COVID-19 Oral Particulate Vaccine

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1		Mohammad Uddin	+ 3137 word(s)	3137	2021-10-14 13:17:13	\|
2	The format is correct	Lindsay Dong	+ 731 word(s)	3868	2021-10-20 03:55:48	\|

This entry is adapted from the peer-reviewed paper 10.3390/vaccines9101086

Particulate vaccines can be administered as either oral solutions or in sublingual or buccal film dosage forms. Besides improved patient compliance, the major advantage of oral, sublingual, and buccal routes of administration is that they can elicit mucosal immunity. Mucosal immunity, along with systemic immunity, can be a strong defense against SARS-CoV-2 as the virus enters the system through inhalation or saliva.

COVID-19 vaccines SARS-CoV-2 pandemic oral particulate vaccine

1. Introduction

Particulate COVID vaccine is a vaccine that can be developed by using nano- or microparticles as platforms. Particles consist of an active principle (drug or biologically active material) that is dissolved, entrapped, or encapsulated ^[1]. Microparticles and nanoparticles can be utilized as drug carriers into which drugs or antigens may be incorporated in the form of solid solutions or solid dispersions. Nano- or microparticles have been shown to enhance the delivery of certain drugs across several natural and artificial membranes. Although the currently marketed mRNA vaccines are in particulate form, these are administered via the intramuscular route. This route of administration is at a disadvantage due to decreased patient compliance associated with injections. Therefore, particulate vaccines that can be administered by some other, painless route such as buccal or sublingual can be a better option for this vaccine. In this article, we will review some of the current COVID-19 vaccine platforms and discuss their limitations. We will further explore the feasibility of developing a COVID vaccine that can be administered orally, sublingually or via the buccal route by utilizing nano- or microparticles as a platform.

2. Limitations of Current COVID-19 Vaccines

2.1. Side Effects

According to the CDC, the most common side effects experienced after receiving the COVID-19 vaccine include pain at the injection site, redness, swelling, tiredness, headache, chills, fever, and nausea. Other effects include sensitive skin, menstrual cycle changes, and blood clotting ^[2]^[3]. Furthermore, because all of the vaccines are administered intramuscularly (IM), they are in a liquid form which needs to be preserved at low temperatures. This is a limitation in many countries with meager resources. Furthermore, the vaccine requires an expensive cold chain network for preservation, storage, and transportation, something that many resource-poor countries cannot afford. Therefore, a vaccine formulation that can be preserved, stored, and transported at room temperature would be most preferable and globally applicable. Furthermore, the IM route of administration involves needles, which many patients have a fear of. The anxiety associated with a needle stick and the aftermath of injection consequences result in hesitation among these patients. Thus, a needle-free delivery system can increase the mass vaccination rate.

2.2. Refusal of Vaccines

One major challenge for mass vaccination is the refusal to be vaccinated. The frequency of vaccine refusal, which is associated with many factors, is increasing worldwide. However, the refusal tendency among the population varies from country to country. A study was conducted by Meriggi, N.F. et al. to analyze COVID-19 vaccine acceptance across 15 survey samples covering 10 low- and middle-income countries (LMICs) in Asia, Africa and South America, Russia (an upper-middle-income country) and the United States, for a total of 44,260 individuals ^[4]. The results showed considerably higher willingness to take a COVID-19 vaccine in LMIC samples (mean 80.3%; median 78%; range 30.1 percentage points) compared with the United States (mean 64.6%) and Russia (mean 30.4%). It was found that the higher vaccine acceptance in LMICs is primarily due to individuals’ interests in personal protection against COVID-19, while concern about side effects is the most common reason for hesitancy ^[4].

2.3. Blood Clotting

The blood clotting effect after COVID vaccination has recently received attention from scientists and media. Blood clotting has mostly occurred as a result of the COVID vaccine produced by Johnson and Johnson. Several cases of blood clotting after vaccination have been reported ^[5]. As of 12 April 2021, more than 6.8 million doses of the Johnson & Johnson (Janssen) vaccine had been administered in the U.S. The CDC and FDA reviewed the data involving six reported U.S. cases of a rare and severe type of blood clot in individuals after receiving the J&J vaccine. In these cases, a type of blood clot called cerebral venous sinus thrombosis (CVST) was seen in combination with low levels of blood platelets (thrombocytopenia). Injections of Johnson & Johnson’s coronavirus vaccine were halted across the USA on 13 April 2021, after federal health agencies called for a pause in the vaccine’s use as they examined the rare blood-clotting disorder that emerged in six recipients. Besides the USA, Johnson & Johnson also delayed the rollout of its vaccine in Europe, where several countries were poised to start administering the vaccine at around the same time. Additionally, South Africa, which was devastated by a more contagious variant of the virus that had emerged there, suspended use of the vaccine. Australia also announced it would not purchase any Johnson & Johnson vaccine ^[6].

2.4. Needle Fear

A study was conducted to evaluate the prevalence of needle fear and summarize the characteristics of individuals who exhibit this fear ^[7]. Most children exhibited needle fear, while prevalence estimates for needle fear ranged from 20–50% in adolescents and 20–30% in young adults. In general, needle fear decreased with increasing age. Both needle fear and needle phobia were more prevalent in females than males. Avoidance of influenza vaccination because of needle fear occurred in 16% of adult patients, 27% of hospital employees, 18% of workers at long-term care facilities, and 8% of healthcare workers at hospitals. Needle fear was common when undergoing venipunctures and blood donations, and in those with chronic conditions requiring injection ^[7]. This fear of needles can result in avoidance of preventative measures and treatment of various diseases, including COVID-19. Currently, all the COVID vaccines are IM injectable. As such, needle fear has hindered mass vaccination thus far during the pandemic.

2.5. Route of Administration

Route of administration plays an important role in vaccination outcomes, as it can affect the extent and quality of immune response ^[8]^[9]. Almost all the current COVID vaccines are designed for intramuscular administration. Since COVID-19 primarily causes respiratory infection, developing mucosal immune protection is critical as it provides additional protection. Thus, mucosal vaccinations (e.g., intranasal, pulmonary, oral) might be superior to parenteral vaccinations.

3. Potential of Micro- or Nano Particulate COVID Vaccines

A particulate COVID vaccine can be produced by loading an antigen or drug of interest into nanoparticles or microparticles. These particles can be administered via the oral, sublingual, or buccal route. Particulate vaccines have been developed and studied before. The measles vaccine’s microparticles were made with biocompatible and biodegradable bovine serum albumin (BSA) polymer and processed by spray-dried production of microparticles. These vaccine microparticles were then incorporated into an orally dissolvable film. The vaccine particles were non-cytotoxic, induced a significant innate immune response, and increased the antigen presentation and co-stimulatory molecule expression of antigen-presenting cells. In vivo, the ODF vaccine formulation was tested in juvenile pigs. After 2 weeks, there was a significantly higher antibody titer plateauing through week 6. The results from this study suggest that the ODF measles vaccine formulation is a viable alternative dosage form for noninvasive immunization ^[10].

A particulate vaccine formulation has huge potential, as the particle can possibly be used as antigen carrier and an adjuvant. Particulate carriers can serve as effective antigen delivery systems that are able to enhance and/or facilitate the uptake of antigens by antigen-presenting cells (APCs) such as dendritic cells (DCs) or macrophages ^[11]^[12]. Furthermore, when delivered orally, particulate vaccine formulations have the ability to protect the integrity of antigens against acidic and enzymatic degradation in the stomach and GI tract until they are delivered to the immune cells ^[13]^[14].

Another advantage of using a particulate vaccine formulation is that it can eliminate the use of adjuvants which have minimal immunogenic effect. The immunologic effect of particulate vaccines is related to the size, stability, antigen-loading and antigen-release kinetic properties of the particle ^[15]. The immune response is also influenced by particle interaction with APCs and antigen presentation and processing by APCs ^[16].

Micro- or nanoparticles have some unique physiochemical properties that make them ideal candidates for vaccine delivery. They have a higher surface-to-volume ratio, small size, the ability to encapsulate various drugs, and tunable surface chemistry, all of which gives them many advantages over their bulky counterparts. These advantages include multivalent surface modification with targeting ligands, efficient navigation of the complex in an in vivo environment, enhanced intracellular trafficking, and the potential for addition of charged particles to increase target selectivity and sustained release of drug ^[17]. These advantages make nanoparticles ideal candidates for formulating vaccine delivery systems that can be applied for COVID vaccines.

The advantages of nanoparticle-based delivery of vaccines and drugs include improved biological stability of the antigen or drug and efficacy in targeting APCs for induction of innate and adaptive immunity due to Class I and Class II presentations ^[18]. Nanoparticles may also provide enhanced intracellular concentrations, controlled release of vaccine antigen or drug, and a reduced number of administrations due to enhanced immune response. Furthermore, nano-sized particles can themselves act as immune stimulating adjuvants. Gamvrellis et al. have shown that a nano-particulate antigen delivery system was able to induce a substantial immune response without inducing any inflammation ^[19].

A nanoparticle formulation of a vaccine is more immunogenic when compared to the solution form of the antigen. It has been found that poly (d, l-lactic-co-glycolic acid) nanoparticles (PLGA-NPs) can be used to formulate a vaccine delivery system which has potential in the development of future therapeutic cancer vaccines ^[20]. This nanoparticle can target dendritic cells (DCs) which can effectively initiate antitumor activity. The PLGA nanoparticle-containing antigens along with immune-stimulatory molecules (adjuvants) can target not only DCs but also provide immune activation and rescue impaired DCs from tumor-induced immunosuppression ^[1]. The authors further assessed the extent of maturation of DCs after treatment with the antigen, monophosphoryl lipid A (MPLA), and encapsulated PLGA nanoparticles. The generation of primary T-cell immune responses elicited by DCs was monitored. Results showed that the high amounts of pro-inflammatory and TH1 (T helper 1) polarizing cytokines and chemokines released by the nanoparticles are greater than that achieved by MPLA in solution ^[21].

Biodegradable and biocompatible polymers, copolymers and lipids can be used for COVID particulate vaccine preparation. It has been found previously that these polymers have been used to prepare nano/micro-particles as vaccine-delivery systems ^[19]^[22]^[23]. The material is selected based on several factors, including biocompatibility, degradation rate, hydrophilicity or lipophilicity, surface charge, and polarity. The SARS-2 virus infects mainly the area of the lungs, therefore nanoparticulate formulation has the advantage in fighting this virus due to their ability to reach deeper into the lung area.

Figure 1 shows how the spray drying method can be utilized for producing nano- or microparticles ^[24]^[25]. A biodegradable polymer-based particulate vaccine can act as an adjuvant itself. Therefore, there may be no need for using salt-based adjuvants, thus, eliminating the adverse effects caused by adjuvants. In addition, it is also possible to increase the efficiency of the particulate vaccine by adding appropriate ligands, charged particles or any other biocompatible chemicals to increase the specificity of the nano- or microparticles for targeted delivery ^[26].

Figure 1. Formulation of microparticles or nanoparticles using spray drying method.

4. Possible Particulate COVID Vaccine Delivery System for Oral, Sublingual and Buccal Administrations

4.1. Oral Administration

Oral administration is the most preferred route for drug delivery as it is the most patient compliant. Oral administration of vaccines is more acceptable to the patient as it is needle-free, easy to administer, requires less-trained personnel for administration, and is easy to apply to the mass population. One of the most common oral vaccines is the oral polio vaccine, which has been used to eradicate polio. The oral polio vaccine has been the mainstay of the global polio eradication initiative (GPEI) in most countries. The polio vaccine allows for the encounter of the polio virus by the immune system to be less threatening while still allowing the body to mount a humoral response for protection against any future exposure to the virus ^[27]. Upon administration, the vaccine elicits a local immune response in the intestinal mucous membranes, a location at which the poliovirus multiplies ^[27]^[28]. After administration, the live-attenuated oral poliovirus vaccine replicates in gut-associated tissues, eliciting mucosal and systemic immunity. The oral polio vaccine is both therapeutic and preventative, protects from disease, and limits poliovirus spread. As such, mass vaccination with the oral polio vaccine has been used as a strategy to end the circulation of all polioviruses ^[29].

Acknowledging this, developing an oral COVID vaccine with high efficiency and low cost will eliminate the limitations that the current vaccines have. The oral route will also eliminate the need for trained personnel to administer the vaccine, which will give the vaccine a more global character as it will be easily available and applicable in resource-poor countries. In addition, oral vaccines have the potential to stimulate mucosa-associated lymphoid tissue (MALT) located in the digestive tract and gut-associated lymphoid tissue (GALT). About half the lymphocytes of the immune system are in the MALT ^[30]. Structurally, MALT tissue ranges from loose, barely organized clusters of lymphoid cells in lamina propria of intestinal villi to well-organized structures such as tonsils, appendix and Peyer’s patches ^[31]. The tonsils are found in three locations: lingual at the base of the tongue, palatine at the sides of the back of the mouth, and pharyngeal, in the adenoids. Also, under the epithelial cell layer of lamina propria and tonsils, there are many B cells, plasma cells, activated TH cells, and macrophages ^[31]. MALT can be functionally divided into effector and inductive sites ^[30]. Inductive sites contain secondary lymphoid tissues in which IgA class switching and clonal expansion of B-cells occurs in response to antigen specific T-cell activation. After activation and IgA class switching, T- and B-cells migrate from inductive sites to effector sites. Effector sites are present in all mucosal tissues as disseminated lymphoid tissues diffusely distributed throughout the lamina or substantia propria ^[30]. In effector sites, secretory IgA, or S-IgA (two IgA molecules joined by a J-chain and bound to a secretory component, an epithelial cell membrane receptor) is secreted across the mucosal epithelium ^[32]. Therefore, oral administration, and even sublingual and buccal administration, takes advantage of this location and structure of MALT tissues. For the SARS-2 virus, an elevated mucosal immune response could serve as a first line of protection against infection. The oral delivery of vaccines as an alternative immunization route and the efficiency of mucosal immunization for different antigens has been studied ^[33]. In addition, the intranasal route of administration for vaccine delivery has been investigated. Results from studies of both oral and intranasal routes of administration show the potential of mucosal immunization with VLP-based HPV vaccines ^[33]^[34]. A COVID vaccine which is mRNA-based is in particulate form with lipids but is injected as a solution via the IM route. Therefore, the vaccine is already in particulate form, which can be converted into microparticles by adding other polymers, and these microparticles can be delivered via the oral route in solution or suspension form.

Also, when dosed intranasally, a vaccine is intrinsically prone to inducing Th17 immune responses ^[35], which may not be ideal for the clearance of SARS-CoV-2 viral particles from the lungs. Another limiting factor for a nasal or pulmonary COVID-19 vaccine is the need for a special and costly delivery device, which may also exert pressure on the vaccine formulation. For example, a loss of virus titer was observed when using a nebulizer to deliver a live virus formulation ^[36]. Therefore, it is not surprising that almost all COVID-19 vaccine candidates advanced to clinical trials are given by injection (see Table 1), although they may not induce specific mucosal immunity ^[37].

Table 1. List of some of the current marketed and investigational vaccine candidates for SARS-CoV-2.

Vaccine Candidates	Classification of Vaccine	Clinical Phase	Lead Development Company/Collaboration
GRAd-COV2	Adenovirus-based vaccine	Phase 1	ReiThera; Leukocare; Univercells; Lazzaro Spallanzani National Institute for Infection
ChAd-SARS-CoV-2-S	Adenovirus-based vaccine	Preclinical	Washington University School of Medicine in St. Louis
LinealDNA	DNA Vaccine	Preclinical	Takis Biotech
AG0301-COVID19	DNA vaccine	Phase 1/2	AnGes, Inc.
GX-19	DNA vaccine	Phase 1/2	Genexine
INO-4800	DNA vaccine (plasmid)	Phase 1/2	Inovio Pharmaceuticals; Center for Pharmaceutical Research, Kansas City. Mo.; University of Pennsylvania, Philadelphia
ZyCoV-D	DNA vaccine (plasmid)	Phase 2	Zydus Cadila
AAVCOVID	Gene-based vaccine	Preclinical	Massachusetts General Hospital; University of Pennsylvania
No name given	gp96-based vaccine	Preclinical	Heat Biologics; University of Miami Miller School of Medicine
No name given	Ii-Key peptide COVID-19 vaccine	Preclinical	Generex Biotechnology
No name given	Inactivated vaccine	Phase 1/2	Research Institute for Biological Safety Problems, Rep of Kazakhstan
No name given	Inactivated vaccine	Phase 3	Wuhan Institute of Biological Products; China National Pharmaceutical Group (Sinopharm); Henan Provincial Center for Disease Control and Prevention
Covaxin	Inactivated vaccine	Phase 2	Bharat Biotech; National Institute of Virology
No name given	Inactivated vaccine	Phase 1/2	Chinese Academy of Medical Sciences, Institute of Medical Biology; West China Second University Hospital, Yunnan Center for Disease Control and Prevention
No name given	Inactivated vaccine	Preclinical	Shenzhen Kangtai Biological Products
BBIBP-CorV	Inactivated vaccine	Phase 3	Beijing Institute of Biological Products; China National Pharmaceutical Group (Sinopharm); Henan Provincial Center for Disease Control and Prevention
CoronaVac	Inactivated vaccine (formalin with alum adjuvant)	Phase 3	Sinovac; Sinovac Research and Development Co., Ltd.
AdCOVID	Intranasal vaccine	Preclinical	Altimmune; University of Alabama at Birmingham
T-COVIDTM	Intranasal vaccine	Preclinical	Altimmune
Bacillus Calmette-Guerin (BCG) vaccine	Live-attenuated vaccine	Phase 2/3	University of Melbourne and Murdoch Children’s Research Institute; Radboud University Medical Center; Faustman Lab at Massachusetts General Hospital
V591	Replicating viral vector	Phase 1	University of Pittsburgh’s Center for Vaccine Research; Themis Biosciences; Institut Pasteur
bacTRL-Spike	Monovalent oral vaccine (bifidobacteria)	Preclinical	Symvivo
COVAX-19	Protein subunit Monovalent spike protein vaccine	Phase 1	Vaxine Pty Ltd.; Royal Adelaide Hospital
No name announced	mRNA lipid nanoparticle	Early research	CanSino Biologics, Precision NanoSystems
mRNA-1273	LNP-encapsulated mRNA vaccine	Phase 3	Moderna; Kaiser Permanente Washington Health Research Institute
BNT162	3 LNP-mRNAs-based vaccine	Phase 3	Pfizer, BioNTech
CVnCoV	mRNA-based vaccine	Phase 1	CureVac
No name given	mRNA-based vaccine	Preclinical	Chulalongkorn University’s Center of Excellence in Vaccine Research and Development
UB-612	Multitope peptide-based vaccine	Phase 1	COVAXX; United Biomedical Inc. (UBI)
JNJ-78436735	Non-replicating viral vector	Phase 3	Johnson & Johnson
Sputnik V COVID-Vac; Гам-КОВИД-Вак²⁰	Non-replicating viral vector Adenovirus-based vaccine	Phase 3	Gamaleya Research Institute, Acellena Contract Drug Research and Development
EpiVacCorona	Peptide vaccine	Phase 1/2	Federal Budgetary Research Institution State Research Center of Virology and Biotechnology
No name given	Plant-based adjuvant vaccine	Phase 1	Medicago; GSK; Dynavax
No name given	Protein subunit vaccine S protein²⁰	Phase 1/2	Sanofi; GlaxoSmithKline
No name given	Protein subunit RBD-based vaccine	Phase 1/2	Kentucky Bioprocessing, Inc.
AdimrSC-2f	Protein subunit vaccine	Phase 1	Adimmune
No name given	Protein subunit vaccine	Phase 1	CSL; The University of Queensland; Seqirus
SCB-2019	Protein subunit vaccine	Phase 1	GlaxoSmithKline, Sanofi, Clover Biopharmaceuticals, Dynavax and Xiamen Innovax; Linear Clinical Research (Australia)
No name given	Protein subunit vaccine	Preclinical	University of Saskatchewan Vaccine and Infectious Disease Organization-International Vaccine Centre
PittCoVacc	Recombinant protein subunit vaccine	Preclinical	UPMC/University of Pittsburgh School of Medicine
RBD-Dimer (relief)	Protein subunit Adjuvanted recombinant protein	Phase 2	Anhui Zhifei Longcom Biopharmaceutical, Institute of Microbiology of the Chinese Academy of Sciences
No name given	Recombinant vaccine	Preclinical	Sanofi, Translate Bio
Ad5-nCoV	Recombinant vaccine (adenovirus type 5 vector)	Phase 3	CanSino Biologics; Tongji Hospital
VXA-CoV2-1	Recombinant vaccine (adenovirus vector)	Phase 1	Vaxart
V590	Recombinant vaccine (stomatitis virus)	Phase 1	Merck; IAVI
DelNS1-2019-nCoV-RBD-OPT1	Replicating viral vector	Phase 1	Xiamen University, Beijing Wantai Biological Pharmacy; Jiangsu Provincial Centre for Disease Control and Prevention
No name announced	Replicating viral vector	Preclinical	Federal Budgetary Research Institution (FBRI); State research center of virology and biotechnology “VECTOR”
AZD1222 ChAdOx1-S²⁰	Non-Replicating viral vector vaccine	Phase 3	The University of Oxford; AstraZeneca; IQVIA; Serum Institute of India
HDT-301	RNA vaccine	Preclinical	University of Washington; National Institutes of Health Rocky Mountain Laboratories; HDT Bio Corp.
LNP-CoVsaRNA	Self-amplifying RNA vaccine	Phase 1/2	Imperial College London
HaloVax	Self-assembling vaccine	Preclinical	Voltron Therapeutics, Inc.; Hoth Therapeutics, Inc.; MGH Vaccine and Immunotherapy Center
LUNAR-COV19 ^[38]	Self-replicating RNA vaccine	Phase 1/2	Arcturus Therapeutics and Duke-NUS Medical School
CDX-005 ^[39]^[40]	Weakened	Phase 1	Codagenix, Serum Institute of India

4.2. Film-Based Particulate COVID Vaccine for Sublingual and Buccal Administration

Although placed in the oral cavity, the administration of drugs via sublingual and buccal routes are different from oral (per oral, PO) administration. Unlike oral routes, sublingual, or buccal routes are systemic, directly accessible to the blood. The nano- or microparticle of vaccine-loaded films can be prepared by solvent casting or using a 3D bioprinter (Figure 2) ^[41]. Instead of passing through the GI tracts such as the esophagus, stomach or intestine, the drug can directly enter the blood through the membrane. Medications taken by buccal or sublingual administration provide consistent drug concentration levels in the blood, dissolve quickly, have immediate onset of action, and can avoid the first pass effect. Since there is no first pass effect, the bioavailability is high. Therefore, compared to oral administration, less drug can be used to elicit the desired effect. Additionally, the patient does not need to swallow the drug in sublingual or buccal administration. Another advantage of buccal and sublingual administration is that they do not subject proteins and/or peptides to the degradation that is usually caused by gastrointestinal administration ^[42]. Also, oral films are easy to prepare, administer, and handle. Normally, any biodegradable and biocompatible polymers can be used to prepare the film, including any other material needed such as a permeation enhancer, plasticizer, etc., in a simple method ^[42]. The most important advantage of buccal and sublingual administration is that the vaccine can produce both systemic and mucosal immunity ^[43]. SARS-2 virus infects the host through the mucosa. Several signs after COVID infection, such as loss of taste, dry mouth, and mucosal lesions such as ulcerations, enanthema, and macules imply that the virus infects the mucosa. However, the mucosal infection has not been completely understood. To address this, Sinjari B et al. and Huang et al. have generated and analyzed two single-cell RNA sequencing datasets of the human minor salivary glands and gingiva. Their studies showed that the oral cavity is an important site for SARS-CoV-2 infection and implicates saliva as a potential route of SARS-CoV-2 transmission ^[44]^[45]. Therefore, an ideal COVID vaccine should induce protective immunity at mucosal sites to act as a first line of defense against infections. However, most of the vaccines currently in use are administered via injection (such as intramuscular route) and have very limited mucosal immunity. However, vaccines administered via mucosal routes have proven to be effective for the induction of both systemic and local immunity ^[46]. Additionally, mucosal immunization via sublingual and buccal administration makes vaccine delivery easier and safer than parenteral administration routes. These are very suitable for mass immunizations during pandemic situations and improve vaccine acceptability, especially among children ^[47]. Therefore, mucosal administration of vaccines via buccal or sublingual routes could be a great choice for mass protection. Among the two, buccal drug delivery was identified as a better option for administration. A quickly-soluble tablet or film dosage form can be used as drug carrier for buccal administration. The quickly-soluble oral film dosage form has several advantages over other dosage forms for vaccines or drugs. Lower bioavailability of solid oral drugs, the inconvenience of administering injections, and inaccurate dosing by liquid formulations have turned the focus of pharmaceutical companies to developing oral film forms of medications that eliminate several of these limitations. Oral films are easy to prepare, administer, and handle. Normally, any biodegradable and biocompatible polymer can be used to prepare the film, including any other material needed such as permeation enhancer, plasticizer, etc., by a simple method.

Figure 2. Formulation of oral dissolving films (ODF) with either microparticles or nanoparticles using 3D bioprinter.

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