6. BREIF RESUME OF THE INTENDED WORK: 6.1 Need for study: Helminthes infections are the most common infections, which affects the large proportions of the world’s population. In the treatment of parasitic diseases, the anti-helmintics drugs are used indiscriminately. About half of the world’s population suffers from Helminthiasis and the number is increasing day by day. It is not only limited to tropical and subtropical countries but is also to endemic in many regions because of poor sanitation, poor family hygiene, malnutrition and crowded living condition. There is an urgent need to apply powerful approaches to formulate a successful anthelmintic dosage forms1&2. The drug used for helminthes worm infections are niclosamide, piperazine, benzimidazoles, pyrantel, levamisole, ivermectin, praziquantel, emodepside and closantel etc. Levamisole, is an anthelminthic and immunomodulator and a more potent levo-rotatory isomer, Hence the name given levamisole. Levamisole has been used in humans to treat parasitic worm infections. For Ascariasis adult: 150 mg as a single dose. Child: 3 mg/kg as a single dose. For Ancylostomiasis adult: 2.5 mg/kg as a single dose, Child: 2.5 mg/kg as a single dose. For mixed ascariasis hookworm infections adult: 2.5 mg/kg as a single dose. Child: 2.5 mg/kg as a single dose. The dose of veterinary usage is 20mg/kg for dogs, monkeys, rats14. It works by paralysing susceptible intestinal worms which are then excreted from the intestines. Levamisole also enhances cellular immune responses in humans. This is well-absorbed from the GI tract. Peak plasma concentrations are achieved in 1.5-2 hours. It metabolise extensively in the liver. Excretion occur mainly in the urine 70% as metabolites and 5% as unchanged drug and small amounts in the faeces. A Pharmaceutical suspension is a coarse dispersion in which internal phase is dispersed uniformly throughout the external phase. The internal phase consisting of insoluble solid particles having a specific range of size which is maintained uniformly throughout the suspending vehicle with aid of single or combination of suspending agent. The external phase suspending medium is generally aqueous in some instance, may be an organic or oily liquid for non oral use. The various advantages of the suspension are they improve chemical stability of certain drug, drug in suspension exhibits higher rate of bioavailability than other dosage forms, bioavailability is in following order Solution > Suspension > Capsule > Compressed Tablet > Coated tablet, Duration and onset of action can be controlled and suspension can mask the unpleasant/ bitter taste of drug13. Classification of suspensions 1. Based on General Classes Oral suspension Externally applied suspension Parenteral suspension 2. Based on Proportion of Solid Particles Dilute suspension (2 to10%w/v solid) Concentrated suspension (50%w/v solid)
3. Based on Electro kinetic Nature of Solid Particles Flocculated suspension Deflocculated suspension 4. Based on Size of Solid Particles Colloidal suspension (< 1 micron) Coarse suspension (>1 micron) Nano suspension (10 ng)13
Features Desired In Pharmaceutical Suspensions:
The suspended particles should not settle rapidly and sediment produced, must be easily re-suspended by the use of moderate amount of shaking. It should be easy to pour yet not watery and no grittiness. It should have pleasing odour, colour and palatability. Good syringeability. It should be physically, chemically and microbiologically stable. 6.2Review of Literature : This comprehensive review briefly describes the history and pharmacology of albendazole as an anthelmintic drug and presents detailed summaries of the efficacy and safety. The incidence of side effects reported in the published literature is very low, with only gastrointestinal side effects occurring with an overall frequency of just >1%. Albendazole's unique broad-spectrum activity is exemplified in the overall cure rates calculated from studies employing the recommended doses for hookworm (78% in 68 studies: 92% for A. duodenale in 23 studies and 75% for N. americanus in 30 studies), A.lumbricoides (95% in 64 studies), T. trichiura (48% in 57 studies), E. vermicularis (98% in 27 studies), S. stercoralis (62% in 19 studies), H. nana (68% in 11 studies), and Taenia spp. (85% in 7 studies). The facts that albendazole is safe and easy to administer, both in treatment of individuals and in treatment of whole communities where it has been given by paramedical and nonmedical personnel, have enabled its use to improve general community health, including the improved nutrition and development of children6.
This review briefly describes the solid lipid nanoparticle suspension enhanced the therapeutic efficacy of praziquantel against tape worm. PZQ-loaded hydrogenated castor oil solid lipid nanoparticle (PZQ-HCO-SLN) suspension was prepared by a hot homogenization and ultrasonication method. Results demonstrate that the PZQ-HCO-SLN suspension is a promising formulation to enhance the therapeutic efficacy of PZQ7.
This review briefly describes the anthelmintic Potential of Mimusops elengi Linn. The aim of present study was to evaluate anthelmintic potential of crude extract and it’s fractions of the leaves of the plant Mimusops elengi(linn.),sapotaceae.The methanolic extract and it’s fractions were used for the bioassay by using adult Indian earthworms pheretima posthuma.The results indicated that the methanolic extract and ethylacetate fraction of the leaves exhibited significant anthelmintic activity with respect to standard and control. Albendazole was included as standard reference and distilled water as control. The paralysis and death of the worms was significantly determined at high concentrations of methanolic extract and it’s ethyl acetate fraction.10
This reviews the prevalence of soil-transmitted helminthic infections in Nigeria and current control efforts. Intestinal helminth infections (Ascaris, Trichuris and hookworm) in Nigeria remain as prevalent as they were in the 1970s. Majority of those affected are young children between the ages of 5 and 14 years living in rural areas and urban slums. Cultural, socio-economic and environmental factors are major contributors to the persistence of these infections. Although the World Health Organization (WHO) recommends chemotherapy for Ascaris, Trichuris and hook worm infections targeted at school-age children as a feasible and cost-effective control strategy, there is no policy- backed approach for helminth control in Nigeria. This paper makes a case for regular school-based programs to deliver chemotherapy so as to reduce the burden of helminth infection in school age children in Nigeria11.
This review briefly describes the efficacy of two netobimin oral suspensions (5% and15%) in sheep naturally infected with Dicrocoelium dendriticum. This study was carried out to compare the efficacy of two suspensions (5% and 15%) of netobimin against Dicrocoelium dendriticum in naturally infected sheep. Fifteen Merino sheep, 4 to 7 years old, were used in this survey. Animals were divided into three equal groups each of five sheep on the basis of bodyweights and D. dendriticum egg counts in per gram faeces. Group A and group B sheep were treated orally with 5% and 15% suspension of netobimin, respectively; both at a dose rate of 20 mg kg−1. Group C sheep were left untreated as controls. Twenty-one days post-treatment all sheep were slaughtered for post- mortem examination. All D. dendriticum from the liver and gall bladder were recovered and counted. The results showed that the efficacy of 5% and 15% suspension of netobimin was 90.80% and 91.50%, respectively, and the use of 15% suspension in sheep is discussed.3
This reviews anthelmintic effect of febantel on various species of gastrointestinal nematodes. Febantel in a 2.5% suspension was given to 99 sheep naturally infected with intestinal nematodes (mainly Trichostrongylus, Ostertagia, Cooperia, Haemonchus, Bunostomum and Nematodirus), from a flock of 209 in Spain (Aragon). A dose of 5 mg/kg was given to 46 sheep and 10 mg/kg to 49 sheep. Eight days later faecal examinations revealed that 43(93.5%) and 47 (95.9%) were free from parasites. In the remaining five animals, numbers of larvae/g of faeces fell from 600-700 to less than 30. Four infected sheep given 25 mg/kg febantel were all parasite-free at PM examination. The preparation was well tolerated and there were no abortions or teratogenic effects4.
This review briefly describes the efficacy of closantel plus albendazole liquid suspension against natural infection of gastrointestinal parasites in camels. Oral administration of closantel in a dose of 10 mg/kg plus albendazole in a dose of 5 mg/kg liquid suspension was studied in 75 camels naturally infected with various types of gastrointestinal parasites. The camels involved were 15 pregnant she- camels, 20 non-pregnant she-camels and 40 male camels of various ages. Each camel received a single oral dose of closantel (10 mg/kg) plus albendazole (5 mg/kg) orally. Two weeks later, 20 camels of this group were re-dosed again with the same dose of the anthelmintic. Fecal egg counts and generic determination of third stage larvae was performed. Results indicated that six different species of gastrointestinal tract parasites were identified in camels. Single treatment of closantel plus albendazole mixture reduced egg counts in camels by 100%, 100%, 98% and 77% for Haemonchus longistipes, Ascaris spp., Monezia expansa and Fasciola hepatica, respectively. However, administration of the drug twice on the base of 2 weeks apart significantly raised the efficacy of the drug for clearance of the parasites from 92.5% to 100% in camels infected with various parasites. Camels were not adversely affected by treatment5.
This reviews effectiveness of Various Anthelmintics in the Treatment of Moniliformiasis. Humans particularly become infected with Moniliformis moniliformis. The effectiveness of pyrantel pamoate, ivermectin, praziquantel, niclosamide, thiabendazole, and mebendazole was evaluated in the treatment of moniliformiasis in laboratory-infected female Wistar rats. The most effective drug in the treatment of moniliformiasis in rats was mebendazole, two doses resulted in a 69% reduction in worm burden after 2 weeks; however, 50% of the rats receiving the treatment died within 2 weeks after first administration of the drug. Two surviving rats that had been treated with mebendazole exhibited evidence of hepatic dysfunction characterized by extremely elevated levels of alkaline phosphatase in conjuction with depressed serum albumin levels. It is hypothesized that Mo. moniliformis may metabolize the drug and release a metabolite that is highly toxic to the host. On the basis of these data, thiabendazole is recommended as the drug of choice for the treatment of human acanthocephaliasis until more extensive testing can be conducted8.
This reviews mebendazole/trichlorfon combination. a new anthelmintic for removing monogenetic trematodes from fish. Mebendazole effectively removed G. elegans after a 24-h. exposure to 0·01 mg l-1, but it had no effect on D. vastator up to 2·0 mg l-1. Trichlorfon was 95% effective on D. vastator between 0·4 and 1·6 mg l-1 after a 24-h exposure, but it had no effect on G. elegans up to 2·0 mg l-1. A combination of mebendazole at 0·4 mg l-1 and trichlorfon at 1·8mgl-1 was 100% effective on both parasites. The minimum effective exposure time was 24 h and shorter exposure times, even at high dose levels, were not effective. The combination had no apparent toxic effect on fish, except possibly catfish, and field tests in various geographical areas of the United States showed that the combination was effective in all cases9.
6.3 Objectives of the study: The aim of the research work is formulation and evaluation of oral suspensions containing an anthelmintic drug (levamisole). The objectives are as follows: 1. Pre formulation studies for selection of suitable excipients to develop the dosage form based on physicochemical properties of drug and excipients. 2. Screening of excipients for compatibility and efficacy for developing the formulation. 3. Carry out pre formulation study of levamisole drug. 4. Preparation of oral suspensions. 5. Evaluation of oral suspensions, in vitro 6. Optimize the formulation using experimental design technique regarding particle size, particle size distribution, crystallinity, zeta potential, stability and release profile etc. 7. Evaluation of formulated product and identification of defects. 8. Study the stability of the optimized formulation following ICH guidelines.
The various components, which are used in suspension formulation, are as follows:12
Components Functions API Active drug substances Wetting They are added to disperse solids in continuous liquid phase. agents Flocculating They are added to floc the drug particles agents Thickeners They are added to increase the viscosity of suspension. Buffers They are added to stabilize the suspension to a desired pH range. and pH adjusting agents Osmotic They are added to adjust osmotic pressure comparable to agents biological fluid. Coloring They are added to impart desired color to suspension and agents Improve drug elegance. Preservatives They are added to prevent microbial growth. External They are added to construct structure of the final suspension. liquid vehicle
7.1 Source of Data : Data will be obtained from - Internet facilities. -Indian genomix company research articles -Literatures and related articles from library of krupanidhi college of pharmacy. -Indian institute of science and other research publications. -Drug information center (Banglore) and current index of medical specialties. 7.2 Matereials and method of collection of data (including sampling procedures if any):
The drug and the excipients will be procured from the industry and Krupanidhi College of Pharmacy. All the reagents to be used will be of analytical grade. The drugs related to physicochemical, physiological and pharmacological details of drug will be collected from drug information center, standard books, and research literature database such as Medline, science direct etc. Experimental data will be collected from the evaluation and designed formulation and then subjecting the formulation to different studies, wetting of the particles, sedimentation, particle size, electrokinetic properties. 7.3 Does the study require any investigations or interventions to be conducted on patients or other human or animals ? If so please describe briefly. -----NO----- 7.4 Has the Ethical Clearance been obtained from your Institution in case of 7.3? ----NOT APPLICABLE---- 8.LIST OF REFERENCES : 1. Gilleard JS. Understanding anthelmintic resistant. International journal parasitology 2006; 36(12): 1227-1239.
2. Piyush yadav, rupali singh. A review on anthelmintic drugs and their future scope. International journal of pharmacy and pharmaceutical science 2011; 3(3):17-21.
3. Senlik B, cirak VY, tinar R. Performed efficacy of two netobimin oral suspensions. Small ruminant research; 80(1): 104-106.
4. Sanchez acedo, Gutierrez galindo J, Castillo Hernandez JA. Anthelmintic effect of febantel on various species of gastrointestinal nematodes. Veterinar- medizinische nachrichten 1980:35-43
5. Al-qudah KM, sharif LA, al-rawashden OF. Efficacy of closantel plus albendazole liquid suspension against natural infection of gastrointestinal parasites. Vetparasitol 1999: 82(2):173-178.
6. Horton J. A review of anthelmintic efficacy and safety. Parasitology2000; 121sppl:113-132.
7. Shuyu xie et al., Solid lipid nanoparticle suspension enhanced the therapeutic efficacy of praziquantel. Int j nano medicine 2011; 6:2367-2374.
8. Dennis J, Richardson and Cheryl d brink. Effectiveness of various anthelmintics in the treatment of Moniliformiasis 2011: 11(8):1151-1156.
9. Beverly A goven, Donald F amend. Mebendazole/trichlorfon combination. Journal of fish biology; 20(4):373-378.
10. Goutam kumar jana et al., evaluation of anthelmintic Potential of Mimusops elengi Linn. Journal of pharmacy research article 2010: 10(3):2514-2515.
11. Olaniyi J Ekundayo, Muktar H Aliyu, Pauline E Jolly. A review of intestinal helminthiasis in Nigeria and the need for school-based intervention. Journal of rural and tropical public health 6, 2007:33-39.
12. Cooper & Gun. Sixth edition. “Dispersed system” tutorial Pharmacy: p.75-78.
13. Dr. Mukesh Gohel et al., Pharmaceutical suspensions review. available from: URL: http://www.pharmainfo.net/free-books/pharmaceutical-suspensionsa-review
14. Koyama K, Oishi T, Ishii A, Deguchi T. Metabolic fate of levamisole in rats, dogs and monkeys1983. Oyo Yakuri26:869-876.