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ISSN 0975 – 8542 Journal of Global Pharma Technology Available Online at www.jgpt.co.in RESEARCH PAPER

ISSN 0975 – 8542

Journal of Global Pharma Technology

Available Online at www.jgpt.co.in

RESEARCH PAPER

FORMULATION AND EVALUATION OF ORALLY DISINTEGRATING TABLETS OF BACLOFEN

Basani G b , Reddy S a , Somagoni J. M. a and Y.M, Rao a *

a University College of Pharmaceutical Sciences,Kakatiya University, Warangal- 506009 (A.P.) India. b Vaagdevi College of Pharmacy, Hanamakonda, Warangal 506001(A.P.) India

*For Correspondence: Email: yamsani123@gmail.com

Abstract: Baclofen is a muscle relaxant and anti spastic. The present investigation deals with the formulation of oral disintegrating tablets of baclofen that disintegrate in the oral cavity upon contact with saliva and there by improve therapeutic efficacy. The ODTs were prepared by direct compression technique. The optimized formulation was also prepared by effervescent method. The influence of superdisintegrants, crosspovidone, croscaremellose sodium and sodium starch glycolate at three levels on disintegration time, wetting time and water absorption ration were studied. Tablets were evaluated for weight and thickness variation, disintegration time, drug content, in vitro dissolution, wetting time and water absorption ratio. The in vitro disintegration time of the best ODTs was found to be 14 sec and 28sec by direct compression and by effervescent method, respectively. Tablets containing crospovidone exhibit quick disintegration time than tablets containing croscaremellose sodium, sodium starch glycolate and effervescent mixture. Good correlation was observed between water absorption ratio and DT. The directly compressible rapidly disintegrating tablets of baclofen with shorter disintegration time, acceptable taste and sufficient hardness could be prepared using crospovidone and other excipients at optimum concentration.

Keywords: Baclofen, superdisintegrants, orally disintegrating tablets, mouth dissolving tablets, rapidly disintegrating tablets, wetting time.

INTRODUCTION

Most pharmaceutical forms for oral administration are formulated for direct ingestion, for chewing, for prior dispersion and /or dissolution in water; some of them are absorbed in mouth (sublingual or buccal tablets). Elderly individuals have difficulty in swallowing when prescribed in conventional tablet and capsule form. [1-3]. The problem of swallowing is also evident in pediatrics, psychiatric as well as travelling patients who may not have ready access to water [4].The rapidly disintegrating tablet in mouth or oro dispersible tablets overcome all the above problems and thus offer an alternate form of oral medication, which provide patient s with a more convenient means of taking

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their medication [5]. Addition of super disintegrating agent in the formulation is one of the approaches to formulate oro dispersible tablets [6-12]. Baclofen is a muscle relaxant and anti spastic. It was selected as drug candidate in this study as it is not available as ODTs in India, which is clinical need .ODTs, is also called as mouth dissolving tablets, orodispersible tablets, quick disintegrating tablets, rapid dissolving tablets, porous tablets, and rapimelts [13]. The objective of the present study was to develop orally disintegrating tablets of baclofen by direct compression and effervescent techniques. I.e. using conventional process and compression equipment so that the technology implementation is easier and cost effective. It was also aimed to evaluate

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these baclofen formulations by in vitro methods and to select the best formulation.

MATERIALS AND METHOD

Baclofen was gift sample from Natco pharma ltd. Hyderabad. Pearlitol SD 200, Tuty-futy flavor were gift samples from FDC laboratories, Pune. Avicel PH102, Crospovidone, Croscaremellose sodium, Sodium starch glycolate, was gift samples from Cadila, Ahmadabad. Aspartame, Aerosil and sodium steryl fumarate were gift samples from Natco pharma ltd. Hyderabad. All the chemicals and reagents used were of analytical or pharmacopoeial grade.

Development

evaluation techniques

of

baclofen

Direct compression

ODTs-

The drug, Pearlitol SD200, Avicel PH102, Flavor and superdisintegrants were passed through 40# mesh. The sifted ingredients were blended for 10 to 15 mins in mortor and pestle. The blend was lubricated with sifted (80#) Sodium stearyl fumarate for 2 mins. The blend was compressed into tablets using 16 station rotary tabletting machines. The composition was given in Table 1 and Table 2.

Table1: Tablet formulations for baclofen ODTs by using Superdisintegrants

Ingredients

Superdisintegrants concentration (%) of C.P/S.S.G/C.C.S

6%

8%

10%

Baclofen

20.00

20.00

20.00

Pearlitol SD200

158.75

153.75

148.75

Avicel PH102

37.5

37.5

37.5

Super

15

20

25

disintegrants

 

Aspertame

12.5

12.5

12.5

Tuty-Futy

3.75

3.75

3.75

Flavour

Aerosil

1.0

1.0

1.0

Sodium

steryl

1.5

1.5

1.5

fumarate

All the amounts given in above tables are in milligrams. Super disintegrants like C.P- crospovidone, S.S.G- sodium starch glycolate, C.C.S- Croscaremellose sodium.

© 2009, JGPT. All Rights Reserved.

Table2: Tablet formulations for baclofen ODTs by using Effervescent mixture

Ingredients

Effervescent mixture(%) of citric acid and Sodium bicarbonate

8 & 10%

10 & 12%

Baclofen

20.00

20.00

Pearlitol SD200

128.75

118.75

Avicel PH102

37.5

37.5

Citric acid

20

25

Sodium

25

30

bicarbonate

Aspertame

12.5

12.5

Tuty-Futy Flavour

3.75

3.75

Aerosil

1.0

1.0

Sodium

steryl

1.5

1.5

fumarate

Effervescent technique

The drug, Pearlitol SD200, Avicel PH102, Flavor and Sodium bicarbonate and citric acid were passed through 40# mesh. The sifted ingredients were blended for 10 to 15 mins in motor and pestle. The blend was lubricated with sifted (80#) for Sodium steryl fumarate 2 mins. The blend was compressed into tablets using 16 station rotary tabletting machine.

ODT evaluation

Weight variation

Twenty tablets from a batch size of 500 were randomly selected from each formulation and weighed using a Shimadzu digital balance. The mean standard deviation (SD) and relative standard deviation (RSD) were recorded.

Thickness variation

Ten tablets from each formulation were taken randomly and their thickness was measured with a digital screw gauge micrometer (Digimatic micrometer,

Mitutoyo, Japan). The mean SD and RSD values were calculated.

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Rao Y. M. et al., Journal of Global Pharma Technology. 2010; 2(3): 137-145

Hardness and friability

Hardness or crushing strength of the tested RDT formulations was measured using the Monsanto hardness tester (Pharmalab, Ahmedabad, India). The friability of a sample of 20 RDTs was measured utilizing

a USP-type Roche friabilator (Pharmalab,

Ahmedabad, India). Pre-weighed tablets

were placed in a plastic chambered

friabilator attached to a motor revolving at

a speed of 25 rpm for 4 min. The tablets

were then de-dusted, reweighed, and percentage weight loss (friability) was

calculated.

Assay

The ODT formulations were assayed for drug content. Ten tablets were randomly selected from each formulation and pulverized to a fine powder. Weighed aliquots containing an amount of powder equivalent to a single dose were taken in triplicate and assayed for the drug content utilizing a UV-VIS spectrophotometer (Model SL-150, Elico Pvt. Ltd., Hyderabad, India) at a wavelength of 223 nm.

Taste evaluation

The taste characteristic of Baclofen ODT formulations with and without Tuty Futy (flavor) and aspartame (sweetener) at varying concentrations ( 1.0, 1.5, 2.0 and 5.0%) was compared in healthy human volunteers as per the protocol (Ethics permit # 16EC/pharm/ku/2005). Optimum concentrations of flavor and sweetener were determined in preliminary studies based on the taste perception. The evaluation was based on the extent to which subjects liked the taste of each ODT. Formulations were rated on a scale of 1 through 5. A ‘5’ was considered to be “extremely desirable” while a ‘1’ was considered as “extremely undesirable” or “no taste.” The volunteers’ spontaneous verbal judgments, immediately after the

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tablet was placed in their mouth and also after 2–3 min, were recorded.

Wetting time

Five circular tissue papers were placed in a petri dish of 10 cm diameter as depicted (Figure 1). Ten milliliters of water containing 0.5% nigrosine, a water-soluble dye, was added to the petri dish. The dye solution was used to identify complete wetting of the tablet surface. A tablet was carefully placed on the surface of the tissue paper in the petri dish at 25°C. The time required for water to reach the upper surface of the tablets and to completely wet them was noted as the wetting time. These measurements were carried out in replicates of six. Wetting time was recorded using a stopwatch.

of six. Wetting time was recorded using a stopwatch. Fig 1: A simple method for measurement

Fig 1: A simple method for measurement of both wetting time and water absorption ratio.

In Vitro disintegration time

10 ml of water at 25°C was placed in a petri dish of 10 cm diameter. The tablet was then carefully positioned in the center of the petri dish and the time required for the tablet to completely disintegrate into fine particles was noted. Measurements were carried out in replicates (n=6) and mean ± SD values were recorded.

In Vitro release studies

Release studies of Baclofen from different formulations were performed according to USP XVIII apparatus II, paddle method utilizing a dissolution system (Disso 2000,

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Rao Y. M. et al., Journal of Global Pharma Technology. 2010; 2(3): 137-145

Lab

India, Thane, India) equipped with an

auto

sampler and fraction collector. Paddle

speed was maintained at 50 rpm and 1000

ml of 0.1N HCl was used as the

dissolution medium. Samples (5 ml) were collected at predetermined time intervals (5, 10, 15, 30, and 45 min) and replaced with equal volume of fresh medium, filtered through a 0.22 m filter and analyzed with a UV— Visible spectrophotometer ( 223 nm). Drug concentration was calculated from a standard calibration plot and expressed as cumulative % drug dissolved. The release studies were performed in replicates of six.

Water absorption ratio (R)

The weight of the tablet prior to placement

in the petri dish was noted (wb) utilizing a Shimadzu digital balance. The wetted tablet was removed and reweighed (wa). Water absorption ratio, R, was then determined according to the following equation. (Figure.1)

R =100 × (w a -w b ) / w b where wb and wa

were tablet weights before and after water

absorption, respectively.

In Vivo disintegration time

Oral DT of the optimized RDT formulation (determined based on its in vitro DT and drug release) was assessed in six healthy male human volunteers according to the procedure described by Abdelbary et al. [14]. The subjects were informed of the purpose and protocol of the study. The institutional ethics committee approved the in vivo study protocol and each subject gave his written consent to participate. As per the protocol (Ethics permit # 17EC/pharm/ku/2005), all volunteers were asked to rinse their mouth with distilled water prior to the test. Tablets were placed on the tongue and a stopwatch was started immediately. Volunteers were allowed to move the tablet against the upper palate of the mouth with their tongue and cause a gentle tumbling action on the tablet without

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chewing it. Time taken for the volunteer to feel that the last noticeable granule had disintegrated in the oral cavity was considered as the in vivo DT. Swallowing of saliva was prohibited during the test, and the mouth was rinsed after each measurement. This experiment was conducted in all six subjects and the mean ±SD were calculated for each.

RESULTS AND DISCUSSIONS

Formulation rationale

An objective of a directly compressible rapidly disintegrating tablet is that it disintegrates or disperses in saliva with in seconds. To achieve such a formulation most of the excipients selected are inherently required to be water soluble. Pearlitol SD 200 utilized in the formulation is a directly compressible grade of mannitol with good flow properties and provides a refreshing or cooling mouth feel due to its negative heat of solution (Rowe et. al., 2003). Pearlitol SD200 was thus used as a bulking agent to achieve the desired tablet weight. Avicel PH102 was included in the formulation as diluent. This grade of microcrystalline cellulose is granular in nature and thus displays excellent flow properties. To impart pleasant taste and improve mouth feel, aspartame and Tuty-Futy flavor were included as sweetening and flavouring agents, Sodium steryl fumarate was employed as a lubricant. Sodium stearyl fumarate was employed as a lubricant instead of magnesium stearate not only because of the metallic taste of the latter, but also due to its water solubility and directly compressible features. Colloidal silicon dioxide (Aerosil), which acts both as a glident and lubricant, also helps in appreciably decreasing tablet friability. This may be due to Aerosil helping in restoring the bonding properties of the excipients. The above considerations must be made for many solid dosage forms. However, superdisintegrants form the core of ODT formulations. Cross povidone

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Rao Y. M. et al., Journal of Global Pharma Technology. 2010; 2(3): 137-145

(CP), cross carmellose sodium (CCS), and sodium starch glycolate (SSG) are three of the most commonly used and highly effective super disintegrants currently included in solid dosage formulations. In this study, effectiveness of CP, CCS, and SSG in the Baclofen ODT formulations was evaluated at three different concentrations. Other formulation components were kept constant. CP polymers are densely cross-linked homopolymers of Nvinyl 2-pyrrolidones. Their porous particle morphology enables them to rapidly absorb liquids into the tablet by capillary action and to generate rapid volume expansion and hydrostatic pressures that result in tablet disintegration (ISP, 2006b). As Yen et al. reported, in addition to its unique particle size and morphology, disintegrant properties of CP are not affected by pH and consequently being non-ionic does not bind to ionic drug moieties (15). In addition, CP can also be used as a solubility enhancer to improve dissolution and, unlike other super disintegrants, does not form a gel at higher concentrations. CCS is cross-linked carboxymethyl cellulose sodium, and is generally used at concentrations of up to 5% w/w as a disintegrant in both wet granulation and direct compression processes. Its unique fibrous nature imparts excellent water wicking properties and cross-linking makes it a hydrophilic and highly absorbent material resulting in excellent swelling properties. CCS swells rapidly up to 4–8 times its original volume on contact with water. Similar to CP, it is also used as a dissolution aid.

SSG, a sodium salt of carboxymethyl ether of starch, is usually employed at

concentrations between 2–8% w/w and a concentration of 4% may be optimum in most cases. Disintegration occurs as a result of rapid uptake of water followed by rapid and enormous swelling, which is its primary mechanism of action. SSG may swell up to 300 times its original volume

in water.

Effervescent disintegration agents evolve gas by means of chemical reaction called effervescent couple. The tablet rapidly disintegrates and carbon dioxide is produced by contact with saliva or aqueous fluid. So the bitter taste of the drugs can be masked by this method. Carbonates such as sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, magnesium carbonate, acids such as citric, tartaric, amalic, fumeric, adipic and succinies are used.

Quality control tests

A number of formulations containing these

three superdisintegrants at different concentrations and effervescent mixture were investigated. In all of the formulations, tablet weight and thickness were measured respectively. Friability values were less than 1% in all cases (Figure. 2) Tablet hardness was maintained at 2.5± 0.5 kg for all of the ODT formulations. Baclofen formulations demonstrated uniform assay and content uniformity, with a mean drug content of 99.0% and relative standard deviation of

3.0%. The results were represented in table

4.

Table 3: Water absorption ratios ‘R’ of different fenoverine rapidly disintegrating tablet formulations

Ingredents

Crosspovdone conc in %

Crosscaremellose sodium conc in %

Sodium glycolate starch conc in %

Citric acid-sodium bi carbonate % conc

 

6

8

10

6

8

10

6

8

10

8&10

10&12

Water

absorption

90

100

120

140

150

160

160

190

200

85

95

ratio®

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Rao Y. M. et al., Journal of Global Pharma Technology. 2010; 2(3): 137-145

Table 4: Mean weights, thickness, wetting time, disintegration time, friability and assay of baclofen ODTs prepared by Direct compression

Formulation

Weight (mg)

Thickness

Wetting

D.T(sec)

% Friability

% Drug

code

(m.m)

time(sec)

content

C.P-6

249±1.92

3.2±0.01

57

20

0.90

94.6

C.P-8

248±1.13

3.19±0.02

50

18

0.82

97.8

C.P-10

250±1.01

3.2±0.01

40

14

0.58

99.6

S.S.G-6

248±1.18

3.18±0.02

98

25

0.43

99.7

S.S.G-8

251±1.12

3.23±0.01

76

22

0.23

98.9

S.S.G-10

249±1.13

3.2±0.05

64

19

0.03

99.3

C.C.S-6

249±1.19

3.19±0.01

65

22

0.04

98.8

C.C.S-8

250±1.12

3.2±0.03

59

19

0.06

99.1

C.C.S-10

251±1.13

3.19±0.02

56

17

0.03

99.9

C.S-8&10%

249±1.12

3.18±0.03

69

35

0.04

99.2

C.S-10&12%

251±1.15

3.2±0.01

60

30

0.05

99.0

C.P- crospovidone, S.S.G- sodium starch glycolate, C.C.S- Croscaremellose sodium. C.S- Citric acid and Sodium Bi Carbonate

Taste evaluation

Preliminary studies were performed to optimize the concentrations of all the excipients used in the formulation other than the superdisintegrants. A single blind study was conducted in healthy male human volunteers (Ethics permit # 16EC/pharm/ ku/2009) to optimize the taste of the ODT formulations. Formulations containing different concentrations of sweetener and flavor were given to subjects who were asked to rate them on a scale of 1 through 5. In this study, formulations without aspartame and Tuty-futy received ratings of ‘1,’ as the formulations were perceived as “no taste” or “undesirable.” Formulations with 2% of sweetener and 0.5%flavor were rated as ‘4,’ which was “slightly sweet” while those with 4% and above were rated as ‘5,’ suggesting that these formulations were “extremely desirable.” Therefore, a formulation containing 5% sweetener and 1.5% flavor was determined to be optimum for a palatable Baclofen ODT formulation.

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ODT formulation. © 2009, JGPT. All Rights Reserved. Fig 2: Friability of different Baclofen ODTs values

Fig 2: Friability of different Baclofen ODTs values represented (n=6) C.P-Cros povidone; S.S.G- Sodium starch glycolate; C.C.S – Croscaremellosesodium; C.S-Citric acid and sodium bicarbonate, 6,8,10 and 8-10are the concentrations of disintegrants

Wetting time

Wetting time was determined for all of the formulations. Wetting time of formulations containing CP was less compared to formulations containing CCS or SSG at equivalent concentrations. (Figure .3)Faster wetting of tablets containing CP might be due to its rapid water absorbing nature involving both capillary and swelling mechanisms. Those results were represented in table 4. It was observed that as the wetting time decreased with increased concentration of superdisintegrants their water absorption ratio increased.

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Rao Y. M. et al., Journal of Global Pharma Technology. 2010; 2(3): 137-145

Journal of Global Pharma Technology. 2010; 2(3): 137-145 Fig 3: Wetting time of different Baclofen ODTs

Fig 3: Wetting time of different Baclofen ODTs values represented (n=6) C.P-Cros povidone; S.S.G-Sodium starch glycolate; C.C.S – Croscaremellosesodium; C.S-Citric acid and sodium bicarbonate, 6,8,10 and 8-10are the concentrations of disintegrants

Water absorption ratio

Water absorption ratio, ‘R,’ of formulations containing SSG and CCS were greater than that of CP containing formulations and SSG demonstrated greater ‘R’ values compared to CCS. These results are consistent with reports describing broad differences in swelling capacity of the superdisintegrants (SSG > CCS > CP>Sodium bicarbonate and citric acd). Water absorption ratio ‘R’ increased with an increase in superdisintegrants concentrations from 6–10% (Table 3). A linear relationship was observed for each of the superdisintegrant types. The increase in ‘R’ was most likely due to increased water uptake capacity of the superdisintegrants at higher concentrations.

In Vitro disintegration time

Disintegration time is an important criterion for selecting an optimum ODT formulation. Several methods have beendescribed for evaluating in vitro and in vivo DT of ODT formulations. In vitro DT was determined following the procedure described in a previous section. It was observed that increasing the superdisintegrant concentration from 4 to 8% resulted in a decrease in DT as depicted in (Figure 4). However, in the case of formulations containing CP and SSG, an increase in superdisintegrant concentration from 6 to 8% did not

© 2009, JGPT. All Rights Reserved.

demonstrate a change in DT. Also, DT of formulations containing CP was lower than those containing SSG at the same concentration which might be attributed due to its rapid water absorbing nature involving both capillary and swelling mechanisms. Those values were repoted in table 4.

swelling mechanisms. Those values were repoted in table 4. Fig 4: Disintegration time of different Baclofen

Fig 4: Disintegration time of different Baclofen ODTs, values represented (n=6) C.P-Cros povidone; S.S.G-Sodium starch glycolate; C.C.S – Croscaremellose sodium; C.S-Citric acid and sodium bicarbonate, 6,8,10 and 8-10are the concentrations of disintegrants.

In Vitro release studies

Dissolution methods for RDTs are similar to approaches taken for conventional tablets, unless taste masking is required, and USP XVIII apparatus II with a paddle speed of 50 rpm is commonly used for in vitro release studies of these formulations. Lower paddle speeds yield more discriminating dissolution profiles since ODT formulations disintegrate rapidly. An increase in superdisintegrant concentration resulted in increased cumulative % drug released in the first 5 min and all of the ODT formulations released 99.0% of the drug within 5 min (Figure 5). CP 10% released 99.9% drug within 5.This values were reported in Table 5. In vitro dissolution profiles Baclofen ODT containing of 10% of C.P, S.S.G, C.C.S and (10&12% of citric acid, sodium bicarbonate) were plotted in Figure.5

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Rao Y. M. et al., Journal of Global Pharma Technology. 2010; 2(3): 137-145

Table5: Cumulative %Drug Release of Baclofen ODTs prepared by direct compression

Formulation code

Cumulative% of Drug Release with in 5 min

C.P-6

90

C.P-8

97

C.P-10

99.9

S.S.G-6

87

S.S.G-8

94

S.S.G-10

99

C.C.S-6

90

C.C.S-8

98

C.C.S-10

99

C.S-8&10%

93

C.S-10&12%

98

99 C.S-8&10% 93 C.S-10&12% 98 Fig 5: In vitro dissolution profile of Baclofen ODTs

Fig 5: In vitro dissolution profile of Baclofen ODTs values represented (n=6) C.P-Cros povidone (10%); S.S.G-Sodium starch glycolate (10%); C.C.S –Croscaremellose sodium(10%); C.S-Citric acid and sodium bicarbonate(10&12%).

In Vivo disintegration time

Considering wetting time, ‘R’ value, in vitro DT, and cumulative % drug released, formulations containing CP was considered to be better than those containing CCS and SSG. Since a significant difference in DT between formulations CP 8 and CP 10 was not observed, CP 10 was considered as the optimal ODT formulation among all of the formulations tested in this study and selected for in vivo DT studies. The test was performed as discussed in an earlier section (Abdelbary et al., 2005). The disintegration time of ODTs containing 10% CP was measured in the mouths of six healthy male human volunteers as per the protocol (Ethics permit # 17EC/pharm/ku/2009). Complete disintegration was achieved at 36.5, 31.7, 35.2, 35.6, 38.1, and 40.9 sec, respectively (mean and SD, 37.16 and 3.05 sec). The

© 2009, JGPT. All Rights Reserved.

same formulation was administered thrice to each individual and the average of triplicate measurements represents an

individual oral DT. Based on these data,

this in vivo study demonstrates the

applicability of the formulated ODT for

potential commercial use. Those values

were reported in table 6.

Table 6: In vivo disitegration results

Human volunteers

In vivo disitegration time in secs

1

36.5

2

31.7

3

35.2

4

35.6

5

38.1

6

40.9

CONCLUSION

The oral disintegrating tablets of baclofen with sufficient mechanical strength, acceptable taste and smaller disintegration time were achieved employing suitable superdisintegrants and other excipients at optimum concentration. Among three superdisintegrants and effervescent mixture, Cross povidone showed better performance in disintegration time when compared to sodium starch glycolate, croscaremellose sodium, and effervescent mixture. The formulations of C.P-10 was found to be best among all other formulations, because it has exhibited faster wetting time, good taste and faster disintegration time when compared to all other formulations.

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