“FORMULATION AND IN VITRO EVALUATION OF FLOATING MICROSPHERES OF AN ANTIVIRAL DRUG”
SYNOPSIS FOR
M.PHARM. DISSERTATION
SUBMITTED TO
RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES,
KARNATAKA
By
MEHUL R THAKKAR
I M.PHARM
DEPARTMENT OF PHARMACEUTICS
DAYANANDASAGARCOLLEGE OF PHARMACY
2009
RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES, KARNATAKA
BANGALORE
ANNEXURE - II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1. / Name of the Candidateand Address / THAKKARMEHUL RAMESHCHANDRA
#70,kasturinagar society,
Near:Gayatri temple,Gungadi Road
Patan,north Gujarat-384265
India.
2. / Name of the Institution / DayanandaSagarCollege of Pharmacy,
Shevige malleshwara hills,
Kumaraswamy layout,
Bangalore – 560 078,
Karnataka.
3. / Course of Study and
Subject / Master of Pharmacy in Pharmaceutics
4. / Date of Admission / 17th Jun -09
- Title of the Topic:
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.
Viral disease is the most prevalent diseases in the modern world. One of the most widely publicized diseases, Acquired immunodeficiency syndrome (AIDS) is caused by the marked progressive failure of the immune system.Although it’s characterized by gradual destruction of cell-mediated (T-cell) immunity, it also affects humoral immunity and autoimmunity because of the central role of the CD4+T lymphocyte in immune reactions. The resultant immunodeficiency makes the patient susceptible to opportunistic infections, unusual cancers and other abnormalities that define AIDS.
Treatment of HIV infection includes three different types of antiretroviral agents :
- Protease inhibitors (PIs), such as ritonavir, indinavir, nelfinavir, and saquinavir
- Nucleoside reverse transcriptase inhibitors (NRTIs), such as zidovudine, didanosine, zalcitabine, lamivudine, and stavudine
- Nonnucleoside reverse transcriptase inhibitors (NNRTIs), such as nevirapine.
7.0 / One of the important reason to formulate the floating antiviral microsphere is for targeting the intracellularly.The conventional dosage forms of antiviral drugs commonly produce serious adverse reactions and toxicities. 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
The floating microspheres of acyclovir1were prepared by emulsion solvent diffusion technique and try ethyl citrate was used as a plasticizer. The Microspheres were evaluated for particle size analysis, drug entrapment, floating ability in vitro drug release and characterized by scanning electron microscopy and X-Ray diffractometry.The floating microspheres were spherical with no visible measure surface irregularity. The in vitro release study indicated that when the polymer concentration was increased and the drug loading was decreased, the release of drug from microsphere was decreased.
The use of floating drug-delivery systems2was 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.
The orlistat3floating microsphereswere prepared usingcalcium silicate, Eudragit S by solvent evaporation method and to evaluate their gastro-retentive and controlled-release properties. The gamma scintigraphy of the optimized formulation was performed in albino rabbits to monitor the transit of floating microspheres in the gastrointestinal tract. The microspheres were found to be regular in shape and highly porous.
Hollow microspheres of cellulose acetate butyrate (CAB) 4and 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 were found to float over the simulated gastric media for more than 10 h.
Floating Microspheres of Verapamil hydrochloride5 were prepared by solvent diffusion evaporation method for improving the drug bioavailability. Cellulose acetate, acrycoat S100 and eudragit S100 were used as polymers. The prepared microspheres exhibited prolonged drug release and remained buoyant for more than 12 h.
The floating microsphereswere prepared with Cimetidine6as model drug for prolongation of gastric residence time by the solvent evaporation methodusing polymers hydroxypropylmethyl cellulose and ethyl cellulose. The prepared microspheres exhibited prolonged drug release (8 h) and remained buoyant for more than 10 h. The floating microspheres were utilized to obtain prolonged and uniform release in the stomach for the development of formulation once daily.
Floating microspheres of Metformin hydrochloride7were prepared by non-aqueous emulsification solvent evaporation technique using ethylcellulose as the rate controlling polymer. 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, surface topography.The developed floating microspheres of metformin hydrochloride were used in clinic for prolonged drug release in stomach for at least 8 h, thereby improving the bioavailability and patient compliance.
Metformin microspheres8 with sodium alginate alone and in combination with gellan were prepared using an emulsion-cross linking method. 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. . The prepared microspheres were found to be discrete and spherical in shape and were successful in sustaining the drugrelease for 8 h.
Hollow microspheres of cellulose acetate loaded with four cardiovascular drugs9 were prepared by a novel solvent diffusion-evaporation method. The oil-in-water emulsion prepared in an aqueous solution of 0.05% poly (vinyl alcohol) medium with ethyl acetate, a water-soluble and less toxic solvent, was used as the dispersing solvent. The microspheres had smooth surfaces, with free-flowing and good-packing properties. Scanning electron microscopy (SEM) confirmed their hollow structures, with sizes in the range 489–350 µm. The microspheres tended to float over the gastric media for more than 12 h. The release of the drugs was controlled for more than 8 h.
Sustained release floating systems for Verapamil hydrochloride10were 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. The formulated tablets 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 Atenolol11that 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 8 h.
A study described the development of an intragastric drug-delivery systemfor Cefuroxime axetil12. The factorial design was employed to evaluate contribution of hydroxypropyl methyl cellulose (HPMC) K4M/HPMC K100 LV ratio and sodium lauryl sulfate (SLS) on drugrelease from HPMC matrices. Tablets were prepared using direct compression technique.All formulations had floating lag times below 2 minutes and constantly floated on dissolution medium for more than 8 h.
Floating tablets of Famotidine13were prepared employing two different grades of methocel K100 and methocel K15M by effervescent technique. Sodium bicarbonate was incorporated as a gas-generating 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. All the prepared batches showed good in vitro buoyancy. It was observed that the tablet remained buoyant for 6-10 h.
The polycarbonate (PC) floating microspheres of acetohydroxamic acid 14 were prepared by emulsion (O/W) solvent evaporation technique. The effect of PC concentration on the morphology, particle size, entrapment efficiency and drug release rate was studied. The drug and PC microspheres both showed anti-H. pylori activity in vivo, but the required dose of acetohydroxamic acid was effectively reduced by a factor of 10 in the case of PC microspheres. The floating microspheres were found to be more effective in the GI tract than the drug because of the prolonged gastric residence time resulting from the excellent buoyancy of the PC.
Microballoons(MB) were prepared using riboflavin15by the emulsion solvent diffusion method using enteric acrylic polymers dissolved in a mixture of dichloromethane and ethanol. The excretion half-life time (t1/2) following administration of MB (particle size: 500–1000μm) exhibiting high buoyancy was longer than that of MB (particle size: <500μm) displaying low buoyancy. Therefore, the intragastric floating properties of MB were potentially beneficial as far as a sustained pharmacological action.
The floating, depot-forming drug delivery system16 for an antidiabetic drug were optimized using cellulose acetate as the polymer to maintain constant plasma drug concentrations over a prolonged period of time for effective control of blood sugar levels. In vitro drug release studies were performed. The prepared microspheres exhibited prolonged drug release (more than 10 h) and remained buoyant for over 10 h.
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 solubilize only in stomach
Drug releases in controlled manner for prolonged period.
Site-specific drug delivery.
Materials and methods
7.1 Source of data:
1) Review of literature from:
a)Journals such as
i)Indian Journal of Pharmaceutical Sciences.
ii)European Journal of Pharmaceutical Sciences.
iii)Journal of Controlled Release.
iv)International Journal of Pharmaceutical Sciences.
v)AAPS Pharm Sci Tech.
vi)Indian Drugs.
vii)Current Drug delivery system.
viii)IJPER
b)J-Gate@Helinet.
2) Laboratory based studies.
7.2 Materials :
Polymers : Different grades of Hydroxy Propyl Methyl Cellulose like
HPMC K4M, HPMC K100M, HPMC E50LV etc.
Cellulose Acetate, Cellulose Acetate Butyrate, Cellulose Acetate Phthalate
7.3 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 vitrodrug release studies, etc
- Preformulation studies standard to development of floating microspheres.
- Selection of excipients and rate control polymer of the formulations and fixing their ranges to be used, To evaluate all the excipients for compatibility study
- Development of formulation based on studies in step1 and step 2.
- Optimization of formulation parameters and drug carrier system using appropriate methods
- Assessment of formulation for in vitro drug release studies.
7.4 - Does the study require any investigations or interventions to be conducted on
Patients or other humans or animals? If so, Please describe briefly.
No
7.5 – Has ethical clearance been obtained from your Institution in case of 7.4?
Not applicable.
8. / List of References:
1. Hemangi Patil. S, Moreshwar Patil. P, Bharat Tekade. W, Vinod Thakare. M and VijayPatil, Formulation and in vitro Evaluation of Floating Microsphere of Acyclovir.Arch Pharm Science & Res.2009;1: 194-198.
2.Zhenqiu Yang , Baozhen Song, Qiaoxia Li, Honglei Fan and Fan Ouyang, Preparation of microspheres with microballoons inside for floating drug-delivery systems. Journal of Applied Polymer Science.2004; 94(1):197-202.
3. SunilJain. K, GovindAgrawal. P and NarendraJain.K,Evaluation of porous carrier-based floating orlistat microspheres for gastric delivery. AAPS Pharm Sci Tech.2008; E 54-E 62.
4. Rokhade Ajit P, Patil Sangamesh A, Belhekar Anaga A, Halligudi Shivraj B, Aminabhavi and Tejraj M, Preparation and evaluation of cellulose acetate butyrate and poly (ethylene oxide) blend microspheres for gastroretentive floating delivery of repaglinide. Journal of AppliedPolymer Science.2007; 105:2764-2771.
5. Yuveraj Singh Tanwar, Pushpendra Singh Naruka and Garima Rain Ojha, Development and evaluation of floating microspheres of verapamil hydrochloride.Brazilian Journal of Pharmaceutical Sciences.2007;4: 529-534.
6.Anand Kumar Srivastava, Devendra Narayanarao and Ridhukar Saurabh Wadhwa, Floating microspheres of cimetidine: Formulation, characterization and in vitro evaluation. Acta Pharm. 2005; 55: 277-285.
7. Asha patel, Subhabrata ray and Ram sharnagat thakur, Invitro evaluation and optimization of controlled release floating drug delivery system of metformin hydrochloride. DARU. 2006; 14(2): 57-64.
8. Balasubramaniam J, Vinay Rao U, Vasudha M, Jeevan Babu and Rajinikanth P S, Sodium Alginate microspheres of Metformin HCl: Formulation and In Vitro evaluation. Current drug delivery. 2007; 4(3):249-56
9. Kumaresh Soppimath. S, Anandrao Kulkarni. R and Tejraj Aminabhavi. M , Development of Hollow Microspheres as Floating Controlled-Release Systems for Cardiovascular Drugs: Preparation and Release Characteristics. Drug development and Industrial Pharmacy. 2001; 27(6): 507-515.
10. 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.India. 2004; 66:1364-1372.
11. 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
12.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.
13. Jaimini M, Rana A.C and Tanwar Y.S, Formulation and evaluation of famotidine floating tablets. Current Drug Delivery. 2007; 4: 51-55.
14. Umamaheshwari R.B.;Jain S.;Bhadra D.;Jain N.K.Floating microspheres bearing acetohydroxamic acid for the treatment of Helicobacter pylori.Journal of Pharmacy and Pharmacology.2003; 12(55):1607-1613
15. Yoshiaki Kawashima , Hirofumi Takeuchi and Hiromitsu Yamamoto,In vitro and in vivo evaluation of riboflavin-containing microballoons for a floating controlled drug delivery system in healthy humans international Journal of Pharmaceutics.2004;275 (1-2): 97-107.
16. Pratim Choudhury K, Museums Kar and Chetan Chauhan S, Cellulose Acetate Microspheres as Floating Depot Systems to Increase Gastric Retention of Antidiabetic Drug: Formulation, Characterization and In Vitro–In Vivo Evaluation. Drug Development and Industrial Pharmacy. 2008; 4 (34): 349-354.
9 / Signature of the candidate: / (Mehul R Thakkar)
10 / Remarks of the Guide: / Requested for clearance and approval
11 / Name and Designation of:
11.1 Guide:
11.2 Signature: / J.Josephine Leno Jenita,
Asst.Professor,
Dept of Pharmaceutics,
DayanandaSagarCollege of Pharmacy,
Kumaraswamy layout,
Bangalore – 560 078.
11.3 Co – guide if any
11.4 Signature / Not applicable
11.5 Head of the Department:
11.6 Signature / Dr. B. WILSON
Professor and HOD
Dept of Pharmaceutics
DayanandaSagarCollege of Pharmacy,
Kumaraswamy layout, Bangalore – 560 078.
12 / 12.1 Remarks of the Principal
12.2 Signature / Dr. V. Murugan
Professor and principal
Dept of Pharmaceutical Chemistry
DayanandaSagarCollege of Pharmacy,
Kumaraswamy layout, Bangalore – 560 078.
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