FORMULATION AND EVALUATION OFDICYCLOMINEHYDRO CHLORIDE SUSTAINED RELEASE TABLETS

M. Pharm Dissertation Protocol Submitted to

Rajiv Gandhi University of Health Sciences, Karnataka

Bangalore– 560 041

By

Mr.SAINI UDAY BHANU,B.Pharm

Under the Guidance of

Mr. SHIVANAND KALYANAPPA,M.Pharm

Asst. Professor

Department of Pharmaceutics

Acharya & B.M.Reddy College of Pharmacy

Soldevanahalli, Chikkabanavara (Post),

Hesaraghatta Main Road, Bangalore – 560 090

2009-2010

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

KARNATAKA, BANGALORE.

ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION

1 / NAME OF THE CANDIDATE ANDADDRESS /

Mr. SAINI UDAY BHANU

H.no:1-2, village: Karnamamidi,
Mandal: Mancherial, Dist: Adilabad,
Andhra Pradesh, 504207.
2 / NAME OF THE
INSTITUTION / Acharya B.M. Reddy college of pharmacy,
Chikkabanavarapost
Hesaraghatta Main Road
Soldevanahalli
Bangalore - 560 090
3 / COURSE OF THE STUDY AND SUBJECT / M. Pharm
(Pharmaceutics)
4 / DATE OF ADMISSION / 11th June 2010
5 / TITLE OF THE PROJECT:-
FORMULATION AND EVALUATION OF DICYCLOMINE HYDRO CHLORIDESUSTAINED RELEASE TABLETS
6
6.1
6.2 / BRIEF RESUME OF INTENDED WORK :-
NEED OF THE STUDY :-
Gastrointestinal tract spasms are convulsive pain attacks projected to the abdomen. They are generated by stimulation of mechanoreceptors in the enteric nervous system with successive maximal increase of gastrointestinal mobility.
Irritable bowel syndrome(IBSorspastic colon) is adiagnosis of exclusion. It is afunctional bowel disordercharacterized by chronicabdominal pain, discomfort, bloating, and alteration of bowel habits.In some cases, the symptoms are relieved bybowel movements.Diarrheaorconstipationmay predominate, or they may alternate. IBS may begin after an infection, astressfullife event, or onset of maturity without any other medical indicators.
IBS can be classified as either diarrhea-predominant (IBS-D), constipation-predominant (IBS-C) or IBS with alternating stool pattern (IBS-A)or pain-predominant In some individuals, IBS may have an acute onset and develop after an infectiousillness characterized by two or more of the following:fever, vomiting, diarrhea, or positive stool culture. This post-infective syndrome has consequently been termed "post-infectious IBS" (IBS-PI).
Most people can control their symptoms with diet, stress management, and prescribed medications. For some people, however, IBS can be disabling. They may be unable to work, attend social events, or even travel short distance.
As many as 20 percent of the adult population, or one in five Americans, have symptoms of IBS, making it one of the most common disorders diagnosed by doctors. It occurs more often in women than in men, and it begins before the age of 35 in about 50 percent of people.
Acute enter colitis is one of the disease categories used for intestinal inflammation caused by external factors such as viruses, bacteria and pharmaceutical agents.
References: bowel syndrome.

Dicyclomine Hydrochloride is an antispasmodic, anticholinergic drug, a medication that reduces the effect of acetylcholine, a chemical released from nerves that stimulates muscles, by blocking the receptors for acetylcholine on smooth muscle (a type of muscle). It also has a direct relaxing effect on smooth muscle.
Dicyclomine Hydrochloride is used to treat or prevent spasm in the muscles of the gastrointestinal tract in the irritable bowel syndrome. In addition, Dicyclomine Hydrochloride inhibits gastrointestinal propulsive motility and decreases gastric acid secretion and controls excessive pharyngeal, tracheal and bronchial secretions.In controlled clinical trials involving over 100 patients who received drug, 82% of patients treated for functional bowel/irritable bowel syndrome with Dicyclomine hydrochloride at initial doses of 160 mg daily demonstrated a favorable clinical response compared with 55% treated with placebo (p<.05). In these trials, most of the side effects were typically anticholinergic in nature and were reported by 61% of thepatients.
References:

REVIEW OF LITERATURE :-
Ibrahim H et al.,developed three coated wire electrodes (CWEs) for the antispasmodic drugs; dicyclomine , mebeverine and drotaverine hydrochlorides based on ion-associate of a heteropoly anion with the drug cation incorporated in membrane sensor modified with graphite and deposited on silver internal solid contact. They compared the characteristics of the new electrodes with characteristics of previously reported traditional liquid inner contact electrodes of the same drugs. They demonstrated the practical utility of each electrode has been d by using potentiometric determination of its respective drug in pharmaceutical preparations both in batch and flow injection conditions.1
Ibrahim Het al., Used five plastic membrane electrodes for the determination of dicyclomine hydrochloride (DcCl).The membranes of these electrodes consist of dicyclominium-silicotungstate (Dc-ST), silicomolybdate (Dc-SM), phosphotungstate (Dc-PT), phosphomolybdate (Dc-PM) or tetraphenylborate (Dc-TPB) ion-associations dispersed in PVC matrix with dibutyl phthalate plasticizer. The electrodes exhibit good selectivity for DcCl with respect to a large number of inorganic cations, organic cations, sugars and amino acids2
Claudio A Let al., investigated the influence of pellet core properties and different coating parameters on in vitro theophylline release. They showed that pellet size and pellet surface have a distinct effect on the release behaviour, with the surface morphology also playing a They compared organic solvent-based and two aqueous dispersion-based polymer systems for sustained-release diffusion membranes were with respect to the influence of coating process parameters. They demonstrated product bed temperature, an important process parameter, proved to be noncritical for the organic solvent-based system within a product bed temperature range of 30-45”C, by well reproducible release values. Release values showed a distinctly higher relative standard deviation at the lower spray rate, probably due to spray losses, the spray rate has to be carefully optimised. They demonstrated compared with organic solvent-based lacquer systems, aqueous latex systems involve higher development and production costs, by the influence of the product bed temperature and the subsequent curing3.
Hoffman A et al., demonstrated features of sustained release (SR) mode of drug administration impact on the magnitude of the pharmacologic response: (a) it minimizes fluctuation in blood drug concentrations (i.e. between peak and trough). Due to the pronounced non-linear relationship between drug concentration and pharmacologic effect (i.e. pharmacodynamics) the impact of this property differs considerably as a function of the shape of the pharmacodynamics profile and the position of the specific range of concentrations on the curve of this profile; (b) it produces a slow input ratewhich tends to minimize the body’s counteraction to the drug’s intervening effect on regulated physiological processes; and(c) it provides a continuous mode of drug administration. This important pharmaco dynamic characteristic may produce, incertain cases, an opposite clinical effect than that attained by an intermittent (pulsatile) mode of administration of the samedrug.4
Reitz Cet al.,focused on the structural characterization of sustained-release lipid matricesprepared by solid lipid extrusion. They analysed drug-containing lipid extrudatesin order to identify differences between the chemical and structural composition of surface and core elements. Independent of the lipid the dissolution from the outer extrudate surfaces was slower compared with dissolution from surfaces prepared by cutting the extrudate.The burst effect was higher for the cross-sections indicating more drug was exposed onthese surfaces. The release from glycerol trimyristate (Dynasan 114®) extrudateswas slowercompared with glycerol palmitostearate (Precirol ATO 5®) extrudates. By solid-state analysisusing DSC, ATR-FTIR and SEM measurements the differences between surface material andcore material could be attributed mainly to morphological differences. Chemical differencesbetween the core and the outer surface were not relevant. The differences between thesurfaces might be explained by the friction induced temperature increase during extrusionin the die plate. Results obtained and a proposed scheme were used to explain theinfluence of different formulation/processing parameters, such as drug particle size andmilling on the drug dissolution behaviour. Small drug particles and intact extrudates are ameans of minimizing the burst release5.
Ishida Met al.,developed and optimised a novel oral controlled delivery system for propranolol hydrochloride (PPL). They determined in vitro dissolution profiles of sustained-release matrix tablets of racemic PPL and compared with the United States Pharmacopeia (USP) tolerance specifications for propranolol hydrochloride extended-release capsules. They investigated the influence of matrix forming agents (native dextran, hydroxypropyl methylcellulose (HPMC), and cetyl alcohol) and binary mixtures of them on PPL release in vitro.They applied a central composite design to the optimizethe sustained-release tablet formulation. They obtained sustained-release matrix tablets with good physical, mechanical and technological properties with a matrix excipient:PPL ratio of 60:40 (w/w), with a dextran:HPMC ratio of 4:1 (w/w) and with a cetyl alcohol amount of 15% (w/w). Established a comparative kinetic study of the present matrix tablets and commercial SUMIAL RETARD capsules (Spain) .The value for the similarity factor (f2 = 69.6) suggested that the dissolution profile of the present two sustained-release oral dosageforms are similar6.
Ishida Met al.,developed and optimized a novel pseudoephedrine hydrochloride (PSE) sustained-release dosage form. The system comprises immediate-release mini-tablets (IRMT) and sustained-release mini-tablets (SRMT) contained inahydroxypropylmethylcellulose (HPMC) capsule. TheIRMTcontained PSE, excipients and low-substituted hydroxypropyl cellulose (a disintegrate), and the tablets were coated with HPMC, a water-soluble polymer. IRMT prepared with varying amounts of low-substituted hydroxypropyl cellulose all dissolved completely within the first 60 min, so low-substituted hydroxypropyl cellulose content does not greatly influence PSE release. The SRMT contained only PSE and excipients, and were coated with amixture of HPMC and the water-insoluble polymer ethylcellulose. They released PSE release profile for the SRMT could be controlled by varying the thickness of the coat, and the lag time could be controlled by varying the amount of ethylcellulose present in the polymer coat. PSE immediately from our encapsulated mini-tablet system and release was sustained over an extended period of time: the PSE in the IRMT dissolved within 60 min, whereas the PSE in the SRMT was released over 8–10 h. This system can be modified to yield various extended drug-release profiles, thereby harnessing the benefits of both SRMT and IRMT7.
Goudanavar P Set al.,Prepared sustained release Microcapsules of Salbutamol Sulphate using cellulose acetate phthalate, cellulose acetate and glyceryl monostearate polymers in different drug polymer ratio and evaluated for drug content, particle size determination and in vitro release behavior as per United states Pharmacopoeia in simulated gastric fluid (pH 1.2 ± 0.1) up to 0-2 hrs and in simulated intestinal fluid (pH 7.5 ± 0.1) up to 2-12 hrs. They prepared three formulations of 1:1, 1:2 and 1:3 in drug polymer ratio for cellulose acetate phthalate and cellulose acetate by solvent evaporation technique and three formulations of glyceryl monostearate by melt dispersion technique. All the formulations shown uniformity in drug content, sieve analysis results indicated that major fraction of microcapsules lies in the range of 425 to 600μm in all formulations and in vitro dissolution studies pointed that only CAP 1 and GMS 1 formulations failed to sustain the drug release up to 12 hrs. They prepared drug release mechanism from microcapsules and found to be diffusion controlled and they followed first order release kinetics. Finally it was concluded that Solbutamol sulphate can be effectively microencapsulated using Cellulose acetate phthalate (CAP) and cellulose acetate by solvent evaporation technique and glyceryl monostearate by melt dispersion technique.8
Abhijit N M et al.,formulated and evaluated a matrix system for sustained and simultaneous delivery of anti-asthmatic drug Salbutamol sulphate which is often indicated for the management of asthma, their frequent dosing may reduce compliance, thus making prolonged release formulation necessary. The matrix tablets prepared by wet granulation method using Ion exchange resins. The granules showed satisfactory flow properties and compressibility. All the five tablet formulations showed acceptable pharmacotechnical properties and complied with the in-house specifications for tested parameters. They evaluated for angle of repose, friability, hardness, disintegration and dissolution.9
Fei W et al .,maintained polymer-based sustained-release delivery systems therapeutic concentration of protein drugs for extended periods of time, there has not been a single product in this category successfully commercialized to date despite clinical and market demands. To achieve successful systems, technical difficulties ranging from protein denaturing during formulation process and the course of prolonged in vivo release, burst release, and incomplete release, to low encapsulation efficiency and formulation complexity have to be simultaneouslyresolved. Reported based on this updated understanding, formulation strategies attempting to address these aspects comprehensively 10
Raghuram Reddy Ket al.,developed once-daily sustained-release matrix tablets of nicorandil, a novel potassium channel opener used in cardiovascular diseases. They prepared tablets by the wet granulation method. Etha-nolic solutions of ethylcellulose (EC), Eudragit RL-100, Eudragit RS-100, and polyvinylpyrrolidone used as granulating agents along with hydrophilic matrix materials like hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose, and sodium alginate. They evaluated granules for angle of repose, bulk density, compressibility index, total porosity, and drug content. The tablets were subjected to thickness, diameter, weight variation test, drug content, hardness, friability, and in vitro release studies. The granules showed satisfactory flow properties, compressibility, and drug content. All the tablet formulations showed acceptable pharmacotechnical properties and com-plied with in-house specifications for tested parameters. Ac-cording to the theoretical release profile calculation, a once-daily sustained-release formulation should release 5.92 mg of nicorandil in 1 hour, like conventional tablets, and 3.21 mg per hour up to 24 hours. The results of dissolution studies indicated that formulation F-I (drug-to-HPMC, 1:4; ethanol as granulating agent) could extend the drug release up to 24 hours. In the further formulation development process, F-IX (drug-to-HPMC, 1:4; EC 4% wt/vol as granulating agent), the most successful formulation of the study, exhibited satisfactory drug release in the initial hours, and the total release pattern was very close to the theoretical re-lease profile. All the formulations (except F-IX) exhibited diffusion-dominated drug release. The mechanism of drug release from F-IX was diffusion coupled with erosion.11
6.3 / OBJECTIVE OF THE STUDY :-
The objectives of the present study is highlighted as given below:
  1. To carry out pre-formulation studies such as angle of repose, bulk density, Carr’s index whichever are required.
  2. To design and develop SR tablet by wet granulation method, dry granulation or direct compression whichever is suitable.
  3. To carry out in-vitro release studies using suitable testing apparatus.
  4. To carry out stability studies on the most satisfactory formulation as per ICH guidelines at 30 ± 2°C (65 ± 5 %RH) and 40 ± 2°C (75 ± 5 %RH).

7
7.1 / MATERIALS AND METHOD :-
SOURCE OF DATA:-
1)The review of literature of the following study has been obtained from the following journals as mentioned below:
a)Journals such as
i)European Journal of Pharmaceutical Sciences
ii)International Journal of Pharmaceutics
iii)Indian Journal of Pharmaceutical Sciences
iv)Asian Journal of Pharmaceutics
2)The review for the forthcoming studies will be taken from the following:
a)World Wide Web.
b)J-Gate@Helinet.
7.2 / METHOD OF COLLECTION OF DATA :-
1.To carry out preformulation study
a)Drug polymer interaction by FTIR.
b) Micrometrics studies
Angle of repose
Bulk density
Percentage Compressibility.
  1. To develop and formulate SR tablets by direct compression/wet granulation methods using various polymers.
  1. Evaluation of the various propertiesof the formulated floating tablets.
a)Physico-chemical properties:-
Diameter and thickness
Hardness and friability
Uniformity of weight and content
b)In vitrodissolution studies will be carried out in a USP Type-II dissolution apparatus containing simulated gastric fluid (pH-1.2, without enzyme) for 12 h.
  1. To carry out short term stability studies on the most satisfactory formulation as per ICHguidelines at 30 ± 2ºC (65 ± 5% RH) and 40 ± 2ºC (75 ± 5%RH).

7.3 / Does the study require any investigation or investigation to be conducted on patient or other humans or animals?
“NO”
7.4 / Has ethical clearance been obtained from your institution in case of 7.3?
“NOT APPLICABLE”
8 / REFERENCES :-
  1. Ibrahim H , Issa Y M , Hazem M A.Improving the detection limits of antispasmodic drugs electrodes by using modified membrane sensors with inner solid contact.J Pharm Biomed Anal2007;44:8- 15.
  1. Ibrahim H, Issa Y M , Hazem M A.Potentiometric flow injection analysis of dicyclomine hydrochloride in serum, urine and milk. Analytica Chimica Act2005;532:79-88.
  1. Claudio A L , Grunenberg P C , Junger H , Laicher A.Influence of process parameters on sustained – release theophylline pellets coated with aqueous polymer dispersions and organic solvent – based polymer solutions.Eur J Pharm Bio pharm 1997;43:149 –57.
  1. Hoffman A. Pharmacodynamic aspects of sustained release preparations. Adv Drug Deliv Rev1998;33:185 – 99.
  1. Reitz C, Strachan C, Kleinebudde P. Solid lipid extrudates as sustained – release matrices:The effect of surface structure on drug release properties. Eur J Pharm sci2008; 35:335 – 343.
  1. Castellanios E, Iraizoz C A , Bataille B, Pedraz J L , Fernand R, Heinamaki J.Development and optimization of a novel sustained – release dextran tablet formulation for propranolol hydrochloride.Int J Pharm.2006;317(1):32-9.
  1. Ishida M, Abe K, Hashizume M, Kawamura M. A novel approach to sustained pseudophedrine release: Differentially coated mini-tablets in HPMC capsules.
Int J Pharm2008;359:46-52
  1. Goudanavar P S,Patil S M, Manavi F V.Design and characterisation of Sustained Release Microcapsules of Salbutamol Sulphate.Int J PharmTech Research2010;2(2):1144-1149.
  1. Abhijit N M, Rahul K G, Smita K P, Bhanudas S K, Prakash N K, Prasad P T, Nachiket S D.Formulation and in vitro – in vivo evaluation of Salbutamol Sulphate sustained release tablets. Der Pharmacia Lettre2010;2(1):546-552.
  1. Fei W , Tuo J.Polymer – Based Sustained – Release Dosage Forms for Protein Drugs, Challenges and Recent Advances AAPS PharmSciTech,2008;9(4).
  1. Raghuram Reddy K , Srinivas M, Srinivas Reddy.Once – Daily Sustained – Release Matrix Tablets of Nicorandil :Formulation and In – Vitro Evaluation.AAPS PharmaSciTech.2003;4(4):61.

9 / Signature of the candidate:
10 / Remarks of the Guide:
11 / Name and Designation of:
11.1 / Institutional Guide: / Dr. Goli Divakar
PRINCIPAL
11.2 / Signature:
11.3 / Co-Guide:
11.4 / Signature:
11.5 / Head of the Department: /
Dr. Kalyani Prakasam
Professor & HOD
11.6 / Signature
12 / 12.1 / Remarks of the Principal
12.2 / Signature / Dr. Goli Divakar
Principal
Acharya & B. M. Reddy
College of Pharmacy,
soldevanahalli,
hesaraghatta main road,
Bangalore-90.

1