Issue:October 2021

DRUG DELIVERY – CAPRO(TM): A New Advance in Polymeric Drug Delivery


The estimated global market size of drug delivery products was $1.4 trillion in 2020. Unfortunately, 40% of marketed drugs and 90% of pipeline drugs (mostly small molecules) are poorly soluble in water, which makes parenteral, topical, and oral de­livery difficult or impossible. In relation, poor solubility often leads to low drug efficacy. Add in the fact that many other hurdles exist in the form of drug loading, stability, controlled release, toxicity, and absorption – it’s not hard to understand the difficulties in bringing new drug products to market. Additionally, biopharma­ceuticals (proteins, peptides, nucleic acids, etc) and combination drug products possess many of these same problematic obstacles that affect efficacy. These challenges, coupled with the complexity and diversity of new pharmaceuticals, have fueled the develop­ment of a novel polymeric drug delivery platform called CAPROTM that overcomes a great many bioavailability and delivery obsta­cles. By leveraging TREKKA Therapeutics proprietary CAPRO poly­mer platform, pharmaceutical and biopharmaceutical companies can improve dosing accuracy, efficacy, and reproducibility in their drug discovery and drug delivery research. In summary, the CAPRO platform is designed to lower costs, reduce side effects, improve patient compliance, and expand drug access though im­proved administration methods.


The demand for pharmaceutical products worldwide is only going to increase in the coming years, as old and emerging dis­eases continue to threaten the well-being of people globally. Drug discovery efforts are expected to intensify, generating a large va­riety of active compounds with vastly different structures and properties. However, it is well known that despite tremendous out­put of the drug discovery process, the success rate of a candidate compound becoming an approved drug product is extremely low. The majority of candidate compounds are discarded due to var­ious hurdles in formulation and preclinical testing (such as issues with solubility, stability, manufacturing, storage, and bioavailabil­ity) before even entering into clinical studies. Therefore, advances in formulation and drug delivery, especially the development of new and versatile biomaterial platforms as effective excipients, may salvage many “difficult,” otherwise triaged, drug com­pounds, and significantly enhance their chance of becoming vi­able drug products. Furthermore, breakthroughs in biomaterial platform technologies will also facilitate life cycle management of existing APIs through reformulation, repurposing of existing APIs for new indications, and development of combination prod­ucts consisting of multiple APIs.


Small-molecule drugs are typically classified by the Biopharmaceutical Clas­sification System (BCS) in terms of their sol­ubility and permeability through biological tissue barriers.1 Of particular challenge are the BCS classes II and IV: both suffer from low aqueous solubility. In fact, 40% of marketed drugs and 90% of pipeline drugs are poorly soluble in water.2 BCS class IV compounds further suffer from low tissue permeability. The absorption of oral drugs takes place in the small intestine, and low solubility limits the maximum drug concentration that can be absorbed. In most cases, slow diffusion is almost always associated with low solubility but can be compounded by small drug surface area and/or slow diffusion rates in the gastroin­testinal (GI) tract. The common problem is that a slow diffusion rate may limit drug absorption, particularly when the solubility of the drug product is so low that the drug concentration must be preserved near its maximum solubility limit so that enough drug can be absorbed during the limited time the drug transits the GI tract. Further, the propensity of many drugs to crystallize is another hurdle that makes drug solubi­lization and absorption difficult.

Current formulation strategies to en­hance drug solubility include solubility en­hancers (such as cyclodextrin, lipids, surfactants), drug micronization, salt for­mation, and amorphous solid dispersion in polymeric excipients for oral delivery.3 Organic solvents, though undesirable, are used in some injectables.4 However, these approaches have a number of weak­nesses. They are not particularly effective toward highly insoluble drugs and not eas­ily adaptable to achieve various drug-re­lease kinetic profiles. Some formulation processes are complex and require spe­cialized equipment. APIs and excipients may be damaged during melting and ex­trusion under high temperature. Certain excipients and solvents can be toxic or cause allergic reaction in some patients. Degradation of common polymer excipi­ent families, such as poly(lactide-co-gly­colide) (PLGA), produces harmful acidic by-products, causing inflammation.5 PLGA undergoes bulk degradation in vivo by hy­drolysis of the ester linkages within the polymer backbone. The reduction of poly­mer molecular weight and erosion of the polymer measured by mass loss are incon­sistent, thus, like other bulk-degrading polymers, it is difficult to control the re­lease kinetics of drugs, especially at high drug loadings. Infiltration of water into the PLGA matrix can also compromise the sta­bility of the drugs during storage and long-term in vivo residence.


Unlike small-molecule drugs, bio­pharmaceuticals, including peptides, pro­teins, nucleic acids (DNA, RNA), are large molecules that present unique challenges.6 A major concern is loss of molecular sta­bility and bioactivity due to degradation by hydrolysis, oxidation, and enzymatic reac­tions and denaturation due to heat, pH, and organic solvents, resulting in short shelf-life and in vivo half-life. Also, large molecular size and surface charges make it difficult for these biomacromolecules to diffuse across tissue and cellular barriers. Additionally, many peptides and proteins are prone to aggregation at high concen­trations, limiting the loading and bioavail­ability of these drugs.

Bulk-degrading polymers, such as PLGA, are widely used for the controlled release of biological macromolecules, es­pecially peptides and proteins.5 Because most peptides and proteins are hy­drophilic, the loading efficiency of these molecules in hydrophobic PLGA is often quite low. The preparation of PLGA formu­lations requires organic solvents at ele­vated temperatures and may cause protein denaturation or aggregation. Residual sol­vent in the drug product can be toxic to the human body. Accumulation of PLGA degradation products results in an acidic environment that can damage and deac­tivate delicate biopharmaceuticals. Also, the drug release rate is difficult to control, due to the random nature of PLGA degra­dation and bulk erosion. Hydrophilic poly­mers, such as polyethylene glycol (PEG), have also been used to facilitate peptide and protein delivery. PEGylation, the con­jugation of PEG to peptide and protein drugs, offers protection against enzymatic degradation, aggregation, and non-spe­cific capture and clearance by the reticu­lar-endothelial system (RES).7 PEGylated drugs show longer in vivo half-life and blood circulation time than non-PEGylated forms. However, PEGylation requires com­plicated and laborious chemical reactions and can be difficult to scale up. Further, hydrogels have been used to encapsulate biopharmaceuticals and provide sustained release; however, the aqueous environ­ment of hydrogels does not protect the cargos from hydrolytic degradation. The release of peptides and proteins from hy­drogels usually lasts for days, rather than weeks or months.


Drug products containing multiple APIs formulated using the same biomate­rial excipients present unique challenges in formulations and delivery.8 APIs may have different molecular size, solubility, miscibility, crystallinity, stability, and reac­tivity. Combining them in the same dosage form and accommodating the disparate needs for solubilization, stabilization, and release profiles will require careful selec­tion of sophisticated solvents and excipi­ents. APIs in combination drugs may act through different synergistic mechanisms to treat diseases. They may have different therapeutic windows (eg, effective and toxic dosing thresholds), different pharma­cokinetic profiles (eg, zero order versus first order versus burst release), different duration of release, and different thera­peutic targets at the organ, tissue, and cel­lular levels. The ideal drug delivery system for combination drugs should be able to package multiple APIs together at high doses, maintain their stability, and modu­late their spatiotemporal release to reach therapeutic targets.


TREKKA’s CAPRO polymers provide a flexible and versatile biomaterial platform to address major challenges in drug for­mulation and delivery. Biodegradable polymers for drug delivery assume a few common physical forms (Figure 1). Hy­drophobic polymers, such as PLGA, can form implantable solid matrices or in­jectable micro/nanoparticles.9 Hydrophilic polymers, such as PEG, can be cross-linked into solvent-saturated gels (hydro­gels). In situ forming systems refer to a liquid precursor turning into a solid matrix or gel after injection into the body.10 Such phase transformation is often achieved through molecular assembly or precipita­tion driven by changes in solvent, temper­ature, or chemical reactivity. In contrast to these current materials, the CAPRO plat­form is based on bulk solvent-free poly­mers in the liquid state (liquid polymers) (Figure 1) – a unique physical state of ma­terials with interesting properties for appli­cations in biomedicine and particularly in drug delivery.

CAPRO polymers exist as either Newtonian fluids or structured liquids at physiological temperature, unlike conventional polymeric biomaterials.

At the molecular level, a typical liquid polymer consists of disentangled chains that are flexible and amorphous with low glass transition (Tg) and melting tempera­tures (Tm).11 These will ensure that such polymers behave as viscous, Newtonian fluids at room and physiological tempera­tures. In some cases, disentangled chains of a liquid polymer can be “structured,” forming a solid-like composite with unique rheological properties.12

Only a handful of synthetic liquid polymers have been reported to date for drug delivery applications. Known as “thermoplastic pastes” or “semi-solid poly­mers,” these materials include poly­orthoesters, alkyl polyesters, star PLA-castor oil, and polycarbonates.11,13 Chemical synthesis of such polymers often requires complicated processes that are difficult to scale up. The biodegradation process of polyester-based materials lacks control, and in some cases, leads to the accumulation of acidic by-products. Fur­thermore, none of these polymers is capa­ble of forming “structured” liquids. The CAPRO polymer platform overcomes these deficiencies and allows for full exploitation of the liquid polymers to address the chal­lenges in drug delivery.


CAPRO polymers are designed specifically to overcome many of the weaknesses of current polymers for drug delivery. The CAPRO polymers share a generic molecular structure consisting of functional blocks and degradable linkers (Figure 2). The highly modular nature of such design makes it possible to generate a large array of polymers with diverse functionalities. The molecular features of the CAPRO polymers can be engineered to create specific interactions with specific APIs in ways that promote drug dissolution and loading, preserve drug stability during storage, and achieve controlled drug re­lease, leading to improved bioavailability and efficacy.

Modular design of CAPRO polymers by combination of a variety of functional blocks with specially designed linkers. An example is the CAP-O series of polymers consisting of PCL functional block and ortho-ester-containing linkers.

One class of CAPRO polymers is the CAP-O series (Figure 2). Here, polycapro­lactone (PCL) is chosen as the primary functional block for its excellent biocom­patibility and low Tg and Tm.16 The linker may contain labile chemical bonds, such as the ortho ester bond, which can deter­mine the kinetics of polymer degradation and in turn, dictate the rate of drug re­lease.17 The length and number of the PCL block (and other potential functional blocks) as well as the chemical structure of the linker can be manipulated independ­ently depending on the need of specific drugs, route of administration, and desir­able pharmacological profiles.


The CAPRO polymer platform is de­veloped to provide solutions to multiple challenges and hurdles in drug formula­tion, manufacturing, storage, administra­tion into patients, and in vivo pharmacological action (Figure 3).

The CAPRO polymer platform addresses a multitude of challenges in drug development.

CAPRO polymers are compatible with both small-molecule and large-molecule APIs as well as combination drugs (Figure 4). For poorly soluble small molecules, the CAPRO polymers serve as “macromolec­ular solvents,” enabling molecular disso­lution of the drugs within the polymers. Large molecules, such as peptides, pro­teins, and nucleic acids, can be incorpo­rated into the CAPRO polymers as particulate dispersion. In relation, they are particularly suited for combination drugs, providing spatially segregated compart­ments for various APIs within the same dosage form.

A wide range of APIs has been incorporated into the CAPRO polymers. These include poorly water-soluble small molecules such as resiquimod (an immunostimulatory adjuvant) and paclitaxel (an anticancer drug), which can be dissolved directly into solvent-free CAPRO at high concentrations. Various peptides and proteins (such as ovalbumin and albumin) have been loaded into CAPRO to form particulate dispersions. Nanoparticles such as silica have been found to form structured liquids with some CAPRO compositions. Finally, total tumor cell lysate has been loaded into CAPRO and tested as a potential cancer vaccine.

Formulation using the CAPRO poly­mers can be very simple. The loading of drugs in the CAPRO polymers can be ac­complished by admixing with or without solvent at moderate temperatures. Solvent-free formulation has the advantage of eliminating the concern of residual solvent in the final drug products and any associ­ated toxicity. Moderate temperature during formulation alleviates the potential risk of heat denaturation and decomposition of certain fragile APIs. The “macromolecular solvent,” ie, the CAPRO polymer, can be designed to bind to APIs through multiple sites of molecular interaction. Such coop­erative binding imparts greater capacity of solubilization and stabilization of the API, resulting in exceptionally higher loading than what is achieved using simple small molecular solvents.

Scaling-Up & Manufacturing
The synthesis of CAPRO polymers is highly scalable. The CAP-O series is syn­thesized in three steps. The CAP-A series (containing acetal linkers) is synthesized in a single step. Synthesis can be conducted either in bulk without solvent or with USP class 3 solvents under moderate tempera­tures. The raw materials used for synthesis are common commercial compounds. We have developed GMP synthesis and purifi­cation protocols to manufacture CAP-O series of polymers in 100- to 200-g scale. Manufacturing of CAPRO-formulated drug products can be conducted using conven­tional admixing devices or standard spray drying apparatus. Furthermore, CAPRO polymers capable of forming structured liquids can be manufactured via 3D print­ing using either temperature-induced so­lidification and/or chemical reactive cross-linking methods. Tableting of CAPRO polymers with API is also possible in the presence of appropriate excipients and particulates.

CAPRO polymers bind to APIs through specific molecular interactions, keeping them solubilized and preventing crystallization during storage. API stabiliza­tion can also be augmented by the CAPRO polymers’ capacity of forming structured liquids, which greatly reduces the molecu­lar mobility of the APIs within “gel-like” matrices. Water-sensitive, fragile APIs can be protected from hydrolysis and other forms of degradation by encapsulation within hydrophobic CAPRO polymers, whereas water-soluble biological APIs can be stabilized within hydrophilic or am­phiphilic CAPRO polymers.

The CAPRO polymer platform is de­signed to adapt to various routes of drug administration. Due to the fact that CAPRO polymers are viscous liquids, CAPRO-for­mulated drug products can be injected lo­cally into the skin or muscle or ocular sites, to form long-acting depots that release drugs sustainably. In addition, certain CAPRO polymers can form emulsions of micro or nano-size droplets or particles and thus can be injected systemically.18 They also can be applied topically to the skin or other mucosal tissues, such as nasal, buccal, sublingual, rectal, vaginal sites, and enhance the permeation of APIs across these tissue barriers. They can also be adapted to form various oral dosage forms, such as tablets, capsules, gels, and emulsions, and be combined with existing excipients for oral drug delivery.

In Vivo Action
As “macromolecular solvents,” CAPRO polymers can enhance the solubil­ity and stability of poorly soluble drugs, re­sulting in more efficient absorption and higher bioavailability. The CAPRO poly­mers can undergo pre-programmed ero­sion and degradation to achieve either sustained long-term drug release, or mod­ified release that maximizes drug absorp­tion and efficacy. Micro and nano-droplets of CAPRO polymers can facilitate the in­tracellular uptake of drugs by specific cell types and the intracellular release of drugs within subcellular compartments. Impor­tantly, the CAPRO polymers themselves are constructed from biocompatible build­ing blocks such as PCL and they break down into nontoxic products, which en­sures safety for human use.


TREKKA Therapeutics flexible and ver­satile CAPRO polymeric drug delivery plat­form has the potential to enormously impact healthcare. Achieving delivery of poorly soluble drugs and biologics will en­hance the efficacy of a wide range of ther­apeutics for the treatment of a wide range of diseases. CAPRO represents a new and better class of excipients and will provide a new avenue for research and develop­ment teams that are dealing with bioavail­ability and efficacy challenges with new or existing compounds.


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Bob Wieden is the President & CEO of TREKKA Therapeutics, LLC, a spin-off company from the University of Minnesota, that was formed to commercialize and develop advanced polymeric biomaterials to improve the efficacy and safety of drugs. He leads the overall strategy and commercialization efforts to bring this disruptive CAPROTM technology solution to market to improve the patient experience and potentially patient outcomes. He is a growth-oriented business builder that has led a plethora of new ventures for Fortune 500 and private enterprises to fill “gaps” in unmet markets and looks to drive new therapeutic concepts to disrupt existing marketplaces. He can be reached at

Dr. Chun Wang is an Associate Professor of Biomedical Engineering, University of Minnesota. He is a Co-founder and CSO of TREKKA Therapeutics. He earned his PhD in Bioengineering at the University of Utah and was an NIH postdoctoral fellow at the Massachusetts Institute of Technology. He was a recipient of the National Science Foundation CAREER Award, Wallace H. Coulter Foundation Early Career Translational Research Award, and McKnight Land-Grant Professorship. He served on the editorial boards of the Journal of Controlled Release (2006-2016) and Advanced Drug Delivery Reviews (since 2010). He has published 100 peer-reviewed research articles and reviews and has given over 120 invited talks. His research interest is in polymer-based therapeutic biomaterials with applications in controlled drug delivery, immunotherapy, medical devices, and regenerative medicine.