Development and Characterisation of Oral Thin Film Formulation, Final Thesis(Ujjwal Mandal) by Prof. Dr. S.Ray(OTF).pptx

ABSTRACT


In the current development of systemic administration of drug substance, Oral thin film (OTF) takes great place over conventional drug delivery systems. It is considered to be a safe and most convenient form of administration. Due to the presence of excessive saliva or oral mucosa, it gives better permeability to a lot of drugs as well as an excellent site for drug absorption. Fast dissolving oral thin film (FDOTF) is expected to gain larger importance for its ability to rapidly dissolve in mouth and direct accessibility into the systemic circulation. OTF is designed as single or multilayer thin films, depending on the therapeutic needs. The films are taken orally and it can be applied on or under the tongue or in the buccal cavity. In a few seconds, OTF dissolves in contact with saliva. Through the oral mucosa drug directly enter the systemic circulation giving a rapid onset of action by avoiding fast pass metabolism. OTF is ideal for pediatric, geriatric, mentally challenged, and bed-ridden patients. Coating and drying of the films could be done using conventional technology leading to quick industrial adaptation. The requirements of a potential dosage form are fulfilled by oral film technology. These are highly portable and patient-friendly dosages forms. The presentation will detail the advances and potential of the OTF.

1. Masters of Pharmacy Department of Pharmaceutics Submitted By Ujjwal Mandal Roll. No.-18920318001 Under the Guidance of Prof. (Dr.) Subhabrata Ray M.Pharm., Ph.D. Principal Development and Characterisation of Oral Thin-film Formulation Dr. B. C. Roy College of Pharmacy and Allied Health Sciences, Durgapur -713206 Affiliated to: Maulana Abul Kalam Azad University of Technology, West Bengal

2. Content Introduction Rationality of the work Aims & Objectives Literature Survey Advantages & Disadvantages of Oral films Plan Of Work Development Of Film Methodologies Evaluations Results & Discussion Conclusion Bibliography 2

3. Introduction Fast dissolving oral film system was first proposed in the 1970s as a choice over traditional dosage form. Flat films, also called oral wafers, oral film, mouth dissolving film, oral strip or buccal strip, etc. The oral route is the most usual route indicating rapid action, absorption, and distribution, through the effects of active ingredients and its medicament. In India, 2015, Central Drugs Standard Control Organisation (CDSCO) approves for manufacture and market of oral film of two medicines, which are Montelukast sodium and Levocetirizine Dihydrochloride for its specific treatment. Fast Dissolving films also have a stable shelf-life of 2-3 years, depending on the API but extremely sensitive environmental effects. Oral thin films are very effective in patients like bedridden, emetic patients, geriatrics, diarrhoea, or coughing for those who have an active lifestyle. 3

4. USFDA defines OTFs as, “a thin, flexible, non-friable polymeric film strip containing one or more dispersed active pharmaceutical ingredients which is intended to be placed on the tongue for rapid disintegration or dissolution in the saliva prior to swallowing for delivery into the gastrointestinal tract”. Oral films are not well defined in the writing but, no doubt it’s a smart drug delivery system for all the types of patient’s groups. 4 Figure.1. Oral Thin ( https://www.biospectrumindia.com/news/43/10301/zim-laboratories-develops-oral-soluble-strips.html , accessed on 17 Jun, 2020 )

5. Rationality of the work 2.1. Clinical Overview Many of patients are not comfortable in administering solid dosage form due to fear of choking, in other hand many of pediatric, geriatric, bedridden, emetic patients, and all those with central nervous system disorders, have difficulty in swallowing or chewing solid dosage forms. 2.2. Pharmaceutical Overview Oral thin film technology can easily overcome this situation, OTF when placed on tip or upper plate of the tongue, instantly wet by saliva as a result it dissolves and release the medication for local and/or systemic absorption. No need for excess water, while traveling. 5

6. 3. Aims & Objective To prepare and evaluate oral thin film formulation. 3.1. Objectives Preformulating Studies of Drug component Drug Excipients Compatibility studies Melting point determination of drug Preparation of standard curve of drug-using Uv -Visible spectroscopy Solubility Studies Dose Calculations 6

7. Exploration of water-soluble polymers for preparation of the thin film Selection of Plasticizer for good properties of the film Design and formulation of OTF Evaluations Tests Stability Study 7 Figure. 2. Application Of Oral Thin film ( http://www.livkonpharma.com/simekon.html , accessed on 16 Jun,2020)

8. 4. Literature Survey A literature survey is an actual significant part of project work or project thesis. Before work, we had to liable for many of the literature studies which help to our work as very supporting background knowledge to set the backbone of work. Various literature tells more about its needs, patient’s demand, and marketing of formulating products. Without a literature survey we cannot stand for its specific work, uses, sweet able ingredients like; Polymer and recent situation of its development. ( Mitra Jelvehgari . et al. Sep.2015) They produced oral film, with Ergotamine Tartrate and Caffeine Anhydrous for migraine therapy. Here used excipients are HPMC, PG, Ethanol, and dichloromethane. Also, they concluded that all the materials are suitable for composition of oral film and all the evaluations are performed. 8

9. ( A.Deepthi , B. Venkateswara Reddy et al. Feb.2014 ) Their study exhibited that formulation of oral films of Zolmitriptan with excipients like sodium starch glycolate, guar gum, sodium alginate and xanthan gum. They used solvent casting method for preparation of oral films. Their work evidently shows that Zolmitriptan drugs can be loaded easily and delivered through oral route. ( Kadam V. S., Bharkad V. B. et al. June 2017 ) Metclopramide HCL strips were formulated by solvent-casting technique using polymers like HPMC E5, E15, K4M, K15 and PEG-400 as plasticizer. The produced strips were evaluated for their thickness, weight uniformity, folding endurance, surface pH, tack test, disintegration time, physical appearance and in-vitro dissolution studies. 9

10. 4.1. Advantages of Oral thin Film Comfort of administration for, geriatric, mentally ill, pediatrics and non-compliant patients. Effective in situations where the quick onset of action required such as in motion sickness, allergic attack, coughing, or asthma. It is a cost-effective, non-fragile, and flexible dosages form. Chemically good stable. Leaves no residue in the oral cavity after administration of dosages form. No need for excess water. Suitable during traveling. No fear of choking. Non-Invasive drug delivery system. 10 Figure. 3. Thin Elegant Film

11. It can be prepared easily. More Patients compliance. 4.2. Disadvantages of Oral Thin Film Maintaining dose uniformity is difficult. OTFs are not official in any pharmacopeia. Limitation of Dose. Limitation of use of drugs, which are not stable in oral pH. 11

12. 4.3. Plan Of work Literature Survey Choice and procurement of drug and excipients Preformulation study including characterization of drug Identification of the drug component Fusion Point UV Spectrum Study FTIR spectrum Study DSC Study Calibration curve of Cilnidipine in Methanol Drug-excipients compatibility study 12

13. Formulation development of fast dissolving film Formulation design for selection and optimization of film-forming polymer concentration Evaluation of fast dissolving film 4.4. Development of the Oral thin film Development or Formulation includes consideration regarding mechanical properties, taste masking, the flash release of drug component, physical appearance, mouthfeel. Here, we can incorporate up to 30mg of the drug component. From the regulatory point, all excipients used should be generally regarded as safe (GRAS) listed and should be used as per Inactive Ingredients Limit (IIG limit). 13

14. 4.4.1. Film Forming polymers Polymer compounds are the backbone of the skinny film. The chemical compound should have good water-soluble properties. This chemical compound ought to have lavish peel, split, and tensile potency for developing a better film. 4.4.1.A. Natural polymers Gum polysaccharides Gelatine Pullulan Starch 4.4.1.B. Synthetic Polymers Hydroxypropyl methylcellulose (HPMC) Polyvinyl alcohol (PVA) Polyvinyl pyrrolidone (PVP) 14 Figure.4. Breath Strips ( http://hyh.com.sg/index.php?route=product/product&product_id=600 , accessed on 16 Jun, 2020 )

15. 4.4.2. Plasticizers A softener is a crucial element of the film. It provides the flexibleness of the strip and improves the breakable properties of the strip. Plasticizer ought to be compatible with the polymer and other excipients. E.g. Glycerol, propylene glycol, low atomic weight polyethylene glycols, etc. 4.4.3. Active pharmaceutical ingredients (API) Generally, 30 mg of active pharmaceutical ingredients could be loaded in the oral strip, due to its limitation, high dose substances are troublesome to load in associate oral strip. 4.4.3.1. Pattern characteristics of APIs Low dose Better Solubility Good Permeability 15

16. Palatability Small Molecular Weight Permanency in saliva 4.4.4. Surfactants Surfactants act like wetting orodispersing agents in order, the film compass dissolved within among seconds and releases API quickly. Some element like Sodium lauryl sulfate and polysorbates are ordinarily used surfactants.[22] 4.4.5. Saliva Stimulating Agent Very little amount of saliva stimulating agents is important (2%-6% w/w), for stimulating of saliva from the salivary gland. E.g. Ascorbic Acid, Mallic Acid, Citric acid, etc. [8] 16

17. 4.4.6. Super Disintegrating Agent Superdisintegrants give rapid disintegration of the film if they are value within the formulation. Super disintegrating element soak water that honour the dispersibility of the system, thereby it rises dissolution and disintegration.[18] E.g.- Sodium Starch Glycolate, Crospovidone , Starch, etc. 4.4.7. Flavoring & Coloring Agents Color and Taste are the crucial section of thin-film technology. Natural sweeteners and simulated sweeteners are applied for flavoring purposes. FD&C permitted colouring agents, natural colouring agents, EU colours, or pigments is embodying up to 1% w/w.[22] The selection of flavour lies on the genre of drug to be loaded. Flavours is used alone or in combination. 17

18. 4.4.8. Sweetening Agent Various sweetening is employed to rise the palatableness of the fast dissolving oral skinny films and visor the bitterness of the system.[6] The sweetening components could be natural as well as pretended like dextrose, sucrose, fructose, , maltose and glucose etc. 4.4.9. Table.1. Drug Profile 18 Name Cilnidipine IUPAC name 3-O-(2-methoxyethyl) 5-O-[(E)-3-phenylprop-2-enyl] 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Structure

19. 19 Dose 2-5 mg daily Color Yellowish White Appearance State Powder Melting Point 110 ºC Bioavailability Low Solubility Very soluble in n-n-dimethyl acetamide Freely soluble in acetone Sparingly soluble in methanol Insoluble in water Molecular Formula C 27 H 28 N 2 O 7 Wavelength 240 nm Category Anti-hypertensive

20. 4.4.9.1. Mechanism of Action ( MoA ): Cilnidipine operate on the L-type calcium channels of blood vessels by obstruction the incoming calcium and suppressing the crinkle of blood vessels, thereby decreasing blood pressure level. 4.4.9.2. Drug Analytical Test 4.4.9.2.1. Fusion Point Test The drug melting point test is finished by the melting point apparatus and by using of Thieles tube. And the observed value of the melting point of cilnidipine is 108 ºC, 104 ºC. 4.4.9.2.2. UV-Spectrometer Study The standard curve of cilnidipine is performed by the solvent of methanol. At First 10 mg of the drug sample is weighed and dissolve in a 10 ml of methanol, this solution named as A (10 μ g/10ml= conc.). From the solution A, we pipette out of different amount of solution and made upto 10 ml using methanol. The absorbance is checked by U.V spectrophotometer in the range of 200-800. In UV Spectro-meter methanol used as a blank and drug sample along with methanol. 20

21. 21 Concentration (ppm) Absorbance 2 0.219 4 0.321 6 0.481 8 0.606 10 0.701 And found ƛ max of cilnidipine is 240 nm. (UV-Spectrophotometer, Shimadzu Uv-1800) Table.2. Conc. Vs Abs Graph.1

22. 4.5. Methodologies for development of Thin film formulation T here are a several methodologies for preparation of thin film. The used method mainly depends on the tract of production of thin-film, Various preparation needs a different type of manner for preparation.[12] Solvent-Casting Method Semi-solid Casting Hot-Melt Extrusion Rolling Method 3D printing Electrospraying 22 Figure.5. Oral Strip (apidds.com/oral-strips-handling/ , accessed on 17 Jun,2020)

23. 23 4.5.A. Solvent Casting Method This could be the foremost wide used methodology for the producing of quick dissolving oral skinny films. Weight of all the ingredients Take distilled water Mixed it properly on magnetic stirrer Stirring for 4hrs. Wait for clear solution Pour the solution in film casting plate or on petri-dish Dried it in hot-air oven for 6-7 hrs at 65º C Add Water Soluble Polymers Add All other Ingredients Confirm the slurry spread uniformly on all over the casting plate Cut in Pieces, pack, and seal 1. Flow-Chart of Solvent-Casting Method

24. 4.6.1. Differential Scanning Calorimetry (DSC) Differential Scanning Calorimetry is rendered to point the compatibilities of medicines with different excipients. DSC of plain drug and with other excipients in the preparation can also be performed. [10] 4.6.2. Morphology studies (Physical Appearance) Surface morphology is studied by lead Scanning Electron Microscopy (SEM). 4.6.3. X-ray diffraction and Raman spectroscopy X-ray diffraction patterns and Raman spectra assist to determining the crystalline or formless nature of the unprocessed APIs and APIs incorporated in films [11]. 4.6.4. Thickness measurements The thickness of every film is surveyed at five various locations (four corners and center ) using Dial calipers micrometer (mm). 24 4.6. Evaluations of Fast Dissolving thin films

25. 4.6.5. Weight variation One cm 2 sample representing five various regions is cut. The weight of each strip is aching and the weight mutation is calculated. 4.6.6. Drug Release test The release of drug from flat films is done by any official’s method like an old method for orally disintegration tablets. 4.6.7. Folding endurance The folding style of the strip is set by frequently flexion on film at the equivalent place until it split. The number of flexions of film is counted and determine as folding capacity [13]. 4.6.8. Tensile strength The durability is decided by the equipment that has two ligaments, the above one is placed and therefore the downcast is movable. The film sample (1×1 cm) is attached between the two ligaments. The strength at tearing and tension is determined.[22]   The % elongation (%E) is calculated running the subsequent equation Where, L o = Original length L s = Length of the strip after elongation   25

26. 4.6.9. Moisture uptake Tests Moisture uptake test is a measured time at water agitation by the dry strips. At first, take a petri-dish and cut a tissue paper because the form of petri-dish, provide 2ml of water employing a pipette. When the dry strip is placed on the wet tissue and a colouring agent AMARANTH put for water contact, and time is measured. Longer time tells about less moisture active. 4.6.10. Disintegration Time Disintegration time is checked by distilled water. Take 30 ml of distilled in a glass beaker and placed it on a heat-generating magnetic stirrer with slow rpm, at 37°C. Then the films cut in 1*1 cm 2 pieces. Placed the film piece underwater with more water contact to surface. Measured the time at which period films disintegrate properly. 4.6.11. Palatability study This study is done based on the taste. All the product variant are rated A, B, and C grades as per the standards. Grades: A= Very good, B= Good, C= Medium [15] 26

27. 4.6.12. Tack Test Tack test is the test of the tacky property of film merchandise. It primarily is finished by Tack Analyser at industrial scale, that’s it tacky or not.[8] 4.6.13. Transparency Transparency or clearness of films shows the physical look of strips. It mainly differs from polymers or their use. More polymer provides less transparency of strips. This is committed by the naked eye.[10] 27 Figure.6 Preparation of Thin Film (College Lab. a ccessed on Nov, 2020)

28. 28 Formulation Codes Polymers (5%) Plasticizer (10 % of polymer) Evaluation Tests DT (Sec.) Thickness (mm) Folding Endurance (Bends) F1 HPMC E-5 (5%) Propylene Glycol (PG) 130 0.06 300+ F2 HPMC E-5 + SSG (2.5%+2.5%) PG 108 0.08 300+ F3 HPMC E-5 + SSG (1.5%+3.5%) PG 85 0.06 300+ F4 PVA + SSG (2.5%+2.5%) PG 48 0.07 300+ F5 PVA (5%) PG 100 0.08 300+ F6 PVA + SSG (2% + 3%) PG 22 0.05 300+ 5. Results & Discussion Table.3. Polymer composition, Amount of Plasticizer, Evaluation Tests like Disintegration time, Thickness and Folding Endurance etc. are given.

29. 29 F7 PVA + SSG (3 % + 2 %) PG 35 0.07 300+ F8 PVA + SSG (2% + 3%) PG + PEG-400(5% of Polymer) 7 0.04 300+ Fl. Codes. Film-forming Quality Texture Transparency Tacky Property F1 ++ ++ +++ + F2 +++ ++ ++ - F3 + + + - F4 +++ ++ +++ + F5 ++ +++ +++ ++ F6 +++ +++ ++ - F7 ++++ +++ ++ + F8 +++ +++ ++++ - ( ++++ = Best, +++ = Very Good, ++ = Good, + = Average, = Poor)   Table 4. Following table results for Film-forming quality, Texture, transparency and Tacky Property etc.

30. 5.1. Discussion: The polymer compound found as the primary material or element for forming up good properties of the skinny film. Variety of polymer differs from its water-soluble capacity or tendency to disintegrate properly. Polymers as HPMC E-5 with other excipients have good properties of the film. But as linked with another polymers, PVA accounted for very good properties of the strip with minimum disintegrating time and several properties are good enough to market film merchandise. A good factor is settling up or choice of polymer concentration, which varies a lot to its physical, and organic properties. The union of PVA and super disintegrating agent (SSG) with plasticizer (PG + PEG-400) offer very fine disintegration time, thickness, less tacky properties, and other properties of films. 30

31. 31 6. Conclusion: The oral route is the most preferable route for the remedy of a medicinal agent by rapid dissolving strip because it has a very lost cost and ease of administration. Many drugs are suitable candidates for incorporating strip formulation. The progression of oral-thin film formulation was successfully produced by using PVA and with other excipients. Moreover, the skinny film had acceptable physical properties, and disintegrate within 5-7 s. It was decided that the union of PVA with plasticizer as Propylene Glycol, Peg-400 need less time to dissolve. Due to pandemics of COVID-19, we did not find time to incorporate drug molecule and execute the further tests. But We achieved a suitable polymer composition for thin strip formulation, which is below or as industrial standard for marketing of FDFs in terms of DT (<10s).

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