Drug candidates commonly fail to complete the development process in clinical trials because their physical properties (particularly solubility) make them difficult to formulate, or because of a poor therapeutic index that leads to toxic effects during the high drug concentrations that occur just after dosing. Other short comings include poor absorption, poor bioavailability, instability, systemic side effects due to an inability to target the drugs, and the inability to control their biodistribution, metabolism and renal or hepatic clearance once administered. Current products on the market can also be improved with regard to such issues. Additionally, the modification of known compounds to improve pharmacokinetic or pharmacodynamic properties or reduce unwanted side effects reduces the risks and cost associated with development of a new drug candidate.
Many peptides of therapeutic interest, such as hormones, soluble receptors, cytokines, enzymes etc are ineffective or inconvenient to administer as long acting drug candidates because of their short half-life and need for frequent repeat dosing. Short half-life is the result of too rapid clearance by the kidneys or liver or proteolytic degradation or immune clearance. There is a need for a delivery mechanism that prolongs half-life while maintaining effective activity.
A number of approaches have been tried to modify a pharmaceutical compound's pharmokinetic profile including the formulation of the pharmaceutical agent in a liposome, micellar or polymeric micelle formulation, as well as covalent attachment of the pharmaceutical agent to a hydrophilic polymer backbone, to improve stability and protect against proteolytic activity or immunoreactivity. Polyethylene glycol (PEG) has been used to attempt to improve half-life of proteins. High molecular weight (MW) PEG conjugated to proteins have been on the market for many years and evidence has recently been found of accumulation of these high MW PEG molecules over time in the kidneys and the choroidal plexus, which is a serious concern for chronic use conditions. These long chain high MW PEG can also make solutions excessively viscose and mask pharmaceutical activity, leading to substantially reduced efficacy. Further, it can be difficult to control PEG size, introducing variability into the finished product. Such variability reduces effectiveness and can impede regulatory approval. Low MW PEG generally has not provided adequate bulk or shielding to achieve the desired half-life improvement.
In spite of the extensive use of PEG for three decades now, there is no general consensus on what is the optimum coverage-density, conformation and molecular weight combination for a given carrier and application (J.-M. Rabanel et al./Journal of Controlled Release 185 (2014) 71-87). Controlling nanoparticle surface properties is a challenging task due to the many constrains that are involved in the design of a particle surface: long circulation time, low non-specific cellular uptake and active targeting have conflicting requirements in terms of surface properties. Target recognition and docking of ligand molecules located at the surface of a PEGylated particle are dependent on the density and thickness of the PEG and the positioning of the ligand.
Maintaining good glucose control has been shown to reduce diabetic complications such as retinopathy, neuropathy and nephropathy, as well as minimise hypoglycaemic events. However, many diabetics find it difficult to achieve good control in part because of compliance issues associated with frequent insulin injections, and the challenges of maintaining steady levels of basal insulin. Ideally injectable basal insulin would correlate to hepatic glucose output, maintain stable plasma glucose both fasting and between meals and prevent ketoacidosis (in T1DM). Daily basal insulin analogs, such as Lantus, Levimir and Tresiba have radically improved the way diabetics manage basal insulin levels, but there is a need to further reduce the frequency of injections and improve the pharmacokinetics of basal insulin to minimise likelihood of hypoglycaemia and other complications.
Currently available basal insulin replacement therapies are deficient in one or more clinically important aspects. For example the basal insulin analog, insulin detemir, possess a duration of activity that is insufficient to provide basal glucose control for a full day when administered daily. Furthermore, the inadvertent omission or delay of a single injection can lead to significant increase in “peak-to-trough” levels of the drug resulting in impaired glucose control. The insolubility mechanisms to prolong insulin release, e.g., the in vivo precipitation of insulin glargine or injection site multihexamers of degludec, increase intra-injection variability resulting in increased variability in the dose-response profile, and the acidity of glargine may cause pain on injection. Some insulin preparations require mixing to insure product uniformity, have increased intra-subject variability, and tend to peak rather than provide an ideal near “flat” pharmacodynamic profile (low peak to trough variations, Cmax to Cmin) necessary to maintain steady basal insulin. The half-life profiles of these daily insulin preparations can be inadequate to provide daily dosing in some patients and twice daily dosing is required for good glucose control. Additionally, some modern basal insulin analogues are not readily mixable with rapid- or immediate-acting insulin formulations. For patients another unpleasant side effect is weight gain, which is commonly experienced with existing basal insulins. Currently available insulin replacement therapies are deficient in one or more clinically important aspects. For example, daily dosing of long-acting basal insulin formulations, such as detemir often do not provide the required basal glucose control for a full day. The loss of activity results in insufficient control and/or hyperglycemia. Furthermore, the omission of a single injection of the current therapies can lead to significant increase in “peak-to-trough” levels of the drug resulting in impaired glucose control. Many current long acting insulin formulations rely on an insoluble state to protract insulin payout. Also some of these products require mechanical mixing to insure product uniformity. Such strategies result in inherently less accurate dosing due to increased intra-injection variability, as well as intra-subject variability. The ultimate result being an increase in the variability in the dose-response profile and result in less than adequate control of blood glucose and a greater susceptibility to life-threatening hypoglycemic episodes. Further, current long acting insulin formulations tend to peak rather than provide an ideal “flat” pharmacodynamic profile necessary to maintain optimal fasting blood glucose for an extended period of time between meals. Clearly, there still exists a critical need for long-lasting insulins that are better suited for basal insulin replacement regimens. In particular, soluble basal insulins that are mixable with prandial insulin formulations, have extended timeaction profiles (i.e., able to adequately control blood glucose levels with an once-daily or less frequent injection), flatter activity, pharmacokinetic profiles (i.e., lower “peak-to-trough” ratios), reduced intra-patient variability (i.e., more predictable time-action profile translating into reduced incidence of hypoglycemia and/or weight gain) and/or lesser injection site irritation or pain upon injection are needed.
A number of patents relate to the conjugation of insulin to PEG, WO02/094200, US 2003-0229010. LY2605541, a construct made from a fast acting insulin analogue conjugated to PEG (˜20 kDa), is in clinical trials (Hansen R J, et al. ADA 2012 abstract 896-P). WO 2006/079641 (novo nordisk) provides small dendrimers conjugated to insulin for pulmonary administration, with a short half-life. Pegylated insulin in PLGA microparticles have shown reduced efficacy, injection site reactions and unwanted burst like release.
In patients with type 2 diabetes, marked obesity, and insulin resistance, total daily insulin doses of 200 to 300 units are often required of which half may be basal insulin. It is desirable to concentrate insulin into a small volume to minimise injection site discomfort or multiple injections. High concentrations of insulin can be difficult to handle and deliver due to high viscosity, precipitation, and side reactions due to disulphide shuffling, from insulin forced into close contact. Similarly, insulin can be highly sensitive to heat and mechanical forces, which can result in precipitation.
Dendrimers are a special class of dendritic polymer with well controlled branched structures that are characterized by higher concentrations of functional moieties per unit of molecular volume than ordinary polymers. (Fréchet and Tomalia “Dendrimers and other Dendritic Polymers”, Wiley and Sons, New York, 2002). Dendrimers offer a high degree of branching, multivalency, globular architecture and well-defined structure and molecular weight. The potential utility of dendritic polymers both as drug delivery vectors and pharmaceutical actives has received increasing interest in recent years.
However, it is still a challenge to prepare well defined dendrimers that circulate in the blood long enough to accumulate at target sites, but that maintain activity. Kaminskas et al (mol. pharm. 2008, VOL. 5, NO. 3, 449-463) describe pegylated dendrimers without pharmaceutical activity delivered i.v. with increased half-life, in normal rats.
An important consideration in the design of a complex compound is the cost of manufacture. A smaller or simpler construct may be more cost efficient to manufacture than a larger construct. Reducing complexity and size of a macromolecule while maintaining efficacy is highly desirable.
It has surprisingly been found that, the pharmacokinetic profile or half-life of a protein or peptide may be significantly improved, without adversely affecting efficacy, by using a pegylated dendritic macromolecule.
The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge, in Australia or any other country, in the field of endeavour to which this specification relates.