These approaches are complicated, as they require specific equipment and handling techniques with limited acceptance.

The polysaccharide pectin is a polymer of α-D-galacturonic acid with 1→4 linkages. This chain is regularly interrupted by some rhamnogalacturonan segments that combine galacturonic acid residues and α-L–rhamnopyranose by a 1→2 linkage. The galacturonic acid of the backbone is partially methyl-esterified. Low-methoxy pectin with degree of esterification less than 50% can form rigid gels by the action of calcium ions or multivalent cations, which cross-link the galacturonic acid chains. Calcium pectinate hydrogels are stable in low pH solution and are being investigated as a carrier material for different controlled release systems. The use of vegetable oil in calcium pectinate beads will provide buoyancy to the beads as well as will control the drug release from the beads. The oil containing beads have limitations of coalescence of oil droplets yield yielding beads of wider particle size distribution, volatilization or leaching of oil⁹.

Ibuprofen is a well known non-steroidal anti-inflammatory agent effective in rheumatic diseases. It is a weak acid having pKa 4.4 and 5.2. It is having irritation potential in stomach due to charged carboxylic acid. It is well absorbed from upper small intestine. Therefore, it was envisaged to develop floating beads of ibuprofen.

MATERIALS AND METHODS:

Materials

Chitosan (degree of deacetylation = 87%) and low methoxy pectin were obtained from TIC Gum Inc. USA, sesame oil was obtained from Samar Chemicals, Nagpur, Ibufrofen was gratis sample from Zim Laboratories, Nagpur, sodium hydroxide, potassium dihydrogen orthophosphate, sodium lauryl sulphate were obtained from Loba Chemie Pvt. Ltd., Conc. Hydrochloric acid was obtained from Rankem Ltd. Calcium chloride, sodium chloride were pbtained from S.D. Fine Chemicals. Ltd. The other reagents and chemicals were of analytical grade.

Methods

Preparation of floating polymeric beads

The formulation of floating beads is shown in table 1. A 5 %w/v solution of low methoxy pectin solution was prepared in distilled water. To it, ibuprofen was added in dosing levels of 25, 50 and 75 %w/v of pectin weight. The dispersion was stirred using mechanical stirrer. Sesame oil was added in 10, 20 and 30 %w/v of volume dispersion. The solution was stirred to make a homogeneous dispersion of oil, drug and pectin.

A 5 %v/v acetic acid solution was prepared in distilled water and to it gradually chitosan (87% degree of deacetylation) was added to make 1 %w/v solution. The solution was kept overnight. In distilled water calcium chloride was dissolved and it was added to solution of chitosan to get 2, 4, and 10 %w/v solution of CaCl₂. Hence the final individual solutions were 1% w/v chitosan containing 2, 4 and 10 %w/v of calcium chloride.

The dispersion of low methoxy pectin, drug and oil was added under stirring through 22 Gauge needle into 1 %w/v chitosan solution in acetic acid containing 2, 4 and 6% CaCl₂solution separately. The curing time for the reaction between pectin, chitosan and CaCl₂ was kept at 30 minutes. The beads were separated by filtration and dried at 37^oC for 24 hours.

Table 1 Formulation batches floating polymeric beads

Formulation batch code	Low methoxy pectin dispersion (%w/v)	Drug loading (%)	Sesame oil (%)	CaCl₂solution (%w/v)
F1	5	25	10	2
F2	5	25	20	2
F3	5	25	30	2
F4	5	50	10	2
F5	5	50	20	2
F6	5	50	30	2
F7	5	75	10	2
F8	5	75	20	2
F9	5	75	30	2
F10	5	25	10	4
F11	5	25	20	4
F12	5	25	30	4
F13	5	50	10	4
F14	5	50	20	4
F15	5	50	30	4
F16	5	75	10	4
F17	5	75	20	4
F18	5	75	30	4
F19	5	25	10	10
F20	5	25	20	10
F21	5	25	30	10
F22	5	50	10	10
F23	5	50	20	10
F24	5	50	30	10
F25	5	75	10	10
F26	5	75	20	10
F27	5	75	30	10

Characterization

Size of beads

In the surface characteristic studies, a chitosan coating over the pectin beads was observed by using MOTIC Software.

Drug content

For determination of drug content, the polymeric beads were sonicated in pH 6.8 phosphate buffer and washed till the total drug removed from the beads. The absorbance was recorded at 221 nm.

In vitro buoyancy test

The floating characteristic of polymeric beads was studied in pH 1.2 buffer containing 0.02% tween 80.

Interaction studies of low methoxy pectin with calcium ions and deacetylated chitosan

Differential Scanning Calorimetry (DSC)

The interaction of low methoxy pectin with calcium ions and chitosan was studied by DSC. The DSC thermogram of calcium pectinate beads containing ibuprofen and sesame oil was recorded. Also, the DSC thermogram of calcium pectinate beads containing ibuprofen, sesame oil and coated with deacetylated chitosan was recorded at a heating rate of 5^oC/minute.

X-ray diffraction spectroscopy

The interaction of low methoxy pectin with chitosan and calcium ions was studied by x-ray diffraction spectroscopy. The x-ray diffraction pattern of calcium pectinate beads containing ibuprofen and sesame oil was recorded. Also, the x-ray diffraction pattern of calcium pectinate beads containing ibuprofen, sesame oil and coated with chitosan was recorded.

FT-IR spectroscopy

The FT-IR spectrum of calcium pectinate beads containing ibuprofen and sesame oil was recorded. Also, the FT-IR spectrum of calcium pectinate beads containing ibuprofen, sesame oil and coated with chitosan was recorded in the stretching frequency range 400 to 4000 cm^-1. For the preparation of samples by KBr press pellet technique, a 3:1 ratio of KBr: sample was used.

In vitro dissolution studies

The in vitro dissolution was carried out in pH 1.2 buffer, pH 6.8 phosphate buffer and pH 1.2 buffer containing 1 %w/v SLS using USP type II dissolution test apparatus at 37±0.5^oC at 75 rpm. The polymeric beads equivalent to 200 mg of ibuprofen were used for dissolution studies. The drug content was measured at 221 nm.

RESULTS AND DISCUSSION:

Determination of drug content

The maximum drug loading was found to be 75% of low methoxy pectin weight used in the formulation of beads.

Determination of size of beads

The diameter of beads studied using MOTIC Software was found to be 100µm±5 µm. In the surface characteristic studies, a chitosan coating over the pectin beads was observed.

In vitro buoyancy studies

The polymeric beads containing 10% sesame oil were found to be non-floating and beads containing 20 and 30% sesame oil were found to show excellent floating characteristic in pH 1.2 buffer.

Interaction study of low methoxy pectin with calcium ions and chitosan

Differential Scanning Calorimetry (DSC)

Figure 1 DSC thermogram of ibuprofen

Figure 2 DSC thermogram of deacetylated chitosan

Figure 3 DSC thermogram of low methoxy pectin

Figure 4 DSC thermogram of ibuprofen loaded polymeric beads of low methoxy pectin and sesame oil cross-linked with calcium chloride

Figure 5 DSC thermogram of ibuprofen loaded polymeric beads of low methoxy pectin and sesame oil cross-linked with calcium chloride and coated with deacetylated chitosan

The thermal transitions and enthalpy values of ibuprofen, deacetylated chitosan, low methoxy pectin, and ibuprofen loaded polymeric beads with and without coating of chitosan are shown in table 2.

Table 2 Thermal transitions and enthalpy values of ibuprofen, deacetylated chitosan, low methoxy pectin, and ibuprofen loaded polymeric beads with and without coating of chitosan

Sample

DSC thermal

transition

(⁰C)

Enthalpy

(J/g)

Ibuprofen

76.89

239.71

286.56

(-)337.33

355.53

501.05

Deacetylated chitosan

60.31

289.80

(-)87.04

826.98

Low methoxy pectin

78.89

150.29

200.79

309.68

(-) 479.38

(-) 115.03

(-) 483.45

1605.25

Polymeric beads of low methoxy pectin and sesame oil cross-linked with calcium chloride

90.78

204.10

313.30

369.22

9999.0

DSC thermogram of polymeric beads of low methoxy pectin and sesame oil cross-linked with calcium chloride and coated with deacetylated chitosan

Glass transition

Onset 42.73

Midpoint 61.60

194.99

----

(-) 30.80

As shown in figure 1, a sharp melting peak at 76.89ºC with an enthalpy value of (-) 337.33 J/g was observed in the DSC thermogram of ibuprofen indicating that heat is absorbed by system for melting process. The other peaks at 239.71 and 286.56ºC are exotheric peaks with enthalpy values of 355.53 and 501.05 J/g respectively indicating heat is liberated by the system.

The DSC thermogram of deacetylated chitosan is shown in figure 2. It has shown a melting peak at 60.31^oC with an enthalpy value of (-) 87.04 J/g. The other peak observed is the exothermic transition at 289.80 with an enthalpy value 826.38 J/g.

The DSC thermogram of low methoxy pectin is shown in figure 3. It has shown a melting peak at 78.89, 204.10, and 313.30^oC with enthalpy values of (-) 479.38, (-) 115.03 and (-) 483.45 respectively. The other peak observed is the exothermic transition at 309.68ºC with an enthalpy value 1605.25 J/g.

The DSC thermogram of polymeric beads of ibuprofen containing low methoxy pectin and sesame oil cross-linked with calcium chloride is shown in figure 4. It has shown the endothermic transitions at 90.78, 204.10, 313.30, with enthalpy values of 9999 J/g for each thermal transition and an exothermic transition at 369.22ºC with enthalpy value of 9999 J/g.

The DSC thermogram of polymeric beads of ibuprofen containing low methoxy pectin and sesame oil cross-linked with calcium chloride and coated with deacetylated chitosan is shown in figure 5. It has shown glass transition as the thermal transition with an onset at 42.73ºC and a midpoint 61.60ºC. An endothermic transition at 194.99ºC with an enthalpy value of (-) 30.80 J/g was observed. It indicates that a transition of the polymer from one rubbery state to glassy state has occurred due to complex formation as evidenced by the glass transition temperature at 42.73^oC. The midpoint of glass transition peak at 61.60ºC is similar to the melting peak of deacetylated chitosan which was observed at 60.31ºC.

From the above thermal transitions, it can be concluded that the endothermic peak of low methoxy pectin which was observed at 150.29ºC with an enthalpy value of (-) 115.03 J/g has been disappeared from the thermogram of polymeric beads of low methoxy pectin and sesame oil cross-linked with calcium chloride. Also the endothermic peak of low methoxy peak which was observed at 78.89ºC was found to be shifted to 90.78ºC indicating more energy was required for the melting due to cross-linking.

FT-IR Spectroscopy

Figure 6 FT-IR spectrum of ibuprofen

Figure 7 FT-IR spectrum of low methoxy pectin

Figure 8 FT-IR spectrum of deacetylated chitosan

Figure 9 FT-IR spectrum of polymeric beads of low methoxy pectin and sesame oil cross-linked with calcium chloride

Figure 10 FT-IR spectrum of polymeric beads of low methoxy pectin and sesame oil cross-linked with calcium chloride and coated with deacetylated chitosan

The FT-IR spectrum of deacetylated chitosan has shown the stretching frequencies at 3500 cm^-1 due to presence of primary amine functional groups. The stretching frequency representing primary amine functional group was absent in the FT-IR spectrum of polymeric beads of low methoxy pectin cross-linked with calcium ions and coated with chitosan. The FT-IR spectras of pectin beads cross-linked with calcium ions and pectin beads cross-linked with calcium ions and coated with chitosan has shown the stretching frequency at 3009 cm^-1 due to = C-H stretching (Aliphatic) functional group. Hence the structural change to alkenes might have occured due to cross-linking of pectin with calcium ions. The stretching frequencies at 1545, 1535 cm^-1 were due to secondary –CONH- stretching or RCO₂ functional groups. The secondary –CONH- stretching might be due to interaction of amine group of chitosan with the carboxylic acid group of the low methoxy pectin. The stretching frequencies observed due to presence of functional groups RCOOH, ester C = O stretching, aldehyde C = O stretching were observed in low methoxy pectin but were absent in polymeric beads of low methoxy pectin containing sesame oil and cross-linked with calcium ions indicates that the carboxylic acid functionality either RCOOH, ester C = O, aldehyde C = O have been utilized for the reaction between negatively charged pectin and positively charged chitosan.

X-ray diffraction spectroscopy

Figure 11 X-ray diffraction pattern of ibuprofen

Figure 12 X-ray diffraction pattern of low methoxy pectin

Figure 13 X-ray diffraction pattern of deacetylated chitosan

Figure 14 X-ray diffraction patterns of polymeric beads of ibuprofen containing low methoxy pectin and sesame oil cross linked with calcium ions

Figure 15 X-ray diffraction pattern of polymeric beads of ibuprofen containing low methoxy pectin, sesame oil cross-linked with calcium ions and coated with deacetylated chitosan

The x-ray diffraction pattern of ibuprofen and low methoxy pectin is shown in figure 11 and 12 respectively. It showed the sharp peak since ibuprofen and low methoxy pectin are present in crystalline state. Whereas, as shown in figure 13, the deacetylated chitosan was present in the amorphous state as evidenced from the diffused pattern. The x-ray diffraction pattern of polymeric beads of ibuprofen containing low methoxy pectin, sesame oil cross-linked with calcium ions is shown in figure 14. It shows the absence of sharp crystalline peaks of either ibuprofen or low methoxy pectin. The x-ray diffraction pattern of polymeric beads of ibuprofen containing low methoxy pectin, sesame oil, cross-linked with calcium ions and coated with deacetylated chitosan are shown in figure 15 which shows the absence of sharp crystalline peaks of either ibuprofen or low methoxy pectin. It indicates the complex formation between low methoxy pectin, calcium chloride and deacetylated chitosan leading to the development of polymeric beads.

Dissolution studies of ibuprofen polymeric beads in pH 1.2 buffer

Figure 16 Release profiles of ibuprofen polymeric beads loaded with 25 % drug, 20 and 30% sesame oil and cross-linked with 2, 4 and 10% CaCl₂ in pH 1.2 buffer

In the in vitro buoyancy studies in pH 1.2 buffer, the polymeric beads containing 10% sesame oil were found to be non-floating. Hence the dissolution studies were carried out using the formulation batches with 20 and 30% sesame oil.

As shown in figure 16, the formulation batches with a drug loading of 25%, and containing 20 and 30% sesame oil and cross-linked with 2, 4 and 10 %w/v CalCl₂, 6 to 8 % drug release was observed in 1 hour and 12 to 14% drug release was observed after 10 hours of dissolution studies. The formulation batches have shown Peppas model as the best fit model of drug release.

Figure 17 Release profiles of ibuprofen polymeric beads loaded with 50 % drug, 20 and 30% sesame oil and cross-linked with 2, 4 and 10% CaCl₂in pH 1.2 buffer

As shown in figure 17, the formulation batches with a drug loading of 50%, with 20 and 30% sesame oil and cross-linked with 2, 4 and 10 %w/v CalCl₂has shown a release of 6 to 7 % drug release in 1 hour and 14 to 18% drug release was observed after 10 hours of dissolution studies. The formulation batch F₅ and F₂₃ have shown matrix as the best fit model, whereas, F₆, F₁₄, F₁₅, F₂₄ has shown Peppas model as the best fit model of drug release.

Figure 18 Release profiles of ibuprofen polymeric beads loaded with 75 % drug, 20 and 30% sesame oil and cross-linked with 2, 4 and 10% CaCl₂ in pH 1.2 buffer

As shown in figure 18, the formulation batches with a drug loading of 75%, with 20 and 30% sesame oil and cross-linked with 2, 4 and 10 %w/v CalCl₂has shown a 4 to 5 % drug release in first hour and 12 to 17% drug release was observed after 10 hours of dissolution studies. The formulation batch F₈, F_9,F₁₇, F₁₈, F₂₇ have shown matrix as the best fit model, whereas, formulation batch F₂₆ has shown Peppas model as the best fit model of drug release.

Dissolution studies of ibuprofen polymeric beads in pH 1.2 buffer containing 1% SLS

The in vitro dissolution of ibuprofen polymeric beads in pH 1.2 buffer has shown 10-19% drug release after 10 hours. It was due to limited solubility of ibuprofen in pH 1.2 buffer. Hence, the drug release studies were carried in pH 1.2 buffer containing 1 %w/v sodium lauryl sulphate. In pH 1.2 buffer containing 0.5 %w/v sodium lauryl sulphate, ibuprofen was found to be partly soluble; hence the proportion of SLS was increased to 1 %w/v. Also, the solubility of ibuprofen in 3 %w/v tween 80 was studied but it was not possible to measure the drug concentration in pH 1.2 buffer containing 3 %w/v tween 80 because the absorbance values at 221 nm were found to be fluctuating and not stable due to lower wavelength 221 nm.

Figure 19 Release profiles of ibuprofen polymeric beads loaded with 25 % drug, 20 and 30% sesame oil and cross-linked with 2, 4 and 10% CaCl₂ in pH 1.2 buffer containing 1% SLS

As shown in figure 19, the formulation batches with a drug loading of 25%, with 20 and 30% sesame oil and cross-linked with 2, 4 and 10 %w/v CalCl₂has shown a release of 22 to 36 % drug release in 1 hour. The formulation batches cross-linked with 2% CaCl₂and 20% oil, a drug release of 62% was observed. Whereas, the formulation batch containing 30% oil and cross-linked with 2% CaCl₂ has shown a drug release of 69% after 10 hours. The drug release was increased when the CaCl₂ concentration was increased from 2 to 4% and in the formulation batches with 20 and 30% oil, 93 and 100% drug release was observed after 10 hours. It indicates that the higher calcium ion concentration has competed with chitosan and hence faster drug release was observed. Similarly, the formulation batches containing 30 and 30% oil and cross-linked with 10% CaCl₂ has shown a drug release of 85 and 100% respectively after 10 hours. The formulation batches F₂ and F₃ has shown Peppas model as best fit model of drug release, whereas, the formulation batches F₁₁, F₁₂, F₂₀, and F₂₁ has shown matrix drug release kinetic model.

Figure 20 Release profiles of ibuprofen polymeric beads loaded with 50 % drug, 20 and 30% sesame oil and cross-linked with 2, 4 and 10% CaCl₂ in pH 1.2 buffer containing 1% SLS

As shown in figure 20, the formulation batches with a drug loading of 50%, with 20 and 30% sesame oil and cross-linked with 2, 4 and 10 %w/v CalCl₂has shown a 19 to 27 % drug release in 1 hour. The formulation batches cross-linked with 2% CaCl₂and 20% oil, a drug release of 61% was observed after 10 hours. Whereas, the formulation batch containing 30% oil and cross-linked with 2% CaCl₂ has shown a drug release of 59% after 10 hours. The drug release was increased when the CaCl₂ concentration was increased from 2 to 4% and in the formulation batches with 20 and 30% oil, 84 and 95% drug release was observed after 10 hours. It indicates that the higher calcium ion concentration has competed with chitosan and hence faster drug release was observed. Similarly, the formulation batches containing 20 and 30% oil and cross-linked with 10% CaCl₂ has shown a drug release of 80 and 93% respectively. The formulation batches F₅, F₆, F₁₄ has shown Peppas model as best fit model of drug release, whereas, the formulation batches F₁₅, F₂₃, F₂₄ has shown matrix drug release kinetic model.

Figure 21 Release profiles of ibuprofen polymeric beads loaded with 75 % drug, 20 and 30% sesame oil and cross-linked with 2, 4 and 10% CaCl2 in pH 1.2 buffer containing 1% SLS

As shown in figure 21, the formulation batches with a drug loading of 75%, with 20 and 30% sesame oil and cross-linked with 2, 4 and 10 % CalCl₂has shown a release of 18 to 31 % drug release in 1 hour. The formulation batches cross-linked with 2% CaCl₂with 20 and 30% sesame oil, a drug release of 53 and 56% respectively was observed after 10 hours. In the formulation batches with 20 and 30% oil, and cross-linked with 4% CaCl₂, 70 and 88% drug release respectively was observed after 10 hours. It indicates that the higher calcium ion concentration has competed with chitosan for forming a complex with chitosan and hence faster drug release was observed. Similarly, the formulation batches containing 20 and 30% oil and cross-linked with 10% CaCl₂ has shown a drug release of 65 and 64% respectively. The formulation batches F₈, F₉, F₁₈ has shown Peppas model of drug release as best fit model, whereas, the formulation batches F₁₇, F₂₆, and F₂₇ has shown matrix drug release kinetic model.

Dissolution studies of ibuprofen polymeric beads in pH 6.8 phosphate buffer

Figure 22 Release profiles of ibuprofen polymeric beads loaded with 25 % drug, 20 and 30% sesame oil and cross-linked with 2, 4 and 10% CaCl₂ in pH 6.8 phosphate buffer

The drug release profiles of ibuprofen polymeric beads with 25% drug loading in pH 6.8 phosphate buffer are shown in figure 22. The formulation batches containing 20 and 30% sesame oil and cross-linked with 2% CaCl₂ has shown complete drug release after 3 hours of dissolution studies. Whereas, when the CaCl₂ concentration was increased to 4%, the complete drug release was observed after 4 hours. The drug release was sustained when the CaCl₂ concentration was increased to 10%. The complete drug release was observed after 6 and 8 hours in case of the formulation containing 20 and 30% respectively oil and cross-linked with 10% CaCl₂.

Figure 23 Release profiles of ibuprofen polymeric beads loaded with 50 % drug, 20 and 30% sesame oil and cross-linked with 2, 4 and 10% CaCl₂ in pH 6.8 phosphate buffer

The release profiles of ibuprofen polymeric beads with 50% drug loading, 20 and 30% sesame oil and cross-linked with 2, 4 and 10% CaCl₂ are shown in figure 23. The formulation batch containing 20 and 30% sesame oil and 2% CaCl₂ has shown a release of 19 and 28 % respectively in first hour and the complete release was observed after 6 hours of dissolution studies. The formulation batches containing 20 and 30% sesame oil and cross-linked with 4% CaCl₂ has shown a release of 8 and 13% after 1 hour and the complete release was observed after 8 hours. The drug release was further sustained in case of the formulation containing 20 and 30% sesame oil and cross-linked with 10% CaCl₂ and 14 and 12% drug release was observed after 1 hour of dissolution studies. After 8 hours, 85 and 58% drug release was observed in case of formulation containing 20 and 30% sesame oil respectively. The proportion of oil when increased from 20 to 30% the drug release was retarded from 85 to 58%. It is due to partitioning of drug into the oil phase and at the same time increase in the rigidity of polymeric network.

Figure 24 Release profiles of ibuprofen polymeric beads loaded with 75% drug, 20 and 30% sesame oil and cross-linked with 2, 4 and 10% CaCl₂ in pH 6.8phosphate buffer

The release profiles of ibuprofen polymeric beads with 75% drug loading, 20 and 30% sesame oil and cross-linked with 2, 4 and 10% CaCl₂ are shown in figure 24 The formulation batch containing 20 and 30% sesame oil and 2% CaCl₂has shown a release of 29.57 and 39.39 % respectively in first hour and the complete release was observed after 6 hours of dissolution studies. The formulation batches containing 20 and 30% sesame oil and cross-linked with 4% CaCl₂ has shown a release of 9.07 and 13.98% after 1 hour and 92.38 and 98.65% drug release was observed after 8 hours. The drug release was further sustained in case of the formulation containing 20 and 30% sesame oil and cross-linked with 10% CaCl₂ and 1.90 and 4.70% drug release was observed after 1 hour of dissolution studies. After 8 hours, 36.28 and 69.68% drug release was observed in case of formulation containing 20 and 30% sesame oil respectively. The drug release was retarded up to 36.28% due to partitioning of drug into the oil phase and at the same time increase in the rigidity of polymeric network by higher concentration of CaCl₂used for the cross-linking purpose.

CONCLUSION:

From above dissolution studies of ibuprofen polymeric beads has show low amount of drug release in pH 1.2 buffer due to limited solubility of drug in acidic media. The dissolution studies in pH 1.2 buffer containing 1% w/v sodium lauryl sulphate has shown increase in drug release due to increased solubility of ibuprofen. Similarly faster drug release was observed in pH 6.8 phophate buffer. Hence, it was concluded that multiple unit floating drug delivery of ibuprofen was developed to control the drug release in acidic condition of stomach and hence the drug delivery can be used to avoid the irritant effect of drug on gastric mucosa.

ACKNOWLEDGEMENT:

The authors are thankful to TIC Gum Inc. USA for the gift samples of low methoxy pectin and chitosan. Also for Zim Laboratories for providing Ibuprofen.

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Received on 30.09.2011

Accepted on 28.10.2011

Research Journal of Pharmaceutical Dosage Forms and Technology. 3(6): Nov.- Dec., 2011, 260-268