FORMULATION DEVELOPMENT AND EVALUATION OF ORAL THIN FILMS- DIPHEN HYDRAMINE HCl

FORMULATION DEVELOPMENT AND EVALUATION OF ORAL THIN FILMS- DIPHEN HYDRAMINE HCl

S. Aruna Jyothi*, P. Mounika, S. Vineesha, Suraiya Mehdia and N. Arun Dutt

St. Marys College of Pharmacy, Secunderabad-500025, Andhra Pradesh, India

ABSTRACT: The aim of this study was to develop a fast releasing oral polymeric thin film, prepared by solvent casting method, with good mechanical properties, instant disintegration and dissolution. Diphenhydramine hydrochloride, an antihistamine drug belonging to BCS class I was used for oral thin film preparation. The formulations from the preliminary trial were analyzed which was applied to optimize the type of polymers (Gelatin and HPMC E15), concentration of polymers, plasticizer (Glycerol, Propylene Glycol, PEG 400), surfactant (TWEEN 80) and sweetener (Mannitol).The resultant films were evaluated for thickness, folding endurance, drug content, Surface pH, in vitro disintegration time, in vitro dissolution  studies .Oral thin films which were prepared with surfactant  showed better results i.e., good disintegrating and dissolution properties than without surfactant. The optimized film disintegrated in less than 30s, releasing more than 90% of drug within 90sec.

Oral thin film, Diphenhydramine Hydrochloride, Gelatin, HPMC E-15, plasticizers

INTRODUCTION:  Oral thin film is a dosage form containing medicinal substances which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue” ¹.

It employs water dissolving polymer which is a hydrocolloid which may be bio adhesive polymer which allows the dosage form to quickly hydrate, adhere, dissolve when placed on the tongue or the oral cavity to provide rapid local and systemic drug delivery ². Due to rapid dissolving of the film, the term soluble film is preferred by FDA, whereas the European Medicines Agency is using orodispersible film ³.

Oral polymeric thin films are the most advanced form of oral solid dosage forms due to more flexibility and comfort. It improves the efficacy of the active pharmaceutical ingredients by dissolving within minute in oral cavity after the contact with less saliva as compared to the fast dissolving tablets, without chewing and no need of water for the administration ⁴.

Oral films are preferred by patients suffering from dysphasia, motion sickness, repeated emesis and mental disorders since they are unable to swallow large amounts of water with dosage forms. The advantages of convenient dosing and portability of oral films have led to a wide applicability of this dosage form in pediatric as well as geriatric patients. The drug used is Diphenhydramine Hydrochloride which is a histamine H1 antagonist and used as an antiemetic, antitussive, for dermatoses and pruritus, for hypersensitivity reactions, as an ingredient in common cold preparations ⁵.

The polymers used are gelatin and HPMCE15. Gelatin is a natural polymer available. Under specific conditions (temperature, solvent, pH) gelatin macromolecules can display flexibility sufficient to realize a wide variety of conformations. HPMC E15 is another polymer used due to its greater disintegration, dissolution and good film forming properties. The important step involved during dissolution of a hydrophilic polymer include absorption of water on polymer, breaking of polymer bonds with a simultaneous creation of water polymer bonds, separation of polymer chains, swelling and finally dispersion of polymer chains in medium ⁶.

The main aim of the present study was to prepare oral thin film of Diphenhydramine HCl for rapid dissolution in oral cavity. The films were prepared by solvent casting method and evaluated. This study optimizes the type, concentration of polymer and also optimizes the plasticizer and its concentration.

MATERIALS AND METHOD:

Materials: Gelatin, HPMC E-15, Ethanol, Tween80, Mannitol, Propylene glycol, Glycerol, PEG 400, Millipore Water. All reagents are of analytical grade.

Preparation of Oral Thin Films:

Solvent casting method ⁷: Oral thin films were prepared by dissolving the polymer (Gelatin or HPMC) in solvent mixture (Millipore water and Ethanol), with continuous stirring Drug, Mannitol is added. To the resulting solution plasticizers (Glycerol, PEG 400, Propylene glycol) and surfactants (Tween 80) are added subsequently and stirred for 15 minutes. These solutions were casted slowly on to a glass plate of diameter 5cm without formation of air bubbles. (Each strip 2*2 cm² consists of 30mg of drug) These plates were kept aside for 48 hrs and dried films are carefully separated from the plate and evaluated. Various formulations were prepared as per table 1 & 2.

TABLE 1: FORMULATIONS WITHOUT SURFACTANT

TABLE 2: FORMULATIONS WITH SURFACTANT

Evaluation of Oral Thin Films:

1. Thickness ⁸: Thickness of the films was measured at five points using micrometer to ensure the uniformity of film thickness. The mean thickness is calculated, the patches having thickness variation greater than 5% were excluded from analysis.
2. Folding endurance ⁸: Folding endurance of film was determined by repeatedly folding the films of uniform cross sectional area (4*4 cm²) until it breaks
3. Swelling index: Swelling index is performed to analyse the swelling of the film due to polymer (Gelatin and HPMC E-15).
4. Drug content: Drug content is determined by taking the film of 4cm² and dissolved in 100ml of phosphate buffer of 6.8pH. Then the solution is suitably diluted and the absorbance was recorded at 259nm.
5. Surface pH: The surface pH of the film was determined by using pH meter. OTF was slightly wet with the help of water. The pH was measured by bringing electrode in contact with the surface of the film. It is necessary to maintain the pH of the film, as an acidic or alkaline pH may cause irritation to the oral mucosa; it was determined to keep the surface pH as close as to neutral as possible.
6. In vitro Disintegration time ^{9, 10}: There are two simple methods in first method; one drop of dissolution medium was dropped from a 10-ml pipette onto the tightly clamped film. The time taken for the water to make a hole through the film was measured as disintegration time (DT). In the second method, 2 ml of water was placed in a petri plate with a film on the surface of water; the time taken for the disintegration of the film was measured. This test was done in triplicates and the average value was taken as disintegration time.
7. In-vitro Dissolution Studies ¹¹: In-vitro dissolution test was carried out in USP II paddle dissolution apparatus with 900ml of phosphate buffer as dissolution media. Temperature was maintained at 37±0.5^oC and set to a 100rpm.A film of 4cm² was cut and stick to the basket side wall.

5ml aliquots of samples was taken for every 30sec and followed by replacement of 5ml fresh phosphate buffer. The withdrawn samples were analysed spectrophotometrically at a wavelength of 259nm.

8. Dissolution rate by Conductometry ¹²:  Dissolution rate can also determined by measuring the conductivity. A beaker with 300ml of water was taken and determined the conductivity of the water to establish the background value. Arrange the conductivity probe, impeller and maintain temperature at 37±0.5^oC. After adhering film to the beaker set the stirrer to 100rpm. Conductivity was measured for every 15 sec until the conductivity remains constant.

RESULTS AND DISCUSSIONS:

Evaluation Parameters:

1. Thickness: The mean thickness of the oral thin films was found to be in the range 0.087mm-0.098mm
2. Folding Endurance: The folding endurance of the oral thin films was found to be in the range 35-180. The films of formulations F8, F12, F14, F15,F16, F17, Fa3, Fa5, Fa6, Fa7, Fa10, Fa12, Fa13,Fa14 shows better plasticity. The remaining formulations are found to be highly brittle.
3. Swelling Index: Swelling index of the oral thin films was found to be in the range 93-157. Polymer of gelatin and HPMC E15 of weight 150mg showed better swelling property.
4. Drug content: The drug content of the oral strip of 4cm² was determined and it varies with the range of 97±0.0 to 99.54%.The drug content was found to be high in F14.As per USP, the drug content was found to be in range of 85-115%.
5. Surface pH: The surface pH of the drug was found to be 6.8- 7.4
6. In-vitro Disintegration test: Formulation containing surfactant showed better disintegration time.Fa6, Fa7, Fa8, Fa13, Fa14 shows better disintegration compared to F8, F12, F14, F15, F16, F17, Fa3, Fa5, Fa10 and Fa12.
7. In vitro dissolution studies: Formulation containing Tween 80 showed maximum drug release within 120 sec the release was found to be 98.8% Fa14, 96.4% Fa7, 94.8% Fa13, 90.8% Fa6 from Table 4. The release of Fa7 is less than Fa14 this can be attributed due to less concentration of surfactant. Fa13 shows less percentage release than Fa14 and Fa7 this can be attributed due to the formation of high viscous solution of gelatin which retards the drug release.

Fa6 shows still lesser due to less surfactant concentration. The formulation without surfactant shows the following order of release F17 (89.2%)> F15 (87.6%) > F13 (85.9%). The other formulation released almost appropriately same amount of drug. The least percentage drug release was found to be F7.

FIG. 1: TIME VS PERCENTAGE DRUG RELEASE OF DIPHENHYDRAMINE HCl IN PBS 6.8pH

Dissolution rate by Conductivity method: Conductivity is determined ionisable components. The film consists of Diphenhydramine HCl which is ionisable. Based on the release of the drug conductivity (µsimen/min) alters.

 TABLE 4: THE FOLLOWING TABLE SHOWS THE PROPERTIES OF THE SUCCESSFUL FORMULATIONS:

 CONCLUSION: Diphenhydramine Hydrochloride oral thin films were successfully prepared by solvent casting method using the following polymers: Gelatin, HPMC E15. 1:1 ratio of drug and polymer ratio was optimized. The films prepared by using Tween 80 which was used as solubilizing agent has more percentage drug release. Among all formulations, Films prepared using HPMC E15 with Tween 80 showed best results.OTF prepared by using HPME15, Platicizers (Glycerol, Propylene Glycol, PEG 400) and solubilizing agent Tween 80 would be promising oral delivery systems for Diphenhydramine Hydrochloride.

REFERENCES:

1. M.D. Nehal Siddiqui, Garima Garg and Pramod Kumar Sharma A Short Review on “A Novel Approach in Oral Fast Dissolving Drug Delivery System and Their Patents”, Advances in Biological Research, 2011; 291-303.
2. Arun Arya, Amrish Chandra, Vijay Sharma and Kamla Pathak. Fast Dissolving Oral Films: An Innovative Drug Delivery System and Dosage Form”, International Journal of Chem. Tech Research, Vol 2, 2010; 576-583.
3. J. Gunjan Patel, A.Darshan Modi, “Formulation, optimization and evaluation of Levocetrizine dihyrochloride oral thin strip”, J Pharm Bioallied Sci. 2012, S35-36
4. Subash Vijaya Kumar, Basani Gavaskar , Guru Sharan, Y. Madhusudan Rao, “Overview on fast dissolving films” International Journal of Pharmacy and Pharmaceutical Sciences, 2010,29-33
5. http://www.drugbank.ca/drugs/DB01075
6. H.N. Joshi, T.D. Wilson, “Calorimetric studies dissolution of HPMC in water”, Journal of Pharmaceutical Sciences 1993; 1033-1038
7. Mahesh A, Shastri N, Sadanandam M. “Development of taste masked fast disintegrating films of levocetirizine dihydrochloride for oral use”. Current Drug Delivery 2010; 7:21-7
8. PK Lakshmi, J sreekanth, Aishwarya Sridharan, “Formulation development of fast releasing oral thin films of Cetriizine dihydrochloride with Eudagrit EPO nad optimization through Taguchi orthogonal Experimental design”, Asian journal of pharmaceutical Sciences,2005
9. Patel AR, Dharmendra S, Jignyasha P, Raval A. Fast dissolving films (FDFS) as a newer venture in fast dissolving dosage forms. Int J Drug Deliv Res 2010; 2:232-46
10. Barnhart. S, Rathborne M, Hadgraft J, Roberts M, Lane M, Thin film oral dosage forms, in: Modified release drug delivery technology 2nd edition, Drugs and the Pharmaceutical Sci.; 209-216.
11. Nishimura, M., K. Matsuura, T. Tsukioka, H. Yamashita, N. Inagaki, T. Sugiyama and Y. Itoh,. In vitro and in vivo characteristics of prochlorperazine oral disintegrating film, International J. Pharmaceutics 2009; 368(1-2): 98-102
12. E. Jayjock, Robert Schmitt, Chilling Chein, Gloria Tirol, “Determination Of fast dissolve Oral Film Dissolution Rate via Conductivity” The Dow Chemical Company 2005.
    

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    How to cite this article:

    Jyothi SA, Mounika P, Vineesha S, MehdiaS and Dutt NA: Formulation development and evaluation of Oral Thin Films –Diphenhydramine HCl. Int J Pharm Sci Res 2013: 4(9); 3484-3488. doi: 10.13040/IJPSR. 0975-8232.4(9).3484-88

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