Formulation and Evaluation of Floating Microballoons of Ibuprofen for the Enhanced Enteric Bioavailability

 

MR Shivalingam*¹, KSG Arul Kumaran², YV Kishore Reddy¹, S Bugga Reddy¹, N Deepika¹, R Padmapriya¹ and P Annapoorna¹

¹Department of Pharmaceutics, Victoria college of Pharmacy, Guntur, Andhrapradesh.

²K.M.C.H.College of Pharmacy, Coimbatore, TamilNadu.

*Corresponding Author E-mail: Shiva24carat@gmail.com

ABSTRACT:

The present study involves the preparation and evaluation of hollow microspheres (microballoons) of ibuprofen by novel emulsion-solvent diffusion method in an attempt to improve the drug enteric bioavailability by prolonging the gastric residence time. Microspheres were prepared by pouring ethanol, DCM solution of the drug and Eudragit RL100 in to an agitated aqueous solution of PVA that was thermally controlled at 40.c. The resulting microspheres were separated by filtration and subjected to various evaluations like micromeritic properties, Morphology study, invitro floating behavior, % drug entrapment and invitro drug release. The micromeritic properties showed the improved physical characteristic of the formulation (F4) over the pure drug. Invitro buoyancy studies showed that prepared microballoons floated continuously over the surface of acidic dissolution media containing surfactant for greater than 12hr. Invitro release studies showed that the formulation (F4) does not show drug release in simulated gastric buffer and the same shows slow and controlled drug release of about 70-80% over a period of 6hr in simulated intestinal medium which proved the enteric release property of microballoons. From the study it may be concluded that microballoons were found to be an ideal device for prolonging residence time of drug in stomach to enhance the enteric bioavailability.

 

 

INTRODUCTION:^{1- 4}

Oral delivery of drugs is by far the most preferable route of drug delivery due to ease of administration, better patient compliance and flexibility in formulation etc. Ibuprofen is easily absorbed from the gastro intestinal tract (GIT) and eliminated quickly from the blood circulation because of shorter half life hence required frequent dosing. To avoid this problem, the oral controlled release (CR) formulation has been developed in an attempt to release the drug slowly and maintain a constant drug concentration in the serum for longer period of time. Such oral drug delivery devices have a restriction due to the gastric retention time (GRT), a physiological limitation. Therefore, prolonged gastric retention is important in achieving control over the GRT because this helps to retain the CR system in the stomach for a longer time in a predictable manner. The controlled gastric retention of solid dosage forms may be achieved by the mechanisms of flotation. NSAIDs are well known for their gastro toxic and duodenotoxic effects.

 

Recently, dosage forms that can precisely control the release rates and target drugs to a specific body site have made an enormous impact in the formulation and development of novel drug delivery systems. Microspheres form an important part of such novel drug delivery systems. They have high drug loading capacity, show excellent invitro floatability and have been widely accepted as a mean to achieve oral and parenteral controlled release. However, the success of these microspheres is limited owing to their short residence time at the site of absorption. At present hollow microsphere was considered to be one of most prominent buoyant system, because they combine advantage of multiple unit system and good floating properties. Hence in the present study an attempt was made to develop gastro retentive floating hollow microspheres of ibuprofen.

 

MATERIALS AND METHODS:

Ibuprofen (99.2%) was purchased from sigma chemical, St.Louis; Mo. Eudragit RL100 was obtained from Rohm pharma, Germany. Dichloromethane, Ethanol, Acetone, PVA, Tween 20, obtained from E.Merck Ltd; Mumbai. All other chemicals used were of analytical grade.

 

Preparation of floating hollow microsphere ⁵

Floating microspheres were prepared by mixing weighed amount of Ibuprofen with Eudragit RL100 (ratios of 1:1, 1:2, 1:3, 1:4) in a solution of DCM and ethanol (l: 1) at room temperature.Glyceryl mono stearate was added as emulsifying agent.  The solution was poured gradually in to 200ml of water containing w/v PVA which is maintained at temperature of 40.c. The resulting solution was stirred at 300rpm for 1 hr. Then the resulting microballoons were then filtered, using Whatman filter paper (No.41; Whatman Brentford, UK) washed with water and dried overnight at 40^.c (Table 1)

 

Table 1: Composition of various Microballoon formulations

Ingredients	F1 (1:1)	F2 (1:2)	F3 (1:3)	F4(1:4)
Ibuprofen(gm)	0.4	0.4	0.4	0.4
Eudragit RL100(gm )	0.4	0.8	1.2	1.6
Glyceryl mono stearate (gm )	0.3	0.4	0.5	0.6
DCM(ml)	10	10	10	10
Ethanol(ml)	10	10	10	10

 

Physicochemical evaluation of floating microspheres

Micromeritic studies:⁶

The prepared hollow floating microspheres were characterized by their micromeritic properties such as true density, compressibility index, Angle of repose and flow property. (Table 2)

 

Morphology:⁷

The surface morphology of the prepared microspheres were observed by SEM (MODEL JSM-5310; JOEL, Tokyo, Japan.The microspheres were examined by SEM at different magnifications (Fig1)

 

SEM image of prepared hollow microspheres

Fig 1: Invitro dissolution studies

 

Size Analysis:^{8, 9}

It is carried out by using a compound microscope at x 45.Dried microspheres were first redispersed in distilled water and placed in a glass slide and the number of divisions of the calibrated eye piece was counted by a micrometer using a stage micrometer. The average size of the particle was determined. (Table 2)

Uniformity index:¹⁰

Uniformity index was calculated by using the formula

UI=D_W/Dn Where D_W is the weight average diameter and Dn is number average diameter. (Table 2)

Determination of percent drug entrapment: ¹¹

The drug content of Eudragit RL 100 microsphere was determined by dispersing 50mg formulation in 10ml of ethanol followed by agitation with a magnetic stirrer for 12hrs to dissolve the polymer and to extract the drug. After filtration through a 5mcg membrane filter (Millipore), the drug concentration in the ethanol phase was determined spectrometrically at 273nm. Eudragit RL100 did not interfere under these conditions. The percentage drug entrapment was calculated as follows (Table 3)

% Drug entrapment= Calculated drug concentration/ Theoretical drug content X100

 

Measurement of buoyancy:¹¹

Microballoons equivalent to 100mg was weighed and transferred to a beaker containing 300ml of 0.1N HCL, pH 1.2 at 37⁰ C.Then the mixture was stirred at 100rpm for a period of 6 hrs using a stirrer and the floating time were recorded. (Table 3)

 

Invitro drug release studies:¹²

The invitro release studies was carried out by USP-II method.Microballons equivalent to 100mg of drug was studied in simulated stomach buffer (900ml) pH  1.2 for a period of 2 hrs and subsequently in simulated phosphate buffer  pH  6.8 maintained at 37.c and 100rpm. The aliquot samples were withdrawn at frequent intervals, suitably diluted and assayed spectrophotometrically at 273nm (Fig 2)

 

Fig 2            

 

RESULTS AND DISCUSSSION:

The microballoons formulated by using drug: polymer ratios 1:4 were selected for further charcterisation.The formation of hollow cavity within the microspheres as well as porous surface structure were clearly evident in the optical and SEM (Fig1).The micromeritic properties revealed the improved physical characteristic of the formulations1:4 in terms of angle of repose, true density and particle size over the pure drug. The drug entrapment % within the hollow sphere cavity was found to be 84%.

Table 2: Micromeritic properties

Formulations	Mean particle size(µm)	Angle of Repose(θ)	Carr’s  index	Bulk density  g/cm3	True density  g/cm3	Uniformity index
F1	189.53	29.53	0.16	0.42	0.43	1.53
F2	283.64	27.46	0.19	0.42	0.42	1.44
F3	306.32	25.62	0.22	0.41	0.44	1.45
F4	348.62	22.32	0.18	0.40	0.42	1.32
pure drug	154.53	29.78	0.24	0.45	0.47	-

 

 

Table 3: Buoyancy and Incorporation efficiency data

Formulations	Buoyancy (%)	Incorporation efficiency (%)
F1	56.56	72.61
F2	63.52	78.66
F3	66.12	81.68
F4	73.32	84.98
pure drug	-	-

 

 

 

 

 

 

The buoyancy test showed the floatation of the microballoons in the gastric buffer pH  1.2 containing Tween 20(4%) as a surfactant up to 3 hours without any considerable drug release in the gastric buffer. The in-vitro drug release from the formulation1:4 was found to be maximum (92%) up to 8 hrs.

 

CONCLUSION:

Microballoons of Ibuprofen prepared with an acrylic polymer (Eudragit RL100) in different ratios by an emulsion solvent diffusion method were optimized with the help of various evaluations. The formulation with drug: polymer ratio 1:4 showed better physicochemical and micromeritic properties in comparison with pure drug. Invitro release profile clearly indicated that the dosage form was intact in the gastric pH for 2hrs and releases the drug in a controlled manner in the intestinal pH up to 8hrs.This study showed that microballoons were an ideal device to prolong the residence time in stomach and to enhance the enteric bioavailability of drug. Also it was noticed from the study that increase in the polymer concentration decreases the drug release from microballoons. This is may be due to the increased thickness of the outer shells of formulated microballoons.

 

REFERENCES:

1.       Desai, S., Bolton, S. A .  Floating controlled-release drug Delivery system: in vitro-in 

 vivo evaluation. Pharm. Res., v.10, p.1321-1325, 1993

2.       Hwang, S.J., Park, H.and Park, K., Crit.Rev.Ther.Drug Del.Syst., 1998, 15,243.

3.       Shivakumar, H.G, Gowda, and PramodKumar, T.M., IndianJ.Pharm.Educ.38 (4)2004, 172.

4.       Mitra SB. Sustained-release oral medicinal delivery Device. US patent 4451260 (1984) 29

5.       Kawashima Y, Niwa T, Takeuchi H, Hino T, Itoh Y.  Hollow microspheres for use as a floating controlled drug delivery system in the stomach. J Pharm Sci. 1992; 81:135-140.

6.       Anperiqdou A,Geogarakis. M. Controlled release salbutamol sulphate microcapsules.Int J.Pharm 1995; 115:1-8.

7.       Longo WE, Iwata H, Lindheimer TA, Goldberg EP.Preparation of hydrophilic albumin  microspheres  using polymeric dispersing agents.J.Pharm Sic 1982:71:1323- 8.

8.       Parikh RH,Parikh J R,Dubey RR, Soni HN,KapadiaKN, Poly(D,L-Lactide-co-Glycolide) microspheres containing 5-flouracil;optimization of process parameters. AARS Pharm Sci Tech 2003;4;1-8.

9.       Capan Y, Jiang G, Giovangali S,Na KH,Deluca PP. Preparation and  characterization of poly (D,L-Lactide-co-glycolide) microspheres for controlled release of Human growth Harmone. AAPS Pharm Sci Tech 2003;4;1-10

10.     Dubey RR (2004). Two stage optimization process for formulation of Chitosan Microspheres. AAPS Pharm. Sci. Tech., 1: 5

11.     Indian Pharmacopoeia (1996). The Controller of Publications, New Delhi, 4th ed., pp.242-243

12.     Niwa.T and Handa.T (1989). Preparation of controlled release of Ibuprofen with acrylic polymers by a novel quasi emulsion solvent diffusion. J. Pharm. Sci., 78(1): 78-68.

 

 

 

Received on 13.12.2009       Modified on 20.02.2010

Accepted on 18.03.2010      © RJPT All right reserved