Description:Technical field
The present disclosure is in relation to fabrication of oral thin film formulations. Particularly, the disclosure is directed towards a platform technology to fabricate Orodispersible Film (ODF) formulations loaded with various active pharmaceutical compositions and/or dietic substances for subjects who are in need thereof.
Background
The process of ‘swallowing’ is a complex series of muscular contractions and coordinated movements of tongue, throat and oesophagus to facilitate movement of food and/or liquid from mouth to the stomach. In conditions such as presbyphagia (age related swallowing problem) and dysphagia (swallowing problem due to medical condition) patients often face considerable problems to swallow the medication. Oral drug delivery is still considered as the most popular route of drug administration. Nonetheless, solid oral dosage formulations such as tablets and capsules are difficult to consume by the patient population who have vomiting tendency, bipolar disorder, oral cancer, and Parkinson’s disease. To circumvent this difficulty, orally disintegrating tablets (ODTs) evolved as an alternative to conventional tablet and capsule formulations. Nonetheless, ODTs face technical challenges such as employing strict dehumidification to maintain stability, taste masking attempts leading to size increase, ‘candy’ perception leading to overconsumption, being brittle in strength, and fear of choking. These limitations are systematically conquered by a new patient-centered pharmaceutical dosage form known as Orodispersible Film formulation. It’s a type of oromucosal preparation with reduced disintegration time in the oral cavity compared to ODTs.
ODFs when administered to tongue are instantly hydrated to rapidly disperse in oral cavity which is swallowed naturally along with saliva to get absorbed into the systemic circulation via the gastro-intestinal tract. Most importantly, ODFs do not require the user to masticate or consume water as seen with administration of traditional solid dosage forms (tablets or capsules). ODFs are fabricated by different methods namely solvent casting method, extrusion method, electrospinning method and printing methods. Nonetheless, each of these traditional methods is associated with various limitations/ challenges in preparing an ideal orodispersible film formulation. Accordingly, the present disclosure is focused in this direction to offer a technology to fabricate ideal orodispersible films loaded with pharmaceutical compositions and/or dietic substances. Additionally, the information disclosed in this background section is only for enhancement of understanding of the general background of the disclosure and should not be taken as an acknowledgement or any form of suggestion that this information forms the prior art already known to a person skilled in the art.
Objectives
First and foremost objective of the present disclosure is to develop a platform technology to fabricate orodispersible films loaded with pharmaceutical compositions and dietic substances.
Secondly, the disclosure is aimed at developing an optimized process to fabricate ideal orodispersible films loaded with pharmaceutical compositions and dietic substances.
Summary
One or more shortcomings of fabricating orodispersible films are overcome and additional advantages are provided through the optimized process as claimed in the present disclosure. Additional features and advantages are realized through the techniques of the present disclosure. Other embodiments and aspects of the disclosure are described in detail herein and are considered a part of the claimed disclosure.
The present disclosure provides a process for preparing a homogeneous, air-bubble free, and rapidly disintegrating ultra thin orodispersible film formulation. The proposed process comprises steps of combining an active ingredient(s) with a first film-forming agent at a ratio ranging from 1:25 to 2:50 to obtain a first mixture. Secondly, combine the first mixture with a plasticizer at a concentration ranging from 2.5% w/v to 7.5% w/v and organoleptic agents to obtain a second mixture. Thirdly, feeding the second mixture into a hot-melt extruder at a rate ranging from 1 to 4 gm/minute to obtain a homogeneously mixed and melted extrude filaments of the mixture via barrels of the extruder. Fourthly, comminuting the extruded filaments to obtain fine powder followed by sieving to obtain uniform-size reduced particles, dissolving the uniform-size reduced particles in a second film-forming solution having concentration ranging from 2% w/v to 8% w/v followed by addition of 1% w/v to 3% w/v second plasticizing agent to obtain a homogeneous casting solution. Thereafter, deaerating the casting solution under vacuum for a time period ranging from 1.5 hours to 3 hours to remove air bubbles from the casting solution followed by layering in an automatic film-forming machine to obtain orodispersible film of thickness ranging from 250 to 300µ; and drying the orodispersible film followed by slitting using a slitting machine, cutting and packaging orodispersible films.
The foregoing summary is illustrative only and is not intended to be in any way limiting. In addition to the illustrative aspects, embodiments, and features described above, further aspects, embodiments, and features will become apparent by reference to the drawings and the following detailed description.
Brief description of the accompanying drawings:
The features of the present disclosure will become more fully apparent from the following description and appended claims, taken in conjunction with the accompanying drawings. Understanding that these drawings depict only several embodiments in accordance with the disclosure and are therefore not to be considered limiting of its scope the disclosure will be described with additional specificity and detail through use of the accompanying drawings.
Figure 1: shows release profile for ODFs of histamine analog
Figure 2: shows release profile for ODFs of non-steroidal anti-inflammatory class of drug
Detailed Description
Before explaining any one embodiment of the present disclosure by way of drawings, experimentation, results, and pertinent procedures, it is to be understood that the disclosure is not limited in its application to the details as explained in below embodiments set forth in the following description or illustrated in the drawings, experimentation and/or results. The disclosure is further capable of other embodiments which can be practiced or carried out in various ways. As such, the language used herein is intended to be given the broadest possible scope and meaning; and the embodiments are meant to be exemplary and not exhaustive. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting.
Definitions:
The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
‘Drug’ shall mean any active pharmaceutical ingredients or any active agent that are associated with an intended therapeutic benefit.
‘Nutrients’ or ‘Micronutrients’ shall mean organic molecules that are essential in small quantities for normal functioning of metabolism in human body – example iron, copper, molybdenum, chlorine, zinc, boron and manganese. Also, it includes vitamins (fat soluble and water soluble vitamins) and phytochemicals/ phyto nutrients. These are also termed as dietic substances.
‘Orodispersible film(s)’ or ODF or ODFs shall mean thin sheets that disintegrate rapidly when placed/ administered to the tongue as they easily get hydrated due to the saliva in oral cavity.
‘Hot-Melt Extrude’ or HME shall mean melting and mechanically processing polymers above its glass transition temperature (Tg) to effect molecular mixing of polymers, plasticizers, drug substances and other agents. In other words, HME is nothing but a process of applying heat and pressure to melt a polymer and force it though an orifice in a continuous process to obtain the extrudate as filaments or pellets. The process of hot melt extrusion is carried out using an extruder, which is nothing but a barrel containing one (single screw) or two co/counter-rotating screws (twin-screw) that help in melting, mixing and conveying the material down the barrel as filaments or pellets.
‘Extruder’ – shall mean the machinery employed in HME is called ‘extruder’ and the mixture that is feed and obtained after the HME process is called as ‘extrude’.
‘Barrel’s’ – shall mean different compartments in the extruder with different processing temperature.
“Film-forming substance” shall mean a substance capable of forming a cohesive, solid or gelatinous film or layer. The film or layer in particular can be formed by casting or otherwise applying a formulation containing the film-forming substance solved or dispersed in a solvent, and optionally further ingredients onto a surface. Preferably, the film-forming substance is a water-soluble polymer such as hydroxypropyl cellulose, pullulan and others that are obvious to a person skilled in the art.
“Plasticizer” shall mean a substance/ agent used to improve the flexibility of the orodispersible film. The plasticizer may be one selected from the group consisting of sorbitol, malitol, xylitol, glycerol, polyethylene glycol, propyleneglycol, hydrogenated starch syrup, starch syrup, triacetin, glycerol oleate, glycerol, sucrose fatty acid ester and double chain fatty acid. Preferably, the plasticizer used in the present invention is glycerol and polyethylene glycol 6000.
“Organoleptic agents” shall mean sweetening agents, coloring agents, and flavoring agents. No coloring agents were employed in the present disclosure.
“Sweetening agents” shall mean agents that impart more pleasant taste to the orodispersible film formulation. Generally, the sweetener may be at least one selected from the group consisting of sucrose, glucose, maltose, sucralose, oligosaccharides dextrin, alpha cyclodextrin, beta cyclodextrin, gamma cyclodextrin, methyl beta cyclodextrin, aspartame, cluster dextrin, invert sugar, fructose, lactose, galactose, starch syrup, sorbitol, malitol, xylitol, erythritol, hydrogenated starch syrup, mannitol, trehalose. Preferably, the orodispersible film of the present invention comprises sucralose or aspartame.
“Flavoring agents” shall mean any natural or artificial flavor or a combination thereof. The natural flavor may include aromatic plants, especially extracts and/oils obtained from leaves, flowers or fruits of such plants and can include spearmint oil, cinnamon oil, peppermint oil, lemon, oil, clove oil, bay oil, thyme oil, nutmeg oil, sage oil, almond oil etc. The artificial flavoring may include synthetic fruit flavors such as lemon, orange, grape, lime, strawberry, etc and other synthetic flavors such as vanilla, chocolate, coffee, cocoa, ginseng, citrus etc. Preferred flavoring agent employed in the present disclosure is peppermint oil.
“Acidic agent” shall mean a substance that serves to control taste together with the sweetener. Besides, it stimulates secretion of saliva in order to dissolve the orodispersible film. The acidic agent may be at least one selected from the group consisting of citric acid, malic acid, fumaric acid, tartaric acid, ascorbic acid, succinic acid, adipic acid, lactic acid. Preferable acidic agent is citric acid.
The present disclosure is in relation to a process for preparing a homogeneous, air-bubble free, and rapidly disintegrating ultra thin orodispersible film formulation. The proposed process comprises steps of combining an active ingredient(s) with a first film-forming agent at a ratio ranging from 1:25 to 2:50 to obtain a first mixture. Secondly, combine the first mixture with plasticizer at a concentration ranging from 2.5% w/v to 7.5% w/v and organoleptic agents to obtain a second mixture. Thirdly, feed the second mixture into a hot-melt extruder at a rate ranging from 1 to 4 gm/minute to obtain a homogeneously mixed and melted extrude filaments of the mixture via barrels of the extruder. Fourthly, comminuting the extruded filaments to obtain fine powder followed by sieving to obtain uniform-size reduced particles, dissolving the uniform-size reduced particles in a second film-forming solution having concentration ranging from 2% w/v to 8% w/v followed by addition of 1% w/v to 3% w/v second plasticizing agent to obtain a homogeneous casting solution. Thereafter, deaerating the casting solution under vacuum for a time period ranging from 1.5 hours to 3 hours to remove air bubbles from the casting solution followed by layering in an automatic film-forming machine to obtain orodispersible film of thickness ranging from 250 to 300µ; and drying the orodispersible film followed by slitting using a slitting machine, cutting and packaging orodispersible films.
In another embodiment of the present disclosure, the extruded filaments of active ingredient(s) and film-forming agent are alternately employed for three dimensional printing of orodispersible film by fused deposition modeling technique. The process comprising steps of developing a model of intended orodispersible film with predetermined size and thickness. Secondly, slice the developed models using a three dimensional builder program and loading the extruded filaments onto a FDM-three dimensional printer. Thereafter, printing ODFs from the extruded filaments at a temperature of 125? ± 10? using a fluid deposition modeling three dimensional printer equipped with hot end extruder having nozzle size of 0.4mm, print bed temperature of 30°C; nozzle travelling speed of 50 mm/s; and layer height ranging from 0.001 to 0.01 mm; and drying the printed films to obtain three dimensional printed orodispersible films.
In yet another embodiment of the present disclosure, the hot-melt extruder comprises co-rotating twin screw extruder operating at a speed ranging from 200 to 400 rpm and a die with predetermined shape having size ranging from 2 to 6 mm.
In still another embodiment of the present disclosure, hot-melt extruder has temperature ranging from 40? to 200?.
In still yet another embodiment of the present disclosure, hot-melt extruder has four barrels, wherein the temperature of barrel one is 40?, barrel two is 80?, barrel three is 150? and barrel four is 200?.
In still yet another embodiment of the present disclosure, the orodispersible films are dried at a temperature ranging from 100? to 120? for a time period ranging from 10 to 20 minutes.
In still yet another embodiment of the present disclosure, the slitting is carried industrially under a tension of 10 to 12 kg.
In still yet another embodiment of the present disclosure, the first and second film-forming agents are selected from a group comprising of hydroxypropyl methylcellulose, pullulan, polyvinyl alcohol, polyvinyl pyrrolidone, maltodextrins, hydroxypropyl cellulose, and trehalose.
In still yet another embodiment of the present disclosure, the plasticizing agents is selected from a group comprising of glycerol, polyethylene glycol, biodegradable surfactants.
The present disclosure provides a homogeneous, air-bubble free, and rapidly disintegrating ultra thin orodispersible film formulation obtained by the process as detailed in the above embodiments.
Additionally, the disclosure is further illustrated by the following examples, which are not to be construed in any way as imposing limitations upon the scope of the present invention. On the contrary, it is to be clearly understood that various other embodiments, modifications, and equivalents thereof, after reading the description herein in conjunction with the drawings and appended claims, may suggest themselves to those skilled in the art without departing from the spirit and scope of the presently disclosed and claimed invention.
Example 1: Fabrication of orodispersible films
ODFs of various drug substances or dietic substances are fabricated by a combination of hot-melt extrusion (HME) method and three dimensional printing method or solvent casting method (SCM). The proposed hybrid method employs the following processing steps, parameters and/or processing conditions:
Example 1a: Preparation of drug substance/ active agents extrude (filaments or pellets) by HME method
The method involves melting and mechanically processing polymeric materials in combination with other active agents above its glass transition temperature (Tg) to effect molecular mixing of all the ingredients thereof. The machinery employed in HME is called ‘extruder’. Generally, the term extrusion or extrude refers to push or to force it out. In this process, the polymer or its composition is melted and forced via the die (orifice) of particular cross-section and cooled or subjected to downstream ancillary equipment for further processing. Refer Table 1 for preparing filaments or pellets of extrude by HME method.

Table 1: Composition to fabricate HME extrudes
Sl. No. Component % Weight
1 Film forming composition: Polyethylene glycol and hydroxypropyl cellulose at a ratio 1:2 optionally along with potato starch (1:2:0.5)
5 to 60
2 Plasticizer composition: Sorbitol and mannitol in combination at a ratio of 1:2
5 to 25
3 Sweetening agents (Sucralose or aspartame) 1 to 3
4 Flavoring agent (Grape or kiwi flavor) 0.5 to 5
5 Saliva stimulating agent (citric acid) 0.1 to 5
6 Engineered active pharmaceutical ingredient (taste masked or coated or size reduced or nanotized) such as aripiprazole or donepezil or prednisolone or cinnarizine or bethistine hydrochloride or diclofenac sodium or melatonin or loperamide hydrochloride or theophylline or iron and other nutrients or dietic substances.

1 to 45

Direct incorporation of drugs into the ODF formulation may not help in obtaining an ideal film formulation. Instead, they can be engineered first by known methods before loading them onto the ODF. For instance, some of the engineering approaches to coat or to mask the taste of drug includes but not limiting to size reduction by ball milling (aripiprazole – size reduction helped in obtaining films without gritty sensation and also helped achieve films with rapid disintegration time of less than 30 seconds), taste masking of donepezil (complexing with ß-cyclodextrins), prednisolone (mesoporous silica nanoparticles), betahistine or cinnarizine hydrochloride (drug resin complex), diclofenac sodium (micropellets), melatonin (solid lipid microparticles) loperamide hydrochloride (tragacanth helps in preventing the transition from one polymorphic form to another) theophylline (matrix particles) and iron (complexing with ß-cyclodextrins) helped obtain ODFs with masked bitter taste of respective drug/ active substances.
Turning now to the present disclosure’s method, it employs the processed or engineering active pharmaceutical ingredient or active agent. Poor solubility is a direct result of a stable crystalline form that water cannot efficiently penetrate through the lattice structure of the drug molecule. Thus, to increase the solubility of the drug, hot-melt extrusion technique was employed.
The steps involved in the process are as follows:
Step 1: Processed drug substance and film-forming composition are combined in a ratio of 1:10 followed by adding plasticizer composition and organoleptic agents such as sweetening, flavoring agents and saliva stimulating agents to obtain the mixture. Alternately, different plasticizers such as tween 80, propylene glycol can also be employed in the fabrication of extrudes. The obtained mixture was feed via the hopper of a hot-melt extruder to obtain extrude of the mixture in the form of filaments or pellets. The HME equipment and the processing conditions employed are as follows:
• Screw type: Twin screw and co-rotating type for mixing, melting and conveying
• Barrels: 4 barrels – B1, B2, B3 and B4
• Feed rate: 1 to 4 grams per minute (equal to 30 Hz)
• Screw speed: 200 to 400 rpm
• Barrel temperature: B1: 40?, B2: 80?, B3: 150? and B4: 200?
• Die size and shape: 2 to 6 mm, preferably 4 mm, round shaped die
• Torque: 17 Nm
The barrel temperature set-up enabled the melting of drug or active agent and polymer melt at their glass transition temperature (Tg). The extruder uses the heat and pressure to generate homogenous mixtures of polymer and drug thereby giving an output of long cylindrical extrudes which are devoid of air bubbles and are free from cracks.
Overall, step 1 of the process helps in turning the poorly soluble crystalline drug substance (poor absorption and low bioavailability) to an amorphous solid dispersion or liquid solution having good absorption and bioavailability.

Example 1b: Fabrication of ODFs by SCM
Step 2: The extrudes of step 1 under example 1a were size reduced to obtain fine particles and were subjected to sieving (# 100 mesh) to obtain uniform-sized particles. It is pertinent to state that to maintain drug uniformity and to prevent drug crystallization leading to non-uniformity, the disclosure employed crystallization inhibitors such as polyvinyl pyrrolidone, poloxamers and polyethylene oxide either alone or in combination. The size reduced particles were combined with a second film-forming/ casting solution selected from the following list identified below:
? A) Film-forming solution comprising of hydroxypropyl cellulose, and polyvinyl pyrrolidone in 1.5:1 ratio at a concentration ranging from 2% w/v to 6% w/v and preferably 4% w/v.
? B) Film-forming solution comprising of hydroxypropyl methylcellulose in combination with propylene glycol (1:1.5 ratio) is employed especially for drugs with high doses (>100 mg) at a concentration ranging from 4% w/v to 6% w/v and preferably 5% w/v.
? C) Film-forming solution comprising of polyethylene oxide, hydroxypropyl methylcellulose (1:2 ratio) is employed especially for combination drug formulations at a concentration ranging from 2% w/v to 6% w/v and preferably 3% w/v.
After combining with the film-forming solution continuous stirring until the size reduced extrude is fully dissolved in the film-forming polymer solution. Thereafter, glycerol or triacetin (acts as a plasticizer) in combination with titanium dioxide was added and stirred under heating to obtain a homogenous mixture. This is followed by deaerating the casting solution under vacuum for a time period of 1.5 hours to 3 hours to remove air bubbles from the casting solution followed by layering in an automatic film-forming machine to obtain orodispersible film of thickness ranging from 250 to 300µ; and drying the orodispersible film at a temperature ranging from 100? to 120? for a time period ranging from 10 to 20 minutes followed by slitting using a slitting machine, cutting and packaging square shaped orodispersible films.
Alternately, the extruded filaments are subjected to three dimensional printing as detailed in the below example:
Example 1c: Fabrication of ODFs by three dimensional printing
The filaments obtained under the above example 1a are subjected fluid deposition modeling three dimensional printing (FDM-3D). First and foremost, the ODF of desired size and thickness models were designed using 3D builder software. Thereafter, the developed models were sliced and converted to g-code format files using known software. ODFs were printed from the extruded filaments using a FDM-3D printer equipped with an E3D v6 Hot End extruder and a standard 0.4 mm nozzle. The ODFs were printed with standard resolution, the raft option was activated, and the printing temperature was 125 °C (nozzle temperature). The following printing parameters were employed: print bed temperature, 30°C; nozzle travelling speed, 50 mm/s; and layer height, 0.001 mm.
The fabricated ODFs were subjected to various characterization studies which are discussed under the following examples.
Example 2: Physical methods for characterization of ODFs of the present disclosure
While various ODFs of different active agents can be fabricated using the process of the present disclosure. For the sake of examples, ODFs of betahistine or cinnarizine hydrochloride fabricated by hot-melt extrusion and solvent casting method and non-steroidal anti-inflammatory drug such as diclofenac sodium prepared by hot-melt extrusion and FDM-3DP are detailed herein below:
(a) Visual inspection: Visual inspection was carried out from sampled ODFs. The ODFs were free from air bubbles.
(b) Shape: The ODFs could be cut into desired shape. For instance, rectangular shaped ODFs were cut using the cutting machine of size ranging 4 cm2 to 6 cm2. These sizes of ODFs are highly comfortable for self-administration by patients/ subjects across all the age groups.
(c) Thickness: Thickness of the ODF is measured using a micrometer (digital) which was found to be ranging from 0.105 to 0.125 Mm.
(d) Average weight: ODFs having an area of 700 mm2 were weighed using an electronic balance. The average weight obtained is a mean weight variation of the film. This gives a general confirmation of the fact that both the drug and excipients are uniformly distributed in the ODF and one has obtained an ODF weighing about 140mg to 150mg.
(e) Folding endurance (FE): This test is performed manually. The ODF of the uniform cross-sectional area is folded repeatedly until it breaks. FE value is the number of times the sample ODF is folded repeatedly without cracking. High FE value is a direct indication to establish the fact that ODF is indeed associated with higher mechanical strength. The FE value for the iron ODFs was ranging from 15 to 20.
Example 3: In-vitro methods for characterization of ODFs of the present disclosure
(a) Disintegration Test: Disintegration of ODF is critical quality attribute that helps in gaining patient compliance. The ODFs are expected to rapidly disintegrate when administered to tongue. There exist several methods for determining the disintegration time of an ODF. Most popular methods are petri dish method, slide frame method, drop method, hollow glass cylinder method, slide frame and ball method and others. In the present disclosure, PharmaTest® - ODF disintegration tester was employed to study the disintegration time of the microencapsulated iron ODF. Standard procedure was followed in testing the disintegration time using disintegration medium - ‘phosphate buffer’ having pH 6.8. It was observed that the disintegration time of all the films was ranging between 20 to 30 seconds.
(b) Estimation of moisture content by Karl Fischer (KF) titration method:
This method helps in determining even the lowest amount of water content in any ODF sample. It employs methanol or anhydrous dimethyl sulfoxide as a solvent. The selected solvent determines the solubility of an ODF for the analysis. In the present method, suitable amount of ODF sample, say 500 mg of ODF sample is transferred into titration vessel and the titration was continued till the electrometric end point. Every time, before adding the sample, titrate the vessels content to electrometric end point to neutralize the moisture interference during the process. The water content in ODF samples was found to be between 6.5 to 7.5% w/w.
(c) Release profile:
Our study focused on developing a taste-masked, stable and sustained release ODFs of anti-vertigo drug betahistine or cinnarizine hydrochloride (drug that is bitter to taste, shorter half-life and highly hygroscopic). Here the drug is primarily complexed with ion exchange resin. The dissolution studies between the ODFs of drug sample and drug-resin complex are captured under Figure 1. From figure 1, it is evident that the drug complexation with resin helps in achieving sustained release ODFs. Similarly, drug release profile from micropellets of diclofenac sodium and its corresponding ODFs is shown in Figure 2. Diclofenac sodium release from uncoated and coated micropellets is shown in Figure 2(A), wherein coated micropellets show prolonged release and increased lag time (micropellets2.5 = 200 min and micropellets5.0 = 240 min) when compared with the uncoated micropellets. Prolonged release increase with increase in amount or thickness of the coating material (mean dissolution time for 80 % release: micropellets2.5 = 449 min and micropellets5.0 = 564 min). Similarly, Figure 2(B), shows dissolution profile of ODFs, wherein prolonged release was seen with ODFs loaded withmicropellets5.0with mean disintegration time for 80 % release was 370 min. On the contrary, for micropellets2.5 it was min, reduced lag time was seen for ODFs and this is probably due to drug release from micropellets during fabrication of ODFs. Accordingly, the disclosure was successful in fabricating fast-disintegrating and prolonged release ODFs of freely water-soluble drug. Nonetheless, polymer selection in fabricating micropellets is critical as it interacts with plasticizers (glycerine or propylene glycol) used for adjusting the mechanical properties in general and tensile strength in particular.
Further, ODFs pose challenges with respect to drug cargo loading and physical stability. In order to enhance these aspects for the model drug ibuprofen, employed ion-pair technology. In this method, they employed alkanolamines and alkylamines as counter ions. Ibuprofen and organic amine (ethanolamine) complex helped in enhancing the miscibility between the drug and the polymer (PVA) which in turn enhanced drug solubility in the polymer by 60 % w/w and stability by 30 % than the pure ibuprofen film per se. The molecular mechanism was investigated by the authors and found that the amino group and hydroxyl group of the counter ions exhibited strong ability to form hydrogen bonding leading to enhance the interaction between the drug and polymer, delaying the onset of sublimation temperature and decreasing the polymer mobility
Example 4: In-vivo methods for characterization of ODFs of the present disclosure
In order to determine the patient/ subject acceptability of sampled ODFs, taste and palatability are crucial factors that need to be determined. Under in vitro conditions, biochemical, biomimetic or ion selective detectors are utilized. The in vivo test in human volunteers is performed for assessing the taste. Before the examination, subjects evaluate their sensory sensibility thresholds for respective tastes, using four standard substances: tartaric acid (sour), sucrose (sweet), sodium chloride (salty), quinine (bitter). It is proposed to conduct the study in the following stages: rinsing the mouth with distilled water, placing the required amount of active and then a film sample with the same active content on the tongue for 30 seconds, spitting the drug and rinsing the mouth with water. For taste evaluation, the scale with the following values is usually utilized: 0 - free of bitter taste, 1 - slightly bitter, 2 - moderately bitter, 3 -very bitter and 4 - extremely bitter to taste. The scores given by volunteers are tabulated in table 3.
Table 3: Volunteer taste scores for a bitter tasting active agent
Formulation Volunteers and average score
1 2 3 4 5 6 7 8 9 10
ODF – 1 (Anti-vertigo) 0 0 0 0 0 1 0 0 0 0
ODF – 2 (NSAIDS) 0 0 0 0 0 1 0 0 0 0

Example 5: Other characterization tests for ODFs fabricated under example 1
(a) Pesticide residue testing: The ODF samples of the present disclosure were tested for presence of pesticides by in-house standard testing procedure. The test procedure involves testing the samples by gas chromatography- mass spectroscopy (GC-MS) method. Almost 144 pesticides were found to be well below the quantification limits (0.01 mg/Kg).
(b) Test for heavy metals: The ODF of the present disclosure were tested for presence of heavy metals by in-house standard testing procedures. The test procedure involves testing the samples by ‘Inductively Coupled Plasma Mass Spectrometry (ICP-MS) for presence of arsenic, cadmium, mercury and lead. All the tested heavy metals were found to less than 0.05 to 0.1 ppm or mg/Kg.
(c) Microorganism: The ODFs of the present disclosure were tested for presence of microorganisms by in-house standard testing procedures. The test procedure involves testing the samples for presence of microorganisms namely yeast and moulds, E.coli (bacteria), Salmonella, Staphylococcus aureus and pseudomonas aeruginosa. Except yeast and moulds (with <10 CFU/g), THE remaining microorganism were absent.
Advantages:
? The platform technology of the present invention is highly advantageous for preparing ODFs loaded with different active pharmaceutical ingredients (prescription based or over the counter products), neutraceuticals, vitamins, herbal ingredients and others.
? The process helps in obtaining orodispersible film formulations that are highly recommended for patients with dysphagia. Additionally, they are preferred by geriatrics, and pediatrics who do not like swallowing a tablet or capsule.
? One of the unique and inventive aspects of the present invention is that a desired ODF of an active substance can even be printed in a pharmacy setting and dispensed to patients as per the required dose.
? Additionally, dosage regimen can be adjusted by printing the ODF of desired strength to a patient with particular disease ailment. Accordingly, customization of drug dose is possible depending on the requirements for the patient as prescribed by the physician.
? ODFs of the present disclosure don’t need water for consumption by the subjects / patients. The saliva in the oral cavity hydrates the film to disintegrate and the disintegrated film is swallowed naturally along with the saliva by the patient.
? ODFs are highly portable and can be self-administrable without the assistance of any nurse or paramedic.

While various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art. The various aspects and embodiments disclosed herein are for purposes of illustration and are not intended to be limiting, with the true scope and spirit being indicated by the following claims.
, Claims:We claim:
1) A process for preparing a homogeneous, air-bubble free, and rapidly disintegrating ultra thin orodispersible film formulation, comprising steps of:
a) combining an active ingredient(s) with a first film-forming agent at a ratio ranging from 1:25 to 2:50 to obtain a first mixture;
b) combining the first mixture obtained under step (a) with a plasticizer at a concentration ranging from 2.5% w/v to 7.5% w/v and organoleptic agents to obtain a second mixture;
c) feeding the second mixture obtained under step (b) into a hot-melt extruder at a rate ranging from 1 to 4 gm/minute to obtain a homogeneously mixed and melted extrude filaments of the mixture via barrels of the extruder;
d) comminuting the extruded filaments obtained under step (c) to obtain fine powder followed by sieving to obtain uniform-size reduced particles;
e) dissolving the uniform-size reduced particles obtained under step (d) in a second film-forming solution having concentration ranging from 2% w/v to 8% w/v followed by addition of 1% w/v to 3% w/v second plasticizing agent to obtain a homogeneous casting solution;
f) deaerating the casting solution obtained under step (e) under vacuum for a time period ranging from 1.5 hours to 3 hours to remove air bubbles from the casting solution followed by layering in an automatic film-forming machine to obtain orodispersible film of thickness ranging from 250 to 300µ; and
g) drying the orodispersible film followed by slitting using a slitting machine, cutting and packaging orodispersible films.
2) The process as claimed in claim 1, wherein the extruded filaments of active ingredient(s) and film-forming agent are alternately employed for three dimensional printing of orodispersible film by fused deposition modeling technique comprising steps of:
a) developing a model of intended orodispersible film with predetermined size and thickness;
b) slicing the developed models using a three dimensional builder program;
c) loading the extruded filaments onto a FDM-three dimensional printer;
d) printing ODFs from the extruded filaments at a temperature of 125? ± 10? using a fluid deposition modeling three dimensional printer equipped with hot end extruder having nozzle size of 0.4mm, print bed temperature of 30°C; nozzle travelling speed of 50 mm/s; and layer height ranging from 0.001 to 0.01 mm; and
e) drying the printed films to obtain three dimensional printed orodispersible films.
3) The process as claimed in claim 1, wherein the hot-melt extruder comprises co-rotating twin screw extruder operating at a speed ranging from 200 to 400 rpm and a die with predetermined shape having size ranging from 2 to 6 mm.
4) The process as claimed in claim 1, wherein the hot-melt extruder has temperature ranging from 40? to 200?.
5) The process as claimed in claim 1, wherein the hot-melt extruder has four barrels, wherein the temperature of barrel one is 40?, barrel two is 80?, barrel three is 150? and barrel four is 200?.
6) The process as claimed in claim 1, wherein said orodispersible films are dried at a temperature ranging from 100? to 120? for a time period ranging from 10 to 20 minutes.
7) The process as claimed in claim 1, wherein said slitting is carried industrially under a tension of 10 to 12 kg.
8) The process as claimed in claim 1, wherein said first and second film-forming agents are selected from a group comprising of hydroxypropyl methylcellulose, pullulan, polyvinyl alcohol, polyvinyl pyrrolidone, maltodextrins, hydroxypropyl cellulose, and trehalose.
9) The process as claimed in claim 1, wherein said plasticizing agents is selected from a group comprising of glycerol, polyethylene glycol, biodegradable surfactants.
10) A homogeneous, air-bubble free, and rapidly disintegrating ultra thin orodispersible film formulation obtained by the process as claimed in claim 1 to 9.