A

RESEARCH
PROPOSAL
ON
FORMULATION AND EVALUATION OF GASTRORETENTIVE
DRUG DELIVERY SYSTEM OF ANTIDIABETIC DRUGS

SUBMITTED BY
Miss. POONAM ANKUSH JADHAV
M. PHARMACY
(PHARMACEUTICS)

UNDER THE GUIDANCE OF

Dr. ASHOK VITTHAL BHOSALE
PRINCIPAL
(PHARMACEUTICS)

P.D.E.A.’S

SHANKARRAO URSAL COLLEGE OF PHARMACEUTICAL

SCIENCES & RESEARCH CENTRE, KHARADI, PUNE-411014.
2022-23

Miss Poonam Ankush Jadhav Dr. Ashok Vitthal Bhosale

(Sign of Researcher) (Sign of Research Guide)
TITLE OF RESEARCH TOPIC: Formulation And Evaluation of Gastro Retentive Drug Delivery
System of antidiabetic drugs

RESEARCHER : Miss. Poonam Ankush Jadhav

RESEARCH GUIDE : Dr. Ashok Vitthal Bhosale

 INTRODUCTION:
One of the major challenges faced by pharmaceutical scientists is to control the delivery rate of actives
to a predetermined site in the body. The prime aim of any drug delivery system is to provide therapeutic
amount of drug to proper site in the body, to punctually achieve and maintain the desired drug
concentration. Most of these drug delivery systems includes polymer which encapsulates drug. Oral
drug delivery systems are used for enhancing therapeutic index of the drug and also for the reduction in
side effects. Oral route is the chosen route for the administration of active and/or therapeutic agents
owing to its low cost of therapy and ease of administration. The efficient oral drug delivery may depend
upon several factors like gastric emptying, gastrointestinal transit time of the drug or dosage form, drug
release from designed dosage form and site of absorption of drug.1
Diabetes mellitus (DM), or simply diabetes, is a group of metabolic diseases in which a person
has high blood sugar, either because the body does not produce enough insulin, or because cells do not
respond to the insulin that is produced. This high blood sugar produces the classical symptoms of
polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger).
Conventionally, diabetes has been divided into three types namely: Type 1 DM or insulin-dependent
diabetes mellitus (IDDM) in which body fails to produce insulin, and presently requires the person
to inject insulin or wear an insulin pump. This is also termed as "juvenile diabetes". Type 2 DM or
non insulin-dependent diabetes mellitus (NIDDM), results from insulin resistance, a condition in
which cells fail to use insulin properly, with or without an absolute insulin deficiency. This type was
previously referred to as or "adult-onset diabetes". The third main type is gestational diabetes which
occurs when women without a previous history of diabetes develop a high blood glucose level during
her pregnancy. It may precede development of type 2 DM.2

GRDDS is an approach to prolong the gastric residence time, thereby aiming site-specific drug
release in the upper GIT for local or systemic effects. Gastro retentive dosage forms can remain in the
gastric region for long periods and hence significantly prolong the gastric retention time (GRT) of drugs.
Prolonged GRT enables the controlled delivery of drugs in stomach which can evade the repeated
administration of dosage form of the drugs with short half-life. Literature suggests that GRDDS has
gained huge popularity in the field of oral drug delivery recently, as it can release the drug slowly that
can combat many shortcomings allied with conventional oral delivery, including poor bioavailability.
Studies demonstrate that the drugs which has to be in the upper part of the GIT, have been prepared as
gastro retentive dosage forms using various approaches. Such formulations improves the therapeutic
efficacy of the drug and enhances the patient compliance. GRDFs have been researched for many
antidiabetic drugs and studies revealed that the gastro retentive form of drug has led to better
management of the disease status. Although, a lot of work has been done, but still there is tremendous
scope to develop such dosage form of antidiabetic drugs.3

The Microsponge Delivery System (MDS) is a patented polymeric system consisting of porous
microspheres. They are tiny sponge like spherical particles that consist of a numerous interlocking
cavities within a non-collapsible structure with a large porous surface through which active ingredient
are released in a controlled manner. Recently their use is also being investigated for oral drug delivery.
The size of the microsponge’s ranges from 5- 300μm in diameter with upto 250000 pores. This results in
a large reservoir within each microsponge, which can be loaded with up to its own weight of active
agent Microsponges having the size ranges from 5-300 μm in diameter. A typical microsponges having
25 μm sphere can have up to 250000 pores and an internal pore structure equivalent to 10 feet in length,
providing a total pore volume of about 1 ml/g for extensive drug retention. For the microsponges the
surface can be varied from 20 to 500 m2 /g and the pore volume range from 0.1 to 0.3 cm3 /g. Because
of this reason microsponges results in a large reservoir within each system and therefore, microsponges
having ability to load the drugs with up to its equivalent weight. In oral applications, the microsponges
system has been shown to increase the rate of solubilization of poorly water soluble drugs by entrapping
such drugs in the pores of microsponges. As the pores of microsponges are very small and the drug
particles during the formulation entrapped within the pores of microsponges and due to size reduction of
drug particles showing the significant increase in the surface area of drugs and thereby greatly increase
the rate of solubilization.4

Advantages of Floating Microsponge Drug Delivery System

  Microsponges exhibit site specific drug delivery system. i.e., Stomach specific
 Microsponges having an efficient drug delivery system for stomach specific delivery
along with high drug loading capacity. i.e., up to 50-60%.
 Due to lower density than the gastric contents, microsponges are being expected to
remain buoyant on the surface of gastric contents.
 Consequently dissolved drug will be released continuously in effective controlled manner
from the floating system
 Microsponges have the ability to entrap wide range of active due to its numerous
interconnected pores, and can adsorb high quantity of active on its surface and/or load
into the bulk of particles.
 Microsponges favourably modifies drug release and provides maximum efficacy.
 Microsponges offers extended product stability over a pH range of 1 to 11.
 They are free flowing, cost effective and stable up to temperature 130°C.

Characteristics of Drugs to be Entrapped in the Microsponges

 Drug should exhibit complete miscibility in polymer.

 It must be inert to polymer and do not increase the viscosity of the resulting preparation
during formulation.
 It should be water immiscible or almost slightly soluble.
 It should be stable in polymerization conditions.
 To obtain the desired release rate for a given period of time, the polymer design of the
microsponge for active must be adjusted and payload.

 RATIONALE AND SIGNIFICANCE OF THE STUDY

For proper cure of the disorder, the medicament has to be taken at regular intervals of time, lifelong.
Conventional antidiabetic oral dosage forms leads to fluctuations in plasma drug concentration and
causes irregular or improper glucose level in the patient.

This shows that there is utmost requirement of the antidiabetic drugs to maintain the blood
glucose level over the extended period of time for better results. Antidiabetic drugs are having strong
rationale for preparing gastro retentive dosage forms as they are absorbed from the upper part of the
GIT.4-8

Literature review revealed that the improved delivery of antidiabetic drugs, with increased
gastric retention period leads to better control of the disease condition.

Many antidiabetic drugs are better absorbed from the upper part of gastrointestinal tract, but they
suffer from the drawback of short residence time in stomach. Moreover, the drugs have a short half life
which demands the repeated administration of the dosage form to maintain the therapeutic level of the
drug in the body.

The suitable approach for attaining predictable and prolonged drug release in GIT is to maintain
residence period in the gastric region by holding the delivery system above the absorption window.
Thereby developing gastroretentive and sustained release dosage forms which are safe and effective than
convention drug delivery systems. These formulations can retain in gastric region for various hours and
release the drug in sustained manner. Prolonged gastric retention helps in improving bioavailability,
solubility profile of drugs which are having less solubility in high pH conditions and reduces wastage of
drug.14

The gastroretentive dosage forms help in overcomings all these drawbacks of antidiabetic drugs
which leads to increase in bioavailability of such drugs and hence helps in better management of
diabetes.

 LITERATURE SURVEY:
1. Aloorkar N.H. et al (2012) found that in oral applications , the microsponge system has been shown to
increase the rate of solubilisation of poorly water soluble drugs. By entrapping such drugs in the
microsponge system’s pores. Because these pores are very small, the drug is in effect reduced to
microscopic particles with resultant increase in surface area and thus greatly increase the rate of
solubilization. An added benefit is that the time it requires for microsponge system to transverse the small
and large intestine is significantly increased thus maximizing the amount of drug that is absorbed.

2. Pushkar R, Sharma et al (2013) studies revealed initial swelling and intact structure of the formulated
tablets. Erosion and diffusion mechanisms were responsible for the sustained release of nateglinide from
formulated matrix tablet.  Pharmacokinetic studies in rabbits confirmed the prolonged release by showing
increase in bioavailability for matrix tablet compared to conventional tablet. 

3. DS Goswami et al (2013) developed Pioglitazone HCl gastroretentive tablets by employing natural

gum (xanthum gum) in comparision to HPMC K 15M, a synthetic cellulose derivative as matrix former.
The tablets were prepared by direct compression method. The prepared tablets were evaluated in terms of
precompression parameters, physical charecteristics, in vitro release, floating duration, and floating lag
time. The results of in vitro release studies showed that optimized formulation (F13) could release the
drug (98%) for 12 hrs and remain buoyant for 12 hrs.

4. Bharath et al (2014) formulated Metaprolol tartarate protein tablets using HPMC 5cps. The results of
the study clearly indicate, a promising potential of the Metaprolol tartarate floating system as an
alternative to the conventional dosage form for sustaining the drug release and improving the
bioavailability.

5. Rajneesh et al (2014) concluded that optimized multi-unit floating microspheres are expected to
provide clinicians with a new choice of an economic safe and more bioavailable formulation in the
effective management of diverse disease.

6. A. Selvapriya et al (2017) - demonstrated successful formulation of Nateglinide microsponges using

Eudragit RS 100 as polymer releases the drug in a controlled manner for an extended period of time.this
helps to maximize the therapeutic effect of the drug reduces the side effect and decreses the frequency of
dosing and improves the patient compliance

7. Swarupa Arvapall et al (2017) formulated and evaluated Glipizide loaded Nanosponge. β-

Cyclodextrin facilitated Nanosponges were prepared by the solvent evaporation technique and
subsequently formulated in a tablet form for immediate release of Glipizide. The Nanosponges
formulations were prepared by solvent evaporation method employing ΒCyclodextrin as a polymer. The
surface morphology, particle size, production yield, and drug entrapment efficiency of Nanosponges were
examined. The formulated nanosponge shows immediate release in tablet formulation.

8. Pankaj V. Ahire et al (2017) considered that the microsponges can be formulated using quasi
emulsion solvent diffusion technique. Thus, this study presents a new approach for the preparation of
modified microsponges with extended release behaviour over a prolonged duration of time which may
reduced dose related side effects. The prepared microsponges exhibited characteristics of an ideal delivery
system.

9. Gunasheela S. et al (2022) reviewed that microsponge delivery techniques provides extended product
stability, enhanced safety, enhanced formulation flexibility, product efficacy and aesthetic appeal with
reduced adverse effects. It is regarded as sfae, due to less bacterial contamination as it doesn’t require
preservatives in the formulation.

10. S.D.Mankar et al (2022) concluded that microsponge drug delivery system was developed to deliver
the pharmaceutical ingredients efficiently at the positioning of administration at a restricted dose. MDS is
predicated on pore size of sponges. The action of microsponges lasts up to 12 hrs.
According to literature survey it was found that after the oral administration the stomach
faces the problem of short gastric retention period time. This result in incomplete absorption of drug. This
shortcoming is prevented by the gastroretentive dosage form which include high density sinking system
that retained at the bottom of stomach, low density floating system causes buoyancy in the gastric fluid,
floating osmotic pump, floating pulsatile delivery system, mucoadhesive systems that causes bioadhesion
to stomach mucosa.
` This system avoids the dose dumping problem and reduces the irritation at the site of
release.Controlled release gastro retentive dosage form prolong the retention time and continues the input
of drug to the upper part of GI tract and improves the bioavailability of the medicament, characterised by
narrow absorption window. Due to this reason gastroretentive dosage form was selected for the present
research work.

 AIM AND OBJECTIVES :

The aim of the present work is to formulate and evaluate the gastroretentive drug delivery system of
antidiabetic drugs. In order to increase their retention in stomach, which ultimately results in the
increase of bioavailability along with extended duration of action.

The objectives of proposed work are -

 To carry out extensive literature survey and review on microsponge drug delivery system.
 To select suitable solvent and polymer for preparation of microsponge.
 To design and optimize the microsponge drug delivery system.
 To analyze drug loading capacity in microsponge.

 To carry out evaluation of optimized formulation.

 To study in vitro drug release profile of the optimized formulation.

 To conduct stability studies of microsponges and developed formulation.

 To carry preliminary in vivo studies.

 MATERIALS AND METHODS

MATERIALS:
Polymers: -

The following polymers are basically used for microsponge preparation.

Inner phase: Eudragit RS 100, Ethyl alcohol or Dichloromethane, Triethyl citrate

Outer phase: Polyvinyl alcohol in water.

METHOD:

. Following are some preparation methods of microsponges.

 Quasi Emulsion Solvent Diffusion Technique

 Liquid -Liquid Suspension Polymerization.
 W/O/W Emulsion Solvent Method
 O/W Emulsion Solvent Diffusion
 Addition of Porogen Method
 Lyophilization Method
 Vibrating Orifice Aerosol Generator Method
 Ultrasound Assisted Production Method
 Electro Hydrodynamic Atomization Method

Preparation of microsponge:

Gastroretentive floating Microsponges were prepared by quasi-emulsion solvent diffusion method using
an external phase containing distilled water and polyvinyl alcohol (PVA). The internal phase was
prepared by adding ethyl cellulose in the organic solvent system consisting of ethanol as good solvent
and Dichloromethane (DCM) as a bridging liquid . To this organic phase, API(Drug) was added and
dissolved completely. At last triethylcitrate (TEC) which was added in organic phase to facilitate the
plasticity. Then, the inner phase was poured into outer phase with stirring. After emulsification, the
mixture was continuously stirred on mechanical stirrer, for a specified time and at a specific
temperature. Once the process was finished, the product was immediately filtered to separate the
microsponges. The product was washed and dried at room temperature for 24 h.
 Evaluation of Microsponges:

1. Particle Size Determination:

i) Particle size determination of loaded as well as blank microscope can be carried out by laser light
diffractometry or any other appropriate method.
ii) Morphology and Surface Topography of Microsponges: Scanning electronic microscopy or
transmission electron microscopy
2. Determination of Loading Efficiency and Production Yield:

The % loading efficiency and % production yield is determined by following formula:

%loading efficiency = actual drug content in microsponges/ theoretical drug content × 100

%Production yield = Production yield theoretical mass (polymer + drug) × 100

3. Compatibility Studies Polymer / Monomer Composition: Differential scanning Calorimetry

4. In vivo study

5. Differential scanning calorimetric analysis: To study physical properties, crystalline or amorphous

nature.

 EXPECTED CONCLUSIONS AND THEIR VALUE (PROBABLE OUTCOME OF THE

PROJECT)
 The aim of research in this topic will be design, development and evaluation of gastroretentive drug
release of antidiabetic formulation by using microsponge drug delivery system.

Polymers which are to be used are safe, biocompatible, and biodegradable and having good entrapment
capacity of actives provides controlled release of drug.

Prepared microsponge system will be increase the rate of solubilization of poorly water soluble drugs by
entrapping them in the microsponge system’s pores. As these pores are very small the drug is in effect
reduced to microscopic particles and the significant increase in the surface area thus greatly increase the
rate of solubilization and improve bioavailability also improve stability by entrapping drugs.

Microsponge entrapped drug which ultimately reduces gastric side effects and make formulation stable
at different GIT environment.

This present study will give release of drug in controlled manner for an extended period of time. This
can help to maximize the therapeutic effect of the drug, reduce side effect, decrease frequency of dosing
and also helps to improve patient compliance.

 PLAN OF WORK:

The plan of work is summarized as follows:-

1. Literature survey

2. Preformulation Study

3. Preparation of gastroretentive microsponges

4. Evaluation of gastroretentive microsponges

5. Stability Study

6. In-vivo study

7. Compilation of data

BIBLIOGRAPHY:

1. Osmania R, Aloorkar N, Bharati U, Thawareb. Microsponges based drug delivery system for
augmented gastroparesis therapy: Formulation, development and evaluation Asian J Pharm Sci. 2015:
442-451.

2. Selvapriya A, Elango K. Formulation and evaluation of Nateglinide microsponges for the treatment
of type II Diabetes mellitus. World journal of pharmacy and pharmaceutical sciences. 2017: Vol 6, Issue
5, 1685-1694.

3. Pushkar R, Sharma, Shaila A, Lewis. Design and In vitro / in vivo evaluation of extended release
matrix tablets of NTG. Journal of Young Pharmacists, 2013; 5: 167-172.

4. Bhadange MD, Darekar AB, Saudagar RB, Design, Development and Evaluation of Bilayer Tablet
using NTG for The management of Diabetes. International Journal of Pharma Sciences and Research,
2015; 6(8): 1086 - 1099.

5. Parveen, R., Singh, A.P., Bhargav, R.K., Verma, A. and Shrivastav, P., 2016. Formulation and
evaluation of floating tablet of Metformin HCL. World Journal of Pharmacy and Pharmaceutical
Science, 5(7), pp.1317-1326.
6. Meka, V. S., Pillai, S., Dharmalingham, S. R., Sheshala, R., Gorajana, A., 2015. Preparation and in
vitro Characterization of a Non-Effervescent Floating Drug Delivery System for Poorly Soluble Drug,
Glipizide. Acta Poloniae Pharmaceutica - Drug Research, 72, pp.193-204

7. Sharma, M., Kohli, S. and Dinda, A., 2015. In vitro and in vivo evaluation of repaglinide loaded
floating microspheres prepared from different viscosity grades of HPMC polymer. Saudi Pharmaceutical
Journal, 23(6), pp.675-682.

8. Kamila, M.M., Mondal, N., Ghosh, L.K. and Gupta, B.K., 2009. Multiunit floating drug delivery
system of rosiglitazone maleate: development, characterization, statistical optimization of drug release
and in vivo evaluation. AAPS PharmSciTech, 10(3), pp. 887–899.

9. Pradhan S.K. Microsponges as the versatile tool for drug delivery system. International journal of
research in pharmacy and chemistry 2011, 1(2) 243-244.

10. Yerram C, Shaik F, Rubia Y. A novel drug delivery system for controlled delivery of topical drugs.
International journal of pharmaceutical research and analysis 2012, 2 (2), 79-80, 84-85.

11. S.D.Mankar, Mahale Gayatri – Review on microsponges a novel drug delivery system. Asian journal
of pharmaceutical research . Vol 12. Issue 3, 2022.

12. Aloorkar N.H., Kulkarni A.S, Ingale D.J., Patil R.A, Microsponges as innovative drug delivery
systems. International Journal pharm Sci Nanotech 2012: 5.

13. Gunasheela S, Vchanfrakala and S.Srinivasan. Microsponge : An adaptable topical drug delivery
system, World journal of advanced research and reviews 2022, 15(01), 396-411.

Miss Poonam A. Jadhav Dr. Ashok V.Bhosale

(Name and Sign. of Candidate) (Name and Sign. of Research Guide)