INTRODUCTION:

The term excipient was derived from Latin word, excipients, which means to receive, to gather, to take out. The quality of formulation depends on active pharmaceutical ingredient (API), production processes and the excipients used. These excipients contribute in a great way to the performance of the API and maintain the safety, efficacy of the product¹. Excipients are primarily used as diluents, binders, disintegrants, adhesives, glidants and sweeteners in conventional dosage forms like tablets and capsules². As the establishment of toxicity and approval from regulatory authorities poses a problem with synthetic excipients, of late more interest is being shown by researchers in herbal excipients.

The drawback posed by heavy metal contamination often associated with herbal excipients is superseded by their lack of toxicity, easy availability, and economic considerations in pharmaceutical industry as compared to their synthetic counterparts. Present day consumers look for natural ingredients in food, drugs, and cosmetics as they believe that anything natural will be more safe and devoid of side effects. The traditional view that excipients are inert and do not exert any therapeutic or biological action or modify the biological action of the drug substance has changed and it is now recognized that excipients can potentially influence the rate and/or extent of absorption of a drug. As herbal excipients are non-toxic and compatible, they have a major role to play in pharmaceutical formulation. Hence, this article gives an overview of natural excipients which are used in conventional dosage forms as well as novel drug delivery systems ^1-3.

PHARMACEUTICAL EXCIPIENT:

Pharmaceutical excipients can be defined as nonactive ingredients that are mixed with therapeutically active compound(s) to form medicines. The ingredient which is not an active compound is regarded as an excipient. Excipients affect the behavior and effectiveness of the drug product more and more functionality and significantly. The variability of active compounds, excipients and process are obvious components for the product variability⁴.

Classification of excipients:

Excipients are commonly classified according to their application and function in the drug products:

· Binders, Diluents

· Lubricants, Glidants, Disintegrants

· Polishing Film formers and coatings agents

· Plasticizers, Colorings

· Suspending agents Preservatives, antioxidants

· Flavorings, Sweeteners, Taste improving agents

· Printing inks, Dispersing agents Gums ⁴

Advantage of herbal excipients:

· Biodegradable:

Naturally occurring polymers produced by all living organisms. They show no adverse effects on the environment or human being.

· Biocompatible and non-toxic:

Chemically, nearly all of these plant materials are carbohydrates in nature and composed of repeating monosaccharide units. Hence they are non-toxic.

· Economic:

They are cheaper and their production cost is less than synthetic material.

· Safe and devoid of side effects:

They are from a natural source and hence, safe and without side effects.

· Easy availability:

In many countries, they are produced due to their application in many industries ⁵

Disadvantages of herbal excipients:

· Microbial contamination:

During production, they are exposed to external environment and hence, there are chances of microbial contamination.

· Variation:

Synthetic manufacturing is controlled procedure with fixed quantities of ingredients while production of natural polymers is dependent on environment and various physical factors.

The uncontrolled rate of hydration:

· Due to differences in the collection of natural materials at different times, as well as differences in region, species, and climate conditions the percentage of chemical constituents present in a given material may vary.

· Slow Process – As the production rate is depends upon the environment and many other factors, it can’t be changed. So, natural polymers have a slow rate of production.

· Heavy metal contamination – There are chances of Heavy metal contamination often associated with herbal excipients ^5,6.

GUMS AND MUCILAGE:

Gums are considered to be pathological products formed following injury to the plant or owing to unfavorable conditions, such as drought, by a breakdown of cell walls (extra cellular formation; gummosis). Mucilage’s are generally normalproducts of metabolism, formed within the cell (intracellular formation) and/or are produced without injury to the plant. Gums readily dissolve in water, whereas, mucilage form slimy masses. Mucilage’s are physiological products ^7.

Classification is based on source:

(a)Marine origin/algal (seaweed) gums: agar, carrageenans, alginic acid, and laminarin;

(b)Plant origin:(i)shrubs/tree exudates: gum arabic, gum ghatti, gum karaya, gum tragacanth, and khaya and albizia gums;

(ii)Seed gums: guar gum, locust bean gum, starch, amylose, and cellulose;

(iii)Extracts: pectin, larch gum;

(iv) Tuber and roots: potato starch;

(c)Animal origin: chitin and chitosan, chondroitin sulfate, and hyaluronic acid;

(d)Microbial origin (bacterial and fungal): xanthan, dextran, curdian, pullulan, zanflo, emulsan, Baker’s yeast glycan, schizophyllan, lentinan, krestin, and scleroglucan.

Guar Gum:

Guar gum derived from the seeds of cyamopsistetragonolobus (Family Leguminosae) is a naturally occurring galactomannan polysaccharide. It is made up of a linear chain of β-D-mannopyranose joined by β-(1–4) linkage with α-D-galactopyranosyl units attached by 1, 6- links in the ratio of 1:22.

Fig.1: Structure of guar gum.

Guar gum is used in colon-delivery systems due to its drug release retarding property and susceptibility to microbial degradation in the large intestine. Selective delivery of 5–ASA to the colon can be achieved using guar gum as a carrier in the form of a compression coating over the drug core⁸. Further, guar gum-based matrix tablets of rofecoxib were prepared for their intended use in the chemoprevention of colorectal cancer. In vivo studies showed delayed Tmax, prolonged absorption time and decreased Cmax indicating that rofecoxib was not released significantly in stomach and small intestine, but was delivered to colon resulting in a slow absorption of the drug and making it available for local action in human colon⁹. Guar gum, in the form of three-layer matrix tablets, is a potential carrier in the design of oral controlled drug delivery systems for highly water-soluble drugs such as trimetazidine dihydrochloride¹⁰.

Gum Acacia:

Gum acacia or gum arabic is the dried gummy exudate obtained from the stem and branches of Acacia senegal (Linne) Willdenow and other related species of acacia (Family Leguminosae). The gum has been recognized as an acidic polysaccharide containing D-galactose, L-arabinose, L-rhamnose, and D-glucuronic acid. Acacia is mainly used in oral and topical pharmaceutical formulations as a suspending and emulsifying agent, often in combination with tragacanth. It is also used in the preparation of pastilles and lozenges and as a tablet binder¹¹.

Sustained release of ferrous sulfate was achieved for 7 h by preparing gum arabic pellets. Release was further sustained for more than 12 h by coating the pellets with polyvinyl acetate and ethylene vinyl acetate, respectively. The gel layer acts as a barrier and retards the rate of diffusion of FeSO4 through the pellet¹². Gum arabic was used as an osmotic, suspending and expanding agent in the preparation of a monolithic osmotic tablet system (MOTS) with two orifices on both side surfaces. Water-insoluble naproxen was selected as the model drug. The optimal MOTS was found to be able to deliver naproxen at a rate of approximately zero order up to 12 h in pH 6.8. Cumulative release at 12 h is 81%, and is independent of environment media and stirring rate. Therefore, these MOTS can be used in the oral drug-controlled delivery field, especially for water-insoluble drugs¹³.

Karaya Gum:

Karaya gum is obtained from Sterculiaurens (Family sterculiaceae) is a partially acetylated polymer of galactose, rhamnose, and glucuronic acid¹¹. Swellable hydrophilic natural gums like xanthan gum and karaya gum were used as release-controlling agents in producing directly compressed matrices. Drug release from xanthan and karaya gum matrices depended on agitation speed, solubility and proportion of drug. Both xanthan and karaya gums produced near zero order drug release with the erosion mechanism playing a dominant role, especially in karaya gum matrices¹⁴. Park et al¹⁵showed that mucoadhesive tablets prepared by karaya gum for buccal delivery, had superior adhesive properties as compared to guar gum and was able to provide zero-order drug release, but concentrations greater than 50% w/w may be required to provide suitable sustained release.

Xanthan Gum:

Xanthan gum is a high molecular weight extra cellular polysaccharide produced by the fermentation of the gram-negative bacterium Xanthomonascampestris. The primary structure of this naturally produced cellulose derivative contains a cellulosic backbone (β-D-glucose residues) and a trisaccharide side chain of β-D-mannose-β-D-glucuronicacid-α-D-mannose attached with alternate glucose residues of the main chain. The terminal D-mannose residue may carry a pyruvate function, the distribution of which is dependent on the bacterial strain and the fermentation conditions. The non-terminal D-mannose unit in the side chain contains an acetyl function. The anionic character of this polymer is due to the presence of both glucuronicacid and pyruvic acid groups in the side chain¹¹ (fig. 2).

Fig. 2:Structure of xanthan gum

In one of the trials, xanthan gum showed a higher ability to retard the drug release than synthetic hydroxypropylmethylcellulose¹⁶. Compaction and compression properties of xanthan gum pellets were evaluated and drug release from tablets made of pellets was characterized. Two types of pellets were prepared by extrusion-spheronisation. Formulations included xanthan gum, at 16% (w/w) and diclofenac sodium or ibuprofen, at 10% (w/w) among other excipients. Physical properties of pellets and tablets were analyzed. Pellets showed close compressibility degrees (49.9% for pellets comprising diclofenac sodium and 48.5% for pellets comprising ibuprofen). The release of the model drug from both type of tablets revealed different behaviours. Tablets made of pellets comprising ibuprofen released the model drug in a bimodal fashion and the release behavior was characterized as Case II transport mechanism (release exponent of 0.93). On the other hand, the release behavior of diclofenac sodium from tablets made of pellets was anomalous (release exponent of 0.70). For the latter case, drug diffusion and erosion were competing mechanisms of drug release¹⁷.

Tragacanth:

This gum is obtained from the branches of Astragalus gummifer, Family Leguminosae. 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 polymers ¹⁸.

TABLE1: SOME RECENTLY INVESTIGATED NATURAL GUMS AND MUCILAGE

Common name	Botanical name	Family	Pharmaceutical applications
Agar	Gelidiumamansii	Gelidaceae	Suspending agent, emulsifying agent, gellingagent in suppositories, surgical lubricant,tablet disintegrates, medium for bacterial culture, laxative ¹⁹.
Albizia Gum	Albiziazygia	Leguminoseae	Tablet binder, coating materials in compression-coated tablets ²⁰
Abelmoschus Gum (Orka gum)	Abelmoschusesculentus	Malvaceae	Suspending agent, disintegrant in low concentrations(4%) ²¹, poor floating capacity in sustained release tablet but with HPMC shows better results. Okra polysaccharide as a microbially triggered material for colon targeted tablet formulation ²²
Tamarind Seed Polysaccharide	Tamarindusindica	Fabaceae	Microspheres preparation (size range of 230-460μm). In another study Diclofenac sodium matrix tablets containing TSP ²³
Locust Bean Gum (Carob gum)	Ceratonia siliqua	Leguminosae	Controlledrelease agent ²⁴
Fenugreek Mucilage	Trigonellafoenum-graceum	Leguminosae	better release retardant ²⁵
Hibiscus Mucilage	Hibiscus rosasinensis	Malvaceae	Sustained relese²⁶
Almond gum	Prunus amygdalus	Rosaceae	emulsifying, thickening, suspending, adhesive, glazing, and stabilizing properties. Drug release increased ²⁷
Neem Gum	Azadirachtaindica	Meliaceae	Controlledrelease agent ²⁸
Aloe Mucilage	Aloe barbadensis	Liliaceae	Controlled release agent ²⁹
Cashew Gum	Anacardiumoccidentale	Anacardiaceae	Gelling property, Controlled release agent³⁰
Moringa oleifera Gum	Moringa oleifera	Moringaceae	Gelling property, Binding agent, Controlled release agent.
Acacia	Acacia Senegal	Combretaceae	Suspending agent, emulsifying agent, binderin tablets, demulcent and emollient incosmetics Osmotic drug delivery ³¹
Bhara gum	Terminalia bellericaroxb	Combretaceae	Microencapsulation ³²
Cactus mucilage	Opuntia ficusindica	----	Gelling agent in sustained drug delivery ³³
Chitosan	----	----	Colonspecific drug delivery, microspheres, carrier for protein as nanoparticles ^34,35
Gellan gum	Pseudomonas elodea	----	Ophthalmic drug delivery, sustaining agent, beads, hydrogels, floating in-situ gelling, controlled release beads ^36,37
Hakea	Hakea gibbosa	Proteaceae	Sustained release and peptide mucoadhesive for buccal delivery ^38,39

Polysaccharides in Pharmaceuticals:

Natural polysaccharides are extensively used for the development of solid dosage forms. These polymers of monosaccharides (sugars) are inexpensive and available in a variety of structures with a variety of properties. They are highly stable, safe, non-toxic, and hydrophilic and gel forming in nature. Pectins, starch, guar gum, amylase and karaya gum are a few polysaccharides commonly used in dosage forms. Non-starch, linear polysaccharides remain intact in the physiological environment of the stomach and the small intestine, but are degraded by the bacterial inhabitants of the human colon which make them potentially useful in targeted delivery systems to the colon⁴⁰.

Pectins:

Pectins are non-starch, linear polysaccharides extracted from the plant cell walls. They are predominantly linear polymers of mainly (1–4)-linked D-galacturonic acid residues interrupted by 1,2- linked L-rhamnose residues with a few hundred to about one thousand building blocks per molecule, corresponding to an average molecular weight of about 50,000 to about 1,80 000⁴⁰. Being soluble in water, pectin is not able to shield its drug load effectively during its passage through the stomach and small intestine. Focus was shifted to the development of less soluble derivatives of pectin which get degraded by the colonic microflora. To overcome the drawback of high solubility of pectin, mixed films of pectin with ethyl cellulose were investigated as a coating material for colon-specific drug delivery. Polymeric hydrogels are widely used as controlled-release matrix tablets. Sungthongjeen et al.⁴¹investigated the high-methoxy pectin for its potential value in controlled-release matrix formulations. A very low solubility pectin-derivative (pectinic acid, degree of methoxylation (4%) was found to be well suited as an excipient for pelletisation by extrusion/spheronisation. Musabayane et al.⁴² investigated the suitability of amidated pectin as a matrix patch for transdermal chloroquine delivery in an effort to mask the bitter taste when orally administered. In relation to the food industry, folic acid incorporated microcapsules were prepared using alginate and combinations of alginate and pectin polymers so as to improve stability of folic acid⁴³. In relation to cosmetics, using citronellal as a model compound, pectin gel formulations were evaluated for controlled fragrance release by kinetic and static methods.pectin/calcium microparticles are promising materials for controlled fragrance release⁴⁴.

Alginates:

Alginates are natural polysaccharide polymers isolated from the brown sea weed (Phaeophyceae). Alginic acid can be converted into its salts, of which sodium alginate is the major form currently used. A linear polymer consisting of D-mannuronic acid and L-guluronic acid residues arranged in blocks in the polymer chain, these homogeneous blocks (composed of either acid residue alone) are separated by blocks made of random or alternating units of mannuronic and guluronic acids. Alginates offer various applications in drug delivery, such as in matrix type alginate gel beads, in liposomes, in modulating gastrointestinal transit time, for local applications and to deliver the bio molecules in tissue engineering applications⁴⁵ (fig. 3).

Bioadhesive sodium alginate microspheres of metoprolol tartrate for intranasal systemic delivery were prepared to avoid the first-pass effect, as an alternative therapy to injection, and to obtain improved therapeutic efficacy in the treatment of hypertension and angina pectoris. A new insert, basically consisting of alginates with different hydroxyethylcellulose content was developed to maintain a constant drug level over a certain period in the eye, which cannot be achieved by conventional eye drop application⁴⁶. 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 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 precipitate with a cross-linking structure. The cross-linking structure might control a highly water-soluble drug release for 24 h⁴⁷. 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 gelification in case of alginate⁴⁸.

Starches:

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 are characteristic of the species, as is also the ratio of the content of the principal constituents, amylose and amylopectin⁴⁹. A number of starches are recognized for pharmaceutical use (fig. 4). These include maize (Zea mays), rice (Oryza sativa), wheat (Triticumae stivum), and potato (Solanum tuberosum)⁵⁰.

Modified starch was tested for general applicability of a new pregelatinized starch product in directly compressible tablet controlled-release matrix systems. To deliver proteins or peptidic drugs orally, microcapsules containing a protein and a proteinase inhibitor were prepared ⁵¹. Acetylating of starch considerably decreases its swelling and enzymatic degradation. Thus, starch-acetate (SA) based delivery systems were tested for controlled drug delivery⁵².

Volatile Oils:

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 origin⁴⁹.

Menthol:

Fig. 5: Menthol

Menthol is obtained by steam distillation of the flowering tops of Menthapiperita belonging to the family Labiatae. A membrane-moderated transdermal therapeutic system (TTS) of nimodipine using 2%w/w hydroxypropylmethylcellulose (HPMC) gel as a reservoir system containing menthol as penetration enhancer and 60%v/v ethanol-water as solvent system was prepared⁵³. Menthol was tested for improving the bioavailability of poorly water-soluble ibuprofen in the rectum with poloxamer⁵⁴. Terpenes such as menthol, cineole and propylene glycol (PG) were tested as chemical enhancers to improve the skin penetration of propranolol. Release and skin permeation kinetics of propranolol from film preparations were examined in in vitro studies using a Franz-type diffusion cell. In vitro skin permeation studies showed that cineole was the most promising enhancer among the enhancers examined⁵⁵.

Caraway:

Fig. 6: a) Carvone b) limonene

Caraway fruit consists of the dried, ripe fruits of Carum carvi (Umbelliferae). The volatile oil consists of the ketone carvone (fig. 6) and the terpene limonene⁴⁹. In another attempt, it was concluded that the limonene-based TTS of nicorandil provided the desired plasma concentration of the drug for the predetermined period of time with minimal fluctuations and improved bioavailability.

CONCLUSION:

Today the stress is on patient compliance and to achieve this objective there is a spurt in the development of NDDS. As the herbal excipients are promising biodegradable materials, these can be chemically compatible with the excipients in drug delivery systems. In addition herbal excipients are non-toxic, freely available, and less expensive compared to their synthetic counterparts. They have 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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Received on 12.03.2017 Accepted on 10.05.2017

Asian J. Pharm. Res. 2017; 7(2): 111-117.

DOI: 10.5958/2231-5691.2017.00019.3