Design and Development of Modified Pulsincap Technique for Oral Controlled Release of Rosiglitazone Maleate
V.V. Nageswara Rao1* , K.V. Ramana Murthy2
1Dept. of Pharmaceutics, St. Ann’s College of Pharmacy, Chirala-523187, Andhra Pradesh, India
2Dept. of Pharmaceutics, University College of Pharmaceutical Sciences, Andhra University, Visakhapatnam, Andhra Pradesh, India.
Corresponding author: voiceofvvnrao@gmail.com
ABSTRACT:
Oral controlled release of rosiglitazone maleate was studied by using modified pulsincap technique. Modified pulsincaps were prepared with different proportions of the hydrophilic polymer, HPMC ( Hydroxy Propyl Methyl Cellulose). Drug-polymer mixtures were prepared in the ratios 5:2, 5:3, 5:4, and 5:5 respectively. The prepared drug-polymer mixtures were evaluated for micromeritic properties and to conform the reproducibility of the method of mixing. Drug-polymer mixture equivalent to 8 mg of rosiglitazone maleate was filled into the hardened body of the capsule for the preparation of modified pulsincaps. The prepared pulsincaps were evaluated for weight variation, drug content and drug release kinetics. Rosiglitazone maleate release from the prepared pulsincaps was uniformly slow and extended for a period of time more than 12 hrs in case of RH5 pulsincaps. The drug release from the prepared pulsincaps followed Zero order kinetics. The Zero order release rate constant K0 was decreased as the polymer concentration increased. The plots of log fraction drug released versus time of all the pulsincaps were found to be linear and found that the mechanisam of drug release followed peppas model. It was found that diffusional exponent (n) values of all the pulsincaps were ranging from 0.5737- 0.6948 indicating that the drug release mechanism followed non-Fickian diffusion. Drug –polymer interaction studies by using FTIR, DSC were performed on the pure drug and drug-polymer mixtures which indicated no drug- polymer interaction.
KEYWORDS: Roseglitazone maleate, pulsincaps, HPMC, Zero order, peppas model.
INTRODUCTION:
One of the fastest threats to public in all countries of the world is diabetes mellitus. It is one of the leading causes of death and adult blindness. As the disease progresses, tissue or vascular damage ensues leading to severe complications such as retinopathy, nephropathy,neuropathy, cardiovascular disease and foot ulceration.1 Rosiglitazone maleate is used as oral hypoglycemic agent in the treatment of diabetes mellitus type-2. Biological half-life of rosiglitazone maleate is 3-4 hrs.2 Due to short biological half life adverse effects and prolonged period of treatment with conventional doses which lead to patient non-compliance. Hence, it is necessary to develop a formulation of controlled release drug delivery system for this drug to improve the therapeutic efficacy and patient compliance. There are only few reports3,4 on the formulation of sustained release product of the drug rosiglitazone maleate.
In the present investigation, it is aimed to prepare modified pulsincaps by modified pulsincap technique for the controlled release of the drug rosiglitazone maleate. Rosiglitazone maleate pulsincaps were prepared with the polymer HPMC 4KM by modified pulsincap technique and were evaluated for uniformity of weight, drug content and drug release kinetics.
MATERIALS AND METHODS:
Materials:
Rosiglitazone maleate and HPMC were obtained as gift samples from M/s DR. Reddys Laboratories Hyderabad. Formaldehyde (AR grade), chromotropic acid (AR grade) and lactose(AR grade) were procured from M/s S.D. Fine Chem. Ltd., Mumbai. Spray dried lactose (pharmatose) was procured from DMV International Mft. of Excipients, Germany.
Insolublization of capsule bodies by formaldehyde vapour treatment :
Size-2 hard gelatin capsule bodies were spreaded as a single layer on a wire mesh and were exposed to formaldehyde vapours for varying periods of time viz., 3,6,10 and 24 hrs. in a desiccator containing formaldehyde solution at the bottom of the desiccator . The exposed capsule bodies were air dried for 4 hrs to remove adhering free formaldehyde and moisture. Again these were dried in a vaccum desiccator over fused calcium chloride for 12hrs and stored in an air tight container. The solublility of these hardened capsules bodies were tested in pH 7.4 phosphate buffer medium.
For the estimation of free formaldehyde content in the treated capsule body,pieces of hardened capsule body were soaked in sulphuric acid solution for 2 hrs in a 50 ml volumetric flask. The volume was adjusted to 50ml. To dissolve pieces completely the contents of the flask was heated on a water bath. To 1ml of this solution, 9ml of chromotropic acid reagent was added in a stoppered graduated tube and heated for 30minutes on a water bath. The developed purple color was measured at 550nm against the reagent blank.
The primary reaction of formaldehyde with gelatin (main constituent of capsule) probably is the formation of methylol amines. The tannin effect is due in a large part to a condensation reaction which transforms the methyl group into cross linking methylene bridges. The occurrence of such condensation reaction was confirmed by Nitschmann5 and his co-workers and Fraenkel and Olcott6. This is an irreversible reaction. Hence, in the present study, the capsule bodies which were exposed to formaldehyde vapours for 10hrs were not dissolved in PH 7.4 phosphate buffer medium even after 48hrs (hardened capsule bodies were softened only after 24hrs). Thus for the present study capsule bodies which were exposed to formaldehyde vapours to10hrs were chosen for the preparation of pulsincaps by modified pulsincap technique. Residual amount of free formaldehyde content in the hardened capsule body was found to be 0.098mg per 39.72 mg of an average capsule body weight.
Pulsincap:
Pulsincap7 is a dosage form consists of a water insoluble body and a water soluble cap. The drug formulation is sealed within the capsule body by means of a hydrogel plug. When the pulsincap is swallowed, the water soluble cap dissolves in the gastric juice and the exposed hydrogel plug begins to swell. At a predetermined time after ingestion, the swollen plug is ejected out and the encapsulated drug formulation is then released into the alimentary tract, where it is dissolved in GI fluid and then absorbed into blood stream. In the present study, the pulsincap was modified by replacing the basic drug mixture with drug - polymer mixture in different ratios and filled into the hardened capsule body and was sealed with unhardened cap of the capsule. The release rate of the drug is controlled by the formation of a viscous hydrogel layer within the capsule body. This modified pulsincap technique controls the drug release rate whereas pulsincap controls the drug release time.
Preparation of Drug - Polymer Mixture:
All the required ingredients used in the preparation of drug - polymer mixtures were passed through mesh No. 100. Accurately weighed quantity of drug and polymer along with other ingredients mixed together in a glass mortar to obtain a homogeneous mixture by using geometric dilution technique. Drug - polymer mixtures were prepared in the ratios 5:2, 5:3, 5:4 and 5:5 by using the polymer HPMC 4 KM as shown in the table No.1. The prepared drug-ploymer mixtures were evaluated for micromeritic properties like bulk density, compressibility index, flow properties and drug content. Three different batches of drug-polymer mixtures were prepared to evaluate batch to batch variations and to conform the reproducibility of method of mixing.
Table 1 : composition of rosiglitazone maleate pulsincaps prepared with HPMC
|
Ingredients (mg) |
R |
RH2 |
RH3 |
RH4 |
RH5 |
|
Rosiglitazone maleate |
8.00 |
8.00 |
8.00 |
8.00 |
8.00 |
|
HPMC 4KM |
|
3.20 |
4.80 |
6.40 |
8.00 |
|
Filler (lactose) |
192.00 |
188.80 |
187.20 |
185.60 |
184.00 |
Drug-polymer interaction studies :
Drug –polymer interaction studies by using FTIR, DSC were performed on the pure drug and drug-polymer mixtures (5:4 and 5:5 ratios).
Prepation of Modified Pulsincaps:
Bodies of the size 2 hard gelatin capsules hardened by formaldehyde vapour treatment for 10 hrs were used for the preparation of modified pulsincaps. Drug - polymer mixture equivalent to 8 mg of rosiglitazone maleate was weighed accurately and filled into the hardened capsule body. The remaining volume of the capsule body was filled with the filler latose. Finally, the soluble cap was locked into the body to form the modified pulsincap. The prepared modified pulsincaps were evaluated for uniformity of weight, drug content, reproducibility of the filling method and for in vitro dissolution studies.
Estimation of Drug Content:
From each batch of the prepared pulsincaps of rosiglitazone maleate, ten pulsincaps were randomly selected and the contents were emptied into a 100 ml volumetric flask containing 50 ml of 0.1N HCl. Then it was sonicated for 5 minutes. The volume was made up to 100 ml with 0.1N HCl. Subsequent dilutions were made with 0.1N HCl. Finally, the solutions were assayed for drug content by measuring optical density values at 312 nm using UV-Visible spectrophotometer(Elico-Model SL-159) against a reagent blank of 0.1 N HCl.
In Vitro Dissolution Studies:
The in vitro dissolution studies were carriedout by using USP XXIV type-II dissolution rate Test apparatus (paddle system). The stirring rate was 50 rpm. 900 ml of 0.1N HCl was used as the dissolution medium and was maintained at 37ºC +- 0.5ºC throughout the experiment. 5 ml samples of dissolution fluid were withdrawn at predetermined time intervals with a pipette fitted with a filter (0.45u). The volume withdrawn at each time interval was replaced with 5 ml of fresh dissolution medium maintained at the same temperature. The collected samples were analysed for the drug content at 312 nm8 using UV-Visible spectrophotometer. Drug release studies were conducted in triplicate.
RESULTS AND DISCUSSION:
The dissolution of the pure drug rosiglitazone maleate from the plain capsule was completed within 15 minutes. The release of the drug rosiglitazone maleate from the pulsincap R was completed within 1 hour. This may be due to hardening of the capsule body. The prepared pulsincaps RH2, RH3, RH4 and RH 5 released the total drug within 5, 8, 10 and 14 hrs respectively. T50 values of the pulsincaps RH2, RH3, RH4 and RH5 were 1.75, 2.70, 3.60 and 5.65 hrs respectively. The drug release from all the pulsincaps RH2, RH3, RH4 and RH5 prepared by using HPMC polymer followed Zero order kinetics (r = 0.9804 – 0.9945). When percent drug released were plotted against time, straight lines were obtained for all the pulsincaps as shown in the figure1. The plots of log fraction drug released versus log time (figure 2) of all the pulsincaps were found to be linear, which indicated that mechanisam of drug release followed peppas - korsmeyer equation . It was found that diffusional exponent (n) values of all the pulsincaps were ranging from 0.5737- 0.6948 indicating that the drug release mechanism followed non-Fickian diffusion. Drug –polymer interaction studies indicated no interaction or complexation in between the drug and the polymer.
As the concentration of the polymer HPMC increased, the rate of the release of the drug was decreased. The retardation in the release of drug from the pulsincaps is due to high swelling nature of the polymer leading to the formation of a thick viscous layer near the opening of the pulsincap thereby preventing free diffusion of the drug through the viscous layer.
Oral controlled release of rosiglitazone maleate formulation could be prepared by modified pulsincap technique with the polymer HPMC 4KM and they exhibited well controlled release of the drug rosiglitazone maleate. Thus, the study can be scaled up for commercial exploitation of this modified pulsincap technique in the development of controlled drug delivery systems for the drug rosiglitazone maleate.
REFERENCES:
1. Arunachalam S, Gunasekaran S. Diabetic research in India and China today: From literature-based mapping to health-care policy. Current Sci.2002; 9(10): 1086–97.
2. Davis SN, Granner DK. Insulin, oral hypoglycemic agents, and the pharmacotherapy of the endocrine pancreas. In: Hardman JG, Limbird LE (eds). The Pharmacological Basis of Therapeutics, 10th edn.McGraw-Hill, New York. 1998; 1357-1358.
3. Ram Chand Dhakar. Sunil K. Prajapati, Sheo Datta Maurya, Anish K. Gupta.Rosiglitazone maleate microspheres for extending drug release:formulation and evaluation. International Journal of Pharma Research and Development – Online.2010;2(10):56-65.
4. Irene N, Sasikanth K. Preparation and in vitro evaluation of rosiglitazone maleate bi layered bioadhesive floating tablets. J. Chem. Pharm. Res. 2011; 3(4):140-149.
5. Nitschmann H, Hadron H. Über ein neues lineares Benzo-dipicolin, das 2, 6-Dimethyl-1, 5-anthrazolinHelv. Chim.Acta. 1944;27: 277.
6. Franenkel-Conrat H, Olcott HS. Reaction of Formaldehyde with Proteins. II. Participation of the Guanidyl Groups and Evidence of Crosslinking. J. Amer.Chem.Soc. 1946; 68: 34.
7. Seshasayana A, Sreenivasa Rao B, Prasanna Raju Y, Cheruvu PS, Ramana Murthy KV. Development of controlled release pulseincap dosage forms for rifampicin. Indian. J. Pharm. Sci.. 2001; 3:337.
8. Gayatri S, Shantha, A., Vaidyalingam V, Ajithadas A. , Niraimathi V.,simultaneous spectrometric estimation of gliclazide and rosiglitazone from its pharmaceutical dosage forms .Indian Drugs, 2004,41(2),112-113.
Received on 01.11.2011 Modified on 23.11.2011
Accepted on 05.12.2011 © RJPT All right reserved
Research J. Pharm. and Tech. 5(1): Jan. 2012; Page 50-52