Formulation and Evaluation of Modified Pulsincap Technique for Oral Controlled Release of Glipizide

V.V. Nageswara Rao¹* , Dr. 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.

ABSTRACT:

In-vitro controlled release of glipizide was studied from modified pulsincaps prepared by using different proportions of the polymer HPMC. Glipizide – HPMC mixtures were prepared in the ratios 5:1, 5:2, 5:3 and 5:4 respectively. These mixtures were evaluated for micromeritic properties and to confirm the reproducibility of method of mixing. Micromertic properties of the pure drug glipizide and glipizide – HPMC mixtures were improved by the incorporation of spray-dried lactose (pharmatose) at 15% of the weight of the drug. Drug polymer interaction studies were performed on the selected drug - polymer mixtures and on the pure drug , glipizide by using FTIR and DSC. These studies showed no drug polymer interactions.Drug - polymer mixture equivalent to 10mg of glipizide was used for the preparation of modified pulsincaps. The prepared modified pulsincaps were evaluated for weight variation, drug content and drug release from the prepared modified pulsincaps. Glipizide release from the prepared modified pulsincaps was slow and extended for a period of time not less than 10 hrs, depending upon the concentration of the polymer used. Drug release was diffusion controlled and followed zero order kinetics. The release of glipizide from GH₁ and GH₂ pulsincaps was close to the release of glipizide from a commercial SR tablet Glytop.

KEYWORDS: Glipizide, , Pulsincaps, HPMC, pharmatose, zero order , peppas model.

INTRODUCTION:

Diabetes is the fifth leading cause of deaths in the U.S. as well as the leading cause of adult blindness and responsible for 50% of heart attacks, 75% of strokes and 85% of gangrenous leg amputations¹. Glipizide is widely prescribed oral hypoglycemic drug in the treatment of type 2 diabetes mellitus. It has short biological half-life (2-4 hrs) ^2. The conventional dosage forms of glipizide suffer from adverse side effects, G.I. Disturbances that may lead to non-compliance to the patient. Hence, it is necessary to develop a formulation of controlled release of drug delivery system for the drug glipizide. There are only a few reports ^3-5 on the formation of oral controlled drug release products of the drug glipizide.

In the present study, glipizide pulsincaps were prepared by modified pulsincap technique with the hydrophilic polymer HPMC 4 KM and were evaluated for uniformitys of weight, uniformity in drug content and in vitro drug release rates. The in vitro drug release rates of the prepared glipizide pulsincaps were compared with the commercially available SR tablet formulation, glytop.

MATERIALS AND METHODS:

Materials:

Glipzide was obtained as a gift sample from Micro Labs Ltd., Pondicherry. HPMC was a gift sample 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.

Insolubilisation of capsule body by formaldehyde vapour technique:

Size 2 hard gelatin capsule bodies of the capsules were placed on a wire mesh and spreaded as a single layer and were exposed to formaldehyde vapours in a desiccators containing formaldehyde solution at the bottom. The capsule bodies were exposed for various periods of time viz., 3, 6, 10 and 24 hrs. The capsule bodies were removed from the desiccator after the required exposure time and were air dried for 4 hrs. to remove adhering free formaldehyde and moisture. Finally, they were dried in a vaccum desiccator over fused calcium chloride for 12 hrs. and stored in a air tight container. These hardened capsules were used in the preparation of pulsincaps. These hardened capsules (formaldehyde treated body with untreated cap) were tested for solubility in phosphate buffer medium of pH 7.4. Free formaldehyde content in treated capsule body was estimated by soaking the pieces of the hardened body capsule in sulphuric acid solution, in a 50 ml volumetric flask for 2 hrs. The contents were thoroughly mixed and the volume was made up to 50 ml. To dissolve the pieces completely, the contents of the volumetric flask were heated on a water bath. To 1 ml of this solution. 9 ml of the chromotropic acid reagent was added in a stoppered graduated test tube and heated for 30 minutes in a boiling water bath. The obtained purple red color was measured at 550 mm against the reagent blank.

The primary reaction of the formaldehyde with gelatin, a protein probably is the formation of methylamines. The tanning effect is due in a large part to a condensation reaction, which transforms the methyl groups into a cross-linking methylene bridges. Nitschmann ⁶ and his coworkers and Fraenkel contrat and Olcott ⁷ confirmed the occurrence of such condensation reaction. This is an irreversible reaction. The bodies of the capsules, which were exposed to formaldehyde vapor treatment about 10 hrs, were only softened after 24 hrs and not dissolved even after 48 hrs. in phosphate buffer medium of pH 7.4. Hence for the present study capsule bodies, which were exposed to formaldehyde, vapours for 10 hrs were chosen. In these capsules residual amount of formaldehyde content in the hardened capsule body was found to be 0.098mg per 39.72mg of the average capsule body weight.

A new technique called pulsincap ⁸ was introduced under timed-release dosage forms. A novel drug delivery system capable of releasing its drug contents at predetermined time or at a specific site in the G.I. tract known as pulsincap. This pulsincap dosage form is a capsule which 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 dissoles in the gastric juice and the exposed hydrogel plug begins to swell. At 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 modied by replacing the basic drug mixture with drug-polymer mixture in different ratios and filled into the hardened capsule body. It 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 where as pulsincap controls the drug release time.

Preparation of Drug-Polymer mixture:

All the ingredients used in the preparation of drug-polymer mixture were passed through mesh no 100. Accurately weighed quantity of drug ingredients were mixed together in a glass motor to obtain a homogeneous mixture by using geometric dilution technique. Drug - polymer mixtures were prepared in the ratios 5:1, 5:2, 5:3 and 5:4 using HPMC as shown in the table No. 1. Three different batches of the Drug-polymer mixtures were prepared to evaluate batch to batch variations and to confirm the reproducibility of the method of mixing. The prepared Drug-polymer mixtures were evaluated for micrometric properties like bulking density, compressibility index, flowing properties and drug content. Spray dried lactose (Pharmatose) was added to pure drug and Drug-polymer mixtures at 10%, 15% and 20% of weight of the drug for improvement in flow properties of Drug - polymer mixtures by adding pharmatose at 15% of weight of the drug. Hence, pharmatose at 15% of weight of the drug was used in the preparation of Drug-polymer mixtures. Drug - polymer interaction studies FTIR and DSC wee performed on the pure drug glipizide and the selected glipizide-HPMC, which showed no chemical interaction or complexation between the drug glipizide and the polymer HPMC.

Table 1 : Composition of Glipizide Pulsincaps prepared with HPMC

Ingredients (mg)	G	GH1	GH2	GH3	GH4
GLIPIZIDE	10.00	10.00	10.00	10.00	10.00
HPMC	_	2.00	4.00	6.00	8.00
PHARM ATOSE	1.50	1.50	1.50	1.50	1.50
FILLER (LACTOSE)	188.50	186.50	184.50	182.50	180.50

Preparation of Modified Pulsincaps:

Bodies of the gelatin capsules of size 2 hardness with formaldehyde for 10 hrs were used for preparing the modified Pulsincaps. Drug-polymer mixture equivalent to 10mg of glipizide was weighed and was filled into the hardened capsule body. The remaining volume of the capsule body was filled with lactose. Finally, the soluble cap was locked into the capsule body to form the modified Pulsincap. The prepared modified Pulsincaps were evaluated for uniformity of weight, drug content and reproducibility of the filling method and in-vitro dissolution studies. Drug - polymer interaction studies FTIR and DSC wee performed on the pure drug glipizide and the selected glipizide-HPMC, which showed no chemical interaction or complexation between the drug glipizide and the polymer HPMC.

Estimation of Drug Content:

Ten pulsincaps were randomly selected from each batch of the prepared pulsincaps and their contents were emptied into a 100 ml volumetric flask containing 50 ml of methanol and it was sonicated for 5 minutes. The volume was made up to 100 ml with the solvent. Subsequent dilutions were made with PH 7.4 phosphate buffer. Finally, the prepared solutions were assayed for drug content by measuring optical density values at 276 nm using UV- Visible spectrophotometer (Elico-Model-SL-159) against a reagent blank of phosphate buffer of pH 7.4.

Dissolution Studies:

Dissolution study was carried out using a USP XX1V type II dissolution rate test apparatus (paddle system). The stirring rate was 50 rpm. 900 ml of pH 7.4 phosphate buffer ⁹ was used as dissolution medium and was maintained at 37⁰C ± 0.5⁰C throughout the experiment. 5ml of samples were withdrawn at predetermined time intervals with a pipette filled with a filter (0.45m). The volume with drawn at each time interval was replaced with 5 ml of fresh dissolution medium maintained at the same temperature. The collected samples were assayed for glipizide at 276 nm ¹⁰ using UV – visible spectrophotometer (Elicomodel, SL-159). The drug release experiments were conducted in triplicate.

RESULTS AND DISCUSSION:

The dissolution studies showed that the release rate of the drug glipizide from the plain capsule was uniform and extended for a period of 4 hrs. The release of the drug glipizide from the pulsincap ‘G’ was uniform and extended for a period of 6 hr. This may be due to hardening of capsule body extending the release of the drug. GH1 and GH2 pulsincaps release the total drug in 11 hrs and 16 hrs respectively. Pulsincaps GH3 and GH4 release 75.96% and 54.24% of drug glipizide within 16 hrs respectively.

The dissolution studies of the prepared pulsincaps G, GH1, GH2, GH3, andGH4 were compared with the dissolution studies of the commercially sustained release tablet, Glytop. The commercially sustained S.R tablet glytop released the total drug within 14 hrs. Time taken for 50% of drug release (T₅₀) was found to be 2.3hrs for glipizide drug without polymer from pulsincap G. T₅₀ value for glipizide drug without polymer from plain capsule was 1.6hr. T₅₀ values for the prepared GH1, GH2, GH3 and GH4 were found to be 5.45, 7.8, 10.98 and 15.20 hrs respectively .T₅₀ value for commercial formulation glytop was found to be 4.7 hrs .

The results indicated that as the concentration of the polymer increases the release rate of the drug was decreasing. The T₅₀ values for the glipizide HPMC ratios of 5:3 and 5:4 were more than 10 hrs. This indicated the retardation in the release of drug from the pulsincap which may be due to high swelling nature of the polymer leading the formation of thick viscous layer near the opening of the pulsincap, thereby preventing free diffusion of the drug through the viscous layer whereas in case of ratios 5:1 and 5:2 this may not be happening due to high concentration of the drug compare to polymer.

The values of correlation coefficient (r) obtained by fitting the dissolution data of glipizide from glipizide pulsincap to five popular release models namely zero order, first order, Higuchi diffusion and Peppas – Korsmeyer equation. The drug release from the glipizide pulsincap (GH1, GH2, GH3 and GH4) prepared by using HPMC polymer followed by zero order kinetics proved by‘r ’ values when % drug released were plotted against time, straight lines were obtained as shown in the figure no1. The decrease in the K₀ values as function of the drug to polymer ratio showed that the drug release rate decreased as the polymer concentration increased. The plots of the log fraction drug released verses log time of all the plipizide-HPMC pulsincaps were found to be linear as given the figure no2. The ‘r’ values of these pulsincaps were very nearer to 1 and further indicating that peppas korsmeyer equation was more suitable for explaining the release kinetics. Diffusional exponent (n) values of all the pulsincaps were ranging from 0.6572-0.07721 indicating that the release mechanism followed non-fickian diffusion. The results of the study indicated that the release of the drug from the glipizide-HPMC polymer follows zero order kinetics via anomalous (non-fickian) diffusion.

The results of the present study thus clearly indicated that the selected antidiabetic drug glipizide, oral controlled release formulations could be prepared by modified pulsincap technique with the polymer HPMC. These formulations exhibited well-controlled release of the drug glipizide. This study can be scaled up for the commercial exploitation of this modified pulsincap technique in the development of controlled drug delivery systems.

Figure 1: Zero order plots of Glipizide Pulsincaps

Figure 2: Peppas plots of Glipizide Pulsincaps

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Received on 01.11.2011

Modified on 07.12.2011

Accepted on 22.01.2012

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Research J. Science and Tech. 4(1): Jan.-Feb. 2012: 9-12