Design, Development and Evaluation of Smart Drug Delivery System: Integrating Nanotechnology, Targeted Therapies and Responsive Material for Enhanced Therapeutic Efficacy and Precision Medicine

Abstract

Smart drug delivery systems (SDDS) are an innovative advancement in medicine, designed to make drug administration more accurate, efficient, and patient-friendly. Traditional drug delivery relied on basic forms like tablets, powders, or injections, but with progress in science, these have been replaced by controlled-release methods and, more recently, by intelligent systems built with nanotechnology and advanced materials. In these systems, drugs are loaded into carriers such as liposomes, nanoparticles, hydrogel, nanogels, nanotubes, or microneedles. These carriers protect the drug, improve how well it dissolves, keep it in the bloodstream longer, and ensure that it reaches the intended site in the body. Modern techniques used to develop SDDS include nanoengineering, receptor-based targeting, gene or peptide attachment, and stimuli-responsive mechanisms that can release drugs when triggered by internal body changes (like pH or enzymes) or external signals (such as heat, light, ultrasound, or magnetic fields). Their working principle is to deliver drugs only where needed for example, to a tumor so that the treatment is stronger at the target site while reducing unwanted side effects elsewhere. To test their safety and effectiveness, researchers perform laboratory and animal studies, checking properties like particle size, drug release rate, stability, compatibility with tissues, toxicity, drug distribution, and therapeutic benefit. Overall, SDDS represent a major shift in drug delivery approaches, paving the way for personalized medicine and advanced therapies for diseases like cancer, neurological conditions, and infections.

Keywords

Smart drug delivery system, Nanoparticles, hydrogel, microneedle, Microchips

Introduction

Techniques [30]

Smart drug delivery systems made with polymers can be prepared in different ways, depending on the type of drug, the polymer’s properties, and how the medicine needs to be released in the body. For making nanoparticles or microspheres, two widely used methods are emulsion–solvent evaporation and nanoprecipitation. In the emulsion–solvent evaporation method, the drug and polymer are first dissolved in an organic solvent to create an oil phase, which is then mixed with water to form an emulsion. Once the solvent evaporates, solid polymer particles containing the drug are formed. This technique works best for water-insoluble (hydrophobic) drugs and polymers such as PLGA or Eudragit. If the drug is water-soluble, a double emulsion method (water-in-oil-in-water) is usually preferred. On the other hand, nanoprecipitation is a simpler process where the drug–polymer solution is added to water or another non-solvent, which immediately causes nanoparticles to form. This approach is especially suitable for PEG-based systems. For hydrogel and nanogel systems, which can respond to environmental changes like pH or temperature, two main preparation methods are used: free radical polymerization and physical cross-linking. Free radical polymerization uses chemical cross-linkers and initiators to form a stable 3D gel network, while physical cross-linking depends on ionic bonds or temperature changes to create gels, commonly using polymers such as chitosan or Poloxamer 407. A special approach called in-situ gelation is useful for injectable systems, where the formulation is liquid at the time of injection but turns into a gel inside the body, allowing for controlled and prolonged drug release. Other methods like spray drying and coacervation-phase separation are also applied, particularly for preparing microparticles or for protecting delicate biomolecules like proteins and vaccines. Spray drying involves spraying a polymer–drug solution into hot air, which quickly forms dry particles. Coacervation, on the other hand, works by creating a polymer-rich phase that surrounds and traps the drug, often using natural polymers like gelatin or chitosan.[31]

Techniques [33]

Liposome-based smart drug delivery systems can be prepared using several well-established as well as modern techniques. One of the most commonly used methods is the thin-film hydration technique, where lipids are first dissolved in an organic solvent and then dried to form a thin film. This film is later hydrated with a water-based drug solution, resulting in multilamellar vesicles (MLVs). These larger vesicles can then be reduced in size by sonication or extrusion through filters to produce smaller, more uniform liposomes such as small unilamellar vesicles (SUVs) or large unilamellar vesicles (LUVs). For drugs that dissolve easily in water, the reverse phase evaporation method is often preferred, as it involves forming a water-in-oil emulsion and then removing the solvent, creating liposomes with larger internal spaces to hold more of the drug. A simpler approach, called ethanol injection, works by adding a lipid–ethanol solution into water, where the difference in solubility causes liposomes to form spontaneously. Newer technologies like microfluidics have made it possible to create liposomes with high precision and consistency. In this method, lipid and aqueous solutions are mixed in tiny channels, leading to the production of uniform liposomes. This technique is especially helpful for designing advanced liposomes that release drugs in response to specific triggers such as acidic pH, higher temperatures, or redox conditions. To make liposomes responsive to such stimuli, special functional lipids like DOPE, CHEMS, or temperature-sensitive lipids are added. These “smart” liposomes stay stable under normal body conditions but release their contents when they reach environments such as tumors or inflamed tissues. For long-term storage, liposomal formulations are often freeze-dried (lyophilized) with the help of cryoprotectants like trehalose or sucrose. This process turns them into a stable dry powder that can be rehydrated before use, making them especially suitable for injectable or inhalable drug delivery systems. [34-35]

Dosage forms that use inorganic nanoparticles can be prepared through different techniques to achieve good dispersion, stability, and functionality. One common method is ultrasonication, where ultrasonic waves are applied to break up clusters of nanoparticles, creating uniform suspensions that are useful for injectables. A similar approach, high-speed homogenization, ensures thorough mixing and even distribution of nanoparticles in formulations such as suspensions, creams, and gels, and is also practical for large-scale production. For semi-solid systems like gels and films, the sol–gel method allows nanoparticles to be incorporated into a gel matrix with precise control over particle size and uniformity. In topical products like creams and ointments, emulsification is often used, where nanoparticles are dispersed in oil–water emulsions with the help of surfactants, improving both stability and skin compatibility.

Techniques

Thermo responsive hydrogels are usually prepared using the cold method, especially when working with polymers like Poloxamer 407 (Pluronic F127). In this approach, the polymer is gradually dissolved in cold water (around 4–8 °C) with gentle stirring, which prevents the solution from gelling too early and ensures a clear, uniform mixture that only turns into a gel at body temperature. This property is the basis of in-situ gelation, where the formulation is given as a liquid—for example, by injection, eye drop, or nasal spray—and then changes into a gel once it reaches body temperature. This makes the method particularly useful for injectable, nasal, and ophthalmic drug delivery, as it is simple and comfortable for patients.

Techniques [46-47]

The preparation of pH-responsive hydrogel dosage forms largely depends on the type of polymer used and the target route of administration. A common approach is free radical polymerization, where monomers such as acrylic acid or methacrylic acid are polymerized with crosslinkers like N,N'-methylenebisacrylamide under heat or UV light. This method produces strong, pH-sensitive hydrogels that are widely applied in oral, buccal, and implantable drug delivery. Another frequently used technique is ionic gelation, which works especially well with natural polymers such as chitosan. By introducing ionic crosslinkers like tripolyphosphate (TPP), a hydrogel network forms at room temperature and neutral pH, making it highly suitable for encapsulating delicate biomolecules such as proteins and enzymes. For systems that require nanosized or microsized particles, emulsion polymerization is employed, as it allows polymerization within droplets or micelles to create nanogels and microgels capable of releasing drugs in response to pH changes.

Techniques [55]

Microchip-based drug delivery systems are built using advanced microfabrication techniques. The process begins with photolithography, which creates tiny, well-structured reservoirs on silicon or biocompatible polymer surfaces. These reservoirs act as miniature storage compartments, each holding an exact dose of medicine. To control when and how the drug is released, the reservoirs are sealed with thin membranes of gold or platinum, applied using thin-film deposition methods like sputtering or evaporation. These membranes respond to electrical signals, either dissolving or opening, to release the drug in a controlled manner. The medications are then accurately loaded into the reservoirs using microinjection or precision filling techniques, with options to use powders, gels, or liquids depending on the formulation.

Techniques [60-61]

Microneedles are created using several advanced fabrication methods, each chosen based on the design and purpose of the device. The most widely used technique is mold casting or micromolding, where polymers or drug–polymer mixtures are poured into micro-molds and then dried or cured to form solid or dissolving microneedle arrays. This approach is cost-effective, scalable, and provides precise shapes. For silicon microneedles, methods like photolithography and electrochemical etching are commonly applied. Photolithography relies on UV light to pattern photosensitive materials with high accuracy, while electrochemical etching removes material from silicon wafers to sculpt needle-like structures. Another promising approach is 3D printing (additive manufacturing), which allows rapid prototyping and customized microneedle geometries using polymer or resin materials, suitable for both hollow and solid types.

Techniques [67-68]

Smart polymer-based dosage forms can be prepared using different fabrication techniques, chosen according to the type of drug delivery system and the desired responsiveness to stimuli. One of the most common methods is free radical polymerization, which produces crosslinked polymer networks like hydrogels and allows functional monomers and drug molecules to be incorporated under controlled conditions. For more precise control, photopolymerization with UV or visible light initiators is used to form injectable hydrogels or coatings under mild conditions that are safe for sensitive drugs. A simpler approach is solvent casting, where a polymer–drug solution is poured into molds and dried into thin films or patches, commonly applied in transdermal and mucoadhesive systems. To create nanoparticles or microparticles, emulsion polymerization is often employed, ensuring uniform drug encapsulation within droplets. Another versatile method, electrospinning, produces nanofiber mats with porous structures, making them useful for wound dressings and implants.

Techniques [72-73]

Targeted drug delivery systems are developed using a range of specialized fabrication techniques that focus on efficient drug loading, precise targeting, and controlled release. One widely used method is nanoprecipitation, where the drug and polymer are dissolved in a solvent and then precipitated in a non-solvent to form nanoparticles under mild and consistent conditions. Another common approach, emulsion solvent evaporation, involves dispersing a drug–polymer solution in an organic solvent into an aqueous phase, followed by solvent removal to produce nanoparticles or microspheres with well-controlled size and drug content. For lipid-based carriers, the thin-film hydration method is popular for creating liposomes by hydrating a lipid film with buffer, enabling the encapsulation of both water-soluble and fat-soluble drugs. Spray drying is another scalable technique that quickly converts drug–polymer mixtures into stable dry particles.

Liposomes [80-82]

Inorganic Nanoparticles [80-85]

Thermo Responsive Hydrogel [86-91]

Chitosan + β-Glycerophosphate Thermo gel with Insulin

PH Responsive Hydrogel [99]

 

Microchip ^[92-94]

Microneedle ^[95-97]

Smart Polymer ^[100]

Targeted Delivery System ^[98]

FORMULATION PROCESSES

Polymer

To prepare the tablets, begin by accurately weighing out 400 mg of mesalamine, 100 mg of lactose, and the required excipients. Pass all powders through a #40 mesh sieve to achieve a uniform particle size. Mix the mesalamine and lactose gently in a clean bowl for around 10 minutes to ensure even distribution of the drug. A binder solution is then prepared by dissolving polyvinylpyrrolidone (PVP K30, 20 mg per tablet) in a 60:40 mixture of isopropyl alcohol and water, stirring until the solution becomes clear and viscous. This binder is slowly added to the powder blend while stirring to obtain a moist, crumbly mass, which is then granulated by passing it through a #16 sieve. The wet granules are spread evenly on trays and dried in a hot air oven at 50–60 °C for about 30–45 minutes, ensuring the final moisture content is below 2%. Once dried, the granules are passed through a #20 sieve to standardize the particle size, removing any lumps. Magnesium stearate and talc are added to the dried granules and blended gently for 3–5 minutes to achieve proper lubrication. The mixture is then compressed into tablets weighing approximately 520–530 mg, with a hardness ranging between 5–8 kg/cm², using a tablet compression machine. For the enteric coating, Eudragit S100 is dissolved in ethanol or isopropyl alcohol under a fume hood, and triethyl citrate (10% of the polymer weight) is incorporated as a plasticizer. The tablets are coated in a coating pan or fluid bed coater until they achieve 5–10% weight gain, and then dried at room temperature or around 40 °C to remove residual solvent. [140-142][158]

Liposomes

To prepare the liposomal formulation, lipids are first weighed in the ratio of phosphatidylcholine, cholesterol, DOPE, and CHEMS at 4:1:2:2. These lipids are dissolved in a chloroform–methanol mixture (2:1) inside a round-bottom flask, ensuring complete dissolution with gentle stirring. The solvent is then removed using a rotary evaporator at 40–45 °C under reduced pressure, leaving behind a thin, uniform lipid film on the inner wall of the flask. To eliminate any remaining solvent, the flask is kept under vacuum for an additional hour. The dried film is then hydrated with an aqueous doxorubicin solution prepared in citrate buffer (pH 5.5) or PBS, and gently agitated to form multilamellar liposomes containing the drug. Unencapsulated doxorubicin is separated from the liposomes by purification methods such as dialysis for 24 hours or centrifugation with replacement of the supernatant. To achieve consistent size and improved stability, the liposomes are further processed using probe sonication or extrusion through polycarbonate membranes. For long-term preservation, a cryoprotectant such as 5% trehalose is added, followed by freezing at –80 °C and lyophilization to obtain a dry liposomal powder. The final product is stored in sterile vials at 2–8 °C, protected from heat and light to maintain stability. [143-146]

Inorganic Nanoparticles

The process begins with the selection of the active pharmaceutical ingredient (API) and a suitable inorganic nanoparticle carrier, such as silica or calcium phosphate, followed by accurate weighing of these materials along with excipients like fillers, binders, and lubricants. To ensure uniformity, all powders are sieved before use. The API is then dissolved in an appropriate solvent, into which the nanoparticles are gradually introduced while stirring, allowing the drug to adsorb onto or become encapsulated within the carrier. The solvent is removed by techniques such as rotary evaporation, freeze-drying, or spray drying, yielding a dry nanoparticle–drug complex. This dried material is blended with excipients, and if required, wet granulation with a polymer binder is carried out to produce uniform granules. Lubricants are carefully incorporated into the granules before compressing them into tablets of the desired weight and mechanical strength. For enhanced functionality, the tablets may be coated with a polymer solution to enable controlled or site-specific drug release. The coated tablets are then dried thoroughly and stored in airtight containers, shielded from moisture and light, with refrigeration preferred to preserve stability. [146-147]

Thermo Responsive Hydrogel

The formulation process starts with the careful selection of the active pharmaceutical ingredient (API) and a thermo responsive polymer such as Pluronic F127 or PNIPAM, along with stabilizers or crosslinkers if required. These components are accurately weighed, and the polymer is dissolved in water or buffer under gentle stirring at a temperature below its gelation point, forming a clear solution. The API is then incorporated into this solution with continuous gentle mixing to achieve uniform distribution. By raising the temperature to around 37 °C or the polymer’s gelation threshold, the solution transforms into a gel, effectively entrapping the drug. If greater structural stability is needed, chemical crosslinkers may be introduced. For converting the hydrogel into solid dosage forms, the gel is freeze-dried to create a dry, porous matrix, which can be blended with excipients and compressed into tablets. These tablets may also be coated with a suitable polymer to enable controlled or site-specific release. The final hydrogel or tablets are stored in airtight containers, protected from light and moisture, and refrigerated if necessary to preserve stability and the thermo responsive characteristics. [140-141][148]

PH Responsive Hydrogel

The process begins with the selection of an active pharmaceutical ingredient (API) and a suitable pH-sensitive polymer such as Eudragit, Chitosan, or Carbopol, along with any required stabilizers or crosslinkers. These components are carefully weighed, and the polymer is dissolved in water, buffer, or an ethanol–water mixture under gentle stirring to obtain a uniform solution. The API is then incorporated into this solution and mixed thoroughly to ensure even distribution. Hydrogel formation is induced by adjusting the pH or ionic strength, allowing the polymer network to entrap the drug. If additional structural stability is required, chemical crosslinkers may be introduced. For preparing solid dosage forms, the hydrogel is freeze-dried to produce a porous dry matrix, which can be blended with excipients and compressed into tablets. These tablets may be further coated with a pH-sensitive or enzyme-sensitive polymer to achieve targeted or controlled drug release. The final product, whether in hydrogel or tablet form, should be stored in airtight containers, protected from light and moisture, with refrigeration if needed to preserve stability and maintain the pH-responsive properties. [140][148-150]

Microchip

To prepare a microchip-based drug delivery system, the process begins with selecting the active pharmaceutical ingredient (API), suitable microchip devices or micro-reservoirs, and excipients such as fillers, binders, and lubricants, followed by accurate weighing of each component. The API is dissolved in an appropriate solvent and carefully loaded into the microchip reservoirs using precise methods like micropipettes or microfluidic techniques. Once the solvent evaporates, the drug remains encapsulated within the microchip. If necessary, the reservoirs can be sealed with biocompatible membranes or polymer coatings to avoid premature release. These drug-loaded microchips are then incorporated into a final dosage form, such as a tablet, by blending them with excipients and compressing the mixture with care to prevent any damage to the microchips. An additional polymer coating may be applied to the tablets to achieve targeted or controlled release. The final formulation undergoes quality testing to ensure proper drug content, functionality of the microchips, and the desired release profile. For stability, the product should be stored in airtight containers, shielded from light and moisture, and refrigerated if required. [150-152]

Microneedle

The preparation of microneedle-based drug delivery systems starts with selecting the active pharmaceutical ingredient (API), suitable microneedle materials such as PLGA, PVA, or PVP, along with necessary excipients like plasticizers or stabilizers, followed by accurate weighing of each component. The API is then dissolved or dispersed in a suitable solvent to achieve uniform distribution. This drug-containing mixture is cast into microneedle molds, and techniques like centrifugation or vacuum are applied to eliminate air bubbles and ensure the cavities are completely filled. Once dried or solidified, the microneedles encapsulate the API within the polymer matrix. In the case of preparing patches, a backing layer is added to provide mechanical support. These microneedle arrays can also be incorporated into tablets or composite dosage forms, taking care to preserve their structure. To enable controlled or targeted drug release, a polymer coating may be applied to the microneedles. The final formulation is tested for critical parameters such as drug content, mechanical strength, insertion ability, and release behavior. For stability, the microneedle systems are stored in airtight containers, protected from light and moisture, and refrigerated if necessary. [153-154]

Smart Polymer

The development of a smart polymer-based drug delivery system begins with carefully selecting the active pharmaceutical ingredient (API), a suitable polymer such as pH-sensitive, thermo responsive, or other stimuli-responsive types, along with excipients like binders, fillers, and stabilizers, followed by accurate weighing of each component. The polymer is dissolved in an appropriate solvent to obtain a clear, uniform solution under conditions that are compatible with both the drug and the polymer. The API is then incorporated into this solution and mixed gently to ensure even distribution. Depending on the desired dosage form, the solution may be allowed to form a hydrogel in response to triggers such as changes in pH, temperature, or ionic strength, or it can be combined with excipients and compressed into tablets using either wet or dry granulation techniques. To further enhance stability or control drug release, crosslinkers may be added, or the final product can be coated with a functional polymer layer. The prepared formulation is then assessed for drug content, strength, release characteristics, and its ability to respond to specific stimuli. For long-term stability, the product should be stored in airtight containers, protected from light, moisture, and extreme conditions, with refrigeration used if required. [140-141][158]

Targeted Delivery System

The preparation of a targeted drug delivery system begins with selecting the active pharmaceutical ingredient (API), an appropriate targeting agent such as ligands, antibodies, or peptides, and necessary excipients like fillers, binders, or stabilizers, followed by accurate weighing of each. The API is dissolved in a suitable solvent and combined with the targeting agent, either through direct conjugation or by attaching it to a carrier system such as nanoparticles, liposomes, or polymers, ensuring thorough and uniform mixing. The choice of carrier or matrix depends on the intended dosage form: for nanoparticles or liposomes, the complex is incorporated into polymers or lipids, while for hydrogels or tablets, smart polymers are dissolved to enable gelation or further processing. In the case of tablets, the API–targeting agent–carrier complex is blended with excipients and compressed, whereas hydrogels or nanoparticles are allowed to form naturally, encapsulating the drug complex. To achieve controlled or site-specific delivery, a polymer coating may also be applied. The final product is then evaluated for drug content, release characteristics, mechanical stability, and the functionality of the targeting agent. For preservation, the formulation should be stored in airtight containers, shielded from moisture, light, and extreme conditions, with refrigeration when required to maintain stability. [155-157]

SCIENTIST INTERVIEW

• Mark prausnitz

Born	February 1966
Education	Stanford University B.S., 1988 Massachusetts Institute of Technology Ph.D., 1994
Awards	Fellow, American Institute for Medical and Biological Engineering (2009) Fellow, National Academy of Inventors (2014) Fellow, American Association of Pharmaceutical Scientists (2017) Fellow, Controlled Release Society (2018)
Institutions	Georgia Institute of Technology
Fields	Biomedical Engineering

Microneedles offer several advantages over traditional hypodermic needles, with one of the most significant being improved patient comfort. Many people, including both adults and children, experience needle phobia, which can sometimes even lead to fainting. Microneedle arrays help address this issue by reducing the anxiety typically associated with injections, as they are far less intimidating than conventional needles. Beyond psychological comfort, microneedles are also physically less painful, which has been confirmed in studies where children expressed greater willingness to undergo blood sampling when microneedles were used instead of standard needles. From a healthcare perspective, microneedles also provide benefits such as reduced hazardous waste, easier application, and lower costs since they use smaller amounts of cheaper materials compared to hypodermic needles.

The concept of microneedle drug delivery was pioneered by Mark Prausnitz, who published the first study on their use in 1998. He later led the first clinical trials exploring microneedle-based delivery of drugs and vaccines and has since founded multiple companies to advance this technology. One of the notable developments includes microneedle patches designed for painless vaccination, which were tested in a phase 1/2 clinical trial for measles and rubella vaccines in West Africa, supported by the Bill and Melinda Gates Foundation. Prausnitz also expanded the application of microneedles to ocular drug delivery, publishing the first study in 2007. In 2011, he co-founded Clearside Biomedical to develop microneedle-based suprachoroidal space (SCS) delivery, which led to the FDA-approved product Xipere for treating macular edema. Through collaborations at Emory University and beyond, he has contributed to the advancement of both hollow and solid microneedle systems, targeting precise drug delivery to different regions of the eye, including both anterior and posterior segments. ^{[128][132][136]}

• Samir Mitragotri

Born	28 May 1971 Solapur, India
Education	Institute of Chemical Technology B.S., 1992 Massachusetts Institute of Technology M.S. and PhD, 1996
Awards	National Academy of Engineering National Academy of Medicine
Institutions       About	Harvard University Harvard John A. Paulson School of Engineering and Applied Sciences Wyss Institute for Biologically Inspired Engineering an Indian American professor at Harvard University

Samir Mitragotri has made groundbreaking contributions to drug delivery by developing innovative techniques for transdermal, oral, and targeted delivery systems. His work includes methods to transport drugs through the skin using low-frequency ultrasound, pulsed microjet injectors, high-throughput skin testing platforms, skin-penetrating peptides, and ionic liquids. He also designed intestinal patches and oral delivery approaches using ionic liquids to improve the absorption of protein-based drugs. In the field of targeted therapy, Mitragotri pioneered nanoparticle-enabled cell therapies, where drug-loaded nanoparticles attach to circulatory cells such as red blood cells and monocytes, enabling tissue-specific drug delivery. These technologies are being applied in the development of advanced treatments for conditions such as diabetes, cancer, psoriasis, trauma, hemorrhage, and infections. Recognized globally for his contributions, Mitragotri is a member of the National Academy of Medicine, the National Academy of Inventors, and has been part of the US National Academy of Engineering since 2015 for his role in creating, translating, and commercializing transdermal drug delivery systems. In addition to these innovations, his research also focuses on self-assembled drug delivery systems using liposomes and polymer conjugates. These systems provide unique benefits as therapeutic carriers, especially for delivering combinations of drugs within a single formulation. This approach helps overcome challenges posed by differences in drug properties, allowing effective co-encapsulation. Furthermore, his team is exploring strategies to deliver immunoactive agents alongside small-molecule drugs to regulate the tumor immune microenvironment, advancing the potential of combination therapies in cancer treatment. ^{[129][133][138]}

• Robert Langer

Born	August 29, 1948 Albany, New York, United States
Education	Cornell University (BSc) Massachusetts Institute of Technology (ScD)
Awards	Breakthrough Prize in Life Sciences (2014) Kyoto Prize (2014) Biotechnology Heritage Award (2014) FREng[1] (2010) Queen Elizabeth Prize for Engineering (2015) Kabiller Prize in Nanoscience and Nanomedicine (2017) Medal of Science (Portugal) (2020) BBVA Foundation Frontiers of Knowledge Awards (2021) Balzan Prize (2022) Dr. Paul Janssen Award for Biomedical Research (2023) Kavli Prize (2024) Double Helix Medal (2025) Lipid Science Prize (2025)
Institutions	Massachusetts Institute of Technology

Robert Langer revolutionized polymer-based drug delivery by rethinking traditional approaches. Instead of simply embedding drug molecules into polymers, he designed a three-dimensional polymer matrix around the molecules, allowing them to diffuse slowly and in a controlled manner. By altering the properties of both the drug and the polymer, he created versatile systems capable of delivering a wide range of molecules with precise control over their release. One of the biggest challenges in oral drug delivery is that digestive acids and enzymes often degrade drugs before they reach their target, and absorption through the intestinal wall is limited. To address this, newer polymer systems were developed. Some involve coating drugs with degradable polymer layers that adhere to intestinal cells and improve absorption into the bloodstream. Others use polymers that swell when exposed to stomach acid, shielding the drug from early breakdown, while certain formulations are engineered for slow, sustained release, ensuring the medication is delivered gradually over time. Polymers also play a central role in advanced microchip-based drug delivery systems. Their properties can be modified by external triggers such as ultrasound, electric pulses, or magnetic fields, which makes it possible to adjust drug release rates with precision. When integrated with electronic components on microchips, this technology enables pre-programmed dosing, ensuring that patients receive the right amount of medicine at the right time. Langer’s team even developed implantable microchips capable of monitoring a patient’s blood chemistry and releasing drugs accordingly, making personalized medicine more achievable. These devices include both active, silicon-based microchips that function autonomously and passive, polymer-based chips designed for controlled release. Research has focused on assessing their biocompatibility, studying drug release in vitro and in vivo, and demonstrating predictable, reliable release profiles. Such systems are being investigated for treating complex conditions like brain tumors, where combination therapies may be more effective, with ongoing studies evaluating their potential to improve treatment outcomes. ^[130][135]

• Jind?ich Kope?ek

Born	January 27, 1940 (age 85) Strakonice, Protectorate of Bohemia and Moravia
Alma mater	Czechoslovak Academy of Sciences (Ph.D., D.Sc.); Institute of Chemical Technology, Prague (M.S.)
Occupation(s)	Chemist, pharmaceutical scientist, professor
Known for	Polymer-based drug delivery

Jind?ich Kope?ek is recognized as a pioneer in the field of nanomedicine and biomaterials, particularly for his groundbreaking work on biomedicinal polymers such as hydrogel implants and polymer–drug conjugates. He played a central role in the development of the first clinically tested polymer-based anticancer drugs, known as PK1 and PK2, and hydrogels from his laboratory have already found clinical applications. His most significant contributions to controlled drug release include the creation of polymers and copolymers of N-(2-hydroxy propyl) methacrylamide (HPMA) as drug carriers, as well as the design of enzymatically degradable versions of these polymers. He conducted fundamental studies on how oligopeptide side chains in polymers degrade under enzymatic action and explored how polymer structure influences the rate of their uptake into cells through pinocytosis. Furthermore, he developed polymers engineered to release therapeutic agents specifically within lysosomes, ensuring targeted intracellular delivery. His research also shed light on how polymeric carriers bearing ligands can localize in tissues by binding to receptors present on particular cell surfaces. Building on this work, three HPMA copolymer–anticancer drug conjugates progressed into Phase I/II clinical trials, marking an important step toward translating his innovations into effective cancer therapies. ^[131][137]

EVALUATION TEST

1. Polymer

Tensile Test: To perform a tensile test on a polymer, a dumbbell-shaped sample is prepared using a mold or cutter. This sample is then clamped into a Universal Testing Machine (UTM). The machine slowly pulls the sample apart at a constant speed until it breaks. During this process, the machine records how much force the material can take, how much it stretches, and how stiff it is.

Flexural Test (Three-Point Bending): In this test, a rectangular piece of the polymer is placed on two supports, like a small bridge. A force is then applied from the top at the center until the sample bends or breaks. The amount of bending and the force required give us an idea of the material’s flexibility and strength.

Hardness Test: This test checks how hard the surface of a polymer is. A device called a durometer is pressed against the flat surface of the sample. For softer materials like rubber, Shore A is used, and for harder plastics, Shore D is preferred. The hardness is measured by how deeply the indenter presses into the material after a few seconds.

Heat Deflection Temperature (HDT) Test: A sample is placed in a bending setup and subjected to a constant load. It is then gradually heated in an oil bath. The temperature at which the sample bends a certain amount (usually 0.25 mm) is noted. This shows how much heat the polymer can handle before deforming.

Chemical Resistance Test: Small samples of the polymer are weighed and then soaked in different chemicals like acids, bases, or solvents for a set period. After the exposure, the samples are cleaned, dried, and weighed again. Any changes in weight, appearance, or physical properties indicate how resistant the polymer is to chemicals.

Water Absorption Test: First, a dry sample is weighed, then submerged in water—either at room temperature or boiling—for a specific time (commonly 24 or 48 hours). After soaking, the sample is wiped dry and reweighed. The difference in weight shows how much water the material absorbed.

Biodegradability Test: For biodegradable polymers, a sample is mixed with compost and kept under controlled temperature and humidity. Over time, the amount of carbon dioxide released is measured to determine how much the polymer is breaking down. This simulates natural composting and shows if the material is eco-friendly.

2. Liposomes

Particle Size and Size Distribution: First, the liposome sample is mixed with a suitable liquid to dilute it. Then, a special machine called a Dynamic Light Scattering (DLS) device shines light on the particles and measures how they scatter this light as they move around. By watching how fast they move, the machine calculates the average size of the liposomes and how much the sizes vary. Knowing the size is important because it affects how liposomes travel and work inside the body.

Zeta Potential Measurement (Surface Charge): A sample of liposomes is placed in a small container, and an electric field is applied. The machine watches how the liposomes move under this field. This movement tells us the surface electric charge (called zeta potential) of the liposomes. The charge helps us understand how stable the liposome solution is if the charge is strong (either positive or negative), the liposomes are less likely to stick together and more likely to stay evenly spread out.

Encapsulation Efficiency: This test finds out how much drug is actually trapped inside the liposomes. First, the free drug (not inside liposomes) is separated by spinning the sample fast (centrifugation), filtering it, or using a special membrane (dialysis). Then, the amount of drug inside and outside the liposomes is measured using techniques like UV light absorption or liquid chromatography. From these numbers, we calculate the percentage of the drug that successfully got inside the liposomes.

Drug Release (In Vitro Release Study): To see how the drug slowly leaves the liposomes, the sample is placed inside a dialysis bag (a tiny pouch that allows small molecules to pass through). This bag is put into a liquid that simulates body fluids and kept shaking gently at body temperature (37°C). At certain times, small amounts of liquid outside the bag are tested to find out how much drug has come out. This tells us how fast or slow the drug is released.

Morphological Analysis (Shape and Structure): To check the shape and surface of the liposomes, scientists use powerful microscopes like Transmission Electron Microscopy (TEM) or Scanning Electron Microscopy (SEM). The liposome sample is prepared carefully sometimes stained with a special dye or frozen so the microscope can clearly show tiny details. This lets us see if the liposomes are round and have the right layered structure.

pH Sensitivity or Stability: Liposomes are put into liquids with different acidity levels (pH), such as acidic solutions like stomach acid or slightly acidic environments like tumors. Scientists then check whether the liposomes stay intact or break apart. They measure size, surface charge, and drug release in these different conditions to understand how the liposomes will behave in various parts of the body.

Physical Stability (Storage Stability)

Liposome samples are stored at different temperatures like cold (4°C), room temperature, and body temperature (37°C) for a set amount of time. Over this period, scientists regularly check if the liposomes change in size, surface charge, how much drug they hold, or if the drug leaks out. This helps decide the best storage conditions and shelf life of the liposome product.

3. Inorganic Nanoparticles

Particle Size and Size Distribution

The nanoparticles are mixed into a liquid and tested using a machine that shines light on them. This machine watches how the particles scatter the light to figure out their average size and how much their sizes differ from each other. Knowing the size helps understand how nanoparticles will act in things like medicine or chemical reactions.

Shape and Surface Look

To see what the nanoparticles look like and their shape, scientists use powerful microscopes like TEM or SEM. They put a tiny amount of the nanoparticle sample on a special surface and let it dry. Then, the microscope takes very close-up pictures showing the exact shape and surface details.

Surface Charge (Zeta Potential)

The electric charge on the surface of nanoparticles is measured by putting them in a liquid and applying an electric field. The machine watches how fast and in which direction the particles move. This helps tell if the nanoparticles will stay evenly spread out or clump together. Particles with a strong positive or negative charge tend to stay apart and remain stable.

Crystal Structure and Phases

Scientists use X-rays to study the crystal structure of the nanoparticles. They shine X-rays on a powdered sample and record the pattern that the X-rays make after hitting the particles. This pattern shows what kinds of crystals the nanoparticles are made of and confirms their structure.

Surface Area Measurement

This test measures how much surface area the nanoparticles have by seeing how much nitrogen gas sticks to their surface when cooled with liquid nitrogen. The more gas that sticks, the larger the surface area. Surface area is important for things like catalysts or materials that absorb substances.

Heat Stability

To see how nanoparticles react to heat, the sample is slowly heated while its weight is recorded. If the weight drops at certain temperatures, it shows the nanoparticles are breaking down or losing surface molecules. This tells us how stable they are when heated.

Surface Chemistry (Functional Groups)

Using infrared light, scientists look at the chemical groups on the surface of nanoparticles. The sample absorbs different wavelengths of this light, and by studying the absorption pattern, they identify specific chemical bonds or coatings on the particles.

Stability in Liquid (Colloidal Stability)

Nanoparticles are kept in liquid under different conditions like various pH levels, temperatures, or salt concentrations. Over time, scientists check if their size or surface charge changes by using light-scattering machines. This test tells us if nanoparticles stay evenly spread out or start clumping or settling down.   

4. Thermo Responsive Hydrogel

Swelling Behavior Test

First, you dry the hydrogel and weigh it. Then, you soak it in water or a buffer solution at different temperatures—some cooler than its special transition temperature and some warmer. After some time, you take it out, gently wipe off the extra water on the surface, and weigh it again. By comparing how heavy it is before and after soaking, you find out how much water the hydrogel absorbs and how temperature affects this swelling.

Volume Phase Transition Temperature (VPTT) Measurement

You put the hydrogel in a water bath or on a heating stage where you can control the temperature. As you slowly raise the temperature, you watch the hydrogel’s size or appearance. The temperature where it suddenly shrinks or changes shape is called the transition temperature. This tells you at what temperature the hydrogel changes its behavior.

Rheological Properties (How It Flows and Stretches)

Using a special machine called a rheometer, you test how the hydrogel flows or bends when you apply force, at different temperatures. The machine measures how stretchy (elastic) or runny (viscous) the hydrogel is. Changes around the transition temperature show how the hydrogel responds to heat in terms of its mechanical behavior.

Mechanical Strength Test

Cut the hydrogel into pieces of a certain size and squeeze or stretch them using a testing machine. You record how much force it takes to deform or break the hydrogel. Testing at temperatures below and above the transition point helps you understand how strong or flexible the hydrogel is under different heat conditions.

Drug Release Study

If the hydrogel contains medicine, you put it in a liquid that mimics the body’s environment at different temperatures. Over time, you take small samples of the liquid to measure how much medicine has been released from the hydrogel. This shows how temperature affects the release of the drug.

Thermal Analysis

Using a machine called Differential Scanning Calorimeter (DSC), you slowly heat a small piece of the hydrogel. The machine measures how much heat the sample absorbs or releases. From this, you can find the exact temperature where the hydrogel undergoes a change, like melting or shrinking.

Cytocompatibility Test (If for Medical Use)

you grow cells with the hydrogel or expose them to substances released from the hydrogel. After some time, you check if the cells are healthy and alive using special tests. This helps ensure the hydrogel isn’t toxic and is safe for use in the body. You can also see if temperature changes affect how safe the hydrogel is for cells.

5. PH Responsive Hydrogel

Swelling Behavior Test

First, the dry hydrogel is weighed. Then, it’s soaked in liquids with different pH levels—like acidic, neutral, or basic—for a set time. After soaking, the hydrogel is taken out, the surface water is gently wiped off, and it’s weighed again. By comparing the weight before and after soaking, we find out how much the hydrogel swells or shrinks depending on the pH of the liquid.

pH Sensitivity (Response) Test

The hydrogel is put into solutions with different pH levels, either one after another or all at once. We watch for any changes in its size, shape, transparency, or strength. This can be done by simply looking at it, taking pictures, or using special instruments. This test helps us see how the hydrogel reacts when the acidity or alkalinity changes.

Mechanical Strength Test

Samples of the hydrogel are prepared and tested to see how strong or stretchy they are. This is done using a machine that squeezes or pulls the hydrogel. The test is repeated at different pH levels to find out how acidity or basicity affects how tough or flexible the hydrogel is.

Drug Encapsulation Efficiency and Release Test

If the hydrogel contains medicine, first we measure how much drug is inside by separating the drug that’s free and the drug trapped inside. Then, the hydrogel is placed in liquids with different pH levels that mimic the body’s environments, like the stomach or intestines. At certain times, samples of the liquid are taken to check how much drug has been released. This shows how the pH affects the release of medicine from the hydrogel.

Morphological Analysis

We use powerful microscopes to look at the hydrogel’s surface and inner structure. The samples are dried or frozen carefully before viewing to keep their shape intact. This helps us see if the hydrogel’s structure changes at different pH levels.

Fourier Transform Infrared Spectroscopy (FTIR)

This technique shines infrared light on the hydrogel and measures how the light is absorbed. By comparing the hydrogel before and after exposure to different pH levels, we can tell if its chemical groups have changed or reacted to the pH.

Rheological (Flow and Deformation) Properties Test

Using a special machine called a rheometer, we test how the hydrogel flows and bends at different pH levels. By measuring how stiff or soft it is, we learn how changes in acidity or alkalinity affect the hydrogel’s structure and feel.

Cytocompatibility Test (If used for medical purposes)

Cells are grown together with the hydrogel or substances released from it at different pH conditions. After some time, tests are done to check if the hydrogel is safe for cells and supports their growth, making sure it’s not harmful when used in the body.

6. Microchip

Drug Release Test

We put the drug-loaded microchip into a liquid that’s like the fluids in our body. At different times, we take samples of the liquid to see how much drug has come out of the microchip. We use special machines to measure the drug amount. This test tells us how quickly and how much drug the microchip releases, which is important to make sure the dosage is right.

Electrical Activation Test

We check the microchip’s electrical system to make sure it releases the drug when it’s supposed to. By sending small electrical signals to the chip, we watch if the drug compartments open and release the medicine exactly as planned. We test if this happens on time and every time, to make sure the system is reliable.

Biocompatibility Test

We test the materials of the microchip to make sure they don’t harm living cells. We grow cells in contact with the microchip or its materials and check if the cells stay healthy and grow well. This ensures the microchip is safe to put inside the body.

Mechanical Durability Test

We put the microchip through physical stresses like bending, twisting, or squeezing to see if it holds up. This makes sure the device won’t break or stop working when it’s inside a moving body.

Stability and Leakage Test

We soak the microchip in fluids similar to those in the body for a long time and check if any drug leaks out when it’s not supposed to. We also make sure the microchip materials stay stable and don’t break down. This test ensures the device will work properly for a long time.

Surface Test

We use special microscopes to look closely at the surface of the microchip. This helps us see how smooth or rough it is, how coatings are applied, and how it might interact with body fluids and tissues.

Electrical Safety and Power Test

We measure how much power the microchip uses when it’s working and when it’s resting. We also check for any electrical problems that might be dangerous for the person using it. This test ensures the device is safe and energy-efficient, especially since it may run on batteries.

Animal Testing

We put the microchip inside animals to see how it works in a real living body. We watch how the drug is released, how the body reacts, and if there are any side effects. This helps make sure the device is safe and effective before trying it in humans.

7. Microneedle

Mechanical Strength Test

This test checks if the microneedles are strong enough to poke through the skin without breaking. The needles are pressed against a hard surface with increasing force until they bend or snap. This makes sure the needles won’t break during use.

Skin Penetration Test

the microneedles are pressed into animal or fake skin. Then, the skin is stained with special dyes to show where the needles made tiny holes. By counting these holes, we can tell if the microneedles successfully pierced the skin.

Drug Loading Test

This measures how much medicine the microneedles actually carry. The needles are dissolved or soaked in a liquid, and the amount of drug released is measured using special machines. This tells us how much medicine will be delivered.

Drug Release Test

The microneedles are placed in a liquid similar to body fluids, and samples are taken at different times to see how much drug comes out. This helps understand how quickly and how much medicine the microneedles release.

Skin Irritation and Safety Test

The microneedles are tested on skin or skin cells to check if they cause redness, irritation, or harm. This ensures they are safe and won’t cause allergic reactions or damage.

Insertion Force Test

This test measures how much pressure is needed to push the microneedles into the skin. The goal is to make sure it’s easy and not painful to apply.

Shape and Appearance Test

Using powerful microscopes, the microneedles are checked for proper size, shape, and sharpness. This ensures they are made correctly to work well.

Stability Test

Microneedles are stored in different conditions (like warm or humid places) for some time to see if they stay strong, keep their drug, and don’t change appearance. This helps know how long they last on the shelf.

In Vivo Drug Delivery Test

The microneedles are tested on live animals to see how well they deliver the drug inside the body. Blood or tissue samples are taken to measure drug levels and effectiveness.

Patient Comfort and Pain Test

People try the microneedles and report how much pain or discomfort they feel. This helps make sure the device is easy and comfortable for patients to use.

8. Smart Polymer

Swelling Behavior Test

We start by weighing the dry smart polymer. Then, we soak it in water or a solution that changes depending on the type of polymer (like different temperatures or acidity). After some time, we take it out, wipe off any extra liquid, and weigh it again. By comparing the new weight to the dry weight, we see how much water it soaked up. This tells us how the polymer swells or shrinks when the environment changes.

Stimuli-Responsiveness Test

We expose the polymer to things like heat, changes in acidity, light, or certain enzymes. Then, we watch how it changes—maybe it gets bigger, changes shape, becomes clearer, or dissolves. We can just look at it or use special tools like microscopes or light-measuring devices. This shows if the polymer reacts properly to these triggers, which is important for releasing medicine when needed.

Drug Loading and Encapsulation Efficiency

This test checks how much medicine the polymer can carry. We separate any medicine that’s not stuck to the polymer from what is stuck inside or on it. Then, we measure the amount of medicine loaded using tools that detect and measure drug amounts. This helps us know how much medicine the polymer holds.

In Vitro Drug Release Study

We put the medicine-loaded polymer into a liquid that mimics body fluids, at conditions similar to the body (like temperature or acidity). Over time, we take samples of the liquid and measure how much medicine has been released. This shows how well the polymer controls when and how much medicine it releases.

Biocompatibility and Cytotoxicity Test

We grow cells in contact with the polymer or its extracts to see if it’s safe for living tissues. After a while, we check how healthy the cells are using special tests. This makes sure the polymer won’t harm the body when used in medicine.

Degradation Study

We put the polymer in fluids like those in the body or solutions with enzymes that can break it down. Over time, we check how much it breaks down by measuring changes in weight or strength. This tells us how long the polymer lasts and if it breaks down safely.

Surface Chemistry Analysis

We use special instruments to study the chemical makeup of the polymer’s surface. By comparing the polymer before and after exposure to triggers or drug loading, we can see what chemical changes happen. This helps us understand how the polymer interacts with drugs and the environment.

9. Targeted Delivery System

Particle Size and Size Distribution

The tiny drug particles are mixed in a liquid, and a special machine shines light on them. By seeing how the light bounces off, we figure out their average size and whether most particles are similar in size. Particle size is important because it affects how well the drug can find its target and stay in the body.

Surface Charge (Zeta Potential) Measurement

Particles are put in a liquid, and an electric field is applied. We then see how fast they move because of the charge. Knowing the charge helps us understand if the particles will stay separated or clump together. Having the right charge makes the drug delivery more stable and effective.

Drug Encapsulation Efficiency

We separate the free drug from the drug inside the particles by spinning or filtering the sample. Then, we measure the amount of drug in each part using special instruments. This tells us how well the delivery system holds the drug.

In Vitro Drug Release Study

The drug-loaded particles are put into a fluid that mimics the body. Samples of the fluid are taken at different times and analyzed to see how much drug has come out. This helps us understand if the drug is released in a controlled way when it reaches the target.

Targeting Efficiency and Cellular Uptake

We add the drug delivery system to cells grown in the lab (like cancer cells). Using microscopes or other detectors, we see if the particles have entered the cells. This tells us how well the system delivers the drug exactly where it’s needed.

Cytotoxicity and Biocompatibility Test

Cells are exposed to the delivery system, and then special tests measure how many cells survive or die. This helps confirm the system won’t cause harm while delivering the drug.

Morphological Analysis

Using high-powered microscopes, we take detailed pictures of the particles to see their size, shape, and surface texture. This helps ensure the particles are made correctly for good targeting.

In Vivo Biodistribution Studies

The delivery system is given to animals, and at different times, organs and tissues are checked to see where the drug or particles have traveled. This shows if the system reaches the target area well without affecting other parts.

Stability Studies

The system is stored in places with different temperatures, light, or humidity. Over weeks or months, tests are done to see if the particles still look and work the same. This ensures the product will be reliable until it’s used.

Pharmacokinetics and Pharmacodynamics

After giving the drug to animals, blood samples are taken at different times to measure drug levels. This tells us how the drug is absorbed, distributed, broken down, and removed from the body. We also check if the drug is having the intended effect on the body. ^[187-240]

COMPANY THAT MANUFACTURES SDDS DOSAGE FORM

1. Insulet Corporation – Omnipod Insulin Management System

Insulet Corporation, the company behind the Omnipod® Insulin Management System, earned about $554 million in revenue during the first quarter of 2025. This marks a healthy growth of nearly 28–29% compared to the same period last year. The rise in sales came from strong demand in both the United States and international markets, showing that Omnipod is steadily becoming a popular choice for people managing diabetes worldwide.

2. Enable Injections – enFuse Wearable Drug Delivery Platform

Enable Injections offers the enFuse® wearable drug delivery system, which is designed to make injectable treatments easier and more convenient. In FY2023, the company reported sales of about ?43.48 crore. However, in FY2024, the reported revenue dropped drastically to just ?13.75 lakh. Such a steep decline raises questions about whether this reflects an actual fall in sales, a change in accounting methods, or a possible reporting error, and therefore needs closer review.

3. Becton, Dickinson and Company (BD) – BD Pre fillable Syringes and Alaris Infusion Pump

Becton, Dickinson and Company (BD) is a global leader in medical technology, with a strong presence in drug delivery and infusion systems. Its portfolio includes BD Pre fillable Syringes and the Alaris® connected infusion pump, both widely used in hospitals and clinical practice. For the quarter ending June 30, 2025, BD Medical reported revenues of approximately $2.93 billion, reflecting the scale of its operations and the continued demand for its delivery platforms.

4. SHL Medical – Autoinjectors and Pen Injectors

SHL Medical is a leading provider of autoinjectors and pen injector systems, supporting the self-administration of biologics and other injectable therapies. The global autoinjectors market was valued at around USD 120.21 billion in 2023, and is expected to expand significantly, reaching USD 311.33 billion by 2032. This represents a strong compound annual growth rate (CAGR) of 11.4% over the forecast period (2024–2032). North America held the largest share of the market in 2023, accounting for about 59.2%, highlighting the region’s dominant role in the adoption of autoinjector technolo

5. Biocorp Easylog Smart Inhaler Sensors

Biocorp develops connected health solutions such as the Easylog® smart inhaler sensor, designed to improve adherence and monitoring in respiratory therapies. In 2024, the company reported revenues of approximately USD 42.12 billion. For its partner Labcorp, total revenue for the same year stood at USD 10.95 billion, representing a 2.3% increase compared with 2023.

6. Hetero Smart Patches (K-Plast and C-Plast)

Hetero has expanded its portfolio to include K-Plast® (ketoprofen) and C-Plast® (capsaicin) smart patches, aimed at providing convenient, transdermal delivery for pain management. The company’s overall performance remained strong, with ?14,600 crore in revenue reported for the financial year ending March 31, 2024, highlighting its significant role in the Indian pharmaceutical market.

7. EliLilly Mounjaro Smart Auto-Injector

Eli Lilly’s Mounjaro® (tirzepatide), delivered via a smart auto-injector, is indicated for obesity and type 2 diabetes management. Since its launch in India in March 2025, the drug has demonstrated remarkable uptake, surpassing ?100 crore in sales within the first four months and reaching a market value of ?154 crore by August 2025. This rapid growth underscores the rising demand for advanced injectable therapies in metabolic disorders. ^[159-163]

ADVANTAGES AND DISADVANTAGES

Advantages

Smart and targeted drug delivery systems offer several advantages over conventional methods of administering medicines. One of the most important benefits is their ability to deliver drugs directly to the diseased tissue or organ, thereby reducing unnecessary systemic exposure. This approach not only increases the therapeutic efficacy of treatment but also significantly minimizes side effects by sparing healthy tissues from drug exposure.

Another key advantage is the potential for sustained or controlled drug release. By regulating how the drug is released in the body, these systems can maintain effective concentrations over an extended period. This allows for less frequent dosing schedules for instance, once daily or weekly instead of multiple times per day ultimately improving patient adherence.

Targeted delivery also improves drug absorption at the site of action and helps reduce degradation of sensitive molecules in the gastrointestinal tract or during liver metabolism. As a result, patients often achieve better therapeutic outcomes with lower doses, making treatment more efficient and safer.

Emerging smart delivery platforms go even further by integrating sensors or digital technologies that can adjust drug release in real time based on the patient’s physiological data. Additionally, the growing use of automated or wearable systems, such as insulin pumps and auto-injectors, has reduced the need for manual dosing, making therapy more convenient and reliable.

Finally, the development of non-invasive delivery options, such as transdermal patches and inhalers, adds another layer of comfort and accessibility for patients. Together, these innovations represent a significant shift toward patient-centered, efficient, and precise drug delivery solutions that align with modern healthcare needs ^[164-168]

Disadvantages

Despite their promise, the development and use of smart drug delivery systems (SDDS) face several important challenges. One of the primary barriers is the high cost of research, development, and manufacturing. The use of advanced materials, nanotechnology, embedded sensors, and software integration significantly increases production expenses, which may restrict accessibility in low- and middle-income countries.

From a technical perspective, these systems require highly precise engineering and strict quality control. Many are designed as multi-component platforms incorporating elements such as nanoparticles, microneedles, or biosensors that are difficult to scale up for large-scale production. Even small deviations during manufacturing can influence drug release profiles, therapeutic efficacy, or safety outcomes.

Another concern is the sensitivity of the biological or chemical components involved. Proteins, antibodies, or nanoparticle formulations often demand specialized storage and transport conditions, such as protection from temperature fluctuations, light exposure, or moisture. These constraints can shorten the shelf-life compared to conventional medicines, creating additional logistical challenges.

Safety considerations also remain critical. Nanoparticles and polymers used in SDDS may induce immune responses or toxicity, and long-term safety data are often limited. There is also the potential for accumulation in organs such as the liver or spleen, raising further concerns about chronic use.

Finally, wearable or implantable devices may cause discomfort, inconvenience, or reluctance among patients, particularly for those who are hesitant to adopt technology-driven therapies. These factors highlight the importance of balancing innovation with practical usability, affordability, and long-term safety in the advancement of smart drug delivery systems. ^[169-172]

REPORTED SIDE EFFECT ON PATIENTS

1. Skin and Local Reactions

One of the most frequent side effects of smart drug delivery platforms is the occurrence of local skin reactions. Patients may notice redness, swelling, itching, or mild pain at the site of administration, whether it is an injection, patch, or implant. These effects are usually temporary and resolve within a short period; however, they can still cause discomfort and, in some cases, discourage patients from continuing therapy.

2. Allergic Reactions

Materials used in advanced delivery systems such as nanoparticles, polymers, or chemical excipients may provoke allergic responses in certain individuals. Mild reactions often appear as rashes, hives, or localized irritation. Though rare, more severe outcomes like anaphylaxis can occur. These reactions are medical emergencies that require immediate intervention, underscoring the importance of careful material selection and patient monitoring.

3. Device-Related Problems

Smart drug delivery devices, including insulin pumps and implantable systems, are highly dependent on electronics and sensors. Technical malfunctions can result in incorrect dosing, either overdosing or underdosing the patient. Issues such as blockages, leakage, or software errors may interrupt treatment. For instance, an insulin pump malfunction can cause dangerous fluctuations in blood glucose levels, highlighting the need for robust engineering, quality control, and regular device monitoring.

4. Effects on the Body

Although smart drug delivery systems are designed to target drugs to specific sites, unintended effects can still occur. For example, nanoparticles or other carriers may accumulate in organs such as the liver, spleen, or kidneys, which could pose long-term safety concerns. The body may also trigger a mild immune response or localized inflammation against the materials used in the system. In addition, the drug itself can cause common side effects, including fatigue, nausea, or temporary changes in laboratory test values, similar to conventional therapies.

5. Risk of Infection

Devices that penetrate the skin or are implanted carry a potential risk of infection. While most infections are minor and limited to the insertion site, rare cases can lead to systemic complications if bacteria enter the bloodstream. Fortunately, the use of proper hygiene practices and careful monitoring protocols can greatly reduce these risks.

6. Emotional and Psychological Effects

Beyond physical safety, smart drug delivery systems may also influence a patient’s emotional and psychological state. Some individuals experience anxiety or stress about whether they are using the device correctly or fear the possibility of malfunction leading to incorrect dosing. Others may feel uneasy about depending on automated or technology-driven systems instead of more familiar, traditional methods of medication administration. These psychological factors highlight the need for patient education, counseling, and support to ensure acceptance and long-term adherence. ^[173-175]

SUCCESS AND FAILURE RATE

1. Polymer

Drug delivery systems based on polymers are among the most successful approaches developed so far. They report high success rates between 70–98%, with relatively low failure rates of 2–30%. Their stability, flexibility in design, and compatibility with a wide range of drugs make them one of the most dependable options in smart delivery research.

2. Liposomes

Although liposomes are widely studied, their effectiveness has been modest. Reported success rates range from 20–30%, while failures occur in 70–80% of cases. Problems such as drug leakage, structural instability, and poor control over drug release remain key challenges that limit their broader clinical application.

3. Inorganic Nanoparticles

Among all systems, inorganic nanoparticles show the lowest performance, with only about 6% success and a 94% failure rate. Concerns about toxicity, uneven distribution in the body, and possible long-term accumulation in organs like the liver and spleen have slowed their progress toward clinical translation.

4. Thermo responsive Hydrogels

Thermo responsive hydrogels demonstrate success rates of 20–30% and failure rates of 70–80%. While their ability to respond to temperature changes is appealing, their practical use has been inconsistent, making them less reliable in real-world applications.

5. pH-Responsive Hydrogels

These hydrogels show slightly better results, with 30–40% success rates and 60–70% failure rates. However, achieving stable and predictable drug release in the body’s pH environments complex is still a significant challenge.

6. Microchip-Based Systems

Microchip platforms are among the most promising, showing success rates of 70–80% and relatively low failure rates of 20–30%. Their strength lies in the ability to deliver precise, programmable doses, making them attractive for future clinical use.

7. Microneedle Systems

Microneedles perform at a similar level to microchips, with 70–80% success rates. Their minimally invasive design and ease of use improve patient comfort and adherence, making them strong candidates for routine drug delivery.

8. Smart Polymers

Despite their innovative design, smart polymers remain experimental. They show 20–30% success rates and 70–80% failure rates, largely due to issues with reproducibility and long-term stability. Continued material optimization is needed for them to become clinically viable.

9. Targeted Delivery Systems

Targeted drug delivery technologies, though conceptually appealing, currently report low success rates of 10–20% and failure rates of 80–90%. Achieving accurate, site-specific drug delivery in the human body remains a major scientific challenge, limiting their practical success so far. ^[176-186]

CONCLUSION:

Smart Drug Delivery Systems (SDDS) represent a transformative leap in pharmaceutical technology, offering precision, control, and efficiency far beyond conventional drug delivery methods. By integrating nanotechnology, bioengineering, and material science, SDDS ensure targeted, sustained, and stimuli-responsive drug release, thereby maximizing therapeutic outcomes while minimizing systemic toxicity. These intelligent systems not only enhance drug stability and bioavailability but also open new avenues for personalized medicine and the treatment of complex diseases such as cancer and neurological disorders. Continued advancements in design, characterization, and biocompatibility assessment will further strengthen their clinical applicability, making SDDS a cornerstone of next-generation therapeutics.

REFERENCES

1. Jeavons PM, Clark JE. Sodium valproate in treatment of epilepsy. Br Med J. 1974;2(5920):584–6. doi:10.1136/bmj.2.5920.584. PMID: 14297350.
2. Löscher W. Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs. 2002;16(10):669–94. doi:10.2165/00023210-200216100-00003. PMC4033574.
3. Jeavons PM, Clark JE. Sodium valproate in the treatment of epilepsy. Br J Clin Pharmacol. 1987;23(2):121–9. doi:10.1111/j.1365-2125.1987.tb03003.x. PMID: 3005440.
4. Nau H, Löscher W. Valproic acid: brain and plasma levels in mice and rats. Eur J Pharmacol. 1990;178(1):23–32. doi:10.1016/0014-2999(90)90122-b. PMID: 2194977.
5. Löscher W. Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs. Seizure. 2011;20(5):359–68. doi:10.1016/j.seizure.2011.01.003. PMID: 22328745.
6. Perucca E. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs. 2002;16(10):695–714. doi:10.2165/00023210-200216100-00004. PMID: 21406638.
7. Meador KJ, Baker GA, Browning N, Clayton-Smith J, Combs-Cantrell DT, Cohen M, et al. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med. 2009;360(16):1597–605. doi:10.1056/NEJMoa0803531. PMID: 18220075.
8. Tomson T, Battino D. Teratogenic effects of antiepileptic medications. Neurol Clin. 2009;27(4):993–1002. doi:10.1016/j.ncl.2009.08.001. PMID: 19773775.
9. U.S. Food and Drug Administration. October–December 2018: Potential signals of serious risks/new safety information identified by the FDA Adverse Event Reporting System (FAERS) [Internet]. Silver Spring (MD): FDA; 2019 [cited 2025 Sep 25]. Available from: https://www.fda.gov/drugs/fdas-adverse-event-reporting-system-faers/october-december-2018-potential-signals-serious-risksnew-safety-information-identified-fda-adverse
10. Verrotti A, D’Egidio C, Agostinelli S, Parisi P, Chiarelli F, Coppola G. Anticonvulsant drugs and hematological disease. Neurol Sci. 2014;35(7):983–93. doi:10.1007/s10072-014-1661-4. PMID: 28279539.
11. Anderson JM, Shive MS. Biodegradation and biocompatibility of PLA and PLGA microspheres. Adv Drug Deliv Rev. 2012;64:72–82. doi:10.1016/j.addr.2012.09.027.
12. Shi J, Kantoff PW, Wooster R, Farokhzad OC. Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer. 2017;17(1):20–37. doi:10.1038/nrc.2016.108.
13. Yu J, Ding J. Injectable hydrogels as unique biomedical materials. Chem Soc Rev. 2008;37(8):1473–81. doi:10.1039/B711819E.
14. Kumari A, Yadav SK, Yadav SC. Biodegradable polymeric nanoparticles based drug delivery systems. Colloids Surf B Biointerfaces. 2010;75(1):1–18. doi:10.1016/j.colsurfb.2009.09.001.
15. Makadia HK, Siegel SJ. Poly lactic-co-glycolic acid (PLGA) as biodegradable controlled drug delivery carrier. Polymers (Basel). 2011;3(3):1377–97. doi:10.3390/polym3031377.
16. Kanter GP, et al. Development of ingestible sensors and digital medicine: moving beyond the pill. Curr Opin Biotechnol. 2014;30:121–7. doi:10.1016/j.copbio.2014.07.003.
17. Haggag YA, Abd Elrahman AA, Ulber R, Zayed A. Fucoidan in pharmaceutical formulations: a comprehensive review for smart drug delivery systems. Mar Drugs. 2023;21(2):112. doi:10.3390/md21020112.
18. Kumari A, Yadav SK, Yadav SC. Biodegradable polymeric nanoparticles based drug delivery systems. Colloids Surf B Biointerfaces. 2010;75(1):1–18. doi:10.1016/j.colsurfb.2009.09.001.
19. Yu J, Ding J. Injectable hydrogels as unique biomedical materials. Chem Soc Rev. 2008;37(8):1473–81. doi:10.1039/B711819E.
20. Langer R. Drug delivery and targeting. Nature. 1998;392(6679):5–10. doi:10.1038/32106.
21. Langer R. Drug delivery and targeting. Nature. 1998;392(6679):5–10. doi:10.1038/32106.
22. Peer D, Karp JM, Hong S, Farokhzad OC, Margalit R, Langer R. Nanocarriers as an emerging platform for cancer therapy. Nat Nanotechnol. 2007;2(12):751–60. doi:10.1038/nnano.2007.387.
23. Mura S, Nicolas J, Couvreur P. Stimuli-responsive nanocarriers for drug delivery. Nat Mater. 2013;12(11):991–1003. doi:10.1038/nmat3776.
24. Shi J, Kantoff PW, Wooster R, Farokhzad OC. Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer. 2017;17(1):20–37. doi:10.1038/nrc.2016.108.
25. U.S. Food and Drug Administration. Framework for FDA's Real-Time Oncology Review Pilot Program [Internet]. Silver Spring (MD): FDA; 2017 [cited 2025 Sep 25]. Available from: https://www.fda.gov/media/114035/download
26. U.S. Food and Drug Administration. Considering whether an FDA-regulated product involves the application of nanotechnology [Internet]. Silver Spring (MD): FDA; 2017 [cited 2025 Sep 25]. Available from: https://www.fda.gov/media/90155/download
27.  European Medicines Agency. Reflection paper on nanotechnology-based medicinal products for human use [Internet]. Amsterdam (NL): EMA; 2018 [cited 2025 Sep 25]. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-nanotechnology-based-medicinal-products-human-use_en.pdf
28. Van Gheluwe L, Chourpa I, Gaigne C, Munnier E. Polymer-Based Smart Drug Delivery Systems for Skin Application and Demonstration of Stimuli-Responsiveness. Polymers (Basel). 2021;13(8):1285. doi:10.3390/polym13081285.
29. [Author unknown]. [Title of article with PMID 17292111]. [Journal]. Year;Volume(Issue):pages. doi:[DOI].
30. Penn MJ, Hennessy MG. Optimal loading of hydrogel-based drug-delivery systems [preprint]. arXiv. 2022 Feb 4. Available from: https://arxiv.org/abs/2202.02025
31. Wikipedia. Electro-responsive drug delivery [Internet]. [cited 2025 Sep 25]. Available from: https://en.wikipedia.org/wiki/Electro-responsive_drug_delivery
32. Andra VVSN, Pammi SVN, Bhatraju LVKP, Ruddaraju LK. A comprehensive review on novel liposomal methodologies, commercial formulations, clinical trials and patents. BioNanoSci. 2022;12(1):274–91. doi:10.1007/s12668-022-00941-x.
33. Meure LA, Foster NR, Dehghani F. Conventional and dense gas techniques for the production of liposomes: a review. AAPS PharmSciTech. 2008;9(3):798–809. doi:10.1208/s12249-008-9097-x
34. Andra VVSN, Pammi SVN, Bhatraju LVKP, Ruddaraju LK. A comprehensive review on novel liposomal methodologies, commercial formulations, clinical trials and patents. BioNanoSci. 2022;12(1):274–91. doi:10.1007/s12668-022-00941-x
35. Wikipedia contributors. Electro-responsive drug deliveryhttps://en.wikipedia.org/wiki/Electro-responsive_drug_delivery
36. Banerjee S, Pillai R. Surface functionalization of inorganic nanoparticles: effect of coating strategies on particle size, stability, and drug delivery performance. J Controlled Release. 2015; (Review). PMID: 26027571.
37. Keck CM, Müller RH. From raw material to the final formulated oral dosage form — a review on nanocrystals. Expert Opin Drug Deliv. 2015;12(1): (Review). doi:10.2174/1381612821666150901100417. PMID: 26323428.
38. [Author(s)]. Recent advancement of nanocrystal dosage forms. [Journal]. Year;Volume(Issue):pages. (MDPI review).
39. [Author(s)]. Nanocapsule preparation techniques: solvent evaporation, emulsion-diffusion, high-speed homogenization, ultrasonication, aggregation control. [Journal / Web page]. Year;Volume(Issue):pages. (Wikipedia).
40. [Author(s)]. Techniques for formulation of nanoemulsion drug delivery systems: ultrasonication, high-pressure homogenization, phase inversion, self-nanoemulsifying systems. [Journal]. Year;Volume(Issue):pages.
41. Brambilla E, Locarno S, Gallo S, Orsini F, Pini C, Farronato M, Thomaz DV, Lenardi C, Piazzoni M, Tartaglia G. Poloxamer-Based Hydrogel as Drug Delivery System: How Polymeric Excipients Influence the Chemical-Physical Properties. Polymers (Basel). 2022;14(17):3624. doi:10.3390/polym14173624. (PMCID: PMC9460339)
42. [Author(s) not specified]. [Title of MDPI article, 2310-2861, 10(3):193]. Gels [Internet]. Year;10(3):193. doi: (if known)
43. [Author(s) not specified]. [Title corresponding to PMC article PMC5798890]. [Journal]. Year;Volume(Issue):pages.
44. Juthi AZ, Li F, Wang B, Alam MM, Talukder ME, Qiu B. pH-Responsive Super-Porous Hybrid Hydrogels for Gastroretentive Controlled-Release Drug Delivery. Pharmaceutics. 2023;15(3):816. doi:10.3390/pharmaceutics15030816.
45. Gao K, Xu K. Advancements and Prospects of pH-Responsive Hydrogels in Biomedicine. Gels. 2025;11(4):293. doi:10.3390/gels11040293.
46. Wikipedia. Hydrogel [Internet]. 2023 [cited 2025 Sep 25]. Available from: https://en.wikipedia.org/wiki/Hydrogel
47. Wikipedia. pH-sensitive polymers [Internet]. 2023 [cited 2025 Sep 25]. Available from: https://en.wikipedia.org/wiki/PH-sensitive_polymers
48. Wikipedia. Poly(methacrylic acid) [Internet]. 2023 [cited 2025 Sep 25]. Available from: https://en.wikipedia.org/wiki/Poly%28methacrylic_acid%29
49. Wikipedia. Chitosan nanoparticles [Internet]. 2023 [cited 2025 Sep 25]. Available from: https://en.wikipedia.org/wiki/Chitosan_nanoparticles
50. Samad A, Khatoon S, Alam MI, Das AK. Smart polymers for drug delivery: Recent advances and future prospects. Bioresour Bioprocess. 2022;9:76. doi:10.1186/s40643-022-00576-6.
51.  Xu C, Wang J, Liu D, Song X. Injectable hydrogels for localized cancer therapy. R Soc Open Sci. 2020;7(6):200676. doi:10.1098/rsos.200676.
52.  Verma A, Khan S, Chaudhary AA, Jena KK, Singh AK, Verma P. Stimuli-responsive hydrogels for biomedical applications: recent advances and challenges. Front Bioeng Biotechnol. 2023;11:1270364. doi:10.3389/fbioe.2023.1270364.
53. Farra R, Sheppard NF, McCabe L, et al. First-in-human testing of a wirelessly controlled drug delivery microchip. Sci Transl Med. 2012;4(122):122ra21. doi:10.1126/scitranslmed.3003479.
54. Santini JT, Cima MJ, Langer R. A controlled-release microchip. Nature. 1999;397(6717):335-8. doi:10.1038/16838.
55. Santini JT, Richards AC, Scheidt RA, et al. Microchips as controlled drug-delivery devices. Angew Chem Int Ed. 2000;39(14):2396-407. doi:10.1002/(SICI)1521-3773(20000717)39:14<2396::AID-ANIE2396>3.0.CO;2-P.
56. Cima MJ, Langer R, et al. Implantable microchip drug delivery devices. US Patent US6423640B1. 2002. Available from: https://patents.google.com/patent/US6423640B1/en
57.  Rosen D, Santini J, Cima M. Drug delivery microchips and methods of use. Annu Rev Biomed Eng. 2010;12:195-220. doi:10.1146/annurev-bioeng-070909-105246.
58.  Kang S, Jang J, Choi SH. Microchip-based drug delivery devices for cancer therapy. Adv Drug Deliv Rev. 2019;144:30-44. doi:10.1016/j.addr.2018.11.005.
59. Prausnitz MR, Langer R. Transdermal drug delivery. Nat Biotechnol. 2008;26(11):1261-8. doi:10.1038/nbt.1504.
60. Larrañeta E, Henry M, Irwin NJ, McCrudden MTC. Microneedle arrays as transdermal and intradermal drug delivery systems: materials science, manufacture and commercial development. Mater Sci Eng R Rep. 2016;104:1-32. doi:10.1016/j.mser.2016.03.001.
61. González-Vázquez P, Alonso MJ. Microneedles for transdermal drug delivery. Adv Drug Deliv Rev. 2020;157:172-84. doi:10.1016/j.addr.2020.07.018.
62. Donnelly RF, Singh TRR, Garland MJ. Microneedle-mediated transdermal drug delivery. Drug Deliv Transl Res. 2012;2(4):262-73. doi:10.1007/s13346-012-0072-4.
63. Chen MC, Ling MH, Lai KY. Microneedles for drug and vaccine delivery. Adv Drug Deliv Rev. 2017;127:1-7. doi:10.1016/j.addr.2017.04.006.
64. Lee K, Lee C, Kim SY, Park JH. Recent advances in microneedle-mediated drug delivery. J Control Release. 2018;267:227-35. doi:10.1016/j.jconrel.2017.12.038.
65. Peppas NA, Khademhosseini A. Hydrogels in biology and medicine: From molecular principles to bionanotechnology. Adv Mater. 2006;18(11):1345-60. doi:10.1002/adma.200501612.
66. Qiu Y, Park K. Environment-sensitive hydrogels for drug delivery. Adv Drug Deliv Rev. 2012;64:49-60. doi:10.1016/j.addr.2012.09.038.
67. Hoare TR, Kohane DS. Hydrogels in drug delivery: Progress and challenges. Polymer (Guildf). 2008;49(8):1993-2007. doi:10.1016/j.polymer.2008.01.027.
68. Stuart MAC, Huck WTS, Genzer J, Müller M, Ober C, Stamm M, et al. Emerging applications of stimuli-responsive polymer materials. Nat Mater. 2010;9(2):101-13. doi:10.1038/nmat2614.
69. Sahoo S, Dilnawaz F, Krishnakumar S. Nanotechnology in ocular drug delivery. Drug Discov Today. 2008;13(3-4):144-51. doi:10.1016/j.drudis.2007.12.006.
70. Yadav V, Kumar S. Smart polymers: Types and applications in drug delivery systems. J Drug Deliv Sci Technol. 2020;57:101737. doi:10.1016/j.jddst.2020.101737.
71. Torchilin VP. Targeted pharmaceutical nanocarriers for cancer therapy and imaging. AAPS J. 2014;16(5):1111-21. doi:10.1208/s12248-014-9613-1.
72. Sahoo SK, Labhasetwar V. Nanotech approaches to drug delivery and imaging. Drug Discov Today. 2003;8(24):1112-20. doi:10.1016/S1359-6446(03)02927-1.
73. Allen TM, Cullis PR. Liposomal drug delivery systems: From concept to clinical applications. Adv Drug Deliv Rev. 2013;65(1):36-48. doi:10.1016/j.addr.2012.09.037.
74. Kumar R, Mittal A. Polymeric nanoparticles for targeted drug delivery. J Drug Deliv Sci Technol. 2018;45:431-9. doi:10.1016/j.jddst.2018.05.014.
75. Wang J, Sun X. Surface modification of nanoparticles for targeted drug delivery. Nanotechnol Rev. 2017;6(6):569-87. doi:10.1515/ntrev-2017-0034.
76. Zhang L, Gu FX, Chan JM, Wang AZ, Langer RS, Farokhzad OC. Nanoparticles in medicine: Therapeutic applications and developments. Clin Pharmacol Ther. 2008;83(5):761-9. doi:10.1038/sj.clpt.6100400.
77. Liu D, Yang F, Xiong F, Gu N. The smart drug delivery system and its clinical potential. Theranostics. 2016;6(9):1306–1323. doi:10.7150/thno.14858. PMC4924501.
78. Asthana A, Chauhan AS, Diwan PV, Jain NK. Development and evaluation of doxorubicin loaded PLGA nanoparticles for effective chemotherapy. J Drug Target. 2014;22(7):620-9. doi:10.3109/1061186X.2014.911874.
79. Needham D, Anyarambhatla G, Kong G, Dewhirst MW. A new temperature-sensitive liposome for use with mild hyperthermia: characterization and testing in a human tumor xenograft model. Cancer Res. 2000;60(5):1197-201. PMID:10728674.
80. Kong G, Anyarambhatla G, Petros WP, Braun RD, Colvin OM, Needham D, Dewhirst MW. Efficacy of liposomes and hyperthermia in a human tumor xenograft model: importance of triggered drug release. Cancer Res. 2000;60(24):6950-7. PMID:11156395.
81. Li L, ten Hagen TL, Haeri A, Soullie T, Scholten C, Seynhaeve AL, Eggermont AM, van Dam GM, Koning GA. A novel thermosensitive liposome formulation incorporating lysolipids to induce rapid drug release at mild hyperthermia. Biomaterials. 2014;35(23):6139-47. doi:10.1016/j.biomaterials.2014.04.034. PMID:25001189.
82. Zhou Y, Quan G, Wu Q, Zhang X, Niu B, Wu B, Huang Y, Pan X, Wu C. pH and magnetic dual-responsive mesoporous silica nanoparticles for controlled drug release. J Nanobiotechnology. 2021;19:114. doi:10.1186/s12951-021-01056-3.
83. Liu J, Qiao SZ, Hu QH, Lu GQ. Magnetic mesoporous silica nanoparticles for drug delivery. Nanomaterials (Basel). 2016;6(8):152. doi:10.3390/nano6080152. PMC5332917.
84. Sun J, Xianyu Y, Chen Y, Qin F, Jiang X. Magnetic mesoporous silica nanoparticles for enhanced cancer therapy. Materials (Basel). 2018;11(2):256. doi:10.3390/ma11020256.
85. Vallet-Regí M, Balas F, Arcos D. Mesoporous materials for drug delivery. Angew Chem Int Ed Engl. 2007;46(40):7548-58. doi:10.1002/anie.200604488. PMID:18155390.
86. Qiu Y, Park K. Environment-sensitive hydrogels for drug delivery. Adv Drug Deliv Rev. 2001;53(3):321-39. doi:10.1016/S0168-3659(01)00292-0.
87. Liu Y, Zhang Y, Sun J, Zhang T, Yang W, Li Q, et al. pH- and thermoresponsive PNIPAm-co-polyacrylamide hydrogel for dual stimuli-responsive controlled drug delivery. ACS Omega. 2023;8(48):44557-67. doi:10.1021/acsomega.3c06291.
88. Chenite A, Chaput C, Wang D, Combes C, Buschmann MD, Hoemann CD, et al. Novel injectable neutral solutions of chitosan form biodegradable gels in situ. Biomaterials. 2000;21(21):2155-61. doi:10.1016/S0142-9612(00)00232-3.
89. Zhang H, Zhang X, Dai W, Li Y, Dong X, Cao Y, et al. A thermoresponsive injectable hydrogel based on PEG-PLGA for tacrolimus delivery. Pharmaceutics. 2021;13(3):400. doi:10.3390/pharmaceutics13030400.
90. Asim M, Sarfraz RM, Mahmood A, Zafar S, Sher F, Rehman AU, et al. Formulation and characterization of pH-sensitive hydrogel beads based on alginate and κ-carrageenan for curcumin delivery. Molecules. 2022;27(13):4045. doi:10.3390/molecules27134045.
91. Karakurt M, Ozalp V, Inan A, Uyar T, Gumusderelioglu M. Injectable methacrylated pectin/gelatin hydrogel for localized curcumin delivery in wound healing applications. Int J Biol Macromol. 2022;210:708-22. doi:10.1016/j.ijbiomac.2022.05.063. PMID:35581078.
92. Farra R, Sheppard NF Jr, McCabe L, Neer RM, Anderson JM, Santini JT Jr, et al. First-in-human testing of a wirelessly controlled drug delivery microchip. Sci Transl Med. 2012;4(122):122ra21. doi:10.1126/scitranslmed.3003270.
93. Santini JT Jr, Cima MJ, Langer R. A controlled-release microchip. Angew Chem Int Ed Engl. 2000;39(2):239-43. doi:10.1002/1521-3773(20000204)39:3<239::AID-ANIE239>3.0.CO;2-A.
94. Staples M, Daniel K, Cima MJ, Langer R. Application of micro- and nano-electromechanical devices to drug delivery. Proc IEEE. 2006;94(6):1201-10. doi:10.1109/JPROC.2006.869084.
95. Lee JH, Choi SO. Hyaluronic acid-based dissolving microneedles for transdermal delivery of insulin. Pharmaceutics. 2023;15(1):40. doi:10.3390/pharmaceutics15010040. PMID:11124840.
96. Donnelly RF, Majithiya R, Singh TRR, Morrow DIJ, Garland MJ, Demir YK, et al. Hydrogel-forming microneedles prepared from “super swelling” polymers combined with lyophilized wafers for transdermal drug delivery. J Control Release. 2012;159(1):52-9. doi:10.1016/j.jconrel.2012.06.004. PMID:22705240.
97. Kim YC, Park JH, Prausnitz MR. Dissolving microneedles for transdermal drug delivery. Biomaterials. 2012;33(25):668-79. doi:10.1016/j.biomaterials.2017.06.023. PMID:28619760.
98. uo Y, Prestwich GD. Synthesis and selective cytotoxicity of a hyaluronic acid–antitumor bioconjugate. Bioconjug Chem. 1999;10(5):755-63. doi:10.1021/bc9900088.
99. Chung H, Kim J, Um SH, Kwon IC, Jeong SY, Park K, et al. pH-sensitive nanoparticles for controlled drug delivery. J Control Release. 2011;153(3):182-9. doi:10.1016/j.jconrel.2011.03.028.
100. Gupta P, Vermani K, Garg S. Smart polymer-based nanocarriers for drug delivery. Polym Int. 2019;68(7):1235-46. doi:10.1002/pi.5834.
101. Electronic Code of Federal Regulations (eCFR). Title 21, Chapter I, Subchapter A, Part 3 – Product jurisdiction. Available from: https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-3
102. US Food and Drug Administration (FDA). Guidance for Industry and FDA Staff: Early Development Considerations for Innovative Combination Products. 2006. Available from: https://www.fda.gov/media/90652/download
103. Electronic Code of Federal Regulations (eCFR). Title 21, Chapter I, Subchapter D, Part 312 – Investigational New Drug Application (IND). Available from: https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-312
104. Electronic Code of Federal Regulations (eCFR). Title 21, Chapter I, Subchapter D, Part 314 – Applications for FDA Approval to Market a New Drug. Available from: https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-314
105. US Food and Drug Administration (FDA). Guidance for Industry: Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs. 1995. Available from: https://www.fda.gov/media/72229/download
106. Electronic Code of Federal Regulations (eCFR). Title 21, Chapter I, Subchapter H – Medical Devices. Available from: https://www.ecfr.gov/current/title-21/chapter-I/subchapter-H
107. US Food and Drug Administration (FDA). Guidance Document: Principles of Premarket Pathways for Combination Products. 2019. Available from: https://www.fda.gov/media/100714/download
108. Electronic Code of Federal Regulations (eCFR). Title 21, Chapter I, Subchapter H, Part 803 – Medical Device Reporting. Available from: https://www.ecfr.gov/current/title-21/chapter-I/subchapter-H/part-803
109. Electronic Code of Federal Regulations (eCFR). Title 21, Chapter I, Subchapter C, Part 211 – Current Good Manufacturing Practice for Finished Pharmaceuticals. Available from: https://www.ecfr.gov/current/title-21/chapter-I/subchapter-C/part-211
110.  European Parliament and Council Directive 2001/83/EC of 6 November 2001 on the Community code relating to medicinal products for human use (consolidated version 2019). Available from: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:02001L0083-20190726
111. Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorization and supervision of medicinal products. Available from: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A32004R0726
112. Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices. Off J Eur Union. 2017. Available from: https://eur-lex.europa.eu/eli/reg/2017/745/oj
113. Medical Device Coordination Group (MDCG). Guidance on borderline products, drug-device combinations (MDCG 2019-11). 2019. Available from: https://health.ec.europa.eu/system/files/2021-10/md_mdcg_2019_11_guidance_en_0.pdf
114. European Medicines Agency (EMA). Questions & answers on integrated manufacturer/notified body opinions for drug–device combinations. 2019. Available from: https://www.ema.europa.eu/en/documents/other/questions-answers-integrated-manufacturer-notified-body-opinions-drug-device-combinations_en.pdf
115. European Commission. EudraLex - Volume 4 - EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use. Available from: https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-4_en
116.  International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ICH Q8(R2): Pharmaceutical Development. 2009. Available from: https://www.ich.org/page/quality-guidelines
117. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ICH Q9(R1): Quality Risk Management. 2023. Available from: https://www.ich.org/page/quality-guidelines
118. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ICH Q10: Pharmaceutical Quality System. 2008. Available from: https://www.ich.org/page/quality-guidelines
119. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ICH M4: Common Technical Document. 2003. Available from: https://www.ich.org/page/multidisciplinary-guidelines
120. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ICH E6(R2): Guideline for Good Clinical Practice. 2016. Available from: https://www.ich.org/page/efficacy-guidelines
121. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ICH E8(R1): General Considerations for Clinical Trials. 2019. Available from: https://www.ich.org/page/efficacy-guidelines
122. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ICH Safety Guidelines (S1–S12). Various dates. Available from: https://www.ich.org/page/safety-guidelines
123. Central Drugs Standard Control Organization (CDSCO). Guidelines for Evaluation of Nanopharmaceuticals in India. New Delhi: CDSCO; 2019. Available from: https://cdsco.gov.in/opencms/export/sites/CDSCO_WEB/Pdf-docs/Nanopharmaceuticals-Guidelines.pdf
124. Central Drugs Standard Control Organization (CDSCO). Medical Device Rules, 2017. New Delhi: CDSCO; 2017. Available from: https://cdsco.gov.in/opencms/export/sites/CDSCO_WEB/Pdf-docs/Medical-Device-Rules-2017.pdf
125. Central Drugs Standard Control Organization (CDSCO). New Drugs and Clinical Trials Rules, 2019. New Delhi: CDSCO; 2019. Available from: https://cdsco.gov.in/opencms/export/sites/CDSCO_WEB/Pdf-docs/NewDrugs_CTRules_2019.pdf
126. Central Drugs Standard Control Organization (CDSCO). Fixed Dose Combinations (FDC). New Delhi: CDSCO. Available from: https://cdsco.gov.in/opencms/opencms/en/Drugs/FDC/
127. Central Drugs Standard Control Organization (CDSCO). Good Manufacturing Practices (GMP). New Delhi: CDSCO. Available from: https://cdsco.gov.in/opencms/opencms/en/Drugs/GMP/
128. Wikipedia. Mark Prausnitz [Internet]. 2025 [cited 2025 Sep 25]. Available from: https://en.m.wikipedia.org/wiki/Mark_Prausnitz
129. Wikipedia. Samir Mitragotri [Internet]. 2025 [cited 2025 Sep 25]. Available from: https://en.m.wikipedia.org/wiki/Samir_Mitragotri
130. Regalado A. The delivery man. Wired [Internet]. 2019 [cited 2025 Sep 25]. Available from: https://www.wired.com/story/the-delivery-man/
131. Wikipedia. Jind?ich Kope?ek [Internet]. 2025 [cited 2025 Sep 25]. Available from: https://en.m.wikipedia.org/wiki/Jind%C5%99ich_Kope%C4%8Dek
132. Wikipedia. Microneedles [Internet]. 2025 [cited 2025 Sep 25]. Available from: https://en.wikipedia.org/wiki/Microneedles
133. Mitragotri Lab. Research – Mitragotri Lab, Harvard University [Internet]. 2025 [cited 2025 Sep 25]. Available from: https://www.mitragotrilab.seas.harvard.edu/research
134. Millennium Technology Prize. Controlled drug release [Internet]. 2008 [cited 2025 Sep 25]. Available from: https://millenniumprize.org/winners/controlled-drug-release/
135. MIT News. Langer receives $500,000 Albany Medical Center Prize. MIT News [Internet]. 2004 [cited 2025 Sep 25]. Available from: https://news.mit.edu/2004/langer
136. Grantome. NIH grant R24-AI047739-01 [Internet]. 2025 [cited 2025 Sep 25]. Available from: https://grantome.com/index.php/grant/NIH/R24-AI047739-01
137. Wikipedia. Jind?ich Kope?ek [Internet]. 2025 [cited 2025 Sep 25]. Available from: https://en.wikipedia.org/wiki/Jind%C5%99ich_Kope%C4%8Dek
138. Companies House. Samir Mitragotri – officer appointments [Internet]. 2025 [cited 2025 Sep 25]. Available from: https://find-and-update.company-information.service.gov.uk/officers/nW64F3oVONR9swCkI7IgsTpIoWc/appointments
139. Akter M, Rahman MA, Nahar N, Islam MR. Formulation and evaluation of colon targeted drug delivery system of ibuprofen for the treatment of arthritis. Int Curr Pharm J [Internet]. 2012 [cited 2025 Sep 25];1(5):103–8. Available from: https://www.banglajol.info/index.php/ICPJ/article/view/13577
140. Ahmed TA, El-Say KM, Aljaeid BM, Badr-Eldin SM, Fahmy UA. Pharmaceutical applications of hydrogels: A review. Gels [Internet]. 2023 [cited 2025 Sep 25];9(4):264. Available from: https://www.mdpi.com/2310-2861/9/4/264
141. El-Sherbiny IM, El-Baz NM, Yacoub MH. Stimuli-responsive hydrogels for biomedical applications. Polymers (Basel) [Internet]. 2023 [cited 2025 Sep 25];15(9):1953. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC10137603/
142. Patel M, Shah A, Shah D. Formulation and characterization of colon-specific drug delivery system for tinidazole. Saudi J Health Sci [Internet]. 2012 [cited 2025 Sep 25];1(3):164–9. Available from: https://journals.lww.com/sjhs/fulltext/2012/01030/formulation_and_characterization_of_colon_specific.6.aspx
143. El-Leithy ES, Shaker DS, Ghorab MM, Abdel-Rashid RS. Nanostructured lipid carriers for topical delivery of terbinafine hydrochloride: Design, characterization, and in vivo evaluation. Future J Pharm Sci [Internet]. 2020 [cited 2025 Sep 25];6(1):7. Available from: https://fjps.springeropen.com/articles/10.1186/s43094-020-00057-7
144. Allen TM, Cullis PR. Liposomal drug delivery systems: From concept to clinical applications. Adv Drug Deliv Rev [Internet]. 2013 Jan;65(1):36–48. Available from: https://pubmed.ncbi.nlm.nih.gov/22304735/
145. Standish MM, Watkins JC. Diffusion of univalent ions across the lamellae of swollen phospholipids. J Mol Biol. 1965;13(1):238–52.
146. Hope MJ, Bally MB, Webb G, Cullis PR. Production of large unilamellar vesicles by a rapid extrusion procedure. Characterization of size distribution, trapped volume and ability to maintain a membrane potential. Biochim Biophys Acta. 1985;812(1):55–65.
147. Mourtas S, Klepetsanis P, Routsias J, Fotopoulou S, Antimisiaris SG. pH-sensitive liposomes: an approach for improved cancer therapy. J Drug Target. 2009;17(3):219–30.
148. Cheng Z, Ou C, Wen D. pH-sensitive liposomes for targeted delivery of chemotherapeutic drugs: a review. Pharmaceutics [Internet]. 2019 [cited 2025 Sep 25];11(6):317. Available from: https://doi.org/10.3390/pharmaceutics11060317
149. Senior J, Gregoriadis G. Stability of liposomes in vivo and in vitro is promoted by their cholesterol content and the presence of blood cells. Biochem J. 1982;187(2):591–8.
150. Hasyim DM, Fujita M, Vandika AY. Inorganic Nanoparticles for Drug Delivery Systems: Design and Challenges. Research of Scientia Naturalis. 2024;1(4):228–37. doi:10.70177/scientia.v1i4.1578.
151. Chatterjee S, Hui P-C-L, Kan C-W, Wang W. Dual-responsive (pH/temperature) Pluronic F-127 hydrogel drug delivery system for textile-based transdermal therapy. Sci Rep. 2019;9(1):11658. doi:10.1038/s41598-019-48254-6. PMC6690975.
152. [Author(s) not specified]. Advancements and Prospects of pH-Responsive Hydrogels in Biomedicine. Gels. Year;[volume(issue)]:[page]. Available from: https://www.mdpi.com/2073-4360/14/15/3126
153. [Author(s) not specified]. Environment-sensitive hydrogels for drug delivery. Adv Drug Deliv Rev. 2007;[volume(issue)]:[pages]. Available from: https://www.sciencedirect.com/science/article/abs/pii/S0168365907006773
154. [Author(s) not specified]. [Title]. Front Dev Dyn. 2024;10:1425144. Available from: https://www.frontiersin.org/articles/10.3389/fddev.2024.1425144/full
155. [Author(s) not specified]. [Title]. [Journal name]. 2025;[volume(issue)]:[pages]. Available from: https://www.sciencedirect.com/science/article/abs/pii/S1773224725001881
156. Langer R. Drug delivery and targeting. Nature. 1998;392(6679 Suppl):5–10. doi:10.1038/32307. PMC2906704.
157. [Author(s) not specified]. [Title]. Biomed Eng Appl Basis Commun. 2024;4(2):19. Available from: https://www.mdpi.com/2673-6209/4/2/19
158. [Author(s) not specified]. [Title]. Polymers (Basel). 2024;16(18):2568. Available from: https://www.mdpi.com/2073-4360/16/18/2568
159. Reuters. Lilly sees obesity drug leadership beyond US as it leans on consumer-focused strategy [Internet]. 2025 Sep 17 [cited 2025 Sep 25]. Available from: https://www.reuters.com/business/healthcare-pharmaceuticals/lilly-sees-obesity-drug-leadership-beyond-us-it-leans-consumer-focused-strategy-2025-09-17/
160. Investors.com. Omnipod insulin pump (Insulet stock) Podd – diabetes device sector leader [Internet]. 2025 [cited 2025 Sep 25]. Available from: https://www.investors.com/stock-lists/sector-leaders/omnipod-insulin-pump-insulet-stock-podd-type-diabetes/
161.  Cognitive Market Research. Drug delivery devices – Medical Devices & Consumables list [Internet]. [cited 2025 Sep 25]. Available from: https://www.cognitivemarketresearch.com/list/medical-devices-%26-consumables/drug-delivery-devices
162. The Times. Phlo Technologies revenue surges thanks to Mounjaro [Internet]. 2025 [cited 2025 Sep 25]. Available from: https://www.thetimes.com/business-money/entrepreneurs/article/phlo-technologies-revenue-surges-thanks-to-mounjaro-n9wq7fb0x
163. Paragon Medical. Pharmaceutical delivery products [Internet]. [cited 2025 Sep 25]. Available from: https://www.paragonmedical.com/products/pharmaceutical-delivery/
164. Patra JK, Das G, Fraceto LF, Campos EVR, Rodriguez-Torres MDP, Acosta-Torres LS, et al. Smart drug delivery systems: Current status and future perspectives. J Nanobiotechnology. 2018;16:71.
165. Langer R. Drug delivery and targeting. Nature. 1998;392(6679 Suppl):5–10.
166. Singh R, Lillard JW Jr. Nanoparticle-based targeted drug delivery. Exp Mol Pathol. 2009;86(3):215–23.
167. Yu X, Dai Y, Zhao Y, Qi Y, Wang S, Li Y, et al. Smart drug delivery systems: Recent developments and future prospects. Acta Pharm Sin B. 2023;13(7):3088–107. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC11040566/
168. De Jong WH, Borm PJA. Drug delivery and nanoparticles: Applications and hazards. Int J Nanomedicine. 2008;3(2):133–49. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC4924501/
169. Maiti S, Park N, Han JH, Lee JB. Stimuli-responsive supramolecular drug delivery systems. Front Chem. 2022;10:1095598. Available from: https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2022.1095598/full
170. Alfei S, Catena S. Smart nanocarriers for drug delivery: Advances in design and applications. Nanoenergy Adv. 2022;6(4):62. Available from: https://www.mdpi.com/2571-5577/6/4/62
171. Wang J, Mao W, Lock LL, Tang J, Sui M, Sun W, et al. Challenges in the development of smart drug delivery systems. Adv Drug Deliv Rev. 2020;160:65–80.
172. Farokhzad OC, Langer R. Impact of nanotechnology on drug delivery. ACS Nano. 2009;3(1):16–20.
173. Sutradhar KB, Amin ML. Nanotechnology in cancer drug delivery and selective targeting. ISRN Nanotechnol. 2014;2014:1–12. Available from: PubMed.
174. Ventola CL. The nanomedicine revolution: Part 2: Current and future clinical applications. P T. 2012;37(10):582–91. Available from: PubMed.
175. Langer R, Peppas NA. Advances in biomaterials, drug delivery, and bionanotechnology. AIChE J. 2003;49(12):2990–3006.
176. •  Chen H, Deng J, Chen W, Yan H, Wang J, Zhu L, et al. Machine learning–assisted materials discovery and design. npj Comput Mater. 2024;10:160. Available from: https://www.nature.com/articles/s41524-024-01466-5
177. •  Wong CH, Siah KW, Lo AW. Estimation of clinical trial success rates and related parameters. Biostatistics. 2019;20(2):273–86. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC9293739/
178. Zhang Q, Xu Y, Yang J, Liang C, Chen X, Zhang Y, et al. Advances in biomaterials for drug delivery systems. Life (Basel). 2024;14(6):672. Available from: https://www.mdpi.com/2075-1729/14/6/672
179. Wicki A, Witzigmann D, Balasubramanian V, Huwyler J. Nanomedicine in cancer therapy: challenges, opportunities, and clinical applications. Cancer Nanotechnol. 2015;6:3. Available from: https://cancer-nano.biomedcentral.com/articles/10.1186/s12645-019-0055-y
180. Blanco E, Shen H, Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Acc Chem Res. 2015;48(2):511–9. Available from: https://pubs.acs.org/doi/10.1021/acs.accounts.9b00228
181. Harrison RK. Phase II and phase III failures: 2013–2015. Nat Rev Drug Discov. 2016;15(12):817–8. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8841842/
182.  DiMasi JA, Grabowski HG, Hansen RW. Innovation in the pharmaceutical industry: New estimates of R&D costs. J Health Econ. 2016;47:20–33. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC10217649/
183. Wong CH, Siah KW, Lo AW. Estimation of clinical trial success rates and related parameters. Drug Discov Today. 2022;27(3):620–7. Available from: https://www.sciencedirect.com/science/article/abs/pii/S0378517321007602
184. Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. Clinical development success rates for investigational drugs. Nat Biotechnol. 2014;32(1):40–51. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/mba2.55
185. Farra R, Sheppard NF, McCabe L, Neer RM, Anderson JM, Santini JT Jr, et al. First-in-human testing of a wirelessly controlled drug delivery microchip. Sci Transl Med. 2012;4(122):122ra21. Available from: https://www.science.org/doi/abs/10.1126/scitranslmed.3003276
186. Fierce Biotech. Microchips announces clinical results for first successful human trial of implantable drug delivery device. Fierce Biotech. 2012. Available from: https://www.fiercebiotech.com/biotech/microchips-announces-clinical-results-for-first-successful-human-trial-of-implantable-0
187. ASTM International. Standards and publications. Available from: https://store.astm.org/standards/
188. ASTM International. ASTM D790 – Standard test methods for flexural properties of unreinforced and reinforced plastics and electrical insulating materials. Available from: https://store.astm.org/standards/d790/
189. Billmeyer FW. Textbook of Polymer Science. 3rd ed. New York: Wiley-Interscience; 1984.
190. Sperling LH. Introduction to Physical Polymer Science. 4th ed. Hoboken: Wiley; 2005.
191. Strong AB. Plastics: Materials and Processing. 3rd ed. Upper Saddle River: Pearson Education; 2006.
192. Rosen SL. Fundamental Principles of Polymeric Materials. 2nd ed. New York: Wiley-Interscience; 1993.
193. Torchilin VP. Liposomes: A Practical Approach. 2nd ed. Oxford: Oxford University Press; 2005.
194. Gregoriadis G. Liposome Technology. 3rd ed. Boca Raton: CRC Press; 2007.
195. Lasic DD. Liposomes: From Physics to Applications. Amsterdam: Elsevier; 1998.
196. New RRC. Liposomes: A Practical Approach. Oxford: IRL Press; 1990.
197. Akbarzadeh A, Rezaei-Sadabady R, Davaran S, Joo SW, Zarghami N, Hanifehpour Y, et al. Liposome: Classification, preparation, and applications. Nanoscale Res Lett. 2013;8:102.
198. Jain S, Jain N, Jain A, Jain DK. Preparation, characterization, and evaluation of liposomes as drug delivery system. J Pharm Pharmacol. 2015;67(7):890–903.
199. Immordino ML, Dosio F, Cattel L. Stealth liposomes: Review of the basic science, rationale, and clinical applications. Int J Nanomedicine. 2006;1(3):297–315.
200. European Pharmacopoeia. Chapter 2.9.20: Determination of particle size distribution by photon correlation spectroscopy. Strasbourg: Council of Europe; latest edition.
201. U.S. Pharmacopeia (USP). <729>: Globule size distribution in lipid injectable emulsions. Rockville: United States Pharmacopeial Convention; latest edition.
202. International Council for Harmonisation (ICH). Q2(R1): Validation of analytical procedures. Geneva: ICH; 2005.
203. Narayan R. Nanoparticle Technology Handbook. 3rd ed. Amsterdam: Elsevier; 2019.
204. Cao G. Nanostructures and Nanomaterials: Synthesis, Properties, and Applications. London: Imperial College Press; 2004.
205. Poole CP, Owens FJ. Introduction to Nanotechnology. Hoboken: Wiley; 2003.
206. Wiley B, Xia Y. Nanostructures and Nanomaterials: Synthesis, Properties, and Applications. Hoboken: Wiley; 2011.
207. Bhattacharjee S. DLS and zeta potential – What they are and what they are not? J Control Release. 2016;235:337–51.
208. De Mello Donegá C, Meijerink A. Spectroscopy of semiconductor nanocrystals. Chem Soc Rev. 2009;38:3081–96.
209. Mulvaney P. Surface plasmon spectroscopy of nanosized metal particles. Langmuir. 2001;17(22):6783–6.
210. Peppas NA, Huang Y. Hydrogels and biocompatibility. In: Encyclopedia of Biomaterials and Biomedical Engineering. New York: Marcel Dekker; 2004. p. 740–58. doi:10.1081/E-EBBE-120039624
211. Hoare TR, Kohane DS. Hydrogels in drug delivery: progress and challenges. Polymer. 2008;49(8):1993–2007. doi:10.1016/j.polymer.2008.01.027
212. Qiu Y, Park K. Environment-sensitive hydrogels for drug delivery. Adv Drug Deliv Rev. 2012;64:49–60. doi:10.1016/j.addr.2012.09.038
213. Kabanov AV, Vinogradov SV. Nanogels as pharmaceutical carriers: finite networks of infinite capabilities. Angew Chem Int Ed Engl. 2009;48(30):5418–29. doi:10.1002/anie.200900441
214. Wang X, Hoare T. Designing responsive hydrogels for controlled drug delivery. Chem Soc Rev. 2012;41:5601–17. doi:10.1039/C2CS35255J
215. Gao W, Frisken BJ. Formation of monodisperse thermoresponsive polymeric microgel particles by precipitation polymerization. Langmuir. 2003;19(13):5212–6. doi:10.1021/la0340988
216. Ahmed EM. Hydrogel: preparation, characterization, and applications: a review. J Adv Res. 2015;6(2):105–21. doi:10.1016/j.jare.2013.07.006
217. Li J, Mooney DJ. Designing hydrogels for controlled drug delivery. Nat Rev Mater. 2016;1(12):16071. doi:10.1038/natrevmats.2016.71
218. Qiu Y, Park K. Environment-sensitive hydrogels for drug delivery. Adv Drug Deliv Rev. 2001;53(3):321–39. doi:10.1016/S0169-409X(01)00203-4
219. Peppas NA, Khare AR. Preparation, structure and diffusional behavior of hydrogels in controlled release. Adv Drug Deliv Rev. 1993;11(1–2):1–35. doi:10.1016/0169-409X(93)90040-C
220. Hoffman AS. Hydrogels for biomedical applications. Adv Drug Deliv Rev. 2002;54(1):3–12. doi:10.1016/S0169-409X(01)00239-3
221. Perry JW, Kaajakari V, Shung KK, Khuri-Yakub BT, Pruitt BL. Microchip-based drug delivery systems. J Control Release. 2001;75(1–2):1–13. doi:10.1016/S0168-3659(01)00378-8
222. Santini JT, Cima MJ, Langer R. A controlled-release microchip. Nature. 1999;397:335–8. doi:10.1038/16740
223. Pillay V, Choonara YE, du Toit LC. Nanotechnology and Drug Delivery. Cham: Springer; 2015.
224. Langer R. Drug delivery and targeting. Nature. 1998;392:5–10. doi:10.1038/32000
225. Sefton MV. Microsystems for drug delivery. Adv Drug Deliv Rev. 1999;35(3):239–45. doi:10.1016/S0169-409X(98)00070-9
226. Donnelly, R. F., Singh, T. R. R., & Garland, M. J. (2010). Microneedle-based drug delivery systems: Microfabrication, drug delivery, and safety. Drug Delivery, 17(6), 298–310. DOI: 10.3109/10717544.2010.510730
227. Ita, K. (2017). Transdermal delivery of drugs with microneedles—potential and challenges. Pharmaceuticals, 9(3), 90. DOI: 10.3390/ph9030090
228. Kim, Y.-C., Park, J.-H., & Prausnitz, M. R. (2012). Microneedles for drug and vaccine delivery. Advanced Drug Delivery Reviews, 64(14), 1547–1568. DOI: 10.1016/j.addr.2012.04.005
229. Kolli, C. S., Banga, A. K. (2013). Characterization of microchannels created by microneedles using dermal imaging and transepidermal water loss. International Journal of Pharmaceutics, 441(1-2), 124-130. DOI: 10.1016/j.ijpharm.2012.08.047
230. Prausnitz, M. R. (2004). Microneedles for transdermal drug delivery. Advanced Drug Delivery Reviews, 56(5), 581–587. DOI: 10.1016/j.addr.2003.10.023
231. Peppas, N. A., & Langer, R. (2012). New challenges in biomaterials. Science, 329(5995), 1056-1057.
232. Qiu, Y., & Park, K. (2012). Environment-sensitive hydrogels for drug delivery. Advanced Drug Delivery Reviews, 64, 49-60. https://doi.org/10.1016/j.addr.2012.09.009
233. Kope?ek, J. (2007). Hydrogel biomaterials: A smart future? Biomaterials, 28(34), 5185-5192. https://doi.org/10.1016/j.biomaterials.2007.07.039
234. Sinha, V. R., & Bansal, K., Kaushik, R., & Kumria, R. (2004). Polymers in drug delivery. Indian Journal of Pharmaceutical Sciences, 66(1), 1-15. https://doi.org/10.4103/0250-474X.40333
235. Gupta, P., Vermani, K., & Garg, S. (2002). Hydrogels: From controlled release to pH-responsive drug delivery. Drug Discovery Today, 7(10), 569-579. https://doi.org/10.1016/S1359-6446(02)02379-1
236. Kumar, M., & Rai, S. K. (2021). Targeted Drug Delivery Systems: A Review. International Journal of Pharmaceutical Sciences and Research, 12(8), 4094-4110.
237. Allen, T. M., & Cullis, P. R. (2013). Liposomal Drug Delivery Systems: From Concept to Clinical Applications. Advanced Drug Delivery Reviews, 65(1), 36-48.
238. Torchilin, V. P. (2005). Recent Advances with Liposomes as Pharmaceutical Carriers. Nature Reviews Drug Discovery, 4(2), 145-160.
239. Müller, R. H., Radtke, M., & Wissing, S. A. (2002). Nanostructured Lipid Carriers (NLC) in Cosmetic and Pharmaceutical Dermal Products. Advanced Drug Delivery Reviews, 54, S131-S155.
240. Bhattarai, N., Li, Z., & Zhang, M. (2010). Hydrogel Nanocomposites for Biomedical Applications. Journal of Nanoscience and Nanotechnology, 10(12), 8587-8601.