Novel drug delivery system: an immense hope for diabetics

Abstract

Context: Existing medication systems for the treatment of diabetes mellitus (DM) are inconvenient and troublesome for effective and safe delivery of drugs to the specific site. Therefore, investigations are desired to deliver antidiabetics using novel delivery approaches followed by their commercialization.

Objective: The present review aims to provide a compilation on the latest development in the field of novel drug delivery systems (NDDSs) for antidiabetics with special emphasis on particulate, vesicular and miscellaneous systems.

Methods: Review of literature (restricted to English language only) was done using electronic databases like Pubmed® and Scirus, i.e. published during 2005–2013. The CIMS/MIMS India Medical Drug Information eBook was used regarding available marketed formulation of antidiabetic drugs. Keywords used were “nanoparticle”, “microparticle”, “liposomes”, “niosomes”, “transdermal systems”, “insulin”, “antidiabetic drugs” and “novel drug delivery systems”. Single inclusion was made for one article. If in vivo study was not done then article was seldom included in the manuscript.

Results: The curiosity to develop NDDSs of antidiabetic drugs with special attention to the nanoparticulate system followed by microparticulate and lipid-based system is found to emerge gradually to overcome the problems associated with the conventional dosage forms and to win the confidence of end users towards the higher acceptability.

Conclusion: In the current scientific panorama when the area of novel drug delivery system has been recognized for its palpable benefits, unique potential of providing physical stability, sustained and site-specific drug delivery for a scheduled period of time can open new vistas for precise, safe and quality treatment of DM.

Keywords:

• Antidiabetic drugs
• diabetes
• drug delivery
• particulate systems
• vesicular systems

Introduction

Diabetes mellitus (DM) has been emerged as an epidemic worldwide in the last few decades and proclaimed as fifth foremost cause of death in most developed and developing countries. According to the latest atlas of International Diabetes Federation (IDF), global dominance of diabetes has touched the figure of 382 million people (5.1 million deaths and 21 million live births were adversely affected by diabetes during pregnancy) which is expected to be 592 million in 2035 (Misra et al., 2011; International Diabetes Federation, 2013).

Diabetes mellitus is a chronic hyperglycemic condition which is described as a metabolic disorder of multiple etiologies, characterized by improper carbohydrate, fat and protein metabolism. There are two broad categories of DM i.e. type 1 and type 2 (T1DM and T2DM). T1DM is primarily caused by absolute deficiency of insulin however, variable degree of insulin resistance, impaired insulin secretion and increased glucose production are the causes of T2DM. T1DM is further classified into type 1A, i.e. autoimmune destruction of β cells and type 1B, i.e. idiopathic insulin deficiency. Apart from two major types of DM, other types are also acknowledged which are represented in Figure 1. All types of DM were supposed to be treatable since 1921 when insulin became available. However, better control of T2DM was seen after administering oral hypoglycemics. Approaches, such as pancreas transplantation and gastric bypass surgery have also been attempted with some degree of success. Gestational DM is suggested to manage during and after pregnancy by modifying life style, such as strict control over diet, regular exercise, routine checkup by analyzing blood sugar levels and special care is mandatory after the delivery of baby as mother could be at a higher risk of developing T2DM (Management of Diabetes, 2012).

Figure 1. Schematic representation of types of DM and their complications.

Though several medications are flooding into the market, complete and successful cure of DM still remain untouched because they offer several adverse effects, like gastric irritation, injection phobia, transient nausea and many more. Therefore, these medications eventually result into the patient incompliance and require highly qualified medical expertise (Tuomilehto et al., 2001; Ensign et al., 2012). Discovering stable/non-invasive drug delivery along with controlled release could prove to be more beneficial. Although precise and safe drug delivery to the specific site for scheduled period of time to get controlled and sustained release remains a touchstone, pharmaceutical researchers have largely endeavored to modify the physical and biological barriers that limit access of drugs to the therapeutic targets.

Novel drug delivery systems (NDDSs) are becoming trendy in recent years because they offer palpable benefits in terms of reduced dosing frequency, increased bioavailability, prevention from degradation specifically against the harsh gastric environment, site specificity and reduced side effects. In vitro, ex vivo and in vivo findings of numerous experimentations worldwide strongly suggested NDDSs as an emerging and promising option to combat major disorders/diseases (Dash & Konkimalla, 2011). Literature revealed that the field of drug delivery has marched at a phenomenal pace and a variety of carrier systems have come to the forefront during the last decade. Therefore, the present article portrays up-to-date advancements on delivery of antidiabetics via novel delivery systems and illustrates the worldly trend of research carried out since 2005 onwards.

Problems posed by the antidiabetics

Antidiabetics are effortlessly accessible in the international market (Table 1). Most of the oral hypoglycemics are available either in the form of tablets and capsules. However, these dosage forms offer various untoward effects/limitations like gastric irritation, diarrhea, loss of appetite, lactic acidosis in people with abnormal kidney or liver function due to gastrointestinal degradation, insolubility in water and do not comply with the safety and efficacy of the patients (http://www.joslin.org/info/oral_diabetes_medications_summary_chart.html). These adverse effects revealed the limited accessibility of conventional dosage forms at desired site of action, higher systemic toxicity, narrow therapeutic window, complex dosing schedule for long-term treatment (Sutradhar & Sumi, 2014). Two major factors required for the drugs to be effective are their optimal concentration at the desired site of action and persistent effective concentration for a longer period of time. After immediate release, oral hypoglycemics get absorb from the biological membranes and move toward the site of action. However, to attain the therapeutic concentration into the blood for whole day, about 2 to 3 doses are required to be administered (Pradhan, 2011; CIMS/MIMS India Medical Drug Information eBook, 2013). Moreover, insulin and peptide drugs namely GLP-1, GLP1RAs are available primarily as subcutaneous (SC) injections while peptide analogues, i.e. DPP-4 inhibitors (vildagliptin, (Galvus), sitagliptin (Januvia), saxagliptin (Onglyza)) are available in the global market as tablets. They have been approved by EU and USFDA for the treatment of DM in last decade. Liraglutide, Exenatide and Albiglutide act through GLP-1 receptors, which are found in brain, lung, pancreatic islets, stomach, heart, intestine and kidney. Due to the susceptibility to the proteolytic degradation in gastric environment and shorter plasma half-life, they are less frequently used for oral administration (Kalra, 2011). Their injections are available in the market but injections of exenatide cause nausea, vomiting and antibody formation when used twice a day, while liraglutide injections cause mild, transient nausea and vomiting when used once a day (Kalra, 2013). Pain at injection site and hence injection phobia is another limitation. Enhancing oral bioavailability of these analogues is a challenge. Therefore, thorough investigation is required in the area of drug delivery which could be possible by examining new and more specific drug delivery carriers (Schmid & Korting, 1996).

Table 1. Some antidiabetic drugs in conventional formulations.

S. No.	Drug/formulation	Indication	Trade name	Manufacturer
1	Insulin injections	T1DM and T2DM	Lantus	Sanofi Aventis
			Humulin&Huminsulin	Eli Lilly
			Insugen (Biocon)
			Wosulin (Wockhardt)	Biocon
			Insuman (Sanofi Aventis)	Wockhardt
				Sanofi Aventis
2	Metformin tablets	Gestational& T2DM, Polycystic syndrome	Glucophage	Bristol Myers Squibb
			Riomet	Ranbaxy
			Obimet	Abbott
			Gluformin	AHPL
3	Glimepiride tablets	T2DM	Amaryl	Sanofi Aventis
			Glimy	Shrrishti HC
			Orinase	CCL
			Glimpid	Ranbaxy Lab.
4	Glibenclamide tablets	T2DM	Daonil&Semi-Daonil	Sanofi Aventis
			Euglucon	AHPL
5	Glipizide tablets	T2DM	Glynase	USV
			Glucotrol	Jenburkt
6	Gliclazide tablets	T2DM	Glizid	Panacea
			Glyloc	Cadila
			Reclide	Dr. Reddy’s
7	Rosiglitazone tablets	T2DM	Avandia	Glaxo Smith Kline
8	Miglitol tablets	T2DM	Glyset	Pharmacia and Upjohn Company
9	Repaglinide tablets	T2DM	Prandin	Novo Nordisk INC
10	Acarbose tablets	T2DM	Glucobay	Bayer
			Precose	Genovate
11	Glibenclamide + Metformin tablets	Gestational & T2DM, Polycystic syndrome	Aviglen Forte &Aviglen-MF	Avinash
			BEN-Q-MET	Q Check
			Benclamet	RPG LS
12	Rosiglitazone + Metformin tablets	T2& Gestational DM	Avandamet	Glaxo Smith Kline
13	Rosiglitazone + Glimepiride tablets	T2DM	Avandaryl	Glaxo Smith Kline
14	Liraglutide injection	T2DM	Victoza	Novo Nordisk
15	Exenatide injection	T2DM	Exapride	Sun pharma

Probable solutions offered by the novel drug delivery systems

Limitations associated with antidiabetics offered the opportunities for the investigators to come up with such delivery systems having improved therapeutic efficacy. Novel drug delivery carrier systems are developed to deliver antidiabetic drugs safely and more precisely to the specific site for scheduled period of time in a controlled manner for better therapeutic effectiveness and henceforth better control over DM. Additionally, alteration in physicochemical and pharmaceutical properties of antidiabetics has avoided/modified the biological barriers that limit availability of actives to the various therapeutic targets. Significant advantages and major limitations of these systems are summarized in Table 2. While an array of investigations have been carried out, strategies to come up with the appropriate carrier systems for antidiabetic delivery are still being made to get widespread recognition in the global market. One such investigation was attempted by one of the authors (Agrawal et al., 2014). The proteolytic stability and antidiabetic potential of insulin were improved by developing folic acid functionalized, polymer stabilized multilayered liposomal carrier for oral administration. Liposomes were reasonably stabilized using negatively charged poly(acrylic acid) and positively charged poly(allyl amine) hydrochloride (i.e. layer by layer coating of polyelectrolytes) as coating materials and folic acid appended as ligand. Folic acid has specificity to the folic acid receptors which are usually present in ample amount over the GI tract. The excellent stability of this newly designed liposomal carrier in simulated biological fluid and hypoglycemic potential in diabetic animals for at least 18 h indicated improved therapeutic profile. In future, this investigation may be converted into a clinical reality after scaling up of this technology at large scale. In the current scientific panorama, when the area of NDDS has been recognized for its palpable benefits, the above kind of investigations can open new vistas for precise, safe and quality treatment of DM.

Table 2. Novel drug delivery systems for antidiabetics – advantages and limitations.

NDDSs	Antidiabetics	Advantages	Limitations
Microparticles	Insulin	Preserved bioactivity (Silva et al., 2006), Improved proteolytic stability (Bowey et al., 2012), Oral/nasal delivery (Wang et al., 2006; Zhang et al., 2011), Protection from acidic pH of stomach (Leong et al., 2011), Improved bio distribution	• Single method can’t be adapted to core materials all the time • Surface modification may not be uniform • Possibility of termination in therapy is very less if once the particles are administered • Process conditions like change in temperature, pH, solvent addition, and evaporation/agitation may influence the stability of core particles • Clear rapidly when taken by reticuloendothelial cells • Sometime premature drug release may be observed • Release characteristic of surface modified carriers are not always reproducible (Executive Summary; Das et al., 2014)
	Glipizide	Reduced dosing frequency and dose-related side effects and obtained sustain release (Madhusudhan et al., 2010; Maiti et al., 2011)
	Glimepiride	Improved dissolution rate (Ilić et al., 2009)
	Exenatide	Preserved the bio-stability during the preparation process, reduced injection site reactions and transient nausea (Ryan et al., 2013).
Nanoparticles	Insulin	Offered non-invasive way for delivery, encourage self-administration in to the patient (Battaglia et al., 2007, Improved effectiveness even for 22 days (Finotelli et al., 2010), Up to 350% enhancement in bioavailability as compared to insulin solution (Peng et al., 2012), Improved systemic absorption by nasal administration (Zhang et al., 2008), Improved hypoglycaemic effect and permeability (Rekha & Sharma, 2009; Damge et al., 2007), Retained bioactivity (Reis et al., 2007), Targeted to the colon for better absorption (Bayat et al., 2008)	• Particles generally seems as “nuisance dusts” and may exhibit toxic biological effects after an unintended administration through inhalation (Gwinn & Vallyathan, 2006) • Proved to be cost ineffective (Coelho et al., 2010) • Production yield is very less, lesser degree of success • Untoward immunogenic reactions may arise • Inadequate availability of toxicity data • Polyelectrolyte modified particle may disturb the ionic strength of the GI fluid (Executive Summary; Das et al., 2014; Jose et al., 2014; Guo et al., 2014).
	Metformin	Reduced dosing frequency (Cetin et al., 2013)
	Glibenclamide	Improved dissolution rate (Yu et al., 2011)
	Repaglinide	Offered prolonged release and avoided associated side effect (Lekshmi et al., 2010)
Liposomes	Insulin and peptide surrogate	Increased retention-time in lungs and hence reduced extra pulmonary side-effects (Huang & Wang, 2006), Improved proteolytic stability in oral administration (Agrawal et al., 2014), Chemical responsive release (Karathanasis et al., 2006), Sustained release and transmucosal delivery (Jain et al., 2007a)	• Coating may often be non-uniform • Entrapment efficiency is less compared to polymeric carrier systems • Leakage is major cause of instability • Sometime cholesterol which is used for bilayer arrangement, autoxidized and results in to leakage (Agrawal et al., 2014) • Possible allergic reaction due to the presence of lipid (Agrawal et al., 2014; Zhang et al., 2014).
Niosomes	Insulin and peptide drugs	Stabilized against enzymatic degradation in oral (Pardakhty et al., 2007) and vaginal delivery (Ning et al., 2005), Prolonged bioactivity for 6 h (Ning et al., 2005)	• Low entrapment efficiency (Pardakhty et al., 2007) • Instability due to alteration in molecular arrangement of surfactants.
	Metformin	Enhanced bioavailability by oral route and avoidance of associated Lactic acidosis (Hasan et al., 2013)
Gastro retentive granules	Repaglinide	Improved bioavailability (Jain et al., 2007b)	These hydrodynamically balanced systems (HBS) are unreliable in prolonging the gastric retention time (GRT) due to their ‘all-or none’ gastric emptying process and may cause variable bioavailability and local irritation due to the local availability of drug in small area of GIT (Jain et al., 2007b).
Transdermal systems	Glipizide	Avoid the side effects like fatal hypoglycemia and gastric disturbances like nausea, vomiting, heartburn, anorexia i.e. associated with the oral delivery (Mutalik et al., 2006)	• Permeation of the drug may vary in different skin type (Cevc, 2003) • Loss of the drug may be more as compare to oral delivery carriers • Electroporation or iontophoresis may change the skin integrity and cause cell damage (Rastogi et al., 2010b) • Use of penetration enhancers may lead to hypersensitivity over the skin (Rastogi et al., 2010a).
	Insulin	Proved as an ideal alternative to the injectables (Rastogi et al., 2010b), Controlled release for at least 8 h (Rastogi et al., 2010a)
	Glimiperide	Enhanced in vivo hypoglycemic efficacy (Ahmed et al., 2014)
Implant	Insulin	Sustained effect for at least 15 days (Kofuji et al., 2005; Chen et al., 2011)	• Individuals may face discomfort and sometime rejection by body defence mechanism (Coelho et al., 2010) • Requires specific medical expertise for implantation • Usually preferred where long term therapy is required
Nanodiamond	Insulin	Improved systemic availability (Shimkunas et al., 2009)	Chemical mediated desorption is required to bring the drug in active form (Shimkunas et al., 2009).
Microgel beads	Insulin	Sustained release (Nishimura et al., 2012)	–

Designing and development of novel drug delivery systems

Researchers in the area of drug delivery are constantly working on designing and development to improve the performance of intelligent drug delivery system with the purpose to maximize therapeutic activity and to minimize undesirable side-effects. It could be achieved by altering the formulation variables like process or concentration (independent variables), which eventually escalate end-user confidence (Pund et al., 2014). Since each delivery system has its own unique pharmaceutical and physiological characteristics; therefore, appropriate consideration of independent variables is very much required in the designing of final product. Acquaintance with physical, chemical and pharmaceutical characteristics of each excipient is also compulsory (Allen, 2008). Factors which are attempted to improve the insulin delivery are oral administration, proteolytic and physical stabilities in harsh biological environment. In this regard, effect of various independent variables, such as polymer/cross-linker concentration, sonication time, stirring speed, cross-linking time has been investigated over the obligatory responses (Cui et al., 2006; Graf et al., 2009). Furthermore, native structure of proteins/peptides, like Glucagon-like peptide 1 (GLP-1), GLP-1 receptors agonist (GLP1RAs) get modified when administered orally, therefore modification of its surface becomes the obligatory step in delivering these drugs before administering (Qi et al., 2013). Lipophilicity and poor water solubility of some oral hypoglycemics, like glibenclimide offered other challenges to the formulation scientist, viz. enhancement of dissolution rate which was attempted to improve solubilization of these drugs in simulated biological fluids by altering various process variables (Nnamani et al., 2010). Similarly, controlled release, consistent drug plasma concentration, improved permeation are also attempted for antidiabetics with shorter biological half-life, variable drug plasma concentration and higher first-pass metabolism. Figure 2 depicts some of the major novel delivery systems particularly employed for DM.

Figure 2. Pictorial representation of NDDSs used for the delivery of antidiabetics.

Mechanism of transport

Depending on various size, shape and integrity, each carrier system has its own mechanism of transport through the biological membranes. Moreover, altering the route of administration may offer other transport mechanism to the carrier systems. A diagrammatic representation of mechanism of drug (fabricated/encapsulated in various novel delivery systems) transport through different biological membranes is shown in Figure 3, revealing mechanism specificity of individual delivery system from various routes of administration, i.e. topical, transdermal, oral, etc. The major transport pathways of particulate system when administered orally are transcellular and paracellular (Cremaschi et al., 1996; Brooking et al., 2001; Illum, 2007). Nanosized particles, i.e. up to 10 nm often pass through the paracellular transport in a restricted quantity because the diameter of the tight junctions is 3.9–8.4 A° while larger particles, i.e. 100–500 nm, follow one of the transcellular transports, such as endocytosis and carrier- or receptor-mediated. Drug available around absorption site (previously released from NDDS) is transported via carrier-, receptor- and/or absorption-mediated transcytosis. Lipoidal carriers get integrated with the cell wall and release the drug inside the cell. Transport of particulate delivery system through skin may follow transcellular, intercellular or transappendageal pathway, whereas vesicular delivery system may follow integration of its lipid bilayer with cell wall or transappendageal pathway (Desai et al., 2010). Most of the transdermal delivery systems are assisted with physical technique, such as microporation, iontophoresis, electroporation, sonophoresis and microneedles, which have been proved to modify the barrier properties of skin. Therefore, it could be inferred that drug may follow more than one transport mechanism.

Figure 3. A diagrammatical representation of transport mechanism of drugs encapsulated in different NDDSs.

Recent advances in antidiabetic drug delivery

Exhaustive literature survey published from January 2005 to December 2013 (Figure 4) indicated keen interest of the researchers to develop NDDSs using antidiabetic drugs which is found to be intensifying gradually. Special attention is being given to nanoparticulate carrier systems followed by microparticulate and lipid-based carriers. Various clinical trials were retrieved from the clinical trials registry of the U.S. National Library of Medicine (www.clinicaltrials.gov; accessed on 4 July 2013) using the key terms “Type 1 Diabetes” and “Type 2 diabetes oral insulin”. Some of them, like inhaled insulin; exubera (Pfizer) gained FDA approval in 2006 but withdrawn from the market early 2007 due to a lack of trade and various safety concerns. Moreover, it was also approved in Europe (EMA) in 2006 but never launched due to multiple concerns and highly restricted indications. Subsequently, in the following months all the companies (Lilly, Novo Nordisk, Sanofi, etc.) have retarded the efforts and currently only Mankind is endeavoring to get the FDA approval with several ambiguous issues (safety, optimal formulation). Furthermore, microporation (a needle-free and pain-free) technique designed to deliver water-soluble drugs, proteins and peptides through skin by creating aqueous micro channels in the stratum corneum is under clinical trial phase II conducted by Altea Therapeutics. Various representative examples of antidiabetic drug-based novel delivery systems are summarized in the following section under the major heading of particulate, vesicular and miscellaneous systems.

Figure 4. Current trend of antidiabetic drug delivery via NDDSs. A graphical representation of number of published articles on anti-diabetic drugs between January 2005–December 2013.

Particulate system

Owing to the revolutionary participation of NDDS in drug delivery, particulate systems are developed periodically by the investigators because of their immense utility. The miniature particles offer even intracellular transport of drugs and attachment of specific ligands make them accessible to the specific receptor/cell/organ. Hence, these systems are considered as most preferred carriers for the delivery of antidiabetic drugs (Liu et al., 2008b). These carriers are categorized into two major classes, i.e. microsized and nanosized. A range of nano-scale drug delivery technologies, such as nanovesicles, nanotubes, micelles, dendrimers, nanoshells and many more have been investigated using variety of materials for instance biologics (lipids, peptides, nucleic acids, polysaccharides), polymers (poly(alkylcyanoacrylate), poly(3-hydroxybutanoic acid), poly(organophosphazene)), silicon, carbon and metal (Hughes, 2005). These systems are fabricated either via matrixing or by encapsulation which control the release by means of diffusion and erosion of drugs from particulate systems (Dash & Konkimalla, 2011).

Microparticulate systems

Microparticle-based therapy allows tailored drug release to the specific treatment site and formulation of various drug–polymer combination. Microparticulate system help in maintaining the therapeutic concentration of drugs (shorter half-life) in plasma for longer period of time by controlling their release. Being small in size, microparticles have larger surface-to-volume ratios and can be developed for the improvement of dissolution rate of practically insoluble drugs. Moreover, to attain optimal therapeutic concentration of drug in systemic circulation, variables, such as dose and release kinetic are manipulated time to time as per the requirement by employing microencapsulation methods, varying drug–polymer ratio etc. (Sinha et al., 2004). Microparticulate systems have been developed for oral (Rekha & Sharma, 2009), topical (Zhao et al., 2010), parenteral (Mesiha et al., 2005) and nasal (Zhang et al., 2008) routes. Literature abounds with the studies that report various type of microparticulate systems, such as magnetic microparticles, solid lipid microparticles, biological microparticles, metal based and polymeric microparticles (Table 3) (Pereswetoff-Morath, 1998; Sinha et al., 2004; Bilati et al., 2005; Hughes, 2005; Dash & Konkimalla, 2011). Concept of microencapsulation has been used to modify drug release pattern and to enhance in vivo hypoglycemic effect of Glipizide and Gliclazide (Madhusudhan et al., 2010; Barakat et al., 2013). To lengthen the life span of insulin via oral route, Furtado et al. (2008) have developed poly(fumaric-co-sebaceous) anhydride microspheres. In double dose experiment it was found that insulin containing microspheres are capable enough to maintain constant plasma glucose level (about 100 mmol/L) during the entire study for at least 15 h. The mechanisms of release of microencapsulated drugs is reported to be erosion or diffusion for matrix type and diffusion for reservoir type (Soppimath et al., 2001; Hughes, 2005). Literature unfolded that, the major transport mechanism of microparticulate systems is transcellular (through endocytosis and carrier- or receptor-mediated transport). It was suggested by Illum (2007) that hydrophilic/hydrophobic nature and size of particles are the limiting factor in the transport through biological membranes. Microsized particles are barely able to cross the mucosal membrane by the paracellular route because normal diameter of the tight junctions is 3.9–8.4 A°. Hence, microparticles cross biological membrane normally via transcellular pathway, i.e. endocytosis (carrier- or receptor-mediated).

Table 3. Recent reports on various microparticulate systems for the treatment of diabetes (Year 2005 onward).

Objective	Materials used	Method used	Hypoglycemia	Further remarks	References
1. Insulin
Oral delivery	Poly(fumaric-co-sebacic) anhydride	Phase inversion nanoencapsulation	>14 h	Altered onset, peak and duration of insulin action	Furtado et al. (2008)
Preservation of protein stability	Alginate	Emulsification and internal gelation	2 h	Decreased hyperglycemia, retained bioactivity of insulin	Silva et al. (2006)
Oral delivery	Alginate & chitosan	Membrane emulsification	60 h	Sustained release of bioactive insulin for 60 h	Zhang et al. (2011)
Oral delivery	Chitosan	SPG membrane emulsification	>14 days	Oral delivery of bioactive insulin provided improved bioadhesion, loading and sustained release (>14 days)	Wei et al. (2010)
Improved Stability	Alginate	Spray drying	88% ± 15% bioactivity retained	Spray drying produced bioactive, spherical particles with average diameter 2.1 ± 0.3 μm and EE 38.2% ± 9.5%	Bowey et al. (2012)
Nasal delivery	Aminatedgelatin microspheres (AG)	Emulsion polymerization	>300 min	Insulin release from AGMS was significantly slower than GMS, but there was no difference in the release of model drugs from two microspheres	Wang et al. (2006)
Oral delivery	Chitosan	Emulsion cross-linking	25% for 3–12 h	Efficient oral delivery was done by particles of 29.5μm particles and 71.6 ± 1.3% encapsulation efficiency	Jose et al. (2012)
Protection from GIT environment	Carboxymethylated kappa-carrageenan	Ionic gelation	12–24 h	Insulin release in SGF was found to be 4.2 ± 0.4% during the first 2 h and complete release in SIF in the next 10 h	Leong et al. (2011)
In vivo multi-day release	PLGA	Single o/w emulsion	>9 days	Formulations with drug content of 14% show very low (<1%) initial release of insulin for one day and near zero order drug release after a lag of 3–4 days	Hinds et al. (2005)
Controlled release	Tristearin/phosphatidylcholine/PEG	Supercritical CO2 gas microatomisation	>5 h	Slow release for about 70–80 h was observed according to a diffusive mechanism	Salmaso et al. (2009)
Controlled release	Fe3+ and dextran sulfate	Layer-by-layer deposition	6 h	Improved glucose tolerance i.e. 2 h from free insulin to 12 h from insulin-loaded MPs with 10 bilayers	Zheng et al. (2009)
2. Glibenclamide
Oral delivery	Phospholipon 90G & Softisan 142	Fusion method	>24 h	Higher glucose–lowering effect than that of market formulations	Nnamani et al. (2010)
3. Glimepiride
Oral delivery	Gelucire 50/13, poloxamer 188 and PEG 6000	Spray congealing	Not yet done	Higher dissolution rate was found using Gelucire 50/13 i.e. about 35.6% in 120 min, followed by poloxamer 188 and PEG 6000 with 29.0% and 28.6%, respectively	Ilić et al. (2009)
4. Glipizide
Prolonged Release	Gellan gum	Ionotropic gelation	Not done	Oral delivery, minimizes dosing frequency and dose-related side effects	Maiti et al. (2011)
Oral sustained release	Eudragit (RS 100 & RL 100)	Emulsion solvent evaporation	Up to 12 h	Prolonged hypoglycemic effect i.e. up to 12 h hence better suited for oral sustained delivery	Madhusudhan et al. (2010)
5. Gliclazide
Controlling systemic absorption	Alginate	Ionotropic gelation	>24 h	Maintained optimum blood glucose level and improved patient compliance by enhancing the systemic absorption of gliclazide	Al-Kassas et al. (2007)
Oral sustained drug delivery	Chitosan	Ionic cross-linking	Up to18 h	Antidiabetic effect was seen after 8 h and lasts up to 18 h compared to gliclazide powder (after 4 h) suggesting sustained release	Barakat & Almurshedi (2011)
Oral sustained drug delivery	Poly-E-capro-lactone, Eudragit RS and ethyl cellulose	Solvent evaporation	MRT of drug for up to 12 h	Plasma concentration of gliclazide in PCL-Eudragit RS or ethyl cellulose microparticles was found to be higher than that observed for its solution after oral administration for extended period of time	Barakat et al. (2013)
Oral delivery	Tamarind seed polysaccharide and alginate	Ionotropic gelation	>12 h	Microspheres were found much useful for prolonged action with maintained blood glucose level and enhance patient compliance	Pal & Nayak (2012)
6. Repaglinide
Controlled Release	Eudragit S and Calcium silicate	Emulsion solvent diffusion	Not done	Easily prepared with good buoyancy, high encapsulation efficiency, and sustained drug release over several hours	Jain et al. (2005)
7. Exenatide
Long-effective, sustained delivery, improved glycemic control	PLGA	Premix membrane emulsification technique, emulsion solvent extraction double-emulsion solvent evaporation	Up to 7–30 days	The bio-stability of exenatide in microspheres was preserved during the preparation process and release, hence reduced side effects Exenatide loaded microspheres were proved to have great potential for clinical use. Exenatide microspheres have also shown significant hypoglycemic activity atleast for one month by controlling plasma glucose similar to that of exenatide solution injected twice daily.	(Liu et al., 2010; Ryan et al., 2013; Qi et al., 2013; Xuan et al., 2013)

Nanoparticulate systems

Relatively higher intracellular uptake of nanoparticulate systems makes them the carriers of choice in delivering antidiabetic drugs (Table 4). Moreover, they have wide size range (1–1000 nm), covering a variety of structures, such as nanospheres, nanocapsules, nanodiamonds and nanofibers (Hamidi et al., 2008; Dash & Konkimalla, 2011). They can be categorized as polymeric NPs, metal-based NPs, lipid-based NPs and biological NPs. Methods adopted to develop these nanostructures are emulsion solvent evaporation, solvent displacement, diffusion solvent evaporation, ionotropic polyelectrolyte pre-gelation, polyelectrolyte complexation, dispersion polymerization, interfacial polymerization of microemulsion, ionic gelation, free-radical precipitation/dispersion, etc. (Cui et al., 2006; Battaglia et al., 2007; Zhang et al., 2008; Graf et al., 2009; Rekha & Sharma, 2009; Woitiski et al., 2010; Dash & Konkimalla, 2011). They have undoubtedly improved the blood glucose lowering potential of drug-like insulin even up to 22 days (Figure 5), protected actives from harsh gastric pH, enhanced bioavailability and reduced dosing frequency (Finotelli et al., 2010; Peng et al., 2012). Liu et al. (2008a) have reflected the potential advantages of nanoparticulate systems, i.e. mainly attributed to their minute size and explicit morphology which makes them able to pass through very fine blood capillaries and protect peptide/peptide surrogate or other contents from deteriorator enzymes. In one of the reports, Soppimath et al. (2001) have published that, the rate of drug release and pattern of NPs degradation depend on desorption of drug molecules adsorbed on surface, matrix diffusion of NP, drug diffusion from polymer shell, matrix erosion of nanoparticles and combination of erosion as well as diffusion. As far as their transport from biological membrane is concerned, authors declared that nanoparticles are transported via both cellular uptake processes, such as transcellular (clathrin- and caveoli-mediated endocytosis, pinocytosis, and less commonly known, phagocytosis) and paracellular pathway (Brooking et al., 2001; Illum, 2007; Jong & Borm, 2008). Furthermore, increased mucoadhesion and retention of nanoparticles in the gastrointestinal tract is due to electrostatic interactions between the positively charged nanoparticles and the negatively charged mucus and endothelial layer, or through a physical capture of the nanoparticle by the mucus layer. These systems have improved oral delivery of poorly adsorbed drugs and proteins by increasing time of retention and extent of interaction with the mucus layer of the intestine. Mucoadhesive polymers, such as Eudragit (Evonik, Essen, Germany), poly(acrylic acid), sodium alginate and chitosan help in mucoadhesiveness, which ensures increased mucosal interaction. Quick exit of nanoparticles can be seen if they are loosely attached to the mucus layer. Therefore, it is preferred to achieve adherence in the deeper mucus layer, which is shed less often and provides a longer interaction with the GI tract. Site specificity and controlled release nature of these systems was also affirmed owing to their biodegradability, pH specificity, ionic and/or temperature sensibility, well-organized drug distribution pattern along with drug protection and lower onset of toxicity (Soppimath et al., 2001; Koo et al., 2005; Hamidi et al., 2008; Jong & Borm, 2008; Faraji & Wipf, 2009).

Figure 5. Reported hypoglycemic effect of insulin fabricated in various NDDSs.

Table 4. Recent reports on different nanoparticulate approaches used for antidiabetics (Year 2005 onward).

Objective	Materials used	Method used	Hypoglycemia	Further remarks	Year Refs.
1. Insulin
Oral peptide delivery	Succinyl and lauryl derivative of chitosan (LSC)	Sodium tripolyphosphate (TPP) cross linking	6 h	Improved release, mucoadhesiveness and permeability	Rekhaand Sharma (2009)
Colon targeting	Chitosan and its quaternized derivatives	Polyelectrolyte complexation	5 h	Better insulin transportation across colon membrane	Bayat et al. (2008)
Sustained release	Poly(alkylcyanoacrylate)	Interfacial polymerization of microemulsion	36 h	Oral delivery by NPs have been achieved along with optimum absorption enhancement	Graf et al. (2009)
Transdermal delivery	DMSO solution	Supercritical antisolvent	–	Release mechanism of insulin was found in accordance with the Fick’s first diffusion law with high permeation rate. Results suggested great potential of TDD system encompassing nanoparticles for the treatment of DM	Zhao et al. (2010)
Improved SC absorption	Poly(isobutylcyanoacrylate)	Anionic in situ polymerization	6 to 72 h	Subcutaneous absorption of entrapped insulin was found significantly better to non-encapsulated insulin	Mesiha et al. (2005)
Permeation enhancement	Trimethyl chitosan (TMC) & its cysteine conjugate	Polyelectrolyte complexation	>8 h	Self-assembled NPs of TMC-Cys and peptides could be an effective and safe carrier for oral delivery as suggested by this study	Yin et al. (2009)
Control insulin release	Poly(lactic-co-glycolic acid) PLGA, PVA	Reverse micelle–solvent evaporation	8 h to 12 h up to 57.4%	NPs are found able to improve the intestinal absorption of insulin	Cui et al. (2006)
Oral delivery	PLGA	Hydrophobic ion pairing	Glycemia reduced to 23.85% for 12 h	Insulin sodium oleate complex loaded PLGA nanoparticles are found to be an effective method for reducing glucose levels as in oral delivery system	Sun et al. (2010)
Sustained delivery	Poly (hydroxyl butyrate-ohydroxy hexanoate)	Solvent evaporation	3 days	5.42% release was found in 8 h and 20% in 31 days, Bioavailability enhanced up to 350% compared to insulin solution	Peng et al. (2012)
Nasal absorption enhancement	PEG-g-chitosan & tripolyphosphate ions	Ionotropic gelation	>5 h	PEG-g-chitosan has improved the systemic absorption of insulin through the nasal mucosa	Zhang et al. (2008)
Pulmonary delivery	Sodium cholate and soya phosphatidyl choline	Reverse micelle-double emulsion	24 h in fasting animals	Improved in vitro and in vivo stability, a pharmacological bioavailability of 24.33% and a relative bioavailability of 22.33% was also observed	Liu et al. (2008a)
Stable peptide delivery	Isovaleric acid, GMS, soy lecithin	Solvent-in-water emulsion–diffusion	Same as insulin alone	Insulin extracted from SLN decreases blood glucose levels quite similar to a conventional insulin suspension and seem to have possibilities as novel system for oral delivery of insulin	Battaglia et al. (2007)
Controlled release	Low-molecular-weight chitosan	Solvent evaporation	>24 h	Burst release for 2 h followed by zero order release along with 95.54% entrapment efficiency was seen	Huang et al. (2009)
Improved oral bioavailability	Alginate, dextran sulfate, oloxamer 188 and chitosan	Ionotropic gelation and polyelectrolyte complexation	40% of glucose level for >24 h	13% oral bioavailability showed a threefold increase in comparison to free insulin	Woitiski et al. (2010)
Sustained action	Chitosan	Ionotropic gelation	>11 h at dose of 100 IU/kg	Pharmacological activity was not observed because of increase in the serum insulin concentration but because of local action of insulin in the intestinal epithelium	Ma et al. (2005)
Oral administration	Poly (-ɛ-caprolactone) & Eudragit RS	Multiple emulsion	>12 h	Hypoglycemia of non-encapsulated insulin was disappeared after 10 h but of encapsulated insulin was seen for >12 h	Damge et al. (2007)
pH sensitive oral delivery	Poly-g-glutamic acid, chitosan	Ionic-gelation	>10 h	Relative bioavailability of insulin was found to be 15.1 ± 0.9%	Sonaje et al. (2009)
Preoral delivery	Dextrans and epichlorohydrin	Emulsion polymerization	>54 h	Burst release was shown initially followed by diffusion controlled first order kinetics with 75–95% release within 48 h	Chalasani et al. (2007)
Trans-nasal delivery	Starch	Cross linking	>6 h	The release rate and higher associated surface could be more amplified when combined with permeation enhancers for making these NPs as an efficient carrier	Jain et al. (2008)
Improved oral bioavailability	Alginate–dextran	Nanoemulsion dispersion followed by triggered in situ gelation	>8 h	Insulin in NPs was found bioactive as demonstrated by in vivo and in vitro bio-assays	Reis et al. (2007)
Magnetic delivery	Fe2O3, sodium alginate, chitosan	Cross linking polymerization	>22 days	50% of the insulin release was found in to water after 800 h of the in-vitro release study	Finotelli et al. (2010)
2. Metformin
Oral sustained release	Eudragit RSPO, Eudragit RSPO and PLGA	Nanoprecipitation	Not done	Sustained release nanoparticles of metformin HCl prepared with reduced dosing frequency and maintained effective plasma concentration which improved patient compliance by reducing the incidence of side-effects	Cetin et al. (2013)
3. Glibenclamide
Stabilization of structure	Polyvinylpyrrolidone and HPMC	Anti-solvent precipitation in high gravity	Not done	Dissolution rate of NPs was found 85% in 5 min as compared to tablets (55% in 5 min) whereas it was found physically stable for >70 days at room temperature	Yu et al. (2011)
4. Glipizide
Sustained release	Poly(D,L-lactic-co-glycolic acid)	Modified emulsification solvent evaporation	In-vivo not done	40% release in 24 h followed by slow release up to 90% within next 48 h, NPs were found stable for 6 months.	Jain & Saraf (2009)
5. Repaglinide
Prolonged drug release	Poly(methylmethacrylate) and PVA	Solvent evaporation	In vivo study is to be done	NPs illustrated prolong drug release and the toxicological studies revealed NPs formulations safe to administer	Lekshmi et al. (2010)
6. Exenatide
Sustained delivery	La-phosphatidylch oline and Pluronic F-68	Layer by layer freeze and drying	24 h	The results demonstrated that the multilayer NPs can be utilized as a delivery vehicle for sustained release of protein-based drugs.	Kim et al. (2013)

Recently, nanomedicine-based oral drug delivery systems for antidiabetics have gained significant attention because of their nano size distribution, site specificity and excellent protection to peptides by maintaining their proteolytic stability in physiological fluids.

Vesicular system

Vesicular systems have immense utility in drug delivery due to the presence of lipid bilayer like arrangement similar to the cell membrane. Delivery of bioactive molecules has been improved by means of an ultra-deformable vesicular carrier. The physicochemical characteristics of drugs, like size, charge, lamellarity, elasticity (Benson, 2006), solubility and thermodynamics get affected (Vinod et al., 2012) by the composition of these carriers. They are reported to deliver drugs, like minoxidil, enoxacin, aceclofenac and estradiol via transdermal route and as a carrier of insulin which improved the proteolytic stability in gastrointestinal tract. These carriers have exhibited safe and sustained delivery of medicaments for longer period of time (Karathanasis et al., 2006; Kumar & Rajeshwarrao, 2011). Their biodegradable nature and uptake via phagocytes (Gupta et al., 2012) provide an opportunity to the formulation scientist to target drugs even inside the cells. Foremost significance of these systems, are to deliver very less soluble drug, improve stability and therapeutic concentration in plasma and reduce dose-dependent toxicity (Huang & Wang, 2006; Karathanasis et al., 2006). On account of which, a variety of vesicular carriers, such as liposomes, niosomes and pharmacosomes has been attempted periodically (Table 5) which are offering various opportunities and challenges for formulation scientists to come up with the improved therapy.

Table 5. Vesicular systems developed for antidiabetic drugs.

Objective	Materials used	Method used	Hypoglycemia	Further remarks	Year Refs.
1. Insulin
Liposomes
Pulmonary delivery	Hydrogenated egg phosphatidylcholine (PC) and egg PC	Film shaking & membrane dialyzing	Up to 6 h	Liposome-mediated pulmonary delivery of insulin promoted increase in the drug retention-time of the lungs, reduction in extra pulmonary side-effects which leads to enhanced therapeutic efficacies.	Huang & Wang (2006)
Triggered Release	Phosphatidyletha nolamine & PC	chemical bridges cleavable	20 h	Euglycemic clamp studies verified triggered insulin release from agglomerated vesicles upon application of cysteine	Karathanasis et al. (2006)
Transmucosal delivery	Phosphotidylcholine, cholesterol, bicinchonic acid	Two-step double emulsification	72 h	These mucoadhesive carriers are best alternative for sustained release of insulin by eliminating invasive medication systems.	Jain et al. (2007a)
Enhanced pulmonary delivery	Soya lecithin, cholesterol	Modified reverse phase evaporation	12 h	Intratracheal instillation of insulin-loaded liposomes showed better hypoglycemic effect with blood glucose at its lower level for a longer period of time and showed bioavailability as high as 38.38%.	Bi et al. (2008)
Niosomes
Sustained oral delivery	Polyoxyethylene alkyl ethers	Film hydration	Not done	Niosomes are found able to stabilize insulin against enzymatic degradation and can be a promising candidates for its oral delivery	Pardakhty et al. (2007)
Vaginal delivery	Span 40 and Span 60	Lipid phase evaporation with sonication.	>350 min	This study revealed niosomal delivery of insulin as an active and effective way for vaginal route	Ning et al. (2005)

Liposomes

Liposomes are artificially prepared vesicular systems chiefly composed of a lipid bilayer. Literature unfolds various types of traditional liposomes, such as uni-lamellar (ULV) or multi-lamellar vesicular systems (MLV) (Ye et al., 2000; Karathanasis et al., 2006). Drugs/actives like cytotoxic, antidiabetics, anti-cancerous, proteinaceous and genetic material have been encapsulated in liposomal systems and it has been proved as a carrier of choice for the drug accumulation at the desired site of action. Several formulation strategies, namely thin film hydration and membrane dialyzing method (Huang & Wang, 2006), two-step double emulsification (Pardakhty et al., 2007), modified reverse phase evaporation (Pardakhty et al., 2007; Misra et al., 2009), etc., are made to develop such liposomes using a variety of polymers. Ye and his colleagues (2000) have developed sustained release liposomal carrier system of insulin and peptides, such as leuprolide, enkephalin and octreotide using DepoFoam technology and revealed higher degree of drug loading and very narrow particle (spherical shape) size distribution. In vitro release and in vivo pharmacodynamic studies suggested their sustained release for several weeks. Another approach like triggered release of insulin by means of liposomal delivery to the lungs has also been attempted (Bi et al., 2008), which ensured extended hypoglycemic effect, i.e. up to 72 h (Pardakhty et al., 2007) with a reduced degree of side effects and improved efficacy. Karathanasis et al. (2006) have developed the inhaler of insulin fabricated in multifunctional liposomal delivery system for its environment-sensitive release after inhaling. Cross-linking of liposomes was made by chemical bridging which was cleavable by cysteine. A rapid release of encapsulated insulin into deep lung took place after the contact of liposomal carrier with cysteine. Today, liposomal technologies have been explored extensively and many of the formulations for antidiabetic drugs are being developed by multinational companies. Some of the formulations have been approved by FDA (Siekmeier & Scheuch, 2008). However, introduction of oral formulation in global market is still awaited.

Niosomes

Niosomes, a non-ionic surfactant vesicles having lamellar structure formed by self-assembly of surfactant molecules. Niosomal vesicular systems are developed to improve the oral bioavailability of poorly water soluble drugs, like Glibenclamide, to reduce dosing frequency and dose-dependent toxicity of the drugs with smaller half-life like Metformin. Hydrophilic -lipophilic balance of surfactants, chemical structure of ingredients and packaging parameters are the key factors behind the formation of bilayer vesicles. A variety of properties of non-ionic surfactant vesicular system are summarized (Bi et al., 2008; Kumar & Rajeshwarrao, 2011). Niosomes have been placed as a system to enhance the bioavailability of drugs having very low aqueous solubility and to make active drug available at the desired site of action in a controlled manner for a longer duration. Insulin-loaded niosomes were also found to have good stability in the presence of proteolytic enzymes of GI tract when sodium deoxycholate was used as a surfactant. Encapsulation of active ingredients in niosomes could prove to be quite appropriate in the reduction of toxicity of antidiabetic drugs, increase absorption, stability and drug action (Pardakhty et al., 2007).

Miscellaneous systems

Novel drug delivery systems are becoming the revolutionary approach in delivering antidiabetic drugs. Numerous efforts have been made till date by the formulation scientists. A report on electroporative delivery of insulin, i.e. encapsulated in the polymer vesicles suggested the usefulness of electroporation in the enhancement of insulin deposition over the skin by measuring the flux in vitro (Rastogi et al., 2010b). Confocal microscopy demonstrated the presence of nanoparticles in the deeper layers of epidermis. In vivo comparison of electroporation of insulin solution and nanoparticles into the skin showed hypoglycemic effect for at least 24 and 36 h, respectively. Therefore, this approach was considered as an alternative to the injectable insulin formulation. Another method of transdermal delivery is microporation, which mechanically creates micropores into the skin by means of thermal, radiofrequency and laser ablation (Banga, 2009). It has been proved as a needle-free and pain-free process to deliver water-soluble drugs, proteins, and peptides through stratum corneum and termed as the PassPort System (Alan & Eric, 2008). Since oral hypoglycemics, like glipizide causes severe hypoglycemia and gastric disturbances in the normal doses and intended to be taken for a longer period of time, so the patient compliance is an important concern. To avoid such limitations, Mutalik et al. (2006) have developed Glipizide containing matrix type transdermal systems (TDDSs) using ethyl cellulose (hydrophobic), polyvinylpyrrolidone (hydrophilic) and Eudragit RL-100 (hydrophilic)/Eudragit RS-100 as polymers. These systems can also be used when immediate termination of the therapy is required. Representative miscellaneous systems are summarized in Table 6. One of such carriers is porous floating granular delivery system of repaglinide (fast and short acting meglitinide analog), which was reported to demonstrate controlled release and augmented gastric retention time of drug (Jain et al., 2007b). Furthermore, a report on nanodiamonds of insulin was published in 2009 (Shimkunas et al., 2009) using pH-dependent polymer. In this investigation, bovine insulin was non-covalently bound to detonated nanodiamonds via physical adsorption in an aqueous solution, which demonstrated pH-dependent desorption and significant insulin release in alkaline environments of sodium hydroxide. In another investigation (Chen et al., 2011), controlled release, glucose responsive, self-assembled multilayer films of insulin have developed for installation beneath the skin. This multilayer film showed continuous release of insulin in vivo after being subcutaneously implanted in streptozotocin-induced diabetic rats and reduced blood glucose level for at least two weeks. It was affirmed that, this system have potential and great future in glucose-responsive delivery of medicaments due to its distinct mechanism.

Table 6. Miscellaneous noteworthy novel carriers for antidiabetics.

Objective	Materials used	Method used	Hypoglycemia	Further remarks	References
1. Insulin
Implantable Systems
Controlled release	Chitosan and sodium hyaluronate	UV-initiated free radical polymerization	-	Subconjunctivally implantable hydrogels have potential for long-term periocular delivery of insulin or other drugs to treat diabetic retinopathy and other retinal diseases.	Misra et al. (2009)
Sustained release gel beads	Chitosan	Chelation with copper ions	15 days	This formulation strategy resulted biocompatible and biodegradable system from which peptide and protein drugs can be encapsulated and targeted.	Kofuji et al. (2005)
Controlled Release	Poly[2-(dimethylamino) ethyl methacrylate	Layer-by-layer	2 weeks	Multilayer film was found to be release enough insulin in vivo in streptocozotin-induced diabetic rats and also found reducing the blood glucose level for a period of 2 weeks.	Chen et al. (2011)
Microgel beads
Sustained Release	Pluronic-LA2-DA macromer	Suspension inverse polymerization	–	Protein stability during encapsulation and after release was confirmed by FTIR, Raman and circular dichroism measurements that revealed the utility of post-fabrication encapsulation technique which is found much unique.	Nishimura et al. (2012)
Nanodiamonds
Improved systemic availability	Nanodiamonds insulin complex	Physical adsorption	–	MTT viability assays and quantitative RT-PCR revealed that bound insulin remains inactive until alkaline-mediated desorption followed by its sorption (insulin in active form).	Shimkunas et al. (2009)
Mesoporous materials
Controlled Release	Folded sheet mesoporous (FSM) silica	Freezing and thawing	–	The smallest pore size of FSM was found suitable for a fast release of insulin while medium-pore FSM with slow release. This shows that the desired release of insulin could be achieved by choosing suitable pore size.	Tozuka et al. (2010)
Transdermal delivery
Transdermal Sustained delivery	PVA, glutaraldehyde	Modulated iontophoresis	8 h	This study revealed the applicability of this system using penetration enhancers in combination for enhancing the flux of molecules such as protein, i.e. insulin to its desired therapeutic levels.	Rastogi et al. (2010a)
Controlled Release	CS and PVA	Cross linking polymerizations	–	In vitro drug release of this system was found in accordance of Fick’s first law of diffusion with high permeation rate (4.421 μg/(cm^2 h)) which suggested it as a promising TDD system for diabetes treatment	Zu et al. (2012)
Transdermal delivery of macromolecules	PEG, e-caprolactone	Electroporation	36 h	Electroporation of polymeric nanoparticles results as an ideal alternative system for injectable administration.	Rastogi et al. (2010b)
2. Glipizide
Transdermal systems
Matrix transdermal systems	PVP/EC and Eudragit RL-100	–	Up to 13% of initial value for 6 weeks	In vivo study revealed its severe hypoglycemic effect in the initial hours and found effective also for long time application. Negligible skin irritation along with better improvement in diabetes is measured compared to oral administration.	Mutalik et al. (2006)
3. Repaglinide
Porous floating granular delivery system
Controlled gastro retentive delivery	HPMC K4M, EC, carbopol 940	Cross-linking polymerizations	–	After formulating relative bioavailability of repaglinide increased 3.8-fold in comparison to that of its marketed capsule with excellent buoyant ability and suitable drug release pattern.	Jain et al. (2007b)

Future prospects

Industries and various leading research institutes are working to develop new ways of administering antidiabetic drugs, from pills to nano and micro structures NDDS-based system. For example, Microcapsule of Octreotide Acetate was prepared by Novartis and clinical trial on human has been completed in 2011 and presently, it is flooding into the market with a brand name SandostatinLAR. This type of practice provides a healthy environment for new NDDSs systems to get into the clinical pipelines. As a consequence, it opens the doors for several other novel systems which are under development. NDDSs of some other drugs, such as Albiglutide nanoparticle (GlaxoSmithKline), Insulin liposome (Phosphagenics, Ltd. Biotek, Andhra Pradesh, India), Transdermal basal insulin patch for the treatment of T1DM (Altea Therapeutics, Clinical Research Center, Atlanta, GA), etc., are in phase II and III of clinical trial and are appeared as a promising option for the delivery of more sensitive drugs. However, progression of NDDS (in case of DM) critically depends on cost, registration, approval procedures. Fortunately, government is highly influenced by the probable outcome from NDDS but little concerned regarding its overall economic impact. Hence, some developed and developing countries decided to provide funds to support the cost of research. Wherever possible, the collaboration amid two or more organizations with multidisciplinary expertise should also be made at global level. Moreover, the protection of intellectual property rights is very important, which offer a huge commercial success of the product after being transferred to the pharmaceutical industry. Furthermore, there is a need to reassess the testing parameters for the evaluation of NDDSs-based products. Toxicological risks, i.e. unique to novel systems, demands amendment in the guidelines in near future. FDA has documented the guideline for “alternative delivery systems” whereas to get the NDDSs-based quality product, specific guidelines are needed in the future. Finally, it could be expected that the success of several over-engineered delivery systems will boost reluctant people to look at NDDSs more closely.

Conclusion

Diabetes mellitus is accounted for extensive health and economic burden annually, however, the development in the field of drug delivery and disease management is stagnant. Simultaneously, the limitations associated with the current marketed formulations demand for easy and non-invasive systems with long lasting hypoglycemic effect and patient compliance. Cognizance of NDDS pertaining to diabetes treatment has risen gradually that is evidenced from nanoparticulate systems in which noteworthy results were found. Moreover, the pharmacoeconomic analysis indicates lower cost of treatment by means of NDDSs. But the commercial, societal and regulatory aspects related with these systems are still ambiguous even when massive research has been done. Therefore, to make these systems available in the global market, their safety profile, safety pharmacology, environmental effects during formulation and their potential effects on the health are to be addressed properly. Furthermore, the developed formulations need to be extensively optimized in different animal species to minimize the incidences of failure at clinical level in different human subjects.

Declaration of interest

The authors declare no conflicts of interest.