Evaluation of modified gum karaya as carrier for the dissolution enhancement of poorly water-soluble drug nimodipine

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Abstract

Modified gum karaya (MGK), a recently developed excipient was evaluated as carrier for dissolution enhancement of poorly soluble drug, nimodipine (NM). The advantages of MGK over the parent gum karaya (GK) were illustrated by differences in the in vitro dissolution profiles of respective solid mixtures prepared by co-grinding technique. The influence of process variable, such as polysaccharide concentration and method of preparation of solid mixture on dissolution rate was studied. Solubility studies were also performed to explain the differences in dissolution rate. Solid mixtures were characterized by differential scanning calorimetry (DSC), X-ray diffraction studies (XRD) and scanning electron microscopy (SEM). The dissolution rate of NM was increased as the MGK concentration increased and optimum ratio was found to be 1:9 w/w ratio (NM:MGK). It is found that method of preparation of solid mixtures was significantly effected the dissolution rate of NM from solid mixtures. The order of method of preparation in according to their Dissolution Efficiency is physical mixture<co-grinding mixture<swollen carrier mixture<kneading mixture (water as kneading agent)<kneading mixture (70% v/v ethanol as kneading agent)<solid dispersion. Though, the solid mixtures prepared by other methods like solid dispersion, swollen carrier mixture and kneading technique gave faster release, co-grinding mixture prepared in 1:9 w/w ratio (NM:MGK) was found to exhibit a significant improvement in dissolution rate without requiring addition of organic solvents or high temperatures for its preparation and the process is less cumbersome. Hence, co-grinding technique appears to be more easier and the most convenient method from a practical point of view.

Introduction

Improvement of oral bioavailability of poorly water-soluble drugs remains one of the most challenging aspects of drug development. Many approaches, such as salt formation, solubilization and particle size reduction have commonly been used to increase dissolution rate and thereby oral absorption and bioavailability of such drugs (Wadke et al., 1989). However, all these techniques have potential limitations (Serajuddin, 1999, Leuner and Dressman, 2000). All poorly soluble drugs are not suitable for improving their solubility by salt formation. Use of co-solvents or surfactants to improve dissolution rate pose problems, such as patient compliance and commercialization. Even though particle size reduction increases the dissolution rate, the formed fine powders showing poor wettability and flow properties (Sjokvist et al., 1989, Temeljotov et al., 1996). Solid dispersion technique has come into existence to eliminate all these problems. This technique has been extensively used to enhance the dissolution characteristics of the sparingly soluble drugs (Iwata and Veda, 1996, Moneghini et al., 1998, Velaz et al., 1998, Chowdary and Rama Rao, 1999, Kohri et al., 1999). However, the practical applicability of these systems has remained limited mainly due to difficulties in methods of preparation (Goldberg et al., 1966, Chiou and Riegelman, 1971), poor reproducibility of physicochemical properties (Mc Gunity et al., 1984), difficulties in dosage form development (Ford and Rubinstein, 1980) and less feasibility for scale up of manufacturing processes (Yakou et al., 1984). Many carriers used in solid dispersions also cause problems due to their hygroscopic nature (Leuner and Dressman, 2000). Hence, continuous search for new carriers and new techniques is going on, which are useful for large-scale manufacturing.

In the last few years, the use of semi-synthetic hydrophilic polymers as carriers to enhance the dissolution rate and bioavallability of poorly water-soluble drugs has been demonstrated by a number of investigators (Giunchedi et al., 1990, Suzuki and Sunada, 1998, Chowdary and Rama Rao, 1999, Yamada et al., 1999). But many of these polymers also limit their application as carriers for dissolution enhancement by their high viscosity (Portero et al., 1998) and toughness (Kohri et al., 1999). Hence, development of carriers with high swelling and low viscosity may offer better alternative to overcome this problem.

The usage of natural polymers as drug carriers is on increasing side because of their low cost, biocompatibility and biodegradability (Sawayanqagi et al., 1983, Imasi et al., 1991, Acaturk et al., 1992, Portero et al., 1998). Gum karaya (GK) is a natural gum exudate of Sterculia urens, a tree native to India belongs to the family ‘Sterculiaceae’ (Gershon and Pader, 1972). It is widely used in food industry, as it is an approved food additive (Amderson, 1989). The wider applications of GK due to its unique features such as high swelling and water retention capacity, high viscosity properties, inherent nature of anti-microbial activity and abundant availability (Gauthami and Bhat, 1992). It is also evidenced from the literature that the GK was used as laxative due to its high swelling ability and formation of discontinuous mucilage (Whistler, 1973). Our research group reported the preparation of modified form of GK (MGK) that has low viscosity and comparable swelling capacity with that of the GK and its applicability as disintegrant (Murali Mohan Babu et al., 2000). As MGK has low viscosity and comparable swelling capacity with that of the GK that are beneficial properties for overcoming the processing and handling problems occurred in the preparation of solid mixtures, the present investigation aimed to study the influence of MGK on dissolution rate of poorly water soluble drug.

The drug selected for the evaluation of MGK as carrier for dissolution enhancement is nimodipine. Nimodipine (NM) is a dihydropyridine calcium blocker, used in the treatment of senile dementia and in the prophylaxis of the vascular hemierania (Manhold, 1985, Freedman and Waters, 1987) The NM is practically insoluble in water (Grunenberg et al., 1995), thereby exhibits low bioavailability after oral administration. Therefore, the improvement of NM dissolution from its oral solid dosage forms is an important issue for enhancing its bioavailability and therapeutic efficiency. Various studies have been conducted in order to increase the NM dissolution rate, mainly via the use of solid dispersions with HPMC (Chowdary et al., 1995), PEG 6000 (Lu et al., 1995) and cyclodextrins (Kopecky et al., 1998).

The effect of various formulation and process variables including type of GK, MGK to NM ratio and method of preparation of solid mixtures on the dissolution rate was investigated. Apparent solubility studies, Scanning Electron Microscopy (SEM), Differential Scanning Calorimetry (DSC), and X-ray diffraction technique (XRD) were used to explain the results.

Section snippets

Materials

Nimodipine was a gift sample from Dr Reddy Laboratories Ltd (Hyderabad, India). Girijan Co-operative Corporation Ltd (Visakhapatnam, India) supplied gum karaya (Grade 1). All other materials were of analytical reagent grade.

Preparation of modified gum karaya

The crude tears of gum were pulverized, sieved through mesh no. 100 and for further studies. Preparation of MGK was done by the method reported by Murali Mohan Babu et al. (2000).

Briefly, powdered gum was taken in a porcelain bowl and subjected to heating using sand bath for

Results and discussion

Research for alternative carriers has been increasing to suit for the industrial applications and to reduce the production cost and toxic effects. Recently, many conventional carriers have been evaluated for their use in new applications. Chitosan (Portero et al., 1998), pregelitinized starch (Chowdary and Rama Rao, 1999), superdisintegrants (Bolhuis et al., 1997) are such carriers which are reported to increase the dissolution rate and efficiency of poorly water-soluble drugs.

GK has some

Conclusion

In conclusion, our studies showed that, MGK could be used as a potential carrier in the dissolution rate enhancement of NM. Though there is no much difference in the crystallinity of NM in GK and MGK solid mixtures (as evident by DSC and XRD patterns), the dissolution rate of NM from solid mixture of GK, was low when compared with solid mixture of MGK. This may be due to the high viscosity generated by GK in the microenvironment of drug–carrier particle during dissolution reducing the diffusion

Acknowledgements

One of the authors (G.V. Murali Mohan Babu) is thankful to M/s Andhra Sugars Ltd, Thanuku (India) for awarding research fellowship. The authors are grateful to M/s Girijan Co-operative Corporation, Visakhapatnam for the facilities and encouragement.

References (42)

  • M. Westerberg et al.

    Physicochemical aspects of drug release. IV. The effect of carrier particle properties on the dissolution rate from ordered mixtures

    Int. J. Pharm.

    (1986)
  • F. Acaturk et al.

    The effect of some natural polymers on the solubility and dissolution characteristics of nifidipine

    Int. J. Pharm.

    (1992)
  • D.M. Amderson

    Evidence for safety of the gum karaya as a food additive

    Food Addit. Contam.

    (1989)
  • K.P.R. Chowdary et al.

    Influence of pregalatinized starch on dissolution of nifedipine

    Int. J. Pharm. Excip.

    (1999)
  • K.P. Chowdary et al.

    Solid dispersions of Nimodipine: physicochemical and dissolution rate studies

    Indian Drugs

    (1995)
  • J.L. Ford et al.

    Formulation and aging of tablets prepared from indomethacin-poly (ethylene glycol) 6000 solid dispersions

    Pharm. Acta Helv.

    (1980)
  • D.D. Freedman et al.

    Nimodipine. Drugs

    (1987)
  • Gauthami, S., Bhat, V.R., 1992. A monograph on Gum Karaya. National Institute of Nutrition, Indian Council of Medical...
  • S.D. Gershon et al.

    Dentrifices

  • P. Giunchedi et al.

    A swellable polymer as carbamazepine dissolution rate enhancer

    Boll. Chim. Farm.

    (1990)
  • A.M. Goldstein et al.

    Gum karaya

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