Formulation Development and Evaluation of Gastro-Retentive Drug (Torsemide) Delivery System for Diuretic Drug

Jagdish Jadhav*, Dharmendra Mundhada, Rajesh Mujoriya

Department of Pharmaceutics, Agnihotri College of Pharmacy, Wardha, Maharashtra

*Corresponding Author E-mail: raj_mujoriya@live.com

ABSTRACT:

Gastro-retentive Drug Delivery System is system which improves the Gastric Residence time and hence improves its bioavailability. In the current study indicates that the optimized gastro-retentive tablet of Torsemide, prepared using Sodium Alginate and HPMC K15M can successfully be employed as an oral controlled release drug delivery system. Tablet was formulated by using different Formulation indicated by F1 to F9 respectively. These formulations were evaluated for the pre compression and post compression parameters. The optimized Formulation was subjected to stability studied at 40ºC under humidity conditions (75%) for a period of four week. From the result it was observed that there was no significant change in physiochemical properties as well as in drug release profile even after storage at 40ºC for four week. In-vitro drug release study of formulation also done for optimized batch after stability study and found unaffected. High floating ability of the formulation is likely to increase its GI residence time, and eventually, improve the extent of bioavailability. Gastroretentive dosage form of Torsemide will reduce the frequency of administration of drug and helps to minimize dose of drug and side effects associated with the drug.

KEYWORDS: Gastro-retentive Drug Delivery System, bioavailability, Sodium Alginate, Torsemide, stability study, GI residence time.

1. INTRODUCTION:

Oral delivery of drugs is by far the most preferable route of drug delivery due to the ease of administration, patient compliance and flexibility in formulation, etc. from immediate release to site specific delivery, oral dosage forms have really progressed. Gastro-retentive Drug Delivery System is system which improves the Gastric Residence time and hence improves its bioavailability. Dosage form with a prolonged GRT, that is gastro retentive dosage forms (GRDFs), will provide us with new and important therapeutic options. GRDFs extend significantly the period of time over which the drugs may be released.

Thus, they not only prolonged dosing intervals, but also increase patient’s compliance beyond the level of existing controlled release dosage forms. This application is especially affective in delivery of sparingly soluble and insoluble drugs. High floating ability of the formulation is likely to increase its GI residence time, and eventually, improve the extent of bioavailability. Gastroretentive dosage form of Torsemide will reduce the frequency of administration of drug and helps to minimize dose of drug and side effects associated with the drug¹.

Advantages of Gastro-Retentive Drug Delivery System²:

· These systems are particularly advantageous for drugs that are specifically absorbed from stomach or the proximal part of the small intestine, e.g., riboflavin and furosemide.

· The fluctuations in plasma drug concentration are minimized, and concentration‐dependent adverse effects that are associated with peak concentrations can be prevented. This feature is of special importance for drugs with a narrow therapeutic index.

· The efficacy of the medicaments administered utilizing the sustained release principle of floating formulation has been found to be independent of the site of particular medicaments.

· Complete absorption of the drug from the floating dosage form is expected even at the alkaline pH of the intestine. The dissolution of the drug in gastric fluid occurs and then the dissolved drug is available for absorption in the small intestine after emptying of the stomach contents.

· Poor absorption is expected when there is vigorous intestinal movement and a shorted transit time as might occur in certain type of diarrhea. Under such circumstances it may be advantageous to keep the drug in floating condition in stomach to get a relatively better response.

· Drugs that have poor bioavailability because of site‐specific absorption from the upper part of the gastrointestinal tract are potential candidates to be formulated as floating drug delivery systems, thereby maximizing their absorption. A significant increase in the bioavailability of floating dosage forms (42.9%) could be achieved as compared with commercially available LASIX tablets (33.4%) and enteric‐coated LASIX‐long product (29.5%).

Limitations of Gastro-Retentive Drug Delivery System³

· A high level of fluid in the stomach is required for drug delivery to float and work efficiently.

· Drugs which have stability and solubility problems in GIT are not suitable candidates for these types of systems.

· Drugs such as nifedipine, which under goes first pass metabolism may not be desirable for the preparation of these types of systems.

· Drugs which are irritant to Gastric mucosa are also not desirable.

· The drug substances that are unstable in the acidic environment of the stomach are not suitable candidates to be incorporated in the systems.

Suitable Drugs for Gastroretention⁴

Delivery of the Drugs in continuous and controlled manner have a lower level of side effects and provide their effects without the need for repeated dosing or with a low dosage frequency. Sustained release in the stomach is also useful for therapeutic agents that the stomach does not readily absorb, since sustained release prolongs the contact time of the agent in the stomach or in the upper part of the small intestine, from where absorption occurs and contact time is limited. Appropriate candidates for controlled release gastroretentive dosage forms are molecules that have poor colonic absorption but are characterized by better absorption properties at the upper parts of the GIT Like -

· Narrow absorption window in GI tract, e.g., riboflavin and Levodopa

· Basically absorbed from stomach and upper part of GIT, e.g., chlordiazepoxide and cinnarazine.

· Drugs that disturb normal colonic bacteria, e.g., amoxicillin, trihydrate.

· Locally active in the stomach, e.g., antacids and misoprostol.

· Drugs that degrade in the colon, e.g., ranitidine HCl and metronidazole

2. MATERIALS AND METHOD:

Torsemide was obtained as gift sample from Anazeal Research Lab, Mumbai. HPMC (HPMC K15 M), Sodium Alginate, Sodium Bicarbonate, Microcrystalline cellulose, Povidone, Magnesium stearate, Talc & Aspartame was obtained from S.D. Fine Chemicals, Mumbai.

3. EXPERIMENTAL DETAILS^5-10

3.1 Characterization of Pure Drug

Pure Drug has been characterize by various parameters like Solubility, Identification by FT-IR, Melting range, Sulphated ash, Loss on drying, Heavy Metals and Assay.

3.2 Preformulation Study

Preformulation testing was done to investigate of physical and chemical Properties of a drug substance alone and when combined with excipients. It is the first step in the rational development of dosage forms.

3.3 Compatibility Study

To analyze the compatibility between Torsemide and excipients proposed to incorporate into the formulation. Torsemide is mixed with excipients in different ratio. These mixtures were kept in a 6ml glass white colour vials and packed properly. These vials are exposed to Room temperature, 30°c / 65% relative humidity and 40˚c / 75%RH.16 gm of blend is prepared which is filled in 3 vials.

3.4 Method of Preparation Tablet by Direct Compression

Drug (10 mg), HPMC in different ratios and excipients were blended using mortar and pestle. The drug and the HPMC were sieved through mesh # 120 before blending. The mixture was evaluated for angle of repose, bulk density and compressibility. The mixture was mixed with 1% magnesium stearate as lubricant and mint as flavoring agent. The powder blends were then compressed by using Fluidpack multistation rotary tablet machine using 8 mm punch. The hardness was adjusted to 2-5 kg/cm².

Table No. 1: Formulation of Tablet

Ingredients(mg)	F1	F2	F3	F4	F5	F6	F7	F8	F9
Torsemide	10	10	10	10	10	10	10	10	10
HPMC	130	130	130	150	150	150	170	170	170
Sodium Alginate	70	90	110	70	90	110	70	90	110
Sodium-bi carbonate	60	60	60	60	60	60	60	60	60
MCC	115	95	75	95	75	55	75	55	35
Magnesium Stearate	15	15	15	15	15	15	15	15	15

4. RESULT:-

4.1 Identification by FT-IR

Fig. No. 1:- IR Spectra of Torsemide Powder

4.2 Characterization of Pure Drug

Table No. 2: Characterization of Pure Drug

Sr. No	Characterization	Specification	Result
1.	Description	White or almost white, crystalline powder, odourless or almost odourless.	A almost white powder
2.	Solubility	Soluble in diethyl ether, acetone. Very slightly soluble in cold water. Slightly soluble in alcohol; more soluble in hot alcohol. Soluble in chloroform, pyridine, benzene, petroleum ether, oils, fats, aqueous solutions of bile salts.	Complies
3.	Identification by FT-IR	To match with working standard	Matches with the working standard
4.	Melting range	147^0C	Complies
5.	Sulphated ash	Not more than 0.1%	Complies
6.	Loss on drying	Not more than 0.5%	Complies
7.	Heavy Metals	20 ppm max	Complies
8.	Assay	98.0-100.5%	Complies

4.3 Preformulation Study

Table 3: Preformulation study of pure drug Torsemide

Sr. No	Characterization	Specification	Result
1	Description	White or almost white, crystalline powder, odourless or almost odourless.	A almost white powder
2	Solubility	Soluble in diethyl ether, acetone. Very slightly soluble in cold water. Slightly soluble in alcohol; more soluble in hot alcohol. Soluble in chloroform, pyridine, benzene, petroleum ether, oils, fats, aqueous solutions of bile salts.	Complies
3.	Melting range	147°C	Complies
4.	Identification by FTIR	To match with working standard	Matches with the working standard
5.	Loss on drying	Not more than 0.5%	Complies
6.	Assay	98.0-100.5%	Complies

4.4 Compatibility Study at Room temperature, 30°c / 65% relative humidity and 40˚c / 75%RH

Table no. 4: Compatibility Study

Sr. No.	Drug + Excipients	Proportion	Initial Observation of color	Final observation		Conclusion
				2^nd week	4^th week
1.	Drug	NA	White	White	White	Compatible
2.	Drug+ MCC (PH-102)	1:10	White	White	White	Compatible
3.	Drug+ HPMC	1:10	Creamy White	Creamy White	Creamy White	Compatible
4.	Drug+ Sodium Alginate	1:10	Pale-Yellowish Brown	Pale-Yellowish Brown	Pale-Yellowish Brown	Compatible
5.	Drug + Sodium bicarbonate	1:10	White	White	White	Compatible

4.5 Evaluation of Floating tablets

Table No. 5: Evaluation of Mouth dissolving tablets

Batch	F1	F2	F3	F4	F5	F6	F7	F8	F9
TEST	MICROMERETIC PROPERTIES
Angle of repose(θ)	35.53 ± 0.45	36.76 ± 0.55	37.13 ± 0.32	35.13 ± 0.40	36 ± 0.26	36.53 ± 0.45	33.3 ± 0.81	34.5 ± 0.7	35.13 ± 0.25
Bulk density (g/ml)	0.375 ± 0.006	0.387 ± 0.005	0.394 ± 0.009	0.349 ± 0.005	0.366 ± 0.004	0.375 ± 0.004	0.338 ± 0.002	0.337 ± 0.003	0.353 ± 0.005
Tapped density (g/ml)	0.479 ± 0.025	0.506 ± 0.005	0.504 ± 0.007	0.456 ± 0.004	0.482 ± 0.004	0.482 ± 0.026	0.338 ± 0.002	0.458 ± 0.003	0.470 ± 0.002
Compressibility Index (%)	21.42 ± 4.47	23.54 ± 1.76	21.75 ± 0.62	21.44 ± 0.81	23.98 ± 1.69	21.97 ± 4.32	23.23 ± 0.44	26.41 ± 0.38	24.92 ± 1.42
Hausener’s ratio	1.27 ± 0.07	1.30 ± 0.03	1.27 ± 0.01	1.30 ± 0.01	1.31 ± 0.02	1.28 ± 0.06	1.30 ± 0.007	1.35 ± 0.007	1.33 ± 0.02
PHYSICAL EVALUATION OF FORMULATED TABLET BATCHES
Thickness (mm)	4.21 ± 0.01	4.16 ± 0.06	4.24 ± 0.04	4.16 ± 0.04	4.26 ± 0.06	4.18 ± 0.07	4.26 ± 0.08	4.22 ± 0.05	4.28 ± 0.07
Hardness (kg/cm^2)±SD	5.22 ± 0.03	5.23 ± 0.02	5.35 ± 0.03	5.21 ± 0.03	5.32 ± 0.02	5.37 ± 0.02	5.21 ± 0.02	5.23 ± 0.01	5.28 ± 0.01
Friability (%) ±SD	0.47 ± 0.05	0.24 ± 0.01	0.27 ± 0.03	0.26 ± 0.015	0.36 ± 0.03	0.46 ± 0.03	0.62 ± 0.02	0.52 ± 0.03	0.48 ± 0.03
Weight Variation (mg) ±SD	400 ± 0.50	390 ± 0.15	405 ± 0.86	400 ± 0.15	380 ± 0.20	410 ± 0.25	415 ± 0.30	400 ± 0.85	28 ± 3.73
Drug Content Uniformity(%)	99.8 ± 0.60	99.3 ± 0.57	98.7 ± 0.98	99.9 ± 0.57	99.1 ± 0.65	98.0 ± 0.98	99.8 ± 0.99	95.11 ± 0.93	92.76 ± 1.64
FLOATING PROPERTY OF TABLET
Floating lag time (Sec)	16	19	23	20	24	30	28	36	42
Total floating duration (Hr.)	12	12	12	12	12	12	12	12	12
SWELLING INDEX OF FORMULATIONS
4 hr	12	42	54	22	52	61	27	52	61
8 hr	28	63	73	38	63	78	43	63	78
12 hr	42	79	84	52	79	86	55	80	89
% DRUG RELEASE
1 hr	54.78 ± 0.912	49.26 ± 0.356	45.15 ± 0.302	46.00 ± 0.294	44.36 ± 0.501	43.15 ± .4983	44.84 ± 0.192	40.42 ± 0.329	34.10 ± 0.310
2 hr	60.63 ± 0.132	59.36 ± 0.204	51.31 ± 0.106	50.36 ± 0.100	49.10 ± 0.329	49.10 ± 0.492	50.56 ± 0.529	44.84 ± 0.592	40.73 ± 0.309
4 hr	68.05 ± 0.32	63.47 ± 0.163	58.57 ± 0.305	60.94 ± 0.203	58.57 ± 0.345	57.15 ± 0.941	60.63 ± 0.183	57.18 ± 0.192	50.68 ± 0.391
6 hr	79.10 ± 0.478	70.42 ± 0.530	65.05 ± 0.405	66.47 ± 0.100	66.47 ± 0.113	64.89 ± 0.132	66.94 ± 0.193	64.10 ± 0.429	57.78 ± 0.451
8 hr	80.52 ± 0.296	84.15 ± 0.174	75.15 ± 0.540	79.10 ± 0.192	75.94 ± 0.183	74.21 ± 0.305	79.42 ± 0.427	73.19 ± 0.539	68.46 ± 0.419
10 hr	99.63 ± 0.461	93.89 ± 0.293	88.15 ± 0.603	91.10 ± 0.109	88.73 ± 0.293	84.47 ± 0.309	90.15 ± 0.509	86.21 ± 0.513	80.68 ± 0.319
12 hr	------	97.26 ± 0.352	94.89 ± 0.305	99.47 ± 0.402	97.42 ± 0.304	93.78 ± 0.394	98.05 ± 0.509	94.42 ± 0.209	87.31 ± 0.209

Table 6: Evaluation of formulation (F4) kept for stability at 40⁰C / 75%RH

Parameter	0 week	1 week	2 weeks	3 weeks	4 weeks
Appearance	White	White	White	White	White
Thickness (mm)	4.16± 0.04	4.16± 0.04	4.16± 0.04	4.16± 0.04	4.16± 0.04
Hardness (Kg/cm2)	5.21± 0.03	5.17± 0.028	5.10± 0.021	5.07± 0.02	5.00± 0.015
Buoyancy Lag time (sec)	20	20	20	18	17
Duration of Floating	>12	>12	>12	>12	>12
Drug content (%)	99.9± 0.57	99.8± 0.99	98.7± 0.98	98.2± 0.95	98.2± 0.95

Table 7: In-vitro drug release study of formulation (F4) kept for stability at 40⁰C / 75%RH:

Time (Hrs)	Cumulative % Drug Release
	0 week	1 week	2 week	3 week	4 week
1	46.00±0.294	46.81±1.07	45.98±0.23	45.73±0.95	45.02±0.12
2	50.36±0.100	50.39±2.62	49.78±0.39	49.11±0.44	48.96±0.16
4	60.94±0.203	60.90±0.34	59.65±0.24	59.11±0.32	60.94±0.43
6	66.47±0.100	65.89±0.25	65.48±0.75	65.08±0.68	64.29±0.20
8	79.10±0.192	79.19±0.53	78.55±0.79	78.23±0.42	77.26±0.40
10	91.10±0.109	91.10±0.77	90.78±1.19	90.45±0.31	90.05±0.39
12	99.47±0.402	99.36±0.38	98.84±0.73	98.57±0.41	98.00±0.17

Fig. No. 2: Comparative study of % Drug release (Batch F1, F2 and F3)

Fig No. 3: Comparative study of % Drug release (Batch F4, F5 and F6)

Fig No. 4: Comparative study of % Drug release (Batch F7, F8 and F9)

5: Comparative dissolution profile of formulation F4 before and after stability study.

4.6 Stability Study

The optimized Formulation was subjected to stability studied at 40ºC under humidity conditions (75%) for a period of four week. Samples were analysed for colour changes appearance, drug content and release characteristics. From the result it was observed that there was no significant change in physiochemical properties as well as in drug release profile even after storage at 40ºC for four week. It may be inferred that there was no degradation and change in the matrix system.

5. DISCUSSIONS:

In the current study indicates that the optimized gastro-retentive tablet of Torsemide, prepared using Sodium Alginate and HPMC K15M can successfully be employed as an oral controlled release drug delivery system. Tablet was formulated by using different Formulation indicated by F1 to F9 respectively. These formulations were evaluated for the pre compression and post compression parameters. The optimized Formulation was subjected to stability studied at 40ºC under humidity conditions (75%) for a period of four week. From the result it was observed that there was no significant change in physiochemical properties as well as in drug release profile even after storage at 40ºC for four week. In-vitro drug release study of formulation also done for optimized batch after stability study and found unaffected. High floating ability of the formulation is likely to increase its GI residence time, and eventually, improve the extent of bioavailability. Gastroretentive dosage form of Torsemide will reduce the frequency of administration of drug and helps to minimize dose of drug and side effects associated with the drug.

6. REFERENCES:

1 Jain AK, Hatila U, A Review On Floating Drug Delivery System, International Journal of Pharmaceutical Studies and Research, 2(3);2011: 01-06.

2 Narang N, An Updated Review On: Floating Drug Delivery System (FDDS), Int J App Pharm, 3(1);2011:17.

3 Ghorpade P, Kamble S, Gastro-Retentive Floating Drug Delivery System Containing Antihypertensive Drug – An Overview, World Journal of Pharaceutical research, 3(5); 2014: 1076-1092.

4 Pande SD, Vaidya PV, Gulhane PN, Floating Drug Delivery System (FDDS): A New Way For Oral Drug Delivery System, International Journal of Pharmaceutical and Clinical Science, 3(1); 2013: 1-13.

5 Singh LP, Rajesh KS, Umalkar D, Chauhan VK, Rana VK, Vasava KS, Floating Effervescent Tablet: A Review, Journal of Pharmaceutical and Biomedical Sciences, 5(11); 2011: 1-6.

6 Chandrasekhara RB, Vidyadhara S, Raghavendra Rao KV, Prakash VK, Umashankar B, Formulation And Evaluation Of Ibruprofen Floating Tablets, International Journal Of Pharmaceutical, Chemical And Biological Sciences, 2(4); 2012: 472-481.

7 Ashok KD, Mohanta GP, Formulation and In Vitro Evaluation Of Famotidine Floating Tablets By Lipid Solid Dispersion Spray Drying Technique, International Journal Of Research In Pharmacy And Chemistry, 2(4); 2012: 996-1000.

8 Patil P, Rao SB, Kulkarni SV, Basavaraj, Surpur C, Ammanage A, Formulation and In Vitro Evaluation of Floating Matrix Tablets of Ofloxacin, Asian J. Res. Pharm. Sci. 1(1); 2011: 17-22.

9 Yadav SK, Kavita K, Tamizhamani T, Formulation and Evaluation of Floating Tablets of RHCL Using Natural and Synthetic Polymers, International Journal of PharmTech Research, 2(2); 2010: 1513-1519.

10 Rangapriya M, Manigandan V, Natarajan R, Mohankumar K, Formulation and evaluation of floating tablets of Pioglitazone hydrochloride, International Journal Of Pharmaceutical and Chemical Sciences, 1(3); 2012:1048-1054.

Received on 01.05.2015 Accepted on 28.06.2015

© Asian Pharma Press All Right Reserved

Asian J. Pharm. Res. 5(3): July- Sept., 2015; Page 125-130

DOI: 10.5958/2231-5691.2015.00019.2