Formulation Optimization & Evaluation Of Oro-Dispersible Film Of Tadalafil

Oral administration of drugs is a highly preferred, economical, and convenient method of medication delivery among other delivery methods. However, certain patients, particularly those in the paediatric and geriatric age groups, experience difficulty swallowing or chewing certain oral solid dosage forms, such as hard gelatin capsules and tablets. They can't take these dose types since they're afraid they'll choke. Fast dissolving drug delivery systems (FDDDS) were developed in a number of ways to get around this. The administration of drugs through the buccal channel is a crucial route. Using the buccal method to give the medicine can help prevent issues such high first-pass metabolism and drug degradation in the gastrointestinal environment. Oral drug delivery system research has resulted in the development of more advanced dosage forms, ranging from straight forward traditional tablets or capsules to modified release tablets or capsules, oral disintegrating tablets, wafer, and the most recent invention of fast dissolving oral thin films. Ultra-thin oral thin films known as "fast dissolving" oral thin films use a hydrophilic polymer, which hydrates or clings quickly to the tongue or buccal canal. Without chewing or drinking, these films breakdown or disintegrate in a matter of seconds to release the active ingredient. Because the mucosa has a highly enriched blood supply, medications are absorbed quickly and become bioavailable instantly. Patient compliance is the reason why oro-dispersible film technology, which is still in its early phases, has a promising future.

Dysphagia, or difficulty swallowing, affects people of all ages, but it is most prevalent among the elderly. It can also occur when taking regular pills and capsules. Numerous illnesses, such as stroke, Parkinson's disease, AIDS, thyroidectomy, head and neck thyroid treatment, and other neurological disorders like cerebral palsy, are linked to dysphagia. Tablet size was the most often voiced concern, followed by form, surface, and flavor. Patients who were traveling and might not have had easy access to water as well as elderly and pediatric patients showed a greater difficulty with swallowing tablets.

Oro-Dispersible Films (ODF^s)⁽¹²⁾ : Strips known as oro-dispersible films (ODFS) are mostly composed of water-soluble polymers, which dissolve in saliva in less than a minute on average. Although it can sound overwhelming, if you have ever used breath-freshening strips, you have direct familiarity with this technology. One benefit of oro-dispersibe film is that it can be used with elderly patients or people who have trouble swallowing pills or capsules.

MATERIALS AND METHODS

Materials: Tadalafil (Yarrow Chem Pvt . Ltd),HPMC 15cps (Medley Pharma Ltd; Andheri) ,Polyethylene Glycol 400 (Jinendra Scientifics, Jalgaon), Citric Acid (Jinendra Scientifics, Jalgaon), Aspartame (Jinendra Scientifics, Jalgaon), SLS (Sodium Lauryl Sulphate) (Jinendra Scientifics, Jalgaon)      

Methods: Characterization of  Tadalafil:

Solubility of Tadalafil : Tadalafil was freely soluble in PEG400.The solubility was determined by PEG , phosphate buffer pH 6.8 & SLS

Melting Point Determination: The melting point of tadalafil was determined by capillary tube method. Fine powder of the drug was filled into a glass capillary tube which was previously sealed at one end. The capillary tube was placed in digital melting point apparatus and subjected to increasing temperatures. Therefore, the temperature at which tadalafil melts was recorded.

Ultraviolet Spectroscopy: The samples were subjected to UV spectrophotometric analysis and were scanned for absorption maxima (? max) in the range of 200 - 400 nm using UV spectrophotometer in an appropriate medium. The obtained data was compared with that of reference values in literature Ultraviolet Spectroscopy: The samples were subjected to UV spectrophotometric analysis and were scanned for absorption maxima (? max) in the range of 200 - 400 nm using UV spectrophotometer in an appropriate medium. The obtained data was compared with that of reference values in literature.

Compatibility Studies: Compatibility of drug and polymers was studied using Fourier Transform Infrared (FTIR) spectroscopy. FTIR Spectrum was recorded between 600-4000 cm-1 using Agilent by KBr Disc method.

Formulation of Placebo Films: Polymers of single or in combination were accurately weighed and dissolved in respective solvent and then casted in a petridish. The films were allowed to dry overnight at room temperature.

Preparation of Oro-Dispersible Film of Tadalafil (By Using TDP/ODF Machine) : Oral fast dissolving film was prepared by solvent casting method.by utilizing 3days procedure.

(Day 1^st) Aqueous solution I was prepared by dissolving film forming polymer & Aqueous solution II is prepared by dissolving pure drug (Tadalafil), sweetener(Aspartame) , and plasticizer(PEG400) in specific proportion of distilled water and allowed to stir for 1 h and kept aside for 1 day to remove all the entrapped air bubbles.

(Day 2^nd ) Aqueous solution I &II were mixed & stirred for 1h & kept aside for to remove all the entrapped air bubbles.

       
           
       
(Day 3^rd) The solutions were cast on TDP/ODF film former machine and dried at 70 ºC. The film was carefully removed from surface of machine and cut according to required size for testing (2 cm length, 2 cm width). The samples were stored in desicator  maintained at a temperature of 30ºC and relative humidity 60% ± 5% until further analysis.

       
           
       
Fig : TDP/ODF Machine used for preparation of film

Calculation of Drug Loaded in the Film

1. For preparation of 10ml solution for Batch size of 5 films
2. Dose Strength of Tadalafil for one film= 10mg
3. For total surface area of dragged film by 10 ml solution
4. 5 × 10 = 50 mg of drug

DoE model Central Composite design) for Oro-Dispersible Film

The optimization software Design of Expert (DoE) of version 13 was applied for the maximum possible runs for the development of oral thin film. The Central Composite  design was selected for 2 factors (independent factors) predicted 9 possible runs and in actual manner get 5 trial batches.

Composition of Batches by Central Composite Design (TDP1-TDP9)
       
           
       

Evaluation of Fast Dissolving Films: The tadalafil films were evaluated for the following properties:

1. General Appearance: This Evaluation were done by visual Perspection .

• Taste
• Odour
• Colour
• Texture
• Surface

2. Weight variation: Weight variation were calculated by weighing any five films from the formulation individually on a digital balance and then computed the average weight.
3. Thickness: The thickness of film was measured by micrometer screw gauge at different strategic locations. Each film was measured at 5 positions (center and four corners) by digital Vernier caliper and the mean thickness was calculated. This is essential to determine uniformity in the thickness of the film as this is directly related to the accuracy of dose in the film.
4. Folding Endurance: Folding endurance was determined by- repeated folding of the film at the same place till the film breaks. The number of times the film was folded without breaking & accordingly computed as the folding endurance value.
5. Surface pH  : The film to be tested placed in petri dish & was  moistened with o.5 ml of distilled water & kept for 30 sec. the pH was noted after bringing the electrode of the pH meter in contact with the surface of the formulation & allowing equilibrium for 1 min.
6. Wetting Time : A circular single tissue paper was placed in th petridish. 6 ml of 1.1% w/v methylene blue solution was added to the petridish. The film was placed on the surface of tissue paper. The time required for the dye to appear on the surface of the film was noted as the wetting time.
7. Moisture Uptake & Moisture Loss : The original weight of the film was  determined first and then the film was placed in a desiccator (including calcium carbonate) for three days to determine the percentage moisture loss. The films were removed and weighed again after three days and the moisture loss were calculated using the formula:

A film's percentage moisture uptake was calculated by exposing it to an atmosphere with a relative humidity of 75%RH at room temperature for seven days and then using the following method to calculate  the moisture Uptake.

8. Disintegration Time:  In vitro disintegration time was determined visually in a glass beaker of 25 ml distilled water with swirling every 10 seconds. The disintegration time is the time when the film starts to break or disintegrates.
9. Drug Content : Take one film (2×2cm²) & dissolve it in pH 6.8 phosphate buffer in a volumetric flask & make up the volume upto q.s. to 100ml .Withdraw 0.5ml solution from prepared solution & diluted to 10ml with phosphate buffer pH 6.8 measure the absorbance of  the solution spectrophotometrically at 290nm
10. In Vitro Dissolution Studies :The release rate of Tadalafil oral thin film was determined using United States Pharmacopoeia (USP) dissolution testing apparatus type 2 (paddle method) .The dissolution test was performed using 900 ml of Phosphate buffer pH 6.8, at 37 ± 0.5^oC and 50 rpm. In specified time intervals (0, 2, 4, 6, 8, 10 min) an aliquot of 5 ml samples of the solution were withdrawn from the dissolution apparatus and with replacement of fresh fluid to dissolution medium. The samples were filtered through whatmann filter paper of 42 µm. Absorbance of these solutions were measured at ?max 290 nm using a UV/Visible Spectrophotometer (shimadzu-1800). The drug release was plotted against time to determine the release profile of various batches.
11. Stability Study⁾ : Stability Studies were carried out as per ICH guidelines Q1A (R2). The optimized formulation was wrapped in aluminum pouch & sealed. It was stored at accelerated (40 ?c ±2 ?c / 75% RH ± 5% RH) conditions for a period of one month. Films were evaluated for weight, folding endurance, disintegration time, drug content and % DR.
12. Tensile strength :

Tensile strength is the maximum stress applied to a point at which the strip specimen breaks. It  was calculated by the applied load at rupture divided by the cross-sectional area of the strip   given in the equation below:

13. Percent elongation:

When stress is applied, a strip sample stretches and this is referred to as strain. Strain is basically the  deformation of strip divided by original dimension of the sample. Generally elongation of strip increases as the plasticizer content increases.

14. Swelling property :  Film swelling studies was conducted using simulated saliva solution. Each film sample was weighed and placed  in a pre-weighed stainless steel wire mesh. The mesh containing film sample was submerged into   15ml medium in a plastic container. Increase in the weight of the film was determined at preset time interval until a constant weight was observed .The degree of swelling was calculated using parameters

         wt-w0/wo,

wt is weight of film at time t, and

wo is weight of film at time zero

RESULTS AND DISCUSSION :

Melting Point Determination :

Melting point of tadalafil was found in the range between 290°C to 295°C.  The reported melting point in the range of tadalafil was 290°C to 300°C. Hence, experimental values were in good agreement with official value.

Ultraviolet Spectroscopy: The values of correlation coefficient for the linear regression equation was found to be 0.9974 for phosphate buffer of pH 6.8 indicating a good positive correlation between concentration of tadalafil  and the corresponding absorbance values.

UV Estimation of Tadalafil :

Determination of Maxima of Tadalafil

The ultraviolet spectrum was recorded in the range 200 nm to 400 nm, the standard solution (100 µg/ml) of pure drug was prepared in phosphate buffer (pH 6.8) + 1 % sodium lauryl sulphate. From the standard solution 2 to 30µ g/ml dilutions were prepared and 10 µg/ml solution was scanned in the range of 200 nm to 400 nm. The solution showed maximum absorbance at 290 nm. At the ?max of 290 nm tadalafil was estimated using phosphate buffer (pH 6.8) + 1% sodium lauryl sulphate.

DSC statement:
       
           
       
Table 2 :Evaluation of Batches of ODF of Tadalafil Generated by CCD

       
           
       
Table 3 :Evaluation of Batches of ODF of Tadalafil Generated by CCD

       
           
       
Table 4 :Evaluation of Batches of ODF of Tadalafil Generated by CCD

       
           
       
Table 5 : Evaluation of Batches of ODF of Tadalafil Generated by CCD

       
           
       
Table 6 : In-Vitro Diffusion Study of Tadalafil ODF 

       
           
       
Table 7: In-Vitro Drug Release (Dissolution) of Optimized Batches of Tadalafil ODF Generated by CCD (TDF1-TDF9)

Fig 9 In-vitro Drug Release of Tadalafil (Dissolution)

STABILITY STUDY

I) Accelerated Stability Study

Stability studies were carried out for 30 days at 40⁰c and 75 % RH. The films were observed for any change in parameters like physical changes, folding endurance, disintegration time, percentage drug content, percentage drug release and other parameters also. ODFs of Tadalafil were found to be physically and chemically stable and showed no significant change in terms of physical characteristics, formulation TDF7 was stable and retained their original properties with minor differences in drug content, %DR and other parameter which are in acceptable limits.

Stability Study of  Optimized Batch of Tadalafil ODF

The general central composite design was applied to optimize the ODF of taste masked Tadalafil. The response surface methodology analyzed data clearly indicate that the %DR, DT, values were mainly depending upon the selected independent variables. The regression equations for the responses fitted in linear  model were generated. ANOVA was used to identify the significant effect. Obtained value of F is larger than critical F-value, the result was found to be significant at that level of probability <0>

Final equation in terms of coded form

% DR= +97.33+(-0.1768)+1.35

Final equation in terms of coded form-

DT= +15.33+(-0.02112)+0.3143

Response 1 Dissolution

       
           
       
Response 2 Disintegration

       
           
       
Table 8 : Fit Summary for Dissolution & Diffusion
Table 9 :Result of Analysis of Variance for Batches by CCD of Tadalafil ODF