Rajiv Gandhi University of Health Sciences s128

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES BANGALORE, KARNATAKA

ANNEXURE – II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. NAME OF THE CANDIDATE AND ADDRESS: PERMANENT ADDRESS: Bhagyashree.k #104,3rd stage,3th block, S N layout Basveshwar nagar Bangalore-79.

2. NAME OF THE INSTITUTE: Krupanidhi College of Pharmacy, Chikka Bellandur, Carmelaram Post, Varthur Hobli, Bangalore –560035. Karnataka 3. COURSE OF THE STUDY & SUBJECT: Master of Pharmacy (Pharmaceutical Technology) 4. DATE OF ADMISSION TO THE 6-July- 2010 COURSE:

5. TITLE OF THE TOPIC:

“FORMULATION AND EVALUATION OF MULTIVITAMIN SOFT GELATIN CAPSULES AND ITS PROCESS OPTIMIZATION”

6. BRIEF RESUME OF THE INTENDED WORK:

6.1 Need of Study:

Gelatin capsules, especially soft gelatin capsules, nearly a century/half a century old dosage forms have become increasingly important as a form of medication since it became feasible, in the 1930's, to manufacture them by making and filling the capsules in a single operation. They are odorless and tasteless, they can be taken easily and, owing to their swelling capability and water solubility, the drugs are readily liberated in the stomach. Numerous drugs which, on account of their sensitivity to oxidation and to light, their thermal stability or their hygroscopicity, may not be processed into other medicinal forms, can be encapsulated without impairment of their function1.

It is estimated that more than 40% of new chemical entities (NCEs) coming out of the current drug discovery process have poor biopharmaceutical properties, such as low aqueous solubility and/or permeability. These suboptimal properties pose significant challenges for the oral absorption of the compounds and for the development of orally bioavailable dosage forms. Development of soft gelatin capsule (softgel) dosage form is of growing interest for the oral delivery of poorly water soluble compounds (BCS class II or class IV). The softgel dosage form offers several advantages over other oral dosage forms, such as formulating a liquid matrix which isdesigned to solubilize and improve the oral bioavailability of a poorly soluble compound as a unit dose solid dosage form2. Soft gelatin capsules serve chiefly for the containment of liquids, i.e. oily solutions, suspensions or emulsions. Vegetable, animal and mineral oils, liquid hydrocarbons, ethereal oils and also polyethylene glycols are also used as fillings. Fats and waxes are also applied or admixed to increase the consistency1.

Soft gelatin capsules generally contain the medicament dissolved or dispersed in oils or hydrophilic liquids (i.e., fill liquid). The inherent flexibility of the soft gelatin capsule is due to the presence of plasticizers and residual moisture in the capsule shell3.

By formulating soft gelatin capsules of multivitamin ,the bioavailability can be increased and encapsulation of several ingredients in multivitamin softgel with dose accuracy, content uniformity, homogenity can be achieved and also opaque, transparent, slippery, odorless and stability can be achieved with increased patient compliance4.

6.2 Objective of Study:

1. The primary objective of this study is to develop and formulate soft gelatin capsule dosage form and optimize the drug delivery of dosage form to achieve a measure in control over the therapeutic effect with improved patient compliance.

2. Evaluation studies Physiochemical tests:  Visual clarity and Appearance.  Shape and size  Thickness of capsule shell  Leaking test for liquid and semi solids content  Percentage of medicament test Standard Official tests:  Content uniformity  Weight variation test  Disintegration test  Dissolution test  Capsule stability5.

6.3 Review of Literature:

1. Michael Kilby et al., studied activity of soft gelatin capsule formulation of saquinavir in combination with two nucleosides in treatment- HIV-1-seropositive persons. It was reported that the formulation of saquinavir soft gelatin capsule (SQV-SGC, Fortovase(tm)) developed at a dose of 1.2 g three times daily, achieves plasma saquinavir (SQV) levels around 8-fold higher than those attained with the saquinavir hard gelatin capsule (SQV-HGC, Invirase)6.

2. Fischer et al., compared the drug release of clomethiazole edisylate soft gelatin capsule with tablets. They established that soft gelatin capsule showed sharp rapid release and improved bioavailability7.

3. Hashitera et al., claimed for the patent on a soft gelatin capsule formulation of a 15-keto- prostaglandin compound, which comprises: a soft gelatin capsule shell comprising gelatin and sugar alcohol as a plasticizer, and a mixture comprising a 15-keto-prostaglandin compound and a pharmaceutically acceptable vehicle which is filled in the shell. By encapsulating the 15-keto- prostaglandin compound in the specified soft gelatin capsule shell, stability of the compound is significantly improved8.

4. Stephen E Daniels et al., worked on Diclofenac potassium liquid filled Soft Gelatin capsule(DPSGC) ,their objective of study was to investigate the efficacy and safety of DPSGC 25 mg in a multicenter, randomized, double-blind, placebo-controlled study in patients experiencing pain. There results indicated that DPSGC reduced pain in patients and this novel formulation of diclofenac potassium may be a practical option for treating mild to moderate acute pain9.

5. Gursharan Moonga worked on hydrophobic drugs having poor bioavailability and when they are compounded in solid dosage forms, the dissolution rate is slow, absorption and the bioavailalabity are also low. Positive results were seen in the case of soft gel of poorly soluble drugs like hydrochlorothiazide, isotretinoin and griseofulvin and bioavailability is improved in the presence of fatty acids e.g. mono or diglycerides10.

6. Michelle Raikes et al., conducted moisture sorption experiments, performed on two different strengths of soft gelatin capsules containing a self emulsifying drug delivery system (SEDDS) .The capsules were exposed to multiple step-wise increasing (12% - 93%) and decreasing (93% - 12%) relative humidity conditions using saturated salt solutions. Additionally, the water content of the capsule fill was measured by Karl Fisher titration after exposure to each relative humidity step to quantitate the water migration through the capsule shell to the fill. And concluded that Moisture sorption data was acquired in the selection of appropriate in-process control ranges for packaging and storage configurations of drug product11.

7. Ighovwerha Ofotokun et al., carried research work on Lopinavir/ritonavir (LPV/r) tablet which was compared to the soft gel capsule (SGC) formulation for the variability, GI tolerability, quality of life (QoL), and formulation preference and after comparing LPV/r SGC to the tablet formulation and concluded that LPV/r-tablet was well tolerated and preferred to the SGC in HIV infected subjects, with stable QoL and appreciable improvement in GI-tolerability12.

8. Rafael Pissinati et al., carried experimentation on enteric coating of soft gelatin capsules by spout bed technique by considering the effect of operating conditions on coating efficiency and product quality and concluded that the coating efficiency value obtained was accurate and the coating efficiency was found to increase with increase in flow rate of spouting gas ratio and disintegration test showed that the gastric-resistant effect was obtained with a certain coating mass13.

9. Saranjith Singh et al., studied alteration of dissolution characteristics on gelatin containing formulation and resulted that the gelatin containing formulation must concern and introduce necessary modification in dissolution tests and reported to use of inhibitors, aldehyde free excipients which explored to stabilize the preparation14.

10. Brox Werner et al., claimed for patent of the process for the manufacture of soft gelatin capsules with gelatin shell, one plasticizer and with one pharmacologically-active substance E.g.:Nifidepine and a solvent. The capsules were dried for 3 days and were stable for 12 months and successfully reported that the capsules, under the same storage conditions were completely stable for 3 year and with 8 and 10 days of drying there was no embrittlement15.

11. Fucella et al., compared the bioavailability and onset of sedation of Temazepam soft gelatin capsule with conventional gelatin, suppositories and solution. The soft gel capsule showed faster absorption and produced higher and earlier peak plasma levels16.

12. Gennadios et al., claimed for patent on a soft gelatin composition compromising:30-60% by weight of a film forming material,5-35% by weight of water dispersable ,25-65% by weight purified water wherein the film-forming material comprises gelatin and gum acacia and resulted with that gelatin-extended capsules were similar to control capsules in terms of physical characteristics, showed increased elasticity in gelatin-gum acaia composition and greater stability17.

13. Borkan et al., patented by aiming in study of a chewable, edible soft gelatin capsule which comprises of a shell containing water, gelatin, plasticizer, and an amount of hydrogenated starch hydrolysate and reported that there was no sticky or gummy residue was found in the mouth of the user after a few seconds of chewing. Finally reported that the capsule was stable and provided with a pleasant taste18.

14. Fritz et al., patented by claiming on method of manufacture of foam gelatin capsules by suitable method involving mixing,melting, microdispersion and molding. And the faom capsules were subjected to evaluation test where it prooved that the additives did not affect the ability to generate a suitable gelatin foam and foam soft gelatin capsules were confirmed to have the desired properties by a standard disintegration test as described in U.S. Pharmacopeia19 .

7. Materials & Methods 7.1 Source of Data: The preliminary data will be obtained from the literature search and experimental work, which includes preformulation, formulation, product evaluation, optimization of formulation and accelerated stability studies.

7.2 Method of Collection of Data (including sampling procedure, if any) :

The physicochemical properties of the drug will be collected from drug information center, various standard Books, journals, websites and other sources like research literature bases data such as Medline, Science Direct etc. The dosage regimen and combination of data will be collected from study of drug, its formulation , through investigation of process and product variables.

The steps involved in such studies are as below :

1. Selection of the capsule size and shape to be used in the formulation. 2. Preformulation studies on different combination of multivitamin and excipients based on compatability study for formulation. The pre manufacturing studies includes the capsule filling ratio,moisture content,wettability,hygroscopicity, iron content,etc.. 3. Formulation of proposed Soft gelatin capsule as oral drug delivery system by suitable methodology like rotary die process, plate process,driping method,etc.. 4. Study the physicochemical characteristics of the formulations as per official and unofficial procedure. 5. To carry out in vitro evaluation for efficacy of the drug as per pharmacopeia. 6. Optimization of the dosage form based on evaluated parameters. 7. To carry out accelerated stability profiling as per ICH guidelines.

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, The study does not require any investigations or interventions to be conducted on patients or other human or animals. 7.4 Has the Ethical Clearance been obtained from your Institution in case of 7

NOT APPLICABLE

8. LIST OF REFERENCES:

1.Brox, Werner, Gabler, Wilfried. Soft gelatin capsule and processes for their manufacture. US Patent 4891229. Jan 1990. URL: http://www.patentstorm.us/patents/4891229/description.html .

2.Rampurna Prasad Gullapalli. Soft gelatin capsule (soft gels). JPS. April 2010;99(10)URL: http://onlinelibrary.wiley.com/doi/10.1002/jps.22151/abstract

3.Sam Ricchezza. Stability storage consideration for soft gelatin capsule. Oct 2010 .URL :http://contractpharma.com/expertopinions/2010/10/13/stability_storage_consideration_soft_gelatin_c apsule.

4.David Backham. Softgel capsule benefits in natural health and pharmaceutical products. Oct 2010 . URL: soft gel caps\softgel-capsule-benefits-in-natural-health-and-pharmaceutical-products- 3401931.html.

5.Dr. Bhawna Bhatt. Pharmaceutical technology capsules. Delhi Institute of pharmaceutical science and research. July 2007 27:19-20.

6.Michael Kilby J, Greg Sfakianos, Nick Gizzi, Peggy Siemon Hryczyk, Eric Ehrensing, Charles Oo, et.al. Safety and pharmacokinetics softgel capsule saquinavir plus minidose ritronavir in human immunodeficiency Virus. Antimicrobial agents chem. 2000 october ;44(10):2672-2678.

7.Fridrun Podzeck and Brian E Jones. Pharmaceutical capsules. 2004(2):226.

8.Hashitera,Yukiko, Hirata Ryu, Harada,Yasuhiro,Soft gelatin capsule formation. US Patent application:20070172523. 2007 July. Available from URL: http://www.freepatentsonline.com/y2007/0172523.html 9.Stephen E Daniels, Douglas R Baum, Francis Clark, Michael H Golf, Mark E McDonnell, Stwphen E Boesing , Diclofenac potassium liquid-filled soft gelatin capsules for the Treatment Of postbunionectomy pain.Current medical research and opinion Oct 2010(26).

10. Gurusharan moonga , “ An overview of drug Delivery Technologies”, http://pharmalicensing.com/public/articles/view/936693102_37d4cd6e18626.

11.Michelle Raikes, Nora Taylor and Cornelia. Moisture sorption experiment on soft gel capsules containing a self emulsifying drug delivery systems. Available from: URL:http://americanpharmaceuticalreview.com/ViewArticle.aspx?ContentID=4248

12.Ighovwerha Ofotokun, Susan K Chuck, Brian Schmotzer, and Kelly L O'Neil. Formulation preference ,tolerability&quality of life assessment following a switch from lopinavir/ritonavir soft gel capsule to tablet in human immunodeficiency virus infected patient. AIDS Resarch Therapy. 2009;6(29).

13. Rafel Pissimati, Wanderly Pereia Oliveira. Enteric Coating of soft gelatin capsules by spouted Bed : Effect of operationg conditions on coating efficiency and on product quality. EJPB. 55(3):331-321.

14. Saranjit Singh, Sariputta P Pakhale. Gelatin Containg Formulations:Change in Dissolution Characteristics.Encyclopedia of Pharmaceutical technology.3rd edi. Oct 2006.. 15.Brox, Werner, Gabler, Neckarstaden. Soft gelatin capsule and their process for manufacture. United states Patent No: 4891229. Jan 1990 . URL: http://www.patentstorm.us/patents/4891229/description.html

16.Pyare seth and Pawan seth. Novel pharmaceutical composition containing hydrophobic practically water insoluble drug absorbed on pharmaceutical excipients as carrier process for their preparation and the said composition.US Patent:4721709. Jan 1988. URL: http://www.patentgenius.com/patent/4721709.html

17. Gennadios, Aristippos . Gum acacia substituted soft gelatin capsules. United states patent:6193999. March 1999. URL: http://www.pharmcast.com/Patents/Yr2001/Feb2001/022701/6193999_Softgel022701.html

18. Borkan, Lionel ,Beny ,Ira R ,Shah, Dilip. Chewable ,edible soft gelatin capsule. United States Patent 4935243.Dec 1988 . URL: http://www.freepatentsonline.com/4935243.html.

19. Wittwer, Fritz , Mayer, Jean Philippe. Foam soft gelatin capsule and there method of manufacture. United States Patent 4609403.Sep 1986 . URL: http://www.freepatentsonline.com/4609403.html.

9. Signature of the Candidate

(BHAGYASHREE .K) 10. Remarks of the Guide:

Soft gelatin capsules are elegant, versatile, single piece unique dosage form ideally suited for encapsulating of wide variety of material .The present study is to develop an multivitamin soft gelatin capsule is of great therapeutic value. Therefore, I recommended this project for the approval & clearance.

11. Name & Designation (in BLOCK LETTERS)

11.1 Guide ASST. PROF: SARITHA ALLADI Department of Pharmaceutical Technology Krupanidhi College of Pharmacy Bangalore – 560035. 11.2 Signature of Guide 11.3 Co-Guide

11.4 Signature of Co-Guide

11.5 Head of the Department

Prof. Dr.R.S THAKUR PROFESSOR AND HEAD Department of Pharmaceutics Krupanidhi College of Pharmacy Bangalore – 560035 11.6 Signature of HOD :

12. 12.1 Remark of the Principal:

12.2 Signature of the Principal

Prof. Dr. PREM KUMAR.N PRINCIPAL Krupanidhi College of Pharmacy, Chikka Bellandur, Carmelaram Post, Varthur Hobli, Bangalore – 560035.