Synopsis of the studies on the use of Lectins in formulations for nasal drug delivery
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\r\n\tThis book intends to provide the reader with a comprehensive overview of the current epidemiology, valuable information in relation to the management of specific poisoning agents, and important evidence-based developments in the toxicology field, with special focus on children, who are a more vulnerable population for severe poisonings. Its aim is to be a practical handbook to aid health care professionals involved in individual care of patients poisoning.
The use of nasal cavity as a route of administration of drugs, specifically systemically acting drugs that pose a delivery challenge, have become an area of great interest to the pharmaceutical companies in the past decade. The physiology of the nasal cavity allows for variety of drug delivery possibilities and destinations which include local, systemic, vaccine, and access to the central nervous system (CNS)[1]
Anatomically, the nasal cavity can be divided into three functional regions (Figure 1):
Vestibular region having an area of 10 to 20 sq.cm and is situated just inside the nostrils. It is covered with stratified, keratinised and squamous epithelium.
Respiratory region having an area of about 130 sq.cm and occupies majority of the nasal cavity and consists of three turbinates namely inferior, middle and superior.
Olfactory region has an area of about 10 - 20 sq.cm. It is located in the roof of the nasal cavity and on the upper part of the nasal septum. It contains the receptors for the sense of smell. Local delivery of drugs in the nasal cavity can be used to treat allergies, congestion and infection. Systemic delivery of the drugs can be used for crisis treatments during a rapid onset of symptoms, daily administration of drugs for long-term treatment of disorders or delivery of peptides or proteins that may be difficult to administer. The nasal cavity can also be used to deliver vaccines including antigens (whole cells, split cells, and surface antigens) and DNA vaccines [1]. The nasal cavity also allows access to the CNS, thus allowing drugs to circumvent the blood-brain barrier (BBB) [1]. It has been suggested that there is free communication between the nasal submucosal interstitial space and the olfactory perinueronal space, which appears to be continuous with a subarachnoid extension that surrounds the olfactory nerve [2].
Nasal Anatomy and Physiology
The pharmaceutical companies are increasingly marketing drugs as nasal formulations, drugs such as sumatriptan, estradiol, buserelin, and calcitonin, all which have shown to have faster onset of action, improved bioavailability, and a better delivery method [3].
There are a number of advantages in using nasal cavity for administration of drugs. Some of the advantages are: avoidance of the gastrointestinal tract along with hepatic first pass metabolism, increased absorption and bioavailability of small and larger drug molecules 4. Furthermore, drugs that have low oral bioavailability have been shown to be successfully delivered systemically using the nasal route; studies have suggested that the nasal route is a great alternative to parenteral route for delivery of protein and peptide drugs [4]. Also due to direct delivery of drugs to the systemic circulation, the onset of pharmacological action is rapid [5].
Administration of lower drug doses through the nasal route, may lead to lower side effects. The convenient delivery of drugs via the nasal route, especially in long-term therapies has proven to increase patience compliance compared to parenteral and injection methods [4]. Lipophilic drugs generally have no trouble being absorbed through the nasal cavity. In fact, the bioavailability of lipophilic drugs been shown to be very close to those of intravenous injection (100% bioavailability), for instance, fentanyl has been shown to have an 80% bioavailability for nasal administration [1].
Even though the nasal cavity has a large surface area along with extensive blood supply, it has been shown that the permeability of the nasal mucosa is low for polar molecules. The limiting-factor for nasal absorption of polar drugs such as peptides and proteins is epithelial membrane permeability. Drugs with molecular weights lower than 1000Da can generally pass the epithelial membrane via transcellular route, receptor mediated transport, vesicular transport, use of concentration gradient force [6], or travelling in the paracellular route through the tight junction between the cells. In fact tight junctions seem to have finite permeability to molecules with molecular radii less than or equal 3.6 A and are essentially impermeable to those with molecular radii greater than or equal to 15 A [7]. Despite the advantages of nasal drug delivery, some of the drugs may also cause inconvenience due to potential for nasal irritation. Pathological conditions such as cold and allergies may alter nasal bioavailability significantly, which can have an effect on the intended pharmacological action [8].
Another factor that plays an imperative role in low membrane transport of nasally administered drug therapeutics is rapid drug clearance by the mucociliary clearance mechanism. This problem is common with drugs that are not easily absorbed across the nasal membrane. It has been shown that drugs that do not readily cross the nasal membrane, whether liquid or power form are removed from the nasal cavity in 15-20 min [9]. Mucociliary clearance tends to decrease the residence time of the administered drug. This problem can be overcome using formulation strategies. Novel delivery platforms based on polymeric drug carriers along with variety of methods that can be used to improve the absorption of drugs through the nasal route will be discussed in the following paper. These delivery systems work by attaching themselves to the mucus layer and thus preventing clearance of the drug delivery system. Some of these delivery systems are still experimental, whereas others have advanced to clinical use. Figure 2 summarizes the various mechanisms involved in mucoadhesion of the main drug carriers discussed in this chapter.
Mechanisms of mucoadhesion by lectins (A), Thiomers (B), Alginate Poly ethylene glycol acrylate (C).
Lectins are classified as a group of structurally diverse proteins [10] that are found in plants as well as in the animal kingdom. They are also found in some microorganisms [11]. Lectins have the capability to identify and bind to specific sugar moieties. The sugar-binding moiety of most lectins is only a small part of the lectin, i.e., a major portion of lectin is not involved in the recognition and binding to the receptor[12]. Lectins also cause agglutination due to their ability to cross link sugar containing macromolecules. Primarily they identify only specific sugars like mannose, glucose, galactose, N-acetyl-glucosamine, N-acetyl galactosmaine, furose and N-acetyl neuramic acid [13]. The various lectins which have shown specific binding to the mucosa include lectins extracted from Ulex europaeus I, soybean, peanut and Lens culinarius. The use of wheat germ agglutinin has been on the rise due to its least immunogenic reactions, amongst available lectins [2]. Lectins have the ability to stay on the cell surface or become internalized via a process called endocytosis if the adhesion is receptor mediated. In this manner lectins offer twin functionality of not only allowing target specific attachment but also a means of delivering the drug through a controlled process to the cells by active cell mediated drug uptake [1]. Lectins have potential to be used in Nasal Drug Delivery, especially where internalization of the drug encapsulated nanoparticles is of particular importance such as DNA delivery[14]. Inspite of lectins offering significant advantages, it is worth noting that such polymers suffer at least in part from premature inactivation by shed off mucus. This phenomenon has been reported to be advantageous, given that the mucus layer provides an initial yet fully reversible binding site followed by distribution of lectin-mediated drug delivery systems to the cell layer[15].
There are three types of lectins - classified based on their molecular structure:
Merolectins: lectins which have one carbohydrate recognising domain [1].
Hololectins: lectins which have two or more carbohydrate recognising domains [1].
Chimerolectins: lectins with additional unrelated domains [1].
Lectins are involved in various biological processes: cell-to-cell recognition and communication, particularly in the mammalian immune system (transendothelial migration), adhesion and attack of infectious agents on host cells, and clearance of glycoproteins from the blood circulation [16]. Lectins are used in conjugation with other mucoadhesive polymers as drug delivery vehicles to the brain or systemic circulation through the nasal cavity. It was observed that negligible penetration of nanoparticles takes place between cells in the nasal epithelium when administered on their own. Secondly, mucociliary clearance reduced the residence time of the particles in the nasal cavity (particles cleared within the nose every 15 to 20min, thus, resulting in incomplete absorption of the formulation. Also it was found that, unmodified nanoparticles distributed in the nasal cavity without selectivity. This resulted in poor brain targeting efficiency of the formulation. To deal with these problems, novel lectin-modified nanoparticles were constructed. The lectin used was wheat germ agglutinin (WGA), which specifically binds to N-acetyl-D-glucosamine and sialic acid moieties, both of which were abundantly observed in the nasal cavity especially in the olfactory mucosa [17].
Factors like low ciliary irritation and high permeability among other considerations favour the potential use of lectins for nasal drug delivery [18]. Studies in animals concluded that lectins have minimal acute irritancy and can be thus be used for further in vivo studies[19]. However, many lectins are toxic or immunogenic especially those obtained from Ricinus communis,\n\t\t\t\tPhaseolus vulgaris and Lycopersicon esculentum and Canavalia ensiformis[5].There is a probability that lectins promote the production of antibodies which could lead to the blockage of lectin-based delivery vehicles. These antibodies may also expose patients to the risk of systemic anaphylaxis on successive exposure. But, by using truncated varieties of lectin molecules as mucoadhesives this potential risk of toxicity may be triumphed over [20].
Mucoadhesive Polymer | Dosage Formulation | Active Ingredient | Reference |
Odorranalectin | Liquid | coumarin-6 | Wu H et al[21] |
wheat germ agglutinin conjugated PEG-PLA nanoparticles | Liquid | coumarin-6 | Liu Q et al[22] |
Solanum tuberosum lectin-conjugated PLGA nanoparticles | Powder | coumarin-6 | Chen J et al [18] |
Synopsis of the studies on the use of Lectins in formulations for nasal drug delivery
Thiomers are mucoadhesive polymers that have side chains carrying thiols which lead to formation of covalent bonds between the cystiene groups in the mucus and the polymer by thiol/disulphide exchange reactions or simple oxidation process. These bonds are also known as disulphide bridges. These bridges sometimes improve mucoadhesion by 100 folds. They also have permeability enhancing effect and ability to control the rate at which drugs are released. This property and increased mucoadhesion leads to higher residence time of the drugs administered in combination with thiomers hence improving their bioavailability [23]. Thiomers are also used in combination with other polymers like chitosan, poly acrylic acid, etc. Due to immobilization of thiol groups, mucoadhesive properties of these polymers are increased by 140 folds and 20 folds respectively [12]. Thus, thiomers are one of the most mucoadhesive polymers known at the present [24]. Thiomers enhance the permeability of drugs with the potential advantage of not being absorbed through the nasal mucosa compared to low molecular weight permeation enhancers. Thus their permeation enhancing effects can be maintained over a longer period of time while excluding systemic toxic effects.[25] Thiomers tend to cause reversible opening of the tight junctions with glutathione as permeation mediator [26]. Thiolated polymers display in situ gelling properties due to the oxidation of thiol groups at physiological pH-values, which results in the formation of inter- and intramolecular disulfide bonds[12]. This increases the viscosity of the formulation coupled with extensive crosslinking due to formation of disulphide bonds with the nasal mucosa, which increases the residence time of the formulation tremendously [27].
Other studies on thiomer combinations with other polymers by Bernkop-Schnurch led to formation of thiolated polycarbophil which increases the uptake of Leu-enkephalin from the nasal mucosa by 82 folds, thus a promising excipient for delivery of Leu-enkephalin through the nasal mucosa[28]. In another study, thiolated polyacrylate microparticles were generated for the nasal delivery of human growth hormone (hGH). The intranasal administration of this microparticulate formulation to rats resulted in a relative bioavailability of 8.11 ± 2.15% that represents a 3-fold improvement compared to microparticles comprising the corresponding unmodified polymer[29].
The nasal route is an attractive alternative to parenteral delivery for a number of therapeutic peptides such as calcitonin, insulin, desmopressin, buserelin and octreotide. However, membrane permeability is low for nasally administered peptides leading to low bioavailabilities, a short local residence time at the site of absorption and a high metabolic turnover in the epithelium. The three major approaches to increase the bioavailability of intranasally administered peptide drugs are (i) the use of permeation enhancers, (ii) incorporation of enzyme inhibitors and (iii) increasing local drug residence time using mucoadhesive polymers. Thiomers are capable of combining most of these strategies. Therefore, thiomers can be used as multifunctional vehicles for systemic nasal peptide delivery[30]. Due to their high molecular mass, thiomers are not absorbed from the nasal mucosa thus systemic toxic effects can be excluded. Ciliary Beat Frequency (CBF) studies with human nasal epithelium cells show that thiomers do not cause any alteration or impact on CBF. Thiomers have also been found in various studies to not cause any irritation to mucosal cells[31]. Table 2 summarizes nasal drug delivery studies with thiomers.
Mucoadhesive Polymer | Dosage Formulation | Active Ingredient | Reference |
Thiomer (polycarbophil-cysteine) | Gel | Leu-enkephalin | Bernkop-Schnürch A et al.[28] |
Thiomer (polycarbophil-cysteine /glutathione gel) | Gel | Human growth Hormone | Leitner VM et al.[32] |
Thiomer (polycarbophil-cysteine) | Microparticles | phosphorothioate antisense oligonucleotide | Vetter A et al[33] |
Thiolated chitosan | Microparticles | insulin | Krauland AH et al[34] |
Use of thiomers in mucoadhesive nasal formulations for systemic delivery
Alginate Polyethylene glycol Acrylate is also known by the acronym Alginate-PEGAc. It has an alginate backbone with acrylated polyethylenglycol groups attached to it. This polymer meshes the properties of alginates (strength, simplicity and gelation) with characteristics specific to the acrylate functionality of PEG like mucoadhesion. PEG’s have the ability to penetrate the mucus surface while the acrylate group of the polymer reacts with the sulphide group of glycoproteins present in the mucus. This results in a strong interaction between the mucus and the polymer [35]. It is expected to be cross-linkable by two different paths: chemically via the acrylate end groups and physically through the alginate backbone [36]. Alginate is a mucoadhesive polysaccharide of 1 → 4 linked α-l-glucuronic acid and β-d-mannuronic acid which binds to the glycoproteins in the mucus through carboxyl–hydroxyl interactions [37]. It is anionic in nature. It is known to undergo ionic sol to gel transition (gelation) upon interaction with multivalent ions such as Ca2+, Fe2+ [38], thus reducing its adhesion to mucosal tissues [39]. On the other hand Poly-Ethylene Glycol (PEG) is an FDA approved polymer. It is non-toxic, non-immunogenic and non-antigenic. It has high solubility in water and rapid in vivo clearance. It also has the ability to form hydrogen bonds with sugar moieties on glycosylated proteins. This causes PEG to form strong bonds with mucus leading to increased mucoadhesion [25].
Poly Acrylic Acid forms hydrogen bonds between its carboxylic acid groups and sialic acid-carboxylic acid groups present in the mucus [40]. The most recent method for synthesis of Alginate PEG-Ac is a two stage procedure. First the synthesis of alginate thiol takes place. In the second stage, a Michael type addition reaction takes place where a nucleophilic addition between PEG-Diacrylate and alginate backbone occurs conjugating the two [25].
Modification of Alginates with addition of acrylic acid is done to optimize its shortcomings such as erosion in neutral pH. Addition of acrylic acid controls the release rate of drugs and also improves its adhesive properties [29]. Also it has been found that at physiological pH of 7.4 both poly acrylic acid and sialic acid undergo ionization, thus repelling each other. This leads to rapid removal of this polymer-based drug delivery system. Addition of PEG results in H-bonding with PAA enhancing the viscosity of the resulting drug delivery vehicle. Addition of PEG to the polymer increases the viscosity of the resulting polymer complex retarding disintegration and removal of the polymer from the mucosal surface thus increasing mucoadhesion [30]. The combination of the three functional moieties of Alginate Polyethylene glycol Acrylate leads to an improved novel polymer that can be used mucoadhesive nasal drug delivery.
There is a great interest in Poloxamer based formulations. A number of reviews have been published describing in detail poloxamer formulations like gels, poloxamer-coated nanoparticles, o/w and w/o emulsions, and solid polymer blends [41]. Poloxamers are made up of non-ionic difunctional triblock[42] copolymers containing a centrally located hydrophobic polypropylene oxide between hydrophilic polyethylene oxides [43, 44]. Aqueous solutions of poloxamers are extremely stable in the presence of acids, alkalis and metal ions. These polymers are readily soluble in aqueous, polar and non-polar organic solvents. Hence, they are widely preferred choice as excipients in formulations [45]. Poloxamers are said to contain thermoreversible property and will convert from a liquid to a gel at body temperature, thus, causing in situ gelation at the site of interest [1] preventing the drug to be removed from the nasal cavity due to mucociliary clearance. This vastly improves the bioavailability of the drug administered. The formation of the gel can be explained as follows. When the poloxamer is cooled, the hydration layer surrounds the poloxamer molecule and hydrophobic portions are separated due to hydrogen bonding. As the temperature increases, desolvation of the hydrophilic chains occurs as the result of breakage of hydrogen bonds. This results into hydrophobic interactions amongst the polypropylene oxide domains and gel gets formed. Hydroxyl groups of the copolymer become more accessible due to hydration[46]. Thus, desolvation caused by increase in temperature and subsequently micellization results in formation of a more closely packed viscous gel [47] Various combinations of poloxamers and other mucoadhesive polymers like polycarbophil and polyethylene oxide have been found to be more advantageous since their combination tends to reduce the gelation temperature of poloxamer. This can help in making a polymer that can gel at the temperature observed in the nasal mucosa[5]. Poloxamers are also known as Pluronics. Pluronics have also been chemically combined with poly(acrylic acid)s like Dihydroxyphenylalanine (DOPA)[31] to produce systems with enhanced adhesion and retention in the nasal cavity.
One of the most promising poloxamer is Poloxamer 407 (Pluronic F127) because of its low toxicity, high solubility, bioadhesion characteristics, and acceptability as drug delivery vehicle [48]. Some of the other investigated combination of poloxamers are polymer pluronic PF127 along with benzalkonium chloride which helped decreased the gelation onset temperature. This combination was prepared for the nasal delivery of Vitamin B12[49]. In another study, poloxamer 407 was combined with a mucoadhesive polymer or polyethylene glycol. The combination allowed the manipulation of the temperature at which the conversion of sol to gel would take place as well as decreasing and increasing the in vitro release of the drug respectively[50]. But work still needs to be done on reducing irritability which is one of the major limitations of these formulations[51]. Controlled release nasal formulations of propranolol have been made using a combination of poloxamers and other mucoadhesive polymers for such as Carbopol 934P. By controlling the release of the drug and by increasing its residence time in the nasal cavity, there was a significant increase in bioavailability of the drug[52]. Poloxamer properties are said to be affected by addition of various additives. Concentration can greatly affect the thermodynamic properties of poloxamer. Water soluble additives also affect the thermodynamic properties. The range at which gelation occurs increases with polymer concentration, whereas addition of sorbitol and PEG 15000 narrows the gel range. Significant enthalpy change occurs in gels containing sorbitol and PEG, indicative of interactions with the polymer during the phase transitions. As the concentration of the polymer increases, the aqueous gels display non-Newtonian characteristics. The hydrophobic interaction of Benzalkonium Chloride and pluronic produces a gel with higher viscosity. Addition of PEG 15000 helps achieve desired gelation characteristics for increased drug loading and use of desired formulation additives [41]. Poloxamers at low concentrations, when dispersed in liquid exist individually as monomolecular micelles. As the concentration of the pluronic in the system increases, it forms multi-molecular aggregates[53]. Different aggregate forms of poloxamers are seen depending on the molecular weight, solvent composition, and temperature[54]. Micellar behavior changes with changes in solvent composition and temperature. Various salts and additives like surfactants, polymers, cosolvents have marked effect on the micellar properties, clouding and solubilization characteristics of pluronic solutions[55]. Salts in the order of Na3PO4 > Na2SO4 > NaCl have been found to lower the critical micellar temperature significantly[56]. Pluronic block copolymers are amongst the most potent drug targeting systems. Recent research on pluronics has generated new findings indicating immuno-modulation and cytotoxicity-promoting properties of Poloxamer 407 revealing significant pharmacological interest. Human trials are in progress based on these results [57]. Along with these new findings and favourable properties, poloxamers have generated immense interest as one of the most promising novel mucoadhesive drug delivery systems. Table 3 shows most of the published studies involving nasal drug delivery with this polymer.
Although several novel strategies are currently used for nasal drug delivery using bio-and muco-adhesion strategies, the potential exists to improve these methods using other strategies such as nanoparticles, bacterial adhesion, altered amino acid sequence, and antibody mechanism. A graphic representation of these methods is shown in Figure 3. Each of these methods is discussed below.
Potential future novel strategies for muco-/bio-adhesive drug delivery using Mucoadhesive Nanoparticles (A), Bacterial Adhesion (B), Altered Amino Acid Sequence (C) and Antibody mechanism (D).
Mucoadhesive Polymer | Dosage Formulation | Active Ingredient | Reference |
Poloxamer 188 or 407 | Nanovescicles | olanzapine | Salama HA et al[58] |
Poloxamer-Chitosan | Gel | (32)P-siRNA dendriplexes | Perez AP et al[59] |
poloxamer 407/ hydroxypropyl-β-cyclodextrin/chitosan | Gel | fexofenadine hydrochloride | Cho HJ et al[47] |
chitosan-poloxamer 188 | Spray | fentanyl | Fisher A et al[60] |
PLGA: Pluronic F68 | Nanoparticles | plasmid DNA | Csaba N et al[61] |
Pluronic F127 (PF127)/ Carbopol 934P | Gel | sumatriptan | Majithiya RJ et al[62] |
poloxamer 407/Polyethylene glycol | Liquid | metoclopramide hydrochloride | Zaki NM et al[63] |
Poloxamer 407 /PEG 4000 | Liquid | Radix Bupleuri | Chen E et al[64] |
Poloxamer 407 | Liquid | tetracosactide | Wüthrich P et al[65] |
Pluronic F127 | Microspheres | Bordetella bronchiseptica multiple antigens containing dermonecrotoxin | Kang ML et al[66] |
Pluronic F127 (F127)/ chitosan | Liquid | tetanus toxoid | Westerink MA et al[67] |
Pluronic PF 127 | Gel | Vitamin B(12) | Pisal SS et al[68] |
poloxamer 188 | Liquid | isosorbide dinitrate | Na L et al[69] |
Application of Poloxamer (pluronics) in formulations for nasal drug delivery
Nanoparticles generally vary in size from 10-1000nm. Biodegradable nanoparticles have been used frequently as drug delivery vehicles due to its better encapsulation efficiency, control release and less toxic properties[70]. They offer enhanced biocompatibility, superior drug/vaccine encapsulation, and convenient release profiles for a number of drugs, vaccines and biomolecules to be used in a variety of applications in the field of medicine[71]. The average pore size of viscoelastic mucus is around 150 ± 50 nm. Thus, formulations of mucoadhesive nanopolymers can lead to effective drug delivery to the target site. Commonly used materials for formulating nanoparticles are poly(lactide-co-glycolide) (PLGA) and Pluronics [55]. PEG coatings have been widely used in the development of polymeric drug carriers, including particles composed of biodegradable polyesters and polyanhydrides. PEG coatings reduce aggregation and enhance the blood circulation times of biodegradable nanoparticles designed for drug delivery[72]. Nanoparticles up to 200 nm in diameter that are coated with a dense layer of non-mucoadhesive PEG polymers, including drug carriers composed entirely of Generally Regarded As Safe(GRAS) components, readily penetrate nasal mucus. The development of polymeric particles with improved sinus mucus penetration capability should encourage the commercial development of new generations of nanoparticle-based intranasal drug delivery systems [46].
Non-denatured bacterial cell envelopes, also known as bacterial ghosts, are produced as a result of plasmid-encoded lysis gene E of bacteriophage in gram-negative bacteria[73]. Due to its hydrophobic nature, gene E product integrates into the inner membrane, resulting in fusion of inner and outer membrane. This leads to the formation of a trans-membrane tunnel[74]. The generated trans-membrane tunnel ranges between 40-80 nm in diameter, through which all cytoplasmic contents are expelled[75]. It is imperative to note that the process of Protein E-specific lysis does not result in physical or chemical denaturation of bacterial surface structures. The bacterial ghosts have been suggested to be a great alternative method for inactivated non-living whole-cell vaccination [76]. Depending on the site-directed sequences included in the fusion, a variety of foreign proteins can be expressed within or on the cell envelop of bacterial ghosts [77]. The advantage of using bacterial ghosts is, bacterial ghosts can be produced in large quantities, do not require the cold-chain-storage system, and are stable for a long time. Further, the size of the foreign protein insert can be very large (>600 amino acids) thus allowing the presence of multiple epitopes simultaneously[78].
The attachment of synthetic or natural macromolecules to mucus or epithelial surface is defined as bioadhesion. Bacteria are capable of adhering to the epithelium surface with aid of fimbriae, which are long, lectin-like proteins found on the surface of many bacterial strains[79]. There is a correlation between the pathogenicity of bacteria and the presence of fimbriae, thus, the adhesion of bacteria to epithelial surfaces can be used as an efficient method of efficient drug-delivery[80].
Bacterial ghosts have been shown to display bio-recognitive abilities which allow their attachment to different surfaces of numerous body tissues depending on the species chosen[81]. Many of these bacterial ghosts are able to bind to surfaces due to the presence of long fimbriae which facilitate the penetration of the mucus covering epithelial tissues[65]. Thus, as a result of the properties of fimbriae a bioadhesive drug delivery system has been developed by using the ghost bacteria with a therapeutic agent coupled to E. coli K99 fimbriae[62]. This strategy may be applied to nasal drug delivery with the intention of reducing mucociliary clearance.
Certain amino acid sequences can be used to promote binding of drug molecules to specific cell surface glycoproteins due to the amino acids having complementary sequences present to these glycoproteins[82]. In certain disease conditions the sequence of glycoproteins is altered. This altered state can be used as a target by complementary amino acid sequences by attaching them to a drug delivery device [66]. Antibodies can be produced against selected molecules present on mucosal surfaces. Due to their high specificity, antibodies can be a rational choice as a polymeric ligand for designing site-specific mucoadhesives. This approach can be useful for targeting drugs to tumour tissues[66] or even normal cells.
There is no question that the nasal route has a great potential for systemic drug delivery. The physiology of the nasal cavity creates a variety of opportunities for drug companies to develop local and systemic drugs. As nose- to- brain delivery makes it possible to by-pass the blood-brain-barrier for certain drugs; administration of drugs via this route for treatment of neurological diseases presents exciting opportunities. Despite the advantages of nasal drug delivery, the absorption and permeability of polar drugs through the nasal mucosa remains a challenge. The mucociliary clearance system compounds the problem by limiting how long the drug stays in the nasal cavity for absorption to take place. Hence several strategies have been developed to enable the drug molecules to attach onto the mucus or epithelial layer, thus preventing them from being cleared from the nasal cavity. The application of lectins, thiomers, alginate poly-ethylene glycol acrylate and poloxamers were discussed in this chapter. These polymers are not the only polymers used for nasal delivery. However, they are among the least reviewed polymers for systemic drug delivery via the nasal route. Other bioadhesive strategies including nanoparticles, bacterial adhesion, altered sequence and antibody strategies can further improve the bioavailability of polar drug molecules delivered via the nasal route. However, a lot of work remains to be done in this area.
Mycobacterium leprae (M. leprae) is an acid fast bacilli that is the causative agent of leprosy disease which mainly effects the skin and peripheral nerves. In olden times leprosy was common in temperate climates (e.g. Europe), today it is mainly confined to tropical and subtropical regions. Mode of transmission in leprosy is mainly through inhalation of droplets containing the bacteria. But skin contact is also claimed by many leprologists. The disabilities and deformities associated with leprosy due to neuropathy leads to long-term consequences, including. This in turn is associated with stigma.
The immunity of the host plays an important role in disease progress and control. Thus, fortunately 95% of patients exposed to M. leprae will not develop this disease. The variation in incubation period ranges from 2 to 20 years, or even longer.
Leprosy has been successfully eliminated as a public health problem in 2000 globally and at the national level in 113 countries out of 122 by 2005 [1]. Elimination of leprosy is defined by World Health Organization as a point prevalence below 1 per 10,000 population [2]. However, the number of new patients diagnosed with leprosy is still significant, at more than 200,000 in 2016 globally. The new case detection rate of the disease (NCDR) is only slowly declining (Figure 1) [3].
Trend in case detection and case detection rate, by WHO region, 2006–2016 [3].
The long incubation period, silent symptoms, long duration MDT and unavailability of effective vaccine makes this disease difficult to identify, treat and eradicate. To add to the misery the stigma associated with the disease is another challenge. In such circumstances, prevention and control of disease gains utmost importance.
In 2017, 192,713 patients were on treatment globally which makes the prevalence rate of 0.25 per 10,000 population [4]. Total of 210,671 new cases were reported in same year from 150 countries making NCDR of 2.77 per 100,000 population. Figure 2 below shows the trends over the past decade (2008–2017) in new case detection of leprosy cases globally in the reporting countries of World Health Organization (WHO) [4].
Country-wise trends of detection of new leprosy cases from 2008 to 2017 [4].
The three main goals of control of leprosy are
To detect the pathology early and treat the patient completely.
To prevent the transmission to the others.
To prevent the disabilities and other complications.
Thus the following modalities are adopted to control leprosy:
Medical measures
Social support
Program management
Evaluation
The control of leprosy starts with the estimation of size and magnitude of the problem. Most common epidemiological survey method of collection of data is “Quick random sample survey.” Information about the prevalence of leprosy, age and sex-wise distribution, various forms of leprosy and the health facilities available should be gathered. Roughly the total prevalence of leprosy in an area would be about 4 times that of the cases found among school children [5, 6]. These estimates are essential to plan, implement and to evaluate the results of the control program.
The objective is to detect all the cases as early as possible and to register them. Active case finding is important as the disease is symptomless in the early stages. Cases can be detected by the Contact surveys, Group surveys and Mass surveys. Contact surveys consists of examination of all household contacts with a lepromatous case, particularly children, in areas with prevalence less than 1 per 1000. Contact surveillance of households is recommended for a minimum period of 10 years after case is declared bacteriologically negative, and for 5 years in households with a non-lepromatous case from the time of diagnosis of the index case. Group surveys are done in areas where prevalence of leprosy is more than 1 in 1000 population. This consists of screening certain groups such as school children, slum dwellers, military recruits, industrial workers, etc. through “Skin camps.” Lastly, mass surveys consists of examination of each and every individual by house-to-house visits in hyperendemic areas (prevalence – 10 or more per 1000 population). These are generally carried out by repeated annual examinations of school children which yield better results at relatively low cost [5, 6]. The data of each case is entered in the standardized proforma developed by WHO.
Since an effective vaccine is unavailable for leprosy the secondary prevention (early treatment) becomes more important. Until 1981, Dapsone (Diamino Diphenyl Sulphone—DDS) was used to treat leprosy which resulted in the development of resistance and relapse, making leprosy control difficult.
Multidrug Therapy: In 1982, WHO recommended Multidrug Therapy (MDT) for all leprosy patients. Introduction of MDT has opened a new avenue in the control of leprosy in the world. Aim of MDT is to convert the infectious case into noninfectious as soon as possible, so as to reduce the reservoir of infection in the community.
The main objectives of MDT are:
To ensure early detection of the cases.
To interrupt the transmission of infection.
To prevent drug resistance, relapse and reaction.
The advantages of MDT over dapsone monotherapy are:
Shorter duration of treatment,
Better patient compliance,
High cure rate,
Cost-effectiveness and
Ease in health delivery system.
There are two types of MDT regimens used depending on the symptoms and signs shown by the patients - Paucibacillary (PB) and Multibacillary (MB). Recommended Regimens are discussed below [3, 5, 6, 7]:
i. Multibacillary leprosy:
MDT is recommended for following groups of patients:
All smear positive cases.
Skin lesions more than five in number.
More than one nerve trunk thickening.
All cases of relapse/reactivation and all cases who have been treated with Dapsone monotherapy earlier.
The drugs used in Multibacillary MDT and dosages are:
Rifampicin: 600 mg once monthly, supervised.
Dapsone: 100 mg daily, self administered.
Clofazimine: 300 mg once monthly, supervised and 50 mg daily, self administered.
Duration of treatment for Multibacillary leprosy is 12 months, can be extended to 18 months and continued where possible up to smear negativity. Sometimes LL/BL patients with high bacilli may need 2–3 years or more of MDT for achieving bacteriological negativity.
ii. Paucibacillary leprosy:
The drugs and dose schedule is:
Rifampicin 600 mg once a month for 6 months supervised.
Dapsone 100 mg daily for 6 months self administered.
Paucibacillary leprosy is treated for 6 months.
MDT is not contraindicated in patients with HIV infection.
Each MDT blister pack contains tablets for 4 weeks treatment. For easy identification color coding of the blister pack is done, that is, with different colors for multibacillary and paucibacillary cases both in adults and children.
The treatment in both PB and MB cases varies depending on the age of the patient. The patients between 10 to 14 years are treated as paediatric cases, while >14 years are considered adult. The standard treatment regimen for MB leprosy in adults is given for 12 months. The drugs in each blister pack are (Figure 3):
Two capsules of Rifampicin of 300 mg (600 mg once a month) to be taken as single dose under supervision.
Clofazimine 3 capsules of 100 mg each to be consumed once a month as single dose under supervision and 50 mg daily for next 28 days.
Dapsone 100 mg as single dose and then daily once for 1 month.
MDT for adult MB type of leprosy [2, 7].
The standard adult treatment regimen for PB leprosy is (Figure 4):
Rifampicin: 600 mg once a month.
Dapsone: 100 mg daily.
Duration: 6 months (6 blister packs of 28 days each).
MDT for adult PB type of leprosy [2, 7].
Treatment regimen for MB leprosy in children (ages 10–14 years) is (Figure 5):
Rifampicin: 450 mg once a month.
Clofazimine: 150 mg once a month, and 50 mg every other day.
Dapsone: 50 mg daily.
Duration: 12 months (12 blister packs of 28 days each).
MDT for pediatric MB type of leprosy [2, 7].
Treatment regimen for PB leprosy in children (ages 10–14 years) is (Figure 6):
Rifampicin: 450 mg once a month.
Dapsone: 50 mg daily.
Duration: 6 months (6 blister packs of 28 days each).
MDT for pediatric PB type of leprosy [2, 7].
MDT is provided free-of-charge globally through an agreement between a pharmaceutical company and WHO. WHO manages distribution of MDT to countries in coordination with national leprosy programs.
Clinical surveillance of the patients after completion of treatment is an important part of MDT to ensure complete cure. For paucibacillary cases follow up for at least once a year for 2 years after completion of treatment and for multibacillary cases at least once a year for 5 years [3, 4, 5].
Early diagnosis of cases, aggressive treatment and proactive measures to avoid complications and disabilities is the backbone for the success of any comprehensive program. In addition to accurate reporting and control measures, effective preventions will be needed to achieve elimination. Search for an effective vaccine either to be used alone or in combination with a drug has been going for a long time.
Presently BCG (Bacillus Calmette-Guerin) is the only vaccine that has shown some protection against M. leprae bacillus. A single dose of BCG gives 50 percent or higher protection against the disease. It is the most widely used vaccine in the world, yet the degree of protection it confers is not yet confirmed. The meta-analysis of many experimental studies concludes that the vaccine gives approximately 26% protection against leprosy. But the protection level decreases with time. To overcome this problem more than one dose of vaccine is advised.
Other variants of vaccination are also suggested.
Adding killed M. leprae to BCG: Various modifications have been suggested, such as the addition of killed M. leprae to BCG. This method almost doubles the vaccine efficacy in some populations as concluded by few studies. But the same cannot be said for patients below 15 years.
Vaccination with M. indicus pranii (Mycobacterium W): This strain discovered in India. Testing of the MIP vaccine took place in 2005 and showed that it was effective for seven to 8 years, after which a booster dose would be needed to maintain the immunity. Recently the vaccine was approved by the Drug Controller General of India to be rolled out in a project involving five districts in the states of Bihar and Gujarat, where there are high rates of leprosy. Leprosy patients and their close contacts will benefit from this project, making India the first country in the world to have a large-scale leprosy vaccination initiative [8].
Another milestone in prevention of leprosy is the discovery of the vaccine candidate, called LepVax. Scientists at Infectious Disease Research Institute (IDRI), along with national and international collaborators including the National Hansen’s Disease Program and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, with financial support from American Leprosy Missions, have developed this leprosy vaccine. Based on the preclinical studies, the LepVax, has progressed to Phase I clinical testing in the United States, the first stage of safety testing in human volunteers. The clinical trial is focused not only on safety but also evaluates the immune response of the individual to the vaccine.
Indian cancer research center (ICRC) bacilli: Another variant belonging to the M. avium intracellulare group, the ICRC bacilli are thought to induce lepromin conversion in lepromatous leprosy patients and in lepromin-negative leprosy-free individuals. Its efficacy was reported to be 65.5 percent [8].
M. vaccae: The studies with this soil-dwelling mycobacterial species combined with BCG showed to provide greater protection against leprosy, but a Vietnamese trial contradicted the results [8].
M. Habana: This bacilli has been reported to induce lepromin conversion when used as a live vaccine in monkeys, and protected mice against the development of leprosy [8].
Chemoprophylaxis alone provides two-year protective window while effective immunization will provide a much broader protective window. Thus many studies and research is going on to provide both chemoprophylaxis and immunization for immediate and short-term protection and longer-term protection respectively. This strategy could have better impact and distinct appeal in controlling and preventing leprosy. Such trials could also provide a gateway for the assessment and implementation of new emerging vaccines (Figure 7).
Locations of leprosy vaccine testing.
Chemoprohylaxis using effective antibiotics focuses on providing protection to people at risk such as close contacts – family members, neighbors, co-workers, health care providers for lepers etc. Due to the stigma of disease the leprosy cases are found in clusters in all endemic regions, rather than being evenly dispersed over the whole area. Thus these high risk people can be identified and prophylaxis provided along with secondary prevention strategies. The process includes focused surveillance, contact tracing, early diagnosis and treatment. This helps in reducing the incidence and breaking the chain of transmission.
Chemoprophylaxis, as recommended by WHO Guideline Development Group (GDG), is done using single dose rifampicin (SDR) for contacts of leprosy patients both in adults and children of 2 years of age and above. Before starting the drug leprosy and TB disease are to be excluded. There should be no contraindications also for the use of rifampicin.
Other important considerations for the implementation of this chemoprophylaxis by programs are:
Adequate management of contacts.
Consent of the index case to disclose his/her disease.
An RCT found that SDR reduces risk of leprosy over 5–6 years in leprosy contacts. For every 1000 contacts treated with SDR, there were four leprosy cases prevented after 1–2 years and three cases prevented after 5–6 years.
Recommended dosage schedules for SDR are given in Table 1.
Age/weight | Rifampicin single dose |
---|---|
Adults (≥15 years) | 600 mg |
10–14 years | 450 mg |
Children 6–9 years (weight ≥ 20 kg) | 300 mg |
Children <20 kg (≥2 years) | 10–15 mg/kg |
Rifampicin dose for chemoprophylaxis [3].
The limitations of this approach are:
The protection is approximately for only 2 years.
High bacillary load cannot be eliminated using single dose.
Specific screening test needed to distinguish between contacts with high and low bacillary load.
Among communicable diseases, leprosy remains a leading cause of peripheral neuropathy and disability in the world, despite extensive efforts to reduce the disease burden. It is an important aspect of leprosy control. It means the medical, surgical, social, educational, and vocational restoration as far as possible of treated patients to normal activity so that they resume their place in the home, in society and industry [5, 6, 7]. Early treatment helps in disability limitation.
Rehabilitation: WHO has defined rehabilitation as “the combined and coordinated use of medical, social, educational and vocational measures for training and retraining the individual to the highest possible level of functional ability.”
Preventive rehabilitation consists of prevention of development of disabilities in a leprosy patient by early diagnosis and prompt treatment. But once the patient becomes handicapped and suffers from the damage caused, should be trained and retrained to the maximum functional ability so that the patient becomes useful to self, to the family and to community at large by various measures such as medical (physical), surgical, psychological, vocational and social rehabilitation (Flow chart 20.10).
Health education is given to the patient, to the family and to the community at large about leprosy. The education should be directed to ensure general public and patients help them develop their own actions and efforts to change the perception about the disease and seeking professional help whenever required. Early recognition of symptoms, prompt diagnosis, health seeking behavior, personal care, treatment adherence and rehabilitation are important aspects of health education. The key messages included are about the cause of disease and the complete cure available to encourage people for early diagnosis and treatment. It also aims at helping people to change their attitude and behavior by removing the misunderstandings and misconceptions. Mass Health education also helps to eradicate social stigma, social ostracism and social prejudice associated with leprosy which is the biggest hindrance for the eradication of disease.
The complications of the disease cause disfigurement and disabilities which in turn gives way to the stigma and strong discrimination of these patients. This results not only in physical and social isolation also financial dependency, ultimately forcing the leprosy patients to beg on streets for their survival. To address this issue WHO introduced the strategy of community-based rehabilitation (CBR). This intended to enhance the quality of life for lepers with disabilities through community initiatives. Community participation and using local resources to support the rehabilitation of people with disabilities within their own communities is the foundation of this concept [9, 10].
“Enhanced Global Strategy for Further Reducing the Disease Burden due to Leprosy for 2011–2015” was launched in 2009 by the World Health Organization. The target of the program was to reduce Grade 2 Disability rate (G2DR) in leprosy patients by at least 35% by the end of 2015 (G2DR is the number of new cases with grade 2 disability per 100,000 population). Since the elimination of leprosy in 2005, the prevalence is very less and thus G2DR has been proposed as an indicator. The advantage of G2DR as indicator is that, it is less susceptible to operational factors such as detection delay and is a more robust marker for mapping cases of leprosy in any country. This will also help the program implementers to focus on interventions that reduce visible deformities by enhancing early detection and treatment of leprosy patients and ultimately reduce the number of new leprosy cases in the population. However by the end of 2015, only Thailand was able to achieve this target [11].
In 2016, WHO launched the “Global Leprosy Strategy 2016–2020: Accelerating towards a leprosy-free world” [9].
The program aims to reinvigorate efforts to control leprosy and avert disabilities, especially among children still affected by the disease in endemic countries.
The strategy is built around three major pillars:
Strengthen government ownership and partnerships;
Stop leprosy and its complications; and
Stop discrimination and promote inclusion.
The strategy of this program is:
To sustain expertise and increase the number of skilled leprosy staff;
To improve the participation of affected persons in leprosy services;
To reduce visible deformities and stigma associated with the disease;
To call for renewed political commitment and enhanced coordination among partners;
To highlight the importance of research and improved data collection and analysis.
The key interventions needed to achieve these targets include:
Early case detection especially in children before visible disabilities occur thus reduce transmission;
In highly endemic areas or communities detection of disease among higher risk groups through campaigns;
Improving health care coverage and access for marginalized populations such as poor patients, patients in the difficult to reach areas and the areas of conflicts.
Customization of the strategic interventions in endemic countries is permitted to suit the national plans to meet the new targets. E.g. Screening all close contacts of persons affected by leprosy; initiating a shorter and uniform treatment regimen; and incorporating specific interventions against stigmatization and discrimination.
Its ultimate goal of this program is to further reduce the global and local leprosy burden, that is, (a) zero disabilities in children with leprosy-affected, (b) G2DR less than one per million population and (c) repeal of laws that discriminate leprosy patients of their rights.
Author declares no conflict of interest.
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