Evaluation of Moringa Oleifera Roots and Flowers for the Preventive and Curative Effects

UNDER THE GUIDANCE OF

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BENGALURU.

ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

T.M.A.E. SOCIETY’S

ENCLOSURE-I

06. BRIEF RESUME OF THE INTENDED WORK

6.1 NEED FOR THE STUDY:-

Oral liquids are homogenous preparations containing one or more active ingredients dissolved or suspended in a suitable vehicle and are intended to be swallowed either undiluted or after dilution.Suspension is a heterogenous system consisting of internal phase or suspended phase, which is made up of the particulate matter, dispersed uniformly with mechanical agitation throughout the external phase with the help of suspending agents, which is generally a liquid or semisolid. The dispersed phase may consist of discrete particles or it may be a network of particles, resulting from particle-particle interaction. The drugs are dispersed as suspensions for different reasons, but the most common one is poor aqueous solubility. The suspension offer greater stability to drug as it is not in solution form and in some cases enhanced bioavailability also occurs1. The suspension can be easily administered to children of different ages by taking the required volume toswallow.

Besides the conventional form, sustained release suspensions can be prepared in order to achieve sustained action by achieving and maintaining a desirable blood concentration of the drug at a roughly constant level for a suitable period of time. The primary object of sustained release drug delivery system is to ensure safety, improve the efficiency of drug and also reduces the dose frequency, which also ultimately results in patient compliance.

A variety of approaches have been investigated for producing sustained release suspension formulations of different drugs. Development of sustained release suspension will avoid fluctuations of drug concentration in blood and exhibit its action for a longer period of time. Clinically sustained release suspensions can also be preferred to achieve a sustained action medication by alleviating the pain during sleep being often helpful in reducing anxiety. Multi unit dosage forms, such as beads or multiparticulates, have gained popularity when compared to non-disintegrating single-unit dosage forms. They distribute more uniformly in the gastrointestinal tract, resulting in more uniform drug absorption and reduced local irritation and also avoid the unwanted intestinal retention of the polymeric material. In addition, multi particulate dosage forms offer the possibility of being formulated as liquid suspensions, which constitute the ideal administration form for pediatric and geriatric patients, because of their ease of swallowing and flexibility in the measurement of doses2. The concept of microparticles can be utilized to provide a more reliable and long lasting release of the drug for local and systemic action. The microparticles alter the absorption of drug, and have been utilized to obtain prolonged and uniform release, afford the possibility of a long lasting and more reliable release of the drug from dosage form and thereby enhancing the bioavailability.

Dextromethorphan is an effective and widely used phenanthrene derived antitussive drug, which has acentral action on the cough centre in the medulla and used inthe treatment of respiratory disorders. Its antitussive effect is similar to codeine, but has no analgesic oraddictive action. It is generally used as an ingredient in cough and cold remedies3.

This drug has a short half-life 1.4 to 3.9 hrs with a bioavailability of 11% and the recommendedoral dose for adults is three to four times in a day which is inconvenient for the patients. Therefore, sustained release dosage forms are necessary to avoidrepeated administration4.

The main purpose in development of sustained release suspension is to obtain a desirable blood concentration of Dextromethorphan and also to maintain the stability of drug. Furthermore, the formulation of a new dosage form as sustained released suspension obviously gives a new vision and may increase the therapeutic possibilities.

Theaim of this study is to develop a sustained release suspension of Dextromethorphan micro particulates with an appropriate polymer to achieve a safe, rapid and more effective dosage form with enhanced stability and allows the ease of administration for pediatric and geriatric patients, thereby eliminating dosing frequency and improving the bioavailability.

Advantages of microspheres: -

1. Taste and odour masking of drug.
2. Protection of drug against the environment (moisture, light, heat and oxidation.).
3. To improve the bioavailability.
4. To decrease the side effects.
5. To reduce the dose frequency.
6. To relative stability.
7. To increase the patient compliance.
8. To have better therapeutic efficacy.
9. To reduce the fluctuation in plasma drug concentration.
10. Safe handling of toxic substances.

ENCLOSURE-II

6.2 REVIEW OF LITERATURE:-

Liandong Hu, et al., developed the dextromethorphan hydrobromide sustained-release(DMB-SR) tablets using floating technique to prolong the gastric residence time and compared theirpharmacokinetic behavior with conventional sustained release tablets. The floating tablets were evaluated foruniformity of weight, hardness, friability, drug content, floating characteristics, in-vitro release and in-vivo bioavailability. The optimized tablets were prepared with HPMC K4M 25 mg, sodium bicarbonate20mg and hexadecanol 18 mg. The prepared tablets could float within 3 min and maintain for more than24 h. The data of physical parameters were all lie within the limits. Drug release at 12 h was more than85%. The comparative pharmacokinetic study was performed by administration of the DMB-SR floatingtablets and conventional DMB-SR tablets. The area under curve of plasma concentration–time (AUC) offloating tablets was slightly higher than that of reference tablets, Tmax was prolonged apparently. Theresults showed the floating tablets are a feasible approach for the sustained-release preparation of drugs,which have limited absorption sites in the stomach.5

Seong Hoon Jeong, et al.,preparedcomplexes of ion-exchange resin andDextromethorphan sustained-release fast-disintegrating tablets (FDTs) using different particle sizes of the resins. Aqueous colloidal dispersions of ethylcellulose (EC) andpoly(vinyl acetate) (Kollicoat® SR30D) were used for fluid-bed coating. Based on drug loading, release profiles, and scanning electron microscopy(SEM) images, the coated particles were granulated with suitable tablet excipients and then compressed into the tablets. Drug release profiles andSEM pictures were compared before and after the manufacturing processes. As the particle size of resins increased, the drug loading and releaserate decreased due to the reduced effective diffusion coefficient and surface area. Higher coating level decreased the release rate further. In contrastto EC, Kollicoat® SR30D coated particles could be compressed into tablets without any rupture or cracks on the coating since the mechanicalproperties of the polymer was more resistant to the manufacturing processes. This resulted in no significant changes in release rates.6

Manish Bhise R, et.al.,developedEudragit RS100 coated ion exchange resinate of Ambroxol Hcl were prepared using Indion-244 by Solvent evaporation method. Among the various formulations of microcapsules prepared, formulation (drug resinate 1:1) and 10% eudragit coating was selected for the formulation into sustained release suspension.Three formulations of suspension were prepared using xanthan gum as suspending agent in three different concentration (0.2,0.3, 0.4% w/v). This suspension was evaluated for physical stability, redispersibility and in-vitro drug release pattern. Theresult showed that the suspension prepared with xanthun gum (0.3%w/v) as a suspending agent showed a optimum drug release and was found to be ideal to be formulated into sustained release dosage form7.

Burcu Devrim, et.al.,preparedreconstitutable suspensions of ibuprofen loaded microspheres were prepared using an acrylic polymer. The microspheres were prepared by the quasi-emulsion solvent diffusion technique. The microspheres used had a mean particle size of 316.6 μm and 99.8% loading efficiency. Xanthan gum was chosen as the suspending agent and D-sorbitol was used to impart palatability . The amount of D-sorbitol affected sedimentation volume and redispersibility properties of suspensions. To ensure minimum drug leakage from the microspheres into the suspension, the pH was buffered at 3.60 using citrate buffer.The ibuprofen content calculated from the suspended microspheres was consistent with that from microspheres alone. The results indicated that no leakage of drug occurred from the microspheres in the suspension on storage.Release rate of ibuprofen from the microspheres suspension and microspheres alone indicated that the suspension medium did not affect the property of drug release. This study suggested that stable suspensions of ibuprofen-loaded microspheres could be formulated with 0.6% w/v xanthan gum by the addition of 20%w/v D-sorbitol8.

Jain DK, et.al.,prepareddry suspensions of Azithromycin andAmbroxol HCl for reconstitution was developed. Reconstitutable oral suspension show adequate chemical stability of the drug during shelf life, avoiding the physical stability problems. Thesedry mixturesrequire the addition of water at the time of dispensing. The preparedsuspensions were evaluated for flow properties, rheological and sedimentation behavior. The reconstitution oralsuspensions of Azithromycin and Ambroxol HCl were found to be stable over its intended shelf life of 15 days afterreconstitution. Formulation with Xanthum gum (1.5% and 0.75%) showed excellent sedimentation volume and degree offlocculation. This was due to the presence of anti caking agents or the granule disintegrant added to theformulations. Also formulation with Acacia (3% and 1.5%) showed good redispersibility9.

Emami J. et.al., prepared microspheres of Theophylline was prepared by spray-drying technique using ethyl cellulose and hydroxyl propyl methyl cellulose phthalate(HPMCP) in different solvents and varying ratio of polymer to drug. The spray-dried micro particles were characterized in terms of shape, drug release and stability. They were formulated and evaluated by dissolution and stability studies. The type of polymer and spray dryer feed solution had a major impact on the in-vitro performance and release of Theophylline from microspheres and suspensions10.

ENCLOSURE-III

6.3 OBJECTIVES OF THE STUDY:-

The objectives of proposed study are as follows:-

1)Preformulation studies of the drug and polymers, drug-excipient compatibility by FT-IR and DSC methods.

2)To develop suitable analytical method for the estimation of the drug.

3)To prepare complex of drug with suitable resin.

4)Evaluation of resin complex.

5)Formulation of microcapsule of drug resinates using polymers like Eudragit, Ethyl cellulose, Hydroxy propyl methyl cellulose phthalate, etc.

6)Characterization of the prepared microcapsule.

7)In-vitro evaluation of the sustained release Dextromethorphanmicrospheres.

8)Drug release kinetics of the prepared microspheres.

9)Development of sustained release suspension containing Dextromethorphan microspheres using various suspending agents.

10)Evaluation of the prepared suspensions for drug content,release rate profile, pH, Sedimentation volume and Redispersibility.

11)In-vitro release profile of the prepared suspensions.

12)Prediction of In-vitro release mechanism.

13)Statistical analysis of the generated data.

ENCLOSURE-IV

07. MATERIALS ANDMETHODS:-

7.1SOURCE OF DATA:-

1. References from library:- S.C.S. College of Pharmacy, Harapanahalli-583131.
2. Journals and publications.
3. Laboratory based studies.
4. Textbook and standard reference books.
5. Internet:-

a.

b.

c.

d.

1. National and international journals and publications.
2. Medline.
3. Helinet for the RGUHS.

ENCLOSURE-V

7.2 METHODS OF COLLECTION OF DATA:-

(Including sampling proceduresif any)

1. From the available literature.
2. The selected drug shall be characterized and evaluated for its physicochemical properties like solubility and compatibility with excipients.

MATERIALS:-

1.Drug: -Anti-tussive such as Dextromethorphan.

2.Polymer: -Eudragit L 100, HPMC K 100, Carbopol , Ethyl cellulose. etc.

1. Solvents:-Water, Alcohol, Acetone, Petroleum ether, Liquidparaffin
2. Excipients:- Magnesium Stearate, Sodium Stearyl Fumarate, Talc, Isopropyl Alcohol.

EQUIPMENTS:-

1. Granulator.
2. FT-IR, UV spectrophotometer.
3. Weighing balance.
4. Tray drier.
5. Double cone blender.
6. Dissolution apparatusStability Chamber.
7. Orbital Shaker.
8. Hot Air Oven.
9. Ultra Sonicator.

A)PREFORMULATION STUDIES:-

1. Drug-polymer compatibility studies using FT-IR and DSC techniques.
2. Construction of the calibration curve for Dextromethorphan by spectrophotometric method to estimate the drug loading efficiency and analysis of in-vitro dissolution samples.
3. To prepare complex of drug with suitable resin.

B)PREPARATION OF MICROSPHERES:-

1. Solvent evaporation method.
2. Emulsion solvent diffusion method.
3. Air SuspensionMethod.
4. Co-acervation Method.

C)EVALUATION OF MICROSPHERES:-

1. Sphericity and surface morphology of microspheres by SEM.
2. Percentage yield.
3. Incorporation efficiency of microspheres.
4. Particle size and distribution by optical microscopy.
5. Drug Entrapment and in-vitro release studies.
6. In -vitro release studies.

D)PREPARATION OF SUSTAINED RELEASE SUSPENSION OF DEXTROMETHORPHAN:-

Suspensions will be prepared using different suspending agents in varying ratio.

E) EVALUATION OF SUSTAINED RELEASE SUSPENSION:-

1. Visual inspection.
2. Uniformity of drug content.
3. In-vitro dissolution studies for ascertaining the sustained release of drug from the formulations.

F) STATISTICAL ANALYSIS OF ALL THE GENERATED DATA:-

Stability studies of best formulations as per ICH guidelines.

CONCLUSION

Based on the above mentioned parameters,sustained release suspensionscontainingDextromethorphan HBr loaded microspheresformulated and evaluated.

ENCLOSURE-VI

7.3Does the study require investigation or intervention to be conducted onpatients, other humans or animals? if so, please describe briefly.

-NO-

7.4Hasethicalclearancebeenobtainedfromethical committeeofinstitution in case of 7.3?

-NOT APPLICABLE-

ENCLOSURE-VII

08. LIST OF REFERENCES:-

1. Sompur CK, Doijid RC, Patil SM, Maske AP. An Approach for development of sustained release suspension. Int J Pharm Bio Sci. 2011;2(2):320-328.
2. Cuna M, Vila JL, Torres D. Controlled release liquid suspension based on ion-exchange particles entrapped with in acrylic microcapsules. Int J Pharm. 2000;199:151-158.
3. Subramania NM, Sekar R, Selvadurai M,. Formulation and evaluation of dextromethorphan hydrobromide sustained release tablets. Drug Deliv. 2008;15:429-435.
4. Silvasti M, Martine P, Tukiainen H, Kokkonen P, Hanninen U, Nykanen S. Pharmacokinetics of dextromethorphan and dextrorphan: a single dose comparison of three preparations in human volunteers. Int J ClinPharmacol Ther Toxicol. 1987;25:493-497.
5. Liandong Hu, Li Li, Xun Yang, Wei Liu, Jianxue Yang, Yanhong Jia, Chuang Shang, Hongxin Xu. Floating matrix dosage form for dextromethorphan hydrobromide based on gas forming technique: In-vitro and in-vivo evaluation in healthy volunteers. Eur J Pharm Sci. 2011;42:99-105.
6. Seong Hoon Jeong, Kinam Park. Development of sustained release fast-disintegrating tablets using various polymer-coated ion-exchange resin complexes. Int J Pharm. 2008;353:195-204.
7. Manish Bhise R, Raju Thenge R, Krodhi Mahajan G, Vaibhav Adhao S, Manish Kadam S. Formulation & evaluation of sustained release suspension of Ambroxol HCl using ion exchange resin. Int J Pharm Tech Res. 2009;1(4):1322-1325.
8. Burcu Devrim, Asuman Bozkair, Kandemir Canefe. Formulation and evaluation of reconstitutable suspensions containing Ibuprofen loaded Eudragit microspheres. Acta Pharm Drug Res.2011;68(4):593-599.
9. Jain DK, Darwhekar GN, Choudhary N. Formulation and evaluation of reconstitutable oral suspension of ambroxol Hcl and azithromycin. Int J Pharm Tech Res. 2011;3(2):741-746.
10. Emami J, Varshosaz J, Ahmadi F. Preparation and evaluation of a liquid sustained-release drug delivery system for theophylline using spray-drying technique.Res Pharm Sci. 2007;2:1-11.