Tabletized Nanomedicine: From the Current Scenario to Developing Future Medicine

Abstract

The limitations of conventional therapeutic treatments prevailed in the development of nanotechnology-based medical formulations, termed nanomedicine. Nanomedicine is an advanced medicine that often consists of therapeutic agent(s) embedded in biodegradable or biocompatible nanomaterial-based formulations. Among nanomedicine approaches, tablet (oral) nanomedicine is still under development. In tabletized nanomedicine, the dynamic interplay between nanoformulations and the intricate milieu of the gastrointestinal tract simulates a pivotal role, particularly accentuating the influence exerted upon the luminal, mucosal, and epithelial cells. In this work, we document the perspectives and opportunities of nanoformulations toward the development of tabletized nanomedicine. This review also unveils the notion of integrating nanomedicine within a tablet formulation, which facilitates the controlled release of drugs, biomolecules, and agent(s) from the formulation to achieve a better therapeutic response. Finally, an attempt was made to explore current trends in nanomedicine technology such as bacteriophage, probiotic, and oligonucleotide tabletized nanomedicine and the combination of nanomedicine with imaging agents, i.e., nanotheranostics.

Graphical Abstract

1. INTRODUCTION

Various polymeric matrices or therapeutic carriers have been utilized for the effective delivery of active pharmaceutical ingredients (APIs). Delivery of therapeutic agents is administered via several routes including intravenous, subcutaneous, intramuscular, intrathecal, rectal, vaginal, oral, sublingual, buccal, ocular, otic, inhalation, nasal, cutaneous, and transdermal routes. Among these, oral delivery remains the primary and most noninvasive route of administration for a broad range of drug molecules. Oral delivery is the safest alternative for patients who requires frequent needle injections. Oral medication offers ease of drug administration, cost-effectiveness, and patient compliance. The adherence of patients to oral medication is notably high in contrast to parenteral routes. Oral administration effectively avoids a multitude of obstacles linked with parenteral routes of administration, including but are not limited to pronounced reactions at injection sites, scarring, and localized skin allergic responses. Nevertheless, oral delivery often results in poor adsorption and susceptibility to proteolytic degradation, such as gastric contents, pepsin, and trypsin, resulting in fast breakdown or biomacromolecular structures, leading to biomacromolecule inactivation.^1–3 In addition, the gastrointestinal (GI) barrier, constituted of dense epithelial layers and a mucus coating, imposes limitations on the absorption of biomacromolecules due to their significant molecular size.⁴

Tablet-based formulation(s) for oral delivery is an established pharmaceutical field that utilizes polymers, excipients, APIs, and other materials. Brockedon secured a patent for a contrivance design to compact two commonly available excipients (sodium and potassium carbonate) into a tablet configuration.⁵ The process of compacting APIs into tablet form generally categorized as die-filling as well as ejection steps. A detailed mechanism and dynamic processes has been documented elsewhere.⁶ The rate at which drugs are released from tablets from these products could be influenced by a variety of factors within the GI tract. Bayer introduced a reformulation of aspirin, which was based on “pro-release technology” utilizing microparticles that are 90% smaller than the particle size of previously used aspirin tablets.⁷ This acts as a faster-acting pain reliever (16–49 min vs 100 min) due to quick dissolution and entry into the bloodstream. Such technologies not only offer a tailored pharmacokinetics (PK) for drugs but also provides additional advantages include reduced medication administration cycles, improved patient adherence, and minimized adverse reactions.⁸ At present, various routes of drug administration such as oral, parental, topical, and rectal are occupied to 60, 27.2, 5.8, and 2.3%, respectively. Of the oral products available, about 72% are formulated to be ingested as solid form.⁹

Nanotechnology and nanomaterials have the potential to increase our understanding by bridging the gaps between biological and physical/materials sciences.¹⁰ Nanomedicine is a branch of medical nanotechnology that is composed of therapeutic molecules or agent(s) that are bound, embedded, encapsulated, or disintegrated within nanoparticles whose diameter is less than 100 nm and formulated with multiple pharmaceutical matrices, fillers, and excipients. Incorporation of therapeutic agents or drug molecules in the nanoparticles and making them into tablets or pills can result in tabletized nanomedicine. Nanoparticles offer many advances in the conventional delivery of agents. For example, (i) the particle size range (10–100 nm) is widely explored for passively targeting tumors and freely bypassing through large pores and achieving higher intratumoral accumulation;^11,12 (ii) nanoparticles can protect drug cargo from stomach degradation; and (iii) targeting peptide coated nanoparticles enhance mucopenetration and absorption in the small intestine.¹³ Overall, nanoparticle-based approaches are widely applicable in diagnosis, detection, treatment, and theranostic areas of medicine. Earlier efforts were made toward drug nanoparticle incorporation into the existing tablet formulations^14–17 to improve the bioavailability of drug(s). Later, a number of beneficial aspects were coined with tabletized nanomedicine. However, a comprehensive review focused on the advancement of nanomedicine in tablet form for enhancing therapeutic advantages is conspicuously absent in the existing literature. Therefore, this review aims to introduce tabletized nanomedicine and its favored controlled release of therapeutics to achieve a better therapeutic response for developing future medicine.

2. METHOD AND LITERATURE SEARCH

This review article is developed based on a PubMed-guided literature search that utilizes the specific keywords liposomes, nanocapsules, nanoparticles, nanosuspensions, and self-nanosized-emulsifying and combined with an oral route and tablet. All reference articles were manually selected for inclusion in this article whose relevance is high and deals with some aspects of nanomaterials and tabletized form. The entire literature search confirms that few reviews exist that deal with nanoformulations in tablet forms but employed either only one type of delivery (buccal, sublingual, stomach, intestine, colonic, etc.) applications or nanomaterial(s) or method of preparation. Based on statistics presented in Figure 1 and Table 1, it is apparent that no research review article is dedicated to the implication of nanomedicine in tablet form.

Figure 1.

Graphical representation of significant implications of “nanomedicines” in drug delivery: liposomes, nanocapsule, nanoparticles, nanosuspension, and self nanosized emulsion formulations for research spanning for broader investigations and those specifically targeting oral drug delivery. The data are derived from PubMed search. The search results are documented from 2018 to 2022 (the search was conducted in March 2023).

Table 1.

Overview of Reviews Related to Tabletized Nanomedicine

review article citation	areas covered in the article
Chakka et al., 202318	This review highlights several aspects of 3D-printed pharmaceutical formulations. These include various dosage forms, controlled release, localized and buccal delivery. Polymeric tablets, polymer films, nanoparticles, and scaffolds were utilized to construct 3D-printed pharmaceuticals.
Mengarda et	In this article, many commonly used nanomaterials such as polymer, lipid, inorganic, and nanocrystal-based particles were utilized to improve helminthiasis
al., 202219	treatment.
Wathoni et	This article primarily focused on various enteric-coated NPs systems for colorectal cancer treatment. This review article documented almost all literature on this
al., 202020	aspect from scientific databases Scopus and PubMed.
Tran et al., 201921	This work comprised of recent advances and concepts to improve dosage forms of drug delivery or targeting systems. Special emphasis was on buccal delivery applications.
Bonde et al., 201822	This review article summarizes various fabrication methods for nanoparticles, lipids, liposomes, polymeric micelle, and nanocapsules for lapatinib LAPA-conjugated diagnostic approaches.
Gedawy etal., 201823	This work dealt with a comprehensive survey and performance of a number of oral insulin administration nanoparticle approaches to overcoming the hurdles facing oral insulin delivery.
Haeri et al., 201824	This article documented the number of nanostructured carriers for sirolimus delivery.
Kaur et al., 201625	This work is devoted to constructing modified nanomaterials tablets form, hydrogel, transdermal films, and beads.
Zhang et al., 201526	This article provides an overview of the utilization of thin film based zein constructs for diverse pharmaceutical applications.
Sung et al., 201227	This document proposed mucus binding and penetrating pH-sensitive formulations that can efficiently infiltrate the mucus layer in the small intestine for insulin delivery.
Wong, 201028	This work covers the design, development, modification, and implications of mucoadhesive dosage forms for oral insulin delivery.
Di Stefano et al., 200929	Solid formulations and liquid forms of formulations were proposed for anti-Parkinson therapy and neurological disorder.
Kato et al., 200330	Chitin and chitosan derivatives as drug carriers for various pharmaceutical agents have been reported.
Current review article	All the above 13 review articles are either based on the types of drug delivery systems used to prepare tabletized nanomedicine or the use of one type of carrier that can be used in tabletized nanomedicine or a particular drug based tabletized nanomedicine. This Review comprehensively covers all types of carriers, drugs, and other agents, and various tablet types that were employed until today in the fields of tabletized nanomedicine. However, it is difficult to compare with each one of the review articles published. It also provides the basics to applications and further translational aspects of tabletized nanomedicine.

Nanomedicine is an advanced field of medicine which often consists of therapeutic agent(s) embedded in biodegradable or biocompatible-based nanoparticle formulations. Among nanomedicine approaches, tablet (oral) nanomedicine is still under development. In tabletized nanomedicine, the interaction between nanoformulation(s) and the gastrointestinal luminal, mucosal, and epithelial cells plays a significant role. Particularly noteworthy is the entrapment of nanoformulations within the mucus layers of the GI epithelium, which can constrain therapeutic effectiveness. In this work, we provide perspectives and opportunities for nanoformulations toward the development of tabletized nanomedicine. This Review presents the notion of incorporating nanomedicine into tablet formulations, which facilitates the controlled release of drug(s) from the formulation to achieve a better therapeutic response. Finally, an attempt was made to explore current trends in nanomedicine technology such as bacteriophage, probiotic, and oligonucleotide tabletized nanomedicine, and the combination of nanomedicine with imaging agents, i.e., nanotheranostics.

3. TABLETIZED NANOMEDICINES: AN ADVANCED APPROACH

A dosage form design creates value to the community by facilitating advancements in patient healthiness. This depends on the effectiveness, safety, and convenience of using the associated technology. In this context, the pharmaceutical sector has shown increased interest in incorporating nanomedicines into their current products. Nonetheless, knowledge in this domain remains nascent, necessitating comprehensive studies to foster growth in this emerging field. Nanomedicines are expected to reach the target site faster. On the contrary, the application of nanomedicines is constrained by their aggregation behavior in aqueous solution.¹⁵ For this, the effective utilization of nanomedicine in tablets is to maintain full dispersion.

The “tabletized nanomedicine” topic suggests it is a concept that facilitates the delivery of medicine in a packaging like a traditional tablet dosage form. It can vary and depends on specific fields of medical applications. Moreover, the key aspects of “tabletized nanomedicine” compared to conventional tablets include but are not limited to the following: a) The tabletized nanomedicine offers the feasibility of nano-(drug) formulations compressed into a tablet form that allows controlled release or targeted delivery of therapeutic agents. b) The tabletized nanomedicine implies a method of delivering therapeutic agents through oral administration for ease of administration and improved patient compliance and usage, thus increasing the acceptance and adoption rates of tabletized nanomedicines. c) This concept also promotes a precise and controlled delivery of nanomedicine, warranting an optimal therapeutic effect. d) Like conventional tablets, tabletized nanomedicine may also involve a focus on scalability and easy mass production. e) It also allows the development of a combination of multiple nanomedicines within a single tablet for achieving synergistic therapeutic benefits. f) Tabletized nanomedicine can protect the drug from degradation and improve absorption and pharmacokinetics of the drugs. g) Tabletized nanomedicine can also be adopted for several therapeutic molecules including small molecules and biomacromolecules (proteins and nucleic acids) which can address various diseases and medical conditions. h) Feasibility of integration with personalized medicine and potential for imaging and diagnostics medical fields.

Altogether, the concept of tabletized nanomedicine or nanomedicine tablet signifies a step forward in drug delivery research. The tabletized nanomedicine takes advantage of nanotechnology and tablet administration for enhanced compliance and improved patient usage. It is highly anticipated that tabletized nanomedicine research and development will likely lead to the development of discoveries in medical fields. However, the existing limited research and literature support that current scenario, it is unclear whether conceptually there is any significant difference between “tabletized nanomedicine” vs “nanomedicine”.

In this section, two examples were presented to demonstrate the approach of tabletized medicine. Oral disintegrating tablets, also known as ODTs, are formulated with various polymers and drug molecules. A well-known paradigm is chitosan nanocapsules containing prednisolone, a corticosteroid used in pediatric asthma treatment. Such tablets are developed through a direct compression method, aiming for swift dissolution within the oral cavity. This unique ODT design allows ease administration without the need for water, thereby enhancing pediatric and geriatric patient’s compliance.³¹ In another work, a pediatric visual preference survey of 3D-printed tablets was conducted. This investigation delved into the crucial aspect of patient acceptance by examining children’s preferences for various Printlets tablets in 3D-printed form. It employed four distinct 3D-printed technologies (digital light processing, DLP; selective laser sintering, SLS; semisolid extrusion, SSE; and fused deposition modeling, FDM) to assess their physical properties. Altogether, the study outcome demonstrated that the DLP 3D-printed tablets have the highest visual appeal (61.7%) among children compared to SLA, SSE, and FDM 3D-printed tablets (21.2, 11.4, and 5.4%), respectively (Figure 2).³² Similarly, the tabletized nanomedicine approach was investigated to on-demand improve amorphous solid dispersion (ASD) inside a tablet. A tablet that is composed of near IR-based nanoparticles combined with polyvinylpyrrolidone (PVP) and celecoxib as a model drug can produce elevated temperatures upon laser activation. Such a phenomenon facilitates the formation of an amorphous solid dispersion ASD in tablets.³³

Figure 2.

(i) Visual appearance data information on tablets that have been prepared by three different 3D printing methods and a pie chart based comparison. (ii) Various age group opinions on the developed tablets. Reprinted with permission under a Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/) from ref 32. Copyright 2020 The Authors, published by MDPI, Basel, Switzerland.

4. ADVANTAGES OF TABLETIZED NANOMEDICINES

This form of nanopharmaceuticals introduces several advantages over free drugs or traditional drug-loaded nanoparticle (nanomedicine) formulations. The outcome of tabletized nanomedicine is linked to the different types of nanoformulation, the nature of the drug encapsulated in nanoformulation, type of tablets, and the targeted disease application. However, a few basic and clinical advantages of tabletized nanomedicine include the following: 1) A frequent and easy-to-administer dosage form potentially improves patient compliance and minimized clinic visits for infusions or injections. 2) Their controlled-release mechanisms offer a sustained delivery of therapeutic agents, which can potentially reduce the number of doses to achieve therapeutic outcome. 3) The inherent enhanced permeation and retention (EPR) effect of tabletized nanomedicine provides higher therapeutic doses of agents at the intended organ and lowers systemic toxicities. Such advantages also reduced clearance and improved biodistribution and pharmacokinetic profiles of developed tabletized nanomedicines. 4) Tabletized nanomedicine can exhibit higher stability and shelf life due to superior protection of sensitive nanomedicine from their degradation. 5) Tabletized nanomedicine can be cost-effective, easy to scale, and integrated for multiple applications, combine therapeutic agents’ delivery, and have multifunctionalities apart from patient acceptance and adoptability. 6) Finally, the regulatory aspects of tablet dosages are essential and needs to be addressed in the future.

Finally, continued research and development efforts will be critical in assessing the extensive use of tabletized nanomedicine in solving potential medical challenges. There are several pieces of evidence in the literature that exhibit therapeutic benefits of tabletized nanomedicine compared to free drug formulations. However, a clear-cut superiority of tabletized nanomedicine over nanomedicine that is not in the tablet form is not well-known or considered. A comparative distinctive characteristics and advantages of tabletized nanomedicine vs nanomedicine and free tabletized medicine in terms of improved therapeutic outcome, reduction of systemic toxicity, and patient compliance aspects are tabulated in Table 2. Altogether, nanomedicine includes a broad range of nano(drug) formulations for medical applications, while tabletized nanomedicine is extension of same therapeutic activity but incorporated into tablet formulations for improved patient compliance. In addition, tabletized nanomedicine offers a junction of nanotechnology, drug delivery, and table-based pharmaceutics and combines the advantages of these basic approaches.

Table 2.

Comparative Advantages of Tabletized Nanomedicine over Free Medicine or Nanomedicine^a

aspects of drug delivery	tabletized nanomedicine	nanomedicine (not in tablet form)	free (drug) medicine in tablet form
dosage form	√	√	√
enhanced stability of drug	√	√	×
patient compliance/acceptance	√	√×	√
molecular action/function	√	√	√
formulation and superior drug delivery	√	√	×
targeted drug delivery	√	√	×
controlled release and EPR effect	√	√	×
improved targeting and bioavailability	√	√	×
diverse applications and versatility	√	√×	×
ease of administration	√	√×	√
multifunctionality	√	√	×
nanoscale precision	√	√	×
personalized medicine	√	√	×

^a√ (check mark) and × (cross mark) represent “follow” and “defy” on the proposed aspects of drug delivery properties.

5. TYPE OF TABLETIZED NANOMEDICINE

The effectiveness of a nanomedicine relies on the promptness of the active therapeutic agent’s availability in systemic circulation. Tablets represent the predominant oral solid dosage form and are commonly favored in development of drugs for their ability to incorporate visual characteristics, such as shape, clarity, brightness, color, and taste. These attributes are advantageous for patients, ensuring a precise dosing pattern, high agreement, and ease of administration. The release rate of a drug from a tablet has a significant effect on bioavailability, in which higher release rates result in higher bioavailability. Within the stomach tract, numerous barriers exist, impeding the bioavailability of therapeutic agents, including mucus, the tightly regulated epithelial layer, immune cells, and an associated vasculature. The tabletized nanomedicines promote the internalization of intestinal cells, facilitating either localized effects within the intestine or the transportation of drugs throughout the body. This section introduces the advancement in the preparation and manufacturing process of different dosage forms and the benefits of tabletized nanomedicine for the pharmaceutical sector (Figure 3). Many of these challenges are overcome by employing sustained release and tabletized nanomedicine dosage ^34,35 forms.

Figure 3.

Tabletized nanoscale delivery approaches for the delivery of therapeutic agent(s). Contents and images are not to scale.

5.1. Enteric-Coated Tabletized Nanomedicines.

Enteric-coating (EC) tablets are the most produced oral pharmaceutical dosage forms. EC-based tablets are often coated with enteric polymers, which are involved as a barrier between the core of the tablet and the surrounding environments. This EC-based tablets shield the drug from conventional degradation process due to stomach acidic pH and enzymatic degradation. This mechanism ensuring the dependable delivery of a concentrated drug payload.³⁶ The coating is often composed of a polymer or substance that is pH-sensitive and avoids the formulation from decomposing within the GI environment. The coating dissipates within minutes to hours, and the drug is delivered into the small intestine since this polymer is sensitive to the pH range of 5.5–7 found in the duodenum. In addition, EC is helpful in minimizing irritation of the gastric mucosa. EC-based tablets or capsules are extensively utilized for the administration of different medications including aspirin, erythromycin, and omeprazole.^37,38 Impermeable polymers, such as phthalates of cellulose, hydroxypropyl methyl cellulose (HPMC), poly (vinyl acetate), methacrylic acid, and methyl methacrylate (Eudragits) are widely used for EC tablet preparations. A recent article documents a number of investigations that are relevant to NP-based drug delivery systems for EC strategies in colorectal cancer.²⁰ This study recognizes a total of 44 drug delivery systems for EC applications. Figure 4 provides a detailed representation of the incorporation of nanomedicine into tablets with enteric coating for oral drug delivery.³⁹

Figure 4.

Schematic presentation of tabletized nanomedicine and enteric coating facilitates colon-specific disintegration and the release of drugs. Images are not to scale. A portion of the content adopted with permission from ref 39. Copyright 2020 Elsevier.

Various types of EC-based oral delivery approaches have been implemented for vitamin D₃ (hydroxyapatite)⁴⁰ and ceftriaxone (chitosan).⁴¹ Khanal et al.⁴² developed an EC bacteriophage tablet for immunocompromised patients (specifically for intensive care units in hospitals). A typical Pseudomonas-targeting phage combined with a binder is useful for the fabrication of tablets. Such tablet preparation approaches are often generated by the spray drying method followed by direct compression of the phage powders. These phage-based EC tablets maintained their inherent structural integrity when subjected to an ex vivo physiological stomach environment. A PEV20-based bacteriophage tablet exhibited stability at physiological temperature (36 and 38 °C), while it resulted in a gradual inactivation of phage at low temperature. The best example of this category of tabletized nanomedicine is gelatin nanoparticles coated with Eudragit-S100.⁴³ This tabletized nanomedicine system aimed to elicit and promote anti-inflammatory properties through the action of 5-amino-salicylic acid, thereby enhancing drug actions. This nanoparticle system evaluation confirms efficient oral delivery of 5-aminosalicylic acid to relieve the severity of DSS-induced ulcerative colitis (Figure 5).

Figure 5.

Scheme representing different steps involved in the generation of formulation of eudragit-S100-coating based 5-aminosalicylic acid-loaded gelatin NPs. Reproduced with permission ref 43. Copyright 2021 Elsevier.

A single step approach can be implemented to generate nanoparticles with core-shell architecture through coaxial electrospray.⁴⁴ This was further modified as EC tabletized nanoparticles by the wet granulation method. Such a unique tablet formulation yields core (Eudragit RS, sustained release property) and shell (Eudragit L100–55, pH sensitive property) structures for efficient drug delivery applications. In another work, the drug molecules were encapsulated within liposomes composed of hydrogenated lecithin and cholesterol. Subsequently, the liposomes were processed via either evaporation or freeze-drying, leading to the formation of a liposome powder. Such a liposome powder-containing tablet protected therapeutic molecule passage through the stomach by an enteric coating.⁴⁵

5.2. Gastro-Retentive Based Tabletized Nanomedicines.

Gastro-retentive tablet (GRT)-based formulations are intended to promote extended gastric retention and the sustained release of oral drug molecules. Numerous strategies exist for augmenting gastric residence time, particularly by utilizing various types of hydrogels or mucoadhesive based systems. They may exhibit high porosity, mucoadhesiveness, flexibility, and swelling capabilities. These are floating systems or hydrodynamically balanced systems, which are designed as single or multiple-unit systems with the specific aim to enhance the gastric residence time of formulation.^46,47 A direct compression method along with a sublimation process is implemented to create GRTs.⁴⁸ The release of the drug was tuned by adjusting the porosity of GRTs by controlling the amount of l-menthol (porogen agent) in the tablets. The sublimation process often utilizes not only to create porosity in tablets but also to decrease their density, thereby facilitating enhanced buoyancy upon exposure to GI simulating fluids. Often a porogen or combination of porogens (l-menthol, camphor, ammonium carbonate, and/or sodium borohydrate) is utilized in the preparation of pharmaceutical formulations.

Zhou et al.⁴⁹ developed superparamagnetic iron oxide nanoparticles (SPIONs)-based GRTs. This system comprises a combination of components, including sodium bicarbonate, HPMC, and mannitol/lactose. These components act as foaming, adhesive, and fillers in the formulation. Sodium bicarbonate catalyzes the generation of carbon dioxide whereas HPMC facilitates the attachment of the materials to the stomach surface, enabling for predetermined dissolution. The magnetic resonance imaging could also be used to monitor the tablet status and SPIONs delivery process (Figure 6). This tablet utilized a stimuli-responsive and triggered release strategy based on in situ bubble generation that can be controlled by ultrasound-mediated force.

Figure 6.

Stimuli responsive and targeted release tabletized nanomedicine. (i) Controlled tablet movement can be achieved by employing an ultrasound method. (ii) Ultrasound-mediated controlled release of SPIONs from tablets. (iii) Visual evidence of ultrasound influence of SPIONPs-loaded tablets on gastric tissue, an example. Reproduced with permission ref 49. Copyright 2020 Elsevier.

Another approach explored for a GRT with a focus on inner structure via 3D printing.⁵⁰ Such a GRT drug delivery system technology offers specific physical parameters, satisfactory retention ability, and predetermined drug release characteristics. By altering the inner structures of the tablet(s), their floating lag time and floating duration and in vivo performance can be regulated. In general, the extent of 3D-printed tablet’s floating characteristics is contingent upon the entrapment of air within the matrix structure. In contrast to conventional tablets relying on floating agents, the air compartments inherent in 3D-printed tablets facilitate immediate buoyancy without necessitating GI’s microenvironment. The gamma scintigraphy study demonstrates in vivo buoyancy of these 3D-printed tablets and were consonant with in vitro buoyancy.⁵⁰ Further, the buoyancy capacity of GRTs can be altered by a fused deposition method.⁵¹ This technology not only provides prolonged gastric residence time but also offers instant floating characteristics. The floating duration of tables that were made with various polymers was noted as hydroxypropyl cellulose (HPC, tablet density 0.69 ± 0.03 mg/mm³) > soluplus (0.72 ± 0.02 mg/mm³) > poly (vinyl alcohol) (PVA, 0.86 ± 0.02 mg/mm³). In the case of HPC and soluplus-based GRTs exhibited zero-order drug release profiles (f ₂ > 50) for sustained release of theophylline drug for 12 h, while PVA-based GRT promotes faster release (complete release in 3 h). A super porous network (SPN)-based system derived from chitosan and PVA by cross-linking with glyoxal in the presence of sodium borohydrate can be another option for producing GRTs. To obtain GRTs, the above SPNs were granulated to a tablet matrix by utilizing HPMC and l-ascorbic acid along with magnesium stearate or metabisulfite, which results in improved absorption in the proximal part of the small intestine.⁵² The SPN-based GRTs yield first-order and Higuchi drug-release models. A schematic representation, floating capacity (buoyancy), and faster drug release profiles of GRTs are presented in Figure 7.

Figure 7.

(i) Schematic route of construction of the GRT. Images are not to scale. (ii) GRT 3-6 tablet (a) exhibited superior floating capacity, while the HPMC tablet (b) sank immediately. (iii) GRTs 1-6, 1-18, and 1-54 disintegrated and released within 4 h; GRTs 3-6 and 6-6 demonstrated an extended-release pattern over 8 h. Reproduced with permission from ref 52. Copyright 2020 Springer Nature.

5.3. Pulsatile Drug-Release Based Tabletized Nanomedicines.

Pulsatile drug delivery systems (PDDS)-based tablets have additional benefits over conventional tablet (dosage) forms.⁵³ The PDDS-based tablets maintain constant drug concentration(s) in the blood and tissues at the right time and amount, and site of action, thereby enhancing the therapeutic efficacy and patient compliance.^54,55 PDDS are available based on time-controlled (erodible coating: bulk, surface, rupturable, and capsule shaped), stimuli-sensitive (thermoresponsive and chemical), and externally regulated (electro-responsive, ultrasonically stimulation, and magnetic induction) approaches.^53,55 Technologies such as 3D printing, Diffucap, Pulsincap, CODAS, IPDAS, OROS, GEOCLOCK, Opana ER, Unipyl, and Ritalina are currently well-known marketed PDDS. Pulsatile release of drugs entails a cyclic pattern of drug liberation occurring at different time intervals. Such design aligns with the circadian rhythm inherent in the human body’s physiological processes, regulated by the suprachiasmatic nucleus situated at the hypothalamic base. Synchronizing medical treatments with biological rhythms offers the potential for optimized therapeutic outcomes while minimizing adverse effects on patients. For example, a remote stimulation by the acoustic radiation force regulates cumulative drug release in situ at predetermined time points.⁵⁶

The PDDS tablet plugs based on time-controlled polymers holds a great promise for celecoxib delivery.⁵⁷ Number of polymers including cellulose, HPMC, and chitosan are well suited for PDDS tablet plugs. This system can reduce inflammatory markers, myeloperoxidase (MPO, intestinal inflammatory marker), tumor necrosis factor-alpha (TNF-α, intestinal inflammation due to alternation in epithelial cell barrier), and interferon-gamma (IFN-γ, inducer of nitric oxide generation in epithelial cells to detect integrity of colonic mucosa).⁵⁷ In such systems, the choice and proportion of diverse hydrophilic polymers in PDDS govern the tablet’s characteristics. Consequently, drug release profiles demonstrated a minimal amount of drug release observed both in gastric (pH 1.2) and intestinal (pH 6.8) environments over an 8 h duration while almost 100% of release in colon mimicking medium (pH 7.4) (Figure 8). In another work, erodible plug tablet using H-pectin, lactose, and 18.1% liquid curcuminloaded SMEDDS (CUR-SMEDDS) exhibits faster curcumin drug release than that of the conventional tablet.⁵⁸

Figure 8.

Optimized celecoxib nanomixed micelles (NMM) are designed by construction with the help of Design-Expert software utilizing celecoxib, pluronic polymer, and bile salt in the thin film hydration method. These NMM are produced for tablet plugs which shows protection against induced colitis (myeloperoxidase level). Reproduced with permission from ref 57. Copyright 2020 Elsevier.

Similarly, a pulsatile capsule made of 75% Carbopol demonstrated attainment of the desired release profile, resulting in the release of 88.35% of the dose. An approach involving the integration of fused deposition modeling 3D printing and hot melt extrusion was proposed for the fabrication of a core-shell tablet. The tablet features a shell comprised of HPMC and PEG 400 on the exterior, tailored for pulsatile release applications.⁵⁵ These tablets offer customizable programming capabilities to achieve personalized lag times in the release of verapamil hydrochloride. Altogether, PDDS are highly suitable to deliver H₂ blockers, B₂ agonist, insulin, sulfonylurea, calcium channel blockers, antihistamines, nonsteroidal anti-inflammatory drugs, proton pump inhibitors, monoamine oxidase-B inhibitors, and taxanes.

5.4. Orally Disintegrating Based Tabletized Nanomedicine.

Orally disintegrating tablets represent solid pharmaceutical formulations engineered to fragment swiftly and disperse upon interaction with saliva or the buccal mucosa within the oral cavity. On the other hand, traditional tablets are designed to be swallowed as a whole. Orally disintegrating tablets are also referred to as orally dissolving tablets. The disintegration time (typically 30 s or 3 min) serves as a critical parameter in the development of ODTs, aligning with regulatory standards set forth by the US Food and Drug Administration (FDA) or the European Pharmacopoeia. Low aqueous solubility of drugs necessitates dissolution augmentation techniques for effective ODT development. Moreover, the capacity for direct drug absorption by the oral mucosa, by passing the GI tract and the initial liver metabolism, stands as an additional advantage of ODTs. A nanoparticle-based on PVP, gum arabic, mannitol, 2-hydroxypropyl-β-cyclodextrin, and methylcellulose for famotidine delivery has been demonstrated by Nagai’s team.⁵⁹ These tablets disaggregate quickly, and particles were leached when they are in contact with water suggesting a better suitability for orally disintegrating tablets.⁵⁹ In this system, disaggregation times (less than 15 s) were optimized by using binder gum arabic formulation code Rp (6–12% gum arabic formulations, Rp.6-Rp.12). In addition, the famotidine nanoparticles 138 ± 6.1 nm (Rp.9 formulations) within the redispersion of the nanoparticles tablet remained nanosized irrespective of the gum arabic content.

The study conducted by Chen et al.⁶⁰ utilized a silicone mold as a fabrication tool. The cooking oil was applied to the surface of the mold to mitigate adhesion issues. The laden nanoemulsion underwent a process of gelation and evaporation in the mold, at a temperature of 70 °C over the course of 1 day. The tablets incorporating drug nanocrystals are devised through a streamlined process. This method presents an efficient and straightforward means of pharmaceutical formulation, promising enhanced efficacy, and controlled release profiles. Interestingly, nanosuspension of doxazosin mesylate was developed as a dosage form of ODTs by employing PVP, poloxamer, and sodium lauryl sulfate.⁶¹ It was also found that doxazosin mesylate nanosuspension resulted as a fastdisintegrating tablet (100% dissolution after 10 min) and significantly reduced mean arterial pressure of hypertensive rats. An improved solubility and dissolution rates were achieved for piroxicam nanocrystal-based ODT formulation.¹⁷ Interestingly, the dissolution kinetics of various above nanocrystal based ODT formulations were methodically juxtaposed against the commercial counterpart Feldene Fast. Notably, the particle size analysis of piroxicam particles postdisaggregation revealed an average 1482 nm with a polydispersity index of 0.92. Additionally, it was conjectured that the presence of xanthan gum leads to a reduction in drug release as well as a dissolution rate. Similarly, chitosan nanoparticles based ODT tablet was formulated meticulously with a sustained-release characteristic.⁶² Due to the inherent benefits associated with nanocrystals, the proposition is to devise ODTs containing vortioxetine, aiming to augment its aqueous solubility, elevate the dissolution properties, and enhance release kinetics, surpassing the dissolution performance of unprocessed drug (60%) within an equivalent time frame.¹⁴ Chen et al.⁶³ further proposed that ODTs containing fast disintegrating nanoparticles may present a superior option for young children. These ODTs were constructed at various compositions of microcrystalline cellulose, lactose, croscarmellose sodium for achieving optimal PDS-enhanced solubility, in vitro drug release (98.50% in 30 min), and integration time (15 s). A subsequent study endeavored to convert microparticles into ODTs through a wet granulation approach for tablet formation.⁶⁴ Such ODTs can accommodate approximately 90% (w/w) drug entrapment. Furthermore, evaluation through disintegration tests revealed that the formulated ODTs can achieve complete dissolution within a time frame of 45 s.

5.5. Buccal and Sublingual Based Tabletized Nanomedicine.

The majority of nonsteroidal anti-inflammatory drugs pose GI concerns upon repeated oral administration. Administration of pharmaceuticals via the buccal route circumvents the hepatic first-pass effect and bypasses the GI tract.^65,66 The mucoadhesive nature is attained by hydrophilic polymers due to their swelling behavior and interaction with the buccal mucosa⁶⁶ (Figure 9). Examples of such swellable polymers include HPMC, PVP, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose (SCMC), and chitosan.^65–67

Figure 9.

(i) Schematic illustration of tabletized nanomedicine for buccal/sublingual (oral) delivery. Washout, burst, pH/enzymatic degradation, osmotic environment in saliva/acids, etc., facilitate the release of drug-loaded NPs. (ii) Various modes of delivery of drugs from tabletized nanomedicine, lumen release, and adherence to mucus or mucosal surface (drug absorption); NPs excretion or degradation (metabolism); cell and tissue accumulation.

Mucoadhesive buccal tablets having chitosan and gelatin microparticles were developed in spray-dried techniques for propranolol hydrochloride delivery.⁶⁸ These preparations comprised different weight ratios of chitosan and gelatin polymers and analyzed in terms of yield and listing, tablets, friability, harness, mucoadhesive properties, drug release, and drug permeation studies. Consequently, tablets with an elevated gelatin content exhibited decreased drug permeation compared to other formulations. Additionally, drug permeation escalated with a higher chitosan content. Integrating the advantageous characteristics of buccal delivery with lipid nanoformulations is a unified and promising approach to drug delivery. A range of solid lipid nanoparticle formulations (particle size, ~162–1100 nm) composed of steric acid, Tween 80, camphor RH40, lecithin, and span 80 for lornoxicam delivery demonstrated effectiveness in lowering percent edema compared to the pure form of lornoxicam or marketed tablets (Eduropan). Upon contact with the buccal mucosa, the polymer chains of the tablet undergo rapid swelling, leading to the establishment of weak bonds and subsequent mucoadhesive interactions. The mucoadhesive strengths of the developed HPMC-based buccal tablets are in the range of 42.5–52.8 g.⁶⁹

5.6. Probiotic Spore Based Tabletized Nanomedicine.

Probiotic therapy has gained considerable attention in medical investigations due to its notable benefits in reinstating equilibrium within the intestinal microbiota, fostering favorable microenvironmental conditions, and fortifying immune system functionality.^70,71 Nevertheless, challenges exist toward an effective way of delivery and the activity of probiotics in the whole complex GIT conditions.⁷² Probiotics can exhibit superior health effects to humans provided in stable form and appropriate amounts. In a recent investigation, a probiotic tablet with pH-sensitive property was developed to shield Lactobacillus reuteri from GI environment. The harvested microbiota and nanoparticles were generated at low temperatures by freezing component, lyophilization, and subsequent compression into tablets.⁷³ The primary probiotic protection achieved from phthalyl inulin nanoparticles is due to their pH-sensitivity, which restricts release of probiotics under an acidic pH environment. This phenomenon was confirmed by short- and long-term cell viability and long-term storage and stability (up to 6 months) assays. Huq et al.⁷⁴ developed cellulose derived nanoconstructs promoting the sustainability of Lactobacillus rhamnosus. It was confirmed an improved survival (65%) of L. rhamnosus achieved with probiotic tablets compared to their polymer-based counterpart tablets.

6. ROLE OF NANOCARRIERS IN TABLETIZED NANOMEDICINE

Orally administered pharmaceutical compounds undergo a multifaceted journey through the gastrointestinal tract, traversing various physiological milieus within the stomach and small intestine, characterized by dynamic alterations in pH levels and the introduction of digestive enzymes. In addition, the stability of nanomedicines can be influenced by factors such as pH and enzymatic digestion, potentially resulting in premature cargo release at unintended sites. Thus, careful considerations are required in the development of tabletized nanomedicines to ensure effective drug transport, protection, and targeted delivery to specific tissues. Hence, it is vital to engineer nanomedicine systems that leverage basic biological mechanisms, such as enhancing adhesive properties for prolonged retention, responsiveness to the local physiological environment, and improved permeation and residence at designated sites. Development of tabletized nanomedicine utilizes various types of nanoparticles including bioresponsive nanomaterials or composite construction of nanomaterials with targeting moieties (Figure 10).⁷⁵

Figure 10.

Construction of tabletized nanomedicine utilizing various nanoparticles for promising therapeutic applications. Drug molecules are packaged in nanoparticles, and these drug-loaded nanoparticles are produced into tabletized nanomedicines. Distinct types of nanoparticles 1–9, respectively (metal or gold nanoparticles, polymeric micelles, iron oxide nanoparticles, silica nanoparticles, nanocrystals, lipid nanoparticles, polymer conjugates, carbon nanotubes, and nanogels) employed for the development of tabletized nanomedicine. In contrast to nanosized formulations, nanomedicine in tablet form offers not only sustained release characteristics but also prolonged residence time within the gastrointestinal tract. Yellow and gray tablets indicate tabletized nanomedicines of uncolored drug NPs and yellow drug NPs.

These tabletized nanomedicines possess characteristics conducive to prolonged and controlled release of drug molecules. They can be applied either locally or systemically, effectively directing the delivered drug to its intended tissue or organ site. Various types of nanovehicles from metal nanoparticles to nanogels have been implemented for nanomedicine applications (Figure 10 and Table 3).

Table 3.

Documentation of Published Literature on Tabletized Nanomedicine: Matrix, Composition, Methods of Preparation, Composition, Advantages, and Their Possible Applications

matrix and ref	nanomedicine and preparation method	composition of tablet	advantage(s)	tabletized nanomedicine out performance
dextran76,77	gold NPs (AuNPs-dSol) freeze-drying	The 10% (w/v) solution of AuNPs-dSol was formulated by binding 10 g of dextran powder.	portable and easy-to-use optical sensors	A 6% (w/v) dextran solution in AuNPs-dSol was utilized to produce AuNPs-dTabs, ensuring prolonged stability of the nanoparticles.
HPMC, sodium alginate, pectin or PVP78	HPMC, Na-alginate, pectin, and PVP NPs compression	Each polymer was physically mixed with 8 mg of the drug.	augmented oral bioavailability, enhanced drug stability, and regulated drug release	These tables demonstrated a drug release duration spanning up to 12 h, contrasting with traditional market tablets, which exhibited a drug release rate exceeding 90% within a 3 h time frame.
pullulan76	gold NPs cast method	30 mL of a 3% (w/v) pullulan solution and 12.5 mL of a 1% (w/v) NaOH solution	accurate detection of glucose in human saliva samples with high specificity and selectivity	The stability of AuNPs-pTab persisted for over 6 months, whereas AuNPs-pSol exhibited declining stability after the initial month.
sorbitol/mannitol79	proliposome compression	The proliposome granules consisted of sorbitol/mannitol in lipid to carrier ratios of either 1:10 or 1:15 w/w.	simplified manufacturing, dosing, transit, storage, and scalable production	These tablets had superior powder flowability, minimal friability, suitable hardness, rapid disintegration time, and consistent weight uniformity in comparison to d-mannitol-based tablets.
mannitol80	preliposomes compression	Lecithin and mannitol were mixed in a ratio of 1:2 (w/w) with empty PreLipo powder.	safeguard and enhance the stability of drugs for oral, buccal, and vaginal delivery	A greater proportion of the drug disintegrated from all PreLipo tablets compared to tablets made from physical mixes.
starch81	liposomes compression	12 mg of magnesium micromotors was blended with 120 mg of active ingredients.	improved absorption and uptake of insulin in the colon	This process resulted a colonic-responsive and effective oral insulin delivery with sufficient drug protection, surpassing the performance of liposomes.
PVA and mannitol82	nanosuspensions freeze-drying	combining components in water and allowing the mixture to cool	prevents gastric degradation	Because of its large crystal size and low water solubility, silymarin dissolves slowly (120 min), whereas the suggested formulation dissolves in 8.9 min.
hypromellose83	nanosuspensions compression	pluronic F-127 hypromellose	improve solubility	The dissolution behavior of ODT displayed a substantially improved dissolution profile.
hydroxy-propyl methylcellulose (HPMC) E584	nanosuspension compression	HPMC and sodium dodecyl sulfate were employed.	nanosuspensions into solid oral dosage forms	In comparison to formulations containing copovidone, the drug released more rapidly from tablets.
PVP K 30, Poloxamer 407, mannitol, and potassium61	nanosuspension freezedrying	Doxazosin mesylate was incorporated into the polymer excipients.	enhanced compliance and ease of administration of drug	These tablets demonstrated a superior disintegration rate as well as enhanced wettability.
Poloxamer 40785	nanosuspension compression	Tablets were produced from a spray-drying method containing the specified excipients.	demonstrated oral bioavailability on par with other proven methods for enhancing oral absorption	These nanosuspension tablets demonstrated a substantial enhancement in dissolution rate than Sporanox.
Poloxamer 188 and HPMC PEO powders and PVP K3086	nanosuspension compression	Rebamipide was successfully dispersed in various polymer matrices.	application on developing tablets with controlled release profile and gastro-retentive dosage purpose	A final composition and the tablet expansion and destruction characteristics regulate the release profile of rebamipide.
trehalose and mannitol87	liposomes compression	Trehalose and mannitol based lipoplexes were efficiently employed to load siRNA by simple mixing.	This study confirms delivery of siRNA via oral route.	Trehalose and mannitol based cationic liposomal tablet formulations indeed an alternative path for oral administration.
Eudragit RS 100 or poly(ε-caprolactone) [PCL]88	nanocapsules compression	Drug was encapsulated into polymer nanocapsules.	improved drug adherence on porcine sublingual mucosa	This study demonstrated that CAR-NC-T are capable to introduce sustained drug release at the mucosa.
PVA and mannitol89	nanocapsules freeze-drying	Nanocapsules were stabilized with sugar and polymer mixture.	improve the physicochemical properties of felodipine	Such stabilized tablets exhibit high porosity which promotes a quick dissolution time and disintegration.
HPMC, MCC, and PVA90	self-microemulsifying compression	Tablet was constructed by mixing astaxanthin with polymer solutions, followed by compression.	The astaxanthin was delivered through SMEDDS tablet for enhanced diffusion and bioavailability.	This type of SMEDDS tablets confirms the feasibility of oral delivery of highly lipophilic molecules.
mannitol91	self-microemulsifying compression	The APIs are can efficiently adsorbed onto SMEDDS.	enhanced solubility and oral delivery of payload	Current study demonstrates feasibility of rapid dissolution of tablets.
PVP, HPMC, and K15 M92	self-microemulsifying compression	These tablets were comprised of celastrol based SMEDDS.	advanced oral delivery capability of SMEDDS	All types of SMEDDS tablets exhibited almost similar maximum serum concentration of drug.
Capmul MCM, castor oil, Kolliphor EL, and Kolliphor RH 4093	self-microemulsifying compression	Resveratrol was loaded into SMEDDS during self-emulsifying step.	enhanced drug bioavailability upon incorporation into SMEDDS	No additional benefits were noted in terms of delivery of resveratrol with SMEDDS compared to microemulsions.
Kollidon CL, Explotab, or Croscarmellose 94	self-microemulsifying compression	These tables were constructed with SMEDDS and a disgregant.	improved drug solubility and dissolution properties	The tablets composed of SMEDDS and a disgregant demonstrated about 6- to 20-fold increased disintegration time.

6.1. Nanoparticle-Based Tablets.

A tablet incorporating gold nanoparticles (AuNPs) was designed by encapsulating AuNPs within dextran matrices.⁷⁶ This design ensures resilience to alkaline conditions while exhibiting heightened responsiveness in acidic environments due to nanogold aggregation within the lower pH range. Along the same lines, AuNPs encapsulated with a pullulan matrix tablet have been generated. The peroxidase catalytic activity of these AuNPs-pullulan tables is showcased through the oxidation of the substrate.⁷⁶ These AuNPs-based tablets provide sensor activity in measuring the levels of glucose and hydrogen peroxide.

A dry tablet formulation of PLGA nanoparticles loaded with dexamethasone was developed for an improved preocular applicator.⁹⁵ This dry tablet exhibited up to 2 h of nanoparticle retention and resulted in an enhanced ophthalmic delivery of drug (2.6-fold) compared to a commercial formulation (Maxidex). Usman et al.⁷⁸ reported a polymer-encapsulated nanoparticles of lornoxicam were compressed into a tablet. The PLGA NPs in tablets were in size distributed from 50 nm to 1.5 μm with drug encapsulation efficiencies of 58–73%. The method applied in this tablet demonstrated to have enhanced release profiles for drugs and stability and its superior bioavailability.

Another example of this category is chitosan-based multifunctional nanoparticles that can be extended for tablet applications.⁹⁶ The therapeutic benefit of these tablets nanocarriers were evaluated in streptozotocin-induced diabetic SD rat model. This data confirms a rise in plasma insulin levels up to the 4 h mark (up to 61.1 ± 7.6 μIU/mL), followed by a gradual decline thereafter. It is noteworthy that the elevated plasma insulin levels persist for an extended duration. In another work, biomimetic nanoparticles, inspired by viruses with mucus-penetrating abilities, were suggested as a solution for oral insulin delivery.⁹⁷ This tablet constructed with cellpenetrating peptide modified nanoparticles not only exhibits mucus-penetrating ability but also facilitates intestinal absorption in vivo.

6.2. Liposome-Based Tablets.

Liposomes (a pioneered discovery by Bangham) are spherical vesicles composed of either single or multiple lipid bilayers surrounded by an aqueous core. They mimic cellular membranes. Liposomes can be produced instantly in water with the dispersion of amphiphilic lipids. Liposomes serve as an excellent therapeutic delivery carrier due to their inherent biocompatibility and biodegradation characteristics. Furthermore, liposomes can be accommodate water-soluble or lipid soluble drug molecules in the core or lipid bilayers, respectively.⁹⁸ A recent study demonstrates the feasibility of liposomal-based tablet preparation.⁷⁹ For this, slurry-driven lipid-enriched powders were compressed into tablets using two individual proliposome formulations, with varying sugar to lipid content. By variation of the ratio of the contents, it was feasible to achieve desired physical properties, such as tablet uniformity, table disintegration time, tablet hardness, powder flowability, and tablet friability. Another subsequent investigation promotes the use of ~2 μm liposomal-based tablets for beclomethasone dipropionate (2 mol %) delivery.⁹⁹ Liposome tablets when hydrated in a nebulizer reservoir exhibited similar nebulization time, but less sputtering time and consistent aerosolization upon nebulization compared to its liposomal powder. Vaní et al.⁸⁰ presented a method involving PreLipo powder combined with metronidazole and mannitol to yield liposomal tablets. This tablet appears to be pale yellowish, nonsticking, and free-flowing with 90% of the particles smaller than their parent drug powder crystals. Similarly, another liposomal based mini-tablet was constructed which exhibits the ability to move autonomously through a medium⁸¹ (Figure 11). Their liposomal construction size appears to be about 84 nm with negative zeta potential. The self-propulsion characteristic was achieved by Mg and Au powders sputtering. A pictorial presentation of micromotor based colon/oral delivery of insulin is illustrated in Figure 11.

Figure 11.

(i, ii) Visual representation of liposome-based micromotor for efficient insulin oral delivery. (iii, iv) In vivo evidence of micromotor successful oral delivery of insulin to digestive tracts confirmed by fluorescence imaging and histological evaluation. Reproduced with permission from ref 81. Copyright 2022 American Chemical Society.

A comparative study aimed at investigating the release and bioavailability of amoxicillin in mini-tablet and lipid/polymer form.¹⁰⁰ Insulin-magnesium containing tablets were not only utilized as micromotors but also capable of adsorbed onto mucus. Such an interface feature limits the nanoparticle entrapment in mucus layers. Additionally, it promotes diffusion capability in the mucus matrix due to low viscosity. This study confirms that both forms were efficient in extending amoxicillin drug action, but the bioavailability of the drug is greater in the lipid nanoparticle tabletized form. However, a mini-tablet form is advised for future drug development due to its simplicity and reproducibility over nanoparticles. Busignies et al.⁸⁷ employed a tablet that can effectively deliver siRNA. They subjected an aqueous suspension of siRNA vector composition (anionic adjuvant and cationic lipids) to freeze-drying in the presence of different lyophilization excipients. This tablet not only holds siRNA but also efficiently delivers and silences its associated gene in mice models of disease. Such unique siRNA encapsulated liposomal formulations can be integrated into an ODT facilitating siRNA release upon contact with the tongue. Additionally, these tablet designs enable controlled release into the digestive tract.

6.3. Nanosuspension-Based Tablets.

Nanosuspension formulations aid in solving the issues related to drug solubility and dispersions, enhancing drug bioavailability, and modifying the drug’s pharmacokinetic profile. Such formulations emerged as dosage forms to improve drug safety and efficacy. A previous study reported that 3² full factorial designs were applied to develop lyophilized nanosuspension tablets with improved physiochemical properties and a quick release of silymarin characteristics.⁸² These tablets were prepared by sonoprecipitation in the size range of ~277 nm followed by a freeze-drying process. The optimized PVA-mannitol based tablets exhibited disintegration time (~14 s), friability (~0.59), and 90% drug release time (~8.9 min). Anup et al.⁸³ developed electrosprayed and lyophilized olanzapine nanosuspensions for orally disintegrating tablet evaluation. The Electrospray method confirms hollow and porous particles with increased surface area and pore radius compared to the physical mixture. At the same pore volume, it is extremely less. However, it is apparent that both nanosuspension formulations exhibited similar hardness, disintegration time, and friability properties. Itraconazole nanosuspensions were widely reported for tablet preparation.^84,101–103 These teams have developed itraconazole nanoformulations by compact nanosuspension-layered sugar beads (blending with excipients, i.e., HPMC, MCC, copovidone or isomalt, crospovidone-PEG 4000, dibasic calcium phosphate, and HPC) and evaluated factors influencing particle size, tablet properties, and dissolution profiles.^84,101 Another itraconazole nanosuspension was formulated into a tablet formulation for direct compression to improve micrometric properties such as flowability and compressibility.⁸⁵

A doxazosin mesylate fast-disintegrating tablet formulation was developed by applying contour plots of nanosuspension that were made using PVP k-30, poloxamer 407 (POX 407), and SDS.⁶¹ The optimized formulations showed ~385–1684 nm in DLS measurements but less than 100 nm in their dried form. Their disintegration times are ~8–13 s and wetting times are ~1–3 s. In addition, these tablets disintegrant 100% dissolution within a few minutes. The administration of doxazosin mesylate nanosuspension derived tablets resulted in a notable decrease in the mean arterial pressure in live hypertensive rats. A combination of salt-cased bilayer matrix tablets with immediate release components (POX 407 or poloxamer 188 (POX 188)) and sustained release layers (poly(ethylene oxide) (PEO and HPMC) were constructed to develop once-a-daily tablet for rebamipide delivery.⁸⁶ The dissolution profiles of these bilayer tablets disintegrate within 2 h in pH 1.2 buffer solution while this phenomenon can be extended to 24 h in pH 6.8 (Figure 12).

Figure 12.

(i) Dissolution test representing physical tablet images of two distinct compositions. (ii) Proposed mechanism for accelerated release of RBM from the NSP-loaded POX 407 and POX 188 combination-based IR layer of the bilayer matrix tablet. Reproduced with permission from ref 86. Copyright 2022 Elsevier.

6.4. Nanocapsule-Based Tablets.

Nanocapsules are vital for the best protection of a broad range of formulations, such as foods and other biological systems. Nanocapsules exhibit smaller particle sizes, leading to a significantly larger surface area compared with their counterpart microcapsules. They are often utilized to enhance the transparency of the formulation. A well-known example is carvedilol-loaded nanocapsules.^88,104 The material composition, lactose, and PVP in the tablets allow the release of polymeric nanocapsules with mucoadhesive properties. These nanocapsules extend the duration of mucosal contact, representing a strategy for sublingual dosage forms. Another study aimed at enhancing the felodipine delivery capacity from tablet(s) that is constructed with polymeric-based nanocapsules.⁸⁹ This characteristic was achieved through the porosity of polymeric nanocapsules, allowing for a higher payload and leading to accelerated dissolution and disintegration rate of tablet matrices. Lin et al.¹⁰⁵ constructed nanocapsules loaded with diallyl trisulfide. These nanoscaled micellar based nanocapsules aids in the incorporation into Caco-2 cells and enable the production of hydrogen sulfide (Figure 13).

Figure 13.

Proposed (left side) and proven (right side) drug delivery system for the luminal surface of colon delivery for the successful repair of colonic inflamed tissues. Reproduced with permission from ref 105. Copyright 2018 Elsevier.

This event repairs colonic inflamed tissue by producing TNF-α and IL-6 (markers of pro-inflammatory cytokines). These nanocapsules are also capable of reducing the myeloperoxidase activity in an inflammatory bowel disease mouse model.

6.5. Self-Micro-Emulsifying Tablets.

The self-microemulsifying drug delivery system (SMEDDS) is considered another class of nanosystems that are often used to improve the solubility and bioavailability of therapeutic agents.^106,107 Lately, SMEDDS were also utilized for the oral administration of lipophilic drugs.^108,109 Oily droplets in SMEDDS promote stability in the gut and penetrate through mucin layers to achieve a greater oral bioavailability. A special class of SMEDDS tablets were prepared for the effective delivery of astaxanthin.⁹⁰ To prepare astaxanthin loaded-SMEDDS a spray-dried method was adopted. The common ingredients of this SMEDDS include microcrystalline cellulose, PVA, HPMC, and other trademark polymers. These SMEDDS not only offered an enhanced dissolution profile of astaxanthin but also promote Caco-2 cellular internalization. For optimal absorption of dutasteride within the gastrointestinal tract, a SMEDDS tablet was proposed. Such tabletized nanomedicine approach enables a convenient route of administration and facilitates higher colon absorption characteristics.⁹¹ This SMEDDS containing Capmul MCM, Captex 355, and Cremophor EL showed improved dissolution in the gastric medium when compared to the dissolution of the conventional product (Avodart) and the raw drug. A study aimed to produce a ticagrelor (TCG) loaded SMEDDS (TCG-SM) in the form of tablets and granules that can enhance the dissolution and the composition (Neusilin US2, Florite R, Avicel PH102, Primellose, Explotab, Kollidon CL, PVP K-30, and magnesium stearate) by keeping a constant amount of TCG-SM (490 mg).

A SMEDDS in gelatin capsule composed of multiple oil components and excipient solutions exhibited similar absorption of cinnarizine in healthy human volunteers, as like commercially available tablets (Sepan).¹¹¹ Qi et al.⁹² proposed SMEDDS dispersible tablets of celastrol for promoting the dissolution and enhancing multiple pharmacokinetic parameters. This was feasible due to their ultrasmaller dispersions (particle size of 25.32 ± 3.26 nm) of SMEDDS. Another study efficiently delivered resveratrol in a preferred SMEDDS tablet dosage form.⁹³ Similarly, a fast-dissolving SMEDDS tablet formulation of glyburide was reported. This SMEDDS tablet facilitates rapid dissolution profiles, i.e., achieving full dissolution within a time frame of less than 15 min. Smith et al.¹¹² proposed a self-nanoemulsifying drug delivery system for buparvaquone (BPQ). This BPQ-SMEDDS demonstrates not only favorable smaller size but also possess controlled release profiles (Figure 15).

Figure 15.

Implication of BPQ SNEDDS pullulan capsules for cumulative BPQ release in (i) simulated gastric fluid, acetate buffer, and phosphate buffer, (ii) in vitro lipolysis of BPQ SNEDDS, (iii, iv) TEM images of BPQ and SNEDDS, (v) SEM image of BPQ solid SNEDDS, and (vi) drug dissolution profiles in simulated SGF and SIF solutions. Reported with permission from ref 112. Copyright 2022 American Chemical Society.

This formulation shows enhanced oral bioavailability over the aqueous BPQ-based dispersions. This resulted in an increased plasma AUC_0–24 by 55% (4-fold higher than previously reported for BPQ nanosystems). Such formulation can be tabletized by utilizing low molecular glycol chitosan polymers for obtaining a better solid dispersion in compressed tablets.

7. PATENTS AND MARKETED PRODUCTS OF TABLETIZED NANOMEDICINE

The tabletized nanomedicine is expected to offer a suitable platform for the oral administration of diverse pharmaceutical dosage forms. Additionally, the design of tabletized nanomedicine aims to enable controlled release of the therapeutics from the tablet compartment, potentially through the opening of the nanoparticle matrices in the tablet in a programmed way. In certain pharmaceutical tabletized nanomedicines (Table 4) drug molecules are functionally connected to the nanoparticle matrices, but they can be separated and release into medium. A few tabletized nanomedicines are currently in market (Table 4) and a few other formulations (Table 5) are under patent protection for future development of tabletized nanomedicine.

Table 4.

Approved Tabletized Nanomedicnes-Based Therapeutic Products

nanosystem	product/brand name	company/alliance	active ingredient	indication and remarks
polymeric systems	Renagel	Genzyme Pharmaceuticals	sevelamer hydrochloride	hyperphosphatemia in dialysis patients
polymeric system	Renvela	Genzyme Pharmaceuticals	sevelamer carbonate	hyperphosphatemia in dialysis patients
nanocrystal-based systems	Rapamune	Wyeth	sirolimus	prevention of organ rejection
nanocrystal-based systems	Tricor	Abbott Laboratories	fenofibrate	hypercholesterolemia
nanocrystal-based systems	Ritalin LA	Novartis	methylphenidate	neurodevelopmental disorders
nanocrystal-based systems	Triglide	Skye Pharma	fenofibrate	lipid disorders
nanocrystal-based systems	Focalin XR	Novartis	dexmethylphenidate	neurodevelopmental disorders

Table 5.

Recent Patent Applications Related to Tabletized Nanomedicnes

patent number and citation	type of tabletized medicines	summary of the invention
US20150164827A1, Rawas et al.113	orally disintegrating nanoparticles	This invention is related to composition and methods of fabrication of epinephrine nanoparticles and their incorporation into ODT tablet for therapeutic applications. These formulations are indeed useful to treat cardiac event and allergic reactions.
US8354094B1, Sung et al.114	enteric coated tableted chitosan shelled nanoparticles	This invention discloses methods of preparation of chitosan-based nanoparticles by combining PGA and other active APIs and subjected to a freeze-drying method to obtain tablets. The composition contains an enteric coating that is useful in this preparation and developing tablet pharmaceuticals.
CN114712318A, Lan et al.115	chewable tablet nanoparticles	The invention relates to the field of biological pharmacy, to a chewable tablet containing astaxanthin nanoparticles, and a preparation method thereof.
WO2004/043440, Soto et al.116	disintegrating tablet nanoparticles	The present invention relates to solid dosage forms of active agents comprising pullulan and having low friability. The active agent can be micrometer-sized or nanoparticulate, and soluble or poorly soluble in water.
US11311572B2, Kobayashi et al.117	effervescent tablet silicon nanoparticles	A method for generating hydrogen according to the present invention comprises an oral solid preparation having hydrogen generation ability and containing silicon fine particles.

Incorporation of epinephrine into nanoparticles and subsequently integration of them into fast-disintegrating tablet form. These pharmaceutical eligible tabletized nanomedicine possess enhanced mucin penetration and absorption characteristics, potentially result in decreased required dosage of epinephrine (US20150164827A1).¹¹³ Another invention encompasses comprising of various chitosan derivative and their nanoparticles, organized into a tabletized nanomedicine form (US8354094B1).¹¹⁴ Such nanoparticles inside the tablets can act as an enteric coating for tabletized nanomedicine. A recent invention proposed for developing chewable tablets CN114712318A.¹¹⁵ The release of astaxanthin from chewable tablets can be controlled without applying heat or pressure. WO2004/043440 also describes the use of one or more surface stabilizing molecules, such as gelatin, in combination with pullulan (a polymeric carbohydrate) to form rapidly disintegrating tablets containing nanoparticles by using a process. of lyophilization.¹¹⁶ Fine silicon based nanoparticles promoted a gastrointestinal tract delivery.¹¹⁷

8. CONCLUSIONS AND FUTURE PROSPECTS

Delivery of drugs through the oral route is a commonly used protocol for several disease treatments. It is the predominant segment of the total drug delivery marketplace. Researchers suggest that the use of nanomedicine methods for manufacturing tabletized nanomedicines may hopefully prevent hurdles with oral drug delivery. Nanomedicines may be developed for different applications by altering their size, shape, and surface chemistry. These are generated in both organic and inorganic materials, and manufacturing of these complex structures proves feasible; it will proceed from preclinical research to clinical applications. Further research is recommended to extend toward cancer, diabetes, Alzheimer’s, amyotrophic lateral sclerosis, liver, and other chronic diseases where frequent and continued long-term medication is needed. The demand persists for nanomedicine presented in tablet form, offering medical advancements beyond at the cellular and molecular scales. However, a notable drawback lies in the discordance of the translation of animal studies into human applications. While the concept of tabletized nanomedicine approach is attractive, further investigations are necessary to instill public confidence.

It is important to bring attention that there are about 58 nanoparticle-based therapies or imaging constructs approved by the US FDA or European Union of European Medicines Agency for various indications. Extending those nanomedicines in tabletized form will be a revolution for future medicine. Similarly, its extension will be useful for immunotherapies and vaccine development. Developing tabletized nanomedicine for microbiome or cell factories that produces or tackle immune and therapeutic aspects of inflammatory, cancer, and immunological diseases.^118,119 Such tabletized cell factories not only restore the host immunity but also improve the richness and diversity of microbiota.^119–122

In addition to the use of nanomedicine in tabletized form, it is interesting to employ tabletized formulation(s) for oligonucleotides and imaging agents’ delivery.^87,123 For example, siRNA lipoplexes were prepared in the form of a tablet.⁸⁷ The dried form of siRNA lipoplex was able to increase the stability of siRNA while maintaining over 60% of the gene-silencing capacity. Similarly, another attempt was successful in terms of delivery of siRNA with bioactive capsule of calcium phosphate nanoparticle formulation in gelatin (freeze-drying method) for colon-specific delivery.¹²⁴ Similarly, an attempt was made to increase the clinical utility of ICG via tabletized nanomedicine by developing chitosan-based ICG films.¹²³ These mold-casted sublingual formulations were obtained with two different release patterns (80% in 4 or 25 h) and offering enhanced systemic absorption and circulation of ICG. These films allow quick detection of inflammation in mouse model. These contents advise that noninvasive diagnosis and treatment are feasible with tabletized nanoformulations and are alternatives to parenteral formulations. Considering the favorable outcome of ICG nanoparticle films, extending its application to tabletized nanoimaging tablets with ICG or other commonly used and FDA approved imaging/contrast agent will be a research era.

Several oral tabletized nanoformulations confirmed the enhanced delivery and bioavailability of insulin and various drug molecules. Along similar lines, pH-sensitive Eudragit polymers have been assembled with porous silicon for antibody delivery (immunoglobulin A-2, IgA2).¹²⁵ This oral tabletized antibody exhibited a minimal release in simulated gastric fluid but showed >50% antibody at a pH of 6.8 or 7.4. A supramolecular immunization with peptides in tablet form (OVAQ11 and dextran/mannose) for sublingual immunization was also explored by a simple lyophilization process which can be a needle-free administration.¹²⁶

Apart from molding, compression, freeze-drying, and other conventional tabletized methods, 3D printing technologies have received much attention.¹²⁷ This technology is already in the implementation of pharmaceutical manufacturing processes upon FDA-approved 3D-printed tablets (Spritam). Hot melt extrusion process based 3D printing is a feasible pharmaceutical approach for scalable and commercial development with a smaller number of additives.¹²⁸ In fact, there are more than 20 pharmaceutical 3D printing-based products in use. This will allow the development of future tabletized nanoformulations which combine nanomedicine possessing diagnostic or detection and or theranostic components for multifunctional clinical applications. A few recent developments demonstrate that potential approaches to manufacturing tablets from smart films or papers, which could serve as advanced therapeutic platforms.^129–131 This smart film-based tablet method was employed for model pharmaceuticals, sucrose, caffeine, and norfloxacin.^129,131,132 Such film-based tablets can not only be simple but also have high industrial adoptability due to their cost-effectiveness.

Figure 14.

Graphical representation of SMEDDS for delivery of ticagrelor using Sol-TCG-SM tablets and TCG-SM tablets exhibited higher dissolution and enhanced bioavailability in pH 1.2, 4.0, and 6.8 media. Reproduced with permission from ref 110. Copyright 2019 Elsevier.