Formulation and Invitro Evaluation of Osmotic Drug Delivery System of Metoprolol Succinate

 

K. Teja Sri*, M. Shalemu Rani, D. Nageswar Rao, M. Naga Raju, K. Narasayah, G. Subba Rao

Sri Siddhartha Pharmacy College, Ammavarithota, Nuzvid-521201, Andhra Pradesh, India.

*Corresponding Author E-mail: teja.kantipudi@gmail.com

Controlled release delivery system provides a uniform concentration of drug at the absorption site and thus after absorption allow maintenance of plasma concentration within a therapeutic range, which minimizes side effects and also reduces the frequency of administration. An appropriately designed osmotically controlled oral drug delivery system (ODDS) can be a major breakthrough. Drug delivery from these systems is not influenced by the different physiological factors within the gut lumen. The main objective of this is to formulate ODDS for metaprolol Succinate that can provide prolonged effect and better patient compliance. Metaprolol is a β1‐ receptor blocking agent. ODDS formulations of metaprolol succinate were prepared using different concentrations of potassium chloride, by direct compression technique. The tablets were coated using coating pan with EC as semi permeable coating membrane. Stainless steel drill pins were used to make an orifice on the tablets. Tablet thickness, hardness, weight variation, drug content analysis and drug release study were performed. With increase in osmogen content and bore size, rate of drug release were found to be increasing an optimum concentration of osmogen and bore size to give a zero order release was identified.

 

 

INTRODUCTION:

In conventional oral drug delivery systems, there is little or no control over release of the drug, and effective concentration at the target site can be achieved by intermittent administration of grossly excessive doses.¹ Moreover, the rate and extent of absorption of drug from conventional formulations may vary greatly, depending on factors such as physico-chemical properties of the drug, presence of excipients, various physiological factors such as the presence or absence of food, pH of the gastrointestinal tract, GI motility, and so on. Uncontrolled rapid release of drug may also cause local GI (or) systemic toxicity. ²Among controlled‐release devices, osmotically driven systems hold a prominent place because of their reliability and ability to deliver the contents at predetermined zero‐order rates for prolonged periods. Osmotic pumps (OP) are standard dosage forms for a constant‐rate drug delivery.³ Osmosis is an aristocratic biophenomenon, which is exploited for development of delivery systems with every desirable property of an ideal controlled drug delivery system.

 

Osmosis refers to the process of movement of solvent from lower concentration of solute towards higher concentration of solute across a semi permeable membrane.⁴Osmotic pumps essentially contain a drug and semi permeable membrane, if drug itself acts as an osmogen (Eg: KCl pumps). If the drug does not possess any osmogenic property, the osmogenic salt and other sugars can be incorporated in the formulation.⁵ Osmogens are freely water soluble and capable of producing osmotic pressure. Osmotic pump has an orifice in order to release the active material.⁶When the system happens to be inside the gastrointestinal tract, the fluid enters the core through the membrane and dissolves the active material.⁷ The osmotic pressure generated in the core induces release of the drug in solution at a slow but constant rate. To gain the advantages of pH and agitation independent release performance leading to similar in vitro/in vivo delivery, osmotically active drug delivery systems have been extensively investigated.⁸Metaprolol is an anti‐hypertensive agent. It has a relatively short biological half‐life and suffers from the hazards of adverse gastrointestinal reactions. Therefore, the development of oral sustained (or) controlled release formulations of this drug is highly desirable. Many efforts have been made towards achieving sustained release formulations of Metaprolol. Hence, the present work was aimed to design, develop and evaluate an oral osmotic delivery system of Metoprolol.

MATERIALS AND METHODS:

Metaprolol succinate was used as a model drug obtained as a gift samples from Ranbaxy. Potassium chloride, Magnesium stearate and Talc were of analytical grade.

 

Drug excipient interaction study

The interaction of drug, osmogen and polymer were studied by FTIR.

 

Preparation of core tablets

Tablets were prepared by the process of direct compression using Potassium chloride as osmotic agent, Micro crystalline cellulose as a polymer, Magnesium stearate and Talc were used as lubricants. They are taken in sufficient quantities, mixed well and passed through the sieve no.14 weighed individually and compressed using a multi station compression tablet machine. Composition of osmotic pump core tablets and coating solution is mentioned in Table-1.

 

Preparation of coated osmotic pump tablets

The core tablets were coated with ethyl cellulose coating solution containing erythrosine as colouring agent and were subjected for drilling with various sized stainless steel drill pins of various diameters 0.3mm, 0.5mm, 0.8mm for making orifice in the tablets 0.3mm, 0.5mm, 0.8mm.

 

Fig 1: I.R spectra of metoprolol succinate.

 

Fig.2: I.R spectra of metoprolol succinate and KCL.

 

Fig 3: I.R spectra of metoprolol succinate and MCC.

 

 

PHYSICAL PROPERTIES OF METAPROLOL SUCCINATE TABLET

Drug excipient interaction study

There were no interaction between drug and excipient important peaks in the drug spectrum remains as such and no shift in the drug peaks in drug and kcl spectra and drug and Micro crystalline cellulose spectra the spectra are given in figure 1-3

 

Hardness

This is the force required to break a tablet in diametric compression. Hardness of the tablets is determined by Monsanto hardness tester which consists of a barrel with a compressible spring. The pointer moving along the gauge in the barrel at which the tablet fractures. The hardness of various core sized metoprolol ODDS tablets are mentioned in Table-2.

 

Tablet size and Thickness

The size and thickness of the tablets were measured by using Vernier Callipers scale.⁹ The thickness of various core sized metoprolol tablets are mentioned in Table-2.

 

Weight variation

Ten tablets were selected at random and average weight was determined. Then individual tablets were weighted and the individual weight was compared with an average weight. Not more than two of the individual weights deviate from the official standard (limit ± 5%).¹⁰ The weight variation of various core sized metoprolol tablets are mentioned in Table-2.

 

Drug content analysis

It was done by spectrophotometric method.¹¹ .Three tablets were taken and powered. From the powder an accurately weighed amount equivalent to 100mg of Metaprolol was weighed and dissolved in distilled water. The solution was suitably diluted and dilute solution was then assayed for the drug content by measuring the absorbance at 222nm using UV – Visible spectrophotometer.¹² The drug content analysis of various core sized tablets are mentioned in Table-2.

 

 

 

Table 1: Composition of osmotic pump core tablets and coating solution

Composition of the core tablets
Ingredients	Core : Osmotic agent
	1:1			1:2			1:3
	Pore size			Pore size			Pore size
	0.3	0.5	0.8	0.3	0.5	0.8	0.3	0.5	0.8
	F1	F2	F3	F4	F5	F6	F7	F8	F9
Metaprolol succinate	40 mg			40 mg			40 mg
Potassium chloride	40 mg			80 mg			120 mg
Micro crystalline cellulose	76 mg			76 mg			76 mg
Magnesium stearate	2 mg			2 mg			2 mg
Talc	2 mg			2 mg			2 mg
Total	160 mg			200 mg			240 mg
Composition of the coating solution
Ethyl cellulose	6gm
Alcohol	100ml
erythrosine	20mg

Table 2: Physical properties of metoprolol ODDS tablets

S No.	Formulation	Hardness (kg/cm²)	Weight variation(mg)	Thickness(cm)	Drug content (%)
1	F1	6.8	159	0.2	98
2	F2	6.8	158	0.2	97
3	F3	6.9	161	0.2	99
4	F4	6.8	200	0.25	99
5	F5	6.6	201	0.25	100
6	F6	6.8	200	0.25	101
7	F7	6.9	240	0.3	96
8	F8	6.8	239	0.3	98
9	F9	6.9	241	0.3	99

 

Table 3: Drug release from ODDS with different orifice diameter

S. No	Time (hrs)	Core : Osmotic agent
		1:1			1:2			1:3
		F1	F2	F3	F4	F5	F6	F7	F8	F9
1	1	7.47	18.37	10.76	7.23	10.18	18.58	10.10	14.02	19.66
2	2	15.39	28.12	20.30	16.25	19.14	27.33	20.33	24.38	32.76
3	3	20.77	35.84	27.89	21.62	26.00	40.89	29.86	33.37	42.18
4	4	29.12	47.06	34.31	30.98	38.01	52.53	36.46	40.49	52.60
5	5	37.57	57.06	47.20	39.88	51.91	60.55	52.66	57.30	65.97
6	6	42.54	65.98	53.14	52.67	60.59	68.07	60.68	65.01	79.83
7	7	56.98	76.91	62.25	60.23	68.11	80.47	68.20	77.40	94.89
8	8	65.64	80.88	80.14	70.92	75.38	85.55	80.61	89.15	99.58

 

Table 4:     Showing release kinetics and Correlation coefficient values

S No	Formulation	Zero order		First order			Peppas
		r	k		r	k	r	n	k
1	F1	0.9933	7.7842		0.9600	-0.1111	0.9909	0.8259	8.6237
2	F2	0.9875	10.9611		0.9836	-0.1908	0.9976	0.7605	16.7067
3	F3	0.9946	9.3193		0.9321	-0.1505	0.9972	0.8759	9.6032
4	F4	0.9945	8.5385		0.9603	-0.1281	0.9883	0.7288	9.4171
5	F5	0.9959	9.6435		0.9717	-0.1549	0.9947	0.8119	9.3324
6	F6	0.9880	11.5002		0.9739	-0.2133	0.9910	0.7736	17.0552
7	F7	0.9958	10.0452		0.9614	-0.1673	0.9950	0.8655	12.6246
8	F8	0.9976	11.0618		0.9304	-0.2096	0.9955	0.8910	13.2258
9	F9	0.9935	13.1913		0.8223	-0.4188	0.9970	0.8168	18.1341

 

In vitro drug release

The drug release studies were carried out using USP type‐I dissolution (Disso 2000) apparatus.¹³ The dissolution vessels filled with 900ml of 0.1N HCl using paddle rotation of 50rpm and temperature was kept constant at 37 ± 0.5⁰C. The time of sampling was every 1 hrs up to 2hrs.¹⁴ 5ml of sample was withdrawn and an equal amount of 0.1N HCl was replaced to maintain sink conditions and after the first hour was replaced with pH 7.4 phosphate buffer and the dissolution was continued for 8 hrs.¹⁵ Samples are directly analyzed by using U.V Spectrophotometer without any dilution. Concentration of the drug was calculated from standard equation obtained from standard curve. Cumulative percentage drug release and percentage drug unreleased was calculated and respective graphs were plotted as shown in Fig.4-11

 

RESULTS AND DISCUSSION:

The interaction of drug and polymer was studied by FTIR which is shown in Fig. 1-3 and it was found that there was no interaction of drug with polymer and other excipients. Physical characteristics like hardness, thickness and weight variation, and drug content are determined and lie with the pharmacopoeial limits .In vitro drug release also determined and formulation F9 showed maximum release of 99% and the order of release was F1>F2>F3>F4<F5>F6>F7>F8>F9. The drug release of metaprolol was determined by using release kinetics and the drug release correlation coefficient values for each drug release kinetics was listed in Table No.4. All the formulations followed zero order release kinetics as shown in Fig 4, 5, 6. Fit into peppas model of fitting as shown in Fig 8,9,10. The dosage form developed was designed as a tablet core coated with a rate‐controlling membrane.

 

Fig 4: Zero order release profile of ODDS For  (F₁ , F₂ , F₃ )

 

Fig 5: Zero order release profile of ODDS for (F₄ , F₅ , F₆ )

 

Fig 6: Zero order release profile of ODDS For  (F₇ , F₈ , F₉ )

 

Fig 7: Drug release from ODDS with different osmogen concentration (F₃ ,F ₆, F₉ )

 

Fig 8: Peppas Plots  for F1, F2, F3

 

Fig 9: Peppas Plots  for F4, F5, F6.

 

Fig 10: Peppas Plots  for F7, F8, F9

 

Fig 11: Peppas Plots for F3, F6, F9

 

Tablet core consists of drug along with osmogen, and other conventional excipients to form the core compartment. The core compartment is surrounded by a membrane consisting of a semipermeable membrane‐forming polymer. The semipermeable membrane‐forming polymer is permeable to aqueous fluids but substantially impermeable to the components of the core. In operation, the core compartment imbibes aqueous fluids from the surrounding environment across the membrane and dissolves the drug. The dissolved drug is released through the pores created after leaching of water‐soluble additive(s) in the membrane. There is an increase in percent of drug release with an increase in orifice diameter as shown in Fig 7. From these results it is obvious that orifice diameter selected for the controlled release formulations appears to be a major factor in determining the release of the drug. The release pattern was found to be faster in the formulations containing higher percentage of osmogen. The results obtained for in‐vitro drug release study is given in Table No. 3. By careful analysis of the dissolution profile of the formulations it was evident that the formulation 1:3with orifice diameter 0.8mm was the best formulation since the percentage release within the first hour was only 19% and the rate of release was found to be constant and sustained over the eight hours period.

 

CONCLUSION:

Oral osmotic pumps are being attempted on certain drugs with a view to provide constant release of the drug to achieve the desired therapeutic efficacy in clinical disorders. The results obtained with osmotic pump of Metaprolol succinate that was developed and evaluated in the present study are encouraging. The formulation F9 with orifice diameter 0.8mm has given the expected results. The delivery rate was found to increase at a constant rate throughout the dissolution study. The percentage release was found to be 99% at the end of the eight hour study was found to be satisfactory. Metaprolol is a potential drug in curing angina, hypertension, and a constant release formulation like an osmotic pump on this drug can be considered as a suitable alternative to currently available formulations of Metaprolol. A detailed experimental and clinical investigation on the osmotic pump of Metaprolol succinate may throw light on its viability for human use.

 

ACKNOWLEDGEMENT:

Authors gratefully acknowledge Ranbaxy Labs, Gurgon for providing gift samples of metoprolol and also extend our thanks to the founder Chairman Mr. M. Mohan Rao and Principal Dr. N. Srinath Nissakara Rao of Sri Siddhartha Pharmacy College, Nuzvid for providing required facilities and immense support in completing this research work.

 

REFERENCES:

1.       Salsa T, Veiga F, Pina ME. Oral controlled release dosage forms I. Cellulose ether polymer in hydrophilic matrices. Drug Dev Ind Pharm 1997; 23: 929–938.

2.       Eckenhoff B, Theeuwes F, Urquhart J. Osmotically activated dosage forms for rate controlled drug delivery. Pharm Technol 1981; 5: 35–44.

3.       Eckenhoff B, Yum SI. The osmotic pump; novel research tool for optimizing drug regimens. Biomaterials 1981; 2: 89–97.

4.       Bindschaedler C, Gurny R, Doelker E. Osmotically controlled drug delivery systems produced from organic solutions and aqueous dispersions of cellulose acetate. J Controlled Release 1986; 4: 203–212.

5.       Verma RK, Mishra B, Garg S. Osmotically controlled oral drug delivery. Drug Dev Ind Pharm 2000; 26: 695–708.

6.       Verma RK, Krishna DM, Garg S. Formulation aspects in the developments of osmotically controlled oral drug delivery system. J Controlled Release 2002; 79: 7–27.

7.       Schultz P, Kleinebudde P. A new multiparticulate delayed release system. Part I: Dissolution properties and release mechanism. J Controlled Release 1997; 47: 181‐189.

8.       Herbig SM, Cardinal JR, Korsmeyer RW, Smith KL. Asymmetricmembrane tablet coatings for osmotic drug delivery. J Controlled Release 1995; 35: 127‐136.

9.       Thombre AG, Cardinal JR, DeNoto AR, Herbig SM, Smith KL.Asymmetric membrane capsules for osmotic drug delivery I. Development of a manufacturing process. J Controlled Release1999; 57: 55‐64.

10.     Liu L, Wang X. Solubility modulated monolithic osmotic pump tablet for atenolol delivery. Eur J Pharm Sci 2008; 68 Suppl 2: 298‐302.

11.     Jensen JL, Appel LE, Clair JH, Zentner GM. Variables that affect the mechanism of drug release from osmotic pumps coated with acrylate/methacrylate copolymer latexes. J Pharm Sci 1995; 84 Suppl 5: 530‐533.

12.     Ramakrishna N , Mishra B. Plasticizer effect and comparative evaluation of cellulose acetate and ethyl cellulose‐HPMC combination coatings as semi permeable membranes for oral osmotic pumps of naproxen sodium. Drug Dev Ind Pharm 2002; 28: 403–412.

13.     Skelly JP, Yamamoto LA, Shah V P, Yau MK, Barr WH. Topographical dissolution characterization for controlled release products: new technique. Drug Dev Ind Pharm 1986;

14.     12: 1159–1175.

15.     14.Ramadan MA, Tawashi R. Effect of hydrodynamic conditions and delivery orifice size on the rate of drug release from elementary osmotic pump system (EOP). Drug Dev Ind Pharm 1987; 13: 235–248.

16.     Santus G, Baker WR. Osmotic drug delivery: a review of patent literature. J Controlled Release 1995; 35:1‐21.