**2. Advances on the melatonin** *per os* **administered modified-release solid formulations**

Scientific research has been conducted for the purpose of MLT evaluation not only towards medicine and clinical evaluation but also towards pharmaceutics [1–3]. Many researchers have studied and managed to produce immediate-release formulations of MLT (tablets, creams, sublingual sprays, nasal preparations, injectables, etc.), in order to facilitate sleep-onset problems. MLT modified-release formulations are clinically more useful in initiating and maintaining sleep in elderly insomniacs than those designed for immediate release. More in particular, the sustained-release dosage form which delivers MLT in a time period over 8 h is of clinical value for those who have disordered circadian rhythms [4, 5]. Therefore, the modified release of MLT from oral solid dosage forms that alter the time and/or the rate of MLT release may provide an alternative for MLT delivery and be useful in the treatment of circadian rhythmic disorders, like insomnia, jet lag, seasonal affective disease, shift work syndrome, etc. [6]. The recent advantages of MLT modified-release *per oral* solid formulations are reviewed below and summarized in **Table 1**.

Aiming at this mode of release of MLT, a series of hydrophilic matrix tablets has been prepared and tested in vitro. The tablets comprised of combinations of excipients (hydroxypropyl methylcellulose K 15 M (HPMC), low-viscosity sodium alginate, Avicel PH 102, etc.) and a variety of cyclodextrins (MLT (guest)-cyclodextrin (host) complexes in 1:1 ratio). The release studies that were performed in two dissolution media (acidic pH 1.2 and basic pH 7.4) suggested that melatonin was released faster from the MLT-cyclodextrin complexes than from the matrix systems possibly due to their increased solubility [7]. In another investigation, a rather unexploited biomaterial for applications in the design of drug delivery systems, the algal sulphated polysaccharide ulvan was used as an excipient in MLT solid dosage forms. The dissolution tests showed that the MLT release from the ulvan-based tablets followed a sigmoidal pattern, which denoted that the drug release is controlled by polymer relaxation and/or erosion [8]. In a similar study, hydrophilic matrix tablets with various excipients (hydroxypropyl methylcellulose K15 M, low-viscosity sodium alginate, lactose monohydrate and polyvinylpyrrolidone M.W.: 10.000 and 55.000) were developed and tested in vitro at two dissolution media (pH 1.2 and 7.4) in order to examine the modified-release characteristics of MLT. The objective was to produce a formulation with a quick initial pace, aiming at a satisfactory sleep onset, followed by a prolonged release that could target poor sleep quality problems. The dissolution results indicated that the combination of the excipients with different physicochemical properties could alter the release of MLT from solid matrix systems [9].

Moreover, researchers have developed matrix tablets comprised of common hydrogels (hydroxypropyl methylcellulose and dextran) to study the influence on the release profile of MLT in vitro and liposomes (of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and dipalmitoylphosphatidylglycerol) incorporating the hormone in order to compare

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**Table 1.**

Immediate and sustained

Immediate and controlled

Per Os *Administered Modified-Release Solid Formulations of Melatonin: A Review of the Latest…*

Modified Matrix tablets HPMC K15 M, MCC, sodium

Nanofibrous electrospun mats incorporated into monolayered and threelayered tablets

Electrospun nanofibres in

Calcium alginate beads in hard gelatin capsules

Solid lipid nanoparticles in hard gelatin capsules

Slow Matrix tablets HPMC, Carbopol 971P, MCC,

Controlled Matrix tablets HPMCK15 M, low-viscosity

Sustained Matrix tablets HPMC, Avicel, Primojel, Ac-Di-Sol,

Delayed Compression-coated tablets Dextran, PVP(M.W.: 10.000), ethyl

Biphasic Matrix tablets Dextran, PVP (10.000), ethyl

*An overview of the recent advantages of MLT modified-release* per oral *solid formulations.*

Coated beads in hard gelatin

capsule

*DPPG: Dipalmitoyl-phosphatidylglycerol.*

capsules

**Delivery system Excipient (s) Reference**

MCC, LM

Liposomes DPPC, DPPG [10]

maize starch

Cab-O-Sil

Beads Sodium alginate, Eudragit® RS100,

Bilayer tablets Dextran, ethyl cellulose (45cps),

*HPMC: Hydroxypropyl methylcellulose, MCC: Microcrystalline cellulose (avicel PH 102), PVP: Polyvinylpyrrolidone, PEO: Polyethylene oxide, CA: Cellulose acetate, LM: Lactose monohydrate, DPPC: 1,2-dipalmitoyl-sn-glycero-3-phosphocholine,* 

10.000 or 55.000)

LM, sodium alginate

sodium alginate

MCC, maize starch

PVP, HPMC

alginate and various cyclodextrins

PVP (M.W.: 10.000 and 55.000), sodium alginate (low viscosity 2%), HPMC K15 M, dextran, MCC, LM

Dextran, MCC, HPMC K15 M,

PVP (M.W.: 1.300.000), CA (M.W.: 50.000), HPMC K15 M, LM

PVP (M.W.: 1.300.000), CA (M.W.: 50.000), hypromellose 2910, PEO (M.W. 900.000 and 400.000)

Polyplasdone, Mg stearate, Talc,

sodium alginate, LM, PVP (M.W.:

aluminum tristearate, polyethylene, glycol 400, liquid paraffin

cellulose (45cps), Avicel PH 102,

cellulose (45cps), MCC, LM,

MCC, LM, sodium alginate

MT-b-CD, HPMC, Carbopol 971P,

Core sugar spheres, Aquacoat**®**, dibutyl sebacate, triethyl citrate,

Stearic acid, Epikuron 200, lactose [16]

Ulvan, HPMC K15 M, low-viscosity sodium alginate, LM, PVP

[7]

[8]

[9]

[10],

[11]

[12]

[13]

[14]

[15]

[17]

[18]

[19]

[19]

[19]

[20]

[20]

*DOI: http://dx.doi.org/10.5772/intechopen.91158*

**Drug release behaviour**


Per Os *Administered Modified-Release Solid Formulations of Melatonin: A Review of the Latest… DOI: http://dx.doi.org/10.5772/intechopen.91158*

*HPMC: Hydroxypropyl methylcellulose, MCC: Microcrystalline cellulose (avicel PH 102), PVP: Polyvinylpyrrolidone, PEO: Polyethylene oxide, CA: Cellulose acetate, LM: Lactose monohydrate, DPPC: 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, DPPG: Dipalmitoyl-phosphatidylglycerol.*

#### **Table 1.**

*An overview of the recent advantages of MLT modified-release* per oral *solid formulations.*

*Melatonin - The Hormone of Darkness and Its Therapeutic Potential and Perspectives*

release formulations with a minimum number of experiments.

**solid formulations**

**2. Advances on the melatonin** *per os* **administered modified-release** 

*oral* solid formulations are reviewed below and summarized in **Table 1**.

cal properties could alter the release of MLT from solid matrix systems [9].

Moreover, researchers have developed matrix tablets comprised of common hydrogels (hydroxypropyl methylcellulose and dextran) to study the influence on the release profile of MLT in vitro and liposomes (of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and dipalmitoylphosphatidylglycerol) incorporating the hormone in order to compare

Aiming at this mode of release of MLT, a series of hydrophilic matrix tablets has been prepared and tested in vitro. The tablets comprised of combinations of excipients (hydroxypropyl methylcellulose K 15 M (HPMC), low-viscosity sodium alginate, Avicel PH 102, etc.) and a variety of cyclodextrins (MLT (guest)-cyclodextrin (host) complexes in 1:1 ratio). The release studies that were performed in two dissolution media (acidic pH 1.2 and basic pH 7.4) suggested that melatonin was released faster from the MLT-cyclodextrin complexes than from the matrix systems possibly due to their increased solubility [7]. In another investigation, a rather unexploited biomaterial for applications in the design of drug delivery systems, the algal sulphated polysaccharide ulvan was used as an excipient in MLT solid dosage forms. The dissolution tests showed that the MLT release from the ulvan-based tablets followed a sigmoidal pattern, which denoted that the drug release is controlled by polymer relaxation and/or erosion [8]. In a similar study, hydrophilic matrix tablets with various excipients (hydroxypropyl methylcellulose K15 M, low-viscosity sodium alginate, lactose monohydrate and polyvinylpyrrolidone M.W.: 10.000 and 55.000) were developed and tested in vitro at two dissolution media (pH 1.2 and 7.4) in order to examine the modified-release characteristics of MLT. The objective was to produce a formulation with a quick initial pace, aiming at a satisfactory sleep onset, followed by a prolonged release that could target poor sleep quality problems. The dissolution results indicated that the combination of the excipients with different physicochemi-

Scientific research has been conducted for the purpose of MLT evaluation not only towards medicine and clinical evaluation but also towards pharmaceutics [1–3]. Many researchers have studied and managed to produce immediate-release formulations of MLT (tablets, creams, sublingual sprays, nasal preparations, injectables, etc.), in order to facilitate sleep-onset problems. MLT modified-release formulations are clinically more useful in initiating and maintaining sleep in elderly insomniacs than those designed for immediate release. More in particular, the sustained-release dosage form which delivers MLT in a time period over 8 h is of clinical value for those who have disordered circadian rhythms [4, 5]. Therefore, the modified release of MLT from oral solid dosage forms that alter the time and/or the rate of MLT release may provide an alternative for MLT delivery and be useful in the treatment of circadian rhythmic disorders, like insomnia, jet lag, seasonal affective disease, shift work syndrome, etc. [6]. The recent advantages of MLT modified-release *per* 

The development of novel pharmaceutical formulations with the optimal release profile is of great importance for cases like melatonin. To this purpose, a series of experiments should be performed, utilizing various excipients at different ratios. These trials could require plenty of working hours, with no guarantee that, indeed, the optimal formulation composition will be reached. Therefore, the employment of a statistical/chemometric approach, such as design of experiments (DoE), can be beneficial for complicated and demanding tasks like the development of modified-

**82**

their release profiles. The results indicated that both formulations (liposomal and solid matrix tablets) could be suitable alternatives for treating sleep-onset/maintenance problems [10].

Once more, aiming at the modified release of MLT, another group of researchers studied the MLT release from monolayered and three-layered tablets, incorporating nanofibrous mats composed of cellulose acetate and polyvinylpyrrolidone. The in vitro dissolution release studies of the MLT formulations in simulated gastrointestinal fluids revealed tableting pressure and pH dependence. Comparing the MLT release from the physical mixture tablets and from the nanofibre-based tablets, it was concluded that the release profile was generally slower than the latter, rendering the formulation suitable for both sleep-onset and maintenance dysfunctions [11]. The same group of researchers produced electrospun-MLT loaded nanofibres (with cellulose acetate, polyvinylpyrrolidone and hydroxypropyl methylcellulose, as excipients) and used them to fill hard gelatin and delayed-release (DRcaps™) capsules. The in vitro dissolution results revealed a modified-release profile of MLT from the fabricated matrices in gastrointestinal-like fluids and suggested that the MLT-loaded nanofibrous mats could exhibit a promising profile for treating sleep problems [12].

Calcium alginate beads were also prepared to investigate the MLT modified release. Excipients utilized in their preparation included calcium alginate, polyvinylpyrrolidone (M.W.: 10.000 and 55.000), hydroxypropyl methylcellulose (M.W.: 15.000 and 100.000), lactose monohydrate and, as a surfactant, sodium lauryl sulphate. The in vitro release of melatonin was investigated at two different pHs (acidic pH 1.2 and basic pH 6.8), and the results concluded that the hormone's release from the beads was reversibly proportional to the extent of their expansion, which depends on the molecular weight/viscosity of the biopolymers present in the beads; the higher the molecular weight/viscosity of the hydrogels, the greater the beads swelling and the less the MLT's release [13].

Another group of researchers prepared a slow-release tablet of MLT with varying quantities of hydroxypropyl methylcellulose K15 M and Carbopol 971P, as well as other excipients (microcrystalline cellulose, maize starch, magnesium stearate and purified talc). The formulations developed showed a slow release of MLT during an 8 h period [14].

To the same end, matrix tablets were formulated using hydroxypropyl methylcellulose and tested in vitro in relation to drug release, as a function of polymer viscosity, drug loading, type and amount of disintegrant, lubricant and glidant and aqueous polymeric coating level, and further compared with two commercial products. The release studies showed that as the polymer viscosity increased, the release decreased, and as the coating level increased, an increased lag time was observed [15]. Other researchers have examined the in vivo sustained release of MLT that was incorporated in solid lipid nanoparticles. The results indicated that solid lipid nanoparticles may act as a reservoir, permitting a constant and prolonged MLT release, after oral administration, which may indicate new possibilities for sustained delivery systems [16].

In another research project, controlled-release matrix tablets of MLT were developed by the use of a computer programme, D-optimal experimental design, aiming at affecting its modified release at simulated gastrointestinal media. The careful selection of the excipients (polyvinylpyrrolidone (M.W.: 10.000 and 55.000), hydroxypropyl methylcellulose K15 M and lactose monohydrate) at their appropriate quantity resulted to the optimal solution and the controlled release of melatonin with the minimal number of experiments [17]. Moreover, in another research, polymer-reinforced and polymer-coated alginate beads with various concentrations of polymer (Eudragit® RSI00) and plasticizer (aluminum tristearate)

**85**

Per Os *Administered Modified-Release Solid Formulations of Melatonin: A Review of the Latest…*

were produced and evaluated in vitro in relation to their controlled-release characteristics as an alternative for oral delivery of MLT. The results indicated that the polymeric reinforcement offered an initial burst release in intestinal fluids, while the coating led to release retardation in both gastric and intestinal fluids. The results also showed that as the polymer concentration increased, the MLT release decreased

Researchers have also probed the MLT release from matrix and compressioncoated tablets that were comprised of combinations of ethyl cellulose, polyvinylpyrrolidone, dextran, low-viscosity sodium alginate, Avicel PH 102 and lactose monohydrate. The results obtained revealed that the initial release of melatonin was more delayed from coated tablets than from the respective uncoated. The matrix tablets showed an initial fast release that followed a sustained mode, demonstrating that the use of various excipients results to different controlled-release

Also, bilayered tablets incorporating an immediate-release layer and a sustainedrelease layer were developed by the same group of researchers using as excipients ethyl cellulose, dextran, low-viscosity sodium alginate, Avicel PH 102, lactose monohydrate, iron oxide pigment red 30 and magnesium stearate. The dissolution results revealed immediate and sustained drug release [19]. Another group of researchers also prepared bilayered tablets of MLT incorporating an immediaterelease part consisting of MLT-*b*-cyclodextrin inclusion complex and a sustainedrelease part containing MLT in hydroxypropyl methylcellulose K15 M and Carbopol 971P. The results showed an initial burst followed by a near zero-order release

Furthermore, scientists have designed an MLT oral formulation to provide immediate and controlled release, which consisted of MLT-loaded sugar beads coated with 20% Aquacoat®. The in vivo results showed average peak plasma concentration at about 600 pg/ml that maintained at approximately 100 pg/ml over

Researchers have also utilized principles of nanotechnology to make micro−/ nanoparticles containing MLT that could be further formulated to solid *per os* modified-release formulations. Thus, MLT was loaded in poly(*D*,*L*-lactide-co-glycolide) nanoparticles and microparticles (diameter of 200 nm and 3.5 mm, respectively). The cumulative release curves for nano- and microparticles revealed that for PLGA nano-10 and PLGA nano-20, approximately 30 and 20% of melatonin were released, respectively, within the first 24 h, as due to the diffusion of melatonin molecules located closer to the particle surface. At the end of 40 days, approximately 65% of the loaded melatonin was released from PLGA nanoparticles by diffusion mechanism [21]. Similarly, MLT was encapsulated into poly(lactic-co-glycolic acid) microspheres, and the release results indicated a dual pattern: a low initial burst release (around 40%) after the first 3 days and a relatively prolonged release over 25 days (around 85% of total MLT release) [22]. Furthermore, scientists have prepared MLT nanocapsules with Eudragit® S100. This formulation revealed a modified-release profile, which when fitted to a monoexponential model revealed that the MLT release

mechanism was controlled by swelling and dissolution of the polymer [23].

In the vast majority of experimental procedures in all scientific fields, the optimal conditions are reached by modifying the levels of one factor at a time (OFAT) while keeping all the rest that seem to affect the response constant.

**3. Employment of DoE for the development of novel MLT** 

in the intestinal fluids, due to coated alginate beads disintegration [18].

*DOI: http://dx.doi.org/10.5772/intechopen.91158*

behaviors [19].

pattern for a period of 8 h [20].

8 h, indicating biphasic release [20].

**modified-release formulations**

#### Per Os *Administered Modified-Release Solid Formulations of Melatonin: A Review of the Latest… DOI: http://dx.doi.org/10.5772/intechopen.91158*

were produced and evaluated in vitro in relation to their controlled-release characteristics as an alternative for oral delivery of MLT. The results indicated that the polymeric reinforcement offered an initial burst release in intestinal fluids, while the coating led to release retardation in both gastric and intestinal fluids. The results also showed that as the polymer concentration increased, the MLT release decreased in the intestinal fluids, due to coated alginate beads disintegration [18].

Researchers have also probed the MLT release from matrix and compressioncoated tablets that were comprised of combinations of ethyl cellulose, polyvinylpyrrolidone, dextran, low-viscosity sodium alginate, Avicel PH 102 and lactose monohydrate. The results obtained revealed that the initial release of melatonin was more delayed from coated tablets than from the respective uncoated. The matrix tablets showed an initial fast release that followed a sustained mode, demonstrating that the use of various excipients results to different controlled-release behaviors [19].

Also, bilayered tablets incorporating an immediate-release layer and a sustainedrelease layer were developed by the same group of researchers using as excipients ethyl cellulose, dextran, low-viscosity sodium alginate, Avicel PH 102, lactose monohydrate, iron oxide pigment red 30 and magnesium stearate. The dissolution results revealed immediate and sustained drug release [19]. Another group of researchers also prepared bilayered tablets of MLT incorporating an immediaterelease part consisting of MLT-*b*-cyclodextrin inclusion complex and a sustainedrelease part containing MLT in hydroxypropyl methylcellulose K15 M and Carbopol 971P. The results showed an initial burst followed by a near zero-order release pattern for a period of 8 h [20].

Furthermore, scientists have designed an MLT oral formulation to provide immediate and controlled release, which consisted of MLT-loaded sugar beads coated with 20% Aquacoat®. The in vivo results showed average peak plasma concentration at about 600 pg/ml that maintained at approximately 100 pg/ml over 8 h, indicating biphasic release [20].

Researchers have also utilized principles of nanotechnology to make micro−/ nanoparticles containing MLT that could be further formulated to solid *per os* modified-release formulations. Thus, MLT was loaded in poly(*D*,*L*-lactide-co-glycolide) nanoparticles and microparticles (diameter of 200 nm and 3.5 mm, respectively). The cumulative release curves for nano- and microparticles revealed that for PLGA nano-10 and PLGA nano-20, approximately 30 and 20% of melatonin were released, respectively, within the first 24 h, as due to the diffusion of melatonin molecules located closer to the particle surface. At the end of 40 days, approximately 65% of the loaded melatonin was released from PLGA nanoparticles by diffusion mechanism [21]. Similarly, MLT was encapsulated into poly(lactic-co-glycolic acid) microspheres, and the release results indicated a dual pattern: a low initial burst release (around 40%) after the first 3 days and a relatively prolonged release over 25 days (around 85% of total MLT release) [22]. Furthermore, scientists have prepared MLT nanocapsules with Eudragit® S100. This formulation revealed a modified-release profile, which when fitted to a monoexponential model revealed that the MLT release mechanism was controlled by swelling and dissolution of the polymer [23].
