I Solid Dispersions Based on Peg 4000, Soluplus® and their Hybrids for Enhanced Delivery of Glimepiride.
ABSTRACT
The present study investigates the possibility of enhancing the solubility, and hence the bioavailability of poorly water soluble glimepiride via formation of polyethylene glycol- polyvinyl caprolactam – polyvinyl acetate grafted copolymer (Soluplus) and PEG 4000 based solid dispersions by solvent evaporation technique.
Different batches of glimepiride solid dispersions (SD) were prepared using solvent evaporation method with Soluplus® and PEG 4000 as polymer matrix at different ratios.
The percentage yield, morphology, drug content, micromeritic properties and drug dissolution studies (in different media: SIF pH 7.4 and SGF 1.2) of the dispersions were evaluated. These formulations were characterized for solid state properties using differential scanning calorimetry (DSC) and fourier transform infrared (FTIR) studies.
The formulations were further evaluated for alloxan-induced antidiabetic and stability studies.The different batches formulated showed excellent morphology, good flow properties, practical yield and drug content.
Solid state characterisation indicated that glimepiride was present in its amorphous form in formulations with Soluplus® and PEG 4000 due to efficient entrapment in the polymer matrix and with no drug-polymer interaction.
The dissolution rate of all the solid dispersions was found to be significantly (P < 0.05) more rapid when compared to pure drug in both media except for P2 solid dispersion when compared with the commercial sample in SIF pH 7.4.
In the first 30 min, percentage (%)drug released from SDs were 65.83 %, 57.93 %, 58.47 %, 51.45 %, 80.83 %, 81.67 %, 84.02 %, 70.97 %,71.13 % and 46.80 % for batches S1, S2, P1, P2, SP1, SP2, SP3, SP4, SP5 and Amaryl®, respectivelyin SIF, pH 7.4.
At the end of 120 min, batch SP3 solid dispersion showed maximum % drug released of 96.11 and 57.08 in SIF pH 7.4 and SGF pH 1.2 respectively, while batch P2 had least % drug released of 74.55 and 40.45 in SIF pH 7.4 and SGF pH 7.4 respectively.
The kinetics of drug release from all the solid dispersions followed first order. Glimepiride in its pure form had very slow dissolution rate, when compared with the solid dispersions.
The blood glucose reduction in albino rats by the solid dispersions was significantly (p < 0.05) more and sustained when compared with the pure drug sample.
The maximum percentage (%) blood glucose reduction of 9.81 % and 8.97 % was achieved in 3 hours for the two groups (A and C, respectively) treated with SDs batch SP1 and SP3. Thus, the solid dispersions prepared with Soluplus® and polyethylene glycol 4000 might be useful for delivering poorly soluble glimepiride with enhanced solubility and dissolution rate.
TABLE OF CONTENT
Title …..i
Certification……ii
Dedication.…..iii
Acknowledgment…….iv
Table of Content……v
List of Tables…..ix
List of Figures…….. x
Abstract……xiii
CHAPTER ONE INTRODUCTION
1.1 Background of study…….1
1.2 Drug profile of glimepiride …2
1.2.1 Definitions ……… 2
1.2.2 Chemistry of glimepiride …. 2
1.2.3 Clinical pharmacology ..3
1.2.4 Dosage and administration…..4
1.2.5 Adverse reactions /side effects………4
1.2.6 Precaution…….5
1.2.7 Drug interactions……… 5
1.2.8 Uses…… 5
1.3 Solid dispersion…… 6
1.3.1 Definition of term…… 6
1.4 Classification of solid dispersions…… 8
1.4.1 Solid state characteristics… 8
1.4.1.1 Drug and polymer exhibiting immiscibility in fluid state…… 8
1.4.1.2 Drug and polymer exhibiting miscibility in fluid state…… 8
1.4.2 Carriers used for formulation… 15
1.4.2.1 First generation………… 15
1.4.2.2 Second generation……. 15
1.4.2.3 Third generation……… 18
1.5 Methods adopted in preparation of solid dispersions…… 19
1.5.1 Fusion method….. 19
1.5.2 Solvent evaporation technique…20
1.5.2.1 Types of solvent evaporation technique … 21
1.5.3 Supercritical fluid technology……. 22
1.5.4 Solvent melt technique…… 25
1.5.5 Hot melt extrusion……… 25
1.5.6 Melt agglomeration process…… 26
1.5.7 Effervescent method……… 26
1.5.8 Adsorption of insoluble carriers…… 27
1.5.9 Co-grinding………… 27
1.6 Characterisation of solid dispersions…… 27
1.6.1 Physical appearance………… 28
1.6.2 Percent practical yield… 28
1.6.3 Drug content…… 28
1.6.4 Aqueous solubility studies……… 28
1.6.5 Dissolution studies…………… 28
1.6.6 Fourier transform infrared (FTIR) spectroscopy…… 29
1.6.7 Thermodynamic methods… 29
1.6.8 Thermal analysis………………… 30
1.6.8.1 Thermo-microscopic methods……………… 30
1.6.8.2 Differential thermal analysis (DTA)… 30
1.6.8.3 Differential scanning calorimetry(DSC)……… 30
1.6.9 X-ray diffraction (XRD)………………… 31
1.6.10 Scanning electron microscopy…… 33
1.7 Factors influencing drug release……… 33
1.8 Advantages of solid dispersions…… 33
1.9 Advantages of solid dispersions over other strategies…… 35
1.10 Limitations of solid dispersions……… 36
1.11 Pharmaceutical applications of solid dispersions……… 37
1.12 Commercial solid dispersion products…… 38
1.13 Recent advances and future aspects………… 46
1.14 Statement of the research problem and justification of study… 48
1.15 Aim of research ……………….50
1.16 Objectives ofresearch………50
1.17 Research hypothesis………….. 51
CHAPTER TWO MATERIALS AND METHODS
2.1 Materials…… 52
2.1.1 Chemical and reagents…… 52
2.1.2 Animals……. 52
2.2 Methods…… 53
2.2.1 Identification of glimepiride…… 53
2.2.2 Preparation of reagents………… 53
2.2.2.1 Preparation of simulated body fluids………..53
2.2.3 Calibration curve of glimepiride…………… 54
2.2.4 Preparation of glimepiride solid dispersions……… 54
2.2.5 Characterisation of solid dispersions…55
2.2.5.1 Differential scanning calorimetry… 55
2.2.5.2 Fourier transform infrared (FTIR) analysis… 55
2.2.6 Estimation of drug contents…………55
2.2.7 Determination of percentage yield……….56
2.2.8 Micromeritic properties of the solid dispersion…… 56
2.2.9 In vitro drug dissolution………………. 57
2.2.10 Determination of invivoantidiabetic activity…… 57
2.2.11 Stability studies……….. 58
2.2.12 Statistical analysis……58
CHAPTER THREE RESULTS AND DISCUSSION
3.1 Identification of pure drug sample…… 60
3.2 Practical yield of solid dispersions. 60
3.3 Morphology and physical appearance…. 60
3.4 Drug content 68
3.5 Micromeritic properties of the solid dispersions….. 68
3.6 Invitro drug dissolution studies……….. 72
3.7 FTIR spectroscopy ………. 79
3.8 Differential Scanning Calorimetry(DSC) ……. 81
3.9 Invivoantidiabetic studies…………………… 98
3.10 Stability studies of the formulations…… 99
CHAPTER FOUR SUMMARY AND CONCLUSIONS
4.1 Summary of results……… 104
4.2 Conclusions ………….105
4.3 Recommendation………105
REFERENCES……….106
APPENDICES…………. 119
INTRODUCTION
Background of the Study
Dissolution is the process by which molecules or ions are transferred from a solid state into solution. The extent to which the dissolution proceeds under a given set of experimental conditions is referred to as the solubility of the solute in the solvent.
The solubility of a substance is a measure of the maximum amount of that substance that can be dissolved in a given amount of solvent to form a stable solution (1).
Solubility of drug entity is an intrinsic factor to its bioavailability and the desired pharmacological activity in the body can only be achieved when the drug molecules are present in the dissolved state at the site of absorption. Drug dissolution and release are crucial and limiting step for drug bioavailability particularly for drugs with low solubility and high permeability.
Many chemical entities are poorly water soluble drugs, not well-absorbed after administration which can detract from the drugs inherent efficacy. By improving the release profile of these drugsit is possible to enhance their bioavailability and reduce their side effects.
Dissolution is therefore essential for a drug to be absorbed through the biological membranes into systemic circulation for therapeutic efficacy(2).
Therefore, the improvement of drug solubility, and hence thereby, its oral bioavailability remains one of the most challenging aspects of drug development process especially for oral drug delivery system.
Many strategies are involved and have been adopted. Solid dispersions is one of the most effective means of improving solubility of poorly water soluble drugs.
REFERENCES
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Kiran T, Nalini S, Sistla R, Sadanandam M. Surface solid dispersion of glimepiride for enhancement of dissolution Int. J. of PharmTech Res. 2009; 1(3): 822-831.
SanofiAventis Pharmaceuticals. Amaryl (glimepiride) tablets 1, 2, and 4 mg prescribing information. Bridgewater, NJ. Jul
Draeger E. Clinical profile of glimepiride. Diabetes Res. Clin. Pract. 1995; 28(1): S139-46. [PubMed 8529506]
Hatziagelaki E, Diamantopoulos E, Halvatsiotis P. The effect of a new sulfonylurea glimepiride (HOE 490) on the blood glucose control of type II diabetics. Diabetes Res. Clin. Pract. 1988; 5(1): S481. [PubMed 2901329]
Avandaryl (rosiglitazone and glimepiride) tablets prescribing information. Research Triangle Park, NC. May 2011.
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