INTRODUCTION:

Among various routes of administratio, oral route continous to be most preferred route due to various advantages including ease of administration, avoidance of pain,versatility and most importantly patient compliance.¹ Fast-dissolving drug-delivery systems were first developed in the late 1970’s forms an alternative to capsules, tablets and syrups for paediatric and geriatric patients who experienced difficulties in swallowing traditional oral solid-dosage forms.²

The new technology of oral fast-dispersing dosage forms is also called as fast dissolve, rapid dissolve, rapid melt or quick disintegration. However, the concept and function of all these dosage forms are similar. As per definition, film is a solid dosage form that can dissolves or disintegrates quickly in the oral cavity, which results in solution or suspension without need for the administration of water, is called as an oral fast-dispersing or fast-dissolving dosage form.³Orally fast-dissolving film is new drug delivery system for the oral delivery of drugs. It was developed on the basis of technology of transdermal patch. The delivery system contains a very thin oral strip, which can be easily placed on patient’s tongue, instantly wet by saliva, the film quickly hydrates and adheres onto the site of application. It then rapidly disintegrates and dissolves to release the medication for oro mucosal and intra gastric absorption.⁴ Research and development in the oral drug de livery segment has led to development of dosage forms from conventional tablets or capsules to sustained release tablets or capsules and later they were developed to oral disintegrating tablet (ODT) to wafer and next to the recently developed oral fast dissolving films (OFDFs). Among the plethora of avenues explored for the rapid drug releasing products, oral strip technology is gaining much attention.⁵Rapidly dissolving films (RDF) were initially introduced into the market as fresheners to breath and personal products of care such as dental care strips and soap strips. However, these dosage forms are introduced in the United States and European pharmaceutical markets for therapeutic benefits. The first of the kind of oral strips (OS) were developed by the major pharmaceutical company Pfizer who named it as Listerine^® pocket packs™ and were used for mouth freshening. Chloraseptic^® strips were the first therapeutic oral thin films (OTF) which contains 7-benzocaine which were used for the treatment of sore throat.⁶ Oral films are a group of flat films which are administered into the oral cavity. Companies having experience in the formulation of polymer coatings which contain active pharmaceutical ingredient (APIs) for transdermal drug delivery capitalized on the opportunity to transform this technology into OTF formats. OTFs are an accepted and proven technology for the systemic delivery of APIs as Over-the counter (OTC) medications and are in the early- to middevelopment stages for prescription drugs.⁷ Oral drug delivery techniques form an integral part of pharmaceutical industry. From the older conventional tablets/capsules to modern-day fast disintegrating and rapidly acting films/tablets, the market has come a long way. Bioavailability of oral solid drugs is low, there may be inconvenience of administering injections, inaccurate dosing by liquid formulations have turned the focus of pharmaceutical companies to develop novel oral dosage forms that eliminate several known limitations. Oral thin films are able to overcome most of these challenges. This concept is not new and several over the counter oral thin films are readily available. Good compliance and acceptance from users and an increasing demand of over the counter oral film products has led to the development of prescription drugs into oral thin films. These films not only offer a range of benefits to specific patient population segments but also provide a number of additional benefits to other stakeholders in the industry. The emerging area has gained attention from both start up and established pharmaceutical firms. Companies are utilizing their thin film technologies to develop different types of oral thin films (e.g. oral dispersible, sublingual, buccal). In addition to the drugs, several vaccines and hormones are also being formulated into oral thin films with the aim of providing improved patient compliance. Some of the key players in this area include MonoSol Rx, Applied Pharma Research/Labtec GmbH, Bio Delivery Sciences and NAL Pharma. Many companies are merging with these technology suppliers and utilizing oral thin films as a life cycle management tool for their branded drugs that have lost patent in other dosage forms. There are not many prescriptions for these dosage forms currently available in the market; however, the pipeline holds a wider promise. Despite the uncertainties related to the development, approval and penetration rate, the market is likely to witness stable growth in the coming decade. Many patients primarily paediatrics, geriatric and dysphasia find it difficult to swallow traditional tablets and capsules. Moreover, some diseases require rapid onset of action. This is possible through injections; some patients, though, find it inconvenient and painful to administer injections. These provide the best alternative dosage form for administering drug for such patients. It is important to highlight that few prescriptions of oral thin film products are commercially available yet in medicine. Several companies are developing innovative technologies to formulate oral thin films, which provide the advantage of rapid dissolution without the need of water and rapid onset of action when delivered through mucosa.⁸ Memantine is an adamantine derivative, which exerts its action through uncompetetive NMDA receptor antagonism and binds more effectively than magnesium ions at the receptor. Therefore it effectively blocks the prolonged influx of calcium ions and pathological levels of glutamate activity. Memantine is most effective when more channels are open and hence it is more effective at blocking the channels in case of moderate to severe disease rather than milder stages.⁹

MATERIALS AND METHODS:

Materials:

Memantine hydrochloride was obtained as a gift sample from Pharmtrain laboratories, Hyderabad, India. Hydroxy propyl methyl cellulose (HPMC E3, E5, E15), Propylene glycol, Tween 80 and citric acid were obtained from SD Fine Chem Ltd, Mumbai. Sorbitol, Aspartame and Pipperment flavour were obtained from Nectar life sciences, Hyderabad. All other chemicals used were of Analytical grade.

Methods:

Preformulation studies:

Calibration curve of Memantine in 7.4 p^H phosphate buffer:

A standard stock solution of Memantine was prepared by dissolving accurately weighed 10mg of Memantine in 7.4 p^H phosphate buffer solution in a 100ml volumetric flask and the volume was made up to 100ml by using 7.4 p^H phosphate buffer solution to obtain a stock solution of 100µg/ml. λmax (lambda max) was determined which is found to be 229nm and was used as analytical wavelength. From stock solution, appropriate aliquots were pipetted into different volumetric flasks and volumes were made up to 10ml with 7.4 p^H phosphate buffer solution so as to get drug concentrations of 1, 2, 3, 4 and 5µg/ml. Absorbance of these drug solutions were estimated at λmax 229nm against a blank of 7.4 p^Hphosphate buffer solution. This procedure was performed in triplicate to validate the calibration curve.

Solubility determination:

Solubility of drug was determined by saturation solubility method. In this an excess amount of drug was added to 25ml of water and placed on a gyratory shaker for 24hr. Then solution was filtered and diluted with water. Absorbance of this sample was found by UV-spectrophotometer and results are interpreted in terms of solubility.

Photostability studies:

Normally 10ml of fresh transparent glass vials with plastic caps were used for compatibility study. The drug is mixed with other excipients in the ratio of 1:1 and exposed to sunlight for a period of 1 month.

Fourier transform infrared radiation:

The infrared absorption spectra of pure drug, pure polymer and physical mixture of drug and polymer were performed for drug polymer interaction studies between 4000 cm^-1to 400 cm^-1by KBr pellet method.

Preparation of mouth dissolving film by using solvent casting method:

Mouth dissolving film of Memantine was prepared by solvent casting technique. Calculated amount of polymer was dissolved in 5 ml of water and stir continuously for 1 hour. Dissolve calculated amount of sweetener (Aspartame), plasticizer (propylene glycol) and sorbitol in 95% ethanol and then added to the polymeric solution. Add saliva stimulating agent (citric acid) to the above and mix well. Dissolve calculated amount of drug (memantine) in 2ml of water and kept on sonication for proper dispersion. Drug solution was then added to the polymeric solution and stirred for 30 minutes using magnetic stirrer. Add tween 80 and flavouring agent (peppermint) during stirring of the solution and continue stirring. Set aside in undisturbed manner until the foam was exhausted. The solution was cast on to glass petri plate of 9cm diameter and were dried at controlled room temperature (25⁰-30⁰ C, 45% RH). Sster it whs exposed to 75⁰C for 30 minutes hnd then it is decrefsed to 45⁰C. Dried film was carefully removed from the petridish and cut into required size (2cm × 2cm) in which 5mg (dose of drug) is incorporated for each film. Prepared films were stored in air tight plastic bags till further use.

Evaluation of oral disintegrating films:

1. Weight uniformity of films:

The cast film was cut at three different places of 2cm size each. Three films were taken from each formulation, weigh individually on electronic balance and the average weights were calculated.

2. Morphological properties:

This parameter was checked simply with visual inspection for physical appearance of films such as color, transparency, homogeneity and evaluation of texture by feel or touch.

3. Thickness uniformity:

All the eight batches prepared were evaluated for thickness by using calibrated Vernier caliper with a least count of 0.01mm. The thickness was measured at three different spots of the films and the average was taken.

4. Folding endurance:

Folding endurance can be measured manually for the prepared film. Flexibility of the film can be measured quantitatively in terms of folding endurance. A film strip was cut (approximately 2*2cm) and it be repeatedly folded at the same place till it broke. Number of times the prepared film could be folded at the same place again without breaking gave the value of folding endurance.

5. Surface p^H:

Surface p^H of the films was determined to detect the possible side effects due to change in p^H in-vivo,since an acidic or alkaline p^H may cause irritation to the buccal mucosa.The film to be tested was placed in a petri dish and was moistened with 0.5 ml of distilled water and kept for 1 hour. The p^H was noted after bringing the electrode of the P^H meter in contact with the surface of the formulation and allowing equilibrating for 1 minute.

6. Drug content uniformity test:

A) Standard solution:

Weigh accurately about 5mg pure memantine hydrochloride drug and transferred it into a 25ml volumetric flask. Add 10ml of p^H 7.4 phosphate buffer and dissolve it by mechanical shaking.Volume was made up to 25ml with the same buffer.The solution was filtered through Whatman filter paper.First few ml of the filtrate was discarded.Then 0.5ml of the filtrate was pipetted out and dilute up to 10ml with phosphate buffer in 10 ml volumetric flask so as to get 10µg/ml final concentrations.This solution was analysed by U.V.Spectrophotometer and record the absorbance at 229nm.

B) Test solution:

One film was dropped into 25ml volumetric flask. Then add 25ml of p^H 7.4 phosphate buffer and dissolve it by mechanical shaking.Volume was made up to 25ml with the same buffer. The solution was filtered through Whatman filter paper. First few ml of the filtrate was discarded. Then 0.5ml of the filtrate was pipetted out and dilute up to 10ml with phosphate buffer in 10ml volumetric flask so as to get 10µg/ml final concentrations. This solution was analysed by U.V. Spectrophotometer and record the absorbance at 229nm. Repeat the same process for three films taking randomly from each formulation. Drug content can be calculated using suitable formula.

7. Invitro disintegration test:

Drop method:

One drop of distilled water was placed by a pipette onto the oral films. The films were placed on a glass slide and then the glass slide was placed planar on a petridish. The time until the film dissolved and cause a hole within the film was measured. The estimations were carried out in a triplicate.

Petridish method:

In this method,one film was added on the surface of 2 ml of distilled water which was placed in a petridish and the time required until the oral film dissolved completely was measured. The estimations were carried out in a triplicate.

8. In vitro dissolution studies:.

The invitro dissolution test was performed in a Ph. Eur. 6.4 Ed. Paddle dissolution apparatus. The dissolution medium consisted of 900mL 7.4 p^H phosphate buffer solution, maintained at 37±0.5°C and stirred at 75rpm. One film was used in each test.Each 5ml Samples of dissolution medium were withdrawn by means of syringe fitted with pre-filter at known intervals of time and drug release was analysed spectrophotometrically at 229nm. The volume withdrawn at each interval was replaced with fresh quantity of dissolution medium. Cumulative percentage drug release of Memantine was calculated and plotted against time.

9. Stability studies:

The stability study was carried out by exposing to different conditions according to ICH guidelines. The film was packed in the aluminium foil and stored in a stability chamber for stability studies. Accelerated stability studies were carried out at 40⁰C/75% RH for the best formulations for 2 months. The films were characterised for the drug content and other parameters during the stability study period.¹⁰

RESULTS AND DISCUSSION

Memantine oral disintegrating films were successfully prepared by solvent casting method. Total 8 formulation trials were finalised by imparting concentration values of polymer and plasticizer. The prepared films were evaluated further by different characterisation tests.

Preformulation studies:

a) Calibration curve of Memantine in 7.4 p^H phosphate buffer solution:

Standard calibration curve of Memantine was drawn by plotting absorbance versus concentration. The λmax of Memantine in 7.4 p^H phosphate buffer solution was found to be 229nm.

Table No. 1: Calibration data of Memantine in 7.4 pH phosphate buffer at 229nm

S. No	Concentration (mcg/ml)	Absorbance*
1	0	0
2	1	0.147
3	2	0.314
4	3	0.481
5	4	0.624
6	5	0.789

Figure 1: Standard calibration curve of Memantine in 7.4 p^H phosphate buffer solution

Solubility:

Solubility of drug was determined by saturation solubility method. The solubility of drug in water was found to be 1.82mg/ml at 25˚C.

Photostability studies:

Photo stability studies were performed in transparent glass vials containing drug and excipients that were exposed to sunlight for a period of 1 month. No colour change was observed after 1 month.

Compatibility study by FTIR:

The compatibility of the drug with polymer was evaluated by using Fourier transform infrared spectroscopy of standard drug and drug with polymer.

FTIR studies:

Figure No 2: FTIR graph of Memantine pure drug

IR band at 3304 cm^-1 indicates presence of -NH stretching of amine, or amide.IR peak at 1648 cm^-1 indicates presence of H₂C=O group attached to -NH. H₂C=O stretching frequency at 1648 cm^-1 indicates strong electron withdrawing effect. The FTIR spectras observed that the characteristic absorption peaks of pure memantine, memantine+HPMC E5 and HPMC E15 were obtained. The spectral suggests that the major peaks for drugs are obtained as nearer value and there were no considerable changes in IR peaks in all physical mixtures of drug and polymers. This indicates that the drugs were molecularly dispersed in the polymers or in drug loaded formulations thus thereby indicating the absence of any interactions.

Figure No 3: FTIR graph of Memantine+HPMC E5

Figure No 4: FTIR graph of Memantine+HPMC E15

Formulation of Memantine fast dissolving films:

The oral disintegrating films of Memantine were prepared by solvent casting method. The films were prepared using HPMC E3, E5 and E15 as film forming polymers. Sorbitol and propylene glycol as plasticizers.

Evaluation of oral disintegrating films:

Weight uniformity test:

The weights of the films were found to be in the range of 90+/-0.5%.

Thickness of films:

The thicknesses of the films were in the range of 0.141mm to 0.146mm.

Folding endurance:

Folding endurance of the films was found to be in the range of 50 to 240.

Surface pH:

The measured surface p^H of all the films were found to be close to neutral which means that they have less po tential to irritate the buccal mucosa and therefore they should be fairly comfortable.

Drug content uniformity test:

The drug content uniformity is performed by taking three films in each formulation trial and the average drug content was calculated.

In vitro disintegration test:

The disintegration time of the prepared films were in the range of 12sec to 28sec.

Table No: 2 Formulation of Memantine oral films

Ingredients	F1	F2	F3	F4	F5	F6	F7	F8
Memantine (mg)	5	5	5	5	5	5	5	5
HPMC E5 (%)	30	35	40	45	-	-	-	-
HPMC E3 (%)	-	-	-	-	40	45	-	-
HPMC E15 (%)	-	-	-	-	-	-	40	45
Propylene glycol(mg)	10	10	10	10	10	10	10	10
Sorbitol (mg)	29.5	24.5	19.5	14.5	19.5	14.5	19.5	14.5
Aspartame (mg)	5	5	5	5	5	5	5	5
Tween 80 (mg)	5	5	5	5	5	5	5	5
Saliva stimulating agent (citric acid) (mg)	5	5	5	5	5	5	5	5
Flavouring agent (mg)	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5
Total wt. (mg)	90	90	90	90	90	90	90	90

Figure 5: Comparative Dissolution profile for F1, F2, F3 and F4

Figure No 6: Comparative Dissolution profile for F5, F6, F7 and F8

Figure No 7: zero order plot for best formulations F4 and F8

Figure No 8: First order plot for best formulations F4 and F8

Curve fitting data of different kinetic models:

The linear regression coefficient of each kinetic model was calculated and pattern of drug release from dosage form is predicted.

Table No 5: curve fitting data of regression coefficient of different kinetic models

Formulation code	Zero order (R)²	First order (R)²
F4	0.801	0.983
F8	0.773	0.939

Stability studies;

Formulations of F4 and F8 were evaluated for stability studies which was stored at 40˚C 75% RH for 60 days and evaluated for their physical appearance, drug content and invitro disintegration time and % drug release at the end of 60 days.

Table No 6: Stability data of formulation F4

Time in months	Formulation F4 stored at 40˚C / 75% RH
Time in months	Physical appearance	Drug content (%)	Disintegration time in sec	% Drug release
Intial	Smooth & elegant	100.18	14	98
After 60days	Smooth & elegant	99.86	13	96

Table No 7: Stability data of formulation F8

Time in months	Formulation F8 stored at 40˚C / 75% RH
Time in months	Physical appearance	Drug content (%)	Disintegration time in sec	% Drug release
Intial	Smooth & elegant	100.53	12	97
After 60days	Smooth & elegant	99.89	11	97

CONCLUSION:

· Memantine orally disintegrating films were successfully prepared with HPMC E5, HPMC E3 and HPMC E15.

· Formulations prepared using HPMC E3 were failed to satisfy the preliminary characteristics due to their poor film forming ability,tackiness and ease of handling/peeling.

· The amount of plasticizer propylene glycol was critical for film formation and separation properties.

· Taste masking was achieved using combination of sweetener aspartame and pippermint flavor.

· Propylene glycol was selected as solubility enhancer during shelf life period.

· Tween 80 was selected as surfactant to enhance dissolution rate of film.

· Acceptable properties were obtained in the batch F-4 and F-8 and in-vitro disintegaration time was below 20 seconds.

· It was concluded that formulations F-4 and F 8were found to be satisfactory batches and were optimized for the desirable properties

LIST OF ABBREVIATIONS:

Table no 8: List of abbreviations

ABBREVIATION	FULL FORM
HPMC	Hydroxy propyl methyl cellulose
NMDA	N-methyl-D-Aspartate
FTIR	Fourier-transform infrared
UV	Ultra violet

ACKNOWLEDGEMENT:

A single flower cannot make a garland or a single star cannot make the beautiful shiny sky in the night. A research work can never be the outcome of a single individual’s talent or efforts.Iam thankful to Mrs. Ishwarya, M. pharm for her valuable suggestions for my research work and I express my deep sense of gratitude to Mr M. Bala venkatareddy, M. pharm and Mr S.K. Madeesh, M. pharm who helped me a lot in pharma train to carry out my research work successful. I express my love and gratitude to my parents and husband for shaping me into a responsible person and whose constant support, guidance has helped me to withstand any challenges in my life. As a final word, I would like to extend my sincere thanks to each and every individual whose name has slipped from my mind have been a source of support and helped me to complete my research work successfully.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

REFERENCES:

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2. Committee for medicinal and products for human use, European medicines agency EMEA, Reflection paper; formulation of choice of the pediatric population. 2006.

3. Desu PK, Nama BBS, Nagalakshmi A. International journal of pharmaceutical research and Bio-Science. IJPRBS, 2013; 2(3): 298-305.

4. Patel RA, Prajapat SD, Fast dissolving films as a newer venture in fast dissolving dosage forms. International Journal Drug Development and Research. 2010; 2(2): 232-246.

5. Bhowmik Debjit, Chiranjib B, Krishnakanth, Pankaj, Margret R Chandira, Fast Dissolving Tablet: An Overview. Journal of Chemical and Pharmaceutical Research. 2009; 1(1): 163-177.

6. Rajni Bala, Pravin pawra, Sushil Khanna, Sandeep Arora.Orally dissolving strips: A new approach to oral drug delivery system, International Journal of Pharmaceutical Investigation. 2013; 3(2): 67-76

7. Vondrak B, Barnhart S. Dissolvable Films for Flexible Product Format in Drug Delivery, Pharmaceutical technoogy Supplement. April 2008.

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10. Shimoda H, Taniguchi K et al. Preparation of a fast dissolving oral thin film containing dexamethasone A possibe appjication to antiemesis during cancer chemotherapy. Eur J Pharm Biopharm. 2009; 73(3): 361-36

Received on 30.06.2020 Modified on 26.02.2021

Research J. Pharm. and Tech 2022; 15(1):17-23.

DOI: 10.52711/0974-360X.2022.00004

Formulation code	F1	F2	F3	F4	F5	F6	F7	F8
Disintegration time(sec)	28	22	19	14	20	15	15	12
Appearance	film is smooth and clear	film is smooth and clear	film is smooth and clear	film is smooth and clear	slightly hazy	slightly hazy	smooth and clear film	smooth and clear film
Folding endurance	92	98	124	157	57	64	152	237
Thickness(mm)	0.142	0.145	0.142	0.146	0.143	0.141	0.144	0.146
Weight variation test	Pass	Pass	Pass	Pass	Pass	Pass	Pass	Pass
Drug content(percentage Assay) (%)	99.27	99.19	99.73	100.18	100.81	99.63	100.11	100.53

Time in min	% Cumulative drug dissolved (%CDD)
Time in min	F1	F2	F3	F4	F5	F6	F7	F8
0	0	0	0	0	0	0	0	0
5	54	51	48	65	55	62	65	68
10	68	59	55	81	67	75	76	85
15	79	69	71	92	84	87	90	93
20	89	87	86	96	93	94	94	97
30	94	91	92	98	96	97	6	97