Academic Sciences

International Journal of Current Pharmaceutical Research

ISSN- 0975-7066 Vol 3, Issue 4, 2011

Review Article

CORDIA DICHOTOMA GUM: A FUNCTIONAL POLYSACCHARIDE FOR PHARMACEUTICAL APPLICATIONS

ANAND S. DESHMUKH A,*, C. MALLIKARJUN SETTY B, ARAVIND M. BADIGER C, MURALIKRISHNA K.S.A
aDepartment of Pharmaceutical Research, Shree Dhanvantary Pharmacy College, Kim,Surat, Gujarat 394110, India, bDepartment of Pharmaceutics, Saraswati College of Pharmaceutical Sciences, Hyderabad, Andra Pradesh, India, cShree Dhanvantary Pharmaceutical Analysis and Research Center, Kim, Surat. Gujarat 394110, India. Email: anand4ds@rediffmail.com

Received: 03 August 2011, Revised and Accepted: 18 September 2011 The medicinally important deciduous plant Cordia dichotoma (Boraginaceae) is widely distributed in India. Its ripe fruit produces a sticky and viscous gum. Cordia dichotoma gum so far, has not gained much identity as pharmaceutical excipient, however recent investigations have shown some very promising and novel applications. This article is aimed at discussing the structural chemistry, functional properties and potential pharmaceutical applications of Cordia dichotoma gum. ABSTRACT Keywords Cordia gum, Emulsifier, Tablet binder and sustained release. The polysaccharide gums represent one of the most abundant industrial raw materials and have been the subject of extensive research over comparable synthetic materials due to their sustainability, biodegradability and safety1. INTRODUCTION average degree of polymerization, determined through end-group analysis, was found to be 1442.

Cordia dichotoma Forst. (Synonym: Cordia obliqua Wiild or Indian cherry), one of 300 species of genus cordia belongs to the family Boraginaceae, is small to moderate-sized deciduous tree available all over India and other warmer regions. The generic name honors a 16th century German botanist and pharmacist, Valerius Cordus (1515-1544). The fruit of Cordia dichotoma is a green-yellow shining globose or ovoid drupe seated in a saucer-like enlarged calyx. It turns black on ripening and the pulp gets viscid and produces a sticky, jelly-like mass called Cordia dichotoma gum. The gum is initially white in color but changes to brownish black on exposure to atmosphere2-6.Traditionally in India its immature fruits called gunda or lassora is used as vegetable and for making pickles after removing the stone and sticky white pulp whereas the matured fruit with sticky pulp is used to make a glue7-9. The other parts of the plant like leaves and bark have been investigated for various pharmacological activities such as analgesic, anti-inflammatory , antioxidant, antitumor 10,4,11,12. Structural elucidation of gum polysaccharide significantly helped in identifying its different polysaccharide fractions and functional properties. Pharmaceutically, Cordia dichotoma gum has been investigated to some conventional dosage form but new studies have shown its various promising and novel applications as pharmaceutical excipient. In light of the above, the present article is aimed at providing a comprehensive review of structural chemistry, functional properties and pharmaceutical applications of Cordia dichotoma gum. Structure

Hydrolysis (1M sulfuric acid, 18 h, 100oC, sealed tube) of fraction-I gave glucose and arabinose, and gas chromatography of the alditol acetates indicated the percentages to be glucose 67.2% and arabinose 32.3%. The identities of these sugars were confirmed by GC-MS. Thus, fraction-I is also an arabinoglucan. Fraction- I was methylated by the Hakomori method, and hydrolysis of the product gave methylated sugars which were identified by GC and GC-MS. These data indicate that arabinopyranose is present at the non-reducing terminals, and that the interior part contains glucopyranosyl residues variously linked 3), (l4), ( l6) and (l (l4,6), and arabinofuranosyl residues linked (l2). Periodate oxidation of fraction-I followed by borohydride reduction and hydrolysis of the product revealed that 64% of the arabinose and 34% of the glucose had remained intact. After a second Smithdegradation, arabinose (98%) survived together with only a trace of glucose.

In another study by the same authors, it has been shown that minor fraction-I (polysaccharide content, 97%) had [] D 22 +75o (c 0.24, 0.l M sodium hydroxide), moved as a single spot in high-voltage electrophoresis, and was eluted as a single component from columns of Sephadex G-200 or DEAE-Cellulose.

The major fraction- II (77%), was found to contain D-glucose and Larabinose in the molar ratio of 21:4. The results of complete acid hydrolysis, permethylation studies, periodate oxidation, and Smith degradation suggested it to be an arabinoglucan, and the backbone of the polysaccharide to be composed of (l 6)-linked Dglucopyranosyl and (1 2)-linked L-arabinofuranosyl residues. The

To elucidate the structure of gum, the neutral polysaccharide was isolated from the fruits of Cordia dichotoma and separated into two fractions namely, fractions-I (23%) and fraction-II (77%), by gel filtration using Sephadex G-100 in 0.1M sodium chloride-0.lM sodium hydroxide.

Both the polysaccharide fractions (-I and - II) have some structural similarities, although fraction -I is unique in possessing (l4) -linked glucopyranosyl residues. The abundance of arabinose residues in fraction-I is greater than that of fraction-II, and the degree of polymerization of the former is higher14. The gum is initially white in color but changes to brownish black on exposure to atmosphere. It is insoluble in organic solvents like methanol, ethanol and chloroform. It is sparingly soluble in water and swells in contact with cold water, giving a highly viscous solution. More viscous solution is reported in warm water15,6. Functional Properties

On chromium trioxide oxidation, fraction-I was found to contain both and glucose residues with the former preponderating. The configuration of the arabinose residues could not be established. However, the ease of hydrolysis of some of the arabinosyl linkages (as apparent from the release of arabinose during the early stages of hydrolysis) indicates that they were present in both furanose and pyranose forms, with either or configuration. An end-group analysis of fraction-I gave an average degree of polymerization of 195.

Deshmukh et al. Viscosity of expressed mucilage was determined using Brooke field viscometer and was found to be 489 cp or 4.89 poise, indicate that the mucilage is colloidal in nature following non-Newtonian bodies which do not settle down quickly16.

Investigation of physicochemical characteristics (Table 1) of Cordia dichotoma gum as per British Pharmacopoeial procedure is carried15. The fruits contain Ca (55mg), P (275mg), Zn (2mg), Fe (6mg), Mn (2mg), Cr (0.2 mg) and Cu (1.6 mg)/100g where Chromium is found to be beneficial in diabetes. Fruits also contain anti-nutritional factors such as phytic acid (355 mg), phytate phosphorus (100 mg) and oxalic acid (250 mg) per 100 g19. Pharmaceutical Applications

The solid content was found to be 1% w/v of expressed mucilage precipitated with 1% Hydrochloric acid or Ethanol17. Further the presence of mucilage was tested by treating the mucilage with ruthenium red solution and Benzidine solution18, formation of pink colour with Ruthenium red solution indicated the presence of mucilage. To know whether the Cordia gum contains the enzymes, it was treated with Benzidine and few drops of hydrogen peroxide, no blue colour formation18, indicated the absence of enzymes. The presence of tannin was tested upon treating the gum with ferric chloride solution. There was no blue precipitation for tannin with ferric chloride solution. To study the toxic effect (if any) of Cordia gum, the toxicity study was conducted on 12 male Swiss Albino rats. Daily 5ml mucilage was orally administered for 7 days and animals were observed for one month. No death or abnormal behavior was noticed. Moreover, this fruit has been traditionally used by the native people without reporting any toxic manifestations. Thus it can be claimed that the gum is safe for use17.

will be a good option as bio-degradable, cheap, economic and easily available emulsifier in the list of pharmaceutical excipient17. Sustained/controlled drug delivery system

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Natural polysaccharides and their derivatives are widely explored in the area of sustained /controlled drug delivery systems to improve patient compliance and to provide extended periods of effective blood-levels. Application of Cordia gum in this area is investigated by various researchers in recent years. An effort has been made to evaluate the efficacy of Cordia gum as a novel sustained release matrix forming material in tablet formulations using diclofenac as model drug. Matrix material

The effect of gum (1, 2, 5 and 10% w/w with respect to total tablet weight) on in vitro drug release profile was examined and compared with a commercially available sustained release diclofenac formulation. It became evident from the study that in vitro dissolution profile of gum formulation C2 (2% w/w) was similar to the marketed product (M). Further, the drug release profiles obeyed first order kinetics (Table 2). Study suggested that Cordia gum may be a suitable option as an excipient for matrix forming agent to impart enteric resistant and sustained drug delivery in tablet or similar formulations of other drugs too21. Further a patent claim describes a new use of natural gum Cordia and new modified gum Cordia as pharmaceutical excipient. This patent discloses that a new modified gum Cordia can be used for enteric resistant, sustained and controlled release agent and also as other pharmaceutical excipient22.

Literature, research articles and patents reveal the following applications of Cordia dichotoma gum in pharmaceuticals. Tablet binder

Narkhede & coworker (2010 & 2011) carried a study to compare the binding effects of isolated Cordia dichotoma mucilage with starch. Mucilage of varying concentrations (8, 10 and 12% w/w) was used to produce aceclofenac tablets by wet granulation method. An increase in gum (binder) concentration led to decrease in friability and increase in disintegration time of the tablets. The results indicate that binding property of gum obtained from Cordia dichotoma (10%w/w) fruit was comparable to starch, hence Cordia gum possess greater potentiality to become the new source of binder and should be exploited for the commercial production of gum15,20. In another study, the fenugreek starch with Cordia gum was compared with gelatin as tablet binder for parcetamol tablets. The Cordia gum exhibited a comparatively higher solubility than fenugreek starch powder and gelatin in cold water. Fenugreek starch with Cordia gum possessed better flow properties than gelatin. The result indicates that in all binder concentrations, comparatively, gelatin showed a faster release of paracetamol than the fenugreek starch and Cordia gum combination of equal concentration. Thus in future fenugreek starch and Cordia gum could compete favorably with gelatin as binder in tablet formulations7. Effort was made to investigate the efficacy of Cordia gum as pharmaceutical excipient, in particular as an emulsifier. For this study, castor oil was taken as a model drug and emulsified with Cordia gum. The comparative stability studies were done with that of the emulsion prepared by taking gum acacia as standard emulsifying agent. It was found that the emulsion prepared with 1.5 %w/v of Cordia gum was far more stable and effective compared to emulsion prepared using 10 %w/v of gum acacia. Thus Cordia gum Emulsifier

Natural gums and polysaccharides attracted researchers for many years due to their utility in formulation of solid dosage forms.

Evaluation of neomycin (0.2 % w/v) loaded transdermal films prepared by Cordia dichotoma gum (10 % w/v) with different percentage of plasticizer and fixed percentage of preservative was carried by comparing the in vivo wound healing property with the marketed formulation. It was observed that the in vivo wound healing property of transdermal films prepared by Cordia gum was similar with marketed product (Table 3). It suggests that Cordia dichotoma gum has enormous potential for use in the preparation and designing of transdermal drug delivery system4. Transdermal Films Microparticulate drug delivery In a patent claim the method is described for preparation of Cordia gum microcapsules using surface polymerization technique. The patent explains the formulation of microcapsules, prepared using 0.5% w/v chitosan (in 5%, v/v acetic acid) and Cordia gum: drug (0.03: 1%, w/w). Prepared microparticles have shown good release characteristics21.

An investigation was made to evaluate and optimize the preparation of a novel polymer-surfactant nanoparticles (using Cordia gum as the polymer) for ophthalmic delivery of fluconazole using response surface methodology. A w/o/w emulsion containing fluconazole and Cordia gum in aqueous phase, methylene chloride as the oily phase, and di-octyl sodium sulfosuccinate and polyvinyl alcohol as the primary and secondary emulsifiers, respectively, was cross-linked by ionic gelation technique to produce fluconazole-loaded nanoreservoir system. Comparison of the in vitro release profile of optimized nanosuspension formulation (Cordia gum 0.85%) with commercial formulation provides comparable corneal permeability of fluconazole across isolated goat cornea, indicating suitability of Cordia gum based nanosuspension formulation in ophthalmic delivery of fluconazole24. Nanoparticles

In another study, sustained release Metformin-loaded gum Cordia/Gellan beads were prepared employing ionic-gelation technique and optimized using response surface methodology. The optimized bead formulation had adequate % entrapment and more than 80% release in 24 h, which were close to the predicted values. Study ensured the suitability of gum Cordia as a potential excipient for sustained release applications23.

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Deshmukh et al.

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Sr. No 1 2 3 4 4 6 7 8 Formulation C1 C2 C3 C4 M

Parameters Solubility

Table 1: Result of Physico-chemical investigation of Cordia dichotoma gum

Moisture sorption study (%) Swelling Index (ml) Bulk Density (g/ml) Tapped density (g/ml) Refractive Index Optical Rotation (1%w/v) hydrolyzed solution pH of 1% w/v solution Zero order R 0.9108 0.9165 0.9289 0.8798 0.9000 1st order R 0.9875 0.9924 0.9923 0.9477 0.9920

Observations Form viscous solution in warm water, Swells in cold water, Insoluble in organic solvents like methanol,ethanol and chloroform NMT 4 NMT 5.8 0.5853 0.8762 1.6765 +1.48 6.0-7.2

Table 2: Cumulative Release and Release Rate Constants of Experimental and Commercial Tablets K (h-1) 4.72 4.49 4.16 3.33 4.55 K (h-1) -0.08 -0.07 -0.06 -0.04 -0.07 Matrix R 0.9399 0.9363 0.9324 0.9363 0.9403 K (h-1) 17.11 16.26 14.97 12.19 16.55 Hix.Crow R 0.9859 0.9820 0.9821 0.9281 0.9753 K (h-1) -0.0230 -0.0211 -0.0188 -0.0137 -0.0214 T 1/2 (h) 8 9 10 12.5 8.5 Q (t) at 24 h 90 85 80 59 84

Correlation coefficient R, K- rate constant values (rate of release), t 1/2 and Q(t) at 24 h (cumulative release at 24 h) according to different kinetic equations for matrix and commercial tablet. M: commercial tablets. All the rate data (K) were found to be significant at the level of p<0.05 assessed by one-way ANOVA followed by Tukey HSD test. Hix. Crow is HixonCrowell Table 3: Results of medicated Cordia dichotoma on excision wound parameters Groups Control Medicated C.dichotoma film Framycetin#
#

%(Sq.mm) Wound Contraction on 10.881.05 18.391.23* 4 Day

th

Marketed formulation; Values are expressed as mean S.E; n=06; *p0.01 and **p0.001 5. 6. 4. 7. 8.

24.150.45**

26.531.20 39.061.51** 8 Day

th

46.751.34**

48.151.89 65.271.25* 12 Day

th

68.651.36**

10.862.34 89.801.25** 16 Day

th

92.822.15**

79.531.00 97.482.13** 18 Day

th

98.850.28**

Period of epithelization (days) 21.000.35 17.500.24** 17.250.26**

Mean size of scar area (mm2) 16.550.86 11.750.28** 10.820.34**

Cordia dichotoma gum is a useful polysaccharide obtained from the fruit pulp. Traditionally it is used as pickles and glue in India. Molecular structure investigation suggests that it has two distinct fractions, I and II, with some structural similarities (arabinoglucan), although fraction -I is unique in possessing (l 4) -linked glucopyranosyl. All the physiochemical properties (like viscosity, charge and surface activity) are a result of these fractions. Our literature survey revealed that, its role in conventional dosage formulations is inadequately investigated (as tablet binder and emulsifier). But, recent studies have identified and established its potential applications in novel drug delivery systems (sustained delivery matrix material, transdermal and particulate delivery system). In conclusion, Cordia dichotoma gum opens a new avenue for future research as functional polysaccharide for pharmaceutical applications. CONCLUSION No conflict of interest. 1. REFERENCES 2. Rana V, Rai P, Tiwary AK, Singh RS, Kennedy JF, Knill CJ. Modified gums: Approaches and applications in drug delivery. Carbohydrate Polymers 2011;83:10311047. Basu NG, Ghosal PK, Thakur S. Structrual studies on a polysaccharide fraction from the fruits of Cordia dichotoma Forst. Carbohydrate Research. 1984;131 139-55. Cordia dichotoma A tree species reference and selection guide. AgroForestryTree Database; 2011 [cited 2011 25 May]; Available from: http://www.worldagroforestrycentre.org/ sea/Products/AFDbases/af/asp/SpeciesInfo.asp?SpID=1777.

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Patil DN, Kulkarni AR, Shahpurkar AA, Patil BS. Release of Drug Neomycin From Cordia dichotoma Transdermal Film. International Journal of Pharma and Bio Sciences. 2010;1(2). Quattrocchi U, editor. CRC World Dictionary of Plant Names: A-C: CRC Press; 2000. Sastri BN, editor. The wealth of India, A Dictionary of Indian Raw materials and Industrial product. New Delhi: CSIR 1950. Doharey V, Sharma N. The permutation role of fenugreek seeds starch and Gunda glue as a binder in Paracetamol tablets. Journal of Pharmaceutical Science and Research. 2010;2(2):64-8. Gunda Pickle Glutinous Fruit Pickle. 2011 [cited 2011 22 May]; Available from: http://nishamadhulika.com/pickles/gunda-picklerecipe.html. Parmar C, Kaushal MK. Cordia obliqua. In Wild fruits New Delhi, India: Kalyani Publishers; 1982. p. 19-22. Agnihotri VK, Srivastava SD, Srivastava SK, Pitre S, Rusia K. Constituents from the seeds of cordia obliqua as potential anti-inflammatory agents. Indian Journal of Pharmaceutical Sciences. 1987;49(2):66-9. Rapisarda A, Ficarra R, Tommasin S, Caldbro ML, Hungsa S. Cordia francisci, C. martinicensis, C. myxa, C. serratifolia and Culmfolia leaves as new source of routine; Analgesic and antiinflammatory activity. Plant Medica. 1992;42:643. Wassel G, El-Menshaw B, Saud A, Meharuna G, El-Merzabani M. Screening of selected plant for Pyrrolizidine alkaloids and antitumor activity. Pharmazine. 1987;42:709. Renimel I, Olivier M, Andre P, Cabalion P, inventor Parfums Christian Dior, assignee. Use of an extract of Cordia dichotoma. US patent US 6,238,674 B1. 2001.

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Deshmukh et al. 14. Basu NG, Ghosal P, Thakur S. Some structural features of an arabinoglucan from the fruits of Cordia dichotoma Forst. Carbohydrate Research. 1986;146:350-1. 15. Narkhede SB, Vidyasagar G, Jadhav AG, Narkhede SP. Isolation and Comparative Evaluation of Cordia dichotoma Forst. Mucilage as a Binding Agent with Standard Binder. Journal of Chemical and Pharmaceutical Research. 2010;2(4):887-91. 16. Martin MR, editor. The Theory and Practice of Industrial Pharmacy. 3rd ed. Bombay, India: Varghese Publishing house; 1987. 17. Dinda SC, Mukharjee B. Gum cordia A new tablet binder and emulsifier. Acta Pharmaceutica Sciencia. 2009;51:189-98. 18. Trease WB, editor. Trease and Evans Pharmacognosy. 15th ed. London: Sounders Company Ltd.; 2002. 19. Khare CP, editor. Indian Medicinal Plants, An Illustrated Dictionary. New Delhi, India: Springer-Verlag Berlin/Heidelberg; 2007. 20. Narkhede SB, Vidyasagar, G., Jadhav, A. G., & Bendale, A. R., . Isolation of Cordia mucilage and its comparative evaluation as

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a binding agent with standard binder. Der Pharmacia Sinica. 2011;2(1):201-7. Mukherjee B, Dinda SC, Barik, BB. Gum Cordia: A Novel Matrix Forming Material for Enteric resistant and Sustained Drug DeliveryA Technical Note. American Association of Pharmaceutical Scientists PharmSciTech. [Brief /Technical Note]. 2008;9(1). Mukherjee B, Dinda SC, inventor New simple microencapsulation coating techniques using gum cordia for enteric resistant, sustained and controlled drug delivery India patent 762/KOL/2007. 2008. Ahuja M, Yadav M, Kumar S. Application of response surface methodology to formulation of ionotropically gelled gum cordia/gellan beads. Carbohydrate Polymers. 2010;80:161-7. Yadav M, Ahuja M. Preparation and evaluation of nanoparticles of gum cordia, an anionic polysaccharide for ophthalmic delivery. Carbohydrate Polymers. 2010;81:871-7.

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