HM Medical Clinic



Herbal Excipients in Novel Drug Delivery Systems
Department of Pharmaceutics, 1Department of Pharmacognosy, Manipal College of Pharmaceutical Sciences,
Manipal-576 104, India Shirwaikar, et al.: Herbal excipients in NDDS
The use of natural excipients to deliver the bioactive agents has been hampered by the synthetic materials. However
advantages offered by these natural excipients are their being non-toxic, less expensive and freely available. The
performance of the excipients partly determines the quality of the medicines. The traditional concept of the
excipients as any component other than the active substance has undergone a substantial evolution from an inert
and cheap vehicle to an essential constituent of the formulation. Excipients are any component other than the active
substance(s) intentionally added to formulation of a dosage form. This article gives an overview of herbal excipients
which are used in conventional dosage forms as well as novel drug delivery systems.

Key words: Polysaccharides, volatile oils, controlled delivery
Excipients are primarily used as diluents, binders, POLYSACCHARIDES IN
disintegrants, adhesives, glidants and sweeteners in conventional dosage forms like tablets and capsules1. As the establishment of toxicity and Natural polysaccharides are extensively used for the approval from regulatory authorities poses a development of solid dosage forms. These polymers problem with synthetic excipients, of late more of monosaccharides (sugars) are inexpensive and interest is being shown by researchers in herbal available in a variety of structures with a variety of excipients. The drawback posed by heavy metal properties. They are highly stable, safe, non-toxic, contamination often associated with herbal and hydrophilic and gel forming in nature. Pectins, excipients is superseded by their lack of toxicity, starch, guar gum, amylase and karaya gum are a few easy availability, and economic considerations polysaccharides commonly used in dosage forms. in pharmaceutical industry as compared to their Non-starch, linear polysaccharides remain intact in synthetic counterparts. Present day consumers the physiological environment of the stomach and look for natural ingredients in food, drugs, and the small intestine, but are degraded by the bacterial cosmetics as they believe that anything natural inhabitants of the human colon which make them will be more safe and devoid of side effects. potentially useful in targeted delivery systems to the colon2.
The traditional view that excipients are inert and do not exert any therapeutic or biological action or modify the biological action of the drug Pectins are non-starch, linear polysaccharides extracted substance has changed and it is now recognized from the plant cell walls. They are predominantly that excipients can potentially influence the rate linear polymers of mainly (1-4)-linked D-galacturonic and/or extent of absorption of a drug. As herbal acid residues interrupted by 1,2- linked L-rhamnose excipients are non toxic and compatible, they have residues with a few hundred to about one thousand a major role to play in pharmaceutical formulation. building blocks per molecule, corresponding to an Hence, this paper is an attempt to review herbal average molecular weight of about 50 000 to about excipients used in NDDS.
1 80 0002. Being soluble in water, pectin is not able to shield its drug load effectively during its passage through the stomach and small intestine. It was found that a coat of considerable thickness was required to protect the drug core in simulated in vivo conditions2. July - August 2008 Indian Journal of Pharmaceutical Sciences Hence the focus was shifted to the development of has potential applications for the transdermal delivery less soluble derivatives of pectin which get degraded of chloroquine and perhaps in the management of by the colonic microflora. Calcium salts of pectin malaria. Calcium pectinate nanoparticles to deliver reduced their solubility by forming an egg-box insulin were prepared as a potential colonic delivery configuration. To overcome the drawback of high system by ionotropic gelation7. In relation to the food solubility of pectin, mixed Þ lms of pectin with ethyl industry, folic acid incorporated microcapsules were cellulose were investigated as a coating material for prepared using alginate and combinations of alginate colon-specific drug delivery. These films combined and pectin polymers so as to improve stability of the colon specific degradation properties of pectin folic acid. Folic acid stability was evaluated with with the protective properties of the water insoluble reference to encapsulation efficiency, gelling and polymer ethyl cellulose2.
hardening of capsules, capsular retention during drying and storage. The blended alginate and pectin Polymeric hydrogels are widely used as controlled- polymer matrix increased the folic acid encapsulation release matrix tablets. Sungthongjeen et al.3 efÞ ciency and reduced leakage from the capsules as investigated the high-methoxy pectin for its potential compared to those made with alginate alone, they value in controlled-release matrix formulations. The showed higher folic acid retention after freeze drying effects of compression force, ratio of drug to pectin, and storage8.
and type of pectin on drug release from matrix tablets were also investigated. The results of the in In relation to cosmetics, using citronellal as a model vitro release studies showed that the drug release compound, pectin gel formulations were evaluated from compressed matrix tablets prepared from pectin for controlled fragrance release by kinetic and static can be modified by changing the amount and the methods. These formulations showed a prolonged type of pectin in the matrix tablets. A very low duration of fragrance release and limitation of solubility pectin-derivative (pectinic acid, degree of fragrance adsorption to the receptor skin layers. methoxylation 4%) was found to be well suited as an The increase in pectin concentrations suppressed excipient for pelletisation by extrusion/spheronisation. the fragrance release by a diffusion mechanism, The capacity as an extrusion aid was found to be thereby proving that pectin/calcium microparticles are high; even formulations containing only 20% pectinic promising materials for controlled fragrance release9.
acid resulted in nearly spherical pellets. All pectinic acid pellets were mechanically stable, had an aspect ratio of approximately 1.15-1.20 and released 30-60% Alginates are natural polysaccharide polymers of a low solubility model drug within 15 min both isolated from the brown sea weed (Phaeophyceae). in simulated gastric ß uid (0.1M HCl) and intestinal Alginic acid can be converted into its salts, of ß uid (phosphate buffer pH 6.8)4.
which sodium alginate is the major form currently used. A linear polymer consisting of D-mannuronic Micro particulate polymeric delivery systems have acid and L-guluronic acid residues arranged in been suggested as a possible approach to improve the blocks in the polymer chain, these homogeneous low bioavailability characteristics shown by standard blocks (composed of either acid residue alone) are ophthalmic vehicles (collyria). In this context pectin separated by blocks made of random or alternating microspheres of piroxicam were prepared by the units of mannuronic and guluronic acids. Alginates spray drying technique. In vivo tests in rabbits with offer various applications in drug delivery, such as dispersions of piroxicam-loaded microspheres also in matrix type alginate gel beads, in liposomes, in indicated a significant improvement of piroxicam modulating gastrointestinal transit time, for local bioavailability in the aqueous humour (2.5-fold) when applications and to deliver the bio molecules in tissue compared with commercial piroxicam eyedrops5.
engineering applications10 (Þ g. 1).
Musabayane et al.6 investigated the suitability of Bioadhesive sodium alginate microspheres of amidated pectin as a matrix patch for transdermal metoprolol tartrate for intranasal systemic delivery chloroquine delivery in an effort to mask the bitter were prepared to avoid the first-pass effect, as an taste when orally administered. The results suggest alternative therapy to injection, and to obtain improved that the pectin-chloroquine patch matrix preparation therapeutic efÞ cacy in the treatment of hypertension Indian Journal of Pharmaceutical Sciences July - August 2008

linking structure might control a highly water-soluble drug release for 24 h13.
In a comparative study, alginate formulation appeared to be better than the polylactide-co-glycolide (PLG) formulation in improving the bioavailability of two clinically important antifungal drugs-clotrimazole and econazole. The nanoparticles were prepared by the emulsion-solvent-evaporation technique in case of PLG and by the cation-induced controlled geliÞ cation in case of alginate14.
It is the principal form of carbohydrate reserve in
green plants and especially present in seeds and
underground organs. Starch occurs in the form of
granules (starch grains), the shape and size of which
Fig. 1: Structure of alginic acid.
are characteristic of the species, as is also the ratio of and angina pectoris. The microspheres were prepared the content of the principal constituents, amylose and using emulsification-cross linking method. In vivo amylopectin. A number of starches are recognized for studies indicated signiÞ cantly improved therapeutic pharmaceutical use (Þ g. 2). These include maize (Zea efficacy of metoprolol from microspheres, with mays), rice (Oryza sativa), wheat (Triticum aestivum), sustained and controlled inhibition of isoprenaline- and potato (Solanum tuberosum)15. induced tachycardia as compared with oral and nasal administration of drug solution11.
ModiÞ ed starch was tested for general applicability of a new pregelatinized starch product in directly A new insert, basically consisting of alginates with compressible controlled-release matrix systems. It different hydroxyethylcellulose content was developed was prepared by enzymatic degradation of potato to maintain a constant drug level over a certain period starch followed by precipitation (retrogradation), in the eye, which cannot be achieved by conventional Þ ltration and washing with ethanol. The advantages eye drop application. This study showed good tolerance of the new calcium-alginate-insert applied to the ocular surface for controlled drug release12. In order to achieve 24 h release profile of water soluble drugs, sodium alginate formulation matrices containing xanthan gum or zinc acetate or both were investigated. The release of the drug from the sodium alginate formulation containing only xanthan gum was completed within 12 h in the simulated intestinal ß uid, while the drug release from the sodium alginate formulation containing only zinc acetate was completed within 2 h in the same medium. Only the sodium alginate formulation, containing both xanthan gum and zinc acetate achieved a 24 h release proÞ le, either in the simulated intestinal ß uid or in the pH change medium (pH 1.2). The helical structure and high viscosity of xanthan gum possibly prevent zinc ions from diffusing out of the ranitidine HCL sodium alginate-xanthan gum-zinc acetate matrix so that zinc ions react with sodium alginate to form zinc alginate Fig. 2: Structures of (A) amylopectin or - amylase and (B)
precipitate with a cross-linking structure. The cross- July - August 2008 Indian Journal of Pharmaceutical Sciences

of the material include ease of tablet preparation, the potential of a constant release rate (zero-order) for an extended period of time and its ability to Gums are translucent and amorphous substances incorporate high percentages of drugs with different produced by the plants. Usually pathological products, physicochemical properties. Release rates from gums are produced when the plant is growing under retrograded pregelatinized starch tablets can be unfavorable conditions or when injured. Gums are enhanced or decreased to the desired profile by plant hydrocolloids and may be anionic or non ionic different parameters like geometries of the tablet, polysaccharides. On hydrolysis gums yield sugar and compaction force and the incorporation of additional salts of uronic acid20.
Guar gum:
To deliver proteins or peptidic drugs orally, Guar gum derived from the seeds of cyamopsis microcapsules containing a protein and a proteinase tetragonolobus (Family Leguminosae) is a naturally inhibitor were prepared. Starch/bovine serum albumin occurring galactomannan polysaccharide. It is made mixed-walled microcapsules were prepared using up of a linear chain of β-D-mannopyranose joined interfacial cross-linking with terephthaloyl chloride. by β-(1-4) linkage with α-D-galactopyranosyl units The microcapsules were loaded with native or amino- attached by 1, 6- links in the ratio of 1:22 (Þ g. 3).
protected aprotinin by incorporating protease inhibitors in the aqueous phase during the cross-linking process. Guar gum is used in colon-delivery systems due to The protective effect of microcapsules with aprotinin its drug release retarding property and susceptibility for bovine serum albumin was revealed in vitro17.
to microbial degradation in the large intestine. Core tablets containing 5-aminosalisylic acid (5-ASA) were Acetylating of starch considerably decreases its prepared by wet granulation with starch paste and swelling and enzymatic degradation. Thus, starch- were compression coated with coating formulations acetate (SA) based delivery systems were tested for containing different quantities of guar gum The study controlled drug delivery. It was proved that acetylation conÞ rmed that selective delivery of 5-ASA to the colon of potato starch can substantially retard drug release can be achieved using guar gum as a carrier in the by preparing and evaluating Þ lms of native starch and form of a compression coating over the drug core21. acetylated starch. Bovine serum albumin (BSA, mol. wt. 68 000), FITC-dextran (mol. wt. 4400), timolol Further, guar gum-based matrix tablets of rofecoxib (mol. wt. 332, log P=1.91) and sotalol-HCl (mol. were prepared for their intended use in the wt. 308, log P=-0.62) were used as model drugs. chemoprevention of colorectal cancer. In vivo studies All the model drugs were released rapidly from the , prolonged absorption time potato starch Þ lm in PBS pH 7.4 with and without indicating that rofecoxib was alpha-amylase in the dissolution medium (t50% not released significantly in stomach and small varied from 0.17 to 3.37 h). When compared to the intestine, but was delivered to colon resulting in a potato starch Þ lm, all the studied drugs were released slow absorption of the drug and making it available at a substantially slower rate from the SA films in for local action in human colon22.
the corresponding media18. A comparative study was carried out to evaluate drug release from the SA microparticles (SA mps) and SA Þ lms. The average degree of acetyl substitution (DS) per glucose residue in the starch was either 1.9 (SA DS 1.9) or 2.6 (SA DS 2.6). Timolol, calcein and BSA were used as model drugs. This study demonstrated the achievement of slow release of different molecular weight model drugs from the SA mps and films as compared to fast release from the native starch preparations19.
Fig. 3: Structure of guar gum.
Indian Journal of Pharmaceutical Sciences July - August 2008 In an attempt to design oral controlled drug delivery Gum arabic was used as an osmotic, suspending and systems for highly water-soluble drugs using guar expanding agent in the preparation of a monolithic gum as a carrier in the form of three-layer matrix osmotic tablet system (MOTS) with two oriÞ ces on tablets, trimetazidine dihydrochloride was chosen as a both side surfaces. Water-insoluble naproxen was model drug because of its high water solubility. Both selected as the model drug. The optimal MOTS matrix tablets as well as three layer matrix tablets was found to be able to deliver naproxen at a rate were prepared and evaluated. The three-layer guar of approximately zero order up to 12 h in pH 6.8. gum matrix tablet provided the required release rate Cumulative release at 12 h is 81%, and is independent on par with the theoretical release rate for guar gum of environment media and stirring rate. Therefore, formulations meant for twice daily administration. these MOTS can be used in the oral drug-controlled delivery Þ eld, especially for water-insoluble drugs28.
The results indicated that guar gum, in the form of three-layer matrix tablets, is a potential carrier in Karaya gum:
the design of oral controlled drug delivery systems Karaya gum is obtained from Sterculia urens (Family for highly water-soluble drugs such as trimetazidine sterculiaceae) is a partially acetylated polymer of dihydrochloride23. The same study was carried out galactose, rhamnose, and glucuronic acid26. Swellable by using metoprolol tartrate a model drug with high hydrophilic natural gums like xanthan gum and solubility. The results indicated that guar gum, in the karaya gum were used as release-controlling agents form of three-layer matrix tablets, is a potential carrier in producing directly compressed matrices. Caffeine in the design of oral controlled drug delivery systems and diclofenac sodium, which are having different for highly water-soluble drugs such as metoprolol solubilities in aqueous medium were selected as model drugs. Gum erosion, hydration and drug release studies were carried out using a dissolution Another water soluble drug, diltiazem HCl has given apparatus (basket method) at two agitation speeds. controlled release comparable with marketed sustained In case of xanthan gum neither agitation speed nor release diltiazem HCl tablets (D-SR tablets), which drug solubility had any significant effect on water are prepared in the form of matrix tablets with guar uptake, but matrices with the lower proportion of gum gum using the wet granulation technique25.
produced a lesser degree of hydration. In contrast, karaya gum displayed a much lower hydration Gum acacia:
capacity and a higher rate of erosion, both markedly Gum acacia or gum arabic is the dried gummy affected by agitation speed. Hence it was concluded exudate obtained from the stem and branches of that drug release from xanthan and karaya gum Acacia senegal (Linne) Willdenow and other related matrices depended on agitation speed, solubility species of acacia (Family Leguminosae). The gum and proportion of drug. Both xanthan and karaya has been recognized as an acidic polysaccharide gums produced near zero order drug release with the containing D-galactose, L-arabinose, L-rhamnose, and erosion mechanism playing a dominant role, especially D-glucuronic acid. Acacia is mainly used in oral and in karaya gum matrices29. Park et al.30 showed that topical pharmaceutical formulations as a suspending mucoadhesive tablets prepared by karaya gum for and emulsifying agent, often in combination with buccal delivery, had superior adhesive properties as tragacanth. It is also used in the preparation of compared to guar gum and was able to provide pastilles and lozenges and as a tablet binder26. zero-order drug release, but concentrations greater than 50% w/w may be required to provide suitable Sustained release of ferrous sulfate was achieved for 7 sustained release.
h by preparing gum arabic pellets. Release was further sustained for more than 12 h by coating the pellets Xanthan gum:
with polyvinyl acetate and ethylene vinyl acetate, Xanthan gum is a high molecular weight extra cellular respectively. An increase in the amount of gum arabic polysaccharide produced by the fermentation of the in the pellets decreased the rate of release due to the gram-negative bacterium Xanthomonas campestris. gelling property of gum arabic. The gel layer acts as The primary structure of this naturally produced a barrier and retards the rate of diffusion of FeSO cellulose derivative contains a cellulosic backbone through the pellet27.
(β-D-glucose residues) and a trisaccharide side chain July - August 2008 Indian Journal of Pharmaceutical Sciences

of β-D-mannose-β-D-glucuronicacid-α-D-mannose surface and the surface of fracture of tablets revealed attached with alternate glucose residues of the main that particles remained as coherent individual units chain. The terminal D-mannose residue may carry after compression process. Pellets showed close a pyruvate function, the distribution of which is compressibility degrees (49.9% for pellets comprising dependent on the bacterial strain and the fermentation diclofenac sodium and 48.5% for pellets comprising conditions. The non-terminal D-mannose unit in the ibuprofen). The release of the model drug from both side chain contains an acetyl function. The anionic type of tablets revealed different behaviours. Tablets character of this polymer is due to the presence of made of pellets comprising ibuprofen released the both glucuronicacid and pyruvic acid groups in the model drug in a bimodal fashion and the release side chain26 (Þ g. 4).
behaviour was characterised as Case II transport mechanism (release exponent of 0.93). On the other In one of the trials, xanthan gum showed a higher hand, the release behaviour of diclofenac sodium ability to retard the drug release than synthetic from tablets made of pellets was anomalous (release hydroxypropylmethylcellulose. Xanthan gum exponent of 0.70). For the latter case, drug diffusion and hydroxypropylmethylcellulose were used as and erosion were competing mechanisms of drug hydrophilic matrixing agents for preparing modiÞ ed release tablets of diltiazem HCl. The amount of hydroxypropylmethylcellulose and xanthan gum By utilizing retention properties of xanthan gum and exhibited signiÞ cant effect on drug release from the releasing properties of galactomannan, desire release tablets prepared by direct compression technique. profile was achieved in delivery of theophylline. It was concluded that by using a suitable blend of Hydrophilic galactomannan is obtained from the hydroxypropylmethylcellulose and xanthan gum seeds of the Brazilian tree Mimosa scabrella (Family desired modiÞ ed drug release could be achieved31.
Leguminosae). The matrices made alone with xanthan gum (X) showed higher drug retention for Compaction and compression properties of xanthan all concentrations, compared with galactomannan (G) gum pellets were evaluated and drug release from matrices that released the drug too fast. The matrices tablets made of pellets was characterized. Two types prepared by combination of both gums were able to of pellets were prepared by extrusion-spheronisation. produce near zero-order drug release. The XG (conc Formulations included xanthan gum, at 16% (w/w) 8%) tablets provided the required release rate (about and diclofenac sodium or ibuprofen, at 10% (w/w) 90% at the end of 8 h), with zero-order release among other excipients. Physical properties of pellets and tablets were analysed. Laser proÞ lometry analysis and scanning electron microscopy of the upper Tragacanth:
This gum is obtained from the branches of Astragalus
, Family Leguminosae20. Tragacanth when
used as the carrier in the formulation of 1- and 3-layer
matrices produced satisfactory release prolongation
either alone or in combination with other polymers34.
Volatile oils are generally mixtures of hydrocarbons and oxygenated compounds derived from these hydrocarbons. Many oils are terpenoid in origin; some of them are aromatic derivatives mixed with terpenes (e.g. cinnamon and clove). A few compounds (e.g. thymol and carvacrol) although aromatic in structure, are terpenoid in origin15 (Þ g. 5).
Fig. 4: Structure of xanthan gum.
Menthol is obtained by steam distillation of the Indian Journal of Pharmaceutical Sciences July - August 2008

ß owering tops of Mentha piperita belonging to the family Labiatae. A membrane-moderated transdermal Caraway fruit consists of the dried, ripe fruits of therapeutic system (TTS) of nimodipine using 2%w/w Carum carvi (Umbelliferae). The volatile oil consists hydroxypropylmethylcellulose (HPMC) gel as a of the ketone carvone (fig. 5c) and the terpene reservoir system containing menthol as penetration limonene15 (Þ g. 5d). In another attempt, a limonene- enhancer and 60%v/v ethanol-water as solvent based transdermal therapeutic system (TTS) was system was prepared. The in vivo evaluation of prepared to study its ability to provide the desired nimodipine TTS patch was carried out to find the steady-state plasma concentration of nicorandil in ability of the fabricated menthol-based TTS patch in human volunteers. It was concluded that the limonene- providing the predetermined plasma concentration of based TTS of nicorandil provided the desired plasma the drug in human volunteers. The results showed concentration of the drug for the predetermined period that the menthol-based TTS patch of nimodipine of time with minimal fluctuations and improved provided steady plasma concentration of the drug with minimal ß uctuations with improved bioavailability in comparison with the immediate release tablet dosage In a similar manner a carvone based and nerodilol based transdermal therapeutic systems were prepared using nicorandil as a model drug. It was concluded Menthol was tested for improving the bioavailability that both TTS of nicorandil provided the desired in of poorly water-soluble ibuprofen in the rectum with vivo controlled-release profile of the drug for the poloxamer. The effects of menthol and poloxamer predetermined period of time39,40.
188 on the aqueous solubility of ibuprofen were investigated. The poloxamer gel with poloxamer 188 and menthol was found to be a more effective rectal dosage form for ibuprofen36. Terpenes such Today the stress is on patient compliance and as menthol (Þ g. 5a), cineole (Þ g. 5b) and propylene to achieve this objective there is a spurt in the glycol (PG) were tested as chemical enhancers to development of NDDS. As the herbal excipients improve the skin penetration of propranolol. Release are promising biodegradable materials, these can and skin permeation kinetics of propranolol from Þ lm be chemically compatible with the excipients in preparations were examined in in vitro studies using drug delivery systems. In addition herbal excipients a Franz-type diffusion cell. In vitro skin permeation are non-toxic, freely available, and less expensive studies showed that cineole was the most promising compared to their synthetic counterparts. They have enhancer among the enhancers examined37.
a major role to play in pharmaceutical industry. Therefore, in the years to come, there is going to be continued interest in the natural excipients to have better materials for drug delivery systems.
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Indian Journal of Pharmaceutical Sciences July - August 2008


a categorización de documentos es el proceso por el cual se asocian una o más categorías a textos escritos en un lenguaje natural basándose tan sólo en su L contenido. Aunque es posible construir de manera "manual" un categorizador, las técnicas estadísticas y, por tanto, automáticas son actualmente las preferidas puesto que no sólo ofrecen un rendimiento muy adecuado sino que resulta mucho más sencillo


Application Note PolarScreen Red™ (Invitrogen) Glucocorticoid Receptor Assay Tecan Infinite™ F500, Fluorescence Polarization The Glucocorticoid Receptor Assay description The Glucocorticoid Receptor (GR) belongs to the important Invitrogen has developed a variety of so called PolarScreenTM superfamily of ligand-activated, intracytoplasmatic