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Development of an Osmotically Controlled Drug-Delivery System of Glipizide
The earliest studies in the field of modified drug delivery date back to the 1950s. Since then, a large number of drug products, mainly in the form of tablets and capsules with controlled-release characteristics, have been introduced. Das and Das predicted a minimum growth of 9% per year for this market through 2007 (1). Various technologies have been investigated to achieve the different types of modified release (e.g., sustained, delayed, pulsatile, targeted, and programmed release). Regardless of the delivery type, the primary mechanisms associated with drug transport in these systems are diffusion, swelling, erosion, ion exchange, and osmotic-transport effect. These mechanisms have been investigated in several studies (2–7).
Glipizide (GLZ), a weak acid (pKa = 5.9) is practically insoluble in acidic environments, highly permeable, and insoluble in water (39 µg/mL). Oral absorption of GLZ is uniform, rapid, and complete; its bioavailability is nearly 100%, and its elimination half-life is 2–4 h (8).
Class II compounds such as GLZ comprise relatively lipophilic and water-insoluble drugs with saturated solubility ≤0.1mg/mL that, when dissolved, are well absorbed from the gastrointestinal tract. Commonly, drugs in this class have variable bioavailability because of the influence of formulation effects and in vivo variables on absorption (9). Scientists try various formulation techniques such as nanoparticles, the addition of surfactants, salt formation, and complexation to change the drugs to Biological Classification System Class I compounds (9–11). Complexation with cyclodextrins (CDs) has been widely used to improve the solubility and dissolution rate of poorly water-soluble drugs (12). CDs also enhance drugs' physical and chemical stability and eliminate unpleasant odors and tastes (13).
Many methods are available for determining the physical nature of an inclusion complex. The inclusion complex can be characterized in the solid state by techniques such as Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) (14). A complex prepared using the solvent-evaporation method in a 2:1 ratio of hydroxypropyl (HP)–β–CD to GLZ enhanced solubility and dissolution. The result could be used to formulate an osmotic-pump tablet.
In the 1970s, Theeuwas introduced an elementary osmotic-pump tablet (EOPT) (2). Because an EOPT is simple to prepare and drug release can be controlled over an extended period, interest in developing EOPTs increased over the past two decades. However, the generic EOPT is only suitable to deliver drugs of moderate solubility. Okimoto investigated osmotic-pump tablets for poorly water-soluble drugs (e.g., testosterone, prednisolone, and chlorpromazine) using sulfobutyl ether-β-cyclodextrin (SBE) 7m-β-CD as a solubilizer and osmotic agent (12, 15).
The authors aimed to develop a new EOPT of GLZ with proper accessorial material after making an inclusion complex of it with HP–β–CD to increase its solubility and deliver it over an extended period of time.
GLZ, microcrystalline cellulose, dicalcium phosphate, spray-dried lactose monohydrate NF, magnesium stearate, and talc were donated by Sword and Shield Pharmaceutical (Chhatral, Gujarat, India). The sample of HP–β –CD (molecular weight of 15000 Da) was a gift from Roquette (Lestrem, France). Sodium chloride and potassium chloride were purchased from S.D. Fine Chem (Mumbai). Various grades of hydroxypropyl methylcellulose (HPMC) were donated by Colorcon Asia Pacific (Singapore). All chemicals and solvents were of analytical-reagent grade.
Phase-solubility studies were carried out by adding 100 mg of drug to screw-capped vials containing various concentrations of a 25-mL aqueous HP–β –CD solution. The solutions were stirred continuously using an electromagnetic stirrer (Labstirrer, Remi Laboratory Instruments, Mumbai) at 25 °C and 37 °C and 300 rpm for 48 h. The solutions were filtered through 0.45-µm membrane filter. The filtrates were suitably diluted with simulated intestinal fluid at pH 6.8 simulated intestinal fluid (SIF) and analyzed spectrophotometrically (Shimazdu-1601 ultraviolet-visible spectrophotometer, Shimadzu, Kyoto, Japan), for the dissolved drug at 276 nm.
Preparation of complexes and physical mixtures. Solvent-evaporation method (coevaporation). An inclusion complex containing various weight ratios (i.e., 1:1, 1:2, and 2:1) of HP–β–CD to GLZ was prepared by the coevaporation method (16). The appropriate amount of HP–β–CD was added to a solution of GLZ (500 mg) in 0.1 N NaOH (10 mL). Next, the solvent was evaporated at 60 °C in an oven. The resulting residue was dried under vacuum at 40 °C for 3 h, ground in a mortar, and passed through an 80# sieve.
Kneading method. The required quantities of HP–β–CD, GLZ, and 0.1 N NaOH (1.5 mL) were mixed together in a mortar to obtain a homogeneous paste. GLZ was then added slowly. During grinding, a small quantity of 0.1 N NaOH (0.5 mL) was added to assist the dissolution of GLZ. The mixture was then ground for 1h. During this process, an appropriate quantity of 0.1 N NaOH was added to the mixture to maintain a suitable consistency. The paste was dried under vacuum at 50 °C for 24 h. The dried complex was pulverized and sieved through an 80# sieve.
Physical mixtures. Physical mixtures (PMs) having the same weight ratios of HP–β–CD to GLZ (i.e., 1:1, 1:2, and 2:1) were prepared by thoroughly mixing appropriate amounts of GLZ and HP–β–CD in a mortar until a homogeneous mixture was obtained.
Characterization of solid dispersion. Infrared (IR) spectroscopic analysis. FTIR spectra of moisture-free powdered samples were obtained using a spectrophotometer (FTIR-8300, Shimadzu) with the potassium-bromide pellet method (i.e., a 5-mg sample in 200 mg of potassium bromide). The scanning range was 400–4000 cm-1 , and the resolution was 1 cm-1 .
DSC analysis. DSC scans of the powdered samples were recorded using DSC with Thermal Data Analyzer trend-line software (DSC 60, Shimadzu). All samples were weighed and heated at a scanning rate of 10 °C/min under dry nitrogen flow (100 mL/min) between 50 and 300 °C. Aluminum pans and lids were used for all samples.
The complexes prepared by the kneading, coevaporation, and physical-mixture methods were assayed for GLZ content by the saturated shaking-flask method (17). Excess amounts of the complex were placed into 10-mL vials containing water. The vials were sealed and shaken for 24 h at room temperature. The solutions were filtered through a 0.45-µm membrane filter. The filtrates were suitably diluted and analyzed spectrophotometrically for the dissolved drug at 276 nm. All assays were performed in triplicate.
Wettability and dissolution studies
Wettability studies were performed using open tubes containing GLZ. Its PMs and inclusion complexes with HP–β–CD were placed with their lower capillary ends dipped into a solution of 0.05% w/v crystal violet and water. The upward migration of the colored front in the capillary tube was recorded as a function of time.
Dissolution studies were performed using Apparatus 2 of USP 30–NF 25 for 120 min. Samples equivalent to 5 mg of drug were added to the dissolution medium (i.e., 500 mL of demineralized water) at a temperature of 37 °C ± 0.5 °C, which was stirred at 50 rpm. Operators withdrew 5-mL samples at intervals of 10, 20, 30, 40, 60, 90, and 120min. The samples were filtered with Whatman filter paper #1 (Whatman International, Maidstone, UK), diluted with SIF, and analyzed at 276 nm using a spectrophotometer. The dissolution study was conducted in triplicate, and mean values were plotted.
Formulation of an elementary osmotic-pump tablet
Coating of core tablet. The core tablets were film coated with a semipermeable membrane of 2.5% w/v cellulose acetate (CA) with castor oil 20% (w/w total weight of CA) as a plasticizer using a conventional, laboratory-model, stainless-steel, 20-cm, pear-shaped, baffled coating pan with a pan-rotating rate of 25 rpm. Core tablets of GLZ were placed in the coating pan along with 100 g of filler tablets made using 9.6-mm round concave punches and containing lactose, dibasic calcium phosphate, starch paste, magnesium stearate, and talc. The inlet air temperature was about 60–70 °C. The manual coating procedure was used based on an intermittent spraying and drying technique. The coated tablets were dried overnight at 50 °C to remove the residual solvent. An orifice (500 µm) through the membrane was made by a mechanical driller.
In vitrodrug-release study of osmotic tablets. In vitro drug release was tested according to the USP 30–NF 25 guidance for modified-release products. The authors used Apparatus 2 at 37 ± 0.5 °C and 50 rpm, testing 500 mL of 0.1 N HCl for the first two hours, followed by 500 mL of SIF. The samples were analyzed at 276 nm. The drug-release study was conducted in triplicate, and mean values were plotted. For comparisons between dissolution profiles of different samples, the authors used Moore and Flanner's model independent mathematical approach of calculating a similarity factor f 2 (18).
Scanning electron microscopy studies
Results and discussion
The plots of drug solubility against the polymer concentration at the investigated temperatures indicate a linear relationship in the investigated polymer concentration range. The solubility of GLZ increased with temperature and carrier concentration.
The solubility of GLZ in pure water at 25 °C was 39 µg/mL. At the highest polymer concentration (50 mM/mL), the solubility increased approximately sixfold and fivefold at 37 °C and 25 °C, respectively.
The stability constant for the complexes at 37 °C, assuming a 1:1 stoichiometry, calculated from the slope of the initial straight portion of the solubility diagram, was 733 M-1 , which indicated a suitable and stable complex formation.
The ΔGt r ° values indicate whether the reaction conditions are favorable or unfavorable for drug solubilization in the aqueous carrier solution. Negative Gibbs free-energy values indicate favorable conditions. ΔGt° and ΔHt° were negative for HP–β–CD, indicating that the transfer of the drug from pure water to polymer solutions is spontaneous. Furthermore, as the polymer concentration increases, ΔHt° decreases, which indicates that the process becomes more favorable with higher polymer concentrations.
DSC thermgrams of coevaporation 2:1 showed no endothermic peak for GLZ, and the endothermic peak of HP–β–CD was appreciably broader. This result seemed to indicate the formation of an inclusion complex.
MDT is the first datum for the cumulative dissolution process that provides an accurate drug-release rate. A high MDT value indicates great drug-retarding ability (18). The MDT of pure GLZ was high (99.64 min). This value decreased greatly after the authors prepared GLZ's inclusion complexes and PM with HP–β–CD, which indicated an increase in dissolution rate. Coevaporation 2:1 had the lowest MDT (12.91 min).
Comparisons between the release profiles of different samples of GLZ were made with similarity factor f 2 . Table III shows that the release profiles of GLZ from all samples (i.e., complexes and PMs of HP–β–CD) and from pure GLZ were dissimilar; f 2 values for these comparisons were less than 50. Coevaporation 2:1, which had a better in vitro dissolution profile, lower MDT, and lower f 2 values, was selected for further formulation of as an EOPT.
Formulation development of an EOPT. The dosage form was designed as a tablet core coated with a semipermeable membrane that had a preformed passageway. The core tablets consisted of a GLZ complex along with osmagent and other conventional excipients. The core compartment was surrounded by a semipermeable membrane. After administration, the core compartment absorbs aqueous fluids from the surrounding environment through the membrane. After coming into contact with the aqueous fluids, the GLZ complex dissolves, and the dissolved drug is released through the drilled orifice.
Core tablets were evaluated for various pharmacotechnical parameters. The tablets' hardness was in the range of 4.0–6.0 kg/cm2 . The percentage friability of all formulations was below 1%, which was within the prescribed limits. Friability directly affects tablet. In a weight-variation test, the pharmacopoeial limit for the percentage deviation of all the tablets was less than 7.5%. The tablets contained 97–102% of the labeled amount of GLZ, thus indicating drug-content uniformity.
Figure 8a shows the membrane structure of batch B before dissolution studies were performed. The surface of the coated tablet was smooth before coming into contact with the aqueous environment, and the coats appeared to be free of defects. Figure 8b shows an SEM micrograph of an excised section of the top surface of the membrane after the dissolution study was performed. It exhibited a surface morphology similar to that in Figure 8a, suggesting that pores had not developed in the membrane or been affected by the in vitro drug-release profile.
The authors' experiment showed that the dissolution rate of GLZ increased when it was dispersed in HP–β–CD. The complex formation was confirmed by DSC and FTIR. The increased dissolution rate in systems containing HP–β–CD was likely the result of the increased wettability and dispersibility of GLZ. Examination of the EOPT indicated that the osmotic promoting agent and swelling polymer significantly affected the in vitro drug-release profile.
Ritesh B. Patel* is a lecturer, and Rakesh P. Patel is an associate professor, both at S.K. Patel College of Pharmaceutical Education and Research, Ganpat University, Ganpat
Vidyanagar, Kherva, Mehsana-Gozaria Highway, PIN-382711, Gujarat, India, email@example.com
*To whom all correspondence should be addressed.
Submitted: Oct. 7, 2009. Accepted: Jan. 13, 2010.
1. N.G. Das and S.K. Das, supplement to Pharm. Tech. 27 (6), 10–16 (2003).
2. F. Theeuwes, J. Pharm. Sci. Technol. 64 (12), 1987–1991 (1975).
3. R.W. Korsmeyer et al., Int. J. Pharm. 15 (1), 25–35 (1983).
4. H. Khurahashi, H. Kami, and H. Sunada, Chem. Pharm. Bull. 44 (4), 829–832 (1996).
5. B. Narasimhan, Adv. Drug Deliv. Rev. 48 (2–3), 195–210 (2001).
6. T. Durig and R. Fassihi, J. Control. Release 67 (1), 37–44 (2000).
7. S.M .Herbig, J.R. Cardinal, and RW. Korsmeyer, J. Control. Release 35 (2–3), 127–136 (1995).
8. Goodman and Gilman's The Pharmacological Basis of Therapeutics, J.G. Hardman, L.E. Limbird, and A.G. Gilman, Eds. (McGraw Hill, New York, 10th ed., 2001), p. 1927.
9. G. Amidon, H. Lennernas, and V.A. Shah, Pharm. Res. 12 (3), 413–420 (1995).
10. J. Dressman, J. Butler, and J. Hempenstall, Pharm. Technol. 25 (7), 68–76 (2001).
11. D. Horter and J. Dressman, Adv. Drug Deliv. Rev. 46 (1), 75–87 (2001).
12. C. Fernandes, M. Vieira, and F. Viega, Eur. J. Pharm. Sci. 15 (1), 79–88 (2002).
13. V.D. Mooter et al., Int. J. Pharm. 164 (1–2), 67–80 (1998).
14. K. Okimoto et al., J. Pharm. Res. 15 (10), 1562–1568 (1998).
15. K. Okimoto, R.A. Rajewski, and V.J. Stella, J. Control. Release 58 (1), 29–38 (1999).
16. C. Leuner and J. Dressman, Eur. J. Pharm. Biopharm. 50 (1), 47–60 (2000).
17. A. Avdeef, Adv. Drug Deliv. Rev. 59 (7), 568–590 (2007).
18. J.W. Moore and H.H. Flanner, Pharm. Technol. 20 (6), 64–74 (1996).