Home Print this page Email this page
Users Online: 2175
Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
REVIEW ARTICLE
Year : 2013  |  Volume : 2  |  Issue : 2  |  Page : 63-68

Novel solid self-emulsifying pellets: An approach for enhanced oral delivery of poorly soluble drug


Department of Pharmaceutics, JSS College of Pharmacy, Ootacamund, Tamil Nadu, India

Date of Web Publication26-Jul-2013

Correspondence Address:
Natarajan Jawahar
Department of Pharmaceutics, JSS College of Pharmacy, Ootacamund - 643 001, Tamil Nadu
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2278-344X.115678

Rights and Permissions
  Abstract 

In recent years, it has been a great challenge for lipophilic drugs to get converted into an orally administered formulation with sufficient bioavailability. Over 40% of the new chemical entities are poorly soluble, which lead to decreased bioavailability, higher inter- and intra-subject variability, and lack of dose proportionality. Self-emulsifying drug delivery system has come to the fore for the enhancement of oral bioavailability. The prime characteristic - their ability to form fine oil-in-water (o/w) emulsion or micro-emulsions upon mild agitation following dilution by an aqueous phase - is quite promising. The present review discusses the feasibility of producing solid self-emulsifying pellets using the extrusion/spheronization technique and their development; it also focuses on related problems and possible future research directions.

Keywords: Extrusion/spheronization, micro-emulsion, self-emulsifying drug delivery system, solid self-emulsifying pellets


How to cite this article:
Jawahar N, Raju B V. Novel solid self-emulsifying pellets: An approach for enhanced oral delivery of poorly soluble drug. Int J Health Allied Sci 2013;2:63-8

How to cite this URL:
Jawahar N, Raju B V. Novel solid self-emulsifying pellets: An approach for enhanced oral delivery of poorly soluble drug. Int J Health Allied Sci [serial online] 2013 [cited 2023 Sep 21];2:63-8. Available from: https://www.ijhas.in/text.asp?2013/2/2/63/115678


  Introduction Top


The oral route of administration has been and still is currently the major route of drug delivery owing to its potential advantages compared to the other routes. Around 40% of probe new drugs are characterized as belonging to class II in the BCS classification (poorly water soluble and highly permeable), giving rise to poor and erratic oral bioavailability. Therefore, dissolution controls the rate of absorption of these drugs from the gastro intestinal tract (GIT). [1],[2] Hence, suitable formulations have to be produced to enhance their bioavailability.

Many strategies have been reported to overcome the problem of solubility arising for BCS class II drugs. Some of these include complexation with cyclodextrins, solid dispersion (suspension), co-precipitation, micronization, salt formation, emulsion, use of micelles, and co-grinding. Although these approaches have been successful in selected cases, they present various drawbacks. [3],[4],[5],[6] However, the approaches of self-emulsifying drug delivery system (SEDDS) and micro-emulsions have been reported to overcome the problems faced by using earlier-mentioned strategies.

SEDDS has come to the fore due to its ability to enhance the bioavailability of poorly water-soluble drugs. They are isotropic mixtures of oils and surfactants, which at times contain hydrophilic solvents and co-solvents. They are generally used in formulations to improve the oral absorption of lipophilic drugs. [7] Oral administration of SEDDS can be in the form of soft or hard gelatin capsules, which form fine and relatively stable o/w emulsions upon aqueous dilution. They immediately spread in the GIT, and the intestine and motility of the stomach provide required the self-emulsification (SE) process. These systems are advantageous in that the form of the drug is in the dissolved form and has a small droplet size, which provide a large interface for drug absorption. The droplet size of these emulsions is between 100 nm and 300 nm, whereas droplet size of self-micro-emulsifying drug delivery systems for transparent micro-emulsions is less than 50 nm. [8]


  Why is Solid Self-Emulsifying pellets (SSEP) Needed? Top


SEDDS, usually formulated in the liquid form, has some disadvantages especially in the manufacturing process, thereby giving rise to high production costs. Moreover, incompatibility problems with the capsule shell are common. Although desirable, it is difficult to incorporate an SE mixture into a solid form. In contrast, the possible advantages of solid self-emulsifying drug delivery (S-SEDDS) have been of interest to researchers. [9],[10] S-SEDDS provides several advantages for pellets, eliciting great interest in its development. As pellets disperse freely in the GIT, drug absorption is maximized and diminution in peek plasma fluctuations occurs, thereby minimizing the potential side effects without lowering drug bioavailability. [11] Common techniques for manufacturing pellets in the pharmaceutical industry are extrusion/spheronization (E/S), solution/suspension layering, and powder layering. E/S has evolved to be the chosen method in the formulation of pellet-based dosage forms as it offers numerous advantages over other methods, including spherical-shaped, narrow size distribution, good flow properties, low friability, and uniform packing characteristics. It is therefore suitable to combine the advantages of SEDDS with those of pellets. However, the development of SSEP is a challenge nonetheless, as high lipid loads often impair pellet formulation. [12]

Development of SSEP

It is a multiple-unit dosage form; Newton et al., (2001) proposed the idea of bringing together the advantages of SEDDS and pellets through the inclusion of SE mixture into micro-crystalline cellulose and the production of pellets by the E/S method. Moreover, in a comparative bioavailability study carried out by Tuleu et al. (2004), it was observed that bioavailability was equivalent when the drug was administered to dogs in SE systems in either a liquid form or a solid pellet dosage form. [13]

Potential advantages of SSEP

  • Flexibility in development of the dosage form [14]
  • Improving safety and efficacy of the bioactive form
  • Reducing intra-and inter-subject variability of plasma profiles [14]
  • Pellets reduce the problem of high local concentration of drugs, thus avoiding GI irritation [14]
  • Protecting drug(s) from the gut environment [14]
  • High drug loading efficiency (up to 98%) [14]
  • Possibility of attaining better stability with pellets.
Specificity

Nature of the oil/surfactant pair, surfactant concentration, oil/surfactant ratio, and temperature are some of the factors that affect the SE process. Only very specific pharmaceutical excipients' combination leads to efficient SSEP. The efficiency with which a drug is incorporated into an SSEP depends on the particular physicochemical compatibility of the drug/system. [15],[16] Hence, it is important to perform solubility studies prior to the formulation to obtain a formulation design.

Selection of excipients for self-emulsification in SSEP

Oils/lipids

Oils/lipids play an essential role in contributing to solubilizing lipophilic drugs in specific amounts, thereby facilitating SE of the drug and increasing the fraction of lipophilic drug transported through the intestinal lymphatic system causing an increase in the absorption through GIT. [17] Both long-chain and medium-chain triglyceride oils may be used for the formulation of SSEP. Hydrolyzed vegetable or edible oils can be successfully used in designing high-soluble lipophilic drugs owing to their formulation and physiological properties. [16]

Surfactant

Non-ionic surfactants with high HLB values are used in the formulation of SSEP. (e.g., Tween, cremophore, labrasol, etc.). To form a suitable SSEP, the strength of a surfactant should vary between 30% and 60% w/w of the formulation. The large quantities of surfactants used in SSEP preparation might irritate the GIT, which leads to the possible consideration of using non-ionic surfactants over ionic ones. Amphiphilic surfactants can dissolve relatively high amounts of hydrophobic drugs, thereby preventing the precipitation of drugs within the GI lumen. [8]

Co-solvents

They help in the dissolution of large quantities of hydrophilic surfactants or hydrophobic drugs in the lipid base. These solvents sometimes play the role of co-surfactant in micro-emulsion systems (e.g., polyethylene glycol, propylene glycol, ethanol, etc.). [16]

Biopharmaceutical aspects

Lipids affect the oral bioavailability of drugs by altering the biopharmaceutical properties such as dissolution rate and solubility in the intestinal fluids, protecting the drug from enzymatic degradation and formation of lipoproteins that enhance lymphatic absorption and distribution of the drugs. This distribution depends on triglyceride chain length, saturation degree, and the volume of lipid administered. In addition, administration of lipophilic drugs with lipids may enhance drug absorption into portal blood compared with non-lipid formulations. [18],[19]

Mechanism of SE

Though not well understood, SE that occurs with the entropy change that favors dispersion is greater than the energy required to increase the surface area of the dispersion. In addition, the free energy of conventional emulsion formation is a direct function of the energy required to create a new surface between the two phases and it can be described by the following equation:

ΔG = ∑ N ∏r 2 σ

Here, G is the free energy associated with the process (ignoring the free energy of mixing), N the number of droplets with radius r, and σ the interfacial energy. With time, the two phases of the emulsion will tend to separate, in order to reduce the interfacial area, and subsequently, the free energy of the systems. [20]

Therefore, conventional emulsifying agents stabilize emulsions resulting from aqueous dilution. This forms a monolayer around the emulsion droplets, reduces the interfacial energy, and provides a barrier for the coalescence. Emulsification requiring very little input energy involves destabilization through the concentration of local interfacial regions. For emulsification to occur, the interfacial structure should not offer any resistance to surface shearing. [21] The free energy required to form the emulsion Should be very low and can be either positive or negative.

Preparation of SSEP by the E/S technique

After selecting suitable excipients, the preparation of the SE mixture includes the following steps:

  • Melting lipid/oil and the surfactant at temperatures below 70°C
  • Dissolving the drug in the above-mentioned mixture with homogenous mixing
  • The ratio of drug and lipid should be more than 1:1 to attain good emulsification
  • Addition of water to the molten lipid blends in the required quantity to attain a creamy mass
  • Relatively sufficient quantity of microcrystalline cellulose (MCC) is required for extrusion. After that, add less percentage of excipients such as diluents and superdisintegrant for immediate release of SE pellets
  • For prolonged release, SE pellets Superdisintegrant should not be included in SE pellets formulation.
The wet mass was used in preparation of SE pellets using the extrusion and spheronization method [Table 1]. [16]
Table 1: Excipients used in self-emulsifying formulations

Click here to view


Other studies on SSEP

Ahmed Abdulla and Karsten Mader studied the design and evaluation of SSEP formulation. They prepared three SE systems separately using Cithoral GMS (mono and di glycerides) and solutol HS 15, to which was added drug, dye, and spin probe. Then it was made a suitable mass for pelletization. The die was used to assess SE and spin probe was used to observe the release kinetics and microenvironment of pellets, during the release process, which were assessed using electron spin resonance spectroscopy. The dissolution profile showed complete release of drug as diazepam from the SE GMS/MCC pellets. It had a 3-fold mode of action compared with non-SE GMS/MCC pellets. [16]

Tuleu et al. conducted a comparative bioavailability study in dogs of an SE formulation of progesterone present in solid (pellet) and liquid forms were compared with an aqueous suspension of progesterone. The in vitro dissolution test showed nearly 100% of progesterone dissolved within 30 min from solid pellets and within 5 min from capsules containing progesterone dissolved in the SE system. From the aqueous suspension, 50% of the drug was released within 60 min. Solid self-emulsifying (SSE) pellets administered orally to the dogs were tested against the same dose of progesterone dissolved in a liquid SE system; it was observed that SSE pellets and SE solution had higher plasma levels of progesterone at each time interval compared to the aqueous suspension of progesterone. [22],[23]

Franceschinis et al. developed a method of producing SSEP by wet granulation: They prepared a binder solution using mono and diglycerides, polysorbate 80, and model drug Nimesulide in different proportions. This oil-surfactant was mixed and then added to water for an SE system. Then granules were prepared using MCC and lactose monohydrate in a granulator. The prepared binder solutions were sprayed on to the granules and pellets were formed by increasing the speed of the granulator. Pellets were able to release significantly smaller droplets with respect to their corresponding emulsions. [9]

Serratoni et al. studied controlled drug release from SSEP. The prepared SE system was formed by mixing oil-surfactant with solubilized drug in appropriate proportions, because a higher quantity of drug incorporated in the SE system leads to precipitation when diluted with water. This SE system was added to MCC and lactose monohydrate, water was added for wet mass, and then it was made suitable to form pellets. These pellets were coated by hydrophilic polymers such as ethyl cellulose and then coated by an aqueous solution of hydroxypropylmethyl cellulose in a fluid bed coater. The advantage of this formulation is enhanced dissolution of the model drug; when dissolution results for the uncoated pellets containing methyl or propyl parabens with or without inclusion of SE systems are compared with immediate release, results shows superior dissolution in SE systems.

Physicochemical characterization of SSEP

Assessment of SE and droplet size

The core of SSEP is SE, which is primarily assessed by the visual method. The efficiency of this process can be estimated by determining the rate of emulsification and droplet size distribution. The size of the emulsion droplet released from the SSEP is determined in water at 37°C and compared to liquid SEDDS. Then the droplet size can be measured by laser diffractometry. [24]

Crystallinity study

Differential scanning calorimetry and X-Ray diffraction studies are used for confirming the drugs present in the amorphous or crystal state in the lipid carrier in SE pellets. [23]

SSEP size analysis

Size analysis is performed using a set of standard sieves of a √2 (square root) progression ranging from 500 to 2800, with 100 g of SSEPs, agitated on a sieve shaker for 20 min. The model size fraction and the interquartile range are estimated from the cumulative percentage undersize curve. The geometrical standard deviation (σg) is determined by the log-normal distribution curve. [25]

SSEP shape analysis

Shape analysis is performed using a stereomicroscope and a digital camera connected to the computer with an image analysis software image C. One thousand pellets are used and for each pellet, 36 Feret diameters are measured to calculate the mean Feret diameter. The maximum Feret diameter and Feret diameter 90° to the maximum Feret diameter are obtained and the aspect ratio is calculated as the ratio between the maximum Feret diameter and the Feret diameter 90°. [26]

Friability testing of SSEP

Friability testing is conducted using a friability tester. A 10 g pellet sample is placed in the drum together with 10 g of glass spheres of 5 mm diameter, and rotated for 10 min at 25 rpm. [15] Pellets are then weighed and then friability is determined.

Drug entrapment studies

Around 10 g of the drug-loaded pellets from the different batches are placed in specified phosphate buffer 1000 ml conical flasks and stirred continuously using magnetic stirrers till the pellets burst completely. Aliquots are taken and the required dilutions were made with methanol and estimated by High pressue liquid chromatography (HPLC). The drug entrapment capacity is calculated using the following formula:

Drug entrapment capacity (%) = (AQ/TQ) × 100

where AQ is the actual quantity of the drug present in the SE pellets and TQ the 100% theoretical quantity of the drug that must be present in the SE pellets.

Disintegration testing of SSEP

Disintegration testing of pellets is measured using a disintegration tester, modified by the installation of a 500 μm mesh at the bottom of tubes. Six pellets are tested in distilled water at 37°C and the end point is considered as the point where no particles are present on the sieve. [15],[27]

Dissolution testing of SSEP

Dissolution is performed using USP II apparatus, with the bath temperature being 37°C. The media to be used are selected depending on the drug present in the SSEP formulation.

Factors influencing SSEP

Polarity of the lipophilic phase[24]

The polarity of the lipid phase is the main factor governing the drug release from SSEP. The high polarity enhances a rapid rate of release of drug into the aqueous phase. The optimum release was obtained with the formulation that had oil phase with the highest polarity.

Nature and dose of the drug in SSEP[24]

Drugs that are administered at high doses are not encouraged for SSEP unless they have extremely good solubility in at least one of the components of SSEP, mostly the lipophilic phase. The drugs that have limited or poor solubility in water and lipids are the most difficult to be formulated by SSEP.

Drawbacks of SSEP

The main drawback in the development of SSEP and other lipid-based formulations is the lack of good in vitro models for the assessment of SE formulations. The traditional dissolution model is not reliable, because these formulations potentially depend on digestion prior to release of the drug. To mimic this, an in vitro model stimulating the digestive process of the duodenum has been developed. This in vitro model needs further development to carry out in vitro/in vivo correlations; therefore, different prototype lipid-based formulations need to be developed and tested in vivo in a suitable animal model. Future studies are required to address the development of the in vitro model. [27]

CMC/quality considerations

  • Initial 30-day safety review based on safety of product
  • 21 CFR 312.23(a) (7): Identification, quality, purity, strength
  • CMC review includes not only drug substance, but also excipients
  • For further guidance: Content and format of investigational new drug applications (INDs).
For Phase 1 Study of Drugs (1995) INDs for Phase 2 and Phase 3 Studies Chemistry, Manufacturing, and Controls Information (2003).

Examples of products available in the market

Lipid-based formulations are recognized as a feasible approach to improving the bioavailability of poorly soluble compounds. However, to date, not many clinical studies have been published. Several drug products intended for oral administration have been marketed utilizing lipid-and surfactant-based formulations. Sandimmune® and Sandimmune Neoral® (cyclosporin A, novartis), Norvir® (ritonavir), and Fortovase® (saquinavir) have been formulated in SEDDS.


  Conclusion Top


It can be concluded that SSEP substantially improves the solubility/dissolution of poor water-soluble drugs. S-SEDDS or SSEP is superior to conventional liquid SEDDS in that it reduces production costs, simplifies the industrial manufacturing process, and improves patient compliance. They can be orally administered easily, as they do not result in GI irritation; moreover, controlled/sustained release of drug is achievable through SE pellets. However, research is still in its nascent stage and further studies are required before more solid SE dosage forms appear in the market. Possible areas of future insight are human bioavailability studies - in vitro/in vivo correlation. There are several aspects requiring further attention: Physical aging phenomenon associated with glyceride, oxidation of vegetable oil, [28] and the interaction between drugs and excipients. Suitable excipient selection is the main hurdle in the formulation of SSEP. Thus, these aspects should represent the future thrust areas for S-SEDDS.

 
  References Top

1.Lipinski C. Poor aqueous solubility-an industry wide problem in drug discovery. Am pharm Rev 2002;5:82-5.  Back to cited text no. 1
    
2.Amidon GL, Lennernäs H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 1995;12:413-20.  Back to cited text no. 2
    
3.Sugimoto M, Okagaki T, Narisawa S, Koida Y, Nakajima K. Improvement of dissolution characteristics and bioavailability of poorly water-soluble drugs by novel co-grinding method using water-soluble polymer. Int J Pharm 1998;160:11-9.  Back to cited text no. 3
    
4.Perng CH, Kearney AS, Patel K, Palepu NR, Zuber G. Investigation of formulation approaches to improve the dissolution of SB-210661, a poorly water soluble 5-lipooxygenase inhibitor. Int J Pharma 1998;176:31-8.  Back to cited text no. 4
    
5.Nazzal S, Guven N, Reddy IK, Khan MA. Preparation and characterization of coenzyme Q10-Eudragit solid dispersion. Drug Dev Ind Pharm 2002;28:49-57.  Back to cited text no. 5
[PUBMED]    
6.Bhatt PP. Osmotic drug delivery systems for poorly water soluble drugs. Pharmaventures Ltd. Oxford, UK; 2004. p. 26-29.  Back to cited text no. 6
    
7.Shah NH, Carvajal MT, Patel CI, Infield MH, Malick AW. Self emulsifying drug delivery systems (SEDDS) with polyglycolized glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs. Int J Pharm 1994:106:15-23.  Back to cited text no. 7
    
8.Franceschinis E, Voinovich D, Grassi M, Perissutti B, Filipovic-Grcic J, Martinac A, et al. Self-emulsifying pellets prepared by wet granulation in high-shear mixer: Influence of formulation variables and preliminary study on the in vitro absorption. Int J Pharm 2005;291:87-97.  Back to cited text no. 8
    
9.Newton M, Petersson J, Podczeck F, Clarke A, Booth S. The influence of formulation variables on the properties of pellets containing a self-emulsifying mixture. J Pharm Sci 2001;90:987-95.  Back to cited text no. 9
[PUBMED]    
10.Ghebre-Sellassie I. Charles Martin (M.B.A.) Limited Preview-2003. Phaarmaceutical Pelletisation Technology. New York: Marcel Dekker; 1989. p. 1-7.  Back to cited text no. 10
    
11.Lurie DJ, Mäder K. Monitoring drug delivery processes by EPR and related techniques: Principles and applications. Adv Drug Deliv Rev 2005;57:1171-90.  Back to cited text no. 11
    
12.Abdalla A, Klein S, Mäder K. A new self-emulsifying drug delivery system (SEDDS) for poorly soluble drugs: Characterization, dissolution, in vitro digestion and incorporation into solid pellets. Eur J Pharm Sci 2008;35:457-64.  Back to cited text no. 12
    
13.Abdalla A, Mäder K. Preparation and characterization of a self-emulsifying pellet formulation. Eur J Pharm Biopharm 2007;66:220-6.  Back to cited text no. 13
    
14.Gursoy RN, Benita S. Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomed Pharmacother 2004;58:173-82.  Back to cited text no. 14
[PUBMED]    
15.Constantinides PP. Lipid microemulsions for improving drug dissolution and oral absorption: Physical and biopharmaceutical aspects. Pharm Res 1995;12:1561-72.  Back to cited text no. 15
[PUBMED]    
16.Khoo SM, Humberstone AJ, Porter CJ, Edwards GA, Charman WN. Formulation design and bioavailability assessment of lipidic self-emulsifying formulations of halofantrine. Int J Pharm 1998;167:155-64.  Back to cited text no. 16
    
17.Patel PA, Chaulang GM, Akolkotkar A, Mutha SS, Handicap SR and Bhosale AV. Self emulsifying drug delivery systems: A Review. Res J Pharm Technol 2008;1:313-23.  Back to cited text no. 17
    
18.Caliph SM, Charman WN, Porter CJ. Effect of short-, medium-, and long-chain fatty acid-based vehicles on the absolute oral bioavailability and intestinal lymphatic transport of halofantrine and assessment of mass balance in lymph-cannulated and non-cannulated rats. J Pharm Sci 2000;89:1073-84.  Back to cited text no. 18
[PUBMED]    
19.Reiss H. Enthropy-Induced dispersion of bulk liquids. J Colloids Interface Sci 1975;53:61-70.  Back to cited text no. 19
    
20.Patel PA, Chaulang GM, Akolkotkar A, Mutha SS, Hardikar SR, Bhosale AV. Self Emulsifying Drug Delivery System: A Review. Research J. Pharm. and Tech 2008,4:313-23.  Back to cited text no. 20
    
21.Jessy Shaji, Digambar Jadhav. Statistical development and optimization of of solid dispersionself-emulsifying pellets. Int J Pharm Rev 2010;4:156-67.  Back to cited text no. 21
    
22.Tuleu C, Newton M, Rose J, Euler D, Saklatvala R, Clarke A, et al. Comparative bioavailability study in dogs of a self-emulsifying formulation of progesterone presented in a pellet and liquid form compared with an aqueous suspension of progesterone. J Pharm Sci 2004;93:1495-502.  Back to cited text no. 22
    
23.Serratoni M, Newton M, Booth S, Clarke A. Controlled drug release from pellets containing water-insoluble drugs dissolved in a self-emulsifying system. Eur J Pharm Biopharm 2007;65:94-8.  Back to cited text no. 23
[PUBMED]    
24.Halbaut L. Oxidative stability of semi-solid excipient mixtures with corn oil and its implication in the degradation of vitamin A. Int J Pharm 1997;147:31-40.  Back to cited text no. 24
    
25.Bouwman AM, Bosma JC, Vonk P, Wesselingh JH, Frijlink HW. Which shape factor(s) best describe granules? Powder Technol 2004;146:66-72.  Back to cited text no. 25
    
26.Anand U. Kyatanwar. Self micro-emulsifying drug delivery system (SMEDDS): Review. J Pharm Res 2010;3:75-83.  Back to cited text no. 26
    
27.Hauss DJ, Fogal SE, Ficorilli JV, Price CA, Roy T, Jayaraj AA, et al. Lipid-based delivery systems for improving the bioavailability and lymphatic transport of a poorly water-soluble LTB4 inhibitor. J Pharm Sci 1998;87:164-9.  Back to cited text no. 27
    
28.Chambin O. Influence of cryogenic grinding on properties of a selfemulsifying formulation. Int J Pharm 2004;278:79-89.  Back to cited text no. 28
    



 
 
    Tables

  [Table 1]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Why is Solid Sel...
Conclusion
References
Article Tables

 Article Access Statistics
    Viewed3609    
    Printed114    
    Emailed1    
    PDF Downloaded351    
    Comments [Add]    

Recommend this journal