Emerging Drug Delivery Technologies in China: 3D-Printed Pharmaceuticals, Dissolvable Microneedles, Hydrogels, and Oral Biologics

Innovative drug delivery systems are transforming previously undruggable or challenging targets into viable therapeutic solutions, while other novel carrier technologies are enhancing the usability of existing drugs, expanding their administration routes, and improving safety profiles.

Recently, VCBeat/VCBeat New Medicine has consecutively hosted multiple salon events related to drug delivery.

[VB Insight Sharing Session] Issue 38: VCBeat/VCBeat New Medicine, in collaboration with Shengshan Capital, BeiGene, and Pinjing Bio, invited experts to discuss various innovative drug delivery technologies.Yang Fan, Executive Deputy Director of the New Drug R&D Center, Guangdong Pharmaceutical University,Jiang Lin, Founder of Qinglan BioYu Yu, Co-founder, CEO and CSO of Kening Biotech,Distinguished Researcher Mai Yanghe, School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen UniversityWang Hua, General Manager of Guangzhou Pinjing Biotechnology and Founder of "Hua's Talk on Medicine"

At the salon, experts shared cutting-edge advancements and industrial developments in their respective technical fields. We have excerpted and compiled some of the content as follows:

Typically, each industrially manufactured pharmaceutical product is available in only a few specifications. However, clinicians often determine the dosage based on patients’ genetic factors (such as gene polymorphisms) and non-genetic factors (including age, height, weight, and body surface area), or adjust the dosage according to physiological monitoring indicators such as blood drug concentration. Particularly for special patient populations like children, the required dosage is often far lower than the available commercial specifications. In such cases, pharmacists perform dose division and dispensing of medications in accordance with medical orders.According to statistics, up to 73.79% of pediatric patients in clinical practice require dose splitting. A maternal and child health hospital collaborating with us performs over one million dose-splitting preparations annually.

For decades, hospital pharmacists have commonly employed methods such as tablet splitting, powdering and repackaging, and liquefaction of solid dosage forms for pediatric dose adjustment.Tablet splitting is limited to dividing tablets into halves or quarters; however, variations in tablet texture can increase the difficulty of this process. For instance, hydrochlorothiazide tablets are highly prone to crumbling during splitting, leading to inaccurate dosing. In contrast, powder grinding and aliquoting rely on visual estimation for equal division. Studies have shown that the relative standard deviation (RSD) in weight ranges from 4.5% to 54.5%, posing a high risk of toxicity for drugs with a narrow therapeutic window, such as aminophylline and phenobarbital. Furthermore, because the medication is in the form of fragments and powder, it has poor palatability and low identifiability when wrapped in paper, making it incompatible with single-dose packaging machines and verification systems.To address the limitations of existing dose-splitting methods, we have researched and developed a 3D printing-based approach for medication dose adjustment.

The equipment for 3D-printed dose-adjustable tablets is operated within a safety cabinet, and all consumables are single-use, thereby preventing cross-contamination. It enables the precise customization of medication dosages. Previously, it was difficult for pharmacists to accurately divide medications into small fractions such as 1/20 or 1/50; due to safety concerns, they tended to underdose, which compromised therapeutic efficacy. Additionally, 3D-printed dose-adjustable tablets can have corresponding letters or dosage information printed on their surfaces, ensuring reliable identification.

3D-printed split-dose tablets have been used by over 20,000 patients. In satisfaction feedback, 66% of patients reported liking them, largely due to concerns about the dosing accuracy of crushed tablets or powders.“The Survey on the Current Status of Pediatric Medication” indicates that 93% of parents receive ground powder medications and are willing to pay extra for pediatric formulations with accurate dosing. Therefore, parents not only support this technology but are also willing to pay for this service.

Intelligent and innovative 3D printing technology for drug dose fractionation complies with China’s hospital pharmacy dispensing regulations. It offers advantages such as precise dosing, controllable quality, simple manufacturing processes, a high degree of mechanization, reduced physical workload for pharmacists, easy identification, and patient-friendly use. Furthermore, it can be integrated with single-dose drug packaging machines and verification systems to achieve full automation in personalized medication management, thereby enhancing medication safety and efficacy while reducing medical risks and the incidence of adverse drug reactions in children. The promotion and implementation of 3D printing-based drug dose fractionation technology will enable clinical delivery of individualized precision pharmaceutical care.

In our previous discussions with colleagues from various organizations about dissolving microneedles, we often encountered certain issues. Dissolving microneedles are, in fact, a dosage form, standing alongside tablets, capsules, and injections as a distinct category, representing an entirely new mode of drug delivery. However, many professionals still struggle to recognize them as a dosage form.

The technologies for dissolvable microneedles are primarily categorized into two types, both of which have been scaled up for mass production in our manufacturing processes.

First is the integrated microneedle,The needle bodies are composed of medicinal solutions. Specifically, the drug is formulated into a solution using pharmaceutical preparation techniques, cast into needles within molds, and then affixed onto a white adhesive film. Upon application, the needles penetrate the stratum corneum to reach the epidermis, achieving intradermal drug delivery depth that targets the lesion directly for therapeutic effect.

Integrated needle systems are particularly well-suited for small-molecule chemical drugs. Among the products we have handled, there are both water-soluble and water-insoluble drugs. We have more extensive experience with water-soluble drugs, as water-insoluble ones present greater technical challenges.

Another process is the layered needle technique,The process involves first applying a drug-loaded solution onto the mold, removing excess solution, then coating with a base film layer; after drying, this forms a dissolving microneedle product with drug-loaded tips.

The layered needle technology is particularly well-suited for macromolecular drugs with low dosages and high unit costs. Our current product allows for removal after just 10 minutes of application, once the needle tips have dissolved within the skin.

Whether using a monolithic needle or a layered needle, we select the most appropriate approach based on the properties of the loaded drug and its in vivo release requirements, thereby achieving precise control over drug loading capacity and release duration.

Two steps are critical to the efficacy of microneedling.

The first step is to ensure that the needle body, made from raw materials and excipients, can penetrate the stratum corneum.To penetrate the skin’s natural barrier, sufficient mechanical strength is required. Currently, there are various needle configurations, including bullet-shaped, okra-shaped, and conical designs; these typically feature relatively blunt tips, causing greater skin trauma. Our leading technology enables the fabrication of finer needles, thereby reducing skin damage.

Step 2: Dissolving microneedle transdermal drug delivery technology can penetrate the stratum corneum of the skin to reach the epidermis., dissolve and release after absorbing interstitial fluid from the epidermis,and delivers the drug components to the lesion site for treatment through the interconnection between the lymphatic and circulatory systems.

Advantages of Dissolving Microneedles: Painless and non-invasive, ensuring the highest patient compliance; shortened treatment course with faster onset of action; significantly reduced drug dosage, amounting to only 1/5 to 1/200 of that required by conventional formulations; and minimized side effects due to the substantial dose reduction.

To date, we have collaborated with multiple domestic pharmaceutical companies on microneedle-based drug delivery for inactivated vaccines, DNA vaccines, small-molecule drugs, and peptide therapeutics, achieving breakthrough progress.

Kening’s three core technology platforms enable precise drug delivery across diverse spatial and temporal scales for small molecules, large molecules, and nucleic acids.

Taking the MeshTech hydrogel-based controlled drug release technology platform as an example, the core of this platform lies in controlling a fundamental microstructural parameter of the gel: the mesh size. The mesh size determines the mobility of drugs within the gel as well as the macroscopic physical properties of the gel. The MeshTech platform is built upon a novel polymer physics theory independently developed by Kening. This theory enables rational design of the gel’s mesh size, thereby facilitating the development of gels with unique properties that meet the requirements for drug delivery.

Our pipeline products developed based on MeshTech are currently focused primarily on the field of ophthalmology.

The first project, MT-1, is a long-acting, sustained-release anti-VEGF protein gel developed for the treatment of macular degeneration. The most significant challenge in the current management of macular degeneration is the need for frequent intravitreal injections of anti-VEGF drugs over many years. The vast majority of patients discontinue treatment due to poor compliance, ultimately leading to vision loss or even blindness. We encapsulate the protein drug within a three-dimensional network formed by cross-linked polymers. By regulating the initial pore size and its dynamic changes, we achieve sustained drug release in the eye for at least six months, demonstrating efficacy for up to half a year in non-human primate models.

Another project, MT-2, is a novel therapeutic agent for dry eye disease developed based on a covalently cross-linked network of low-density hyaluronic acid. Currently, most dry eye medications have a single mechanism of action, short duration of effect on the ocular surface, and suboptimal response rates. MT-2 combines potent anti-inflammatory effects with long-lasting ocular surface lubrication. It has demonstrated significant efficacy in spontaneous canine models of dry eye disease that are non-responsive to cyclosporine. After one month of treatment, more than 50% of the cyclosporine-nonresponsive dogs showed improvement in at least four clinical signs. We believe that MT-2 has the potential to become the new standard of care for dry eye disease, offering improved therapeutic options for patients.

Biologics are playing an increasingly significant role in the pharmaceutical industry, with their structures becoming ever more complex. Currently, biopharmaceutical products are predominantly administered via injection, with a limited number of long-acting injectables available, while oral formulations remain exceedingly rare. However, from the perspective of patient use, oral administration continues to be one of the most preferred routes of drug delivery on the market.

Currently, the most popular area for oral biologics is GLP-1 analogs. My own analysis suggests this is primarily driven by the market launch of semaglutide.

Why Are Oral Biologics So Challenging? The primary reason is undoubtedly that the gastrointestinal system degrades and metabolizes the protein structure of biologics.The development of oral biologics primarily faces two challenges. One is stability: how to prevent degradation of biologics by enzymes and the acidic or alkaline environment in the gastrointestinal tract. The other is permeability: how to enable large-molecule biologics to penetrate the intestinal epithelium.

To address these two issues, it is essential first to select an appropriate absorption site based on the characteristics of biologic drugs. The oral cavity, which is part of the gastrointestinal tract, has seen the emergence of certain oral disintegrating formulations. The stomach is characterized by rapid transit; for instance, the absorption site for oral semaglutide is designed to be the stomach. The intestine offers a longer residence time and a relatively thin intestinal wall that facilitates permeation; however, the abundant protease environment within the intestine poses significant challenges to drug stability. Although the colon is often overlooked, it actually provides the longest residence time.

Once the drug reaches the selected site, there are three challenges to overcome for its absorption. The first is penetrating the surface mucosal layer; the second is that tight junctions (TJs) between cells are difficult to penetrate; and the third is the method of drug delivery.

What makes oral vaccines unique is that M cells on the intestinal wall can directly trigger an immune response, so they can be effective without penetrating the cell membrane.

Specific solutions to the two challenges are as follows. Regarding stability, protease inhibitors can be incorporated. Our research has also demonstrated that not all peptide structures are highly susceptible to degradation; certain cyclic peptides, particularly those containing disulfide bonds, exhibit relatively greater stability. In terms of permeability, gel-based formulations or device-mediated delivery systems can be employed to prolong mucosal residence time and enhance intestinal wall permeability. Additionally, surfactants may be used to improve solubility across the intestinal epithelium, while nanotechnology approaches can be leveraged to increase drug penetration.