DEVELOPMENT OF RECONSTITUTABLE SUSTAINED RELEASE SUSPENSION OF ACECLOFENAC MULTIPARTICULATES

SYNOPSIS FOR

M.PHARM DISSERTATION

SUBMITTED

TO

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

BANGALORE, KARNATAKA.

BY

Mr. HARISH T

Ι M.PHARM (2011-2012)

DEPARTMENT OF PHARMACEUTICS

M.S.RAMAIAH COLLEGE OF PHARMACY

BANGALORE- 560 054

KARNATAKA

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR P.G. DISSERTATION

1. / NAME OF THE CANDIDATE AND ADDRESS(IN BLOCK LETTERS) / Mr. HARISH T
S/O LATE SURYA PRAKASH T
D.No-49, 1st CROSS, BDA LAYOUT ,
OPP PG BOYS HOSTEL-05, BANGALORE UNIVERSITY, MARIYAPPANPALYA , GNANABHARATHI, BANGALORE-56.
2. /

NAME OF THE INSTITUTION

/ M.S.RAMAIAH COLLEGE OF PHARMACY
M.S.R.NAGAR
M.S.R.I.T POST
BANGALORE-560 054.
3. /

COURSE OF STUDY AND SUBJECT

/

MASTER OF PHARMACY

IN

PHARMACEUTICS

4. /

DATE OF THE ADMISSION

/ 01st JULY 2011
5.
6.
7.
8. /

TITLE OF THE TOPIC

“DEVELOPMENT OF RECONSTITUTABLE SUSTAINED RELEASE SUSPENSION OF ACECLOFENAC MICROPATICULATES”.
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 through out the external phase with the help of suspending agents, which is generally a liquid or semisolid. The particle size in the suspension ranges above 0.1µm. 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 adapting the volume to swallow.
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 in blood drug concentration 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 dosages forms, such as beads or multiparticulates, have gained in popularity when compared to non-disintegrating single-unit dosages 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 pediatrics 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 longer lasting and more reliable release of the drug from dosage form and thereby enhancing the bioavailability.
Aceclofenacis anon-steroidal anti-inflammatory drug(NSAID). It is used for the relief of pain and inflammation inrheumatoid arthritis,osteoarthritisandankylosing spondylitis. The dose is 100mg twice daily. Aceclofenac is a poorly water soluble drug under BCS class II, with molecular formula C16H13Cl2No4 , molecular weight 354.184 and it chemically is 2-((2-(2-(2, 6- dichloro phenyl)amino)phenyl)acetyl)oxy). Aceclofenac has higher anti-inflammatory action than conventional NSAIDs. It is acytokine inhibitor. Aceclofenac works by blocking the action of a substance in the body called cyclo-oxygenase. Cyclo-oxygenase is involved in the production ofprostaglandins, which cause pain, swelling and inflammation3. The half life of aceclofenac was 3-4 hours, due to which it requires frequent administartion to maintain the therapeutic effect for a long period of time. Administering several times a day will result in GIT disturbances, peptic ulcers and GI bleeding.
The main purpose in development of reconstitutable sustained release suspension is to obtain a desirable blood concentration of aceclofenac and also to maintain the stability of drug after reconstitution. Furthermore, the formulation of a new dosage form as sustained released suspension obviously gives a new vision and may increase the therapeutic possibilities. The aim of this study is to develop a reconstitutable sustained release suspension of aceclofenac micro particulates with an appropriate polymer to achieve a safe, rapid and cost effective dosage form with enhanced stability and allows the ease of administration for pediatric and geraitric patients, thereby eliminating dosing frequency and improving the thearpeutic efficacy.
6.2 REVIEW OF LITERATURE
·  Aceclofenac microspheres were prepared by solvent evaporation technique using Eudragit (S100, RL100, RS100) as a release retard material. The prepared microspheres were evaluated for drug content, particle size, micro meritic properties and in-vitro drug release studies. The results showed that with increase in the polymer concentration, the particle size increased4.
·  Delayed release microspheres of aceclofenac were formulated using an enteric polymer, cellulose acetate phthalate prepared by solvent evaporation technique. The microspheres were characterized for particle size, scanning electron microscopy, percentage yield, drug entrapment and in-vitro release kinetics. The results revealed that HPMCP exhibits positive influence where as Eudragit L100 and Eudragit S100 exhibits negative effect on the drug release rate of CAP microspheres5.
·  The influence of formulation parameters in the preparation of sustained release aceclofenac loaded PLGA microspheres by emulsion solvent diffusion technique was studied. Prepared microspheres were optimized and evaluated for different parameters and the best formulation was subjected to in-vitro drug release studies. It was concluded that sustained release aceclofenac microspheres can be successfully prepared with increased therapeutic value and reduced side effects6.
·  Aceclofenac was microencapsulated using rosin by o/w emulsion solvent evaporation technique. The effect of three formulation variables including the drug: polymer ratio, emulsifier (polyvinyl alcohol) concentration and amount of organic solvent (dichloromethane) were examined. The prepared batches were characterized for particle size distribution, encapsulation efficiency and in-vitro release behavior. Drug: polymer concentrations were varied to obtain optimum release profile for sustaining the action of the drug7.
·  Microspheres of theophylline was prepared by spray-drying technique using ethyl cellulose and hydroxy 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 suspensions8.
·  Aceclofenac microspheres using albumin was prepared by heat denaturation method. Results of FTIR spectral and DSC studies showed that there was no significant interaction between the drug and polymer. The maximum yield of the microspheres was found to be 96.99% and the encapsulation efficiency was found to be 65.2%. The prepared albumin microspheres released the drug completely within 10 hours at lower drug to polymer ratio. At ratio of more than 1:2, the drug release was sustained over a period of 12 hours. The microspheres showed similar release profile as compared to the marketed sample. The microspheres were discrete, spherical and uniform in shape. The particle size was of the microspheres was found to be 99.6 μm. The prepared microspheres showed minor changes in particle size only under long term stability study with no appreciable change in drug content proving good stability of the product conducted both in accelerated and long term stability studies. The present study signifies the utility of microspheres in retarding the drug release. This may in turn reduces the frequency of dosing, there by improving the patient compliance9.
·  A mucoadhesive suspension containing Ciprofloxacin was formulated and its in-vitro anti-bacterial activity was studied and compared with its conventional immediate release preparation. It was found that the newly designed mucoadhesive formulation showed much larger zones of inhibition against all the strains used in the study than the conventional immediate release preparation. In addition, this novel formulation and even the standard discs of Ciprofloxacin produced more or less similar zones of inhibition. However, the conventional immediate release preparation was much inferior to the standard discs as far as the zones of inhibition were concerned10.
·  An attempt has been made to mask the taste of Itopride hydrochloride, by employing complexation with various ion-exchange resins like doshion P 542, Tulsion 344, Indion 234, Indion 204, Kyron T 114 and to formulate in to a suspension. The prepared suspensions were evaluated for taste, drug content, particle size, viscosity, sedimentation volume, drug release and accelerated stability studies. Among the various resins, Kyron T 114 was found mask the drug satisfactorily. The developed formulation was an additional advantage like simplification of manufacturing procedure and is economical. The drug release studies showed that complete drug was released within 20 min. The manufacturing procedure was found to be reproducible and formulations were stable after one month of accelerated stability studies11.
·  Ampicillin trihydrate was formulate into ready mix oral suspension with improved stability and shelf life. In the first approach of preparation, water was used as suspending medium and pH of the formulations was chosen is in the range of 5 to 6.5. In the second approach, oils like fractionated coconut oil and refined sunflower oil were used as suspending media. The content uniformity of the prepared formulations was analyzed and found to be with in the limits. Physical characteristics like sedimentation volume, ease of redispersability and viscosity were evaluated. Particle size determination revealed that majority of the particles was in the size range of 15‐ 75 μm. In- vitro dissolution studies were carried out and all the formulations showed 100% dissolution at 50th minute. Stability studies were carried out at 250C/60% RH and 300C/60% RH for 90 days. The drug content , Sedimentation volume, viscosity, ease of redispersability, particle size distribution and in-vitro dissolution were analysed 12.
·  An attempt was made to mask the intensely bitter taste of tinidazole (TNZ) and to formulate a palatable liquid formulation of the taste-masked drug, by novel Ion Exchange Resin (IER) method to overcome taste problem. Taste masking was done by complexing TNZ with Kyron T-114, Kyron T-134 and Indion 214 in different ratios. Formulation containing resinates were tested for drug content,in- vitrodrug release, taste masking, stability study, and molecular property. The resinates prepared with drug-Kyron T-134 ratio (1:2) at pH 8, gave maximum drug loading. Suspension containing the resinates showed more than 80%In vitrodrug release within 30 min. The Prepared formulation showed good stability and retained its palatable taste. Thus, the “patient friendly dosage form” of bitter drugs, especially for pediatric, geriatric, bedridden, and non cooperative patients, were successfully formulated using this technology13.
·  Eudragit 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. The result 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 form14.
·  Reconstitutable 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 od 20%w/v D-sorbitol15.
·  Sustained release tablets of freely water soluble Dextromethorphan HBr were formulated with non-swellable waxy polymer Compritol888 by dry granulation method. The matrix tablets of Dextromethorphan HBr were prepared by direct compression of granules, physical mixture of drug and polymer was found compatible after comparative study for three months. Matrix tablets were evaluated for hardness, friability and weight variation. The tablet were capsulated with loading dose of drug.In vitrodrug release study was performed using USPXXIII apparatus (basket type) in HCl pH 1.2 for two hrs and in phosphate buffer pH 6.8 for 10 hrs. Dissolution study showed that polymers can sustain the release of drug for up to 12 hrs. Comparison ofIn -vitrorelease of the Dextromethorphan HBr with existing sustained release suspension (Delsym) clearly indicated the advantage of present formulation in terms of release equivalence, patient compliance by using simple dry granulation method. The equivalent formulation was developed using dry granulation method which showed advantages in the terms of patient compliance, safety, and better transportation over existing suspension formulation16.
·  Bioadhesive microspheres of aceclofenac were prepared by double emulsion solvent evaporation method. The prepared microspheres were free flowing and spherical in shape and characterized for drug loading, mucoadhesion test, infrared spectroscopy (IR), differential scanning colorimetry (DSC) and scanning electron microscopy (SEM). The in-vitro release studies were performed using pH 6.8 phosphate buffer. The drug loaded microspheres in a ratio of 1:5 showed 38% of drug entrapment; percentage mucoadhesion was 79 % and 89 % release in 10 h. The infrared spectra and DSC showed stable character of aceclofenac in the drug loaded microspheres and revealed the absence of drug-polymer interactions. SEM studies showed that the microspheres are spherical and porous in nature17.