RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA
BANGALORE
ANNEXURE – II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1. / Name of the Candidate & Address (in block letters) / : / MS. LAEEQ FARHANAW/o Mohd. Mumtaz Ahmed,
Plot No.30, GDA Layout,
Behind Mohammadi Function Hall,
Sangtrashwadi,
GULBARGA – 585101
2. / Name of the Institution / : / H.K.E. SOCIETY’S COLLEGE OF PHARMACY
SEDAM ROAD, GULBARGA-585 105
3. / Course of Study and Subject / : / M.PHARM(PHARMACEUTICAL TECHNOLOGY)
4. / Date of Admission to Course / : / 31st May, 2007
5. / Title of the Topic / : / PREPARATION AND EVALUATION OF RECTAL SUPPOSITORIES OF CARVEDILOL
6. / Brief resume of the intended work
6.1 Need for the study:
Suppositories are medicated solid drug delivery systems generally intended for use in rectum1. Several unwanted side effects and disadvantages inherent to oral therapy led to focused attention on the rectal route for administering drugs, especially, in Europe. Rectal suppositories are much preferred in pediatric and geriatric patients with difficulties in swallowing solid oral dosage forms. These are also the dosage forms of choice for unconscious, semi-conscious patients and those suffering from nausea, vomiting, gastrointestinal ulcers, etc. Major factors affecting the absorption of drugs from suppositories are anorectal physiology, suppository vehicle and the physicochemical properties of the drug2.
Suppositories generally carry medicaments such as emollients, astringents, antiseptic and local anaesthetics to exert local action on the rectal mucosa. They are often used as a means of projecting medicaments such as hypnotics, tranquilizers, antispasmodics, antiemetics, anti hypertensives, anti inflammatory agents (NSAIDS) etc for systemic action. The advantage of administration of such medicaments in the form of suppositories is that portal (hepatic) circulation is bypassed and thus preventing or retarding the biotransformation (first pass effect) of drugs in the liver. Similarly pH conditions and activities of gastrointestinal enzymes are bypassed. Drugs such as NSAIDS that cause gastric irritation leading to gastrointestinal ulceration and bleeding can be safely administered by rectal route. Sometimes suppositories can give blood levels comparable even to the intravenous injections, except for a 30 minutes lag period. In view of the above considerations, suppositories can be stated as having greatest potential as convenient dosage forms in the treatment of chronic health disorders such as rheumatism and cardiovascular diseases, especially among the elderly patients.
Carvedilol3 (non-cardioselective b-blocker) is an antihypertensive used in management of hypertension, angina pectoris and heart failure. But its oral bioavailability is about 25-35% only due to significant degree of first pass metabolism. The drug carvedilol has gastrointestinal side effects such as diarrhea, gastrointestinal pain, gastric irritation. These side effects of the drug can be overcome by administering it as suppositories for rectal use.
6.2 Review of Literature:
Literature review shows no published reports of any work on the suppositories of Carvedilol. Some of the published reports of various other medicaments including antihypertensive drugs are:
Ø The comparative bioavailability of cisapride 30mg suppository and three 5mg oral tablets has been studied4. This work indicated that the relative bioavailability of the drug from suppository was 43% of that of the tablet.
Ø Sastri MS et al5 studied the pharmacokinetic and pharmacodynamic performance of matrix based slow release propranolol hydrochloride suppositories in rabbits and reported that the maximum relative bioavailability of propranolol from suppositories was 87.8%, there has been minimum of about 40-50% of the beta blockade during 1-9 hours post administration and stated that good correlation between pharmacokinetic and pharmacodynamic performances was observed.
Ø Effect of rectal dose of cisapride on delayed gastric emptying has been studied6. This study showed that a single suppository dose of cisapride 60mg significantly accelerates gastric emptying of the solid phase of a meal and radio-opaque markers in patients with previously demonstrated delayed gastric emptying.
Ø Rama Rao P et al7 formulated PEG based diltiazem suppositories and compared the relative bioavailability of the drug after oral and rectal administration. The relative bioavailability of diltiazem hydrochloride was about 75% greater after rectal administration compared to the oral route; hence, concluded that biotransformation of diltiazem by liver, intestine and lungs can be avoided by administering the drug as a rectal suppository.
Ø In vitro release of diclofenac sodium from suppositories containing different concentrations of both Witepsol W-35 and Witepsol E-85 and the physicochemical properties of the diclofenac sodium suppository formulations has been reported8. The results showed that the area under the drug release curve increased and mean drug release time decreased with increased concentration of Witepsol W-35 in the diclofenac suppositories.
Ø Liquid suppositories of propranolol using thermally gelling suppository base and the effect of mucoadhesive polymer on the bioavailability of the drug was studied9. The study indicated that rectal bioavailability was increased as mucoadhesive force increased.
Ø Formulation and in vitro characterization of chloroquine phosphate suppositories has been reported10. The displacement values of the drug with different bases were determined; medicated suppositories were prepared and evaluated for pharmacopoeial specifications. Theobroma oil, PEG suppositories complied with the requirements, but the later base provided a better dissolution performance (with minimum 70% in the first hour).
Ø Enhanced absorption of indomethacin after oral or rectal administration of a self-emulsifying system containing indomethacin to rats has been reported by Kim JY and Ku YS11. Their study demonstrated that the presence of self-emulsifying system (30% w/w tween 85 and 70% w/w ethyl oleate) enhanced the oral absorption of the drug by 57% and rectal absorption by 41%.
Ø The effect of drug solubility on the in vitro availability rate from suppositories with polyethylene glycol excipients has been studied12. Factors involved in the availability mechanism of different drugs from suppositories with PEG were examined using an in-vitro model of the rectal compartment with a porous membrane simulating the rectal barrier. Drugs less soluble in water showed a greater availability from PEG suppositories.
Ø In vitro drug liberation and kinetics of sustained release indomethacin suppository have been reported13. In this study, suppositories containing ethyl cellulose microcapsules of indomethacin in PEG and Witepsol H-15 bases were formulated and evaluated for in vitro drug release. Comparative results of SR suppositories with that of the conventional ones showed that the former has sustained effect up to 480 minutes in vitro.
Ø Enhanced rectal bioavailability of Ibuprofen in rats by poloxamer 188 and menthol has been reported14. This study showed that menthol improved the dissolution rates, rectal bioavailability of Ibuprofen from poloxamer gels.
Ø Design and evaluation of sustain release suppositories of nimesulide has been reported15. The unconventional non-melting, non disintegrating suppositories were prepared by fusion method using polymers such as agar, PEG 6000 and sodium carboxy methylcellulose. Among the various formations, the formulation with agar (4%) PEG-6000 (4%) and sodium carboxymethyl cellulose (1.5%) showed maximum drug release (93.69%) by concentration independent manner.
Ø Mucoadhesive effect of carbopol on drug release rate from double phased suppositories of propranolol hydrochloride was reported by Basavaraj BV et al16. The results suggest that double phased suppositories with varied carbopol concentration can produce rectal stagnation and moderate drug release facilitating drug absorption in the lower rectum. This approach is highly beneficial for enhancing the bioavailability of drugs undergoing extensive first pass metabolism.
6.3 Objectives of the study:
In the present work, studies will be carried on the preparation and evaluation of rectal suppositories of carvedilol by fusion method, with a view to avoid potential adverse effects of the drugs such as gastric irritation leading to ulceration and bleeding, improving bioavailability and patient compliance.
The prepared formulations will be evaluated for physical appearance, uniformity of mix, weight uniformity, drug content uniformity, melting range (time) test, softening time, fragility / breaking test, in vitro drug release.
7. / MATERIALS AND METHODS:
7.1 Source of data:
a) Internet
b) Gulbarga University Library, Gulbarga.
c) I.I.C.T. Library, Hyderabad
d) International Pharmaceutical Abstracts.
7.2 Method of Collection of Data:
The suppositories will be prepared by fusion method using hydrophobic (Witepsol) and hydrophilic (water soluble) bases such as poly ethylene glycols, glycerol-gelatin and agar.
The prepared suppositories will be evaluated for physical appearance by visual examination. The uniformity of mix is determined by slicing the suppositories longitudinally and examining for uniform distribution of the drug within the base.
a) Drug Content uniformity: Drug content uniformity of prepared suppositories is determined by crushing 5 suppositories in a glass mortar and powder equivalent to 100mg of the drug is dissolved or extracted with pH 7.4 buffer, methanol or other suitable organic solvents. Drug content is estimated in the filtered aliquots spectrophometrically after appropriate dilution with same solvent. The average of three determinations is taken as the drug content of the suppositories.
b) Melting Range (Time) Test: The time taken by the suppository to melt completely when immersed in constant temperature 37º±1ºC water bath is called as melting range of the suppositories and is measured using tablet disintegration test apparatus.
c) Softening (Time) Test: The softening test is intended to determine the time which elapses until a suppository maintained in water softens to the extent that it no longer offers resistance when a defined weight is applied. The softening time of suppositories is determined by using the apparatus as described in British Pharmacopoeia 1998.
d) Weight Uniformity: Twenty suppositories are weighed individually and the average weight and deviations from the average weight are calculated. No suppository should deviate fro the average weight by more than 5% except that two should not deviate by more than 10%.
e) Fragility / Breaking test: The crushing strength will be determined for measuring fragility or brittleness of suppositories which asses whether suppositories will be able to withstand the shocks during packaging, transpiration and handling. This test will be performed by using the apparatus as described by Larry JC et al1.
f) In vitro drug release study: In vitro drug release studies will be carried out for 8-10 hours using dialysis tube method using magnetic stirrer or USP tablet dissolution test apparatus using basket stirrer. The dissolution medium (250ml) is maintained at 37º±1ºC. The samples withdrawn at specified time intervals will be assayed for percent drug release spectrophotometrically.
g) Stability studies: Stability studies of the promising suppository formulation will be carried out at 4ºC (refrigerator) and at room temperature (25±3º/C) over a period of 3 (Three) months.
7.3 Does the study require any investigation or intervention to be conducted on patients or other humans or animals? If so, please describe briefly.
Not under the plan of our work.
7.4 Has ethical clearance been obtained from your institution in case of 7.3.
Not applicable.
8. / LIST OF REFERENCES:
1. Larry JC, Herbert AL, Suppositories, In: Lachman L, Lieberman HA and Kanig JC (Eds.), The Theory and Practice of Industrial Pharmacy, 3rd edn., Varghese Publishing House, Bombay, 1987, 564-87.
2. Lawrence HB (Ed.); Remington: The Science and Practice of Pharmacy, 19th edn, Mack Publishing House, New York, 1995, 1577.
3. Martindale: The Complete Drug Reference, Thirty-third edn., Pharmaceutical Press, London, 2002; pp. 855.
4. Hender T, Hender J, Gellin F, Haung ML, Vande PS, Woestenborghs R et al. Comparative bioavailability of Cisapride suppository and tablet formulation in healthy volunteers. E.J. Clin. Pharmaco., 1990; 38(6): 629-31.
5. Sastri MS, Satyanarayana MV, Krishna DR, Diwan PV. In vitro and in vivo studies on slow release propranolol hydrochloride suppositories. Pharmacokinetic and Pharmacodynaimc evaluation. Arzneimittel-Forchung., 1993; 43(3): 320-23.
6. Brummer JM, Schoenmakers EAJM, Kumerink GJ, Heidendal GAK, Sander DGM, Stockbrugger RW. The Effect of single rectal dose of cisapride on delayed gastric emptying. Aliment Pharmacol Ther., 1997; 11 (4): 781-85.
7. Rama Rao P, Vijay Kumar D, Diwan PV. Comparative pharmacokinetic evaluation of compressed rectal suppositories of diltiazem hydrochloride. Ind. J. Pharmaco., 1998; 30(3): 191-94.
8. Iwata M, Takayama K, Takahashi Y, Obata Y, Shirotaka S. Release of diclofenac sodium from suppositories consisting of Witepsols as a base. Japanese J. Hosp. Pharm., 1998; 24(4): 357-62.
9. Ryu JM, Chug SJ, Lee MH, Kim CK, Chang KS. Increased bioavailability of propranolol in rats by retaining thermally gelling liquid suppositories. J. Control Release, 1999; 59(2): 163-72.
10. Rishiraj C, Harsha B.Patel, Rajan DS, Jayanthi C, Suresh B. Formulation and in vitro characterization of chloroquine phosphate suppositories. The Eastern Pharmacist 1999; 42: 117-18.
11. Kim JY, Ku YS. Enhanced absorption of Indomethacin after oral or rectal administration of self-emulsifying system containing indomethacin to rats. Int. J. Pharm., 2000; 194(1): 81-89.
12. Realdon N, Ragazzi E. Effect of drug solubility on in vitro availability rate from suppositories with polyethylene glycol excipients. Pharmazie, 2001; 56(2): 163-67.
13. Uzunkaya G, Bergiadi N. In vitro drug liberation and kinetics of sustained release indomethacin suppository. IL Farmaco, 2003; 58(7): 509-12.
14. Yong CS, Yang CH, Rhee JD, Lee BJ, Kim DC, Kim DD et al. Enhanced rectal bioavailability of Ibuprofen in rats by poloxamer 188 and menthol. Int. J. Pharm., 2004; 269(1): 169-76.
15. Jawahar N, Jayaprakash S, Maria Gerald Rajan NS, Nagarajan M, Dhachina Murthi D, Jibie S et al. Design and evaluation of sustained release suppositories of nimesulide. Indian J. Pharm. Sci., 2005; 67(5): 558-61.
16. Basavaraj BV, Sindhu Abraham, Deveswaran R, Bharat S, Madhavan V. Mucoadhesive effect of carbopol on drug release rate from double phased suppositories. Asian J. Pharm., 2007; 1(1): 93-95.
9. / Signature of Candidate / [LAEEQ FARHANA]
10. / Remarks of the Guide / Rectal suppositories of certain drugs such as antihistamines and antihypertensives help to improve bioavailability of the drugs, since the rectal route of administration bypasses hepatic first-pass metabolism.
11. / Name & Designation of (in block letters)
11.1 Guide / Dr. P.V. SWAMY
M.Pharm., Ph.D.
PROFESSOR
DEPT. OF PHARMACEUTICAL TECHNOLOGY
H.K.E.S’s COLLEGE OF PHARMACY, GULBARGA.
11.2 Signature
11.3 Co-Guide: /
M.V. RAMPURE
M.Pharm.LECTURER
DEPT. OF PHARMACEUTICAL TECHNOLOGY
H.K.E.S’s COLLEGE OF PHARMACY, GULBARGA.
11.4 Signature
12. / 12.1 Remarks of the Chairman & Principal
12.2 Signature
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