Study on formulation of sub-coating of lansoprazole loading core pellets – Luong Quang Anh

Journal of military pharmaco-medicine n o 4-2018 152 STUDY ON FORMULATION OF SUB-COATING OF LANSOPRAZOLE LOADING CORE PELLETS Luong Quang Anh*; Nguyen Ngoc Chien*; Nguyen Dang Hoa** SUMMARY Objectives: To study formulation of sub-coating of lansoprazole (LPZ) loading core pellets. Methods: The drug loading core pellets and sub-coating pellets were coated by using fluidized bed coater. Spectrophotometric method was used to determine the drug content and percentage of drug release from pellets. The influences of polyethylene glycol 6000, lutrol F127, talcum and solid content on the productivity of pellets, dissolution of LPZ from drug loading core pellets in phosphate buffer of pH 6.8 were evaluated. Results: Formulation of sub-coating of LPZ loading core pellets was established containing polyvinyl alcohol (5%), polyethylen glycol 6000 (1.5%), lutrol F127 (1%), titan dioxide (2%), talcum (2%). Weight of solid ingredients at 12.5% was chosen. LPZ loading core pellets were sub-coated with polyvinyl alcohol up to 7.5% weight gain. The sub-coating membrane was created to protect LPZ loading core pellets from acidic environment, and to avoid the interaction between the membrane and enteric coating. Conclusion: The sub-coating for LPZ loading core pellets was performed successfully in laboratory. * Keywords: Lansoprazole; Pellet; Sub-coating. INTRODUCTION Lansoprazole reduces gastric acidity, an important factor in healing acid-related disorders such as gastric ulcers, duodenal ulcers, and reflux oesophagitis. LPZ was used to treat gastro-oesophageal reflux, ulcers, acid-related dyspepsia, etc [2, 9]. The drug belongs to proton pump inhibitor group. In previous research, LPZ was loaded onto inert core pellets to form a drug layer using fluidized bed coater. In fact, it is necessary to formulate an enteric coating for pellets containing LPZ due to the degradation of the active pharmaceutical ingredient as LPZ in acidic medium [3, 6]. However, the acidity of enteric coating polymers requires a sub-coating for drug loading core pellets to create the stable LPZ pellets. In this study, formulation of sub-coating for LPZ loading core pellets was performed by fluidized bed coating method. * National Institute of Burn ** Hanoi University of Pharmacy Corresponding author: Luong Quang Anh ([email protected]) Date received: 02/02/2018 Date accepted: 26/03/2018 Journal of military pharmaco-medicine n o 4-2018 153 MATERIALS AND METHODS 1. Materials and equipments. LPZ was purchased from India (USP). EudragitđL100 was obtained from Evonik (Germany). Lutrol F127 (lutrol) was provided from USA. PVA (polyvinyl alcohol), PEG (polyethylene glycol) 6000, titan dioxide, talcum, inert core pellets and other excipients were suitable for pharmaceutical standards. MeOH (methanol) and all other ingredients used were of analytical grade. The study used equipments as follows: the Diosna spray coater and Caleva mini coater were from Germany and England, respectively. The Hitachi UV spectrophotometer was from Japan and Erweka dissolution equipment was from Germany. 2. Methods. * Drug loading and sub-coating: Inert core spheres were taken for drug loading to formulate the LPZ core pellets, and sub-coating was conducted immediately after drug loading using fluidized bed coating method. The amounts of inert spheres were placed into a laboratory Diosna spray coater with the following parameters: 1.0 mm nozzle- needle, atomizing pressure of 1.5 - 2.0 bar, inlet air temperature of 500C, inlet air of 90%, spray rate of 4.8 - 6.6 mL/min, and pipe diameter of 1.2 mm for drug loading. Sub-coating was performed using Caleva mini coater with the following parameters: an atomizing pressure of 1.0 bar, an inlet air temperature of 420C, an inlet air of 80%, a spray rate of 0.7 mL/min, and pipe diameter of 1.2 mm. After finishing coating, pellets were dried for 15 minutes in a fluid bed coating system and stabilized for 24 hours. * Calculation of coating productivity: H = mM x 100% H: Coating productivity (%); m: Weight gain of pellets after coating (g); M: Weight of solid ingredients in coating suspension/solution used (g). * Calculation of coating percentage: D = (a/b - 1) x 100% D: Coating percentage (%); a: Weight of pellets after coating (mg); b: Weight of pellets before coating (mg). * Drug content: Drug content assays were performed by using MeOH as a soluble solvent. The filtered solutions after extraction process were measured by UV spectrophotometer at 283 nm. The amount of LPZ contained in each formulation was determined by using a standard solution (concentration of LPZ at 10 àg/mL). * In vitro dissolution studies: The release of LPZ from pellets (30 mg LPZ, approximately) in 900 mL phosphate buffer solution (pH 6.8) was determined by using the Erweka equipment with paddle at 37 ± 0.5ºC and 75 rpm. After 60 minutes, LPZ was determined by spectrophotometric method similar to drug content section. * Gastric acid resistant test: Erweka equipment with paddle at 37 ± 0.5ºC and 75 rpm was used. An amount of enteric coated pellets equivalent to Journal of military pharmaco-medicine n o 4-2018 154 30 mg LPZ was poured into vessels containing 500 mL of 0.1 N HCl dissolution medium. After 60 minutes, enteric coated pellets were calculated about the criteria of color change and percentage of color change pellets in acidic medium. RESULTS AND DISCUSSION 1. Influences of PEG 6000 on coating productivity and drug release. PEG 6000 was used as plasticizer in sub-coating formulation, and it may affect the coating productivity and enduring property of coating layer, which influences the drug release [1]. Sub-coating was performed into drug loading pellets without changing the amount of PVA, lutrol, titan dioxide, talcum (5%; 1%; 2%; 1.5%; respectively). Percentage of PEG 6000 was from 1.0 to 1.5. The results were showed in table 1. Table 1: Influences of PEG 6000 on coating productivity and drug release. Parameters CT1 CT2 CT3 PEG 6000 (%) 1.0 1.25 1.5 LPZ release (%) 89.29 90.85 90.46 Productivity (%) 69.24 76.65 85.89 The sub-coating productivity was indirect proportion to the percentage of PEG 6000 while LPZ release was unchanged. The maximal productivity was 85.89% when percentage of PEG 6000 was 1.5%. 2. Influences of lutrol on coating productivity and drug release. Lutrol is a block copolymer referred to as poloxamer 407, and it was continually used in formulation of subcoating because of its anti-humidity [1, 8]. The influences of lutrol on coating productivity and drug release was showed in table 2. Table 2: Influences of lutrol on coating productivity and drug release. Parameters CT4 CT3 CT5 CT6 Lutrol (%) 0.5 1.0 1.5 2.0 LPZ release (%) 84.62 90.46 89.68 90.03 Productivity (%) 76.27 85.89 81.62 75.56 Coating process - ++ -- -- (Note: (+), (-) showed the grade of coating process by observing) The results showed that the sub- coating productivity and LPZ release were in direct proportion to the percentage of lutrol, respectively. When the percentage of lutrol was higher (above 1%), the coating productivity reduced and coating process was negative because of increased viscosity of coating suspension/solution. 3. Influences of talcum weight on coating productivity. Table 3: Influences of talcum weight on coating productivity. Parameters CT7 CT8 CT3 CT9 Talcum (%) 0.5 1.0 1.5 2.0 LPZ release (%) 91.05 90.32 90.46 90.55 Productivity (%) 79.22 81.49 85.89 75.67 Coating process - - ++ + (Note: (+), (-) showed the grade of coating process by observing) The sub-coating process using CT7 and CT8 (the percentage of talcum was 0.5 and 1.0, correlatively) showed double Journal of military pharmaco-medicine n o 4-2018 155 or triple gluey pellets, which leads to reduce the sub-coating productivity (approximately 80%). The optimal sub- coating productivity was 85.89% when the percentage of talcum was 1.5% (CT3). Nevertheless, an increase in percentage of talcum (2.0%, CT9) was not directly proportional to the sub-coating productivity. For this reason, the formulation of CT3 is the optimal preparation at 20 g batches using Caleva mini coater. The CT3 and CT9 were continually applied at higher batches (150 g, Diosa fluidized bed coater), and the outcomes showed that CT3 was not appropriate to formulate the good sub- coating pellets because of decreased coating productivity (gluey pellets were seen). Meanwhile, the formulation of CT9 showed advantage coating process, satisfactory productivity (90%), and the drug release was above 90%. Consequently, CT9 was chosen for preparing the sub-coating pellets. 4. Influences of weight of solid ingredients in coating suspension/solution on coating productivity and drug release. The sub-coating layer was formed onto LPZ loading pellets with weight of solid ingredients changed (from 7.5% to 15%). The influences of weight of solid ingredients in coating suspension/solution on coating productivity and drug release were showed in table 4. Table 4: Influences of weight of solid ingredients in coating suspension/solution on coating productivity and drug release. Parameters CT10 CT9 CT11 CT12 Weight of solid ingredients (%) 7.5 11.5 12.5 19 LPZ release (%) 89.36 90.55 91.12 - Productivity (%) 81.35 75.67 75.30 - Coating process ++ ++ + - (Notes: (-): The parameter was not to be performed due to negative property of coating process. (+), (-) showed the grade of coating process by observing) The results showed the influences of weight of solid agents on sub-coating productivity. At the low weight of solid agents, the sub-coating process was favourable and the productivity was high but it required much time (CT10). Conversely, at the high weight of solid ingredients, time for coating was lessen, but the excipients was seen not to be completely adherent to the surface of drug loading pellets. Hence, weight of solid ingredients at 12.5% (CT11) was chosen to ensure the optimal sub-coating process and productivity, and to save time for preparation at the same batches or scaled-up batches. Journal of military pharmaco-medicine n o 4-2018 156 5. Influences of sub-coating percentage on productivity, drug release from sub-coated pellets and gastric acid resistance of enteric coating. The sub-coating pellets using the formulation CT11 were coated by Eudragit L100 (weight gain of sub-coating membranes ranged from 5% to 10%). The enteric polymer, TEC, titan dioxide, talcum were dispersed and dissolved in the mixture of ethanol and purified water. Gastric acid resistant test was performed with regard to the prepared enteric coated pellets in the environment of 0.1 N HCl dissolution medium to evaluate the protective effect of enteric coated layer. The results showed in table 5. Table 5: Influences of sub-coating percentage on productivity, drug release from sub-coated pellets and gastric acid resistance of enteric coating. Weight gain of sub-coating (%) 5 7.5 10 Weight gain of enteric coating (%) 25 LPZ release (%) 91.12 91.62 91.24 Sub-coating productivity (%) 75.30 76.25 75.46 Time (minutes) for pellets changing its color in pH 1.2a 30 56 57 Percentage of enteric coated pellets changed its color after 60 minutes in pH 1.2b 25.40 2.26 2.02 (Note: The parameter a and b were evaluated by observing and counting) The drug release in buffer pH 6.8 from sub-coated pellets was unchanged in spite of raising percentage of sub-coating membrane. Besides, the sub-coating productivity also was not changed. After enteric coating, pellets were tested in acidic medium to assess the influences of weight gain of sub-coating membrane to gastric acid resistance of enteric coated pellets. The results showed that pellets changed to orange color after 30 minutes at 5% weight gain of sub- coating. This time for color changed pellets was about 60 minutes at 7.5% and 10% weight gain of sub-coating. In addition, percentage of enteric coated pellets changed its color after 60 minutes in pH 1.2 medium was very low (approximately 2%). As a result, weight gain of sub-coating contributes to increase acid resistant property of enteric coated pellets through the role of its second protective layer for LPZ loading core pellets. Moreover, when weight gain of sub-coating was 7.5% or above, drug release from sub-coated pellets was not affected in phosphate buffer pH 6.8 (more 90% after 60 minutes of dissolution experiment). CONCLUSION Formulation of sub-coating of lansoprazole loading core pellets was established containing polyvinyl alcohol (5%), polyethylen glycol 6000 (1.5%), Journal of military pharmaco-medicine n o 4-2018 157 lutrol F127 (1%), titan dioxide (2%), talcum (2%). Weight of solid ingredients at 12.5% was chosen. The suitable excipients were dispersed and dissolved in coating solven. The LPZ loading core pellets were sub-coated with polyvinyl alcohol up to 7.5% weight gain. REFERENCES 1. Hoàng Ngọc Hựng, Vũ Chu Hựng. Tỏ dược và chất phụ gia dựng trong dược phẩm, mỹ phẩm và thực phẩm. Nhà xuất bản Y học. 2006. 2. Ashraf R et al. Effect of pH and time on the dissolution studies of lansoprazole. J Curr Pharm Res. 2012, 4 (4), pp.27-28. 3. Chakravarthy K.K et al. Formulation and evaluation of enteric coated pellets of omeprazole. J Drug Dev Res. 2012, 4 (4), pp.257-264. 4. Hirjau M et al. Pelletization techniques used in pharmaceutical fields. Practica Pharmaceutic. 2011, 4 (3-4), pp.206-211. 5. Horn J.R et al. Similarities and differences among delayed release proton- pump inhibitor formulations. Aliment Pharmacol Ther. 2005, 22, pp.20-24. 6. Jayakar B et al. Formulation and evaluation of modified release capsules of lansoprazole. The Pharm Res. 2010, 4, pp.61- 73. 7. Rahman M.A et al. Recent advances in pelletization technique for oral drug delivery: A review. Current Drug Dev. 2009, 6 (1), pp.122-129. 8. Rowe R.C et al. Handbook of Pharmaceutical excipients. Pharmaceutical Press. 2009. 9. Shi S et al. Proton pump inhibitor: an update their clinical use and pharmacokinetics. Eur J Clin Pharmacol. 2008, 64, pp.935-951.