantially free of tetradentate ligands or ligands of higher denticity. In an embodiment, the composition of the system of the invention is substantially free of zinc binding species having a logK with respect to zinc ion binding of 10-12.3 at 25 °C. 25 “Substantially free” means that the concentration of zinc binding species which have a logK metal binding stability constant with respect to zinc binding as specified (such as EDTA) is less than 0.1 mM, such as less than 0.05 mM, such as less than 0.04 mM or less than 0.01 mM.
30
Where present, zinc ion binding species which have acid forms (e.g. citric acid) may be introduced into the aqueous compositions of the system of the invention in the form of a salt of the acid, such as a sodium salt (e.g. trisodium citrate). Alternatively, they can be introduced in the form of the acid with subsequent adjustment of pH to the required level. The present inventors have 35 found that in some circumstances introducing the acid form (such as citric acid) into the composition instead of the salt form (e.g. trisodium citrate) may have advantages in terms of providing superior chemical and physical stability. Thus, in an embodiment, the source of the citrate as zinc ion binding species is citric acid. 40
In an embodiment, the composition comprises (i) an insulin compound (e.g. an insulin compound other than insulin glargine), (ii) ionic zinc, (iii) a zinc binding species selected from diethylenetriamine (DETA) and
13
triethylenetetramine (TETA), and (iv) an alkyl glycoside as non-ionic surfactant. Such a composition may, for example. be substantially free of ethylenediaminetetraacetate (EDTA) and any other zinc binding species having a logK with respect to zinc ion binding of more than 12.3 at 25 °C. The zinc binding species may, for example, be present at a concentration of about 0.05 mM or 5 more e.g. 0.05-5 mM, e.g. 0.05-2 mM. The molar ratio of ionic zinc to the zinc binding species in the composition may, for example, be 2:1 to 1:10.
In an embodiment, the composition comprises (i) an insulin compound,
(ii) ionic zinc, (iii) a zinc binding species at a concentration of 1 mM or more 10 selected from species having a logK with respect to zinc ion binding in the range 4.5-10 at 25 °C, (iv) a zinc binding species selected from species having a logK with respect to zinc ion binding of more than 12.3 at 25 °C at a concentration of less than about 0.3 mM, and (v) an alkyl glycoside as non-ionic surfactant. In an embodiment, the zinc binding species having a logK with respect to zinc ion 15 binding of more than 12.3 at 25 °C is present in the composition at a concentration of between about 0.01 mM and about 0.3 mM. In an embodiment, the zinc binding species having a logK with respect to zinc ion binding of more than 12.3 at 25 °C is selected from ethylenediaminetetraacetate (EDTA), ethyleneglycoltetraacetate (EGTA), tetraethylenepentamine, N-(2-20 hydroxyethyl)ethylenedinitrilotriacetate (HEDTA), 1-methyl-ethylenedinitrilotriacetate (PDTA), 1-ethyl-ethylenedinitrilotriacetate, 1-propyl- thylenedinitrilotriacetate, 1-carboxyethylene-ethylenedinitrilotriacetate, triethylenetetranitrilohexaacetate, tetraethylenepentanitriloheptaacetate (TPHA) and tris(2-aminoethyl)amine (Tren), and especially is EDTA. For example, the 25 molar ratio of ionic zinc to EDTA as zinc binding species having a logK with respect to zinc ion binding of more than 12.3 at 25 °C is 2:1 to 25:1. In an embodiment, the zinc binding species having a logK with respect to zinc ion binding in the range 4.5-10 at 25 °C is selected from citrate, pyrophosphate, aspartate, glutamate, cysteine, cystine, glutathione, ethylenediamine and 30 histidine and especially is citrate. In an embodiment, the zinc binding species having a logK with respect to zinc ion binding in the range 4.5-10 at 25 °C is present at a concentration of 1-50 mM. In an embodiment, the molar ratio of ionic zinc to zinc binding species having a logK with respect to zinc ion binding in the range 4.5-10 at 25 °C is 1:3 to 1:500. 35
The compositions of the system of the invention contain an alkyl glycoside as a non-ionic surfactant. In one embodiment, the alkyl glycoside is selected from the group consisting of dodecyl maltoside, dodecyl glucoside, octyl glucoside, octyl maltoside, decyl glucoside, decyl glucopyranoside, decyl maltoside, tridecyl 40 glucoside, tridecyl maltoside, tetradecyl glucoside, tetradecyl maltoside, hexadecyl glucoside, hexadecyl maltoside, sucrose monooctanoate, sucrose monodecanoate, sucrose monododecanoate, sucrose monotridecanoate, sucrose monotetradecanoate and sucrose monohexadecanoate. In one
14
embodiment, the alkyl glycoside is dodecyl maltoside or decyl glucopyranoside. In one preferred embodiment, the alkyl glycoside is dodecyl maltoside.
The concentration of the alkyl glycoside in the composition will typically be in the range 1-1000 μg/ml, e.g. 5-500 μg/ml, e.g. 10-200 μg/ml, such as 10-100 5 μg/ml or around 50 μg/ml. In one embodiment, the non-ionic surfactant is present at a concentration of 10-400 μg/ml e.g. 20-400 μg/ml, 50-400 μg/ml, 10-300 μg/ml, 20-300 μg/ml, 50-300 μg/ml, 10-200 μg/ml, 20-200 μg/ml, 50-200 μg/ml, 10-100 μg/ml, 20-100 μg/ml or 50-100 μg/ml.
10
In another embodiment, the concentration of insulin compound is 800-1000 U/ml and the non-ionic surfactant is present at a concentration of 50-200 μg/ml. In this embodiment, suitably the non-ionic surfactant is dodecyl maltoside.
In one embodiment, the composition of the system of the invention 15 comprises (i) an insulin compound at a concentration of 50-500 U/ml (ii) ionic zinc, (iii) optionally citrate as a zinc binding species at a concentration of 1 mM or more, and (iv) a non-ionic surfactant which is an alkyl glycoside; and wherein the composition is substantially free of EDTA and any other zinc binding species having a logK with respect to zinc ion binding of more than 12.3 at 25 ° C. 20 Suitably, the citrate may be present in the composition at a concentration of 10-30 mM e.g. 10-20 mM e.g. 15-25 mM e.g. 20-30 mM.
In another embodiment, the composition of the system of the invention comprises (i) an insulin compound at a concentration of 400-1000 U/ml e.g. 500-25 1000 U/ml (ii) ionic zinc, (iii) optionally citrate as a zinc binding species at a concentration of 1 mM or more, and (iv) a non-ionic surfactant which is an alkyl glycoside; and wherein the composition is substantially free of EDTA and any other zinc binding species having a logK with respect to zinc ion binding of more than 12.3 at 25 °C. Suitably, the citrate may be present in the composition at a 30 concentration of 30-50 mM, e.g. 30-40 mM e.g. 35-45 mM e.g. 40-50 mM. In one embodiment, the citrate is present in the composition at a concentration of 30-60 mM.
Suitably the pH of the composition of the system of the invention is in the 35 range 5.5-9.0 e.g. in the range 7.0-7.5. In order to minimise injection pain, the pH is preferably close to physiological pH (around pH 7.4). In one embodiment of the system of the invention, the pH is in the range 7.0-8.0 e.g. 7.5. In another embodiment of the system, the pH is in the range 7.6-8.0 e.g. 7.8.
40
Suitably, the composition of the system of the invention comprises a buffer (e.g. one or more buffers) in order to stabilise the pH of the composition, which can also be selected to enhance protein stability. In one embodiment, a buffer is selected to have a pKa close to the pH of the composition; for example,
15
histidine is suitably employed as a buffer when the pH of the composition is in the range 5.0-7.0. Such a buffer may be employed in a concentration of 0.5-20 mM e.g. 2-5 mM. If histidine is included in the composition as a zinc binding species it will also have a buffering role at this pH. In another embodiment, the composition comprises a phosphate buffer. Sodium phosphate is suitably 5 employed as a buffer when the pH of the composition is in the range 6.1-8.1. Such a buffer may be employed in a concentration of 0.5-20 mM e.g. 2-5 mM, e.g. 2 mM. Alternatively, in another embodiment, the composition of the system of the invention is further stabilised as disclosed in WO2008/084237 (herein incorporated by reference in its entirety), which describes a composition 10 comprising a protein and one or more additives, characterised in that the system is substantially free of a conventional buffer, i.e. a compound with an ionisable group having a pKa within 1 unit of the pH of the composition at the intended temperature range of storage of the composition, such as 25 °C. In this embodiment, the pH of the composition is set to a value at which the composition 15 has maximum measurable stability with respect to pH; the one or more additives (displaced buffers) are capable of exchanging protons with the insulin compound and have pKa values at least 1 unit more or less than the pH of the composition at the intended temperature range of storage of the composition. The additives may have ionisable groups having pKa between 1 to 5 pH units, preferably 20 between 1 to 3 pH units, most preferably from 1.5 to 2.5 pH units, of the pH of the aqueous composition at the intended temperature range of storage of the composition (e.g. 25 °C). Such additives may typically be employed at a concentration of 0.5-10 mM e.g. 2-5 mM.
25
The compositions of the system cover a wide range of osmolarity, including hypotonic, isotonic and hypertonic compositions. Preferably, the composition of the system of the invention is substantially isotonic. Suitably the osmolarity of the composition is selected to minimize pain according to the route of administration e.g. upon injection. Preferred compositions have an osmolarity 30 in the range of about 200 to about 500 mOsm/L. Preferably, the osmolarity is in the range of about 250 to about 350 mOsm/L. More preferably, the osmolarity is about 300 mOsm/L.
Tonicity of the composition may be adjusted with a tonicity modifying 35 agent (e.g. one or more tonicity modifying agents). Thus, the composition of the system of the invention may further comprise a tonicity modifying agent (e.g. one or more tonicity modifying agents). The tonicity modifying agent may be charged or uncharged. Examples of charged tonicity modifying agents include salts such as a combination of sodium, potassium, magnesium or calcium ions, with 40 chloride, sulfate, carbonate, sulfite, nitrate, lactate, succinate, acetate or maleate ions (especially sodium chloride or sodium sulphate, particularly sodium chloride).
16
In one embodiment, the charged tonicity modifying agent is sodium chloride. The insulin compound compositions of the system of the invention may contain a residual NaCl concentration of 2-4 mM as a result of the use of standard acidification and subsequent neutralization steps employed in preparing insulin compositions. Amino acids such as arginine, glycine or histidine may also 5 be used for this purpose. Charged tonicity modifying agent (e.g. NaCl) may be used at a concentration of 100–300 mM, e.g. around 150 mM. Preferably, the chloride is present at a concentration of >60 mM e.g. >65 mM, >75 mM, >80 mM, >90 mM, >100 mM, >120 mM or >140 mM.
10
Suitably an uncharged rather than a charged tonicity modifying agent is used when the concentration of insulin compound in the composition is 400 U/ml or more.
Examples of uncharged tonicity modifying agents include sugars, sugar 15 alcohols and other polyols, such as trehalose, sucrose, mannitol, glycerol, 1,2-propanediol, raffinose, lactose, dextrose, sorbitol or lactitol (especially trehalose, mannitol, glycerol or 1,2-propanediol, particularly glycerol). In one embodiment, the uncharged tonicity modifying agent is selected from the group consisting of trehalose, mannitol, glycerol and 1,2-propanediol. In another embodiment, the 20 uncharged tonicity modifying agent is glycerol. Uncharged tonicity modifying agent is preferably used at a concentration of 200–500 mM, e.g. around 300 mM. Another range of interest is 100-500 mM. In one embodiment, the uncharged tonicity modifying agent in the composition is at a concentration of 100–300 mM, e.g. 150–200 mM, 170-180 mM or around 174 mM. In one embodiment, the 25 uncharged tonicity modifying agent in the composition is glycerol at a concentration of 100–300 mM, e.g. 150-200 mM, 170-180 mM or around 174 mM.
In one embodiment, the composition of the system of the invention 30 comprises <10 mM chloride (e.g. sodium chloride), for example <9 mM, <8 mM, <7 mM, <6 mM or <5 mM, or is substantially free of chloride (e.g. sodium chloride) i.e. no chloride is added to the composition beyond any chloride that may be contributed as part of pH adjustment.
35
When the insulin compound is insulin lispro, the tonicity is suitably adjusted using an uncharged tonicity modifying agent, preferably at a concentration of 200–500 mM, e.g. around 300 mM. In this embodiment, the uncharged tonicity modifying agent is suitably selected from the group consisting of trehalose, mannitol, glycerol and 1,2-propanediol (most suitably glycerol). In 40 another embodiment, the uncharged tonicity modifying agent is used at a concentration of 100–300 mM, e.g. 150–200 mM, 170-180 mM or around 174 mM. In one embodiment, the uncharged tonicity modifying agent is glycerol at a
17
concentration of 100–300 mM, e.g. 150-200 mM, 170-180 mM or around 174
mM.
When the insulin compound is insulin aspart, the tonicity is suitably
5 adjusted using an uncharged tonicity modifying agent, preferably at a
concentration of 200–500 mM, e.g. around 300 mM. In this embodiment, the
uncharged tonicity modifying agent is suitably selected from the group consisting
of trehalose, mannitol, glycerol and 1,2-propanediol (most suitably glycerol). In
another embodiment, the uncharged tonicity modifying agent is used at a
10 concentration of 100–300 mM, e.g. 150–200 mM, 170-180 mM or around 174
mM. In one embodiment, the uncharged tonicity modifying agent is glycerol at a
concentration of 100–300 mM, e.g. 150-200 mM, 170-180 mM or around 174
mM.
15 When the insulin compound is insulin glulisine, the tonicity is suitably
adjusted using an uncharged tonicity modifying agent, preferably at a
concentration of 200–500 mM, e.g. around 300 mM. In this embodiment, the
uncharged tonicity modifying agent is suitably selected from the group consisting
of trehalose, mannitol, glycerol and 1,2-propanediol (most suitably glycerol). In
20 another embodiment, the uncharged tonicity modifying agent is used at a
concentration of 100–300 mM, e.g. 150–200 mM, 170-180 mM or around 174
mM. In one embodiment, the uncharged tonicity modifying agent is glycerol at a
concentration of 100–300 mM, e.g. 150-200 mM, 170-180 mM or around 174
mM.
25
The ionic strength of a composition of the system of the invention may be
calculated according to the formula I:
=
= 
n
X 1
2
x x I 0.5 c z
in which cx is molar concentration of ion x (mol L-1), zx is the absolute value of the
charge of ion x and the sum covers all ions (n) present in the composition,
30 wherein the contribution of the insulin compound and zinc binding species (if
present) should be ignored for the purposes of the calculation. The contribution of
ionic zinc should be included. For zwitterions, the absolute value of the charge
is the total charge excluding polarity, e.g. for glycine the possible ions have
absolute charge of 0, 1 or 2 and for aspartate the possible ions have absolute
35 charge of 0, 1, 2 or 3.
In an embodiment, particularly wherein the concentration of insulin
compound is 400 U/mL or more, the ionic strength of the composition is suitably
less than 40 mM, 30 mM, less than 20 mM or less than 10 mM.
40
18
In one embodiment the composition of the system of the invention
comprises (i) an insulin compound at a concentration 400-1000 U/ml e.g. 500-
1000 U/ml (ii) ionic zinc, (iii) optionally citrate as a zinc binding species at a
concentration of 1 mM or more, and (iv) an alkyl glycoside as a non-ionic
5 surfactant; wherein the composition is substantially free of EDTA and any other
zinc binding species having a logK with respect to zinc ion binding of more than
12.3 at 25 °C, and wherein the ionic strength of the composition is less than
40 mM, said ionic strength being calculated using the formula I:
=
= 
n
X 1
2
x x I 0.5 c z
10 in which cx is molar concentration of ion x (mol L-1), zx is the absolute value of the
charge of ion x and the sum covers all ions (n) present in the composition,
wherein the contribution of the insulin compound and zinc binding species (if
present) should be ignored for the purposes of the calculation. The contribution of
ionic zinc should be included. Suitably, the citrate is present in the composition
15 at a concentration of 30-50 mM e.g. 40-50 mM. Suitably the ionic strength of the
composition is less than 40 mM calculated using Formula I. Suitably, the
formulation of the invention comprises <10 mM chloride (e.g. sodium chloride),
for example <9 mM, <8 mM, <7 mM, <6 mM or <5 mM, or is substantially free of
chloride (e.g. sodium chloride) i.e. no chloride is added to the formulation beyond
20 any chloride that may be contributed as part of pH adjustment. In one
embodiment, the composition comprises an uncharged tonicity modifying agent.
In one embodiment, the insulin compound is present at a concentration of
400-1000 U/ml, e.g. >400-1000 U/ml, 500-1000 U/ml, e.g. >500-1000 U/ml, 600-
25 1000 U/ml, >600-1000 U/ml, 700-1000 U/ml, >700-1000 U/ml, 750-1000 U/ml,
>750-1000 U/ml, 800-1000 U/ml, >800-1000 U/ml, 900-1000 U/ml, >900-1000
U/ml or 1000 U/ml, and the ionic strength taking account of ions in the
composition except for the zinc binding species, the insulin compound and the
ionic zinc is less than 30 mM, e.g. less than 20 mM, e.g. less than 10 mM such
30 as 1-10 mM. In a further embodiment, the ionic strength taking account of ions in
the composition except for the zinc binding species, the insulin compound and
the ionic zinc is less than 25 mM, less than 20 mM, less than 15 mM, or less than
10 mM, or is in the range 5-<30 mM, 5-30 mM, 5-20 mM, 2-20 mM, 1-10 mM, 2-
10 mM or 5-10 mM.
35
When the insulin compound is insulin lispro at a concentration of 400-
1000 U/ml, e.g. >400-1000 U/ml, 500-1000 U/ml, e.g. >500-1000 U/ml, 600-1000
U/ml, >600-1000 U/ml, 700-1000 U/ml, >700-1000 U/ml, 750-1000 U/ml, >750-
1000 U/ml, 800-1000 U/ml, >800-1000 U/ml, 900-1000 U/ml, >900-1000 U/ml or
40 1000 U/ml, the ionic strength of the composition is suitably kept to a minimum
level since higher ionic strength compositions are less stable than lower ionic
strength compositions, particularly at high concentrations of insulin. Suitably the
19
ionic strength taking account of ions in the composition except for the zinc binding species, the insulin compound and the ionic zinc is less than 30 mM, e.g. less than 20 mM, e.g. less than 10 mM such as 1-10 mM. In particular, the ionic strength taking account of ions in the composition except for the zinc binding species, the insulin compound and the ionic zinc is less than 25 mM, less than 20 5 mM, less than 15 mM, or less than 10 mM, or is in the range 5-<30 mM, 5-30 mM, 5-20 mM, 2-20 mM, 1-10 mM, 2-10 mM or 5-10 mM.
When the insulin compound is insulin aspart at a concentration of 400-1000 U/ml, e.g. >400-1000 U/ml, 500-1000 U/ml e.g. >500-1000 U/ml, 600-1000 10 U/ml, >600-1000 U/ml, 700-1000 U/ml, >700-1000 U/ml, 750-1000 U/ml, >750-1000 U/ml, 800-1000 U/ml, >800-1000 U/ml, 900-1000 U/ml, >900-1000 U/ml or 1000 U/ml, the ionic strength of the composition is suitably kept to a minimum level since higher ionic strength compositions are less stable than lower ionic strength compositions. Suitably the ionic strength taking account of ions in the 15 composition except for the zinc binding species, the insulin compound and the ionic zinc is less than 30 mM, e.g. less than 20 mM, e.g. less than 10 mM. In particular, the ionic strength taking account of ions in the composition except for the zinc binding species, the insulin compound and the ionic zinc is less than 25 mM, less than 20 mM, less than 15 mM, or less than 10 mM, or is in the range 5-20 <30 mM, 5-30 mM, 5-20 mM, 2-20 mM, 1-10 mM, 2-10 mM or 5-10 mM. The tonicity may suitably be adjusted using an uncharged tonicity modifying agent.
When the insulin compound is insulin glulisine at a concentration of 400-1000 U/ml, e.g. >400-1000 U/ml, 500-1000 U/ml e.g. >500-1000 U/ml, 600-1000 25 U/ml, >600-1000 U/ml, 700-1000 U/ml, >700-1000 U/ml, 750-1000 U/ml, >750-1000 U/ml, 800-1000 U/ml, >800-1000 U/ml, 900-1000 U/ml, >900-1000 U/ml or 1000 U/ml, the ionic strength of the composition is suitably kept to a minimum level since higher ionic strength compositions may be less stable than lower ionic strength compositions. Suitably the ionic strength taking account of ions in the 30 composition except for the zinc binding species, the insulin compound and the ionic zinc is less than 30 mM, e.g. less than 20 mM, e.g. less than 10 mM. In particular, the ionic strength taking account of ions in the composition except for the zinc binding species, the insulin compound and ionic zinc is less than 25 mM, less than 20 mM, less than 15 mM, or less than 10 mM, or is in the range 5-<30 35 mM, 5-30 mM, 5-20 mM, 2-20 mM, 1-10 mM, 2-10 mM or 5-10 mM.
The composition of the system of the invention may optionally further comprise a preservative (e.g. one or more preservatives). One or more preservatives may be employed. In one embodiment, the preservative is 40 selected from the group consisting of phenol, m-cresol, chlorocresol, benzyl alcohol, propylparaben, methylparaben, benzalkonium chloride and benzethonium chloride.
20
The composition of the system of the invention may optionally further comprise nicotinamide. The presence of nicotinamide may further increase the speed of onset of action of insulin formulated in compositions of the system of the invention. Suitably, the concentration of nicotinamide is in the range 10-150 mM, preferably in the range 20-100 mM, such as around 80 mM. 5
The composition of the system of the invention may optionally further comprise nicotinic acid or a salt thereof. The presence of nicotinic acid or a salt thereof may also further increase the speed of onset of action of insulin formulated in compositions of the system of the invention. Suitably, the 10 concentration of nicotinic acid or a salt thereof is in the range 10-150 mM, preferably in the range 20-100 mM, such as around 80 mM. Example salts include metal salts such as sodium, potassium and magnesium salts.
Typically, one of nicotinamide and nicotinic acid (or as salt thereof) may 15 be included in the composition but not both.
In an embodiment, the composition comprises (i) an insulin compound, (ii) ionic zinc, (iii) a nicotinic compound, (iv) an alkyl glycoside as a non-ionic surfactant; and (v) a salt selected from the salts formed between Group 1 metals 20 and a mono or divalent anion. In an embodiment, the nicotinic compound is nicotinamide or nicotinic acid or a salt thereof. In an embodiment, the nicotinic compound is present in the composition at a concentration of 10-150 mM. In an embodiment, the Group 1 metal is sodium. In an embodiment, the salt is the sodium salt of a mono or divalent anion. In an embodiment, the anion is chloride 25 or acetate. Thus, for example, the salt is sodium chloride or sodium acetate. In an embodiment, the salt is present in the composition at a concentration of 30-200 mM.
The composition of the system of the invention may optionally further 30 comprise treprostinil or a salt thereof. The presence of the treprostinil may further increase the speed of onset of action of insulin formulated in compositions of the system of the invention. Suitably, the concentration of treprostinil in the composition is in the range of 0.1-12 μg/ml e.g. 0.1-10 μg/ml, 0.1-9 μg/ml, 0.1-8 μg/ml, 0.1-7 μg/ml, 0.1-6 μg/ml, 0.1-5 μg/ml, 0.1-4 μg/ml, 0.1-3 μg/ml, 0.1-2 35 μg/ml, 0.5-2 μg/ml or about 1 μg/ml.
In one embodiment, the composition does not contain a vasodilator. In a further embodiment, the composition does not contain treprostinil, nicotinamide, nicotinic acid or a salt thereof. 40
Compositions of the system may optionally include other beneficial components including stabilising agents. For example, amino acids such as arginine or proline may be included which may have stabilising properties. Thus,
21
in one embodiment, the compositions of the system comprise arginine.
In an embodiment of the invention the compositions are free of acids selected from glutamic acid, ascorbic acid, succinic acid, aspartic acid, maleic acid, fumaric acid, adipic acid and acetic acid and are also free from the 5 corresponding ionic forms of these acids.
In an embodiment of the invention the compositions of the system are free of arginine.
10
In an embodiment of the invention the compositions of the system are free of protamine and protamine salts.
In an embodiment of the invention the compositions of the system are free of magnesium ions. 15
The addition of magnesium ions e.g. in the form of magnesium chloride may provide a stabilising effect. Thus, in an embodiment of the invention the composition contains magnesium ions e.g. MgCl2.
20
In an embodiment of the invention the compositions of the system are free of calcium ions.
Compositions of the system may further comprise an additional therapeutically active agent (an “active agent”), in particular an agent of use in 25 the treatment of diabetes (i.e. in addition to the insulin compound in particular the rapid-acting insulin compound) e.g. an amylin analogue or a GLP-1 agonist. In one embodiment, the composition further comprises an amylin analogue such as pramlintide, suitably at a concentration of 0.1-10 mg/ml e.g. 0.2-6 mg/ml. In one embodiment, the composition further comprises a GLP-1 agonist such as 30 liraglutide, dulaglutide, albiglutide, exenatide or lixisenatide, suitably at a concentration of 10 μg/ml to 50 mg/ml e.g. 200 μg/ml to 10 mg/ml or 1 mg/ml to 10 mg/ml.
Suitably the compositions of the system are sufficiently stable that the 35 concentration of high molecular weight species remains low upon extended storage. The term “high molecular weight species” as used herein, refers to any irreversibly formed component of the protein content which has an apparent molecular weight at least about double the molecular weight of the parent insulin compound, as detected by a suitable analytical method, such as size-exclusion 40 chromatography. That is, high molecular weight species are multimeric aggregates of the parent insulin compound. The multimeric aggregates may comprise the parent protein molecules with considerably altered conformation or they may be an assembly of the parent protein units in the native or near-native
22
conformation. The determination of high molecular weight species can be done using methods known in the art, including size exclusion chromatography, electrophoresis, analytical ultracentrifugation, light scattering, dynamic light scattering, static light scattering and field flow fractionation.
5
Suitably the compositions of the system are sufficiently stable that they remain substantially free of visible particles after storage at 30°C for at least one month or more, two months or more, or three months or more. Visible particles are suitably detected using the 2.9.20. European Pharmacopoeia Monograph (Particulate Contamination: Visible Particles). For example, a composition is 10 substantially free of visible particles if it has a Visual score according to Visual Assessment Scoring Method B of 1, 2 or 3, especially 1 or 2 according to the definition given in the Examples section.
Suitably the compositions of the system are sufficiently stable that there is 15 minimal increase in soluble aggregates such as <0.5%, <0.2% or <0.1% increase after storage at 30°C for one month or more, two months or more or three months or more. Soluble aggregates are suitable detected using SEC (see General Methods).
20
Suitably the compositions of the system are sufficiently stable that the concentration of related species remains low upon extended storage. The term “related species” as used herein, refers to any component of the protein content formed by a chemical modification of the parent insulin compound, particularly desamido or cyclic imide forms of insulin. Related species are suitably detected 25 by RP-HPLC.
In a preferred embodiment, the composition of the system of the invention retains at least 95%, e.g. at least 96%, e.g. at least 97%, e.g. at least 98%, e.g. at least 99% parent insulin compound (by weight of total protein) after storage at 30 30°C for one, two or three months. The percentage of insulin compound (by weight of total protein) may be determined by size-exclusion chromatography or RP-HPLC.
In a preferred embodiment, the composition of the system of the invention 35 comprises no more than 4% (by weight of total protein), preferably no more than 2% high molecular weight species (e.g. visible particles and/or soluble aggregates) after storage at 30°C for one, two or three months.
In a preferred embodiment, the composition of the system of the invention 40 comprises no more than 4% (by weight of total protein), preferably no more than 2%, preferably no more than 1% A-21 desamido form of the insulin compound after storage at 30°C for one, two or three months.
23
In preferred embodiments, a composition of the system of the invention should exhibit an increase in high molecular weight species (e.g. visible particles and/or soluble aggregates) during storage which is at least 10% lower, preferably at least 25% lower, more preferably at least 50% lower, than a composition lacking the non-ionic surfactant but otherwise identical, following storage under 5 the same conditions (e.g. 30°C) and length of time (e.g. one, two or three months).
In preferred embodiments, a composition of the system of the invention should exhibit an increase in related species during storage which is at least 10% 10 lower, preferably at least 25% lower, more preferably at least 50% lower, than a composition lacking the non-ionic surfactant but otherwise identical, following storage under the same conditions (e.g. 30°C) and length of time (e.g. one, two or three months).
15
The speed of action of a composition of the system of the invention may be determined in the Diabetic Pig Pharmacokinetic/Pharmacodynamic Model (see Examples, General Methods (c)). In preferred embodiments, a composition of the present invention exhibits a Tmax (i.e. time to peak insulin concentration) that is at least 20% shorter, preferably at least 30% shorter than a composition 20 lacking the zinc binding species having a logK with respect to zinc ion binding in the range 4.5-12.3 (e.g. in the range 4.5-10) at 25 °C but otherwise identical, using the model. In preferred embodiments, a composition of the present invention exhibits an area under the curve on the pharmacodynamics profile within the first 45 minutes after injection that is at least 20% greater, preferably at 25 least 30% greater than a composition lacking the zinc binding species having a logK with respect to zinc ion binding in the range 4.5-12.3 (e.g. in the range 4.5-10) at 25 °C but otherwise identical, using the model.
In one embodiment, the composition of the system of the invention 30 comprises (i) insulin lispro at a concentration of 400-1000 U/ml e.g. 500-1000 U/ml, (ii) ionic zinc, (iii) optionally a zinc binding species at a concentration of 1 mM or more selected from species having a logK with respect to zinc ion binding in the range 4.5-12.3 at 25 °C e.g. citrate, and (iv) a non-ionic surfactant which is an alkyl glycoside; and wherein the composition is substantially free of EDTA and 35 any other zinc binding species having a logK with respect to zinc ion binding of more than 12.3 at 25 °C, which exhibits a Tmax (i.e. time to peak insulin concentration) that is at least 20% shorter, preferably at least 30% shorter than an aqueous composition consisting of: insulin lispro (100 U/ml), sodium phosphate (13.2 mM), glycerol (174 mM), m-cresol (29 mM), ionic zinc (19.7 40 μg/ml, excluding counter-ion) adjusted to pH 7.3, using the Diabetic Pig Pharmacokinetic/Pharmacodynamic Model (see Examples, General Methods (c)). In another embodiment, the present invention provides a composition comprising (i) insulin lispro at a concentration of 400-1000 U/ml e.g. 500-1000
24
U/ml, (ii) ionic zinc, (iii) optionally a zinc binding species at a concentration of 1 mM or more selected from species having a logK with respect to zinc ion binding in the range 4.5-12.3 at 25 °C e.g. citrate, and (iv) a non-ionic surfactant which is an alkyl glycoside; and wherein the composition is substantially free of EDTA and any other zinc binding species having a logK with respect to zinc ion binding of 5 more than 12.3 at 25 °C, which exhibits an area under the curve on the pharmacodynamics profile within the first 45 minutes after injection that is at least 20% greater, preferably at least 30% greater than an aqueous composition consisting of: insulin lispro (100 U/ml), sodium phosphate (13.2 mM), glycerol (174 mM), m-cresol (29 mM), ionic zinc (19.7 μg/ml, excluding counter-ion) 10 adjusted to pH 7.3, using the Diabetic Pig Pharmacokinetic/Pharmacodynamic Model (see Examples, General Methods (c)).
In one embodiment, the composition of the system of the invention comprises (i) insulin aspart at a concentration of 400-1000 U/ml e.g. 500-1000 15 U/ml, (ii) ionic zinc, (iii) optionally a zinc binding species at a concentration of 1 mM or more selected from species having a logK with respect to zinc ion binding in the range 4.5-12.3 at 25 °C e.g. citrate, and (iv) a non-ionic surfactant which is an alkyl glycoside; and wherein the composition is substantially free of EDTA and any other zinc binding species having a logK with respect to zinc ion binding of 20 more than 12.3 at 25 °C, which exhibits a Tmax (i.e. time to peak insulin concentration) that is at least 20% shorter, preferably at least 30% shorter than an aqueous composition consisting of: insulin aspart (100 U/ml), sodium phosphate (7 mM), glycerol (174 mM), sodium chloride (10 mM), phenol (15.9 mM), m-cresol (15.9 mM) and ionic zinc (19.7 μg/ml, excluding counter-anion) 25 adjusted to pH 7.4, using the Diabetic Pig Pharmacokinetic/Pharmacodynamic Model (see Examples, General Methods (c)). In another embodiment, the present invention provides a composition comprising (i) insulin aspart at a concentration of 400-1000 U/ml e.g. 500-1000 U/ml, (ii) ionic zinc, (iii) optionally a zinc binding species at a concentration of 1 mM or more selected from species 30 having a logK with respect to zinc ion binding in the range 4.5-12.3 at 25 °C e.g. citrate, and (iv) a non-ionic surfactant which is an alkyl glycoside; and wherein the composition is substantially free of EDTA and any other zinc binding species having a logK with respect to zinc ion binding of more than 12.3 at 25 °C, which exhibits an area under the curve on the pharmacodynamics profile within the first 35 45 minutes after injection that is at least 20% greater, preferably at least 30% greater than an aqueous composition consisting of: insulin aspart (100 U/ml), sodium phosphate (7 mM), glycerol (174 mM), sodium chloride (10 mM), phenol (15.9 mM), m-cresol (15.9 mM) and ionic zinc (19.7 μg/ml, excluding counter-anion) adjusted to pH 7.4, using the Diabetic Pig 40 Pharmacokinetic/Pharmacodynamic Model (see Examples, General Methods (c)).
25
In preferred embodiments, a composition of the system of the invention is bioequivalent to a standard composition comprising the insulin compound at 100 U/ml.
As used herein, “bioequivalent” means that the composition of the system 5 of the invention has an equivalent or similar pharmacokinetic/pharmacodynamic (PK/PD) profile to a standard composition. For example, the composition of the system of the invention exhibits a TMAX or T½MAX (measured in accordance with the Diabetic Pig Pharmacokinetic/Pharmacodynamic Model described in section (c) of General Methods) which is substantially the same as (e.g. within ±20% of, 10 e.g. within ±10% of) that of the standard composition. Bioequivalence can also be established by applying the Student’s t-test to the pharmacokinetic/pharmacodynamics results achieved using two different compositions as described in the diabetic pig pharmacokinetic/pharmacodynamic model described in section (c) of General Methods. 15
By “standard composition” is meant a commercially available composition of the same insulin compound at a concentration of 100 U/ml such as HUMALOG® (for insulin lispro) or NOVORAPID® (for insulin aspart) or APIDRA® (for insulin glulisine). 20
In one embodiment, the composition of the system of the invention comprises an insulin compound at a concentration of 400-1000 U/mL e.g. 500-1000 U/mL and wherein the composition is bioequivalent to a standard composition comprising the insulin compound at a concentration of 100 U/mL. In 25 another embodiment, the absorption of insulin compound into the blood stream of the mammal after administration using the system is bioequivalent to a standard composition at a concentration comprising the insulin compound at a concentration of 100 U/mL. In another embodiment, the glucose reduction response caused by administration of a given amount of insulin compound to the 30 mammal using the system is bioequivalent to a standard composition comprising the insulin compound at a concentration of 100 U/mL.
In one embodiment, a composition of the system of the invention wherein the insulin compound is insulin lispro is bioequivalent to a commercial 35 composition of insulin lispro at a concentration of 100 U/ml e.g. an aqueous composition consisting of: insulin lispro (100 U/ml), sodium phosphate (13.2 mM), glycerol (174 mM), m-cresol (29 mM), ionic zinc (19.7 μg/ml, excluding counter-ion) adjusted to pH 7.3 (i.e. the composition of HUMALOG®).
40
In one embodiment, a composition of the system of the invention wherein the insulin compound is insulin aspart is bioequivalent to a commercial composition of insulin aspart at a concentration of 100 U/ml e.g. an aqueous composition consisting of: insulin aspart (100 U/ml), sodium phosphate (7 mM),
26
glycerol (174 mM), sodium chloride (10 mM), phenol (15.9 mM), m-cresol (15.9 mM) and ionic zinc (19.7 μg/ml, excluding counter-anion) adjusted to pH 7.4 (i.e. the composition of NOVORAPID®).
According to further aspects of the invention, there is provided a 5 composition of the system of the invention for use in the treatment of a subject suffering from diabetes mellitus. There is also provided a method of treatment of diabetes mellitus which comprises administering to a subject in need thereof an effective amount of a composition of the system of the invention.
10
In one embodiment, the composition of the system of the invention is co-administered with a long acting insulin such as insulin glargine or insulin degludec, suitably at a concentration of 50-1000 U/ml e.g. 100-500 U/ml or 100-200 U/ml.
15
The composition of the system of the invention is for administration by infusion, preferably by subcutaneous infusion.
Pumps of the system of the invention may, for example, be syringe pumps wherein the insulin reservoir is in the form of a small syringe and the insulin 20 composition is dispensed by the action of a moveable piston. Various mechanisms can be used to exert the appropriate force onto the piston to deliver the require dose accurately, including (but not limited to) electromechanical effect, piezoelectric effect or electrochemical effect (expansion via electrochemical formation of a gas). Alternatively, the system of the invention 25 may rely on a different pumping mechanism that does not require a syringe and a piston, such as the wax actuated technology (see WO2015/114374, Cellnovo)) or the MICRO-DELIVERY® technology from Tandem ensuring accurate delivery of dose.
30
The system of the invention can deliver the insulin composition to the mammal at a set basal rate. In one embodiment, the pump delivers the insulin compound in the composition to the mammal at a set basal rate e.g. 0.1-20 U/hr e.g.1-20 U/hr e.g. 1-10 U/hr e.g. 0.1-10 U/hr. The system of the invention may optionally comprise a controller for controlling the basal rate e.g. a controller for 35 controlling the dose and frequency of administration of composition to the mammal.
The pump of the system may deliver the composition in pulses. Such pulses of the pump may have a pulse volume of 0.001-1 μL e.g. 0.005-0.1 μL, 40 e.g. 0.005-0.05 μL. In one embodiment, each pulse delivers 0.001-1 U e.g. 0.001-0.1 U of insulin compound. Such pulses of the pump may deliver 0.05-50 ng e.g. 0.5 ng, e.g. 1 ng, e.g. 5 ng, e.g. 10 ng, e.g. 20 ng, e.g. 50 ng of alkyl glycoside. Preferably, the ratio between the dose of insulin compound delivered
27
(U) and the pulse volume (μL) is at least 0.4:1 e.g. at least 0.5: 1, e.g. at least 0.6:1. In an embodiment, the pump will deliver 10-1000 pulses per hour e.g. 10-500, e.g. 10-250, e.g. 10-200, e.g. 10-150, e.g. 10-100, e.g. 10-75, e.g. 10-50 pulses per hour. In a particular embodiment, the pump will deliver 10-100 pulses per hour. In one embodiment, the pump will deliver 20-1000 pulses per hour e.g. 5 20-500, e.g. 20-250, e.g. 20-200, e.g. 20-150, e.g. 20-100, e.g. 20-75, e.g. 20-50 pulses per hour. In a particular embodiment, the pump will deliver 20-100 pulses per hour. In an embodiment, the pump will deliver 30-1000 pulses per hour e.g. 30-500, e.g. 30-100, e.g. 30-75, e.g. 30-50 pulses per hour. In a particular embodiment, the pump will deliver 30-100 pulses per hour. In an embodiment, 10 the pump will deliver 40-1000 pulses per hour e.g. 40-250 e.g.100-500, e.g. 100-1000, e.g. 500-1000 pulses per hour. The system of the invention may optionally comprise a controller for controlling the size and frequency of the pulses.
The pump of the system may deliver the insulin compound in the 15 composition to the mammal in a bolus dose. Administration of a bolus dose should suitably occur in the window between 15 minutes before eating (i.e. before start of a meal) and 15 minutes after eating (i.e. after end of a meal). In one embodiment, the bolus dose is 1-100 U e.g. 1-10 U, e.g. 2-20 U, e.g. 5-50 U, e.g. 10-100 U, e.g. 50-100 U. 20
The reservoir of the system which comprises the aqueous liquid pharmaceutical composition for delivery by means of said pump will typically have a total volume of up to 3 mL e.g. 3 mL, e.g. 2 mL, e.g. 1 mL. The system may comprise one or more further reservoirs. In one embodiment, the further 25 reservoirs comprise an aqueous liquid pharmaceutical composition comprising an insulin compound as active ingredient. In another embodiment, the further reservoirs comprise an aqueous composition comprising an active ingredient which is not an insulin compound.
30
Reservoirs of the system are retained in containers e.g. cartridges or syringes. Containers may be a replaceable or refillable component of the system.
The system may optionally further comprise a glucose sensor and control 35 means to direct the pump to deliver a dose of insulin compound based on information received from the glucose sensor. The glucose sensor provides glucose readings at regular intervals, e.g. every 5 minutes. This is referred to as the Continuous Glucose Monitoring (CGM).
40
The system of the invention may be either be an open-loop system or a closed-loop system.
28
In an open-loop system the infusion pump supplies a predetermined amount of Insulin and the wearer is expected to manually adjust the dosing based on the CGM readings to ensure the glucose level remains within the required range.
5
In a closed-loop system, a disposable sensor measures interstitial glucose levels, which are fed through wireless transmission into the insulin pump controlled by an algorithm controlling delivery of insulin into the subcutaneous tissue. In such system, involvement of wearer to maintain the blood glucose control is minimal. Such a closed loop system is sometimes referred to as an 10 artificial pancreas. The success of the closed-loop system algorithms depends considerably on the speed of onset of the insulin compound used in the pump. The more rapid the onset is the more accurately can the algorithm correct the insulin level to ensure the blood glucose remains within the normal range as much as possible. 15
Another aspect of the invention is a medical infusion pump system comprising a reservoir comprising a plurality of doses of the composition and a pump adapted for automatic or remote operation such that upon automatic or remote operation one or more doses of the composition is administered to the 20 body e.g. subcutaneously or intramuscularly. Such devices may be worn on the outside of the body or implanted in the body.
In one embodiment, the system may be worn on the surface of the body. Suitably, the system is worn on the surface of the body for 1 day or more, e.g. 2 25 days or more, e.g. 3 days or more, e.g. 5 days or more, e.g. 7 days or more.
We claim:
1. A medical infusion pump system comprising a pump and a reservoir comprising an aqueous liquid pharmaceutical composition for delivery by means of said pump to a mammal wherein the composition comprises (i) 5 an insulin compound, (ii) ionic zinc and (iii) an alkyl glycoside as a non-ionic surfactant.
2. A system according to claim 1, wherein the insulin compound is not insulin glargine.
3. A system according to claim 1, wherein the insulin compound is insulin 10 lispro.
4. A system according to claim 1, wherein the insulin compound is insulin aspart.
5. A system according to claim 1, wherein the insulin compound is insulin glulisine. 15
6. A system according to claim 1, wherein the insulin compound is recombinant human insulin.
7. A system according to claim 1, wherein the insulin compound is not recombinant human insulin.
8. The system according to any one of claims 1 to 6, wherein the insulin 20 compound is present at a concentration of 10-1000 U/ml.
9. The system according to claim 8, wherein the insulin compound is present at a concentration of 50-1000 U/ml.
10. The system according to claim 8, wherein the insulin compound is present at a concentration of 10-250 U/ml. 25
11. The system according to claim 9, wherein the insulin compound is present at a concentration of 400-1000 U/ml.
12. The system according to claim 11, wherein the insulin compound is present at a concentration of 500-1000 U/ml e.g. 600-1000 U/ml, e.g. 700-1000 U/ml, e.g. 800-1000 U/ml, e.g. 900-1000 U/ml, e.g. 1000 U/ml. 30
13. The system according to any one of claims 1 to 12, wherein the ionic zinc is present at a concentration of more than 0.05% by weight of zinc based on the weight of insulin compound in the composition.
14. The system according to claim 13, wherein the ionic zinc is present at a concentration of more than 0.5% by weight of zinc based on the weight of 35 insulin compound in the composition.
15. The system according to claim 14, wherein the ionic zinc is present at a concentration of 0.5-1% by weight of zinc based on the weight of insulin compound in the composition.
16. The system according to any one of claims 1 to 15, wherein the 40 composition further comprises a zinc binding species at a concentration of 1 mM or more selected from species having a logK with respect to zinc ion binding in the range 4.5-12.3 at 25 °C.
95
17. The system according to any one of claims 1 to 16, wherein the composition is substantially free of EDTA and any other zinc binding species having a logK with respect to zinc ion binding of more than 12.3 at 25 °C.
18. The system according to claim 16 or 17, wherein the zinc binding species 5 is selected from citrate, pyrophosphate, aspartate, glutamate, cysteine, cystine, glutathione, ethylenediamine, histidine, DETA and TETA.
19. The system according to claim 18, wherein the zinc binding species is citrate.
20. The system according to claim 19, wherein the source of the citrate is 10 citric acid.
21. The system according to any one of claims 16 to 20, wherein the zinc binding species having a logK with respect to zinc ion binding in the range 4.5-12.3 is present at a concentration of 1-50 mM.
22. The system according to any one of claims 16 to 21, wherein the molar 15 ratio of ionic zinc to zinc binding species is 1:3 to 1:175.
23. The system according to claim 16 or claim 17, wherein the zinc binding species at a concentration of 1 mM or more is selected from species having a logK with respect to zinc ion binding in the range 4.5-10 at 25 °C.
24. The system according to claim 16 or claim 17, which is substantially free 20 of zinc binding species having a logK with respect to zinc ion binding of 10-12.3 at 25 °C.
25. The system according to any one of claims 1 to 24, wherein the alkyl glycoside is selected from the group consisting of dodecyl maltoside, dodecyl glucoside, octyl glucoside, octyl maltoside, decyl glucoside, decyl 25 maltoside, decyl glucopyranoside, tridecyl glucoside, tridecyl maltoside, tetradecyl glucoside, tetradecyl maltoside, hexadecyl glucoside, hexadecyl maltoside, sucrose monooctanoate, sucrose monodecanoate, sucrose monododecanoate, sucrose monotridecanoate, sucrose monotetradecanoate and sucrose monohexadecanoate. 30
26. The system according to claim 25, wherein the alkyl glycoside is dodecyl maltoside or decyl glucopyranoside.
27. The system according to claim 26, wherein the alkyl glycoside is dodecyl maltoside.
28. The system according to any one of claims 1 to 27, wherein the alkyl 35 glycoside is present at a concentration of 1-1000 μg/ml e.g. 5-500 μg/ml, 10-200 μg/ml, 10-100 μg/ml or around 50 μg/ml.
29. The system according to claim 28, wherein the alkyl glycoside is present at a concentration of 10-400 μg/ml e.g. 20-400 μg/ml, 50-400 μg/ml, 10-300 μg/ml, 20-300 μg/ml, 50-300 μg/ml, 10-200 μg/ml, 20-200 μg/ml, 50-40 200 μg/ml, 10-100 μg/ml, 20-100 μg/ml or 50-100 μg/ml.
30. The system according to any one of claims 1 to 29, wherein the composition further comprises a tonicity modifying agent.
96
31. The system according to claim 30, wherein the tonicity modifying agent is
an uncharged tonicity modifying agent.
32. The system according to claim 31, wherein the uncharged tonicity
modifying agent is selected from the group consisting of trehalose,
5 mannitol, glycerol and 1,2-propanediol.
33. The system according to claim 32, wherein the uncharged tonicity
modifying agent is glycerol.
34. The system according to claim 30, wherein the tonicity modifying agent is
a charged tonicity modifying agent.
10 35. The system according to claim 34, wherein the charged tonicity modifying
agent is sodium chloride.
36. The system according to claim 34 or claim 35, wherein the chloride is
present at a concentration of >60 mM e.g. >65 mM, >75 mM, >80 mM,
>90 mM, >100 mM, >120 mM or >140 mM.
15 37. The system according to any one of claims 1 to 31, wherein the ionic
strength of the composition excluding any zinc binding species and the
insulin compound is <40 mM, e.g. <30 mM, <20 mM or <10 mM, wherein
ionic strength is calculated according to the formula I:
=
= 
n
X 1
2
x x I 0.5 c z
20 in which cx is molar concentration of ion x (mol L-1), zx is the absolute
value of the charge of ion x and the sum covers all ions (n) present in the
composition, wherein the contribution of the insulin compound and zinc
binding species (if present) should be ignored for the purposes of the
calculation.
25 38. The system according to any one of claims 1 to 37, wherein the
composition is substantially isotonic.
39. The system according to any one of claims 1 to 38, wherein the pH of the
composition is in the range 5.5 to 9.0.
40. The system according to claim 39, wherein the pH is in the range 7.0 to
30 7.5 e.g. 7.4.
41. The system according to claim 39, wherein the pH is in the range 7.6 to
8.0 e.g. 7.8.
42. A system according to claim 40 or claim 41, which comprises a phosphate
buffer e.g. sodium phosphate.
35 43. The system according to any of claims 1 to 42, wherein the composition
further comprises a preservative.
44. The system according to claim 43, wherein the preservative is selected
from the group consisting of phenol, m-cresol, chlorocresol, benzyl
alcohol, propylparaben, methylparaben, benzalkonium chloride and
40 benzethonium chloride.
45. The system according to any one of claims 1 to 44, wherein the
composition further comprises nicotinamide.
97
46. The system according to any one of claims 1 to 45, wherein the composition further comprises nicotinic acid or a salt thereof.
47. The system according to any one of claims 1 to 46, wherein the composition further comprises treprostinil or a salt thereof.
48. The system according to claim 1, wherein the composition comprises (i) 5 an insulin compound at a concentration of 50-500 U/ml (ii) ionic zinc, (iii) optionally citrate as a zinc binding species at a concentration of 1 mM or more, and (iv) a non-ionic surfactant which is an alkyl glycoside; and wherein the composition is substantially free of EDTA and any other zinc binding species having a logK with respect to zinc ion binding of more 10 than 12.3 at 25 °C.
49. The system according to claim 48, wherein the citrate is present in the composition at a concentration of 10-30 mM.
50. The system according to claim 1, wherein the composition comprises (i) an insulin compound at a concentration of 400-1000 U/ml e.g. 500-1000 15 U/ml (ii) ionic zinc, (iii) optionally citrate as a zinc binding species at a concentration of 1 mM or more, and (iv) a non-ionic surfactant which is an alkyl glycoside; and wherein the composition is substantially free of EDTA and any other zinc binding species having a logK with respect to zinc ion binding of more than 12.3 at 25°C. 20
51. The system according to claim 50, wherein the citrate is present in the composition at a concentration of 30-60 mM.
52. The system according to claim 1, wherein the composition comprises (i) an insulin compound (ii) ionic zinc, (iii) a zinc binding species selected from diethylenetriamine (DETA) and triethylenetetramine (TETA), and (iv) 25 an alkyl glycoside as non-ionic surfactant.
53. The system according to claim 1, wherein the composition comprises (i) an insulin compound, (ii) ionic zinc, (iii) a zinc binding species at a concentration of 1 mM or more selected from species having a logK with respect to zinc ion binding in the range 4.5-10 at 25 °C, (iv) a zinc binding 30 species selected from species having a logK with respect to zinc ion binding of more than 12.3 at 25 °C at a concentration of less than about 0.3 mM, and (v) an alkyl glycoside as non-ionic surfactant.
54. The system according to claim 1, wherein the composition comprises (i) an insulin compound, (ii) ionic zinc, (iii) a nicotinic compound (iv) an alkyl 35 glycoside as a non-ionic surfactant; and (v) a salt selected from the salts formed between Group 1 metals and a mono or divalent anion.
55. The system according to any one of claims 1 to 54, wherein the composition comprises an insulin compound at a concentration of 400-1000 U/mL e.g. 500-1000 U/mL and wherein the composition is 40 bioequivalent to a standard composition comprising the insulin compound at a concentration of 100 U/mL.
56. The system according to any one of claims 1 to 54, wherein the absorption of insulin compound into the blood stream of the mammal after
98
administration using the system is bioequivalent to a standard composition comprising the insulin compound at a concentration of 100 U/mL.
57. The system according to any one of claims 1 to 54, wherein the glucose reduction response caused by administration of a given amount of insulin 5 compound to the mammal using the system is bioequivalent to a standard composition comprising the insulin compound at a concentration of 100 U/mL.
58. The system according to any one of claims 1 to 57, comprising a controller for controlling the dose and frequency of administration of 10 composition to the mammal.
59. The system according to any one of claims 1 to 58, wherein the pump delivers the insulin compound in the composition to the mammal at a set basal rate e.g. 0.1-20 U/hr.
60. The system according to any one of claims 1 to 59, wherein the pump 15 delivers the composition in pulses.
61. The system according to claim 60, wherein the pulses have a pulse volume of 0.001-1 μL e.g. 0.005-0.1 μL e.g. 0.005-0.05 μL.
62. The system according to claim 60, wherein each pulse delivers 0.001-1 U e.g. 0.001-0.1 U insulin compound. 20
63. The system according to claim 60, wherein each pulse delivers 0.05-50 ng e.g. 0.5 ng alkyl glycoside.
64. The system according to any one of claims 60 to 63, wherein the ratio between the dose of insulin compound delivered (U) and the pulse volume (μL) is at least 0.4:1 e.g. at least 0.5: 1 e.g. at least 0.6:1. 25
65. The system according to any one of claims 60 to 64, wherein the pump delivers 10-1000 pulses per hour e.g. 10-500, e.g. 10-250, e.g. 10-200, e.g. 10-150, e.g. 10-100, e.g. 10-75, e.g. 10-50 pulses per hour.
66. The system according to any one of claims 1 to 58, wherein the pump delivers the insulin compound in the composition to the mammal in a 30 bolus dose.
67. The system according to claim 66, wherein the bolus dose is 1-100 U.
68. The system according to any one of claims 1 to 67, wherein the reservoir has a total volume of up to 3 mL e.g. 3 mL e.g. 2 mL e.g. 1 mL.
69. A system according to any one of claims 1 to 68, comprising one or more 35 further reservoirs.
70. A system according to claim 69, wherein one or more further reservoirs comprise an aqueous liquid pharmaceutical composition comprising an insulin compound as active ingredient.
71. A system according to claim 69 or 70, wherein one or more further 40 reservoirs comprise an aqueous liquid pharmaceutical composition comprising an active ingredient which is not an insulin compound.
72. The system according to any one of claims 1 to 71, which is an open-loop system or a closed-loop system.
99
73. The system according to any one of claims 1 to 72, wherein the system is worn on the surface of the body.
74. The system according to claim 73, wherein the system is worn on the surface of the body for 1 day or more, e.g. 2 days or more, e.g. 3 days or more, e.g. 5 days or more, e.g. 7 days or more. 5
75. The system according to any one of claims 1 to 74, which comprises at least one cannula or needle in fluid communication with the pump or the at least one reservoir for subcutaneously infusing the insulin composition into the mammal.
76. The system according to claims 73 or 74, wherein the system is a patch 10 pump system.
77. The system according to any one of claims 1 to 72, wherein the system is implanted in the body.
78. The system according to any one of claims 1 to 77, wherein the composition is more stable (e.g. forms fewer visible particles and/or 15 soluble aggregates) than an identical composition in the absence of alkyl glycoside in-use i.e. during operation of the pump for 3 days or more.
79. The system according to any one of claims 1 to 78, wherein the system further comprises a glucose sensor and control means to direct the pump to deliver a dose of insulin compound based on information received from 20 the glucose sensor.
80. The system for use according to any one of claims 1 to 79, wherein the system administers the composition subcutaneously to the mammal.
81. The system according to any one of claims 1 to 80, for use in the treatment of diabetes mellitus in said mammal. 25
82. The system for use according to claim 81, wherein the mammal is a human.
83. A method of treatment of diabetes mellitus which comprises administering to a mammal in need thereof an effective amount of an insulin compound containing composition via a pump using a system according to any one 30 of claims 1 to 80.
84. The method according to claim 83, wherein the mammal is a human.
85. Use of an alkyl glycoside as a non-ionic surfactant to improve the stability of an insulin compound in an aqueous liquid pharmaceutical composition in a medical infusion pump system comprising a pump and an aqueous 35 composition for delivery by means of said pump to a mammal, wherein the composition comprises (i) an insulin compound, (ii) ionic zinc and (iii) an alkyl glycoside as a non-ionic surfactant.
40
100
86. A method of improving the stability of an insulin compound to be
administered by a medical infusion pump system, which comprises adding
an alkyl glycoside to an aqueous liquid pharmaceutical composition
comprising the insulin compound and ionic zinc.