IMPROVEMENT OF DISSOLUTION CHaracteristics OF A POORLY SOLUBLE ANTI DIABETIC DRUG BY SOLID DISPERSION TECHNIQUE

SYNOPSIS FOR

M.PHARM DISSERTATION

SUBMITTED TO

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

BENGALURU, KARNATAKA.

SUBMITTED BY

Ms. VIRITHA PHILLIPS

DEPARTMENT OF PHARMACEUTICS

UNDER THE GUIDANCE OF

Mrs. SAYANI BHATTACHARYYA

THE OXFORD COLLEGE OF PHARMACY,

BENGALURU –560 068

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

BANGALORE, KARNATAKA.

ANNEXURE – II

Proforma for Registration of Subject for Dissertation

1. / Name of the candidate and address / Ms. VIRITHA PHILLIPS
DEPARTMENT OF PHARMACEUTICS,
THE OXFORD COLLEGE OF PHARMACY,
No.6/9, 1st CROSS, BEGUR ROAD,
HONGASANDRA, BENGALURU –560 068
KARNATAKA.
PERMANENT ADDRESS
H. NO: 24-2-1464,
MILITARY COLONY,
DARGAMITTA.
A.K. NAGAR POST,
NELLORE
PIN-524004
2. / Name of the institution / THE OXFORD COLLEGE OF PHARMACY,
No.6/9, 1st CROSS, BEGUR ROAD,
HONGASANDRA, BENGALURU –560 068
KARNATAKA.
3. / Course of study and subject / Master of Pharmacy in Pharmaceutics
4. / Date of admission to course / 09/11/ 2010
5. / Title of the topic:
“IMPROVEMENT OF DISSOLUTION CHaracteristics OF A POORLY SOLUBLE ANTI DIABETIC DRUG BY SOLID DISPERSION TECHNIQUE”
6.
7.
8. / Brief Resume of Intended Work:
6.1: Need for the Study:
Ø  Diabetes mellitus is a chronic metabolic disorder characterised by a high blood glucose concentration-hyperglycaemia (fasting plasma glucose > 7.0 mmol/l, or plasma glucose > 11.1 mmol/l2 hours after a meal)-caused by insulin deficiency, often combined with insulin resistance1. This is because pancreas does not produce any insulin, or not enough, to help glucose enter into body’s cells – or the insulin that is produced does not work properly.
Ø  This diabetes mellitus are of two types2
1.  Type I - Insulin dependent diabetes mellitus (IDDM)
2.  Type II – Non Insulin dependent diabetes mellitus (NIDDM)
Ø  Antidiabetic medications treat diabetes by lowering glucose levels.
Ø  The oral hypoglycaemic drugs are classified3 into Sulfonyl ureas (first and second generation), Biguanides, Phenyl alanine analogues, Thiazolidinediones and α glucosidase inhibitors.
Ø  In above classes Sulfonyl ureas have poor solubility and bioavailability.
Ø  The poorly water-soluble drugs often show an erratic dissolution profile4 in gastrointestinal fluids, which consequently results in variable oral bioavailability and low absorption rate.
Ø  The efforts to improve dissolution and solubility of poorly soluble drugs are one of the most important tasks in drug development. Different methods have been introduced to enhance dissolution rate and thereby oral absorption and bioavailability of such drugs5.
Ø  To improve the dissolution and bioavailability of poorly soluble drugs, researchers have employed various techniques6, such as micronization, salt formation, complexation with polymers, change in physical form7, use of prodrug and drug derivatization, alteration in pH, and addition of surfactants.
Ø  Among various approaches, Solid dispersions are one of the most promising strategies to improve the oral bioavailability of poorly soluble active pharmaceutical ingredients because it is simple, economic, and advantageous8 and this solid dispersion has shown promising results in improving solubility, wettability, dissolution rate of drug and subsequently its bioavailability9
Ø  The term solid dispersion10 refers to a group of solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug. They are usually presented as amorphous products, mainly obtained by two major different methods, for example, melting and solvent evaporation.
Ø  Recently, surfactants11 have been included to stabilize the formulations, thus avoiding drug recrystallization and potentiating their solubility.
Ø  Polymers12 works as a very good carrier because of their chemical and pharmacological properties to enhance bio availability of drugs and by virtue of their water solubility leads high degree of solubilisation of poorly soluble drugs.
6.2: Review of literature:
1.  Gliclazide is an anti-diabetic drug that is poorly soluble in water. This paper describes an approach to improve the dissolution rate of Gliclazide by using solid dispersions (SDs) in polyethylene glycol 4000 (PEG 4000). The phase-solubility behaviour of Gliclazide in the presence of various concentrations of PEG 4000 in 0.1 N HCl at 37 °C was obtained. The solubility of Gliclazide increased with increasing amounts of PEG 4000 in water. The Gibbs free energy (∆Gotr) values were all negative. The solid dispersions were prepared with a solvent-melting method using different concentrations of PEG 4000. X-ray diffraction, infrared spectroscopy and DSC were used to examine the physicochemical characteristics of solid dispersions of Gliclazide and PEG. The dissolution rate of Gliclazide in SDs with PEG 4000 was enhanced. The FT-IR spectroscopic studies showed the presence of intermolecular hydrogen bonding between Gliclazide and PEG 4000 in the solid state. The DSC and XRD studies indicate the amorphous and microcrystalline states of Gliclazide in SDs w PEG 4000.13
2.  The enhancement of the solubility of Glibenclamide (GCM), a poorly water soluble anti-diabetes drug, by co-grinding it with highly branched cyclic dextrin (HBCD) using a ball mill. Highly branched cyclic dextrin (HBCD) is a novel cyclic glucan produced from waxy corn starch by the cyclization reaction of a branching enzyme. When GCM crystals were co-ground with HBCD for 2h, the solubility of GCM was improved to 12.4μg/ml, while the concentration of HBCD was 5.0mg/ml. Additionally, the GCM solubilised with HBCD was chemically stable in aqueous solution for at least 1week at room temperature. The peak intensity assigned to crystalline GCM disappeared after co-grinding it by observing its powder X-ray diffraction pattern, which means that the crystalline structure of GCM could be disrupted. In the DSC measurement, the ground mixture showed a single endothermic peak, even though a temperature depression of the endothermic peak due to GCM crystal was observed. After the co-grinding, two sharp
peaks assigned to sulfonylurea and benzyl carbonyl stretching bands varied to broaden the peak to around 1640cm−1in the C=O stretching region. These results suggested the formation of solid dispersion between GCM and HBCD.14
3.  The Solubility is the phenomenon of dissolution of solid in liquid phase to give a homogenous system. Solubility is one of the important parameter to achieve desired concentration of drug in systemic circulation for pharmacological response to be shown. Poorly water soluble drugs often require high doses in order to reach therapeutic plasma concentrations after oral administration. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities. Any drug to be absorbed must be present in the form of an aqueous solution at the site of absorption. Water is the solvent of choice for liquid pharmaceutical formulations. Most of drugs weakly acidic and weakly basic with poor aqueous solubility. Hence various techniques are used for the improvement of the solubility of poorly water-soluble drugs include micronization, chemical modification, pH adjustment, solid dispersion, complexation, co‐solvency, micellar solubilization, hydrotropy etc. The purpose of this review article is to describe the techniques of solubilizaton for the attainment of effective absorption and improved bioavailability15.
4.  Glibenclamide (GLB), which is a second generation anti-diabetic drug used for the treatment of Type –II Diabetes. The drawback of the drug is, it is practically insoluble in water and so possesses poor solubility, GI absorption and bioavailability. Hence the objective of the work is to develop fast dissolving tablets of Glibenclamide using crospovidone (CP) as super disintegrating agent. The kneading mixtures of Glibenclamide were prepared with crospovidone in the weight ratios of 1:0.5, 1:1 and 1:1.5. The mixture, GLB : CP (1:1.5) (KM) exhibited highest dissolution rate of 99.8% in 45 min. FT-IR analysis of the selected kneading mixture indicated the absence of drug polymer interaction. Hence the tablets were prepared by using the kneading mixture GLB : CP (1:1.5) (KM) by wet granulation method. Various formulations were tried and the FDT was selected which possessed optimum characteristics of disintegration time of 20 sec, hardness of 3.5 kg/cm and friability of 0.34±0.61%.There is 99.9% of drug release in 20 min. The FDTs were stable without any significant changes in their initial properties of hardness, friability, disintegration time and % drug release upon storage for 4 weeks.16
5.  The surface solid dispersions using water-insoluble carriers like crospovidone, croscarmellose sodium, sodium starch glycolate, pre-gelatinized starch, potato starch and Avicel PH 101 were investigated to enhance the dissolution rate of the Glimepiride, a poorly water insoluble drug. The effect of various carriers on dissolution profile was studied using presence absence model. The surface solid dispersion on crospovidone with drug to carrier ratio of 1:19 showed highest dissolution rate with the dissolution efficiency of 81.89% in comparison to pure drug (22.88%) and physical mixture (35.96%). The surface solid dispersion on crospovidone was characterized by powder X-ray diffractometry, differential scanning colorimetry, Fourier transform infrared spectroscopy, gas chromatography and scanning electron microscopy. The optimized dispersion was formulated into tablets by wet granulation method. These tablets, apart from fulfilling the official and other specifications, exhibited higher rates of dissolution and dissolution efficiency values17
6.  The physicochemical properties of Glimepiride in SDs with PEG20000. The phase solubility behaviour of Glimepiride in presence of various concentrations of PEG 20000 in pH 7.4 buffer was obtained at 370C. The solubility of Glimepiride increased with increasing amount of PEG 20000 in pH 7.4 buffer. Gibbs free energy (ΔGotr) values were all negative, indicating the spontaneous nature of Glimepiride solubilization and ΔGotr decreased with increase in the PEG 20000 concentration, demonstrating that the reaction conditions became more favourable as the concentration of PEG 20000 increased. The SDs of Glimepiride with PEG 20000 were prepared at 1:1, 1:3and 1:5 (Glimepiride: PEG 20000) ratio by melting method. Evaluation of the properties of the SDs was performed by using dissolution, Fourier-transform infrared (FT-IR) spectroscopy and X-ray diffraction (XRD) studies. The SDs of Glimepiride with PEG 20000 exhibited
enhanced dissolution rate of Glimepiride, and the rate increased with increasing concentration of PEG 20000 in SDs. Mean dissolution time (MDT) of Glimepiride decreased significantly after preparation of SDs and physical mixture with PEG 20000. The FT-IR spectroscopic studies showed the stability of Glimepiride and absence of well-defined Glimepiride-PEG 20000 interaction. The XRD studies indicated the amorphous state of Glimepiride in SDs of Glimepiride with PEG 20000.18
7.  The development of a potent anti‐inflammatory analgesic agent indicated for acute and chronic treatment of Rheumatoid arthritis, Osteoarthritis, and Ankylosing spondylytis. Paracetamol is poor water soluble and may show dissolution limited absorption. The solid dispersion of Paracetamol by physical triturating method, and fusion method were prepared using 1:1, 1:4 and 1:5 ratios of drug and polymers (PEG 4000, PEG 6000 and urea). The solid dispersion (SD) was characterized for physical appearance, solubility, IR, and in vitro dissolution studies. FT-IR study revealed that drug was stable in SDs. Solubility of Paracetamol from SDs increased in distilled water. The drug content was found to be high and uniformly distributed in the all formulation. The in vitro dissolution studies were carried using USP type XXVII (paddle) type dissolution apparatus. The prepared dispersion showed marked increase in the dissolution rate of Paracetamol than that of pure drug. The dispersion with PEG 6000 (1:5) by fusion method showed faster dissolution rate (107.26%) as compared to other dispersions with PEG 4000 and urea (1:4 and 1:5) whichever prepared by physical mixture (PM) and fusion method). Of the three carriers used, dissolution of the drug was more in PEG 6000 based SDs. It is concluded that dissolution of the Paracetamol could be improved by the solid dispersion and PEG 6000 based solid dispersions were more effective in enhancing the dissolution19.
8.  The Solid dispersions have attracted considerable interest as an efficient means of improving the dissolution rate and hence the bioavailability of a range of hydrophobic drugs. This article reviews the various preparation
techniques for solid dispersion and compiles some of the recent technology transfers. The different types of solid dispersions based on the molecular arrangement have been highlighted. Some of the practical aspects to be considered for the preparation of solid dispersions, such as selection of carrier and methods of physicochemical characterization, along with an insight into the molecular arrangement of drugs in solid dispersions are also discussed. Finally, an in-depth rationale for limited commercialization of solid dispersions and recent revival has been considered.20
9.  The aqueous solution and dissolution of Nitrazepam were increased using solid dispersion technique. The solid dispersion with polyethylene glycol (PEG) and polyvinyl pyrolidone (PVP) polymers of different molecular weights. The solid dispersions were evaluated for drug content and dissolution rate. The dissolution rates were affected by the solvent used, molecular weight of the polymer, drug : polymer ratio and the technique employed. The solid dispersion with PVP 44000, solvent chloroform and drug : polymer 1:19 (batch L1) displayed maximum aqueous solubility and the best dissolution rate, studies showed a change in the physical state of the drug from crystalline to amorphous form in solid dispersion. The tablet prepared with batch L1 showed drug releases in nearly zero order fashion in comparison to the marketed product. The stability studies carried out at three different temperature showed no change in the drug content of the prepared tablets.21
10.  Improving the dissolution of poorly water-soluble drug, Aceclofenac. It is very slightly soluble in water and hence orally administered drug is less bioavailable. In order to enhance the bioavailability it is necessary to improve its solubility, hence the solid dispersion technique was adopted to enhance solubility. The solid dispersions were prepared in different proportions using hydrophilic carriers like urea and mannitol. The dissolution rate studies were performed in both simulated gastric fluid and
simulated intestinal fluid. It is observed that the dissolution was affected by the acidity of the medium. Solid dispersions gave faster dissolution rate when compared to corresponding physical mixture and pure drug. In vivo absorption and anti-inflammatory activity studies of solid dispersions also confirmed the above results. The FT-IR and DSC studies revealed that there is no interaction between drug and carriers and the drug, Aceclofenac is stable in solid dispersions.22
6.3 Objective of the study:
Ø  In the present work attempt will be made to improve the bioavailability of poorly soluble antidiabetic drugs by solid dispersion method.