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ORIGINAL ARTICLE
Year : 2010  |  Volume : 1  |  Issue : 1  |  Page : 56-67 Table of Contents     

In-Vitro characterization of gastroretentive microballoons prepared by the emulsion solvent diffusion method


College of Pharmacy, IPS Academy, Rajendra Nagar, A.B. Road, Indore, India

Date of Submission20-Jan-2010
Date of Decision19-Feb-2010
Date of Acceptance17-Mar-2010
Date of Web Publication2-Nov-2010

Correspondence Address:
Akash Yadav
College of Pharmacy, IPS Academy, Rajendra Nagar, A.B. Road, Indore
India
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Source of Support: None, Conflict of Interest: None


PMID: 22247832

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   Abstract 

Microballoons floatable on JPXIII No.1 solution were developed as a dosage form capable of floating in the stomach. Microballoons were prepared by the emulsion solvent diffusion method using enteric acrylic and other polymers with drug in a mixture of dichloromethane and ethanol. It was found that preparation temperature determined the formation of cavity inside the microsphere and the surface smoothness, determining the floatability and the drug release rate of the microballoons. The correlation between the buoyancy of microballoons and their physical properties, e.g. apparent density and roundness of microballoons were elucidated. The drug loading efficiency of microballoons was also determined. The optimum loading amount of metformin in the microballoons was found to impart ideal floatable properties to the microballoons. By fitting the data into zero order, first order and Highuchi model it was concluded that the release followed zero order release.

Keywords: Floating controlled drug delivery system, Gastroretentive, Microballoons, Emulsion solvent diffusion method, Metformin, Buoyancy.


How to cite this article:
Yadav A, Jain DK. In-Vitro characterization of gastroretentive microballoons prepared by the emulsion solvent diffusion method. J Adv Pharm Technol Res 2010;1:56-67

How to cite this URL:
Yadav A, Jain DK. In-Vitro characterization of gastroretentive microballoons prepared by the emulsion solvent diffusion method. J Adv Pharm Technol Res [serial online] 2010 [cited 2019 Oct 21];1:56-67. Available from: http://www.japtr.org/text.asp?2010/1/1/56/70524


   Introduction Top


Various types of drug delivery systems for oral administration such as drug release rate-controlled delivery systems, time­-controlled delivery systems and site-specific delivery systems have been extensively developed [1] . In the cases of rate-controlled and time-controlled delivery systems, sustained drug absorption time is limited to the transit time of the dosage form through the absorption site because, thereafter, the released drug is not absorbed. Thus, when a drug possesses a narrow 'absorption window', design of the sustained release preparation requires both prolongation of gastrointestinal transit of the dosage form and controlled drug release [3] . A dosage form targeting the gastrointestinal tract is designed to release a drug at a gastrointestinal site. [4]

Several gastrointestinal targeting dosage forms, including intragastric floating systems, high density systems, mucoadhesive systems adhering to the gastric mucosal surface to extend gastric residence time, magnetic systems, unfoldable extendible or swellable systems and superporous hydrogel systems have been developed [5],[6] . A swellable system must be compressible to a small size and expandable to a sufficiently large size to prevent the transit through the pylorus following oral administration. On the other hand, an intragastric floating system can remain in the stomach, resulting in better drug absorption at the proximal small intestine as well as in the stomach [7],[8] . A hydrodynamically balanced system (HBS) was initially described as a floating device with a density lower than that of water. A disadvantage of this system is the high variability of gastrointestinal transit time, due to its all-or-nothing emptying process [9],[10] . Therefore, a multiple-unit floating system that can be distributed widely throughout the gastrointestinal tract, providing the possibility of achieving a longer-lasting and more reliable release of drugs, has been sought. [11],[12] .

In the present work a multiple-unit intragastric floating system involving microballoons with excellent buoyant properties were developed. This gastrointestinal transit-controlled preparation is designed to float on gastric juice with a specific density of less than one. This property results in delayed transit through the stomach, which could be applicable for a drug (metformin) absorbed mainly at the proximal part of small intestine. In the present study, optimum preparation temperature with respect to microballoons cavity formation and factors influencing the buoyancy properties of microballoons were examined. The efficiency of drug entrapment into microballoons and the buoyancy properties of the microballoons were also investigated.


   Materials and Methods Top


2.1 Materials

Metformin was obtained as a gift sample from Sohan Health Care Pvt. Ltd Pune, as a model drug. Eudragit S100, Eudragit L100, Eudragit L100-55 (Rohm Pharma Gmbh, Germany) were utilized as an enteric polymers. Ethyl Cellulose, Hydroxy propyl methyl cellulose (HPMC) and Hydroxy propyl methyl cellulose phthalate were purchased from CDH Lab, New Delhi. Monostearin (Han-i Chemical, Japan) served as a wall membrane reinforcing agent and poly vinyl alcohol (PVA-120) functioned as a dispersing agent. All other solvents and reagents were purchased from Ranbaxy Chemicals, India and were of analytical grade.

2.2 Preparation of microballoons

Microballoons were prepared employing emulsion solvent diffusion method. Metformin, polymers and monostearin were dissolved in a mixture of dichloromethane and ethanol at room temperature in order to generate microballoons. The resulting solution was introduced into an aqueous solution of polyvinyl alcohol (0.75 w/v%, 200 ml) at 40 o C. Resultant emulsion was stirred at 300 rpm with a propeller type agitator for one h. The finely dispersed droplets of the polymer solution of drug were solidified in the aqueous phase via diffusion of the solvent. The dichloromethane that evaporated from the solidified droplet was removed by an aspirator, leaving the cavity of the microballoons filled with water. After agitating the system for one h, the resulting polymeric particulate systems were sieved between 500 and 1000 μm and dried overnight at 40 o C to produce microballoons. [13],[14]

2.3 Observation of microballoons

Microballoons were observed using a scanning electron microphotograph (SEM) (JSM-T330A, Nihon Densi, Japan). To investigate the internal morphology, microballoons were divided into two pieces with a knife.

2.4. Measurement of physicochemical properties of microballoons

2.4.1. Recovery


Recovery of microballoons containing a drug was determined by the weight ratio of the dried microballoons to the loading amount of the drug, polymers and monostearin. [15]

2.4.2. Buoyancy

Microballoons (100 mg) were dispersed in JP XIII No.1 solution composed of HCl and NaCl (300 ml, pH 1.2, 37 o C) containing Tween 20 (0.02 w/v%) to simulate gastric fluid. The mixture was stirred with a paddle stirrer at 100 rpm. After 12 h, the layer of buoyant particles was pipetted and the floating particles were separated by filtration. Particles in the sinking particulate layer were

separated by filtration. The particles were dried at 40 o C overnight. Weight was measured and buoyancy was determined by the weight ratio of the floating particles to the sum of floating and sinking particles. [16]

2.4.3. Apparent particle density

Apparent particle density was determined by the projective image count method as follows. Microballoons were placed on a glass plate. Heywood diameter and microballoons number were measured by an Image Processing and Analysis System (Q5001W, Leica, Japan). Subsequently, the apparent particle density was calculated according to Eq. (1) [17] .

Apparent particle density = W/V = W/∑ (ηd 3 n/6) Eq. (1)

Where, W = weight of microballoons, V = volume of microballoons, d = Heywood diameter, and n = number of micro balloons.

2.4.4. Roundness

Roundness of microballoons was measured by an Image Processing and Analysis System (Q5001W, Leica, Japan). In this system, roundness was calculated according to Eq. (2) [18] .

Roundness of microballoons = L24S Eq. (2)

Where, L = circumference of a projective image and S = area of a projective image. When the roundness of microballoons was close to one, the microballoons closely resembled spherical particles.

2.4.5. Drug content

Dried microballoons containing a drug were dissolved in a mixture of dichloromethane and ethanol (1:1 v/v) by ultrasonication. The dissolved drug amount was measured spectrophotometrically with a UV detector (UV-160A, Shimadzu, Japan) (233 nm). Drug content of microballoons was calculated according to Eq. (3) [19],[20]

Drug Content (%) = Weight of drug in microballoons / Weight of microballoons recovered x 100 Eq. (3).

2.4.6. Drug release

The level of drug release from microballoons having diameters of between 500 and 1000 mm was measured by the paddle method at 100 rpm specified in JP XIII as follows. Microballoons (100 mg) were dispersed in JP XIII No.1 solution composed of HCl and NaCl (300 ml, pH 1.2, 37 o C) containing Tween 20 (0.02 w/v%) to simulate gastric fluid or JP XIII No.2 solution composed of NaOH and KH 2 PO 4 (300 ml, pH 6.8, 37 o C) containing Tween 80 (0.5 w/v%) to solubilized drug. The level of the drug release was determined spectrophotometrically employing a UV detector (UV-160A, Shimadzu, Japan). [21],[22]

2.5. Identification of crystalline form of the drug in microballoons

The crystalline form of the drug dispersed in the crust of the microballoons and in the physical mixture of drug and Eudragit S100 and monostearin was analyzed by X-ray powder diffractometry (XD-3A, Shimadzu, Japan).


   Results and Discussion Top


3.1 Drug release properties of microballoons

Microballoons were developed as novel delivery systems available for metformin drug. Microballoons having diameters of between 500 and 1000 mm are characterized by a spherical cavity enclosed within a hard polymer shell, which exhibits thickness of between 100 and 200 μm. Metformin was efficiently entrapped within the shell of microballoons as proved by the absence of drug remaining in aqueous solution after the process. The efficiency of drug entrapment into microballoons could be ascribed to the distribution coefficient between water and dichloromethane under the preparation conditions. Buoyancy and drug release from metformin microballoons in JPXIII No.1 solution with 0.02 w/v % Tween 20 are illustrated in [Figure 2]. Buoyancy of the microballoons decreased with increasing drug release rate.[Figure 1]
Figure 1 :Scanning electron microphotograph of cross section of micro balloon

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Figure 2 :Buoyancy and drug release from metformin micro balloons (pH 1.2)

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In the case of metformin, the drug release profile of microballoons were linear when plotted in the Higuchi equation. These findings indicated that the shell structure of the microballoons was a polymeric matrix containing dispersed drug. Drug release rate was determined by the diffusion of drug from the rigid matrix structure of the shell of the microballoons. When the loading amount of metformin was 0.2 g or greater, the drug release profile of the microballoons exhibited a drug release burst at the initial stage. Following the initial burst, metformin release became slow and prolonged, indicating that metformin release rate was determined by the diffusion of drug from the rigid matrix structure of the shell. In order to explain the initial burst, further investigations were conducted employing scanning electron microphotography and X-ray powder diffraction.

Scanning electron microphotographs of metformin containing microballoons are displayed in [Figure 3], illustrates the presence of numerous small pores on the surface of metformin containing microballoons, probably arising as a trace of solvent evaporation during the process. The surfaces of the metformin microballoons were covered with needle like crystals.
Figure 3 :Scanning electron photomicrograph (SEM) of metformin microballoons

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X-ray powder diffraction patterns of metformin containing microballoons are displayed in [Figure 4]. The component ratio of the physical mixture was identical to those of microballoons; namely, the drug/EudragitS100/monostearin ratio was 2:10:5. In the case of metformin containing microballoons, original crystals were present, as indicated by characteristic peak patterns of the X-ray diffraction. As previously noted, the surfaces of metformin containing microballoons were covered with needle-like crystals. Therefore, the initial burst was attributed to the dissolution of metformin crystals present on the surfaces at release test in JPXIII No.1 solution supplemented with 0.02 w/v% Tween 20. In addition, buoyancy of metformin containing microballoons rapidly decreased due to the initial burst. This was because many macro pores were left on the surface through which the dissolution medium easily penetrated with reducing buoyancy after dissolving the crystals. [Figure 5] displays scanning electron photomicrographs of microballoons (loading amount of metformin: 0.1, 0.2, 0.5 and 1.0 g).
Figure 4 :X-Ray powder diffraction pattern of metformin microballoons (1) Metformin, (2) Eudragit S100, (3) Monostearin, (4) Physical mixture (Metformin: Eudragit S100: Monostearin = 2:10:5), (5) Microballoons.

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Figure 5 :Scanning electron microphotographs of appearance of metformin microballoons (a) Metformin 0.5 g, (b) Metformin 0.2 g, (c) Metformin 0.5 g and (d) Metformin 1.0 g

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3.2. Control of drug release by mixing polymers

When the loading amount of metformin was 0.1 g, the initial burst was not observed; moreover, little metformin was released from microballoons in JPXIII No.1 solution containing 0.02 w/v% Tween 20. This phenomenon appeared to afford low bioavailability for a drug absorbed mainly at the proximal small intestine, such as metformin. Thus, in order to modulate the drug release rate from the microballoons, they were prepared by mixing hydrophilic or hydrophobic polymer in Eudragit S100.

Physicochemical properties of metformin containing microballoons prepared using mixed polymers are presented in [Table 1]. Scanning electron microphotographs of microballoons and plots of metformin release from micro-balloons in JP XIII No.1 solution supplemented with 0.02 w/ v% Tween 20 (pH 1.2) are displayed in [Figure 6] and [Figure 7], respectively.
Table 1 :Physicochemical properties of metformin containing microballoons

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Figure 6 :Scanning electron microphotographs appearance of metformin microballoons (a) Eudragit S100/L100 = 9:1, (b) Eudragit S100/L100-55, (c) Eudragit S100 /HPMCP = 9:1, (d) Eudragit S100/HPMC = 9:1, (e) Eudragit S100/EC = 9:1

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Figure 7 :Metformin release from microballoons in JP XIII No. 1 solution containing 0.02w/v% Tween 20 (pH 1.2). O, Eudragit S100/ Eudragit L100 = 9:1, , Eudragit S100/ Eudragit L100-55: 9:1, , Eudragit S100/ HPMCP: 9:1, , Eudragit S100/ HPMC: 9:1 and , Eudragit S100/ EC: 9:1.

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In the case of hydroxypropylmethylcellulose (HPMC), irrespective of high apparent particle density, buoyancy was high. HPMC was considerably soluble and gelled in JPXIII No.1 solution. Additionally, roundness of microballoons possessing smooth surfaces was close to one. Thus, buoyancy appeared to be high due to the difficulty in penetration of JPXIII No.1 solution through the rigid smooth surfaces.

In the case of ethyl cellulose (EC), many needle-like particles were present on the surface. The release profile of the microballoons exhibited a burst of metformin during the initial stage, followed by a plateau pattern for 12 h. In addition, buoyancy appeared to be high as a consequence of hydrophobic properties of the EC polymer. Consequently, mixing hydrophilic polymers such as Eudragit L100, Eudragit L100-55 or HPMC in the shell of microballoons afforded elevated metformin release from microballoons. In conclusion, the drug release property and buoyancy of microballoons could be determined by apparent particle density, surface topography and wettability of microballoons.

3.3 Metformin release from microballoons prepared by mixing HPMC with Eudragit S100

It was found that the drug release rate and buoyancy of microballoons prepared by co-formulating HPMC was relatively improved due to gelation in JPXIII No.1 solution. Therefore, the effect of HPMC mixing ratio on physicochemical properties and drug releasing behaviors of the microballoons were investigated as shown in [Table 2] and [Figure 8]. Although the recovery of microballoons appeared unchanged by HPMC ratio, the buoyancy decreased with increasing HPMC ratio. These results were attributable to the conversion of spherical microballoons to needle like particles possessing no hollow structure.
Table 2 :Physiochemical properties of metformin micro balloons

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In addition, the JPXIII No.1 solution can readily penetrate into microballoons due to the increased dissolution of HPMC in the solution. The amount of metformin released from microballoons in JPXIII No. 1 solution containing 0.02 w/v% Tween 20 (pH 1.2) increased with increasing HPMC ratio. This behavior was explained by the increased contact area of particles with the medium due to the poor buoyancy associated with increased HPMC ratio. The amount of metformin released from microballoons in JP XIII No. 2 solution supplemented with 0.5 w/v% Tween 80 (pH 6.8) significantly increased in association with increased HPMC ratio. In conclusion, a recommendable preparation formulation of microballoon to increase the bioavailability of metformin absorbed mainly at the proximal part of small intestine (pH 4-6.5) was metformin 0.5 g, Eudragit S100 0.9 g, HPMC 0.1 g and monostearin 0.5 g due to their desired drug release and floatable properties.


   Conclusion Top


Microballoons with enteric acrylic polymers such as Eudragit S100 floatable in JPXIII No. 1 solution were successfully prepared by the emulsion solvent diffusion method. The drug metformin could be enclosed in the shell of microballoons forming a matrix-like structure. The drug dispersed in the shell as an amorphous or crystalline state, depending upon the loading amount of drug, was released following Higuchi kinetics or some other method, respectively. The crystalline drug adsorbed on the surface of microballoons caused an initial burst release. The buoyancy of microballoons decreased with increasing drug release rate. By co­formulating mixed polymers, the drug release and buoyancy of microballoons were modified depending upon their apparent density, surface topography and wettability. Upon incorporation of hydrophilic polymers such as HPMC in the shell of microballoons, the amount of metformin released from microballoons could be enhanced.

Metformin released properties of the microballoons were influenced by the pH of the release test solution; the amount of metformin released from microballoons in JP XIII No. 2 solution (pH 6.8) significantly increased in association with increased HPMC ratio. A preparation formulation of microballoon to increase the amount of metformin released from microballoons maintaining high buoyancy could be provided; metformin 0.5 g, Eudragit S100 0.9 g, HPMC 0.1 g and monostearin 0.5.


   Acknowledgement Top


The authors are grateful to the Sohan Health Care Pvt. Ltd. Pune for providing free gift sample of the drug metformin. The authors are also acknowledged College of Pharmacy, IPS Academy, Indore for providing research facility.[23]

 
   References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
 
 
    Tables

  [Table 1], [Table 2]


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