CHAPTER 7: DESIGN DEVELOPMENT AND EVALUATION OF ORAL SOFT GEL OF LORNOXICAM

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1 DESIGN DEVELOPMENT AND EVALUATION OF ORAL SOFT GEL CHAPTER 7: DESIGN DEVELOPMENT AND EVALUATION OF ORAL SOFT GEL OF LORNOXICAM 7. Introduction Oral route is most preferred route by patient. Drug delivery to geriatric and paediatric patient is always a challenge. Recently, more stress is laid down on the development of organoleptically elegant and patient friendly drug delivery system for paediatric and geriatric patients (Wadhwani et al. 56 and Bhusan et al. 32). Many patients, elders and person with dysphagia find it difficult to swallow the tablets and hard gelatin capsules which results in high incidence of noncompliance and ineffective therapy. The patients with dysphagia can be choked by water while consuming liquid formulation, which can be eliminated by administering liquid formulations with high viscosity (Yokoyama et al.).the gel dosage form can be swallowed easily without water and are soft and smooth (Ninomiya et al.). The problem of dose measurement by patients is outweighed as oral medicated gels are to be packed in unit dose (Lohani et al.). The gel dosage form can be versatile in nature in the sense that it can be used as such or it can be taken with food items such as biscuits and breads (Gohel et al. 2). Gels are formed by aggregation of polymers with minimum two components; the gelling agent and the fluid component. Gellan gum, carrageenan, pectin, sodium alginate and gelatin are widely used gelling agents in pharmaceutical industries. Free carboxylate groups are present in the structure of gum which is anionic in nature and thus it would undergo ionic gelation in the presence of cations such as Ca ++, Mg ++, K +, Na + and H + from acid (Morries et al. ). The mechanism of gelation involves the formation of double helical junction zones from random coil chains (coil-to-helix transition) followed by aggregation of double helical 69

2 CHAPTER-7 segments to form a three-dimensional network by complexation with cations and hydrogen bonding with water (Grasdalen et al. 37). Aggregation behaviour is affected by the ph of the solution (Horinak et al. 223). By varying the concentration of gum and cation, gels with different gel strength and gel texture can be manufactured. Lornoxicam is used as pain killer in which immediate release and immediate action is necessary and thus formulating oral soft gel of lornoxicam is of preference. Lornoxicam has bitter taste. The taste perception of bitter drugs is experienced in the mouth at taste buds. Taste masking has become a potential tool to improve patient compliance (Balfour et al. 639) Taste masking by sweetening agent was done in case of gels as gel formulation allows to incorporate high quantity of sweetener. Preliminary trials were performed for selection of gelling agent. Finally the optimization of gelling agent and sodium citrate was done using experimental design. The gels were evaluated for parameters for viscosity and drug release study. 7.2 Materials Kelcogel (dry gellan gum powder) was kindly gifted form CP Kelco (USA). Lornoxicam was gifted by Hetero drugs Ltd. (Hyderabad, India). Polyethylene glycol 4 (PEG 4) and citric acid was procured from Laser Laboratories (India). Methylparaben and propylparaben were procured from Apex Pharmaceuticals (India). Aspartame, Microcrystalline cellulose (MCC), sucrose and sodium citrate were kindly gifted from Lincoln Pharmaceuticals Ltd. (India). Food grade sucrose was procured from the local market. 7.3 Methods 7.3. Preformulation study FTIR of lornoxicam and gel formulation of lornoxicam containing all excipients of OSG was done to check the drug excipients compatibility Preliminary trials All the required ingredients of the formulation were weighed accurately. Gelling agent- gum was dispersed in 2 ml of distilled water maintained at 95 C. The dispersion was stirred at 95 C for 2 min using a magnetic stirrer. LXM was added with stirring. Then sucrose, MCC, citric acid, and preservatives (methylparaben) were added with stirring. Finally, required amount of sodium citrate was dissolved in ml of distilled water and added to the mixture. 7

3 DESIGN DEVELOPMENT AND EVALUATION OF ORAL SOFT GEL The weight of the gel was monitored continuously during manufacturing and finally it was adjusted to the 25 gm with distilled water. The mixture was allowed to cool to room temperature to form gel Selection of gelling agent Gels were prepared as stated above wherein the selection of gelling agent was done varying the concentration as.3%,.4% and.5 %. OG -3, OG 4-6, OG 7-9 and OG -2 were prepared of gellan gum, pectin, guar gum and sodium alginate respectively of stated concentration as shown in table 7.. The prepared gel was evaluated for ph, Gel form retention, syneresis during storage at room temperature, viscosity, Ease of removal from container, Drug content and % Drug release after 2 min. Table: 7. Selection of gelling gum Ingredients OG OG2 OG 3 OG4 OG5 OG6 OG7 OG8 OG9 OG OG OG2 Lornoxicam 2 mg Gellan gum(%) Pectin (%) Guar gum (%) Sodium alginate (%) MCC (%) Citric acid (%) Sodium citrate (%) Sucrose (%) Aspartame (%)

4 CHAPTER-7 Ingredients OG OG2 OG 3 OG4 OG5 OG6 OG7 OG8 OG9 OG OG OG2 Methyl paraben (%) Water qs. 25 g 25g 25g 25g 25g 25g 25g 25g 25g 25g 25g 25g Optimization of concentration of pectin To reduce the syneresis and leave no liquid in container, pectin was required to be added to the gel. The optimization of pectin concentration was done in batches OG 3-4 as shown in table 7.2. The prepared gel was evaluated for ph, Gel form retention,syneresis during storage at room temperature, viscosity, Ease of removal from container, Drug content and % Drug release after 2 min. Table: 7.2 Optimizing the concentration of pectin Ingredients OG3 OG4 OG 5 Lornoxicam 2 mg Gellan gum (%) Pectin (%)..2.3 MCC (%) Citric acid (%) Sodium citrate (%) Sucrose (%) Aspartame (%) Methyl paraben (%) Water qs. 25 g 25g 25g Study the effect of sodium citrate on gel form To observe the effect of sequestering agent-sodium citrate on gelation, syneresis and drug release, batches OG 6-8 were formulated. The prepared gel was evaluated for ph, Gel form 72

5 DESIGN DEVELOPMENT AND EVALUATION OF ORAL SOFT GEL retention, syneresis during storage at room temperature, viscosity, ease of removal from container, drug content and % drug release after 2 min. Table: 7.3 Study the effect of sodium citrate on gel form Ingredients OG6 OG7 OG 8 Lornoxicam 2 mg Gellan gum (%) Pectin (%) MCC (%) Citric acid (%) Sodium citrate (%) Sucrose (%) Aspartame (%) Methyl paraben (%) Water qs. 25 g 25g 25g Formulation optimization of OSG using 3 2 Factorial design To select ideal proportion of gellan gum and sodium citrate, factorial design approach was used. The design and response summary data represented in table 7.5. The polynomial equation was generated using multiple linear regression analysis (Moneghini et al. 297). This study investigated utility of a 2-factor, 3-level design and optimization process for oral soft gel of LXM. Amount of Gellan gum (A) and Amount of sodium citrate (B) were selected as the independent variables whereas viscosity (Y ) and (Y 2 ) Drug release in 2 min (Y 2 ) were selected as dependent variables. Independent factors were selected at 3 different levels as mentioned in table 7.4. The prepared Oral soft gels of LXM were evaluated for dissolution study. The design responses were analyzed using ANOVA in MS Excel 27 and polynomial equation was generated for each response. 73

6 CHAPTER-7 Table: 7.4 Independent variable Levels in coded form Independent variable levels - Concentration of Gellan gum (%) Concentration of sodium citrate (%) Table: 7.5 Layout of design OSG formulations Batch no. Coded valve Actual value A B Concentration of Gellan gum (%) Concentration of sodium citrate (%) OSG OSG OSG OSG OSG OSG OSG OSG OSG OSG The response surface methodology is a collection of mathematical and statistical techniques used for modeling and analysis of problems in which a response of interest is influenced by several variable and the objectives is to optimize this response. The run or formulations, which are designed based on factorial design, were evaluated for the response. The response values are subjected to multiple regressions analysis to find out the relationship between the 74

7 DESIGN DEVELOPMENT AND EVALUATION OF ORAL SOFT GEL factor used and the response value obtained (Sastry et al. 2). The multiple linear regression analysis was done using DESIGN EXPERT 9 trial version, which specially meant for effective optimization process. One random check points covering the entire range of experimental domain were carried out to determine the validity of the model generated. Subsequently, the resultant experimental data of the response properties were quantitatively compared with those of the predicted values. Predicted values were compared with the resulting experimental values and the percentage bias was calculated. The composition of checkpoint formulations OSG is shown in Table 7.6 Table: 7.6 Composition of design batches of OSG formulations Ingredients OSG OSG2 OSG 3 OSG4 OSG5 OSG6 OSG7 OSG8 OSG9 OSG Lornoxicam 2 mg Gellan gum (%) Pectin (%) MCC (%) Citric acid (%) Sodium citrate (%) Sucrose (%) Aspartame (%) Methyl paraben (%) Water qs. 25 g 25g 25g 25g 25g 25g 25g 25g 25g 25g 75

8 CHAPTER Evaluation of Oral soft gels of LXM (Jain et al.) Following studies were carried out for evaluation of oral soft gel of lornoxicam General appearance Texture and clarity of the soft gel was evaluated in terms of stickiness and grittiness by mildly rubbing the gel between two fingers. Consistency and odour were also evaluated by physical observation Rheological measurement Viscosity of all the batches of soft gels was measured using Brookfield DV-II+Pro viscometer. The lornoxicam containing soft jelly was squeezed out from the polyethylene plastic mould by making a cut of uniform size on the mould and viscosity was measured using spindle number LV4 at the rotation of 5 rpm at room temperature. The viscosity measurements were made in triplicate using fresh samples each time (Mohapatraet al. 72) ph of the soft jelly The ph of the final gel has got influence not only on stability, but also on the taste. The ph of oral soft jelly was measured using Electroquip Digital ph meter at room temperature (Ishibashi er al.) Syneresis Syneresis is one of the major problems associated with low acylated guar gum gels. Syneresis means contraction of gel upon standing and separation of water from the gel. Syneresis is more pronounced in the gels where lower concentration of gelling agent is used. Gels were kept under scrutiny for signs of syneresis. The gels showing signs of syneresis were rejected and not considered for further studies (Yokoyama et al.) Drug content jellies were taken from jelly mould in a beaker and their average weight was determined They were broken to gel consistency. Then gel equivalent to mg of lornoxicam was taken in ml volumetric flask and dissolved in 7 ml of water with vigorous shaking for 5- minutes. Finally the volume was made up to mark with water. Then it was analyzed usinguv spectroscopically at 378 nm (Mohapatra et al 72). 76

9 DESIGN DEVELOPMENT AND EVALUATION OF ORAL SOFT GEL In vitro drug release studies In vitro drug release studies was carried out using USP dissolution apparatus 2 using paddle at a speed of rpm using 9 ml of.n HCl and phosphate buffer ph 6.8 as dissolution media at 37±2 C. The ready to use soft jelly (5 gm) containing 4mg of lornoxicam was used in the dissolution test. Five milliliters of sample was withdrawn at the interval of every five minutes and the drug solution was replaced with the same volume of dissolution media maintained at 37±2 C. One milliliter of the filtered sample was diluted up to 5 ml with dissolution media and absorbance was measured at 378 nm using spectrophotometrically Texture analysis Instrumental texture analysis is mainly concerned with the evaluation of mechanical characteristics where a material is subjected to a controlled force from which a deformation curve of its response is generated (Balfour et al. 639). For evaluating texture properties of oral soft gel, a travelling hemispherical probe was used in this deformation method using the Brookfield QTS-25 texture analyzer. Simple penetrometry, where the probe comes into contact with the sample creating both compressive and shear (cutting) forces as penetration increases. The technique aims to imitate the subjective test technique of pressing the gel surface with a finger. A 2 mm diameter hemispherical probe was used to replicate the geometry of a finger pressed into the sample. The travelling probe is directly connected to a load cell which measures sample response as a function of probe penetration Stability studies of soft gel A physically stable oral jelly retains its viscosity, color, clarity, taste, and odor throughout its shelf-life. Gels were checked for syneresis during storage. A freshly made sample should serve as a reference standard for subjective evaluations. The samples were kept at different temperatures (-8 C and room temperature) for four weeks. The samples of soft gel were observed for ph, viscosity, and appearance at the interval of one week. All the measurements were performed after allowing the samples to be equilibrated at 25 C for two hours (Mohapatra et al 72). 7.4 Results and discussion 7.4. Preformulation study Lornoxicam is bitter in taste. In formulation of oral soft gel there was 6% sucrose and.4% aspartame used which could easily mask the bitter taste of drug. Thus in this formulation there was no need of any other taste masking approach only sweeteners were sufficient. 77

10 CHAPTER-7 Peak present in LXM was retained in gel form of lornoxicam containing all the excipients of OSG. This was indicating stability of LXM during processing and compatibility with the excipients as shown in fig 7.. a) b) Figure: 7. a) FTIR of LXM and b) FTIR of LXM oral soft gel Preliminary trials for OSGs Initially in batches OS -2 gels were prepared for the selection of gelling agent wherein varied concentration as 3%, 4% and 5 % were used containing gellan gum, pectin, guar gum and sodium alginate in OG -3, OG 4-6,OG 7-9 and OS -2 respectively. From the results in table 7.7, it was found that as the concentration of gelling agent increased, the viscosity was increased.gel with gellan gum as gelling agent OS -3 shows good gel form, viscosity with no or less liquid remaining on removal from container only problem was syneresis.gel with guar gum OS 7-9 and sodium alginate OS -2 has poor to good gel form but liquid was remained separated on removal from container, thus found difficult to remove completely so this gums are omitted in further trials. In case of pectin OS 4-6, there was no syneresis and less liquid remained separated so in further trials, pectin and gellan gum were combined in view to remove the problem of syneresis and get sufficient viscosity. 78

11 DESIGN DEVELOPMENT AND EVALUATION OF ORAL SOFT GEL Table: 7.7 Evaluation of batches OS-2 Evaluation * OG OG2 OG 3 OG4 OG5 OG6 ph 6.2±.2 6.4±.5 6.7± ±.56 6.± ±.9 Gel form retention Syneresis during storage at room temperature viscosity (cps) Ease of removal from container poor good Very good poor poor good Little syneresis Little syneresis Intensified over time Little syneresis No syneresis No syneresis 859±7 3589± ±3 259±2 28±4 4365±3 easy to remove and small amount of liquid remained Easy to remove and small amount of liquid remained easy to remove and no liquid remained Liquid spills and difficult to remove large amount of liquid remaining and difficulty in removal Easy to remove and small amount of liquid remained Drug content (%) % Drug release after 2 min 98.89± ± ± ± ± ± ± ± ± ± ± ±.48 *n=3 Mean ± SD of 3 experiments Evaluation * OG7 OG8 OG9 OG OG OG2 ph 6.3± ± ±.2 6.± ±.82 Gel form poor poor good poor good good retention Syneresis Intensified Little Little Intensified Little Little during storage over time Syneresis Syneresis over time Syneresis Syneresis at room temperature Viscosity (cps) 867± 568± ±24 649±3 3458±8 542±9 Ease of Large Large Easy to Liquid spills Large Easy to 79

12 CHAPTER-7 removal from amount of amount of remove and out and amount of remove and container liquid liquid small difficulty in liquid small remaining remaining amount of removal remaining amount of and and liquid and liquid difficulty in difficulty in remaining difficulty in remaining removal removal removing Drug (%) content 98.82± ± ± ± ± ±.78 % Drug release after 2 min 93.25± ± ± ± ± ±.59 *n=3 Mean ± SD of 3 experiments To reduce the syneresis of gel, pectin was added to the gel. The optimization of pectin concentration was done in batches OG 3-4 containing.,.2 and.3% respectively. As shown in table 7.8 preparation with % pectin had little liquid separation of liquid after removal from container.as the concentration of pectin was increased in the preparation, the gel form was improving and no syneresis was obtained. There was no major difference in gel form quality after 2% of increase in pectin concentration; only viscosity was increasing whereby the drug release was decreasing. Thus 2% pectin was incorporated to the gel formulation along with gellan gum as gelling agent. Table: 7.8 Evaluation of batches OS 3-5 Evaluation * OG3 OG4 OG 5 ph 6.5±.5 5.9±.2 6.9±.25 Gel form retention good Very good Very good Syneresis during storage at room temperature Almost no syneresis Almost no syneresis Almost no syneresis Viscosity (cps) 5429±5 889±2 9857±2 Ease of removal from container Easy to remove and small amount of liquid remaining easy to remove and no liquid remain easy to remove and no liquid remain Drug content (%) 98.59± ± ±.78 % Drug release after 2 min 87.25± ±.58 6±.23 *n=3 Mean ± SD of 3 experiments 8

13 DESIGN DEVELOPMENT AND EVALUATION OF ORAL SOFT GEL To observe the effect of sequestering agent-sodium citrate on gelation, syneresis and drug release batches OG 6-8 were formulated. The ph of the jelly preparation in the form of solution just before gelation was adjusted preferably to 4. or more upto 7. This was because when ph was below 4, jelly preparation liable to cause syneresis and stability of the preparation deteriorates in some cases. When the ph was 6 or more close to neutrality, the jelly preparation was found excellent in stability. Therefore, the ph of the formulated gels was adjusted and maintained in between 5 and 7. It was observed that with increasing concentration of sodium citrate, the ph was increased which leads to increase in syneresis, With increase in concentration of sodium citrate, it led to increase in gelation thus increase in viscosity and decrease in drug release. Table: 7.9 Evaluation of batches OS 6-8 Evaluation * OG6 OG7 OG 8 ph 6.5±.5 7.9±.2 8.9±.25 Gel form retention good good Poor Syneresis during storage at room temperature Little syneresis Almost no Little syneresis syneresis viscosity (cps) 5429±5 789±2 7857±2 Ease of removal from container easy to remove and easy to remove easy to remove and small amount of and no liquid no liquid remain liquid remaining remain Drug content (%) 98.59± ± ±.78 % Drug release after 2 min 89.25± ±.58 78±.23 *n=3 Mean ± SD of 3 experiments Optimization of Formulation compositions of OSGs by experimental design To select ideal proportion of gellan gum and sodium citrate, factorial design was used. After applying design, the response was recorded and analysis of data was carried out using ANOVA in MS Excel. Using the regression coefficient of each factor, the polynomial equation for the each response was generated. 8

14 CHAPTER-7 The response variable considered for optimization of viscosity (Y) and Y 2 (Y2) drug release in 2 minutes. The results of response were depicted in table 7.. Results of other evaluation parameters were shown in table 7. The optimized formulation was obtained by applying constraints (goals) on dependent (response) and independent variables (factors). Constraints were selected based on minimum and maximum limits obtained from response. Constraints for responses and factors are shown in table 7.2 Table: 7. Results of dependent responses Batch no. Coded valve Actual value Responses A B A(%) B(%) Viscosity (cps) % drug release in 2 min OSG ± 8± OSG ±7 7±.5 OSG ±9 8±.54 OSG ±5 63± OSG ± 67± OSG ±2 83± OSG ±5 89±.3 OSG ±8 84±. OSG ±5 5±.6 OSG ±2 83.9±.4 *n=3 Mean ± SD of 3 experiments 82

15 DESIGN DEVELOPMENT AND EVALUATION OF ORAL SOFT GEL Table: 7. Evaluation parameters of factorial batches of OSGs Evaluation * OSG OSG2 OSG 3 OSG4 OSG5 OSG6 OSG7 OSG8 OSG9 ph 6.8± 4.2±.3 5.6±. 5.8±. 6.3±. 4.5± ±. 6.5± ± Gel retention form Good Good Good Good Good Good Good Good Good Syneresis No Intensifi Little Intensifi No Little Little No Little during ed ed storage at room temperature Ease of Easy to remove and no liquid separates in container after removal removal from container Drug ± 99.42± 98.8± 99.25± 99.2± 99.8± 99.58± content ± ± *n=3 Mean ± SD of 3 experiments Table: 7.2 Formulations constraints for dependent and independent variables in OSG formulations Name Goal Lower Limit Upper Limit Concentration of Gellan gum (%) In range.3.7 Concentration of sodium citrate (%) In range.3.5 Viscosity (cps) In range Drug release in. N HCl in 2 min (%) In range 7 83

16 CHAPTER-7 Response : Viscosity (Y) The fitted full model equation relating the response viscosity to the transformed factor is shown in following equation. The equation obtained as follows Viscosity (Y) = *A +69.6*B (i) The coefficients b and b 2 are positive. The viscosity for the 9 batches show a variation, that is, the response ranged from a minimum 22 to maximum of 345 cps. It may be concluded that at higher levels of A(concentration of gellan gum) and B (concentration of sodium citrate ) the viscosity increases. The level B shows less significant effect than A on the viscosity.the value of correlation co-efficient R 2 was found to be.99, indicating a good fit. The surface and contour plots are shown in fig.7.2. Design-Expert Software Factor Coding: Actual viscosity (cps) Design Points X = A: concentration of gellan gum X2 = B: concentration of sodium citrate B : c o n c e n tr a tio n o f s o d iu m c itr a te ( % viscosity (cps) 6 8 Design-Expert Software Factor Coding: Actual viscosity (cps) Design points above predicted value Design points below predicted value X = A: concentration of gellan gum X2 = B: concentration of sodium citrate v i s c o s i t y ( c p s ) A: concentration of gellan gum (%) -.5 B: concentration of sodium citrate (%) A: concentration of gellan gum (%) Figure: 7.2 Contour and surface plot for the effect of A and B on viscosity Response 2: Drug release in 2min (Y 2 ) Y2 The full model polynomial equation obtained was as follows Y 2 (Y2) = Drug release after 2 min(%) = * A-7.5 * B (ii) The drug release for the 9 batches shown a variation, that is, the response ranged from a minimum 58% to maximum of 93 %. The value of correlation co-efficient R 2 was found to be.99, indicating a good fit. b and b2 both are negative, It may be concluded that at higher levels of A(amount of gellan gum ) and higher level of B (amount of sodium citrate) the drug release increases. The level B shows less significant effect than A on the drug release. Surface and counter plot are shown in fig

17 DESIGN DEVELOPMENT AND EVALUATION OF ORAL SOFT GEL Design-Expert Software Factor Coding: Actual % drug release in 2 min (%) Design Points 89 5 X = A: concentration of gellan gum X2 = B: concentration of sodium citrate B : c o n c e n tr a tio n o f s o d iu m c itr a te ( % % drug release in 2 min (%) Design-Expert Software Factor Coding: Actual % drug release in 2 min (%) Design points above predicted value Design points below predicted value 89 5 X = A: concentration of gellan gum X2 = B: concentration of sodium citrate % d r u g r e l e a s e i n 2 m i n ( % ) A: concentration of gellan gum (%) B: concentration of sodium citrate (%) A: concentration of gellan gum (%) Figure: 7.3 Contour and surface plot for the effect of A and B on Y 2 Table: 7.3 Results of p values, regression coefficient and F values for various responses. p values of coefficient R 2 F Significance F Bo b b2 Viscosity( cps) % Drug release in 2 minutes E In case of dependent variable, viscosity and drug relase in 2 minutes as shown in table 7.3, the p value for X2, X and X22 was found to be greater than.5, which was rendered insignificant. while p value for other term X and X2, were found to be less than.5.thus X and X2 shown significant effect on viscosity and drug release in 2 minutes. For the optimization of oral soft gel of LXM, constraints were fixed for all factors and response. Constraints were set according to formulation of oral soft gel using minimum amount of excipients, which would give desired response values. In the present study, our aim was viscosity should be sufficient and more than 7 % dissolution of drug within 2 min with controlled friability. In optimization, desirability. indicated that optimum formulation was achieved at 3% gellan gum and 3% of sodium citrate as shown in Fig

18 CHAPTER-7 Design-Expert Software Factor Coding: Actual Desirability Design Points X = A: concentration of gellan gum X2 = B: concentration of sodium citrate B : c o n c e n t r a t i o n o f s o d i u m c i t r a t e ( % ) Prediction Desirability Design-Expert Software Factor Coding: Actual Desirability X = A: concentration of gellan gum X2 = B: concentration of sodium citrate D e s ir a b ilit y A: concentration of gellan gum (%) B: concentration of sodium citrate (%) A: concentration of gellan gum (%) Design-Expert Software Factor Coding: Actual Overlay Plot viscosity % drug release in 2 min Design Points X = A: concentration of gellan gum X2 = B: concentration of sodium citrate B : c o n c e n t r a t i o n o f s o d i u m c i t r a t e ( % ) Overlay Plot viscosity: % drug release in X X2.725 % drug release in 2 min: A: concentration of gellan gum (%) Figure: 7.4 Desirability and overlay plot for optimization Validation of optimization technique was done by preparing checkpoint batch OSG and responses were evaluated. Check point batch was compared for predicted value with observed value in table 7.4. Observed value was found close to the predicted value, which indicated good correlation of results. Table: 7.4 Comparison of predicted value and observed values of all responses for OSG batch Comparison of predicted value and observed values of all responses Batch Viscosity (cps) Drug release in 2 minutes (%) Observed value Predicted value Observed value Predicted value OSG Drug release profile of design batches were shown in fig 7.5 and

19 cummulativ % drug release cummulative % drug release DESIGN DEVELOPMENT AND EVALUATION OF ORAL SOFT GEL Time in minutes OSG OSG 2 OSG 3 OSG 4 OSG 5 OSG 6 OSG 7 OSG 8 OSG 9. Figure: 7.5 Drug release profile in artificial salivary fluid (ph-6.8) of design batches Time in minutes OSG OSG 2 OSG 3 OSG 4 OSG 5 OSG 6 OSG 7 OSG 8 OSG 9 Figure: 7.6 Drug release profile in. N HCl of design batches Optimized batch OSG 7 having viscosity 22 and 89 % drug release within 2 min Texture analysis The optimized batch was analysed for consistency or viscosity in texture analyser. As the texture analyzer probe penetrated lornoxicam gel, a small constant force was needed to reach the breaking point imitated the initial biting resistance or gel firmness, i.e. a bearing load of 85g/ mm as presented in Figure

20 CHAPTER-7 Load v Distance Load (g) Marker Time: Dist: Load: Marker 2 Time: Dist: Load: Difference Time: Dist: Load: Current test data Distance (mm) Figure 7.7: Graph of load Vs distance in texture analyser Stability studies of optimized batch The optimized batch was kept at different temperatures (-8 C and room temperature) for four weeks. The oral soft gel was observed for ph, viscosity, and appearance at the interval of two weeks. There was no syneresis observed in any of condition. General appearance of gel was retained with the easy of removal from container and no liquid retained at end. Oral soft gel was found to be stable for four weeks in both temperature conditions. Drug release in month was taken as reference and dissolution in, 2,3, 4, 5, 6 months were taken as test respectively and f 2 ( similarity factor) and t stat was calculated. From the result table it was found that f 2 value for drug release after,2,3,4,5,6 months were between 5 and. This proved that there was similarity in drug release. The dosage form had remained stable. As the result showed that t cal was less than t cri in drug release after,2,3,4,5,6 months. Thus there was insignificant difference in drug release upon the storage of drug for 6 months. Thus the optimized dosage was found stable. 88

21 cummulative % drug release DESIGN DEVELOPMENT AND EVALUATION OF ORAL SOFT GEL Table: 7.5 Stability study of optimized oral soft gel of LXM Sr.N o Storage condition Week Drug release in 2 minutes (%) t stat Tcri t cri f 2 valve ph Viscosity (cps) Drug content (%). Initial 89.9± ± ± ± ± ± C ± ± ± ± ± ±.6 25 ± 5 C ± ± ±.58 *n=3 Mean ± SD of 3 experiments Time (minutes) week 2 at 2-8 degree C week 4 at 2-8 degree C Initial drug release week 2 at 25 degree C week 4 at 25 degree C Figure 7.8: Drug release profile of stability batch in. N HCl 89

22 CHAPTER Conclusion It was found that the optimized soft gel with.3% gellan gum,. 2% pectin and.3% sodium citrate gave 89 % of lornoxicam release in 2 minutes in stomach as well as in mouth. OSG so formed was substantially stable at both room temperature and also at low temperature, thus storage at room temperature is possible. Also, the gel showed good taste masking with acceptable mouth feel. Thus, OSG can be a better preference for paediatric patients suffering from pain wherein gel can be spread on bread or chappati and can be administered. 7.6 References Balfour JA, Fitton A, Barradell LB, Lornoxicam. A review of its pharmacology and therapeutic potential in the management of painful and inflammatory conditions. Drugs5.4 (996): Print. Gohel MC, Parikh RK, Nagori SA, Shah SN, Dabhi MR. Preparation and Evaluation of Soft Gellan Gum Gel Containing Paracetamol. Indian J Pharm Sci 7.2(29):2 24. Print. Grasdalen H, Smidsrod O. Gelation of gellan gum. Carbohydrate Polymer 7 (987): Print. Horinak J, Kani K, Hori Y, Maeda S. Effect of ph on the conformation of gellan chains in aqueous systems. Biophy Chem (24): Print. Ishibashi M, Endo M, Miwa Y. Gel preparation for oral administration. 28: US Patent No. US28/687 A.Print. Jain DK, Darwhekar GN, Gupta V. Formulation and Evaluation of Oral Soft Jelly Containing Metformin Hydrochloride and Glimepiride. PHARMATUTOR ART Web. Assessed date 8/2/24 Lohani A. Development and Evaluation of Ciprofloxacin Hydrochloride Soft Gel for Oral Administration. Pharmatutor Art Assessed date 2/2/24 Mohapatra A, Parikh RK, Gohel MC. Formulation development and Evaluation of Patient Friendly Dosage Form of Metformin hydrochloride, part II: Oral soft gel. Asian J. Pharm 2 (28): Print. Moneghini M, Carcano A, Perissutti B, Rubessa F. Formulation design studies of atenolol tablets. Pharma Development Technolology 5 (2): Print. Morries J, DeWille N, Snowden G, Chandler M, Gunn A, Mulchandani R, et al. Gellan gum to improve physical stability of liquid nutritional products. 2: US Patent No. US

23 DESIGN DEVELOPMENT AND EVALUATION OF ORAL SOFT GEL Ninomiya H, Shimizu T, Dairaku M, Komagata T. Jellied medicinal composition for oral administration. 999:U.S Patent No 5,932,235. Print. Sastry VS, Reddy KI, Khan MA. Atenolol gastrointestinal therapeutic system: optimization of formulation variables using response surface methodology. Journal of Control Release 45( 997):2-3.Print. Wadhwani AR, Prabhu NB, Nandkarni MA, Amin PD. Consumer friendly mucolytic formulations. Indian J Pharma Sci 7(24):56-7. Print. Bhusan SY, Sambhaji SP, Anant RP, Kakasaheb RM, New drug delivery system for elderly. Indian Drugs 37(2): Print. Yokoyama H, Hirata A, Hamamoto H, Ishibashi M, Yamasaki K, Fujii T. Biguanide drug containing jelly preparation. 27: U.S Patent app A. Print. Yokoyama H, Hirata A, Hamamoto H. Biguanide drug containing jelly preparation. 27: US Patent No. US27/53939A. Print. 9