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“FORMULATION AND IN VITRO EVALUATION OF
FLOATING MICROSPHERES OF AN ANTIDIABETIC DRUG”
SYNOPSIS FOR REGISTRATION
OF
M.PHARM DISSERTATION
Submitted to
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
KARNATAKA
By
SRAVANI .A
I M.PHARM
Department Of Pharmaceutics
DAYANANDA SAGAR COLLEGE OF PHARMACY
2008
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA
BANGALORE
ANNEXURE - II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
Sravani.A
#26,Pragathi layout, 14 th Cross,
Bhuvaneshwarinagar, Dasarahalli, Hebbal,
Bangalore 560024
1.
Name of the Candidate
and Address
2.
Name of the Institution
3.
Course of Study and
Subject
M. Pharm
Pharmaceutics
4.
Date of Admission
30 th May -08
Dayananda Sagar College of Pharmacy,
Kumaraswamy layout, Bangalore – 560 078
5. Title of the Topic:
“FORMULATION AND IN VITRO EVALUATION OF FLOATING
MICROSPHERES OF AN ANTIDIABETIC DRUG”
6.0
Brief resume of the intended work:
6.1 – Need for the study:
Conventional oral dosage forms offer no control over drug delivery, leading to
fluctuations in plasma drug level. Various approaches have been worked out to improve the
retention of oral dosage form in the stomach, e.g. floating systems, swelling and expanding
systems, bioadhesive systems, high density systems. One such approach is Floating
Microspheres (Hollow Microspheres). Gastro-retentive floating microspheres are low-density
systems that have sufficient buoyancy to float over gastric contents and remain in stomach for
prolonged period. The drug is released slowly at desired rate resulting in increased gastric
retention with reduced fluctuations in plasma drug concentration. Floating microspheres
improves the patient compliance by decreasing dosing frequency, increase the therapeutic
effect of short half-life drugs and enhance absorption of drugs which solubilise only in
stomach by increasing gastric retention time due to buoyancy.
Type 2 diabetes is one of the most prevalent diseases in the modern world. Diabetes is
currently the fourth leading cause of death by disease in the United States. Type 2 diabetes
represents 98% of all diabetes among patients older than 45 years of age. There are two
widely accepted hypotheses about origin of type 2 diabetes. First one is related to insufficient
insulin secretion from beta cells. The second hypothesis is related to insulin resistance in the
peripheral tissues. The beta cells initially compensate the normal glucose metabolism by
increasing insulin secretion. However, when the demand for insulin exceeds the ability of
beta cells to compensate, it leads to pancreatic exhaustion.
If the patients fail to achieve near target blood glucose levels from non pharmacological
treatment, then pharmacotherapy is added to diet and exercise plan. Pharmacotherapy
includes oral anti diabetic drugs. . The sulphonylureas and biguanides are the most commonly
prescribed categories of medications for oral anti diabetic therapy. They are safe, have better
tolerability and superior pharmacodynamic effects.
Among the various Antidiabetic drugs used, metformin hydrochloride (biguanides),
Glipizide, Glimepride, Glibenclamide, (sulphonyl urea), Repaglinide (non sulphonyl urea)
and Rosiglitazone maleate (thiazolidinedione) are very widely accepted drugs.
The absorption of sulphonyl ureas is erractic in diabetic patients due to the impaired gastric
emptying. To overcome these drawbacks the present study is focused on the formulation of
floating microspheres with prolonged gastric retentive behaviour.
6.2 Review of literature
Hollow microspheres of cellulose acetate butyrate (CAB)1 and poly ethylene oxide (PEO)
were prepared by emulsion-solvent evaporation method. Repaglinide was successfully
encapsulated into floating microspheres. Various formulations were prepared by varying the
ratio of CAB and PEO, drug loading and concentration of poly vinyl alcohol (PVA) solution.
Encapsulation of the drug upto 95% was achieved. The microspheres tend to float over the
simulated gastric media for more than 10 hrs.
The use of floating drug-delivery systems2 was one method that is used to achieve prolonged
gastric residence times. A novel, multiple-unit, floating drug-delivery system of microspheres
with micro balloons inside from xanthan gum (XG) and gelatin (GA) were developed by a
water-in-oil method. With Theophylline as the model drug, four formulations (FI-FIV) with
different ratios of the two polymers were prepared. The size distribution, drug-encapsulation
efficiency, floating behavior, release characteristics, and morphological properties were
investigated. The ratio of the two polymers influenced the size distribution, encapsulation
efficiency, and drug release appreciably.
Floating microspheres of Verapamil hydrochloride3 were prepared for improving the drug
bioavailability by prolongation of gastric residence time. Cellulose acetate, acrycoat S100
and eudragit S100 microspheres loaded with verapamil hydrochloride were prepared by
solvent diffusion evaporation method. The prepared microspheres exhibited prolonged drug
release and remained buoyant for more than 12 hrs.
The floating microspheres were prepared with Cimetidine4 as model drug for prolongation of
gastric
residence
time
by
the
solvent
evaporation
method
using
polymers
hydroxypropylmethyl cellulose and ethyl cellulose. The prepared microspheres exhibited
prolonged drug release (8 hrs) and remained buoyant for > 10 hrs. The floating microspheres
have been utilized to obtain prolonged and uniform release in the stomach for the
development of formulation once daily.
Floating microspheres of Metformin hydrochloride5 were prepared by non-aqueous
emulsification solvent evaporation technique using ethylcellulose as the rate controlling
polymer containing 250 mg of metformin hydrochloride.
Its in vitro performance was
evaluated by the usual pharmacopoeial standards and other tests such as drug polymer
compatibility (FTIR scan), yield (%), particle size analysis, drug entrapment efficiency,
surfacetopography and
in vitro floatation and release studies. The developed floating
microspheres of metformin hydrochloride may be used in clinic for prolonged drug release in
stomach for at least 8 hrs, thereby improving the bioavailability and patient compliance.
Optimization of floatation and drug release pattern to match target release profile was
investigated.
A bilayer floating tablet was prepared for Tizanidine hydrochloride6 using direct compression
technology. HPMC, sodium bicarbonate and starch 1500 formed the floating layer. The
release layer contained tizanidine hydrochloride and various polymers. Because of sodium
bicarbonate added to the floating layer, when immersed in 0.1N HCl the tablet expands and
rises to the surface, the drug is gradually released. In vivo gastro retentive study of tablets
gave successful results by floating in gastric content over period of 6 hrs.
Floating tablets of Carbamazepine7 were developed using melt granulation technique. Bees
wax was used as a hydrophobic meltable material. Hydroxypropylmethylcellulose, sodium
bicarbonate and ethyl cellulose were used as matrixing agent, gas-generating agent and
floating enhancer, respectively.
A gastro retentive floating controlled drug delivery system containing Glipizide
8
was
prepared in the form of tablet. Ten formulations containing retardant materials such as
HPMC4K and eudrajit RS100, alkanising agent sodium bicarbonate and other release
promoters such as sodium lauryl sulphate and polyvinyl pyrrolidone were used. Tablets
remained buoyant over 8 hrs in the release medium.
Sustained release floating systems for Verapamil hydrochloride9 were prepared by using
different
hydrocolloid
polymers
including
hydroxypropylmethylcellulose(HPMC),
hydroxypropylcellulose (HPC), ethyl cellulose (EC) and Carbopol (CP). Floating was
achieved by adding an effervescent mixture of sodium bicarbonate and anhydrous citric acid.
Tableting of granules containing various verapamil: HPMC-4000 ratio showed excellent
buoyancy and slow release prome. Results also revealed that floatation was able to delay the
gastric emptying of verapamil tablet in beagle dogs for more than four hours compared to
almost one hour for a control tablet devoid of the gel forming polymer and the gas generating
mixture.
A study was conducted in optimization and evaluation of the floating tablets of Atenolol10
that prolongs the gastric residence time. Semisynthetic polymers, HPMC K4M, HPMC
K100M and natural polymer, Xanthan gum were used as release retarding agents. Sodium
bicarbonate was used as a gas-generating agent. Dicalcium phosphate was used as a
channeling agent. The floating matrix tablets of Atenolol were prepared by direct
compression method. The concentration of polymers and a gas-generating agent was
optimized to get the controlled release of atenolol for 8hrs.The prepared tablets were
evaluated for their physicochemical parameters and found to be within the range.
A study described the development of an intragastric drug-delivery system11 for Cefuroxime
axetil. The factorial design was employed to evaluate contribution of hydroxypropyl methyl
cellulose (HPMC) K4M/HPMC K100 LV ratio (polymer blend) and sodium lauryl sulfate
(SLS) on drug release from HPMC matrices. Tablets were prepared using direct compression
technique. Formulations were evaluated for in vitro buoyancy and drug release study using
United States Pharmacopeia (USP) 24 paddle-type dissolution apparatus using 0.1N HCl as a
dissolution medium. Multiple regression analysis was performed for factorial design batches
to evaluate the response. All formulations had floating lag times below 2 minutes and
constantly floated on dissolution medium for more than 8 hrs.
Floating tablets of Famotidine12 were prepared employing two different grades of methocel
K100 and methocel K15M by effervescent technique; these grades of methocel were
evaluated for their gel forming properties. Sodium bicarbonate was incorporated as a gasgenerating agent. The floating tablets were evaluated for uniformity of weight, hardness,
friability, drug content, in vitro buoyancy and dissolution studies. The effect of citric acid on
drug release profile and floating properties was investigated. The prepared tablets exhibited
satisfactory physicochemical characteristics. All the prepared batches showed good in vitro
buoyancy. The tablet swelled radially and axially during in vitro buoyancy studies. It was
observed that the tablet remained buoyant for 6-10 hrs.
Metformin microspheres13 with sodium alginate alone and in combination with gellan were
prepared using an emulsion-cross linking method. 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 concentration. In case of
microspheres containing both sodium alginate and gellan, the mean diameter and the
incorporation efficiency were higher than the corresponding microspheres containing only
alginate, both increasing with an increase in proportion of gellan. The prepared microspheres
were found to be discrete and spherical in shape and were successful in sustaining the drug
release for 8 hrs.
6.3 Objective of the study:





Improves patient compliance by decreasing dosing frequency.
Gastric retention time is increased because of buoyancy.
Enhanced absorption of drugs which solubilise only in stomach
Drug releases in controlled manner for prolonged period.
Site-specific drug delivery to stomach can be achieved.
7.0
Materials and methods
7.1 Source of data:
Official Pharmacopoeia, Standard books, International journal of Pharmaceutical
sciences, Journal of applied polymer science, Brazilian Journal of Pharmaceutical Sciences,
Indian journal of Pharmaceutical sciences, IJPER, Current drug delivery system,
Pharmaceutical database and internet.
7.2 Method of collection of the data
Experimental data will be collected from the evaluation of designed formulation and then
subjecting to different studies such as preformulation, physico-chemical characteristics of
microspheres like particle size, morphology using SEM, incorporation efficiency and in vitro
drug release studies, etc
1. Preformulation studies standard to development of floating microspheres.
2. Selection of excipients and rate control polymer of the formulations and fixing their
ranges to be used.
3. Development of formulation based on studies in step1 and step 2.
4. Optimization of the formulations.
7.3 - Does the study require any investigations or interventions to be conducted on
patients or other humans or animals? If so, Please describe briefly.
No
7.4 – Has ethical clearance been obtained from your Institution in case of 7.3?
Not applicable.
8.
List of References:
1. Rokhade Ajit P, Patil Sangamesh A, Belhekar Anaga A, Halligudi Shivraj B, Aminabhavi
Tejraj M, Preparation and evaluation of cellulose acetate butyrate and poly (ethylene oxide)
blend microspheres for gastroretentive floating delivery of repaglinide. Journal of Applied
Polymer Science. 2007; 105: 2764-2771.
2. Zhenqiu Yang , Baozhen Song, Qiaoxia Li, Honglei Fan, Fan Ouyang, Preparation of
microspheres with microballoons inside for floating drug-delivery systems. Journal of
Applied Polymer Science. 2004; 94:1,197-202.
3. Yuveraj Singh Tanwar, Pushpendra Singh Naruka, Garima Rani Ojha, Development and
evaluation of floating microspheres of verapamil hydrochloride. Brazilian Journal of
Pharmaceutical Sciences. 2007; 4: 529-534.
4. Anand Kumar Srivastava, Devendra Narayanarao, Ridhukar Saurabh Wadhwa, Floating
microspheres of cimetidine: Formulation, characterization and in vitro evaluation. Acta
Pharm. 2005; 55: 277-285.
5. Asha patel, Subhabrata ray, Ram sharnagat thakur , Invitro evaluation and optimization of
controlled release floating drug delivery system of metformin hydrochloride. DARU volume.
14, 2006; 2, 57-64.
6. Chaudhari pravin, Chaudhari shilpa, Barhate nilesh, Mistry chetan and Kolsure pramod,
Design and evaluation of bilayer floating tablets of tizanidine hydro chloride. Indian
J.Pharm.Educ.Res. 2008; 42 (1):36-47.
7. Patel DM, Patel NM, Pandya NN, Jogani PD, Formulation and optimization of
carbamazepine floating tablets. Indian J.Pharm Sci. 2007; 69:763-7.
8. Prabhakara Prabhu, Harish Nayari M. Gulzar Ahmed M, Brijesh Yadav, Narayana
Charyulu R, SatyanarayanaD, and Subramanayam E.V.S, Formulation and invitro evaluation
of gastric oral floating tablets of glipizide. Indian J.Pharm.Educ.Res. 2008; 42 (2):174-183.
9. Seham A. Elkheshen, Alaa Eldeen B. Yassin, SaIeh Alsuwayeh, and Fayza A. AlkhaIed,
Invitro and invivo evalution of floating controlled release dosage forms of verapamil
hydrochloride. Pharm.Ind. 2004; 66:1364-1372.
10. Vijay Daulatrao Havaldar, Ajit Shankarrao Kulkarni, Remeth Jacky Dias, Kailas Krishnat
Mali, Optimization and invitro evaluation of floating tablets of atenolol. Journal of Pharmacy
Research. 2008; 1:73-78.
11.Viral F Patel, Natavarlal M Patel, Intragastric floating drug delivery system of cefuroxime
axetil: in vitro evaluation. AAPS Pharm Sci Tech. 2006; 7 (1) E1.
12. Jaimini M, Rana A.C and Tanwar Y.S, Formulation and evaluation of famotidine floating
tablets. Current Drug Delivery. 2007; 4: 51-55.
13. Balasubramaniam J, Vinay U Rao, Vasudha M, Jeevan Babu, Rajinikanth P S, Sodium
Alginate microspheres of Metformin HCl: Formulation and In Vitro evaluation.
Curr.Drug.Deliv. 2007; 4(3):249-56
Signature of the candidate:
9
(Sravani.A)
10
Remarks of the Guide:
11
Name and Designation of:
11.1 Guide:
Requested for clearance and approval
J.Josephine Leno Jenita,
Asst.Professor,
Dept of Pharmaceutics,
Dayananda Sagar College of Pharmacy,
Kumaraswamy layout,
Bangalore – 560 078.
11.2 Signature:
11.3 Co – guide if any
11.4 Signature
Not applicable
11.5 Head of the Department:
Dr. Arshia Shariff
Professor and HOD
Dept of Pharmaceutics
Dayananda Sagar College of Pharmacy,
Kumaraswamy layout, Bangalore – 560 078.
11.6 Signature
12
12.1 Remarks of the Principal
Dr. V. Murugan
Professor and principal
Dept of Pharmaceutical Chemistry
Dayananda Sagar College of Pharmacy,
Kumaraswamy layout, Bangalore – 560 078.
12.2 Signature