Analysis of Sustained Unleash Indefinite Quantity Type of Anti-Diabetic Coordination of Deliquescent Polymers
Received: 15-Feb-2014 / Accepted Date: 25-Mar-2014 / Published Date: 02-Apr-2014 DOI: 10.4172/2329-9053.1000R1-002
Abstract
Antidiabetic complex, the sole offered biguanide, remains the primary line medical care for treating kind a pair of DM acts by decreasing internal organ aldohexose output and peripheral hypoglycemic agent resistance. It's comparatively short plasma half-life, low absolute bioavailability. The requirement for the administration for 2 to a few times each day once larger doses area unit needed will decrease the patient compliance. Sustained unharness formulations may that will} maintain plasma level for 8-12 hrs might spare for daily dose. Anti-diabetic HCl presents important challenges because of its poor inherent sponginess, high dose and high water solubility. This study was to style antidiabetic extended unharness by victimisation hydrophilic controlled unharness polymers polyvinyl pyrollidone, metal carboxy methyl radical polyose, polyoxrs301, carbapol 971P by wet granulation technique. The developed granules mix was evaluated by tapped density, bulk density, sponginess index, Hausner’s quantitative relation. Invitro dissolution studies were administrated in hydrogen ion concentration half-dozen.8 phosphate buffer victimisation the equipment kind a pair of paddle kind represented within the USP treatise. In F1-F2 path the discharge rate wasn't controlled as per the uspxx111 take a look at four parameters. in F3 path {the unharness|the discharge} rate was maintained and satisified with the innovater In F4-F5 path rate of drug release wasn't satisified with the parameters. Among these formulations F6 path was optimized as a result of it shows similar pattern with the pioneer. The optimized batch follows higuchi expression. there have been no important physical and chemical properties of optimized F6 batch and once 3 months short term stability studies were done.
Keywords: Antidiabetic complex; Controlled tablets; In vitro dissolution studies
Introduction
Pharmaceutical tablets area unit solid dose type, ready by pressing or moulding a drug(s) powder with or while not additives [1-5]. They vary in form and take issue greatly in size, form and weight, reckoning on the number of medical substance and therefore the supposed mode of administration. Tablets is engulfed whole, chewed or placed underneath the tongue (sublingual) or within the pocket (buccal tablet) [6-10].
Increased complications and expense concerned in promoting of recent drug entities has centered bigger attention on the event of sustained unharness (SR) or controlled unharness (CR) drug delivery systems [11]. Sustained or Controlled unharness delivery systems are able to do foreseeable and duplicatable unharness rates, extended period of activity for brief half-life medication, belittled toxicity and reduction of needed dose, optimized medical care and higher patient compliance.
The goal of sustained unharness dose type is to keep up therapeutic blood or tissue level of the drug for extended amount of your time. This is often usually accomplished by trying to get “Zero order” unharness from the dose type [12]. Zero order unharness constitutes drug unharness from the dose type that is freelance of the number of the drug within the delivery system. Sustained unharness systems usually don't attain this sort of unharness and frequently attempt to mimic Zero order unharness by providing drug in slow “first order” fashion (i.e., concentration dependent) [13].
Theoretical Summary
The basic goal of medical care is to realize a gentle - state blood or tissue level that's therapeutically effective and nontoxic for extended amount of your time. Modified-release delivery systems are also divided handily into four categories:
Delayed unharness
Sustain unharness
Site-specific targeting
Receptor targeting
Delayed unharness systems area unit those who use repetitive, intermittent dosing of a drug from one or a lot of immediate-release units incorporated into one dose type. Example delayed unharness system embody repeat action tablets, capsules and enteric coated pill wherever regular unharness is achieved by barrier coating [14-17].
Sustain unharness system includes associate degree drug delivery systems that achieves slow unharness of drug over an extended amount of your time. If the systems will offer some management, whether or not this is often of temporal or special nature, or both, of drug unharness within the body, or in different words, the system is successful at maintaining constant drug levels within the target tissue or cells, it's thought-about as controlled unharness systems [18].
Physico-Chemical Factors Influencing Oral Controlled Unharness Dose Type [19]
Dose size
For orally administered systems, there's associate degree higher limit to the majority size of the dose to be administered. Normally one dose of zero.5 to one gram is taken into account outside.
Ionization, pKa and liquid solubility
The hydrogen ion concentration partition hypothesis merely states that the unchanged variety of a drug species is preferentially absorbed through several body tissues so it's vital to notice the connection between pKa of the compound and its hygroscopic surroundings. For several compounds the positioning of most absorption also will be the realm within which the drug is least soluble. For standard dose forms the drug will usually totally dissolve within the abdomen and so be absorbed within the alkalic hydrogen ion concentration of the gut. For dissolution of diffusion controlled forms, a lot of of the drug can arrive within the intestine in solid type. This implies that the solubility of the drug is probably going to alter many orders of magnitude throughout its unharness.
Partition constant
The compounds with a comparatively high partition coefficient area unit preponderantly super molecule soluble and simply penetrate membranes ensuing high bioavailability. Compounds with terribly low partition constant can have problem in penetrating membranes ensuing poor bioavailability. Moreover partitioning effects apply equally to diffusion through chemical compound membranes [7].
Drug Stability
Medication that area unit unstable within the abdomen is placed during a slowly soluble type or have their unharness delayed till they reach the tiny gut but, such a technique would be harmful for medication that either area unit unstable within the intestine or endure intensive gut wall metabolism, as detected within the belittled bioavailability of some anticholinergic medication from controlled /sustained unharness formulations.
Biological Factors Influencing Oral Sustained Unharnesses Dose Form
Biological Life
Therapeutic compounds with short half-life area unit wonderful candidates for controlled unharness preparations. Drug with terribly short half-life would force overly massive amounts of drug in every dose unit to keep up controlled effects, therefore forcing the dose type itself to become large to be administered. Compounds with comparatively long lives, usually bigger than eight hours area unit usually not utilized in controlled unharness dose forms since their result is already sustained and conjointly GI transit time is 8-12 hrs [8]. Medication with short half-lives need frequent dosing so as to attenuate fluctuations in blood levels related to standard oral dose regimens. so controlled unharness dose forms would seem terribly fascinating for medication. Infact sustained unharness formulations of glucocorticoid sodium orthophosphate, a methyl radical glucocorticoid are shown to be equally effective as standard tablets, providing no benefits over the latter [20].
Absorption
The characteristics of absorption of a drug will greatly have an effect on its quality as a controlled unharness product. Assumptive the transit time of most medication and devices within the hygroscopic regions before unharness is complete [21]. The absorption rate constant is a noticeable rate constant. It ought to essentially be the discharge rate constant of the drug from dose type.
Classes Of Matrix Systems
The matrix system is divided into 2 classes reckoning on the categories of retarding agent or chemical compound materials [22-26].
Hydrophobic matrix system
This is the sole system wherever the employment of chemical compound isn't essential to produce controlled drug unharness, though insoluble polymers are used. Because the term suggests, the first rate-controlling elements of hydrophobic matrix area unit water insoluble in nature. To modulate drug unharness, it should be necessary to include soluble ingredients like milk sugar into formulation [24]. The presence of insoluble ingredient within the formulations helps to keep up the physical dimension of hydrophobic matrix throughout drug unharnesses. As such, diffusion of active ingredient from the system is that the unharness mechanism, and therefore the corresponding unharness characteristic is represented by Higuchi equation referred to as root of your time unharness kinetic (Higuchi, 1963). The root of your time unharness profile is predicted with a porous stone, wherever the discharge from such system is proportional to the drug loading. Additionally, hydrophobic matrix systems usually aren't appropriate for insoluble drug as a result of the concentration gradient is simply too low to render adequate drug unharness [27]. As such, reckoning on actual ingredient properties or formulation style, incomplete drug unharness inside the GI transit time could be a potential risk and wish to be portrayed throughout the event. With the growing desires for improvement of medical care, matrix systems providing programmable rates of delivery become a lot of vital. Constant rate delivery forever has been one in every of the first targets of controlled unharness system particularly for drug with slim therapeutic index [28].
Hydrophilic Matrix System
The primary rate limiting ingredients of hydrophilic matrix area unit polymers that may swell on contact with solution and type a gel layer on the surface of the system. Once the discharge medium (i.e., water) is thermodynamically compatible with a chemical compound, the solvent penetrates into the free areas between organic compound chains. The chemical compound could endure a relaxation method, because of the strain of the penetrated solvent, so the chemical compound chains become a lot of versatile and therefore the matrix swells. This permits the encapsulated drug to diffuse earlier out of the matrix. On the opposite hand, it'd take longer for drug to diffuse out of the matrix since the diffusion path is elongated by matrix swelling. Moreover, it's been wide legendary that swelling and diffusion aren't the sole factors that verify the speed of drug unharness [29-31]. For dissoluble chemical compound matrix, chemical compound dissolution is another vital mechanism that may modulate the drug delivery rate. Whereas either swelling or dissolution is the predominant issue for a selected kind of polymers, in most cases drug unharnesses mechanics could be results of a mix of those 2 mechanisms. The presence of water decreases the glassy-rubbery temperature (for HPMC from 184°C to below 37°C), giving rise to transformation of glassy chemical compound to rubbery section (gel layer). The improved motility of the chemical compound chain favours the transport of dissolved drug. Chemical compound relaxation phenomena verify the swelling or volume increase of the matrix. Reckoning on the chemical compound characteristics, the chemical compound quantity within the rubbery section, at the surface of the matrix, might reach the unsnarling concentration; the gel layer varies in thickness and therefore the matrix dissolves or erodes. The concentration at that chemical compound chains is thought-about disentangled was incontestable to correspond to associate degree abrupt modification within the physics properties of the gel [32]. Showed a relationship between physics behaviour of HPMC gels and their erosion rate, orthodox that the polymer-polymer and polymer-water interaction area unit to blame for the gel network structure and its sensitivity to erosion. In turn, they have an effect on drug unharness rate within the case of poorly soluble medication. Swelling controlled unharness systems area unit based mostly upon these principles. Because of the elastic properties of the chemical compound that area unit increased by the presence of cross-linked network, abnormal penetrant transport is ascertained. This behaviour is sure by pure Fickian diffusion and case II transport. Therefore, transport is reduced to a few driving forces.
Compression of Tablets [33]
Direct compression
Direct compression name implies pressing tablets directly from pulverized materials while not modifying the physical nature of the materials itself. Direct compression is usually in serious trouble the crystalline materials having sensible physical properties needed for formation of excellent tablets. Main advantage of direct compression is it saves time compared to different ways of compression like wet granulation.
Wet Granulation
Most generally used and most general technique of pill preparation is by wet granulation technique. Wet granulation forms the granules by binding the powders alongside associate degree adhesion rather than by compaction [16]. The wet granulation technique is finished by adding a matter, suspension or suspension containing binder this will be liquid or non-liquid that is accessorial to the dry combine powder. Normally the mass ought to be damp instead of wet or paste simply. The physical phenomenon forces and capillary pressure area unit primarily to blame for initial granules formation. The most advantage is it meets the all needs for pill formation and main disadvantage is it needs several steps in method that is time intense.
Dry Granulation
The dry granulation method is employed to make granules while not employing a liquid resolution. This sort of method is usually recommended for product, that area unit sensitive to wet and warmth. Forming granules while not wet needs compacting and densifying the powders. Dry granulation is done on a pill press victimisation slugging tooling. On large-scale roller compactor usually noted as a chilsonator [11]. The compacted mass is termed slugs and therefore the method is understood as slugging. The slug’s area unit then screened or polished to supply a granular variety of pill materials that have the nice flow properties than original powder mixture.
The main advantage of dry granulation is it needs less instrumentality and eliminates the addition of wet and therefore the application of warmth, as found in wet massing and drying steps of the wet granulation technique.
Studies of Tablets
Preformulation studies
Before evaluation of drug substances into a dose form, it's essential that activity graph, drug & chemical compound ought to be with chemicals and physically characterized. Preformulation studies provide the knowledge required to outline the character of the drug substance and supply a framework for the drug combination with pharmaceutical excipients within the fabrication of a dose type [34].
Construction of Activity Curve
An accurately weighed a hundred mg of ant diabetic drug was dissolved in phosphate buffer of pH half-dozen.8 on an individual basis and compose the quantity up to a hundred metric capacity unit during a meter flask (Stock Solution: I, a thousand μg/ml) . From this ten metric capacity unit of resolution were measuring instrument out and compose the quantity up to a hundred metric capacity unit (Stock Solution: II, 100 μg/ml). Then the aliquots were ready, whose concentration starting from zero to12μg/ml and also the absorbance was measured at 233 nm. By victimization ultraviolet light photometer (Shimadzu, Model No: 2450) against the blank [35].
Controlled unharness tablets style
The design of tablets concerned numerous compromises on the part of the formulator, to provide desired product properties. It involves the proper choice and balance of excipients materials for active ingredients to attain the specified response [36].
Based on primary info collected from market samples and former expertise with the producing of assorted merchandise, the subsequent tentative product specifications were planned before beginning the formulation trials.
Discussion
Formulations of antidiabetic drug coordination compound was ready with polymers Polyvinyl pyrollidone, poly olefin compound, Carbopol and carboxy ethylcellulose Na individual and combination of polymers by wet granulation technique and direct compression technique.
In F1 formulation polyvinyl pyrollidone k-90 was used as a binder in granulation method. Whereas within the dissolution method the share of chemical compound wasn't maintained.
In F2-F3 formulation the share of chemical compound was multiplied wherever the discharge of the drug was preserved and conformed the share of chemical compound was maintained at 25-30%. In F2-F3 the Carbopol was used as binder wherever that Carbopol has gel forming and swelling nature was ascertained once each sublimate water and IPA was used as a binder resolution, wherever the medicinal drug chemical properties weren't glad.
In F4 formulations polythene compound was used as an immediate compression method wherever the hardness of granules was vary and not glad in dissolution parameters.
In F5 formulation polythene compound was used as binder wherever the granules hardness was glad with dissolution parameters.
In F6 formulation combination of polymers polyvinyl pyrollidone k90 was used as a intra granulation method and Carbopol was used as a additional granulation method wherever the drug unharness profile was glad with the mastermind drug unharness profile and also the method of drug unharness was ascertained with official pharmacokinetic parameters wherever Higuchi method wherever the drug unharness was diffusion and dissolution method.
In F7 method Na carboxy methylcellulose was used as a binder. Wherever the physical and chemical properties were glad. In dissolution method drug unharness undergoes diffusion method and swelling property was ascertained and it had been preserved upon eight hours.
In F8 method combination of polymers was used wherever the drug unharnesses was slow and it had been not glad with the physical and chemical properties.
Upon all higher than formulations F6 was glad with the physical and chemical properties and it had been unharness of drug from the chemical compound was follow initial order method and dissolution and diffusion method matched with the Higuchi method.
Conclusion
Extended unharness tablets of antidiabetic drug coordination compound were ready by wet granulation methodology victimization Carbopol 71G, Na carboxy alkyl radical polyose, polyvinyl pyrrolidine (K-90), polyox. The drug and excipients compatability was studied by FT-IR that showed no physico-chemical interaction. The mixture of polymers used as Carbopol 971 P and radical radical alkyl group polyose was granular mix. Conjointly it's finished that it improves the drug unharness at tenth hour. The kinetic treatment of the drug unharness information of the ready formulations followed zero order drug unharness the ready formulations followed Higuchi profile. It indicated that drug unharness was diffusion controlled and directly proportional to square root of your time. On comparison equation of line and parametric statistic (R2) with mastermind, the formulation F6 shows similarity of results with mastermind, thus F6 was thought of as formulation extending eighty nine.4% of drug was discharged at the tip of 10 hrs. The soundness studies were applied for amount of half-dozen months as per ICH pointers, there’s no vital change in dissolution profile and alternative parameters of the optimized formulation F6 were in acceptable limits.
References
- Nunez DA, Schiaffino S, Roldán EJA (2013) Comparison of Two Formulations of Sodium Divalproate Plasma Concentrations after a Single 500 mg Oral Dose in Healthy Subjects, and Stochastic Sub-analysis of the Individual “Clinical Perceptible†Levels. J BioequivAvailab 5: 197-200.
- PatrÃcia S, Heloisa S, Eliana BS, Maria HAS, Teresa CTD (2012) Analysis of in vivo absorption of didanosine tablets in male adult dogs by HPLC. J Pharm Anal 2: 29-34.
- ZakiRayad NM (2011) Laboratory-based Prediction of Drug Biopharmaceutical Properties. J BioequivAvailab 3: x-xi.
- El-Khordagui LK (2012) Microneedles: An Emerging Approach for Active Transdermal Delivery of Insulin. J BioequivAvailab 4: xxxi-xxxiii.
- Deshmukh R (2012) Modeling and Simulation in Drug Discovery and Development. J BioequivAvailab 4: xxvii-xxviii.
- Seenivasan P, Chowdary KPR, Uma MR, Murthy JSN (2013) Design and evaluation of glipizide CR tablets employing starch acetate as rate controlling matrix former. J Pharm Res 6: 653-655.
- Joseph JLJ, Vijaya C, Wilson B (2013) Development, characterization and evaluation of antiretroviral drug – Didanosine loaded serum albumin nanocarriers for an antiretroviral therapy. J pahrm res 7: 712-719.
- Zafar F, Naveed S (2013) Need for the Rational Use of Antibacterial in Paediatric Population. J BioequivAvailab 5: 260-263.
- Babu B, Meyyanathan SN, Gowramma B, Muralidharan S, Elango K, et al. (2012) Pharmacokinetic Evaluation of Newly Developed Oral Immediate Release and Sustained Release Dosage Forms of Losartan Potassium. J BioequivAvailab 4: 121-127.
- Jia-Gen W, Tingting G, Hong-Yuan Z, Yi-Yun X, Xiu-Zhen Z, et al. (2011) Preparation and Optimization of PEG-PLGA Loaded with Vincristine Sulfate and its In vitro Release. J BioequivAvailab 3: 211-214.
- Balabathula P, Janagam DR, Mittal NK, Mandal B, Thoma LA, et al. (2013) Rapid Quantitative Evaluation of Amphotericin B in Human Plasma, by Validated HPLC Method. J BioequivAvailab 5: 121-124.
- Ferrero C, Castellanos MR (2014) In vitro release testing of matrices based on starch–methyl methacrylate copolymers: Effect of tablet crushing force, dissolution medium pH and stirring rate. Int J Pharmac 461: 270-279.
- Karwa M, Arora S, Agrawal SG (2013) Recent Regulatory Amendment in Schedule Y: Impact on Bioequivalence Studies Conducted In India. J Bioequiv Availab 5: 174-176.
- Zhao Q, Purohit V, Cai J, LaBadie RR, Chandra R (2013) Relative Bioavailability of a Fixed-Combination Tablet Formulation of Azithromycin and Chloroquine in Healthy Adult Subjects. J BioequivAvailab 5: 001-005.
- Valenzuela F, Davila G, Ibañez Y, Garcia L, Crownover P, et al. (2011) Relative Bioavailability of Chewable and Conventional Film-Coated Tablet Formulations of Sildenafil 100 mg in Healthy Volunteers Under Fasting Conditions. J Bioequiv Availab 3: 207-210.
- Suresh Kumar R, Sri Syamala U, Revathi P, Sumanth D, Raghuveer P, et al. (2013) Self Nanoemulsifying Drug Delivery System of Olanzapine for Enhanced Oral Bioavailability: In vitro, In vivo Characterisation and In vitro -In vivo Correlation. J BioequivAvailab 5: 201-208.
- Al-Ghananaeem A (2013) Sublingual and Nasal Transmucosal Drug Delivery for Breakthrough Pain: A Frontier in Cancer Therapy. J Bioequiv Availab 5: e29.
- Feng Y, Wang N (2013) The New Generation of Drug Discovery and its Analytical Technologies. J Bioequiv Availab 5: e42.
- Jampilek J (2013) Transdermal Application of Drugs and Techniques Affecting Skin Barrier. J Bioequiv Availab 5: 233-235.
- Nystrom EB, Kornelia S, Marco M, Flueck L, Holzer C, et al. (2014) Retrocyte Display technology: Generation and screeng of a high diversity cellular antibody library. Methods 65: 57-67.
- Ohishi M, Shioda T, Jun-ichi S (2007) Retro-transduction by virus pseudotyped with glycoprotein of vesicular stomatitis virus. Virology 362: 131-138.
- Rai MK, Goyal R, Srivatsava K, Siddiqui MK, Chawla A (2009) Pin32 Pharmacoeconomic Relevance of Anti-Retro Viral Therapy (Art) in Low and Middle Income Countries. Value in Health 12: A115.
- Ramos M, Beltran A, Valdes A, Peltzer MA, Jimenez A, et al. (2013) Carvacrol and Thymol for Fresh Food Packaging. J Bioequiv Availab 5: 154-160.
- Junior EA, Duarte LF, Suenaga EM, de Carvalho Cruz A, Nakaie CR (2011) Comparative Bioavailability of Two Quetiapine Formulations in Healthy Volunteers after a Single Dose Administration. J Bioequiv Availab 3: 178-181.
- Susantakumar P, Gaur A, Sharma P (2011) Comparative Pharmacokinetics, Safety and Tolerability Evaluation of Acyclovir IR 800 Mg Tablet in Healthy Indian Adult Volunteers Under Fasting and Non-fasting Conditions. J Bioequiv Availab 3: 128-138.
- Bragatto MS, dos Santos MB, Pugens Pinto AM, Gomes E, Angonese NT, et al. (2011) Comparison between Pharmacokinetic and Pharmacodynamic of Single-Doses of Furosemide 40 mg Tablets. J Bioequiv Availab 3: 191-197.
- Dey S, Bhaskar M, Sankha C, Malay KD, Samarendu S (2014) Polymers derived from Xanthomonascampesteris and Cyamopsistetragonolobus used as retardant materials for the formulation of sustained release floating matrix tablet of atenolol. Int J Biol Macromolecule.
- Grund J, Korber M, Roland B (2013) Predictability of drug release from water-insoluble polymeric matrix tablets. Europ J Pharm Biopharm 85: 650-655.
- Alvi SN, Dgither SA, Hammami MM (2013) Development and Validation of LC-MS/MS Method for Determination of Testosterone Level in Human Saliva Using Lovastatin as Internal Standard. J Bioequiv Availab 5: 228-232.
- Tsume Y, Amidon GL, Takeuchi S (2013) Dissolution Effect of Gastric and Intestinal pH fora BCS class II drug, Pioglitazone: New in vitro Dissolution System to Predict in vivo Dissolution. J Bioequiv Availab 5: 224-227
- Nichols AI, Richards LS, Behrle JA, Posener JA, Fruncillo R, et al. (2013) Effects of Age and Sex on the Pharmacokinetics, Safety, and Tolerability of Oral Desvenlafaxine in Healthy Adults. J Bioequiv Availab 5: 088-094.
- Semdé R, Yameogo JB, Toe Djiguemde NLSM, Nao R, Gnoula C, et al. (2012) Evaluation of the Bioequivalence Documentation Required For Registration of Generic Drug Products in Burkina Faso: Methodology of Implementation and Impact. J Bioequiv Availab 4: 134-138.
- Patrica S, George GG, Humberto GF, Elina BS, Maria HA (2012) Preparation of gastro-resistant pellets containing chitosan microspheres for improvement of oral didanosine bioavailability. J Pharm Anal 2: 188-192.
- Saeed S, Lain C, Waseem K, Ali N (2013) The influence of vitamin E succinate on the stability of polyethylene oxide PEO controlled release matrix tablets. Colloids and Surfaces B: Biointerfaces 111: 486-492.
- Bhople A, Deshpande S, Sheiakh S, Patange H, Chandewar A, et al. (2013) Formulation and Development of Ketorolac Tromethmaine Ophthalmic Solution. J Bioequiv Availab 5: 099-109.
- Madhavi N, Sudhakar B, Ravikanth PV, Mohon K, Ramana Murthy K (2012) Formulation and Evaluation of Phenytoin Sodium Sustained Release Matrix Tablet. J Bioequiv Availab 4: 128-133.
Citation: Chandra VV, Deepthi T, Sashikanth S, Lavanya Y, Damodar R (2014) Analysis of Sustained Unleash Indefinite Quantity Type of Anti-Diabetic Coordination of Deliquescent Polymers. J Mol Pharm Org Process Res 2: R1-002. DOI: 10.4172/2329-9053.1000R1-002
Copyright: ©2014 Chandra VV, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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