Natural polymers: Best carriers for improving bioavailability of poorly water soluble drugs in solid dispersions

Year 2013, Volume: 17 Issue: 2, 65 - 72, 07.03.2014

Sandip Sapkal Mahesh Narkhede Mukesh Babhulkar Gautam Mehetre Ashish Rathi

Abstract

ABSTRACT
Natural polymers and its modified forms can be used as best alternative for improving bioavailability
of poorly water soluble drugs in solid dispersion. Most of the natural polymers
are hydrophilic and having high swelling capacity. Recent trend towards the use of natural
polymer demands the replacement of synthetic additives with natural ones. Many plant derived
natural polymers are studied for use in solid dispersion systems, out of which natural
gums, cyclodextrin and carbohydrate are most extensively studied and used. This review
discusses about the majority of these natural polymers, its uses and some recent investigations
about modification of natural polymer in solid dispersion systems.
KEYWORDS: Modified natural gum, carbohydrate, dissolution enhancement, solid dispersion

Keywords

Modified natural gum , carbohydrate , dissolution enhancement , solid dispersion.

References

• Natural gums and its modified forms Locust bean gum, Karaya gum, Guar gum, Xanthan gum, Hupu gum, Aegle marmalos gum etc. (6-12) Cyclodextrins ,  &  Cyclodextrin, Hydroxypropyl -Cyclodextrin, meta hydrated-Cyclodextrin. (18-27) Carbohydrates Lactose, corn starch, Sorbitol, Mannitol, Chitosan, Maltose etc. (28-34) Miscellaneous Gelatin, Egg albumin, Skimmed milk, Silica gel, Urea etc. (35-39) NATURAL GUMS AND ITS MODIFIED FORMS Natural gums, polysaccharides & their derivatives represents group of polymers widely used in pharmaceutical dosage forms. Polysaccharides are the choice of materials among the hydrophilic polymers used, because they are non-toxic & acceptable by the regulatory authority. Natural gums like Guar gum, Xanthan gum, Locust bean gum etc when used in optimum concentration lead to increase in dissolution rate due to low viscosity and high swelling capacity which offers better alternative for these types of polymers (5). The dissolution rate of drugs from the formulations containing viscous carriers is generally low due to the formation of gel layer on the hydrated surfaces, which prevents the drug release during dissolution. This can be overcome during tablet formulation by adding disintegrants. Pulverization of the product is also another important draw back with the high viscosity carriers, which can be overcome by using decreasing order of polymer/drug ratio during formulation. However, it is reported that the swelling ability of the carrier improves dissolution rate of poorly water soluble drug. As the viscosity of the carrier reduces the dissolution rate, it is useful to modify the gum in such a way that its swelling ability remains same and viscosity reduced. This can be achieved by heating (6). Solid dispersions (SDs) of Lovastatin (LS) were prepared by modified locust bean gum (MLBG) as a carrier. The locust bean gum (LBG) was modified by heating and there observed irreversible decrease in viscosity, whereas swelling property remains unaffected. The advantage of modification of LBG was illustrated by difference in dissolution profiles of their SD. The result of solubility study showed increase in solubility of LS with increase in concentration of MLBG. It was found that the dissolution rate of LS from its SD was dependent on the method of preparation of solid dispersions. Dissolution study revealed that the modified solvent evaporation is most convenient and effective method for solubility enhancement of poorly water soluble drug LS, among various methods of preparation of SD. Increased wettability, dispersibility, and solubilization effect of LBG and MLBG enhances the solubility of LS . In vivo study indicates better performance of SD than LS as there observed significant reduction in activity of HMG Co A reductase enzyme. Overall studies showed that MLBG could be used as a potential carrier in the dissolution rate enhancement of Lovastatin (6). Solid dispersions of Nimodipine (NM) were prepared by Modified gum karaya (MGK); on the basis of same mechanisms i.e. Modifying the gum in such a way that it’s swelling ability is remained same and viscosity is reduced. It is found that method of preparation of solid mixtures was significantly affected the dissolution rate of NM from solid mixtures. 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. No drug carrier interaction in the solid mixtures has been evidenced, increased wettability, dispersibility and reduced crystallinity of NM can account for the increased dissolution rate in systems containing GK or MGK. In conclusion, above studies showed that, MGK could be used as a potential carrier in the dissolution rate enhancement of NM (7). Solid dispersions of Licofelone were prepared by using Guar gum (GG) and Modified guar gum (MGG). Modified guar gum (MGG) was prepared using heat treatment (125-130 o C for 2 to 3 hours) method. The physical and co-grinding mixtures of licofelone with GG and MGG were prepared in 1:6 drugs to gum ratio. The results of present investigation indicated that co-grinding mixture of licofelone with modified guar gum could be useful in developing an oral dosage form with increased solubility and hence improved dissolution and oral bioavailability of poorly water soluble drug. Due to the swelling nature of the carrier, the extensive surface of carrier is increased during dissolution, and the dissolution rate of deposited drug is markedly enhanced. Water retention capacity of carrier is the amount of water retained in it that indicates ability of carrier towards hydrophilic nature (8). The solubility of Cefixime is increased by preparing its solid dispersions using natural polymer, Guar gum. Various techniques used for preparing solid dispersions are by physical mixture, kneading and solvent evaporation methods using different drug-polymer ratio. The result obtained from above studies indicated that, the solubility and dissolution of Cefixime solid dispersions was improved as compared to pure drug by all the methods employed. A maximum increase in dissolution rate was obtained with Cefixime: guar gum solid dispersion with a weight ratio of 1:3 prepared by solvent evaporation method. The observed increase in the solubility of Cefixime in solid dispersions is thought to be attributable to the solubilization effect of the guar gum. Thus it can be concluded that the solubility of the poorly soluble drug, Cefixime can be improved markedly by using solid dispersion technique and the carrier, guar gum has increased the dissolution of the drug without any interaction (9). The enhancement of dissolution profile of Gliclazide (GLZ) was carried out using Xanthan gum, Guar gum and Hupu gum as carriers by solid dispersion technique. Among the solid dispersions prepared formulation prepared by co-grinding method using Guar gum as carrier in 1:3 ratio shown the better release of Gliclazide (96.79 %) with in 60 min. The FTIR spectrum of pure drug, xanthan gum, guar gum, hupu gum and solid dispersion prepared by co-grinding method were obtained which shows no chemical interaction between drug and polymers. The enhanced dissolution may be due to enhanced wettability and dispersibility of drug in dissolution medium (10). Solid dispersions of Glimepiride were prepared by Modified gum karaya (MGK), by solvent evaporation method. Maximum solubility and invitro dissolution were observed with solid dispersion of Modified gum karaya (MGK). No significant enhancement of dissolution characteristics were observed in corresponding physical mixture. Low viscosity with comparable swelling characteristics as compared to Gum karaya (GK) of modified form of gum karaya may lead to improvement in dissolution behavior of solid dispersion batches. The dissolution enhancement occurs due to conversion of crystalline form to amorphous form (11). Solid dispersions of Aceclofenac were prepared by using Aegle marmalos gum (AMG) and Modified Aegle marmalos gum (MAMG). Modified Aegle marmalos gum (MAMG) was prepared using heat treatment technique. Effect of polymer concentration and methods of preparation on solubility enhancement were studied using solubility and dissolution studies, respectively. The result of solubility study showed increase in solubility of Aceclofenac with increase in concentration of AMG and MAMG, and change of technique from physical mixture to co-grinding to solid dispersion. Increased wettability, surface area and solubilization effect of AMG and MAMG enhances solubility in water. From study it can be concluded that, MAMG could be used as a potential carrier in the dissolution rate enhancement of Aceclofenac (12). CYCLODEXTRINS Cyclodextrins although belongs to the category of carbohydrate but its wide applications and role in dissolution enhancement make it deserving candidate to be described separately (13). Cyclodextrins (CD) are cyclic oligomers typically composed of 6–8 glucose units. CDs represent a class of solubilizing agents that form non-covalent, dynamic complexes with lipophilic molecules by inclusion. The inclusion complex modifies temporarily the physical properties of the substance, governed by the equilibrium constant between the free drug, free CDs and the drug-CD complex; the drug will be released constantly and rapidly on dilution. CDs have been demonstrated to improve the stability of substances like proteins or peptides. The CDs that are approved for pharmaceutical products can be classified into three major types differing only in their molecular weight and respective central cavity diameter. Alphacyclodextrin (α-CD) has a molecular weight of 972 and a central cavity diameter of around 5A˚, these increases to MW 1135 and 2A˚ for β-CD and MW 1297 and 8A˚ for γ-CD, respectively (14).
• β -Cyclodextrins act as dissolution enhancers because it consist truncated cone type structure. The outer surface is hydrophilic due to the presence of hydroxyl groups and the interior of the cone is hydrophobic due to presence of glycosidic ether oxygen at O-4 and the hydrogen attached to C-3 and C-5 and thereby provides a lipophillic microenvironment into which drug can enter and can be partially or fully included without covalent bonding, while outer hydrophilic environment contributes to drug dissolution. The water molecules located inside the cavity cannot satisfy their hydrogen bonding potentials; therefore they are of higher enthalpy. The energy is lowHabib MJ. Pharmaceutical Solid Dispersion Technology. Technomic Publishing, Lancaster, Pennysylvania, 2001.
• Patel DB, Patel MM. Natural Excipient in controlled Drug Delivery Systems. J Pharmacy Res 2009; 2:900-7.
• Shirwaikar A, Shirwaikar A, Prabu SL, Kumar GA. Herbal excipients in novel drug delivery systems. Indian J Pharm Sci 2008;70:415-22.
• Tiwari R, Tiwari G, Srivastava B, Rai AK. Solid Dispersions: An Overview to Modify Bioavailability of Poorly Water Soluble Drugs. Int J PharmTech Res 2009; 1:1338-49.
• Chowdary K, Mohapatra P, Krishna MM. Evaluation of olibanum and its resin as rate controlling matrix for controlled release of diclofenac. Ind J Pharm Sci 2006; 68:497-500.
• Patel M, Tekade A, Gattani S, Surana S. Solubility enhancement of lovastatin by modified locust bean gum using solid dispersion techniques. AAPS PharmSciTech 2008;9:1262-9.
• Murali Mohan Babu GV, Prasad ChD, Ramana Murthy KV. Evaluation of modified gum karaya as carrier for the dissolution enhancement of poorly water-soluble drug nimodipine. Int J Pharm 2002;234:1-17.
• Shah V, Patel D, Mane S,Upadhyay U. Solubility and dissolution rate enhancement of licofelone by using modified guar gum. Int J PharmTech Res 2010; 2:1847-54.
• Aleti SR, Rangaraju D, Kant A, Shankraiah MM, Venkatesh JS, Rao RN, Nagesh C. Solubility and dissolution enhancement of cefixime using natural polymer by solid dispersion technique. Int J Res Pharm Chem 2011; 1:283-8.
• Kaza R, Kumar AG, Charan YR, Vamsidhar HK, Raghava SV, Kumar VR. A study on the dissolution enhancement of gliclazide using natural polymers. IJIPR 2012; 3:194-8.
• Nagpal M, Rajera R, Nagpal K, Rakha P, Singh S, Mishra D. Dissolution enhancement of glimeride using modified gum karaya as a carrier, Int J Pharm investigation 2012; 2:42-7.
• Kulkarni U, Raghavendra Rao NG. Design and development of aceclofenac fast dissolving tablets by amorphous solid dispersion techniques using modified Aegle marmalos gum. IJPRD 2011; 3:201-10.
• Saharan VA, Kukkar V, Kataria M, Gera M, Choudhury PK. Dissolution Enhancement of Drugs Part II: Effect of Carriers. Int J Health Res 2009; 2:207-23.
• Davis ME, Brewster ME, Cyclodextrin-based pharmaceutics: past, present and future. Nat Rev Drug Dis 2004; 3:1023–35.
• Chowdary KPR. Cyclodextrins as drug carriers. Indian Pharmacist 2003; II: 11-4.
• Parikh RK, Mansuri NS, Gohel MC, Soniwala MM. Dissolution enhancement of nimesulide using complexation and salt formation techniques. Indian Drugs 2005; 42:149-53.
• Sinco TJ. Complexation and protein binding. In: Martin A, Martin As. Martin’s physical pharmacy and pharmaceutical sciences. V. New delhi: Wolters Kluwer Health (India) Pvt ltd; 2007.
• Guyot M, Fawaz F, Bildet J, Bonini F, Lagueny AM. Physicochemical characterization and dissolution of norfloxacin/cyclodextrin inclusion compounds and PEG solid dispersions. Int J Pharm 1995; 123:53-63.
• Moyano JR, Blanco MJA, Gines JM, Giordano F. Solidstate characterization and dissolution characteristics of gliclazide-beta-cyclodextrin inclusion complexes. Int J Pharm 1997; 148:211-17.
• El-Zein H, Riad L, El-Bary AA. Enhancement of carbamazepine dissolution: in vitro and in vivo evaluation. Int J Pharm 1998; 168:209-20.
• Rogers TL, Nelsen AC, Hu J, Brown JN, Sarkari M, Young TJ, Johnston KP, Williams RO 3rd. A novel particle engineering technology to enhance dissolution of poorly water soluble drugs: spray-freezing into liquid. Eur J Pharm Biopharm 2002; 54:271-80.
• Aithal KS, Nalini K, Udupa N, Sreenivasan KK. Enhanced fluorescence emission of norfloxacin on complexation with cyclodextrin. Indian Drugs 2005; 42:162-6.
• Kavitha K, Srinivasa RA, Nalini CN. An Investigation on Enhancement of Solubility of 5 Fluorouracil by Applying Complexation Technique- Characterization, Dissolution and Molecular-Modeling Studies. J Appl Pharm Sci 2013; 3:162-6.
• Derle D, Boddu SHS, Magar M. Studies on the preparation, characterization and solubility of betacyclodextrin satranidazole inclusion complexes. Indian J Pharm Educ Res 2006; 40:232-6.
• Suresh S, Shivakumar HN, Kumar GK. Effect of beta cyclodextrin complexation on the solubility and dissolution rate of carbamazepine from tablets. Indian J Pharm Sci 2006; 301-7.