Perspective

Therapeutic Delivery

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Challenges in the delivery of peptide drugs: an industry perspective

Due mainly to their poor stability and short plasma half-life, peptides are usually administered by injection, often several times daily. Injectable sustained-release formulations of peptides based on biodegradable polymer microparticles or implants early demonstrated the power of drug delivery technologies to enhance patient adherence and convenience, and increase safety and efficacy. Injectable sustainedrelease formulations are likely to remain a significant part of new peptide products. However, a new generation of technologies that enable solvent-free formulations and manufacturing processes, injection through narrow gauge needles and ready-to-use presentations will be increasingly used. In addition, the tremendous developments in noninvasive routes of delivery are likely to result in more and more peptides being delivered by the oral, transdermal, nasal or inhalation routes.

Peptides are oligomers of amino acids (AAs) linked by amide bonds. They are usually distinguished from proteins by their lower molecular weight, although the cut off usually set around 50 AAs may appear as quite arbitrary. Hence, insulin which contains 51 AAs and has a molecular weight of 5.8 kDa is usually considered as the border and can be referred to as either a peptide or a protein. Interest in therapeutic peptides exploded with advances in synthetic chemistry, more particularly using solid-phase peptide synthesis that made the manufacture of libraries of related compounds for screening feasible, and gave industrial access to pharmaceutical grade purity peptides with an acceptable yield. Peptides make attractive drug candidates due to their specificity, potency and low toxicity, but present particular challenges for their delivery to the site of action, due to their short half-life, their poor stability and high potential for proteolytic degradation. Their molecular weight, their susceptibility to extreme pH values of the gastro-intestinal tract and their enzymatic degradation mean that they are usually poorly absorbed across epithelial membranes, and exhibit low oral bioavailability. For this reason, they are

10.4155/TDE.14.111  © 2015 Future Science Ltd

Andrew L Lewis1 & Joël Richard*,1 Ipsen, 20 Rue Ethé Virton, 28109 Dreux, France *Author for correspondence: Tel.: +33 2 37 65 46 10 Fax: +33 2 37 65 46 35 [email protected] 1

most frequently administered by injection, although a variety of nonparenteral routes are employed by currently marketed peptide products (Figure 1) . Today, those peptides that are delivered via alternative routes to injection are either used for local action, or are highly potent, providing the expected pharmacological effect while showing a very low (and often variable) single digit% relative bioavailability. In addition, peptides are often rapidly metabolized or cleared from the circulation, and can require injection several times daily, which is inconvenient for patients and can affect treatment adherence/compliance. Mainly for this reason, by far the most successful advanced formulations to date have been injectable sustained-release (SR) formulations, with three of the five commercialized blockbuster peptide products based on these technologies – all using poly(α-hydroxy acids), mostly poly(lactic-co-glycolic)acid (PLGA) – to form slow release polymer matrices (Table 1) . An interesting observation is that the three blockbuster sustainedrelease PLGA -based products continue to make significant sales long after the patents on the formulated peptides have expired – likely in part due to the numerous hurdles for

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Key terms Microparticles: Spherical or irregular shaped particles usually within the size range 5–300 μm. Ready-to-use: Drug products not requiring any preparation procedures prior to administration. Burst release: Drug released from sustained release formulations in the first few hours after administration.

producing and registering formulations that produce similar pharmacological effects over the same time period (called ‘hybrid’ formulations). While injectable SR formulations are likely to continue to be important for peptide medicines, significant advances in peptide delivery via alternative routes have been made over the last few decades, and will be utilized more widely – to improve patient adherence, increase efficacy or reduce toxicity. In this article, we will review recent progress made in peptide delivery technologies with particular emphasis on those that have entered clinical trials. Injectable SR delivery systems: a long way from biodegradable microspheres to liquid ready-to-use formulations in prefilled syringes As already discussed, by far the most successful injectable SR peptide delivery technology is based on controlled release of the active pharmaceutical ingredient (API) from a matrix of PLGA polymers. These polymers were first investigated for this purpose in the late 1960s and 1970s, having already been used for biodegradable sutures, and were attractive candidates for use in parenteral drug delivery due to their biocompatibility, nonimmunogenicity and biodegradation into nontoxic endogenous by-products which are readily excreted via the Krebs’ cycle [1] . The first product to reach the market was Decapeptyl® LP, a 1 month PLGA microparticle formulation of triptorelin, initially developed by the Southern Research Institute for

1% 4% 2%1% 1% 1% 9% 9% 11%

61%

Injection Topical Nasal Oral Ophthalmic Inhalation Buccal/ sublingual Otic Transdermal Other

Figure 1. Routes of delivery of marketed peptide products (PharmacircleTM ).

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Debiopharm, and which was launched in Europe in 1986 [2] . The clear advantage of PLGA-based formul­ ations is their regulatory acceptability, after having a long history of safe use in medical devices and delivering a range of different drugs including small molecules and peptides. Their mechanisms of degradation have been well characterized and parameters to adjust polymer degradation rate (which controls drug release rate) are well established – polymer molecular weight, lactide:glycolide ratio and polymer end-group [1,3,4] . Furthermore, a plethora of formulation optimization strategies have been developed that enable an additional level of control over drug release, such as the use of porogens, polymer blends and use of complexing agents, and a number of different manufacturing processes for different drug delivery systems have been developed [5–9] . However, there are numerous limitations to PLGA-based delivery systems and their manufacturing techniques that are providing significant opportunities for new technologies to take over the lead position and bring attractive differentiation features for new peptide delivery systems. Firstly, many of the manufacturing technologies developed to produce these SR delivery systems use significant amounts of organic solvents, such as chlorinated solvents. These are processes based on phase separation (coacervation) or emulsion/solvent extraction methods [8] . In some cases, even organic solvents such as N-methylpyrrolidone are an integral part of the in situ solidifying PLGA/PLA depot systems [10,11] . This is a major issue as currently in Europe the Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) legislation is being launched [12] . This requires companies to evaluate the potential impact on both human health and the environment of chemicals used in production, and minimize the use of those considered harmful. As many microparticle manufacturing processes use large amounts of toxic solvents such as dichloromethane, it has become very unlikely that new products could be manufactured using these processes and there is a significant incentive to reduce their use. The second key limitation of PLGA microparticle formulations is that they must be resuspended in an injection vehicle immediately prior to injection. This multistep process can be technically challenging for untrained end-users and means that these formulations often have to be administered by healthcare professionals. Thirdly, in order to avoid needle blockages, the suspended microparticles have to be administered via relatively large gauge needles – a 23G needle is currently the smallest used in a marketed PLGA microparticle product (Table 1) . Implants such as Zoladex®

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Challenges in the delivery of peptide drugs 

which has been commercialized for decades, need to go through even larger needle gauges, and require the use of local anaesthetic prior to insertion. This is a clear drawback versus more recent products, as progress in both the usability of injection pen devices and the production of narrow gauge needles have meant that patients (even children and those with poor dexterity) can self-administer subcutaneous injections and quite often do not feel an injection via a 31G needle. Therefore, it seems that a key factor classically driving the development of SR formulations (i.e., injection pain and fear) has become less important than it once was, and at the same time the established SR technologies produce formulations that may seem more complicated to administer. Next generation of injectable sustained release technologies Taken together, the drivers outlined above have stimulated the development of alternative injectable SR delivery systems and manufacturing processes with the aim of making them more patient (or end-user) friendly, improving the compliance to the treatment and the quality of life of the patients. In particular, efforts have been focussed on developing products with the following characteristics: • Injectable through narrow gauge needles (25–31G); • Ready-to-use syringes);

presentations

(e.g.,

prefilled

• Water-based formulations; • Solvent-free manufacturing technologies. Next generation manufacturing technologies As Table 1 shows, the majority of injectable SR formulations are microparticle suspensions or polymer implants, with microparticle formulations having the advantage of being injectable through narrower gauge needles, but the disadvantage that they require resuspension prior to administration. Still, the needle gauges used are much larger than those used for immediate-release formulations. One strategy to improve the injectability of microparticle formulations is to improve control of the particle size of the drug product. Smaller microparticles with a tighter size distribution should be injectable through narrower gauges needles, although it should be born in mind that as the particle size decreases, the surface area to volume ratio of the formulation will increase, and this is likely to impact upon the release rate (particularly burst release) [13–15] . Several manufacturing techniques

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Perspective

have been developed to address this point, including membrane emulsification [16] , microfluidics [17,18] and flow-focussing [19] and are capable of producing essentially mono-disperse populations of microparticles of a defined particle size. Many of these processes have the advantage that they are amenable to in-line monitoring and can potentially be run continuously. They do however still require potentially large amounts of solvents, and still develop oil-water interfaces at which secondary and tertiary polypeptide structures may be lost [20] . Furthermore, given the investment required and regulatory complexity of replacing an already fully validated industrial scale manufacturing process with an entirely new one, the likelihood of these new processes to be used for product lifecycle management (to enable injectability through a narrower gauge needle) is extremely unlikely, and they are most likely to find application in the development of generics/hydrids or SR formulations of new chemical entities. Solvent free formulation & manufacturing technologies The development of injectable SR formulations without using organic solvents has both focussed on novel formulation technologies (e.g., aqueous and lipid formulations) and novel processing methods (e.g., supercritical fluid based processes). For example, in the Particles from Gas Saturated Solution (PGSS), the encapsulating polymer is liquefied by plasticization using supercritical (sc) CO2 rather than through dissolution in organic solvent, and this allows drugs to be homogeneously mixed into the plasticized polymer (typically a PLGA polymer) before depressurization through a nozzle and resolidification (encapsulation) [21–24] . The advantage of this process is that it is entirely solvent free (including water), operates at ambient temperatures and avoids shear stress and the generation of o/w interfaces during manufacture. It is therefore ideal for labile APIs, particularly large peptides and proteins. However, this process still produces microparticles that require resuspension in a delivery vehicle and that may require injection through needles of a similar size to conventional processes. In addition, with these systems, the release period of the peptides might also be quite limited, typically a few days to a few weeks, due to the difficult challenge of controlling the relatively high porosity of the microparticles generated by depressurization. Ready-to-use injectable sustained release products In an attempt to simplify the reconstitution and administration procedure, various devices have been developed, such as dual-chamber syringes in which the

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Osteoporosis Osteoporosis

Goserelin

Triptorelin

Lanreotide

Leuprolide

Histrelin

Calcitonin

Calcitonin

Zoladex®

Byetta® / Bydureon® Exenatide

 

Sandostatin® LAR

 

Decapeptyl®

Somatuline® Autogel®

Eligard®

Supprelin® LA

Miacalcin®

Precocious puberty

Prostate cancer

Acromegaly cancer

Prostate cancer

Acromegaly cancer

Prostate cancer

2005

1995

2007

2002

2001

1986

2011†

2005†

1996

1998

2003

1989

1996

0.01 #

0.28 ¶

0.06

0.25 §

0.25

0.3

 

0.5

1.0

1.6

1.7

2.0

4.3

First Sales approval (2013, US $Billion)

Nasal

Nasal

s.c.

s.c.

s.c.

s.c./ i.m

 

s.c.

s.c.

i.m.

s.c /i.v

i.m.

s.c.

Route

N/A

N/A

 

19– 20G

18G

21G

23G‡

31G†

14G

19G

n.s

22G

29G

N/A

N/A

N/A

0.25– 0.5

 

1.5

0.65‡

0.04†

N/A

2

1 – 3.5

1

1

PLGA glucose star polymer

–

PLGA microparticles

–

Drug delivery technology

od

od

12 month SR

1, 3, 4, 6 month SR

1 month SR

Immediate release and 1, 3, 4, 6 month SR

Once weekly†

Twice daily†

N-methylpyrolidone/ PLGA injection vehicle mixed immediately prior to administration

Peptide self-assembly

Coacervation, lyophilization, melt extrusion and insoluble salts

Coacervation‡

Solution†

Melt extrusion

Coacervation

Lyophilization

Emulsion/solvent extraction

Solution

Manufacturing

Nasal spray

Nasal spray

Solution

Solution

Nonbiodegradable 3.5cm × 3 mm implant cylindrical polymeric reservoir

In situ solidifying PLGA depot

Nanotubes

Lyophilizate PLGA microparticles

PLGA microparticles‡

 –

1 and 3 month PLGA implant SR

1 month SR

Immediate release

1, 3, 4, 6 month SR

Immediate release

Needle Dose Dosing gauge volume schedule (ml)

Byetta. ‡ Bydureon. § 2009 data. ¶ 2007 data. # 2010 data. B.d: Twice-a-day; I.m.: Intramusclar; I.v.: Intravenous; N/A: Not available; n.s.: Non specified; Od: Once-a-day; PLGA: Poly(lactic-co-glycolic)acid; S.c.: Subcutaneous; SR: Sustained-release; Tds: Three-times-aday.

†

Fortical

Diabetes

Octreotide

Velcade®

®

Bortezomib Myeloma

Prostate cancer

Leuprolide

Lupron® Depot

Multiple sclerosis

Glatiramer acetate

Copaxone®

Indication(s)

Peptide

Product

Table 1. Leading peptide products (excluding insulin) and their delivery systems.

Perspective  Lewis & Richard

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Byetta. Bydureon. § 2009 data. ¶ 2007 data. # 2010 data. B.d: Twice-a-day; I.m.: Intramusclar; I.v.: Intravenous; N/A: Not available; n.s.: Non specified; Od: Once-a-day; PLGA: Poly(lactic-co-glycolic)acid; S.c.: Subcutaneous; SR: Sustained-release; Tds: Three-times-aday. ‡

†

Solution Nasal spray bd N/A N/A Nasal N/A Nafarelin Synarel®

Endometriosis, 1990 IVF

Solution Nasal spray tds N/A N/A Nasal N/A Buserelin Suprefact®

Endometriosis, 1990 IVF

Needle Dose Dosing gauge volume schedule (ml) Route First Sales approval (2013, US $Billion) Indication(s) Peptide Product

Table 1. Leading peptide products (excluding insulin) and their delivery systems (cont.).

Drug delivery technology

Manufacturing

Challenges in the delivery of peptide drugs 

Perspective

delivery vehicle is kept separate from the microparticles until immediately before administration (e.g., Lupron® Depot and Bydureon®), thus avoiding the need for multiple needles (one to transfer the injection vehicle to the vial containing the microparticles, and one for drug administration). While these go some of the way toward simplifying administration, they still require multistep processes and could not be described as ready-to-use systems which is most effectively addressed through novel formulation technologies. For example, lipid-based liquid crystal systems composed of glycerol mono- or dioleate together with a watermiscible co-solvent (ethanol, propylene glycol) and a nonionic surfactant have been known for some time to be able to sustain the release of co-formulated APIs [25,26] . By modifying the surfactant and water content, different liquid crystalline phases can be formed with the cubic and reverse hexagonal phases most amenable to sustained release. The formulations can be prepared as ready-to-use prefilled syringes, injectable through 23–27G needles, and following injection form a depot in situ as the interstitial water enters the depot and the co-solvent leaches out. This technology named FluidCrystal® has been developed to an advanced stage by Camurus, and has successfully completed Phase II clinical trials showing a 1-month pharmacokinetic profile in humans as well as interesting pharmacodynamic properties. It has recently entered Phase III clinical trials for a SR formulation of the peptide octreotide. This technology holds significant promise. However, the presence of a water-miscible co-solvent in the formulation might still be a significant draw back and the ease with which it can be scaled up is yet to be confirmed, as the consistent formation of the correct liquid crystalline phase will be essential to its performance, and this could potentially very easily be effected by mass transfer effects during scale up. A number of alternative formulation technologies able to produce ready-to-use injectable SR formulations free of organic solvents have also been developed using novel polymeric systems. These technologies offer a clear advantage over established in situ solidifying polymeric implant technologies as case reports are emerging of tolerability issues with the solvents used in Eligard® for example [27] . Apidel have developed short derivatives of poly(lactic acid) (PLA) with hexyl side chains. These polymers are viscous lipophilic liquids at room temperature due to the low molecular weight of the polymer (lower than 500 g/mole), that biodegrade after injection to lactic acid, and related hexyl derivatives. APIs are dispersed in the polymer using cryogenic milling, and can then be loaded into prefilled syringes. This technology is currently preclinical, but was used to develop a ready-to-use, solvent-free SR formulation

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Perspective  Lewis & Richard of triptorelin able to control release of the peptide for 6 months in rats and injectable through a 21G needle [28] . Heron Pharmaceuticals (previously AP Pharma) have developed the novel poly(ortho ester) polymers for injectable SR formulations, initially developed by Jorg Heller [29] . The potential advantage of these polymers is that they biodegrade via surface erosion and their degradation rate (and therefore the release rate) is claimed to be more readily controllable. In addition, they do not suffer from the drop in pH in the center of the delivery system observable with the poly(α-hydroxy acid) formulations that degrade via bulk hydrolysis. Formulations prepared using these polymers can be formulated as ready-to-use viscous semisolids, and prepared as prefilled syringes. These polymers have been used to deliver a variety of different molecules including peptides, proteins and plasmid DNA and in drug targeting, but the furthest developed product is an injectable SR formulation of granisetron (Sustol®) which has completed Phase III [30–33] . The main disadvantage of these polymers is that they still have to be administered through large gauge needles and degrade into a multitude of degradation products, the safety of each of these having to be validated, which will complicate development and likely limit polymer selection. Another solvent-free water-based technology developed by Flamel Technologies use a poly(L-glutamic acid) polymer hydrophobically modified by α-tocopherol residues (Medusa® technology) to form aqueous colloidal hydrogels with a particle size of 15–50 nm. These hydrogels are able to control the release of co-formulated proteins and peptides, which they claim form noncovalent associations with the polymer. This association can be controlled through adjustment of the hydrogel: API ratio, the length of the poly(L-glutamate) chain and the amount of vitamin E. The formulations can be prepared in prefilled syringes and are injectable through 27G– 31G needles. They have demonstrated sustained release of IFN-α and IL-2 in man for periods of up to a week and claim that up to 2 weeks of sustained release is possible [34] . How effective the technology is at delivering smaller peptides is unclear, and a challenge in developing any product with this technology would be the fact that the polymer would be considered as a novel excipient and the development and regulatory risk associated with that. This is likely to lead to it being initially used to deliver an already marketed API in order to reduce program risk, or where it can be used to address a significant unmet need with a compelling business case that can justify the level of risk. Peptide self-assembly One innovative and unique approach to developing SR peptide formulations is based on their remarkable

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capacity to self-assemble into liquid crystalline superstructures. The first product to reach the market that exploited this behavior was Somatuline® Autogel® (containing the peptide lanreotide) which was first launched for the treatment of acromegaly in 2001. A PLGA microparticle formulation of the peptide (Somatuline® LA) had already been developed and was on the market. This was injected intramuscularly every 2 weeks, and intensive research was focussed on developing a ready-to-use subcutaneous formulation that could sustain release of the peptide for at least 1 month. During this work, it was observed that under the appropriate conditions, the peptide was able to form a gel due to the self-assembly of the peptide into nanotubes. These nanotubes are composed of 26 helicoidal, laterally assembled filaments, themselves formed from two proto-filaments (one internal to the nanotube, one external) made up of dimer building blocks in antiparallel β-sheet networks stabilized by hydrogen bonding  [35,36] . The two proto-filaments interact via π–π stacking of the aromatic side chains to form the filaments that make up the nanotubes [37–39] . The 24 nm hollow nanotubes are then organized in a liquid crystal hexagonal columnar phase. Importantly this process is reversible and following injection, the peptide is slowly released from the depot, it is thought from the ends of the nanotubes. The Somatuline® Autogel® formulation contains the peptide alone, water and a salt, and provides therapeutic levels of the peptide for a period of at least a month after injection. Since its launch, other peptides like gonadotropin-releasing hormone (GnRH) analogs have been shown to exhibit a similar behavior, forming amyloid fibrils as highly organized peptide aggregates, as shown by electron microscopy after in vitro incubation during 8–30 days. Formation of amyloid fibrils correlates with long acting behavior of these analogs and strong birefringence at injection site shows GnRH analogs form the fibril network in vivo. These stable fibrils gradually release monomeric functional analogs only at their termini, which guarantees a controlled and slow release [40] The clear advantages of self-assembled peptide approach are the simplicity of the formulations and the high, achievable deliverable dose – by delivering 60 to 120 mg lanreotide/month, Somatuline® Autogel® is, to our knowledge, the highest dose injectable SR peptide product on the market. Future perspective The pain and invasiveness of injections, disposal issues associated with used needles and relatively complicated administration protocols means that alternative routes of delivery are likely to be increasingly used in the future for the delivery of peptides. However, the

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Challenges in the delivery of peptide drugs 

decision making processes made by end-users (patients, carers, health-care professionals) and prescribers is complex and can be counter intuitive. For example, in China, the intravenous route of delivery is used far more commonly than in Western cultures due to a variety of historical and cultural reasons including that it is perceived to be more efficacious by patients [41] . The oral route is generally thought to be most preferred route, but this is not always the case. For example, Fransen et al. evaluated the pharmacokinetics, pharmacodynamics and patient perceptions of three different formulations (two nasal, one sublingual) of the peptide desmopressin. The patients overwhelmingly preferred the nasal formulations; two examples of patient feedback were that the nasal sprays were ‘fastest and simplest’ and the ‘sublingual tablet dissolved too slowly’ [42] . This study highlights the need to obtain an in-depth understanding of the disease, the patient, the treatment(s), the end users and prescribers and the importance of careful design of the dosage form during development. It should also be borne in mind that the primary concern of most patients and prescribers is the safety and efficacy of their treatment, and if a peptide is to be switched from an injectable route to another route of delivery it is essential that safety and efficacy are maintained. In fact in numerous cases novel delivery technologies can actually increase efficacy and/or reduce toxicity and this added value is perhaps the main driver for the use of advanced drug delivery systems. Oral peptide delivery

As discussed above, the oral route is generally considered the most preferable and patient-friendly route of drug delivery. In fact there are already some peptides that are delivered orally (Table 2), but the majority of them are not absorbed appreciably and only act locally, for example, as antibiotics or directly on receptors in the gut epithelium. The number of these peptides that are cyclic is striking, and may be a reflection of additional stability of these structures in the GI tract. There is a compelling physiological case to be made for the oral delivery of many other peptides, particularly those whose principle site of action is in the liver (e.g., insulin and the GLP-1 analogs) and can therefore benefit from delivery directly to the site of action via the hepatic portal vein; however, their low oral bioavailability has to date limited the exploitation of this delivery route. Two of the marketed orally delivered products that are absorbed orally are desmopressin and cyclosporine (Table 2) . These are key products as they demonstrate that oral peptide products can be successfully developed and the business case positive despite low bioavailability and its impact upon the

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Perspective

cost of goods. That said, the low and variable oral bioavailability has limited wider use of the oral route for most peptides and significant efforts have been made to overcome the variety of barriers to systemic absorption of peptides from the gastrointestinal tract, which are reviewed elsewhere [43] . There are now a number of companies commercializing oral peptide delivery technologies, and many are now in late stage clinical trials (Table 3) , and it might not be too long before the oral route is a feasible delivery route for a larger number of peptides. The furthest advanced technology is that of Enteris Biopharma (previously Unigene) who completed a Phase III clinical trial on the oral delivery of salmon calcitonin. Their Peptelligence® technology consists of an absorption enhancer (acylcarnitine) together with an organic acid enzyme inhibitor (citric acid) in the form of coated granules and antioxidants in an enteric coated tablet. The coating of the organic acid granules prevents acid degradation of the peptide in the tablet on storage [44,45] . This technology has been demonstrated both preclinically (in rats and dogs) and clinically to enhance the oral bioavailability of formulated peptides. The furthest advanced program was an oral formulation of salmon calcitonin which completed a randomized, double blind, double dummy, active and placebo controlled multiple dose Phase III clinical trial in 565 postmenopausal osteoporotic patients [46] . The results showed that the oral calcitonin formulation achieved a higher increase in lumbar spine bone mineral density (BMD) than the marketed nasal spray and the placebo (1.5 ± 3.2 vs 0.78 ± 2.9 and 0.5 ± 3.2%, respectively). The oral formulation also resulted in greater improvements in trochanteric and total proximal femur BMD than the nasal spray. This increased efficacy may be due to the increased systemic peptide exposure achieved from the oral formulation [47] although the relative bioavailability of the oral formulation to the nasal formulation has not been reported. Upon completion of this pivotal study, the study sponsor (Tarsa Therapeutics) was expected to file for marketing authorization, but shortly afterward in a cruel twist of fate, both the FDA and EMA reviewed the use of calcitonin in osteoporosis and advised against its use due to a possible increased risk of certain types of cancer. It should be noted that the technology was also used to develop an oral formulation of parathyroid hormone (PTH) that completed a Phase II clinical trial also in osteoporosis compared with the injectable product (Forteo). The oral PTH formulation was found to increase bone density, but less than that observed in the injectable treatment group [48] . However, an important finding of this study was that the pharmacokinetics was highly reproducible over time 6 months apart.

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Table 2. Some of the marketed oral peptide products and key properties. Product Colomycin

®

Indication

Peptide

MW (g/mole) Bioavailability

Infection

Colistin sulfate 1268

Not appreciably absorbed from GI tract

Comment Cyclic peptide

Neoral® Sandimmune®

Immunosuppression Cyclosporine

1202

High variability; Cyclic peptide, estimated to be 6 – 10% practically insoluble in (Sandimmune); Neoral water (SEDDS formulation) has 50% greater AUC and 100% higher Cmax

Cytorest®

Leucopenia

Cytochrome c

12000

Not reported

Minrin® Minrin® Melt

Nocturia

Desmopressin Acetate hydrate

1183

5% compared with Soluble sale of cyclic intranasal DDAVP, peptide. and about 0.16% absolute bioavailability. Sublingual (melt) formulation achieves 0.25%

Cachexon®

AIDS-related cachexia

Glutathione

307

Unknown

Tripeptide also found in a number of health supplements

Linzess®

Irritable bowel syndrome, constipation

Linaclotide

1527

Not appreciably absorbed from GI tract; locally acts on luminal epithelium

Cyclic peptide agonist of guanylatecyclase 2C derived from E; colienterotoxin

Ceredist® Ceredist® OD (orally disintegrating)

Spinocerebellar ataxia

Taltirelin hydrate

477

 

Practically insoluble thyrotropin releasing hormone (TRH) analog; centrally acting

Angiovag®

Pharyngitis

Tyrothricin

1228

Local action

Cyclic polypeptide, practically insoluble

Vancocin®

Infection

Vancomycin hydrochloride

1485

Poorly absorbed – generally not detectable in blood (varies patient to patient)

Tricyclic glycopeptide antibiotic, freely soluble

Chiasma are also completing Phase III clinical trials in an oral formulation of octreotide – Octreolin® -based on their transient permeation enhancer technology. The transient permeation enhancer technology consists of freeze drying the peptide in a polymer matrix (e.g., polyvinylpyrrolidone) with an absorption enhancer such as the medium chain fatty acid salt, sodium octanoate. This powder is then suspended in an oily medium such as castor oil and loaded into enteric coated capsules. They claim that these formulations protect the peptide from enzymatic digestion and transiently open tight junctions. In a series of Phase I clinical trials, in healthy volunteers they demonstrated that Octreolin® is safe and well tolerated, and can achieve dose dependent increases in Cmax [49,50] . The absorption of the delivered peptide was significantly affected by

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Marketed in Japan

taking the capsule after a meal and the proton pump inhibitor esomeprazole, it was thought due to the associated gastric pH changes affecting the region of the GI tract where the peptide is released from the capsule. An oral dose of 20 mg octreotide was shown to achieve similar pharmacokinetics as 0.1 mg injected subcutaneously indicating a relative bioavailability of less than 1% and importantly demonstrated suppression of GH secretion following a GHRH induction test [49] . Perhaps due to both the theoretical physiological suitability and the size of the market, numerous companies are attempting to orally deliver antidiabetic peptide hormones – primarily insulin and the GLP-1 analogs. For example, Merrion, in partnership with Novo Nordisk have completed Phase I trials using their GIPET® technology to deliver both insulin and

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Challenges in the delivery of peptide drugs 

GLP-1 analogs. GIPET® exploits the ability of medium chain fatty acids, in particular sodium caprate to open tight junctions and like Chiasma and Unigene technologies, also uses an enteric coating to ensure the peptide is released in the small intestine. It has just been announced that the Phase I on NN1956 has been successfully completed, but the data have not yet been published [51] . Biocon have been developing an oral insulin using conjugation to protect the insulin from the harsh environment of the GI tract. The API is a conjugate of insulin with PEG and glycolipids or fatty acids which are hydrolyzed in the blood stream to release the native insulin. This conjugate is formulated with an absorption enhancer (e.g., sodium caprate or a bile salt). This product completed Phase III with mixed results, missing the primary endpoint of lowering HbA1c levels by 0.7% versus placebo although subsets of patients appeared to respond. However, numerous secondary endpoints were met, for example, reduction in postprandial glucose levels, and this program is still ongoing in partnership with BMS [52] . Oramed are also developing an oral insulin pill, and have recently completed a Phase IIa clinical trial. Oramed’s technology incorporates with the peptide an enzyme inhibitor (e.g., soy bean trypsin inhibitor and aprotinin) and an absorption enhancer (e.g., EDTA or bile salt), suspended in omega-3 fatty acids in an enteric coated capsule. The formulations were reported to be safe and

Perspective

well tolerated, and showed trends toward sustained reduction in night time, day time and mean fasting glucose concentrations compared with placebo [53] . This product is now progressing into Phase IIb [54] . The buccal and sublingual route of delivery avoids some of the challenges faced by delivery via the small intestine (e.g., fewer peptidase enzymes, pH closer to neutral), and might therefore be seen as an attractive route of delivery. Indeed remarkable bioavailabilities of 47% in man have been reported of GLP-1 formulated in a buccal patch designed to adhere to the buccal epithelia and provide unidirectional diffusion of the API to avoid loss of the drug to the mouth and eventually the stomach [55,56] . This program does not appear to be ongoing, but at least another company – MidaSol (a joint venture between MidaTech and Monosol) has developed a similar buccal patch that delivers insulin using gold nanoparticles that associate with the API and claim this facilitates absorption across the buccal epithelium. This successfully completed a Phase I trial in healthy volunteers that examined its pharmaco­ kinetics, and safety and efficacy and is now moving into a Phase II trial in patients. As few of these studies have yet been published in peer-reviewed journals, it is difficult to evaluate the quality of the data and compare the delivery systems, but it is clear that not only there is tremendous interest in oral peptide delivery, but also that there are

Table 3. Selected oral peptide delivery technologies in clinical development. Company

Peptide

Technology

Stage of development

Enteris Biopharma

Calcitonin

Enteric coated capsule containing peptide with absorption enhancer (acyl carnitine) and enzyme inhibitor (organic acid)

Phase III

Chiasma

Octreotide

Enteric coated liquid filled capsules containing a suspension of drug particles in oils

Phase III

Biocon

Insulin conjugate

Peptide conjugate prodrug technology in which the peptide is covalently linked to PEG, glycolipids or fatty acids and formulated with absorption enhancers

Phase III

Oramed

Insulin and exenatide

Peptide with absorption enhancer and enzyme inhibitors in enteric coated tablet/ capsule

Phase II

Merrion

Insulin and GLP-1

Enteric coated tablets containing medium chain fatty acids (sodium caprate) as a absorption enhancer

Phase I

MidaTech

Insulin and GLP-1

Surface modified gold nanoparticles complexed with peptides and formulated into adhesive buccal patch

Phase I

Emisphere

Insulin and GLP-1 analogs

Based on absorption enhancers SNAC, SNAD, 5-CNAC

Phase I

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Key term Transepithelial delivery: Promoting or enabling transport of molecules across epithelial monolayers such as the skin, and nasal, gastrointestinal and buccal mucosae.

numerous technologies that have been developed with significant potential to meet the need. One issue that perhaps requires further discussion is the focus of many of these technologies on insulin delivery. As mentioned above, there are compelling physiological (delivery to the liver via the hepatic portal vein) and commercial reasons (large, growing market, cheap and readily available API) to apply oral peptide delivery technologies to insulin; however, it is a much greater technical challenge than a number of alternative peptides. In particular, firstly, it is relatively large and susceptible to aggregation in the presence of ions and transepithelial delivery systems generally show relative bioavailabilities that are inversely proportional to molecular weight, hence with other smaller peptides higher bioavailabilities should be achievable and success more likely. Secondly, and perhaps most importantly, insulin has a relatively narrow therapeutic index and it is essential that the pharmacokinetics are reproducible from day to day, month to month, year to year. If bioavailability is low, there is likely to be high variability so it is essential to achieve bioavailabilities likely greater than 10%. Furthermore, bearing in mind patients are likely to want to take oral tablets for postprandial glucose control, food effects on performance of the delivery system are likely to be important and potentially quite likely to influence pharmacokinetics and bioavailability. Thirdly, clinical development of

insulin products is relatively complex (due to its clinical pharmacology) while other peptides may not need so many, large clinical studies in order to demonstrate the effectiveness of the delivery technology and safety and efficacy of the product. Lastly, it could perhaps be questioned whether this patient group really want an oral formulation as out of all patients they are the most used to injecting themselves every day (with basal and fast acting insulins) and an oral formulation cannot be expected to entirely replace all of these injections. Transdermal peptide delivery

In recent years, most efforts to facilitate transdermal absorption of proteins and peptides by temporarily breaching the stratum corneum using heat or radiofrequencies have been terminated. The PLEASE® system from Pantec Biosolutions that uses a laser beam to form temporary channels in the stratum corneum is still being developed with triptorelin in Phase I and FSH in Phase II. In parallel microneedle delivery technologies, many of which are in clinical development (Table 4), have experienced a striking growth and obtained many successes. Microneedles are micron-sized features made of a variety of materials that can be alone or in an array on a patch. They are just long enough to penetrate the stratum corneum, but too short to reach the nerves in the skin and therefore offer a painless method of drug delivery. The first microneedle drug delivery patent was published by Alza Corporation in the 1970s, and remained the only patent for over two decades before an explosion in activity as developments in micromanufacturing technologies, many coming from the electronics industry, enabled their development.

Table 4. Selected transdermal microneedle technologies in clinical development. Company

Peptide

Technology

Stage of Comments development

Nanopass

Synthetic peptide immuno-regulatory epitopes (SPIRE) peptides developed by Circassia

Micronjet hollow silicon microneedle device

Phase III

Zosano

PTH and GLP-1

Solid, coated Phase II microneedle patch

Demonstrated increased efficacy of transdermal PTH and room temperature stable formulation

3M

BA058

Solid coated liquid Phase II crystalline polymer microneedles

Demonstrated efficacy although lower increase in bone density than s.c injection

Corium

PTH

Dissolvable Phase I polysaccharide microneedle patch

The first dissolvable microneedle technology delivering an API to enter clinical development

Demonstrated dose sparing effect/increased immunogenicity

API: Active pharmacuetical ingredient; PTH: Parathyroid hormone; s.c.: Subcutaneous.

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One area of particular interest in is vaccination as the depth of delivery achieved by microneedles allows the Langerhans cells in the skin to be targeted, and this can result in improved immunogenicity/dose sparing effect [57] . With this in mind, the furthest advanced technology is Nanopass’ MicronJet® device which is being used by Circassia to deliver their synthetic peptide immuno-regulatory epitopes (SPIRE) peptides for cat allergy, which is in Phase III clinical development [58] . The MicronJet® device consists of three hollow microneedles made out of a single silicon crystal mounted on a standard syringe fitting, and can therefore be used as a direct replacement to a hypodermic needle for intradermal injection. The principle advantages are the ease of administration (relative to the Mantoux technique) and that it is essentially pain free, as well as the dose sparing effect and the enhanced immunogenicity that the technology allows. Systemic peptide delivery using microneedles usually results in incredibly rapid delivery (shorter Tmax, higher Cmax, faster elimination). This can be advantageous for peptide hormones, such as PTH, that require sharp peaks in plasma levels in order to be efficacious and three companies are developing microneedle patch formulations of PTH and its derivatives. Corium have a dissolvable microneedle technology and have completed a Phase I clinical trial in healthy volunteers with a PTH microneedle patch. They have reported that the treatment was safe and well tolerated and achieved similar peptide exposure to the subcutaneous injection. Radius have developed a microneedle patch formulation of the novel synthetic peptide analog of human parathyroid hormone-related protein (PTHrP) abaloparatide – referred to as BA058 – for the treatment of osteoporosis. They are using 3M’s sMTS technology, which are solid coated microneedles made out of a liquid crystalline polymer. They recently completed a Phase II clinical trial in patients, and demonstrated a significant increase in bone mineral density (BMD) although it was not as high as that seen following subcutaneous injection [59] . Lastly Zosano have completed a Phase II clinical trial using patches of titanium microneedles coated with PTH [60] . They managed to

Perspective

achieve a 40% bioavailability relative to the subcutaneous injection, and not only showed a similar increase in hip bone mineral density to the injection, but a significantly higher increase in lumbar spine BMD [61] . Furthermore, the microneedle formulation is stable for 2 years at room temperature while Forteo, the marketed injectable formulation, requires storage in the fridge adding another competitive advantage. Increasing the efficacy of the peptide by delivering it through an alternative route is a significant achievement and demonstrates the huge potential of these technologies. Nasal & inhaled peptide delivery

The ease of administration, good blood supply and absorptive epithelium make the nasal route an attractive route for drug delivery. Actually, a number of peptide products are already formulated as nasal sprays (Table 1) . However, these peptides are generally highly potent with a wide therapeutic index and can therefore be safe and efficacious with low (and consequently) variable absorption. Typically the bioavailability of the marketed peptides is between 1 and 3% relative to subcutaneous injection. In order for the nasal route to be more widely used for systemic delivery, much higher bioavailabilities would be necessary (to reduce the cost of goods) and ideally, as for the other routes of delivery, some positive impact on safety and efficacy demonstrated. Up until recently this has been limited by the poor tolerability of absorption enhancers in the nasal cavity, but a new generation of absorption enhancers has been developed with tremendous potential and have entered clinical development (Table 5) . The furthest advanced is CPEX Pharmaceuticals’ cyclopentadecalactone (CPE-215) absorption enhancer. CPE-215 is a naturally occurring product that is used as a food additive and is on the FDA’s Inactive Ingredients list. CPEX Pharmaceuticals used the absorption enhancer to develop Nasulin® – nasal insulin – and achieved the impressive relative bioavailability of 20% in man in a Phase I PK/PD study and showed that it was both faster and shorter acting than s.c. injection and therefore better suited for prandial insulin. The development of Nasulin® appears to have

Table 5. Selected nasal peptide delivery technologies in clinical development. Company

Peptide

Technology

Stage of development

Serenity Pharmaceuticals Ser-120 (vasopressin analog)

Cyclopentadecalactone (CPE-125) absorption enhancer

Phase III

Aegis Therapeutics

PTH

Alkyl saccharide absorption enhancers

Phase II

Critical Pharmaceuticals

PTH and hGH

PEGylated fatty acid absorption enhancers

Phase I

hGH: Human growth hormone; PTH: Parathyroid hormone.

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Perspective  Lewis & Richard been stopped, and CPEX themselves have been bought out, but the technology is currently in Phase III clinical trials for Serenity Pharmaceuticals’/Allergan’s vasopressin analog nasal spray. Aegis Therapeutics have developed the Intravail® absorption enhancers for nasal protein and peptide delivery and report very high relative bioavailabilities of some large proteins, at least in animal models. The Intravail® absorption enhancers are alkyl saccharides, in particular N-dodecyl-b-D-maltoside and can be used up to a concentration of at least 0.125%, although above that histological changes can be seen in the nasal mucosa [62] . This has been used to develop a nasal spray formulation of PTH (ZT-031) by Azelon Therapeutics. In nonhuman primates, it achieved a relative bioavailability of 11–39% depending on the concentration of absorption enhancer used and the product entered clinical development, completing Phase II in 2012 [63] . Critical Pharmaceuticals have developed the CriticalSorb absorption enhancer system based on a mixture of PEGylated fatty acids (primarily PEG-hydroxystearate) for use in nasal, and potentially oral delivery, of proteins and peptides [64–66] . Preclinically they have demonstrated bioavailability of nasal insulin of approximately 100% relative to subcutaneous injection [64] . The furthest advanced product developed with this technology is a nasal spray of human growth hormone (hGH) a 22 kDa protein. The nasal spray achieved a relative hGH bioavailability of 50% in rats, 40% in rabbits and 20% in nonhuman primates – note that as bioavailability of transpithelially delivered peptides and proteins is generally inversely proportional to molecular weight, it is reasonable to expect smaller peptides can achieve even higher absorption [64] . This has completed two Phase I pharmacokinetic/pharmacodynamics studies where it was reported to be safe and well tolerated and importantly induce IGF-1 to a similar extent as the s.c. injection and therefore has tremendous potential to be efficacious. A Phase I clinical trial on a nasal formulation of PTH using this technology is currently underway [67] . This absorption enhancer therefore has considerable potential to facilitate systemic delivery of nasally administered peptides and proteins. With respect to inhaled peptide delivery, most companies working in the space left following the commercial failure of Exubera®, the first inhaled insulin developed by Pfizer. However, at least two companies continue to believe that this could be an attractive treatment option for diabetics. The furthest advanced is Mannkind Corporation who following a turbulent development program have demonstrated the safety and efficacy of their inhaled insulin (Afrezza®) in

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several Phase III clinical studies, importantly showing that their product increases efficacy (improved control of blood glucose) and reduces toxicity (reduced frequency of hypoglycaemic events) compared with subcutaneous injection. They have submitted their Marketing Authorization Application to the FDA. The technology (Technosphere®) is based on a novel excipient diketylpiperizine that enables the formation of uniform peptide particles with a 2 μm diameter. The FDA stated in their initial review that the excipient does not work as an absorption enhancer and does not compromise the integrity of the airway epithelia. However, as the FDA requested Pfizer to perform numerous postmarketing studies so as to evaluate the safety of Exubera® on long term use, there might be likely the same requirement for Afrezza® too. Should the long term safety of the delivery system be demonstrated, there could be increasing interest in the inhaled route of delivery for other peptides, particularly those that benefit from rapid absorption. Peptide targeting

The specificity, ease of manufacture and potency of peptides make them attractive candidates for use either as targeting ligands for various drug delivery systems (e.g., nanoparticles and liposomes) or to enable delivery to different physiological sites (e.g., delivery across the blood-brain-barrier (BBB) or intracellular receptors). For example, BIND Therapeutics are developing a range of targeted polymeric nanoparticles they have called Accurins manufactured by nanoparcipitation of PLGA/PLA-PEG block co-polymers decorated with targeting ligands (small molecules, peptides, proteins and antibodies). The PLGA/PLA core can encapsulate and control the release of a drug such as a cytotoxic, while the PEG corona prolongs the circulation time of the administered nanoparticles. Their lead product candidate is BIND-014 - PLGA/PLA nanoparticles containing docetaxel decorated with a peptoid targeting the Prostate Specific Membrane Antigen (PSMA) – a transmembrane protein preferentially expressed on prostate cancer cells and the vasculature of nonprostate solid tumors – is currently in Phase II clinical trials for prostate cancer and non-small-cell lung carcinoma [68] . Another notable example is BBB Therapeutics who are utilizing glutathione-targeted stealth liposomes encapsulating doxorubicin to promote delivery of the cytotoxic across the blood-brain-barrier for brain cancer. Once more a PEG coating prolongs circulation time and minimizes uptake by the reticuloendothelial system, but in this case the targeting ligand (glutathione) promotes BBB crossing using a ‘Trojan horse’ mechanism [69] . This product (2B3–101) is currently in Phase II clinical trials.

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Financial & competing interests disclosure AL Lewis has share options in Critical Pharmaceuticals. AL Lewis is an employee of Ipsen. J Richard is an employee of Ipsen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a

Perspective

financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Executive summary • Peptide therapeutics have been around for decades, but in the recent years, there has been an increasing interest from pharmaceutical companies in developing new peptide drugs. By improving design, synthesis and delivery technologies to overcome many barriers for effective treatments, the industry has realized their strong potential, seeing them as more flexible and cost–effective than their biologic equivalents. • Peptides are attractive drug candidates with a bright future due to their specificity, potency and low toxicity, but present particular challenges for their delivery to the site of action, due to their short half-life, their poor stability and high potential for proteolytic degradation, and for these reasons, they are mostly administered by injection. • Early successes in reducing injection frequency through the development of injectable sustained-release formulations demonstrated the power of drug delivery technologies to meet unmet needs and develop enhanced drug products. • Injectable sustained-release formulations are likely to remain a major component of the peptide delivery market; however, new technologies have been developed that overcome issues with conventional technologies including solvent free formulations and processes, injectability through narrow gauge needles and ready-to-use formulations. • Great strides have been made in technologies that enable delivery via alternative routes of delivery, with many in late stage clinical trials, and in the next future, an increasing number of peptides are likely to be delivered orally, transdermally and nasally. • Peptide drugs will help the industry to make great progresses in many therapeutic areas, most notably oncology, metabolic disorders and cardiovascular diseases. • In the next 2 years, new formulations and devices for noninvasive routes of administration (oral, transdermal) are going to reach the market, and novel peptide constructs and delivery systems will make it possible to improve intracellular trafficking and efficiently hit intracellular targets and other challenging physiological sites, such as the CNS. 7

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