Oral Thin Films as Placebo Substrate: Current Innovation in Printing Technology

The achievements of new drug development over the last few years have been greater than ever before. The new concepts of the dosage forms design and innovation of manufacturing technology have a strong influence on the pharmaceutical development of new drugs. Recently, demands for a unique approach for individualised and customised medicines with the usage of different types of printing technologies. i.e. 2D and 3D printing technology. 2D printing is the phenomenon of putting an image or design on edible substrate. Despite the advantages to drug administration, oral route is the first choice by patients as Oral Film Technology (OFT) is gaining much attention. As 2D printing technology has been adapted in manufacturing of printed Oral Thin films. Drug loaded printing ink was developed with their optimized properties and printing was carried out on the placebo substrate i.e oral thin film. New manufacturing techniques for formulation of printed oral thin films are related to the drop on demand technology, flexographic method extrusion-based methodology   , which mainly includes the semi-solid extrusion (SSE) and the fused deposition modelling (FDM), based 3D printing.

API-containing dispersions and solutions   that were formulated in water, ethanol or other organic solvents with different viscosities, have already been applied onto OTFs. Other than execution of printing innovation, the influences of the OTF substrate on the resulting film quality should not be neglected. Previous study demonstrated that placebo substrate of OTF have a great influence on behaviours printing technologies and performance of printing ink.¹ Here we are mainly focusing of the placebo substrate used in printing of oral thin films. OTFs are selected because of its ease of administration, attractiveness, flexibility, and patient compliance, drug administration via the oral route is the most convenient option.

In Drop on demand technique, the high viscous solutions or hydrogel suspensions are extruded to obtain single layer structures with edible carrier substrate ^2. In case of inkjet bioprinting, low viscous solutions like solutions are deposited as droplets at high shear rates. For both types of ink solution properties requires edible paper to print 2D design which have mechanical properties, adherence property with the printing ink, absorption capacity to print viable type of design printing on substrate. Selection of placebo substrate is dependent on the newtanion and non-newtanian properties of the printing inks. The use of a range of different substrates, including edible substrates such as icing sheets, polymeric and starch films, and non-edible substrates, such as paper and acetate, has been reported.

The properties of the substrate that contribute to the control of the printed substances will be many such as porosity and surface energy. Additionally, the surface roughness, elevated loading capacity, capillary action, and chemical components on the surface will play an integral role.³ A substrate should be able to absorb an adequate amount of the deposited ink to achieve a sufficient dose of the printed drugs in the dosage form.⁴ This review will introduce some 2D printing technologies suitable for pharmaceutical manufacturing and their applications to the development of printed oral thin films, indicating the feasibility of this technology in regular commercial production.

Oral thin films (OTFs):

Oro-dispersible films are single or multilayer sheets built of the right materials that are intended to swiftly release the loaded active ingredient in the mouth, creating a thin suspension or solution in the saliva without mastication or water intake. These oral thin films are designed in such a way that water is not necessary for administration since they immediately break apart within a few seconds, releasing the medication into the mouth. When placed on the tongue, Oral Thin films quickly hydrate by soaking up saliva once the dosage form's active pharmaceutical ingredient disintegrates and/or dissolves. These thin films come in a variety of sizes and forms. These have great mucoadhesion and quick release and dissolution. These movies are useful for patients who are bedridden, emetic, experiencing diarrhoea, an allergic attack, or coughing and lead an active lifestyle. They are also useful for children, the elderly, and patients who are paediatric or geriatric. Additionally, it is helpful for localised actions like local anaesthesia for toothaches, mouth ulcers, or teething.⁵

Advantages

• Ease of administration
• Convenient in dosing
• Zero chance of choking
• Increased steadiness
• Better compliance from the patient
• Taste of bitter drugs can be masked
• Site specific and has local action
• Rapid drug release due to rapid disintegration and dissolution of films

Disadvantages

• Unlike orally dissolving tablets, these OTFs cannot have a higher dose added to them.
• Because of its hygroscopic nature and the need for specialist, packaging, longer preservation is problematic.
• It is prohibited to provide medications that are unstable at buccal pH.
• A lengthy period of no eating or drinking after ingesting ODFs.
• Compared to oral dissolving pills, these films are prepared using pricey methods.

Printing technologies for film-based drug delivery systems⁶

Inkjet Printing Method:

In general, inkjet printing describes systems which use pattern generating devices to digitally control and place small liquid drops on a substrate. In pharmaceuticals, appropriate mixtures of drug, along with suitable excipients (known as ink) are deposited as small drops in a layer wise fashion on a suitable substrate. Continuous inkjet printing (CIJ) and drop on demand (DoD) are the two main inkjet printing platforms.

1. Continuous Inkjet Printer: As the name suggests, continuous inkjet printers eject stream of liquid droplets on a substrate continuously, even when the droplets are not necessary. Here, a pressure wave is generated into the ink stream, which breaks up the ink into uniform-sized droplets by means of vibration of the nozzle and then ejects the droplets out of the nozzle. Since it ejects droplets continuously, this technology leads to the wastage of ink. The advantages of this printing technology include high-speed continuous droplet generation, due to which the nozzle does not get clogged easily. Disadvantages include low-resolution and expensive maintenance.
2. Drop-on-Demand Inkjet Printer: In these printers, drops of liquid are ejected from the printhead due to a trigger signal, only when it is necessary, and the drops are deposited onto a substrate. This type of printer typically contains many nozzles. Contrasting the continuous inkjet printer where ejection of droplets is due to the external pressure, drop-on-demand inkjet printers have the drops kinetic energy derived from sources close to each nozzle and located within the printhead. This technology is relatively simple, offers high precision, and is low cost. Drop-on-demand inkjet printer can be further classified, based on the type of printhead, into thermal inkjet and piezoelectric inkjet printer. These can also be classified into drop-on-drop or drop-on-solid on the basis of the substrate on which the printhead deposits the drops.

1. Thermal Inkjet Printer (TIJ): 

Here, thermal energy is the trigger mechanism used to discharge droplets, which then exit the nozzle. The printheads have resistors embedded in them which are in immediate exposure with the fluid (ink) and which upon induction of electric current produce heat. This heat then results in the formation of a bubble within the volatile fluid, which then expands and ejects a small volume of fluid out of the nozzle forming a droplet. The main limitation of this technique is the use of high temperatures (200–300°C) of the resistor, which might lead to the degradation of thermolabile active ingredients.⁷

Fig. 1 Schematic diagram of 2D printing Process using Pneumatic Based printer

2. Piezoelectric inkjet printer (PIJ):

This technology composes of a piezoelectric element that changes its shape in response to an electric voltage. This generates a pressure, which leads to the fluid (ink) being ejected out of the nozzle. After the element gets back to its actual shape, the nozzle is reloaded with the fluid and is ready to be activated again. The main advantages of this technique include its operability at room temperatures using less volatile and more biocompatible fluids. In this technology “valve jet” or “electromagnetic” printing was used as pharmaceutical printing, which was based on miniature solenoid valves. A glass inkjet tool was developed to eject droplets at high frequencies. UV curing has been used to harden materials rapidly on-demand in the inkjet printing industry. The ink used here contains crosslinking functional groups which get triggered by light and a photo-initiator is often used to promote this process.⁸

Fig.2 Schematic diagram of 2D printing Process using Thermal Inkjet printer (20)

Categories of various films for Oral drug delivery

The thin film mainly made of hydrophilic polymers is a rapidly developing area in oral dosage form that rapidly dissolves on the tongue or buccal cavity, delivering the drug to the systemic circulation via dissolution when contact with liquid is made. Oromucosal film preparations are placed in the mouth to dissolves rapidly (orodispersible film, ODF) or are attached to the mucosal tissue (mucoadhesive buccal film, MBF) , quickly releasing the drug by dissolving or adhering in the mucosa with saliva within a few seconds due to it contains water-soluble polymers when it placed in the mouth cavity or on the tongue may dissolve according to the definition of the European Pharmacopoeia, which introduced these novel dosage forms in 2012. As OTFs may be described as an alternative per oral dosage form, MBFs also offer a variety of drug delivery options, such as oral patches, which have accessibility of larger surface area leads to quick disintegration and dissolution in the oral cavity within seconds due to rapid wetting by saliva. The description ‘buccal’ film or patch is most common; however, the film may be applied onto other Oromucosal sites such as the sublingual, gingival, and palatal or labial tissue. Furthermore, the films may consist of a single layer or multiple layers.⁹

METHOD OF PREPARATION OF PLACEBO SUBSTRATE: -

There are five methods, which are used alone or in a combination with the following process for the manufacture of the fast-dissolving oral films

1. Solvent casting
2. Semisolid casting
3. Hot melt extrusion
4. Solid dispersion extrusion
5. Rolling

1. Solvent casting

Water soluble polymers and plasticizers are dissolved in a acceptable volatile solvent like Ethanol or distilled water to form a clear viscous solution. Solution is stirred for 2hrs in the magnetic stirrer and kept aside active pharmaceutical ingredient and other ingredients are dissolved in aqueous solvent and are combined with the bulk. The entrapped air is separate by vacuum Finally the solution is casted into a acceptable Petri dish and dried in an oven at 50 oC for 24 hrs Film is cut into desired size and shape.^10,21

2. Semisolid casting

Solution of water-soluble film forming polymer is prepared It is poured into the solution of acid insoluble polymers in the ratio of 1:4. A gel mass is obtained by the incorporation of relevant quantity of plasticizer it is casted into the films or ribbons by using heat-controlled drums. The diameter of the film should be about 0.015 - 0.05 inches.¹¹

3. Hot melt extrusion

In hot melt extrusion method essentially, the drug is mixed with carrier in solid form. Then dried granular material is introduced into the extruder. The short speed should set at 15 rpm to process the granules inside the barrel of the extruder for approximately 3 – 4 min. The processing temperatures should be 800C (zone 1), 1150C (zone 2), 1000C (zone 3) and 650C (zone 4). The extrudate (T = 650C) then depressed into a cylindrical calendar to obtain a film. There are certain comforts of hot melt extrusion.¹¹

Types of placebo substrate for printing: -

1. Non-porous substrate: -The non-porous substrate has ability that any kind of liquid and air cannot penetrate on it, and they just remain on the surface. In this type of substrate liquid spots solidify in the shape of spherical caps. Printed spots solidify in the form of solid protuberances shaped as spherical caps.³
2. Porous substrate: -A coating with pores and pinhole defects creates ways for corrosive fluids or aggressive chemicals to attack the substrate material and leads to structure failure. A porous surface may also be known as a porous substrate. In Hydrophilic porous film where the spots are gets spreads. Here, the ink was absorbed within the film.¹²
3. Solid foams as substrate: -These are thick, hygroscopic soft sponge-like substrates which had a superior absorption capacity and fast penetration speed for the different solvents due to While the printing technology already enables a precise dosing of fluids, there is still a high need of suitable, edible templates with elevated loading capacity. The open cell pore structure and higher porosity as compared to no plasticized additive-free foam.¹²

Different polymers used in substrate preparation: -

Different types of polymers used for the preparation of substrate were listed as follows: (Refer Table No 1)

1. Cellulose based substrate: -Cellulose derivatives are polysaccharides composed of linear chains of β (1–4) glucosides units with methyl, hydroxypropyl or carboxyl substituents. Only four cellulose derivative forms are used for edible coatings or films: Hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), Carboxymethylcellulose (CMC)or Methyl cellulose (MC).¹³
2. Gelatin based substrate: - Gelatin preparation may or may not involve alkaline pretreatment, which resulting in greater viscosity and acid pretreatment (type A gelatin) uses pig skin, whereas the alkaline pretreatment (type B gelatin) uses cattle hides and bones. All types of gelatin have similar composition, containing water, a small amount of minerals and pure connective tissue protein.13 The mechanical properties and film forming ability of gelatin films are directly related to the molecular weight, i.e., the higher the average molecular weight, the better the quality of the film. An alternative to enhance the gelatin-based films properties that has attracted the interest of researchers is related to the reinforcement of 3D printed patches.¹⁴
3. Corn starch-based substrate: -Corn starch is widely used in the form of biodegradable films in varied applications because it is a renewable, abundant, and inexpensive material.  Corn starch contains a high amount of amylose, at approximately 25%, thus it can be utilized in developing the film matrix. Increase of nutmeg oil nano emulsion concentration could increase the film thickness.¹⁵
4. Pullulan based substrate: - Pullulan (PUL) is an exopolysaccharide polymer that is garnering attention for OFs, due to its biocompatibility, biodegradability, and non-mutagenic, non-carcinogenic and immuno-neutrality properties Furthermore, as a biopolymer. Pullulan is abundant, biodegradable, and sustainable for the environment. Recently, the suitability of PUL for OFs has been explored because of its excellent film-forming properties and it has demonstrated considerable mechanical strength and water-solubility, as well as being odourless and tasteless. Moreover, PUL based films exhibit fast disintegration times Despite its remarkable versatility and unique characteristics, the shortcomings of pullulan are its brittleness and high cost.¹⁶

Table no. 1 - Recent works on natural and synthetic polymeric thin films and drug used in printed ink formulations of printing technology.

Printing patterns on the placebo substrate:

On the substrate, various printing patterns can be considered. Print on the entire surface of the base film or just the centre portion with the drug-loaded ink. For specific low-dose formulations, point-by-point printing technologies seem viable. One way to make printed fixed-dose combinations easily identifiable is to employ two or more distinct dyed inks with different APIs. Another approach is line printing, which involves using asymmetrically placed lines to provide different dosing possibilities based on the cutting pattern. creating ink formulations that enable the construction of arbitrary geometric structures to regulate medication release in response to variations in the placebo substrate's surface area.⁶ (Refer Table No.02)

Table No 02: Various Technology and their printing Pattern as per literature survey