Formulation and invitro evaluation of delayed release multiple unit pellets of Lansoprazole in capsules

 

Suresh Kolli¹*, K. Vijayasri², P.N. Murthy¹

¹Department of Pharmaceutics, Royal College of Pharmacy and Health Sciences, Berhampur, India.

²Department of Pharmaceutics, Malla Reddy College of Pharmacy, Secunderabad, India.

 

 

ABSTRACT:

The present research was aimed to formulate and evaluate Lansoprazole delayed release multiple unit pellets in capsules. Lansoprazole degrades in the acidic environment of the stomach. It is also unstable under conditions of high temperature and high humidity which leads to therapeutic inefficiency. Hence it is important to bypass the acidic pH of the stomach. Protection of drug from acidic environment is done by coating the drug with enteric polymer. In the present study, successive layers of drug layer, barrier layer and enteric layer was coated on the inert sugar spheres by using solution/suspension layering technique in Fluidized bed processor (FBP). The prepared drug layered and barrier layered pellets were evaluated for % yield. The prepared lubricated pellets were evaluated for flow properties i.e., bulk density, tapped density, compressibility index and hausner’s ratio. Lubricated pellets filled into size ‘1’ capsules and evaluated for drug content, drug content resisted in acid, invitro drug release studies and compared with the marketed product. The dissimilarity and similarity factors for the optimized and marketed formulations were found to be 84.29. Accelerated Stability Testing (AST) was performed as per the ICH guidelines at 40±5°C/75±5% RH for 6 months and found satisfactory.

 

 

 

INTRODUCTION:

Lansoprazole, a proton pump inhibitor indicated for the treatment of duodenal ulcer, gastric ulcer, gastro intestinal reflux disorder, erosive esophagitis, zollinger-ellison syndrome, acid-related dyspepsia and as an adjuvant in the eradication of H. pylori. It belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the (H+, K+)-ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the parietal cell, lansoprazole has been characterized as a gastric acid (proton)-pump inhibitor, in that it blocks the final step of acid production. After oral administration, lansoprazole significantly decreases the basal acid output and significantly increase the mean gastric pH and percent of time the gastric pH was greater than 3-4. It also significantly reduces meal-stimulated gastric acid output and secretion volume, as well as pentagastrin-stimulated acid output. In patients with hypersecretion of acid, this drug significantly reduces basal and pentagastrin-stimulated gastric acid secretion. It inhibits the normal increases in secretion volume, acidity and acid output induced by insulin¹.

 

Lansoprazole is a BCS class –II drug and thus its having limited aqueous solubility, high permeability. There are instances where the rate of dissolution is rate limiting factor for poorly soluble drugs⁶. Furthermore, lansoprazole degrades in a highly acidic environment and it is also unstable under conditions of high temperature and also high humidity⁵. The degradation of this drug in the acidic environment of stomach leads to therapeutic inefficiency¹. In order to bypass the acidic pH of the stomach, one of the proven approaches is formulation of delayed release dosage forms² (single unit or multiple units). Compared to single units, Multiple unit particulate system shows better invitro release behavior than other dosage forms⁴.

 

In view of the advantages of multiple unit particulate systems like good flowability, compact structure, easy to dispensability⁸, the present study was aimed to formulate delayed release multiple unit pellets of lansoprazole by solution/suspension layering technique³ using different enteric polymer in a Fluidized bed processor (FBP) and then filled into capsules for oral administration. The process involves three successive layering’s of Drug, barrier and Enteric layers onto the non-pareil seeds (sugar spheres). Incorporation of pH adjuster (magnesium carbonate) in drug layer has been utilized to maintain the micro-environmental pH in a range that will increase drug solubility and improve stability during manufacture and storage⁹. The type of coating technique strongly affects the film micro environment and thus affects the drug release mechanism and rate from pellets coated with polymer blends⁷. Hence, suitable pH dependent enteric polymer was selected which protects the drug from acidic environment and releases the drug at a controlled pH i.e., after 5.5. Presence of protective coating (barrier layer) acts as a physical barrier between the drug and free carboxyl groups of enteric coating polymer¹⁰, and prevent the degradation of the drug due to direct contact of the enteric coating polymer.

 

MATERIALS AND METHODS:

Materials

Lansoprazole (Hetero Drugs Ltd.), Sugar spheres (IPS), Hydroxypropyl cellulose (HPC) (Aqualon), Povidone (PVP K-17) (), Hypromellose, 5 cps (HPMC) (), Sucrose (), L-HPC (LH-31) (), Corn starch (Basf), Magnesium carbonate (Merck), Sodium lauryl sulphate (Merck), Methacrylic acid copolymer type C (Degussa), HP 55 (), Triethyl citrate (Morflex), Polyethylene glycol 400 (Clariant), Polysorbate 80 (Croda Chemicals), Talc (Luzenac), Acetone (), Ethanol () and purified water. All chemicals and reagents were of analytical grade.

 

Formulation of Lansoprazole delayed release pellets

Delayed release pellets of Lansoprazole were prepared by solution/suspension layering on to the inert sugar spheres. Solution/suspension layering, a pelletization technique that converts fine powders or granules of bulk drugs and excipients into small, free-flowing, spherical or semi-spherical units¹¹ by fluidized bed processor with a bottom-spray (Wurster type) [Model No: Pam Glatt GPCG 1.1].

 

Lansoprazole delayed release formulation comprises of a core (sugar spheres of 750 micron size) onto which a succession of a drug layer containing lansoprazole, a barrier /layer and enteric layer comprising of enteric polymer. Application of each layer is in the form of suspension. Each layer is spray coated and dried prior to the application of the next successive coating.

 

i)        Drug coating suspension:

HPC (L-Type) or HPMC 5 cps or PVP K-17 was added to the purified water (80%) under continuous stirring and stirred continuously to get a clear solution. Then added SLS slowly to the above solution under continuous stirring and continued stirring to get clear solution. Then Sucrose, Magnesium Carbonate (light/heavy), Corn Starch and LHPC (LH-31) was added slowly one after one to the above solution and stirred for 30 minutes. Then, Lansoprazole was added slowly under stirring and add remaining purified water (20%) under continuous stirring and stirring was continued for 60 minutes to get homogeneous suspension.

 

Table 1: Optimization of Drug Layer of Lansoprazole DR capsules 30 mg

Ingredients	mg/unit
	LD1	LD2	LD3	LD4	LD5	LD6	LD7	LD8
Sugar Spheres (#20/#25)	150.00	150.00	150.00	150.00	150.00	150.00	150.00	150.00
Lansoprazole	30.00	30.00	30.00	30.00	30.00	30.00	30.00	30.00
Sucrose	20.00	20.00	20.00	20.00	20.00	20.00	20.00	20.00
Magnesium Carbonate (Light)	22.00	22.00	22.00	22.00	-	-	-	-
Magnesium Carbonate (Heavy)	-	-	-	-	22.00	22.00	22.00	22.00
Corn Starch	5.00	5.00	5.00	5.00	5.00	5.00	5.00	5.00
L-HPC (LH31)	20.00	20.00	27.00	27.00	27.00	27.00	27.00	27.00
HPC (L-type)	-	-	-	6.00	6.00	-	-	-
SLS	5.00	5.00	5.00	5.00	5.00	5.00	5.00	5.00
Povidone (PVP K-17)	5.00	10.00	10.00	-	-	-	-	-
HPMC, E5	-	-		-	-	3.00	6.00	9.00
Purified Water	qs	qs	qs	qs	qs	qs	qs	qs
Weight of Drug Layered pellets	257.00	262.00	269.00	265.00	265.00	262.00	265.00	268.00
Yield	75%	80%	84%	90%	97%	82%	86%	91%

 

(ii) Barrier coating suspension:

Binder (HPMC 5 cps/ HPC) was added slowly to the purified water (75%), under continuous stirring. Then sucrose was added under stirring to get a clear solution. Corn starch and LHPC (LH-31) were added slowly under continuous stirring and stirred for 30 minutes to get uniform suspension. Then, remaining purified water (25%) was added to the above suspension and stirred for 30 minutes to get uniform suspension.

 

Table 2: Optimization of Barrier Layer of Lansoprazole DR capsules 30 mg

Ingredients	mg/unit
	LD5B1	LD5B2	LD5B3	LD5B4	LD5B5	LD5B6
Drug Pellets	265.00	265.00	265.00	265.00	265.00	265.00
Sucrose	25.00	25.00	25.00	25.00	25.00	25.00
Corn Starch	-	-	6.00	6.00	10.00	14.00
L-HPC (LH31)	5.00	5.00	5.00	5.00	5.00	5.00
HPC (L Type)	3.00	-	3.00	-	5.00	5.00
HPMC, 5 cps	-	3.00	-	3.00	-	-
Purified water	qs	qs	qs	qs	qs	qs
Weight of Barrier Layered pellets	298.00	298.00	304.00	304.00	310.00	314.00
	87%	88%	90%	88%	98%	85%

 

(iii) Enteric- polymer coating dispersion:

Polymer (Methacrylic acid copolymer sifted through mesh #80 or HP 55) was added slowly to the purified water / solvent (Acetone/Ethanol) (70%) under stirring and stirred for 20 minutes. Plasticizer (PEG 400 or TEC) was taken into a beaker and purified water (10%) was added and mixed for 5-10 minutes. Then polysorbate 80 was added to the plasticizer solution and stirred for 10 minutes. This was added to the above polymer dispersion under stirring. Talc was added to the above dispersion under stirring. The remaining quantity of purified water (10%) was added to the above dispersion under stirring.  The suspension was kept under continuous stirring during the coating process.

 

Table 3: Optimization of Enteric Layer of Lansoprazole DR capsules 30 mg

 

Table 4: Lubrication of Enteric pellets

 

 

Table 5: Process parameters of FBP

Process parameters	Drug coating	Barrier coating	Enteric coating
Inlet temperature (°C)	50-55	40-70	38-42
Product temperature (°C)	38-42	38-42	28-35
Exhaust temperature (°C)	35-40	30-35	30-35
Drive speed (CFM)	40-65	40-60	40-65
Atomization (Barr)	1.0-2.0	1.0-2.0	1.0-2.0
Spray rate (g/min)	2-8	5-12	2-8
Wurster height (mm)	20-50	20-50	20-50

                                           

Evaluation

Sifting, Lubrication and Capsule filling: After coating, pellets were sifted to get a size fraction (#14/#25), lubricated with talc and filled in desired size capsules. (Table-4)

 

The prepared lubricated pellets were evaluated for flow properties i.e., bulk density, tapped density, compressibility index and hausner’s ratio. Lubricated pellets were filled into capsules and evaluated for weight variation, lock length, drug content, drug content resisted in acid, invitro drug release studies and compared with the marketed product. The dissimilarity and similarity factors for the optimized and marketed formulations were evaluated. Accelerated Stability Testing (AST) was performed as per the ICH guidelines at 40±5°C/75±5% RH for 6 months.

 

(i)      Assay method of Lansoprazole Delayed Release Pellets/Capsules 30 mg

Preparation of HPLC Diluent:

Preparation of Mobile Phase: Prepared a degassed mixture of water, acetonitrile and triethlyamine in ratio 60:40:1v/v and adjusted the pH to 7.0±0.05 with ortho phosphoric acid.

 

Internal standard solution: Dissolve an accurately weighed quantity of 4’-ethoxyacetophenone in acetonitrile to obtain a solution having a known concentration of about 7.5 mg per mL.

 

Standard preparation: Dissolved an accurately weighed quantity of Lansoprazole in a mixture of 0.1M sodium hydroxide and acetonitrile (3:2) to obtain a solution having a known concentration of 3.0 mg per mL. Transfer red 25.0 mL of this solution and 5.0 mL of Internal standard solution to a 50-mL volumetric flask, dilute with Diluent to volume, and mix. Quantitatively dilute with Diluent to obtain a solution having a known concentration of about 0.1 mg of Lansoprazole per mL.

 

Assay preparation: Transferred the contents of not fewer than 10 Capsules, equivalent to about 300 mg of lansoprazole, to a 300-mL conical flask containing 60.0 mL of 0.1 M sodium hydroxide, and sonicate until completely disintegrated. Add 20.0 mL of acetonitrile and 20.0 mL of Internal standard solution, shake well, and centrifuge a portion of the suspension. Quantitatively dilute a volume of the supernatant with Diluent to obtain a solution containing about 0.1 mg of lansoprazole per mL, and pass through a membrane filter having a 0.5-µm or finer porosity.

 

Chromatographic system: The liquid chromatograph is equipped with a 285-nm detector and a 4.6-mm × 25-cm column that contains 5-µm packing L1. The flow rate is about 1 mL per minute. Chromatograph the Resolution solution, and record the peak responses as directed for Procedure: the resolution, R, between the two major peaks is not less than 5. Chromatograph the Standard preparation, and record the peak responses as directed for Procedure: the relative standard deviation for replicate injections is not more than 2.0%.

 

Procedure:

Separately inject equal volumes (about 10 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the peak responses.

Calculate the quantity, in mg, of lansoprazole (C16H14F3N3O2S) in each Capsule taken by the formula:

(LC/D)(RU / RS)

in which L is the labeled quantity, in mg, of lansoprazole in each Capsule taken; C is the concentration, in mg per mL, of USP Lansoprazole RS in the Standard preparation; D is the concentration, in mg per mL, of lansoprazole in the Assay preparation, based on the labeled quantity of lansoprazole in the Capsules taken and the extent of dilution; and RU and RS are the peak response ratios obtained from the Assay preparation and the Standard preparation, respectively

 

Acceptance Criteria: Lansoprazole Delayed-Release Capsules contain not less than 90.0 percent and not more than 110.0 percent of the labeled amount of lansoprazole (C₁₆H₁₄F₃N₃O₂S).

 

(ii)    Dissolution method for Lansoprazole Delayed Release Pellets/Capsules 30 mg

Capsules were subjected to a dissolution study in 500mL of 0.1N HCl. After 1hr, 25mL of 0.1N HCl was discarded. 425mL of buffer was added to each vessel. pH was adjusted to 6.8 and dissolution was continued to 60minutes using a USP Type II apparatus. 10mL of samples were withdrawn from each dissolution vessel at regular intervals, sample solution was immediately transferred into test tubes containing 1mL of 0.25N NaOH in a test tube. The amount of samples of aliquots taken was replaced with equal volume of dissolution and medium was maintained at 37±0.5°C. The collected sample was filtered through 0.45μm membrane filter.

 

Acid Stage

Acid stage conditions: 0.1 N hydrochloric acid; 500 mL, USP apparatus 2 (paddle), 75 rpm, Time: 60 minutes.

 

Procedure:

Withdraw a 25mL aliquot and then proceed immediately as directed for Test solution in the Buffer stage, leaving the remaining 475mL in the vessel for use in the Buffer stage. Using a filtered portion of the aliquot, determine the amount of lansoprazole dissolved by employing UV absorption at the wavelength of maximum absorbance at about 306 nm, using Acid stage medium as the blank. Concomitantly determine the absorbance of the Acid stage test solution in comparison with a Standard solution of USP Lansoprazole RS having a known concentration equivalent to about 8% of the labeled amount of lansoprazole dissolved per 500 mL of Acid stage medium. [NOTE—A volume of methanol not to exceed 0.5% of the total volume of the Standard solution may be used to dissolve USP Lansoprazole RS prior to dilution with Acid stage medium.]

Acceptance Criteria:  Not more than 10% of the labeled amount of lansoprazole is dissolved in 60 minutes.

 

Buffer Stage

Buffer concentrate: Transfer 65.4g of monobasic sodium phosphate, 28.2g of sodium hydroxide, and 12g of sodium dodecyl sulfate to a suitable container, and add enough water to dissolve. Dilute with water to 4L, and mix well.

 

Blank solution:  Prepare a mixture of Acid stage medium and Buffer concentrate (19:17). Adjust, if necessary, with either phosphoric acid or sodium hydroxide to a pH of 6.8.

 

Test solution: Add 425mL of Buffer concentrate to the remaining 475mL of solution in each vessel from the Acid stage. Adjust, if necessary, with either phosphoric acid or sodium hydroxide to a pH of 6.8.

 

Buffer stage conditions: USP apparatus 2 (paddle), 75 rpm, Time: 10, 20, 30, 45 and 60 minutes.

 

Procedure: 

Determine the amount of C₁₆H₁₄F₃N₃O₂S dissolved in filtered portions of the Test solution, using the difference between the absorbances at the wavelengths of about 286nm and 650nm, with Blank solution as the blank. Concomitantly determine the absorbances of the Test solution in comparison with a Standard solution of USP Lansoprazole RS having a known concentration equivalent to about 70% of the labeled amount of lansoprazole dissolved in 900mL of Blank solution. [NOTE—An amount of methanol not to exceed 2% of the total volume of the Standard solution may be used to dissolve USP Lansoprazole RS prior to dilution with Blank solution.]

 

Acceptance Criteria:  Not less than 80% (Q) of the labeled amount of C₁₆H₁₄F₃N₃O₂S is dissolved in 60minutes.

 

RESULTS AND DISCUSSION:

Evaluation of drug layered and barrier layered pellets

Drug layering was performed on the sugar spheres by using solution/suspension layering technique in fluid bed processor, using different binders and binder concentrations (Table 1). Main aim of barrier layering is to protect the drug layered pellets from enteric polymer coating and environmental conditions (Table 2). The drug layered and barrier layered pellets were evaluated for % yield by weight to ensure 100% layering of drug layer and barrier layer.

Evaluation of Enteric polymer layered and Lubricated pellets

Barrier layered pellets were enteric coated with enteric coating polymer and then lubricated with talc. The flow properties like bulk density, tapped density, compressibility index and hausner’s ratio of lubricated pellets of different formulations were studied and found to have good flow for all formulations.

 

Table 6: Flow properties of Lubricated pellets Lansoprazole DR capsules 30 mg

 

 

Evaluation of Lansoprazole Delayed Release Capsules 30 mg

Lubricated pellets were filled into size ‘1’ capsules and the different formulations were evaluated for assay, acid resistance and dissolution profile. Similarity and dissimilarity factors of different formulations and marketed product was evaluated and detailed in below table.

Acceptance criteria as per USP:

Assay (% Drug content): 90 % - 110%

Drug release in acid: NMT 10%

 

 

Table 7: Evaluation of lubricated pellets filled into capsules of Lansoprazole DR capsules 30 mg

Parameters	Marketed product	Lubricated Pellets
		LD5 B4E1	LD5 B4E2	LD5 B5E3	LD5 B5E4	LD5 B5E5	LD5 B5E6	LD5 B5E7	LD5 B6E8	LD5 B5E9
Assay (% Drug content)	99.6 ±0.16	99 ±0.40	99 ±0.33	99.2 ±0.43	99.2 ±0.20	99.3 ±0.55	99.24 ±0.62	99.2 ±0.23	99.4 ±0.15	99.1 ±0.65
Acid resistance	98.9 ±0.27	90 ±0.52	94 ±0.42	92 ±0.40	96 ±0.73	99 ±0.47	99.6 ±0.64	97.2 ±0.31	97.4 ±0.16	99.2 ±0.10
Acid release	0.7±0.22	9.0±0.46	5±0.38	7.2±0.42	3.2±0.47	0.3±0.51	0.36±0.63	2.0±0.27	2.0±0.15	0.1±0.38
Dissolution profile
Time (Mins)
10	63	78	75	76	70	65	60	69	59	67
20	87	87	84	85	84	85	85	89	85	88
30	98	90	94	92	94	96	97	96	96	97
45	99	91	94	91	96	98	99	97	97	99
60	98	90	93	91	95	98	98	95	95	98
F2	-	49.44	58.72	54.61	67.8	84.29	81.87	72.66	76.89	78.87
F1	-	8.76	6.52	8.09	4.49	1.57	1.35	3.37	2.92	1.35

 

 

Stability

Stability studies were conducted for the optimized formulation at 40ºC / 75% RH for 6 months. Samples were filled in high density polyethylene container and stored in a stability chamber (Thermo lab). Samples were analyzed for assay, acid resistance and dissolution at the end of 1^st, 3^rd and 6^th month¹⁶ and found to be stable.

 

CONCLUSION:

Lansoprazole is an acid labile drug which degrades at acidic pH of stomach. In order to delay the release in the stomach and promote the drug release in the intestine, enteric coating of the drug was attempted. Drug loading on the sugar spheres was done by using different binders i.e., HPMC 3cps, HPC and povidone (k-17) with different concentrations. The amount of drug bound to sugar spheres increases with an increased concentration of HPC (LH-31) (7.662% and 10.15%). E8 enteric coated formulation was optimized at an average weight build up of 17 % w/w, Plasticizer concentration was optimized at 33.3% w/w of dry polymer weight. E8 formulation was found to be optimized because of similar release profile when compared to reference and is confirmed by the similarity factor. Based on the results, it was concluded that the optimized formulation of Lansoprazole (MUPS) delayed release pellets in capsules 30mg (E8) is found to achieve the effective drug levels in the intestine.

 

REFERENCES:

1.        Brahmanker DM. Biopharmaceutics and pharmacokinetics a treatise, 2nd ed, 27-35, (2009).

2.        Rang HP and Dale MM. Pharmacology, 5th ed, 248-249, (2006).

3.        Leon Lachman, Herbert A. The theory and practice of industrial pharmacy, 3rd ed, 331-332, (1987).

4.        Rakhee AS and Anand SS. Formulation development and evaluation of phenyl propanolamine hydrochloride sustained release pellets: Effect of different solvent used for coating solution on the release process. Journal of   Pharmacy Research. 2011; 4(8): 2831-2835.

5.        Parag AK, Abhijeet DK, Jay A. Pelletization techniques as a pharmaceutical tool in the multiparticulate drug delivery system: A review. International   Journal of Drug Formulation and Research.  2010; 1(1): 89-118.

6.        Tetsuro T, Tadashi M, Toshio K and Shinichiro H. Stabilization of a new antiulcer drug (Lansoprazole) in the solid dosage form. Drug Development and Industrial Pharmacy. 1992; 18: 1437-1447.

7.        Lecomte F, Siepmann J, Walther M and MacRae JR.  Polymer blends used for the coating of multiparticulates: Comparison of aqueous and organic coating techniques. Pharmaceutical Research. 2004; 21:882-890.doi:10.1023/B: PHAM.0000026443.71935.cb..

8.        Rangasamy Manivannan, Kugalur Ganesan Parthiban, Gummudavelly Sandeep, Ayyasamy Balasubramaniam and Natesan Senthilkumar. Multiparticlate drug delivery systems: Pellet and Pelletization technique. Drug Invention Today. 2010; 2(5): 233-237.

9.        Carstensen, J., T. Solid State Stability. In: Rhodes, C. T. (ed.) Drug Stability, Principles and Practices. 2000; 145-189.

10.      Bruce LD and JJ K. The influence of polymer sub coats and pellet formulation on the release of chlorpheniramin maleate   from enteric coated pellets. Drug Development and Industrial Pharmacy. 2003; 9: 909-924.

11.      Gothi G.D., Parikh B.N., Patel T.D., Patel B.N., Patel C.N., and Patel D.B. pelletization. Journal of Global Pharma Technology. 2010; 2(1): 45-57.

12.      Gowda DV, Rajesh N, Shivakumar HG, Siddaramaiah and Nawaz Mahammed. Development and evaluation of oral controlled release from aceclofenac sodium pellets. Pharma Science Monitor An International Journal of Pharmaceutical Sciences. 2011; (2): 82-104.

13.      Rajesh. N, Siddaramaiah and Gowda DV. Formulation and evaluation of controlled release behaviour of diltiazem hydrochloride from the pellets of chitosan and microcrystalline cellulose blends. Pharma Science Monitor An International Journal of Pharmaceutical Sciences. 2011; 2(2): 153-171.

14.      Subramanyam CVS. Text Book of Pharmaceutics. 2nd ed, 2000; 211-222.

15.      M. Anand Kumar, Dr. P. K. Lakshmi, Dr. J. Balasubramaniam. Formulation development and invitro evaluation of Tamsulosin HCl extended release pellets. International Journal of Pharm Tech Research. 2011; 3(2): 968-979.

16.      Wei HE, Li-Fang FAN, Qing DU, Bai XIANG, Chun-Lei LI, Min BAI, Yong-Zhen Chang and De-Ying CAO. Design and in vitro/in vivo evaluation of multi-layer film coated pellets for Omeprazole. Chem. Pharm. Bull.  2009; 57(2): 122-128.

 

 

Received on 27.04.2021           Modified on 19.05.2021

Accepted on 24.05.2021         © RJPT All right reserved