FORMULATION AND VALIDATION OF METFORMIN NANOPARTICLE TABLETS
M. PHARM DISSERTATION PROTOCOL
SUBMITTED TO THE
RAJIV GANDHI UNIVERSITY OF HEALTH
SCIENCES, KARNATAKA, BANGALORE
BY
SANJEEV PRATAP SINGH SENGAR
UNDER THE GUIDANCE OF
Mr. CHETAN B.P M.Pharm.
ASSTPROFESSOR
P. G. DEPARTMENT OF QUALITY ASSURANCE
PRIYADARSHINI COLLEGE OF PHARMACY,
KORATAGERE-572129
2012-13
Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore
Annexure – II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
01 / Name and Address of the Candidate / SANJEEV PRATAP SINGH SENGAR PRIYADARSHINI COLLEGE OF PHARMACY KORATAGERE-57212902 / Name of the Institution / PRIYADARSHINI COLLEGE OF PHARMACY KORATAGERE , TUMKUR (DIST)-572129
03 / Course of the Study
Branch / M. Pharm.,
Quality Assurance
04 / Date of Admission to course / 28/05/2012
05 / Title of the Topic / FORMULATION AND VALIDATION OF METFORMIN NANOPARTICLE TABLETS
06 /
Brief resume of the intended work
6.1. Need for the Study /Enclosure – I
6.2. Review of the Literature / Enclosure – II6.3. Objective of the Study
/ Enclosure – III07 /
Materials and Methods
7.1. Source of data /Enclosure – IV
7.2. Methods of collection of data
/ Enclosure – V7.3. Does the study require any
Investigations on animals?
If yes give details / -No-
7.4. Has ethical clearance been
obtained from your institution
In case of 7.3. / -NOT APPLICABLE-
08 /
List of References
/ Enclosure – VI09 /
Signature of the candidate
/ (SANJEEV PRATAP)10 / Remarks of the Guide / As the aim of the present work is for the development of ideal formulation of metformin nanoparticles, the outcome of the present work may be helpful in its usage for chronic disease condition.
11 / Name and Designation of
(In Block Letters)
11.1..Signature
11.3.Co-Guide (if any)
11.4.Signature
11.5. Head of the Department
11.6.Signature / Mr. CHETAN B.P
M.Pharm,
ASSTPROFESSOR
QUALITY ASSURANCE
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Mr. CHETAN B.P
M.Pharm,
ASSTPROFESSOR
QUALITY ASSURANCE
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12 / Remarks of the Principal
12.1. Signature / The present study is permitted to perform in the Quality Assurance laboratory of our institution by above said student.
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ENCLOSURE-I
06. Brief resume of Intended Work
6.1 Need for the study.
Diabetes mellitus commonly known as Diabetes is one of the major causes of death and disability in the world. Latest WHO estimate for the number of people with diabetes worldwide is 171million, which is likely to be at least 366 million by 20301. Hence, the focus of medical community is on the prevention and treatment of the disease, as is evident from the rising number of research papers every year on the subject. Diabetes mellitus is a chronic metabolic disorder characterized by high blood glucose concentrations (hyperglycemia) caused by insulin deficiency and it is often combined with insulin resistance. Among different types of diabetes, Type-2 diabetes, that is Non-Insulin Dependent Diabetes Mellitus (NIDDM) affects major portion of diabetic population.
Among various class of drugs used for management of NIDDM, biguanides are one of the important and widely used chemotherapeutic agents for NIDDM 2. Among biguanides, Metformin is widely used for management of NIDDM. Metformin is known to exhibit its anti-diabetic action by acting as AMPK activator. Metformin belongs to BCS class III (high-solubility low-permeability) 3. In spite of its favorable clinical response and lack of significant effects, chronic therapy with Metformin suffers from certain specific problems, of which the most prominent being the high dose (1.5-2.0g/day) and low bioavailability (60%). Bioavailability of Metformin further decreases due to low absorption with food intake which is indicated by decrease in tmax by up to 35 minutes. Most of these drawbacks may be attributed to its low permeability. Therefore, there are continued efforts to improve the pharmaceutical formulation of Metformin in order to achieve an optimal therapy. These efforts mainly focus on controlled release (CR)/slow release( SR) forms of the drug including the sophisticated gastro retentive systems, preparation of its microspheres, niosomes etc., However, bioavailability of the drug has been found to be reduced further with CR dosage forms, probably due to the fact that, passage of the CR single unit dosage forms from absorption region of the drug is faster than its release and most of the drug released at the colon where Metformin is poorly absorbed4 .
Now a days, nanoparticular concept of drug delivery system is gaining importance due to various reasons. Nanoparticles are defined as particulate dispersions or solid particles with a size in the range of 10-1000nm. In nanoparticular concept of drug delivery system, the drug is dissolved, entrapped, encapsulated or attached to a nanoparticle matrix. Depending upon the method of preparation, nanoparticle, nanospheres or nanocapsules can be obtained. The system can be used for various routes of administration including oral, nasal, parenteral, intra-ocular etc. There are reports that nanoparticular drug delivery systems possess various advantages over their corresponding conventional drug delivery systems. Some of them are
· Particle size and surface characteristics of nanoparticle can be easily manipulated to achieve both passive and active drug targeting for various routes of drug administration.
· Controlled release and particle degradation characteristics can be readily modulated by the choice of matrix constituents. Drug loading is relatively high and drugs can be incorporated into the systems without any chemical reaction; this is an important factor for preserving the drug activity.
· Site-specific targeting can be achieved by attaching targeting ligands to surface of particles or use of magnetic guidance 5.
Absorption enhancers are class of excipients which increases the intestinal absorption of the drug so as to overcome the poor permeability characteristic nature of drug. Enormous progress has been made in recent past in which absorption enhancers are used successfully for increasing the absorption of poor permeable drugs 6.
Process validation is an integral part development of novel formulations. Process validation is the means of ensuring and providing documentary evidence that processes (within their specified design parameters) are capable of consistently producing a finished product of the required quality. Process validation is carried out in every step of development of novel formulation to ensure the quality of finished product. In the present work also, the concept of process validation will be utilized for selecting an ideal formulation 7.
Inspired by the wide range of advantages offered by nanoparticles for delivery of poorly permeable drugs and significance of absorption enhancers in increasing the absorption of poor permeable drugs, in the present work an attempt will be made to prepared Metformin Nanoparticles and thus prepared nanoparticles will be formulated using various absorption enhancers in order to get an ideal formulation which is devoid of permeability problems. Validation of process employed for preparing nanoparticles and formulation of nanoparticles into tablets will also be carried out.
ENCLOSURE-II
6.2 Review of Literature:
Metformin is a BCS Class III (high-solubility, low-permeability) drug widely used in type-2 diabetes mellitus. Because of its low permeability, many attempts are made to increase the permeability of Metformin by converting Metformin in to proniosoms, microsphere, nanospheres, or nanocapsules for increasing the absorption of the drug so also increase the permeability of the drug by using various absorption enhancers. Some of the literature reports are cited below.
1. Metformin microspheres with sodium alginate alone and in combination with gellan were prepared using an emulsion-cross linking method. The prepared microspheres were evaluated for their physico-chemical characteristics like particle size, morphology using SEM, incorporation efficiency, equilibrium water content (swelling) and in vitro drug release. The effect of various formulation variables like polymer concentration (sodium alginate; and proportion of gellan in microspheres prepared by a combination of sodium alginate and gellan), drug loading, cross-linking agent concentration and cross-linking time on the in vitro dissolution of the prepared microspheres were evaluated. The results showed that both the particle size and the incorporation efficiency were proportional to the polymer concentration8.
2. Metformin is prepared as a solid dispersion using methocel K 100M as the
carrier by the solvent evaporation and co grinding method. The influence of drug polymer ratio on drug release was studied by dissolution tests. Characterization was performed by Fourier transformation spectroscopy (FTIR), ultraviolet, differential scanning calorimetry (DSC) and x-ray powder diffractometry. The optimized formulation was subjected to accelerated stability testing and the release data were examined kinetically. Solid dispersion with 1:4 and 1:5 ratio of drug to polymer obtained by solvent evaporation and co-grinding were selected as the best candidates suitable for prolongedss oral dosage form of Metformin9.
3. Sustained release matrix tablet of Metformin HCl 500mg was prepared by using the response surface methodology. The tablet was prepared by using non aqueous wet granulation method by using various matrix forming polymers. The formulated tablets followed Higuchi drug release kinetics and diffusion was the dominant mechanism of the drug release, resulting in regulated and complete release in 8 hours. The polymer and binder had significant effect on the drug release from the tablet. Validation of optimization of study, performed using 8 confirmatory runs indicated very high degree of prognostic ability of response surface methodology 10.
4. Metformin hydrochloride (Metformin HCl) was formulated as a hydrophobic matrix sustained release tablet employing wax materials and the sustained release behavior of the fabricated tablet was investigated. Sustained release matrix tablets containing 500 mg Metformin HCl were developed using different bees wax combinations. The tablets were prepared by wet granulation technique. The formulation was optimized on the basis of acceptable tablet properties and in vitro drug release. The resulting formulation produced monolithic tablets with optimum hardness, uniform thickness, consistent weight uniformity and low friability11.
5. Microspheres of Metformin hydrochlorides were prepared by using ethyl cellulose as the polymer and evaluated for the encapsulation efficiency and release characteristics in vitro and in vivo; utilizing different microencapsulation techniques. Different proportions of polymer were used to obtain varying drug-polymer ratios. Physical properties, loading efficiency and dissolution rate were dependent on the method chosen for preparation and also on the drug-to-polymer ratio. The addition of surfactant during emulsification and petroleum ether in non-solvent addition process affected release of drug and also size distribution of microspheres. To investigate the type of mechanism that occurs, dissolution data were plotted according to different kinetic models. In vitro release studies show first order and Higuchi model release characteristics being exhibited. All the results were treated statistically to validate the findings. Significant differences in percentage yield, entrapment efficiency and sustaining capacity were seen with microspheres prepared by two different methods. In vivo studies in normal and hyperglycemic mice show faster glucose reduction with microspheres prepared by the evaporation method, whereas the release sustaining effect was more pronounced with microspheres prepared by the non-solvent addition method 12.
6. Mucoadhesive polymer-coated pellets containing Metformin hydrochloride were prepared by the powder-layering technique using a centrifugal fluidizing (CF)-granulator. Four high-viscosity polymers were applied to make the pellets: 1) hydroxyl methylcellulose (HPMC), 2) sodium alginate (Na-Alg), 3) HPMC/Carbopol, and 4) sodium carboxyl methylcellulose (Na-CMC). The physical crushing test, mucoadhesive test, zeta-potential test, in vitro release study and observation of gastro retention state of the dosage form were performed to investigate the pellets. The strong adhesive interaction between the Na-CMC-coated pellets and the mucin disc was obtained by mucoadhesive test. Na-Alg was most effective among the polymers used in changing the value of zeta potential of the mucin solution by the interaction between a polymer and a mucin particle. Results from drug dissolution study showed that over 95% of the drug from all the four pellets was released before 2 h, while Na-CMC- and Na-Alg-coated pellets showed a moderate sustained-release in SGF (simulated gastric fluid) and SIF (simulated intestine fluid), respectively. In conclusion, Na-CMC and Na-Alg seem to be promising candidates for Mucoadhesive formulation and further studies to improve the sustained-release property are underway for achieving the ultimate goal of once-a-day formulation of Metformin hydrochloride 13.
7. There are reports in which chitosan microspheres of Metformin hydrochloride was attempted. The microspheres were prepared by denaturation process to retard the drug release and to obtain maximum drug loading. The prepared microspheres of Metformin hydrochloride were characterized by loading efficiency, % entrapment, optical microscopy, scanning electron microscopy and release characteristics. The morphology of the microspheres was well within permissible limits, with size in the range of 200 to 250m. The drug release was sustained for more than 8 hrs. The drug release followed Higuchi kinetics, indicating diffusion controlled drug release 14.
ENCLOSURE -III
6.3 Objectives of the study:
In the present work an attempt will be made to prepare Metformin Nanoparticles by suitable literature method and formulation of the prepared Metformin encapsulated/ loaded Nanoparticles will be carried out by using suitable absorption enhancers. Thus prepared formulations will be validated for selecting an ideal formulation by employing various parameters. The steps which are intended to be carried out are as follows.
Step-1: Preparation of Metformin Nanoparticles.
Step-2: Characterization of Metformin Nanoparticles15.
Step-3: Validation of preparation methods employed for formulation of Metformin
Nanoparticles.
Step-4: Formulation of Metformin Nanoparticles into tablets using suitable absorption
enhancers.
Step-5: Validation of prepared formulation by using various physic-chemical
parameters16.
ENCLOSURE – IV
7. Material & methods:
7.1 Source of data:
The primary data required for designing the work will be collected from
1. Various national and international journals available in college library,
2. From various open access journals available in internet.
3. From helinet service of RGUHS, Bangalore.
4. From various reference books available in college library.
5. From various search engines like google.com, ask.com etc.,
6. By referring various journals from libraries of Indian Institute of Science, Bangalore, Libraries of various Universities like Kuvempu University, Shankargatta, Karnataka University, Dharwad.