formulation and characterisation of fast dissloving film of granisetron hydrochloride by prashant...

FORMULATION AND CHARACTERISATION OF FAST DISSLOVING FILM OF GRANISETRON HYDROCHLORIDE

By Prashant Patel(M.pharm sem-2)

Department of pharmaceutical technology

Guided by:Dr. Dhagla Ram Chaudhary

Department of Pharmaceutical technology

Indukaka Ipcowala college of pharmacy

Introduction

Selection of Drug-Granisetron HCL (GRN)

Aim and Objectives

Review of literature

Plan of work

Content

other

Capsules

Tablets

Introduction

Tablets and capsules constitute a major portion of the drug delivery systems that are currently available.

However, many patient groups such as elderly, children, and patients mentally retarded, uncooperative, nauseated, or on reduced liquid intake diets have difficulty in swallowing these dosage forms.

In some cases like motion sickness, sudden episodes of allergic attack, coughing, hypertension, vomiting and during unavailability of water, swallowing conventional tablets is difficult.

To fulfill these medical needs, formulators have devoted considerable efforts in developing a novel type of dosage form for oral administration known as oral fast dissolving dosage forms [1].

Fast dissolving Drug delivery system

Fast dissolving drug-delivery systems were first developed in the late 1970s as an alternative to conventional dosage forms.[2]

Fast dissolving or quick dissolving dosage forms have possessed great importance in the pharmaceutical field due to their unique properties and advantages.

They undergo disintegration in the salivary fluids of the oral cavity within a minute, where they release the active pharmaceutical ingredient.

The first developed fast-dissolving dosage form consisted in tablet form, and the rapid disintegrating properties were obtained through a special process or formulation modifications [4].

Advantages of FDF

Rapid onset of action than tablets Destructive acidic environment of stomach can be

avoided Delivery can also be terminated relatively easily if

required [2]. Availability of larger surface area that leads to rapid

disintegrating and dissolution in the oral cavity. The disadvantages of most oral dissolving tablets is

that they are fragile and brittle, which warrants special package for protection during storage and transportation. Since the films are flexible they are not as fragile. Hence, there is ease of transportation and during consumer handling and storage.

As compared to drops or syrup formulations, precision in the administered dose is ensured from each of the strips.

No need of water has led to better acceptability amongst the dysphasic patients, repeated emesis, motion sickness, and mental disorders as they are unable to swallow large quantity of water [6].

The dosage form can be consumed at anyplace and anytime as per convenience of the individual.

Since the first pass effect can be reduced due to pre gastric absorption and absorption in oral cavity, there can be reduction in the dose which can lead to reduction in side effects associated with the molecule.

Selection of Drug-Granisetron HCL (GRN)

Granisetron HCl is a selective 5HT3 antagonist. It is a novel antiemetic drug, given for prevention of chemotherapy-induced nausea and for pre-and post-surgical nausea and vomiting.[7]

The drug is well absorbed from GIT, but its bioavailability (60%) is low due to extensive first pass metabolism.

It is very soluble in water. It is selected as a drug candidate, as it is not available in

such dosage form. And in general, emesis is preceded with nausea and in such condition it is difficult to administer drug with a glass of water; hence it is beneficial to administer such drugs as fast dissolving films with good mouth feel.[8]

Among 5-HT3 receptor antagonists, GRN may have less side effects, lower occurrence of drug–drug interaction and relatively longer half-life(4-6 hours in healthy patients, 9-12 hours in cancer patients) in the body.

Granisetron lacks the sedative, dysphoric, and extrapyramidal symptoms associated with other non-5HT 3 receptor antagonists such as droperidol and metoclopramide.

Granisetron is significantly more effective than the traditional antiemetics; droperidol and metoclopramide for the treatment of Post Operative Nausea and Vomiting (PONV).

It has greater affinity for the 5-HT3 receptor than ondansetron, and has twice the duration of action. [9]

It is also cost effective compare to other drug agents for this treatment.

Aim and Objectives

The aim of this work is formulation and characterization of fast dissolving film of Granisetron hydrochloride by using different water soluble/swellable polymers with taste masking.

In the present study attempt will be made to formulate a “patient friendly” dosage form of fast dissolving oral film of Granisetron hydrochloride - a possible application to anti emesis.

The present study is planned with the following objectives: To achieve quick release of drug for quick on set of action. To provide more patient compliance.

To evaluate the formulations with respect to various physical parameters. (Physical appearance, surface texture, thickness of film, swelling index, moisture uptake, folding endurance, surface pH).

To evaluate the films with respect to drug estimation, in-vitro disintegration time and in-vitro dissolution rate studies.

To characterize the formulation with respect to drug-excipient interaction studies.

To carry out stability studies as per ICH guidelines.

Review of Literature

Hiroyoshi Tanaka et al., compared the efficacy of the selective 5-hydroxytryptamine 3 receptor antagonist granisetron with that of the traditional antiemetics droperidol and metoclopramide in the treatment of established PONV after breast surgery

Result: A significantly higher proportion of patients who received granisetron (88%) were emesis free (no nausea, retching, or vomiting) compared with those who received droperidol (64%) or metoclopramide (56%). [9]


Tawfik DS et al., evaluated the antiemetic effectiveness and clinical usefulness of granisetron in comparison to dexamethasone in the prevention of postoperative vomiting in children undergoing strabismus surgery.

Result: The number of children who suffered severe vomiting (2 times or more) were 14,13,3 out of 30 in placebo, dexamethazon and granisetron group and it was found that it reduced significantly in granisetron group.

Conclusion: The prophylactic use of granisetron is effective in preventing post operative retching and vomiting and improving the outcome measure as after strabismus repair in children. [10]


Yvonne E et al., compared the efficacy and tolerability of granisetron, ondansetron and tropisetron in controlling acute nausea and vomiting.

Several large randomised, comparative studies have compared granisetron (3mg single dose, equivalent to 40 [mu]g/kg in a 75kg person) with 2 other 5-HT3 antagonists, ondansetron (8 or 32mg single dose, or 8mg prophylactically then 8mg every 8 hours) and tropisetron (5mg single dose).

Result: No significant differences were reported among the 3 agents in the control of acute nausea and vomiting, except in the complete control of acute vomiting in study, where granisetron had amodest statistical advantage over ondansetron but not tropisetron. However, in crossover studies, significantly more patients preferred granisetron to either ondansetron or tropisetron. [11]


Greg L et al., Pharmacoeconomic Evaluation of Granisetron: In economic analyses conducted in France, a single

dose of granisetron 3mg was associated with a mean direct treatment cost per patient (or per well-controlled patient) approximately 50% lower than that for ondansetron 8mg intravenously followed by 8mg orally every 8 hours for 3 days, in patients receiving single-dose chemotherapy.

Direct costs per patient were approximately 20 to 30% lower with granisetron (usually 3 mg/day) than ondansetron (usually 24 to 32 mg/day intravenously) in patients receiving chemotherapy fractionated over several days. [12]


S. J. Gibbs et al., carried out A Pilot Study to Evaluate the Cost-Effectiveness of Ondansetron and Granisetron in Fractionated Total Body Irradiation.

The duration of the antiemetic effect of granisetron was examined in a pilot study of patients (n = 26) undergoing a standard emetogenic stimulus in the form of total body irradiation fractionated over 3-4 days, in a randomized comparison with twice daily ondansetron.

Result: The cost per patient in this study was £48 for granisetron and £54 for ondansetron. [13]


Author Name of journal Study result

Renuka Mishra and Avani Amin[3]

Indian Journal of Pharmaceutical Education and Research

Formulation and Characterization of Rapidly Dissolving Films ofCetirizine hydrochloride using Pullulan as a Film Forming Agent

The result revealed that the prepared films exhibited satisfactory thickness, tensile strength, percentage elongation and elastic modulus. In vitro dissolution studies and In vitro disintegration studies were found to be satisfactory

Francesco Cilurzo, Irma E. Cupone, Paola Minghetti, Francesca Selmin, Luisa Montanari [4]

European Journal of Pharmaceutics and Bio pharmaceutics

prepared fast dissolving film of piroxicam using maltodextrin with low dextrose equivalent as film forming material and suitable plasticizer and its concentration used for film formation using casting and solvent evaporation method.

Fast dissolving films of piroxicam showed high loading capacity of dose with improved dissolution rate

Author Name of journal

Study result

N.L Prasanthi, C. Sowmya Krishna, M. Eswar Gupta, S.S. Manikiran and N. Rama Rao [14]

Scholars Research Library

in this study sublingual fast dissolving films for an antiasthamatic drug were prepared by solvent evaporation technique using different water soluble polymer. The Tween 80 is used as a solubilizing agent and an Aspartame is used as a sweetener.

Prepared films were clear, transparent and smooth surface. Film containing hydroxyl propyl methylcellulose (2%w/w), Tween 80 (0.5%w/w) and Aspartame (0.5% w/w) showed optimum performance against all other prepared formulations

Hiroyoshi Shimoda, Kazumi Taniguchi, Misao Nishimura, Katsuhiko Matsuura, Tadao Tsukioka,Hirotaka Yamashita [15]

European Journal of Pharmaceutics and Biopharmaceutics

prepared fast dissolving oral thin film containing dexamethasone by using various type of polymer like polyethylene glycol, microcrystalline cellulose, HPCM, Polysorbate 80

there were no significant differences in pharmacokinetic parameters obtained from rats with oral administration of dexamethasone suspension and those with topical application of film to oral cavity. Therefore fast disintegrating oral film is considered to be useful for cancer patient with disturbance in eating and swallowing who receive radiotherapy or high to moderate emetogenic anti-cancer drugs

Author Name of journal

Study result

Khanusiya A.Qadir, Charyulu RN, Prabhu P, Bhatt S, Shastry CS.[16]

International Research Journal Of Pharmacy

the films of loratadine were prepared by using polymers such as hydroxypropyl methylcellulose (HPMC) & polyvinyl pyrrolidone (PVP) and hydroxypropyl cellulose (HPC) in different ratios with suitable plasticizer like propylene glycol and sweetener like aspartame by solvent casting method.

Disintegration time of the films was found to be decreased with increase in the concentration of the HPMC 15cps polymer. From the present investigation it can be conclude that fast dissolving film formulation can be a potential novel drug dosage form for pediatric, geriatric and also for general population

Kulkarni A. S., Deokule H.A., Mane M.S. and Ghadge D. M. [17]

Journal of Current Pharmaceutical Research

prepared fast dissolving strips by solvent casting method, using various polymers such as HPMC E-15, HPMC K4M, HPMC E-5, PVA, PVP, Gelatin, Eudragit RL 100 and pullulan

study concluded that the pullulan is the best film forming agent.

Dhagla Ram Choudhary, Vishnu A Patel, Usmangani K Chhalotiya, Harsha V Patel, Aliasgar J Kundawala.[18]

Journal of Pharmacy Research

developed fast dissolving films of levocetirizine for the treatment of acute allergic rhinitis and chronic urticaria using different grades of methocel K3, E3, E5, and E15

Optimized films were evaluated form mechanical properties; the research work done here suggested the exciting possibility of levocetirizine as fast dissolving film

Author Name of journal Study result

Ming J. Chen, Gloria Tirol, Robert Schmitt,Chiling Chien, Ahmed Dualeh.[19]

Poster presented at the 2006 Annual Meeting and Exposition of theAmerican Association of Pharmaceutical Scientists

Fast dissolving Films were prepared using a solvent casting Technique by using different polymers e.g. cellulose ether METHOCEL HPMC E3 and METHOCEL A3, poly(ethylene)oxide POLYOX N 10, N-80, N-750 and WSR 205, pullulan, CMC Cekol 30, PVP K-90, gelatin, sodium alginate, and hydroxypropylcellulose MW 93,000.

An increase in glycerol content resulted in a marked decrease in the film strength of the formulated METHOCEL HPMC E50 films. The desirable fast disintegration and mechanical properties can be tailored with poly (ethylene oxide) and HPMC. The formulated HPMC and poly (ethylene oxide) films result in good mouth feel, with no sticky feeling or formation of a highly viscous gel in the mouth.

Yoshifumi Murata, Takashi Isobe, Kyoko Kofuji, Norihisa Nishida and Ryosei Kamaguchi.[20]

MDPI journals materials

developed fast dissolving film using natural polysaccharides such as pullulan and films was loaded with pilocarpine, lidocaine and dexamethasone as a model drugs

All films prepared with polysaccharides readily swelled in dissolution medium, released the incorporated compound, and subsequently disintegrated. The release of dexamethasone from the films was complete after 15 min, although this release rate was slightly slower than that of pilocarpine or lidocaine.

Plan of work

• Literature Survey

• Selection of drug: Granisetron and formulation: FDF

• Material procurement

• Preformulation study followed by identification of procured materials

• Taste masking using suitable method

• Formulation development by suitable method using different polymers

• Evaluation of mechanical properties and various physical parameters• evaluation with respect to drug estimation, in-vitro disintegration time and in-vitro dissolution rate studies.• Stability study as per ICH guide line

• Thesis write up including summery and conclusion

References

1. Sivakranth M, Abdul S. “ Formulation and evaluation of oral fast dissolving tablets of sildenafil citrate” International journal of pharmacy and pharmaceutical sciences,2010; 112-121

2. Nehal M D, Garg G, Sharma P. “ A short review on a novel approach in oral fast dissolving drug delivery system and their patents” Advanced in biological research,2011; 291-303

3. Mishra R, Amin A. “ Formulation and characterization of rapidly dissolving films of cetirizine hydrochloride using pullulan as a film forming agent” Indian journal of pharmaceutical education and research, 2010; 71-77

4. Cilurzo F, Cupane I, Minghetti P. “ Fast dissolving films of maltodextrins” European journal of pharmaceutics and biopharmaceutics,2008; 895-900

5. Kumar S V, Gavaskar B, Gurusharan Y. “ Overview of fast dissolving films” International journal of pharmacy and pharmaceutical sciences,2010; 29-33

6. Dixit R P, Puthli S P. “Oral strip technology: overview and future potential” Journal of controlled release, 2009; 94-107

7. Nagendra K, Raju S A, Shirsand S B. “Formulation design of novel fast dissolving tablet of granisetron hydrochloride using super disintegrant blend for improved efficacy” International journal of research in ayurved and pharmacy, 2010, 468-474

8. Doh H J,Jung Y, Balakrishan P, Cho H J, Kim D D. “A novel lipid nanoemulsion system for improved premeation of granisetron” Colloids and surface B: Biointerface, 2012, 475-80

9. Fujii Y, Tanaka H, Kawasaki T. “A comparison of granisentron, domperidol, and metoclopramide in the treatment of established nausea and vomiting after breast surgery: A double-bling,randomized,controlled trial” Clinical Therapeurics, 2003, 1142-59

10. Hala M B, Hakim A, Tawfik D S, Raheb M S, Mohamed A. “A comparative study: Dexametasone versus granisetron in prevention of post operative vomiting in pediatric patients undergoing strabismus surgery” Australian journal of basic and applied science, 2011, 170-73

11. Yarker, Yvonne E.; Tavish M C, Donna. “Granisetron: An Update of its Therapeutic Use in Nausea and Vomiting Induced by Antineoplastic Therapy” Drugs, 1994, 761-793

12. Plosker, Greg L; Benfield, Paul. “Granisetron: A Pharmacoeconomic Evaluation of its Use in the Prophylaxis of Chemotherapy-Induced Nausea and Vomiting” Pharmacoeconomics, 1996, 357-74

13. Gibbs S J, Cassoni S N. “A Pilot Study to Evaluate the Cost-Effectiveness of Ondansetron and Granisetron in Fractionated Total Body Irradiation” Clinical Oncology, 1996, 182-184

14. Pranshathi N L, Sowmya Krishna C, Eswar Gupta. “Design and Development of Sublingual Fast Dissolving Films for an Antiasthmatic Drug” Scholars Research Library, 2011, 382-395

15. Shimoda H, Taniguchi K, Nishimura M, Matsuura K, Tsukioka T, Yamashita H ,Inagaki N,Hirano K, Yamamoto M, Kinosada Y,Itoh Y. “Preparation of a fast dissolving oral thin film containing dexamethasone: A possible application to antiemesis during cancer chemotherapy” European Journal of Pharmaceutics and Bio pharmaceutics , 2009, 361–365

16. Khanusiya A Q, Charyulu R N, Prabhu P, Bhatt S, Shastry C S. “Formulation And Evaluation Of Fast Dissolving Films Of Loratadine For Sublingual Use” International Research Journal Of Pharmacy, 2012, 157-161

17. Kulkarni A S, Deokule H A, Mane M S, and Ghadge D M. “Exploration of different polymers for use in the formulation of oral fast dissolving strips” Journal of Current Pharmaceutical Research , 2010; 33-35

18. Choudhary D R, Patel V A, Chhalotiya1 U K, Patel H V, Kundawala1 A J. “Formulation and Evaluation of Fast Dissolving Film of Levocetirizine Dihydrochloride Using Different Grades of Methocel” Journal of Pharmacy Research, 2011, 2919-2924

19. Ming J, Gloria , Robert S, Chiling C, Ahmed D. “Film-Forming Polymers in Fast-Dissolve Oral Films” American Association of Pharmaceutical Scientists, 2006, 1-5

20. Murata Y, Takashi I, Kyoko K , Nishida N and Kamaguchi R. “Preparation of Fast Dissolving Films for Oral Dosage from Natural Polysaccharides” Materials, 2010, 4291-4299

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